A 19-year-old man with Duchenne Muscular Dystrophy (DMD) presented to the Emergency Department (ED) for left knee pain after ejection from his motorized wheelchair at a low velocity. In the ED, he developed increasing respiratory distress.

When addressing a new problem in a patient with a chronic condition, it is crucial to first understand the chronic condition and then consider whether the presenting symptoms relate to that condition or stem from an unrelated inciting event.

Patients with DMD are at risk of pulmonary complications relating to their underlying disease. For instance, dysphagia and ineffective cough can predispose them to recurrent aspiration pneumonitis and/or pneumonia, whereas decreased lung compliance (from scoliosis, atelectasis, and/or pulmonary fibrosis) and respiratory muscle weakness can progress to ventilatory failure. In addition, patients with DMD are at risk for pulmonary thromboembolism in the setting of immobility. Patients with DMD may also develop congestive heart failure resulting from myocardial fibrosis and nonischemic cardiomyopathy.

The ejection from his wheelchair signals potential trauma-associated conditions that could explain his respiratory distress. Respiratory complications of blunt thoracic trauma include pulmonary contusion, pneumothorax, flail chest (resulting from fractured ribs), and acute respiratory distress syndrome (ARDS). Lower extremity injury can result in venous thrombosis and pulmonary thromboembolism. While classically associated with long bone fractures, fat embolism syndrome (FES) may rarely occur with rib fractures and soft-tissue trauma. Respiratory compromise may also result from cervical spinal cord injury or severe anemia from trauma-associated hemorrhage.

Additional past medical history included growth hormone deficiency, migraine headaches, osteoporosis secondary to chronic steroid use, cardiac fibrosis of the inferolateral wall and septum with a baseline left ventricular ejection fraction of 65%, and atrial fibrillation. His medications included calcium carbonate, vitamin D, omeprazole, lisinopril, metoprolol, prednisone, escitalopram, and testosterone. Physical examination revealed an ill-appearing obese man in respiratory distress. Temperature was 37.3°C, heart rate was 102 beats per minute (bpm), blood pressure was 110/74 mm Hg. His oxygen saturation was 93% with a respiratory rate of 25 breaths per minute while breathing ambient air. His lung sounds were clear, and his heart was without murmur. The left knee was diffusely tender to palpation without specific point tenderness. Strength was 2/5 with flexion and extension at the bilateral knees and hips and 3/5 flexion and extension at the bilateral elbows. He reported this level of weakness was his baseline. Radiographs revealed a minimally displaced Salter Harris II fracture (fracture line through the metaphysis and growth plate) of the left distal femur. His fracture was splinted early in his ED course. During his ED evaluation, the patient had acute worsening of tachycardia to 130 bpm, increased respiratory rate of 34 breaths per minute, and hypoxemia with an oxygen saturation of 83% on ambient air. He was placed on 3 L/min of oxygen via nasal cannula with improvement in his oxygen saturation to 90%. A chest radiograph was unremarkable, without evidence of pneumothorax, effusion, or pneumonia. The patient was admitted to the hospital.

The acute onset of tachypnea, tachycardia, and hypoxia, accompanied by a clear lung exam and normal chest radiograph, increases the likelihood of a pulmonary embolism. Obesity, testosterone therapy, and trauma increase his susceptibility to venous thromboembolism, while a distal femur fracture increases his risk for FES. Acute pulmonary aspiration often presents with initially absent or subtle radiographic findings. An arterial blood gas analysis would determine the presence and extent of an alveolar-arterial (A-a) gradient; a normal A-a gradient is seen in hypoventilation, while an elevated A-a gradient is seen in conditions affecting gas exchange, including pulmonary emboli and alveolar filling processes. His hypoxemia only partially corrects with supplemental oxygen, raising the possibility of capillary or anatomic shunting. Capillary shunting may occur with atelectasis, aspiration/pneumonia and pulmonary edema, whereas anatomic shunting can be intra-cardiac (eg, patent foramen ovale or septic defect) or intrapulmonary (eg, arteriovenous malformations). Patients with pulmonary emboli may also develop right-to-left shunting because of increased pulmonary vascular resistance, although hypoxemia with pulmonary emboli largely relates to ventilation/perfusion mismatch and decreased level of mixed venous blood oxygen (PvO₂).

This patient’s complex medical history warrants a broadened differential with consideration of his cardiac history, including myocardial fibrosis and arrhythmia, and the impact of exposure to steroids on his immune and musculoskeletal systems. He has a history of atrial fibrillation, and an electrocardiogram is warranted to determine the underlying rhythm. Prolonged periods of rapid ventricular response may lead to tachycardia-induced cardiomyopathy. Myocardial fibrosis may progress despite use of angiotensin-converting enzyme inhibitors and is associated with systolic and/or diastolic dysfunction, although neither the examination findings provided nor the chest radiograph are suggestive of decompensated heart failure. Chronic exposure to corticosteroids (used in DMD to improve muscle strength and function) may predispose to numerous infectious and metabolic complications. Up to 10%-15% of patients with Pneumocystis jirovecii pneumonia may present with a normal chest radiograph. Acute adrenal insufficiency can present with tachycardia, weakness, and respiratory distress, so recent prednisone dose changes or interruptions should be assessed.

The patient’s respiratory status worsened. In light of his complex medical history, he was transferred to a children’s hospital for a higher level of care with a presumptive diagnosis of aspiration pneumonia. Upon reassessment at the new facility, the patient reported an ongoing and severe headache since his initial injury. NSAIDs had been given prior to transfer. His exam continued to be significant for tachycardia, tachypnea, and hypoxemia. His cardiac and lung examinations were otherwise normal. A comprehensive metabolic panel, procalcitonin, complete blood count with differential, and lactate were normal; his C-reactive protein (CRP) was 46.8 mg/dL (Normal <8 mg/dL). A computed tomography (CT) angiogram of the chest revealed small multifocal nodular ground-glass opacities, especially in the lower lobes, concerning for microatelectasis, multifocal pneumonia, or aspiration pneumonia. After consultation with pediatric pulmonology consultants, antimicrobials were held during the initial phase of work-up.

CRP elevation is nonspecific and signals the presence of focal or systemic inflammation and is often elevated to a milder extent in obese patients with DMD. While normal procalcitonin argues against bacterial pneumonia, the precise level can be informative, and serial procalcitonin values may be more helpful than a single value. Although antecedent respiratory symptoms were not mentioned, viral or fungal pneumonia can present insidiously. An occult malignancy may be incidentally discovered when patients present for unrelated issues, although this and other sources of elevated CRP (eg, exacerbation of an autoimmune disease or drug reaction) remain less likely given the acuity of his presentation. Acute pulmonary embolism may be associated with a systemic inflammatory response and elevation in CRP.

In addition to the radiographic differential diagnosis already presented, the appearance of multifocal opacifications with hypoxemia raises the possibility of pulmonary infarcts or noncardiogenic pulmonary edema.

On hospital day 2, the patient continued to complain of “the worst headache of his life” as well as blurry vision and seeing “dark spots.” His headache did not improve with NSAIDs. A noncontrast CT scan of the head was normal. Neurology was consulted. Given his symptoms, history of migraines, stable neurological examination, and normal head CT, he was diagnosed with migraines and administered fluids, prochlorperazine, diphenhydramine, ondansetron, and NSAIDs. His headache continued and he continued to require supplemental oxygen.

The combination of hypoxemia, severe headache, and vision changes remains consistent with systemic emboli caused by thromboembolism or fat embolism. Headache assessment must also involve screening for “red flags,” which include sudden onset, antecedent head trauma, systemic illness (eg, fever or meningismus), focal neurologic findings, papilledema, changes with position or Valsalva, and immunosuppression. Although primary headache syndromes (eg, migraines or tension and cluster headache) may be triggered in the setting of trauma and systemic illness, “the worst headache of my life” is a concerning symptom that warrants urgent attention. While this invokes the possibility of a subarachnoid hemorrhage (SAH), headache severity is nonspecific, and rapid onset (ie, thunderclap headache) would be more suggestive. After 6 hours of symptoms, the sensitivity of head CT for detecting SAH declines, and lumbar puncture would be warranted to evaluate for xanthochromia.

His blurry vision and dark spots require testing of visual acuity and visual fields, as well as fundoscopic examination to assess for embolic phenomena or papilledema. Migraine is classically associated with “positive” or scintillating scotomata, although dark spots may occur. The presence of horizontal diplopia would indicate a cranial nerve VI palsy, which can occur with increased intracranial pressure. Visual-field cuts may also present as blurry vision, and monocular vs binocular deficits signal whether the issue is anterior or involving/posterior to the optic chiasm, respectively. Magnetic resonance imaging (MRI) may reveal the presence or sequelae of cerebral emboli (eg, fat emboli), including vasogenic edema.

Dilated fundus examination revealed Purtscher retinopathy: bilateral cotton-wool spots and larger areas of retinal whitening (Purtscher flecken).

Typical findings of Purtscher retinopathy include Purtscher flecken, cotton-wool spots, retinal hemorrhage, and optic disc edema. Purtscher retinopathy is classically associated with severe head trauma. Without associated head trauma, the term “Purtscher-like retinopathy” is used. Conditions that can cause Purtscher-like retinopathy include pancreatitis, vasculitis, microangiopathy, chronic renal failure, and systemic embolization. The most likely source of systemic embolization remains fat emboli stemming from his femur fracture. Treatment of FES is largely supportive.

The possibility of fat emboli had been repeatedly raised by the patient’s mother since admission. While providers had considered this a possibility, it was discounted early on because of the minor nature of the patient’s orthopedic trauma, the lack of clear radiographic evidence for pulmonary emboli on chest CT, and the normal head CT. The findings on the ophthalmologist’s fundoscopic examination led the primary team to reconsider FES, along with thromboemboli and pancreatitis. Lipase was normal. MRI of the brain with contrast revealed >20 microinfarcts in the bilateral hemispheres, left corpus callosum, and bilateral basal ganglia. The CT angiogram of the chest was rereviewed; the pediatric radiologists suggested that microinfarcts could explain the patchy small ground glass opacities seen in the lungs. A transthoracic echocardiogram and electrocardiogram were normal. The diagnosis of FES was made, and the patient was started on aspirin and enoxaparin prophylaxis. His headache and respiratory status improved, and he was discharged home with close follow-up.

FES is a rare complication associated with long bone fractures and orthopedic manipulation.^1,2 The exact mechanism of fat emboli production is unknown, but two theories prevail. The mechanical theory states that an outside mechanical source causes bone marrow contents or adipose tissue contents to be dislodged into the circulation where they travel through the venous circulation to become embedded in the lungs.^1,2 These fragments may also migrate to the arterial circulation, through a patent foramen ovale or intrapulmonary shunts, leading to end organ damage.^1,2 The biochemical theory suggests that fat emboli in the venous circulation precipitate an inflammatory and prothrombotic cascade that triggers fibrin production, platelet aggregation, and release of free fatty acids into the circulation, predisposing patients to develop multifocal systemic emboli.¹

Although the classic triad in FES includes respiratory symptoms, rash, and CNS symptoms, all three findings are only present in 1%-29% of cases.^1,2 Respiratory abnormalities, ranging from tachypnea and dyspnea to ARDS and hypoxic respiratory failure, occur in up to 75% of patients with FES.¹ Central nervous system (CNS) complications, including headache, confusion, coma, seizures, and death caused by cerebral ischemia, occur in up to 86% of patients.^1,2 Petechiae may occur in 20%-60% of patients and are usually located on nondependent regions of the body such as the head, neck, and chest.

• FES is a rare condition that most commonly manifests with respiratory, neurological, and cutaneous findings.
• Patients with Duchenne’s Muscular Dystrophy are likely at increased risk for FES even with minor trauma; this makes wheelchair restraints and safe transfers fundamental.
• Patients with medical complexity and their caregivers are key members of the diagnostic team.

A 19-year-old man with Duchenne Muscular Dystrophy (DMD) presented to the Emergency Department (ED) for left knee pain after ejection from his motorized wheelchair at a low velocity. In the ED, he developed increasing respiratory distress.

When addressing a new problem in a patient with a chronic condition, it is crucial to first understand the chronic condition and then consider whether the presenting symptoms relate to that condition or stem from an unrelated inciting event.

Patients with DMD are at risk of pulmonary complications relating to their underlying disease. For instance, dysphagia and ineffective cough can predispose them to recurrent aspiration pneumonitis and/or pneumonia, whereas decreased lung compliance (from scoliosis, atelectasis, and/or pulmonary fibrosis) and respiratory muscle weakness can progress to ventilatory failure. In addition, patients with DMD are at risk for pulmonary thromboembolism in the setting of immobility. Patients with DMD may also develop congestive heart failure resulting from myocardial fibrosis and nonischemic cardiomyopathy.

The ejection from his wheelchair signals potential trauma-associated conditions that could explain his respiratory distress. Respiratory complications of blunt thoracic trauma include pulmonary contusion, pneumothorax, flail chest (resulting from fractured ribs), and acute respiratory distress syndrome (ARDS). Lower extremity injury can result in venous thrombosis and pulmonary thromboembolism. While classically associated with long bone fractures, fat embolism syndrome (FES) may rarely occur with rib fractures and soft-tissue trauma. Respiratory compromise may also result from cervical spinal cord injury or severe anemia from trauma-associated hemorrhage.

Additional past medical history included growth hormone deficiency, migraine headaches, osteoporosis secondary to chronic steroid use, cardiac fibrosis of the inferolateral wall and septum with a baseline left ventricular ejection fraction of 65%, and atrial fibrillation. His medications included calcium carbonate, vitamin D, omeprazole, lisinopril, metoprolol, prednisone, escitalopram, and testosterone. Physical examination revealed an ill-appearing obese man in respiratory distress. Temperature was 37.3°C, heart rate was 102 beats per minute (bpm), blood pressure was 110/74 mm Hg. His oxygen saturation was 93% with a respiratory rate of 25 breaths per minute while breathing ambient air. His lung sounds were clear, and his heart was without murmur. The left knee was diffusely tender to palpation without specific point tenderness. Strength was 2/5 with flexion and extension at the bilateral knees and hips and 3/5 flexion and extension at the bilateral elbows. He reported this level of weakness was his baseline. Radiographs revealed a minimally displaced Salter Harris II fracture (fracture line through the metaphysis and growth plate) of the left distal femur. His fracture was splinted early in his ED course. During his ED evaluation, the patient had acute worsening of tachycardia to 130 bpm, increased respiratory rate of 34 breaths per minute, and hypoxemia with an oxygen saturation of 83% on ambient air. He was placed on 3 L/min of oxygen via nasal cannula with improvement in his oxygen saturation to 90%. A chest radiograph was unremarkable, without evidence of pneumothorax, effusion, or pneumonia. The patient was admitted to the hospital.

The acute onset of tachypnea, tachycardia, and hypoxia, accompanied by a clear lung exam and normal chest radiograph, increases the likelihood of a pulmonary embolism. Obesity, testosterone therapy, and trauma increase his susceptibility to venous thromboembolism, while a distal femur fracture increases his risk for FES. Acute pulmonary aspiration often presents with initially absent or subtle radiographic findings. An arterial blood gas analysis would determine the presence and extent of an alveolar-arterial (A-a) gradient; a normal A-a gradient is seen in hypoventilation, while an elevated A-a gradient is seen in conditions affecting gas exchange, including pulmonary emboli and alveolar filling processes. His hypoxemia only partially corrects with supplemental oxygen, raising the possibility of capillary or anatomic shunting. Capillary shunting may occur with atelectasis, aspiration/pneumonia and pulmonary edema, whereas anatomic shunting can be intra-cardiac (eg, patent foramen ovale or septic defect) or intrapulmonary (eg, arteriovenous malformations). Patients with pulmonary emboli may also develop right-to-left shunting because of increased pulmonary vascular resistance, although hypoxemia with pulmonary emboli largely relates to ventilation/perfusion mismatch and decreased level of mixed venous blood oxygen (PvO₂).

This patient’s complex medical history warrants a broadened differential with consideration of his cardiac history, including myocardial fibrosis and arrhythmia, and the impact of exposure to steroids on his immune and musculoskeletal systems. He has a history of atrial fibrillation, and an electrocardiogram is warranted to determine the underlying rhythm. Prolonged periods of rapid ventricular response may lead to tachycardia-induced cardiomyopathy. Myocardial fibrosis may progress despite use of angiotensin-converting enzyme inhibitors and is associated with systolic and/or diastolic dysfunction, although neither the examination findings provided nor the chest radiograph are suggestive of decompensated heart failure. Chronic exposure to corticosteroids (used in DMD to improve muscle strength and function) may predispose to numerous infectious and metabolic complications. Up to 10%-15% of patients with Pneumocystis jirovecii pneumonia may present with a normal chest radiograph. Acute adrenal insufficiency can present with tachycardia, weakness, and respiratory distress, so recent prednisone dose changes or interruptions should be assessed.

The patient’s respiratory status worsened. In light of his complex medical history, he was transferred to a children’s hospital for a higher level of care with a presumptive diagnosis of aspiration pneumonia. Upon reassessment at the new facility, the patient reported an ongoing and severe headache since his initial injury. NSAIDs had been given prior to transfer. His exam continued to be significant for tachycardia, tachypnea, and hypoxemia. His cardiac and lung examinations were otherwise normal. A comprehensive metabolic panel, procalcitonin, complete blood count with differential, and lactate were normal; his C-reactive protein (CRP) was 46.8 mg/dL (Normal <8 mg/dL). A computed tomography (CT) angiogram of the chest revealed small multifocal nodular ground-glass opacities, especially in the lower lobes, concerning for microatelectasis, multifocal pneumonia, or aspiration pneumonia. After consultation with pediatric pulmonology consultants, antimicrobials were held during the initial phase of work-up.

CRP elevation is nonspecific and signals the presence of focal or systemic inflammation and is often elevated to a milder extent in obese patients with DMD. While normal procalcitonin argues against bacterial pneumonia, the precise level can be informative, and serial procalcitonin values may be more helpful than a single value. Although antecedent respiratory symptoms were not mentioned, viral or fungal pneumonia can present insidiously. An occult malignancy may be incidentally discovered when patients present for unrelated issues, although this and other sources of elevated CRP (eg, exacerbation of an autoimmune disease or drug reaction) remain less likely given the acuity of his presentation. Acute pulmonary embolism may be associated with a systemic inflammatory response and elevation in CRP.

In addition to the radiographic differential diagnosis already presented, the appearance of multifocal opacifications with hypoxemia raises the possibility of pulmonary infarcts or noncardiogenic pulmonary edema.

On hospital day 2, the patient continued to complain of “the worst headache of his life” as well as blurry vision and seeing “dark spots.” His headache did not improve with NSAIDs. A noncontrast CT scan of the head was normal. Neurology was consulted. Given his symptoms, history of migraines, stable neurological examination, and normal head CT, he was diagnosed with migraines and administered fluids, prochlorperazine, diphenhydramine, ondansetron, and NSAIDs. His headache continued and he continued to require supplemental oxygen.

The combination of hypoxemia, severe headache, and vision changes remains consistent with systemic emboli caused by thromboembolism or fat embolism. Headache assessment must also involve screening for “red flags,” which include sudden onset, antecedent head trauma, systemic illness (eg, fever or meningismus), focal neurologic findings, papilledema, changes with position or Valsalva, and immunosuppression. Although primary headache syndromes (eg, migraines or tension and cluster headache) may be triggered in the setting of trauma and systemic illness, “the worst headache of my life” is a concerning symptom that warrants urgent attention. While this invokes the possibility of a subarachnoid hemorrhage (SAH), headache severity is nonspecific, and rapid onset (ie, thunderclap headache) would be more suggestive. After 6 hours of symptoms, the sensitivity of head CT for detecting SAH declines, and lumbar puncture would be warranted to evaluate for xanthochromia.

His blurry vision and dark spots require testing of visual acuity and visual fields, as well as fundoscopic examination to assess for embolic phenomena or papilledema. Migraine is classically associated with “positive” or scintillating scotomata, although dark spots may occur. The presence of horizontal diplopia would indicate a cranial nerve VI palsy, which can occur with increased intracranial pressure. Visual-field cuts may also present as blurry vision, and monocular vs binocular deficits signal whether the issue is anterior or involving/posterior to the optic chiasm, respectively. Magnetic resonance imaging (MRI) may reveal the presence or sequelae of cerebral emboli (eg, fat emboli), including vasogenic edema.

Dilated fundus examination revealed Purtscher retinopathy: bilateral cotton-wool spots and larger areas of retinal whitening (Purtscher flecken).

Typical findings of Purtscher retinopathy include Purtscher flecken, cotton-wool spots, retinal hemorrhage, and optic disc edema. Purtscher retinopathy is classically associated with severe head trauma. Without associated head trauma, the term “Purtscher-like retinopathy” is used. Conditions that can cause Purtscher-like retinopathy include pancreatitis, vasculitis, microangiopathy, chronic renal failure, and systemic embolization. The most likely source of systemic embolization remains fat emboli stemming from his femur fracture. Treatment of FES is largely supportive.

The possibility of fat emboli had been repeatedly raised by the patient’s mother since admission. While providers had considered this a possibility, it was discounted early on because of the minor nature of the patient’s orthopedic trauma, the lack of clear radiographic evidence for pulmonary emboli on chest CT, and the normal head CT. The findings on the ophthalmologist’s fundoscopic examination led the primary team to reconsider FES, along with thromboemboli and pancreatitis. Lipase was normal. MRI of the brain with contrast revealed >20 microinfarcts in the bilateral hemispheres, left corpus callosum, and bilateral basal ganglia. The CT angiogram of the chest was rereviewed; the pediatric radiologists suggested that microinfarcts could explain the patchy small ground glass opacities seen in the lungs. A transthoracic echocardiogram and electrocardiogram were normal. The diagnosis of FES was made, and the patient was started on aspirin and enoxaparin prophylaxis. His headache and respiratory status improved, and he was discharged home with close follow-up.

FES is a rare complication associated with long bone fractures and orthopedic manipulation.^1,2 The exact mechanism of fat emboli production is unknown, but two theories prevail. The mechanical theory states that an outside mechanical source causes bone marrow contents or adipose tissue contents to be dislodged into the circulation where they travel through the venous circulation to become embedded in the lungs.^1,2 These fragments may also migrate to the arterial circulation, through a patent foramen ovale or intrapulmonary shunts, leading to end organ damage.^1,2 The biochemical theory suggests that fat emboli in the venous circulation precipitate an inflammatory and prothrombotic cascade that triggers fibrin production, platelet aggregation, and release of free fatty acids into the circulation, predisposing patients to develop multifocal systemic emboli.¹

Although the classic triad in FES includes respiratory symptoms, rash, and CNS symptoms, all three findings are only present in 1%-29% of cases.^1,2 Respiratory abnormalities, ranging from tachypnea and dyspnea to ARDS and hypoxic respiratory failure, occur in up to 75% of patients with FES.¹ Central nervous system (CNS) complications, including headache, confusion, coma, seizures, and death caused by cerebral ischemia, occur in up to 86% of patients.^1,2 Petechiae may occur in 20%-60% of patients and are usually located on nondependent regions of the body such as the head, neck, and chest.

• FES is a rare condition that most commonly manifests with respiratory, neurological, and cutaneous findings.
• Patients with Duchenne’s Muscular Dystrophy are likely at increased risk for FES even with minor trauma; this makes wheelchair restraints and safe transfers fundamental.
• Patients with medical complexity and their caregivers are key members of the diagnostic team.

A 19-year-old man with Duchenne Muscular Dystrophy (DMD) presented to the Emergency Department (ED) for left knee pain after ejection from his motorized wheelchair at a low velocity. In the ED, he developed increasing respiratory distress.

When addressing a new problem in a patient with a chronic condition, it is crucial to first understand the chronic condition and then consider whether the presenting symptoms relate to that condition or stem from an unrelated inciting event.

Patients with DMD are at risk of pulmonary complications relating to their underlying disease. For instance, dysphagia and ineffective cough can predispose them to recurrent aspiration pneumonitis and/or pneumonia, whereas decreased lung compliance (from scoliosis, atelectasis, and/or pulmonary fibrosis) and respiratory muscle weakness can progress to ventilatory failure. In addition, patients with DMD are at risk for pulmonary thromboembolism in the setting of immobility. Patients with DMD may also develop congestive heart failure resulting from myocardial fibrosis and nonischemic cardiomyopathy.

The ejection from his wheelchair signals potential trauma-associated conditions that could explain his respiratory distress. Respiratory complications of blunt thoracic trauma include pulmonary contusion, pneumothorax, flail chest (resulting from fractured ribs), and acute respiratory distress syndrome (ARDS). Lower extremity injury can result in venous thrombosis and pulmonary thromboembolism. While classically associated with long bone fractures, fat embolism syndrome (FES) may rarely occur with rib fractures and soft-tissue trauma. Respiratory compromise may also result from cervical spinal cord injury or severe anemia from trauma-associated hemorrhage.

Additional past medical history included growth hormone deficiency, migraine headaches, osteoporosis secondary to chronic steroid use, cardiac fibrosis of the inferolateral wall and septum with a baseline left ventricular ejection fraction of 65%, and atrial fibrillation. His medications included calcium carbonate, vitamin D, omeprazole, lisinopril, metoprolol, prednisone, escitalopram, and testosterone. Physical examination revealed an ill-appearing obese man in respiratory distress. Temperature was 37.3°C, heart rate was 102 beats per minute (bpm), blood pressure was 110/74 mm Hg. His oxygen saturation was 93% with a respiratory rate of 25 breaths per minute while breathing ambient air. His lung sounds were clear, and his heart was without murmur. The left knee was diffusely tender to palpation without specific point tenderness. Strength was 2/5 with flexion and extension at the bilateral knees and hips and 3/5 flexion and extension at the bilateral elbows. He reported this level of weakness was his baseline. Radiographs revealed a minimally displaced Salter Harris II fracture (fracture line through the metaphysis and growth plate) of the left distal femur. His fracture was splinted early in his ED course. During his ED evaluation, the patient had acute worsening of tachycardia to 130 bpm, increased respiratory rate of 34 breaths per minute, and hypoxemia with an oxygen saturation of 83% on ambient air. He was placed on 3 L/min of oxygen via nasal cannula with improvement in his oxygen saturation to 90%. A chest radiograph was unremarkable, without evidence of pneumothorax, effusion, or pneumonia. The patient was admitted to the hospital.

The acute onset of tachypnea, tachycardia, and hypoxia, accompanied by a clear lung exam and normal chest radiograph, increases the likelihood of a pulmonary embolism. Obesity, testosterone therapy, and trauma increase his susceptibility to venous thromboembolism, while a distal femur fracture increases his risk for FES. Acute pulmonary aspiration often presents with initially absent or subtle radiographic findings. An arterial blood gas analysis would determine the presence and extent of an alveolar-arterial (A-a) gradient; a normal A-a gradient is seen in hypoventilation, while an elevated A-a gradient is seen in conditions affecting gas exchange, including pulmonary emboli and alveolar filling processes. His hypoxemia only partially corrects with supplemental oxygen, raising the possibility of capillary or anatomic shunting. Capillary shunting may occur with atelectasis, aspiration/pneumonia and pulmonary edema, whereas anatomic shunting can be intra-cardiac (eg, patent foramen ovale or septic defect) or intrapulmonary (eg, arteriovenous malformations). Patients with pulmonary emboli may also develop right-to-left shunting because of increased pulmonary vascular resistance, although hypoxemia with pulmonary emboli largely relates to ventilation/perfusion mismatch and decreased level of mixed venous blood oxygen (PvO₂).

This patient’s complex medical history warrants a broadened differential with consideration of his cardiac history, including myocardial fibrosis and arrhythmia, and the impact of exposure to steroids on his immune and musculoskeletal systems. He has a history of atrial fibrillation, and an electrocardiogram is warranted to determine the underlying rhythm. Prolonged periods of rapid ventricular response may lead to tachycardia-induced cardiomyopathy. Myocardial fibrosis may progress despite use of angiotensin-converting enzyme inhibitors and is associated with systolic and/or diastolic dysfunction, although neither the examination findings provided nor the chest radiograph are suggestive of decompensated heart failure. Chronic exposure to corticosteroids (used in DMD to improve muscle strength and function) may predispose to numerous infectious and metabolic complications. Up to 10%-15% of patients with Pneumocystis jirovecii pneumonia may present with a normal chest radiograph. Acute adrenal insufficiency can present with tachycardia, weakness, and respiratory distress, so recent prednisone dose changes or interruptions should be assessed.

The patient’s respiratory status worsened. In light of his complex medical history, he was transferred to a children’s hospital for a higher level of care with a presumptive diagnosis of aspiration pneumonia. Upon reassessment at the new facility, the patient reported an ongoing and severe headache since his initial injury. NSAIDs had been given prior to transfer. His exam continued to be significant for tachycardia, tachypnea, and hypoxemia. His cardiac and lung examinations were otherwise normal. A comprehensive metabolic panel, procalcitonin, complete blood count with differential, and lactate were normal; his C-reactive protein (CRP) was 46.8 mg/dL (Normal <8 mg/dL). A computed tomography (CT) angiogram of the chest revealed small multifocal nodular ground-glass opacities, especially in the lower lobes, concerning for microatelectasis, multifocal pneumonia, or aspiration pneumonia. After consultation with pediatric pulmonology consultants, antimicrobials were held during the initial phase of work-up.

CRP elevation is nonspecific and signals the presence of focal or systemic inflammation and is often elevated to a milder extent in obese patients with DMD. While normal procalcitonin argues against bacterial pneumonia, the precise level can be informative, and serial procalcitonin values may be more helpful than a single value. Although antecedent respiratory symptoms were not mentioned, viral or fungal pneumonia can present insidiously. An occult malignancy may be incidentally discovered when patients present for unrelated issues, although this and other sources of elevated CRP (eg, exacerbation of an autoimmune disease or drug reaction) remain less likely given the acuity of his presentation. Acute pulmonary embolism may be associated with a systemic inflammatory response and elevation in CRP.

In addition to the radiographic differential diagnosis already presented, the appearance of multifocal opacifications with hypoxemia raises the possibility of pulmonary infarcts or noncardiogenic pulmonary edema.

On hospital day 2, the patient continued to complain of “the worst headache of his life” as well as blurry vision and seeing “dark spots.” His headache did not improve with NSAIDs. A noncontrast CT scan of the head was normal. Neurology was consulted. Given his symptoms, history of migraines, stable neurological examination, and normal head CT, he was diagnosed with migraines and administered fluids, prochlorperazine, diphenhydramine, ondansetron, and NSAIDs. His headache continued and he continued to require supplemental oxygen.

The combination of hypoxemia, severe headache, and vision changes remains consistent with systemic emboli caused by thromboembolism or fat embolism. Headache assessment must also involve screening for “red flags,” which include sudden onset, antecedent head trauma, systemic illness (eg, fever or meningismus), focal neurologic findings, papilledema, changes with position or Valsalva, and immunosuppression. Although primary headache syndromes (eg, migraines or tension and cluster headache) may be triggered in the setting of trauma and systemic illness, “the worst headache of my life” is a concerning symptom that warrants urgent attention. While this invokes the possibility of a subarachnoid hemorrhage (SAH), headache severity is nonspecific, and rapid onset (ie, thunderclap headache) would be more suggestive. After 6 hours of symptoms, the sensitivity of head CT for detecting SAH declines, and lumbar puncture would be warranted to evaluate for xanthochromia.

His blurry vision and dark spots require testing of visual acuity and visual fields, as well as fundoscopic examination to assess for embolic phenomena or papilledema. Migraine is classically associated with “positive” or scintillating scotomata, although dark spots may occur. The presence of horizontal diplopia would indicate a cranial nerve VI palsy, which can occur with increased intracranial pressure. Visual-field cuts may also present as blurry vision, and monocular vs binocular deficits signal whether the issue is anterior or involving/posterior to the optic chiasm, respectively. Magnetic resonance imaging (MRI) may reveal the presence or sequelae of cerebral emboli (eg, fat emboli), including vasogenic edema.

Dilated fundus examination revealed Purtscher retinopathy: bilateral cotton-wool spots and larger areas of retinal whitening (Purtscher flecken).

Typical findings of Purtscher retinopathy include Purtscher flecken, cotton-wool spots, retinal hemorrhage, and optic disc edema. Purtscher retinopathy is classically associated with severe head trauma. Without associated head trauma, the term “Purtscher-like retinopathy” is used. Conditions that can cause Purtscher-like retinopathy include pancreatitis, vasculitis, microangiopathy, chronic renal failure, and systemic embolization. The most likely source of systemic embolization remains fat emboli stemming from his femur fracture. Treatment of FES is largely supportive.

The possibility of fat emboli had been repeatedly raised by the patient’s mother since admission. While providers had considered this a possibility, it was discounted early on because of the minor nature of the patient’s orthopedic trauma, the lack of clear radiographic evidence for pulmonary emboli on chest CT, and the normal head CT. The findings on the ophthalmologist’s fundoscopic examination led the primary team to reconsider FES, along with thromboemboli and pancreatitis. Lipase was normal. MRI of the brain with contrast revealed >20 microinfarcts in the bilateral hemispheres, left corpus callosum, and bilateral basal ganglia. The CT angiogram of the chest was rereviewed; the pediatric radiologists suggested that microinfarcts could explain the patchy small ground glass opacities seen in the lungs. A transthoracic echocardiogram and electrocardiogram were normal. The diagnosis of FES was made, and the patient was started on aspirin and enoxaparin prophylaxis. His headache and respiratory status improved, and he was discharged home with close follow-up.

FES is a rare complication associated with long bone fractures and orthopedic manipulation.^1,2 The exact mechanism of fat emboli production is unknown, but two theories prevail. The mechanical theory states that an outside mechanical source causes bone marrow contents or adipose tissue contents to be dislodged into the circulation where they travel through the venous circulation to become embedded in the lungs.^1,2 These fragments may also migrate to the arterial circulation, through a patent foramen ovale or intrapulmonary shunts, leading to end organ damage.^1,2 The biochemical theory suggests that fat emboli in the venous circulation precipitate an inflammatory and prothrombotic cascade that triggers fibrin production, platelet aggregation, and release of free fatty acids into the circulation, predisposing patients to develop multifocal systemic emboli.¹

Although the classic triad in FES includes respiratory symptoms, rash, and CNS symptoms, all three findings are only present in 1%-29% of cases.^1,2 Respiratory abnormalities, ranging from tachypnea and dyspnea to ARDS and hypoxic respiratory failure, occur in up to 75% of patients with FES.¹ Central nervous system (CNS) complications, including headache, confusion, coma, seizures, and death caused by cerebral ischemia, occur in up to 86% of patients.^1,2 Petechiae may occur in 20%-60% of patients and are usually located on nondependent regions of the body such as the head, neck, and chest.

• FES is a rare condition that most commonly manifests with respiratory, neurological, and cutaneous findings.
• Patients with Duchenne’s Muscular Dystrophy are likely at increased risk for FES even with minor trauma; this makes wheelchair restraints and safe transfers fundamental.
• Patients with medical complexity and their caregivers are key members of the diagnostic team.

This article is the first in a series on maternal mortality.

“You’re in really bad shape, kid. I don’t know if you’re gonna live through the night. I’m going to do everything I can to save your life, but the truth is you might die.”

If Timoria McQueen Saba imagined the words she would hear in the moments after she gave birth, those likely weren’t among them. But then she started to bleed. The energy around her shifted; she felt the urgency and intensity in the room, and she could see it – reflected from the television monitor over her bed – in the faces of her care team. After her husband and newborn daughter were led from the room, she did, in fact, hear those words.

They were spoken by a surgeon called in after efforts to control the bleeding failed – emetic words that joined forces with her hemorrhaging and confusion and fear, and as she began to vomit, her eyelids felt heavy. She fought to keep them open, sensing that if she closed them they might never open again.

In 2018 alone, similar words perhaps were spoken to the 658 U.S. women who suffered maternal complications and whose eyes never did open again. This is the latest official maternal mortality data from the Centers for Disease Control and Prevention.

Ms. Saba’s eyes, however, remained open through her birth trauma and through the PTSD that followed. A fierce advocate for maternal health, she shares her story often, as she did during a panel discussion at the American College of Obstetricians and Gynecologists’ annual meeting in May 2019, in an effort to improve outcomes for other women and families.

But her story unfolded nearly a decade ago and those eyes still are seeing women die from childbirth. Despite her efforts and the efforts of countless other individuals and organizations working to improve maternal outcomes, the new CDC data show that the United States has the highest maternal mortality rate of any similarly wealthy industrialized nation.

“I cannot believe I’m still talking about this issue,” Ms. Saba told a standing-room-only crowd and her copanelists Neel T. Shah, MD, and Charles S. Johnson IV, whose wife, Kira, died in 2016 during surgery for bleeding complications following the birth of their second child. “If all the people who I’d written to had just listened maybe once and tried to propel my message forward back then, Charles would be in a much better situation and so would his children.”

Mr. Johnson said that for 10 hours he and other family members pleaded for help for Kira, a healthy, vibrant women he described as “sunshine personified.”

She showed signs of postpartum bleeding after delivering a healthy baby boy by C-section, but a “STAT CT” order went unheeded for hours before she was finally taken for surgery.

“You’re walking down this corridor, you get to this point, these double doors open, and you just can’t go any further – and that was the last time I saw my wife alive,” he said. “When they took Kira back into the operating room, there were three-and-a-half liters of blood in her abdomen, and her heart stopped immediately.

Kira Johnson died April 13, 2016.

“I’m not here to tell you what I think, I’m here to tell you what I know, and that’s that Kira deserved so much better, and that Kira’s not alone, and that women all over this country deserve so much better.”

The U.S. maternal mortality crisis

Dr. Shah, an ob.gyn. at Beth Israel Deaconess Medical Center and director of the Delivery Decisions Initiative at Harvard Medical School’s Ariadne Labs, both in Boston, where he has “been on this mission to improve safety in childbirth for years now,” echoed Ms. Saba’s dismay regarding the pace of progress.

“It’s not just about the present, it’s about the future, it’s about the pact that every generation ought to have with the next one to leave things at least as well as they found them. And when it comes to the health of our moms in this country, we are not doing that,” he said. “An American mom today is 50% more likely to die in childbirth than her own mother was, and 3-4 times more likely to die if she’s black than if she’s white.”

Indeed, the data released Jan. 30 by the CDC’s National Center for Health Statistics (NCHS) – the first on maternal mortality released by the agency since 2007 – show a U.S. maternal mortality rate of 17.4 maternal deaths per 100,000 live births in 2018.

The rate is higher than the 12.7 per 100,000 live births reported in 2007, but the increase is attributable mostly to changes in data collection and reporting methods. In 2003, “a consensus process recommended that all states add a standardized ‘checkbox’ to improve the identification of maternal deaths,” and implementation wasn’t complete until 2017 as “funding, technology, and state laws allowed,” meaning 2018 was the first year that data were reported in a standardized fashion across states, the CDC explained in a press release.

The data demonstrate ongoing wide racial/ethnic disparities: the maternal mortality rates for non-Hispanic black women, non-Hispanic white women, and Hispanic women were 37.1, 14.7, and 11.8 per 100,000 live births, consistent with earlier data.

Further, the rates for women aged 40 years and over were nearly eightfold higher than for those under age 25 years (81.9 vs. 10.6 per 100,000 live births).

CDC officials noted, however, that inconsistencies in reporting still leave some question about the accuracy of the data, stating in the release that “NCHS has identified instances where application of the checkbox information according to coding rules led to misclassification of maternal deaths.”

The agency is making changes in rules and reporting to ensure greater accuracy, but the numbers nevertheless reveal a startling truth: “The United States is the most dangerous place to deliver a baby in the industrialized world.”

 

Progress and challenges

Rebekah Gee, MD, an ob.gyn. who served for 4 years as Secretary of the Louisiana Department of Health before leaving the position in January, made that statement during another panel discussion at ACOG 2019 – The President’s Panel: Maternal Mortality: Progress Toward Prevention – which was moderated by Lisa M. Hollier, MD, now the immediate past president of ACOG.

Texas Children&#039;s Hospital

That’s not to say progress hasn’t been or can’t be made, Dr. Gee said.

In fact, quality improvement measures she facilitated in Louisiana led to a 25% reduction in infant mortality and a 10% reduction in neonatal intensive care unit admissions, demonstrating the potential for improvement with such initiatives, but addressing maternal issues is a greater challenge, she said.

“I think part of the sad truth is that we really focus on babies first, not moms ... and that needs to change,” Dr. Gee said.

Dr. Hollier focused much of her attention during her tenure as ACOG president on doing just that, particularly through an emphasis on heart disease, which is the leading cause of U.S. maternal deaths in pregnancy and the postpartum period.

In an interview, she shared her thoughts on the progress achieved and the work that remains.

ACOG was instrumental in the enactment of the Preventing Maternal Deaths Act of 2018, which appropriated funding for Enhancing Reviews and Surveillance to Eliminate Maternal Mortality (ERASE MM), a CDC initiative to support state-based maternal mortality review committees, said Dr. Hollier, professor of obstetrics and gynecology at Baylor College of Medicine, Houston.

“The really great news is that almost immediately after passage of the legislation, the CDC put out the notice of the funding opportunity, and they were able to provide 24 awards supporting 25 states,” she said.

ERASE MM will enhance state data collection and availability and enable a level of data sharing that “will really add strength and depth to reporting from the maternal mortality review committees, which really provides us with the best information we have to truly understand the causes, the contributing factors, and the strategies that can be put in place to prevent future maternal deaths.”

Further, the Alliance for Innovation on Maternal Health (AIM) program, a cooperative agreement with the Health Resources and Services Administration (HRSA) Maternal and Child Health Bureau to improve safety and outcomes through evidence-based patient safety bundles, was extended, and in May 2019, ACOG updated its guidance on managing cardiac contributors to maternal mortality, releasing its “Pregnancy and Heart Disease” Practice Bulletin, she said.

Dr. Hollier continues in her quest for improved maternal outcomes. She is slated to deliver a keynote address at the American College of Cardiology/World Congress of Cardiology conference March 28 in Chicago.

“I’m so excited ... to talk about the new guidelines that we’ve put out and to really talk about how cardiologists and ob.gyns. can work together to improve women’s health outcomes,” she said, adding that she already is seeing a strengthening of such partnerships.

A number of academic institutions are developing “pregnancy heart teams” to identify and care for women who have or develop heart disease during pregnancy.

“This type of collaboration ... is going to be essential to address mortality from cardiovascular causes and from cardiomyopathy, which accounts for about 25% of all maternal mortality,” she said. “The next area where we really need some buy-in is from our emergency physicians.”

Enhanced collaboration with emergency physicians and other specialties present opportunities to better identify and address pregnancy-related complications and sequelae, she said.

“Women are dying because they’re not being diagnosed,” she added. “We have to raise that level of awareness – it’s just absolutely critical.”
 

Identifying and addressing drivers of the crisis

Dr. Gee further emphasized the importance of addressing maternal health, noting that for every woman who dies from maternal causes, 100 experience maternal morbidity.

“It’s startling and it’s scary,” she said. “We are looking at this not just as a problem of outcomes, but a problem of racial inequity and racial bias and implicit bias.”

When she and her team assessed maternal mortality in Louisiana, they looked specifically at whether each death could have been prevented if, for example, blood was given sooner, cardiomyopathy was recognized sooner, or hypertension was treated on time.

“When we looked at these numbers ... when we looked at white women, 9% of the time we could have done better with our medical care; with black women, 59% of the time we could have saved her life with better care,” said Dr Gee, who is a gratis assistant professor of obstetrics and gynecology at Louisiana State University, New Orleans. “And if that doesn’t convince you that racial bias is an incredibly important thing to address – that we need to have a conversation about and address at a national level – I don’t know what would.”

In fact, numerous health, societal, socioeconomic, and other factors – some known, some yet to be identified, and many inter-related – are among the drivers of the U.S. maternal mortality crisis. In the coming months, an Ob.Gyn. News team will examine several of these drivers in depth. We’ll look specifically at the role of racism and bias, and at urban-rural disparities in access and outcomes – especially for women of color and indigenous women. We’ll address the scope and impact of each, successes and failures in addressing the problems, and ongoing initiatives.

Follow us for insights from experts, researchers, practicing physicians, and patients and families affected by the maternal mortality crisis, and stay with us through coverage of ACOG 2020 for perspective on what, specifically, ob.gyns. can do about it.

Mr. Johnson proposed a starting point:

“Here’s the good news – you guys ready for this? We can fix this,” he said, adding that the solution starts with “speaking Timoria’s name ... speaking the name of Kira Dixon Johnson ... speaking the names of these women and then asking the people that are around you, ‘What are we prepared to do to make sure that this doesn’t happen to other women.’ ”

sworcester@mdedge.com

This article is the first in a series on maternal mortality.

“You’re in really bad shape, kid. I don’t know if you’re gonna live through the night. I’m going to do everything I can to save your life, but the truth is you might die.”

If Timoria McQueen Saba imagined the words she would hear in the moments after she gave birth, those likely weren’t among them. But then she started to bleed. The energy around her shifted; she felt the urgency and intensity in the room, and she could see it – reflected from the television monitor over her bed – in the faces of her care team. After her husband and newborn daughter were led from the room, she did, in fact, hear those words.

They were spoken by a surgeon called in after efforts to control the bleeding failed – emetic words that joined forces with her hemorrhaging and confusion and fear, and as she began to vomit, her eyelids felt heavy. She fought to keep them open, sensing that if she closed them they might never open again.

In 2018 alone, similar words perhaps were spoken to the 658 U.S. women who suffered maternal complications and whose eyes never did open again. This is the latest official maternal mortality data from the Centers for Disease Control and Prevention.

Ms. Saba’s eyes, however, remained open through her birth trauma and through the PTSD that followed. A fierce advocate for maternal health, she shares her story often, as she did during a panel discussion at the American College of Obstetricians and Gynecologists’ annual meeting in May 2019, in an effort to improve outcomes for other women and families.

But her story unfolded nearly a decade ago and those eyes still are seeing women die from childbirth. Despite her efforts and the efforts of countless other individuals and organizations working to improve maternal outcomes, the new CDC data show that the United States has the highest maternal mortality rate of any similarly wealthy industrialized nation.

“I cannot believe I’m still talking about this issue,” Ms. Saba told a standing-room-only crowd and her copanelists Neel T. Shah, MD, and Charles S. Johnson IV, whose wife, Kira, died in 2016 during surgery for bleeding complications following the birth of their second child. “If all the people who I’d written to had just listened maybe once and tried to propel my message forward back then, Charles would be in a much better situation and so would his children.”

Mr. Johnson said that for 10 hours he and other family members pleaded for help for Kira, a healthy, vibrant women he described as “sunshine personified.”

She showed signs of postpartum bleeding after delivering a healthy baby boy by C-section, but a “STAT CT” order went unheeded for hours before she was finally taken for surgery.

“You’re walking down this corridor, you get to this point, these double doors open, and you just can’t go any further – and that was the last time I saw my wife alive,” he said. “When they took Kira back into the operating room, there were three-and-a-half liters of blood in her abdomen, and her heart stopped immediately.

Kira Johnson died April 13, 2016.

“I’m not here to tell you what I think, I’m here to tell you what I know, and that’s that Kira deserved so much better, and that Kira’s not alone, and that women all over this country deserve so much better.”

The U.S. maternal mortality crisis

Dr. Shah, an ob.gyn. at Beth Israel Deaconess Medical Center and director of the Delivery Decisions Initiative at Harvard Medical School’s Ariadne Labs, both in Boston, where he has “been on this mission to improve safety in childbirth for years now,” echoed Ms. Saba’s dismay regarding the pace of progress.

“It’s not just about the present, it’s about the future, it’s about the pact that every generation ought to have with the next one to leave things at least as well as they found them. And when it comes to the health of our moms in this country, we are not doing that,” he said. “An American mom today is 50% more likely to die in childbirth than her own mother was, and 3-4 times more likely to die if she’s black than if she’s white.”

Indeed, the data released Jan. 30 by the CDC’s National Center for Health Statistics (NCHS) – the first on maternal mortality released by the agency since 2007 – show a U.S. maternal mortality rate of 17.4 maternal deaths per 100,000 live births in 2018.

The rate is higher than the 12.7 per 100,000 live births reported in 2007, but the increase is attributable mostly to changes in data collection and reporting methods. In 2003, “a consensus process recommended that all states add a standardized ‘checkbox’ to improve the identification of maternal deaths,” and implementation wasn’t complete until 2017 as “funding, technology, and state laws allowed,” meaning 2018 was the first year that data were reported in a standardized fashion across states, the CDC explained in a press release.

The data demonstrate ongoing wide racial/ethnic disparities: the maternal mortality rates for non-Hispanic black women, non-Hispanic white women, and Hispanic women were 37.1, 14.7, and 11.8 per 100,000 live births, consistent with earlier data.

Further, the rates for women aged 40 years and over were nearly eightfold higher than for those under age 25 years (81.9 vs. 10.6 per 100,000 live births).

CDC officials noted, however, that inconsistencies in reporting still leave some question about the accuracy of the data, stating in the release that “NCHS has identified instances where application of the checkbox information according to coding rules led to misclassification of maternal deaths.”

The agency is making changes in rules and reporting to ensure greater accuracy, but the numbers nevertheless reveal a startling truth: “The United States is the most dangerous place to deliver a baby in the industrialized world.”

 

Progress and challenges

Rebekah Gee, MD, an ob.gyn. who served for 4 years as Secretary of the Louisiana Department of Health before leaving the position in January, made that statement during another panel discussion at ACOG 2019 – The President’s Panel: Maternal Mortality: Progress Toward Prevention – which was moderated by Lisa M. Hollier, MD, now the immediate past president of ACOG.

Texas Children&#039;s Hospital

That’s not to say progress hasn’t been or can’t be made, Dr. Gee said.

In fact, quality improvement measures she facilitated in Louisiana led to a 25% reduction in infant mortality and a 10% reduction in neonatal intensive care unit admissions, demonstrating the potential for improvement with such initiatives, but addressing maternal issues is a greater challenge, she said.

“I think part of the sad truth is that we really focus on babies first, not moms ... and that needs to change,” Dr. Gee said.

Dr. Hollier focused much of her attention during her tenure as ACOG president on doing just that, particularly through an emphasis on heart disease, which is the leading cause of U.S. maternal deaths in pregnancy and the postpartum period.

In an interview, she shared her thoughts on the progress achieved and the work that remains.

ACOG was instrumental in the enactment of the Preventing Maternal Deaths Act of 2018, which appropriated funding for Enhancing Reviews and Surveillance to Eliminate Maternal Mortality (ERASE MM), a CDC initiative to support state-based maternal mortality review committees, said Dr. Hollier, professor of obstetrics and gynecology at Baylor College of Medicine, Houston.

“The really great news is that almost immediately after passage of the legislation, the CDC put out the notice of the funding opportunity, and they were able to provide 24 awards supporting 25 states,” she said.

ERASE MM will enhance state data collection and availability and enable a level of data sharing that “will really add strength and depth to reporting from the maternal mortality review committees, which really provides us with the best information we have to truly understand the causes, the contributing factors, and the strategies that can be put in place to prevent future maternal deaths.”

Further, the Alliance for Innovation on Maternal Health (AIM) program, a cooperative agreement with the Health Resources and Services Administration (HRSA) Maternal and Child Health Bureau to improve safety and outcomes through evidence-based patient safety bundles, was extended, and in May 2019, ACOG updated its guidance on managing cardiac contributors to maternal mortality, releasing its “Pregnancy and Heart Disease” Practice Bulletin, she said.

Dr. Hollier continues in her quest for improved maternal outcomes. She is slated to deliver a keynote address at the American College of Cardiology/World Congress of Cardiology conference March 28 in Chicago.

“I’m so excited ... to talk about the new guidelines that we’ve put out and to really talk about how cardiologists and ob.gyns. can work together to improve women’s health outcomes,” she said, adding that she already is seeing a strengthening of such partnerships.

A number of academic institutions are developing “pregnancy heart teams” to identify and care for women who have or develop heart disease during pregnancy.

“This type of collaboration ... is going to be essential to address mortality from cardiovascular causes and from cardiomyopathy, which accounts for about 25% of all maternal mortality,” she said. “The next area where we really need some buy-in is from our emergency physicians.”

Enhanced collaboration with emergency physicians and other specialties present opportunities to better identify and address pregnancy-related complications and sequelae, she said.

“Women are dying because they’re not being diagnosed,” she added. “We have to raise that level of awareness – it’s just absolutely critical.”
 

Identifying and addressing drivers of the crisis

Dr. Gee further emphasized the importance of addressing maternal health, noting that for every woman who dies from maternal causes, 100 experience maternal morbidity.

“It’s startling and it’s scary,” she said. “We are looking at this not just as a problem of outcomes, but a problem of racial inequity and racial bias and implicit bias.”

When she and her team assessed maternal mortality in Louisiana, they looked specifically at whether each death could have been prevented if, for example, blood was given sooner, cardiomyopathy was recognized sooner, or hypertension was treated on time.

“When we looked at these numbers ... when we looked at white women, 9% of the time we could have done better with our medical care; with black women, 59% of the time we could have saved her life with better care,” said Dr Gee, who is a gratis assistant professor of obstetrics and gynecology at Louisiana State University, New Orleans. “And if that doesn’t convince you that racial bias is an incredibly important thing to address – that we need to have a conversation about and address at a national level – I don’t know what would.”

In fact, numerous health, societal, socioeconomic, and other factors – some known, some yet to be identified, and many inter-related – are among the drivers of the U.S. maternal mortality crisis. In the coming months, an Ob.Gyn. News team will examine several of these drivers in depth. We’ll look specifically at the role of racism and bias, and at urban-rural disparities in access and outcomes – especially for women of color and indigenous women. We’ll address the scope and impact of each, successes and failures in addressing the problems, and ongoing initiatives.

Follow us for insights from experts, researchers, practicing physicians, and patients and families affected by the maternal mortality crisis, and stay with us through coverage of ACOG 2020 for perspective on what, specifically, ob.gyns. can do about it.

Mr. Johnson proposed a starting point:

“Here’s the good news – you guys ready for this? We can fix this,” he said, adding that the solution starts with “speaking Timoria’s name ... speaking the name of Kira Dixon Johnson ... speaking the names of these women and then asking the people that are around you, ‘What are we prepared to do to make sure that this doesn’t happen to other women.’ ”

sworcester@mdedge.com

This article is the first in a series on maternal mortality.

“You’re in really bad shape, kid. I don’t know if you’re gonna live through the night. I’m going to do everything I can to save your life, but the truth is you might die.”

If Timoria McQueen Saba imagined the words she would hear in the moments after she gave birth, those likely weren’t among them. But then she started to bleed. The energy around her shifted; she felt the urgency and intensity in the room, and she could see it – reflected from the television monitor over her bed – in the faces of her care team. After her husband and newborn daughter were led from the room, she did, in fact, hear those words.

They were spoken by a surgeon called in after efforts to control the bleeding failed – emetic words that joined forces with her hemorrhaging and confusion and fear, and as she began to vomit, her eyelids felt heavy. She fought to keep them open, sensing that if she closed them they might never open again.

In 2018 alone, similar words perhaps were spoken to the 658 U.S. women who suffered maternal complications and whose eyes never did open again. This is the latest official maternal mortality data from the Centers for Disease Control and Prevention.

Ms. Saba’s eyes, however, remained open through her birth trauma and through the PTSD that followed. A fierce advocate for maternal health, she shares her story often, as she did during a panel discussion at the American College of Obstetricians and Gynecologists’ annual meeting in May 2019, in an effort to improve outcomes for other women and families.

But her story unfolded nearly a decade ago and those eyes still are seeing women die from childbirth. Despite her efforts and the efforts of countless other individuals and organizations working to improve maternal outcomes, the new CDC data show that the United States has the highest maternal mortality rate of any similarly wealthy industrialized nation.

“I cannot believe I’m still talking about this issue,” Ms. Saba told a standing-room-only crowd and her copanelists Neel T. Shah, MD, and Charles S. Johnson IV, whose wife, Kira, died in 2016 during surgery for bleeding complications following the birth of their second child. “If all the people who I’d written to had just listened maybe once and tried to propel my message forward back then, Charles would be in a much better situation and so would his children.”

Mr. Johnson said that for 10 hours he and other family members pleaded for help for Kira, a healthy, vibrant women he described as “sunshine personified.”

She showed signs of postpartum bleeding after delivering a healthy baby boy by C-section, but a “STAT CT” order went unheeded for hours before she was finally taken for surgery.

“You’re walking down this corridor, you get to this point, these double doors open, and you just can’t go any further – and that was the last time I saw my wife alive,” he said. “When they took Kira back into the operating room, there were three-and-a-half liters of blood in her abdomen, and her heart stopped immediately.

Kira Johnson died April 13, 2016.

“I’m not here to tell you what I think, I’m here to tell you what I know, and that’s that Kira deserved so much better, and that Kira’s not alone, and that women all over this country deserve so much better.”

The U.S. maternal mortality crisis

Dr. Shah, an ob.gyn. at Beth Israel Deaconess Medical Center and director of the Delivery Decisions Initiative at Harvard Medical School’s Ariadne Labs, both in Boston, where he has “been on this mission to improve safety in childbirth for years now,” echoed Ms. Saba’s dismay regarding the pace of progress.

“It’s not just about the present, it’s about the future, it’s about the pact that every generation ought to have with the next one to leave things at least as well as they found them. And when it comes to the health of our moms in this country, we are not doing that,” he said. “An American mom today is 50% more likely to die in childbirth than her own mother was, and 3-4 times more likely to die if she’s black than if she’s white.”

Indeed, the data released Jan. 30 by the CDC’s National Center for Health Statistics (NCHS) – the first on maternal mortality released by the agency since 2007 – show a U.S. maternal mortality rate of 17.4 maternal deaths per 100,000 live births in 2018.

The rate is higher than the 12.7 per 100,000 live births reported in 2007, but the increase is attributable mostly to changes in data collection and reporting methods. In 2003, “a consensus process recommended that all states add a standardized ‘checkbox’ to improve the identification of maternal deaths,” and implementation wasn’t complete until 2017 as “funding, technology, and state laws allowed,” meaning 2018 was the first year that data were reported in a standardized fashion across states, the CDC explained in a press release.

The data demonstrate ongoing wide racial/ethnic disparities: the maternal mortality rates for non-Hispanic black women, non-Hispanic white women, and Hispanic women were 37.1, 14.7, and 11.8 per 100,000 live births, consistent with earlier data.

Further, the rates for women aged 40 years and over were nearly eightfold higher than for those under age 25 years (81.9 vs. 10.6 per 100,000 live births).

CDC officials noted, however, that inconsistencies in reporting still leave some question about the accuracy of the data, stating in the release that “NCHS has identified instances where application of the checkbox information according to coding rules led to misclassification of maternal deaths.”

The agency is making changes in rules and reporting to ensure greater accuracy, but the numbers nevertheless reveal a startling truth: “The United States is the most dangerous place to deliver a baby in the industrialized world.”

 

Progress and challenges

Rebekah Gee, MD, an ob.gyn. who served for 4 years as Secretary of the Louisiana Department of Health before leaving the position in January, made that statement during another panel discussion at ACOG 2019 – The President’s Panel: Maternal Mortality: Progress Toward Prevention – which was moderated by Lisa M. Hollier, MD, now the immediate past president of ACOG.

Texas Children&#039;s Hospital

That’s not to say progress hasn’t been or can’t be made, Dr. Gee said.

In fact, quality improvement measures she facilitated in Louisiana led to a 25% reduction in infant mortality and a 10% reduction in neonatal intensive care unit admissions, demonstrating the potential for improvement with such initiatives, but addressing maternal issues is a greater challenge, she said.

“I think part of the sad truth is that we really focus on babies first, not moms ... and that needs to change,” Dr. Gee said.

Dr. Hollier focused much of her attention during her tenure as ACOG president on doing just that, particularly through an emphasis on heart disease, which is the leading cause of U.S. maternal deaths in pregnancy and the postpartum period.

In an interview, she shared her thoughts on the progress achieved and the work that remains.

ACOG was instrumental in the enactment of the Preventing Maternal Deaths Act of 2018, which appropriated funding for Enhancing Reviews and Surveillance to Eliminate Maternal Mortality (ERASE MM), a CDC initiative to support state-based maternal mortality review committees, said Dr. Hollier, professor of obstetrics and gynecology at Baylor College of Medicine, Houston.

“The really great news is that almost immediately after passage of the legislation, the CDC put out the notice of the funding opportunity, and they were able to provide 24 awards supporting 25 states,” she said.

ERASE MM will enhance state data collection and availability and enable a level of data sharing that “will really add strength and depth to reporting from the maternal mortality review committees, which really provides us with the best information we have to truly understand the causes, the contributing factors, and the strategies that can be put in place to prevent future maternal deaths.”

Further, the Alliance for Innovation on Maternal Health (AIM) program, a cooperative agreement with the Health Resources and Services Administration (HRSA) Maternal and Child Health Bureau to improve safety and outcomes through evidence-based patient safety bundles, was extended, and in May 2019, ACOG updated its guidance on managing cardiac contributors to maternal mortality, releasing its “Pregnancy and Heart Disease” Practice Bulletin, she said.

Dr. Hollier continues in her quest for improved maternal outcomes. She is slated to deliver a keynote address at the American College of Cardiology/World Congress of Cardiology conference March 28 in Chicago.

“I’m so excited ... to talk about the new guidelines that we’ve put out and to really talk about how cardiologists and ob.gyns. can work together to improve women’s health outcomes,” she said, adding that she already is seeing a strengthening of such partnerships.

A number of academic institutions are developing “pregnancy heart teams” to identify and care for women who have or develop heart disease during pregnancy.

“This type of collaboration ... is going to be essential to address mortality from cardiovascular causes and from cardiomyopathy, which accounts for about 25% of all maternal mortality,” she said. “The next area where we really need some buy-in is from our emergency physicians.”

Enhanced collaboration with emergency physicians and other specialties present opportunities to better identify and address pregnancy-related complications and sequelae, she said.

“Women are dying because they’re not being diagnosed,” she added. “We have to raise that level of awareness – it’s just absolutely critical.”
 

Identifying and addressing drivers of the crisis

Dr. Gee further emphasized the importance of addressing maternal health, noting that for every woman who dies from maternal causes, 100 experience maternal morbidity.

“It’s startling and it’s scary,” she said. “We are looking at this not just as a problem of outcomes, but a problem of racial inequity and racial bias and implicit bias.”

When she and her team assessed maternal mortality in Louisiana, they looked specifically at whether each death could have been prevented if, for example, blood was given sooner, cardiomyopathy was recognized sooner, or hypertension was treated on time.

“When we looked at these numbers ... when we looked at white women, 9% of the time we could have done better with our medical care; with black women, 59% of the time we could have saved her life with better care,” said Dr Gee, who is a gratis assistant professor of obstetrics and gynecology at Louisiana State University, New Orleans. “And if that doesn’t convince you that racial bias is an incredibly important thing to address – that we need to have a conversation about and address at a national level – I don’t know what would.”

In fact, numerous health, societal, socioeconomic, and other factors – some known, some yet to be identified, and many inter-related – are among the drivers of the U.S. maternal mortality crisis. In the coming months, an Ob.Gyn. News team will examine several of these drivers in depth. We’ll look specifically at the role of racism and bias, and at urban-rural disparities in access and outcomes – especially for women of color and indigenous women. We’ll address the scope and impact of each, successes and failures in addressing the problems, and ongoing initiatives.

Follow us for insights from experts, researchers, practicing physicians, and patients and families affected by the maternal mortality crisis, and stay with us through coverage of ACOG 2020 for perspective on what, specifically, ob.gyns. can do about it.

Mr. Johnson proposed a starting point:

“Here’s the good news – you guys ready for this? We can fix this,” he said, adding that the solution starts with “speaking Timoria’s name ... speaking the name of Kira Dixon Johnson ... speaking the names of these women and then asking the people that are around you, ‘What are we prepared to do to make sure that this doesn’t happen to other women.’ ”

sworcester@mdedge.com

The Trump Administration is looking to telehealth services to play a more prominent role in helping mitigate the spread of COVID-19 by expanding existing benefits for Medicare beneficiaries.

“Medicare can pay for office, hospital, and other visits furnished via telehealth across the country and including in patients’ places of residence, starting March 6, 2020,” the Centers for Medicare & Medicaid Services said in a fact sheet issued March 17.

Some of the existing benefits were previously limited to rural communities.

“Medicare beneficiaries across the nation, no matter where they live, will now be able to receive a wide range of services via telehealth without ever having to leave home,” CMS Administrator Seema Verma said during a March 17 White House press briefing on administration actions to contain the spread of COVID-19. “These services can also be provided in a variety of settings, including nursing homes, hospital outpatient departments, and more.”

That means that seniors can continue to receive their routine care without having to leave the home and risk infection, or they can get medical guidance if they have mild symptoms, which would help mitigate the spread to others.

“This shift is very important for clinicians and providers who, over the coming weeks, will face considerable strain on their time and resources,” Dr. Verma said. “[It] allows the health care system to prioritize care for those who have more needs or who are in dire need, and it also preserves protective equipment.”

A range of providers will be able to deliver telehealth services, including doctors, nurse practitioners, clinical psychologists, and licensed clinical social workers. Visits using the telehealth services will be considered the same as in-person visits and will be paid as if the patient were seen in the office.

This expansion of Medicare telehealth services will continue for the duration of the COVID-19 public health emergency.

“In addition, the [Health and Human Services’] office of inspector general is providing flexibility for health care providers to reduce or waive cost-sharing for telehealth visits paid by federal health care programs,” the fact sheet states. CMS also said it will not conduct audits to ensure that an established relationship exists between the provider and the patient – a prior requirement for telehealth billing – during this public health emergency.

Billing for virtual check-ins, which are essentially brief conversations that may not require a full visit to the physician office, needs an established relationship between the practice and the patient. Likewise, for e-visits, which include non–face-to-face communications through online patient portals, billing can occur only when there is an established patient relationship.

Key to the expansion is that it will cover the entire United States and will not be limited to rural areas.

Dr. Verma also noted that the administration “will be temporarily suspending certain HIPAA requirements so that doctors can provide telehealth with their own phones.”

She noted this was all a part of mitigation efforts to limit the spread of COVID-19.

“As we are encouraging Americans to stay home whenever possible, we don’t want our Medicare policies getting in the way,” she said, adding that state Medicaid agencies can expand their telehealth services without the approval of CMS during this emergency.

gtwachtman@mdedge.com

The Trump Administration is looking to telehealth services to play a more prominent role in helping mitigate the spread of COVID-19 by expanding existing benefits for Medicare beneficiaries.

“Medicare can pay for office, hospital, and other visits furnished via telehealth across the country and including in patients’ places of residence, starting March 6, 2020,” the Centers for Medicare & Medicaid Services said in a fact sheet issued March 17.

Some of the existing benefits were previously limited to rural communities.

“Medicare beneficiaries across the nation, no matter where they live, will now be able to receive a wide range of services via telehealth without ever having to leave home,” CMS Administrator Seema Verma said during a March 17 White House press briefing on administration actions to contain the spread of COVID-19. “These services can also be provided in a variety of settings, including nursing homes, hospital outpatient departments, and more.”

That means that seniors can continue to receive their routine care without having to leave the home and risk infection, or they can get medical guidance if they have mild symptoms, which would help mitigate the spread to others.

“This shift is very important for clinicians and providers who, over the coming weeks, will face considerable strain on their time and resources,” Dr. Verma said. “[It] allows the health care system to prioritize care for those who have more needs or who are in dire need, and it also preserves protective equipment.”

A range of providers will be able to deliver telehealth services, including doctors, nurse practitioners, clinical psychologists, and licensed clinical social workers. Visits using the telehealth services will be considered the same as in-person visits and will be paid as if the patient were seen in the office.

This expansion of Medicare telehealth services will continue for the duration of the COVID-19 public health emergency.

“In addition, the [Health and Human Services’] office of inspector general is providing flexibility for health care providers to reduce or waive cost-sharing for telehealth visits paid by federal health care programs,” the fact sheet states. CMS also said it will not conduct audits to ensure that an established relationship exists between the provider and the patient – a prior requirement for telehealth billing – during this public health emergency.

Billing for virtual check-ins, which are essentially brief conversations that may not require a full visit to the physician office, needs an established relationship between the practice and the patient. Likewise, for e-visits, which include non–face-to-face communications through online patient portals, billing can occur only when there is an established patient relationship.

Key to the expansion is that it will cover the entire United States and will not be limited to rural areas.

Dr. Verma also noted that the administration “will be temporarily suspending certain HIPAA requirements so that doctors can provide telehealth with their own phones.”

She noted this was all a part of mitigation efforts to limit the spread of COVID-19.

“As we are encouraging Americans to stay home whenever possible, we don’t want our Medicare policies getting in the way,” she said, adding that state Medicaid agencies can expand their telehealth services without the approval of CMS during this emergency.

gtwachtman@mdedge.com

The Trump Administration is looking to telehealth services to play a more prominent role in helping mitigate the spread of COVID-19 by expanding existing benefits for Medicare beneficiaries.

“Medicare can pay for office, hospital, and other visits furnished via telehealth across the country and including in patients’ places of residence, starting March 6, 2020,” the Centers for Medicare & Medicaid Services said in a fact sheet issued March 17.

Some of the existing benefits were previously limited to rural communities.

“Medicare beneficiaries across the nation, no matter where they live, will now be able to receive a wide range of services via telehealth without ever having to leave home,” CMS Administrator Seema Verma said during a March 17 White House press briefing on administration actions to contain the spread of COVID-19. “These services can also be provided in a variety of settings, including nursing homes, hospital outpatient departments, and more.”

That means that seniors can continue to receive their routine care without having to leave the home and risk infection, or they can get medical guidance if they have mild symptoms, which would help mitigate the spread to others.

“This shift is very important for clinicians and providers who, over the coming weeks, will face considerable strain on their time and resources,” Dr. Verma said. “[It] allows the health care system to prioritize care for those who have more needs or who are in dire need, and it also preserves protective equipment.”

A range of providers will be able to deliver telehealth services, including doctors, nurse practitioners, clinical psychologists, and licensed clinical social workers. Visits using the telehealth services will be considered the same as in-person visits and will be paid as if the patient were seen in the office.

This expansion of Medicare telehealth services will continue for the duration of the COVID-19 public health emergency.

“In addition, the [Health and Human Services’] office of inspector general is providing flexibility for health care providers to reduce or waive cost-sharing for telehealth visits paid by federal health care programs,” the fact sheet states. CMS also said it will not conduct audits to ensure that an established relationship exists between the provider and the patient – a prior requirement for telehealth billing – during this public health emergency.

Billing for virtual check-ins, which are essentially brief conversations that may not require a full visit to the physician office, needs an established relationship between the practice and the patient. Likewise, for e-visits, which include non–face-to-face communications through online patient portals, billing can occur only when there is an established patient relationship.

Key to the expansion is that it will cover the entire United States and will not be limited to rural areas.

Dr. Verma also noted that the administration “will be temporarily suspending certain HIPAA requirements so that doctors can provide telehealth with their own phones.”

She noted this was all a part of mitigation efforts to limit the spread of COVID-19.

“As we are encouraging Americans to stay home whenever possible, we don’t want our Medicare policies getting in the way,” she said, adding that state Medicaid agencies can expand their telehealth services without the approval of CMS during this emergency.

gtwachtman@mdedge.com

Coronavirus disease (COVID-19) was declared a pandemic by the World Health Organization on March 11. This rapidly spreading disease is caused by the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The infection has spread to more than 140 countries, including the United States. As of March 16, more than 170,400 people had tested positive for SARS-CoV-2 and more than 6,619 people have died across the globe.

The number of new COVID-19 cases appears to be decreasing in China, but the number of cases are rapidly increasing worldwide. Based on available data, primarily from China, children (aged 0-19 years) account for only about 2% of all cases. Despite the probable low virulence and incidence of infection in children, they could act as potential vectors and transmit infection to more vulnerable populations. As of March 16, approximately 3,823 cases and more than 67 deaths had been reported in the United States with few pediatric patients testing positive for the disease.

SARS-CoV2 transmission mainly occurs via respiratory route through close contact with infected individuals and through fomites. The incubation period ranges from 2-14 days with an average of about 5 days. Adult patients present with cough and fever, which may progress to lower respiratory tract symptoms, including shortness of breath. Approximately 10% of all patients develop severe disease and acute respiratory distress syndrome (ARDS), requiring mechanical ventilation.

COVID-19 carries a mortality rate of up to 3%, but has been significantly higher in the elderly population, and those with chronic health conditions. Available data so far shows that children are at lower risk and the severity of the disease has been milder compared to adults. The reasons for this are not clear at this time. As of March 16, there were no reported COVID-19 related deaths in children under age 9 years.
 

The pediatric population: Disease patterns and transmission

The epidemiology and spectrum of disease for COVID-19 is poorly understood in pediatrics because of the low number of reported pediatric cases and limited data available from these patients. Small numbers of reported cases in children has led some to believe that children are relatively immune to the infection by SARS-CoV-2. However, Oifang et al. found that children are equally as likely as adults to be infected.¹

Liu et al. found that of 366 children admitted to a hospital in Wuhan with respiratory infections in January 2020, 1.6% (six patients) cases were positive for SARS-CoV-2.² These six children were aged 1-7 years and had all been previously healthy; all six presented with cough and fever of 102.2° F or greater. Four of the children also had vomiting. Laboratory findings were notable for lymphopenia (six of six), leukopenia (four of six), and neutropenia (3/6) with mild to moderate elevation in C-reactive protein (6.8-58.8 mg/L). Five of six children had chest CT scans. One child’s CT scan showed “bilateral ground-glass opacities” (similar to what is reported in adults), three showed “bilateral patchy shadows,” and one was normal. One child (aged 3 years) was admitted to the ICU. All of the children were treated with supportive measures, empiric antibiotics, and antivirals (six of six received oseltamivir and four of six received ribavirin). All six children recovered completely and their median hospital stay was 7.5 days with a range of 5-13 days.

Xia et al. reviewed 20 children (aged 1 day to 14 years) admitted to a hospital in Wuhan during Jan. 23–Feb. 8.³ The study reported that fever and cough were the most common presenting symptoms (approximately 65%). Less common symptoms included rhinorrhea (15%), diarrhea (15%), vomiting (10%), and sore throat (5%). WBC count was normal in majority of children (70%) with leukopenia in 20% and leukocytosis in 10%. Lymphopenia was noted to be 35%. Elevated procalcitonin was noted in 80% of children, although the degree of elevation is unclear. In this study, 8 of 20 children were coinfected with other respiratory pathogens such as influenza, respiratory syncytial virus, mycoplasma, and cytomegalovirus. All children had chest CT scans. Ten of 20 children had bilateral pulmonary lesions, 6 of 20 had unilateral pulmonary lesions, 12 of 20 had ground-glass opacities and 10 of 20 had lung consolidations with halo signs.

Wei et al., retrospective chart review of nine infants admitted for COVID-19 found that all nine had at least one infected family member.⁴ This study reported that seven of nine were female infants, four of nine had fever, two had mild upper respiratory infection symptoms, and one had no symptoms. The study did report that two infants did not have any information available related to symptoms. None of the infants developed severe symptoms or required ICU admission.

Current challenges

Given the aggressive transmission of COVID-19, these numbers seem to be increasing exponentially with a significant impact on the life of the entire country. Therefore, we must focus on containing the spread and mitigating the transmission with a multimodality approach.

Some of the initial challenges faced by physicians in the United States were related to difficulty in access to testing in persons under investigation (PUI), which in turn resulted in a delay in diagnosis and infection control. At this time, the need is to increase surge testing capabilities across the country through a variety of innovative approaches including public-private partnerships with commercial labs through Emergency Use Authorization (EUA) issued by the Centers for Disease Control and Prevention and the Department of Health and Human Services. To minimize exposure to health care professionals, telemedicine and telehealth capabilities should be exploited. This will minimize the exposure to infected patients and reduce the need for already limited personal protective equipment (PPE). As the number of cases rise, hospitals should expect and prepare for a surge in COVID-19–related hospitalizations and health care utilization.
 

Conclusion

Various theories are being proposed as to why children are not experiencing severe disease with COVID-19. Children may have cross-protective immunity from infection with other coronaviruses. Children may not have the same exposures from work, travel, and caregiving that adults experience as they are typically exposed by someone in their home. At this time, not enough is known about clinical presentations in children as the situation continues to evolve across the globe.

Respiratory infections in children pose unique infection control challenges with respect to compliant hand hygiene, cough etiquette, and the use of PPE when indicated. There is also concern for persistent fecal shedding of virus in infected pediatric patients, which could be another mode of transmission.⁶ Children could, however, be very efficient vectors of COVID-19, similar to flu, and potentially spread the pathogen to very vulnerable populations leading to high morbidity and mortality. School closures are an effective social distancing measure needed to flatten the curve and avoid overwhelming the health care structure of the United States.
 

Dr. Konanki is a board-certified pediatrician doing inpatient work at Wellspan Chambersburg Hospital and outpatient work at Keystone Pediatrics in Chambersburg, Pa. He also serves as the physician member of the hospital’s Code Blue Jr. committee and as a member of Quality Metrics committee at Keystone Health. Dr. Tirupathi is the medical director of Keystone Infectious Diseases/HIV in Chambersburg, Pa., and currently chair of infection prevention at Wellspan Chambersburg and Waynesboro (Pa.) Hospitals. He also is the lead physician for antibiotic stewardship at these hospitals. Dr. Palabindala is hospital medicine division chief at the University of Mississippi Medical Center, Jackson.

References

1. Bi Q et al. Epidemiology and transmission of COVID-19 in Shenzhen China: Analysis of 391 cases and 1,286 of their close contacts. medRxiv 2020.03.03.20028423.

2. Liu W et al. Detection of Covid-19 in children in early January 2020 in Wuhan, China. N Engl J Med. 2020 Mar 12. doi: 10.1056/NEJMc2003717.

3. Xia W et al. Clinical and CT features in pediatric patients with COVID‐19 infection: Different points from adults. Pediatr Pulmonol. 2020 Mar 5. doi: 10.1002/ppul.24718.

4. Wei M et al. Novel Coronavirus infection in hospitalized infants under 1 year of age in China. JAMA. 2020 Feb. 14. doi: 10.1001/jama.2020.2131.

5. Huijun C et al. Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: A retrospective review of medical records. Lancet. 2020 Mar 7 395;10226:809-15.

6. Xu Y et al. Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding. Nat Med. 2020 Mar 13. doi. org/10.1038/s41591-020-0817-4.

Coronavirus disease (COVID-19) was declared a pandemic by the World Health Organization on March 11. This rapidly spreading disease is caused by the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The infection has spread to more than 140 countries, including the United States. As of March 16, more than 170,400 people had tested positive for SARS-CoV-2 and more than 6,619 people have died across the globe.

The number of new COVID-19 cases appears to be decreasing in China, but the number of cases are rapidly increasing worldwide. Based on available data, primarily from China, children (aged 0-19 years) account for only about 2% of all cases. Despite the probable low virulence and incidence of infection in children, they could act as potential vectors and transmit infection to more vulnerable populations. As of March 16, approximately 3,823 cases and more than 67 deaths had been reported in the United States with few pediatric patients testing positive for the disease.

SARS-CoV2 transmission mainly occurs via respiratory route through close contact with infected individuals and through fomites. The incubation period ranges from 2-14 days with an average of about 5 days. Adult patients present with cough and fever, which may progress to lower respiratory tract symptoms, including shortness of breath. Approximately 10% of all patients develop severe disease and acute respiratory distress syndrome (ARDS), requiring mechanical ventilation.

COVID-19 carries a mortality rate of up to 3%, but has been significantly higher in the elderly population, and those with chronic health conditions. Available data so far shows that children are at lower risk and the severity of the disease has been milder compared to adults. The reasons for this are not clear at this time. As of March 16, there were no reported COVID-19 related deaths in children under age 9 years.
 

The pediatric population: Disease patterns and transmission

The epidemiology and spectrum of disease for COVID-19 is poorly understood in pediatrics because of the low number of reported pediatric cases and limited data available from these patients. Small numbers of reported cases in children has led some to believe that children are relatively immune to the infection by SARS-CoV-2. However, Oifang et al. found that children are equally as likely as adults to be infected.¹

Liu et al. found that of 366 children admitted to a hospital in Wuhan with respiratory infections in January 2020, 1.6% (six patients) cases were positive for SARS-CoV-2.² These six children were aged 1-7 years and had all been previously healthy; all six presented with cough and fever of 102.2° F or greater. Four of the children also had vomiting. Laboratory findings were notable for lymphopenia (six of six), leukopenia (four of six), and neutropenia (3/6) with mild to moderate elevation in C-reactive protein (6.8-58.8 mg/L). Five of six children had chest CT scans. One child’s CT scan showed “bilateral ground-glass opacities” (similar to what is reported in adults), three showed “bilateral patchy shadows,” and one was normal. One child (aged 3 years) was admitted to the ICU. All of the children were treated with supportive measures, empiric antibiotics, and antivirals (six of six received oseltamivir and four of six received ribavirin). All six children recovered completely and their median hospital stay was 7.5 days with a range of 5-13 days.

Xia et al. reviewed 20 children (aged 1 day to 14 years) admitted to a hospital in Wuhan during Jan. 23–Feb. 8.³ The study reported that fever and cough were the most common presenting symptoms (approximately 65%). Less common symptoms included rhinorrhea (15%), diarrhea (15%), vomiting (10%), and sore throat (5%). WBC count was normal in majority of children (70%) with leukopenia in 20% and leukocytosis in 10%. Lymphopenia was noted to be 35%. Elevated procalcitonin was noted in 80% of children, although the degree of elevation is unclear. In this study, 8 of 20 children were coinfected with other respiratory pathogens such as influenza, respiratory syncytial virus, mycoplasma, and cytomegalovirus. All children had chest CT scans. Ten of 20 children had bilateral pulmonary lesions, 6 of 20 had unilateral pulmonary lesions, 12 of 20 had ground-glass opacities and 10 of 20 had lung consolidations with halo signs.

Wei et al., retrospective chart review of nine infants admitted for COVID-19 found that all nine had at least one infected family member.⁴ This study reported that seven of nine were female infants, four of nine had fever, two had mild upper respiratory infection symptoms, and one had no symptoms. The study did report that two infants did not have any information available related to symptoms. None of the infants developed severe symptoms or required ICU admission.

Current challenges

Given the aggressive transmission of COVID-19, these numbers seem to be increasing exponentially with a significant impact on the life of the entire country. Therefore, we must focus on containing the spread and mitigating the transmission with a multimodality approach.

Some of the initial challenges faced by physicians in the United States were related to difficulty in access to testing in persons under investigation (PUI), which in turn resulted in a delay in diagnosis and infection control. At this time, the need is to increase surge testing capabilities across the country through a variety of innovative approaches including public-private partnerships with commercial labs through Emergency Use Authorization (EUA) issued by the Centers for Disease Control and Prevention and the Department of Health and Human Services. To minimize exposure to health care professionals, telemedicine and telehealth capabilities should be exploited. This will minimize the exposure to infected patients and reduce the need for already limited personal protective equipment (PPE). As the number of cases rise, hospitals should expect and prepare for a surge in COVID-19–related hospitalizations and health care utilization.
 

Conclusion

Various theories are being proposed as to why children are not experiencing severe disease with COVID-19. Children may have cross-protective immunity from infection with other coronaviruses. Children may not have the same exposures from work, travel, and caregiving that adults experience as they are typically exposed by someone in their home. At this time, not enough is known about clinical presentations in children as the situation continues to evolve across the globe.

Respiratory infections in children pose unique infection control challenges with respect to compliant hand hygiene, cough etiquette, and the use of PPE when indicated. There is also concern for persistent fecal shedding of virus in infected pediatric patients, which could be another mode of transmission.⁶ Children could, however, be very efficient vectors of COVID-19, similar to flu, and potentially spread the pathogen to very vulnerable populations leading to high morbidity and mortality. School closures are an effective social distancing measure needed to flatten the curve and avoid overwhelming the health care structure of the United States.
 

Dr. Konanki is a board-certified pediatrician doing inpatient work at Wellspan Chambersburg Hospital and outpatient work at Keystone Pediatrics in Chambersburg, Pa. He also serves as the physician member of the hospital’s Code Blue Jr. committee and as a member of Quality Metrics committee at Keystone Health. Dr. Tirupathi is the medical director of Keystone Infectious Diseases/HIV in Chambersburg, Pa., and currently chair of infection prevention at Wellspan Chambersburg and Waynesboro (Pa.) Hospitals. He also is the lead physician for antibiotic stewardship at these hospitals. Dr. Palabindala is hospital medicine division chief at the University of Mississippi Medical Center, Jackson.

References

1. Bi Q et al. Epidemiology and transmission of COVID-19 in Shenzhen China: Analysis of 391 cases and 1,286 of their close contacts. medRxiv 2020.03.03.20028423.

2. Liu W et al. Detection of Covid-19 in children in early January 2020 in Wuhan, China. N Engl J Med. 2020 Mar 12. doi: 10.1056/NEJMc2003717.

3. Xia W et al. Clinical and CT features in pediatric patients with COVID‐19 infection: Different points from adults. Pediatr Pulmonol. 2020 Mar 5. doi: 10.1002/ppul.24718.

4. Wei M et al. Novel Coronavirus infection in hospitalized infants under 1 year of age in China. JAMA. 2020 Feb. 14. doi: 10.1001/jama.2020.2131.

5. Huijun C et al. Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: A retrospective review of medical records. Lancet. 2020 Mar 7 395;10226:809-15.

6. Xu Y et al. Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding. Nat Med. 2020 Mar 13. doi. org/10.1038/s41591-020-0817-4.

Coronavirus disease (COVID-19) was declared a pandemic by the World Health Organization on March 11. This rapidly spreading disease is caused by the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The infection has spread to more than 140 countries, including the United States. As of March 16, more than 170,400 people had tested positive for SARS-CoV-2 and more than 6,619 people have died across the globe.

The number of new COVID-19 cases appears to be decreasing in China, but the number of cases are rapidly increasing worldwide. Based on available data, primarily from China, children (aged 0-19 years) account for only about 2% of all cases. Despite the probable low virulence and incidence of infection in children, they could act as potential vectors and transmit infection to more vulnerable populations. As of March 16, approximately 3,823 cases and more than 67 deaths had been reported in the United States with few pediatric patients testing positive for the disease.

SARS-CoV2 transmission mainly occurs via respiratory route through close contact with infected individuals and through fomites. The incubation period ranges from 2-14 days with an average of about 5 days. Adult patients present with cough and fever, which may progress to lower respiratory tract symptoms, including shortness of breath. Approximately 10% of all patients develop severe disease and acute respiratory distress syndrome (ARDS), requiring mechanical ventilation.

COVID-19 carries a mortality rate of up to 3%, but has been significantly higher in the elderly population, and those with chronic health conditions. Available data so far shows that children are at lower risk and the severity of the disease has been milder compared to adults. The reasons for this are not clear at this time. As of March 16, there were no reported COVID-19 related deaths in children under age 9 years.
 

The pediatric population: Disease patterns and transmission

The epidemiology and spectrum of disease for COVID-19 is poorly understood in pediatrics because of the low number of reported pediatric cases and limited data available from these patients. Small numbers of reported cases in children has led some to believe that children are relatively immune to the infection by SARS-CoV-2. However, Oifang et al. found that children are equally as likely as adults to be infected.¹

Liu et al. found that of 366 children admitted to a hospital in Wuhan with respiratory infections in January 2020, 1.6% (six patients) cases were positive for SARS-CoV-2.² These six children were aged 1-7 years and had all been previously healthy; all six presented with cough and fever of 102.2° F or greater. Four of the children also had vomiting. Laboratory findings were notable for lymphopenia (six of six), leukopenia (four of six), and neutropenia (3/6) with mild to moderate elevation in C-reactive protein (6.8-58.8 mg/L). Five of six children had chest CT scans. One child’s CT scan showed “bilateral ground-glass opacities” (similar to what is reported in adults), three showed “bilateral patchy shadows,” and one was normal. One child (aged 3 years) was admitted to the ICU. All of the children were treated with supportive measures, empiric antibiotics, and antivirals (six of six received oseltamivir and four of six received ribavirin). All six children recovered completely and their median hospital stay was 7.5 days with a range of 5-13 days.

Xia et al. reviewed 20 children (aged 1 day to 14 years) admitted to a hospital in Wuhan during Jan. 23–Feb. 8.³ The study reported that fever and cough were the most common presenting symptoms (approximately 65%). Less common symptoms included rhinorrhea (15%), diarrhea (15%), vomiting (10%), and sore throat (5%). WBC count was normal in majority of children (70%) with leukopenia in 20% and leukocytosis in 10%. Lymphopenia was noted to be 35%. Elevated procalcitonin was noted in 80% of children, although the degree of elevation is unclear. In this study, 8 of 20 children were coinfected with other respiratory pathogens such as influenza, respiratory syncytial virus, mycoplasma, and cytomegalovirus. All children had chest CT scans. Ten of 20 children had bilateral pulmonary lesions, 6 of 20 had unilateral pulmonary lesions, 12 of 20 had ground-glass opacities and 10 of 20 had lung consolidations with halo signs.

Wei et al., retrospective chart review of nine infants admitted for COVID-19 found that all nine had at least one infected family member.⁴ This study reported that seven of nine were female infants, four of nine had fever, two had mild upper respiratory infection symptoms, and one had no symptoms. The study did report that two infants did not have any information available related to symptoms. None of the infants developed severe symptoms or required ICU admission.

Current challenges

Given the aggressive transmission of COVID-19, these numbers seem to be increasing exponentially with a significant impact on the life of the entire country. Therefore, we must focus on containing the spread and mitigating the transmission with a multimodality approach.

Some of the initial challenges faced by physicians in the United States were related to difficulty in access to testing in persons under investigation (PUI), which in turn resulted in a delay in diagnosis and infection control. At this time, the need is to increase surge testing capabilities across the country through a variety of innovative approaches including public-private partnerships with commercial labs through Emergency Use Authorization (EUA) issued by the Centers for Disease Control and Prevention and the Department of Health and Human Services. To minimize exposure to health care professionals, telemedicine and telehealth capabilities should be exploited. This will minimize the exposure to infected patients and reduce the need for already limited personal protective equipment (PPE). As the number of cases rise, hospitals should expect and prepare for a surge in COVID-19–related hospitalizations and health care utilization.
 

Conclusion

Various theories are being proposed as to why children are not experiencing severe disease with COVID-19. Children may have cross-protective immunity from infection with other coronaviruses. Children may not have the same exposures from work, travel, and caregiving that adults experience as they are typically exposed by someone in their home. At this time, not enough is known about clinical presentations in children as the situation continues to evolve across the globe.

Respiratory infections in children pose unique infection control challenges with respect to compliant hand hygiene, cough etiquette, and the use of PPE when indicated. There is also concern for persistent fecal shedding of virus in infected pediatric patients, which could be another mode of transmission.⁶ Children could, however, be very efficient vectors of COVID-19, similar to flu, and potentially spread the pathogen to very vulnerable populations leading to high morbidity and mortality. School closures are an effective social distancing measure needed to flatten the curve and avoid overwhelming the health care structure of the United States.
 

Dr. Konanki is a board-certified pediatrician doing inpatient work at Wellspan Chambersburg Hospital and outpatient work at Keystone Pediatrics in Chambersburg, Pa. He also serves as the physician member of the hospital’s Code Blue Jr. committee and as a member of Quality Metrics committee at Keystone Health. Dr. Tirupathi is the medical director of Keystone Infectious Diseases/HIV in Chambersburg, Pa., and currently chair of infection prevention at Wellspan Chambersburg and Waynesboro (Pa.) Hospitals. He also is the lead physician for antibiotic stewardship at these hospitals. Dr. Palabindala is hospital medicine division chief at the University of Mississippi Medical Center, Jackson.

References

1. Bi Q et al. Epidemiology and transmission of COVID-19 in Shenzhen China: Analysis of 391 cases and 1,286 of their close contacts. medRxiv 2020.03.03.20028423.

2. Liu W et al. Detection of Covid-19 in children in early January 2020 in Wuhan, China. N Engl J Med. 2020 Mar 12. doi: 10.1056/NEJMc2003717.

3. Xia W et al. Clinical and CT features in pediatric patients with COVID‐19 infection: Different points from adults. Pediatr Pulmonol. 2020 Mar 5. doi: 10.1002/ppul.24718.

4. Wei M et al. Novel Coronavirus infection in hospitalized infants under 1 year of age in China. JAMA. 2020 Feb. 14. doi: 10.1001/jama.2020.2131.

5. Huijun C et al. Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: A retrospective review of medical records. Lancet. 2020 Mar 7 395;10226:809-15.

6. Xu Y et al. Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding. Nat Med. 2020 Mar 13. doi. org/10.1038/s41591-020-0817-4.

In December, at a major breast cancer conference, some attendees couldn’t find a seat and were told to leave an overcrowded session on immunotherapy for metastatic triple-negative breast cancer (TNBC). They refused, and pushed in to hear what was being said.

The crowd might have been surprised to learn that the main draw of the event, a successful new drug, was not all it might have been for women with the disease, being handicapped by a test that determines who is eligible for it.

“That room was overpacked ― there were five people deep against the wall. ... It was amazing,” said Janice Cowden of Bradenton, Florida. She attended the meeting, the San Antonio Breast Cancer Symposium, as a patient advocate.

Cowden lives with metastatic TNBC, which is known for poor prognoses, aggressiveness, and a lack of targeted treatment options. “Stage IV is a state of desperation. We just want something to work,” she said.

That’s why the conference room was packed – the session was focused on something that had been found to work – the immunotherapy atezolizumab (Tecentriq, Genentech/Roche).

Atezolizumab had recently been conditionally approved for first-line use in advanced TNBC, having been shown to significantly slow disease progression and, in some patients, to possibly improve survival. A pair of medical oncologists reviewed the clinical trial data during the session.

One important point from the trial data was that the benefit was greater in patients whose tumors had the biomarker PD-L1, and so the Food and Drug Administration approval of the drug specified that it should be used only in those patients.

The drug approval was accompanied by approval of a companion diagnostic test used to identify this PD-L1-positive subgroup of patients, the Ventana SP142 Assay (Roche Diagnostics).

At the meeting, pathologist David Rimm, MD, of Yale University, New Haven, Connecticut, discussed the biomarker PD-L1 and the test. Rimm had a subtle but unsettling message about the crucial test: that the SP142 diagnostic assay, when used by increasing numbers of pathologists, resulted in increasing rates of PD-L1 scores that were not concordant.

A related meeting poster, presented the next day with Rimm as senior author, was more explicit and concluded that “more than half of the pathologists in real-world situations may mis- assign” patient scores with SP142 (and another Roche assay) because of wide variability in readouts.

“They’ve made a test that is inadequate – it just doesn’t work. It’s like flipping a coin,” he told Medscape Medical News about Roche’s SP142 assay in everyday practice.

The general problem is not a new one – for some years there have been problems with the use of PD-L1 as a biomarker for immunotherapy and with assays for that biomarker, with many groups questioning both accuracy and reproducibility. But the problems with SP142 are “the most egregious,” said Rimm, who has served as a paid consultant to Roche Diagnostics in the past.

In clinical practice, Rimm’s overall message is that because of the difficulty of reading SP142 assay results, some TNBC patients who were PD-L1-positive would not get the drug, and some who were not positive would get the drug.

Patient advocate Cowden was not worried about overtreatment. She was concerned about patients who “might die without receiving a potentially life-extending treatment.”

In an essay in the Pathologist, Rimm echoed that sentiment about undertreatment (as well as overtreatment) with atezolizumab for breast cancer: “In all cases, the patients are the potential victims, but this appears to be completely under the radar of the hype surrounding this new drug.”
 

Roche Disputes Problems With Assay

Roche, manufacturer of both atezolizumab and the companion diagnostic test, disputes that there is a problem.

The FDA and multiple health authorities worldwide have approved atezolizumab and the companion diagnostic SP142 assay for use in TNBC, points out Eslie Dennis, MD, vice president of medical affairs at Roche Tissue Diagnostics.

“The role of a companion diagnostic assay is to discriminate between responders and non-responders for a specific therapeutic product in a specific indication, with a cut-off based on clinical outcomes,” she wrote in an email to Medscape Medical News.

Data from the pivotal IMpassion130 trial show that the assay was effective at that task. Among the 369 patients in the 902-patient trial whose tumors were ≥1% positive for PD-L1, those treated with atezolizumab (and nab-paclitaxel; n = 185) had a median progression-free survival (PFS) of 7.4 months, vs. 4.8 months among those treated with placebo (and nab-paclitaxel; n = 184) (P < .0001).

“Exploratory analysis showed no [PFS] benefit in PD-L1-negative patients as tested by the SP142 assay [in IMpassion130],” Dennis and three other physicians write in a reply to Rimm in a letter published in July 2019 in the Pathologist.

The same held true for overall survival in exploratory analysis – there was no benefit with atezolizumab among the PD-L1-negative patients, they write.

Notably, overall survival benefit for patients who were PD-L1 positive was about 10 months (at the first interim analysis; at the second analysis, the benefit dropped to 7 months and was not statistically significant).

But Rimm points out that the pivotal trial used only one pathologist in a central lab to determine PD-L1 status, who was undoubtedly an expert with the SP142 assay.

Further, Rimm observes that additional data submitted to the FDA to show that SP142 test results are reproducible outside of the pivotal trial setting were performed with only three pathologists and thus unsurprisingly yielded high rates of agreement – all above 90%.

The data from both of these circumstances are problematic, Rimm said, because in the real world, hundreds of pathologists will score the SP142 assay – all in the context of a busy day reading a variety of other tests for other diseases.

It’s one thing to get an FDA approval for an assay, and it’s another thing to be a reliable, well-functioning assay in the real world, he summarized.

Last year, Roberto Salgado, MD, PhD, a pathologist at the Université Libre de Bruxelles, Belgium, commented that “a positive phase III trial should not be taken as a guarantee that the assay used in the trial can be implemented in daily practice” in an opinion piece in the Pathologist.
 

SP142 Identifies the “Fewest Possible Patients”

The SP142 assay has been shown in multiple studies to have lower sensitivity for PD-L1 than other competing PD-L1 assays, said Rimm, citing examples such as a 2017 study and a 2018 study.

Angela DeMichele, MD, a medical oncologist at the University of Pennsylvania in Philadelphia, agreed and explained what that meant in practical terms for women whose tumors are tested with SP142. “It means that the test is going to identify the fewest possible PD-L1-positive patients [relative to the other available assays],” she said. “It [the SP142 assay] is far from a perfect test for this situation,” added DeMichele, an expert on biomarkers in breast cancer clinical trials.

She said that biomarker tests, like many products of science, tend to become dated with the passage of time, as more is learned about the target and new assays are developed. “Unfortunately, you can’t change assays midstream,” said DeMichele. She has received a grant from Roche and Stand Up to Cancer to study atezolizumab and another drug in a clinical trial among patients with metastatic TNBC who have minimal residual disease.

DeMichele also said that “David Rimm is one of the most knowledgeable people in the world about this issue.”

But DeMichelle also points out the practical: “We’re stuck as clinicians” because regulatory bodies and insurance companies only pay for atezolizumab when the SP142 assay indicates PD-L1 positivity. That’s not the case in Europe, where health authorities do not specify which PD-L1 assay is to be used with atezolizumab for breast cancer, pointed out Belgium’s Salgado last year.
 

Another Level of Complexity

At the immunotherapy session in San Antonio, Rimm discussed the results of a study of 68 TNBC archived cases in which specimens were stained with the SP142 assay at Yale and were distributed via electronic images to 19 pathologists at 14 institutions across the United States for PD-L1 scoring.

The study, coauthored by academics from Iowa, Texas A&M, UC San Diego, Mayo Clinic, Memorial Sloan Kettering, and others, used a novel method to determine the minimum number of evaluators needed to estimate “concordance” or agreement about a test result among large numbers of readers. The consensus/agreement was as high as 80% when eight or fewer pathologists’ scores were compared, but was as low as 40% when results from more than eight pathologists were included, said Rimm.

These are some of the data that led him to declare that using the assay is no better than flipping a coin.

Yes, PD-L1 testing is a challenge, and it has “introduced another level of complexity” for pathologists in reading assays, write experts Emina Torlakovic, MD, University of Saskatchewan, Canada, and Allen Gown, MD, PhenoPath Laboratories, Seattle, in response to Rimm last year.

But there is “poor” consensus among pathologists, they point out, “for many scoring systems that are still clinically applied (such as Gleason grading).” Consensus “improves with education and training,” the pair add. To that end, Roche has initiated a global training program for pathologists using the SP142 assay for TNBC. At San Antonio, Roche’s Dennis reported that among 432 pathologists from 58 countries, there was overall agreement of 98.2% in scoring assays.

Rimm commented that such high agreement would not be a surprise if testing took place soon after any such training program.

In an email to Medscape Medical News, Torlakovic encouraged pathologists who wish to practice their skill in interpreting assays, including SP142, to visit CBQAReadout.ca, a testing site. The site, which was founded by Torlakovic and may be one of a kind, offers CME credits and is sponsored by independent pathology organizations, such as CAP-ACP and the Saskatchewan Health Authority, as well as pharmaceutical companies, including Roche.

No Clue

Patient advocate Cowden believes the controversy about PD-L1 testing for atezolizumab is largely unknown among breast cancer patients. She learned about SP142 assay ambiguities in San Antonio, when the Florida Breast Cancer Foundation funded her trip to the meeting and the Alamo Breast Cancer Foundation asked her to write a report on Rimm’s presentation.

Cowden is a member of a Facebook group for stage IV TNBC, which has about 1500 members. She estimates that 75%-80% would be willing to try atezolizumab “no matter what,” meaning they don’t care about PD-L1 positivity being associated with efficacy.

The Facebook group members “know there is a test and if you are positive, there is an immunotherapy for their breast cancer,” said Cowden.

None know that women may be excluded from treatment because of shortcomings with the SP142 test. “They have no clue,” she said.

Rimm and DeMichele have financial ties to Roche and other companies. Dennis is an employee of Roche. Torlakovic has ties to multiple companies, including Roche, for whom she has acted as a paid consultant, grant recipient, and paid lecturer. Gown did not respond to a request for financial disclosures. Cowden reports no relevant financial relationships.

This article first appeared on Medscape.com.

In December, at a major breast cancer conference, some attendees couldn’t find a seat and were told to leave an overcrowded session on immunotherapy for metastatic triple-negative breast cancer (TNBC). They refused, and pushed in to hear what was being said.

The crowd might have been surprised to learn that the main draw of the event, a successful new drug, was not all it might have been for women with the disease, being handicapped by a test that determines who is eligible for it.

“That room was overpacked ― there were five people deep against the wall. ... It was amazing,” said Janice Cowden of Bradenton, Florida. She attended the meeting, the San Antonio Breast Cancer Symposium, as a patient advocate.

Cowden lives with metastatic TNBC, which is known for poor prognoses, aggressiveness, and a lack of targeted treatment options. “Stage IV is a state of desperation. We just want something to work,” she said.

That’s why the conference room was packed – the session was focused on something that had been found to work – the immunotherapy atezolizumab (Tecentriq, Genentech/Roche).

Atezolizumab had recently been conditionally approved for first-line use in advanced TNBC, having been shown to significantly slow disease progression and, in some patients, to possibly improve survival. A pair of medical oncologists reviewed the clinical trial data during the session.

One important point from the trial data was that the benefit was greater in patients whose tumors had the biomarker PD-L1, and so the Food and Drug Administration approval of the drug specified that it should be used only in those patients.

The drug approval was accompanied by approval of a companion diagnostic test used to identify this PD-L1-positive subgroup of patients, the Ventana SP142 Assay (Roche Diagnostics).

At the meeting, pathologist David Rimm, MD, of Yale University, New Haven, Connecticut, discussed the biomarker PD-L1 and the test. Rimm had a subtle but unsettling message about the crucial test: that the SP142 diagnostic assay, when used by increasing numbers of pathologists, resulted in increasing rates of PD-L1 scores that were not concordant.

A related meeting poster, presented the next day with Rimm as senior author, was more explicit and concluded that “more than half of the pathologists in real-world situations may mis- assign” patient scores with SP142 (and another Roche assay) because of wide variability in readouts.

“They’ve made a test that is inadequate – it just doesn’t work. It’s like flipping a coin,” he told Medscape Medical News about Roche’s SP142 assay in everyday practice.

The general problem is not a new one – for some years there have been problems with the use of PD-L1 as a biomarker for immunotherapy and with assays for that biomarker, with many groups questioning both accuracy and reproducibility. But the problems with SP142 are “the most egregious,” said Rimm, who has served as a paid consultant to Roche Diagnostics in the past.

In clinical practice, Rimm’s overall message is that because of the difficulty of reading SP142 assay results, some TNBC patients who were PD-L1-positive would not get the drug, and some who were not positive would get the drug.

Patient advocate Cowden was not worried about overtreatment. She was concerned about patients who “might die without receiving a potentially life-extending treatment.”

In an essay in the Pathologist, Rimm echoed that sentiment about undertreatment (as well as overtreatment) with atezolizumab for breast cancer: “In all cases, the patients are the potential victims, but this appears to be completely under the radar of the hype surrounding this new drug.”
 

Roche Disputes Problems With Assay

Roche, manufacturer of both atezolizumab and the companion diagnostic test, disputes that there is a problem.

The FDA and multiple health authorities worldwide have approved atezolizumab and the companion diagnostic SP142 assay for use in TNBC, points out Eslie Dennis, MD, vice president of medical affairs at Roche Tissue Diagnostics.

“The role of a companion diagnostic assay is to discriminate between responders and non-responders for a specific therapeutic product in a specific indication, with a cut-off based on clinical outcomes,” she wrote in an email to Medscape Medical News.

Data from the pivotal IMpassion130 trial show that the assay was effective at that task. Among the 369 patients in the 902-patient trial whose tumors were ≥1% positive for PD-L1, those treated with atezolizumab (and nab-paclitaxel; n = 185) had a median progression-free survival (PFS) of 7.4 months, vs. 4.8 months among those treated with placebo (and nab-paclitaxel; n = 184) (P < .0001).

“Exploratory analysis showed no [PFS] benefit in PD-L1-negative patients as tested by the SP142 assay [in IMpassion130],” Dennis and three other physicians write in a reply to Rimm in a letter published in July 2019 in the Pathologist.

The same held true for overall survival in exploratory analysis – there was no benefit with atezolizumab among the PD-L1-negative patients, they write.

Notably, overall survival benefit for patients who were PD-L1 positive was about 10 months (at the first interim analysis; at the second analysis, the benefit dropped to 7 months and was not statistically significant).

But Rimm points out that the pivotal trial used only one pathologist in a central lab to determine PD-L1 status, who was undoubtedly an expert with the SP142 assay.

Further, Rimm observes that additional data submitted to the FDA to show that SP142 test results are reproducible outside of the pivotal trial setting were performed with only three pathologists and thus unsurprisingly yielded high rates of agreement – all above 90%.

The data from both of these circumstances are problematic, Rimm said, because in the real world, hundreds of pathologists will score the SP142 assay – all in the context of a busy day reading a variety of other tests for other diseases.

It’s one thing to get an FDA approval for an assay, and it’s another thing to be a reliable, well-functioning assay in the real world, he summarized.

Last year, Roberto Salgado, MD, PhD, a pathologist at the Université Libre de Bruxelles, Belgium, commented that “a positive phase III trial should not be taken as a guarantee that the assay used in the trial can be implemented in daily practice” in an opinion piece in the Pathologist.
 

SP142 Identifies the “Fewest Possible Patients”

The SP142 assay has been shown in multiple studies to have lower sensitivity for PD-L1 than other competing PD-L1 assays, said Rimm, citing examples such as a 2017 study and a 2018 study.

Angela DeMichele, MD, a medical oncologist at the University of Pennsylvania in Philadelphia, agreed and explained what that meant in practical terms for women whose tumors are tested with SP142. “It means that the test is going to identify the fewest possible PD-L1-positive patients [relative to the other available assays],” she said. “It [the SP142 assay] is far from a perfect test for this situation,” added DeMichele, an expert on biomarkers in breast cancer clinical trials.

She said that biomarker tests, like many products of science, tend to become dated with the passage of time, as more is learned about the target and new assays are developed. “Unfortunately, you can’t change assays midstream,” said DeMichele. She has received a grant from Roche and Stand Up to Cancer to study atezolizumab and another drug in a clinical trial among patients with metastatic TNBC who have minimal residual disease.

DeMichele also said that “David Rimm is one of the most knowledgeable people in the world about this issue.”

But DeMichelle also points out the practical: “We’re stuck as clinicians” because regulatory bodies and insurance companies only pay for atezolizumab when the SP142 assay indicates PD-L1 positivity. That’s not the case in Europe, where health authorities do not specify which PD-L1 assay is to be used with atezolizumab for breast cancer, pointed out Belgium’s Salgado last year.
 

Another Level of Complexity

At the immunotherapy session in San Antonio, Rimm discussed the results of a study of 68 TNBC archived cases in which specimens were stained with the SP142 assay at Yale and were distributed via electronic images to 19 pathologists at 14 institutions across the United States for PD-L1 scoring.

The study, coauthored by academics from Iowa, Texas A&M, UC San Diego, Mayo Clinic, Memorial Sloan Kettering, and others, used a novel method to determine the minimum number of evaluators needed to estimate “concordance” or agreement about a test result among large numbers of readers. The consensus/agreement was as high as 80% when eight or fewer pathologists’ scores were compared, but was as low as 40% when results from more than eight pathologists were included, said Rimm.

These are some of the data that led him to declare that using the assay is no better than flipping a coin.

Yes, PD-L1 testing is a challenge, and it has “introduced another level of complexity” for pathologists in reading assays, write experts Emina Torlakovic, MD, University of Saskatchewan, Canada, and Allen Gown, MD, PhenoPath Laboratories, Seattle, in response to Rimm last year.

But there is “poor” consensus among pathologists, they point out, “for many scoring systems that are still clinically applied (such as Gleason grading).” Consensus “improves with education and training,” the pair add. To that end, Roche has initiated a global training program for pathologists using the SP142 assay for TNBC. At San Antonio, Roche’s Dennis reported that among 432 pathologists from 58 countries, there was overall agreement of 98.2% in scoring assays.

Rimm commented that such high agreement would not be a surprise if testing took place soon after any such training program.

In an email to Medscape Medical News, Torlakovic encouraged pathologists who wish to practice their skill in interpreting assays, including SP142, to visit CBQAReadout.ca, a testing site. The site, which was founded by Torlakovic and may be one of a kind, offers CME credits and is sponsored by independent pathology organizations, such as CAP-ACP and the Saskatchewan Health Authority, as well as pharmaceutical companies, including Roche.

No Clue

Patient advocate Cowden believes the controversy about PD-L1 testing for atezolizumab is largely unknown among breast cancer patients. She learned about SP142 assay ambiguities in San Antonio, when the Florida Breast Cancer Foundation funded her trip to the meeting and the Alamo Breast Cancer Foundation asked her to write a report on Rimm’s presentation.

Cowden is a member of a Facebook group for stage IV TNBC, which has about 1500 members. She estimates that 75%-80% would be willing to try atezolizumab “no matter what,” meaning they don’t care about PD-L1 positivity being associated with efficacy.

The Facebook group members “know there is a test and if you are positive, there is an immunotherapy for their breast cancer,” said Cowden.

None know that women may be excluded from treatment because of shortcomings with the SP142 test. “They have no clue,” she said.

Rimm and DeMichele have financial ties to Roche and other companies. Dennis is an employee of Roche. Torlakovic has ties to multiple companies, including Roche, for whom she has acted as a paid consultant, grant recipient, and paid lecturer. Gown did not respond to a request for financial disclosures. Cowden reports no relevant financial relationships.

This article first appeared on Medscape.com.

In December, at a major breast cancer conference, some attendees couldn’t find a seat and were told to leave an overcrowded session on immunotherapy for metastatic triple-negative breast cancer (TNBC). They refused, and pushed in to hear what was being said.

The crowd might have been surprised to learn that the main draw of the event, a successful new drug, was not all it might have been for women with the disease, being handicapped by a test that determines who is eligible for it.

“That room was overpacked ― there were five people deep against the wall. ... It was amazing,” said Janice Cowden of Bradenton, Florida. She attended the meeting, the San Antonio Breast Cancer Symposium, as a patient advocate.

Cowden lives with metastatic TNBC, which is known for poor prognoses, aggressiveness, and a lack of targeted treatment options. “Stage IV is a state of desperation. We just want something to work,” she said.

That’s why the conference room was packed – the session was focused on something that had been found to work – the immunotherapy atezolizumab (Tecentriq, Genentech/Roche).

Atezolizumab had recently been conditionally approved for first-line use in advanced TNBC, having been shown to significantly slow disease progression and, in some patients, to possibly improve survival. A pair of medical oncologists reviewed the clinical trial data during the session.

One important point from the trial data was that the benefit was greater in patients whose tumors had the biomarker PD-L1, and so the Food and Drug Administration approval of the drug specified that it should be used only in those patients.

The drug approval was accompanied by approval of a companion diagnostic test used to identify this PD-L1-positive subgroup of patients, the Ventana SP142 Assay (Roche Diagnostics).

At the meeting, pathologist David Rimm, MD, of Yale University, New Haven, Connecticut, discussed the biomarker PD-L1 and the test. Rimm had a subtle but unsettling message about the crucial test: that the SP142 diagnostic assay, when used by increasing numbers of pathologists, resulted in increasing rates of PD-L1 scores that were not concordant.

A related meeting poster, presented the next day with Rimm as senior author, was more explicit and concluded that “more than half of the pathologists in real-world situations may mis- assign” patient scores with SP142 (and another Roche assay) because of wide variability in readouts.

“They’ve made a test that is inadequate – it just doesn’t work. It’s like flipping a coin,” he told Medscape Medical News about Roche’s SP142 assay in everyday practice.

The general problem is not a new one – for some years there have been problems with the use of PD-L1 as a biomarker for immunotherapy and with assays for that biomarker, with many groups questioning both accuracy and reproducibility. But the problems with SP142 are “the most egregious,” said Rimm, who has served as a paid consultant to Roche Diagnostics in the past.

In clinical practice, Rimm’s overall message is that because of the difficulty of reading SP142 assay results, some TNBC patients who were PD-L1-positive would not get the drug, and some who were not positive would get the drug.

Patient advocate Cowden was not worried about overtreatment. She was concerned about patients who “might die without receiving a potentially life-extending treatment.”

In an essay in the Pathologist, Rimm echoed that sentiment about undertreatment (as well as overtreatment) with atezolizumab for breast cancer: “In all cases, the patients are the potential victims, but this appears to be completely under the radar of the hype surrounding this new drug.”
 

Roche Disputes Problems With Assay

Roche, manufacturer of both atezolizumab and the companion diagnostic test, disputes that there is a problem.

The FDA and multiple health authorities worldwide have approved atezolizumab and the companion diagnostic SP142 assay for use in TNBC, points out Eslie Dennis, MD, vice president of medical affairs at Roche Tissue Diagnostics.

“The role of a companion diagnostic assay is to discriminate between responders and non-responders for a specific therapeutic product in a specific indication, with a cut-off based on clinical outcomes,” she wrote in an email to Medscape Medical News.

Data from the pivotal IMpassion130 trial show that the assay was effective at that task. Among the 369 patients in the 902-patient trial whose tumors were ≥1% positive for PD-L1, those treated with atezolizumab (and nab-paclitaxel; n = 185) had a median progression-free survival (PFS) of 7.4 months, vs. 4.8 months among those treated with placebo (and nab-paclitaxel; n = 184) (P < .0001).

“Exploratory analysis showed no [PFS] benefit in PD-L1-negative patients as tested by the SP142 assay [in IMpassion130],” Dennis and three other physicians write in a reply to Rimm in a letter published in July 2019 in the Pathologist.

The same held true for overall survival in exploratory analysis – there was no benefit with atezolizumab among the PD-L1-negative patients, they write.

Notably, overall survival benefit for patients who were PD-L1 positive was about 10 months (at the first interim analysis; at the second analysis, the benefit dropped to 7 months and was not statistically significant).

But Rimm points out that the pivotal trial used only one pathologist in a central lab to determine PD-L1 status, who was undoubtedly an expert with the SP142 assay.

Further, Rimm observes that additional data submitted to the FDA to show that SP142 test results are reproducible outside of the pivotal trial setting were performed with only three pathologists and thus unsurprisingly yielded high rates of agreement – all above 90%.

The data from both of these circumstances are problematic, Rimm said, because in the real world, hundreds of pathologists will score the SP142 assay – all in the context of a busy day reading a variety of other tests for other diseases.

It’s one thing to get an FDA approval for an assay, and it’s another thing to be a reliable, well-functioning assay in the real world, he summarized.

Last year, Roberto Salgado, MD, PhD, a pathologist at the Université Libre de Bruxelles, Belgium, commented that “a positive phase III trial should not be taken as a guarantee that the assay used in the trial can be implemented in daily practice” in an opinion piece in the Pathologist.
 

SP142 Identifies the “Fewest Possible Patients”

The SP142 assay has been shown in multiple studies to have lower sensitivity for PD-L1 than other competing PD-L1 assays, said Rimm, citing examples such as a 2017 study and a 2018 study.

Angela DeMichele, MD, a medical oncologist at the University of Pennsylvania in Philadelphia, agreed and explained what that meant in practical terms for women whose tumors are tested with SP142. “It means that the test is going to identify the fewest possible PD-L1-positive patients [relative to the other available assays],” she said. “It [the SP142 assay] is far from a perfect test for this situation,” added DeMichele, an expert on biomarkers in breast cancer clinical trials.

She said that biomarker tests, like many products of science, tend to become dated with the passage of time, as more is learned about the target and new assays are developed. “Unfortunately, you can’t change assays midstream,” said DeMichele. She has received a grant from Roche and Stand Up to Cancer to study atezolizumab and another drug in a clinical trial among patients with metastatic TNBC who have minimal residual disease.

DeMichele also said that “David Rimm is one of the most knowledgeable people in the world about this issue.”

But DeMichelle also points out the practical: “We’re stuck as clinicians” because regulatory bodies and insurance companies only pay for atezolizumab when the SP142 assay indicates PD-L1 positivity. That’s not the case in Europe, where health authorities do not specify which PD-L1 assay is to be used with atezolizumab for breast cancer, pointed out Belgium’s Salgado last year.
 

Another Level of Complexity

At the immunotherapy session in San Antonio, Rimm discussed the results of a study of 68 TNBC archived cases in which specimens were stained with the SP142 assay at Yale and were distributed via electronic images to 19 pathologists at 14 institutions across the United States for PD-L1 scoring.

The study, coauthored by academics from Iowa, Texas A&M, UC San Diego, Mayo Clinic, Memorial Sloan Kettering, and others, used a novel method to determine the minimum number of evaluators needed to estimate “concordance” or agreement about a test result among large numbers of readers. The consensus/agreement was as high as 80% when eight or fewer pathologists’ scores were compared, but was as low as 40% when results from more than eight pathologists were included, said Rimm.

These are some of the data that led him to declare that using the assay is no better than flipping a coin.

Yes, PD-L1 testing is a challenge, and it has “introduced another level of complexity” for pathologists in reading assays, write experts Emina Torlakovic, MD, University of Saskatchewan, Canada, and Allen Gown, MD, PhenoPath Laboratories, Seattle, in response to Rimm last year.

But there is “poor” consensus among pathologists, they point out, “for many scoring systems that are still clinically applied (such as Gleason grading).” Consensus “improves with education and training,” the pair add. To that end, Roche has initiated a global training program for pathologists using the SP142 assay for TNBC. At San Antonio, Roche’s Dennis reported that among 432 pathologists from 58 countries, there was overall agreement of 98.2% in scoring assays.

Rimm commented that such high agreement would not be a surprise if testing took place soon after any such training program.

In an email to Medscape Medical News, Torlakovic encouraged pathologists who wish to practice their skill in interpreting assays, including SP142, to visit CBQAReadout.ca, a testing site. The site, which was founded by Torlakovic and may be one of a kind, offers CME credits and is sponsored by independent pathology organizations, such as CAP-ACP and the Saskatchewan Health Authority, as well as pharmaceutical companies, including Roche.

No Clue

Patient advocate Cowden believes the controversy about PD-L1 testing for atezolizumab is largely unknown among breast cancer patients. She learned about SP142 assay ambiguities in San Antonio, when the Florida Breast Cancer Foundation funded her trip to the meeting and the Alamo Breast Cancer Foundation asked her to write a report on Rimm’s presentation.

Cowden is a member of a Facebook group for stage IV TNBC, which has about 1500 members. She estimates that 75%-80% would be willing to try atezolizumab “no matter what,” meaning they don’t care about PD-L1 positivity being associated with efficacy.

The Facebook group members “know there is a test and if you are positive, there is an immunotherapy for their breast cancer,” said Cowden.

None know that women may be excluded from treatment because of shortcomings with the SP142 test. “They have no clue,” she said.

Rimm and DeMichele have financial ties to Roche and other companies. Dennis is an employee of Roche. Torlakovic has ties to multiple companies, including Roche, for whom she has acted as a paid consultant, grant recipient, and paid lecturer. Gown did not respond to a request for financial disclosures. Cowden reports no relevant financial relationships.

This article first appeared on Medscape.com.

For patients undergoing transcatheter aortic valve replacement, using a specific orientation at deployment may optimize valve alignment and potentially preserve coronary access, at least for some devices, results of a pilot imaging study suggest.

In particular, positioning the Evolut THV (Medtronic) at a certain way at deployment led to an improvement in commissural alignment and a significant reduction in coronary artery overlap, according to authors of the study, led by Gilbert H. L. Tang, MD, MSc, MBA, surgical director of the structural heart program at Mount Sinai Health System, and associate professor of cardiovascular surgery, Mount Sinai Medical Center, New York.

Likewise, a specific positioning of the commissural post at deployment appeared to improve alignment and reduce coronary overlap when using the ACURATE-neo (Boston Scientific), though results with this transcatheter heart valve need to be considered preliminary because of the smaller number of cases, Dr. Tang said in an interview.

By contrast, initial deployment orientation of the SAPIEN 3 (Edwards Lifesciences) did not seem to have an impact on final orientation or neocommissural overlap with arteries in this study by Dr. Tang and colleagues, which was published in JACC: Cardiovascular Interventions and had been planned for presentation at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.

Improved positioning may have important future implications for patients undergoing transcatheter aortic valve replacement (TAVR), particularly if they are younger and therefore perhaps more likely than older patients to undergo a procedure requiring coronary access at some point in the future, according to Dr. Tang.

“Right now, device design does not permit us to have consistent commissural alignment,” said Dr. Tang in the interview. “What this study shows is that, with modification of delivery catheter insertion technique, at least for the EVOLUT valve, we can improve commissural alignment and hypothetically speaking, improve the likelihood of coronary access.”

While the technique modifications described by Dr. Tang and colleagues are commendable, the overall impact on commissural alignment and coronary overlap are “modest” and do not solve the problem, according to Hasan Jilaihawi, MD, associate professor of medicine and cardiothoracic surgery at NYU Langone Health, New York.

Instead, the onus should be on the device manufacturers to develop solutions that allow for better alignment between their devices and patients’ commissures, said Dr. Jilaihawi.

“We need really industry to focus wholeheartedly on this,” Dr. Jilaihawi said in an interview. “I think they will, and there will be some discussions about focusing on [commissural alignment], but I think it’s coming really very late.”

Dr. Tang agreed on the need for increased focus on achieving commissural alignment. Of note, he said, there are newer transcatheter heart valves under study that may be more likely to achieve alignment and reduce the possibility of severe coronary overlap, including the JenaValve (JenaValve Technology) and the J-Valve (JC Medical).

“We hope that manufacturers can design valves that would improve commissural alignment for these patients, so that in 10 or even 20 years’ time, when these patients require reintervention, we won’t have to do surgery because the valves are not aligned,” said Dr. Tang. “Ideally, we might have to do one surgical intervention in their lifetime, but really what we are talking about now is the lifetime management of these patients as the coronary artery disease progresses, and also the aortic valve disease returns with the prosthetic valve.”

The pilot imaging study by Dr. Tang and colleagues included a total of 828 patients undergoing TAVR, including 483 treated with SAPIEN 3, 245 with Evolut, and 100 with ACURATE-neo.

To track deployment orientation, the SAPIEN 3 cases had a commissure crimped at 3, 6, 9, or 12 o’clock orientation relative to the delivery catheter. However, crimping orientation at initial deployment did not appear to have an impact on the final orientation, with overall incidence of severe coronary overlap of 36.6% for the left main coronary artery (LMCA), 23.6% for the right coronary artery (RCA), and 51.3% for one or both, according to the report.

For 107 cases treated with Evolut, the investigators sought to have a marker on the device (known as the “hat” marker) oriented to the outer curve of the descending aorta; to do that, they inserted the delivery catheter with the flush port at the 3 o’clock position. Those cases with the hat marker at the outer curve or the center front had improved commissural alignment as compared to those with the hat at the inner curve or center back, according to investigators. The incidence of coronary overlap with the LMCA was 15.7% for those with the hat at the outer curve or center front, compared to 66.0% for those with the hat at the inner curve or center back (P < .001), and the differences in coronary overlap were likewise significantly different in favor of the outer curve/center front for the RCA or both coronaries.

Finally, the incidence of coronary overlap with the ACURATE-neo was much lower when the commissural post at initial deployment was at the center back or inner curve, and in a few cases where the operators tried to torque the delivery catheter to position the commissural post to the inner curve, commissural alignment was achieved in about three-quarters of the patients (five of seven cases).

This is believed to be the first study to systematically characterize how the initial orientation of different transcatheter heart valves impact commissural alignment and coronary overlap, according to Dr. Tang and coinvestigators.

Dr. Jilaihawi, who was not involved in the study, said the investigators studied this phenomenon in a “very detailed, methodical fashion,” but emphasized the need for new device innovations to improve alignment and overlap.

“Their efforts weren’t completely in vain, but they really made a small difference in something that is too important to be [addressed] in a kind of ‘MacGyver’ approach to this problem,” he said in the interview.

Disclosures reported by Dr. Tang were related to Edwards Lifesciences (physician proctor) and Medtronic (physician proctor, consultant). Coauthors reported disclosures related to Edwards, Medtronic, and Boston Scientific, among others.

SOURCE: ACC 20. Tang GHL et al. JACC Cardiovasc Interv. 2020 Mar 16. doi: 10.1016/j.jcin.2020.02.005.

For patients undergoing transcatheter aortic valve replacement, using a specific orientation at deployment may optimize valve alignment and potentially preserve coronary access, at least for some devices, results of a pilot imaging study suggest.

In particular, positioning the Evolut THV (Medtronic) at a certain way at deployment led to an improvement in commissural alignment and a significant reduction in coronary artery overlap, according to authors of the study, led by Gilbert H. L. Tang, MD, MSc, MBA, surgical director of the structural heart program at Mount Sinai Health System, and associate professor of cardiovascular surgery, Mount Sinai Medical Center, New York.

Likewise, a specific positioning of the commissural post at deployment appeared to improve alignment and reduce coronary overlap when using the ACURATE-neo (Boston Scientific), though results with this transcatheter heart valve need to be considered preliminary because of the smaller number of cases, Dr. Tang said in an interview.

By contrast, initial deployment orientation of the SAPIEN 3 (Edwards Lifesciences) did not seem to have an impact on final orientation or neocommissural overlap with arteries in this study by Dr. Tang and colleagues, which was published in JACC: Cardiovascular Interventions and had been planned for presentation at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.

Improved positioning may have important future implications for patients undergoing transcatheter aortic valve replacement (TAVR), particularly if they are younger and therefore perhaps more likely than older patients to undergo a procedure requiring coronary access at some point in the future, according to Dr. Tang.

“Right now, device design does not permit us to have consistent commissural alignment,” said Dr. Tang in the interview. “What this study shows is that, with modification of delivery catheter insertion technique, at least for the EVOLUT valve, we can improve commissural alignment and hypothetically speaking, improve the likelihood of coronary access.”

While the technique modifications described by Dr. Tang and colleagues are commendable, the overall impact on commissural alignment and coronary overlap are “modest” and do not solve the problem, according to Hasan Jilaihawi, MD, associate professor of medicine and cardiothoracic surgery at NYU Langone Health, New York.

Instead, the onus should be on the device manufacturers to develop solutions that allow for better alignment between their devices and patients’ commissures, said Dr. Jilaihawi.

“We need really industry to focus wholeheartedly on this,” Dr. Jilaihawi said in an interview. “I think they will, and there will be some discussions about focusing on [commissural alignment], but I think it’s coming really very late.”

Dr. Tang agreed on the need for increased focus on achieving commissural alignment. Of note, he said, there are newer transcatheter heart valves under study that may be more likely to achieve alignment and reduce the possibility of severe coronary overlap, including the JenaValve (JenaValve Technology) and the J-Valve (JC Medical).

“We hope that manufacturers can design valves that would improve commissural alignment for these patients, so that in 10 or even 20 years’ time, when these patients require reintervention, we won’t have to do surgery because the valves are not aligned,” said Dr. Tang. “Ideally, we might have to do one surgical intervention in their lifetime, but really what we are talking about now is the lifetime management of these patients as the coronary artery disease progresses, and also the aortic valve disease returns with the prosthetic valve.”

The pilot imaging study by Dr. Tang and colleagues included a total of 828 patients undergoing TAVR, including 483 treated with SAPIEN 3, 245 with Evolut, and 100 with ACURATE-neo.

To track deployment orientation, the SAPIEN 3 cases had a commissure crimped at 3, 6, 9, or 12 o’clock orientation relative to the delivery catheter. However, crimping orientation at initial deployment did not appear to have an impact on the final orientation, with overall incidence of severe coronary overlap of 36.6% for the left main coronary artery (LMCA), 23.6% for the right coronary artery (RCA), and 51.3% for one or both, according to the report.

For 107 cases treated with Evolut, the investigators sought to have a marker on the device (known as the “hat” marker) oriented to the outer curve of the descending aorta; to do that, they inserted the delivery catheter with the flush port at the 3 o’clock position. Those cases with the hat marker at the outer curve or the center front had improved commissural alignment as compared to those with the hat at the inner curve or center back, according to investigators. The incidence of coronary overlap with the LMCA was 15.7% for those with the hat at the outer curve or center front, compared to 66.0% for those with the hat at the inner curve or center back (P < .001), and the differences in coronary overlap were likewise significantly different in favor of the outer curve/center front for the RCA or both coronaries.

Finally, the incidence of coronary overlap with the ACURATE-neo was much lower when the commissural post at initial deployment was at the center back or inner curve, and in a few cases where the operators tried to torque the delivery catheter to position the commissural post to the inner curve, commissural alignment was achieved in about three-quarters of the patients (five of seven cases).

This is believed to be the first study to systematically characterize how the initial orientation of different transcatheter heart valves impact commissural alignment and coronary overlap, according to Dr. Tang and coinvestigators.

Dr. Jilaihawi, who was not involved in the study, said the investigators studied this phenomenon in a “very detailed, methodical fashion,” but emphasized the need for new device innovations to improve alignment and overlap.

“Their efforts weren’t completely in vain, but they really made a small difference in something that is too important to be [addressed] in a kind of ‘MacGyver’ approach to this problem,” he said in the interview.

Disclosures reported by Dr. Tang were related to Edwards Lifesciences (physician proctor) and Medtronic (physician proctor, consultant). Coauthors reported disclosures related to Edwards, Medtronic, and Boston Scientific, among others.

SOURCE: ACC 20. Tang GHL et al. JACC Cardiovasc Interv. 2020 Mar 16. doi: 10.1016/j.jcin.2020.02.005.

For patients undergoing transcatheter aortic valve replacement, using a specific orientation at deployment may optimize valve alignment and potentially preserve coronary access, at least for some devices, results of a pilot imaging study suggest.

In particular, positioning the Evolut THV (Medtronic) at a certain way at deployment led to an improvement in commissural alignment and a significant reduction in coronary artery overlap, according to authors of the study, led by Gilbert H. L. Tang, MD, MSc, MBA, surgical director of the structural heart program at Mount Sinai Health System, and associate professor of cardiovascular surgery, Mount Sinai Medical Center, New York.

Likewise, a specific positioning of the commissural post at deployment appeared to improve alignment and reduce coronary overlap when using the ACURATE-neo (Boston Scientific), though results with this transcatheter heart valve need to be considered preliminary because of the smaller number of cases, Dr. Tang said in an interview.

By contrast, initial deployment orientation of the SAPIEN 3 (Edwards Lifesciences) did not seem to have an impact on final orientation or neocommissural overlap with arteries in this study by Dr. Tang and colleagues, which was published in JACC: Cardiovascular Interventions and had been planned for presentation at the joint scientific sessions of the American College of Cardiology and the World Heart Federation. ACC organizers chose to present parts of the meeting virtually after COVID-19 concerns caused them to cancel the meeting.

Improved positioning may have important future implications for patients undergoing transcatheter aortic valve replacement (TAVR), particularly if they are younger and therefore perhaps more likely than older patients to undergo a procedure requiring coronary access at some point in the future, according to Dr. Tang.

“Right now, device design does not permit us to have consistent commissural alignment,” said Dr. Tang in the interview. “What this study shows is that, with modification of delivery catheter insertion technique, at least for the EVOLUT valve, we can improve commissural alignment and hypothetically speaking, improve the likelihood of coronary access.”

While the technique modifications described by Dr. Tang and colleagues are commendable, the overall impact on commissural alignment and coronary overlap are “modest” and do not solve the problem, according to Hasan Jilaihawi, MD, associate professor of medicine and cardiothoracic surgery at NYU Langone Health, New York.

Instead, the onus should be on the device manufacturers to develop solutions that allow for better alignment between their devices and patients’ commissures, said Dr. Jilaihawi.

“We need really industry to focus wholeheartedly on this,” Dr. Jilaihawi said in an interview. “I think they will, and there will be some discussions about focusing on [commissural alignment], but I think it’s coming really very late.”

Dr. Tang agreed on the need for increased focus on achieving commissural alignment. Of note, he said, there are newer transcatheter heart valves under study that may be more likely to achieve alignment and reduce the possibility of severe coronary overlap, including the JenaValve (JenaValve Technology) and the J-Valve (JC Medical).

“We hope that manufacturers can design valves that would improve commissural alignment for these patients, so that in 10 or even 20 years’ time, when these patients require reintervention, we won’t have to do surgery because the valves are not aligned,” said Dr. Tang. “Ideally, we might have to do one surgical intervention in their lifetime, but really what we are talking about now is the lifetime management of these patients as the coronary artery disease progresses, and also the aortic valve disease returns with the prosthetic valve.”

The pilot imaging study by Dr. Tang and colleagues included a total of 828 patients undergoing TAVR, including 483 treated with SAPIEN 3, 245 with Evolut, and 100 with ACURATE-neo.

To track deployment orientation, the SAPIEN 3 cases had a commissure crimped at 3, 6, 9, or 12 o’clock orientation relative to the delivery catheter. However, crimping orientation at initial deployment did not appear to have an impact on the final orientation, with overall incidence of severe coronary overlap of 36.6% for the left main coronary artery (LMCA), 23.6% for the right coronary artery (RCA), and 51.3% for one or both, according to the report.

For 107 cases treated with Evolut, the investigators sought to have a marker on the device (known as the “hat” marker) oriented to the outer curve of the descending aorta; to do that, they inserted the delivery catheter with the flush port at the 3 o’clock position. Those cases with the hat marker at the outer curve or the center front had improved commissural alignment as compared to those with the hat at the inner curve or center back, according to investigators. The incidence of coronary overlap with the LMCA was 15.7% for those with the hat at the outer curve or center front, compared to 66.0% for those with the hat at the inner curve or center back (P < .001), and the differences in coronary overlap were likewise significantly different in favor of the outer curve/center front for the RCA or both coronaries.

Finally, the incidence of coronary overlap with the ACURATE-neo was much lower when the commissural post at initial deployment was at the center back or inner curve, and in a few cases where the operators tried to torque the delivery catheter to position the commissural post to the inner curve, commissural alignment was achieved in about three-quarters of the patients (five of seven cases).

This is believed to be the first study to systematically characterize how the initial orientation of different transcatheter heart valves impact commissural alignment and coronary overlap, according to Dr. Tang and coinvestigators.

Dr. Jilaihawi, who was not involved in the study, said the investigators studied this phenomenon in a “very detailed, methodical fashion,” but emphasized the need for new device innovations to improve alignment and overlap.

“Their efforts weren’t completely in vain, but they really made a small difference in something that is too important to be [addressed] in a kind of ‘MacGyver’ approach to this problem,” he said in the interview.

Disclosures reported by Dr. Tang were related to Edwards Lifesciences (physician proctor) and Medtronic (physician proctor, consultant). Coauthors reported disclosures related to Edwards, Medtronic, and Boston Scientific, among others.

SOURCE: ACC 20. Tang GHL et al. JACC Cardiovasc Interv. 2020 Mar 16. doi: 10.1016/j.jcin.2020.02.005.

The novel coronavirus, SARS-CoV-2, remains viable in aerosols for hours and on surfaces for days, according to a new study.

The data indicate that the stability of the new virus is similar to that of SARS-CoV-1, which caused the SARS epidemic, researchers report in an article published on the medRxivpreprint server. (The posted article has been submitted for journal publication but has not been peer reviewed.)

Transmission of SARS-CoV-2, which causes COVID-19, has quickly outstripped the pace of the 2003 SARS epidemic. “Superspread” of the earlier disease arose from infection during medical procedures, in which a single infected individual seeded many secondary cases. In contrast, the novel coronavirus appears to be spread more through human-to-human transmission in a variety of settings.

However, it’s not yet known the extent to which asymptomatic or presymptomatic individuals spread the new virus through daily routine.

To investigate how long SARS-CoV-2 remains infective in the environment, Neeltje van Doremalen, PhD, of the Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, in Hamilton, Montana, and colleagues conducted simulation experiments in which they compared the viability of SARS-CoV-2 with that of SARS-CoV-1 in aerosols and on surfaces.

Among patients infected with SARS-CoV-2, viral loads in the upper respiratory tract are high; as a consequence, respiratory secretion in the form of aerosols (<5 μm) or droplets (>5 mcm) is likely, the authors note.

van Doremalen and colleagues used nebulizers to generate aerosols. Samples of SARS-CoV-1 and SARS-CoV-2 were collecting at 0, 30, 60, 120, and 180 minutes on a gelatin filter. The researchers then tested the infectivity of the viruses on Vero cells grown in culture.

They found that SARS-CoV-2 was largely stable through the full 180-minute test, with only a slight decline at 3 hours. This time course is similar to that of SARS-CoV-1; both viruses have a median half-life in aerosols of 2.7 hours (range, 1.65 hr for SARS-CoV-1, vs 7.24 hr for SARS-CoV-2).

The researchers then tested the viruses on a variety of surfaces for up to 7 days, using humidity values and temperatures designed to mimic “a variety of household and hospital situations.” The volumes of viral exposures that the team used were consistent with amounts found in the human upper and lower respiratory tracts.

For example, they applied 50 mcL of virus-containing solution to a piece of cardboard and then swabbed the surface, at different times, with an additional 1 mcL of medium. Each surface assay was replicated three times.

The novel coronavirus was most stable on plastic and stainless steel, with some virus remaining viable up to 72 hours. However, by that time the viral load had fallen by about three orders of magnitude, indicating exponential decay. This profile was remarkably similar to that of SARS-CoV-1, according to the authors.

However, the two viruses differed in staying power on copper and cardboard. No viable SARS-CoV-2 was detectable on copper after 4 hours or on cardboard after 24 hours. In contrast, SARS-CoV-1 was not viable beyond 8 hours for either copper or cardboard.

“Taken together, our results indicate that aerosol and fomite transmission of HCoV-19 [SARS-CoV-2] are plausible, as the virus can remain viable in aerosols for multiple hours and on surfaces up to days,” the authors conclude.

Andrew Pekosz, PhD, codirector of the Center of Excellence in Influenza Research and Surveillance and director of the Center for Emerging Viruses and Infectious Diseases at the Johns Hopkins Center for Global Health, Baltimore, Maryland, applauds the real-world value of the experiments.

“The PCR [polymerase chain reaction] test used [in other studies] to detect SARS-CoV-2 just detects the virus genome. It doesn’t tell you if the virus was still infectious, or ‘viable.’ That’s why this study is interesting,” Pekosz said. “It focuses on infectious virus, which is the virus that has the potential to transmit and infect another person. What we don’t know yet is how much infectious (viable) virus is needed to initiate infection in another person.”

He suggests that further investigations evaluate other types of environmental surfaces, including lacquered wood that is made into desks and ceramic tiles found in bathrooms and kitchens.

One limitation of the study is that the data for experiments on cardboard were more variable than the data for other surfaces tested.

The investigators and Pekosz have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

The novel coronavirus, SARS-CoV-2, remains viable in aerosols for hours and on surfaces for days, according to a new study.

The data indicate that the stability of the new virus is similar to that of SARS-CoV-1, which caused the SARS epidemic, researchers report in an article published on the medRxivpreprint server. (The posted article has been submitted for journal publication but has not been peer reviewed.)

Transmission of SARS-CoV-2, which causes COVID-19, has quickly outstripped the pace of the 2003 SARS epidemic. “Superspread” of the earlier disease arose from infection during medical procedures, in which a single infected individual seeded many secondary cases. In contrast, the novel coronavirus appears to be spread more through human-to-human transmission in a variety of settings.

However, it’s not yet known the extent to which asymptomatic or presymptomatic individuals spread the new virus through daily routine.

To investigate how long SARS-CoV-2 remains infective in the environment, Neeltje van Doremalen, PhD, of the Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, in Hamilton, Montana, and colleagues conducted simulation experiments in which they compared the viability of SARS-CoV-2 with that of SARS-CoV-1 in aerosols and on surfaces.

Among patients infected with SARS-CoV-2, viral loads in the upper respiratory tract are high; as a consequence, respiratory secretion in the form of aerosols (<5 μm) or droplets (>5 mcm) is likely, the authors note.

van Doremalen and colleagues used nebulizers to generate aerosols. Samples of SARS-CoV-1 and SARS-CoV-2 were collecting at 0, 30, 60, 120, and 180 minutes on a gelatin filter. The researchers then tested the infectivity of the viruses on Vero cells grown in culture.

They found that SARS-CoV-2 was largely stable through the full 180-minute test, with only a slight decline at 3 hours. This time course is similar to that of SARS-CoV-1; both viruses have a median half-life in aerosols of 2.7 hours (range, 1.65 hr for SARS-CoV-1, vs 7.24 hr for SARS-CoV-2).

The researchers then tested the viruses on a variety of surfaces for up to 7 days, using humidity values and temperatures designed to mimic “a variety of household and hospital situations.” The volumes of viral exposures that the team used were consistent with amounts found in the human upper and lower respiratory tracts.

For example, they applied 50 mcL of virus-containing solution to a piece of cardboard and then swabbed the surface, at different times, with an additional 1 mcL of medium. Each surface assay was replicated three times.

The novel coronavirus was most stable on plastic and stainless steel, with some virus remaining viable up to 72 hours. However, by that time the viral load had fallen by about three orders of magnitude, indicating exponential decay. This profile was remarkably similar to that of SARS-CoV-1, according to the authors.

However, the two viruses differed in staying power on copper and cardboard. No viable SARS-CoV-2 was detectable on copper after 4 hours or on cardboard after 24 hours. In contrast, SARS-CoV-1 was not viable beyond 8 hours for either copper or cardboard.

“Taken together, our results indicate that aerosol and fomite transmission of HCoV-19 [SARS-CoV-2] are plausible, as the virus can remain viable in aerosols for multiple hours and on surfaces up to days,” the authors conclude.

Andrew Pekosz, PhD, codirector of the Center of Excellence in Influenza Research and Surveillance and director of the Center for Emerging Viruses and Infectious Diseases at the Johns Hopkins Center for Global Health, Baltimore, Maryland, applauds the real-world value of the experiments.

“The PCR [polymerase chain reaction] test used [in other studies] to detect SARS-CoV-2 just detects the virus genome. It doesn’t tell you if the virus was still infectious, or ‘viable.’ That’s why this study is interesting,” Pekosz said. “It focuses on infectious virus, which is the virus that has the potential to transmit and infect another person. What we don’t know yet is how much infectious (viable) virus is needed to initiate infection in another person.”

He suggests that further investigations evaluate other types of environmental surfaces, including lacquered wood that is made into desks and ceramic tiles found in bathrooms and kitchens.

One limitation of the study is that the data for experiments on cardboard were more variable than the data for other surfaces tested.

The investigators and Pekosz have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

The novel coronavirus, SARS-CoV-2, remains viable in aerosols for hours and on surfaces for days, according to a new study.

The data indicate that the stability of the new virus is similar to that of SARS-CoV-1, which caused the SARS epidemic, researchers report in an article published on the medRxivpreprint server. (The posted article has been submitted for journal publication but has not been peer reviewed.)

Transmission of SARS-CoV-2, which causes COVID-19, has quickly outstripped the pace of the 2003 SARS epidemic. “Superspread” of the earlier disease arose from infection during medical procedures, in which a single infected individual seeded many secondary cases. In contrast, the novel coronavirus appears to be spread more through human-to-human transmission in a variety of settings.

However, it’s not yet known the extent to which asymptomatic or presymptomatic individuals spread the new virus through daily routine.

To investigate how long SARS-CoV-2 remains infective in the environment, Neeltje van Doremalen, PhD, of the Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, in Hamilton, Montana, and colleagues conducted simulation experiments in which they compared the viability of SARS-CoV-2 with that of SARS-CoV-1 in aerosols and on surfaces.

Among patients infected with SARS-CoV-2, viral loads in the upper respiratory tract are high; as a consequence, respiratory secretion in the form of aerosols (<5 μm) or droplets (>5 mcm) is likely, the authors note.

van Doremalen and colleagues used nebulizers to generate aerosols. Samples of SARS-CoV-1 and SARS-CoV-2 were collecting at 0, 30, 60, 120, and 180 minutes on a gelatin filter. The researchers then tested the infectivity of the viruses on Vero cells grown in culture.

They found that SARS-CoV-2 was largely stable through the full 180-minute test, with only a slight decline at 3 hours. This time course is similar to that of SARS-CoV-1; both viruses have a median half-life in aerosols of 2.7 hours (range, 1.65 hr for SARS-CoV-1, vs 7.24 hr for SARS-CoV-2).

The researchers then tested the viruses on a variety of surfaces for up to 7 days, using humidity values and temperatures designed to mimic “a variety of household and hospital situations.” The volumes of viral exposures that the team used were consistent with amounts found in the human upper and lower respiratory tracts.

For example, they applied 50 mcL of virus-containing solution to a piece of cardboard and then swabbed the surface, at different times, with an additional 1 mcL of medium. Each surface assay was replicated three times.

The novel coronavirus was most stable on plastic and stainless steel, with some virus remaining viable up to 72 hours. However, by that time the viral load had fallen by about three orders of magnitude, indicating exponential decay. This profile was remarkably similar to that of SARS-CoV-1, according to the authors.

However, the two viruses differed in staying power on copper and cardboard. No viable SARS-CoV-2 was detectable on copper after 4 hours or on cardboard after 24 hours. In contrast, SARS-CoV-1 was not viable beyond 8 hours for either copper or cardboard.

“Taken together, our results indicate that aerosol and fomite transmission of HCoV-19 [SARS-CoV-2] are plausible, as the virus can remain viable in aerosols for multiple hours and on surfaces up to days,” the authors conclude.

Andrew Pekosz, PhD, codirector of the Center of Excellence in Influenza Research and Surveillance and director of the Center for Emerging Viruses and Infectious Diseases at the Johns Hopkins Center for Global Health, Baltimore, Maryland, applauds the real-world value of the experiments.

“The PCR [polymerase chain reaction] test used [in other studies] to detect SARS-CoV-2 just detects the virus genome. It doesn’t tell you if the virus was still infectious, or ‘viable.’ That’s why this study is interesting,” Pekosz said. “It focuses on infectious virus, which is the virus that has the potential to transmit and infect another person. What we don’t know yet is how much infectious (viable) virus is needed to initiate infection in another person.”

He suggests that further investigations evaluate other types of environmental surfaces, including lacquered wood that is made into desks and ceramic tiles found in bathrooms and kitchens.

One limitation of the study is that the data for experiments on cardboard were more variable than the data for other surfaces tested.

The investigators and Pekosz have disclosed no relevant financial relationships.

This article first appeared on Medscape.com.

The novel coronavirus (2019-nCoV) shows evidence of causing gastrointestinal symptoms and has the potential to be transmitted by the fecal-oral route, according to a new report from physicians at Shanghai Jiao Tong University, published online (Gastroenterology. 2020 March 3. doi: 10.1053/j.gastro.2020.02.054).

The virus’s respiratory symptoms are well documented and suggest primary transmission by droplet or contact, while other symptoms such as diarrhea, nausea, vomiting, and abdominal discomfort are less common and appear to vary between populations. The SARS coronavirus showed up in stool, even sometimes in patients discharged from the hospital. In a study of hospitalized patients in Wuhan, China, 10.1% of coronavirus patients had diarrhea and nausea in the 1-2 days before onset of fever and dyspnea. The first U.S. patient to be diagnosed had a 2-day history of nausea and vomiting, and had a loose bowel movement on the second day in the hospital. Clinicians later confirmed the presence of viral RNA in both the patient’s stool and airway.

The authors say that researchers in China have isolated viral RNA from the stool of two patients (unpublished), and it has been found in saliva, suggesting the possibility of the salivary gland as an infection or transmission route.

The authors maintain that previous studies likely overlooked or neglected patients who had mild intestinal symptoms. “Many efforts should be made to be alert on the initial digestive symptoms of COVID-19 for early detection, early diagnosis, early isolation and early intervention,” the authors wrote.

Like other coronaviruses, it appears that 2019-nCoV infects cells through an interaction between viral transmembrane spike glycoprotein (S-protein) receptor-binding domain, and the cell receptors angiotensin-converting enzyme 2 (ACE-2) and host cellular transmembrane serine protease (TMPRSS). Transcriptome analysis has shown that human lung AT2 cells express ACE-2 and TMPRSS, but esophagus upper and stratified epithelial cells also express both factors, as do stratified epithelial cells and absorptive enterocytes in the ileum and colon.

The researchers call for investigation into ACE-2 fusion proteins and TMPRSS inhibitors for diagnosis, prophylaxis, or treatment of COVID-19.

The authors also noted that COVID-19 has been linked to mild to moderate liver injury as revealed by elevated aminotransferases, hypoproteinemia and prothrombin time prolongation. This also has precedent in that the SARS coronavirus can infect the liver, and biopsies revealed mitoses and apoptosis, along with other abnormalities. SARS-associated hepatitis may be the result of viral hepatitis, immune overreaction, or a secondary effect of antiviral medications or other drugs. Little is known to date about the ability of 2019-nCoV to infect the liver, but single-cell RNA sequencing data from two distinct cohorts showed more ACE-2 expression in cholangiocytes (59.7%) than hepatocytes (2.6%), which indicates that the virus might directly affect intrahepatic bile ducts.

The authors had no sources of funding or financial conflicts.

SOURCE: GU J et al. Gastroenterology. 2020 March 3. doi: 10.1053/j.gastro.2020.02.054.

*This story was updated on 4/10.2020.

The novel coronavirus (2019-nCoV) shows evidence of causing gastrointestinal symptoms and has the potential to be transmitted by the fecal-oral route, according to a new report from physicians at Shanghai Jiao Tong University, published online (Gastroenterology. 2020 March 3. doi: 10.1053/j.gastro.2020.02.054).

The virus’s respiratory symptoms are well documented and suggest primary transmission by droplet or contact, while other symptoms such as diarrhea, nausea, vomiting, and abdominal discomfort are less common and appear to vary between populations. The SARS coronavirus showed up in stool, even sometimes in patients discharged from the hospital. In a study of hospitalized patients in Wuhan, China, 10.1% of coronavirus patients had diarrhea and nausea in the 1-2 days before onset of fever and dyspnea. The first U.S. patient to be diagnosed had a 2-day history of nausea and vomiting, and had a loose bowel movement on the second day in the hospital. Clinicians later confirmed the presence of viral RNA in both the patient’s stool and airway.

The authors say that researchers in China have isolated viral RNA from the stool of two patients (unpublished), and it has been found in saliva, suggesting the possibility of the salivary gland as an infection or transmission route.

The authors maintain that previous studies likely overlooked or neglected patients who had mild intestinal symptoms. “Many efforts should be made to be alert on the initial digestive symptoms of COVID-19 for early detection, early diagnosis, early isolation and early intervention,” the authors wrote.

Like other coronaviruses, it appears that 2019-nCoV infects cells through an interaction between viral transmembrane spike glycoprotein (S-protein) receptor-binding domain, and the cell receptors angiotensin-converting enzyme 2 (ACE-2) and host cellular transmembrane serine protease (TMPRSS). Transcriptome analysis has shown that human lung AT2 cells express ACE-2 and TMPRSS, but esophagus upper and stratified epithelial cells also express both factors, as do stratified epithelial cells and absorptive enterocytes in the ileum and colon.

The researchers call for investigation into ACE-2 fusion proteins and TMPRSS inhibitors for diagnosis, prophylaxis, or treatment of COVID-19.

The authors also noted that COVID-19 has been linked to mild to moderate liver injury as revealed by elevated aminotransferases, hypoproteinemia and prothrombin time prolongation. This also has precedent in that the SARS coronavirus can infect the liver, and biopsies revealed mitoses and apoptosis, along with other abnormalities. SARS-associated hepatitis may be the result of viral hepatitis, immune overreaction, or a secondary effect of antiviral medications or other drugs. Little is known to date about the ability of 2019-nCoV to infect the liver, but single-cell RNA sequencing data from two distinct cohorts showed more ACE-2 expression in cholangiocytes (59.7%) than hepatocytes (2.6%), which indicates that the virus might directly affect intrahepatic bile ducts.

The authors had no sources of funding or financial conflicts.

SOURCE: GU J et al. Gastroenterology. 2020 March 3. doi: 10.1053/j.gastro.2020.02.054.

*This story was updated on 4/10.2020.

The novel coronavirus (2019-nCoV) shows evidence of causing gastrointestinal symptoms and has the potential to be transmitted by the fecal-oral route, according to a new report from physicians at Shanghai Jiao Tong University, published online (Gastroenterology. 2020 March 3. doi: 10.1053/j.gastro.2020.02.054).

The virus’s respiratory symptoms are well documented and suggest primary transmission by droplet or contact, while other symptoms such as diarrhea, nausea, vomiting, and abdominal discomfort are less common and appear to vary between populations. The SARS coronavirus showed up in stool, even sometimes in patients discharged from the hospital. In a study of hospitalized patients in Wuhan, China, 10.1% of coronavirus patients had diarrhea and nausea in the 1-2 days before onset of fever and dyspnea. The first U.S. patient to be diagnosed had a 2-day history of nausea and vomiting, and had a loose bowel movement on the second day in the hospital. Clinicians later confirmed the presence of viral RNA in both the patient’s stool and airway.

The authors say that researchers in China have isolated viral RNA from the stool of two patients (unpublished), and it has been found in saliva, suggesting the possibility of the salivary gland as an infection or transmission route.

The authors maintain that previous studies likely overlooked or neglected patients who had mild intestinal symptoms. “Many efforts should be made to be alert on the initial digestive symptoms of COVID-19 for early detection, early diagnosis, early isolation and early intervention,” the authors wrote.

Like other coronaviruses, it appears that 2019-nCoV infects cells through an interaction between viral transmembrane spike glycoprotein (S-protein) receptor-binding domain, and the cell receptors angiotensin-converting enzyme 2 (ACE-2) and host cellular transmembrane serine protease (TMPRSS). Transcriptome analysis has shown that human lung AT2 cells express ACE-2 and TMPRSS, but esophagus upper and stratified epithelial cells also express both factors, as do stratified epithelial cells and absorptive enterocytes in the ileum and colon.

The researchers call for investigation into ACE-2 fusion proteins and TMPRSS inhibitors for diagnosis, prophylaxis, or treatment of COVID-19.

The authors also noted that COVID-19 has been linked to mild to moderate liver injury as revealed by elevated aminotransferases, hypoproteinemia and prothrombin time prolongation. This also has precedent in that the SARS coronavirus can infect the liver, and biopsies revealed mitoses and apoptosis, along with other abnormalities. SARS-associated hepatitis may be the result of viral hepatitis, immune overreaction, or a secondary effect of antiviral medications or other drugs. Little is known to date about the ability of 2019-nCoV to infect the liver, but single-cell RNA sequencing data from two distinct cohorts showed more ACE-2 expression in cholangiocytes (59.7%) than hepatocytes (2.6%), which indicates that the virus might directly affect intrahepatic bile ducts.

The authors had no sources of funding or financial conflicts.

SOURCE: GU J et al. Gastroenterology. 2020 March 3. doi: 10.1053/j.gastro.2020.02.054.

*This story was updated on 4/10.2020.

LOS ANGELES – Although recent findings from circumscribed patient populations enrolled in intervention studies have shown improved survival rates in patients with a recent intracerebral hemorrhagic stroke, data from a large, observational study in the Netherlands suggested a much darker real-world picture, with a 6-month mortality of 64% identified in a total cohort of nearly 15,000 people followed prospectively starting in 1990.

Mitchel L. Zoler/MDedge News

In striking contrast to the survival pattern over time of patients in the same Dutch study who had a first acute ischemic stroke, which showed a statistically significant and meaningful cut in mortality for ischemic stroke patients during the 25-year period examined, survival rates for patients during the first months following a first intracerebral hemorrhage (ICH) stayed flat during 1991-2015, Reem Waziry, MD, said at the International Stroke Conference sponsored by the American Heart Association.

“The promising treatment advances [applied to patients] in the recent ICH trials may not be reflected in community-based treatment,” suggested Dr. Waziry, a research and teaching fellow in clinical epidemiology at the Harvard School of Public Health in Boston.

The data she reported came from the Rotterdam Study, which followed unselected, older people in the Rotterdam community with no stroke history, and during 25 years of monitoring identified 162 incident ICH strokes and 988 acute ischemic strokes. Concurrently with Dr. Waziry’s talk at the conference, the data she reported were published in Stroke. The data she reported also showed that, during the 25 years studied, mortality at 3 years following a first ICH stroke rose to 73% on average.

During her talk, Dr. Waziry also presented an unpublished comparison of the 64% 6-month mortality in the Rotterdam Study with the 3- to 6-month mortality reported in the control arms of four recent, randomized intervention trials, including the MISTIE III trial. Among the four randomized trials Dr. Waziry selected to make this post-hoc comparison, the study with the highest mortality among control patients was MISTIE III, which showed about 25% mortality after 6 months. In contrast, the 19% 6-month mortality among ischemic stroke patients in the Rotterdam Study was roughly similar to the mortality seem in the control arms of some recent studies of interventions for patients with acute ischemic stroke.

The Rotterdam Study receives no commercial funding. Dr. Waziry had no disclosures.

mzoler@mdedge.com

SOURCE: Waziry R et al. ISC 2020, Abstract LB14.

LOS ANGELES – Although recent findings from circumscribed patient populations enrolled in intervention studies have shown improved survival rates in patients with a recent intracerebral hemorrhagic stroke, data from a large, observational study in the Netherlands suggested a much darker real-world picture, with a 6-month mortality of 64% identified in a total cohort of nearly 15,000 people followed prospectively starting in 1990.

Mitchel L. Zoler/MDedge News

In striking contrast to the survival pattern over time of patients in the same Dutch study who had a first acute ischemic stroke, which showed a statistically significant and meaningful cut in mortality for ischemic stroke patients during the 25-year period examined, survival rates for patients during the first months following a first intracerebral hemorrhage (ICH) stayed flat during 1991-2015, Reem Waziry, MD, said at the International Stroke Conference sponsored by the American Heart Association.

“The promising treatment advances [applied to patients] in the recent ICH trials may not be reflected in community-based treatment,” suggested Dr. Waziry, a research and teaching fellow in clinical epidemiology at the Harvard School of Public Health in Boston.

The data she reported came from the Rotterdam Study, which followed unselected, older people in the Rotterdam community with no stroke history, and during 25 years of monitoring identified 162 incident ICH strokes and 988 acute ischemic strokes. Concurrently with Dr. Waziry’s talk at the conference, the data she reported were published in Stroke. The data she reported also showed that, during the 25 years studied, mortality at 3 years following a first ICH stroke rose to 73% on average.

During her talk, Dr. Waziry also presented an unpublished comparison of the 64% 6-month mortality in the Rotterdam Study with the 3- to 6-month mortality reported in the control arms of four recent, randomized intervention trials, including the MISTIE III trial. Among the four randomized trials Dr. Waziry selected to make this post-hoc comparison, the study with the highest mortality among control patients was MISTIE III, which showed about 25% mortality after 6 months. In contrast, the 19% 6-month mortality among ischemic stroke patients in the Rotterdam Study was roughly similar to the mortality seem in the control arms of some recent studies of interventions for patients with acute ischemic stroke.

The Rotterdam Study receives no commercial funding. Dr. Waziry had no disclosures.

mzoler@mdedge.com

SOURCE: Waziry R et al. ISC 2020, Abstract LB14.

LOS ANGELES – Although recent findings from circumscribed patient populations enrolled in intervention studies have shown improved survival rates in patients with a recent intracerebral hemorrhagic stroke, data from a large, observational study in the Netherlands suggested a much darker real-world picture, with a 6-month mortality of 64% identified in a total cohort of nearly 15,000 people followed prospectively starting in 1990.

Mitchel L. Zoler/MDedge News

In striking contrast to the survival pattern over time of patients in the same Dutch study who had a first acute ischemic stroke, which showed a statistically significant and meaningful cut in mortality for ischemic stroke patients during the 25-year period examined, survival rates for patients during the first months following a first intracerebral hemorrhage (ICH) stayed flat during 1991-2015, Reem Waziry, MD, said at the International Stroke Conference sponsored by the American Heart Association.

“The promising treatment advances [applied to patients] in the recent ICH trials may not be reflected in community-based treatment,” suggested Dr. Waziry, a research and teaching fellow in clinical epidemiology at the Harvard School of Public Health in Boston.

The data she reported came from the Rotterdam Study, which followed unselected, older people in the Rotterdam community with no stroke history, and during 25 years of monitoring identified 162 incident ICH strokes and 988 acute ischemic strokes. Concurrently with Dr. Waziry’s talk at the conference, the data she reported were published in Stroke. The data she reported also showed that, during the 25 years studied, mortality at 3 years following a first ICH stroke rose to 73% on average.

During her talk, Dr. Waziry also presented an unpublished comparison of the 64% 6-month mortality in the Rotterdam Study with the 3- to 6-month mortality reported in the control arms of four recent, randomized intervention trials, including the MISTIE III trial. Among the four randomized trials Dr. Waziry selected to make this post-hoc comparison, the study with the highest mortality among control patients was MISTIE III, which showed about 25% mortality after 6 months. In contrast, the 19% 6-month mortality among ischemic stroke patients in the Rotterdam Study was roughly similar to the mortality seem in the control arms of some recent studies of interventions for patients with acute ischemic stroke.

The Rotterdam Study receives no commercial funding. Dr. Waziry had no disclosures.

mzoler@mdedge.com

SOURCE: Waziry R et al. ISC 2020, Abstract LB14.

The Get With the Guidelines – Stroke program is finally turning its attention to hemorrhagic strokes after having spurred improved patient management performance from participating U.S. stroke centers since its start in 2003 with a focus on acute ischemic stroke.

The advisers who craft policy for Get With the Guidelines – Stroke (GWTG–S) are planning to launch a pilot program later in 2020 that will initiate data monitoring and quality improvement aimed at optimizing care for patients following an intracerebral hemorrhage (ICH) starting at 15 U.S. stroke centers, with announcement of these 15 participating centers expected later in 2020. The program will start by targeting nine specific, evidence-based, key aspects of the acute management of ICH patients, said Kevin N. Sheth, MD, professor of neurology and neurosurgery, and chief of neurocritical care and emergency neurology at Yale University in New Haven, Conn, and a volunteer expert who is part of the team developing the ICH initiative.

According to Dr. Sheth, the nine imperatives of acute ICH care that the program plans to monitor at participating centers are:

• Obtain a baseline severity score.
• Identify etiology as spontaneous or treatment related.
• Perform coagulopathy reversal or anticoagulant reversal.
• Administer venous thromboembolism prophylaxis.
• Apply dysphagia screening within 24 hours, and delay oral intake until patient passes dysphagia screen.
• Provide patient management in a multidisciplinary stroke or ICU unit.
• Prescribe appropriate blood pressure treatment at discharge.
• Perform assessment for rehabilitation.
• Avoid prescribing corticosteroids and other contraindicated drugs.

GWTG–S is adopting these metrics for assessing the acute care of ICH patients based largely on the recommendations of an expert 2018 panel organized by the American Heart Association and American Stroke. Association that proposed a set of performance measures for the care of ICH patients. This set of performance measures served as the primary basis for designing the new GWTG–S program, along with considerations of feasibility for collecting data on these measures, Dr. Sheth said in an interview. “We hope to make it easy” for centers to collect the data needed to participate.

The existing GWTG–S program is now 17-years old, and has spread to nearly 2,400 U.S. stroke centers as of early 2020, but the time has come to broaden its reach to patients with ICH and the programs that treat these patients, Dr. Sheth said. After years of nihilism about the prospects for patients following an ICH stroke, survival rates have increased, presenting “an opportunity to optimize care, for quality improvement,” he explained. “It’s a huge shift.” ICH patients “do better than we used to think.”

mzoler@mdedge.com

The Get With the Guidelines – Stroke program is finally turning its attention to hemorrhagic strokes after having spurred improved patient management performance from participating U.S. stroke centers since its start in 2003 with a focus on acute ischemic stroke.

The advisers who craft policy for Get With the Guidelines – Stroke (GWTG–S) are planning to launch a pilot program later in 2020 that will initiate data monitoring and quality improvement aimed at optimizing care for patients following an intracerebral hemorrhage (ICH) starting at 15 U.S. stroke centers, with announcement of these 15 participating centers expected later in 2020. The program will start by targeting nine specific, evidence-based, key aspects of the acute management of ICH patients, said Kevin N. Sheth, MD, professor of neurology and neurosurgery, and chief of neurocritical care and emergency neurology at Yale University in New Haven, Conn, and a volunteer expert who is part of the team developing the ICH initiative.

According to Dr. Sheth, the nine imperatives of acute ICH care that the program plans to monitor at participating centers are:

• Obtain a baseline severity score.
• Identify etiology as spontaneous or treatment related.
• Perform coagulopathy reversal or anticoagulant reversal.
• Administer venous thromboembolism prophylaxis.
• Apply dysphagia screening within 24 hours, and delay oral intake until patient passes dysphagia screen.
• Provide patient management in a multidisciplinary stroke or ICU unit.
• Prescribe appropriate blood pressure treatment at discharge.
• Perform assessment for rehabilitation.
• Avoid prescribing corticosteroids and other contraindicated drugs.

GWTG–S is adopting these metrics for assessing the acute care of ICH patients based largely on the recommendations of an expert 2018 panel organized by the American Heart Association and American Stroke. Association that proposed a set of performance measures for the care of ICH patients. This set of performance measures served as the primary basis for designing the new GWTG–S program, along with considerations of feasibility for collecting data on these measures, Dr. Sheth said in an interview. “We hope to make it easy” for centers to collect the data needed to participate.

The existing GWTG–S program is now 17-years old, and has spread to nearly 2,400 U.S. stroke centers as of early 2020, but the time has come to broaden its reach to patients with ICH and the programs that treat these patients, Dr. Sheth said. After years of nihilism about the prospects for patients following an ICH stroke, survival rates have increased, presenting “an opportunity to optimize care, for quality improvement,” he explained. “It’s a huge shift.” ICH patients “do better than we used to think.”

mzoler@mdedge.com

The Get With the Guidelines – Stroke program is finally turning its attention to hemorrhagic strokes after having spurred improved patient management performance from participating U.S. stroke centers since its start in 2003 with a focus on acute ischemic stroke.

The advisers who craft policy for Get With the Guidelines – Stroke (GWTG–S) are planning to launch a pilot program later in 2020 that will initiate data monitoring and quality improvement aimed at optimizing care for patients following an intracerebral hemorrhage (ICH) starting at 15 U.S. stroke centers, with announcement of these 15 participating centers expected later in 2020. The program will start by targeting nine specific, evidence-based, key aspects of the acute management of ICH patients, said Kevin N. Sheth, MD, professor of neurology and neurosurgery, and chief of neurocritical care and emergency neurology at Yale University in New Haven, Conn, and a volunteer expert who is part of the team developing the ICH initiative.

According to Dr. Sheth, the nine imperatives of acute ICH care that the program plans to monitor at participating centers are:

• Obtain a baseline severity score.
• Identify etiology as spontaneous or treatment related.
• Perform coagulopathy reversal or anticoagulant reversal.
• Administer venous thromboembolism prophylaxis.
• Apply dysphagia screening within 24 hours, and delay oral intake until patient passes dysphagia screen.
• Provide patient management in a multidisciplinary stroke or ICU unit.
• Prescribe appropriate blood pressure treatment at discharge.
• Perform assessment for rehabilitation.
• Avoid prescribing corticosteroids and other contraindicated drugs.

GWTG–S is adopting these metrics for assessing the acute care of ICH patients based largely on the recommendations of an expert 2018 panel organized by the American Heart Association and American Stroke. Association that proposed a set of performance measures for the care of ICH patients. This set of performance measures served as the primary basis for designing the new GWTG–S program, along with considerations of feasibility for collecting data on these measures, Dr. Sheth said in an interview. “We hope to make it easy” for centers to collect the data needed to participate.

The existing GWTG–S program is now 17-years old, and has spread to nearly 2,400 U.S. stroke centers as of early 2020, but the time has come to broaden its reach to patients with ICH and the programs that treat these patients, Dr. Sheth said. After years of nihilism about the prospects for patients following an ICH stroke, survival rates have increased, presenting “an opportunity to optimize care, for quality improvement,” he explained. “It’s a huge shift.” ICH patients “do better than we used to think.”

mzoler@mdedge.com