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Acquired Factor VIII Deficiency Presenting as Compartment Syndrome
Compartment syndrome occurs when the interstitial tissue pressures within a confined space are elevated to a level at which the arterial perfusion is diminished. Multiple etiologies exist and can be extrinsic (a cast that is too tight or prolonged compression on a limb), iatrogenic (aggressive resuscitation, drug infiltration, arterial puncture, or a spontaneous bleed from anticoagulation), and traumatic (fracture, snake envenomation, circumferential burn, or electrocution). If the compartments are not released, irreversible changes happen to the cells, including nerve and muscle death.1 Definitive management of this emergency requires prompt fasciotomy to decompress the compartment(s).1-3
Case Presentation
A 76-year-old right-handed woman with a history of chronic obstructive pulmonary disease, hypertension, and hyperlipidemia presented to the emergency department with 2 days of extensive right upper extremity ecchymosis and severe pain that was localized to her forearm (Figure 1). She was taking low-dose aspirin (81 mg/d) for left subclavian stenosis and over-the-counter ginkgo biloba. Leading up to the presentation, the patient was able to perform routine household chores, including yard work, cleaning, and taking care of her cats. Wrist and elbow X-rays were negative for a fracture. An upper extremity ultrasound found no venous occlusion. A computed tomography (CT) angiogram of her arm and chest found diffuse edema around the right elbow and forearm without pulmonary or right upper extremity emboli, fractures, hematoma, abscess, or air in the tissues.
The plastic surgery service was consulted. The patient was found to have a very tense forearm and pain to passive digital extension. The 2-point discrimination and pulses were intact. The patient was diagnosed with compartment syndrome based on the examination alone and gave consent for an emergent forearm and hand fasciotomy. A carpal tunnel release and a standard S-shaped volar forearm fasciotomy release were performed, which provided immediate decompression (Figure 2). The rest of the hand and extremity were soft. Edematous, healthy flexor muscle belly was identified without a hematoma. Most of the forearm wound was left open because the skin could not be reapproximated. Oxidized regenerated cellulose (Surgicel) was placed around the wound edges and the muscle was covered with a nonadherent dressing. Hemoglobin on admission was 12.9 g/dL(reference range, 12 to 16 g/dL). Kidney function was within normal limits. The rest of the complete blood count was unremarkable. Postoperative hemoglobin was 8.6 g/dL. Over the next several days, the patient's skin edges and muscle bellies continued to slowly bleed, and her hemoglobin fell to 5.6 g/dL by postoperative Day 2. The bleeding was managed with topical oxidized regenerated cellulose, thrombin spray, a hemostatic dressing made with kaolin (QuikClot), and a transfusion of 2 units of packed red blood cells.
A hematology consultation was requested. The patient was noted to have an elevated partial thromboplastin time (PTT) since admission measuring between 39.9 to 61.7 seconds (reference range, 26.2 to 37.2 seconds) and a normal prothrombin time test with an international normalized ratio. A PTT measured 17 months prior to admission was within the normal range. She reported no personal or family history of bleeding disorders. Until recently, she had never had easy bruisability. She reported no history of heavy menses or epistaxis. The patient had no children and had never been pregnant. She had tolerated an exploratory laparotomy 40 years prior to admission without bleeding complications and had never required blood transfusions before. A PTT 1:1 mixing study revealed incomplete correction. Subsequent workup included factor VIII (FVIII) activity, factor IX activity, factor XI activity, von Willebrand factor antigen, ristocetin cofactor assay, and von Willebrand factor multimers. FVIII activity was severely reduced at 7.8% (reference, > 54%) with a positive Bethesda assay of 300 to 400 Bodansky units (BU), indicating a strong FVIII inhibitor was present and establishing a diagnosis of acquired hemophilia A. Further workup for secondary causes of acquired hemophilia A including abdominal and pelvic CT, serum protein electrophoresis, and serum free light chains, were negative. She was started on prednisone 1 mg/kg daily and rituximab 375 mg/m2. Her hemoglobin stabilized, and she required no further blood transfusions.
The patient underwent wound closure on postoperative Day 11. At the time of the second surgery, there was still no improvement in her FVIII levels or PTT; therefore, 70 mcg/kg of recombinant coagulation-activated FVII was given just before surgery with no bleeding complications. The skin was closed primarily except for the most distal 3 cm (Figure 3). Due to concerns regarding further bleeding with skin graft, the remaining wound was allowed to close by secondary intention. As a precaution, the wound was covered with oxidized regenerated cellulose and thrombin spray. The patient continued to progress postoperatively without bleeding complications or a need for additional transfusions. She was seen by the hand therapist before and after the second surgery to help with edema management and joint mobility. She completed 4 weekly doses of 375 mg/m² rituximab and prednisone was tapered by 10 mg weekly.
Three weeks after starting treatment, her PTT normalized, and her FVIII increased to 33.7%. The Bethesda assay remained high at 198 BU, although it was lower than at admission. She was discharged home with dressing changes and monthly follow-up appointments. The wounds were fully closed at her 3-month appointment when she proudly demonstrated full digital extension and flexion into her palm.
Discussion
Forearm compartment syndrome is most often caused by fractures—distal radius in adults and supracondylar in children.2 This case initially presented as a diagnostic puzzle to the emergency department due to the patient’s lucid review of several days of nontraumatic injury.
The clinical hallmarks of compartment syndrome are the 5 Ps: pain, pallor, paresthesia, paralysis, and pulselessness. Patients will describe the pain as out of proportion to the nature of the injury; the compartments will be tense and swollen, they will have pain to passive muscle stretch, and sensation will progressively diminish. Distal pulses are the last to go, and permanent tissue damage can still occur when pulses are present.1
Compartment Syndrome
Compartment syndrome is generally a clinical diagnosis; however, in patients who are sedated or uncooperative, or if the clinical findings are equivocal, the examination can be supplemented with intercompartmental pressures using an arterial line transducer system.2 In general, a tissue pressure of 30 mm Hg or a 20- to 30-mm Hg difference between the diastolic and compartment pressures are indications for fasciotomy.1 The hand is treated with an open carpal tunnel release, interosseous muscle release through 2 dorsal hand incisions, and thenar and hypothenar muscle release. The forearm is treated through a curved volar incision that usually decompresses the dorsal compartment, as it did in our patient. If pressures are still high in the forearm, a longitudinal dorsal incision over the mobile wad is necessary. Wounds can be closed primarily days later, left open to close by secondary intention, or reconstructed with skin grafts.2 In our patient, compartment syndrome was isolated to her forearm and the carpal tunnel release was performed prophylactically since it did not add significant time or morbidity to the surgery.
Nontraumatic upper extremity compartment syndrome is rare. A 2021 review of acute nontraumatic upper extremity compartment syndrome found a bleeding disorder as the etiology in 3 cases published in the literature between 1993 and 2016.4 One of these cases was secondary to a known diagnosis of hemophilia A in a teenager.5 Ogrodnik and colleagues described a spontaneous hand hematoma secondary to previously undiagnosed acquired hemophilia A and Waldenström macroglobulinemia.4 Ilyas and colleagues described a spontaneous hematoma in the forearm dorsal compartment in a 67-year-old woman, which presented as compartment syndrome and elevated PTT and led to a diagnosis of acquired FVIII inhibitor. The authors recommended prompt hematology consultation to coordinate treatment once this diagnosis issuspected.6 Compartment syndrome also has been found to develop slowly over weeks in patients with acquired FVIII deficiency, suggesting a high index of suspicion and frequent examinations are needed when patients with known acquired hemophilia A present with a painful extremity.7
Nontraumatic compartment syndrome in the lower extremity in patients with previously undiagnosed acquired hemophilia A has also been described in the literature.8-11 Case reports describe the delay in diagnosis as the patients were originally seen by clinicians for lower extremity pain and swelling within days of presenting to the emergency room with compartment syndrome. Persistent bleeding and abnormal laboratory results prompted further tests and examinations.8,9,11 This underscores the need to be suspicious of this unusual pathology without a history of trauma.
Acquired Hemophilia A
Acquired hemophilia A is an autoimmune disease most often found in older individuals, with a mean age of approximately 70 years.12 It is caused by the spontaneous production of neutralizing immunoglobin autoantibodies that target endogenous FVIII. Many cases are idiopathic; however, up to 50% of cases are associated with underlying autoimmunity, malignancy (especially lymphoproliferative disorders), or pregnancy. It often presents as bleeding that is subcutaneous or in the gastrointestinal system, muscle, retroperitoneal space, or genitourinary system. Unlike congenital hemophilia A, joint bleeding is rare.13
The diagnosis is suspected with an isolated elevated PTT in the absence of other coagulation abnormalities. A 1:1 mixing study will typically show incomplete correction, which suggests the presence of an inhibitor. FVIII activity is reduced, and the FVIII inhibitor is confirmed with the Bethesda assay. Clinically active bleeding is treated with bypassing agents such as recombinant coagulation-activated FVII, activated prothrombin complex concentrates such as anti-inhibitor coagulant complex (FEIBA), or recombinant porcine FVIII.12,14 Not all patients require hemostatic treatment, but close monitoring, education, recognition, and immediate treatment, if needed, are indicated.13 Immunosuppressive therapy (corticosteroids, rituximab, and/or cyclophosphamide) is prescribed to eradicate the antibodies and induce remission.12
Conclusions
An older woman without a preceding trauma was diagnosed with an unusual case of acute compartment syndrome in the forearm. No hematoma was found, but muscle and skin bleeding plus an elevated PTT prompted a hematology workup, and, ultimately, the diagnosis of FVIII inhibitor secondary to acquired hemophilia A.
While a nontraumatic cause of compartment syndrome is rare, it should be considered in differential diagnosis for clinicians who see hand and upper extremity emergencies. An isolated elevated PTT in a patient with a bleed should raise suspicions and trigger immediate further evaluation. Once suspected, multidisciplinary treatment is indicated for immediate and long-term successful outcomes.
Acknowledgments
This manuscript is the result of work supported withresources and the use of facilities at the North Florida/South Georgia Veterans Health System, Gainesville, Florida.
1. Leversedge FJ, Moore TJ, Peterson BC, Seiler JG 3rd. Compartment syndrome of the upper extremity. J Hand Surg Am. 2011;36:544-559. doi:10.1016/j.jhsa.2010.12.008
2. Kalyani BS, Fisher BE, Roberts CS, Giannoudis PV. Compartment syndrome of the forearm: a systematic review. J Hand Surg Am. 2011;36:535-543. doi:10.1016/j.jhsa.2010.12.007
3. Steadman W, Wu R, Hamilton AT, Richardson MD, Wall CJ. Review article: a comprehensive review of unusual causes of acute limb compartment syndrome. Emerg Med Australas. 2022;34:871-876. doi:10.1111/1742-6723.14098
4. Ogrodnik J, Oliver JD, Cani D, Boczar D, Huayllani MT, Restrepo DJ, et al. Clinical case of acute non-traumatic hand compartment syndrome and systematic review for the upper extremity. Hand (N Y). 2021;16:285-291. doi:10.1177/1558944719856106
5. Kim J, Zelken J, Sacks JM. Case report. Spontaneous forearm compartment syndrome in a boy with hemophilia a: a therapeutic dilemma. Eplasty. 2013:13:e16.
6. Ilyas AM, Wisbeck JM, Shaffer GW, Thoder JJ. Upper extremity compartment syndrome secondary to acquired factor VIII inhibitor. A case report. J Bone Joint Surg Am. 2005;87:1606-1608. doi:10.2106/JBJS.C.01720
7. Adeclat GJ, Hayes M, Amick M, Kahan J, Halim A. Acute forearm compartment syndrome in the setting of acquired hemophilia A. Case Reports Plast Surg Hand Surg. 2022;9:140-144. doi:10.1080/23320885.2022.2071274
8. Abudaqqa RY, Arun KP, Mas AJA, Abushaaban FA. Acute atraumatic compartment syndrome of the thigh due to acquired coagulopathy disorder: a case report in known healthy patient. J Orthop Case Rep. 2021;11:59-62. doi:10.13107/jocr.2021.v11.i08.2366
9. Alidoost M, Conte GA, Chaudry R, Nahum K, Marchesani D. A unique presentation of spontaneous compartment syndrome due to acquired hemophilia A and associated malignancy: case report and literature review. World J Oncol. 2020;11:72-75. doi:10.14740/wjon1260
10. Jentzsch T, Brand-Staufer B, Schäfer FP, Wanner GA, Simmen H-P. Illustrated operative management of spontaneous bleeding and compartment syndrome of the lower extremity in a patient with acquired hemophilia A: a case report. J Med Case Rep. 2014;8:132. doi:10.1186/1752-1947-8-132
11. Pham TV, Sorenson CA, Nable JV. Acquired factor VIII deficiency presenting with compartment syndrome. Am J Emerg Med. 2014;32:195.e1-2. doi:10.1016/j.ajem.2013.09.022
12. Tiede A, Zieger B, Lisman T. Acquired bleeding disorders. Haemophilia. 2022;28(suppl 4):68-76. doi:10.1111/hae.14548
13. Kruse-Jarres R, Kempton CL, Baudo F, Collins PW, Knoebl P, Leissinger CA, et al. Acquired hemophilia A: updated review of evidence and treatment guidance. Am J Hematol. 2017;92:695-705. doi:10.1002/ajh.24777
14. Ilkhchoui Y, Koshkin E, Windsor JJ, Petersen TR, Charles M, Pack JD. Perioperative management of acquired hemophilia A: a case report and review of literature. Anesth Pain Med. 2013;4:e11906. doi:10.5812/aapm.11906
Compartment syndrome occurs when the interstitial tissue pressures within a confined space are elevated to a level at which the arterial perfusion is diminished. Multiple etiologies exist and can be extrinsic (a cast that is too tight or prolonged compression on a limb), iatrogenic (aggressive resuscitation, drug infiltration, arterial puncture, or a spontaneous bleed from anticoagulation), and traumatic (fracture, snake envenomation, circumferential burn, or electrocution). If the compartments are not released, irreversible changes happen to the cells, including nerve and muscle death.1 Definitive management of this emergency requires prompt fasciotomy to decompress the compartment(s).1-3
Case Presentation
A 76-year-old right-handed woman with a history of chronic obstructive pulmonary disease, hypertension, and hyperlipidemia presented to the emergency department with 2 days of extensive right upper extremity ecchymosis and severe pain that was localized to her forearm (Figure 1). She was taking low-dose aspirin (81 mg/d) for left subclavian stenosis and over-the-counter ginkgo biloba. Leading up to the presentation, the patient was able to perform routine household chores, including yard work, cleaning, and taking care of her cats. Wrist and elbow X-rays were negative for a fracture. An upper extremity ultrasound found no venous occlusion. A computed tomography (CT) angiogram of her arm and chest found diffuse edema around the right elbow and forearm without pulmonary or right upper extremity emboli, fractures, hematoma, abscess, or air in the tissues.
The plastic surgery service was consulted. The patient was found to have a very tense forearm and pain to passive digital extension. The 2-point discrimination and pulses were intact. The patient was diagnosed with compartment syndrome based on the examination alone and gave consent for an emergent forearm and hand fasciotomy. A carpal tunnel release and a standard S-shaped volar forearm fasciotomy release were performed, which provided immediate decompression (Figure 2). The rest of the hand and extremity were soft. Edematous, healthy flexor muscle belly was identified without a hematoma. Most of the forearm wound was left open because the skin could not be reapproximated. Oxidized regenerated cellulose (Surgicel) was placed around the wound edges and the muscle was covered with a nonadherent dressing. Hemoglobin on admission was 12.9 g/dL(reference range, 12 to 16 g/dL). Kidney function was within normal limits. The rest of the complete blood count was unremarkable. Postoperative hemoglobin was 8.6 g/dL. Over the next several days, the patient's skin edges and muscle bellies continued to slowly bleed, and her hemoglobin fell to 5.6 g/dL by postoperative Day 2. The bleeding was managed with topical oxidized regenerated cellulose, thrombin spray, a hemostatic dressing made with kaolin (QuikClot), and a transfusion of 2 units of packed red blood cells.
A hematology consultation was requested. The patient was noted to have an elevated partial thromboplastin time (PTT) since admission measuring between 39.9 to 61.7 seconds (reference range, 26.2 to 37.2 seconds) and a normal prothrombin time test with an international normalized ratio. A PTT measured 17 months prior to admission was within the normal range. She reported no personal or family history of bleeding disorders. Until recently, she had never had easy bruisability. She reported no history of heavy menses or epistaxis. The patient had no children and had never been pregnant. She had tolerated an exploratory laparotomy 40 years prior to admission without bleeding complications and had never required blood transfusions before. A PTT 1:1 mixing study revealed incomplete correction. Subsequent workup included factor VIII (FVIII) activity, factor IX activity, factor XI activity, von Willebrand factor antigen, ristocetin cofactor assay, and von Willebrand factor multimers. FVIII activity was severely reduced at 7.8% (reference, > 54%) with a positive Bethesda assay of 300 to 400 Bodansky units (BU), indicating a strong FVIII inhibitor was present and establishing a diagnosis of acquired hemophilia A. Further workup for secondary causes of acquired hemophilia A including abdominal and pelvic CT, serum protein electrophoresis, and serum free light chains, were negative. She was started on prednisone 1 mg/kg daily and rituximab 375 mg/m2. Her hemoglobin stabilized, and she required no further blood transfusions.
The patient underwent wound closure on postoperative Day 11. At the time of the second surgery, there was still no improvement in her FVIII levels or PTT; therefore, 70 mcg/kg of recombinant coagulation-activated FVII was given just before surgery with no bleeding complications. The skin was closed primarily except for the most distal 3 cm (Figure 3). Due to concerns regarding further bleeding with skin graft, the remaining wound was allowed to close by secondary intention. As a precaution, the wound was covered with oxidized regenerated cellulose and thrombin spray. The patient continued to progress postoperatively without bleeding complications or a need for additional transfusions. She was seen by the hand therapist before and after the second surgery to help with edema management and joint mobility. She completed 4 weekly doses of 375 mg/m² rituximab and prednisone was tapered by 10 mg weekly.
Three weeks after starting treatment, her PTT normalized, and her FVIII increased to 33.7%. The Bethesda assay remained high at 198 BU, although it was lower than at admission. She was discharged home with dressing changes and monthly follow-up appointments. The wounds were fully closed at her 3-month appointment when she proudly demonstrated full digital extension and flexion into her palm.
Discussion
Forearm compartment syndrome is most often caused by fractures—distal radius in adults and supracondylar in children.2 This case initially presented as a diagnostic puzzle to the emergency department due to the patient’s lucid review of several days of nontraumatic injury.
The clinical hallmarks of compartment syndrome are the 5 Ps: pain, pallor, paresthesia, paralysis, and pulselessness. Patients will describe the pain as out of proportion to the nature of the injury; the compartments will be tense and swollen, they will have pain to passive muscle stretch, and sensation will progressively diminish. Distal pulses are the last to go, and permanent tissue damage can still occur when pulses are present.1
Compartment Syndrome
Compartment syndrome is generally a clinical diagnosis; however, in patients who are sedated or uncooperative, or if the clinical findings are equivocal, the examination can be supplemented with intercompartmental pressures using an arterial line transducer system.2 In general, a tissue pressure of 30 mm Hg or a 20- to 30-mm Hg difference between the diastolic and compartment pressures are indications for fasciotomy.1 The hand is treated with an open carpal tunnel release, interosseous muscle release through 2 dorsal hand incisions, and thenar and hypothenar muscle release. The forearm is treated through a curved volar incision that usually decompresses the dorsal compartment, as it did in our patient. If pressures are still high in the forearm, a longitudinal dorsal incision over the mobile wad is necessary. Wounds can be closed primarily days later, left open to close by secondary intention, or reconstructed with skin grafts.2 In our patient, compartment syndrome was isolated to her forearm and the carpal tunnel release was performed prophylactically since it did not add significant time or morbidity to the surgery.
Nontraumatic upper extremity compartment syndrome is rare. A 2021 review of acute nontraumatic upper extremity compartment syndrome found a bleeding disorder as the etiology in 3 cases published in the literature between 1993 and 2016.4 One of these cases was secondary to a known diagnosis of hemophilia A in a teenager.5 Ogrodnik and colleagues described a spontaneous hand hematoma secondary to previously undiagnosed acquired hemophilia A and Waldenström macroglobulinemia.4 Ilyas and colleagues described a spontaneous hematoma in the forearm dorsal compartment in a 67-year-old woman, which presented as compartment syndrome and elevated PTT and led to a diagnosis of acquired FVIII inhibitor. The authors recommended prompt hematology consultation to coordinate treatment once this diagnosis issuspected.6 Compartment syndrome also has been found to develop slowly over weeks in patients with acquired FVIII deficiency, suggesting a high index of suspicion and frequent examinations are needed when patients with known acquired hemophilia A present with a painful extremity.7
Nontraumatic compartment syndrome in the lower extremity in patients with previously undiagnosed acquired hemophilia A has also been described in the literature.8-11 Case reports describe the delay in diagnosis as the patients were originally seen by clinicians for lower extremity pain and swelling within days of presenting to the emergency room with compartment syndrome. Persistent bleeding and abnormal laboratory results prompted further tests and examinations.8,9,11 This underscores the need to be suspicious of this unusual pathology without a history of trauma.
Acquired Hemophilia A
Acquired hemophilia A is an autoimmune disease most often found in older individuals, with a mean age of approximately 70 years.12 It is caused by the spontaneous production of neutralizing immunoglobin autoantibodies that target endogenous FVIII. Many cases are idiopathic; however, up to 50% of cases are associated with underlying autoimmunity, malignancy (especially lymphoproliferative disorders), or pregnancy. It often presents as bleeding that is subcutaneous or in the gastrointestinal system, muscle, retroperitoneal space, or genitourinary system. Unlike congenital hemophilia A, joint bleeding is rare.13
The diagnosis is suspected with an isolated elevated PTT in the absence of other coagulation abnormalities. A 1:1 mixing study will typically show incomplete correction, which suggests the presence of an inhibitor. FVIII activity is reduced, and the FVIII inhibitor is confirmed with the Bethesda assay. Clinically active bleeding is treated with bypassing agents such as recombinant coagulation-activated FVII, activated prothrombin complex concentrates such as anti-inhibitor coagulant complex (FEIBA), or recombinant porcine FVIII.12,14 Not all patients require hemostatic treatment, but close monitoring, education, recognition, and immediate treatment, if needed, are indicated.13 Immunosuppressive therapy (corticosteroids, rituximab, and/or cyclophosphamide) is prescribed to eradicate the antibodies and induce remission.12
Conclusions
An older woman without a preceding trauma was diagnosed with an unusual case of acute compartment syndrome in the forearm. No hematoma was found, but muscle and skin bleeding plus an elevated PTT prompted a hematology workup, and, ultimately, the diagnosis of FVIII inhibitor secondary to acquired hemophilia A.
While a nontraumatic cause of compartment syndrome is rare, it should be considered in differential diagnosis for clinicians who see hand and upper extremity emergencies. An isolated elevated PTT in a patient with a bleed should raise suspicions and trigger immediate further evaluation. Once suspected, multidisciplinary treatment is indicated for immediate and long-term successful outcomes.
Acknowledgments
This manuscript is the result of work supported withresources and the use of facilities at the North Florida/South Georgia Veterans Health System, Gainesville, Florida.
Compartment syndrome occurs when the interstitial tissue pressures within a confined space are elevated to a level at which the arterial perfusion is diminished. Multiple etiologies exist and can be extrinsic (a cast that is too tight or prolonged compression on a limb), iatrogenic (aggressive resuscitation, drug infiltration, arterial puncture, or a spontaneous bleed from anticoagulation), and traumatic (fracture, snake envenomation, circumferential burn, or electrocution). If the compartments are not released, irreversible changes happen to the cells, including nerve and muscle death.1 Definitive management of this emergency requires prompt fasciotomy to decompress the compartment(s).1-3
Case Presentation
A 76-year-old right-handed woman with a history of chronic obstructive pulmonary disease, hypertension, and hyperlipidemia presented to the emergency department with 2 days of extensive right upper extremity ecchymosis and severe pain that was localized to her forearm (Figure 1). She was taking low-dose aspirin (81 mg/d) for left subclavian stenosis and over-the-counter ginkgo biloba. Leading up to the presentation, the patient was able to perform routine household chores, including yard work, cleaning, and taking care of her cats. Wrist and elbow X-rays were negative for a fracture. An upper extremity ultrasound found no venous occlusion. A computed tomography (CT) angiogram of her arm and chest found diffuse edema around the right elbow and forearm without pulmonary or right upper extremity emboli, fractures, hematoma, abscess, or air in the tissues.
The plastic surgery service was consulted. The patient was found to have a very tense forearm and pain to passive digital extension. The 2-point discrimination and pulses were intact. The patient was diagnosed with compartment syndrome based on the examination alone and gave consent for an emergent forearm and hand fasciotomy. A carpal tunnel release and a standard S-shaped volar forearm fasciotomy release were performed, which provided immediate decompression (Figure 2). The rest of the hand and extremity were soft. Edematous, healthy flexor muscle belly was identified without a hematoma. Most of the forearm wound was left open because the skin could not be reapproximated. Oxidized regenerated cellulose (Surgicel) was placed around the wound edges and the muscle was covered with a nonadherent dressing. Hemoglobin on admission was 12.9 g/dL(reference range, 12 to 16 g/dL). Kidney function was within normal limits. The rest of the complete blood count was unremarkable. Postoperative hemoglobin was 8.6 g/dL. Over the next several days, the patient's skin edges and muscle bellies continued to slowly bleed, and her hemoglobin fell to 5.6 g/dL by postoperative Day 2. The bleeding was managed with topical oxidized regenerated cellulose, thrombin spray, a hemostatic dressing made with kaolin (QuikClot), and a transfusion of 2 units of packed red blood cells.
A hematology consultation was requested. The patient was noted to have an elevated partial thromboplastin time (PTT) since admission measuring between 39.9 to 61.7 seconds (reference range, 26.2 to 37.2 seconds) and a normal prothrombin time test with an international normalized ratio. A PTT measured 17 months prior to admission was within the normal range. She reported no personal or family history of bleeding disorders. Until recently, she had never had easy bruisability. She reported no history of heavy menses or epistaxis. The patient had no children and had never been pregnant. She had tolerated an exploratory laparotomy 40 years prior to admission without bleeding complications and had never required blood transfusions before. A PTT 1:1 mixing study revealed incomplete correction. Subsequent workup included factor VIII (FVIII) activity, factor IX activity, factor XI activity, von Willebrand factor antigen, ristocetin cofactor assay, and von Willebrand factor multimers. FVIII activity was severely reduced at 7.8% (reference, > 54%) with a positive Bethesda assay of 300 to 400 Bodansky units (BU), indicating a strong FVIII inhibitor was present and establishing a diagnosis of acquired hemophilia A. Further workup for secondary causes of acquired hemophilia A including abdominal and pelvic CT, serum protein electrophoresis, and serum free light chains, were negative. She was started on prednisone 1 mg/kg daily and rituximab 375 mg/m2. Her hemoglobin stabilized, and she required no further blood transfusions.
The patient underwent wound closure on postoperative Day 11. At the time of the second surgery, there was still no improvement in her FVIII levels or PTT; therefore, 70 mcg/kg of recombinant coagulation-activated FVII was given just before surgery with no bleeding complications. The skin was closed primarily except for the most distal 3 cm (Figure 3). Due to concerns regarding further bleeding with skin graft, the remaining wound was allowed to close by secondary intention. As a precaution, the wound was covered with oxidized regenerated cellulose and thrombin spray. The patient continued to progress postoperatively without bleeding complications or a need for additional transfusions. She was seen by the hand therapist before and after the second surgery to help with edema management and joint mobility. She completed 4 weekly doses of 375 mg/m² rituximab and prednisone was tapered by 10 mg weekly.
Three weeks after starting treatment, her PTT normalized, and her FVIII increased to 33.7%. The Bethesda assay remained high at 198 BU, although it was lower than at admission. She was discharged home with dressing changes and monthly follow-up appointments. The wounds were fully closed at her 3-month appointment when she proudly demonstrated full digital extension and flexion into her palm.
Discussion
Forearm compartment syndrome is most often caused by fractures—distal radius in adults and supracondylar in children.2 This case initially presented as a diagnostic puzzle to the emergency department due to the patient’s lucid review of several days of nontraumatic injury.
The clinical hallmarks of compartment syndrome are the 5 Ps: pain, pallor, paresthesia, paralysis, and pulselessness. Patients will describe the pain as out of proportion to the nature of the injury; the compartments will be tense and swollen, they will have pain to passive muscle stretch, and sensation will progressively diminish. Distal pulses are the last to go, and permanent tissue damage can still occur when pulses are present.1
Compartment Syndrome
Compartment syndrome is generally a clinical diagnosis; however, in patients who are sedated or uncooperative, or if the clinical findings are equivocal, the examination can be supplemented with intercompartmental pressures using an arterial line transducer system.2 In general, a tissue pressure of 30 mm Hg or a 20- to 30-mm Hg difference between the diastolic and compartment pressures are indications for fasciotomy.1 The hand is treated with an open carpal tunnel release, interosseous muscle release through 2 dorsal hand incisions, and thenar and hypothenar muscle release. The forearm is treated through a curved volar incision that usually decompresses the dorsal compartment, as it did in our patient. If pressures are still high in the forearm, a longitudinal dorsal incision over the mobile wad is necessary. Wounds can be closed primarily days later, left open to close by secondary intention, or reconstructed with skin grafts.2 In our patient, compartment syndrome was isolated to her forearm and the carpal tunnel release was performed prophylactically since it did not add significant time or morbidity to the surgery.
Nontraumatic upper extremity compartment syndrome is rare. A 2021 review of acute nontraumatic upper extremity compartment syndrome found a bleeding disorder as the etiology in 3 cases published in the literature between 1993 and 2016.4 One of these cases was secondary to a known diagnosis of hemophilia A in a teenager.5 Ogrodnik and colleagues described a spontaneous hand hematoma secondary to previously undiagnosed acquired hemophilia A and Waldenström macroglobulinemia.4 Ilyas and colleagues described a spontaneous hematoma in the forearm dorsal compartment in a 67-year-old woman, which presented as compartment syndrome and elevated PTT and led to a diagnosis of acquired FVIII inhibitor. The authors recommended prompt hematology consultation to coordinate treatment once this diagnosis issuspected.6 Compartment syndrome also has been found to develop slowly over weeks in patients with acquired FVIII deficiency, suggesting a high index of suspicion and frequent examinations are needed when patients with known acquired hemophilia A present with a painful extremity.7
Nontraumatic compartment syndrome in the lower extremity in patients with previously undiagnosed acquired hemophilia A has also been described in the literature.8-11 Case reports describe the delay in diagnosis as the patients were originally seen by clinicians for lower extremity pain and swelling within days of presenting to the emergency room with compartment syndrome. Persistent bleeding and abnormal laboratory results prompted further tests and examinations.8,9,11 This underscores the need to be suspicious of this unusual pathology without a history of trauma.
Acquired Hemophilia A
Acquired hemophilia A is an autoimmune disease most often found in older individuals, with a mean age of approximately 70 years.12 It is caused by the spontaneous production of neutralizing immunoglobin autoantibodies that target endogenous FVIII. Many cases are idiopathic; however, up to 50% of cases are associated with underlying autoimmunity, malignancy (especially lymphoproliferative disorders), or pregnancy. It often presents as bleeding that is subcutaneous or in the gastrointestinal system, muscle, retroperitoneal space, or genitourinary system. Unlike congenital hemophilia A, joint bleeding is rare.13
The diagnosis is suspected with an isolated elevated PTT in the absence of other coagulation abnormalities. A 1:1 mixing study will typically show incomplete correction, which suggests the presence of an inhibitor. FVIII activity is reduced, and the FVIII inhibitor is confirmed with the Bethesda assay. Clinically active bleeding is treated with bypassing agents such as recombinant coagulation-activated FVII, activated prothrombin complex concentrates such as anti-inhibitor coagulant complex (FEIBA), or recombinant porcine FVIII.12,14 Not all patients require hemostatic treatment, but close monitoring, education, recognition, and immediate treatment, if needed, are indicated.13 Immunosuppressive therapy (corticosteroids, rituximab, and/or cyclophosphamide) is prescribed to eradicate the antibodies and induce remission.12
Conclusions
An older woman without a preceding trauma was diagnosed with an unusual case of acute compartment syndrome in the forearm. No hematoma was found, but muscle and skin bleeding plus an elevated PTT prompted a hematology workup, and, ultimately, the diagnosis of FVIII inhibitor secondary to acquired hemophilia A.
While a nontraumatic cause of compartment syndrome is rare, it should be considered in differential diagnosis for clinicians who see hand and upper extremity emergencies. An isolated elevated PTT in a patient with a bleed should raise suspicions and trigger immediate further evaluation. Once suspected, multidisciplinary treatment is indicated for immediate and long-term successful outcomes.
Acknowledgments
This manuscript is the result of work supported withresources and the use of facilities at the North Florida/South Georgia Veterans Health System, Gainesville, Florida.
1. Leversedge FJ, Moore TJ, Peterson BC, Seiler JG 3rd. Compartment syndrome of the upper extremity. J Hand Surg Am. 2011;36:544-559. doi:10.1016/j.jhsa.2010.12.008
2. Kalyani BS, Fisher BE, Roberts CS, Giannoudis PV. Compartment syndrome of the forearm: a systematic review. J Hand Surg Am. 2011;36:535-543. doi:10.1016/j.jhsa.2010.12.007
3. Steadman W, Wu R, Hamilton AT, Richardson MD, Wall CJ. Review article: a comprehensive review of unusual causes of acute limb compartment syndrome. Emerg Med Australas. 2022;34:871-876. doi:10.1111/1742-6723.14098
4. Ogrodnik J, Oliver JD, Cani D, Boczar D, Huayllani MT, Restrepo DJ, et al. Clinical case of acute non-traumatic hand compartment syndrome and systematic review for the upper extremity. Hand (N Y). 2021;16:285-291. doi:10.1177/1558944719856106
5. Kim J, Zelken J, Sacks JM. Case report. Spontaneous forearm compartment syndrome in a boy with hemophilia a: a therapeutic dilemma. Eplasty. 2013:13:e16.
6. Ilyas AM, Wisbeck JM, Shaffer GW, Thoder JJ. Upper extremity compartment syndrome secondary to acquired factor VIII inhibitor. A case report. J Bone Joint Surg Am. 2005;87:1606-1608. doi:10.2106/JBJS.C.01720
7. Adeclat GJ, Hayes M, Amick M, Kahan J, Halim A. Acute forearm compartment syndrome in the setting of acquired hemophilia A. Case Reports Plast Surg Hand Surg. 2022;9:140-144. doi:10.1080/23320885.2022.2071274
8. Abudaqqa RY, Arun KP, Mas AJA, Abushaaban FA. Acute atraumatic compartment syndrome of the thigh due to acquired coagulopathy disorder: a case report in known healthy patient. J Orthop Case Rep. 2021;11:59-62. doi:10.13107/jocr.2021.v11.i08.2366
9. Alidoost M, Conte GA, Chaudry R, Nahum K, Marchesani D. A unique presentation of spontaneous compartment syndrome due to acquired hemophilia A and associated malignancy: case report and literature review. World J Oncol. 2020;11:72-75. doi:10.14740/wjon1260
10. Jentzsch T, Brand-Staufer B, Schäfer FP, Wanner GA, Simmen H-P. Illustrated operative management of spontaneous bleeding and compartment syndrome of the lower extremity in a patient with acquired hemophilia A: a case report. J Med Case Rep. 2014;8:132. doi:10.1186/1752-1947-8-132
11. Pham TV, Sorenson CA, Nable JV. Acquired factor VIII deficiency presenting with compartment syndrome. Am J Emerg Med. 2014;32:195.e1-2. doi:10.1016/j.ajem.2013.09.022
12. Tiede A, Zieger B, Lisman T. Acquired bleeding disorders. Haemophilia. 2022;28(suppl 4):68-76. doi:10.1111/hae.14548
13. Kruse-Jarres R, Kempton CL, Baudo F, Collins PW, Knoebl P, Leissinger CA, et al. Acquired hemophilia A: updated review of evidence and treatment guidance. Am J Hematol. 2017;92:695-705. doi:10.1002/ajh.24777
14. Ilkhchoui Y, Koshkin E, Windsor JJ, Petersen TR, Charles M, Pack JD. Perioperative management of acquired hemophilia A: a case report and review of literature. Anesth Pain Med. 2013;4:e11906. doi:10.5812/aapm.11906
1. Leversedge FJ, Moore TJ, Peterson BC, Seiler JG 3rd. Compartment syndrome of the upper extremity. J Hand Surg Am. 2011;36:544-559. doi:10.1016/j.jhsa.2010.12.008
2. Kalyani BS, Fisher BE, Roberts CS, Giannoudis PV. Compartment syndrome of the forearm: a systematic review. J Hand Surg Am. 2011;36:535-543. doi:10.1016/j.jhsa.2010.12.007
3. Steadman W, Wu R, Hamilton AT, Richardson MD, Wall CJ. Review article: a comprehensive review of unusual causes of acute limb compartment syndrome. Emerg Med Australas. 2022;34:871-876. doi:10.1111/1742-6723.14098
4. Ogrodnik J, Oliver JD, Cani D, Boczar D, Huayllani MT, Restrepo DJ, et al. Clinical case of acute non-traumatic hand compartment syndrome and systematic review for the upper extremity. Hand (N Y). 2021;16:285-291. doi:10.1177/1558944719856106
5. Kim J, Zelken J, Sacks JM. Case report. Spontaneous forearm compartment syndrome in a boy with hemophilia a: a therapeutic dilemma. Eplasty. 2013:13:e16.
6. Ilyas AM, Wisbeck JM, Shaffer GW, Thoder JJ. Upper extremity compartment syndrome secondary to acquired factor VIII inhibitor. A case report. J Bone Joint Surg Am. 2005;87:1606-1608. doi:10.2106/JBJS.C.01720
7. Adeclat GJ, Hayes M, Amick M, Kahan J, Halim A. Acute forearm compartment syndrome in the setting of acquired hemophilia A. Case Reports Plast Surg Hand Surg. 2022;9:140-144. doi:10.1080/23320885.2022.2071274
8. Abudaqqa RY, Arun KP, Mas AJA, Abushaaban FA. Acute atraumatic compartment syndrome of the thigh due to acquired coagulopathy disorder: a case report in known healthy patient. J Orthop Case Rep. 2021;11:59-62. doi:10.13107/jocr.2021.v11.i08.2366
9. Alidoost M, Conte GA, Chaudry R, Nahum K, Marchesani D. A unique presentation of spontaneous compartment syndrome due to acquired hemophilia A and associated malignancy: case report and literature review. World J Oncol. 2020;11:72-75. doi:10.14740/wjon1260
10. Jentzsch T, Brand-Staufer B, Schäfer FP, Wanner GA, Simmen H-P. Illustrated operative management of spontaneous bleeding and compartment syndrome of the lower extremity in a patient with acquired hemophilia A: a case report. J Med Case Rep. 2014;8:132. doi:10.1186/1752-1947-8-132
11. Pham TV, Sorenson CA, Nable JV. Acquired factor VIII deficiency presenting with compartment syndrome. Am J Emerg Med. 2014;32:195.e1-2. doi:10.1016/j.ajem.2013.09.022
12. Tiede A, Zieger B, Lisman T. Acquired bleeding disorders. Haemophilia. 2022;28(suppl 4):68-76. doi:10.1111/hae.14548
13. Kruse-Jarres R, Kempton CL, Baudo F, Collins PW, Knoebl P, Leissinger CA, et al. Acquired hemophilia A: updated review of evidence and treatment guidance. Am J Hematol. 2017;92:695-705. doi:10.1002/ajh.24777
14. Ilkhchoui Y, Koshkin E, Windsor JJ, Petersen TR, Charles M, Pack JD. Perioperative management of acquired hemophilia A: a case report and review of literature. Anesth Pain Med. 2013;4:e11906. doi:10.5812/aapm.11906
Prognostication in Hospice Care: Challenges, Opportunities, and the Importance of Functional Status
Predicting life expectancy and providing an end-of-life diagnosis in hospice and palliative care is a challenge for most clinicians. Lack of training, limited communication skills, and relationships with patients are all contributing factors. These skills can improve with the use of functional scoring tools in conjunction with the patient’s comorbidities and physical/psychological symptoms. The Palliative Performance Scale (PPS), Karnofsky Performance Scale (KPS), and Eastern Cooperative Oncology Group Performance Status Scale (ECOG) are commonly used functional scoring tools.
The PPS measures 5 functional dimensions including ambulation, activity level, ability to administer self-care, oral intake, and level of consciousness.1 It has been shown to be valid for a broad range of palliative care patients, including those with advanced cancer or life-threatening noncancer diagnoses in hospitals or hospice care.2 The scale, measured in 10% increments, runs from 100% (completely functional) to 0% (dead). A PPS ≤ 70% helps meet hospice eligibility criteria.
The KPS evaluates functional impairment and helps with prognostication. Developed in 1948, it evaluates a patient’s functional ability to tolerate chemotherapy, specifically in lung cancer, and has since been validated to predict mortality across older adults and in chronic disease populations.3,4 The KPS is also measured in 10% increments ranging from 100% (completely functional without assistance) to 0% (dead). A KPS ≤ 70% assists with hospice eligibility criteria (Table 1).5
Developed in 1974, the ECOG has been identified as one of the most important functional status tools in adult cancer care.6 It describes a cancer patient’s functional ability, evaluating their ability to care for oneself and participate in daily activities.7 The ECOG is a 6-point scale; patients can receive scores ranging from 0 (fully active) to 5 (dead). An ECOG score of 4 (sometimes 3) is generally supportive of meeting hospice eligibility (Table 2).6
CASE Presentation
An 80-year-old patient was admitted to the hospice service at the Veterans Affairs Puget Sound Health Care System (VAPSHCS) community living center (CLC) in Tacoma, Washington, from a community-based acute care hospital. His medical history included prostate cancer with metastasis to his pelvis and type 2 diabetes mellitus, which was stable with treatment with oral medication. Six weeks earlier the patient reported a severe frontal headache that was not responding to over-the-counter analgesics. After 2 days with these symptoms, including a ground-level fall without injuries, he presented to the VAPSHCS emergency department (ED) where a complete neurological examination, including magnetic resonance imaging, revealed a left frontoparietal brain lesion that was 4.2 cm × 3.4 cm × 4.2 cm.
The patient experienced a seizure during his ED evaluation and was admitted for treatment. He underwent a craniotomy where most, but not all the lesions were successfully removed. Postoperatively, the patient exhibited right-sided neglect, gait instability, emotional lability, and cognitive communication disorder. The patient completed 15 of 20 planned radiation treatments but declined further radiation or chemotherapy. The patient decided to halt radiation treatments after being informed by the oncology service that the treatments would likely only add 1 to 2 months to his overall survival, which was < 6 months. The patient elected to focus his goals of care on comfort, dignity, and respect at the end of life and accepted recommendations to be placed into end-of-life hospice care. He was then transferred to the VAPSHCS CLC in Tacoma, Washington, for hospice care.
Upon admission, the patient weighed 94 kg, his vital signs were within reference range, and he reported no pain or headaches. His initial laboratory results revealed a 13.2 g/dL hemoglobin, 3.6 g/dL serum albumin, and a 5.5% hemoglobin A1c, all of which fall into a normal reference range. He had a reported ECOG score of 3 and a KPS score of 50% by the transferring medical team. The patient’s medications included scheduled dexamethasone, metformin, senna, levetiracetam, and as-needed midazolam nasal spray for breakthrough seizures. He also had as-needed acetaminophen for pain. He was alert, oriented ×3, and fully ambulatory but continuously used a 4-wheeled walker for safety and gait instability.
After the patient’s first night, the hospice team met with him to discuss his understanding of his health issues. The patient appeared to have low health literacy but told the team, “I know I am dying.” He had completed written advance directives and a Portable Order for Life-Sustaining Treatment indicating that life-sustaining treatments, including cardiopulmonary resuscitation, supplemental mechanical feeding, or intubation, were not to be used to keep him alive.
At his first 90-day recertification, the patient had gained 8 kg and laboratory results revealed a 14.6 g/dL hemoglobin, 3.8 g/dL serum albumin, and a 6.1% hemoglobin A1c. His ECOG score remained at 3, but his KPS score had increased to 60%. The patient exhibited no new neurologic symptoms or seizures and reported no headaches but had 2 ground-level falls without injury. On both occasions the patient chose not to use his walker to go to the bathroom because it was “too far from my bed.” Per VA policy, after discussions with the hospice team, he was recertified for 90 more days of hospice care. At the end of 6 months in CLC, the patient’s weight remained stable, as did his complete blood count and comprehensive medical panel. He had 1 additional noninjurious ground-level fall and again reported no pain and no use of as-needed acetaminophen. His only medical complication was testing positive for COVID-19, but he remained asymptomatic. The patient was graduated from hospice care and referred to a nearby non-VA adult family home in the community after 180 days. At that time his ECOG score was 2 and his KPS score had increased to 70%.
DISCUSSION
Primary brain tumors account for about 2% of all malignant neoplasms in adults. About half of them represent gliomas. Glioblastoma multiforme derived from neuroepithelial cells is the most frequent and deadly primary malignant central nervous system tumor in adults.8 About 50% of patients with glioblastomas are aged ≥ 65 years at diagnosis.9 A retrospective study of Centers for Medicare and Medicaid Services claims data paired with the Surveillance, Epidemiology, and End Results database indicated a median survival of 4 months for patients with glioblastoma multiforme aged > 65 years, including all treatment modalities.10 Surgical resection combined with radiation and chemotherapy offers the best prognosis for the preservation of neurologic function.11 However, comorbidities, adverse drug effects, and the potential for postoperative complications pose significant risks, especially for older patients. Ultimately, goals of care conversations and advance directives play a very important role in evaluating benefits vs risks with this malignancy.
Our patient was aged 80 years and had previously been diagnosed with metastatic prostate malignancy. His goals of care focused on spending time with his friends, leaving his room to eat in the facility dining area, and continuing his daily walks. He remained clear that he did not want his care team to institute life-sustaining treatments to be kept alive and felt the information regarding the risks vs benefits of accepting chemotherapy was not aligned with his goals of care. Over the 6 months that he received hospice care, he gained weight, improved his hemoglobin and serum albumin levels, and ambulated with the use of a 4-wheeled walker. As the patient exhibited no functional decline or new comorbidities and his functional status improved, the clinical staff felt he no longer needed hospice services. The patient had an ECOG score of 2 and a KPS score of 70% at his hospice graduation.
Medical prognostication is one of the biggest challenges clinicians face. Clinicians are generally “over prognosticators,” and their thoughts tend to be based on the patient relationship, overall experiences in health care, and desire to treat and cure patients.12 In hospice we are asked to define the usual, normal, or expected course of a disease, but what does that mean? Although metastatic malignancies usually have a predictable course in comparison to diagnoses such as dementia, chronic obstructive pulmonary disease, or congestive heart failure, the challenges to improve prognostic ability andpredict disease course continue.13-15 Focusing on functional status, goals of care, and comorbidities are keys to helping with prognosis. Given the challenge, we find the PPS, KPS, and ECOG scales important tools.
When prognosticating, we attempt to define quantity and quality of life (which our patients must define independently or from the voice of their surrogate) and their ability to perform daily activities. Quality of life in patients with glioblastoma is progressively and significantly impacted due to the emergence of debilitating neurologic symptoms arising from infiltrative tumor growth into functionally intact brain tissue that restricts and disrupts normal day-to-day activities. However, functional status plays a significant role in helping the hospice team improve its overall prognosis.
Conclusions
This case study illustrates the difficulty that comes with prognostication(s) despite a patient's severely morbid disease, history of metastatic prostate cancer, and advanced age. Although a diagnosis may be concerning, documenting a patient’s status using functional scales prior to hospice admission and during the recertification process is helpful in prognostication. Doing so will allow health care professionals to have an accepted medical standard to use regardless how distinct the patient's diagnosis. The expression, “as the disease does not read the textbook,” may serve as a helpful reminder in talking with patients and their families. This is important as most patient’s clinical disease courses are different and having the opportunity to use performance status scales may help improve prognostic skills.
1. Cleary TA. The Palliative Performance Scale (PPSv2) Version 2. In: Downing GM, ed. Medical Care of the Dying. 4th ed. Victoria Hospice Society, Learning Centre for Palliative Care; 2006:120.
2. Palliative Performance Scale. ePrognosis, University of California San Francisco. Accessed June 14, 2024. https://eprognosis.ucsf.edu/pps.php
3. Karnofsky DA, Burchenal JH. The Clinical Evaluation of Chemotherapeutic Agents in Cancer. In: MacLeod CM, ed. Evaluation of Chemotherapeutic Agents. Columbia University Press; 1949:191-205.
4. Khalid MA, Achakzai IK, Ahmed Khan S, et al. The use of Karnofsky Performance Status (KPS) as a predictor of 3 month post discharge mortality in cirrhotic patients. Gastroenterol Hepatol Bed Bench. 2018;11(4):301-305.
5. Karnofsky Performance Scale. US Dept of Veterans Affairs. Accessed June 14, 2024. https://www.hiv.va.gov/provider/tools/karnofsky-performance-scale.asp
6. Mischel A-M, Rosielle DA. Eastern Cooperative Oncology Group Performance Status. Palliative Care Network of Wisconsin. December 10, 2021. Accessed June 14, 2024. https://www.mypcnow.org/fast-fact/eastern-cooperative-oncology-group-performance-status/
7. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-655.
8. Nizamutdinov D, Stock EM, Dandashi JA, et al. Prognostication of survival outcomes in patients diagnosed with glioblastoma. World Neurosurg. 2018;109:e67-e74. doi:10.1016/j.wneu.2017.09.104
9. Kita D Ciernik IFVaccarella S Age as a predictive factor in glioblastomas: population-based study. Neuroepidemiology. 2009;33(1):17-22. doi:10.1159/000210017
10. Jordan JT, Gerstner ER, Batchelor TT, Cahill DP, Plotkin SR. Glioblastoma care in the elderly. Cancer. 2016;122(2):189-197. doi:10.1002/cnr.29742
11. Brown, NF, Ottaviani D, Tazare J, et al. Survival outcomes and prognostic factors in glioblastoma. Cancers (Basel). 2022;14(13):3161. doi:10.3390/cancers14133161
12. Christalakis NA. Death Foretold: Prophecy and Prognosis in Medical Care. University of Chicago Press; 2000.
13. Weissman DE. Determining Prognosis in Advanced Cancer. Palliative Care Network of Wisconsin. January 28, 2019. Accessed June 14, 2014. https://www.mypcnow.org/fast-fact/determining-prognosis-in-advanced-cancer/
14. Childers JW, Arnold R, Curtis JR. Prognosis in End-Stage COPD. Palliative Care Network of Wisconsin. February 11, 2019. Accessed June 14, 2024. https://www.mypcnow.org/fast-fact/prognosis-in-end-stage-copd/
15. Reisfield GM, Wilson GR. Prognostication in Heart Failure. Palliative Care Network of Wisconsin. February 11, 2019. Accessed June 14, 2024. https://www.mypcnow.org/fast-fact/prognostication-in-heart-failure/
Predicting life expectancy and providing an end-of-life diagnosis in hospice and palliative care is a challenge for most clinicians. Lack of training, limited communication skills, and relationships with patients are all contributing factors. These skills can improve with the use of functional scoring tools in conjunction with the patient’s comorbidities and physical/psychological symptoms. The Palliative Performance Scale (PPS), Karnofsky Performance Scale (KPS), and Eastern Cooperative Oncology Group Performance Status Scale (ECOG) are commonly used functional scoring tools.
The PPS measures 5 functional dimensions including ambulation, activity level, ability to administer self-care, oral intake, and level of consciousness.1 It has been shown to be valid for a broad range of palliative care patients, including those with advanced cancer or life-threatening noncancer diagnoses in hospitals or hospice care.2 The scale, measured in 10% increments, runs from 100% (completely functional) to 0% (dead). A PPS ≤ 70% helps meet hospice eligibility criteria.
The KPS evaluates functional impairment and helps with prognostication. Developed in 1948, it evaluates a patient’s functional ability to tolerate chemotherapy, specifically in lung cancer, and has since been validated to predict mortality across older adults and in chronic disease populations.3,4 The KPS is also measured in 10% increments ranging from 100% (completely functional without assistance) to 0% (dead). A KPS ≤ 70% assists with hospice eligibility criteria (Table 1).5
Developed in 1974, the ECOG has been identified as one of the most important functional status tools in adult cancer care.6 It describes a cancer patient’s functional ability, evaluating their ability to care for oneself and participate in daily activities.7 The ECOG is a 6-point scale; patients can receive scores ranging from 0 (fully active) to 5 (dead). An ECOG score of 4 (sometimes 3) is generally supportive of meeting hospice eligibility (Table 2).6
CASE Presentation
An 80-year-old patient was admitted to the hospice service at the Veterans Affairs Puget Sound Health Care System (VAPSHCS) community living center (CLC) in Tacoma, Washington, from a community-based acute care hospital. His medical history included prostate cancer with metastasis to his pelvis and type 2 diabetes mellitus, which was stable with treatment with oral medication. Six weeks earlier the patient reported a severe frontal headache that was not responding to over-the-counter analgesics. After 2 days with these symptoms, including a ground-level fall without injuries, he presented to the VAPSHCS emergency department (ED) where a complete neurological examination, including magnetic resonance imaging, revealed a left frontoparietal brain lesion that was 4.2 cm × 3.4 cm × 4.2 cm.
The patient experienced a seizure during his ED evaluation and was admitted for treatment. He underwent a craniotomy where most, but not all the lesions were successfully removed. Postoperatively, the patient exhibited right-sided neglect, gait instability, emotional lability, and cognitive communication disorder. The patient completed 15 of 20 planned radiation treatments but declined further radiation or chemotherapy. The patient decided to halt radiation treatments after being informed by the oncology service that the treatments would likely only add 1 to 2 months to his overall survival, which was < 6 months. The patient elected to focus his goals of care on comfort, dignity, and respect at the end of life and accepted recommendations to be placed into end-of-life hospice care. He was then transferred to the VAPSHCS CLC in Tacoma, Washington, for hospice care.
Upon admission, the patient weighed 94 kg, his vital signs were within reference range, and he reported no pain or headaches. His initial laboratory results revealed a 13.2 g/dL hemoglobin, 3.6 g/dL serum albumin, and a 5.5% hemoglobin A1c, all of which fall into a normal reference range. He had a reported ECOG score of 3 and a KPS score of 50% by the transferring medical team. The patient’s medications included scheduled dexamethasone, metformin, senna, levetiracetam, and as-needed midazolam nasal spray for breakthrough seizures. He also had as-needed acetaminophen for pain. He was alert, oriented ×3, and fully ambulatory but continuously used a 4-wheeled walker for safety and gait instability.
After the patient’s first night, the hospice team met with him to discuss his understanding of his health issues. The patient appeared to have low health literacy but told the team, “I know I am dying.” He had completed written advance directives and a Portable Order for Life-Sustaining Treatment indicating that life-sustaining treatments, including cardiopulmonary resuscitation, supplemental mechanical feeding, or intubation, were not to be used to keep him alive.
At his first 90-day recertification, the patient had gained 8 kg and laboratory results revealed a 14.6 g/dL hemoglobin, 3.8 g/dL serum albumin, and a 6.1% hemoglobin A1c. His ECOG score remained at 3, but his KPS score had increased to 60%. The patient exhibited no new neurologic symptoms or seizures and reported no headaches but had 2 ground-level falls without injury. On both occasions the patient chose not to use his walker to go to the bathroom because it was “too far from my bed.” Per VA policy, after discussions with the hospice team, he was recertified for 90 more days of hospice care. At the end of 6 months in CLC, the patient’s weight remained stable, as did his complete blood count and comprehensive medical panel. He had 1 additional noninjurious ground-level fall and again reported no pain and no use of as-needed acetaminophen. His only medical complication was testing positive for COVID-19, but he remained asymptomatic. The patient was graduated from hospice care and referred to a nearby non-VA adult family home in the community after 180 days. At that time his ECOG score was 2 and his KPS score had increased to 70%.
DISCUSSION
Primary brain tumors account for about 2% of all malignant neoplasms in adults. About half of them represent gliomas. Glioblastoma multiforme derived from neuroepithelial cells is the most frequent and deadly primary malignant central nervous system tumor in adults.8 About 50% of patients with glioblastomas are aged ≥ 65 years at diagnosis.9 A retrospective study of Centers for Medicare and Medicaid Services claims data paired with the Surveillance, Epidemiology, and End Results database indicated a median survival of 4 months for patients with glioblastoma multiforme aged > 65 years, including all treatment modalities.10 Surgical resection combined with radiation and chemotherapy offers the best prognosis for the preservation of neurologic function.11 However, comorbidities, adverse drug effects, and the potential for postoperative complications pose significant risks, especially for older patients. Ultimately, goals of care conversations and advance directives play a very important role in evaluating benefits vs risks with this malignancy.
Our patient was aged 80 years and had previously been diagnosed with metastatic prostate malignancy. His goals of care focused on spending time with his friends, leaving his room to eat in the facility dining area, and continuing his daily walks. He remained clear that he did not want his care team to institute life-sustaining treatments to be kept alive and felt the information regarding the risks vs benefits of accepting chemotherapy was not aligned with his goals of care. Over the 6 months that he received hospice care, he gained weight, improved his hemoglobin and serum albumin levels, and ambulated with the use of a 4-wheeled walker. As the patient exhibited no functional decline or new comorbidities and his functional status improved, the clinical staff felt he no longer needed hospice services. The patient had an ECOG score of 2 and a KPS score of 70% at his hospice graduation.
Medical prognostication is one of the biggest challenges clinicians face. Clinicians are generally “over prognosticators,” and their thoughts tend to be based on the patient relationship, overall experiences in health care, and desire to treat and cure patients.12 In hospice we are asked to define the usual, normal, or expected course of a disease, but what does that mean? Although metastatic malignancies usually have a predictable course in comparison to diagnoses such as dementia, chronic obstructive pulmonary disease, or congestive heart failure, the challenges to improve prognostic ability andpredict disease course continue.13-15 Focusing on functional status, goals of care, and comorbidities are keys to helping with prognosis. Given the challenge, we find the PPS, KPS, and ECOG scales important tools.
When prognosticating, we attempt to define quantity and quality of life (which our patients must define independently or from the voice of their surrogate) and their ability to perform daily activities. Quality of life in patients with glioblastoma is progressively and significantly impacted due to the emergence of debilitating neurologic symptoms arising from infiltrative tumor growth into functionally intact brain tissue that restricts and disrupts normal day-to-day activities. However, functional status plays a significant role in helping the hospice team improve its overall prognosis.
Conclusions
This case study illustrates the difficulty that comes with prognostication(s) despite a patient's severely morbid disease, history of metastatic prostate cancer, and advanced age. Although a diagnosis may be concerning, documenting a patient’s status using functional scales prior to hospice admission and during the recertification process is helpful in prognostication. Doing so will allow health care professionals to have an accepted medical standard to use regardless how distinct the patient's diagnosis. The expression, “as the disease does not read the textbook,” may serve as a helpful reminder in talking with patients and their families. This is important as most patient’s clinical disease courses are different and having the opportunity to use performance status scales may help improve prognostic skills.
Predicting life expectancy and providing an end-of-life diagnosis in hospice and palliative care is a challenge for most clinicians. Lack of training, limited communication skills, and relationships with patients are all contributing factors. These skills can improve with the use of functional scoring tools in conjunction with the patient’s comorbidities and physical/psychological symptoms. The Palliative Performance Scale (PPS), Karnofsky Performance Scale (KPS), and Eastern Cooperative Oncology Group Performance Status Scale (ECOG) are commonly used functional scoring tools.
The PPS measures 5 functional dimensions including ambulation, activity level, ability to administer self-care, oral intake, and level of consciousness.1 It has been shown to be valid for a broad range of palliative care patients, including those with advanced cancer or life-threatening noncancer diagnoses in hospitals or hospice care.2 The scale, measured in 10% increments, runs from 100% (completely functional) to 0% (dead). A PPS ≤ 70% helps meet hospice eligibility criteria.
The KPS evaluates functional impairment and helps with prognostication. Developed in 1948, it evaluates a patient’s functional ability to tolerate chemotherapy, specifically in lung cancer, and has since been validated to predict mortality across older adults and in chronic disease populations.3,4 The KPS is also measured in 10% increments ranging from 100% (completely functional without assistance) to 0% (dead). A KPS ≤ 70% assists with hospice eligibility criteria (Table 1).5
Developed in 1974, the ECOG has been identified as one of the most important functional status tools in adult cancer care.6 It describes a cancer patient’s functional ability, evaluating their ability to care for oneself and participate in daily activities.7 The ECOG is a 6-point scale; patients can receive scores ranging from 0 (fully active) to 5 (dead). An ECOG score of 4 (sometimes 3) is generally supportive of meeting hospice eligibility (Table 2).6
CASE Presentation
An 80-year-old patient was admitted to the hospice service at the Veterans Affairs Puget Sound Health Care System (VAPSHCS) community living center (CLC) in Tacoma, Washington, from a community-based acute care hospital. His medical history included prostate cancer with metastasis to his pelvis and type 2 diabetes mellitus, which was stable with treatment with oral medication. Six weeks earlier the patient reported a severe frontal headache that was not responding to over-the-counter analgesics. After 2 days with these symptoms, including a ground-level fall without injuries, he presented to the VAPSHCS emergency department (ED) where a complete neurological examination, including magnetic resonance imaging, revealed a left frontoparietal brain lesion that was 4.2 cm × 3.4 cm × 4.2 cm.
The patient experienced a seizure during his ED evaluation and was admitted for treatment. He underwent a craniotomy where most, but not all the lesions were successfully removed. Postoperatively, the patient exhibited right-sided neglect, gait instability, emotional lability, and cognitive communication disorder. The patient completed 15 of 20 planned radiation treatments but declined further radiation or chemotherapy. The patient decided to halt radiation treatments after being informed by the oncology service that the treatments would likely only add 1 to 2 months to his overall survival, which was < 6 months. The patient elected to focus his goals of care on comfort, dignity, and respect at the end of life and accepted recommendations to be placed into end-of-life hospice care. He was then transferred to the VAPSHCS CLC in Tacoma, Washington, for hospice care.
Upon admission, the patient weighed 94 kg, his vital signs were within reference range, and he reported no pain or headaches. His initial laboratory results revealed a 13.2 g/dL hemoglobin, 3.6 g/dL serum albumin, and a 5.5% hemoglobin A1c, all of which fall into a normal reference range. He had a reported ECOG score of 3 and a KPS score of 50% by the transferring medical team. The patient’s medications included scheduled dexamethasone, metformin, senna, levetiracetam, and as-needed midazolam nasal spray for breakthrough seizures. He also had as-needed acetaminophen for pain. He was alert, oriented ×3, and fully ambulatory but continuously used a 4-wheeled walker for safety and gait instability.
After the patient’s first night, the hospice team met with him to discuss his understanding of his health issues. The patient appeared to have low health literacy but told the team, “I know I am dying.” He had completed written advance directives and a Portable Order for Life-Sustaining Treatment indicating that life-sustaining treatments, including cardiopulmonary resuscitation, supplemental mechanical feeding, or intubation, were not to be used to keep him alive.
At his first 90-day recertification, the patient had gained 8 kg and laboratory results revealed a 14.6 g/dL hemoglobin, 3.8 g/dL serum albumin, and a 6.1% hemoglobin A1c. His ECOG score remained at 3, but his KPS score had increased to 60%. The patient exhibited no new neurologic symptoms or seizures and reported no headaches but had 2 ground-level falls without injury. On both occasions the patient chose not to use his walker to go to the bathroom because it was “too far from my bed.” Per VA policy, after discussions with the hospice team, he was recertified for 90 more days of hospice care. At the end of 6 months in CLC, the patient’s weight remained stable, as did his complete blood count and comprehensive medical panel. He had 1 additional noninjurious ground-level fall and again reported no pain and no use of as-needed acetaminophen. His only medical complication was testing positive for COVID-19, but he remained asymptomatic. The patient was graduated from hospice care and referred to a nearby non-VA adult family home in the community after 180 days. At that time his ECOG score was 2 and his KPS score had increased to 70%.
DISCUSSION
Primary brain tumors account for about 2% of all malignant neoplasms in adults. About half of them represent gliomas. Glioblastoma multiforme derived from neuroepithelial cells is the most frequent and deadly primary malignant central nervous system tumor in adults.8 About 50% of patients with glioblastomas are aged ≥ 65 years at diagnosis.9 A retrospective study of Centers for Medicare and Medicaid Services claims data paired with the Surveillance, Epidemiology, and End Results database indicated a median survival of 4 months for patients with glioblastoma multiforme aged > 65 years, including all treatment modalities.10 Surgical resection combined with radiation and chemotherapy offers the best prognosis for the preservation of neurologic function.11 However, comorbidities, adverse drug effects, and the potential for postoperative complications pose significant risks, especially for older patients. Ultimately, goals of care conversations and advance directives play a very important role in evaluating benefits vs risks with this malignancy.
Our patient was aged 80 years and had previously been diagnosed with metastatic prostate malignancy. His goals of care focused on spending time with his friends, leaving his room to eat in the facility dining area, and continuing his daily walks. He remained clear that he did not want his care team to institute life-sustaining treatments to be kept alive and felt the information regarding the risks vs benefits of accepting chemotherapy was not aligned with his goals of care. Over the 6 months that he received hospice care, he gained weight, improved his hemoglobin and serum albumin levels, and ambulated with the use of a 4-wheeled walker. As the patient exhibited no functional decline or new comorbidities and his functional status improved, the clinical staff felt he no longer needed hospice services. The patient had an ECOG score of 2 and a KPS score of 70% at his hospice graduation.
Medical prognostication is one of the biggest challenges clinicians face. Clinicians are generally “over prognosticators,” and their thoughts tend to be based on the patient relationship, overall experiences in health care, and desire to treat and cure patients.12 In hospice we are asked to define the usual, normal, or expected course of a disease, but what does that mean? Although metastatic malignancies usually have a predictable course in comparison to diagnoses such as dementia, chronic obstructive pulmonary disease, or congestive heart failure, the challenges to improve prognostic ability andpredict disease course continue.13-15 Focusing on functional status, goals of care, and comorbidities are keys to helping with prognosis. Given the challenge, we find the PPS, KPS, and ECOG scales important tools.
When prognosticating, we attempt to define quantity and quality of life (which our patients must define independently or from the voice of their surrogate) and their ability to perform daily activities. Quality of life in patients with glioblastoma is progressively and significantly impacted due to the emergence of debilitating neurologic symptoms arising from infiltrative tumor growth into functionally intact brain tissue that restricts and disrupts normal day-to-day activities. However, functional status plays a significant role in helping the hospice team improve its overall prognosis.
Conclusions
This case study illustrates the difficulty that comes with prognostication(s) despite a patient's severely morbid disease, history of metastatic prostate cancer, and advanced age. Although a diagnosis may be concerning, documenting a patient’s status using functional scales prior to hospice admission and during the recertification process is helpful in prognostication. Doing so will allow health care professionals to have an accepted medical standard to use regardless how distinct the patient's diagnosis. The expression, “as the disease does not read the textbook,” may serve as a helpful reminder in talking with patients and their families. This is important as most patient’s clinical disease courses are different and having the opportunity to use performance status scales may help improve prognostic skills.
1. Cleary TA. The Palliative Performance Scale (PPSv2) Version 2. In: Downing GM, ed. Medical Care of the Dying. 4th ed. Victoria Hospice Society, Learning Centre for Palliative Care; 2006:120.
2. Palliative Performance Scale. ePrognosis, University of California San Francisco. Accessed June 14, 2024. https://eprognosis.ucsf.edu/pps.php
3. Karnofsky DA, Burchenal JH. The Clinical Evaluation of Chemotherapeutic Agents in Cancer. In: MacLeod CM, ed. Evaluation of Chemotherapeutic Agents. Columbia University Press; 1949:191-205.
4. Khalid MA, Achakzai IK, Ahmed Khan S, et al. The use of Karnofsky Performance Status (KPS) as a predictor of 3 month post discharge mortality in cirrhotic patients. Gastroenterol Hepatol Bed Bench. 2018;11(4):301-305.
5. Karnofsky Performance Scale. US Dept of Veterans Affairs. Accessed June 14, 2024. https://www.hiv.va.gov/provider/tools/karnofsky-performance-scale.asp
6. Mischel A-M, Rosielle DA. Eastern Cooperative Oncology Group Performance Status. Palliative Care Network of Wisconsin. December 10, 2021. Accessed June 14, 2024. https://www.mypcnow.org/fast-fact/eastern-cooperative-oncology-group-performance-status/
7. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-655.
8. Nizamutdinov D, Stock EM, Dandashi JA, et al. Prognostication of survival outcomes in patients diagnosed with glioblastoma. World Neurosurg. 2018;109:e67-e74. doi:10.1016/j.wneu.2017.09.104
9. Kita D Ciernik IFVaccarella S Age as a predictive factor in glioblastomas: population-based study. Neuroepidemiology. 2009;33(1):17-22. doi:10.1159/000210017
10. Jordan JT, Gerstner ER, Batchelor TT, Cahill DP, Plotkin SR. Glioblastoma care in the elderly. Cancer. 2016;122(2):189-197. doi:10.1002/cnr.29742
11. Brown, NF, Ottaviani D, Tazare J, et al. Survival outcomes and prognostic factors in glioblastoma. Cancers (Basel). 2022;14(13):3161. doi:10.3390/cancers14133161
12. Christalakis NA. Death Foretold: Prophecy and Prognosis in Medical Care. University of Chicago Press; 2000.
13. Weissman DE. Determining Prognosis in Advanced Cancer. Palliative Care Network of Wisconsin. January 28, 2019. Accessed June 14, 2014. https://www.mypcnow.org/fast-fact/determining-prognosis-in-advanced-cancer/
14. Childers JW, Arnold R, Curtis JR. Prognosis in End-Stage COPD. Palliative Care Network of Wisconsin. February 11, 2019. Accessed June 14, 2024. https://www.mypcnow.org/fast-fact/prognosis-in-end-stage-copd/
15. Reisfield GM, Wilson GR. Prognostication in Heart Failure. Palliative Care Network of Wisconsin. February 11, 2019. Accessed June 14, 2024. https://www.mypcnow.org/fast-fact/prognostication-in-heart-failure/
1. Cleary TA. The Palliative Performance Scale (PPSv2) Version 2. In: Downing GM, ed. Medical Care of the Dying. 4th ed. Victoria Hospice Society, Learning Centre for Palliative Care; 2006:120.
2. Palliative Performance Scale. ePrognosis, University of California San Francisco. Accessed June 14, 2024. https://eprognosis.ucsf.edu/pps.php
3. Karnofsky DA, Burchenal JH. The Clinical Evaluation of Chemotherapeutic Agents in Cancer. In: MacLeod CM, ed. Evaluation of Chemotherapeutic Agents. Columbia University Press; 1949:191-205.
4. Khalid MA, Achakzai IK, Ahmed Khan S, et al. The use of Karnofsky Performance Status (KPS) as a predictor of 3 month post discharge mortality in cirrhotic patients. Gastroenterol Hepatol Bed Bench. 2018;11(4):301-305.
5. Karnofsky Performance Scale. US Dept of Veterans Affairs. Accessed June 14, 2024. https://www.hiv.va.gov/provider/tools/karnofsky-performance-scale.asp
6. Mischel A-M, Rosielle DA. Eastern Cooperative Oncology Group Performance Status. Palliative Care Network of Wisconsin. December 10, 2021. Accessed June 14, 2024. https://www.mypcnow.org/fast-fact/eastern-cooperative-oncology-group-performance-status/
7. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-655.
8. Nizamutdinov D, Stock EM, Dandashi JA, et al. Prognostication of survival outcomes in patients diagnosed with glioblastoma. World Neurosurg. 2018;109:e67-e74. doi:10.1016/j.wneu.2017.09.104
9. Kita D Ciernik IFVaccarella S Age as a predictive factor in glioblastomas: population-based study. Neuroepidemiology. 2009;33(1):17-22. doi:10.1159/000210017
10. Jordan JT, Gerstner ER, Batchelor TT, Cahill DP, Plotkin SR. Glioblastoma care in the elderly. Cancer. 2016;122(2):189-197. doi:10.1002/cnr.29742
11. Brown, NF, Ottaviani D, Tazare J, et al. Survival outcomes and prognostic factors in glioblastoma. Cancers (Basel). 2022;14(13):3161. doi:10.3390/cancers14133161
12. Christalakis NA. Death Foretold: Prophecy and Prognosis in Medical Care. University of Chicago Press; 2000.
13. Weissman DE. Determining Prognosis in Advanced Cancer. Palliative Care Network of Wisconsin. January 28, 2019. Accessed June 14, 2014. https://www.mypcnow.org/fast-fact/determining-prognosis-in-advanced-cancer/
14. Childers JW, Arnold R, Curtis JR. Prognosis in End-Stage COPD. Palliative Care Network of Wisconsin. February 11, 2019. Accessed June 14, 2024. https://www.mypcnow.org/fast-fact/prognosis-in-end-stage-copd/
15. Reisfield GM, Wilson GR. Prognostication in Heart Failure. Palliative Care Network of Wisconsin. February 11, 2019. Accessed June 14, 2024. https://www.mypcnow.org/fast-fact/prognostication-in-heart-failure/
Impact of VA Hematology/Oncology Clinical Pharmacy Practitioners in the Review of Community Prescriptions for Specialty Medications
The value of a hematology/oncology clinical pharmacy practitioner (CPP) has been validated in several studies documenting their positive impact on patient outcomes, supportive care management, laboratory monitoring, medication error identification, and drug expenditure.1-6 With> 200 oncology-related US Food and Drug Administration approval notifications published from 2020 to 2023, it is no surprise that national trends in oncology drug clinic expenditures increased from $39.9 billion in 2020 to $44.1 billion in 2021.7,8 With the rapidly changing treatment landscape, new drug approvals, and risk of polypharmacy, oral anticancer agents carry a high risk for medication errors.4 Additional challenges include complex dosing regimens and instructions, adherence issues, drug interactions, adjustments for organ dysfunction, and extensive adverse effect (AE) profiles.
Because of the niche and complexity of oral anticancer agents, trained CPPs havehematology/oncology education and expertise that pharmacists without specialized training lack. A survey of 243 nonspecialized community pharmacists that assessed their knowledge of oral anticancer therapies revealed that only about half of the knowledge questions were answered correctly, illustrating an education gap among these pharmacists.9 The Hematology/Oncology Pharmacist Association's suggests that best practices for managing oral oncology therapy should include comprehensive medication review by an oncology-trained pharmacist for each prescription.10
The US Department of Veterans Affairs (VA) community care network, which was established by the MISSION Act, allows covered access for eligible veterans in the local community outside of the VA network. Unfortunately, this dual-system use of health care could increase the risk of poorly coordinated care and has been associated with the risk of inappropriate prescribing.11,12 It is unclear how many private practices enrolled in the community care program have access to oncology-trained pharmacists. Specialized pharmaceutical reviews of oral anticancer medication prescriptions from these practices are vital for veteran care. This study evaluates the clinical and financial interventions of hematology/oncology CPPs review of specialty hematology/oncology prescriptions from community care health care practitioners (HCPs) at the Veterans Affairs North Texas Health Care System (VANTHCS) in Dallas.
METHODS
This study is a retrospective review of Computerized Patient Record System (CPRS) records of patients at VANTHCS from January 1, 2015, to June 30, 2023. Patients included were aged ≥ 18 years, enrolled in the VA community care program, received a specialty hematology/oncology medication that was dispensed through VA pharmacies or VA-contracted pharmacies, and had an hematology/oncology CPP medication review documented in CPRS. The primary aim of this study was to assess the number and types of clinical interventions performed. A clinical intervention was defined as a documented communication attempt with a community care HCP or direct communication with a patient to address a specific medication-related issue noted during CPP review.
Review of specialty hematology/oncology medications by a hematology/oncology CPP included evaluation of therapy indication, such as whether the prescription meets clinical guidelines, VA criteria for use, or other clinical literature as judged appropriate by the CPP. In some cases, the CPP requested that the community care HCP prescribe a more cost-effective or formulary-preferred agent. Each prescription was reviewed for dosage and formulation appropriateness, drug interactions with available medication lists, baseline laboratory test completion, and recommended supportive care medicines. At times, patient counseling is completed as part of the clinical review. When necessary, CPPs could discuss patient cases with a VA-employed oncologist for further oversight regarding appropriateness and safety. Secondary outcomes included the number of interventions accepted or denied by the prescriber provider and cost savings.
Data collected included the type of malignancy, hematology/oncology specialty medication requested, number and type of interventions sent to the community care prescriber, number of interventions accepted or denied by the community care prescriber, and whether the CPP conducted patient counseling or dispensed or denied the product. Cost savings were calculated for medications that were denied or changed to a formulary preferred or cost-effective agent using pricing data from the National Acquisition Center Contract Catalog or Federal Supply Schedule Service as of April 2024.
RESULTS
A total of 221 hematology/oncology prescriptions met inclusion criteria. Among patients receiving these prescriptions, the median age was 70 years and 91% were male. The most common malignancies included 31 instances of multiple myeloma (14%), 26 for chronic lymphocytic leukemia (12%), 24 for prostate cancer (11%), 23 for glioblastoma/brain cancer (10%), 18 for renal cell carcinoma (8%), 17 for colorectal cancer (8%), and 15 for acute myeloid leukemia (7%). Clinical interventions by the hematology/oncology CPP were completed for 82 (37%) of the 221 prescriptions. One clinical intervention was communicated directly to the patient, and attempts were made to communicate with the community care HCP for the remaining 81 prescriptions. The CPP documented 97 clinical interventions for the 82 prescriptions (Table 1). The most commonly documented clinical interventions included: 25 for managing/preventing a drug interaction (26%), 24 for dose adjustment request (25%), 13 for prescription denial (13%), and 11 for requesting the use of a preferred or more cost-effective product (11%). Of note, 16 patients (7%) received counseling from the hematology/oncology CPP. Ten patients (5%) received counseling alone with no other intervention and did not meet the definition of a clinical intervention.
The most frequent prescriptions requiring intervention included 8 for enzalutamide, 7 for venetoclax, 6 for ibrutinib, and 5 each for lenalidomide, cabozantinib, and temozolomide. Among the 97 interventions, 68 were approved (70%), 15 received no response (16%), and 14 were denied by the community care HCP (14%). Despite obtaining no response or intervention denial from the community care HCP, hematology/oncology CPPs could approve these prescriptions if clinically appropriate, and their reasoning was documented. Table 2 further describes the types of interventions that were denied or obtained no response by the community care practitioner. Among the prescriptions denied by the hematology/oncology CPP, 11 were rejected for off-label indications and/or did not have support through primary literature, national guidelines, or VA criteria for use. Only 2 prescriptions were denied for safety concerns.
These documented clinical interventions had financial implications. For drugs with available cost data, requesting the use of a preferred/cost-effective product led to estimated savings of at least $263,536 over the study period with some ongoing cost savings. Prescription denials led to further estimated savings of $186,275 per month, although this is limited by the lack of known costs of alternative therapies the community care physicians chose.
DISCUSSION
More than one-third of prescriptions required clinical interventions, and 70% of these interventions were accepted by the community care prescriber, demonstrating the CPP’s essential role. Results indicate that most CPP clinical interventions involved clarifying and correcting doses, managing pertinent drug interactions, and ensuring appropriate use of medications according to clinical and national VA guidelines. Other studies have examined the impact of CPPs on patient care and cancer treatment.5,6 The randomized, multicenter AMBORA trial found that clinical pharmacist support reduced severe AEs and medication errors related to oral anticancer agents.5 The per-patient mean number of medication errors found by pharmacist review was 1.7 (range, 0 to 9), with most medication errors noted at the prescribing stage.5 Suzuki and colleagues analyzed data from 35,062 chemotherapy regimens and found that 53.1% of the chemotherapy prescriptions were modified because of pharmacist interventions.6 The most common reason for prescription modifications was prescription error.
Most of the clinical interventions in this study were accepted by community HCPs, indicating that these prescribers are receptive to hematology/oncology CPP input. Among those with no response, most were in relation to recommendations regarding drug interactions. In most of these cases, the drug interaction was not clinically concerning enough to require a response before the CPP approved the prescription. Therefore, it is unknown whether the outside HCP implemented the clinical recommendations. The most common types of clinical interventions the community care HCP declined were dose adjustment requests or requests to switch to a more cost-effective/formulary-preferred agent. In these cases, the prescriber’s preference was documented and, if clinically appropriate, approved by the CPP.
Although the financial implications of CPP clinical interventions were only marginally evaluated in this review, results suggest that cost savings by requests to switch to a cost-effective/formulary preferred agent or prescription denials are substantial. Because of changes in prescription costs over time, it is possible that savings from CPP intervention were greater than calculations using current Federal Supply Schedule Service pricing. The total impact of CPP prescription interventions on reducing or preventing hospitalizations or AEs is not known from this review, but other data suggest that cost savings may benefit the system.13,14
Limitations
This study's retrospective design is a limitation because practice patterns at the VANTHCS involving multiple hematology/oncology CPPs review of community care prescriptions might have evolved over time. The total financial implications of CPP interventions cannot fully be elucidated. The cost of alternative therapies used for patients who received a prescription denial is not factored into this review.
Conclusions
VANTHCS CPPs played an essential role in reviewing anticancer medication prescriptions from community care prescribers. In this study, CPP clinical interventions were completed for more than one-third of the prescriptions and the community-based HCP approved most of these interventions. These changes also resulted in financial benefits.
These findings add to the body of literature emphasizing the need for hematology/oncology-trained CPPs to review anticancer prescriptions and treatment plans. Our review could be used to justify CPP involvement in community care specialty medication review at VA facilities that do not currently have CPP involvement.
1. Shah NN, Casella E, Capozzi D, et al. Improving the safety of oral chemotherapy at an academic medical center. J Oncol Pract. 2016;12(1):e71-e76. doi:10.1200/JOP.2015.007260
2. Gatwood J, Gatwood K, Gabre E, Alexander M. Impact of clinical pharmacists in outpatient oncology practices: a review. Am J Health Syst Pharm. 2017;74(19):1549-1557. doi:10.2146/ajhp160475
3. Lankford C, Dura J, Tran A, et al. Effect of clinical pharmacist interventions on cost in an integrated health system specialty pharmacy. J Manag Care Spec Pharm. 2021;27(3):379-384. doi:10.18553/jmcp.2021.27.3.379
4. Schlichtig K, Dürr P, Dörje F, Fromm MF. Medication errors during treatment with new oral anticancer agents: consequences for clinical practice based on the AMBORA Study. Clin Pharmacol Ther. 2021;110(4):1075-1086. doi:10.1002/cpt.2338
5. Dürr P, Schlichtig K, Kelz C, et al. The randomized AMBORA Trial: impact of pharmacological/pharmaceutical care on medication safety and patient-reported outcomes during treatment with new oral anticancer agents. J Clin Oncol. 2021;39(18):1983-1994. doi:10.1200/JCO.20.03088
6. Suzuki S, Chan A, Nomura H, Johnson PE, Endo K, Saito S. Chemotherapy regimen checks performed by pharmacists contribute to safe administration of chemotherapy. J Oncol Pharm Pract. 2017;23(1):18-25. doi:10.1177/1078155215614998
7. Tichy EM, Hoffman JM, Suda KJ, et al. National trends in prescription drug expenditures and projections for 2022. Am J Health Syst Pharm. 2022;79(14):1158-1172. doi:10.1093/ajhp/zxac102
8. US Food and Drug Administration. Oncology (cancer)/hematologic malignancies approval notifications. 2023.
9. O’Bryant CL, Crandell BC. Community pharmacists’ knowledge of and attitudes toward oral chemotherapy. J Am Pharm Assoc (2003). 2008;48(5):632-639. doi:10.1331/JAPhA.2008.07082
10. Mackler E, Segal EM, Muluneh B, Jeffers K, Carmichael J. 2018 hematology/oncology pharmacist association best practices for the management of oral oncolytic therapy: pharmacy practice standard. J Oncol Pract. 2019;15(4):e346-e355. doi:10.1200/JOP.18.00581
11. Thorpe JM, Thorpe CT, Schleiden L, et al. Association between dual use of Department of Veterans Affairs and Medicare part D drug benefits and potentially unsafe prescribing. JAMA Intern Med. 2019;179(11):1584-1586. doi:10.1001/jamainternmed.2019.2788
12. Thorpe JM, Thorpe CT, Gellad WF, et al. Dual health care system use and high-risk prescribing in patients with dementia: a national cohort study. Ann Intern Med. 2017;166(3):157-163. doi:10.7326/M16-0551
13. Chen P-Z, Wu C-C, Huang C-F. Clinical and economic impact of clinical pharmacist intervention in a hematology unit. J Oncol Pharm Pract. 2020;26(4):866-872. doi:10.1177/1078155219875806
14. Dalton K, Byrne S. Role of the pharmacist in reducing healthcare costs: current insights. Integr Pharm Res Pract. 2017;6:37-46. doi:10.2147/IPRP.S108047
The value of a hematology/oncology clinical pharmacy practitioner (CPP) has been validated in several studies documenting their positive impact on patient outcomes, supportive care management, laboratory monitoring, medication error identification, and drug expenditure.1-6 With> 200 oncology-related US Food and Drug Administration approval notifications published from 2020 to 2023, it is no surprise that national trends in oncology drug clinic expenditures increased from $39.9 billion in 2020 to $44.1 billion in 2021.7,8 With the rapidly changing treatment landscape, new drug approvals, and risk of polypharmacy, oral anticancer agents carry a high risk for medication errors.4 Additional challenges include complex dosing regimens and instructions, adherence issues, drug interactions, adjustments for organ dysfunction, and extensive adverse effect (AE) profiles.
Because of the niche and complexity of oral anticancer agents, trained CPPs havehematology/oncology education and expertise that pharmacists without specialized training lack. A survey of 243 nonspecialized community pharmacists that assessed their knowledge of oral anticancer therapies revealed that only about half of the knowledge questions were answered correctly, illustrating an education gap among these pharmacists.9 The Hematology/Oncology Pharmacist Association's suggests that best practices for managing oral oncology therapy should include comprehensive medication review by an oncology-trained pharmacist for each prescription.10
The US Department of Veterans Affairs (VA) community care network, which was established by the MISSION Act, allows covered access for eligible veterans in the local community outside of the VA network. Unfortunately, this dual-system use of health care could increase the risk of poorly coordinated care and has been associated with the risk of inappropriate prescribing.11,12 It is unclear how many private practices enrolled in the community care program have access to oncology-trained pharmacists. Specialized pharmaceutical reviews of oral anticancer medication prescriptions from these practices are vital for veteran care. This study evaluates the clinical and financial interventions of hematology/oncology CPPs review of specialty hematology/oncology prescriptions from community care health care practitioners (HCPs) at the Veterans Affairs North Texas Health Care System (VANTHCS) in Dallas.
METHODS
This study is a retrospective review of Computerized Patient Record System (CPRS) records of patients at VANTHCS from January 1, 2015, to June 30, 2023. Patients included were aged ≥ 18 years, enrolled in the VA community care program, received a specialty hematology/oncology medication that was dispensed through VA pharmacies or VA-contracted pharmacies, and had an hematology/oncology CPP medication review documented in CPRS. The primary aim of this study was to assess the number and types of clinical interventions performed. A clinical intervention was defined as a documented communication attempt with a community care HCP or direct communication with a patient to address a specific medication-related issue noted during CPP review.
Review of specialty hematology/oncology medications by a hematology/oncology CPP included evaluation of therapy indication, such as whether the prescription meets clinical guidelines, VA criteria for use, or other clinical literature as judged appropriate by the CPP. In some cases, the CPP requested that the community care HCP prescribe a more cost-effective or formulary-preferred agent. Each prescription was reviewed for dosage and formulation appropriateness, drug interactions with available medication lists, baseline laboratory test completion, and recommended supportive care medicines. At times, patient counseling is completed as part of the clinical review. When necessary, CPPs could discuss patient cases with a VA-employed oncologist for further oversight regarding appropriateness and safety. Secondary outcomes included the number of interventions accepted or denied by the prescriber provider and cost savings.
Data collected included the type of malignancy, hematology/oncology specialty medication requested, number and type of interventions sent to the community care prescriber, number of interventions accepted or denied by the community care prescriber, and whether the CPP conducted patient counseling or dispensed or denied the product. Cost savings were calculated for medications that were denied or changed to a formulary preferred or cost-effective agent using pricing data from the National Acquisition Center Contract Catalog or Federal Supply Schedule Service as of April 2024.
RESULTS
A total of 221 hematology/oncology prescriptions met inclusion criteria. Among patients receiving these prescriptions, the median age was 70 years and 91% were male. The most common malignancies included 31 instances of multiple myeloma (14%), 26 for chronic lymphocytic leukemia (12%), 24 for prostate cancer (11%), 23 for glioblastoma/brain cancer (10%), 18 for renal cell carcinoma (8%), 17 for colorectal cancer (8%), and 15 for acute myeloid leukemia (7%). Clinical interventions by the hematology/oncology CPP were completed for 82 (37%) of the 221 prescriptions. One clinical intervention was communicated directly to the patient, and attempts were made to communicate with the community care HCP for the remaining 81 prescriptions. The CPP documented 97 clinical interventions for the 82 prescriptions (Table 1). The most commonly documented clinical interventions included: 25 for managing/preventing a drug interaction (26%), 24 for dose adjustment request (25%), 13 for prescription denial (13%), and 11 for requesting the use of a preferred or more cost-effective product (11%). Of note, 16 patients (7%) received counseling from the hematology/oncology CPP. Ten patients (5%) received counseling alone with no other intervention and did not meet the definition of a clinical intervention.
The most frequent prescriptions requiring intervention included 8 for enzalutamide, 7 for venetoclax, 6 for ibrutinib, and 5 each for lenalidomide, cabozantinib, and temozolomide. Among the 97 interventions, 68 were approved (70%), 15 received no response (16%), and 14 were denied by the community care HCP (14%). Despite obtaining no response or intervention denial from the community care HCP, hematology/oncology CPPs could approve these prescriptions if clinically appropriate, and their reasoning was documented. Table 2 further describes the types of interventions that were denied or obtained no response by the community care practitioner. Among the prescriptions denied by the hematology/oncology CPP, 11 were rejected for off-label indications and/or did not have support through primary literature, national guidelines, or VA criteria for use. Only 2 prescriptions were denied for safety concerns.
These documented clinical interventions had financial implications. For drugs with available cost data, requesting the use of a preferred/cost-effective product led to estimated savings of at least $263,536 over the study period with some ongoing cost savings. Prescription denials led to further estimated savings of $186,275 per month, although this is limited by the lack of known costs of alternative therapies the community care physicians chose.
DISCUSSION
More than one-third of prescriptions required clinical interventions, and 70% of these interventions were accepted by the community care prescriber, demonstrating the CPP’s essential role. Results indicate that most CPP clinical interventions involved clarifying and correcting doses, managing pertinent drug interactions, and ensuring appropriate use of medications according to clinical and national VA guidelines. Other studies have examined the impact of CPPs on patient care and cancer treatment.5,6 The randomized, multicenter AMBORA trial found that clinical pharmacist support reduced severe AEs and medication errors related to oral anticancer agents.5 The per-patient mean number of medication errors found by pharmacist review was 1.7 (range, 0 to 9), with most medication errors noted at the prescribing stage.5 Suzuki and colleagues analyzed data from 35,062 chemotherapy regimens and found that 53.1% of the chemotherapy prescriptions were modified because of pharmacist interventions.6 The most common reason for prescription modifications was prescription error.
Most of the clinical interventions in this study were accepted by community HCPs, indicating that these prescribers are receptive to hematology/oncology CPP input. Among those with no response, most were in relation to recommendations regarding drug interactions. In most of these cases, the drug interaction was not clinically concerning enough to require a response before the CPP approved the prescription. Therefore, it is unknown whether the outside HCP implemented the clinical recommendations. The most common types of clinical interventions the community care HCP declined were dose adjustment requests or requests to switch to a more cost-effective/formulary-preferred agent. In these cases, the prescriber’s preference was documented and, if clinically appropriate, approved by the CPP.
Although the financial implications of CPP clinical interventions were only marginally evaluated in this review, results suggest that cost savings by requests to switch to a cost-effective/formulary preferred agent or prescription denials are substantial. Because of changes in prescription costs over time, it is possible that savings from CPP intervention were greater than calculations using current Federal Supply Schedule Service pricing. The total impact of CPP prescription interventions on reducing or preventing hospitalizations or AEs is not known from this review, but other data suggest that cost savings may benefit the system.13,14
Limitations
This study's retrospective design is a limitation because practice patterns at the VANTHCS involving multiple hematology/oncology CPPs review of community care prescriptions might have evolved over time. The total financial implications of CPP interventions cannot fully be elucidated. The cost of alternative therapies used for patients who received a prescription denial is not factored into this review.
Conclusions
VANTHCS CPPs played an essential role in reviewing anticancer medication prescriptions from community care prescribers. In this study, CPP clinical interventions were completed for more than one-third of the prescriptions and the community-based HCP approved most of these interventions. These changes also resulted in financial benefits.
These findings add to the body of literature emphasizing the need for hematology/oncology-trained CPPs to review anticancer prescriptions and treatment plans. Our review could be used to justify CPP involvement in community care specialty medication review at VA facilities that do not currently have CPP involvement.
The value of a hematology/oncology clinical pharmacy practitioner (CPP) has been validated in several studies documenting their positive impact on patient outcomes, supportive care management, laboratory monitoring, medication error identification, and drug expenditure.1-6 With> 200 oncology-related US Food and Drug Administration approval notifications published from 2020 to 2023, it is no surprise that national trends in oncology drug clinic expenditures increased from $39.9 billion in 2020 to $44.1 billion in 2021.7,8 With the rapidly changing treatment landscape, new drug approvals, and risk of polypharmacy, oral anticancer agents carry a high risk for medication errors.4 Additional challenges include complex dosing regimens and instructions, adherence issues, drug interactions, adjustments for organ dysfunction, and extensive adverse effect (AE) profiles.
Because of the niche and complexity of oral anticancer agents, trained CPPs havehematology/oncology education and expertise that pharmacists without specialized training lack. A survey of 243 nonspecialized community pharmacists that assessed their knowledge of oral anticancer therapies revealed that only about half of the knowledge questions were answered correctly, illustrating an education gap among these pharmacists.9 The Hematology/Oncology Pharmacist Association's suggests that best practices for managing oral oncology therapy should include comprehensive medication review by an oncology-trained pharmacist for each prescription.10
The US Department of Veterans Affairs (VA) community care network, which was established by the MISSION Act, allows covered access for eligible veterans in the local community outside of the VA network. Unfortunately, this dual-system use of health care could increase the risk of poorly coordinated care and has been associated with the risk of inappropriate prescribing.11,12 It is unclear how many private practices enrolled in the community care program have access to oncology-trained pharmacists. Specialized pharmaceutical reviews of oral anticancer medication prescriptions from these practices are vital for veteran care. This study evaluates the clinical and financial interventions of hematology/oncology CPPs review of specialty hematology/oncology prescriptions from community care health care practitioners (HCPs) at the Veterans Affairs North Texas Health Care System (VANTHCS) in Dallas.
METHODS
This study is a retrospective review of Computerized Patient Record System (CPRS) records of patients at VANTHCS from January 1, 2015, to June 30, 2023. Patients included were aged ≥ 18 years, enrolled in the VA community care program, received a specialty hematology/oncology medication that was dispensed through VA pharmacies or VA-contracted pharmacies, and had an hematology/oncology CPP medication review documented in CPRS. The primary aim of this study was to assess the number and types of clinical interventions performed. A clinical intervention was defined as a documented communication attempt with a community care HCP or direct communication with a patient to address a specific medication-related issue noted during CPP review.
Review of specialty hematology/oncology medications by a hematology/oncology CPP included evaluation of therapy indication, such as whether the prescription meets clinical guidelines, VA criteria for use, or other clinical literature as judged appropriate by the CPP. In some cases, the CPP requested that the community care HCP prescribe a more cost-effective or formulary-preferred agent. Each prescription was reviewed for dosage and formulation appropriateness, drug interactions with available medication lists, baseline laboratory test completion, and recommended supportive care medicines. At times, patient counseling is completed as part of the clinical review. When necessary, CPPs could discuss patient cases with a VA-employed oncologist for further oversight regarding appropriateness and safety. Secondary outcomes included the number of interventions accepted or denied by the prescriber provider and cost savings.
Data collected included the type of malignancy, hematology/oncology specialty medication requested, number and type of interventions sent to the community care prescriber, number of interventions accepted or denied by the community care prescriber, and whether the CPP conducted patient counseling or dispensed or denied the product. Cost savings were calculated for medications that were denied or changed to a formulary preferred or cost-effective agent using pricing data from the National Acquisition Center Contract Catalog or Federal Supply Schedule Service as of April 2024.
RESULTS
A total of 221 hematology/oncology prescriptions met inclusion criteria. Among patients receiving these prescriptions, the median age was 70 years and 91% were male. The most common malignancies included 31 instances of multiple myeloma (14%), 26 for chronic lymphocytic leukemia (12%), 24 for prostate cancer (11%), 23 for glioblastoma/brain cancer (10%), 18 for renal cell carcinoma (8%), 17 for colorectal cancer (8%), and 15 for acute myeloid leukemia (7%). Clinical interventions by the hematology/oncology CPP were completed for 82 (37%) of the 221 prescriptions. One clinical intervention was communicated directly to the patient, and attempts were made to communicate with the community care HCP for the remaining 81 prescriptions. The CPP documented 97 clinical interventions for the 82 prescriptions (Table 1). The most commonly documented clinical interventions included: 25 for managing/preventing a drug interaction (26%), 24 for dose adjustment request (25%), 13 for prescription denial (13%), and 11 for requesting the use of a preferred or more cost-effective product (11%). Of note, 16 patients (7%) received counseling from the hematology/oncology CPP. Ten patients (5%) received counseling alone with no other intervention and did not meet the definition of a clinical intervention.
The most frequent prescriptions requiring intervention included 8 for enzalutamide, 7 for venetoclax, 6 for ibrutinib, and 5 each for lenalidomide, cabozantinib, and temozolomide. Among the 97 interventions, 68 were approved (70%), 15 received no response (16%), and 14 were denied by the community care HCP (14%). Despite obtaining no response or intervention denial from the community care HCP, hematology/oncology CPPs could approve these prescriptions if clinically appropriate, and their reasoning was documented. Table 2 further describes the types of interventions that were denied or obtained no response by the community care practitioner. Among the prescriptions denied by the hematology/oncology CPP, 11 were rejected for off-label indications and/or did not have support through primary literature, national guidelines, or VA criteria for use. Only 2 prescriptions were denied for safety concerns.
These documented clinical interventions had financial implications. For drugs with available cost data, requesting the use of a preferred/cost-effective product led to estimated savings of at least $263,536 over the study period with some ongoing cost savings. Prescription denials led to further estimated savings of $186,275 per month, although this is limited by the lack of known costs of alternative therapies the community care physicians chose.
DISCUSSION
More than one-third of prescriptions required clinical interventions, and 70% of these interventions were accepted by the community care prescriber, demonstrating the CPP’s essential role. Results indicate that most CPP clinical interventions involved clarifying and correcting doses, managing pertinent drug interactions, and ensuring appropriate use of medications according to clinical and national VA guidelines. Other studies have examined the impact of CPPs on patient care and cancer treatment.5,6 The randomized, multicenter AMBORA trial found that clinical pharmacist support reduced severe AEs and medication errors related to oral anticancer agents.5 The per-patient mean number of medication errors found by pharmacist review was 1.7 (range, 0 to 9), with most medication errors noted at the prescribing stage.5 Suzuki and colleagues analyzed data from 35,062 chemotherapy regimens and found that 53.1% of the chemotherapy prescriptions were modified because of pharmacist interventions.6 The most common reason for prescription modifications was prescription error.
Most of the clinical interventions in this study were accepted by community HCPs, indicating that these prescribers are receptive to hematology/oncology CPP input. Among those with no response, most were in relation to recommendations regarding drug interactions. In most of these cases, the drug interaction was not clinically concerning enough to require a response before the CPP approved the prescription. Therefore, it is unknown whether the outside HCP implemented the clinical recommendations. The most common types of clinical interventions the community care HCP declined were dose adjustment requests or requests to switch to a more cost-effective/formulary-preferred agent. In these cases, the prescriber’s preference was documented and, if clinically appropriate, approved by the CPP.
Although the financial implications of CPP clinical interventions were only marginally evaluated in this review, results suggest that cost savings by requests to switch to a cost-effective/formulary preferred agent or prescription denials are substantial. Because of changes in prescription costs over time, it is possible that savings from CPP intervention were greater than calculations using current Federal Supply Schedule Service pricing. The total impact of CPP prescription interventions on reducing or preventing hospitalizations or AEs is not known from this review, but other data suggest that cost savings may benefit the system.13,14
Limitations
This study's retrospective design is a limitation because practice patterns at the VANTHCS involving multiple hematology/oncology CPPs review of community care prescriptions might have evolved over time. The total financial implications of CPP interventions cannot fully be elucidated. The cost of alternative therapies used for patients who received a prescription denial is not factored into this review.
Conclusions
VANTHCS CPPs played an essential role in reviewing anticancer medication prescriptions from community care prescribers. In this study, CPP clinical interventions were completed for more than one-third of the prescriptions and the community-based HCP approved most of these interventions. These changes also resulted in financial benefits.
These findings add to the body of literature emphasizing the need for hematology/oncology-trained CPPs to review anticancer prescriptions and treatment plans. Our review could be used to justify CPP involvement in community care specialty medication review at VA facilities that do not currently have CPP involvement.
1. Shah NN, Casella E, Capozzi D, et al. Improving the safety of oral chemotherapy at an academic medical center. J Oncol Pract. 2016;12(1):e71-e76. doi:10.1200/JOP.2015.007260
2. Gatwood J, Gatwood K, Gabre E, Alexander M. Impact of clinical pharmacists in outpatient oncology practices: a review. Am J Health Syst Pharm. 2017;74(19):1549-1557. doi:10.2146/ajhp160475
3. Lankford C, Dura J, Tran A, et al. Effect of clinical pharmacist interventions on cost in an integrated health system specialty pharmacy. J Manag Care Spec Pharm. 2021;27(3):379-384. doi:10.18553/jmcp.2021.27.3.379
4. Schlichtig K, Dürr P, Dörje F, Fromm MF. Medication errors during treatment with new oral anticancer agents: consequences for clinical practice based on the AMBORA Study. Clin Pharmacol Ther. 2021;110(4):1075-1086. doi:10.1002/cpt.2338
5. Dürr P, Schlichtig K, Kelz C, et al. The randomized AMBORA Trial: impact of pharmacological/pharmaceutical care on medication safety and patient-reported outcomes during treatment with new oral anticancer agents. J Clin Oncol. 2021;39(18):1983-1994. doi:10.1200/JCO.20.03088
6. Suzuki S, Chan A, Nomura H, Johnson PE, Endo K, Saito S. Chemotherapy regimen checks performed by pharmacists contribute to safe administration of chemotherapy. J Oncol Pharm Pract. 2017;23(1):18-25. doi:10.1177/1078155215614998
7. Tichy EM, Hoffman JM, Suda KJ, et al. National trends in prescription drug expenditures and projections for 2022. Am J Health Syst Pharm. 2022;79(14):1158-1172. doi:10.1093/ajhp/zxac102
8. US Food and Drug Administration. Oncology (cancer)/hematologic malignancies approval notifications. 2023.
9. O’Bryant CL, Crandell BC. Community pharmacists’ knowledge of and attitudes toward oral chemotherapy. J Am Pharm Assoc (2003). 2008;48(5):632-639. doi:10.1331/JAPhA.2008.07082
10. Mackler E, Segal EM, Muluneh B, Jeffers K, Carmichael J. 2018 hematology/oncology pharmacist association best practices for the management of oral oncolytic therapy: pharmacy practice standard. J Oncol Pract. 2019;15(4):e346-e355. doi:10.1200/JOP.18.00581
11. Thorpe JM, Thorpe CT, Schleiden L, et al. Association between dual use of Department of Veterans Affairs and Medicare part D drug benefits and potentially unsafe prescribing. JAMA Intern Med. 2019;179(11):1584-1586. doi:10.1001/jamainternmed.2019.2788
12. Thorpe JM, Thorpe CT, Gellad WF, et al. Dual health care system use and high-risk prescribing in patients with dementia: a national cohort study. Ann Intern Med. 2017;166(3):157-163. doi:10.7326/M16-0551
13. Chen P-Z, Wu C-C, Huang C-F. Clinical and economic impact of clinical pharmacist intervention in a hematology unit. J Oncol Pharm Pract. 2020;26(4):866-872. doi:10.1177/1078155219875806
14. Dalton K, Byrne S. Role of the pharmacist in reducing healthcare costs: current insights. Integr Pharm Res Pract. 2017;6:37-46. doi:10.2147/IPRP.S108047
1. Shah NN, Casella E, Capozzi D, et al. Improving the safety of oral chemotherapy at an academic medical center. J Oncol Pract. 2016;12(1):e71-e76. doi:10.1200/JOP.2015.007260
2. Gatwood J, Gatwood K, Gabre E, Alexander M. Impact of clinical pharmacists in outpatient oncology practices: a review. Am J Health Syst Pharm. 2017;74(19):1549-1557. doi:10.2146/ajhp160475
3. Lankford C, Dura J, Tran A, et al. Effect of clinical pharmacist interventions on cost in an integrated health system specialty pharmacy. J Manag Care Spec Pharm. 2021;27(3):379-384. doi:10.18553/jmcp.2021.27.3.379
4. Schlichtig K, Dürr P, Dörje F, Fromm MF. Medication errors during treatment with new oral anticancer agents: consequences for clinical practice based on the AMBORA Study. Clin Pharmacol Ther. 2021;110(4):1075-1086. doi:10.1002/cpt.2338
5. Dürr P, Schlichtig K, Kelz C, et al. The randomized AMBORA Trial: impact of pharmacological/pharmaceutical care on medication safety and patient-reported outcomes during treatment with new oral anticancer agents. J Clin Oncol. 2021;39(18):1983-1994. doi:10.1200/JCO.20.03088
6. Suzuki S, Chan A, Nomura H, Johnson PE, Endo K, Saito S. Chemotherapy regimen checks performed by pharmacists contribute to safe administration of chemotherapy. J Oncol Pharm Pract. 2017;23(1):18-25. doi:10.1177/1078155215614998
7. Tichy EM, Hoffman JM, Suda KJ, et al. National trends in prescription drug expenditures and projections for 2022. Am J Health Syst Pharm. 2022;79(14):1158-1172. doi:10.1093/ajhp/zxac102
8. US Food and Drug Administration. Oncology (cancer)/hematologic malignancies approval notifications. 2023.
9. O’Bryant CL, Crandell BC. Community pharmacists’ knowledge of and attitudes toward oral chemotherapy. J Am Pharm Assoc (2003). 2008;48(5):632-639. doi:10.1331/JAPhA.2008.07082
10. Mackler E, Segal EM, Muluneh B, Jeffers K, Carmichael J. 2018 hematology/oncology pharmacist association best practices for the management of oral oncolytic therapy: pharmacy practice standard. J Oncol Pract. 2019;15(4):e346-e355. doi:10.1200/JOP.18.00581
11. Thorpe JM, Thorpe CT, Schleiden L, et al. Association between dual use of Department of Veterans Affairs and Medicare part D drug benefits and potentially unsafe prescribing. JAMA Intern Med. 2019;179(11):1584-1586. doi:10.1001/jamainternmed.2019.2788
12. Thorpe JM, Thorpe CT, Gellad WF, et al. Dual health care system use and high-risk prescribing in patients with dementia: a national cohort study. Ann Intern Med. 2017;166(3):157-163. doi:10.7326/M16-0551
13. Chen P-Z, Wu C-C, Huang C-F. Clinical and economic impact of clinical pharmacist intervention in a hematology unit. J Oncol Pharm Pract. 2020;26(4):866-872. doi:10.1177/1078155219875806
14. Dalton K, Byrne S. Role of the pharmacist in reducing healthcare costs: current insights. Integr Pharm Res Pract. 2017;6:37-46. doi:10.2147/IPRP.S108047
Several Skin Conditions More Likely in Children With Obesity
TORONTO — results of new research show.
The retrospective cohort study found markedly higher rates of skin infections, atopic dermatitis (AD), and acanthosis nigricans among children with overweight, compared with children with average weight.
“Many conditions associated with obesity are strong predictors of cardiovascular mortality as these children age, so doctors can play a key role in advocating for weight loss strategies in this population,” lead study author Samantha Epstein, third-year medical student at Case Western Reserve University, Cleveland, Ohio, said in an interview. The findings were presented at the annual meeting of the Society for Pediatric Dermatology.
Previous research has linked obesity, a chronic inflammatory condition, to psoriasis, AD, hidradenitis suppurativa (HS), acne vulgaris, infections, and rosacea in adults. However, there’s scant research exploring the connection between obesity and cutaneous conditions in children.
According to the Cleveland Clinic, childhood obesity is defined as a body mass index, which is weight in kg divided by the square of height in m2, at or above the 95th percentile for age and sex in children aged 2 years or older.
For the study, Ms. Epstein and coauthor Sonal D. Shah, MD, associate professor, Department of Dermatology, Case Western Reserve University, and a board-certified pediatric dermatologist accessed a large national research database and used diagnostic codes to identify over 1 million children (mean age, 8.5 years). Most (about 44%) were White; about one-quarter were Black. The groups were propensity matched, so there were about equal numbers of youngsters with and without obesity and of boys and girls.
They collected data on AD, HS, rosacea, psoriasis, and acanthosis nigricans (a thickened purplish discoloration typically found in body folds around the armpits, groin, and neck). They also gathered information on comorbidities.
Acanthosis nigricans, which is linked to metabolic syndrome, type 2 diabetes, and insulin resistance , was more prevalent among children with obesity (20,885 cases in the with-obesity group and 336 in the without-obesity group, for a relative risk [RR] of 62.16 and an odds ratio [OR] of 64.38).
Skin and subcutaneous tissue infections were also more common among those with obesity (14,795 cases) vs 4720 cases among those without obesity (RR, 3.14; OR, 3.2). As for AD, there were 11,892 cases in the with-obesity group and 2983 in the without-obesity group (RR, 3.99; OR, 4.06). There were 1166 cases of psoriasis among those with obesity and 408 among those without obesity (RR, 2.86; OR, 2.88).
HS (587 cases in the with-obesity group and 70 in the without-obesity group; RR, 8.39; OR, 8.39) and rosacea (351 in the with-obesity group and 138 in the without-obesity group; RR, 2.54; OR, 2.55) were the least common skin conditions.
Higher Comorbidity Rates
Compared with their average-weight counterparts, the children with obesity had higher rates of comorbidities, including type 2 diabetes. Ms. Epstein noted that children with diabetes and obesity had increased risks for every skin condition except for infections of the skin and subcutaneous tissue when compared with children without obesity.
Such infections were the most common skin conditions among children without obesity. “This was expected just due to the fact that children are outside, they’re playing in the grass and the dirt, and they get infected,” said Ms. Epstein. Still, these infections were three times more common in youngsters with obesity.
Although acanthosis nigricans is “highly correlated” with type 2 diabetes, “not as many children as we would expect in this population have developed type 2 diabetes,” said Ms. Epstein. This might make some sense, though, because these children are still quite young. “When dermatologists recognize this skin condition, they can advocate for weight loss management to try to prevent it.”
Other conditions seen more often in the overweight children with overweight included: hypertension, hyperlipidemia, obstructive sleep apnea, polycystic ovarian syndrome, attention-deficit/hyperactivity disorder, major depressive disorder, depressive episodes, and anxiety (all P < .001).
Commenting on the results, Sonia Havele, MD, a pediatrician and dermatology resident at Children’s Mercy Hospital, Kansas City, Missouri, said in an interview that the study reflects trends that she and her colleagues see in clinic: There are more common skin conditions in their patients with obesity.
She agreed that it offers an opening for education. “The results of this study highlight the opportunity we have as pediatric dermatologists to provide additional counseling on obesity and offer referrals to our colleagues in endocrinology, gastroenterology, and nutrition if needed.”
No conflicts of interest were reported.
TORONTO — results of new research show.
The retrospective cohort study found markedly higher rates of skin infections, atopic dermatitis (AD), and acanthosis nigricans among children with overweight, compared with children with average weight.
“Many conditions associated with obesity are strong predictors of cardiovascular mortality as these children age, so doctors can play a key role in advocating for weight loss strategies in this population,” lead study author Samantha Epstein, third-year medical student at Case Western Reserve University, Cleveland, Ohio, said in an interview. The findings were presented at the annual meeting of the Society for Pediatric Dermatology.
Previous research has linked obesity, a chronic inflammatory condition, to psoriasis, AD, hidradenitis suppurativa (HS), acne vulgaris, infections, and rosacea in adults. However, there’s scant research exploring the connection between obesity and cutaneous conditions in children.
According to the Cleveland Clinic, childhood obesity is defined as a body mass index, which is weight in kg divided by the square of height in m2, at or above the 95th percentile for age and sex in children aged 2 years or older.
For the study, Ms. Epstein and coauthor Sonal D. Shah, MD, associate professor, Department of Dermatology, Case Western Reserve University, and a board-certified pediatric dermatologist accessed a large national research database and used diagnostic codes to identify over 1 million children (mean age, 8.5 years). Most (about 44%) were White; about one-quarter were Black. The groups were propensity matched, so there were about equal numbers of youngsters with and without obesity and of boys and girls.
They collected data on AD, HS, rosacea, psoriasis, and acanthosis nigricans (a thickened purplish discoloration typically found in body folds around the armpits, groin, and neck). They also gathered information on comorbidities.
Acanthosis nigricans, which is linked to metabolic syndrome, type 2 diabetes, and insulin resistance , was more prevalent among children with obesity (20,885 cases in the with-obesity group and 336 in the without-obesity group, for a relative risk [RR] of 62.16 and an odds ratio [OR] of 64.38).
Skin and subcutaneous tissue infections were also more common among those with obesity (14,795 cases) vs 4720 cases among those without obesity (RR, 3.14; OR, 3.2). As for AD, there were 11,892 cases in the with-obesity group and 2983 in the without-obesity group (RR, 3.99; OR, 4.06). There were 1166 cases of psoriasis among those with obesity and 408 among those without obesity (RR, 2.86; OR, 2.88).
HS (587 cases in the with-obesity group and 70 in the without-obesity group; RR, 8.39; OR, 8.39) and rosacea (351 in the with-obesity group and 138 in the without-obesity group; RR, 2.54; OR, 2.55) were the least common skin conditions.
Higher Comorbidity Rates
Compared with their average-weight counterparts, the children with obesity had higher rates of comorbidities, including type 2 diabetes. Ms. Epstein noted that children with diabetes and obesity had increased risks for every skin condition except for infections of the skin and subcutaneous tissue when compared with children without obesity.
Such infections were the most common skin conditions among children without obesity. “This was expected just due to the fact that children are outside, they’re playing in the grass and the dirt, and they get infected,” said Ms. Epstein. Still, these infections were three times more common in youngsters with obesity.
Although acanthosis nigricans is “highly correlated” with type 2 diabetes, “not as many children as we would expect in this population have developed type 2 diabetes,” said Ms. Epstein. This might make some sense, though, because these children are still quite young. “When dermatologists recognize this skin condition, they can advocate for weight loss management to try to prevent it.”
Other conditions seen more often in the overweight children with overweight included: hypertension, hyperlipidemia, obstructive sleep apnea, polycystic ovarian syndrome, attention-deficit/hyperactivity disorder, major depressive disorder, depressive episodes, and anxiety (all P < .001).
Commenting on the results, Sonia Havele, MD, a pediatrician and dermatology resident at Children’s Mercy Hospital, Kansas City, Missouri, said in an interview that the study reflects trends that she and her colleagues see in clinic: There are more common skin conditions in their patients with obesity.
She agreed that it offers an opening for education. “The results of this study highlight the opportunity we have as pediatric dermatologists to provide additional counseling on obesity and offer referrals to our colleagues in endocrinology, gastroenterology, and nutrition if needed.”
No conflicts of interest were reported.
TORONTO — results of new research show.
The retrospective cohort study found markedly higher rates of skin infections, atopic dermatitis (AD), and acanthosis nigricans among children with overweight, compared with children with average weight.
“Many conditions associated with obesity are strong predictors of cardiovascular mortality as these children age, so doctors can play a key role in advocating for weight loss strategies in this population,” lead study author Samantha Epstein, third-year medical student at Case Western Reserve University, Cleveland, Ohio, said in an interview. The findings were presented at the annual meeting of the Society for Pediatric Dermatology.
Previous research has linked obesity, a chronic inflammatory condition, to psoriasis, AD, hidradenitis suppurativa (HS), acne vulgaris, infections, and rosacea in adults. However, there’s scant research exploring the connection between obesity and cutaneous conditions in children.
According to the Cleveland Clinic, childhood obesity is defined as a body mass index, which is weight in kg divided by the square of height in m2, at or above the 95th percentile for age and sex in children aged 2 years or older.
For the study, Ms. Epstein and coauthor Sonal D. Shah, MD, associate professor, Department of Dermatology, Case Western Reserve University, and a board-certified pediatric dermatologist accessed a large national research database and used diagnostic codes to identify over 1 million children (mean age, 8.5 years). Most (about 44%) were White; about one-quarter were Black. The groups were propensity matched, so there were about equal numbers of youngsters with and without obesity and of boys and girls.
They collected data on AD, HS, rosacea, psoriasis, and acanthosis nigricans (a thickened purplish discoloration typically found in body folds around the armpits, groin, and neck). They also gathered information on comorbidities.
Acanthosis nigricans, which is linked to metabolic syndrome, type 2 diabetes, and insulin resistance , was more prevalent among children with obesity (20,885 cases in the with-obesity group and 336 in the without-obesity group, for a relative risk [RR] of 62.16 and an odds ratio [OR] of 64.38).
Skin and subcutaneous tissue infections were also more common among those with obesity (14,795 cases) vs 4720 cases among those without obesity (RR, 3.14; OR, 3.2). As for AD, there were 11,892 cases in the with-obesity group and 2983 in the without-obesity group (RR, 3.99; OR, 4.06). There were 1166 cases of psoriasis among those with obesity and 408 among those without obesity (RR, 2.86; OR, 2.88).
HS (587 cases in the with-obesity group and 70 in the without-obesity group; RR, 8.39; OR, 8.39) and rosacea (351 in the with-obesity group and 138 in the without-obesity group; RR, 2.54; OR, 2.55) were the least common skin conditions.
Higher Comorbidity Rates
Compared with their average-weight counterparts, the children with obesity had higher rates of comorbidities, including type 2 diabetes. Ms. Epstein noted that children with diabetes and obesity had increased risks for every skin condition except for infections of the skin and subcutaneous tissue when compared with children without obesity.
Such infections were the most common skin conditions among children without obesity. “This was expected just due to the fact that children are outside, they’re playing in the grass and the dirt, and they get infected,” said Ms. Epstein. Still, these infections were three times more common in youngsters with obesity.
Although acanthosis nigricans is “highly correlated” with type 2 diabetes, “not as many children as we would expect in this population have developed type 2 diabetes,” said Ms. Epstein. This might make some sense, though, because these children are still quite young. “When dermatologists recognize this skin condition, they can advocate for weight loss management to try to prevent it.”
Other conditions seen more often in the overweight children with overweight included: hypertension, hyperlipidemia, obstructive sleep apnea, polycystic ovarian syndrome, attention-deficit/hyperactivity disorder, major depressive disorder, depressive episodes, and anxiety (all P < .001).
Commenting on the results, Sonia Havele, MD, a pediatrician and dermatology resident at Children’s Mercy Hospital, Kansas City, Missouri, said in an interview that the study reflects trends that she and her colleagues see in clinic: There are more common skin conditions in their patients with obesity.
She agreed that it offers an opening for education. “The results of this study highlight the opportunity we have as pediatric dermatologists to provide additional counseling on obesity and offer referrals to our colleagues in endocrinology, gastroenterology, and nutrition if needed.”
No conflicts of interest were reported.
FROM SPD 2024
Generalized Fixed Drug Eruptions Require Urgent Care: A Case Series
Recognizing cutaneous drug eruptions is important for treatment and prevention of recurrence. Fixed drug eruptions (FDEs) typically are harmless but can have major negative cosmetic consequences for patients. In its more severe forms, patients are at risk for widespread epithelial necrosis with accompanying complications. We report 1 patient with generalized FDE and 2 with generalized bullous FDE. We also discuss the recognition and treatment of the condition. Two patients previously had been diagnosed with systemic lupus erythematosus (SLE).
Case Series
Patient 1—A 60-year-old woman presented to dermatology with a rash on the trunk and groin folds of 4 days’ duration. She had a history of SLE and cutaneous lupus treated with hydroxychloroquine 200 mg twice daily and topical corticosteroids. She had started sulfamethoxazole-trimethoprim for a urinary tract infection with a rash appearing 1 day later. She reported burning skin pain with progression to blisters that “sloughed” off. She denied any known history of allergy to sulfa drugs. Prior to evaluation by dermatology, she visited an urgent care facility and was prescribed hydroxyzine and intramuscular corticosteroids. At presentation to dermatology 3 days after taking sulfamethoxazole-trimethoprim, she had annular flaccid bullae and superficial erosions with dusky borders on the right posterior thigh, right side of the chest, left inframammary fold, and right inguinal fold (Figure 1). She had no ocular, oral, or vaginal erosions. A diagnosis of generalized bullous FDE was favored over erythema multiforme or Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Shave biopsies from lesions on the right posterior thigh and right inguinal fold demonstrated interface dermatitis with epidermal necrosis, pigment incontinence, and numerous eosinophils. Direct immunofluorescence of the perilesional skin was negative for immunoprotein deposition. These findings were consistent with the clinical impression of generalized bullous FDE. Prior to receiving the histopathology report, the patient was initiated on a regimen of cyclosporine 5 mg/kg/d in the setting of normal renal function and followed until the eruption resolved completely. Cyclosporine was tapered at 2 weeks and discontinued at 3 weeks.
Patient 2—A 32-year-old woman presented for follow-up management of discoid lupus erythematosus. She had a history of systemic and cutaneous lupus, juvenile rheumatoid arthritis, and mixed connective tissue disease managed with prednisone, hydroxychloroquine, azathioprine, and belimumab. Physical examination revealed scarring alopecia with dyspigmentation and active inflammation consistent with uncontrolled cutaneous lupus. However, she also had oval-shaped hyperpigmented patches over the left breast, clavicle, and anterior chest consistent with a generalized FDE (Figure 2). The patient did not recall a history of similar lesions and could not identify a possible trigger. She was counseled on possible culprits and advised to avoid unnecessary medications. She had an unremarkable clinical course; therefore, no further intervention was necessary.
Patient 3—A 33-year-old man presented to the emergency department with a painful rash on the chest and back of 2 days’ duration that began 1 hour after taking naproxen (dosage unknown) for back pain. He had no notable medical history. The patient stated that the rash had slowly worsened and started to develop blisters. He visited an urgent care facility 1 day prior to the current presentation and was started on a 5-day course of prednisone 40 mg daily; the first 2 doses did not help. He denied any mucosal involvement apart from a tender lesion on the penis. He reported a history of an allergic reaction to penicillin. Physical examination revealed extensive dusky violaceous annular plaques with erythematous borders across the anterior and posterior trunk (Figure 3). Multiple flaccid bullae developed within these plaques, involving 15% of the body surface area. He was diagnosed with generalized bullous FDE based on the clinical history and histopathology. He was admitted to the burn intensive care unit and treated with cyclosporine 3 mg/kg/d with subsequent resolution of the eruption.
Comment
Presentation of FDEs—A fixed drug eruption manifests with 1 or more well-demarcated, red or violaceous, annular patches that resolve with postinflammatory hyperpigmentation; it occasionally may manifest with bullae. Initial eruptions may occur up to 2 weeks following medication exposure, but recurrent eruptions usually happen within minutes to hours later. They often are in the same location as prior lesions. A fixed drug eruption can be solitary, scattered, or generalized; a generalized FDE typically demonstrates multiple bilateral lesions that may itch, burn, or cause no symptoms. Patients can experience an FDE at any age, though the median age is reported as 35 to 60 years of age.1 A fixed drug eruption usually occurs after ingestion of oral medications, though there have been a few reports with iodinated contrast.2 Well-known culprits include antibiotics (eg, sulfamethoxazole-trimethoprim, tetracyclines, penicillins/cephalosporins, quinolones, dapsone), nonsteroidal anti-inflammatory drugs, acetaminophen (eg, paracetamol), barbiturates, antimalarials, and anticonvulsants. It also can occur with vaccines or with certain foods (fixed food eruption).3,4 Clinicians may try an oral drug challenge to identify the cause of an FDE, but in patients with a history of a generalized FDE, the risk for developing an increasingly severe reaction with repeated exposure to the medication is too high.5
Histopathology—Patch testing at the site of prior eruption with suspected drug culprits may be useful.6 Histopathology of FDE typically demonstrates vacuolar changes at the dermoepidermal junction with a lichenoid lymphocytic infiltrate. Early lesions often show a predominance of eosinophils. Subepidermal clefting is a feature of the bullous variant. In an active lesion, there are large numbers of CD8+ T lymphocytes expressing natural killer cell–associated molecules.7 The pathologic mechanism is not well understood, though it has been hypothesized that memory CD8+ cells are maintained in specific regions of the epidermis by IL-15 produced in the microenvironment and are activated upon rechallenge.7Considerations in Generalized Bullous FDE—Generalized FDE is defined in the literature as an FDE with involvement of 3 of 6 body areas: head, neck, trunk, upper limbs, lower limbs, and genital area. It may cover more or less than 10% of the body surface area.8-10 Although an isolated FDE frequently is asymptomatic and may not be cause for alarm, recurring drug eruptions increase the risk for development of generalized bullous FDE. Generalized bullous FDE is a rare subset. It is frequently misdiagnosed, and data on its incidence are uncertain.11 Of note, several pathologies causing bullous lesions may be in the differential diagnosis, including bullous pemphigoid; pemphigus vulgaris; bullous SLE; or bullae from cutaneous lupus, staphylococcal scalded skin syndrome, erythema multiforme, or SJS/TEN.12 When matched for body surface area involvement with SJS/TEN, generalized bullous FDE shares nearly identical mortality rates10; therefore, these patients should be treated with the same level of urgency and admitted to a critical care or burn unit, as they are at serious risk for infection and other complications.13
Clinical history and presentation along with histopathologic findings help to narrow down the differential diagnosis. Clinically, generalized bullous FDE does not affect the surrounding skin and manifests sooner after drug exposure (1–24 hours) with less mucosal involvement than SJS/TEN.9 Additionally, SJS/TEN patients frequently have generalized malaise and/or fever, while generalized bullous FDE patients do not. Finally, patients with generalized bullous FDE may report a history of a cutaneous eruption similar in morphology or in the same location.
Histopathologically, generalized bullous FDE may be similar to FDE with the addition of a subepidermal blister. Generalized bullous FDE patients have greater eosinophil infiltration and dermal melanophages than patients with SJS/TEN.9 Cellular infiltrates in generalized bullous FDE include more dermal CD41 cells, such as Foxp31 regulatory T cells; fewer intraepidermal CD561 cells; and fewer intraepidermal cells with granulysin.9 Occasionally, generalized bullous FDE causes full-thickness necrosis. In those cases, generalized bullous FDE cannot reliably be distinguished from other conditions with epidermal necrolysis on histopathology.13
FDE Diagnostics—A cytotoxin produced by
Management—Avoidance of the inciting drug often is sufficient for patients with an FDE, as demonstrated in patient 2 in our case series. Clinicians also should counsel patients on avoidance of potential cross-reacting drugs. Symptomatic treatment for itch or pain is appropriate and may include antihistamines or topical steroids. Nonsteroidal anti-inflammatory drugs may exacerbate or be causative of FDE. For generalized bullous FDE, cyclosporine is favored in the literature15,16 and was used to successfully treat both patients 1 and 3 in our case series. A short course of systemic corticosteroids or intravenous immunoglobulin also may be considered. Mild cases of generalized bullous FDE may be treated with close outpatient follow-up (patient 1), while severe cases require inpatient or even critical care monitoring with aggressive medical management to prevent the progression of skin desquamation (patient 3). Patients with severe oral lesions may require inpatient support for fluid maintenance.
Lupus History—Two patients in our case series had a history of lupus. Lupus itself can cause primary bullous lesions. Similar to FDE, bullous SLE can involve sun-exposed and nonexposed areas of the skin as well as the mucous membranes with a predilection for the lower vermilion lip.17 In bullous SLE, tense subepidermal blisters with a neutrophil-rich infiltrate form due to circulating antibodies to type VII collagen. These blisters have an erythematous or urticated base, most commonly on the face, upper trunk, and proximal extremities.18 In both SLE with skin manifestations and lupus limited to the skin, bullae may form due to extensive vacuolar degeneration. Similar to TEN, they can form rapidly in a widespread distribution.17 However, there is limited mucosal involvement, no clear drug association, and a better prognosis. Bullae caused by lupus will frequently demonstrate deposition of immunoproteins IgG, IgM, IgA, and complement component 3 at the basement membrane zone in perilesional skin on direct immunofluorescence. However, negative direct immunofluorescence does not rule out lupus.12 At the same time, patients with lupus frequently have comorbidities requiring multiple medications; the need for these medications may predispose patients to higher rates of cutaneous drug eruptions.19 To our knowledge, there is no known association between FDE and lupus.
Conclusion
Patients with acute eruptions following the initiation of a new prescription or over-the-counter medication require urgent evaluation. Generalized bullous FDE requires timely diagnosis and intervention. Patients with lupus have an increased risk for cutaneous drug eruptions due to polypharmacy. Further investigation is necessary to determine if there is a pathophysiologic mechanism responsible for the development of FDE in lupus patients.
- Anderson HJ, Lee JB. A review of fixed drug eruption with a special focus on generalized bullous fixed drug eruption. Medicina (Kaunas). 2021;57:925.
- Gavin M, Sharp L, Walker K, et al. Contrast-induced generalized bullous fixed drug eruption resembling Stevens-Johnson syndrome. Proc (Bayl Univ Med Cent). 2019;32:601-602.
- Kabir S, Feit EJ, Heilman ER. Generalized fixed drug eruption following Pfizer-BioNtech COVID-19 vaccination. Clin Case Rep. 2022;10:E6684.
- Choi S, Kim SH, Hwang JH, et al. Rapidly progressing generalized bullous fixed drug eruption after the first dose of COVID-19 messenger RNA vaccination. J Dermatol. 2023;50:1190-1193.
- Mahboob A, Haroon TS. Drugs causing fixed eruptions: a study of 450 cases. Int J Dermatol. 1998;37:833-838.
- Shiohara T. Fixed drug eruption: pathogenesis and diagnostic tests. Curr Opin Allergy Clin Immunol. 2009;9:316-321.
- Mizukawa Y, Yamazaki Y, Shiohara T. In vivo dynamics of intraepidermal CD8+ T cells and CD4+ T cells during the evolution of fixed drug eruption. Br J Dermatol. 2008;158:1230-1238.
- Lee CH, Chen YC, Cho YT, et al. Fixed-drug eruption: a retrospective study in a single referral center in northern Taiwan. Dermatologica Sinica. 2012;30:11-15.
- Cho YT, Lin JW, Chen YC, et al. Generalized bullous fixed drug eruption is distinct from Stevens-Johnson syndrome/toxic epidermal necrolysis by immunohistopathological features. J Am Acad Dermatol. 2014;70:539-548.
- Lipowicz S, Sekula P, Ingen-Housz-Oro S, et al. Prognosis of generalized bullous fixed drug eruption: comparison with Stevens-Johnson syndrome and toxic epidermal necrolysis. Br J Dermatol. 2013;168:726-732.
- Patel S, John AM, Handler MZ, et al. Fixed drug eruptions: an update, emphasizing the potentially lethal generalized bullous fixed drug eruption. Am J Clin Dermatol. 2020;21:393-399.
- Ranario JS, Smith JL. Bullous lesions in a patient with systemic lupus erythematosus. J Clin Aesthet Dermatol. 2014;7:44-49.
- Perron E, Viarnaud A, Marciano L, et al. Clinical and histological features of fixed drug eruption: a single-centre series of 73 cases with comparison between bullous and non-bullous forms. Eur J Dermatol. 2021;31:372-380.
- Chen CB, Kuo KL, Wang CW, et al. Detecting lesional granulysin levels for rapid diagnosis of cytotoxic T lymphocyte-mediated bullous skin disorders. J Allergy Clin Immunol Pract. 2021;9:1327-1337.e3.
- Beniwal R, Gupta LK, Khare AK, et al. Cyclosporine in generalized bullous-fixed drug eruption. Indian J Dermatol. 2018;63:432-433.
- Vargas Mora P, García S, Valenzuela F, et al. Generalized bullous fixed drug eruption successfully treated with cyclosporine. Dermatol Ther. 2020;33:E13492.
- Montagnon CM, Tolkachjov SN, Murrell DF, et al. Subepithelial autoimmune blistering dermatoses: clinical features and diagnosis. J Am Acad Dermatol. 2021;85:1-14.
- Sebaratnam DF, Murrell DF. Bullous systemic lupus erythematosus. Dermatol Clin. 2011;29:649-653.
- Zonzits E, Aberer W, Tappeiner G. Drug eruptions from mesna. After cyclophosphamide treatment of patients with systemic lupus erythematosus and dermatomyositis. Arch Dermatol. 1992;128:80-82.
Recognizing cutaneous drug eruptions is important for treatment and prevention of recurrence. Fixed drug eruptions (FDEs) typically are harmless but can have major negative cosmetic consequences for patients. In its more severe forms, patients are at risk for widespread epithelial necrosis with accompanying complications. We report 1 patient with generalized FDE and 2 with generalized bullous FDE. We also discuss the recognition and treatment of the condition. Two patients previously had been diagnosed with systemic lupus erythematosus (SLE).
Case Series
Patient 1—A 60-year-old woman presented to dermatology with a rash on the trunk and groin folds of 4 days’ duration. She had a history of SLE and cutaneous lupus treated with hydroxychloroquine 200 mg twice daily and topical corticosteroids. She had started sulfamethoxazole-trimethoprim for a urinary tract infection with a rash appearing 1 day later. She reported burning skin pain with progression to blisters that “sloughed” off. She denied any known history of allergy to sulfa drugs. Prior to evaluation by dermatology, she visited an urgent care facility and was prescribed hydroxyzine and intramuscular corticosteroids. At presentation to dermatology 3 days after taking sulfamethoxazole-trimethoprim, she had annular flaccid bullae and superficial erosions with dusky borders on the right posterior thigh, right side of the chest, left inframammary fold, and right inguinal fold (Figure 1). She had no ocular, oral, or vaginal erosions. A diagnosis of generalized bullous FDE was favored over erythema multiforme or Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Shave biopsies from lesions on the right posterior thigh and right inguinal fold demonstrated interface dermatitis with epidermal necrosis, pigment incontinence, and numerous eosinophils. Direct immunofluorescence of the perilesional skin was negative for immunoprotein deposition. These findings were consistent with the clinical impression of generalized bullous FDE. Prior to receiving the histopathology report, the patient was initiated on a regimen of cyclosporine 5 mg/kg/d in the setting of normal renal function and followed until the eruption resolved completely. Cyclosporine was tapered at 2 weeks and discontinued at 3 weeks.
Patient 2—A 32-year-old woman presented for follow-up management of discoid lupus erythematosus. She had a history of systemic and cutaneous lupus, juvenile rheumatoid arthritis, and mixed connective tissue disease managed with prednisone, hydroxychloroquine, azathioprine, and belimumab. Physical examination revealed scarring alopecia with dyspigmentation and active inflammation consistent with uncontrolled cutaneous lupus. However, she also had oval-shaped hyperpigmented patches over the left breast, clavicle, and anterior chest consistent with a generalized FDE (Figure 2). The patient did not recall a history of similar lesions and could not identify a possible trigger. She was counseled on possible culprits and advised to avoid unnecessary medications. She had an unremarkable clinical course; therefore, no further intervention was necessary.
Patient 3—A 33-year-old man presented to the emergency department with a painful rash on the chest and back of 2 days’ duration that began 1 hour after taking naproxen (dosage unknown) for back pain. He had no notable medical history. The patient stated that the rash had slowly worsened and started to develop blisters. He visited an urgent care facility 1 day prior to the current presentation and was started on a 5-day course of prednisone 40 mg daily; the first 2 doses did not help. He denied any mucosal involvement apart from a tender lesion on the penis. He reported a history of an allergic reaction to penicillin. Physical examination revealed extensive dusky violaceous annular plaques with erythematous borders across the anterior and posterior trunk (Figure 3). Multiple flaccid bullae developed within these plaques, involving 15% of the body surface area. He was diagnosed with generalized bullous FDE based on the clinical history and histopathology. He was admitted to the burn intensive care unit and treated with cyclosporine 3 mg/kg/d with subsequent resolution of the eruption.
Comment
Presentation of FDEs—A fixed drug eruption manifests with 1 or more well-demarcated, red or violaceous, annular patches that resolve with postinflammatory hyperpigmentation; it occasionally may manifest with bullae. Initial eruptions may occur up to 2 weeks following medication exposure, but recurrent eruptions usually happen within minutes to hours later. They often are in the same location as prior lesions. A fixed drug eruption can be solitary, scattered, or generalized; a generalized FDE typically demonstrates multiple bilateral lesions that may itch, burn, or cause no symptoms. Patients can experience an FDE at any age, though the median age is reported as 35 to 60 years of age.1 A fixed drug eruption usually occurs after ingestion of oral medications, though there have been a few reports with iodinated contrast.2 Well-known culprits include antibiotics (eg, sulfamethoxazole-trimethoprim, tetracyclines, penicillins/cephalosporins, quinolones, dapsone), nonsteroidal anti-inflammatory drugs, acetaminophen (eg, paracetamol), barbiturates, antimalarials, and anticonvulsants. It also can occur with vaccines or with certain foods (fixed food eruption).3,4 Clinicians may try an oral drug challenge to identify the cause of an FDE, but in patients with a history of a generalized FDE, the risk for developing an increasingly severe reaction with repeated exposure to the medication is too high.5
Histopathology—Patch testing at the site of prior eruption with suspected drug culprits may be useful.6 Histopathology of FDE typically demonstrates vacuolar changes at the dermoepidermal junction with a lichenoid lymphocytic infiltrate. Early lesions often show a predominance of eosinophils. Subepidermal clefting is a feature of the bullous variant. In an active lesion, there are large numbers of CD8+ T lymphocytes expressing natural killer cell–associated molecules.7 The pathologic mechanism is not well understood, though it has been hypothesized that memory CD8+ cells are maintained in specific regions of the epidermis by IL-15 produced in the microenvironment and are activated upon rechallenge.7Considerations in Generalized Bullous FDE—Generalized FDE is defined in the literature as an FDE with involvement of 3 of 6 body areas: head, neck, trunk, upper limbs, lower limbs, and genital area. It may cover more or less than 10% of the body surface area.8-10 Although an isolated FDE frequently is asymptomatic and may not be cause for alarm, recurring drug eruptions increase the risk for development of generalized bullous FDE. Generalized bullous FDE is a rare subset. It is frequently misdiagnosed, and data on its incidence are uncertain.11 Of note, several pathologies causing bullous lesions may be in the differential diagnosis, including bullous pemphigoid; pemphigus vulgaris; bullous SLE; or bullae from cutaneous lupus, staphylococcal scalded skin syndrome, erythema multiforme, or SJS/TEN.12 When matched for body surface area involvement with SJS/TEN, generalized bullous FDE shares nearly identical mortality rates10; therefore, these patients should be treated with the same level of urgency and admitted to a critical care or burn unit, as they are at serious risk for infection and other complications.13
Clinical history and presentation along with histopathologic findings help to narrow down the differential diagnosis. Clinically, generalized bullous FDE does not affect the surrounding skin and manifests sooner after drug exposure (1–24 hours) with less mucosal involvement than SJS/TEN.9 Additionally, SJS/TEN patients frequently have generalized malaise and/or fever, while generalized bullous FDE patients do not. Finally, patients with generalized bullous FDE may report a history of a cutaneous eruption similar in morphology or in the same location.
Histopathologically, generalized bullous FDE may be similar to FDE with the addition of a subepidermal blister. Generalized bullous FDE patients have greater eosinophil infiltration and dermal melanophages than patients with SJS/TEN.9 Cellular infiltrates in generalized bullous FDE include more dermal CD41 cells, such as Foxp31 regulatory T cells; fewer intraepidermal CD561 cells; and fewer intraepidermal cells with granulysin.9 Occasionally, generalized bullous FDE causes full-thickness necrosis. In those cases, generalized bullous FDE cannot reliably be distinguished from other conditions with epidermal necrolysis on histopathology.13
FDE Diagnostics—A cytotoxin produced by
Management—Avoidance of the inciting drug often is sufficient for patients with an FDE, as demonstrated in patient 2 in our case series. Clinicians also should counsel patients on avoidance of potential cross-reacting drugs. Symptomatic treatment for itch or pain is appropriate and may include antihistamines or topical steroids. Nonsteroidal anti-inflammatory drugs may exacerbate or be causative of FDE. For generalized bullous FDE, cyclosporine is favored in the literature15,16 and was used to successfully treat both patients 1 and 3 in our case series. A short course of systemic corticosteroids or intravenous immunoglobulin also may be considered. Mild cases of generalized bullous FDE may be treated with close outpatient follow-up (patient 1), while severe cases require inpatient or even critical care monitoring with aggressive medical management to prevent the progression of skin desquamation (patient 3). Patients with severe oral lesions may require inpatient support for fluid maintenance.
Lupus History—Two patients in our case series had a history of lupus. Lupus itself can cause primary bullous lesions. Similar to FDE, bullous SLE can involve sun-exposed and nonexposed areas of the skin as well as the mucous membranes with a predilection for the lower vermilion lip.17 In bullous SLE, tense subepidermal blisters with a neutrophil-rich infiltrate form due to circulating antibodies to type VII collagen. These blisters have an erythematous or urticated base, most commonly on the face, upper trunk, and proximal extremities.18 In both SLE with skin manifestations and lupus limited to the skin, bullae may form due to extensive vacuolar degeneration. Similar to TEN, they can form rapidly in a widespread distribution.17 However, there is limited mucosal involvement, no clear drug association, and a better prognosis. Bullae caused by lupus will frequently demonstrate deposition of immunoproteins IgG, IgM, IgA, and complement component 3 at the basement membrane zone in perilesional skin on direct immunofluorescence. However, negative direct immunofluorescence does not rule out lupus.12 At the same time, patients with lupus frequently have comorbidities requiring multiple medications; the need for these medications may predispose patients to higher rates of cutaneous drug eruptions.19 To our knowledge, there is no known association between FDE and lupus.
Conclusion
Patients with acute eruptions following the initiation of a new prescription or over-the-counter medication require urgent evaluation. Generalized bullous FDE requires timely diagnosis and intervention. Patients with lupus have an increased risk for cutaneous drug eruptions due to polypharmacy. Further investigation is necessary to determine if there is a pathophysiologic mechanism responsible for the development of FDE in lupus patients.
Recognizing cutaneous drug eruptions is important for treatment and prevention of recurrence. Fixed drug eruptions (FDEs) typically are harmless but can have major negative cosmetic consequences for patients. In its more severe forms, patients are at risk for widespread epithelial necrosis with accompanying complications. We report 1 patient with generalized FDE and 2 with generalized bullous FDE. We also discuss the recognition and treatment of the condition. Two patients previously had been diagnosed with systemic lupus erythematosus (SLE).
Case Series
Patient 1—A 60-year-old woman presented to dermatology with a rash on the trunk and groin folds of 4 days’ duration. She had a history of SLE and cutaneous lupus treated with hydroxychloroquine 200 mg twice daily and topical corticosteroids. She had started sulfamethoxazole-trimethoprim for a urinary tract infection with a rash appearing 1 day later. She reported burning skin pain with progression to blisters that “sloughed” off. She denied any known history of allergy to sulfa drugs. Prior to evaluation by dermatology, she visited an urgent care facility and was prescribed hydroxyzine and intramuscular corticosteroids. At presentation to dermatology 3 days after taking sulfamethoxazole-trimethoprim, she had annular flaccid bullae and superficial erosions with dusky borders on the right posterior thigh, right side of the chest, left inframammary fold, and right inguinal fold (Figure 1). She had no ocular, oral, or vaginal erosions. A diagnosis of generalized bullous FDE was favored over erythema multiforme or Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Shave biopsies from lesions on the right posterior thigh and right inguinal fold demonstrated interface dermatitis with epidermal necrosis, pigment incontinence, and numerous eosinophils. Direct immunofluorescence of the perilesional skin was negative for immunoprotein deposition. These findings were consistent with the clinical impression of generalized bullous FDE. Prior to receiving the histopathology report, the patient was initiated on a regimen of cyclosporine 5 mg/kg/d in the setting of normal renal function and followed until the eruption resolved completely. Cyclosporine was tapered at 2 weeks and discontinued at 3 weeks.
Patient 2—A 32-year-old woman presented for follow-up management of discoid lupus erythematosus. She had a history of systemic and cutaneous lupus, juvenile rheumatoid arthritis, and mixed connective tissue disease managed with prednisone, hydroxychloroquine, azathioprine, and belimumab. Physical examination revealed scarring alopecia with dyspigmentation and active inflammation consistent with uncontrolled cutaneous lupus. However, she also had oval-shaped hyperpigmented patches over the left breast, clavicle, and anterior chest consistent with a generalized FDE (Figure 2). The patient did not recall a history of similar lesions and could not identify a possible trigger. She was counseled on possible culprits and advised to avoid unnecessary medications. She had an unremarkable clinical course; therefore, no further intervention was necessary.
Patient 3—A 33-year-old man presented to the emergency department with a painful rash on the chest and back of 2 days’ duration that began 1 hour after taking naproxen (dosage unknown) for back pain. He had no notable medical history. The patient stated that the rash had slowly worsened and started to develop blisters. He visited an urgent care facility 1 day prior to the current presentation and was started on a 5-day course of prednisone 40 mg daily; the first 2 doses did not help. He denied any mucosal involvement apart from a tender lesion on the penis. He reported a history of an allergic reaction to penicillin. Physical examination revealed extensive dusky violaceous annular plaques with erythematous borders across the anterior and posterior trunk (Figure 3). Multiple flaccid bullae developed within these plaques, involving 15% of the body surface area. He was diagnosed with generalized bullous FDE based on the clinical history and histopathology. He was admitted to the burn intensive care unit and treated with cyclosporine 3 mg/kg/d with subsequent resolution of the eruption.
Comment
Presentation of FDEs—A fixed drug eruption manifests with 1 or more well-demarcated, red or violaceous, annular patches that resolve with postinflammatory hyperpigmentation; it occasionally may manifest with bullae. Initial eruptions may occur up to 2 weeks following medication exposure, but recurrent eruptions usually happen within minutes to hours later. They often are in the same location as prior lesions. A fixed drug eruption can be solitary, scattered, or generalized; a generalized FDE typically demonstrates multiple bilateral lesions that may itch, burn, or cause no symptoms. Patients can experience an FDE at any age, though the median age is reported as 35 to 60 years of age.1 A fixed drug eruption usually occurs after ingestion of oral medications, though there have been a few reports with iodinated contrast.2 Well-known culprits include antibiotics (eg, sulfamethoxazole-trimethoprim, tetracyclines, penicillins/cephalosporins, quinolones, dapsone), nonsteroidal anti-inflammatory drugs, acetaminophen (eg, paracetamol), barbiturates, antimalarials, and anticonvulsants. It also can occur with vaccines or with certain foods (fixed food eruption).3,4 Clinicians may try an oral drug challenge to identify the cause of an FDE, but in patients with a history of a generalized FDE, the risk for developing an increasingly severe reaction with repeated exposure to the medication is too high.5
Histopathology—Patch testing at the site of prior eruption with suspected drug culprits may be useful.6 Histopathology of FDE typically demonstrates vacuolar changes at the dermoepidermal junction with a lichenoid lymphocytic infiltrate. Early lesions often show a predominance of eosinophils. Subepidermal clefting is a feature of the bullous variant. In an active lesion, there are large numbers of CD8+ T lymphocytes expressing natural killer cell–associated molecules.7 The pathologic mechanism is not well understood, though it has been hypothesized that memory CD8+ cells are maintained in specific regions of the epidermis by IL-15 produced in the microenvironment and are activated upon rechallenge.7Considerations in Generalized Bullous FDE—Generalized FDE is defined in the literature as an FDE with involvement of 3 of 6 body areas: head, neck, trunk, upper limbs, lower limbs, and genital area. It may cover more or less than 10% of the body surface area.8-10 Although an isolated FDE frequently is asymptomatic and may not be cause for alarm, recurring drug eruptions increase the risk for development of generalized bullous FDE. Generalized bullous FDE is a rare subset. It is frequently misdiagnosed, and data on its incidence are uncertain.11 Of note, several pathologies causing bullous lesions may be in the differential diagnosis, including bullous pemphigoid; pemphigus vulgaris; bullous SLE; or bullae from cutaneous lupus, staphylococcal scalded skin syndrome, erythema multiforme, or SJS/TEN.12 When matched for body surface area involvement with SJS/TEN, generalized bullous FDE shares nearly identical mortality rates10; therefore, these patients should be treated with the same level of urgency and admitted to a critical care or burn unit, as they are at serious risk for infection and other complications.13
Clinical history and presentation along with histopathologic findings help to narrow down the differential diagnosis. Clinically, generalized bullous FDE does not affect the surrounding skin and manifests sooner after drug exposure (1–24 hours) with less mucosal involvement than SJS/TEN.9 Additionally, SJS/TEN patients frequently have generalized malaise and/or fever, while generalized bullous FDE patients do not. Finally, patients with generalized bullous FDE may report a history of a cutaneous eruption similar in morphology or in the same location.
Histopathologically, generalized bullous FDE may be similar to FDE with the addition of a subepidermal blister. Generalized bullous FDE patients have greater eosinophil infiltration and dermal melanophages than patients with SJS/TEN.9 Cellular infiltrates in generalized bullous FDE include more dermal CD41 cells, such as Foxp31 regulatory T cells; fewer intraepidermal CD561 cells; and fewer intraepidermal cells with granulysin.9 Occasionally, generalized bullous FDE causes full-thickness necrosis. In those cases, generalized bullous FDE cannot reliably be distinguished from other conditions with epidermal necrolysis on histopathology.13
FDE Diagnostics—A cytotoxin produced by
Management—Avoidance of the inciting drug often is sufficient for patients with an FDE, as demonstrated in patient 2 in our case series. Clinicians also should counsel patients on avoidance of potential cross-reacting drugs. Symptomatic treatment for itch or pain is appropriate and may include antihistamines or topical steroids. Nonsteroidal anti-inflammatory drugs may exacerbate or be causative of FDE. For generalized bullous FDE, cyclosporine is favored in the literature15,16 and was used to successfully treat both patients 1 and 3 in our case series. A short course of systemic corticosteroids or intravenous immunoglobulin also may be considered. Mild cases of generalized bullous FDE may be treated with close outpatient follow-up (patient 1), while severe cases require inpatient or even critical care monitoring with aggressive medical management to prevent the progression of skin desquamation (patient 3). Patients with severe oral lesions may require inpatient support for fluid maintenance.
Lupus History—Two patients in our case series had a history of lupus. Lupus itself can cause primary bullous lesions. Similar to FDE, bullous SLE can involve sun-exposed and nonexposed areas of the skin as well as the mucous membranes with a predilection for the lower vermilion lip.17 In bullous SLE, tense subepidermal blisters with a neutrophil-rich infiltrate form due to circulating antibodies to type VII collagen. These blisters have an erythematous or urticated base, most commonly on the face, upper trunk, and proximal extremities.18 In both SLE with skin manifestations and lupus limited to the skin, bullae may form due to extensive vacuolar degeneration. Similar to TEN, they can form rapidly in a widespread distribution.17 However, there is limited mucosal involvement, no clear drug association, and a better prognosis. Bullae caused by lupus will frequently demonstrate deposition of immunoproteins IgG, IgM, IgA, and complement component 3 at the basement membrane zone in perilesional skin on direct immunofluorescence. However, negative direct immunofluorescence does not rule out lupus.12 At the same time, patients with lupus frequently have comorbidities requiring multiple medications; the need for these medications may predispose patients to higher rates of cutaneous drug eruptions.19 To our knowledge, there is no known association between FDE and lupus.
Conclusion
Patients with acute eruptions following the initiation of a new prescription or over-the-counter medication require urgent evaluation. Generalized bullous FDE requires timely diagnosis and intervention. Patients with lupus have an increased risk for cutaneous drug eruptions due to polypharmacy. Further investigation is necessary to determine if there is a pathophysiologic mechanism responsible for the development of FDE in lupus patients.
- Anderson HJ, Lee JB. A review of fixed drug eruption with a special focus on generalized bullous fixed drug eruption. Medicina (Kaunas). 2021;57:925.
- Gavin M, Sharp L, Walker K, et al. Contrast-induced generalized bullous fixed drug eruption resembling Stevens-Johnson syndrome. Proc (Bayl Univ Med Cent). 2019;32:601-602.
- Kabir S, Feit EJ, Heilman ER. Generalized fixed drug eruption following Pfizer-BioNtech COVID-19 vaccination. Clin Case Rep. 2022;10:E6684.
- Choi S, Kim SH, Hwang JH, et al. Rapidly progressing generalized bullous fixed drug eruption after the first dose of COVID-19 messenger RNA vaccination. J Dermatol. 2023;50:1190-1193.
- Mahboob A, Haroon TS. Drugs causing fixed eruptions: a study of 450 cases. Int J Dermatol. 1998;37:833-838.
- Shiohara T. Fixed drug eruption: pathogenesis and diagnostic tests. Curr Opin Allergy Clin Immunol. 2009;9:316-321.
- Mizukawa Y, Yamazaki Y, Shiohara T. In vivo dynamics of intraepidermal CD8+ T cells and CD4+ T cells during the evolution of fixed drug eruption. Br J Dermatol. 2008;158:1230-1238.
- Lee CH, Chen YC, Cho YT, et al. Fixed-drug eruption: a retrospective study in a single referral center in northern Taiwan. Dermatologica Sinica. 2012;30:11-15.
- Cho YT, Lin JW, Chen YC, et al. Generalized bullous fixed drug eruption is distinct from Stevens-Johnson syndrome/toxic epidermal necrolysis by immunohistopathological features. J Am Acad Dermatol. 2014;70:539-548.
- Lipowicz S, Sekula P, Ingen-Housz-Oro S, et al. Prognosis of generalized bullous fixed drug eruption: comparison with Stevens-Johnson syndrome and toxic epidermal necrolysis. Br J Dermatol. 2013;168:726-732.
- Patel S, John AM, Handler MZ, et al. Fixed drug eruptions: an update, emphasizing the potentially lethal generalized bullous fixed drug eruption. Am J Clin Dermatol. 2020;21:393-399.
- Ranario JS, Smith JL. Bullous lesions in a patient with systemic lupus erythematosus. J Clin Aesthet Dermatol. 2014;7:44-49.
- Perron E, Viarnaud A, Marciano L, et al. Clinical and histological features of fixed drug eruption: a single-centre series of 73 cases with comparison between bullous and non-bullous forms. Eur J Dermatol. 2021;31:372-380.
- Chen CB, Kuo KL, Wang CW, et al. Detecting lesional granulysin levels for rapid diagnosis of cytotoxic T lymphocyte-mediated bullous skin disorders. J Allergy Clin Immunol Pract. 2021;9:1327-1337.e3.
- Beniwal R, Gupta LK, Khare AK, et al. Cyclosporine in generalized bullous-fixed drug eruption. Indian J Dermatol. 2018;63:432-433.
- Vargas Mora P, García S, Valenzuela F, et al. Generalized bullous fixed drug eruption successfully treated with cyclosporine. Dermatol Ther. 2020;33:E13492.
- Montagnon CM, Tolkachjov SN, Murrell DF, et al. Subepithelial autoimmune blistering dermatoses: clinical features and diagnosis. J Am Acad Dermatol. 2021;85:1-14.
- Sebaratnam DF, Murrell DF. Bullous systemic lupus erythematosus. Dermatol Clin. 2011;29:649-653.
- Zonzits E, Aberer W, Tappeiner G. Drug eruptions from mesna. After cyclophosphamide treatment of patients with systemic lupus erythematosus and dermatomyositis. Arch Dermatol. 1992;128:80-82.
- Anderson HJ, Lee JB. A review of fixed drug eruption with a special focus on generalized bullous fixed drug eruption. Medicina (Kaunas). 2021;57:925.
- Gavin M, Sharp L, Walker K, et al. Contrast-induced generalized bullous fixed drug eruption resembling Stevens-Johnson syndrome. Proc (Bayl Univ Med Cent). 2019;32:601-602.
- Kabir S, Feit EJ, Heilman ER. Generalized fixed drug eruption following Pfizer-BioNtech COVID-19 vaccination. Clin Case Rep. 2022;10:E6684.
- Choi S, Kim SH, Hwang JH, et al. Rapidly progressing generalized bullous fixed drug eruption after the first dose of COVID-19 messenger RNA vaccination. J Dermatol. 2023;50:1190-1193.
- Mahboob A, Haroon TS. Drugs causing fixed eruptions: a study of 450 cases. Int J Dermatol. 1998;37:833-838.
- Shiohara T. Fixed drug eruption: pathogenesis and diagnostic tests. Curr Opin Allergy Clin Immunol. 2009;9:316-321.
- Mizukawa Y, Yamazaki Y, Shiohara T. In vivo dynamics of intraepidermal CD8+ T cells and CD4+ T cells during the evolution of fixed drug eruption. Br J Dermatol. 2008;158:1230-1238.
- Lee CH, Chen YC, Cho YT, et al. Fixed-drug eruption: a retrospective study in a single referral center in northern Taiwan. Dermatologica Sinica. 2012;30:11-15.
- Cho YT, Lin JW, Chen YC, et al. Generalized bullous fixed drug eruption is distinct from Stevens-Johnson syndrome/toxic epidermal necrolysis by immunohistopathological features. J Am Acad Dermatol. 2014;70:539-548.
- Lipowicz S, Sekula P, Ingen-Housz-Oro S, et al. Prognosis of generalized bullous fixed drug eruption: comparison with Stevens-Johnson syndrome and toxic epidermal necrolysis. Br J Dermatol. 2013;168:726-732.
- Patel S, John AM, Handler MZ, et al. Fixed drug eruptions: an update, emphasizing the potentially lethal generalized bullous fixed drug eruption. Am J Clin Dermatol. 2020;21:393-399.
- Ranario JS, Smith JL. Bullous lesions in a patient with systemic lupus erythematosus. J Clin Aesthet Dermatol. 2014;7:44-49.
- Perron E, Viarnaud A, Marciano L, et al. Clinical and histological features of fixed drug eruption: a single-centre series of 73 cases with comparison between bullous and non-bullous forms. Eur J Dermatol. 2021;31:372-380.
- Chen CB, Kuo KL, Wang CW, et al. Detecting lesional granulysin levels for rapid diagnosis of cytotoxic T lymphocyte-mediated bullous skin disorders. J Allergy Clin Immunol Pract. 2021;9:1327-1337.e3.
- Beniwal R, Gupta LK, Khare AK, et al. Cyclosporine in generalized bullous-fixed drug eruption. Indian J Dermatol. 2018;63:432-433.
- Vargas Mora P, García S, Valenzuela F, et al. Generalized bullous fixed drug eruption successfully treated with cyclosporine. Dermatol Ther. 2020;33:E13492.
- Montagnon CM, Tolkachjov SN, Murrell DF, et al. Subepithelial autoimmune blistering dermatoses: clinical features and diagnosis. J Am Acad Dermatol. 2021;85:1-14.
- Sebaratnam DF, Murrell DF. Bullous systemic lupus erythematosus. Dermatol Clin. 2011;29:649-653.
- Zonzits E, Aberer W, Tappeiner G. Drug eruptions from mesna. After cyclophosphamide treatment of patients with systemic lupus erythematosus and dermatomyositis. Arch Dermatol. 1992;128:80-82.
Practice Points
- Although localized fixed drug eruption (FDE) is a relatively benign diagnosis, generalized bullous FDE requires urgent management and may necessitate intensive burn care.
- Patients with lupus are at increased risk for drug eruptions due to polypharmacy, and there is a wide differential for bullous eruptions in these patients.
Two New Studies on Benzoyl Peroxide Provide Reassuring Data on Safety
Two .
Earlier this year, controversy erupted after an independent lab Valisure petitioned the US Food and Drug Administration (FDA) to recall acne products with BP because it found extremely high levels of the carcinogen benzene. In the research, the lab directors contended that the products can form over 800 times the “conditionally restricted” FDA concentration limit of 2 parts per million (ppm) of benzene, with both prescription and over-the-counter (OTC) products affected. The issue, according to the lab’s report, is one of degradation, not contamination; BP can decompose into benzene. Exposures to benzene have been linked with a higher risk for leukemia and other blood cancers.
(“Conditionally restricted” means that the maximum of 2 ppm only applies to a drug product in which the use of benzene is unavoidable in order to produce a drug product with a significant therapeutic advance, according to FDA guidance.)
Critics of the report questioned the method used to test the products, calling for more “real-world” use data, and said the temperature used may not be what is expected with everyday use.
Now, both new studies are reassuring about the safety of the products, John Barbieri, MD, MBA, assistant professor of dermatology at Harvard Medical School and director of the Advanced Acne Therapeutics Clinic at Brigham and Women’s Hospital, Boston, said in a telephone interview. He was a coauthor of both studies. A leading dermatologist not involved in the new research reviewed the findings and agreed.
One study using data from the National Health and Nutrition Examination Survey compared blood levels of benzene between 14 people who had used BP products and 65 people without a history of BP product use, finding no difference between the groups .
The other, much larger study analyzed electronic health records of more than 27,000 patients with acne using BP products, comparing them with more than 27,000 controls who did not use the products. The patients were followed for 10 years after the use of BP products began, and no increased risk for cancer, either blood cancers or solid tumors, was found.
The studies were recently published in the Journal of the American Academy of Dermatology.
“Both studies are well done,” said Henry W. Lim, MD, former chair of the Department of Dermatology and senior vice president for academic affairs at Henry Ford Health, Detroit. Dr. Lim, a former president of the American Academy of Dermatology, reviewed the results of both studies.
“These studies indicate that [a] report of detection of benzene in [BP] products exposed to high temperature does not have any relevant clinical significance, both in terms of blood levels and in terms of internal cancer,” Dr. Lim said. “This is consistent with the clinical experience of practicing dermatologists; no internal side effects have been observed in patients using [BP products].”
Further Details
Under high temperatures, or over a long period, BP can decompose to benzene, a colorless, flammable liquid with a sweet odor. Benzene is formed from natural processes such as forest fires and volcanoes, according to the American Cancer Society, and is found in the air, cigarette smoke, some foods (at low levels), and contaminated drinking water. It’s one of the 20 widely used chemicals involved in making plastics, resins, detergents, and pesticides, among other products.
In the study evaluating blood levels, the researchers matched 14 people who used BP products currently with 65 controls who did not. Five (36%) of those using the products had detectable blood levels; 21 (32%) of those who did not use them did. There was no association between BP exposure and detectable blood benzene levels (odds ratio, 1.12; P = .80).
In the larger study, the researchers used the TriNetX US Collaborative Network database, comparing more than 27,000 patients treated with BP products for acne with more than 27,000 patients aged 12-40 years who had a diagnosis of nevus or seborrheic keratosis with no exposure to prescribed BP or any diagnosis of acne, hidradenitis suppurativa, or rosacea. The researchers looked at the database over the subsequent 10 years to determine the risk for either blood cancers or internal malignancies.
Compared with patients diagnosed with nevus or seborrheic keratosis, those with acne treated with BP had no significant difference in the risk for lymphoma (hazard ratio [HR], 1.00), leukemia (HR, 0.91), any lymphoma or leukemia (HR, 1.04), and internal malignancies (HR, 0.93).
The findings suggest no increased risk for malignancy, the researchers said, although they acknowledged study limitations, such as possible misclassification of BP exposure due to OTC availability and other issues.
Value of BP Treatments
BP is the “go-to” acne treatment, as Dr. Barbieri pointed out. “It’s probably the number one treatment for acne,” and there’s no substitute for it and it’s one of the most effective topical acne treatments, he noted.
Despite the reassuring findings, Dr. Barbieri repeated advice he gave soon after the Valisure report was released. Use common sense and don’t store BP-containing products in hot cars or other hot environments. In warmer climates, refrigeration could be considered, he said. Discard old products. Manufacturers should use cold-chain storage from the manufacturing site to retail or pharmacy sale sites, he added.
FDA and Citizen Petition Status
Asked about the status of the petition from Valisure, an FDA spokesperson said: “The FDA does not comment on the status of pending petitions.”
Dr. Barbieri and Dr. Lim had no relevant disclosures. There were no funding sources for either of the two studies.
A version of this article first appeared on Medscape.com.
Two .
Earlier this year, controversy erupted after an independent lab Valisure petitioned the US Food and Drug Administration (FDA) to recall acne products with BP because it found extremely high levels of the carcinogen benzene. In the research, the lab directors contended that the products can form over 800 times the “conditionally restricted” FDA concentration limit of 2 parts per million (ppm) of benzene, with both prescription and over-the-counter (OTC) products affected. The issue, according to the lab’s report, is one of degradation, not contamination; BP can decompose into benzene. Exposures to benzene have been linked with a higher risk for leukemia and other blood cancers.
(“Conditionally restricted” means that the maximum of 2 ppm only applies to a drug product in which the use of benzene is unavoidable in order to produce a drug product with a significant therapeutic advance, according to FDA guidance.)
Critics of the report questioned the method used to test the products, calling for more “real-world” use data, and said the temperature used may not be what is expected with everyday use.
Now, both new studies are reassuring about the safety of the products, John Barbieri, MD, MBA, assistant professor of dermatology at Harvard Medical School and director of the Advanced Acne Therapeutics Clinic at Brigham and Women’s Hospital, Boston, said in a telephone interview. He was a coauthor of both studies. A leading dermatologist not involved in the new research reviewed the findings and agreed.
One study using data from the National Health and Nutrition Examination Survey compared blood levels of benzene between 14 people who had used BP products and 65 people without a history of BP product use, finding no difference between the groups .
The other, much larger study analyzed electronic health records of more than 27,000 patients with acne using BP products, comparing them with more than 27,000 controls who did not use the products. The patients were followed for 10 years after the use of BP products began, and no increased risk for cancer, either blood cancers or solid tumors, was found.
The studies were recently published in the Journal of the American Academy of Dermatology.
“Both studies are well done,” said Henry W. Lim, MD, former chair of the Department of Dermatology and senior vice president for academic affairs at Henry Ford Health, Detroit. Dr. Lim, a former president of the American Academy of Dermatology, reviewed the results of both studies.
“These studies indicate that [a] report of detection of benzene in [BP] products exposed to high temperature does not have any relevant clinical significance, both in terms of blood levels and in terms of internal cancer,” Dr. Lim said. “This is consistent with the clinical experience of practicing dermatologists; no internal side effects have been observed in patients using [BP products].”
Further Details
Under high temperatures, or over a long period, BP can decompose to benzene, a colorless, flammable liquid with a sweet odor. Benzene is formed from natural processes such as forest fires and volcanoes, according to the American Cancer Society, and is found in the air, cigarette smoke, some foods (at low levels), and contaminated drinking water. It’s one of the 20 widely used chemicals involved in making plastics, resins, detergents, and pesticides, among other products.
In the study evaluating blood levels, the researchers matched 14 people who used BP products currently with 65 controls who did not. Five (36%) of those using the products had detectable blood levels; 21 (32%) of those who did not use them did. There was no association between BP exposure and detectable blood benzene levels (odds ratio, 1.12; P = .80).
In the larger study, the researchers used the TriNetX US Collaborative Network database, comparing more than 27,000 patients treated with BP products for acne with more than 27,000 patients aged 12-40 years who had a diagnosis of nevus or seborrheic keratosis with no exposure to prescribed BP or any diagnosis of acne, hidradenitis suppurativa, or rosacea. The researchers looked at the database over the subsequent 10 years to determine the risk for either blood cancers or internal malignancies.
Compared with patients diagnosed with nevus or seborrheic keratosis, those with acne treated with BP had no significant difference in the risk for lymphoma (hazard ratio [HR], 1.00), leukemia (HR, 0.91), any lymphoma or leukemia (HR, 1.04), and internal malignancies (HR, 0.93).
The findings suggest no increased risk for malignancy, the researchers said, although they acknowledged study limitations, such as possible misclassification of BP exposure due to OTC availability and other issues.
Value of BP Treatments
BP is the “go-to” acne treatment, as Dr. Barbieri pointed out. “It’s probably the number one treatment for acne,” and there’s no substitute for it and it’s one of the most effective topical acne treatments, he noted.
Despite the reassuring findings, Dr. Barbieri repeated advice he gave soon after the Valisure report was released. Use common sense and don’t store BP-containing products in hot cars or other hot environments. In warmer climates, refrigeration could be considered, he said. Discard old products. Manufacturers should use cold-chain storage from the manufacturing site to retail or pharmacy sale sites, he added.
FDA and Citizen Petition Status
Asked about the status of the petition from Valisure, an FDA spokesperson said: “The FDA does not comment on the status of pending petitions.”
Dr. Barbieri and Dr. Lim had no relevant disclosures. There were no funding sources for either of the two studies.
A version of this article first appeared on Medscape.com.
Two .
Earlier this year, controversy erupted after an independent lab Valisure petitioned the US Food and Drug Administration (FDA) to recall acne products with BP because it found extremely high levels of the carcinogen benzene. In the research, the lab directors contended that the products can form over 800 times the “conditionally restricted” FDA concentration limit of 2 parts per million (ppm) of benzene, with both prescription and over-the-counter (OTC) products affected. The issue, according to the lab’s report, is one of degradation, not contamination; BP can decompose into benzene. Exposures to benzene have been linked with a higher risk for leukemia and other blood cancers.
(“Conditionally restricted” means that the maximum of 2 ppm only applies to a drug product in which the use of benzene is unavoidable in order to produce a drug product with a significant therapeutic advance, according to FDA guidance.)
Critics of the report questioned the method used to test the products, calling for more “real-world” use data, and said the temperature used may not be what is expected with everyday use.
Now, both new studies are reassuring about the safety of the products, John Barbieri, MD, MBA, assistant professor of dermatology at Harvard Medical School and director of the Advanced Acne Therapeutics Clinic at Brigham and Women’s Hospital, Boston, said in a telephone interview. He was a coauthor of both studies. A leading dermatologist not involved in the new research reviewed the findings and agreed.
One study using data from the National Health and Nutrition Examination Survey compared blood levels of benzene between 14 people who had used BP products and 65 people without a history of BP product use, finding no difference between the groups .
The other, much larger study analyzed electronic health records of more than 27,000 patients with acne using BP products, comparing them with more than 27,000 controls who did not use the products. The patients were followed for 10 years after the use of BP products began, and no increased risk for cancer, either blood cancers or solid tumors, was found.
The studies were recently published in the Journal of the American Academy of Dermatology.
“Both studies are well done,” said Henry W. Lim, MD, former chair of the Department of Dermatology and senior vice president for academic affairs at Henry Ford Health, Detroit. Dr. Lim, a former president of the American Academy of Dermatology, reviewed the results of both studies.
“These studies indicate that [a] report of detection of benzene in [BP] products exposed to high temperature does not have any relevant clinical significance, both in terms of blood levels and in terms of internal cancer,” Dr. Lim said. “This is consistent with the clinical experience of practicing dermatologists; no internal side effects have been observed in patients using [BP products].”
Further Details
Under high temperatures, or over a long period, BP can decompose to benzene, a colorless, flammable liquid with a sweet odor. Benzene is formed from natural processes such as forest fires and volcanoes, according to the American Cancer Society, and is found in the air, cigarette smoke, some foods (at low levels), and contaminated drinking water. It’s one of the 20 widely used chemicals involved in making plastics, resins, detergents, and pesticides, among other products.
In the study evaluating blood levels, the researchers matched 14 people who used BP products currently with 65 controls who did not. Five (36%) of those using the products had detectable blood levels; 21 (32%) of those who did not use them did. There was no association between BP exposure and detectable blood benzene levels (odds ratio, 1.12; P = .80).
In the larger study, the researchers used the TriNetX US Collaborative Network database, comparing more than 27,000 patients treated with BP products for acne with more than 27,000 patients aged 12-40 years who had a diagnosis of nevus or seborrheic keratosis with no exposure to prescribed BP or any diagnosis of acne, hidradenitis suppurativa, or rosacea. The researchers looked at the database over the subsequent 10 years to determine the risk for either blood cancers or internal malignancies.
Compared with patients diagnosed with nevus or seborrheic keratosis, those with acne treated with BP had no significant difference in the risk for lymphoma (hazard ratio [HR], 1.00), leukemia (HR, 0.91), any lymphoma or leukemia (HR, 1.04), and internal malignancies (HR, 0.93).
The findings suggest no increased risk for malignancy, the researchers said, although they acknowledged study limitations, such as possible misclassification of BP exposure due to OTC availability and other issues.
Value of BP Treatments
BP is the “go-to” acne treatment, as Dr. Barbieri pointed out. “It’s probably the number one treatment for acne,” and there’s no substitute for it and it’s one of the most effective topical acne treatments, he noted.
Despite the reassuring findings, Dr. Barbieri repeated advice he gave soon after the Valisure report was released. Use common sense and don’t store BP-containing products in hot cars or other hot environments. In warmer climates, refrigeration could be considered, he said. Discard old products. Manufacturers should use cold-chain storage from the manufacturing site to retail or pharmacy sale sites, he added.
FDA and Citizen Petition Status
Asked about the status of the petition from Valisure, an FDA spokesperson said: “The FDA does not comment on the status of pending petitions.”
Dr. Barbieri and Dr. Lim had no relevant disclosures. There were no funding sources for either of the two studies.
A version of this article first appeared on Medscape.com.
Greater Transparency of Oncologists’ Pharma Relationships Needed
The findings reflect limited awareness in low-income countries about what scenarios constitute a conflict of interest, first author, Khalid El Bairi, MD, said during an interview. “There is a lack of training in ethics and integrity in medical schools [in countries in Africa], so people are not informed about conflicts of interest,” continued Dr. El Bairi, who presented the new research at the annual meeting of the American Society of Clinical Oncology. “There is also a lack of policies in universities and hospitals to guide clinicians about conflict of interest reporting.”
Overall, 58.5% of survey participants categorized honoraria as a conflict of interest that required disclosure, while 50% said the same of gifts from pharmaceutical representatives, and 44.5% identified travel grants for attending conferences as conflicts of interests. The report was published in JCO Global Oncology. Less often considered conflicts of interest were personal and institutional research funding, trips to conferences, consulting or advisory roles, food and beverages, expert testimony, and sample drugs provided by the pharmaceutical industry.
Just 24% of participants indicated that all of the listed items were deemed conflicts of interest. The survey — called Oncology Transparency Under Scrutiny and Tracking, or ONCOTRUST-1 — considered the perceptions of 200 oncologists, about 70% of whom practice in low- and middle-income countries.
What’s more, 37.5% of respondents identified fear of losing financial support as a reason not to report a conflict of interest. Still, 75% indicated that industry-sponsored speaking does not affect treatment decisions, and 60% said conflicts of interest do not impair objective appraisal of clinical trials.
Dr. El Bairi, a research associate in the department of medical oncology at Mohammed VI University Hospital, Oujda, Morocco, and his colleagues undertook the study in part because of an editorial published in The Lancet Oncology last year. First author Fidel Rubagumya, MD, a consultant oncologist and director of research at Rwanda Military Hospital, Kigali, and colleagues called for more research on the ties between oncologists and industry in Africa. The ONCOTRUST-1 findings set the stage for a planned follow-up study, which aims to compare views surrounding conflicts of interests between oncologists in different economic settings.
Open Payments Houses US Physicians’ Conflicts of Interest
To be sure, many authors of research published in major US journals are based outside of the United States. According to JAMA Network Open, 69% of submissions to the journal are from international authors. However, Dr. El Bairi also raised other potential signs of industry influence that he said need global discussion, such as the role of pharmaceutical companies in presentations of clinical trial findings at large cancer societies’ conferences, a shift toward progression-free survival as the endpoint in clinical cancer trials, and the rise of third-party writing assistance.
“There are two sides of the story,” Dr. El Bairi said. “The good side is that unfortunately, sometimes [industry money is] the only way for African oncologists to go abroad for training, to conferences for their continuous medical education. The bad is now we may harm patients, we might harm science by having conflicts of interest not reported.”
Unlike other countries, the United States has plentiful data on the scale of physicians’ financial conflicts of interest in the form of the Open Payments platform. Championed by Sen. Chuck Grassley (R-Iowa), the federal repository of payments to doctors and teaching hospitals by drug and medical device companies was established as part of the Affordable Care Act (ACA).
The health care reform law, which passed in 2010, requires pharmaceutical companies and medical device makers to report this information.
From 2013 to 2021, the pharmaceutical and medical device industry paid physicians $12.1 billion, according to a research letter published in JAMA in March of 2024 that reviewed Open Payments data.
Ranked by specialty, hematologists and oncologists received the fourth-largest amount of money in aggregate, the study shows. Their total of $825.8 million trailed only physicians in orthopedics ($1.36 billion), neurology and psychiatry ($1.32 billion) and cardiology ($1.29 billion). What’s more, this specialty had the biggest share of physicians taking industry money, with 74.2% of hematologists and oncologists receiving payments.
The payments from industry include fees for consulting services and speaking, as well as food and beverages, travel and lodging, education, gifts, grants, and honoraria.
Joseph S. Ross, MD, MHS, one of the JAMA study’s coauthors, said in an interview that the continued prevalence of such funding runs counter to the expectation behind the measure, which was that transparency would lead to physicians’ becoming less likely to accept a payment.
“We as a profession need to take a cold hard look in the mirror,” he said, referring to physicians in general.
Dr. Ross, professor of medicine at Yale University School of Medicine, New Haven, Connecticut, said he hopes that the profession will self-police, and that patients will make a bigger deal of the issue. Still, he acknowledged that “the vast majority” of patient advocacy groups, too, are funded by the pharmaceutical industry.
Exposing Industry Payments May Have Perverse Effect
A growing body of research explores the effect that physicians’ financial relationships with pharmaceutical companies can have on their prescribing practices. Indeed, oncologists taking industry payments seem to be more likely to prescribe nonrecommended and low-value drugs in some clinical settings, according to a study published in The BMJ last year.
That study’s first author, Aaron P. Mitchell, MD, a medical oncologist and assistant attending physician at Memorial Sloan Kettering Cancer Center, New York City, suggested in an interview that exposing industry payments to the sunlight may have had a perverse effect on physicians.
“There’s this idea of having license to do something,” Dr. Mitchell said, speaking broadly about human psychology rather than drawing on empirical data. “You might feel a little less bad about then prescribing more of that company’s drug, because the disclosure has already been done.”
The influence of pharmaceutical industry money on oncologists goes beyond what’s prescribed to which treatments get studied, approved, and recommended by guidelines, Dr. Mitchell said. He was also first author of a 2016 paper published in JAMA Oncology that found 86% of authors of the National Comprehensive Cancer Network guidelines had at least one conflict of interest reported on Open Systems in 2014.
Meanwhile, the fact that physicians’ payments from industry are a matter of public record on Open Systems has not guaranteed that doctors will disclose their conflicts of interest in other forums. A study published in JAMA earlier this year, for which Dr. Mitchell served as first author, found that almost one in three physicians endorsing drugs and devices on the social media platform X failed to disclose that the manufacturer paid them.
The lack of disclosure seems to extend beyond social media. A 2018 study published in JAMA Oncology found that 32% of oncologist authors of clinical drug trials for drugs approved over a 20-month period from 2016 to 2017 did not fully disclose payments from the trial sponsor when checked against the Open Payments database.
A lion’s share of industry payments within oncology appears to be going to a small group of high-profile physicians, suggested a 2022 study published in JCO Oncology Practice. It found that just 1% of all US oncologists accounted for 37% of industry payments, with each receiving more than $100,000 a year.
Experts: Professional Societies Should Further Limit Industry Payments
While partnerships between drug companies and physicians are necessary and have often been positive, more than disclosure is needed to minimize the risk of patient harm, according to an editorial published in March in JCO Oncology Practice. In it, Nina Niu Sanford, MD, a radiation oncologist UT Southwestern Medical Center, Dallas, and Bishal Gyawali, MD, PhD, a medical oncologist at Queen’s University, Kingston, Ontario, Canada, argue that following a specific blueprint could help mitigate financial conflicts of interest.
For starters, Dr. Sanford and Dr. Gyawali contend in the editorial that the maximum general payment NCCN members are allowed to receive from industry should be $0, compared with a current bar of $20,000 from a single entity or $50,000 from all external entities combined. They also urge professional societies to follow the current policy of the American Society of Clinical Oncology and ban members serving in their leadership from receiving any general payments from the industry.
The authors further suggest that investigators of clinical trials should be barred from holding stock for the drug or product while it is under study and that editorialists should not have conflicts of interest with the company whose drug or product they are discussing.
Pharmaceutical money can harm patients in ways that are not always obvious, Dr. Gyawali said in an interview.
“It can dominate the conversation by removing critical viewpoints from these top people about certain drugs,” he said. “It’s not always about saying good things about the drug.”
For instance, he suggested, a doctor receiving payments from Pfizer might openly criticize perceived flaws in drugs from other companies but refrain from weighing in negatively on a Pfizer drug.
From 2016 to 2018, industry made general payments to more than 52,000 physicians for 137 unique cancer drugs, according to a separate 2021 study published in the Journal of Cancer Policy, for which Dr. Gyawali served as one of the coauthors.
The results suggest that pharmaceutical money affects the entire cancer system, not relatively few oncology leaders. The amounts and dollar values grew each year covered by the study, to nearly 466,000 payments totaling $98.5 million in 2018.
Adriane Fugh-Berman, MD, professor of pharmacology and physiology at Georgetown University, Washington, DC, and director of PharmedOut, a Georgetown-based project that advances evidence-based prescribing and educates healthcare professionals about pharmaceutical marketing practices, has called for a ban on industry gifts to physicians.
When a publication asks physicians to disclose relevant conflicts of interest, physicians may choose not to disclose, because they don’t feel that their conflicts are relevant, Dr. Fugh-Berman said. Drug and device makers have also grown sophisticated about how they work with physicians, she suggested. “It’s illegal to market a drug before it comes on the market, but it’s not illegal to market the disease,” said Dr. Fugh-Berman, noting that drugmakers often work on long timelines.
“The doctor is going around saying we don’t have good therapies. They’re not pushing a drug. And so they feel totally fine about it.”
Anecdotally, Dr. Fugh-Berman noted that, if anything, speaking fees and similar payments only improve doctors’ reputations. She said that’s especially true if the physicians are paid by multiple companies, on the supposed theory that their conflicts of interest cancel each other out.
“I’m not defending this,” added Dr. Fugh-Berman, observing that, at the end of the day, such conflicts may go against the interests of patients.
“Sometimes the best drugs are older, generic, cheap drugs, and if oncologists or other specialists are only choosing among the most promoted drugs, they’re not necessarily choosing the best drugs.”
Beyond any prestige, doctors have other possible nonfinancial incentives for receiving industry payments. “It’s the relationships,” Dr. Fugh-Berman said. “Companies are very good at offering friendship.”
Dr. El Bairi reported NCODA leadership and honoraria along with expert testimony through techspert.io. Dr. Ross reported that he is a deputy editor of JAMA but was not involved in decisions regarding acceptance of or the review of the manuscript he authored and discussed in this article. Dr. Ross also reported receiving grants from the Food and Drug Administration, Johnson & Johnson, the Medical Device Innovation Consortium, the Agency for Healthcare Research and Quality, and the National Heart, Lung, and Blood Institute. He was an expert witness in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen that was settled in 2022. Dr. Mitchell reported no relevant financial relationships. Dr. Gyawali reported a consulting or advisory role with Vivio Health. Dr. Fugh-Berman reported being an expert witness for plaintiffs in complaints about drug and device marketing practices.
The findings reflect limited awareness in low-income countries about what scenarios constitute a conflict of interest, first author, Khalid El Bairi, MD, said during an interview. “There is a lack of training in ethics and integrity in medical schools [in countries in Africa], so people are not informed about conflicts of interest,” continued Dr. El Bairi, who presented the new research at the annual meeting of the American Society of Clinical Oncology. “There is also a lack of policies in universities and hospitals to guide clinicians about conflict of interest reporting.”
Overall, 58.5% of survey participants categorized honoraria as a conflict of interest that required disclosure, while 50% said the same of gifts from pharmaceutical representatives, and 44.5% identified travel grants for attending conferences as conflicts of interests. The report was published in JCO Global Oncology. Less often considered conflicts of interest were personal and institutional research funding, trips to conferences, consulting or advisory roles, food and beverages, expert testimony, and sample drugs provided by the pharmaceutical industry.
Just 24% of participants indicated that all of the listed items were deemed conflicts of interest. The survey — called Oncology Transparency Under Scrutiny and Tracking, or ONCOTRUST-1 — considered the perceptions of 200 oncologists, about 70% of whom practice in low- and middle-income countries.
What’s more, 37.5% of respondents identified fear of losing financial support as a reason not to report a conflict of interest. Still, 75% indicated that industry-sponsored speaking does not affect treatment decisions, and 60% said conflicts of interest do not impair objective appraisal of clinical trials.
Dr. El Bairi, a research associate in the department of medical oncology at Mohammed VI University Hospital, Oujda, Morocco, and his colleagues undertook the study in part because of an editorial published in The Lancet Oncology last year. First author Fidel Rubagumya, MD, a consultant oncologist and director of research at Rwanda Military Hospital, Kigali, and colleagues called for more research on the ties between oncologists and industry in Africa. The ONCOTRUST-1 findings set the stage for a planned follow-up study, which aims to compare views surrounding conflicts of interests between oncologists in different economic settings.
Open Payments Houses US Physicians’ Conflicts of Interest
To be sure, many authors of research published in major US journals are based outside of the United States. According to JAMA Network Open, 69% of submissions to the journal are from international authors. However, Dr. El Bairi also raised other potential signs of industry influence that he said need global discussion, such as the role of pharmaceutical companies in presentations of clinical trial findings at large cancer societies’ conferences, a shift toward progression-free survival as the endpoint in clinical cancer trials, and the rise of third-party writing assistance.
“There are two sides of the story,” Dr. El Bairi said. “The good side is that unfortunately, sometimes [industry money is] the only way for African oncologists to go abroad for training, to conferences for their continuous medical education. The bad is now we may harm patients, we might harm science by having conflicts of interest not reported.”
Unlike other countries, the United States has plentiful data on the scale of physicians’ financial conflicts of interest in the form of the Open Payments platform. Championed by Sen. Chuck Grassley (R-Iowa), the federal repository of payments to doctors and teaching hospitals by drug and medical device companies was established as part of the Affordable Care Act (ACA).
The health care reform law, which passed in 2010, requires pharmaceutical companies and medical device makers to report this information.
From 2013 to 2021, the pharmaceutical and medical device industry paid physicians $12.1 billion, according to a research letter published in JAMA in March of 2024 that reviewed Open Payments data.
Ranked by specialty, hematologists and oncologists received the fourth-largest amount of money in aggregate, the study shows. Their total of $825.8 million trailed only physicians in orthopedics ($1.36 billion), neurology and psychiatry ($1.32 billion) and cardiology ($1.29 billion). What’s more, this specialty had the biggest share of physicians taking industry money, with 74.2% of hematologists and oncologists receiving payments.
The payments from industry include fees for consulting services and speaking, as well as food and beverages, travel and lodging, education, gifts, grants, and honoraria.
Joseph S. Ross, MD, MHS, one of the JAMA study’s coauthors, said in an interview that the continued prevalence of such funding runs counter to the expectation behind the measure, which was that transparency would lead to physicians’ becoming less likely to accept a payment.
“We as a profession need to take a cold hard look in the mirror,” he said, referring to physicians in general.
Dr. Ross, professor of medicine at Yale University School of Medicine, New Haven, Connecticut, said he hopes that the profession will self-police, and that patients will make a bigger deal of the issue. Still, he acknowledged that “the vast majority” of patient advocacy groups, too, are funded by the pharmaceutical industry.
Exposing Industry Payments May Have Perverse Effect
A growing body of research explores the effect that physicians’ financial relationships with pharmaceutical companies can have on their prescribing practices. Indeed, oncologists taking industry payments seem to be more likely to prescribe nonrecommended and low-value drugs in some clinical settings, according to a study published in The BMJ last year.
That study’s first author, Aaron P. Mitchell, MD, a medical oncologist and assistant attending physician at Memorial Sloan Kettering Cancer Center, New York City, suggested in an interview that exposing industry payments to the sunlight may have had a perverse effect on physicians.
“There’s this idea of having license to do something,” Dr. Mitchell said, speaking broadly about human psychology rather than drawing on empirical data. “You might feel a little less bad about then prescribing more of that company’s drug, because the disclosure has already been done.”
The influence of pharmaceutical industry money on oncologists goes beyond what’s prescribed to which treatments get studied, approved, and recommended by guidelines, Dr. Mitchell said. He was also first author of a 2016 paper published in JAMA Oncology that found 86% of authors of the National Comprehensive Cancer Network guidelines had at least one conflict of interest reported on Open Systems in 2014.
Meanwhile, the fact that physicians’ payments from industry are a matter of public record on Open Systems has not guaranteed that doctors will disclose their conflicts of interest in other forums. A study published in JAMA earlier this year, for which Dr. Mitchell served as first author, found that almost one in three physicians endorsing drugs and devices on the social media platform X failed to disclose that the manufacturer paid them.
The lack of disclosure seems to extend beyond social media. A 2018 study published in JAMA Oncology found that 32% of oncologist authors of clinical drug trials for drugs approved over a 20-month period from 2016 to 2017 did not fully disclose payments from the trial sponsor when checked against the Open Payments database.
A lion’s share of industry payments within oncology appears to be going to a small group of high-profile physicians, suggested a 2022 study published in JCO Oncology Practice. It found that just 1% of all US oncologists accounted for 37% of industry payments, with each receiving more than $100,000 a year.
Experts: Professional Societies Should Further Limit Industry Payments
While partnerships between drug companies and physicians are necessary and have often been positive, more than disclosure is needed to minimize the risk of patient harm, according to an editorial published in March in JCO Oncology Practice. In it, Nina Niu Sanford, MD, a radiation oncologist UT Southwestern Medical Center, Dallas, and Bishal Gyawali, MD, PhD, a medical oncologist at Queen’s University, Kingston, Ontario, Canada, argue that following a specific blueprint could help mitigate financial conflicts of interest.
For starters, Dr. Sanford and Dr. Gyawali contend in the editorial that the maximum general payment NCCN members are allowed to receive from industry should be $0, compared with a current bar of $20,000 from a single entity or $50,000 from all external entities combined. They also urge professional societies to follow the current policy of the American Society of Clinical Oncology and ban members serving in their leadership from receiving any general payments from the industry.
The authors further suggest that investigators of clinical trials should be barred from holding stock for the drug or product while it is under study and that editorialists should not have conflicts of interest with the company whose drug or product they are discussing.
Pharmaceutical money can harm patients in ways that are not always obvious, Dr. Gyawali said in an interview.
“It can dominate the conversation by removing critical viewpoints from these top people about certain drugs,” he said. “It’s not always about saying good things about the drug.”
For instance, he suggested, a doctor receiving payments from Pfizer might openly criticize perceived flaws in drugs from other companies but refrain from weighing in negatively on a Pfizer drug.
From 2016 to 2018, industry made general payments to more than 52,000 physicians for 137 unique cancer drugs, according to a separate 2021 study published in the Journal of Cancer Policy, for which Dr. Gyawali served as one of the coauthors.
The results suggest that pharmaceutical money affects the entire cancer system, not relatively few oncology leaders. The amounts and dollar values grew each year covered by the study, to nearly 466,000 payments totaling $98.5 million in 2018.
Adriane Fugh-Berman, MD, professor of pharmacology and physiology at Georgetown University, Washington, DC, and director of PharmedOut, a Georgetown-based project that advances evidence-based prescribing and educates healthcare professionals about pharmaceutical marketing practices, has called for a ban on industry gifts to physicians.
When a publication asks physicians to disclose relevant conflicts of interest, physicians may choose not to disclose, because they don’t feel that their conflicts are relevant, Dr. Fugh-Berman said. Drug and device makers have also grown sophisticated about how they work with physicians, she suggested. “It’s illegal to market a drug before it comes on the market, but it’s not illegal to market the disease,” said Dr. Fugh-Berman, noting that drugmakers often work on long timelines.
“The doctor is going around saying we don’t have good therapies. They’re not pushing a drug. And so they feel totally fine about it.”
Anecdotally, Dr. Fugh-Berman noted that, if anything, speaking fees and similar payments only improve doctors’ reputations. She said that’s especially true if the physicians are paid by multiple companies, on the supposed theory that their conflicts of interest cancel each other out.
“I’m not defending this,” added Dr. Fugh-Berman, observing that, at the end of the day, such conflicts may go against the interests of patients.
“Sometimes the best drugs are older, generic, cheap drugs, and if oncologists or other specialists are only choosing among the most promoted drugs, they’re not necessarily choosing the best drugs.”
Beyond any prestige, doctors have other possible nonfinancial incentives for receiving industry payments. “It’s the relationships,” Dr. Fugh-Berman said. “Companies are very good at offering friendship.”
Dr. El Bairi reported NCODA leadership and honoraria along with expert testimony through techspert.io. Dr. Ross reported that he is a deputy editor of JAMA but was not involved in decisions regarding acceptance of or the review of the manuscript he authored and discussed in this article. Dr. Ross also reported receiving grants from the Food and Drug Administration, Johnson & Johnson, the Medical Device Innovation Consortium, the Agency for Healthcare Research and Quality, and the National Heart, Lung, and Blood Institute. He was an expert witness in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen that was settled in 2022. Dr. Mitchell reported no relevant financial relationships. Dr. Gyawali reported a consulting or advisory role with Vivio Health. Dr. Fugh-Berman reported being an expert witness for plaintiffs in complaints about drug and device marketing practices.
The findings reflect limited awareness in low-income countries about what scenarios constitute a conflict of interest, first author, Khalid El Bairi, MD, said during an interview. “There is a lack of training in ethics and integrity in medical schools [in countries in Africa], so people are not informed about conflicts of interest,” continued Dr. El Bairi, who presented the new research at the annual meeting of the American Society of Clinical Oncology. “There is also a lack of policies in universities and hospitals to guide clinicians about conflict of interest reporting.”
Overall, 58.5% of survey participants categorized honoraria as a conflict of interest that required disclosure, while 50% said the same of gifts from pharmaceutical representatives, and 44.5% identified travel grants for attending conferences as conflicts of interests. The report was published in JCO Global Oncology. Less often considered conflicts of interest were personal and institutional research funding, trips to conferences, consulting or advisory roles, food and beverages, expert testimony, and sample drugs provided by the pharmaceutical industry.
Just 24% of participants indicated that all of the listed items were deemed conflicts of interest. The survey — called Oncology Transparency Under Scrutiny and Tracking, or ONCOTRUST-1 — considered the perceptions of 200 oncologists, about 70% of whom practice in low- and middle-income countries.
What’s more, 37.5% of respondents identified fear of losing financial support as a reason not to report a conflict of interest. Still, 75% indicated that industry-sponsored speaking does not affect treatment decisions, and 60% said conflicts of interest do not impair objective appraisal of clinical trials.
Dr. El Bairi, a research associate in the department of medical oncology at Mohammed VI University Hospital, Oujda, Morocco, and his colleagues undertook the study in part because of an editorial published in The Lancet Oncology last year. First author Fidel Rubagumya, MD, a consultant oncologist and director of research at Rwanda Military Hospital, Kigali, and colleagues called for more research on the ties between oncologists and industry in Africa. The ONCOTRUST-1 findings set the stage for a planned follow-up study, which aims to compare views surrounding conflicts of interests between oncologists in different economic settings.
Open Payments Houses US Physicians’ Conflicts of Interest
To be sure, many authors of research published in major US journals are based outside of the United States. According to JAMA Network Open, 69% of submissions to the journal are from international authors. However, Dr. El Bairi also raised other potential signs of industry influence that he said need global discussion, such as the role of pharmaceutical companies in presentations of clinical trial findings at large cancer societies’ conferences, a shift toward progression-free survival as the endpoint in clinical cancer trials, and the rise of third-party writing assistance.
“There are two sides of the story,” Dr. El Bairi said. “The good side is that unfortunately, sometimes [industry money is] the only way for African oncologists to go abroad for training, to conferences for their continuous medical education. The bad is now we may harm patients, we might harm science by having conflicts of interest not reported.”
Unlike other countries, the United States has plentiful data on the scale of physicians’ financial conflicts of interest in the form of the Open Payments platform. Championed by Sen. Chuck Grassley (R-Iowa), the federal repository of payments to doctors and teaching hospitals by drug and medical device companies was established as part of the Affordable Care Act (ACA).
The health care reform law, which passed in 2010, requires pharmaceutical companies and medical device makers to report this information.
From 2013 to 2021, the pharmaceutical and medical device industry paid physicians $12.1 billion, according to a research letter published in JAMA in March of 2024 that reviewed Open Payments data.
Ranked by specialty, hematologists and oncologists received the fourth-largest amount of money in aggregate, the study shows. Their total of $825.8 million trailed only physicians in orthopedics ($1.36 billion), neurology and psychiatry ($1.32 billion) and cardiology ($1.29 billion). What’s more, this specialty had the biggest share of physicians taking industry money, with 74.2% of hematologists and oncologists receiving payments.
The payments from industry include fees for consulting services and speaking, as well as food and beverages, travel and lodging, education, gifts, grants, and honoraria.
Joseph S. Ross, MD, MHS, one of the JAMA study’s coauthors, said in an interview that the continued prevalence of such funding runs counter to the expectation behind the measure, which was that transparency would lead to physicians’ becoming less likely to accept a payment.
“We as a profession need to take a cold hard look in the mirror,” he said, referring to physicians in general.
Dr. Ross, professor of medicine at Yale University School of Medicine, New Haven, Connecticut, said he hopes that the profession will self-police, and that patients will make a bigger deal of the issue. Still, he acknowledged that “the vast majority” of patient advocacy groups, too, are funded by the pharmaceutical industry.
Exposing Industry Payments May Have Perverse Effect
A growing body of research explores the effect that physicians’ financial relationships with pharmaceutical companies can have on their prescribing practices. Indeed, oncologists taking industry payments seem to be more likely to prescribe nonrecommended and low-value drugs in some clinical settings, according to a study published in The BMJ last year.
That study’s first author, Aaron P. Mitchell, MD, a medical oncologist and assistant attending physician at Memorial Sloan Kettering Cancer Center, New York City, suggested in an interview that exposing industry payments to the sunlight may have had a perverse effect on physicians.
“There’s this idea of having license to do something,” Dr. Mitchell said, speaking broadly about human psychology rather than drawing on empirical data. “You might feel a little less bad about then prescribing more of that company’s drug, because the disclosure has already been done.”
The influence of pharmaceutical industry money on oncologists goes beyond what’s prescribed to which treatments get studied, approved, and recommended by guidelines, Dr. Mitchell said. He was also first author of a 2016 paper published in JAMA Oncology that found 86% of authors of the National Comprehensive Cancer Network guidelines had at least one conflict of interest reported on Open Systems in 2014.
Meanwhile, the fact that physicians’ payments from industry are a matter of public record on Open Systems has not guaranteed that doctors will disclose their conflicts of interest in other forums. A study published in JAMA earlier this year, for which Dr. Mitchell served as first author, found that almost one in three physicians endorsing drugs and devices on the social media platform X failed to disclose that the manufacturer paid them.
The lack of disclosure seems to extend beyond social media. A 2018 study published in JAMA Oncology found that 32% of oncologist authors of clinical drug trials for drugs approved over a 20-month period from 2016 to 2017 did not fully disclose payments from the trial sponsor when checked against the Open Payments database.
A lion’s share of industry payments within oncology appears to be going to a small group of high-profile physicians, suggested a 2022 study published in JCO Oncology Practice. It found that just 1% of all US oncologists accounted for 37% of industry payments, with each receiving more than $100,000 a year.
Experts: Professional Societies Should Further Limit Industry Payments
While partnerships between drug companies and physicians are necessary and have often been positive, more than disclosure is needed to minimize the risk of patient harm, according to an editorial published in March in JCO Oncology Practice. In it, Nina Niu Sanford, MD, a radiation oncologist UT Southwestern Medical Center, Dallas, and Bishal Gyawali, MD, PhD, a medical oncologist at Queen’s University, Kingston, Ontario, Canada, argue that following a specific blueprint could help mitigate financial conflicts of interest.
For starters, Dr. Sanford and Dr. Gyawali contend in the editorial that the maximum general payment NCCN members are allowed to receive from industry should be $0, compared with a current bar of $20,000 from a single entity or $50,000 from all external entities combined. They also urge professional societies to follow the current policy of the American Society of Clinical Oncology and ban members serving in their leadership from receiving any general payments from the industry.
The authors further suggest that investigators of clinical trials should be barred from holding stock for the drug or product while it is under study and that editorialists should not have conflicts of interest with the company whose drug or product they are discussing.
Pharmaceutical money can harm patients in ways that are not always obvious, Dr. Gyawali said in an interview.
“It can dominate the conversation by removing critical viewpoints from these top people about certain drugs,” he said. “It’s not always about saying good things about the drug.”
For instance, he suggested, a doctor receiving payments from Pfizer might openly criticize perceived flaws in drugs from other companies but refrain from weighing in negatively on a Pfizer drug.
From 2016 to 2018, industry made general payments to more than 52,000 physicians for 137 unique cancer drugs, according to a separate 2021 study published in the Journal of Cancer Policy, for which Dr. Gyawali served as one of the coauthors.
The results suggest that pharmaceutical money affects the entire cancer system, not relatively few oncology leaders. The amounts and dollar values grew each year covered by the study, to nearly 466,000 payments totaling $98.5 million in 2018.
Adriane Fugh-Berman, MD, professor of pharmacology and physiology at Georgetown University, Washington, DC, and director of PharmedOut, a Georgetown-based project that advances evidence-based prescribing and educates healthcare professionals about pharmaceutical marketing practices, has called for a ban on industry gifts to physicians.
When a publication asks physicians to disclose relevant conflicts of interest, physicians may choose not to disclose, because they don’t feel that their conflicts are relevant, Dr. Fugh-Berman said. Drug and device makers have also grown sophisticated about how they work with physicians, she suggested. “It’s illegal to market a drug before it comes on the market, but it’s not illegal to market the disease,” said Dr. Fugh-Berman, noting that drugmakers often work on long timelines.
“The doctor is going around saying we don’t have good therapies. They’re not pushing a drug. And so they feel totally fine about it.”
Anecdotally, Dr. Fugh-Berman noted that, if anything, speaking fees and similar payments only improve doctors’ reputations. She said that’s especially true if the physicians are paid by multiple companies, on the supposed theory that their conflicts of interest cancel each other out.
“I’m not defending this,” added Dr. Fugh-Berman, observing that, at the end of the day, such conflicts may go against the interests of patients.
“Sometimes the best drugs are older, generic, cheap drugs, and if oncologists or other specialists are only choosing among the most promoted drugs, they’re not necessarily choosing the best drugs.”
Beyond any prestige, doctors have other possible nonfinancial incentives for receiving industry payments. “It’s the relationships,” Dr. Fugh-Berman said. “Companies are very good at offering friendship.”
Dr. El Bairi reported NCODA leadership and honoraria along with expert testimony through techspert.io. Dr. Ross reported that he is a deputy editor of JAMA but was not involved in decisions regarding acceptance of or the review of the manuscript he authored and discussed in this article. Dr. Ross also reported receiving grants from the Food and Drug Administration, Johnson & Johnson, the Medical Device Innovation Consortium, the Agency for Healthcare Research and Quality, and the National Heart, Lung, and Blood Institute. He was an expert witness in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen that was settled in 2022. Dr. Mitchell reported no relevant financial relationships. Dr. Gyawali reported a consulting or advisory role with Vivio Health. Dr. Fugh-Berman reported being an expert witness for plaintiffs in complaints about drug and device marketing practices.
FROM ASCO 2024
Munchausen Syndrome by Proxy: Be Aware of Cutaneous Signs
TORONTO — Be suspicious if a child with a severe dermatologic condition is unresponsive to treatment, especially if their parent or caregiver exhibits deceptive behavior.
These could be red flags for Munchausen syndrome by proxy (MSBP), also known as factitious disorder.
“The No. 1 thing dermatologists can do in situations like this is be open to thinking outside the box and ask themselves the difficult question: Could this be something the parent is inflicting on the child,” Kelly Frasier, DO, a dermatology clinical trials and epidemiology research fellow at Northwell Health, Poughkeepsie, New York, said in an interview.
She provided a review on advancing the understanding of the dermatologic manifestations of MSBP during a poster session at the annual meeting of the Society for Pediatric Dermatology (SPD). Dr. Frasier has a particular interest in psychodermatology — she was a mental health therapist before going to medical school.
MSBP is a type of abuse intentionally inflicted by a caregiver typically on their child “for some ulterior motive,” usually to seek attention or sympathy and not for material or financial gain, explained Dr. Frasier. People with MSBP seek medical help for exaggerated or fabricated symptoms in their child. They may alter medical tests, falsify medical records, or induce symptoms in their child.
To do this, these abusers may apply any number of caustic household products, including glue, directly to the child’s skin or even in formula. Dr. Frasier shared a picture of a baby whose formula had been doctored with a caustic substance that had dripped onto his neck and face, causing a rash with blisters.
In addition to blistering, cutaneous manifestations of MSBP can include severe bruising. Or the child may present with signs similar to those of granuloma annulare (a benign condition characterized by small, raised bumps) or cicatricial pemphigoid (a rare, chronic autoimmune blistering disorder) or may have recurrent nail avulsion, purpura, or coagulopathy, said Dr. Frasier.
In almost all cases of MSBP (an estimated 96%), the abuse is inflicted by the mother, who may have a preexisting mental illness. “Usually, a psychological disorder is at play, such as depression or anxiety,” said Dr. Frasier.
Some evidence suggests that, in cases of MSBP, the caregiver may have a personality disorder such as borderline or histrionic personality disorder — or may have suffered abuse or neglect as a child or is experiencing major stress, which some evidence suggests can trigger MSPB, she added.
This type of abuse is rarely seen in children older than 6 years, likely because they get wise to what’s going on and are better able to fight back or resist as they get older, Dr. Fraser noted.
High Mortality Rate
It’s critical that cases of MSBP are identified early. While a small proportion of child abuse cases involve MSBP, the mortality rate is extremely high, about 10%, research suggests, said Dr. Frasier.
Dermatologists should be skeptical if the child’s condition hasn’t improved despite trying numerous treatments that normally would have some effect. “If you’re doing everything you can to treat something that’s usually pretty simple in terms of what you normally see clinically and how you treat it, and you’re not seeing any improvement or things continue to get worse, that’s definitely a sign something else may be going on,” Dr. Frasier said.
Another suspicious sign is inflammation that continues “for weeks or months” and “doesn’t match up with actual lab markers and lab values,” said Dr. Frasier.
Other signs of possible MSBP include evidence of chemicals in the child’s blood, stool, or urine, or the child’s condition improves while in the hospital, but symptoms return after returning home.
Also be aware of the interaction between the parent and child, said Dr. Frasier. “See if you can pick up that something else might be going on, especially if the symptoms aren’t lining up very well with what you’re physically seeing and what your clinical impression is.”
And be suspicious of a parent’s inappropriate behavior; for example, they seem to be deliberately making symptoms worse or appear overly distraught. The seemingly caring parent could be overcompensating for what she’s doing at home, “and she wants to make sure it doesn’t appear that way,” said Dr. Frasier.
To help determine if some sort of trauma is occurring at home, the child would ideally be separated from the caregiver, perhaps with a nurse or other member of the interdisciplinary medical team, Dr. Frasier said.
It appears that pediatric dermatologists are already aware of the importance of protecting children from abuse. During a presentation at the meeting on child abuse and maltreatment in dermatology, not specifically on MSBP, Romy Cho, MD, assistant professor, Department of Pediatrics, University of Toronto, who is involved with the SCAN Program at The Hospital for Sick Children, Toronto, Canada, polled the audience on whether they had ever contacted child protective services (CPS). Almost 80% said they had.
That’s good news for Dr. Frasier. “We have to be willing to contact CPS if we think there’s something going on, and be more open to that because it’s better to be safe than sorry, especially in cases involving children.”
Dr. Frasier and Dr. Cho had no relevant disclosures.
A version of this article first appeared on Medscape.com.
TORONTO — Be suspicious if a child with a severe dermatologic condition is unresponsive to treatment, especially if their parent or caregiver exhibits deceptive behavior.
These could be red flags for Munchausen syndrome by proxy (MSBP), also known as factitious disorder.
“The No. 1 thing dermatologists can do in situations like this is be open to thinking outside the box and ask themselves the difficult question: Could this be something the parent is inflicting on the child,” Kelly Frasier, DO, a dermatology clinical trials and epidemiology research fellow at Northwell Health, Poughkeepsie, New York, said in an interview.
She provided a review on advancing the understanding of the dermatologic manifestations of MSBP during a poster session at the annual meeting of the Society for Pediatric Dermatology (SPD). Dr. Frasier has a particular interest in psychodermatology — she was a mental health therapist before going to medical school.
MSBP is a type of abuse intentionally inflicted by a caregiver typically on their child “for some ulterior motive,” usually to seek attention or sympathy and not for material or financial gain, explained Dr. Frasier. People with MSBP seek medical help for exaggerated or fabricated symptoms in their child. They may alter medical tests, falsify medical records, or induce symptoms in their child.
To do this, these abusers may apply any number of caustic household products, including glue, directly to the child’s skin or even in formula. Dr. Frasier shared a picture of a baby whose formula had been doctored with a caustic substance that had dripped onto his neck and face, causing a rash with blisters.
In addition to blistering, cutaneous manifestations of MSBP can include severe bruising. Or the child may present with signs similar to those of granuloma annulare (a benign condition characterized by small, raised bumps) or cicatricial pemphigoid (a rare, chronic autoimmune blistering disorder) or may have recurrent nail avulsion, purpura, or coagulopathy, said Dr. Frasier.
In almost all cases of MSBP (an estimated 96%), the abuse is inflicted by the mother, who may have a preexisting mental illness. “Usually, a psychological disorder is at play, such as depression or anxiety,” said Dr. Frasier.
Some evidence suggests that, in cases of MSBP, the caregiver may have a personality disorder such as borderline or histrionic personality disorder — or may have suffered abuse or neglect as a child or is experiencing major stress, which some evidence suggests can trigger MSPB, she added.
This type of abuse is rarely seen in children older than 6 years, likely because they get wise to what’s going on and are better able to fight back or resist as they get older, Dr. Fraser noted.
High Mortality Rate
It’s critical that cases of MSBP are identified early. While a small proportion of child abuse cases involve MSBP, the mortality rate is extremely high, about 10%, research suggests, said Dr. Frasier.
Dermatologists should be skeptical if the child’s condition hasn’t improved despite trying numerous treatments that normally would have some effect. “If you’re doing everything you can to treat something that’s usually pretty simple in terms of what you normally see clinically and how you treat it, and you’re not seeing any improvement or things continue to get worse, that’s definitely a sign something else may be going on,” Dr. Frasier said.
Another suspicious sign is inflammation that continues “for weeks or months” and “doesn’t match up with actual lab markers and lab values,” said Dr. Frasier.
Other signs of possible MSBP include evidence of chemicals in the child’s blood, stool, or urine, or the child’s condition improves while in the hospital, but symptoms return after returning home.
Also be aware of the interaction between the parent and child, said Dr. Frasier. “See if you can pick up that something else might be going on, especially if the symptoms aren’t lining up very well with what you’re physically seeing and what your clinical impression is.”
And be suspicious of a parent’s inappropriate behavior; for example, they seem to be deliberately making symptoms worse or appear overly distraught. The seemingly caring parent could be overcompensating for what she’s doing at home, “and she wants to make sure it doesn’t appear that way,” said Dr. Frasier.
To help determine if some sort of trauma is occurring at home, the child would ideally be separated from the caregiver, perhaps with a nurse or other member of the interdisciplinary medical team, Dr. Frasier said.
It appears that pediatric dermatologists are already aware of the importance of protecting children from abuse. During a presentation at the meeting on child abuse and maltreatment in dermatology, not specifically on MSBP, Romy Cho, MD, assistant professor, Department of Pediatrics, University of Toronto, who is involved with the SCAN Program at The Hospital for Sick Children, Toronto, Canada, polled the audience on whether they had ever contacted child protective services (CPS). Almost 80% said they had.
That’s good news for Dr. Frasier. “We have to be willing to contact CPS if we think there’s something going on, and be more open to that because it’s better to be safe than sorry, especially in cases involving children.”
Dr. Frasier and Dr. Cho had no relevant disclosures.
A version of this article first appeared on Medscape.com.
TORONTO — Be suspicious if a child with a severe dermatologic condition is unresponsive to treatment, especially if their parent or caregiver exhibits deceptive behavior.
These could be red flags for Munchausen syndrome by proxy (MSBP), also known as factitious disorder.
“The No. 1 thing dermatologists can do in situations like this is be open to thinking outside the box and ask themselves the difficult question: Could this be something the parent is inflicting on the child,” Kelly Frasier, DO, a dermatology clinical trials and epidemiology research fellow at Northwell Health, Poughkeepsie, New York, said in an interview.
She provided a review on advancing the understanding of the dermatologic manifestations of MSBP during a poster session at the annual meeting of the Society for Pediatric Dermatology (SPD). Dr. Frasier has a particular interest in psychodermatology — she was a mental health therapist before going to medical school.
MSBP is a type of abuse intentionally inflicted by a caregiver typically on their child “for some ulterior motive,” usually to seek attention or sympathy and not for material or financial gain, explained Dr. Frasier. People with MSBP seek medical help for exaggerated or fabricated symptoms in their child. They may alter medical tests, falsify medical records, or induce symptoms in their child.
To do this, these abusers may apply any number of caustic household products, including glue, directly to the child’s skin or even in formula. Dr. Frasier shared a picture of a baby whose formula had been doctored with a caustic substance that had dripped onto his neck and face, causing a rash with blisters.
In addition to blistering, cutaneous manifestations of MSBP can include severe bruising. Or the child may present with signs similar to those of granuloma annulare (a benign condition characterized by small, raised bumps) or cicatricial pemphigoid (a rare, chronic autoimmune blistering disorder) or may have recurrent nail avulsion, purpura, or coagulopathy, said Dr. Frasier.
In almost all cases of MSBP (an estimated 96%), the abuse is inflicted by the mother, who may have a preexisting mental illness. “Usually, a psychological disorder is at play, such as depression or anxiety,” said Dr. Frasier.
Some evidence suggests that, in cases of MSBP, the caregiver may have a personality disorder such as borderline or histrionic personality disorder — or may have suffered abuse or neglect as a child or is experiencing major stress, which some evidence suggests can trigger MSPB, she added.
This type of abuse is rarely seen in children older than 6 years, likely because they get wise to what’s going on and are better able to fight back or resist as they get older, Dr. Fraser noted.
High Mortality Rate
It’s critical that cases of MSBP are identified early. While a small proportion of child abuse cases involve MSBP, the mortality rate is extremely high, about 10%, research suggests, said Dr. Frasier.
Dermatologists should be skeptical if the child’s condition hasn’t improved despite trying numerous treatments that normally would have some effect. “If you’re doing everything you can to treat something that’s usually pretty simple in terms of what you normally see clinically and how you treat it, and you’re not seeing any improvement or things continue to get worse, that’s definitely a sign something else may be going on,” Dr. Frasier said.
Another suspicious sign is inflammation that continues “for weeks or months” and “doesn’t match up with actual lab markers and lab values,” said Dr. Frasier.
Other signs of possible MSBP include evidence of chemicals in the child’s blood, stool, or urine, or the child’s condition improves while in the hospital, but symptoms return after returning home.
Also be aware of the interaction between the parent and child, said Dr. Frasier. “See if you can pick up that something else might be going on, especially if the symptoms aren’t lining up very well with what you’re physically seeing and what your clinical impression is.”
And be suspicious of a parent’s inappropriate behavior; for example, they seem to be deliberately making symptoms worse or appear overly distraught. The seemingly caring parent could be overcompensating for what she’s doing at home, “and she wants to make sure it doesn’t appear that way,” said Dr. Frasier.
To help determine if some sort of trauma is occurring at home, the child would ideally be separated from the caregiver, perhaps with a nurse or other member of the interdisciplinary medical team, Dr. Frasier said.
It appears that pediatric dermatologists are already aware of the importance of protecting children from abuse. During a presentation at the meeting on child abuse and maltreatment in dermatology, not specifically on MSBP, Romy Cho, MD, assistant professor, Department of Pediatrics, University of Toronto, who is involved with the SCAN Program at The Hospital for Sick Children, Toronto, Canada, polled the audience on whether they had ever contacted child protective services (CPS). Almost 80% said they had.
That’s good news for Dr. Frasier. “We have to be willing to contact CPS if we think there’s something going on, and be more open to that because it’s better to be safe than sorry, especially in cases involving children.”
Dr. Frasier and Dr. Cho had no relevant disclosures.
A version of this article first appeared on Medscape.com.
FROM SPD 2024
More Illnesses Possible Related Linked to Counterfeit Botulinum Toxin Reported
— two in the intensive care unit. None of the cases required intubation, according to an announcement of an investigation into these reports in by the Centers for Disease Control and Prevention (CDC).
The report, published online in the Morbidity and Mortality Weekly Report, notes that the four patients in Tennessee received counterfeit BoNT, while product information was not available for the three cases in New York City. “However, one person reported paying less than US wholesale acquisition cost for the administered product, and another reported that the product had been purchased overseas,” the authors of the report wrote. The development underscores that BoNT injections “should be administered only by licensed and trained providers using recommended doses of FDA [Food and Drug Admininstration]-approved products.”
This report follows a CDC advisory published in April 2024 of at least 22 people from 11 states who reported serious reactions after receiving botulinum toxin injections from unlicensed or untrained individuals or in nonhealthcare settings, such as homes and spas.
The median age of the women in the July report was 48 years, and signs and symptoms included ptosis, dry mouth, dysphagia, shortness of breath, and weakness. Onset occurred between February 23 and March 7, 2024.
“This investigation did not determine why these illnesses occurred after cosmetic BoNT injections; potential reasons might include use of counterfeit BoNT, which might be more potent or contain harmful additional ingredients or higher susceptibility to BoNT effects among some persons,” the investigators wrote. They recommended further studies to describe the clinical spectrum of cosmetic BoNT injection effects such as severity of signs and symptoms.
For cases of suspected systemic botulism, the CDC recommends calling the local or state health department for consultation and antitoxin release (as well as information on reporting adverse events). Alternatively, the 24/7 phone number for the CDC clinical botulism service is 770-488-7100.
A version of this article first appeared on Medscape.com.
— two in the intensive care unit. None of the cases required intubation, according to an announcement of an investigation into these reports in by the Centers for Disease Control and Prevention (CDC).
The report, published online in the Morbidity and Mortality Weekly Report, notes that the four patients in Tennessee received counterfeit BoNT, while product information was not available for the three cases in New York City. “However, one person reported paying less than US wholesale acquisition cost for the administered product, and another reported that the product had been purchased overseas,” the authors of the report wrote. The development underscores that BoNT injections “should be administered only by licensed and trained providers using recommended doses of FDA [Food and Drug Admininstration]-approved products.”
This report follows a CDC advisory published in April 2024 of at least 22 people from 11 states who reported serious reactions after receiving botulinum toxin injections from unlicensed or untrained individuals or in nonhealthcare settings, such as homes and spas.
The median age of the women in the July report was 48 years, and signs and symptoms included ptosis, dry mouth, dysphagia, shortness of breath, and weakness. Onset occurred between February 23 and March 7, 2024.
“This investigation did not determine why these illnesses occurred after cosmetic BoNT injections; potential reasons might include use of counterfeit BoNT, which might be more potent or contain harmful additional ingredients or higher susceptibility to BoNT effects among some persons,” the investigators wrote. They recommended further studies to describe the clinical spectrum of cosmetic BoNT injection effects such as severity of signs and symptoms.
For cases of suspected systemic botulism, the CDC recommends calling the local or state health department for consultation and antitoxin release (as well as information on reporting adverse events). Alternatively, the 24/7 phone number for the CDC clinical botulism service is 770-488-7100.
A version of this article first appeared on Medscape.com.
— two in the intensive care unit. None of the cases required intubation, according to an announcement of an investigation into these reports in by the Centers for Disease Control and Prevention (CDC).
The report, published online in the Morbidity and Mortality Weekly Report, notes that the four patients in Tennessee received counterfeit BoNT, while product information was not available for the three cases in New York City. “However, one person reported paying less than US wholesale acquisition cost for the administered product, and another reported that the product had been purchased overseas,” the authors of the report wrote. The development underscores that BoNT injections “should be administered only by licensed and trained providers using recommended doses of FDA [Food and Drug Admininstration]-approved products.”
This report follows a CDC advisory published in April 2024 of at least 22 people from 11 states who reported serious reactions after receiving botulinum toxin injections from unlicensed or untrained individuals or in nonhealthcare settings, such as homes and spas.
The median age of the women in the July report was 48 years, and signs and symptoms included ptosis, dry mouth, dysphagia, shortness of breath, and weakness. Onset occurred between February 23 and March 7, 2024.
“This investigation did not determine why these illnesses occurred after cosmetic BoNT injections; potential reasons might include use of counterfeit BoNT, which might be more potent or contain harmful additional ingredients or higher susceptibility to BoNT effects among some persons,” the investigators wrote. They recommended further studies to describe the clinical spectrum of cosmetic BoNT injection effects such as severity of signs and symptoms.
For cases of suspected systemic botulism, the CDC recommends calling the local or state health department for consultation and antitoxin release (as well as information on reporting adverse events). Alternatively, the 24/7 phone number for the CDC clinical botulism service is 770-488-7100.
A version of this article first appeared on Medscape.com.
FROM THE MMWR
Study Detects Bacteria in Tattoo, Permanent Makeup Inks
When US researchers tested 75 unopened and sealed tattoo and permanent makeup inks from 14 different manufacturers, they discovered that about 35% of the products were contaminated with bacteria.
They detected both aerobic bacteria and anaerobic bacteria, which thrive in low-oxygen environments like the dermal layer of the skin.
“This suggests that contaminated tattoo inks could be a source of infection from both types of bacteria,” Seong-Jae Peter Kim, PhD, a microbiologist with the Division of Microbiology, National Center for Toxicological Research, US Food and Drug Administration, who worked on the study, said in a news release.
The findings “are concerning,” said Waleed Javaid, MD, professor of medicine and director of infection prevention and control for the Mount Sinai Health System in New York City. “This contamination poses a significant health risk, as these inks are injected into the dermal layer of the skin, creating an environment conducive to bacterial infections,” said Dr. Javaid, who wasn’t involved in the study, which was published online in Applied and Environmental Microbiology.
New Body Art Culture
Tattoos are more popular than ever, and it is estimated that at least 32% of people in the United States have at least one tattoo. And the rise in popularity has coincided with an increase in ink-related infections.
This new research joins previous studies that have demonstrated that commercial tattoo and permanent makeup inks are often contaminated with pathogenic microorganisms.
Of the 75 ink samples that Dr. Kim and colleagues tested, 26 were contaminated with 34 bacterial isolates classified into 14 genera and 22 species. Among the 34 bacterial isolates, 19 were identified as possibly pathogenic bacterial strains.
Two species — Cutibacterium acnes (four strains) and Staphylococcus epidermidis (two strains) — were isolated under anaerobic conditions.
Two possibly pathogenic bacterial strains — Staphylococcus saprophyticus and C acnes — were isolated from the same two ink samples, indicating that tattoo and permanent makeup inks can harbor both aerobic (S saprophyticus) and anaerobic (C acnes) bacteria.
There was no significant association between sterility claims on the ink label and the absence of bacterial contamination.
“The presence of bacteria like Cutibacterium acnes and Staphylococcus epidermidis, which can cause skin infections and other complications, underscores the potential danger to individuals receiving tattoos or permanent makeup,” Dr. Javaid explained.
The results “emphasize the importance of monitoring these products for both aerobic and anaerobic bacteria, including possibly pathogenic microorganisms,” Dr. Kim said in the news release.
The next steps, according to the researchers, include developing more efficient and accurate microbial detection methods for tattoo inks to streamline the monitoring process and examining the occurrence, co-occurrence, and diversity of microbial contaminants in tattoo inks to prevent future contamination.
Counseling Patients
Healthcare professionals play a “crucial role in counseling patients about the risks associated with tattoos. They should inform patients about the potential for infections, allergic reactions, and other complications related to tattooing and permanent ink,” said Dr. Javaid.
Specific advice can include ensuring that the tattoo parlor adheres to strict hygiene practices and verifying that tattoo inks are from reputable sources and, if possible, have undergone sterilization.
Clinicians should discuss the importance of proper aftercare to minimize the risk for infection, recommend patients with compromised immune systems or skin conditions to reconsider getting a tattoo, and encourage patients to be aware of the signs of infection and to seek medical attention promptly if any symptoms arise.
“Enhanced regulatory measures would help reduce the risk of infections and ensure safer tattooing practices for consumers,” Dr. Javaid said. The findings of Dr. Kim and colleagues “indicate that current manufacturing and sterilization processes are inadequate.”
Regulations could include stricter manufacturing standards to ensure sterility, the mandatory testing of inks for microbial contamination before they reach the market, clear labeling requirements that accurately reflect the sterility and safety of products, and regular inspections and audits of tattoo ink manufacturers, he said, which could encourage the development of more effective sterilization techniques to eliminate bacterial contamination.
The FDA has created a document — Think Before You Ink: Tattoo Safety — for consumers who are considering getting a tattoo.
A version of this article first appeared on Medscape.com.
When US researchers tested 75 unopened and sealed tattoo and permanent makeup inks from 14 different manufacturers, they discovered that about 35% of the products were contaminated with bacteria.
They detected both aerobic bacteria and anaerobic bacteria, which thrive in low-oxygen environments like the dermal layer of the skin.
“This suggests that contaminated tattoo inks could be a source of infection from both types of bacteria,” Seong-Jae Peter Kim, PhD, a microbiologist with the Division of Microbiology, National Center for Toxicological Research, US Food and Drug Administration, who worked on the study, said in a news release.
The findings “are concerning,” said Waleed Javaid, MD, professor of medicine and director of infection prevention and control for the Mount Sinai Health System in New York City. “This contamination poses a significant health risk, as these inks are injected into the dermal layer of the skin, creating an environment conducive to bacterial infections,” said Dr. Javaid, who wasn’t involved in the study, which was published online in Applied and Environmental Microbiology.
New Body Art Culture
Tattoos are more popular than ever, and it is estimated that at least 32% of people in the United States have at least one tattoo. And the rise in popularity has coincided with an increase in ink-related infections.
This new research joins previous studies that have demonstrated that commercial tattoo and permanent makeup inks are often contaminated with pathogenic microorganisms.
Of the 75 ink samples that Dr. Kim and colleagues tested, 26 were contaminated with 34 bacterial isolates classified into 14 genera and 22 species. Among the 34 bacterial isolates, 19 were identified as possibly pathogenic bacterial strains.
Two species — Cutibacterium acnes (four strains) and Staphylococcus epidermidis (two strains) — were isolated under anaerobic conditions.
Two possibly pathogenic bacterial strains — Staphylococcus saprophyticus and C acnes — were isolated from the same two ink samples, indicating that tattoo and permanent makeup inks can harbor both aerobic (S saprophyticus) and anaerobic (C acnes) bacteria.
There was no significant association between sterility claims on the ink label and the absence of bacterial contamination.
“The presence of bacteria like Cutibacterium acnes and Staphylococcus epidermidis, which can cause skin infections and other complications, underscores the potential danger to individuals receiving tattoos or permanent makeup,” Dr. Javaid explained.
The results “emphasize the importance of monitoring these products for both aerobic and anaerobic bacteria, including possibly pathogenic microorganisms,” Dr. Kim said in the news release.
The next steps, according to the researchers, include developing more efficient and accurate microbial detection methods for tattoo inks to streamline the monitoring process and examining the occurrence, co-occurrence, and diversity of microbial contaminants in tattoo inks to prevent future contamination.
Counseling Patients
Healthcare professionals play a “crucial role in counseling patients about the risks associated with tattoos. They should inform patients about the potential for infections, allergic reactions, and other complications related to tattooing and permanent ink,” said Dr. Javaid.
Specific advice can include ensuring that the tattoo parlor adheres to strict hygiene practices and verifying that tattoo inks are from reputable sources and, if possible, have undergone sterilization.
Clinicians should discuss the importance of proper aftercare to minimize the risk for infection, recommend patients with compromised immune systems or skin conditions to reconsider getting a tattoo, and encourage patients to be aware of the signs of infection and to seek medical attention promptly if any symptoms arise.
“Enhanced regulatory measures would help reduce the risk of infections and ensure safer tattooing practices for consumers,” Dr. Javaid said. The findings of Dr. Kim and colleagues “indicate that current manufacturing and sterilization processes are inadequate.”
Regulations could include stricter manufacturing standards to ensure sterility, the mandatory testing of inks for microbial contamination before they reach the market, clear labeling requirements that accurately reflect the sterility and safety of products, and regular inspections and audits of tattoo ink manufacturers, he said, which could encourage the development of more effective sterilization techniques to eliminate bacterial contamination.
The FDA has created a document — Think Before You Ink: Tattoo Safety — for consumers who are considering getting a tattoo.
A version of this article first appeared on Medscape.com.
When US researchers tested 75 unopened and sealed tattoo and permanent makeup inks from 14 different manufacturers, they discovered that about 35% of the products were contaminated with bacteria.
They detected both aerobic bacteria and anaerobic bacteria, which thrive in low-oxygen environments like the dermal layer of the skin.
“This suggests that contaminated tattoo inks could be a source of infection from both types of bacteria,” Seong-Jae Peter Kim, PhD, a microbiologist with the Division of Microbiology, National Center for Toxicological Research, US Food and Drug Administration, who worked on the study, said in a news release.
The findings “are concerning,” said Waleed Javaid, MD, professor of medicine and director of infection prevention and control for the Mount Sinai Health System in New York City. “This contamination poses a significant health risk, as these inks are injected into the dermal layer of the skin, creating an environment conducive to bacterial infections,” said Dr. Javaid, who wasn’t involved in the study, which was published online in Applied and Environmental Microbiology.
New Body Art Culture
Tattoos are more popular than ever, and it is estimated that at least 32% of people in the United States have at least one tattoo. And the rise in popularity has coincided with an increase in ink-related infections.
This new research joins previous studies that have demonstrated that commercial tattoo and permanent makeup inks are often contaminated with pathogenic microorganisms.
Of the 75 ink samples that Dr. Kim and colleagues tested, 26 were contaminated with 34 bacterial isolates classified into 14 genera and 22 species. Among the 34 bacterial isolates, 19 were identified as possibly pathogenic bacterial strains.
Two species — Cutibacterium acnes (four strains) and Staphylococcus epidermidis (two strains) — were isolated under anaerobic conditions.
Two possibly pathogenic bacterial strains — Staphylococcus saprophyticus and C acnes — were isolated from the same two ink samples, indicating that tattoo and permanent makeup inks can harbor both aerobic (S saprophyticus) and anaerobic (C acnes) bacteria.
There was no significant association between sterility claims on the ink label and the absence of bacterial contamination.
“The presence of bacteria like Cutibacterium acnes and Staphylococcus epidermidis, which can cause skin infections and other complications, underscores the potential danger to individuals receiving tattoos or permanent makeup,” Dr. Javaid explained.
The results “emphasize the importance of monitoring these products for both aerobic and anaerobic bacteria, including possibly pathogenic microorganisms,” Dr. Kim said in the news release.
The next steps, according to the researchers, include developing more efficient and accurate microbial detection methods for tattoo inks to streamline the monitoring process and examining the occurrence, co-occurrence, and diversity of microbial contaminants in tattoo inks to prevent future contamination.
Counseling Patients
Healthcare professionals play a “crucial role in counseling patients about the risks associated with tattoos. They should inform patients about the potential for infections, allergic reactions, and other complications related to tattooing and permanent ink,” said Dr. Javaid.
Specific advice can include ensuring that the tattoo parlor adheres to strict hygiene practices and verifying that tattoo inks are from reputable sources and, if possible, have undergone sterilization.
Clinicians should discuss the importance of proper aftercare to minimize the risk for infection, recommend patients with compromised immune systems or skin conditions to reconsider getting a tattoo, and encourage patients to be aware of the signs of infection and to seek medical attention promptly if any symptoms arise.
“Enhanced regulatory measures would help reduce the risk of infections and ensure safer tattooing practices for consumers,” Dr. Javaid said. The findings of Dr. Kim and colleagues “indicate that current manufacturing and sterilization processes are inadequate.”
Regulations could include stricter manufacturing standards to ensure sterility, the mandatory testing of inks for microbial contamination before they reach the market, clear labeling requirements that accurately reflect the sterility and safety of products, and regular inspections and audits of tattoo ink manufacturers, he said, which could encourage the development of more effective sterilization techniques to eliminate bacterial contamination.
The FDA has created a document — Think Before You Ink: Tattoo Safety — for consumers who are considering getting a tattoo.
A version of this article first appeared on Medscape.com.
FROM APPLIED AND ENVIRONMENTAL MICROBIOLOGY