instruction stringlengths 34 186 | input stringlengths 2.02k 93.8k | output stringlengths 2 418 | meta_questiontype stringclasses 6 values | meta_inputlicense stringclasses 6 values | meta_pmid stringlengths 8 8 | meta_safetyreportid int64 9.51M 21M | meta_articlepubdate stringlengths 4 10 |
|---|---|---|---|---|---|---|---|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Dysphagia'. | An atypical presentation of Salmonella enterica ser Dublin in an immunocompromised patient.
Mycotic aneurysms of the carotid artery are a rare entity that can be fatal if not diagnosed promptly. We present a 60-year-old man with a tender left-sided neck mass due to a ruptured aneurysm of the left internal carotid artery. Cultures taken intraoperatively grew Salmonella enterica ser Dublin.
INTRODUCTION
Infection with Salmonella enterica usually results in a self-limited gastroenteritis characterized by fever, diarrhea, and less often nausea, vomiting and headache. However, according to CDC data, ~8% of laboratory confirmed cases are complicated by bacteremia, arteritis, meningitis and osteomyelitis [1]. Occasionally, extraintestinal infections result in infected or mycotic aneurysms. In the USA, Staphylococcus is the most common organism associated with mycotic aneurysms, whereas Salmonella is much more common in East Asian countries such as China [2]. Mycotic aneurysms associated with Salmonella infection rupture over 50% of the time and if untreated have a mortality ranging from 16 to 44% [2]. Thus, prompt recognition and treatment are key to improved patient outcomes. We report the first published case of a middle-aged man who developed a carotid mycotic aneurysm due S. enterica ser Dublin, a serovar that is usually associated with cattle (ground beef and unpasteurized milk).
CASE REPORT
A 60-year-old man with a history of metastatic prostate cancer (treated with docetaxel ~2 weeks prior to presentation), hypertension, hyperlipidemia, paroxysmal atrial fibrillation (on rivaroxaban) and right knee osteoarthritis (status post total knee replacement) presented to the emergency room with left sided neck pain and swelling. He first noted left sided neck pain 1 to 2 weeks prior to presentation. Initially, he noted some discomfort and a small nodule on his left neck. However, the nodule grew over time and the pain progressed to the point where he noted discomfort with swallowing and breathing. Accordingly, he presented to our medical center for care. On the day of admission, he was febrile (38.7°C), tachycardic (122), hypertensive (152/94). Fortunately, despite the tender neck swelling, there was no airway compromise.
The physical exam revealed a tender non-pulsatile mass on the left neck extending to the angle of the mandible. A computed tomography (CT) scan of the neck with contrast revealed a focal outpouching of the left carotid artery (Fig. 1). There also appeared to be a mass encircling the left carotid artery (4.3 cm × 2.5 cm × 3 cm) with lateral displacement and compression of the left jugular vein.
Figure 1 CT scan (coronal) of neck with contrast showing thrombosed aneurysm of the left internal carotid artery (arrow)
A vascular surgery consultation was obtained and given concern for a contained ruptured aneurysm, the patient was taken to the operating room (OR). During the surgery, an aneurysm with a posterior perforation and contained rupture was noted (Fig. 2). Pathological specimens from the surgical site were notable for significant atherosclerotic disease. Also, purulence was noted along with extravasated blood and cultures taken from intraoperative specimens revealed pan sensitive S. enterica ser Dublin. The affected and ulcerated portion of the carotid artery was excised and replaced via end-to-end anastomoses with a bovine mesenteric vein graft. Interestingly, all peripheral blood cultures were negative for bacterial growth. He was treated with ceftriaxone 2 grams IV daily for at least 6 weeks.
Figure 2 Perforated posterior wall of the left internal carotid artery seen intraoperatively (arrow)
DISCUSSION
We report the case of a middle-aged man who presented with a subacute painful neck swelling that was due to a ruptured mycotic aneurysm of the left carotid artery. Given his history of cancer, a malignant metastasis was among the differential diagnoses. However, CT imaging helped us to quickly narrow the list of possibilities.
The concern for a ruptured aneurysm prompted a vascular surgery consultation and ultimately surgical exploration. The aneurysm was found to be infected with Salmonella. Mycotic aneurysms of the carotid artery are relatively rare and those due to Salmonella spp. are even rarer. Our review of the literature revealed ~22 published cases of a carotid mycotic aneurysm due to Salmonella spp. Mycotic aneurysms tend to involve the aorta causing aortitis with or without aneurysm formation [3]. Only ~5% of mycotic aneurysms involve the carotid artery. In general, male gender is a risk factor for development of mycotic aneurysm [4]. Other risk factors include age >50, diabetes, hypertension and atherosclerosis [2, 4]. Our patient had many of the traditional risk factors. He was also fully anticoagulated while the aneurysm was developing and had recently been treated with chemotherapy. We suspect that these factors likely contributed to his presentation as well.
We did not identify a discrete episode of gastroenteritis or bacteremia. He had been taking chemotherapy ~2 weeks prior to presentation so typical symptoms such as diarrhea, nausea and vomiting might have been misattributed to medication side effects. There are a few published case reports of mycotic aneurysms due to Salmonella with negative blood cultures [5–7]. This may reflect the fact that gram negative bacteremia is frequently transient.
The standard management of mycotic aneurysms is open surgical repair. There are multiple case reports describing an endovascular approach, but studies comparing endovascular versus open repairs are lacking [4]. A minimum of 6 weeks of antibiotic therapy is often recommended although there are no data to support a specific duration of treatment [6].
The Maryland State Health Department performed the microbiological testing in this case and confirmed the Dublin serotype, which usually causes gastroenteritis in both cattle and humans [8]. There are very few case reports of mycotic abdominal aneurysms due to the Dublin serotype [2]. To our knowledge, this is the first published case of carotid mycotic aneurysm associated with the Dublin serotype. Although most Salmonella spp outbreaks have been linked to eggs, poultry and occasionally pet reptiles, outbreaks due to S. enterica ser Dublin have been linked to the consumption of contaminated ground beef and raw or unpasteurized milk. The Centers for Disease Control reported an outbreak of the Dublin serotype in 2019 that involved eight states. The outbreak was linked to ground beef [9].
This case report brings into focus several important clinical and epidemiological points. First, an infected aneurysm should be considered in the differential diagnosis for a patient who is febrile and presents with a tender neck mass. Second, since mycotic aneurysms frequently rupture, prompt referral to a vascular surgeon is paramount. Finally, since our patient likely contracted S. enterica ser Dublin from ground beef or milk, it is imperative that we continue surveillance for this organism in our environment.
ACKNOWLEDGMENTS
None.
FUNDING STATEMENT
The authors received no specific funding for this work.
ETHICAL APPROVAL
This Case Report does not require IRB approval as it is not considered research and does not contain any of the 18 HIPAA identifiers.
CONSENT
A signed written consent was obtained from the patient for this case report.
GUARANTOR
Adrien L. Janvier. | DOCETAXEL, RIVAROXABAN | DrugsGivenReaction | CC BY-NC | 33542826 | 19,062,457 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Dyspnoea'. | An atypical presentation of Salmonella enterica ser Dublin in an immunocompromised patient.
Mycotic aneurysms of the carotid artery are a rare entity that can be fatal if not diagnosed promptly. We present a 60-year-old man with a tender left-sided neck mass due to a ruptured aneurysm of the left internal carotid artery. Cultures taken intraoperatively grew Salmonella enterica ser Dublin.
INTRODUCTION
Infection with Salmonella enterica usually results in a self-limited gastroenteritis characterized by fever, diarrhea, and less often nausea, vomiting and headache. However, according to CDC data, ~8% of laboratory confirmed cases are complicated by bacteremia, arteritis, meningitis and osteomyelitis [1]. Occasionally, extraintestinal infections result in infected or mycotic aneurysms. In the USA, Staphylococcus is the most common organism associated with mycotic aneurysms, whereas Salmonella is much more common in East Asian countries such as China [2]. Mycotic aneurysms associated with Salmonella infection rupture over 50% of the time and if untreated have a mortality ranging from 16 to 44% [2]. Thus, prompt recognition and treatment are key to improved patient outcomes. We report the first published case of a middle-aged man who developed a carotid mycotic aneurysm due S. enterica ser Dublin, a serovar that is usually associated with cattle (ground beef and unpasteurized milk).
CASE REPORT
A 60-year-old man with a history of metastatic prostate cancer (treated with docetaxel ~2 weeks prior to presentation), hypertension, hyperlipidemia, paroxysmal atrial fibrillation (on rivaroxaban) and right knee osteoarthritis (status post total knee replacement) presented to the emergency room with left sided neck pain and swelling. He first noted left sided neck pain 1 to 2 weeks prior to presentation. Initially, he noted some discomfort and a small nodule on his left neck. However, the nodule grew over time and the pain progressed to the point where he noted discomfort with swallowing and breathing. Accordingly, he presented to our medical center for care. On the day of admission, he was febrile (38.7°C), tachycardic (122), hypertensive (152/94). Fortunately, despite the tender neck swelling, there was no airway compromise.
The physical exam revealed a tender non-pulsatile mass on the left neck extending to the angle of the mandible. A computed tomography (CT) scan of the neck with contrast revealed a focal outpouching of the left carotid artery (Fig. 1). There also appeared to be a mass encircling the left carotid artery (4.3 cm × 2.5 cm × 3 cm) with lateral displacement and compression of the left jugular vein.
Figure 1 CT scan (coronal) of neck with contrast showing thrombosed aneurysm of the left internal carotid artery (arrow)
A vascular surgery consultation was obtained and given concern for a contained ruptured aneurysm, the patient was taken to the operating room (OR). During the surgery, an aneurysm with a posterior perforation and contained rupture was noted (Fig. 2). Pathological specimens from the surgical site were notable for significant atherosclerotic disease. Also, purulence was noted along with extravasated blood and cultures taken from intraoperative specimens revealed pan sensitive S. enterica ser Dublin. The affected and ulcerated portion of the carotid artery was excised and replaced via end-to-end anastomoses with a bovine mesenteric vein graft. Interestingly, all peripheral blood cultures were negative for bacterial growth. He was treated with ceftriaxone 2 grams IV daily for at least 6 weeks.
Figure 2 Perforated posterior wall of the left internal carotid artery seen intraoperatively (arrow)
DISCUSSION
We report the case of a middle-aged man who presented with a subacute painful neck swelling that was due to a ruptured mycotic aneurysm of the left carotid artery. Given his history of cancer, a malignant metastasis was among the differential diagnoses. However, CT imaging helped us to quickly narrow the list of possibilities.
The concern for a ruptured aneurysm prompted a vascular surgery consultation and ultimately surgical exploration. The aneurysm was found to be infected with Salmonella. Mycotic aneurysms of the carotid artery are relatively rare and those due to Salmonella spp. are even rarer. Our review of the literature revealed ~22 published cases of a carotid mycotic aneurysm due to Salmonella spp. Mycotic aneurysms tend to involve the aorta causing aortitis with or without aneurysm formation [3]. Only ~5% of mycotic aneurysms involve the carotid artery. In general, male gender is a risk factor for development of mycotic aneurysm [4]. Other risk factors include age >50, diabetes, hypertension and atherosclerosis [2, 4]. Our patient had many of the traditional risk factors. He was also fully anticoagulated while the aneurysm was developing and had recently been treated with chemotherapy. We suspect that these factors likely contributed to his presentation as well.
We did not identify a discrete episode of gastroenteritis or bacteremia. He had been taking chemotherapy ~2 weeks prior to presentation so typical symptoms such as diarrhea, nausea and vomiting might have been misattributed to medication side effects. There are a few published case reports of mycotic aneurysms due to Salmonella with negative blood cultures [5–7]. This may reflect the fact that gram negative bacteremia is frequently transient.
The standard management of mycotic aneurysms is open surgical repair. There are multiple case reports describing an endovascular approach, but studies comparing endovascular versus open repairs are lacking [4]. A minimum of 6 weeks of antibiotic therapy is often recommended although there are no data to support a specific duration of treatment [6].
The Maryland State Health Department performed the microbiological testing in this case and confirmed the Dublin serotype, which usually causes gastroenteritis in both cattle and humans [8]. There are very few case reports of mycotic abdominal aneurysms due to the Dublin serotype [2]. To our knowledge, this is the first published case of carotid mycotic aneurysm associated with the Dublin serotype. Although most Salmonella spp outbreaks have been linked to eggs, poultry and occasionally pet reptiles, outbreaks due to S. enterica ser Dublin have been linked to the consumption of contaminated ground beef and raw or unpasteurized milk. The Centers for Disease Control reported an outbreak of the Dublin serotype in 2019 that involved eight states. The outbreak was linked to ground beef [9].
This case report brings into focus several important clinical and epidemiological points. First, an infected aneurysm should be considered in the differential diagnosis for a patient who is febrile and presents with a tender neck mass. Second, since mycotic aneurysms frequently rupture, prompt referral to a vascular surgeon is paramount. Finally, since our patient likely contracted S. enterica ser Dublin from ground beef or milk, it is imperative that we continue surveillance for this organism in our environment.
ACKNOWLEDGMENTS
None.
FUNDING STATEMENT
The authors received no specific funding for this work.
ETHICAL APPROVAL
This Case Report does not require IRB approval as it is not considered research and does not contain any of the 18 HIPAA identifiers.
CONSENT
A signed written consent was obtained from the patient for this case report.
GUARANTOR
Adrien L. Janvier. | DOCETAXEL, RIVAROXABAN | DrugsGivenReaction | CC BY-NC | 33542826 | 19,062,457 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypertension'. | An atypical presentation of Salmonella enterica ser Dublin in an immunocompromised patient.
Mycotic aneurysms of the carotid artery are a rare entity that can be fatal if not diagnosed promptly. We present a 60-year-old man with a tender left-sided neck mass due to a ruptured aneurysm of the left internal carotid artery. Cultures taken intraoperatively grew Salmonella enterica ser Dublin.
INTRODUCTION
Infection with Salmonella enterica usually results in a self-limited gastroenteritis characterized by fever, diarrhea, and less often nausea, vomiting and headache. However, according to CDC data, ~8% of laboratory confirmed cases are complicated by bacteremia, arteritis, meningitis and osteomyelitis [1]. Occasionally, extraintestinal infections result in infected or mycotic aneurysms. In the USA, Staphylococcus is the most common organism associated with mycotic aneurysms, whereas Salmonella is much more common in East Asian countries such as China [2]. Mycotic aneurysms associated with Salmonella infection rupture over 50% of the time and if untreated have a mortality ranging from 16 to 44% [2]. Thus, prompt recognition and treatment are key to improved patient outcomes. We report the first published case of a middle-aged man who developed a carotid mycotic aneurysm due S. enterica ser Dublin, a serovar that is usually associated with cattle (ground beef and unpasteurized milk).
CASE REPORT
A 60-year-old man with a history of metastatic prostate cancer (treated with docetaxel ~2 weeks prior to presentation), hypertension, hyperlipidemia, paroxysmal atrial fibrillation (on rivaroxaban) and right knee osteoarthritis (status post total knee replacement) presented to the emergency room with left sided neck pain and swelling. He first noted left sided neck pain 1 to 2 weeks prior to presentation. Initially, he noted some discomfort and a small nodule on his left neck. However, the nodule grew over time and the pain progressed to the point where he noted discomfort with swallowing and breathing. Accordingly, he presented to our medical center for care. On the day of admission, he was febrile (38.7°C), tachycardic (122), hypertensive (152/94). Fortunately, despite the tender neck swelling, there was no airway compromise.
The physical exam revealed a tender non-pulsatile mass on the left neck extending to the angle of the mandible. A computed tomography (CT) scan of the neck with contrast revealed a focal outpouching of the left carotid artery (Fig. 1). There also appeared to be a mass encircling the left carotid artery (4.3 cm × 2.5 cm × 3 cm) with lateral displacement and compression of the left jugular vein.
Figure 1 CT scan (coronal) of neck with contrast showing thrombosed aneurysm of the left internal carotid artery (arrow)
A vascular surgery consultation was obtained and given concern for a contained ruptured aneurysm, the patient was taken to the operating room (OR). During the surgery, an aneurysm with a posterior perforation and contained rupture was noted (Fig. 2). Pathological specimens from the surgical site were notable for significant atherosclerotic disease. Also, purulence was noted along with extravasated blood and cultures taken from intraoperative specimens revealed pan sensitive S. enterica ser Dublin. The affected and ulcerated portion of the carotid artery was excised and replaced via end-to-end anastomoses with a bovine mesenteric vein graft. Interestingly, all peripheral blood cultures were negative for bacterial growth. He was treated with ceftriaxone 2 grams IV daily for at least 6 weeks.
Figure 2 Perforated posterior wall of the left internal carotid artery seen intraoperatively (arrow)
DISCUSSION
We report the case of a middle-aged man who presented with a subacute painful neck swelling that was due to a ruptured mycotic aneurysm of the left carotid artery. Given his history of cancer, a malignant metastasis was among the differential diagnoses. However, CT imaging helped us to quickly narrow the list of possibilities.
The concern for a ruptured aneurysm prompted a vascular surgery consultation and ultimately surgical exploration. The aneurysm was found to be infected with Salmonella. Mycotic aneurysms of the carotid artery are relatively rare and those due to Salmonella spp. are even rarer. Our review of the literature revealed ~22 published cases of a carotid mycotic aneurysm due to Salmonella spp. Mycotic aneurysms tend to involve the aorta causing aortitis with or without aneurysm formation [3]. Only ~5% of mycotic aneurysms involve the carotid artery. In general, male gender is a risk factor for development of mycotic aneurysm [4]. Other risk factors include age >50, diabetes, hypertension and atherosclerosis [2, 4]. Our patient had many of the traditional risk factors. He was also fully anticoagulated while the aneurysm was developing and had recently been treated with chemotherapy. We suspect that these factors likely contributed to his presentation as well.
We did not identify a discrete episode of gastroenteritis or bacteremia. He had been taking chemotherapy ~2 weeks prior to presentation so typical symptoms such as diarrhea, nausea and vomiting might have been misattributed to medication side effects. There are a few published case reports of mycotic aneurysms due to Salmonella with negative blood cultures [5–7]. This may reflect the fact that gram negative bacteremia is frequently transient.
The standard management of mycotic aneurysms is open surgical repair. There are multiple case reports describing an endovascular approach, but studies comparing endovascular versus open repairs are lacking [4]. A minimum of 6 weeks of antibiotic therapy is often recommended although there are no data to support a specific duration of treatment [6].
The Maryland State Health Department performed the microbiological testing in this case and confirmed the Dublin serotype, which usually causes gastroenteritis in both cattle and humans [8]. There are very few case reports of mycotic abdominal aneurysms due to the Dublin serotype [2]. To our knowledge, this is the first published case of carotid mycotic aneurysm associated with the Dublin serotype. Although most Salmonella spp outbreaks have been linked to eggs, poultry and occasionally pet reptiles, outbreaks due to S. enterica ser Dublin have been linked to the consumption of contaminated ground beef and raw or unpasteurized milk. The Centers for Disease Control reported an outbreak of the Dublin serotype in 2019 that involved eight states. The outbreak was linked to ground beef [9].
This case report brings into focus several important clinical and epidemiological points. First, an infected aneurysm should be considered in the differential diagnosis for a patient who is febrile and presents with a tender neck mass. Second, since mycotic aneurysms frequently rupture, prompt referral to a vascular surgeon is paramount. Finally, since our patient likely contracted S. enterica ser Dublin from ground beef or milk, it is imperative that we continue surveillance for this organism in our environment.
ACKNOWLEDGMENTS
None.
FUNDING STATEMENT
The authors received no specific funding for this work.
ETHICAL APPROVAL
This Case Report does not require IRB approval as it is not considered research and does not contain any of the 18 HIPAA identifiers.
CONSENT
A signed written consent was obtained from the patient for this case report.
GUARANTOR
Adrien L. Janvier. | DOCETAXEL, RIVAROXABAN | DrugsGivenReaction | CC BY-NC | 33542826 | 19,058,832 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Infective aneurysm'. | An atypical presentation of Salmonella enterica ser Dublin in an immunocompromised patient.
Mycotic aneurysms of the carotid artery are a rare entity that can be fatal if not diagnosed promptly. We present a 60-year-old man with a tender left-sided neck mass due to a ruptured aneurysm of the left internal carotid artery. Cultures taken intraoperatively grew Salmonella enterica ser Dublin.
INTRODUCTION
Infection with Salmonella enterica usually results in a self-limited gastroenteritis characterized by fever, diarrhea, and less often nausea, vomiting and headache. However, according to CDC data, ~8% of laboratory confirmed cases are complicated by bacteremia, arteritis, meningitis and osteomyelitis [1]. Occasionally, extraintestinal infections result in infected or mycotic aneurysms. In the USA, Staphylococcus is the most common organism associated with mycotic aneurysms, whereas Salmonella is much more common in East Asian countries such as China [2]. Mycotic aneurysms associated with Salmonella infection rupture over 50% of the time and if untreated have a mortality ranging from 16 to 44% [2]. Thus, prompt recognition and treatment are key to improved patient outcomes. We report the first published case of a middle-aged man who developed a carotid mycotic aneurysm due S. enterica ser Dublin, a serovar that is usually associated with cattle (ground beef and unpasteurized milk).
CASE REPORT
A 60-year-old man with a history of metastatic prostate cancer (treated with docetaxel ~2 weeks prior to presentation), hypertension, hyperlipidemia, paroxysmal atrial fibrillation (on rivaroxaban) and right knee osteoarthritis (status post total knee replacement) presented to the emergency room with left sided neck pain and swelling. He first noted left sided neck pain 1 to 2 weeks prior to presentation. Initially, he noted some discomfort and a small nodule on his left neck. However, the nodule grew over time and the pain progressed to the point where he noted discomfort with swallowing and breathing. Accordingly, he presented to our medical center for care. On the day of admission, he was febrile (38.7°C), tachycardic (122), hypertensive (152/94). Fortunately, despite the tender neck swelling, there was no airway compromise.
The physical exam revealed a tender non-pulsatile mass on the left neck extending to the angle of the mandible. A computed tomography (CT) scan of the neck with contrast revealed a focal outpouching of the left carotid artery (Fig. 1). There also appeared to be a mass encircling the left carotid artery (4.3 cm × 2.5 cm × 3 cm) with lateral displacement and compression of the left jugular vein.
Figure 1 CT scan (coronal) of neck with contrast showing thrombosed aneurysm of the left internal carotid artery (arrow)
A vascular surgery consultation was obtained and given concern for a contained ruptured aneurysm, the patient was taken to the operating room (OR). During the surgery, an aneurysm with a posterior perforation and contained rupture was noted (Fig. 2). Pathological specimens from the surgical site were notable for significant atherosclerotic disease. Also, purulence was noted along with extravasated blood and cultures taken from intraoperative specimens revealed pan sensitive S. enterica ser Dublin. The affected and ulcerated portion of the carotid artery was excised and replaced via end-to-end anastomoses with a bovine mesenteric vein graft. Interestingly, all peripheral blood cultures were negative for bacterial growth. He was treated with ceftriaxone 2 grams IV daily for at least 6 weeks.
Figure 2 Perforated posterior wall of the left internal carotid artery seen intraoperatively (arrow)
DISCUSSION
We report the case of a middle-aged man who presented with a subacute painful neck swelling that was due to a ruptured mycotic aneurysm of the left carotid artery. Given his history of cancer, a malignant metastasis was among the differential diagnoses. However, CT imaging helped us to quickly narrow the list of possibilities.
The concern for a ruptured aneurysm prompted a vascular surgery consultation and ultimately surgical exploration. The aneurysm was found to be infected with Salmonella. Mycotic aneurysms of the carotid artery are relatively rare and those due to Salmonella spp. are even rarer. Our review of the literature revealed ~22 published cases of a carotid mycotic aneurysm due to Salmonella spp. Mycotic aneurysms tend to involve the aorta causing aortitis with or without aneurysm formation [3]. Only ~5% of mycotic aneurysms involve the carotid artery. In general, male gender is a risk factor for development of mycotic aneurysm [4]. Other risk factors include age >50, diabetes, hypertension and atherosclerosis [2, 4]. Our patient had many of the traditional risk factors. He was also fully anticoagulated while the aneurysm was developing and had recently been treated with chemotherapy. We suspect that these factors likely contributed to his presentation as well.
We did not identify a discrete episode of gastroenteritis or bacteremia. He had been taking chemotherapy ~2 weeks prior to presentation so typical symptoms such as diarrhea, nausea and vomiting might have been misattributed to medication side effects. There are a few published case reports of mycotic aneurysms due to Salmonella with negative blood cultures [5–7]. This may reflect the fact that gram negative bacteremia is frequently transient.
The standard management of mycotic aneurysms is open surgical repair. There are multiple case reports describing an endovascular approach, but studies comparing endovascular versus open repairs are lacking [4]. A minimum of 6 weeks of antibiotic therapy is often recommended although there are no data to support a specific duration of treatment [6].
The Maryland State Health Department performed the microbiological testing in this case and confirmed the Dublin serotype, which usually causes gastroenteritis in both cattle and humans [8]. There are very few case reports of mycotic abdominal aneurysms due to the Dublin serotype [2]. To our knowledge, this is the first published case of carotid mycotic aneurysm associated with the Dublin serotype. Although most Salmonella spp outbreaks have been linked to eggs, poultry and occasionally pet reptiles, outbreaks due to S. enterica ser Dublin have been linked to the consumption of contaminated ground beef and raw or unpasteurized milk. The Centers for Disease Control reported an outbreak of the Dublin serotype in 2019 that involved eight states. The outbreak was linked to ground beef [9].
This case report brings into focus several important clinical and epidemiological points. First, an infected aneurysm should be considered in the differential diagnosis for a patient who is febrile and presents with a tender neck mass. Second, since mycotic aneurysms frequently rupture, prompt referral to a vascular surgeon is paramount. Finally, since our patient likely contracted S. enterica ser Dublin from ground beef or milk, it is imperative that we continue surveillance for this organism in our environment.
ACKNOWLEDGMENTS
None.
FUNDING STATEMENT
The authors received no specific funding for this work.
ETHICAL APPROVAL
This Case Report does not require IRB approval as it is not considered research and does not contain any of the 18 HIPAA identifiers.
CONSENT
A signed written consent was obtained from the patient for this case report.
GUARANTOR
Adrien L. Janvier. | DOCETAXEL, RIVAROXABAN | DrugsGivenReaction | CC BY-NC | 33542826 | 19,062,457 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neck pain'. | An atypical presentation of Salmonella enterica ser Dublin in an immunocompromised patient.
Mycotic aneurysms of the carotid artery are a rare entity that can be fatal if not diagnosed promptly. We present a 60-year-old man with a tender left-sided neck mass due to a ruptured aneurysm of the left internal carotid artery. Cultures taken intraoperatively grew Salmonella enterica ser Dublin.
INTRODUCTION
Infection with Salmonella enterica usually results in a self-limited gastroenteritis characterized by fever, diarrhea, and less often nausea, vomiting and headache. However, according to CDC data, ~8% of laboratory confirmed cases are complicated by bacteremia, arteritis, meningitis and osteomyelitis [1]. Occasionally, extraintestinal infections result in infected or mycotic aneurysms. In the USA, Staphylococcus is the most common organism associated with mycotic aneurysms, whereas Salmonella is much more common in East Asian countries such as China [2]. Mycotic aneurysms associated with Salmonella infection rupture over 50% of the time and if untreated have a mortality ranging from 16 to 44% [2]. Thus, prompt recognition and treatment are key to improved patient outcomes. We report the first published case of a middle-aged man who developed a carotid mycotic aneurysm due S. enterica ser Dublin, a serovar that is usually associated with cattle (ground beef and unpasteurized milk).
CASE REPORT
A 60-year-old man with a history of metastatic prostate cancer (treated with docetaxel ~2 weeks prior to presentation), hypertension, hyperlipidemia, paroxysmal atrial fibrillation (on rivaroxaban) and right knee osteoarthritis (status post total knee replacement) presented to the emergency room with left sided neck pain and swelling. He first noted left sided neck pain 1 to 2 weeks prior to presentation. Initially, he noted some discomfort and a small nodule on his left neck. However, the nodule grew over time and the pain progressed to the point where he noted discomfort with swallowing and breathing. Accordingly, he presented to our medical center for care. On the day of admission, he was febrile (38.7°C), tachycardic (122), hypertensive (152/94). Fortunately, despite the tender neck swelling, there was no airway compromise.
The physical exam revealed a tender non-pulsatile mass on the left neck extending to the angle of the mandible. A computed tomography (CT) scan of the neck with contrast revealed a focal outpouching of the left carotid artery (Fig. 1). There also appeared to be a mass encircling the left carotid artery (4.3 cm × 2.5 cm × 3 cm) with lateral displacement and compression of the left jugular vein.
Figure 1 CT scan (coronal) of neck with contrast showing thrombosed aneurysm of the left internal carotid artery (arrow)
A vascular surgery consultation was obtained and given concern for a contained ruptured aneurysm, the patient was taken to the operating room (OR). During the surgery, an aneurysm with a posterior perforation and contained rupture was noted (Fig. 2). Pathological specimens from the surgical site were notable for significant atherosclerotic disease. Also, purulence was noted along with extravasated blood and cultures taken from intraoperative specimens revealed pan sensitive S. enterica ser Dublin. The affected and ulcerated portion of the carotid artery was excised and replaced via end-to-end anastomoses with a bovine mesenteric vein graft. Interestingly, all peripheral blood cultures were negative for bacterial growth. He was treated with ceftriaxone 2 grams IV daily for at least 6 weeks.
Figure 2 Perforated posterior wall of the left internal carotid artery seen intraoperatively (arrow)
DISCUSSION
We report the case of a middle-aged man who presented with a subacute painful neck swelling that was due to a ruptured mycotic aneurysm of the left carotid artery. Given his history of cancer, a malignant metastasis was among the differential diagnoses. However, CT imaging helped us to quickly narrow the list of possibilities.
The concern for a ruptured aneurysm prompted a vascular surgery consultation and ultimately surgical exploration. The aneurysm was found to be infected with Salmonella. Mycotic aneurysms of the carotid artery are relatively rare and those due to Salmonella spp. are even rarer. Our review of the literature revealed ~22 published cases of a carotid mycotic aneurysm due to Salmonella spp. Mycotic aneurysms tend to involve the aorta causing aortitis with or without aneurysm formation [3]. Only ~5% of mycotic aneurysms involve the carotid artery. In general, male gender is a risk factor for development of mycotic aneurysm [4]. Other risk factors include age >50, diabetes, hypertension and atherosclerosis [2, 4]. Our patient had many of the traditional risk factors. He was also fully anticoagulated while the aneurysm was developing and had recently been treated with chemotherapy. We suspect that these factors likely contributed to his presentation as well.
We did not identify a discrete episode of gastroenteritis or bacteremia. He had been taking chemotherapy ~2 weeks prior to presentation so typical symptoms such as diarrhea, nausea and vomiting might have been misattributed to medication side effects. There are a few published case reports of mycotic aneurysms due to Salmonella with negative blood cultures [5–7]. This may reflect the fact that gram negative bacteremia is frequently transient.
The standard management of mycotic aneurysms is open surgical repair. There are multiple case reports describing an endovascular approach, but studies comparing endovascular versus open repairs are lacking [4]. A minimum of 6 weeks of antibiotic therapy is often recommended although there are no data to support a specific duration of treatment [6].
The Maryland State Health Department performed the microbiological testing in this case and confirmed the Dublin serotype, which usually causes gastroenteritis in both cattle and humans [8]. There are very few case reports of mycotic abdominal aneurysms due to the Dublin serotype [2]. To our knowledge, this is the first published case of carotid mycotic aneurysm associated with the Dublin serotype. Although most Salmonella spp outbreaks have been linked to eggs, poultry and occasionally pet reptiles, outbreaks due to S. enterica ser Dublin have been linked to the consumption of contaminated ground beef and raw or unpasteurized milk. The Centers for Disease Control reported an outbreak of the Dublin serotype in 2019 that involved eight states. The outbreak was linked to ground beef [9].
This case report brings into focus several important clinical and epidemiological points. First, an infected aneurysm should be considered in the differential diagnosis for a patient who is febrile and presents with a tender neck mass. Second, since mycotic aneurysms frequently rupture, prompt referral to a vascular surgeon is paramount. Finally, since our patient likely contracted S. enterica ser Dublin from ground beef or milk, it is imperative that we continue surveillance for this organism in our environment.
ACKNOWLEDGMENTS
None.
FUNDING STATEMENT
The authors received no specific funding for this work.
ETHICAL APPROVAL
This Case Report does not require IRB approval as it is not considered research and does not contain any of the 18 HIPAA identifiers.
CONSENT
A signed written consent was obtained from the patient for this case report.
GUARANTOR
Adrien L. Janvier. | DOCETAXEL, RIVAROXABAN | DrugsGivenReaction | CC BY-NC | 33542826 | 19,058,832 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Purulence'. | An atypical presentation of Salmonella enterica ser Dublin in an immunocompromised patient.
Mycotic aneurysms of the carotid artery are a rare entity that can be fatal if not diagnosed promptly. We present a 60-year-old man with a tender left-sided neck mass due to a ruptured aneurysm of the left internal carotid artery. Cultures taken intraoperatively grew Salmonella enterica ser Dublin.
INTRODUCTION
Infection with Salmonella enterica usually results in a self-limited gastroenteritis characterized by fever, diarrhea, and less often nausea, vomiting and headache. However, according to CDC data, ~8% of laboratory confirmed cases are complicated by bacteremia, arteritis, meningitis and osteomyelitis [1]. Occasionally, extraintestinal infections result in infected or mycotic aneurysms. In the USA, Staphylococcus is the most common organism associated with mycotic aneurysms, whereas Salmonella is much more common in East Asian countries such as China [2]. Mycotic aneurysms associated with Salmonella infection rupture over 50% of the time and if untreated have a mortality ranging from 16 to 44% [2]. Thus, prompt recognition and treatment are key to improved patient outcomes. We report the first published case of a middle-aged man who developed a carotid mycotic aneurysm due S. enterica ser Dublin, a serovar that is usually associated with cattle (ground beef and unpasteurized milk).
CASE REPORT
A 60-year-old man with a history of metastatic prostate cancer (treated with docetaxel ~2 weeks prior to presentation), hypertension, hyperlipidemia, paroxysmal atrial fibrillation (on rivaroxaban) and right knee osteoarthritis (status post total knee replacement) presented to the emergency room with left sided neck pain and swelling. He first noted left sided neck pain 1 to 2 weeks prior to presentation. Initially, he noted some discomfort and a small nodule on his left neck. However, the nodule grew over time and the pain progressed to the point where he noted discomfort with swallowing and breathing. Accordingly, he presented to our medical center for care. On the day of admission, he was febrile (38.7°C), tachycardic (122), hypertensive (152/94). Fortunately, despite the tender neck swelling, there was no airway compromise.
The physical exam revealed a tender non-pulsatile mass on the left neck extending to the angle of the mandible. A computed tomography (CT) scan of the neck with contrast revealed a focal outpouching of the left carotid artery (Fig. 1). There also appeared to be a mass encircling the left carotid artery (4.3 cm × 2.5 cm × 3 cm) with lateral displacement and compression of the left jugular vein.
Figure 1 CT scan (coronal) of neck with contrast showing thrombosed aneurysm of the left internal carotid artery (arrow)
A vascular surgery consultation was obtained and given concern for a contained ruptured aneurysm, the patient was taken to the operating room (OR). During the surgery, an aneurysm with a posterior perforation and contained rupture was noted (Fig. 2). Pathological specimens from the surgical site were notable for significant atherosclerotic disease. Also, purulence was noted along with extravasated blood and cultures taken from intraoperative specimens revealed pan sensitive S. enterica ser Dublin. The affected and ulcerated portion of the carotid artery was excised and replaced via end-to-end anastomoses with a bovine mesenteric vein graft. Interestingly, all peripheral blood cultures were negative for bacterial growth. He was treated with ceftriaxone 2 grams IV daily for at least 6 weeks.
Figure 2 Perforated posterior wall of the left internal carotid artery seen intraoperatively (arrow)
DISCUSSION
We report the case of a middle-aged man who presented with a subacute painful neck swelling that was due to a ruptured mycotic aneurysm of the left carotid artery. Given his history of cancer, a malignant metastasis was among the differential diagnoses. However, CT imaging helped us to quickly narrow the list of possibilities.
The concern for a ruptured aneurysm prompted a vascular surgery consultation and ultimately surgical exploration. The aneurysm was found to be infected with Salmonella. Mycotic aneurysms of the carotid artery are relatively rare and those due to Salmonella spp. are even rarer. Our review of the literature revealed ~22 published cases of a carotid mycotic aneurysm due to Salmonella spp. Mycotic aneurysms tend to involve the aorta causing aortitis with or without aneurysm formation [3]. Only ~5% of mycotic aneurysms involve the carotid artery. In general, male gender is a risk factor for development of mycotic aneurysm [4]. Other risk factors include age >50, diabetes, hypertension and atherosclerosis [2, 4]. Our patient had many of the traditional risk factors. He was also fully anticoagulated while the aneurysm was developing and had recently been treated with chemotherapy. We suspect that these factors likely contributed to his presentation as well.
We did not identify a discrete episode of gastroenteritis or bacteremia. He had been taking chemotherapy ~2 weeks prior to presentation so typical symptoms such as diarrhea, nausea and vomiting might have been misattributed to medication side effects. There are a few published case reports of mycotic aneurysms due to Salmonella with negative blood cultures [5–7]. This may reflect the fact that gram negative bacteremia is frequently transient.
The standard management of mycotic aneurysms is open surgical repair. There are multiple case reports describing an endovascular approach, but studies comparing endovascular versus open repairs are lacking [4]. A minimum of 6 weeks of antibiotic therapy is often recommended although there are no data to support a specific duration of treatment [6].
The Maryland State Health Department performed the microbiological testing in this case and confirmed the Dublin serotype, which usually causes gastroenteritis in both cattle and humans [8]. There are very few case reports of mycotic abdominal aneurysms due to the Dublin serotype [2]. To our knowledge, this is the first published case of carotid mycotic aneurysm associated with the Dublin serotype. Although most Salmonella spp outbreaks have been linked to eggs, poultry and occasionally pet reptiles, outbreaks due to S. enterica ser Dublin have been linked to the consumption of contaminated ground beef and raw or unpasteurized milk. The Centers for Disease Control reported an outbreak of the Dublin serotype in 2019 that involved eight states. The outbreak was linked to ground beef [9].
This case report brings into focus several important clinical and epidemiological points. First, an infected aneurysm should be considered in the differential diagnosis for a patient who is febrile and presents with a tender neck mass. Second, since mycotic aneurysms frequently rupture, prompt referral to a vascular surgeon is paramount. Finally, since our patient likely contracted S. enterica ser Dublin from ground beef or milk, it is imperative that we continue surveillance for this organism in our environment.
ACKNOWLEDGMENTS
None.
FUNDING STATEMENT
The authors received no specific funding for this work.
ETHICAL APPROVAL
This Case Report does not require IRB approval as it is not considered research and does not contain any of the 18 HIPAA identifiers.
CONSENT
A signed written consent was obtained from the patient for this case report.
GUARANTOR
Adrien L. Janvier. | DOCETAXEL, RIVAROXABAN | DrugsGivenReaction | CC BY-NC | 33542826 | 19,058,832 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pyrexia'. | An atypical presentation of Salmonella enterica ser Dublin in an immunocompromised patient.
Mycotic aneurysms of the carotid artery are a rare entity that can be fatal if not diagnosed promptly. We present a 60-year-old man with a tender left-sided neck mass due to a ruptured aneurysm of the left internal carotid artery. Cultures taken intraoperatively grew Salmonella enterica ser Dublin.
INTRODUCTION
Infection with Salmonella enterica usually results in a self-limited gastroenteritis characterized by fever, diarrhea, and less often nausea, vomiting and headache. However, according to CDC data, ~8% of laboratory confirmed cases are complicated by bacteremia, arteritis, meningitis and osteomyelitis [1]. Occasionally, extraintestinal infections result in infected or mycotic aneurysms. In the USA, Staphylococcus is the most common organism associated with mycotic aneurysms, whereas Salmonella is much more common in East Asian countries such as China [2]. Mycotic aneurysms associated with Salmonella infection rupture over 50% of the time and if untreated have a mortality ranging from 16 to 44% [2]. Thus, prompt recognition and treatment are key to improved patient outcomes. We report the first published case of a middle-aged man who developed a carotid mycotic aneurysm due S. enterica ser Dublin, a serovar that is usually associated with cattle (ground beef and unpasteurized milk).
CASE REPORT
A 60-year-old man with a history of metastatic prostate cancer (treated with docetaxel ~2 weeks prior to presentation), hypertension, hyperlipidemia, paroxysmal atrial fibrillation (on rivaroxaban) and right knee osteoarthritis (status post total knee replacement) presented to the emergency room with left sided neck pain and swelling. He first noted left sided neck pain 1 to 2 weeks prior to presentation. Initially, he noted some discomfort and a small nodule on his left neck. However, the nodule grew over time and the pain progressed to the point where he noted discomfort with swallowing and breathing. Accordingly, he presented to our medical center for care. On the day of admission, he was febrile (38.7°C), tachycardic (122), hypertensive (152/94). Fortunately, despite the tender neck swelling, there was no airway compromise.
The physical exam revealed a tender non-pulsatile mass on the left neck extending to the angle of the mandible. A computed tomography (CT) scan of the neck with contrast revealed a focal outpouching of the left carotid artery (Fig. 1). There also appeared to be a mass encircling the left carotid artery (4.3 cm × 2.5 cm × 3 cm) with lateral displacement and compression of the left jugular vein.
Figure 1 CT scan (coronal) of neck with contrast showing thrombosed aneurysm of the left internal carotid artery (arrow)
A vascular surgery consultation was obtained and given concern for a contained ruptured aneurysm, the patient was taken to the operating room (OR). During the surgery, an aneurysm with a posterior perforation and contained rupture was noted (Fig. 2). Pathological specimens from the surgical site were notable for significant atherosclerotic disease. Also, purulence was noted along with extravasated blood and cultures taken from intraoperative specimens revealed pan sensitive S. enterica ser Dublin. The affected and ulcerated portion of the carotid artery was excised and replaced via end-to-end anastomoses with a bovine mesenteric vein graft. Interestingly, all peripheral blood cultures were negative for bacterial growth. He was treated with ceftriaxone 2 grams IV daily for at least 6 weeks.
Figure 2 Perforated posterior wall of the left internal carotid artery seen intraoperatively (arrow)
DISCUSSION
We report the case of a middle-aged man who presented with a subacute painful neck swelling that was due to a ruptured mycotic aneurysm of the left carotid artery. Given his history of cancer, a malignant metastasis was among the differential diagnoses. However, CT imaging helped us to quickly narrow the list of possibilities.
The concern for a ruptured aneurysm prompted a vascular surgery consultation and ultimately surgical exploration. The aneurysm was found to be infected with Salmonella. Mycotic aneurysms of the carotid artery are relatively rare and those due to Salmonella spp. are even rarer. Our review of the literature revealed ~22 published cases of a carotid mycotic aneurysm due to Salmonella spp. Mycotic aneurysms tend to involve the aorta causing aortitis with or without aneurysm formation [3]. Only ~5% of mycotic aneurysms involve the carotid artery. In general, male gender is a risk factor for development of mycotic aneurysm [4]. Other risk factors include age >50, diabetes, hypertension and atherosclerosis [2, 4]. Our patient had many of the traditional risk factors. He was also fully anticoagulated while the aneurysm was developing and had recently been treated with chemotherapy. We suspect that these factors likely contributed to his presentation as well.
We did not identify a discrete episode of gastroenteritis or bacteremia. He had been taking chemotherapy ~2 weeks prior to presentation so typical symptoms such as diarrhea, nausea and vomiting might have been misattributed to medication side effects. There are a few published case reports of mycotic aneurysms due to Salmonella with negative blood cultures [5–7]. This may reflect the fact that gram negative bacteremia is frequently transient.
The standard management of mycotic aneurysms is open surgical repair. There are multiple case reports describing an endovascular approach, but studies comparing endovascular versus open repairs are lacking [4]. A minimum of 6 weeks of antibiotic therapy is often recommended although there are no data to support a specific duration of treatment [6].
The Maryland State Health Department performed the microbiological testing in this case and confirmed the Dublin serotype, which usually causes gastroenteritis in both cattle and humans [8]. There are very few case reports of mycotic abdominal aneurysms due to the Dublin serotype [2]. To our knowledge, this is the first published case of carotid mycotic aneurysm associated with the Dublin serotype. Although most Salmonella spp outbreaks have been linked to eggs, poultry and occasionally pet reptiles, outbreaks due to S. enterica ser Dublin have been linked to the consumption of contaminated ground beef and raw or unpasteurized milk. The Centers for Disease Control reported an outbreak of the Dublin serotype in 2019 that involved eight states. The outbreak was linked to ground beef [9].
This case report brings into focus several important clinical and epidemiological points. First, an infected aneurysm should be considered in the differential diagnosis for a patient who is febrile and presents with a tender neck mass. Second, since mycotic aneurysms frequently rupture, prompt referral to a vascular surgeon is paramount. Finally, since our patient likely contracted S. enterica ser Dublin from ground beef or milk, it is imperative that we continue surveillance for this organism in our environment.
ACKNOWLEDGMENTS
None.
FUNDING STATEMENT
The authors received no specific funding for this work.
ETHICAL APPROVAL
This Case Report does not require IRB approval as it is not considered research and does not contain any of the 18 HIPAA identifiers.
CONSENT
A signed written consent was obtained from the patient for this case report.
GUARANTOR
Adrien L. Janvier. | DOCETAXEL, RIVAROXABAN | DrugsGivenReaction | CC BY-NC | 33542826 | 19,058,832 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Salmonellosis'. | An atypical presentation of Salmonella enterica ser Dublin in an immunocompromised patient.
Mycotic aneurysms of the carotid artery are a rare entity that can be fatal if not diagnosed promptly. We present a 60-year-old man with a tender left-sided neck mass due to a ruptured aneurysm of the left internal carotid artery. Cultures taken intraoperatively grew Salmonella enterica ser Dublin.
INTRODUCTION
Infection with Salmonella enterica usually results in a self-limited gastroenteritis characterized by fever, diarrhea, and less often nausea, vomiting and headache. However, according to CDC data, ~8% of laboratory confirmed cases are complicated by bacteremia, arteritis, meningitis and osteomyelitis [1]. Occasionally, extraintestinal infections result in infected or mycotic aneurysms. In the USA, Staphylococcus is the most common organism associated with mycotic aneurysms, whereas Salmonella is much more common in East Asian countries such as China [2]. Mycotic aneurysms associated with Salmonella infection rupture over 50% of the time and if untreated have a mortality ranging from 16 to 44% [2]. Thus, prompt recognition and treatment are key to improved patient outcomes. We report the first published case of a middle-aged man who developed a carotid mycotic aneurysm due S. enterica ser Dublin, a serovar that is usually associated with cattle (ground beef and unpasteurized milk).
CASE REPORT
A 60-year-old man with a history of metastatic prostate cancer (treated with docetaxel ~2 weeks prior to presentation), hypertension, hyperlipidemia, paroxysmal atrial fibrillation (on rivaroxaban) and right knee osteoarthritis (status post total knee replacement) presented to the emergency room with left sided neck pain and swelling. He first noted left sided neck pain 1 to 2 weeks prior to presentation. Initially, he noted some discomfort and a small nodule on his left neck. However, the nodule grew over time and the pain progressed to the point where he noted discomfort with swallowing and breathing. Accordingly, he presented to our medical center for care. On the day of admission, he was febrile (38.7°C), tachycardic (122), hypertensive (152/94). Fortunately, despite the tender neck swelling, there was no airway compromise.
The physical exam revealed a tender non-pulsatile mass on the left neck extending to the angle of the mandible. A computed tomography (CT) scan of the neck with contrast revealed a focal outpouching of the left carotid artery (Fig. 1). There also appeared to be a mass encircling the left carotid artery (4.3 cm × 2.5 cm × 3 cm) with lateral displacement and compression of the left jugular vein.
Figure 1 CT scan (coronal) of neck with contrast showing thrombosed aneurysm of the left internal carotid artery (arrow)
A vascular surgery consultation was obtained and given concern for a contained ruptured aneurysm, the patient was taken to the operating room (OR). During the surgery, an aneurysm with a posterior perforation and contained rupture was noted (Fig. 2). Pathological specimens from the surgical site were notable for significant atherosclerotic disease. Also, purulence was noted along with extravasated blood and cultures taken from intraoperative specimens revealed pan sensitive S. enterica ser Dublin. The affected and ulcerated portion of the carotid artery was excised and replaced via end-to-end anastomoses with a bovine mesenteric vein graft. Interestingly, all peripheral blood cultures were negative for bacterial growth. He was treated with ceftriaxone 2 grams IV daily for at least 6 weeks.
Figure 2 Perforated posterior wall of the left internal carotid artery seen intraoperatively (arrow)
DISCUSSION
We report the case of a middle-aged man who presented with a subacute painful neck swelling that was due to a ruptured mycotic aneurysm of the left carotid artery. Given his history of cancer, a malignant metastasis was among the differential diagnoses. However, CT imaging helped us to quickly narrow the list of possibilities.
The concern for a ruptured aneurysm prompted a vascular surgery consultation and ultimately surgical exploration. The aneurysm was found to be infected with Salmonella. Mycotic aneurysms of the carotid artery are relatively rare and those due to Salmonella spp. are even rarer. Our review of the literature revealed ~22 published cases of a carotid mycotic aneurysm due to Salmonella spp. Mycotic aneurysms tend to involve the aorta causing aortitis with or without aneurysm formation [3]. Only ~5% of mycotic aneurysms involve the carotid artery. In general, male gender is a risk factor for development of mycotic aneurysm [4]. Other risk factors include age >50, diabetes, hypertension and atherosclerosis [2, 4]. Our patient had many of the traditional risk factors. He was also fully anticoagulated while the aneurysm was developing and had recently been treated with chemotherapy. We suspect that these factors likely contributed to his presentation as well.
We did not identify a discrete episode of gastroenteritis or bacteremia. He had been taking chemotherapy ~2 weeks prior to presentation so typical symptoms such as diarrhea, nausea and vomiting might have been misattributed to medication side effects. There are a few published case reports of mycotic aneurysms due to Salmonella with negative blood cultures [5–7]. This may reflect the fact that gram negative bacteremia is frequently transient.
The standard management of mycotic aneurysms is open surgical repair. There are multiple case reports describing an endovascular approach, but studies comparing endovascular versus open repairs are lacking [4]. A minimum of 6 weeks of antibiotic therapy is often recommended although there are no data to support a specific duration of treatment [6].
The Maryland State Health Department performed the microbiological testing in this case and confirmed the Dublin serotype, which usually causes gastroenteritis in both cattle and humans [8]. There are very few case reports of mycotic abdominal aneurysms due to the Dublin serotype [2]. To our knowledge, this is the first published case of carotid mycotic aneurysm associated with the Dublin serotype. Although most Salmonella spp outbreaks have been linked to eggs, poultry and occasionally pet reptiles, outbreaks due to S. enterica ser Dublin have been linked to the consumption of contaminated ground beef and raw or unpasteurized milk. The Centers for Disease Control reported an outbreak of the Dublin serotype in 2019 that involved eight states. The outbreak was linked to ground beef [9].
This case report brings into focus several important clinical and epidemiological points. First, an infected aneurysm should be considered in the differential diagnosis for a patient who is febrile and presents with a tender neck mass. Second, since mycotic aneurysms frequently rupture, prompt referral to a vascular surgeon is paramount. Finally, since our patient likely contracted S. enterica ser Dublin from ground beef or milk, it is imperative that we continue surveillance for this organism in our environment.
ACKNOWLEDGMENTS
None.
FUNDING STATEMENT
The authors received no specific funding for this work.
ETHICAL APPROVAL
This Case Report does not require IRB approval as it is not considered research and does not contain any of the 18 HIPAA identifiers.
CONSENT
A signed written consent was obtained from the patient for this case report.
GUARANTOR
Adrien L. Janvier. | DOCETAXEL, RIVAROXABAN | DrugsGivenReaction | CC BY-NC | 33542826 | 19,065,688 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Swelling'. | An atypical presentation of Salmonella enterica ser Dublin in an immunocompromised patient.
Mycotic aneurysms of the carotid artery are a rare entity that can be fatal if not diagnosed promptly. We present a 60-year-old man with a tender left-sided neck mass due to a ruptured aneurysm of the left internal carotid artery. Cultures taken intraoperatively grew Salmonella enterica ser Dublin.
INTRODUCTION
Infection with Salmonella enterica usually results in a self-limited gastroenteritis characterized by fever, diarrhea, and less often nausea, vomiting and headache. However, according to CDC data, ~8% of laboratory confirmed cases are complicated by bacteremia, arteritis, meningitis and osteomyelitis [1]. Occasionally, extraintestinal infections result in infected or mycotic aneurysms. In the USA, Staphylococcus is the most common organism associated with mycotic aneurysms, whereas Salmonella is much more common in East Asian countries such as China [2]. Mycotic aneurysms associated with Salmonella infection rupture over 50% of the time and if untreated have a mortality ranging from 16 to 44% [2]. Thus, prompt recognition and treatment are key to improved patient outcomes. We report the first published case of a middle-aged man who developed a carotid mycotic aneurysm due S. enterica ser Dublin, a serovar that is usually associated with cattle (ground beef and unpasteurized milk).
CASE REPORT
A 60-year-old man with a history of metastatic prostate cancer (treated with docetaxel ~2 weeks prior to presentation), hypertension, hyperlipidemia, paroxysmal atrial fibrillation (on rivaroxaban) and right knee osteoarthritis (status post total knee replacement) presented to the emergency room with left sided neck pain and swelling. He first noted left sided neck pain 1 to 2 weeks prior to presentation. Initially, he noted some discomfort and a small nodule on his left neck. However, the nodule grew over time and the pain progressed to the point where he noted discomfort with swallowing and breathing. Accordingly, he presented to our medical center for care. On the day of admission, he was febrile (38.7°C), tachycardic (122), hypertensive (152/94). Fortunately, despite the tender neck swelling, there was no airway compromise.
The physical exam revealed a tender non-pulsatile mass on the left neck extending to the angle of the mandible. A computed tomography (CT) scan of the neck with contrast revealed a focal outpouching of the left carotid artery (Fig. 1). There also appeared to be a mass encircling the left carotid artery (4.3 cm × 2.5 cm × 3 cm) with lateral displacement and compression of the left jugular vein.
Figure 1 CT scan (coronal) of neck with contrast showing thrombosed aneurysm of the left internal carotid artery (arrow)
A vascular surgery consultation was obtained and given concern for a contained ruptured aneurysm, the patient was taken to the operating room (OR). During the surgery, an aneurysm with a posterior perforation and contained rupture was noted (Fig. 2). Pathological specimens from the surgical site were notable for significant atherosclerotic disease. Also, purulence was noted along with extravasated blood and cultures taken from intraoperative specimens revealed pan sensitive S. enterica ser Dublin. The affected and ulcerated portion of the carotid artery was excised and replaced via end-to-end anastomoses with a bovine mesenteric vein graft. Interestingly, all peripheral blood cultures were negative for bacterial growth. He was treated with ceftriaxone 2 grams IV daily for at least 6 weeks.
Figure 2 Perforated posterior wall of the left internal carotid artery seen intraoperatively (arrow)
DISCUSSION
We report the case of a middle-aged man who presented with a subacute painful neck swelling that was due to a ruptured mycotic aneurysm of the left carotid artery. Given his history of cancer, a malignant metastasis was among the differential diagnoses. However, CT imaging helped us to quickly narrow the list of possibilities.
The concern for a ruptured aneurysm prompted a vascular surgery consultation and ultimately surgical exploration. The aneurysm was found to be infected with Salmonella. Mycotic aneurysms of the carotid artery are relatively rare and those due to Salmonella spp. are even rarer. Our review of the literature revealed ~22 published cases of a carotid mycotic aneurysm due to Salmonella spp. Mycotic aneurysms tend to involve the aorta causing aortitis with or without aneurysm formation [3]. Only ~5% of mycotic aneurysms involve the carotid artery. In general, male gender is a risk factor for development of mycotic aneurysm [4]. Other risk factors include age >50, diabetes, hypertension and atherosclerosis [2, 4]. Our patient had many of the traditional risk factors. He was also fully anticoagulated while the aneurysm was developing and had recently been treated with chemotherapy. We suspect that these factors likely contributed to his presentation as well.
We did not identify a discrete episode of gastroenteritis or bacteremia. He had been taking chemotherapy ~2 weeks prior to presentation so typical symptoms such as diarrhea, nausea and vomiting might have been misattributed to medication side effects. There are a few published case reports of mycotic aneurysms due to Salmonella with negative blood cultures [5–7]. This may reflect the fact that gram negative bacteremia is frequently transient.
The standard management of mycotic aneurysms is open surgical repair. There are multiple case reports describing an endovascular approach, but studies comparing endovascular versus open repairs are lacking [4]. A minimum of 6 weeks of antibiotic therapy is often recommended although there are no data to support a specific duration of treatment [6].
The Maryland State Health Department performed the microbiological testing in this case and confirmed the Dublin serotype, which usually causes gastroenteritis in both cattle and humans [8]. There are very few case reports of mycotic abdominal aneurysms due to the Dublin serotype [2]. To our knowledge, this is the first published case of carotid mycotic aneurysm associated with the Dublin serotype. Although most Salmonella spp outbreaks have been linked to eggs, poultry and occasionally pet reptiles, outbreaks due to S. enterica ser Dublin have been linked to the consumption of contaminated ground beef and raw or unpasteurized milk. The Centers for Disease Control reported an outbreak of the Dublin serotype in 2019 that involved eight states. The outbreak was linked to ground beef [9].
This case report brings into focus several important clinical and epidemiological points. First, an infected aneurysm should be considered in the differential diagnosis for a patient who is febrile and presents with a tender neck mass. Second, since mycotic aneurysms frequently rupture, prompt referral to a vascular surgeon is paramount. Finally, since our patient likely contracted S. enterica ser Dublin from ground beef or milk, it is imperative that we continue surveillance for this organism in our environment.
ACKNOWLEDGMENTS
None.
FUNDING STATEMENT
The authors received no specific funding for this work.
ETHICAL APPROVAL
This Case Report does not require IRB approval as it is not considered research and does not contain any of the 18 HIPAA identifiers.
CONSENT
A signed written consent was obtained from the patient for this case report.
GUARANTOR
Adrien L. Janvier. | DOCETAXEL, RIVAROXABAN | DrugsGivenReaction | CC BY-NC | 33542826 | 19,058,832 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Tachycardia'. | An atypical presentation of Salmonella enterica ser Dublin in an immunocompromised patient.
Mycotic aneurysms of the carotid artery are a rare entity that can be fatal if not diagnosed promptly. We present a 60-year-old man with a tender left-sided neck mass due to a ruptured aneurysm of the left internal carotid artery. Cultures taken intraoperatively grew Salmonella enterica ser Dublin.
INTRODUCTION
Infection with Salmonella enterica usually results in a self-limited gastroenteritis characterized by fever, diarrhea, and less often nausea, vomiting and headache. However, according to CDC data, ~8% of laboratory confirmed cases are complicated by bacteremia, arteritis, meningitis and osteomyelitis [1]. Occasionally, extraintestinal infections result in infected or mycotic aneurysms. In the USA, Staphylococcus is the most common organism associated with mycotic aneurysms, whereas Salmonella is much more common in East Asian countries such as China [2]. Mycotic aneurysms associated with Salmonella infection rupture over 50% of the time and if untreated have a mortality ranging from 16 to 44% [2]. Thus, prompt recognition and treatment are key to improved patient outcomes. We report the first published case of a middle-aged man who developed a carotid mycotic aneurysm due S. enterica ser Dublin, a serovar that is usually associated with cattle (ground beef and unpasteurized milk).
CASE REPORT
A 60-year-old man with a history of metastatic prostate cancer (treated with docetaxel ~2 weeks prior to presentation), hypertension, hyperlipidemia, paroxysmal atrial fibrillation (on rivaroxaban) and right knee osteoarthritis (status post total knee replacement) presented to the emergency room with left sided neck pain and swelling. He first noted left sided neck pain 1 to 2 weeks prior to presentation. Initially, he noted some discomfort and a small nodule on his left neck. However, the nodule grew over time and the pain progressed to the point where he noted discomfort with swallowing and breathing. Accordingly, he presented to our medical center for care. On the day of admission, he was febrile (38.7°C), tachycardic (122), hypertensive (152/94). Fortunately, despite the tender neck swelling, there was no airway compromise.
The physical exam revealed a tender non-pulsatile mass on the left neck extending to the angle of the mandible. A computed tomography (CT) scan of the neck with contrast revealed a focal outpouching of the left carotid artery (Fig. 1). There also appeared to be a mass encircling the left carotid artery (4.3 cm × 2.5 cm × 3 cm) with lateral displacement and compression of the left jugular vein.
Figure 1 CT scan (coronal) of neck with contrast showing thrombosed aneurysm of the left internal carotid artery (arrow)
A vascular surgery consultation was obtained and given concern for a contained ruptured aneurysm, the patient was taken to the operating room (OR). During the surgery, an aneurysm with a posterior perforation and contained rupture was noted (Fig. 2). Pathological specimens from the surgical site were notable for significant atherosclerotic disease. Also, purulence was noted along with extravasated blood and cultures taken from intraoperative specimens revealed pan sensitive S. enterica ser Dublin. The affected and ulcerated portion of the carotid artery was excised and replaced via end-to-end anastomoses with a bovine mesenteric vein graft. Interestingly, all peripheral blood cultures were negative for bacterial growth. He was treated with ceftriaxone 2 grams IV daily for at least 6 weeks.
Figure 2 Perforated posterior wall of the left internal carotid artery seen intraoperatively (arrow)
DISCUSSION
We report the case of a middle-aged man who presented with a subacute painful neck swelling that was due to a ruptured mycotic aneurysm of the left carotid artery. Given his history of cancer, a malignant metastasis was among the differential diagnoses. However, CT imaging helped us to quickly narrow the list of possibilities.
The concern for a ruptured aneurysm prompted a vascular surgery consultation and ultimately surgical exploration. The aneurysm was found to be infected with Salmonella. Mycotic aneurysms of the carotid artery are relatively rare and those due to Salmonella spp. are even rarer. Our review of the literature revealed ~22 published cases of a carotid mycotic aneurysm due to Salmonella spp. Mycotic aneurysms tend to involve the aorta causing aortitis with or without aneurysm formation [3]. Only ~5% of mycotic aneurysms involve the carotid artery. In general, male gender is a risk factor for development of mycotic aneurysm [4]. Other risk factors include age >50, diabetes, hypertension and atherosclerosis [2, 4]. Our patient had many of the traditional risk factors. He was also fully anticoagulated while the aneurysm was developing and had recently been treated with chemotherapy. We suspect that these factors likely contributed to his presentation as well.
We did not identify a discrete episode of gastroenteritis or bacteremia. He had been taking chemotherapy ~2 weeks prior to presentation so typical symptoms such as diarrhea, nausea and vomiting might have been misattributed to medication side effects. There are a few published case reports of mycotic aneurysms due to Salmonella with negative blood cultures [5–7]. This may reflect the fact that gram negative bacteremia is frequently transient.
The standard management of mycotic aneurysms is open surgical repair. There are multiple case reports describing an endovascular approach, but studies comparing endovascular versus open repairs are lacking [4]. A minimum of 6 weeks of antibiotic therapy is often recommended although there are no data to support a specific duration of treatment [6].
The Maryland State Health Department performed the microbiological testing in this case and confirmed the Dublin serotype, which usually causes gastroenteritis in both cattle and humans [8]. There are very few case reports of mycotic abdominal aneurysms due to the Dublin serotype [2]. To our knowledge, this is the first published case of carotid mycotic aneurysm associated with the Dublin serotype. Although most Salmonella spp outbreaks have been linked to eggs, poultry and occasionally pet reptiles, outbreaks due to S. enterica ser Dublin have been linked to the consumption of contaminated ground beef and raw or unpasteurized milk. The Centers for Disease Control reported an outbreak of the Dublin serotype in 2019 that involved eight states. The outbreak was linked to ground beef [9].
This case report brings into focus several important clinical and epidemiological points. First, an infected aneurysm should be considered in the differential diagnosis for a patient who is febrile and presents with a tender neck mass. Second, since mycotic aneurysms frequently rupture, prompt referral to a vascular surgeon is paramount. Finally, since our patient likely contracted S. enterica ser Dublin from ground beef or milk, it is imperative that we continue surveillance for this organism in our environment.
ACKNOWLEDGMENTS
None.
FUNDING STATEMENT
The authors received no specific funding for this work.
ETHICAL APPROVAL
This Case Report does not require IRB approval as it is not considered research and does not contain any of the 18 HIPAA identifiers.
CONSENT
A signed written consent was obtained from the patient for this case report.
GUARANTOR
Adrien L. Janvier. | DOCETAXEL, RIVAROXABAN | DrugsGivenReaction | CC BY-NC | 33542826 | 19,058,832 | 2021-01 |
What was the outcome of reaction 'Aneurysm ruptured'? | An atypical presentation of Salmonella enterica ser Dublin in an immunocompromised patient.
Mycotic aneurysms of the carotid artery are a rare entity that can be fatal if not diagnosed promptly. We present a 60-year-old man with a tender left-sided neck mass due to a ruptured aneurysm of the left internal carotid artery. Cultures taken intraoperatively grew Salmonella enterica ser Dublin.
INTRODUCTION
Infection with Salmonella enterica usually results in a self-limited gastroenteritis characterized by fever, diarrhea, and less often nausea, vomiting and headache. However, according to CDC data, ~8% of laboratory confirmed cases are complicated by bacteremia, arteritis, meningitis and osteomyelitis [1]. Occasionally, extraintestinal infections result in infected or mycotic aneurysms. In the USA, Staphylococcus is the most common organism associated with mycotic aneurysms, whereas Salmonella is much more common in East Asian countries such as China [2]. Mycotic aneurysms associated with Salmonella infection rupture over 50% of the time and if untreated have a mortality ranging from 16 to 44% [2]. Thus, prompt recognition and treatment are key to improved patient outcomes. We report the first published case of a middle-aged man who developed a carotid mycotic aneurysm due S. enterica ser Dublin, a serovar that is usually associated with cattle (ground beef and unpasteurized milk).
CASE REPORT
A 60-year-old man with a history of metastatic prostate cancer (treated with docetaxel ~2 weeks prior to presentation), hypertension, hyperlipidemia, paroxysmal atrial fibrillation (on rivaroxaban) and right knee osteoarthritis (status post total knee replacement) presented to the emergency room with left sided neck pain and swelling. He first noted left sided neck pain 1 to 2 weeks prior to presentation. Initially, he noted some discomfort and a small nodule on his left neck. However, the nodule grew over time and the pain progressed to the point where he noted discomfort with swallowing and breathing. Accordingly, he presented to our medical center for care. On the day of admission, he was febrile (38.7°C), tachycardic (122), hypertensive (152/94). Fortunately, despite the tender neck swelling, there was no airway compromise.
The physical exam revealed a tender non-pulsatile mass on the left neck extending to the angle of the mandible. A computed tomography (CT) scan of the neck with contrast revealed a focal outpouching of the left carotid artery (Fig. 1). There also appeared to be a mass encircling the left carotid artery (4.3 cm × 2.5 cm × 3 cm) with lateral displacement and compression of the left jugular vein.
Figure 1 CT scan (coronal) of neck with contrast showing thrombosed aneurysm of the left internal carotid artery (arrow)
A vascular surgery consultation was obtained and given concern for a contained ruptured aneurysm, the patient was taken to the operating room (OR). During the surgery, an aneurysm with a posterior perforation and contained rupture was noted (Fig. 2). Pathological specimens from the surgical site were notable for significant atherosclerotic disease. Also, purulence was noted along with extravasated blood and cultures taken from intraoperative specimens revealed pan sensitive S. enterica ser Dublin. The affected and ulcerated portion of the carotid artery was excised and replaced via end-to-end anastomoses with a bovine mesenteric vein graft. Interestingly, all peripheral blood cultures were negative for bacterial growth. He was treated with ceftriaxone 2 grams IV daily for at least 6 weeks.
Figure 2 Perforated posterior wall of the left internal carotid artery seen intraoperatively (arrow)
DISCUSSION
We report the case of a middle-aged man who presented with a subacute painful neck swelling that was due to a ruptured mycotic aneurysm of the left carotid artery. Given his history of cancer, a malignant metastasis was among the differential diagnoses. However, CT imaging helped us to quickly narrow the list of possibilities.
The concern for a ruptured aneurysm prompted a vascular surgery consultation and ultimately surgical exploration. The aneurysm was found to be infected with Salmonella. Mycotic aneurysms of the carotid artery are relatively rare and those due to Salmonella spp. are even rarer. Our review of the literature revealed ~22 published cases of a carotid mycotic aneurysm due to Salmonella spp. Mycotic aneurysms tend to involve the aorta causing aortitis with or without aneurysm formation [3]. Only ~5% of mycotic aneurysms involve the carotid artery. In general, male gender is a risk factor for development of mycotic aneurysm [4]. Other risk factors include age >50, diabetes, hypertension and atherosclerosis [2, 4]. Our patient had many of the traditional risk factors. He was also fully anticoagulated while the aneurysm was developing and had recently been treated with chemotherapy. We suspect that these factors likely contributed to his presentation as well.
We did not identify a discrete episode of gastroenteritis or bacteremia. He had been taking chemotherapy ~2 weeks prior to presentation so typical symptoms such as diarrhea, nausea and vomiting might have been misattributed to medication side effects. There are a few published case reports of mycotic aneurysms due to Salmonella with negative blood cultures [5–7]. This may reflect the fact that gram negative bacteremia is frequently transient.
The standard management of mycotic aneurysms is open surgical repair. There are multiple case reports describing an endovascular approach, but studies comparing endovascular versus open repairs are lacking [4]. A minimum of 6 weeks of antibiotic therapy is often recommended although there are no data to support a specific duration of treatment [6].
The Maryland State Health Department performed the microbiological testing in this case and confirmed the Dublin serotype, which usually causes gastroenteritis in both cattle and humans [8]. There are very few case reports of mycotic abdominal aneurysms due to the Dublin serotype [2]. To our knowledge, this is the first published case of carotid mycotic aneurysm associated with the Dublin serotype. Although most Salmonella spp outbreaks have been linked to eggs, poultry and occasionally pet reptiles, outbreaks due to S. enterica ser Dublin have been linked to the consumption of contaminated ground beef and raw or unpasteurized milk. The Centers for Disease Control reported an outbreak of the Dublin serotype in 2019 that involved eight states. The outbreak was linked to ground beef [9].
This case report brings into focus several important clinical and epidemiological points. First, an infected aneurysm should be considered in the differential diagnosis for a patient who is febrile and presents with a tender neck mass. Second, since mycotic aneurysms frequently rupture, prompt referral to a vascular surgeon is paramount. Finally, since our patient likely contracted S. enterica ser Dublin from ground beef or milk, it is imperative that we continue surveillance for this organism in our environment.
ACKNOWLEDGMENTS
None.
FUNDING STATEMENT
The authors received no specific funding for this work.
ETHICAL APPROVAL
This Case Report does not require IRB approval as it is not considered research and does not contain any of the 18 HIPAA identifiers.
CONSENT
A signed written consent was obtained from the patient for this case report.
GUARANTOR
Adrien L. Janvier. | Recovering | ReactionOutcome | CC BY-NC | 33542826 | 19,065,688 | 2021-01 |
What was the outcome of reaction 'Aortitis salmonella'? | An atypical presentation of Salmonella enterica ser Dublin in an immunocompromised patient.
Mycotic aneurysms of the carotid artery are a rare entity that can be fatal if not diagnosed promptly. We present a 60-year-old man with a tender left-sided neck mass due to a ruptured aneurysm of the left internal carotid artery. Cultures taken intraoperatively grew Salmonella enterica ser Dublin.
INTRODUCTION
Infection with Salmonella enterica usually results in a self-limited gastroenteritis characterized by fever, diarrhea, and less often nausea, vomiting and headache. However, according to CDC data, ~8% of laboratory confirmed cases are complicated by bacteremia, arteritis, meningitis and osteomyelitis [1]. Occasionally, extraintestinal infections result in infected or mycotic aneurysms. In the USA, Staphylococcus is the most common organism associated with mycotic aneurysms, whereas Salmonella is much more common in East Asian countries such as China [2]. Mycotic aneurysms associated with Salmonella infection rupture over 50% of the time and if untreated have a mortality ranging from 16 to 44% [2]. Thus, prompt recognition and treatment are key to improved patient outcomes. We report the first published case of a middle-aged man who developed a carotid mycotic aneurysm due S. enterica ser Dublin, a serovar that is usually associated with cattle (ground beef and unpasteurized milk).
CASE REPORT
A 60-year-old man with a history of metastatic prostate cancer (treated with docetaxel ~2 weeks prior to presentation), hypertension, hyperlipidemia, paroxysmal atrial fibrillation (on rivaroxaban) and right knee osteoarthritis (status post total knee replacement) presented to the emergency room with left sided neck pain and swelling. He first noted left sided neck pain 1 to 2 weeks prior to presentation. Initially, he noted some discomfort and a small nodule on his left neck. However, the nodule grew over time and the pain progressed to the point where he noted discomfort with swallowing and breathing. Accordingly, he presented to our medical center for care. On the day of admission, he was febrile (38.7°C), tachycardic (122), hypertensive (152/94). Fortunately, despite the tender neck swelling, there was no airway compromise.
The physical exam revealed a tender non-pulsatile mass on the left neck extending to the angle of the mandible. A computed tomography (CT) scan of the neck with contrast revealed a focal outpouching of the left carotid artery (Fig. 1). There also appeared to be a mass encircling the left carotid artery (4.3 cm × 2.5 cm × 3 cm) with lateral displacement and compression of the left jugular vein.
Figure 1 CT scan (coronal) of neck with contrast showing thrombosed aneurysm of the left internal carotid artery (arrow)
A vascular surgery consultation was obtained and given concern for a contained ruptured aneurysm, the patient was taken to the operating room (OR). During the surgery, an aneurysm with a posterior perforation and contained rupture was noted (Fig. 2). Pathological specimens from the surgical site were notable for significant atherosclerotic disease. Also, purulence was noted along with extravasated blood and cultures taken from intraoperative specimens revealed pan sensitive S. enterica ser Dublin. The affected and ulcerated portion of the carotid artery was excised and replaced via end-to-end anastomoses with a bovine mesenteric vein graft. Interestingly, all peripheral blood cultures were negative for bacterial growth. He was treated with ceftriaxone 2 grams IV daily for at least 6 weeks.
Figure 2 Perforated posterior wall of the left internal carotid artery seen intraoperatively (arrow)
DISCUSSION
We report the case of a middle-aged man who presented with a subacute painful neck swelling that was due to a ruptured mycotic aneurysm of the left carotid artery. Given his history of cancer, a malignant metastasis was among the differential diagnoses. However, CT imaging helped us to quickly narrow the list of possibilities.
The concern for a ruptured aneurysm prompted a vascular surgery consultation and ultimately surgical exploration. The aneurysm was found to be infected with Salmonella. Mycotic aneurysms of the carotid artery are relatively rare and those due to Salmonella spp. are even rarer. Our review of the literature revealed ~22 published cases of a carotid mycotic aneurysm due to Salmonella spp. Mycotic aneurysms tend to involve the aorta causing aortitis with or without aneurysm formation [3]. Only ~5% of mycotic aneurysms involve the carotid artery. In general, male gender is a risk factor for development of mycotic aneurysm [4]. Other risk factors include age >50, diabetes, hypertension and atherosclerosis [2, 4]. Our patient had many of the traditional risk factors. He was also fully anticoagulated while the aneurysm was developing and had recently been treated with chemotherapy. We suspect that these factors likely contributed to his presentation as well.
We did not identify a discrete episode of gastroenteritis or bacteremia. He had been taking chemotherapy ~2 weeks prior to presentation so typical symptoms such as diarrhea, nausea and vomiting might have been misattributed to medication side effects. There are a few published case reports of mycotic aneurysms due to Salmonella with negative blood cultures [5–7]. This may reflect the fact that gram negative bacteremia is frequently transient.
The standard management of mycotic aneurysms is open surgical repair. There are multiple case reports describing an endovascular approach, but studies comparing endovascular versus open repairs are lacking [4]. A minimum of 6 weeks of antibiotic therapy is often recommended although there are no data to support a specific duration of treatment [6].
The Maryland State Health Department performed the microbiological testing in this case and confirmed the Dublin serotype, which usually causes gastroenteritis in both cattle and humans [8]. There are very few case reports of mycotic abdominal aneurysms due to the Dublin serotype [2]. To our knowledge, this is the first published case of carotid mycotic aneurysm associated with the Dublin serotype. Although most Salmonella spp outbreaks have been linked to eggs, poultry and occasionally pet reptiles, outbreaks due to S. enterica ser Dublin have been linked to the consumption of contaminated ground beef and raw or unpasteurized milk. The Centers for Disease Control reported an outbreak of the Dublin serotype in 2019 that involved eight states. The outbreak was linked to ground beef [9].
This case report brings into focus several important clinical and epidemiological points. First, an infected aneurysm should be considered in the differential diagnosis for a patient who is febrile and presents with a tender neck mass. Second, since mycotic aneurysms frequently rupture, prompt referral to a vascular surgeon is paramount. Finally, since our patient likely contracted S. enterica ser Dublin from ground beef or milk, it is imperative that we continue surveillance for this organism in our environment.
ACKNOWLEDGMENTS
None.
FUNDING STATEMENT
The authors received no specific funding for this work.
ETHICAL APPROVAL
This Case Report does not require IRB approval as it is not considered research and does not contain any of the 18 HIPAA identifiers.
CONSENT
A signed written consent was obtained from the patient for this case report.
GUARANTOR
Adrien L. Janvier. | Recovered | ReactionOutcome | CC BY-NC | 33542826 | 19,062,457 | 2021-01 |
What was the outcome of reaction 'Neck pain'? | An atypical presentation of Salmonella enterica ser Dublin in an immunocompromised patient.
Mycotic aneurysms of the carotid artery are a rare entity that can be fatal if not diagnosed promptly. We present a 60-year-old man with a tender left-sided neck mass due to a ruptured aneurysm of the left internal carotid artery. Cultures taken intraoperatively grew Salmonella enterica ser Dublin.
INTRODUCTION
Infection with Salmonella enterica usually results in a self-limited gastroenteritis characterized by fever, diarrhea, and less often nausea, vomiting and headache. However, according to CDC data, ~8% of laboratory confirmed cases are complicated by bacteremia, arteritis, meningitis and osteomyelitis [1]. Occasionally, extraintestinal infections result in infected or mycotic aneurysms. In the USA, Staphylococcus is the most common organism associated with mycotic aneurysms, whereas Salmonella is much more common in East Asian countries such as China [2]. Mycotic aneurysms associated with Salmonella infection rupture over 50% of the time and if untreated have a mortality ranging from 16 to 44% [2]. Thus, prompt recognition and treatment are key to improved patient outcomes. We report the first published case of a middle-aged man who developed a carotid mycotic aneurysm due S. enterica ser Dublin, a serovar that is usually associated with cattle (ground beef and unpasteurized milk).
CASE REPORT
A 60-year-old man with a history of metastatic prostate cancer (treated with docetaxel ~2 weeks prior to presentation), hypertension, hyperlipidemia, paroxysmal atrial fibrillation (on rivaroxaban) and right knee osteoarthritis (status post total knee replacement) presented to the emergency room with left sided neck pain and swelling. He first noted left sided neck pain 1 to 2 weeks prior to presentation. Initially, he noted some discomfort and a small nodule on his left neck. However, the nodule grew over time and the pain progressed to the point where he noted discomfort with swallowing and breathing. Accordingly, he presented to our medical center for care. On the day of admission, he was febrile (38.7°C), tachycardic (122), hypertensive (152/94). Fortunately, despite the tender neck swelling, there was no airway compromise.
The physical exam revealed a tender non-pulsatile mass on the left neck extending to the angle of the mandible. A computed tomography (CT) scan of the neck with contrast revealed a focal outpouching of the left carotid artery (Fig. 1). There also appeared to be a mass encircling the left carotid artery (4.3 cm × 2.5 cm × 3 cm) with lateral displacement and compression of the left jugular vein.
Figure 1 CT scan (coronal) of neck with contrast showing thrombosed aneurysm of the left internal carotid artery (arrow)
A vascular surgery consultation was obtained and given concern for a contained ruptured aneurysm, the patient was taken to the operating room (OR). During the surgery, an aneurysm with a posterior perforation and contained rupture was noted (Fig. 2). Pathological specimens from the surgical site were notable for significant atherosclerotic disease. Also, purulence was noted along with extravasated blood and cultures taken from intraoperative specimens revealed pan sensitive S. enterica ser Dublin. The affected and ulcerated portion of the carotid artery was excised and replaced via end-to-end anastomoses with a bovine mesenteric vein graft. Interestingly, all peripheral blood cultures were negative for bacterial growth. He was treated with ceftriaxone 2 grams IV daily for at least 6 weeks.
Figure 2 Perforated posterior wall of the left internal carotid artery seen intraoperatively (arrow)
DISCUSSION
We report the case of a middle-aged man who presented with a subacute painful neck swelling that was due to a ruptured mycotic aneurysm of the left carotid artery. Given his history of cancer, a malignant metastasis was among the differential diagnoses. However, CT imaging helped us to quickly narrow the list of possibilities.
The concern for a ruptured aneurysm prompted a vascular surgery consultation and ultimately surgical exploration. The aneurysm was found to be infected with Salmonella. Mycotic aneurysms of the carotid artery are relatively rare and those due to Salmonella spp. are even rarer. Our review of the literature revealed ~22 published cases of a carotid mycotic aneurysm due to Salmonella spp. Mycotic aneurysms tend to involve the aorta causing aortitis with or without aneurysm formation [3]. Only ~5% of mycotic aneurysms involve the carotid artery. In general, male gender is a risk factor for development of mycotic aneurysm [4]. Other risk factors include age >50, diabetes, hypertension and atherosclerosis [2, 4]. Our patient had many of the traditional risk factors. He was also fully anticoagulated while the aneurysm was developing and had recently been treated with chemotherapy. We suspect that these factors likely contributed to his presentation as well.
We did not identify a discrete episode of gastroenteritis or bacteremia. He had been taking chemotherapy ~2 weeks prior to presentation so typical symptoms such as diarrhea, nausea and vomiting might have been misattributed to medication side effects. There are a few published case reports of mycotic aneurysms due to Salmonella with negative blood cultures [5–7]. This may reflect the fact that gram negative bacteremia is frequently transient.
The standard management of mycotic aneurysms is open surgical repair. There are multiple case reports describing an endovascular approach, but studies comparing endovascular versus open repairs are lacking [4]. A minimum of 6 weeks of antibiotic therapy is often recommended although there are no data to support a specific duration of treatment [6].
The Maryland State Health Department performed the microbiological testing in this case and confirmed the Dublin serotype, which usually causes gastroenteritis in both cattle and humans [8]. There are very few case reports of mycotic abdominal aneurysms due to the Dublin serotype [2]. To our knowledge, this is the first published case of carotid mycotic aneurysm associated with the Dublin serotype. Although most Salmonella spp outbreaks have been linked to eggs, poultry and occasionally pet reptiles, outbreaks due to S. enterica ser Dublin have been linked to the consumption of contaminated ground beef and raw or unpasteurized milk. The Centers for Disease Control reported an outbreak of the Dublin serotype in 2019 that involved eight states. The outbreak was linked to ground beef [9].
This case report brings into focus several important clinical and epidemiological points. First, an infected aneurysm should be considered in the differential diagnosis for a patient who is febrile and presents with a tender neck mass. Second, since mycotic aneurysms frequently rupture, prompt referral to a vascular surgeon is paramount. Finally, since our patient likely contracted S. enterica ser Dublin from ground beef or milk, it is imperative that we continue surveillance for this organism in our environment.
ACKNOWLEDGMENTS
None.
FUNDING STATEMENT
The authors received no specific funding for this work.
ETHICAL APPROVAL
This Case Report does not require IRB approval as it is not considered research and does not contain any of the 18 HIPAA identifiers.
CONSENT
A signed written consent was obtained from the patient for this case report.
GUARANTOR
Adrien L. Janvier. | Recovering | ReactionOutcome | CC BY-NC | 33542826 | 19,058,832 | 2021-01 |
What was the outcome of reaction 'Swelling'? | An atypical presentation of Salmonella enterica ser Dublin in an immunocompromised patient.
Mycotic aneurysms of the carotid artery are a rare entity that can be fatal if not diagnosed promptly. We present a 60-year-old man with a tender left-sided neck mass due to a ruptured aneurysm of the left internal carotid artery. Cultures taken intraoperatively grew Salmonella enterica ser Dublin.
INTRODUCTION
Infection with Salmonella enterica usually results in a self-limited gastroenteritis characterized by fever, diarrhea, and less often nausea, vomiting and headache. However, according to CDC data, ~8% of laboratory confirmed cases are complicated by bacteremia, arteritis, meningitis and osteomyelitis [1]. Occasionally, extraintestinal infections result in infected or mycotic aneurysms. In the USA, Staphylococcus is the most common organism associated with mycotic aneurysms, whereas Salmonella is much more common in East Asian countries such as China [2]. Mycotic aneurysms associated with Salmonella infection rupture over 50% of the time and if untreated have a mortality ranging from 16 to 44% [2]. Thus, prompt recognition and treatment are key to improved patient outcomes. We report the first published case of a middle-aged man who developed a carotid mycotic aneurysm due S. enterica ser Dublin, a serovar that is usually associated with cattle (ground beef and unpasteurized milk).
CASE REPORT
A 60-year-old man with a history of metastatic prostate cancer (treated with docetaxel ~2 weeks prior to presentation), hypertension, hyperlipidemia, paroxysmal atrial fibrillation (on rivaroxaban) and right knee osteoarthritis (status post total knee replacement) presented to the emergency room with left sided neck pain and swelling. He first noted left sided neck pain 1 to 2 weeks prior to presentation. Initially, he noted some discomfort and a small nodule on his left neck. However, the nodule grew over time and the pain progressed to the point where he noted discomfort with swallowing and breathing. Accordingly, he presented to our medical center for care. On the day of admission, he was febrile (38.7°C), tachycardic (122), hypertensive (152/94). Fortunately, despite the tender neck swelling, there was no airway compromise.
The physical exam revealed a tender non-pulsatile mass on the left neck extending to the angle of the mandible. A computed tomography (CT) scan of the neck with contrast revealed a focal outpouching of the left carotid artery (Fig. 1). There also appeared to be a mass encircling the left carotid artery (4.3 cm × 2.5 cm × 3 cm) with lateral displacement and compression of the left jugular vein.
Figure 1 CT scan (coronal) of neck with contrast showing thrombosed aneurysm of the left internal carotid artery (arrow)
A vascular surgery consultation was obtained and given concern for a contained ruptured aneurysm, the patient was taken to the operating room (OR). During the surgery, an aneurysm with a posterior perforation and contained rupture was noted (Fig. 2). Pathological specimens from the surgical site were notable for significant atherosclerotic disease. Also, purulence was noted along with extravasated blood and cultures taken from intraoperative specimens revealed pan sensitive S. enterica ser Dublin. The affected and ulcerated portion of the carotid artery was excised and replaced via end-to-end anastomoses with a bovine mesenteric vein graft. Interestingly, all peripheral blood cultures were negative for bacterial growth. He was treated with ceftriaxone 2 grams IV daily for at least 6 weeks.
Figure 2 Perforated posterior wall of the left internal carotid artery seen intraoperatively (arrow)
DISCUSSION
We report the case of a middle-aged man who presented with a subacute painful neck swelling that was due to a ruptured mycotic aneurysm of the left carotid artery. Given his history of cancer, a malignant metastasis was among the differential diagnoses. However, CT imaging helped us to quickly narrow the list of possibilities.
The concern for a ruptured aneurysm prompted a vascular surgery consultation and ultimately surgical exploration. The aneurysm was found to be infected with Salmonella. Mycotic aneurysms of the carotid artery are relatively rare and those due to Salmonella spp. are even rarer. Our review of the literature revealed ~22 published cases of a carotid mycotic aneurysm due to Salmonella spp. Mycotic aneurysms tend to involve the aorta causing aortitis with or without aneurysm formation [3]. Only ~5% of mycotic aneurysms involve the carotid artery. In general, male gender is a risk factor for development of mycotic aneurysm [4]. Other risk factors include age >50, diabetes, hypertension and atherosclerosis [2, 4]. Our patient had many of the traditional risk factors. He was also fully anticoagulated while the aneurysm was developing and had recently been treated with chemotherapy. We suspect that these factors likely contributed to his presentation as well.
We did not identify a discrete episode of gastroenteritis or bacteremia. He had been taking chemotherapy ~2 weeks prior to presentation so typical symptoms such as diarrhea, nausea and vomiting might have been misattributed to medication side effects. There are a few published case reports of mycotic aneurysms due to Salmonella with negative blood cultures [5–7]. This may reflect the fact that gram negative bacteremia is frequently transient.
The standard management of mycotic aneurysms is open surgical repair. There are multiple case reports describing an endovascular approach, but studies comparing endovascular versus open repairs are lacking [4]. A minimum of 6 weeks of antibiotic therapy is often recommended although there are no data to support a specific duration of treatment [6].
The Maryland State Health Department performed the microbiological testing in this case and confirmed the Dublin serotype, which usually causes gastroenteritis in both cattle and humans [8]. There are very few case reports of mycotic abdominal aneurysms due to the Dublin serotype [2]. To our knowledge, this is the first published case of carotid mycotic aneurysm associated with the Dublin serotype. Although most Salmonella spp outbreaks have been linked to eggs, poultry and occasionally pet reptiles, outbreaks due to S. enterica ser Dublin have been linked to the consumption of contaminated ground beef and raw or unpasteurized milk. The Centers for Disease Control reported an outbreak of the Dublin serotype in 2019 that involved eight states. The outbreak was linked to ground beef [9].
This case report brings into focus several important clinical and epidemiological points. First, an infected aneurysm should be considered in the differential diagnosis for a patient who is febrile and presents with a tender neck mass. Second, since mycotic aneurysms frequently rupture, prompt referral to a vascular surgeon is paramount. Finally, since our patient likely contracted S. enterica ser Dublin from ground beef or milk, it is imperative that we continue surveillance for this organism in our environment.
ACKNOWLEDGMENTS
None.
FUNDING STATEMENT
The authors received no specific funding for this work.
ETHICAL APPROVAL
This Case Report does not require IRB approval as it is not considered research and does not contain any of the 18 HIPAA identifiers.
CONSENT
A signed written consent was obtained from the patient for this case report.
GUARANTOR
Adrien L. Janvier. | Recovering | ReactionOutcome | CC BY-NC | 33542826 | 19,058,832 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Bacillus infection'. | Use of various immunotherapies for refractory ulcerative colitis in a person living with HIV: a case report.
Cancer therapies include several immune checkpoint or anticytokine therapies whereas ulcerative colitis treatments consist of anticytokine therapies. The development of tolerance and immunogical effects of these agents in people living with HIV are not well assessed as these persons are often excluded from clinical trials. Herein, we report a case of a Caucasian woman who received multiple sequential immunotherapies for severe ulcerative colitis. Due to steroid-refractory disease, receipt of maximal doses of mesalamine and initial repeated decline of surgical intervention, she went on to receive biologic immune inhibitors like tumor necrosis fator-α blockers infliximab and adalimumab, the α4β7integrin blocker vedolizumab, anti-interleukin 12/23 blocker ustekinumab and Janus Kinase inihibitor tofacitinib without achieving remission. Only minor infectious complications were encountered and no significant changes in CD4 count nor CD4/CD8 ratio occurred. This case provides support for the safety and tolerability of the above immunotherapies in people living with HIV with suppressed viral load on antiretroviral therapy.
INTRODUCTION
In the management of ulcerative colitis (UC), one provides immunosuppressive therapy with the hope of tempering excessive inflammation while preserving immune function. However, if the proper balance between immunosuppression and immune preservation is not achieved, an individual will be tipped into immunodeficiency with increased infection risk. People living with HIV (PLWH) are often excluding from clinical trials involving biologics based on concerns of additive immunosuppression and infection risk. Consequently, little data are available to guide clinicians in managing PLWH who suffer from advanced inflammatory bowel disease (IBD). Herein, we present the case of young woman with HIV infection and extensive UC refractory to many therapies. Following repeated decline of surgical intervention, she was treated with multiple sequential immunomodulators and did not experience any major adverse effects.
CASE REPORT
A 36-year-old, Canadian-born Caucasian woman was diagnosed with HIV in 2008. She began antiretroviral therapy with tenofovir disoproxil 300 mg/emtracitabine 200 mg orally once daily and raltegravir 400 mg orally twice daily in 2012, when her CD4 count rapidly dropped to 86 cells/mm3. Later that year, she began experiencing frequent episodes of bloody diarrhea, with up to 20 stools daily, with cramping, rectal bleeding and elevated C-reactive protein (CRP). Stool was repeatedly negative for Clostridium difficile and ova and parasites. Colonoscopy demonstrated severe pancolitis and biopsies consistent with active UC with acute cryptitis, crypt abcesses with lymphoid hyperplasia, focal erosions, acute inflammatory exudate with architectural disortion. Hematoxylin and eosin stains for cytomegalovirus and histochemical exams for Herpes Simplex Virus I/II were negative. Despite high doses of oral prednisone (40–60 mg daily) and several emergency room visits to receive intravenous (IV) methylprednisolone for flares, she was deemed steroid-refractory.
Later that year, she received maximum doses of oral mesalamine and 6-mercaptopurine, as well as mesalamine suppositories and enemas. She then received infliximab (2012–2013), an antitumor necrois fator-α (anti-TNFα) monoclonal antibody, until antibody formation. Despite maximum doses of adalimumab (2014), her UC remained refractory although no antibodies were detected using a drug-tolerant assay and medication levels were therapeutic (>12 μg/ml, the highest limit of detection). Attempts to taper her steroids resulted in flare-ups and a cushingoid feature. She declined colectomy as she felt this would interfere with her lifestyle, especially since she was getting married, and concerns about her future fertility.
One of the options explored was the use of vedolizumab, a monoclonal antibody against α4β7 integrin, via a clinical trial. However, due to the patient’s HIV infection she was not eligible to participate in any of the recruiting trials at the centre as HIV infection is frequently an exclusion criteria. Colonoscopy in 2015 revealed severe inflammation with ulcerations and friability consistent with Mayo 3 colitis, despite high-dose steroids and adalimumab, an anti-TNFα monoclonal antibody, at a dose of 80 mg weekly. By December 2015, vedolizumab was obtained through standard of care and initiated at 300 mg IV at weeks 0 and 2, 6 (loading dose) and then every 8 weeks thereafter as a maintenance dose. She was still bleeding from the rectum and had decreased weight, therefore daily prednisone 10 mg orally was maintained. She achieved clinical remission by March 2016 and steroids were stopped. Two months later, she developed right foot cellulitis following a minor trauma during a pedicure and required 48 hours of IV followed by oral antibiotics.
Colonoscopy in June 2016, 3 months after stopping steroids, showed worsening condition with Mayo 3 colitis, so she was changed to vedolizumab 300 mg IV q 4 weeks and prednisone increased to 40 mg orally (po) daily. Anti-α4β7 antibodies were not detected. She was passing bright red blood per rectum 12 times in 24 hours and having five stools per 24 hours with lower abdominal cramping and rectal pain. Janus kinase (JAK) inhibitor, tofacitinab 10 mg po twice daily, was initiated October 2016 and prednisone 40 mg po daily maintained. Symptoms persisted requiring admission for IV prednisolone, but she continued to decline surgical colectomy. She also developed a bacterial vaginitis treated with metronidazole cream and later a skin furuncle, treated with oral antibiotics.
Following tofacitinib, she received interleukin 12/23 inhibitor ustekinumab March–September 2017. She gained 30 pounds in 1 year (body mass index 37), increased abdominal fat and bilateral cataracts due to cortisone. Attempts to decrease prednisone below 30 mg daily led to bloody diarrhea (12–17 bowel movements daily). She eventually accepted to undergo subtotal abdominal colectomy (pathology shown in Fig. 1) with rectal stump and temporary end ileostomy by June 2018. She improved and was seen for follow-up a month post-op, at which time she was having increasing right lower quadrant pain and rising CRP. A computed tomography scan demonstrated collections in the subcutaneous fat surrounding the ostomy and a second collection centimeter with rim enhancement and fat stranding. These were drained and cultures grew E. coli and B. fragilis. She responded to IV antibiotics for 3 days followed by oral step-down antibiotics to complete 2 weeks. Eight months following her colectomy, she developed polyarthralgia in her interphalangeal joints, wrists, shoulders, knees and feet with a normal CRP and a negative Rheumatoid Factor while off prednisone, thought to be either inflammatory or mechanical polyarthralgia. Pathology on surveillance sigmoidoscopy March 2019 demonstrated chronic active proctitis with ulceration consistent with chronic idiopathic IBD. Throughout this entire time, her CD4 range was between 400 and 900 cells/mm3, with CD4/CD8 ratio of 0.41:1.12, and HIV viral load remained suppressed since November 2012.
Figure 1 Colonic resection histology. The colonic mucosa shows characteristic features of chronic ulcerative colitis including crypt architecture alteration, cryptitis, crypt abscess and focal mucosa ulceration. There is no evidence of dysplasia.
DISCUSSION
Due to repeated decline of surgery in order to preserve her quality of life and fertility, this woman with HIV and refractory UC received all available conventional therapies including mesalamine, glucocorticoids, thiopurines, antagonists to TNF- α, IL-12/23 blockers and anti-α4 β7 integrin. She also received a small-molecule JAK inhibitor. TNF-α inhibitors and α4β7 integrin blockers are used with extreme caution in PLWH due to concerns of additional immunosuppression and subsequent infection risk. However, during her 6 years of being on immunosuppressants, the patient only experienced one episode of cellulitis, bacterial vaginosis, a skin furuncle and peristomal abscesses, all of which were easily managed with traditional therapies. Another concern with the use of integrin receptor antagonists in PLWH, although rare, is the possibility of Progressive Multifocal Leukoencephalopathy due to John Cunningham (JC) virus [1]. Our patient underwent blood plasma JC virus testing prior to vedolizumab initiation and this polymerase chain reaction testing was negative. She also denied any neurological signs or symptoms throughout treatment.
This woman’s case demonstrates that the spectrum of drug classes available and sequential use of biologics for treatment of UC were safe in this patient with well-controlled HIV infection ART, including an TNF-α blocker, JK inhibitor, IL-12/23 blocker and the α4β7 integrin blocker vedolizumab. Our patient did not incur any significant changes in her CD4 count nor CD4/CD8 ratio during the course of her treatments and infections were relatively minor. Although we did not use combination biologics in this patient, their efficacy and safety for IBD and other and other inflammatory diseases associated was explored in a systematic review of observational studies which did not find any differences related to improvements in disease condition, adverse effects or infection rates in patients receiving combined treatment compared to placebo groups [2]. A clinical trial (NCT02764762) examining efficacy and safety of combined vedolizumab, adalimumab and oral methotrexate in patients with Crohn’s Disease is in progress [3]. Until evidence from clinical trials is available on efficacy and safety of biologics and combination therapy in PLWH, case reports and case series provide a channel for dissemination of these experiences within the medical community.
ACKNOWLEDGMENTS
The authors thank Pathologist, Dr Zu-hua Gao, for provision of the histology image. No funding was received for the preparation of this manuscript.
CONFLICTS OF INTEREST STATEMENT
None declared.
FUNDING
No funding was received for the preparation of this manuscript.
ETHICS APPROVAL
The authors received ethical approval for publication of the case report.
CONSENT TO PUBLISH
The patient provided informed written consent for the preparation of this case report and publication of data and pathological image in an open access journal. The participant understood that the details/images would be freely available on the internet and may be seen by the general public. A copy of the written consent is available for review by the editor of the journal.
GUARANTOR
Dr Costiniuk is the guarantor of the case report. | ADALIMUMAB, CORTISONE, INFLIXIMAB, MERCAPTOPURINE, MESALAMINE, METHYLPREDNISOLONE, PREDNISOLONE, PREDNISONE, RALTEGRAVIR, TOFACITINIB, USTEKINUMAB, VEDOLIZUMAB | DrugsGivenReaction | CC BY-NC | 33542833 | 19,114,036 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Bacterial vulvovaginitis'. | Use of various immunotherapies for refractory ulcerative colitis in a person living with HIV: a case report.
Cancer therapies include several immune checkpoint or anticytokine therapies whereas ulcerative colitis treatments consist of anticytokine therapies. The development of tolerance and immunogical effects of these agents in people living with HIV are not well assessed as these persons are often excluded from clinical trials. Herein, we report a case of a Caucasian woman who received multiple sequential immunotherapies for severe ulcerative colitis. Due to steroid-refractory disease, receipt of maximal doses of mesalamine and initial repeated decline of surgical intervention, she went on to receive biologic immune inhibitors like tumor necrosis fator-α blockers infliximab and adalimumab, the α4β7integrin blocker vedolizumab, anti-interleukin 12/23 blocker ustekinumab and Janus Kinase inihibitor tofacitinib without achieving remission. Only minor infectious complications were encountered and no significant changes in CD4 count nor CD4/CD8 ratio occurred. This case provides support for the safety and tolerability of the above immunotherapies in people living with HIV with suppressed viral load on antiretroviral therapy.
INTRODUCTION
In the management of ulcerative colitis (UC), one provides immunosuppressive therapy with the hope of tempering excessive inflammation while preserving immune function. However, if the proper balance between immunosuppression and immune preservation is not achieved, an individual will be tipped into immunodeficiency with increased infection risk. People living with HIV (PLWH) are often excluding from clinical trials involving biologics based on concerns of additive immunosuppression and infection risk. Consequently, little data are available to guide clinicians in managing PLWH who suffer from advanced inflammatory bowel disease (IBD). Herein, we present the case of young woman with HIV infection and extensive UC refractory to many therapies. Following repeated decline of surgical intervention, she was treated with multiple sequential immunomodulators and did not experience any major adverse effects.
CASE REPORT
A 36-year-old, Canadian-born Caucasian woman was diagnosed with HIV in 2008. She began antiretroviral therapy with tenofovir disoproxil 300 mg/emtracitabine 200 mg orally once daily and raltegravir 400 mg orally twice daily in 2012, when her CD4 count rapidly dropped to 86 cells/mm3. Later that year, she began experiencing frequent episodes of bloody diarrhea, with up to 20 stools daily, with cramping, rectal bleeding and elevated C-reactive protein (CRP). Stool was repeatedly negative for Clostridium difficile and ova and parasites. Colonoscopy demonstrated severe pancolitis and biopsies consistent with active UC with acute cryptitis, crypt abcesses with lymphoid hyperplasia, focal erosions, acute inflammatory exudate with architectural disortion. Hematoxylin and eosin stains for cytomegalovirus and histochemical exams for Herpes Simplex Virus I/II were negative. Despite high doses of oral prednisone (40–60 mg daily) and several emergency room visits to receive intravenous (IV) methylprednisolone for flares, she was deemed steroid-refractory.
Later that year, she received maximum doses of oral mesalamine and 6-mercaptopurine, as well as mesalamine suppositories and enemas. She then received infliximab (2012–2013), an antitumor necrois fator-α (anti-TNFα) monoclonal antibody, until antibody formation. Despite maximum doses of adalimumab (2014), her UC remained refractory although no antibodies were detected using a drug-tolerant assay and medication levels were therapeutic (>12 μg/ml, the highest limit of detection). Attempts to taper her steroids resulted in flare-ups and a cushingoid feature. She declined colectomy as she felt this would interfere with her lifestyle, especially since she was getting married, and concerns about her future fertility.
One of the options explored was the use of vedolizumab, a monoclonal antibody against α4β7 integrin, via a clinical trial. However, due to the patient’s HIV infection she was not eligible to participate in any of the recruiting trials at the centre as HIV infection is frequently an exclusion criteria. Colonoscopy in 2015 revealed severe inflammation with ulcerations and friability consistent with Mayo 3 colitis, despite high-dose steroids and adalimumab, an anti-TNFα monoclonal antibody, at a dose of 80 mg weekly. By December 2015, vedolizumab was obtained through standard of care and initiated at 300 mg IV at weeks 0 and 2, 6 (loading dose) and then every 8 weeks thereafter as a maintenance dose. She was still bleeding from the rectum and had decreased weight, therefore daily prednisone 10 mg orally was maintained. She achieved clinical remission by March 2016 and steroids were stopped. Two months later, she developed right foot cellulitis following a minor trauma during a pedicure and required 48 hours of IV followed by oral antibiotics.
Colonoscopy in June 2016, 3 months after stopping steroids, showed worsening condition with Mayo 3 colitis, so she was changed to vedolizumab 300 mg IV q 4 weeks and prednisone increased to 40 mg orally (po) daily. Anti-α4β7 antibodies were not detected. She was passing bright red blood per rectum 12 times in 24 hours and having five stools per 24 hours with lower abdominal cramping and rectal pain. Janus kinase (JAK) inhibitor, tofacitinab 10 mg po twice daily, was initiated October 2016 and prednisone 40 mg po daily maintained. Symptoms persisted requiring admission for IV prednisolone, but she continued to decline surgical colectomy. She also developed a bacterial vaginitis treated with metronidazole cream and later a skin furuncle, treated with oral antibiotics.
Following tofacitinib, she received interleukin 12/23 inhibitor ustekinumab March–September 2017. She gained 30 pounds in 1 year (body mass index 37), increased abdominal fat and bilateral cataracts due to cortisone. Attempts to decrease prednisone below 30 mg daily led to bloody diarrhea (12–17 bowel movements daily). She eventually accepted to undergo subtotal abdominal colectomy (pathology shown in Fig. 1) with rectal stump and temporary end ileostomy by June 2018. She improved and was seen for follow-up a month post-op, at which time she was having increasing right lower quadrant pain and rising CRP. A computed tomography scan demonstrated collections in the subcutaneous fat surrounding the ostomy and a second collection centimeter with rim enhancement and fat stranding. These were drained and cultures grew E. coli and B. fragilis. She responded to IV antibiotics for 3 days followed by oral step-down antibiotics to complete 2 weeks. Eight months following her colectomy, she developed polyarthralgia in her interphalangeal joints, wrists, shoulders, knees and feet with a normal CRP and a negative Rheumatoid Factor while off prednisone, thought to be either inflammatory or mechanical polyarthralgia. Pathology on surveillance sigmoidoscopy March 2019 demonstrated chronic active proctitis with ulceration consistent with chronic idiopathic IBD. Throughout this entire time, her CD4 range was between 400 and 900 cells/mm3, with CD4/CD8 ratio of 0.41:1.12, and HIV viral load remained suppressed since November 2012.
Figure 1 Colonic resection histology. The colonic mucosa shows characteristic features of chronic ulcerative colitis including crypt architecture alteration, cryptitis, crypt abscess and focal mucosa ulceration. There is no evidence of dysplasia.
DISCUSSION
Due to repeated decline of surgery in order to preserve her quality of life and fertility, this woman with HIV and refractory UC received all available conventional therapies including mesalamine, glucocorticoids, thiopurines, antagonists to TNF- α, IL-12/23 blockers and anti-α4 β7 integrin. She also received a small-molecule JAK inhibitor. TNF-α inhibitors and α4β7 integrin blockers are used with extreme caution in PLWH due to concerns of additional immunosuppression and subsequent infection risk. However, during her 6 years of being on immunosuppressants, the patient only experienced one episode of cellulitis, bacterial vaginosis, a skin furuncle and peristomal abscesses, all of which were easily managed with traditional therapies. Another concern with the use of integrin receptor antagonists in PLWH, although rare, is the possibility of Progressive Multifocal Leukoencephalopathy due to John Cunningham (JC) virus [1]. Our patient underwent blood plasma JC virus testing prior to vedolizumab initiation and this polymerase chain reaction testing was negative. She also denied any neurological signs or symptoms throughout treatment.
This woman’s case demonstrates that the spectrum of drug classes available and sequential use of biologics for treatment of UC were safe in this patient with well-controlled HIV infection ART, including an TNF-α blocker, JK inhibitor, IL-12/23 blocker and the α4β7 integrin blocker vedolizumab. Our patient did not incur any significant changes in her CD4 count nor CD4/CD8 ratio during the course of her treatments and infections were relatively minor. Although we did not use combination biologics in this patient, their efficacy and safety for IBD and other and other inflammatory diseases associated was explored in a systematic review of observational studies which did not find any differences related to improvements in disease condition, adverse effects or infection rates in patients receiving combined treatment compared to placebo groups [2]. A clinical trial (NCT02764762) examining efficacy and safety of combined vedolizumab, adalimumab and oral methotrexate in patients with Crohn’s Disease is in progress [3]. Until evidence from clinical trials is available on efficacy and safety of biologics and combination therapy in PLWH, case reports and case series provide a channel for dissemination of these experiences within the medical community.
ACKNOWLEDGMENTS
The authors thank Pathologist, Dr Zu-hua Gao, for provision of the histology image. No funding was received for the preparation of this manuscript.
CONFLICTS OF INTEREST STATEMENT
None declared.
FUNDING
No funding was received for the preparation of this manuscript.
ETHICS APPROVAL
The authors received ethical approval for publication of the case report.
CONSENT TO PUBLISH
The patient provided informed written consent for the preparation of this case report and publication of data and pathological image in an open access journal. The participant understood that the details/images would be freely available on the internet and may be seen by the general public. A copy of the written consent is available for review by the editor of the journal.
GUARANTOR
Dr Costiniuk is the guarantor of the case report. | ADALIMUMAB, CORTISONE, INFLIXIMAB, MERCAPTOPURINE, MESALAMINE, METHYLPREDNISOLONE, PREDNISOLONE, PREDNISONE, RALTEGRAVIR, TOFACITINIB, USTEKINUMAB, VEDOLIZUMAB | DrugsGivenReaction | CC BY-NC | 33542833 | 19,114,036 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cataract'. | Use of various immunotherapies for refractory ulcerative colitis in a person living with HIV: a case report.
Cancer therapies include several immune checkpoint or anticytokine therapies whereas ulcerative colitis treatments consist of anticytokine therapies. The development of tolerance and immunogical effects of these agents in people living with HIV are not well assessed as these persons are often excluded from clinical trials. Herein, we report a case of a Caucasian woman who received multiple sequential immunotherapies for severe ulcerative colitis. Due to steroid-refractory disease, receipt of maximal doses of mesalamine and initial repeated decline of surgical intervention, she went on to receive biologic immune inhibitors like tumor necrosis fator-α blockers infliximab and adalimumab, the α4β7integrin blocker vedolizumab, anti-interleukin 12/23 blocker ustekinumab and Janus Kinase inihibitor tofacitinib without achieving remission. Only minor infectious complications were encountered and no significant changes in CD4 count nor CD4/CD8 ratio occurred. This case provides support for the safety and tolerability of the above immunotherapies in people living with HIV with suppressed viral load on antiretroviral therapy.
INTRODUCTION
In the management of ulcerative colitis (UC), one provides immunosuppressive therapy with the hope of tempering excessive inflammation while preserving immune function. However, if the proper balance between immunosuppression and immune preservation is not achieved, an individual will be tipped into immunodeficiency with increased infection risk. People living with HIV (PLWH) are often excluding from clinical trials involving biologics based on concerns of additive immunosuppression and infection risk. Consequently, little data are available to guide clinicians in managing PLWH who suffer from advanced inflammatory bowel disease (IBD). Herein, we present the case of young woman with HIV infection and extensive UC refractory to many therapies. Following repeated decline of surgical intervention, she was treated with multiple sequential immunomodulators and did not experience any major adverse effects.
CASE REPORT
A 36-year-old, Canadian-born Caucasian woman was diagnosed with HIV in 2008. She began antiretroviral therapy with tenofovir disoproxil 300 mg/emtracitabine 200 mg orally once daily and raltegravir 400 mg orally twice daily in 2012, when her CD4 count rapidly dropped to 86 cells/mm3. Later that year, she began experiencing frequent episodes of bloody diarrhea, with up to 20 stools daily, with cramping, rectal bleeding and elevated C-reactive protein (CRP). Stool was repeatedly negative for Clostridium difficile and ova and parasites. Colonoscopy demonstrated severe pancolitis and biopsies consistent with active UC with acute cryptitis, crypt abcesses with lymphoid hyperplasia, focal erosions, acute inflammatory exudate with architectural disortion. Hematoxylin and eosin stains for cytomegalovirus and histochemical exams for Herpes Simplex Virus I/II were negative. Despite high doses of oral prednisone (40–60 mg daily) and several emergency room visits to receive intravenous (IV) methylprednisolone for flares, she was deemed steroid-refractory.
Later that year, she received maximum doses of oral mesalamine and 6-mercaptopurine, as well as mesalamine suppositories and enemas. She then received infliximab (2012–2013), an antitumor necrois fator-α (anti-TNFα) monoclonal antibody, until antibody formation. Despite maximum doses of adalimumab (2014), her UC remained refractory although no antibodies were detected using a drug-tolerant assay and medication levels were therapeutic (>12 μg/ml, the highest limit of detection). Attempts to taper her steroids resulted in flare-ups and a cushingoid feature. She declined colectomy as she felt this would interfere with her lifestyle, especially since she was getting married, and concerns about her future fertility.
One of the options explored was the use of vedolizumab, a monoclonal antibody against α4β7 integrin, via a clinical trial. However, due to the patient’s HIV infection she was not eligible to participate in any of the recruiting trials at the centre as HIV infection is frequently an exclusion criteria. Colonoscopy in 2015 revealed severe inflammation with ulcerations and friability consistent with Mayo 3 colitis, despite high-dose steroids and adalimumab, an anti-TNFα monoclonal antibody, at a dose of 80 mg weekly. By December 2015, vedolizumab was obtained through standard of care and initiated at 300 mg IV at weeks 0 and 2, 6 (loading dose) and then every 8 weeks thereafter as a maintenance dose. She was still bleeding from the rectum and had decreased weight, therefore daily prednisone 10 mg orally was maintained. She achieved clinical remission by March 2016 and steroids were stopped. Two months later, she developed right foot cellulitis following a minor trauma during a pedicure and required 48 hours of IV followed by oral antibiotics.
Colonoscopy in June 2016, 3 months after stopping steroids, showed worsening condition with Mayo 3 colitis, so she was changed to vedolizumab 300 mg IV q 4 weeks and prednisone increased to 40 mg orally (po) daily. Anti-α4β7 antibodies were not detected. She was passing bright red blood per rectum 12 times in 24 hours and having five stools per 24 hours with lower abdominal cramping and rectal pain. Janus kinase (JAK) inhibitor, tofacitinab 10 mg po twice daily, was initiated October 2016 and prednisone 40 mg po daily maintained. Symptoms persisted requiring admission for IV prednisolone, but she continued to decline surgical colectomy. She also developed a bacterial vaginitis treated with metronidazole cream and later a skin furuncle, treated with oral antibiotics.
Following tofacitinib, she received interleukin 12/23 inhibitor ustekinumab March–September 2017. She gained 30 pounds in 1 year (body mass index 37), increased abdominal fat and bilateral cataracts due to cortisone. Attempts to decrease prednisone below 30 mg daily led to bloody diarrhea (12–17 bowel movements daily). She eventually accepted to undergo subtotal abdominal colectomy (pathology shown in Fig. 1) with rectal stump and temporary end ileostomy by June 2018. She improved and was seen for follow-up a month post-op, at which time she was having increasing right lower quadrant pain and rising CRP. A computed tomography scan demonstrated collections in the subcutaneous fat surrounding the ostomy and a second collection centimeter with rim enhancement and fat stranding. These were drained and cultures grew E. coli and B. fragilis. She responded to IV antibiotics for 3 days followed by oral step-down antibiotics to complete 2 weeks. Eight months following her colectomy, she developed polyarthralgia in her interphalangeal joints, wrists, shoulders, knees and feet with a normal CRP and a negative Rheumatoid Factor while off prednisone, thought to be either inflammatory or mechanical polyarthralgia. Pathology on surveillance sigmoidoscopy March 2019 demonstrated chronic active proctitis with ulceration consistent with chronic idiopathic IBD. Throughout this entire time, her CD4 range was between 400 and 900 cells/mm3, with CD4/CD8 ratio of 0.41:1.12, and HIV viral load remained suppressed since November 2012.
Figure 1 Colonic resection histology. The colonic mucosa shows characteristic features of chronic ulcerative colitis including crypt architecture alteration, cryptitis, crypt abscess and focal mucosa ulceration. There is no evidence of dysplasia.
DISCUSSION
Due to repeated decline of surgery in order to preserve her quality of life and fertility, this woman with HIV and refractory UC received all available conventional therapies including mesalamine, glucocorticoids, thiopurines, antagonists to TNF- α, IL-12/23 blockers and anti-α4 β7 integrin. She also received a small-molecule JAK inhibitor. TNF-α inhibitors and α4β7 integrin blockers are used with extreme caution in PLWH due to concerns of additional immunosuppression and subsequent infection risk. However, during her 6 years of being on immunosuppressants, the patient only experienced one episode of cellulitis, bacterial vaginosis, a skin furuncle and peristomal abscesses, all of which were easily managed with traditional therapies. Another concern with the use of integrin receptor antagonists in PLWH, although rare, is the possibility of Progressive Multifocal Leukoencephalopathy due to John Cunningham (JC) virus [1]. Our patient underwent blood plasma JC virus testing prior to vedolizumab initiation and this polymerase chain reaction testing was negative. She also denied any neurological signs or symptoms throughout treatment.
This woman’s case demonstrates that the spectrum of drug classes available and sequential use of biologics for treatment of UC were safe in this patient with well-controlled HIV infection ART, including an TNF-α blocker, JK inhibitor, IL-12/23 blocker and the α4β7 integrin blocker vedolizumab. Our patient did not incur any significant changes in her CD4 count nor CD4/CD8 ratio during the course of her treatments and infections were relatively minor. Although we did not use combination biologics in this patient, their efficacy and safety for IBD and other and other inflammatory diseases associated was explored in a systematic review of observational studies which did not find any differences related to improvements in disease condition, adverse effects or infection rates in patients receiving combined treatment compared to placebo groups [2]. A clinical trial (NCT02764762) examining efficacy and safety of combined vedolizumab, adalimumab and oral methotrexate in patients with Crohn’s Disease is in progress [3]. Until evidence from clinical trials is available on efficacy and safety of biologics and combination therapy in PLWH, case reports and case series provide a channel for dissemination of these experiences within the medical community.
ACKNOWLEDGMENTS
The authors thank Pathologist, Dr Zu-hua Gao, for provision of the histology image. No funding was received for the preparation of this manuscript.
CONFLICTS OF INTEREST STATEMENT
None declared.
FUNDING
No funding was received for the preparation of this manuscript.
ETHICS APPROVAL
The authors received ethical approval for publication of the case report.
CONSENT TO PUBLISH
The patient provided informed written consent for the preparation of this case report and publication of data and pathological image in an open access journal. The participant understood that the details/images would be freely available on the internet and may be seen by the general public. A copy of the written consent is available for review by the editor of the journal.
GUARANTOR
Dr Costiniuk is the guarantor of the case report. | ADALIMUMAB, CORTISONE, INFLIXIMAB, MERCAPTOPURINE, MESALAMINE, METHYLPREDNISOLONE, PREDNISOLONE, PREDNISONE, RALTEGRAVIR, TOFACITINIB, USTEKINUMAB, VEDOLIZUMAB | DrugsGivenReaction | CC BY-NC | 33542833 | 19,114,036 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cellulitis'. | Use of various immunotherapies for refractory ulcerative colitis in a person living with HIV: a case report.
Cancer therapies include several immune checkpoint or anticytokine therapies whereas ulcerative colitis treatments consist of anticytokine therapies. The development of tolerance and immunogical effects of these agents in people living with HIV are not well assessed as these persons are often excluded from clinical trials. Herein, we report a case of a Caucasian woman who received multiple sequential immunotherapies for severe ulcerative colitis. Due to steroid-refractory disease, receipt of maximal doses of mesalamine and initial repeated decline of surgical intervention, she went on to receive biologic immune inhibitors like tumor necrosis fator-α blockers infliximab and adalimumab, the α4β7integrin blocker vedolizumab, anti-interleukin 12/23 blocker ustekinumab and Janus Kinase inihibitor tofacitinib without achieving remission. Only minor infectious complications were encountered and no significant changes in CD4 count nor CD4/CD8 ratio occurred. This case provides support for the safety and tolerability of the above immunotherapies in people living with HIV with suppressed viral load on antiretroviral therapy.
INTRODUCTION
In the management of ulcerative colitis (UC), one provides immunosuppressive therapy with the hope of tempering excessive inflammation while preserving immune function. However, if the proper balance between immunosuppression and immune preservation is not achieved, an individual will be tipped into immunodeficiency with increased infection risk. People living with HIV (PLWH) are often excluding from clinical trials involving biologics based on concerns of additive immunosuppression and infection risk. Consequently, little data are available to guide clinicians in managing PLWH who suffer from advanced inflammatory bowel disease (IBD). Herein, we present the case of young woman with HIV infection and extensive UC refractory to many therapies. Following repeated decline of surgical intervention, she was treated with multiple sequential immunomodulators and did not experience any major adverse effects.
CASE REPORT
A 36-year-old, Canadian-born Caucasian woman was diagnosed with HIV in 2008. She began antiretroviral therapy with tenofovir disoproxil 300 mg/emtracitabine 200 mg orally once daily and raltegravir 400 mg orally twice daily in 2012, when her CD4 count rapidly dropped to 86 cells/mm3. Later that year, she began experiencing frequent episodes of bloody diarrhea, with up to 20 stools daily, with cramping, rectal bleeding and elevated C-reactive protein (CRP). Stool was repeatedly negative for Clostridium difficile and ova and parasites. Colonoscopy demonstrated severe pancolitis and biopsies consistent with active UC with acute cryptitis, crypt abcesses with lymphoid hyperplasia, focal erosions, acute inflammatory exudate with architectural disortion. Hematoxylin and eosin stains for cytomegalovirus and histochemical exams for Herpes Simplex Virus I/II were negative. Despite high doses of oral prednisone (40–60 mg daily) and several emergency room visits to receive intravenous (IV) methylprednisolone for flares, she was deemed steroid-refractory.
Later that year, she received maximum doses of oral mesalamine and 6-mercaptopurine, as well as mesalamine suppositories and enemas. She then received infliximab (2012–2013), an antitumor necrois fator-α (anti-TNFα) monoclonal antibody, until antibody formation. Despite maximum doses of adalimumab (2014), her UC remained refractory although no antibodies were detected using a drug-tolerant assay and medication levels were therapeutic (>12 μg/ml, the highest limit of detection). Attempts to taper her steroids resulted in flare-ups and a cushingoid feature. She declined colectomy as she felt this would interfere with her lifestyle, especially since she was getting married, and concerns about her future fertility.
One of the options explored was the use of vedolizumab, a monoclonal antibody against α4β7 integrin, via a clinical trial. However, due to the patient’s HIV infection she was not eligible to participate in any of the recruiting trials at the centre as HIV infection is frequently an exclusion criteria. Colonoscopy in 2015 revealed severe inflammation with ulcerations and friability consistent with Mayo 3 colitis, despite high-dose steroids and adalimumab, an anti-TNFα monoclonal antibody, at a dose of 80 mg weekly. By December 2015, vedolizumab was obtained through standard of care and initiated at 300 mg IV at weeks 0 and 2, 6 (loading dose) and then every 8 weeks thereafter as a maintenance dose. She was still bleeding from the rectum and had decreased weight, therefore daily prednisone 10 mg orally was maintained. She achieved clinical remission by March 2016 and steroids were stopped. Two months later, she developed right foot cellulitis following a minor trauma during a pedicure and required 48 hours of IV followed by oral antibiotics.
Colonoscopy in June 2016, 3 months after stopping steroids, showed worsening condition with Mayo 3 colitis, so she was changed to vedolizumab 300 mg IV q 4 weeks and prednisone increased to 40 mg orally (po) daily. Anti-α4β7 antibodies were not detected. She was passing bright red blood per rectum 12 times in 24 hours and having five stools per 24 hours with lower abdominal cramping and rectal pain. Janus kinase (JAK) inhibitor, tofacitinab 10 mg po twice daily, was initiated October 2016 and prednisone 40 mg po daily maintained. Symptoms persisted requiring admission for IV prednisolone, but she continued to decline surgical colectomy. She also developed a bacterial vaginitis treated with metronidazole cream and later a skin furuncle, treated with oral antibiotics.
Following tofacitinib, she received interleukin 12/23 inhibitor ustekinumab March–September 2017. She gained 30 pounds in 1 year (body mass index 37), increased abdominal fat and bilateral cataracts due to cortisone. Attempts to decrease prednisone below 30 mg daily led to bloody diarrhea (12–17 bowel movements daily). She eventually accepted to undergo subtotal abdominal colectomy (pathology shown in Fig. 1) with rectal stump and temporary end ileostomy by June 2018. She improved and was seen for follow-up a month post-op, at which time she was having increasing right lower quadrant pain and rising CRP. A computed tomography scan demonstrated collections in the subcutaneous fat surrounding the ostomy and a second collection centimeter with rim enhancement and fat stranding. These were drained and cultures grew E. coli and B. fragilis. She responded to IV antibiotics for 3 days followed by oral step-down antibiotics to complete 2 weeks. Eight months following her colectomy, she developed polyarthralgia in her interphalangeal joints, wrists, shoulders, knees and feet with a normal CRP and a negative Rheumatoid Factor while off prednisone, thought to be either inflammatory or mechanical polyarthralgia. Pathology on surveillance sigmoidoscopy March 2019 demonstrated chronic active proctitis with ulceration consistent with chronic idiopathic IBD. Throughout this entire time, her CD4 range was between 400 and 900 cells/mm3, with CD4/CD8 ratio of 0.41:1.12, and HIV viral load remained suppressed since November 2012.
Figure 1 Colonic resection histology. The colonic mucosa shows characteristic features of chronic ulcerative colitis including crypt architecture alteration, cryptitis, crypt abscess and focal mucosa ulceration. There is no evidence of dysplasia.
DISCUSSION
Due to repeated decline of surgery in order to preserve her quality of life and fertility, this woman with HIV and refractory UC received all available conventional therapies including mesalamine, glucocorticoids, thiopurines, antagonists to TNF- α, IL-12/23 blockers and anti-α4 β7 integrin. She also received a small-molecule JAK inhibitor. TNF-α inhibitors and α4β7 integrin blockers are used with extreme caution in PLWH due to concerns of additional immunosuppression and subsequent infection risk. However, during her 6 years of being on immunosuppressants, the patient only experienced one episode of cellulitis, bacterial vaginosis, a skin furuncle and peristomal abscesses, all of which were easily managed with traditional therapies. Another concern with the use of integrin receptor antagonists in PLWH, although rare, is the possibility of Progressive Multifocal Leukoencephalopathy due to John Cunningham (JC) virus [1]. Our patient underwent blood plasma JC virus testing prior to vedolizumab initiation and this polymerase chain reaction testing was negative. She also denied any neurological signs or symptoms throughout treatment.
This woman’s case demonstrates that the spectrum of drug classes available and sequential use of biologics for treatment of UC were safe in this patient with well-controlled HIV infection ART, including an TNF-α blocker, JK inhibitor, IL-12/23 blocker and the α4β7 integrin blocker vedolizumab. Our patient did not incur any significant changes in her CD4 count nor CD4/CD8 ratio during the course of her treatments and infections were relatively minor. Although we did not use combination biologics in this patient, their efficacy and safety for IBD and other and other inflammatory diseases associated was explored in a systematic review of observational studies which did not find any differences related to improvements in disease condition, adverse effects or infection rates in patients receiving combined treatment compared to placebo groups [2]. A clinical trial (NCT02764762) examining efficacy and safety of combined vedolizumab, adalimumab and oral methotrexate in patients with Crohn’s Disease is in progress [3]. Until evidence from clinical trials is available on efficacy and safety of biologics and combination therapy in PLWH, case reports and case series provide a channel for dissemination of these experiences within the medical community.
ACKNOWLEDGMENTS
The authors thank Pathologist, Dr Zu-hua Gao, for provision of the histology image. No funding was received for the preparation of this manuscript.
CONFLICTS OF INTEREST STATEMENT
None declared.
FUNDING
No funding was received for the preparation of this manuscript.
ETHICS APPROVAL
The authors received ethical approval for publication of the case report.
CONSENT TO PUBLISH
The patient provided informed written consent for the preparation of this case report and publication of data and pathological image in an open access journal. The participant understood that the details/images would be freely available on the internet and may be seen by the general public. A copy of the written consent is available for review by the editor of the journal.
GUARANTOR
Dr Costiniuk is the guarantor of the case report. | ADALIMUMAB, CORTISONE, INFLIXIMAB, MERCAPTOPURINE, MESALAMINE, METHYLPREDNISOLONE, PREDNISOLONE, PREDNISONE, RALTEGRAVIR, TOFACITINIB, USTEKINUMAB, VEDOLIZUMAB | DrugsGivenReaction | CC BY-NC | 33542833 | 19,114,036 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Central obesity'. | Use of various immunotherapies for refractory ulcerative colitis in a person living with HIV: a case report.
Cancer therapies include several immune checkpoint or anticytokine therapies whereas ulcerative colitis treatments consist of anticytokine therapies. The development of tolerance and immunogical effects of these agents in people living with HIV are not well assessed as these persons are often excluded from clinical trials. Herein, we report a case of a Caucasian woman who received multiple sequential immunotherapies for severe ulcerative colitis. Due to steroid-refractory disease, receipt of maximal doses of mesalamine and initial repeated decline of surgical intervention, she went on to receive biologic immune inhibitors like tumor necrosis fator-α blockers infliximab and adalimumab, the α4β7integrin blocker vedolizumab, anti-interleukin 12/23 blocker ustekinumab and Janus Kinase inihibitor tofacitinib without achieving remission. Only minor infectious complications were encountered and no significant changes in CD4 count nor CD4/CD8 ratio occurred. This case provides support for the safety and tolerability of the above immunotherapies in people living with HIV with suppressed viral load on antiretroviral therapy.
INTRODUCTION
In the management of ulcerative colitis (UC), one provides immunosuppressive therapy with the hope of tempering excessive inflammation while preserving immune function. However, if the proper balance between immunosuppression and immune preservation is not achieved, an individual will be tipped into immunodeficiency with increased infection risk. People living with HIV (PLWH) are often excluding from clinical trials involving biologics based on concerns of additive immunosuppression and infection risk. Consequently, little data are available to guide clinicians in managing PLWH who suffer from advanced inflammatory bowel disease (IBD). Herein, we present the case of young woman with HIV infection and extensive UC refractory to many therapies. Following repeated decline of surgical intervention, she was treated with multiple sequential immunomodulators and did not experience any major adverse effects.
CASE REPORT
A 36-year-old, Canadian-born Caucasian woman was diagnosed with HIV in 2008. She began antiretroviral therapy with tenofovir disoproxil 300 mg/emtracitabine 200 mg orally once daily and raltegravir 400 mg orally twice daily in 2012, when her CD4 count rapidly dropped to 86 cells/mm3. Later that year, she began experiencing frequent episodes of bloody diarrhea, with up to 20 stools daily, with cramping, rectal bleeding and elevated C-reactive protein (CRP). Stool was repeatedly negative for Clostridium difficile and ova and parasites. Colonoscopy demonstrated severe pancolitis and biopsies consistent with active UC with acute cryptitis, crypt abcesses with lymphoid hyperplasia, focal erosions, acute inflammatory exudate with architectural disortion. Hematoxylin and eosin stains for cytomegalovirus and histochemical exams for Herpes Simplex Virus I/II were negative. Despite high doses of oral prednisone (40–60 mg daily) and several emergency room visits to receive intravenous (IV) methylprednisolone for flares, she was deemed steroid-refractory.
Later that year, she received maximum doses of oral mesalamine and 6-mercaptopurine, as well as mesalamine suppositories and enemas. She then received infliximab (2012–2013), an antitumor necrois fator-α (anti-TNFα) monoclonal antibody, until antibody formation. Despite maximum doses of adalimumab (2014), her UC remained refractory although no antibodies were detected using a drug-tolerant assay and medication levels were therapeutic (>12 μg/ml, the highest limit of detection). Attempts to taper her steroids resulted in flare-ups and a cushingoid feature. She declined colectomy as she felt this would interfere with her lifestyle, especially since she was getting married, and concerns about her future fertility.
One of the options explored was the use of vedolizumab, a monoclonal antibody against α4β7 integrin, via a clinical trial. However, due to the patient’s HIV infection she was not eligible to participate in any of the recruiting trials at the centre as HIV infection is frequently an exclusion criteria. Colonoscopy in 2015 revealed severe inflammation with ulcerations and friability consistent with Mayo 3 colitis, despite high-dose steroids and adalimumab, an anti-TNFα monoclonal antibody, at a dose of 80 mg weekly. By December 2015, vedolizumab was obtained through standard of care and initiated at 300 mg IV at weeks 0 and 2, 6 (loading dose) and then every 8 weeks thereafter as a maintenance dose. She was still bleeding from the rectum and had decreased weight, therefore daily prednisone 10 mg orally was maintained. She achieved clinical remission by March 2016 and steroids were stopped. Two months later, she developed right foot cellulitis following a minor trauma during a pedicure and required 48 hours of IV followed by oral antibiotics.
Colonoscopy in June 2016, 3 months after stopping steroids, showed worsening condition with Mayo 3 colitis, so she was changed to vedolizumab 300 mg IV q 4 weeks and prednisone increased to 40 mg orally (po) daily. Anti-α4β7 antibodies were not detected. She was passing bright red blood per rectum 12 times in 24 hours and having five stools per 24 hours with lower abdominal cramping and rectal pain. Janus kinase (JAK) inhibitor, tofacitinab 10 mg po twice daily, was initiated October 2016 and prednisone 40 mg po daily maintained. Symptoms persisted requiring admission for IV prednisolone, but she continued to decline surgical colectomy. She also developed a bacterial vaginitis treated with metronidazole cream and later a skin furuncle, treated with oral antibiotics.
Following tofacitinib, she received interleukin 12/23 inhibitor ustekinumab March–September 2017. She gained 30 pounds in 1 year (body mass index 37), increased abdominal fat and bilateral cataracts due to cortisone. Attempts to decrease prednisone below 30 mg daily led to bloody diarrhea (12–17 bowel movements daily). She eventually accepted to undergo subtotal abdominal colectomy (pathology shown in Fig. 1) with rectal stump and temporary end ileostomy by June 2018. She improved and was seen for follow-up a month post-op, at which time she was having increasing right lower quadrant pain and rising CRP. A computed tomography scan demonstrated collections in the subcutaneous fat surrounding the ostomy and a second collection centimeter with rim enhancement and fat stranding. These were drained and cultures grew E. coli and B. fragilis. She responded to IV antibiotics for 3 days followed by oral step-down antibiotics to complete 2 weeks. Eight months following her colectomy, she developed polyarthralgia in her interphalangeal joints, wrists, shoulders, knees and feet with a normal CRP and a negative Rheumatoid Factor while off prednisone, thought to be either inflammatory or mechanical polyarthralgia. Pathology on surveillance sigmoidoscopy March 2019 demonstrated chronic active proctitis with ulceration consistent with chronic idiopathic IBD. Throughout this entire time, her CD4 range was between 400 and 900 cells/mm3, with CD4/CD8 ratio of 0.41:1.12, and HIV viral load remained suppressed since November 2012.
Figure 1 Colonic resection histology. The colonic mucosa shows characteristic features of chronic ulcerative colitis including crypt architecture alteration, cryptitis, crypt abscess and focal mucosa ulceration. There is no evidence of dysplasia.
DISCUSSION
Due to repeated decline of surgery in order to preserve her quality of life and fertility, this woman with HIV and refractory UC received all available conventional therapies including mesalamine, glucocorticoids, thiopurines, antagonists to TNF- α, IL-12/23 blockers and anti-α4 β7 integrin. She also received a small-molecule JAK inhibitor. TNF-α inhibitors and α4β7 integrin blockers are used with extreme caution in PLWH due to concerns of additional immunosuppression and subsequent infection risk. However, during her 6 years of being on immunosuppressants, the patient only experienced one episode of cellulitis, bacterial vaginosis, a skin furuncle and peristomal abscesses, all of which were easily managed with traditional therapies. Another concern with the use of integrin receptor antagonists in PLWH, although rare, is the possibility of Progressive Multifocal Leukoencephalopathy due to John Cunningham (JC) virus [1]. Our patient underwent blood plasma JC virus testing prior to vedolizumab initiation and this polymerase chain reaction testing was negative. She also denied any neurological signs or symptoms throughout treatment.
This woman’s case demonstrates that the spectrum of drug classes available and sequential use of biologics for treatment of UC were safe in this patient with well-controlled HIV infection ART, including an TNF-α blocker, JK inhibitor, IL-12/23 blocker and the α4β7 integrin blocker vedolizumab. Our patient did not incur any significant changes in her CD4 count nor CD4/CD8 ratio during the course of her treatments and infections were relatively minor. Although we did not use combination biologics in this patient, their efficacy and safety for IBD and other and other inflammatory diseases associated was explored in a systematic review of observational studies which did not find any differences related to improvements in disease condition, adverse effects or infection rates in patients receiving combined treatment compared to placebo groups [2]. A clinical trial (NCT02764762) examining efficacy and safety of combined vedolizumab, adalimumab and oral methotrexate in patients with Crohn’s Disease is in progress [3]. Until evidence from clinical trials is available on efficacy and safety of biologics and combination therapy in PLWH, case reports and case series provide a channel for dissemination of these experiences within the medical community.
ACKNOWLEDGMENTS
The authors thank Pathologist, Dr Zu-hua Gao, for provision of the histology image. No funding was received for the preparation of this manuscript.
CONFLICTS OF INTEREST STATEMENT
None declared.
FUNDING
No funding was received for the preparation of this manuscript.
ETHICS APPROVAL
The authors received ethical approval for publication of the case report.
CONSENT TO PUBLISH
The patient provided informed written consent for the preparation of this case report and publication of data and pathological image in an open access journal. The participant understood that the details/images would be freely available on the internet and may be seen by the general public. A copy of the written consent is available for review by the editor of the journal.
GUARANTOR
Dr Costiniuk is the guarantor of the case report. | ADALIMUMAB, CORTISONE, INFLIXIMAB, MERCAPTOPURINE, MESALAMINE, METHYLPREDNISOLONE, PREDNISOLONE, PREDNISONE, RALTEGRAVIR, TOFACITINIB, USTEKINUMAB, VEDOLIZUMAB | DrugsGivenReaction | CC BY-NC | 33542833 | 19,114,036 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Colitis ulcerative'. | Use of various immunotherapies for refractory ulcerative colitis in a person living with HIV: a case report.
Cancer therapies include several immune checkpoint or anticytokine therapies whereas ulcerative colitis treatments consist of anticytokine therapies. The development of tolerance and immunogical effects of these agents in people living with HIV are not well assessed as these persons are often excluded from clinical trials. Herein, we report a case of a Caucasian woman who received multiple sequential immunotherapies for severe ulcerative colitis. Due to steroid-refractory disease, receipt of maximal doses of mesalamine and initial repeated decline of surgical intervention, she went on to receive biologic immune inhibitors like tumor necrosis fator-α blockers infliximab and adalimumab, the α4β7integrin blocker vedolizumab, anti-interleukin 12/23 blocker ustekinumab and Janus Kinase inihibitor tofacitinib without achieving remission. Only minor infectious complications were encountered and no significant changes in CD4 count nor CD4/CD8 ratio occurred. This case provides support for the safety and tolerability of the above immunotherapies in people living with HIV with suppressed viral load on antiretroviral therapy.
INTRODUCTION
In the management of ulcerative colitis (UC), one provides immunosuppressive therapy with the hope of tempering excessive inflammation while preserving immune function. However, if the proper balance between immunosuppression and immune preservation is not achieved, an individual will be tipped into immunodeficiency with increased infection risk. People living with HIV (PLWH) are often excluding from clinical trials involving biologics based on concerns of additive immunosuppression and infection risk. Consequently, little data are available to guide clinicians in managing PLWH who suffer from advanced inflammatory bowel disease (IBD). Herein, we present the case of young woman with HIV infection and extensive UC refractory to many therapies. Following repeated decline of surgical intervention, she was treated with multiple sequential immunomodulators and did not experience any major adverse effects.
CASE REPORT
A 36-year-old, Canadian-born Caucasian woman was diagnosed with HIV in 2008. She began antiretroviral therapy with tenofovir disoproxil 300 mg/emtracitabine 200 mg orally once daily and raltegravir 400 mg orally twice daily in 2012, when her CD4 count rapidly dropped to 86 cells/mm3. Later that year, she began experiencing frequent episodes of bloody diarrhea, with up to 20 stools daily, with cramping, rectal bleeding and elevated C-reactive protein (CRP). Stool was repeatedly negative for Clostridium difficile and ova and parasites. Colonoscopy demonstrated severe pancolitis and biopsies consistent with active UC with acute cryptitis, crypt abcesses with lymphoid hyperplasia, focal erosions, acute inflammatory exudate with architectural disortion. Hematoxylin and eosin stains for cytomegalovirus and histochemical exams for Herpes Simplex Virus I/II were negative. Despite high doses of oral prednisone (40–60 mg daily) and several emergency room visits to receive intravenous (IV) methylprednisolone for flares, she was deemed steroid-refractory.
Later that year, she received maximum doses of oral mesalamine and 6-mercaptopurine, as well as mesalamine suppositories and enemas. She then received infliximab (2012–2013), an antitumor necrois fator-α (anti-TNFα) monoclonal antibody, until antibody formation. Despite maximum doses of adalimumab (2014), her UC remained refractory although no antibodies were detected using a drug-tolerant assay and medication levels were therapeutic (>12 μg/ml, the highest limit of detection). Attempts to taper her steroids resulted in flare-ups and a cushingoid feature. She declined colectomy as she felt this would interfere with her lifestyle, especially since she was getting married, and concerns about her future fertility.
One of the options explored was the use of vedolizumab, a monoclonal antibody against α4β7 integrin, via a clinical trial. However, due to the patient’s HIV infection she was not eligible to participate in any of the recruiting trials at the centre as HIV infection is frequently an exclusion criteria. Colonoscopy in 2015 revealed severe inflammation with ulcerations and friability consistent with Mayo 3 colitis, despite high-dose steroids and adalimumab, an anti-TNFα monoclonal antibody, at a dose of 80 mg weekly. By December 2015, vedolizumab was obtained through standard of care and initiated at 300 mg IV at weeks 0 and 2, 6 (loading dose) and then every 8 weeks thereafter as a maintenance dose. She was still bleeding from the rectum and had decreased weight, therefore daily prednisone 10 mg orally was maintained. She achieved clinical remission by March 2016 and steroids were stopped. Two months later, she developed right foot cellulitis following a minor trauma during a pedicure and required 48 hours of IV followed by oral antibiotics.
Colonoscopy in June 2016, 3 months after stopping steroids, showed worsening condition with Mayo 3 colitis, so she was changed to vedolizumab 300 mg IV q 4 weeks and prednisone increased to 40 mg orally (po) daily. Anti-α4β7 antibodies were not detected. She was passing bright red blood per rectum 12 times in 24 hours and having five stools per 24 hours with lower abdominal cramping and rectal pain. Janus kinase (JAK) inhibitor, tofacitinab 10 mg po twice daily, was initiated October 2016 and prednisone 40 mg po daily maintained. Symptoms persisted requiring admission for IV prednisolone, but she continued to decline surgical colectomy. She also developed a bacterial vaginitis treated with metronidazole cream and later a skin furuncle, treated with oral antibiotics.
Following tofacitinib, she received interleukin 12/23 inhibitor ustekinumab March–September 2017. She gained 30 pounds in 1 year (body mass index 37), increased abdominal fat and bilateral cataracts due to cortisone. Attempts to decrease prednisone below 30 mg daily led to bloody diarrhea (12–17 bowel movements daily). She eventually accepted to undergo subtotal abdominal colectomy (pathology shown in Fig. 1) with rectal stump and temporary end ileostomy by June 2018. She improved and was seen for follow-up a month post-op, at which time she was having increasing right lower quadrant pain and rising CRP. A computed tomography scan demonstrated collections in the subcutaneous fat surrounding the ostomy and a second collection centimeter with rim enhancement and fat stranding. These were drained and cultures grew E. coli and B. fragilis. She responded to IV antibiotics for 3 days followed by oral step-down antibiotics to complete 2 weeks. Eight months following her colectomy, she developed polyarthralgia in her interphalangeal joints, wrists, shoulders, knees and feet with a normal CRP and a negative Rheumatoid Factor while off prednisone, thought to be either inflammatory or mechanical polyarthralgia. Pathology on surveillance sigmoidoscopy March 2019 demonstrated chronic active proctitis with ulceration consistent with chronic idiopathic IBD. Throughout this entire time, her CD4 range was between 400 and 900 cells/mm3, with CD4/CD8 ratio of 0.41:1.12, and HIV viral load remained suppressed since November 2012.
Figure 1 Colonic resection histology. The colonic mucosa shows characteristic features of chronic ulcerative colitis including crypt architecture alteration, cryptitis, crypt abscess and focal mucosa ulceration. There is no evidence of dysplasia.
DISCUSSION
Due to repeated decline of surgery in order to preserve her quality of life and fertility, this woman with HIV and refractory UC received all available conventional therapies including mesalamine, glucocorticoids, thiopurines, antagonists to TNF- α, IL-12/23 blockers and anti-α4 β7 integrin. She also received a small-molecule JAK inhibitor. TNF-α inhibitors and α4β7 integrin blockers are used with extreme caution in PLWH due to concerns of additional immunosuppression and subsequent infection risk. However, during her 6 years of being on immunosuppressants, the patient only experienced one episode of cellulitis, bacterial vaginosis, a skin furuncle and peristomal abscesses, all of which were easily managed with traditional therapies. Another concern with the use of integrin receptor antagonists in PLWH, although rare, is the possibility of Progressive Multifocal Leukoencephalopathy due to John Cunningham (JC) virus [1]. Our patient underwent blood plasma JC virus testing prior to vedolizumab initiation and this polymerase chain reaction testing was negative. She also denied any neurological signs or symptoms throughout treatment.
This woman’s case demonstrates that the spectrum of drug classes available and sequential use of biologics for treatment of UC were safe in this patient with well-controlled HIV infection ART, including an TNF-α blocker, JK inhibitor, IL-12/23 blocker and the α4β7 integrin blocker vedolizumab. Our patient did not incur any significant changes in her CD4 count nor CD4/CD8 ratio during the course of her treatments and infections were relatively minor. Although we did not use combination biologics in this patient, their efficacy and safety for IBD and other and other inflammatory diseases associated was explored in a systematic review of observational studies which did not find any differences related to improvements in disease condition, adverse effects or infection rates in patients receiving combined treatment compared to placebo groups [2]. A clinical trial (NCT02764762) examining efficacy and safety of combined vedolizumab, adalimumab and oral methotrexate in patients with Crohn’s Disease is in progress [3]. Until evidence from clinical trials is available on efficacy and safety of biologics and combination therapy in PLWH, case reports and case series provide a channel for dissemination of these experiences within the medical community.
ACKNOWLEDGMENTS
The authors thank Pathologist, Dr Zu-hua Gao, for provision of the histology image. No funding was received for the preparation of this manuscript.
CONFLICTS OF INTEREST STATEMENT
None declared.
FUNDING
No funding was received for the preparation of this manuscript.
ETHICS APPROVAL
The authors received ethical approval for publication of the case report.
CONSENT TO PUBLISH
The patient provided informed written consent for the preparation of this case report and publication of data and pathological image in an open access journal. The participant understood that the details/images would be freely available on the internet and may be seen by the general public. A copy of the written consent is available for review by the editor of the journal.
GUARANTOR
Dr Costiniuk is the guarantor of the case report. | ADALIMUMAB, CORTISONE, INFLIXIMAB, MERCAPTOPURINE, MESALAMINE, METHYLPREDNISOLONE, PREDNISOLONE, PREDNISONE, RALTEGRAVIR, TOFACITINIB, USTEKINUMAB, VEDOLIZUMAB | DrugsGivenReaction | CC BY-NC | 33542833 | 19,114,036 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cushingoid'. | Use of various immunotherapies for refractory ulcerative colitis in a person living with HIV: a case report.
Cancer therapies include several immune checkpoint or anticytokine therapies whereas ulcerative colitis treatments consist of anticytokine therapies. The development of tolerance and immunogical effects of these agents in people living with HIV are not well assessed as these persons are often excluded from clinical trials. Herein, we report a case of a Caucasian woman who received multiple sequential immunotherapies for severe ulcerative colitis. Due to steroid-refractory disease, receipt of maximal doses of mesalamine and initial repeated decline of surgical intervention, she went on to receive biologic immune inhibitors like tumor necrosis fator-α blockers infliximab and adalimumab, the α4β7integrin blocker vedolizumab, anti-interleukin 12/23 blocker ustekinumab and Janus Kinase inihibitor tofacitinib without achieving remission. Only minor infectious complications were encountered and no significant changes in CD4 count nor CD4/CD8 ratio occurred. This case provides support for the safety and tolerability of the above immunotherapies in people living with HIV with suppressed viral load on antiretroviral therapy.
INTRODUCTION
In the management of ulcerative colitis (UC), one provides immunosuppressive therapy with the hope of tempering excessive inflammation while preserving immune function. However, if the proper balance between immunosuppression and immune preservation is not achieved, an individual will be tipped into immunodeficiency with increased infection risk. People living with HIV (PLWH) are often excluding from clinical trials involving biologics based on concerns of additive immunosuppression and infection risk. Consequently, little data are available to guide clinicians in managing PLWH who suffer from advanced inflammatory bowel disease (IBD). Herein, we present the case of young woman with HIV infection and extensive UC refractory to many therapies. Following repeated decline of surgical intervention, she was treated with multiple sequential immunomodulators and did not experience any major adverse effects.
CASE REPORT
A 36-year-old, Canadian-born Caucasian woman was diagnosed with HIV in 2008. She began antiretroviral therapy with tenofovir disoproxil 300 mg/emtracitabine 200 mg orally once daily and raltegravir 400 mg orally twice daily in 2012, when her CD4 count rapidly dropped to 86 cells/mm3. Later that year, she began experiencing frequent episodes of bloody diarrhea, with up to 20 stools daily, with cramping, rectal bleeding and elevated C-reactive protein (CRP). Stool was repeatedly negative for Clostridium difficile and ova and parasites. Colonoscopy demonstrated severe pancolitis and biopsies consistent with active UC with acute cryptitis, crypt abcesses with lymphoid hyperplasia, focal erosions, acute inflammatory exudate with architectural disortion. Hematoxylin and eosin stains for cytomegalovirus and histochemical exams for Herpes Simplex Virus I/II were negative. Despite high doses of oral prednisone (40–60 mg daily) and several emergency room visits to receive intravenous (IV) methylprednisolone for flares, she was deemed steroid-refractory.
Later that year, she received maximum doses of oral mesalamine and 6-mercaptopurine, as well as mesalamine suppositories and enemas. She then received infliximab (2012–2013), an antitumor necrois fator-α (anti-TNFα) monoclonal antibody, until antibody formation. Despite maximum doses of adalimumab (2014), her UC remained refractory although no antibodies were detected using a drug-tolerant assay and medication levels were therapeutic (>12 μg/ml, the highest limit of detection). Attempts to taper her steroids resulted in flare-ups and a cushingoid feature. She declined colectomy as she felt this would interfere with her lifestyle, especially since she was getting married, and concerns about her future fertility.
One of the options explored was the use of vedolizumab, a monoclonal antibody against α4β7 integrin, via a clinical trial. However, due to the patient’s HIV infection she was not eligible to participate in any of the recruiting trials at the centre as HIV infection is frequently an exclusion criteria. Colonoscopy in 2015 revealed severe inflammation with ulcerations and friability consistent with Mayo 3 colitis, despite high-dose steroids and adalimumab, an anti-TNFα monoclonal antibody, at a dose of 80 mg weekly. By December 2015, vedolizumab was obtained through standard of care and initiated at 300 mg IV at weeks 0 and 2, 6 (loading dose) and then every 8 weeks thereafter as a maintenance dose. She was still bleeding from the rectum and had decreased weight, therefore daily prednisone 10 mg orally was maintained. She achieved clinical remission by March 2016 and steroids were stopped. Two months later, she developed right foot cellulitis following a minor trauma during a pedicure and required 48 hours of IV followed by oral antibiotics.
Colonoscopy in June 2016, 3 months after stopping steroids, showed worsening condition with Mayo 3 colitis, so she was changed to vedolizumab 300 mg IV q 4 weeks and prednisone increased to 40 mg orally (po) daily. Anti-α4β7 antibodies were not detected. She was passing bright red blood per rectum 12 times in 24 hours and having five stools per 24 hours with lower abdominal cramping and rectal pain. Janus kinase (JAK) inhibitor, tofacitinab 10 mg po twice daily, was initiated October 2016 and prednisone 40 mg po daily maintained. Symptoms persisted requiring admission for IV prednisolone, but she continued to decline surgical colectomy. She also developed a bacterial vaginitis treated with metronidazole cream and later a skin furuncle, treated with oral antibiotics.
Following tofacitinib, she received interleukin 12/23 inhibitor ustekinumab March–September 2017. She gained 30 pounds in 1 year (body mass index 37), increased abdominal fat and bilateral cataracts due to cortisone. Attempts to decrease prednisone below 30 mg daily led to bloody diarrhea (12–17 bowel movements daily). She eventually accepted to undergo subtotal abdominal colectomy (pathology shown in Fig. 1) with rectal stump and temporary end ileostomy by June 2018. She improved and was seen for follow-up a month post-op, at which time she was having increasing right lower quadrant pain and rising CRP. A computed tomography scan demonstrated collections in the subcutaneous fat surrounding the ostomy and a second collection centimeter with rim enhancement and fat stranding. These were drained and cultures grew E. coli and B. fragilis. She responded to IV antibiotics for 3 days followed by oral step-down antibiotics to complete 2 weeks. Eight months following her colectomy, she developed polyarthralgia in her interphalangeal joints, wrists, shoulders, knees and feet with a normal CRP and a negative Rheumatoid Factor while off prednisone, thought to be either inflammatory or mechanical polyarthralgia. Pathology on surveillance sigmoidoscopy March 2019 demonstrated chronic active proctitis with ulceration consistent with chronic idiopathic IBD. Throughout this entire time, her CD4 range was between 400 and 900 cells/mm3, with CD4/CD8 ratio of 0.41:1.12, and HIV viral load remained suppressed since November 2012.
Figure 1 Colonic resection histology. The colonic mucosa shows characteristic features of chronic ulcerative colitis including crypt architecture alteration, cryptitis, crypt abscess and focal mucosa ulceration. There is no evidence of dysplasia.
DISCUSSION
Due to repeated decline of surgery in order to preserve her quality of life and fertility, this woman with HIV and refractory UC received all available conventional therapies including mesalamine, glucocorticoids, thiopurines, antagonists to TNF- α, IL-12/23 blockers and anti-α4 β7 integrin. She also received a small-molecule JAK inhibitor. TNF-α inhibitors and α4β7 integrin blockers are used with extreme caution in PLWH due to concerns of additional immunosuppression and subsequent infection risk. However, during her 6 years of being on immunosuppressants, the patient only experienced one episode of cellulitis, bacterial vaginosis, a skin furuncle and peristomal abscesses, all of which were easily managed with traditional therapies. Another concern with the use of integrin receptor antagonists in PLWH, although rare, is the possibility of Progressive Multifocal Leukoencephalopathy due to John Cunningham (JC) virus [1]. Our patient underwent blood plasma JC virus testing prior to vedolizumab initiation and this polymerase chain reaction testing was negative. She also denied any neurological signs or symptoms throughout treatment.
This woman’s case demonstrates that the spectrum of drug classes available and sequential use of biologics for treatment of UC were safe in this patient with well-controlled HIV infection ART, including an TNF-α blocker, JK inhibitor, IL-12/23 blocker and the α4β7 integrin blocker vedolizumab. Our patient did not incur any significant changes in her CD4 count nor CD4/CD8 ratio during the course of her treatments and infections were relatively minor. Although we did not use combination biologics in this patient, their efficacy and safety for IBD and other and other inflammatory diseases associated was explored in a systematic review of observational studies which did not find any differences related to improvements in disease condition, adverse effects or infection rates in patients receiving combined treatment compared to placebo groups [2]. A clinical trial (NCT02764762) examining efficacy and safety of combined vedolizumab, adalimumab and oral methotrexate in patients with Crohn’s Disease is in progress [3]. Until evidence from clinical trials is available on efficacy and safety of biologics and combination therapy in PLWH, case reports and case series provide a channel for dissemination of these experiences within the medical community.
ACKNOWLEDGMENTS
The authors thank Pathologist, Dr Zu-hua Gao, for provision of the histology image. No funding was received for the preparation of this manuscript.
CONFLICTS OF INTEREST STATEMENT
None declared.
FUNDING
No funding was received for the preparation of this manuscript.
ETHICS APPROVAL
The authors received ethical approval for publication of the case report.
CONSENT TO PUBLISH
The patient provided informed written consent for the preparation of this case report and publication of data and pathological image in an open access journal. The participant understood that the details/images would be freely available on the internet and may be seen by the general public. A copy of the written consent is available for review by the editor of the journal.
GUARANTOR
Dr Costiniuk is the guarantor of the case report. | ADALIMUMAB, CORTISONE, INFLIXIMAB, MERCAPTOPURINE, MESALAMINE, METHYLPREDNISOLONE, PREDNISOLONE, PREDNISONE, RALTEGRAVIR, TOFACITINIB, USTEKINUMAB, VEDOLIZUMAB | DrugsGivenReaction | CC BY-NC | 33542833 | 19,114,036 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Use of various immunotherapies for refractory ulcerative colitis in a person living with HIV: a case report.
Cancer therapies include several immune checkpoint or anticytokine therapies whereas ulcerative colitis treatments consist of anticytokine therapies. The development of tolerance and immunogical effects of these agents in people living with HIV are not well assessed as these persons are often excluded from clinical trials. Herein, we report a case of a Caucasian woman who received multiple sequential immunotherapies for severe ulcerative colitis. Due to steroid-refractory disease, receipt of maximal doses of mesalamine and initial repeated decline of surgical intervention, she went on to receive biologic immune inhibitors like tumor necrosis fator-α blockers infliximab and adalimumab, the α4β7integrin blocker vedolizumab, anti-interleukin 12/23 blocker ustekinumab and Janus Kinase inihibitor tofacitinib without achieving remission. Only minor infectious complications were encountered and no significant changes in CD4 count nor CD4/CD8 ratio occurred. This case provides support for the safety and tolerability of the above immunotherapies in people living with HIV with suppressed viral load on antiretroviral therapy.
INTRODUCTION
In the management of ulcerative colitis (UC), one provides immunosuppressive therapy with the hope of tempering excessive inflammation while preserving immune function. However, if the proper balance between immunosuppression and immune preservation is not achieved, an individual will be tipped into immunodeficiency with increased infection risk. People living with HIV (PLWH) are often excluding from clinical trials involving biologics based on concerns of additive immunosuppression and infection risk. Consequently, little data are available to guide clinicians in managing PLWH who suffer from advanced inflammatory bowel disease (IBD). Herein, we present the case of young woman with HIV infection and extensive UC refractory to many therapies. Following repeated decline of surgical intervention, she was treated with multiple sequential immunomodulators and did not experience any major adverse effects.
CASE REPORT
A 36-year-old, Canadian-born Caucasian woman was diagnosed with HIV in 2008. She began antiretroviral therapy with tenofovir disoproxil 300 mg/emtracitabine 200 mg orally once daily and raltegravir 400 mg orally twice daily in 2012, when her CD4 count rapidly dropped to 86 cells/mm3. Later that year, she began experiencing frequent episodes of bloody diarrhea, with up to 20 stools daily, with cramping, rectal bleeding and elevated C-reactive protein (CRP). Stool was repeatedly negative for Clostridium difficile and ova and parasites. Colonoscopy demonstrated severe pancolitis and biopsies consistent with active UC with acute cryptitis, crypt abcesses with lymphoid hyperplasia, focal erosions, acute inflammatory exudate with architectural disortion. Hematoxylin and eosin stains for cytomegalovirus and histochemical exams for Herpes Simplex Virus I/II were negative. Despite high doses of oral prednisone (40–60 mg daily) and several emergency room visits to receive intravenous (IV) methylprednisolone for flares, she was deemed steroid-refractory.
Later that year, she received maximum doses of oral mesalamine and 6-mercaptopurine, as well as mesalamine suppositories and enemas. She then received infliximab (2012–2013), an antitumor necrois fator-α (anti-TNFα) monoclonal antibody, until antibody formation. Despite maximum doses of adalimumab (2014), her UC remained refractory although no antibodies were detected using a drug-tolerant assay and medication levels were therapeutic (>12 μg/ml, the highest limit of detection). Attempts to taper her steroids resulted in flare-ups and a cushingoid feature. She declined colectomy as she felt this would interfere with her lifestyle, especially since she was getting married, and concerns about her future fertility.
One of the options explored was the use of vedolizumab, a monoclonal antibody against α4β7 integrin, via a clinical trial. However, due to the patient’s HIV infection she was not eligible to participate in any of the recruiting trials at the centre as HIV infection is frequently an exclusion criteria. Colonoscopy in 2015 revealed severe inflammation with ulcerations and friability consistent with Mayo 3 colitis, despite high-dose steroids and adalimumab, an anti-TNFα monoclonal antibody, at a dose of 80 mg weekly. By December 2015, vedolizumab was obtained through standard of care and initiated at 300 mg IV at weeks 0 and 2, 6 (loading dose) and then every 8 weeks thereafter as a maintenance dose. She was still bleeding from the rectum and had decreased weight, therefore daily prednisone 10 mg orally was maintained. She achieved clinical remission by March 2016 and steroids were stopped. Two months later, she developed right foot cellulitis following a minor trauma during a pedicure and required 48 hours of IV followed by oral antibiotics.
Colonoscopy in June 2016, 3 months after stopping steroids, showed worsening condition with Mayo 3 colitis, so she was changed to vedolizumab 300 mg IV q 4 weeks and prednisone increased to 40 mg orally (po) daily. Anti-α4β7 antibodies were not detected. She was passing bright red blood per rectum 12 times in 24 hours and having five stools per 24 hours with lower abdominal cramping and rectal pain. Janus kinase (JAK) inhibitor, tofacitinab 10 mg po twice daily, was initiated October 2016 and prednisone 40 mg po daily maintained. Symptoms persisted requiring admission for IV prednisolone, but she continued to decline surgical colectomy. She also developed a bacterial vaginitis treated with metronidazole cream and later a skin furuncle, treated with oral antibiotics.
Following tofacitinib, she received interleukin 12/23 inhibitor ustekinumab March–September 2017. She gained 30 pounds in 1 year (body mass index 37), increased abdominal fat and bilateral cataracts due to cortisone. Attempts to decrease prednisone below 30 mg daily led to bloody diarrhea (12–17 bowel movements daily). She eventually accepted to undergo subtotal abdominal colectomy (pathology shown in Fig. 1) with rectal stump and temporary end ileostomy by June 2018. She improved and was seen for follow-up a month post-op, at which time she was having increasing right lower quadrant pain and rising CRP. A computed tomography scan demonstrated collections in the subcutaneous fat surrounding the ostomy and a second collection centimeter with rim enhancement and fat stranding. These were drained and cultures grew E. coli and B. fragilis. She responded to IV antibiotics for 3 days followed by oral step-down antibiotics to complete 2 weeks. Eight months following her colectomy, she developed polyarthralgia in her interphalangeal joints, wrists, shoulders, knees and feet with a normal CRP and a negative Rheumatoid Factor while off prednisone, thought to be either inflammatory or mechanical polyarthralgia. Pathology on surveillance sigmoidoscopy March 2019 demonstrated chronic active proctitis with ulceration consistent with chronic idiopathic IBD. Throughout this entire time, her CD4 range was between 400 and 900 cells/mm3, with CD4/CD8 ratio of 0.41:1.12, and HIV viral load remained suppressed since November 2012.
Figure 1 Colonic resection histology. The colonic mucosa shows characteristic features of chronic ulcerative colitis including crypt architecture alteration, cryptitis, crypt abscess and focal mucosa ulceration. There is no evidence of dysplasia.
DISCUSSION
Due to repeated decline of surgery in order to preserve her quality of life and fertility, this woman with HIV and refractory UC received all available conventional therapies including mesalamine, glucocorticoids, thiopurines, antagonists to TNF- α, IL-12/23 blockers and anti-α4 β7 integrin. She also received a small-molecule JAK inhibitor. TNF-α inhibitors and α4β7 integrin blockers are used with extreme caution in PLWH due to concerns of additional immunosuppression and subsequent infection risk. However, during her 6 years of being on immunosuppressants, the patient only experienced one episode of cellulitis, bacterial vaginosis, a skin furuncle and peristomal abscesses, all of which were easily managed with traditional therapies. Another concern with the use of integrin receptor antagonists in PLWH, although rare, is the possibility of Progressive Multifocal Leukoencephalopathy due to John Cunningham (JC) virus [1]. Our patient underwent blood plasma JC virus testing prior to vedolizumab initiation and this polymerase chain reaction testing was negative. She also denied any neurological signs or symptoms throughout treatment.
This woman’s case demonstrates that the spectrum of drug classes available and sequential use of biologics for treatment of UC were safe in this patient with well-controlled HIV infection ART, including an TNF-α blocker, JK inhibitor, IL-12/23 blocker and the α4β7 integrin blocker vedolizumab. Our patient did not incur any significant changes in her CD4 count nor CD4/CD8 ratio during the course of her treatments and infections were relatively minor. Although we did not use combination biologics in this patient, their efficacy and safety for IBD and other and other inflammatory diseases associated was explored in a systematic review of observational studies which did not find any differences related to improvements in disease condition, adverse effects or infection rates in patients receiving combined treatment compared to placebo groups [2]. A clinical trial (NCT02764762) examining efficacy and safety of combined vedolizumab, adalimumab and oral methotrexate in patients with Crohn’s Disease is in progress [3]. Until evidence from clinical trials is available on efficacy and safety of biologics and combination therapy in PLWH, case reports and case series provide a channel for dissemination of these experiences within the medical community.
ACKNOWLEDGMENTS
The authors thank Pathologist, Dr Zu-hua Gao, for provision of the histology image. No funding was received for the preparation of this manuscript.
CONFLICTS OF INTEREST STATEMENT
None declared.
FUNDING
No funding was received for the preparation of this manuscript.
ETHICS APPROVAL
The authors received ethical approval for publication of the case report.
CONSENT TO PUBLISH
The patient provided informed written consent for the preparation of this case report and publication of data and pathological image in an open access journal. The participant understood that the details/images would be freely available on the internet and may be seen by the general public. A copy of the written consent is available for review by the editor of the journal.
GUARANTOR
Dr Costiniuk is the guarantor of the case report. | ADALIMUMAB, CORTISONE, INFLIXIMAB, MERCAPTOPURINE, MESALAMINE, METHYLPREDNISOLONE, PREDNISOLONE, PREDNISONE, RALTEGRAVIR, TOFACITINIB, USTEKINUMAB, VEDOLIZUMAB | DrugsGivenReaction | CC BY-NC | 33542833 | 19,114,036 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Escherichia infection'. | Use of various immunotherapies for refractory ulcerative colitis in a person living with HIV: a case report.
Cancer therapies include several immune checkpoint or anticytokine therapies whereas ulcerative colitis treatments consist of anticytokine therapies. The development of tolerance and immunogical effects of these agents in people living with HIV are not well assessed as these persons are often excluded from clinical trials. Herein, we report a case of a Caucasian woman who received multiple sequential immunotherapies for severe ulcerative colitis. Due to steroid-refractory disease, receipt of maximal doses of mesalamine and initial repeated decline of surgical intervention, she went on to receive biologic immune inhibitors like tumor necrosis fator-α blockers infliximab and adalimumab, the α4β7integrin blocker vedolizumab, anti-interleukin 12/23 blocker ustekinumab and Janus Kinase inihibitor tofacitinib without achieving remission. Only minor infectious complications were encountered and no significant changes in CD4 count nor CD4/CD8 ratio occurred. This case provides support for the safety and tolerability of the above immunotherapies in people living with HIV with suppressed viral load on antiretroviral therapy.
INTRODUCTION
In the management of ulcerative colitis (UC), one provides immunosuppressive therapy with the hope of tempering excessive inflammation while preserving immune function. However, if the proper balance between immunosuppression and immune preservation is not achieved, an individual will be tipped into immunodeficiency with increased infection risk. People living with HIV (PLWH) are often excluding from clinical trials involving biologics based on concerns of additive immunosuppression and infection risk. Consequently, little data are available to guide clinicians in managing PLWH who suffer from advanced inflammatory bowel disease (IBD). Herein, we present the case of young woman with HIV infection and extensive UC refractory to many therapies. Following repeated decline of surgical intervention, she was treated with multiple sequential immunomodulators and did not experience any major adverse effects.
CASE REPORT
A 36-year-old, Canadian-born Caucasian woman was diagnosed with HIV in 2008. She began antiretroviral therapy with tenofovir disoproxil 300 mg/emtracitabine 200 mg orally once daily and raltegravir 400 mg orally twice daily in 2012, when her CD4 count rapidly dropped to 86 cells/mm3. Later that year, she began experiencing frequent episodes of bloody diarrhea, with up to 20 stools daily, with cramping, rectal bleeding and elevated C-reactive protein (CRP). Stool was repeatedly negative for Clostridium difficile and ova and parasites. Colonoscopy demonstrated severe pancolitis and biopsies consistent with active UC with acute cryptitis, crypt abcesses with lymphoid hyperplasia, focal erosions, acute inflammatory exudate with architectural disortion. Hematoxylin and eosin stains for cytomegalovirus and histochemical exams for Herpes Simplex Virus I/II were negative. Despite high doses of oral prednisone (40–60 mg daily) and several emergency room visits to receive intravenous (IV) methylprednisolone for flares, she was deemed steroid-refractory.
Later that year, she received maximum doses of oral mesalamine and 6-mercaptopurine, as well as mesalamine suppositories and enemas. She then received infliximab (2012–2013), an antitumor necrois fator-α (anti-TNFα) monoclonal antibody, until antibody formation. Despite maximum doses of adalimumab (2014), her UC remained refractory although no antibodies were detected using a drug-tolerant assay and medication levels were therapeutic (>12 μg/ml, the highest limit of detection). Attempts to taper her steroids resulted in flare-ups and a cushingoid feature. She declined colectomy as she felt this would interfere with her lifestyle, especially since she was getting married, and concerns about her future fertility.
One of the options explored was the use of vedolizumab, a monoclonal antibody against α4β7 integrin, via a clinical trial. However, due to the patient’s HIV infection she was not eligible to participate in any of the recruiting trials at the centre as HIV infection is frequently an exclusion criteria. Colonoscopy in 2015 revealed severe inflammation with ulcerations and friability consistent with Mayo 3 colitis, despite high-dose steroids and adalimumab, an anti-TNFα monoclonal antibody, at a dose of 80 mg weekly. By December 2015, vedolizumab was obtained through standard of care and initiated at 300 mg IV at weeks 0 and 2, 6 (loading dose) and then every 8 weeks thereafter as a maintenance dose. She was still bleeding from the rectum and had decreased weight, therefore daily prednisone 10 mg orally was maintained. She achieved clinical remission by March 2016 and steroids were stopped. Two months later, she developed right foot cellulitis following a minor trauma during a pedicure and required 48 hours of IV followed by oral antibiotics.
Colonoscopy in June 2016, 3 months after stopping steroids, showed worsening condition with Mayo 3 colitis, so she was changed to vedolizumab 300 mg IV q 4 weeks and prednisone increased to 40 mg orally (po) daily. Anti-α4β7 antibodies were not detected. She was passing bright red blood per rectum 12 times in 24 hours and having five stools per 24 hours with lower abdominal cramping and rectal pain. Janus kinase (JAK) inhibitor, tofacitinab 10 mg po twice daily, was initiated October 2016 and prednisone 40 mg po daily maintained. Symptoms persisted requiring admission for IV prednisolone, but she continued to decline surgical colectomy. She also developed a bacterial vaginitis treated with metronidazole cream and later a skin furuncle, treated with oral antibiotics.
Following tofacitinib, she received interleukin 12/23 inhibitor ustekinumab March–September 2017. She gained 30 pounds in 1 year (body mass index 37), increased abdominal fat and bilateral cataracts due to cortisone. Attempts to decrease prednisone below 30 mg daily led to bloody diarrhea (12–17 bowel movements daily). She eventually accepted to undergo subtotal abdominal colectomy (pathology shown in Fig. 1) with rectal stump and temporary end ileostomy by June 2018. She improved and was seen for follow-up a month post-op, at which time she was having increasing right lower quadrant pain and rising CRP. A computed tomography scan demonstrated collections in the subcutaneous fat surrounding the ostomy and a second collection centimeter with rim enhancement and fat stranding. These were drained and cultures grew E. coli and B. fragilis. She responded to IV antibiotics for 3 days followed by oral step-down antibiotics to complete 2 weeks. Eight months following her colectomy, she developed polyarthralgia in her interphalangeal joints, wrists, shoulders, knees and feet with a normal CRP and a negative Rheumatoid Factor while off prednisone, thought to be either inflammatory or mechanical polyarthralgia. Pathology on surveillance sigmoidoscopy March 2019 demonstrated chronic active proctitis with ulceration consistent with chronic idiopathic IBD. Throughout this entire time, her CD4 range was between 400 and 900 cells/mm3, with CD4/CD8 ratio of 0.41:1.12, and HIV viral load remained suppressed since November 2012.
Figure 1 Colonic resection histology. The colonic mucosa shows characteristic features of chronic ulcerative colitis including crypt architecture alteration, cryptitis, crypt abscess and focal mucosa ulceration. There is no evidence of dysplasia.
DISCUSSION
Due to repeated decline of surgery in order to preserve her quality of life and fertility, this woman with HIV and refractory UC received all available conventional therapies including mesalamine, glucocorticoids, thiopurines, antagonists to TNF- α, IL-12/23 blockers and anti-α4 β7 integrin. She also received a small-molecule JAK inhibitor. TNF-α inhibitors and α4β7 integrin blockers are used with extreme caution in PLWH due to concerns of additional immunosuppression and subsequent infection risk. However, during her 6 years of being on immunosuppressants, the patient only experienced one episode of cellulitis, bacterial vaginosis, a skin furuncle and peristomal abscesses, all of which were easily managed with traditional therapies. Another concern with the use of integrin receptor antagonists in PLWH, although rare, is the possibility of Progressive Multifocal Leukoencephalopathy due to John Cunningham (JC) virus [1]. Our patient underwent blood plasma JC virus testing prior to vedolizumab initiation and this polymerase chain reaction testing was negative. She also denied any neurological signs or symptoms throughout treatment.
This woman’s case demonstrates that the spectrum of drug classes available and sequential use of biologics for treatment of UC were safe in this patient with well-controlled HIV infection ART, including an TNF-α blocker, JK inhibitor, IL-12/23 blocker and the α4β7 integrin blocker vedolizumab. Our patient did not incur any significant changes in her CD4 count nor CD4/CD8 ratio during the course of her treatments and infections were relatively minor. Although we did not use combination biologics in this patient, their efficacy and safety for IBD and other and other inflammatory diseases associated was explored in a systematic review of observational studies which did not find any differences related to improvements in disease condition, adverse effects or infection rates in patients receiving combined treatment compared to placebo groups [2]. A clinical trial (NCT02764762) examining efficacy and safety of combined vedolizumab, adalimumab and oral methotrexate in patients with Crohn’s Disease is in progress [3]. Until evidence from clinical trials is available on efficacy and safety of biologics and combination therapy in PLWH, case reports and case series provide a channel for dissemination of these experiences within the medical community.
ACKNOWLEDGMENTS
The authors thank Pathologist, Dr Zu-hua Gao, for provision of the histology image. No funding was received for the preparation of this manuscript.
CONFLICTS OF INTEREST STATEMENT
None declared.
FUNDING
No funding was received for the preparation of this manuscript.
ETHICS APPROVAL
The authors received ethical approval for publication of the case report.
CONSENT TO PUBLISH
The patient provided informed written consent for the preparation of this case report and publication of data and pathological image in an open access journal. The participant understood that the details/images would be freely available on the internet and may be seen by the general public. A copy of the written consent is available for review by the editor of the journal.
GUARANTOR
Dr Costiniuk is the guarantor of the case report. | ADALIMUMAB, CORTISONE, INFLIXIMAB, MERCAPTOPURINE, MESALAMINE, METHYLPREDNISOLONE, PREDNISOLONE, PREDNISONE, RALTEGRAVIR, TOFACITINIB, USTEKINUMAB, VEDOLIZUMAB | DrugsGivenReaction | CC BY-NC | 33542833 | 19,114,036 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Furuncle'. | Use of various immunotherapies for refractory ulcerative colitis in a person living with HIV: a case report.
Cancer therapies include several immune checkpoint or anticytokine therapies whereas ulcerative colitis treatments consist of anticytokine therapies. The development of tolerance and immunogical effects of these agents in people living with HIV are not well assessed as these persons are often excluded from clinical trials. Herein, we report a case of a Caucasian woman who received multiple sequential immunotherapies for severe ulcerative colitis. Due to steroid-refractory disease, receipt of maximal doses of mesalamine and initial repeated decline of surgical intervention, she went on to receive biologic immune inhibitors like tumor necrosis fator-α blockers infliximab and adalimumab, the α4β7integrin blocker vedolizumab, anti-interleukin 12/23 blocker ustekinumab and Janus Kinase inihibitor tofacitinib without achieving remission. Only minor infectious complications were encountered and no significant changes in CD4 count nor CD4/CD8 ratio occurred. This case provides support for the safety and tolerability of the above immunotherapies in people living with HIV with suppressed viral load on antiretroviral therapy.
INTRODUCTION
In the management of ulcerative colitis (UC), one provides immunosuppressive therapy with the hope of tempering excessive inflammation while preserving immune function. However, if the proper balance between immunosuppression and immune preservation is not achieved, an individual will be tipped into immunodeficiency with increased infection risk. People living with HIV (PLWH) are often excluding from clinical trials involving biologics based on concerns of additive immunosuppression and infection risk. Consequently, little data are available to guide clinicians in managing PLWH who suffer from advanced inflammatory bowel disease (IBD). Herein, we present the case of young woman with HIV infection and extensive UC refractory to many therapies. Following repeated decline of surgical intervention, she was treated with multiple sequential immunomodulators and did not experience any major adverse effects.
CASE REPORT
A 36-year-old, Canadian-born Caucasian woman was diagnosed with HIV in 2008. She began antiretroviral therapy with tenofovir disoproxil 300 mg/emtracitabine 200 mg orally once daily and raltegravir 400 mg orally twice daily in 2012, when her CD4 count rapidly dropped to 86 cells/mm3. Later that year, she began experiencing frequent episodes of bloody diarrhea, with up to 20 stools daily, with cramping, rectal bleeding and elevated C-reactive protein (CRP). Stool was repeatedly negative for Clostridium difficile and ova and parasites. Colonoscopy demonstrated severe pancolitis and biopsies consistent with active UC with acute cryptitis, crypt abcesses with lymphoid hyperplasia, focal erosions, acute inflammatory exudate with architectural disortion. Hematoxylin and eosin stains for cytomegalovirus and histochemical exams for Herpes Simplex Virus I/II were negative. Despite high doses of oral prednisone (40–60 mg daily) and several emergency room visits to receive intravenous (IV) methylprednisolone for flares, she was deemed steroid-refractory.
Later that year, she received maximum doses of oral mesalamine and 6-mercaptopurine, as well as mesalamine suppositories and enemas. She then received infliximab (2012–2013), an antitumor necrois fator-α (anti-TNFα) monoclonal antibody, until antibody formation. Despite maximum doses of adalimumab (2014), her UC remained refractory although no antibodies were detected using a drug-tolerant assay and medication levels were therapeutic (>12 μg/ml, the highest limit of detection). Attempts to taper her steroids resulted in flare-ups and a cushingoid feature. She declined colectomy as she felt this would interfere with her lifestyle, especially since she was getting married, and concerns about her future fertility.
One of the options explored was the use of vedolizumab, a monoclonal antibody against α4β7 integrin, via a clinical trial. However, due to the patient’s HIV infection she was not eligible to participate in any of the recruiting trials at the centre as HIV infection is frequently an exclusion criteria. Colonoscopy in 2015 revealed severe inflammation with ulcerations and friability consistent with Mayo 3 colitis, despite high-dose steroids and adalimumab, an anti-TNFα monoclonal antibody, at a dose of 80 mg weekly. By December 2015, vedolizumab was obtained through standard of care and initiated at 300 mg IV at weeks 0 and 2, 6 (loading dose) and then every 8 weeks thereafter as a maintenance dose. She was still bleeding from the rectum and had decreased weight, therefore daily prednisone 10 mg orally was maintained. She achieved clinical remission by March 2016 and steroids were stopped. Two months later, she developed right foot cellulitis following a minor trauma during a pedicure and required 48 hours of IV followed by oral antibiotics.
Colonoscopy in June 2016, 3 months after stopping steroids, showed worsening condition with Mayo 3 colitis, so she was changed to vedolizumab 300 mg IV q 4 weeks and prednisone increased to 40 mg orally (po) daily. Anti-α4β7 antibodies were not detected. She was passing bright red blood per rectum 12 times in 24 hours and having five stools per 24 hours with lower abdominal cramping and rectal pain. Janus kinase (JAK) inhibitor, tofacitinab 10 mg po twice daily, was initiated October 2016 and prednisone 40 mg po daily maintained. Symptoms persisted requiring admission for IV prednisolone, but she continued to decline surgical colectomy. She also developed a bacterial vaginitis treated with metronidazole cream and later a skin furuncle, treated with oral antibiotics.
Following tofacitinib, she received interleukin 12/23 inhibitor ustekinumab March–September 2017. She gained 30 pounds in 1 year (body mass index 37), increased abdominal fat and bilateral cataracts due to cortisone. Attempts to decrease prednisone below 30 mg daily led to bloody diarrhea (12–17 bowel movements daily). She eventually accepted to undergo subtotal abdominal colectomy (pathology shown in Fig. 1) with rectal stump and temporary end ileostomy by June 2018. She improved and was seen for follow-up a month post-op, at which time she was having increasing right lower quadrant pain and rising CRP. A computed tomography scan demonstrated collections in the subcutaneous fat surrounding the ostomy and a second collection centimeter with rim enhancement and fat stranding. These were drained and cultures grew E. coli and B. fragilis. She responded to IV antibiotics for 3 days followed by oral step-down antibiotics to complete 2 weeks. Eight months following her colectomy, she developed polyarthralgia in her interphalangeal joints, wrists, shoulders, knees and feet with a normal CRP and a negative Rheumatoid Factor while off prednisone, thought to be either inflammatory or mechanical polyarthralgia. Pathology on surveillance sigmoidoscopy March 2019 demonstrated chronic active proctitis with ulceration consistent with chronic idiopathic IBD. Throughout this entire time, her CD4 range was between 400 and 900 cells/mm3, with CD4/CD8 ratio of 0.41:1.12, and HIV viral load remained suppressed since November 2012.
Figure 1 Colonic resection histology. The colonic mucosa shows characteristic features of chronic ulcerative colitis including crypt architecture alteration, cryptitis, crypt abscess and focal mucosa ulceration. There is no evidence of dysplasia.
DISCUSSION
Due to repeated decline of surgery in order to preserve her quality of life and fertility, this woman with HIV and refractory UC received all available conventional therapies including mesalamine, glucocorticoids, thiopurines, antagonists to TNF- α, IL-12/23 blockers and anti-α4 β7 integrin. She also received a small-molecule JAK inhibitor. TNF-α inhibitors and α4β7 integrin blockers are used with extreme caution in PLWH due to concerns of additional immunosuppression and subsequent infection risk. However, during her 6 years of being on immunosuppressants, the patient only experienced one episode of cellulitis, bacterial vaginosis, a skin furuncle and peristomal abscesses, all of which were easily managed with traditional therapies. Another concern with the use of integrin receptor antagonists in PLWH, although rare, is the possibility of Progressive Multifocal Leukoencephalopathy due to John Cunningham (JC) virus [1]. Our patient underwent blood plasma JC virus testing prior to vedolizumab initiation and this polymerase chain reaction testing was negative. She also denied any neurological signs or symptoms throughout treatment.
This woman’s case demonstrates that the spectrum of drug classes available and sequential use of biologics for treatment of UC were safe in this patient with well-controlled HIV infection ART, including an TNF-α blocker, JK inhibitor, IL-12/23 blocker and the α4β7 integrin blocker vedolizumab. Our patient did not incur any significant changes in her CD4 count nor CD4/CD8 ratio during the course of her treatments and infections were relatively minor. Although we did not use combination biologics in this patient, their efficacy and safety for IBD and other and other inflammatory diseases associated was explored in a systematic review of observational studies which did not find any differences related to improvements in disease condition, adverse effects or infection rates in patients receiving combined treatment compared to placebo groups [2]. A clinical trial (NCT02764762) examining efficacy and safety of combined vedolizumab, adalimumab and oral methotrexate in patients with Crohn’s Disease is in progress [3]. Until evidence from clinical trials is available on efficacy and safety of biologics and combination therapy in PLWH, case reports and case series provide a channel for dissemination of these experiences within the medical community.
ACKNOWLEDGMENTS
The authors thank Pathologist, Dr Zu-hua Gao, for provision of the histology image. No funding was received for the preparation of this manuscript.
CONFLICTS OF INTEREST STATEMENT
None declared.
FUNDING
No funding was received for the preparation of this manuscript.
ETHICS APPROVAL
The authors received ethical approval for publication of the case report.
CONSENT TO PUBLISH
The patient provided informed written consent for the preparation of this case report and publication of data and pathological image in an open access journal. The participant understood that the details/images would be freely available on the internet and may be seen by the general public. A copy of the written consent is available for review by the editor of the journal.
GUARANTOR
Dr Costiniuk is the guarantor of the case report. | ADALIMUMAB, CORTISONE, INFLIXIMAB, MERCAPTOPURINE, MESALAMINE, METHYLPREDNISOLONE, PREDNISOLONE, PREDNISONE, RALTEGRAVIR, TOFACITINIB, USTEKINUMAB, VEDOLIZUMAB | DrugsGivenReaction | CC BY-NC | 33542833 | 19,114,036 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapy non-responder'. | Use of various immunotherapies for refractory ulcerative colitis in a person living with HIV: a case report.
Cancer therapies include several immune checkpoint or anticytokine therapies whereas ulcerative colitis treatments consist of anticytokine therapies. The development of tolerance and immunogical effects of these agents in people living with HIV are not well assessed as these persons are often excluded from clinical trials. Herein, we report a case of a Caucasian woman who received multiple sequential immunotherapies for severe ulcerative colitis. Due to steroid-refractory disease, receipt of maximal doses of mesalamine and initial repeated decline of surgical intervention, she went on to receive biologic immune inhibitors like tumor necrosis fator-α blockers infliximab and adalimumab, the α4β7integrin blocker vedolizumab, anti-interleukin 12/23 blocker ustekinumab and Janus Kinase inihibitor tofacitinib without achieving remission. Only minor infectious complications were encountered and no significant changes in CD4 count nor CD4/CD8 ratio occurred. This case provides support for the safety and tolerability of the above immunotherapies in people living with HIV with suppressed viral load on antiretroviral therapy.
INTRODUCTION
In the management of ulcerative colitis (UC), one provides immunosuppressive therapy with the hope of tempering excessive inflammation while preserving immune function. However, if the proper balance between immunosuppression and immune preservation is not achieved, an individual will be tipped into immunodeficiency with increased infection risk. People living with HIV (PLWH) are often excluding from clinical trials involving biologics based on concerns of additive immunosuppression and infection risk. Consequently, little data are available to guide clinicians in managing PLWH who suffer from advanced inflammatory bowel disease (IBD). Herein, we present the case of young woman with HIV infection and extensive UC refractory to many therapies. Following repeated decline of surgical intervention, she was treated with multiple sequential immunomodulators and did not experience any major adverse effects.
CASE REPORT
A 36-year-old, Canadian-born Caucasian woman was diagnosed with HIV in 2008. She began antiretroviral therapy with tenofovir disoproxil 300 mg/emtracitabine 200 mg orally once daily and raltegravir 400 mg orally twice daily in 2012, when her CD4 count rapidly dropped to 86 cells/mm3. Later that year, she began experiencing frequent episodes of bloody diarrhea, with up to 20 stools daily, with cramping, rectal bleeding and elevated C-reactive protein (CRP). Stool was repeatedly negative for Clostridium difficile and ova and parasites. Colonoscopy demonstrated severe pancolitis and biopsies consistent with active UC with acute cryptitis, crypt abcesses with lymphoid hyperplasia, focal erosions, acute inflammatory exudate with architectural disortion. Hematoxylin and eosin stains for cytomegalovirus and histochemical exams for Herpes Simplex Virus I/II were negative. Despite high doses of oral prednisone (40–60 mg daily) and several emergency room visits to receive intravenous (IV) methylprednisolone for flares, she was deemed steroid-refractory.
Later that year, she received maximum doses of oral mesalamine and 6-mercaptopurine, as well as mesalamine suppositories and enemas. She then received infliximab (2012–2013), an antitumor necrois fator-α (anti-TNFα) monoclonal antibody, until antibody formation. Despite maximum doses of adalimumab (2014), her UC remained refractory although no antibodies were detected using a drug-tolerant assay and medication levels were therapeutic (>12 μg/ml, the highest limit of detection). Attempts to taper her steroids resulted in flare-ups and a cushingoid feature. She declined colectomy as she felt this would interfere with her lifestyle, especially since she was getting married, and concerns about her future fertility.
One of the options explored was the use of vedolizumab, a monoclonal antibody against α4β7 integrin, via a clinical trial. However, due to the patient’s HIV infection she was not eligible to participate in any of the recruiting trials at the centre as HIV infection is frequently an exclusion criteria. Colonoscopy in 2015 revealed severe inflammation with ulcerations and friability consistent with Mayo 3 colitis, despite high-dose steroids and adalimumab, an anti-TNFα monoclonal antibody, at a dose of 80 mg weekly. By December 2015, vedolizumab was obtained through standard of care and initiated at 300 mg IV at weeks 0 and 2, 6 (loading dose) and then every 8 weeks thereafter as a maintenance dose. She was still bleeding from the rectum and had decreased weight, therefore daily prednisone 10 mg orally was maintained. She achieved clinical remission by March 2016 and steroids were stopped. Two months later, she developed right foot cellulitis following a minor trauma during a pedicure and required 48 hours of IV followed by oral antibiotics.
Colonoscopy in June 2016, 3 months after stopping steroids, showed worsening condition with Mayo 3 colitis, so she was changed to vedolizumab 300 mg IV q 4 weeks and prednisone increased to 40 mg orally (po) daily. Anti-α4β7 antibodies were not detected. She was passing bright red blood per rectum 12 times in 24 hours and having five stools per 24 hours with lower abdominal cramping and rectal pain. Janus kinase (JAK) inhibitor, tofacitinab 10 mg po twice daily, was initiated October 2016 and prednisone 40 mg po daily maintained. Symptoms persisted requiring admission for IV prednisolone, but she continued to decline surgical colectomy. She also developed a bacterial vaginitis treated with metronidazole cream and later a skin furuncle, treated with oral antibiotics.
Following tofacitinib, she received interleukin 12/23 inhibitor ustekinumab March–September 2017. She gained 30 pounds in 1 year (body mass index 37), increased abdominal fat and bilateral cataracts due to cortisone. Attempts to decrease prednisone below 30 mg daily led to bloody diarrhea (12–17 bowel movements daily). She eventually accepted to undergo subtotal abdominal colectomy (pathology shown in Fig. 1) with rectal stump and temporary end ileostomy by June 2018. She improved and was seen for follow-up a month post-op, at which time she was having increasing right lower quadrant pain and rising CRP. A computed tomography scan demonstrated collections in the subcutaneous fat surrounding the ostomy and a second collection centimeter with rim enhancement and fat stranding. These were drained and cultures grew E. coli and B. fragilis. She responded to IV antibiotics for 3 days followed by oral step-down antibiotics to complete 2 weeks. Eight months following her colectomy, she developed polyarthralgia in her interphalangeal joints, wrists, shoulders, knees and feet with a normal CRP and a negative Rheumatoid Factor while off prednisone, thought to be either inflammatory or mechanical polyarthralgia. Pathology on surveillance sigmoidoscopy March 2019 demonstrated chronic active proctitis with ulceration consistent with chronic idiopathic IBD. Throughout this entire time, her CD4 range was between 400 and 900 cells/mm3, with CD4/CD8 ratio of 0.41:1.12, and HIV viral load remained suppressed since November 2012.
Figure 1 Colonic resection histology. The colonic mucosa shows characteristic features of chronic ulcerative colitis including crypt architecture alteration, cryptitis, crypt abscess and focal mucosa ulceration. There is no evidence of dysplasia.
DISCUSSION
Due to repeated decline of surgery in order to preserve her quality of life and fertility, this woman with HIV and refractory UC received all available conventional therapies including mesalamine, glucocorticoids, thiopurines, antagonists to TNF- α, IL-12/23 blockers and anti-α4 β7 integrin. She also received a small-molecule JAK inhibitor. TNF-α inhibitors and α4β7 integrin blockers are used with extreme caution in PLWH due to concerns of additional immunosuppression and subsequent infection risk. However, during her 6 years of being on immunosuppressants, the patient only experienced one episode of cellulitis, bacterial vaginosis, a skin furuncle and peristomal abscesses, all of which were easily managed with traditional therapies. Another concern with the use of integrin receptor antagonists in PLWH, although rare, is the possibility of Progressive Multifocal Leukoencephalopathy due to John Cunningham (JC) virus [1]. Our patient underwent blood plasma JC virus testing prior to vedolizumab initiation and this polymerase chain reaction testing was negative. She also denied any neurological signs or symptoms throughout treatment.
This woman’s case demonstrates that the spectrum of drug classes available and sequential use of biologics for treatment of UC were safe in this patient with well-controlled HIV infection ART, including an TNF-α blocker, JK inhibitor, IL-12/23 blocker and the α4β7 integrin blocker vedolizumab. Our patient did not incur any significant changes in her CD4 count nor CD4/CD8 ratio during the course of her treatments and infections were relatively minor. Although we did not use combination biologics in this patient, their efficacy and safety for IBD and other and other inflammatory diseases associated was explored in a systematic review of observational studies which did not find any differences related to improvements in disease condition, adverse effects or infection rates in patients receiving combined treatment compared to placebo groups [2]. A clinical trial (NCT02764762) examining efficacy and safety of combined vedolizumab, adalimumab and oral methotrexate in patients with Crohn’s Disease is in progress [3]. Until evidence from clinical trials is available on efficacy and safety of biologics and combination therapy in PLWH, case reports and case series provide a channel for dissemination of these experiences within the medical community.
ACKNOWLEDGMENTS
The authors thank Pathologist, Dr Zu-hua Gao, for provision of the histology image. No funding was received for the preparation of this manuscript.
CONFLICTS OF INTEREST STATEMENT
None declared.
FUNDING
No funding was received for the preparation of this manuscript.
ETHICS APPROVAL
The authors received ethical approval for publication of the case report.
CONSENT TO PUBLISH
The patient provided informed written consent for the preparation of this case report and publication of data and pathological image in an open access journal. The participant understood that the details/images would be freely available on the internet and may be seen by the general public. A copy of the written consent is available for review by the editor of the journal.
GUARANTOR
Dr Costiniuk is the guarantor of the case report. | ADALIMUMAB, EMTRICITABINE\TENOFOVIR DISOPROXIL, INFLIXIMAB, MERCAPTOPURINE, MESALAMINE, METHYLPREDNISOLONE, PREDNISOLONE, PREDNISONE, RALTEGRAVIR, TOFACITINIB, USTEKINUMAB, VEDOLIZUMAB | DrugsGivenReaction | CC BY-NC | 33542833 | 19,710,764 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Weight increased'. | Use of various immunotherapies for refractory ulcerative colitis in a person living with HIV: a case report.
Cancer therapies include several immune checkpoint or anticytokine therapies whereas ulcerative colitis treatments consist of anticytokine therapies. The development of tolerance and immunogical effects of these agents in people living with HIV are not well assessed as these persons are often excluded from clinical trials. Herein, we report a case of a Caucasian woman who received multiple sequential immunotherapies for severe ulcerative colitis. Due to steroid-refractory disease, receipt of maximal doses of mesalamine and initial repeated decline of surgical intervention, she went on to receive biologic immune inhibitors like tumor necrosis fator-α blockers infliximab and adalimumab, the α4β7integrin blocker vedolizumab, anti-interleukin 12/23 blocker ustekinumab and Janus Kinase inihibitor tofacitinib without achieving remission. Only minor infectious complications were encountered and no significant changes in CD4 count nor CD4/CD8 ratio occurred. This case provides support for the safety and tolerability of the above immunotherapies in people living with HIV with suppressed viral load on antiretroviral therapy.
INTRODUCTION
In the management of ulcerative colitis (UC), one provides immunosuppressive therapy with the hope of tempering excessive inflammation while preserving immune function. However, if the proper balance between immunosuppression and immune preservation is not achieved, an individual will be tipped into immunodeficiency with increased infection risk. People living with HIV (PLWH) are often excluding from clinical trials involving biologics based on concerns of additive immunosuppression and infection risk. Consequently, little data are available to guide clinicians in managing PLWH who suffer from advanced inflammatory bowel disease (IBD). Herein, we present the case of young woman with HIV infection and extensive UC refractory to many therapies. Following repeated decline of surgical intervention, she was treated with multiple sequential immunomodulators and did not experience any major adverse effects.
CASE REPORT
A 36-year-old, Canadian-born Caucasian woman was diagnosed with HIV in 2008. She began antiretroviral therapy with tenofovir disoproxil 300 mg/emtracitabine 200 mg orally once daily and raltegravir 400 mg orally twice daily in 2012, when her CD4 count rapidly dropped to 86 cells/mm3. Later that year, she began experiencing frequent episodes of bloody diarrhea, with up to 20 stools daily, with cramping, rectal bleeding and elevated C-reactive protein (CRP). Stool was repeatedly negative for Clostridium difficile and ova and parasites. Colonoscopy demonstrated severe pancolitis and biopsies consistent with active UC with acute cryptitis, crypt abcesses with lymphoid hyperplasia, focal erosions, acute inflammatory exudate with architectural disortion. Hematoxylin and eosin stains for cytomegalovirus and histochemical exams for Herpes Simplex Virus I/II were negative. Despite high doses of oral prednisone (40–60 mg daily) and several emergency room visits to receive intravenous (IV) methylprednisolone for flares, she was deemed steroid-refractory.
Later that year, she received maximum doses of oral mesalamine and 6-mercaptopurine, as well as mesalamine suppositories and enemas. She then received infliximab (2012–2013), an antitumor necrois fator-α (anti-TNFα) monoclonal antibody, until antibody formation. Despite maximum doses of adalimumab (2014), her UC remained refractory although no antibodies were detected using a drug-tolerant assay and medication levels were therapeutic (>12 μg/ml, the highest limit of detection). Attempts to taper her steroids resulted in flare-ups and a cushingoid feature. She declined colectomy as she felt this would interfere with her lifestyle, especially since she was getting married, and concerns about her future fertility.
One of the options explored was the use of vedolizumab, a monoclonal antibody against α4β7 integrin, via a clinical trial. However, due to the patient’s HIV infection she was not eligible to participate in any of the recruiting trials at the centre as HIV infection is frequently an exclusion criteria. Colonoscopy in 2015 revealed severe inflammation with ulcerations and friability consistent with Mayo 3 colitis, despite high-dose steroids and adalimumab, an anti-TNFα monoclonal antibody, at a dose of 80 mg weekly. By December 2015, vedolizumab was obtained through standard of care and initiated at 300 mg IV at weeks 0 and 2, 6 (loading dose) and then every 8 weeks thereafter as a maintenance dose. She was still bleeding from the rectum and had decreased weight, therefore daily prednisone 10 mg orally was maintained. She achieved clinical remission by March 2016 and steroids were stopped. Two months later, she developed right foot cellulitis following a minor trauma during a pedicure and required 48 hours of IV followed by oral antibiotics.
Colonoscopy in June 2016, 3 months after stopping steroids, showed worsening condition with Mayo 3 colitis, so she was changed to vedolizumab 300 mg IV q 4 weeks and prednisone increased to 40 mg orally (po) daily. Anti-α4β7 antibodies were not detected. She was passing bright red blood per rectum 12 times in 24 hours and having five stools per 24 hours with lower abdominal cramping and rectal pain. Janus kinase (JAK) inhibitor, tofacitinab 10 mg po twice daily, was initiated October 2016 and prednisone 40 mg po daily maintained. Symptoms persisted requiring admission for IV prednisolone, but she continued to decline surgical colectomy. She also developed a bacterial vaginitis treated with metronidazole cream and later a skin furuncle, treated with oral antibiotics.
Following tofacitinib, she received interleukin 12/23 inhibitor ustekinumab March–September 2017. She gained 30 pounds in 1 year (body mass index 37), increased abdominal fat and bilateral cataracts due to cortisone. Attempts to decrease prednisone below 30 mg daily led to bloody diarrhea (12–17 bowel movements daily). She eventually accepted to undergo subtotal abdominal colectomy (pathology shown in Fig. 1) with rectal stump and temporary end ileostomy by June 2018. She improved and was seen for follow-up a month post-op, at which time she was having increasing right lower quadrant pain and rising CRP. A computed tomography scan demonstrated collections in the subcutaneous fat surrounding the ostomy and a second collection centimeter with rim enhancement and fat stranding. These were drained and cultures grew E. coli and B. fragilis. She responded to IV antibiotics for 3 days followed by oral step-down antibiotics to complete 2 weeks. Eight months following her colectomy, she developed polyarthralgia in her interphalangeal joints, wrists, shoulders, knees and feet with a normal CRP and a negative Rheumatoid Factor while off prednisone, thought to be either inflammatory or mechanical polyarthralgia. Pathology on surveillance sigmoidoscopy March 2019 demonstrated chronic active proctitis with ulceration consistent with chronic idiopathic IBD. Throughout this entire time, her CD4 range was between 400 and 900 cells/mm3, with CD4/CD8 ratio of 0.41:1.12, and HIV viral load remained suppressed since November 2012.
Figure 1 Colonic resection histology. The colonic mucosa shows characteristic features of chronic ulcerative colitis including crypt architecture alteration, cryptitis, crypt abscess and focal mucosa ulceration. There is no evidence of dysplasia.
DISCUSSION
Due to repeated decline of surgery in order to preserve her quality of life and fertility, this woman with HIV and refractory UC received all available conventional therapies including mesalamine, glucocorticoids, thiopurines, antagonists to TNF- α, IL-12/23 blockers and anti-α4 β7 integrin. She also received a small-molecule JAK inhibitor. TNF-α inhibitors and α4β7 integrin blockers are used with extreme caution in PLWH due to concerns of additional immunosuppression and subsequent infection risk. However, during her 6 years of being on immunosuppressants, the patient only experienced one episode of cellulitis, bacterial vaginosis, a skin furuncle and peristomal abscesses, all of which were easily managed with traditional therapies. Another concern with the use of integrin receptor antagonists in PLWH, although rare, is the possibility of Progressive Multifocal Leukoencephalopathy due to John Cunningham (JC) virus [1]. Our patient underwent blood plasma JC virus testing prior to vedolizumab initiation and this polymerase chain reaction testing was negative. She also denied any neurological signs or symptoms throughout treatment.
This woman’s case demonstrates that the spectrum of drug classes available and sequential use of biologics for treatment of UC were safe in this patient with well-controlled HIV infection ART, including an TNF-α blocker, JK inhibitor, IL-12/23 blocker and the α4β7 integrin blocker vedolizumab. Our patient did not incur any significant changes in her CD4 count nor CD4/CD8 ratio during the course of her treatments and infections were relatively minor. Although we did not use combination biologics in this patient, their efficacy and safety for IBD and other and other inflammatory diseases associated was explored in a systematic review of observational studies which did not find any differences related to improvements in disease condition, adverse effects or infection rates in patients receiving combined treatment compared to placebo groups [2]. A clinical trial (NCT02764762) examining efficacy and safety of combined vedolizumab, adalimumab and oral methotrexate in patients with Crohn’s Disease is in progress [3]. Until evidence from clinical trials is available on efficacy and safety of biologics and combination therapy in PLWH, case reports and case series provide a channel for dissemination of these experiences within the medical community.
ACKNOWLEDGMENTS
The authors thank Pathologist, Dr Zu-hua Gao, for provision of the histology image. No funding was received for the preparation of this manuscript.
CONFLICTS OF INTEREST STATEMENT
None declared.
FUNDING
No funding was received for the preparation of this manuscript.
ETHICS APPROVAL
The authors received ethical approval for publication of the case report.
CONSENT TO PUBLISH
The patient provided informed written consent for the preparation of this case report and publication of data and pathological image in an open access journal. The participant understood that the details/images would be freely available on the internet and may be seen by the general public. A copy of the written consent is available for review by the editor of the journal.
GUARANTOR
Dr Costiniuk is the guarantor of the case report. | ADALIMUMAB, CORTISONE, INFLIXIMAB, MERCAPTOPURINE, MESALAMINE, METHYLPREDNISOLONE, PREDNISOLONE, PREDNISONE, RALTEGRAVIR, TOFACITINIB, USTEKINUMAB, VEDOLIZUMAB | DrugsGivenReaction | CC BY-NC | 33542833 | 19,114,036 | 2021-01 |
What was the administration route of drug 'EMTRICITABINE\TENOFOVIR DISOPROXIL'? | Use of various immunotherapies for refractory ulcerative colitis in a person living with HIV: a case report.
Cancer therapies include several immune checkpoint or anticytokine therapies whereas ulcerative colitis treatments consist of anticytokine therapies. The development of tolerance and immunogical effects of these agents in people living with HIV are not well assessed as these persons are often excluded from clinical trials. Herein, we report a case of a Caucasian woman who received multiple sequential immunotherapies for severe ulcerative colitis. Due to steroid-refractory disease, receipt of maximal doses of mesalamine and initial repeated decline of surgical intervention, she went on to receive biologic immune inhibitors like tumor necrosis fator-α blockers infliximab and adalimumab, the α4β7integrin blocker vedolizumab, anti-interleukin 12/23 blocker ustekinumab and Janus Kinase inihibitor tofacitinib without achieving remission. Only minor infectious complications were encountered and no significant changes in CD4 count nor CD4/CD8 ratio occurred. This case provides support for the safety and tolerability of the above immunotherapies in people living with HIV with suppressed viral load on antiretroviral therapy.
INTRODUCTION
In the management of ulcerative colitis (UC), one provides immunosuppressive therapy with the hope of tempering excessive inflammation while preserving immune function. However, if the proper balance between immunosuppression and immune preservation is not achieved, an individual will be tipped into immunodeficiency with increased infection risk. People living with HIV (PLWH) are often excluding from clinical trials involving biologics based on concerns of additive immunosuppression and infection risk. Consequently, little data are available to guide clinicians in managing PLWH who suffer from advanced inflammatory bowel disease (IBD). Herein, we present the case of young woman with HIV infection and extensive UC refractory to many therapies. Following repeated decline of surgical intervention, she was treated with multiple sequential immunomodulators and did not experience any major adverse effects.
CASE REPORT
A 36-year-old, Canadian-born Caucasian woman was diagnosed with HIV in 2008. She began antiretroviral therapy with tenofovir disoproxil 300 mg/emtracitabine 200 mg orally once daily and raltegravir 400 mg orally twice daily in 2012, when her CD4 count rapidly dropped to 86 cells/mm3. Later that year, she began experiencing frequent episodes of bloody diarrhea, with up to 20 stools daily, with cramping, rectal bleeding and elevated C-reactive protein (CRP). Stool was repeatedly negative for Clostridium difficile and ova and parasites. Colonoscopy demonstrated severe pancolitis and biopsies consistent with active UC with acute cryptitis, crypt abcesses with lymphoid hyperplasia, focal erosions, acute inflammatory exudate with architectural disortion. Hematoxylin and eosin stains for cytomegalovirus and histochemical exams for Herpes Simplex Virus I/II were negative. Despite high doses of oral prednisone (40–60 mg daily) and several emergency room visits to receive intravenous (IV) methylprednisolone for flares, she was deemed steroid-refractory.
Later that year, she received maximum doses of oral mesalamine and 6-mercaptopurine, as well as mesalamine suppositories and enemas. She then received infliximab (2012–2013), an antitumor necrois fator-α (anti-TNFα) monoclonal antibody, until antibody formation. Despite maximum doses of adalimumab (2014), her UC remained refractory although no antibodies were detected using a drug-tolerant assay and medication levels were therapeutic (>12 μg/ml, the highest limit of detection). Attempts to taper her steroids resulted in flare-ups and a cushingoid feature. She declined colectomy as she felt this would interfere with her lifestyle, especially since she was getting married, and concerns about her future fertility.
One of the options explored was the use of vedolizumab, a monoclonal antibody against α4β7 integrin, via a clinical trial. However, due to the patient’s HIV infection she was not eligible to participate in any of the recruiting trials at the centre as HIV infection is frequently an exclusion criteria. Colonoscopy in 2015 revealed severe inflammation with ulcerations and friability consistent with Mayo 3 colitis, despite high-dose steroids and adalimumab, an anti-TNFα monoclonal antibody, at a dose of 80 mg weekly. By December 2015, vedolizumab was obtained through standard of care and initiated at 300 mg IV at weeks 0 and 2, 6 (loading dose) and then every 8 weeks thereafter as a maintenance dose. She was still bleeding from the rectum and had decreased weight, therefore daily prednisone 10 mg orally was maintained. She achieved clinical remission by March 2016 and steroids were stopped. Two months later, she developed right foot cellulitis following a minor trauma during a pedicure and required 48 hours of IV followed by oral antibiotics.
Colonoscopy in June 2016, 3 months after stopping steroids, showed worsening condition with Mayo 3 colitis, so she was changed to vedolizumab 300 mg IV q 4 weeks and prednisone increased to 40 mg orally (po) daily. Anti-α4β7 antibodies were not detected. She was passing bright red blood per rectum 12 times in 24 hours and having five stools per 24 hours with lower abdominal cramping and rectal pain. Janus kinase (JAK) inhibitor, tofacitinab 10 mg po twice daily, was initiated October 2016 and prednisone 40 mg po daily maintained. Symptoms persisted requiring admission for IV prednisolone, but she continued to decline surgical colectomy. She also developed a bacterial vaginitis treated with metronidazole cream and later a skin furuncle, treated with oral antibiotics.
Following tofacitinib, she received interleukin 12/23 inhibitor ustekinumab March–September 2017. She gained 30 pounds in 1 year (body mass index 37), increased abdominal fat and bilateral cataracts due to cortisone. Attempts to decrease prednisone below 30 mg daily led to bloody diarrhea (12–17 bowel movements daily). She eventually accepted to undergo subtotal abdominal colectomy (pathology shown in Fig. 1) with rectal stump and temporary end ileostomy by June 2018. She improved and was seen for follow-up a month post-op, at which time she was having increasing right lower quadrant pain and rising CRP. A computed tomography scan demonstrated collections in the subcutaneous fat surrounding the ostomy and a second collection centimeter with rim enhancement and fat stranding. These were drained and cultures grew E. coli and B. fragilis. She responded to IV antibiotics for 3 days followed by oral step-down antibiotics to complete 2 weeks. Eight months following her colectomy, she developed polyarthralgia in her interphalangeal joints, wrists, shoulders, knees and feet with a normal CRP and a negative Rheumatoid Factor while off prednisone, thought to be either inflammatory or mechanical polyarthralgia. Pathology on surveillance sigmoidoscopy March 2019 demonstrated chronic active proctitis with ulceration consistent with chronic idiopathic IBD. Throughout this entire time, her CD4 range was between 400 and 900 cells/mm3, with CD4/CD8 ratio of 0.41:1.12, and HIV viral load remained suppressed since November 2012.
Figure 1 Colonic resection histology. The colonic mucosa shows characteristic features of chronic ulcerative colitis including crypt architecture alteration, cryptitis, crypt abscess and focal mucosa ulceration. There is no evidence of dysplasia.
DISCUSSION
Due to repeated decline of surgery in order to preserve her quality of life and fertility, this woman with HIV and refractory UC received all available conventional therapies including mesalamine, glucocorticoids, thiopurines, antagonists to TNF- α, IL-12/23 blockers and anti-α4 β7 integrin. She also received a small-molecule JAK inhibitor. TNF-α inhibitors and α4β7 integrin blockers are used with extreme caution in PLWH due to concerns of additional immunosuppression and subsequent infection risk. However, during her 6 years of being on immunosuppressants, the patient only experienced one episode of cellulitis, bacterial vaginosis, a skin furuncle and peristomal abscesses, all of which were easily managed with traditional therapies. Another concern with the use of integrin receptor antagonists in PLWH, although rare, is the possibility of Progressive Multifocal Leukoencephalopathy due to John Cunningham (JC) virus [1]. Our patient underwent blood plasma JC virus testing prior to vedolizumab initiation and this polymerase chain reaction testing was negative. She also denied any neurological signs or symptoms throughout treatment.
This woman’s case demonstrates that the spectrum of drug classes available and sequential use of biologics for treatment of UC were safe in this patient with well-controlled HIV infection ART, including an TNF-α blocker, JK inhibitor, IL-12/23 blocker and the α4β7 integrin blocker vedolizumab. Our patient did not incur any significant changes in her CD4 count nor CD4/CD8 ratio during the course of her treatments and infections were relatively minor. Although we did not use combination biologics in this patient, their efficacy and safety for IBD and other and other inflammatory diseases associated was explored in a systematic review of observational studies which did not find any differences related to improvements in disease condition, adverse effects or infection rates in patients receiving combined treatment compared to placebo groups [2]. A clinical trial (NCT02764762) examining efficacy and safety of combined vedolizumab, adalimumab and oral methotrexate in patients with Crohn’s Disease is in progress [3]. Until evidence from clinical trials is available on efficacy and safety of biologics and combination therapy in PLWH, case reports and case series provide a channel for dissemination of these experiences within the medical community.
ACKNOWLEDGMENTS
The authors thank Pathologist, Dr Zu-hua Gao, for provision of the histology image. No funding was received for the preparation of this manuscript.
CONFLICTS OF INTEREST STATEMENT
None declared.
FUNDING
No funding was received for the preparation of this manuscript.
ETHICS APPROVAL
The authors received ethical approval for publication of the case report.
CONSENT TO PUBLISH
The patient provided informed written consent for the preparation of this case report and publication of data and pathological image in an open access journal. The participant understood that the details/images would be freely available on the internet and may be seen by the general public. A copy of the written consent is available for review by the editor of the journal.
GUARANTOR
Dr Costiniuk is the guarantor of the case report. | Oral | DrugAdministrationRoute | CC BY-NC | 33542833 | 19,710,764 | 2021-01 |
What was the administration route of drug 'METHYLPREDNISOLONE'? | Use of various immunotherapies for refractory ulcerative colitis in a person living with HIV: a case report.
Cancer therapies include several immune checkpoint or anticytokine therapies whereas ulcerative colitis treatments consist of anticytokine therapies. The development of tolerance and immunogical effects of these agents in people living with HIV are not well assessed as these persons are often excluded from clinical trials. Herein, we report a case of a Caucasian woman who received multiple sequential immunotherapies for severe ulcerative colitis. Due to steroid-refractory disease, receipt of maximal doses of mesalamine and initial repeated decline of surgical intervention, she went on to receive biologic immune inhibitors like tumor necrosis fator-α blockers infliximab and adalimumab, the α4β7integrin blocker vedolizumab, anti-interleukin 12/23 blocker ustekinumab and Janus Kinase inihibitor tofacitinib without achieving remission. Only minor infectious complications were encountered and no significant changes in CD4 count nor CD4/CD8 ratio occurred. This case provides support for the safety and tolerability of the above immunotherapies in people living with HIV with suppressed viral load on antiretroviral therapy.
INTRODUCTION
In the management of ulcerative colitis (UC), one provides immunosuppressive therapy with the hope of tempering excessive inflammation while preserving immune function. However, if the proper balance between immunosuppression and immune preservation is not achieved, an individual will be tipped into immunodeficiency with increased infection risk. People living with HIV (PLWH) are often excluding from clinical trials involving biologics based on concerns of additive immunosuppression and infection risk. Consequently, little data are available to guide clinicians in managing PLWH who suffer from advanced inflammatory bowel disease (IBD). Herein, we present the case of young woman with HIV infection and extensive UC refractory to many therapies. Following repeated decline of surgical intervention, she was treated with multiple sequential immunomodulators and did not experience any major adverse effects.
CASE REPORT
A 36-year-old, Canadian-born Caucasian woman was diagnosed with HIV in 2008. She began antiretroviral therapy with tenofovir disoproxil 300 mg/emtracitabine 200 mg orally once daily and raltegravir 400 mg orally twice daily in 2012, when her CD4 count rapidly dropped to 86 cells/mm3. Later that year, she began experiencing frequent episodes of bloody diarrhea, with up to 20 stools daily, with cramping, rectal bleeding and elevated C-reactive protein (CRP). Stool was repeatedly negative for Clostridium difficile and ova and parasites. Colonoscopy demonstrated severe pancolitis and biopsies consistent with active UC with acute cryptitis, crypt abcesses with lymphoid hyperplasia, focal erosions, acute inflammatory exudate with architectural disortion. Hematoxylin and eosin stains for cytomegalovirus and histochemical exams for Herpes Simplex Virus I/II were negative. Despite high doses of oral prednisone (40–60 mg daily) and several emergency room visits to receive intravenous (IV) methylprednisolone for flares, she was deemed steroid-refractory.
Later that year, she received maximum doses of oral mesalamine and 6-mercaptopurine, as well as mesalamine suppositories and enemas. She then received infliximab (2012–2013), an antitumor necrois fator-α (anti-TNFα) monoclonal antibody, until antibody formation. Despite maximum doses of adalimumab (2014), her UC remained refractory although no antibodies were detected using a drug-tolerant assay and medication levels were therapeutic (>12 μg/ml, the highest limit of detection). Attempts to taper her steroids resulted in flare-ups and a cushingoid feature. She declined colectomy as she felt this would interfere with her lifestyle, especially since she was getting married, and concerns about her future fertility.
One of the options explored was the use of vedolizumab, a monoclonal antibody against α4β7 integrin, via a clinical trial. However, due to the patient’s HIV infection she was not eligible to participate in any of the recruiting trials at the centre as HIV infection is frequently an exclusion criteria. Colonoscopy in 2015 revealed severe inflammation with ulcerations and friability consistent with Mayo 3 colitis, despite high-dose steroids and adalimumab, an anti-TNFα monoclonal antibody, at a dose of 80 mg weekly. By December 2015, vedolizumab was obtained through standard of care and initiated at 300 mg IV at weeks 0 and 2, 6 (loading dose) and then every 8 weeks thereafter as a maintenance dose. She was still bleeding from the rectum and had decreased weight, therefore daily prednisone 10 mg orally was maintained. She achieved clinical remission by March 2016 and steroids were stopped. Two months later, she developed right foot cellulitis following a minor trauma during a pedicure and required 48 hours of IV followed by oral antibiotics.
Colonoscopy in June 2016, 3 months after stopping steroids, showed worsening condition with Mayo 3 colitis, so she was changed to vedolizumab 300 mg IV q 4 weeks and prednisone increased to 40 mg orally (po) daily. Anti-α4β7 antibodies were not detected. She was passing bright red blood per rectum 12 times in 24 hours and having five stools per 24 hours with lower abdominal cramping and rectal pain. Janus kinase (JAK) inhibitor, tofacitinab 10 mg po twice daily, was initiated October 2016 and prednisone 40 mg po daily maintained. Symptoms persisted requiring admission for IV prednisolone, but she continued to decline surgical colectomy. She also developed a bacterial vaginitis treated with metronidazole cream and later a skin furuncle, treated with oral antibiotics.
Following tofacitinib, she received interleukin 12/23 inhibitor ustekinumab March–September 2017. She gained 30 pounds in 1 year (body mass index 37), increased abdominal fat and bilateral cataracts due to cortisone. Attempts to decrease prednisone below 30 mg daily led to bloody diarrhea (12–17 bowel movements daily). She eventually accepted to undergo subtotal abdominal colectomy (pathology shown in Fig. 1) with rectal stump and temporary end ileostomy by June 2018. She improved and was seen for follow-up a month post-op, at which time she was having increasing right lower quadrant pain and rising CRP. A computed tomography scan demonstrated collections in the subcutaneous fat surrounding the ostomy and a second collection centimeter with rim enhancement and fat stranding. These were drained and cultures grew E. coli and B. fragilis. She responded to IV antibiotics for 3 days followed by oral step-down antibiotics to complete 2 weeks. Eight months following her colectomy, she developed polyarthralgia in her interphalangeal joints, wrists, shoulders, knees and feet with a normal CRP and a negative Rheumatoid Factor while off prednisone, thought to be either inflammatory or mechanical polyarthralgia. Pathology on surveillance sigmoidoscopy March 2019 demonstrated chronic active proctitis with ulceration consistent with chronic idiopathic IBD. Throughout this entire time, her CD4 range was between 400 and 900 cells/mm3, with CD4/CD8 ratio of 0.41:1.12, and HIV viral load remained suppressed since November 2012.
Figure 1 Colonic resection histology. The colonic mucosa shows characteristic features of chronic ulcerative colitis including crypt architecture alteration, cryptitis, crypt abscess and focal mucosa ulceration. There is no evidence of dysplasia.
DISCUSSION
Due to repeated decline of surgery in order to preserve her quality of life and fertility, this woman with HIV and refractory UC received all available conventional therapies including mesalamine, glucocorticoids, thiopurines, antagonists to TNF- α, IL-12/23 blockers and anti-α4 β7 integrin. She also received a small-molecule JAK inhibitor. TNF-α inhibitors and α4β7 integrin blockers are used with extreme caution in PLWH due to concerns of additional immunosuppression and subsequent infection risk. However, during her 6 years of being on immunosuppressants, the patient only experienced one episode of cellulitis, bacterial vaginosis, a skin furuncle and peristomal abscesses, all of which were easily managed with traditional therapies. Another concern with the use of integrin receptor antagonists in PLWH, although rare, is the possibility of Progressive Multifocal Leukoencephalopathy due to John Cunningham (JC) virus [1]. Our patient underwent blood plasma JC virus testing prior to vedolizumab initiation and this polymerase chain reaction testing was negative. She also denied any neurological signs or symptoms throughout treatment.
This woman’s case demonstrates that the spectrum of drug classes available and sequential use of biologics for treatment of UC were safe in this patient with well-controlled HIV infection ART, including an TNF-α blocker, JK inhibitor, IL-12/23 blocker and the α4β7 integrin blocker vedolizumab. Our patient did not incur any significant changes in her CD4 count nor CD4/CD8 ratio during the course of her treatments and infections were relatively minor. Although we did not use combination biologics in this patient, their efficacy and safety for IBD and other and other inflammatory diseases associated was explored in a systematic review of observational studies which did not find any differences related to improvements in disease condition, adverse effects or infection rates in patients receiving combined treatment compared to placebo groups [2]. A clinical trial (NCT02764762) examining efficacy and safety of combined vedolizumab, adalimumab and oral methotrexate in patients with Crohn’s Disease is in progress [3]. Until evidence from clinical trials is available on efficacy and safety of biologics and combination therapy in PLWH, case reports and case series provide a channel for dissemination of these experiences within the medical community.
ACKNOWLEDGMENTS
The authors thank Pathologist, Dr Zu-hua Gao, for provision of the histology image. No funding was received for the preparation of this manuscript.
CONFLICTS OF INTEREST STATEMENT
None declared.
FUNDING
No funding was received for the preparation of this manuscript.
ETHICS APPROVAL
The authors received ethical approval for publication of the case report.
CONSENT TO PUBLISH
The patient provided informed written consent for the preparation of this case report and publication of data and pathological image in an open access journal. The participant understood that the details/images would be freely available on the internet and may be seen by the general public. A copy of the written consent is available for review by the editor of the journal.
GUARANTOR
Dr Costiniuk is the guarantor of the case report. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33542833 | 19,710,764 | 2021-01 |
What was the administration route of drug 'PREDNISOLONE'? | Use of various immunotherapies for refractory ulcerative colitis in a person living with HIV: a case report.
Cancer therapies include several immune checkpoint or anticytokine therapies whereas ulcerative colitis treatments consist of anticytokine therapies. The development of tolerance and immunogical effects of these agents in people living with HIV are not well assessed as these persons are often excluded from clinical trials. Herein, we report a case of a Caucasian woman who received multiple sequential immunotherapies for severe ulcerative colitis. Due to steroid-refractory disease, receipt of maximal doses of mesalamine and initial repeated decline of surgical intervention, she went on to receive biologic immune inhibitors like tumor necrosis fator-α blockers infliximab and adalimumab, the α4β7integrin blocker vedolizumab, anti-interleukin 12/23 blocker ustekinumab and Janus Kinase inihibitor tofacitinib without achieving remission. Only minor infectious complications were encountered and no significant changes in CD4 count nor CD4/CD8 ratio occurred. This case provides support for the safety and tolerability of the above immunotherapies in people living with HIV with suppressed viral load on antiretroviral therapy.
INTRODUCTION
In the management of ulcerative colitis (UC), one provides immunosuppressive therapy with the hope of tempering excessive inflammation while preserving immune function. However, if the proper balance between immunosuppression and immune preservation is not achieved, an individual will be tipped into immunodeficiency with increased infection risk. People living with HIV (PLWH) are often excluding from clinical trials involving biologics based on concerns of additive immunosuppression and infection risk. Consequently, little data are available to guide clinicians in managing PLWH who suffer from advanced inflammatory bowel disease (IBD). Herein, we present the case of young woman with HIV infection and extensive UC refractory to many therapies. Following repeated decline of surgical intervention, she was treated with multiple sequential immunomodulators and did not experience any major adverse effects.
CASE REPORT
A 36-year-old, Canadian-born Caucasian woman was diagnosed with HIV in 2008. She began antiretroviral therapy with tenofovir disoproxil 300 mg/emtracitabine 200 mg orally once daily and raltegravir 400 mg orally twice daily in 2012, when her CD4 count rapidly dropped to 86 cells/mm3. Later that year, she began experiencing frequent episodes of bloody diarrhea, with up to 20 stools daily, with cramping, rectal bleeding and elevated C-reactive protein (CRP). Stool was repeatedly negative for Clostridium difficile and ova and parasites. Colonoscopy demonstrated severe pancolitis and biopsies consistent with active UC with acute cryptitis, crypt abcesses with lymphoid hyperplasia, focal erosions, acute inflammatory exudate with architectural disortion. Hematoxylin and eosin stains for cytomegalovirus and histochemical exams for Herpes Simplex Virus I/II were negative. Despite high doses of oral prednisone (40–60 mg daily) and several emergency room visits to receive intravenous (IV) methylprednisolone for flares, she was deemed steroid-refractory.
Later that year, she received maximum doses of oral mesalamine and 6-mercaptopurine, as well as mesalamine suppositories and enemas. She then received infliximab (2012–2013), an antitumor necrois fator-α (anti-TNFα) monoclonal antibody, until antibody formation. Despite maximum doses of adalimumab (2014), her UC remained refractory although no antibodies were detected using a drug-tolerant assay and medication levels were therapeutic (>12 μg/ml, the highest limit of detection). Attempts to taper her steroids resulted in flare-ups and a cushingoid feature. She declined colectomy as she felt this would interfere with her lifestyle, especially since she was getting married, and concerns about her future fertility.
One of the options explored was the use of vedolizumab, a monoclonal antibody against α4β7 integrin, via a clinical trial. However, due to the patient’s HIV infection she was not eligible to participate in any of the recruiting trials at the centre as HIV infection is frequently an exclusion criteria. Colonoscopy in 2015 revealed severe inflammation with ulcerations and friability consistent with Mayo 3 colitis, despite high-dose steroids and adalimumab, an anti-TNFα monoclonal antibody, at a dose of 80 mg weekly. By December 2015, vedolizumab was obtained through standard of care and initiated at 300 mg IV at weeks 0 and 2, 6 (loading dose) and then every 8 weeks thereafter as a maintenance dose. She was still bleeding from the rectum and had decreased weight, therefore daily prednisone 10 mg orally was maintained. She achieved clinical remission by March 2016 and steroids were stopped. Two months later, she developed right foot cellulitis following a minor trauma during a pedicure and required 48 hours of IV followed by oral antibiotics.
Colonoscopy in June 2016, 3 months after stopping steroids, showed worsening condition with Mayo 3 colitis, so she was changed to vedolizumab 300 mg IV q 4 weeks and prednisone increased to 40 mg orally (po) daily. Anti-α4β7 antibodies were not detected. She was passing bright red blood per rectum 12 times in 24 hours and having five stools per 24 hours with lower abdominal cramping and rectal pain. Janus kinase (JAK) inhibitor, tofacitinab 10 mg po twice daily, was initiated October 2016 and prednisone 40 mg po daily maintained. Symptoms persisted requiring admission for IV prednisolone, but she continued to decline surgical colectomy. She also developed a bacterial vaginitis treated with metronidazole cream and later a skin furuncle, treated with oral antibiotics.
Following tofacitinib, she received interleukin 12/23 inhibitor ustekinumab March–September 2017. She gained 30 pounds in 1 year (body mass index 37), increased abdominal fat and bilateral cataracts due to cortisone. Attempts to decrease prednisone below 30 mg daily led to bloody diarrhea (12–17 bowel movements daily). She eventually accepted to undergo subtotal abdominal colectomy (pathology shown in Fig. 1) with rectal stump and temporary end ileostomy by June 2018. She improved and was seen for follow-up a month post-op, at which time she was having increasing right lower quadrant pain and rising CRP. A computed tomography scan demonstrated collections in the subcutaneous fat surrounding the ostomy and a second collection centimeter with rim enhancement and fat stranding. These were drained and cultures grew E. coli and B. fragilis. She responded to IV antibiotics for 3 days followed by oral step-down antibiotics to complete 2 weeks. Eight months following her colectomy, she developed polyarthralgia in her interphalangeal joints, wrists, shoulders, knees and feet with a normal CRP and a negative Rheumatoid Factor while off prednisone, thought to be either inflammatory or mechanical polyarthralgia. Pathology on surveillance sigmoidoscopy March 2019 demonstrated chronic active proctitis with ulceration consistent with chronic idiopathic IBD. Throughout this entire time, her CD4 range was between 400 and 900 cells/mm3, with CD4/CD8 ratio of 0.41:1.12, and HIV viral load remained suppressed since November 2012.
Figure 1 Colonic resection histology. The colonic mucosa shows characteristic features of chronic ulcerative colitis including crypt architecture alteration, cryptitis, crypt abscess and focal mucosa ulceration. There is no evidence of dysplasia.
DISCUSSION
Due to repeated decline of surgery in order to preserve her quality of life and fertility, this woman with HIV and refractory UC received all available conventional therapies including mesalamine, glucocorticoids, thiopurines, antagonists to TNF- α, IL-12/23 blockers and anti-α4 β7 integrin. She also received a small-molecule JAK inhibitor. TNF-α inhibitors and α4β7 integrin blockers are used with extreme caution in PLWH due to concerns of additional immunosuppression and subsequent infection risk. However, during her 6 years of being on immunosuppressants, the patient only experienced one episode of cellulitis, bacterial vaginosis, a skin furuncle and peristomal abscesses, all of which were easily managed with traditional therapies. Another concern with the use of integrin receptor antagonists in PLWH, although rare, is the possibility of Progressive Multifocal Leukoencephalopathy due to John Cunningham (JC) virus [1]. Our patient underwent blood plasma JC virus testing prior to vedolizumab initiation and this polymerase chain reaction testing was negative. She also denied any neurological signs or symptoms throughout treatment.
This woman’s case demonstrates that the spectrum of drug classes available and sequential use of biologics for treatment of UC were safe in this patient with well-controlled HIV infection ART, including an TNF-α blocker, JK inhibitor, IL-12/23 blocker and the α4β7 integrin blocker vedolizumab. Our patient did not incur any significant changes in her CD4 count nor CD4/CD8 ratio during the course of her treatments and infections were relatively minor. Although we did not use combination biologics in this patient, their efficacy and safety for IBD and other and other inflammatory diseases associated was explored in a systematic review of observational studies which did not find any differences related to improvements in disease condition, adverse effects or infection rates in patients receiving combined treatment compared to placebo groups [2]. A clinical trial (NCT02764762) examining efficacy and safety of combined vedolizumab, adalimumab and oral methotrexate in patients with Crohn’s Disease is in progress [3]. Until evidence from clinical trials is available on efficacy and safety of biologics and combination therapy in PLWH, case reports and case series provide a channel for dissemination of these experiences within the medical community.
ACKNOWLEDGMENTS
The authors thank Pathologist, Dr Zu-hua Gao, for provision of the histology image. No funding was received for the preparation of this manuscript.
CONFLICTS OF INTEREST STATEMENT
None declared.
FUNDING
No funding was received for the preparation of this manuscript.
ETHICS APPROVAL
The authors received ethical approval for publication of the case report.
CONSENT TO PUBLISH
The patient provided informed written consent for the preparation of this case report and publication of data and pathological image in an open access journal. The participant understood that the details/images would be freely available on the internet and may be seen by the general public. A copy of the written consent is available for review by the editor of the journal.
GUARANTOR
Dr Costiniuk is the guarantor of the case report. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33542833 | 19,710,764 | 2021-01 |
What was the administration route of drug 'PREDNISONE'? | Use of various immunotherapies for refractory ulcerative colitis in a person living with HIV: a case report.
Cancer therapies include several immune checkpoint or anticytokine therapies whereas ulcerative colitis treatments consist of anticytokine therapies. The development of tolerance and immunogical effects of these agents in people living with HIV are not well assessed as these persons are often excluded from clinical trials. Herein, we report a case of a Caucasian woman who received multiple sequential immunotherapies for severe ulcerative colitis. Due to steroid-refractory disease, receipt of maximal doses of mesalamine and initial repeated decline of surgical intervention, she went on to receive biologic immune inhibitors like tumor necrosis fator-α blockers infliximab and adalimumab, the α4β7integrin blocker vedolizumab, anti-interleukin 12/23 blocker ustekinumab and Janus Kinase inihibitor tofacitinib without achieving remission. Only minor infectious complications were encountered and no significant changes in CD4 count nor CD4/CD8 ratio occurred. This case provides support for the safety and tolerability of the above immunotherapies in people living with HIV with suppressed viral load on antiretroviral therapy.
INTRODUCTION
In the management of ulcerative colitis (UC), one provides immunosuppressive therapy with the hope of tempering excessive inflammation while preserving immune function. However, if the proper balance between immunosuppression and immune preservation is not achieved, an individual will be tipped into immunodeficiency with increased infection risk. People living with HIV (PLWH) are often excluding from clinical trials involving biologics based on concerns of additive immunosuppression and infection risk. Consequently, little data are available to guide clinicians in managing PLWH who suffer from advanced inflammatory bowel disease (IBD). Herein, we present the case of young woman with HIV infection and extensive UC refractory to many therapies. Following repeated decline of surgical intervention, she was treated with multiple sequential immunomodulators and did not experience any major adverse effects.
CASE REPORT
A 36-year-old, Canadian-born Caucasian woman was diagnosed with HIV in 2008. She began antiretroviral therapy with tenofovir disoproxil 300 mg/emtracitabine 200 mg orally once daily and raltegravir 400 mg orally twice daily in 2012, when her CD4 count rapidly dropped to 86 cells/mm3. Later that year, she began experiencing frequent episodes of bloody diarrhea, with up to 20 stools daily, with cramping, rectal bleeding and elevated C-reactive protein (CRP). Stool was repeatedly negative for Clostridium difficile and ova and parasites. Colonoscopy demonstrated severe pancolitis and biopsies consistent with active UC with acute cryptitis, crypt abcesses with lymphoid hyperplasia, focal erosions, acute inflammatory exudate with architectural disortion. Hematoxylin and eosin stains for cytomegalovirus and histochemical exams for Herpes Simplex Virus I/II were negative. Despite high doses of oral prednisone (40–60 mg daily) and several emergency room visits to receive intravenous (IV) methylprednisolone for flares, she was deemed steroid-refractory.
Later that year, she received maximum doses of oral mesalamine and 6-mercaptopurine, as well as mesalamine suppositories and enemas. She then received infliximab (2012–2013), an antitumor necrois fator-α (anti-TNFα) monoclonal antibody, until antibody formation. Despite maximum doses of adalimumab (2014), her UC remained refractory although no antibodies were detected using a drug-tolerant assay and medication levels were therapeutic (>12 μg/ml, the highest limit of detection). Attempts to taper her steroids resulted in flare-ups and a cushingoid feature. She declined colectomy as she felt this would interfere with her lifestyle, especially since she was getting married, and concerns about her future fertility.
One of the options explored was the use of vedolizumab, a monoclonal antibody against α4β7 integrin, via a clinical trial. However, due to the patient’s HIV infection she was not eligible to participate in any of the recruiting trials at the centre as HIV infection is frequently an exclusion criteria. Colonoscopy in 2015 revealed severe inflammation with ulcerations and friability consistent with Mayo 3 colitis, despite high-dose steroids and adalimumab, an anti-TNFα monoclonal antibody, at a dose of 80 mg weekly. By December 2015, vedolizumab was obtained through standard of care and initiated at 300 mg IV at weeks 0 and 2, 6 (loading dose) and then every 8 weeks thereafter as a maintenance dose. She was still bleeding from the rectum and had decreased weight, therefore daily prednisone 10 mg orally was maintained. She achieved clinical remission by March 2016 and steroids were stopped. Two months later, she developed right foot cellulitis following a minor trauma during a pedicure and required 48 hours of IV followed by oral antibiotics.
Colonoscopy in June 2016, 3 months after stopping steroids, showed worsening condition with Mayo 3 colitis, so she was changed to vedolizumab 300 mg IV q 4 weeks and prednisone increased to 40 mg orally (po) daily. Anti-α4β7 antibodies were not detected. She was passing bright red blood per rectum 12 times in 24 hours and having five stools per 24 hours with lower abdominal cramping and rectal pain. Janus kinase (JAK) inhibitor, tofacitinab 10 mg po twice daily, was initiated October 2016 and prednisone 40 mg po daily maintained. Symptoms persisted requiring admission for IV prednisolone, but she continued to decline surgical colectomy. She also developed a bacterial vaginitis treated with metronidazole cream and later a skin furuncle, treated with oral antibiotics.
Following tofacitinib, she received interleukin 12/23 inhibitor ustekinumab March–September 2017. She gained 30 pounds in 1 year (body mass index 37), increased abdominal fat and bilateral cataracts due to cortisone. Attempts to decrease prednisone below 30 mg daily led to bloody diarrhea (12–17 bowel movements daily). She eventually accepted to undergo subtotal abdominal colectomy (pathology shown in Fig. 1) with rectal stump and temporary end ileostomy by June 2018. She improved and was seen for follow-up a month post-op, at which time she was having increasing right lower quadrant pain and rising CRP. A computed tomography scan demonstrated collections in the subcutaneous fat surrounding the ostomy and a second collection centimeter with rim enhancement and fat stranding. These were drained and cultures grew E. coli and B. fragilis. She responded to IV antibiotics for 3 days followed by oral step-down antibiotics to complete 2 weeks. Eight months following her colectomy, she developed polyarthralgia in her interphalangeal joints, wrists, shoulders, knees and feet with a normal CRP and a negative Rheumatoid Factor while off prednisone, thought to be either inflammatory or mechanical polyarthralgia. Pathology on surveillance sigmoidoscopy March 2019 demonstrated chronic active proctitis with ulceration consistent with chronic idiopathic IBD. Throughout this entire time, her CD4 range was between 400 and 900 cells/mm3, with CD4/CD8 ratio of 0.41:1.12, and HIV viral load remained suppressed since November 2012.
Figure 1 Colonic resection histology. The colonic mucosa shows characteristic features of chronic ulcerative colitis including crypt architecture alteration, cryptitis, crypt abscess and focal mucosa ulceration. There is no evidence of dysplasia.
DISCUSSION
Due to repeated decline of surgery in order to preserve her quality of life and fertility, this woman with HIV and refractory UC received all available conventional therapies including mesalamine, glucocorticoids, thiopurines, antagonists to TNF- α, IL-12/23 blockers and anti-α4 β7 integrin. She also received a small-molecule JAK inhibitor. TNF-α inhibitors and α4β7 integrin blockers are used with extreme caution in PLWH due to concerns of additional immunosuppression and subsequent infection risk. However, during her 6 years of being on immunosuppressants, the patient only experienced one episode of cellulitis, bacterial vaginosis, a skin furuncle and peristomal abscesses, all of which were easily managed with traditional therapies. Another concern with the use of integrin receptor antagonists in PLWH, although rare, is the possibility of Progressive Multifocal Leukoencephalopathy due to John Cunningham (JC) virus [1]. Our patient underwent blood plasma JC virus testing prior to vedolizumab initiation and this polymerase chain reaction testing was negative. She also denied any neurological signs or symptoms throughout treatment.
This woman’s case demonstrates that the spectrum of drug classes available and sequential use of biologics for treatment of UC were safe in this patient with well-controlled HIV infection ART, including an TNF-α blocker, JK inhibitor, IL-12/23 blocker and the α4β7 integrin blocker vedolizumab. Our patient did not incur any significant changes in her CD4 count nor CD4/CD8 ratio during the course of her treatments and infections were relatively minor. Although we did not use combination biologics in this patient, their efficacy and safety for IBD and other and other inflammatory diseases associated was explored in a systematic review of observational studies which did not find any differences related to improvements in disease condition, adverse effects or infection rates in patients receiving combined treatment compared to placebo groups [2]. A clinical trial (NCT02764762) examining efficacy and safety of combined vedolizumab, adalimumab and oral methotrexate in patients with Crohn’s Disease is in progress [3]. Until evidence from clinical trials is available on efficacy and safety of biologics and combination therapy in PLWH, case reports and case series provide a channel for dissemination of these experiences within the medical community.
ACKNOWLEDGMENTS
The authors thank Pathologist, Dr Zu-hua Gao, for provision of the histology image. No funding was received for the preparation of this manuscript.
CONFLICTS OF INTEREST STATEMENT
None declared.
FUNDING
No funding was received for the preparation of this manuscript.
ETHICS APPROVAL
The authors received ethical approval for publication of the case report.
CONSENT TO PUBLISH
The patient provided informed written consent for the preparation of this case report and publication of data and pathological image in an open access journal. The participant understood that the details/images would be freely available on the internet and may be seen by the general public. A copy of the written consent is available for review by the editor of the journal.
GUARANTOR
Dr Costiniuk is the guarantor of the case report. | Oral | DrugAdministrationRoute | CC BY-NC | 33542833 | 19,710,764 | 2021-01 |
What was the administration route of drug 'RALTEGRAVIR'? | Use of various immunotherapies for refractory ulcerative colitis in a person living with HIV: a case report.
Cancer therapies include several immune checkpoint or anticytokine therapies whereas ulcerative colitis treatments consist of anticytokine therapies. The development of tolerance and immunogical effects of these agents in people living with HIV are not well assessed as these persons are often excluded from clinical trials. Herein, we report a case of a Caucasian woman who received multiple sequential immunotherapies for severe ulcerative colitis. Due to steroid-refractory disease, receipt of maximal doses of mesalamine and initial repeated decline of surgical intervention, she went on to receive biologic immune inhibitors like tumor necrosis fator-α blockers infliximab and adalimumab, the α4β7integrin blocker vedolizumab, anti-interleukin 12/23 blocker ustekinumab and Janus Kinase inihibitor tofacitinib without achieving remission. Only minor infectious complications were encountered and no significant changes in CD4 count nor CD4/CD8 ratio occurred. This case provides support for the safety and tolerability of the above immunotherapies in people living with HIV with suppressed viral load on antiretroviral therapy.
INTRODUCTION
In the management of ulcerative colitis (UC), one provides immunosuppressive therapy with the hope of tempering excessive inflammation while preserving immune function. However, if the proper balance between immunosuppression and immune preservation is not achieved, an individual will be tipped into immunodeficiency with increased infection risk. People living with HIV (PLWH) are often excluding from clinical trials involving biologics based on concerns of additive immunosuppression and infection risk. Consequently, little data are available to guide clinicians in managing PLWH who suffer from advanced inflammatory bowel disease (IBD). Herein, we present the case of young woman with HIV infection and extensive UC refractory to many therapies. Following repeated decline of surgical intervention, she was treated with multiple sequential immunomodulators and did not experience any major adverse effects.
CASE REPORT
A 36-year-old, Canadian-born Caucasian woman was diagnosed with HIV in 2008. She began antiretroviral therapy with tenofovir disoproxil 300 mg/emtracitabine 200 mg orally once daily and raltegravir 400 mg orally twice daily in 2012, when her CD4 count rapidly dropped to 86 cells/mm3. Later that year, she began experiencing frequent episodes of bloody diarrhea, with up to 20 stools daily, with cramping, rectal bleeding and elevated C-reactive protein (CRP). Stool was repeatedly negative for Clostridium difficile and ova and parasites. Colonoscopy demonstrated severe pancolitis and biopsies consistent with active UC with acute cryptitis, crypt abcesses with lymphoid hyperplasia, focal erosions, acute inflammatory exudate with architectural disortion. Hematoxylin and eosin stains for cytomegalovirus and histochemical exams for Herpes Simplex Virus I/II were negative. Despite high doses of oral prednisone (40–60 mg daily) and several emergency room visits to receive intravenous (IV) methylprednisolone for flares, she was deemed steroid-refractory.
Later that year, she received maximum doses of oral mesalamine and 6-mercaptopurine, as well as mesalamine suppositories and enemas. She then received infliximab (2012–2013), an antitumor necrois fator-α (anti-TNFα) monoclonal antibody, until antibody formation. Despite maximum doses of adalimumab (2014), her UC remained refractory although no antibodies were detected using a drug-tolerant assay and medication levels were therapeutic (>12 μg/ml, the highest limit of detection). Attempts to taper her steroids resulted in flare-ups and a cushingoid feature. She declined colectomy as she felt this would interfere with her lifestyle, especially since she was getting married, and concerns about her future fertility.
One of the options explored was the use of vedolizumab, a monoclonal antibody against α4β7 integrin, via a clinical trial. However, due to the patient’s HIV infection she was not eligible to participate in any of the recruiting trials at the centre as HIV infection is frequently an exclusion criteria. Colonoscopy in 2015 revealed severe inflammation with ulcerations and friability consistent with Mayo 3 colitis, despite high-dose steroids and adalimumab, an anti-TNFα monoclonal antibody, at a dose of 80 mg weekly. By December 2015, vedolizumab was obtained through standard of care and initiated at 300 mg IV at weeks 0 and 2, 6 (loading dose) and then every 8 weeks thereafter as a maintenance dose. She was still bleeding from the rectum and had decreased weight, therefore daily prednisone 10 mg orally was maintained. She achieved clinical remission by March 2016 and steroids were stopped. Two months later, she developed right foot cellulitis following a minor trauma during a pedicure and required 48 hours of IV followed by oral antibiotics.
Colonoscopy in June 2016, 3 months after stopping steroids, showed worsening condition with Mayo 3 colitis, so she was changed to vedolizumab 300 mg IV q 4 weeks and prednisone increased to 40 mg orally (po) daily. Anti-α4β7 antibodies were not detected. She was passing bright red blood per rectum 12 times in 24 hours and having five stools per 24 hours with lower abdominal cramping and rectal pain. Janus kinase (JAK) inhibitor, tofacitinab 10 mg po twice daily, was initiated October 2016 and prednisone 40 mg po daily maintained. Symptoms persisted requiring admission for IV prednisolone, but she continued to decline surgical colectomy. She also developed a bacterial vaginitis treated with metronidazole cream and later a skin furuncle, treated with oral antibiotics.
Following tofacitinib, she received interleukin 12/23 inhibitor ustekinumab March–September 2017. She gained 30 pounds in 1 year (body mass index 37), increased abdominal fat and bilateral cataracts due to cortisone. Attempts to decrease prednisone below 30 mg daily led to bloody diarrhea (12–17 bowel movements daily). She eventually accepted to undergo subtotal abdominal colectomy (pathology shown in Fig. 1) with rectal stump and temporary end ileostomy by June 2018. She improved and was seen for follow-up a month post-op, at which time she was having increasing right lower quadrant pain and rising CRP. A computed tomography scan demonstrated collections in the subcutaneous fat surrounding the ostomy and a second collection centimeter with rim enhancement and fat stranding. These were drained and cultures grew E. coli and B. fragilis. She responded to IV antibiotics for 3 days followed by oral step-down antibiotics to complete 2 weeks. Eight months following her colectomy, she developed polyarthralgia in her interphalangeal joints, wrists, shoulders, knees and feet with a normal CRP and a negative Rheumatoid Factor while off prednisone, thought to be either inflammatory or mechanical polyarthralgia. Pathology on surveillance sigmoidoscopy March 2019 demonstrated chronic active proctitis with ulceration consistent with chronic idiopathic IBD. Throughout this entire time, her CD4 range was between 400 and 900 cells/mm3, with CD4/CD8 ratio of 0.41:1.12, and HIV viral load remained suppressed since November 2012.
Figure 1 Colonic resection histology. The colonic mucosa shows characteristic features of chronic ulcerative colitis including crypt architecture alteration, cryptitis, crypt abscess and focal mucosa ulceration. There is no evidence of dysplasia.
DISCUSSION
Due to repeated decline of surgery in order to preserve her quality of life and fertility, this woman with HIV and refractory UC received all available conventional therapies including mesalamine, glucocorticoids, thiopurines, antagonists to TNF- α, IL-12/23 blockers and anti-α4 β7 integrin. She also received a small-molecule JAK inhibitor. TNF-α inhibitors and α4β7 integrin blockers are used with extreme caution in PLWH due to concerns of additional immunosuppression and subsequent infection risk. However, during her 6 years of being on immunosuppressants, the patient only experienced one episode of cellulitis, bacterial vaginosis, a skin furuncle and peristomal abscesses, all of which were easily managed with traditional therapies. Another concern with the use of integrin receptor antagonists in PLWH, although rare, is the possibility of Progressive Multifocal Leukoencephalopathy due to John Cunningham (JC) virus [1]. Our patient underwent blood plasma JC virus testing prior to vedolizumab initiation and this polymerase chain reaction testing was negative. She also denied any neurological signs or symptoms throughout treatment.
This woman’s case demonstrates that the spectrum of drug classes available and sequential use of biologics for treatment of UC were safe in this patient with well-controlled HIV infection ART, including an TNF-α blocker, JK inhibitor, IL-12/23 blocker and the α4β7 integrin blocker vedolizumab. Our patient did not incur any significant changes in her CD4 count nor CD4/CD8 ratio during the course of her treatments and infections were relatively minor. Although we did not use combination biologics in this patient, their efficacy and safety for IBD and other and other inflammatory diseases associated was explored in a systematic review of observational studies which did not find any differences related to improvements in disease condition, adverse effects or infection rates in patients receiving combined treatment compared to placebo groups [2]. A clinical trial (NCT02764762) examining efficacy and safety of combined vedolizumab, adalimumab and oral methotrexate in patients with Crohn’s Disease is in progress [3]. Until evidence from clinical trials is available on efficacy and safety of biologics and combination therapy in PLWH, case reports and case series provide a channel for dissemination of these experiences within the medical community.
ACKNOWLEDGMENTS
The authors thank Pathologist, Dr Zu-hua Gao, for provision of the histology image. No funding was received for the preparation of this manuscript.
CONFLICTS OF INTEREST STATEMENT
None declared.
FUNDING
No funding was received for the preparation of this manuscript.
ETHICS APPROVAL
The authors received ethical approval for publication of the case report.
CONSENT TO PUBLISH
The patient provided informed written consent for the preparation of this case report and publication of data and pathological image in an open access journal. The participant understood that the details/images would be freely available on the internet and may be seen by the general public. A copy of the written consent is available for review by the editor of the journal.
GUARANTOR
Dr Costiniuk is the guarantor of the case report. | Oral | DrugAdministrationRoute | CC BY-NC | 33542833 | 19,710,764 | 2021-01 |
What was the administration route of drug 'TOFACITINIB'? | Use of various immunotherapies for refractory ulcerative colitis in a person living with HIV: a case report.
Cancer therapies include several immune checkpoint or anticytokine therapies whereas ulcerative colitis treatments consist of anticytokine therapies. The development of tolerance and immunogical effects of these agents in people living with HIV are not well assessed as these persons are often excluded from clinical trials. Herein, we report a case of a Caucasian woman who received multiple sequential immunotherapies for severe ulcerative colitis. Due to steroid-refractory disease, receipt of maximal doses of mesalamine and initial repeated decline of surgical intervention, she went on to receive biologic immune inhibitors like tumor necrosis fator-α blockers infliximab and adalimumab, the α4β7integrin blocker vedolizumab, anti-interleukin 12/23 blocker ustekinumab and Janus Kinase inihibitor tofacitinib without achieving remission. Only minor infectious complications were encountered and no significant changes in CD4 count nor CD4/CD8 ratio occurred. This case provides support for the safety and tolerability of the above immunotherapies in people living with HIV with suppressed viral load on antiretroviral therapy.
INTRODUCTION
In the management of ulcerative colitis (UC), one provides immunosuppressive therapy with the hope of tempering excessive inflammation while preserving immune function. However, if the proper balance between immunosuppression and immune preservation is not achieved, an individual will be tipped into immunodeficiency with increased infection risk. People living with HIV (PLWH) are often excluding from clinical trials involving biologics based on concerns of additive immunosuppression and infection risk. Consequently, little data are available to guide clinicians in managing PLWH who suffer from advanced inflammatory bowel disease (IBD). Herein, we present the case of young woman with HIV infection and extensive UC refractory to many therapies. Following repeated decline of surgical intervention, she was treated with multiple sequential immunomodulators and did not experience any major adverse effects.
CASE REPORT
A 36-year-old, Canadian-born Caucasian woman was diagnosed with HIV in 2008. She began antiretroviral therapy with tenofovir disoproxil 300 mg/emtracitabine 200 mg orally once daily and raltegravir 400 mg orally twice daily in 2012, when her CD4 count rapidly dropped to 86 cells/mm3. Later that year, she began experiencing frequent episodes of bloody diarrhea, with up to 20 stools daily, with cramping, rectal bleeding and elevated C-reactive protein (CRP). Stool was repeatedly negative for Clostridium difficile and ova and parasites. Colonoscopy demonstrated severe pancolitis and biopsies consistent with active UC with acute cryptitis, crypt abcesses with lymphoid hyperplasia, focal erosions, acute inflammatory exudate with architectural disortion. Hematoxylin and eosin stains for cytomegalovirus and histochemical exams for Herpes Simplex Virus I/II were negative. Despite high doses of oral prednisone (40–60 mg daily) and several emergency room visits to receive intravenous (IV) methylprednisolone for flares, she was deemed steroid-refractory.
Later that year, she received maximum doses of oral mesalamine and 6-mercaptopurine, as well as mesalamine suppositories and enemas. She then received infliximab (2012–2013), an antitumor necrois fator-α (anti-TNFα) monoclonal antibody, until antibody formation. Despite maximum doses of adalimumab (2014), her UC remained refractory although no antibodies were detected using a drug-tolerant assay and medication levels were therapeutic (>12 μg/ml, the highest limit of detection). Attempts to taper her steroids resulted in flare-ups and a cushingoid feature. She declined colectomy as she felt this would interfere with her lifestyle, especially since she was getting married, and concerns about her future fertility.
One of the options explored was the use of vedolizumab, a monoclonal antibody against α4β7 integrin, via a clinical trial. However, due to the patient’s HIV infection she was not eligible to participate in any of the recruiting trials at the centre as HIV infection is frequently an exclusion criteria. Colonoscopy in 2015 revealed severe inflammation with ulcerations and friability consistent with Mayo 3 colitis, despite high-dose steroids and adalimumab, an anti-TNFα monoclonal antibody, at a dose of 80 mg weekly. By December 2015, vedolizumab was obtained through standard of care and initiated at 300 mg IV at weeks 0 and 2, 6 (loading dose) and then every 8 weeks thereafter as a maintenance dose. She was still bleeding from the rectum and had decreased weight, therefore daily prednisone 10 mg orally was maintained. She achieved clinical remission by March 2016 and steroids were stopped. Two months later, she developed right foot cellulitis following a minor trauma during a pedicure and required 48 hours of IV followed by oral antibiotics.
Colonoscopy in June 2016, 3 months after stopping steroids, showed worsening condition with Mayo 3 colitis, so she was changed to vedolizumab 300 mg IV q 4 weeks and prednisone increased to 40 mg orally (po) daily. Anti-α4β7 antibodies were not detected. She was passing bright red blood per rectum 12 times in 24 hours and having five stools per 24 hours with lower abdominal cramping and rectal pain. Janus kinase (JAK) inhibitor, tofacitinab 10 mg po twice daily, was initiated October 2016 and prednisone 40 mg po daily maintained. Symptoms persisted requiring admission for IV prednisolone, but she continued to decline surgical colectomy. She also developed a bacterial vaginitis treated with metronidazole cream and later a skin furuncle, treated with oral antibiotics.
Following tofacitinib, she received interleukin 12/23 inhibitor ustekinumab March–September 2017. She gained 30 pounds in 1 year (body mass index 37), increased abdominal fat and bilateral cataracts due to cortisone. Attempts to decrease prednisone below 30 mg daily led to bloody diarrhea (12–17 bowel movements daily). She eventually accepted to undergo subtotal abdominal colectomy (pathology shown in Fig. 1) with rectal stump and temporary end ileostomy by June 2018. She improved and was seen for follow-up a month post-op, at which time she was having increasing right lower quadrant pain and rising CRP. A computed tomography scan demonstrated collections in the subcutaneous fat surrounding the ostomy and a second collection centimeter with rim enhancement and fat stranding. These were drained and cultures grew E. coli and B. fragilis. She responded to IV antibiotics for 3 days followed by oral step-down antibiotics to complete 2 weeks. Eight months following her colectomy, she developed polyarthralgia in her interphalangeal joints, wrists, shoulders, knees and feet with a normal CRP and a negative Rheumatoid Factor while off prednisone, thought to be either inflammatory or mechanical polyarthralgia. Pathology on surveillance sigmoidoscopy March 2019 demonstrated chronic active proctitis with ulceration consistent with chronic idiopathic IBD. Throughout this entire time, her CD4 range was between 400 and 900 cells/mm3, with CD4/CD8 ratio of 0.41:1.12, and HIV viral load remained suppressed since November 2012.
Figure 1 Colonic resection histology. The colonic mucosa shows characteristic features of chronic ulcerative colitis including crypt architecture alteration, cryptitis, crypt abscess and focal mucosa ulceration. There is no evidence of dysplasia.
DISCUSSION
Due to repeated decline of surgery in order to preserve her quality of life and fertility, this woman with HIV and refractory UC received all available conventional therapies including mesalamine, glucocorticoids, thiopurines, antagonists to TNF- α, IL-12/23 blockers and anti-α4 β7 integrin. She also received a small-molecule JAK inhibitor. TNF-α inhibitors and α4β7 integrin blockers are used with extreme caution in PLWH due to concerns of additional immunosuppression and subsequent infection risk. However, during her 6 years of being on immunosuppressants, the patient only experienced one episode of cellulitis, bacterial vaginosis, a skin furuncle and peristomal abscesses, all of which were easily managed with traditional therapies. Another concern with the use of integrin receptor antagonists in PLWH, although rare, is the possibility of Progressive Multifocal Leukoencephalopathy due to John Cunningham (JC) virus [1]. Our patient underwent blood plasma JC virus testing prior to vedolizumab initiation and this polymerase chain reaction testing was negative. She also denied any neurological signs or symptoms throughout treatment.
This woman’s case demonstrates that the spectrum of drug classes available and sequential use of biologics for treatment of UC were safe in this patient with well-controlled HIV infection ART, including an TNF-α blocker, JK inhibitor, IL-12/23 blocker and the α4β7 integrin blocker vedolizumab. Our patient did not incur any significant changes in her CD4 count nor CD4/CD8 ratio during the course of her treatments and infections were relatively minor. Although we did not use combination biologics in this patient, their efficacy and safety for IBD and other and other inflammatory diseases associated was explored in a systematic review of observational studies which did not find any differences related to improvements in disease condition, adverse effects or infection rates in patients receiving combined treatment compared to placebo groups [2]. A clinical trial (NCT02764762) examining efficacy and safety of combined vedolizumab, adalimumab and oral methotrexate in patients with Crohn’s Disease is in progress [3]. Until evidence from clinical trials is available on efficacy and safety of biologics and combination therapy in PLWH, case reports and case series provide a channel for dissemination of these experiences within the medical community.
ACKNOWLEDGMENTS
The authors thank Pathologist, Dr Zu-hua Gao, for provision of the histology image. No funding was received for the preparation of this manuscript.
CONFLICTS OF INTEREST STATEMENT
None declared.
FUNDING
No funding was received for the preparation of this manuscript.
ETHICS APPROVAL
The authors received ethical approval for publication of the case report.
CONSENT TO PUBLISH
The patient provided informed written consent for the preparation of this case report and publication of data and pathological image in an open access journal. The participant understood that the details/images would be freely available on the internet and may be seen by the general public. A copy of the written consent is available for review by the editor of the journal.
GUARANTOR
Dr Costiniuk is the guarantor of the case report. | Oral | DrugAdministrationRoute | CC BY-NC | 33542833 | 19,710,764 | 2021-01 |
What was the administration route of drug 'VEDOLIZUMAB'? | Use of various immunotherapies for refractory ulcerative colitis in a person living with HIV: a case report.
Cancer therapies include several immune checkpoint or anticytokine therapies whereas ulcerative colitis treatments consist of anticytokine therapies. The development of tolerance and immunogical effects of these agents in people living with HIV are not well assessed as these persons are often excluded from clinical trials. Herein, we report a case of a Caucasian woman who received multiple sequential immunotherapies for severe ulcerative colitis. Due to steroid-refractory disease, receipt of maximal doses of mesalamine and initial repeated decline of surgical intervention, she went on to receive biologic immune inhibitors like tumor necrosis fator-α blockers infliximab and adalimumab, the α4β7integrin blocker vedolizumab, anti-interleukin 12/23 blocker ustekinumab and Janus Kinase inihibitor tofacitinib without achieving remission. Only minor infectious complications were encountered and no significant changes in CD4 count nor CD4/CD8 ratio occurred. This case provides support for the safety and tolerability of the above immunotherapies in people living with HIV with suppressed viral load on antiretroviral therapy.
INTRODUCTION
In the management of ulcerative colitis (UC), one provides immunosuppressive therapy with the hope of tempering excessive inflammation while preserving immune function. However, if the proper balance between immunosuppression and immune preservation is not achieved, an individual will be tipped into immunodeficiency with increased infection risk. People living with HIV (PLWH) are often excluding from clinical trials involving biologics based on concerns of additive immunosuppression and infection risk. Consequently, little data are available to guide clinicians in managing PLWH who suffer from advanced inflammatory bowel disease (IBD). Herein, we present the case of young woman with HIV infection and extensive UC refractory to many therapies. Following repeated decline of surgical intervention, she was treated with multiple sequential immunomodulators and did not experience any major adverse effects.
CASE REPORT
A 36-year-old, Canadian-born Caucasian woman was diagnosed with HIV in 2008. She began antiretroviral therapy with tenofovir disoproxil 300 mg/emtracitabine 200 mg orally once daily and raltegravir 400 mg orally twice daily in 2012, when her CD4 count rapidly dropped to 86 cells/mm3. Later that year, she began experiencing frequent episodes of bloody diarrhea, with up to 20 stools daily, with cramping, rectal bleeding and elevated C-reactive protein (CRP). Stool was repeatedly negative for Clostridium difficile and ova and parasites. Colonoscopy demonstrated severe pancolitis and biopsies consistent with active UC with acute cryptitis, crypt abcesses with lymphoid hyperplasia, focal erosions, acute inflammatory exudate with architectural disortion. Hematoxylin and eosin stains for cytomegalovirus and histochemical exams for Herpes Simplex Virus I/II were negative. Despite high doses of oral prednisone (40–60 mg daily) and several emergency room visits to receive intravenous (IV) methylprednisolone for flares, she was deemed steroid-refractory.
Later that year, she received maximum doses of oral mesalamine and 6-mercaptopurine, as well as mesalamine suppositories and enemas. She then received infliximab (2012–2013), an antitumor necrois fator-α (anti-TNFα) monoclonal antibody, until antibody formation. Despite maximum doses of adalimumab (2014), her UC remained refractory although no antibodies were detected using a drug-tolerant assay and medication levels were therapeutic (>12 μg/ml, the highest limit of detection). Attempts to taper her steroids resulted in flare-ups and a cushingoid feature. She declined colectomy as she felt this would interfere with her lifestyle, especially since she was getting married, and concerns about her future fertility.
One of the options explored was the use of vedolizumab, a monoclonal antibody against α4β7 integrin, via a clinical trial. However, due to the patient’s HIV infection she was not eligible to participate in any of the recruiting trials at the centre as HIV infection is frequently an exclusion criteria. Colonoscopy in 2015 revealed severe inflammation with ulcerations and friability consistent with Mayo 3 colitis, despite high-dose steroids and adalimumab, an anti-TNFα monoclonal antibody, at a dose of 80 mg weekly. By December 2015, vedolizumab was obtained through standard of care and initiated at 300 mg IV at weeks 0 and 2, 6 (loading dose) and then every 8 weeks thereafter as a maintenance dose. She was still bleeding from the rectum and had decreased weight, therefore daily prednisone 10 mg orally was maintained. She achieved clinical remission by March 2016 and steroids were stopped. Two months later, she developed right foot cellulitis following a minor trauma during a pedicure and required 48 hours of IV followed by oral antibiotics.
Colonoscopy in June 2016, 3 months after stopping steroids, showed worsening condition with Mayo 3 colitis, so she was changed to vedolizumab 300 mg IV q 4 weeks and prednisone increased to 40 mg orally (po) daily. Anti-α4β7 antibodies were not detected. She was passing bright red blood per rectum 12 times in 24 hours and having five stools per 24 hours with lower abdominal cramping and rectal pain. Janus kinase (JAK) inhibitor, tofacitinab 10 mg po twice daily, was initiated October 2016 and prednisone 40 mg po daily maintained. Symptoms persisted requiring admission for IV prednisolone, but she continued to decline surgical colectomy. She also developed a bacterial vaginitis treated with metronidazole cream and later a skin furuncle, treated with oral antibiotics.
Following tofacitinib, she received interleukin 12/23 inhibitor ustekinumab March–September 2017. She gained 30 pounds in 1 year (body mass index 37), increased abdominal fat and bilateral cataracts due to cortisone. Attempts to decrease prednisone below 30 mg daily led to bloody diarrhea (12–17 bowel movements daily). She eventually accepted to undergo subtotal abdominal colectomy (pathology shown in Fig. 1) with rectal stump and temporary end ileostomy by June 2018. She improved and was seen for follow-up a month post-op, at which time she was having increasing right lower quadrant pain and rising CRP. A computed tomography scan demonstrated collections in the subcutaneous fat surrounding the ostomy and a second collection centimeter with rim enhancement and fat stranding. These were drained and cultures grew E. coli and B. fragilis. She responded to IV antibiotics for 3 days followed by oral step-down antibiotics to complete 2 weeks. Eight months following her colectomy, she developed polyarthralgia in her interphalangeal joints, wrists, shoulders, knees and feet with a normal CRP and a negative Rheumatoid Factor while off prednisone, thought to be either inflammatory or mechanical polyarthralgia. Pathology on surveillance sigmoidoscopy March 2019 demonstrated chronic active proctitis with ulceration consistent with chronic idiopathic IBD. Throughout this entire time, her CD4 range was between 400 and 900 cells/mm3, with CD4/CD8 ratio of 0.41:1.12, and HIV viral load remained suppressed since November 2012.
Figure 1 Colonic resection histology. The colonic mucosa shows characteristic features of chronic ulcerative colitis including crypt architecture alteration, cryptitis, crypt abscess and focal mucosa ulceration. There is no evidence of dysplasia.
DISCUSSION
Due to repeated decline of surgery in order to preserve her quality of life and fertility, this woman with HIV and refractory UC received all available conventional therapies including mesalamine, glucocorticoids, thiopurines, antagonists to TNF- α, IL-12/23 blockers and anti-α4 β7 integrin. She also received a small-molecule JAK inhibitor. TNF-α inhibitors and α4β7 integrin blockers are used with extreme caution in PLWH due to concerns of additional immunosuppression and subsequent infection risk. However, during her 6 years of being on immunosuppressants, the patient only experienced one episode of cellulitis, bacterial vaginosis, a skin furuncle and peristomal abscesses, all of which were easily managed with traditional therapies. Another concern with the use of integrin receptor antagonists in PLWH, although rare, is the possibility of Progressive Multifocal Leukoencephalopathy due to John Cunningham (JC) virus [1]. Our patient underwent blood plasma JC virus testing prior to vedolizumab initiation and this polymerase chain reaction testing was negative. She also denied any neurological signs or symptoms throughout treatment.
This woman’s case demonstrates that the spectrum of drug classes available and sequential use of biologics for treatment of UC were safe in this patient with well-controlled HIV infection ART, including an TNF-α blocker, JK inhibitor, IL-12/23 blocker and the α4β7 integrin blocker vedolizumab. Our patient did not incur any significant changes in her CD4 count nor CD4/CD8 ratio during the course of her treatments and infections were relatively minor. Although we did not use combination biologics in this patient, their efficacy and safety for IBD and other and other inflammatory diseases associated was explored in a systematic review of observational studies which did not find any differences related to improvements in disease condition, adverse effects or infection rates in patients receiving combined treatment compared to placebo groups [2]. A clinical trial (NCT02764762) examining efficacy and safety of combined vedolizumab, adalimumab and oral methotrexate in patients with Crohn’s Disease is in progress [3]. Until evidence from clinical trials is available on efficacy and safety of biologics and combination therapy in PLWH, case reports and case series provide a channel for dissemination of these experiences within the medical community.
ACKNOWLEDGMENTS
The authors thank Pathologist, Dr Zu-hua Gao, for provision of the histology image. No funding was received for the preparation of this manuscript.
CONFLICTS OF INTEREST STATEMENT
None declared.
FUNDING
No funding was received for the preparation of this manuscript.
ETHICS APPROVAL
The authors received ethical approval for publication of the case report.
CONSENT TO PUBLISH
The patient provided informed written consent for the preparation of this case report and publication of data and pathological image in an open access journal. The participant understood that the details/images would be freely available on the internet and may be seen by the general public. A copy of the written consent is available for review by the editor of the journal.
GUARANTOR
Dr Costiniuk is the guarantor of the case report. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33542833 | 19,710,764 | 2021-01 |
What was the dosage of drug 'EMTRICITABINE\TENOFOVIR DISOPROXIL'? | Use of various immunotherapies for refractory ulcerative colitis in a person living with HIV: a case report.
Cancer therapies include several immune checkpoint or anticytokine therapies whereas ulcerative colitis treatments consist of anticytokine therapies. The development of tolerance and immunogical effects of these agents in people living with HIV are not well assessed as these persons are often excluded from clinical trials. Herein, we report a case of a Caucasian woman who received multiple sequential immunotherapies for severe ulcerative colitis. Due to steroid-refractory disease, receipt of maximal doses of mesalamine and initial repeated decline of surgical intervention, she went on to receive biologic immune inhibitors like tumor necrosis fator-α blockers infliximab and adalimumab, the α4β7integrin blocker vedolizumab, anti-interleukin 12/23 blocker ustekinumab and Janus Kinase inihibitor tofacitinib without achieving remission. Only minor infectious complications were encountered and no significant changes in CD4 count nor CD4/CD8 ratio occurred. This case provides support for the safety and tolerability of the above immunotherapies in people living with HIV with suppressed viral load on antiretroviral therapy.
INTRODUCTION
In the management of ulcerative colitis (UC), one provides immunosuppressive therapy with the hope of tempering excessive inflammation while preserving immune function. However, if the proper balance between immunosuppression and immune preservation is not achieved, an individual will be tipped into immunodeficiency with increased infection risk. People living with HIV (PLWH) are often excluding from clinical trials involving biologics based on concerns of additive immunosuppression and infection risk. Consequently, little data are available to guide clinicians in managing PLWH who suffer from advanced inflammatory bowel disease (IBD). Herein, we present the case of young woman with HIV infection and extensive UC refractory to many therapies. Following repeated decline of surgical intervention, she was treated with multiple sequential immunomodulators and did not experience any major adverse effects.
CASE REPORT
A 36-year-old, Canadian-born Caucasian woman was diagnosed with HIV in 2008. She began antiretroviral therapy with tenofovir disoproxil 300 mg/emtracitabine 200 mg orally once daily and raltegravir 400 mg orally twice daily in 2012, when her CD4 count rapidly dropped to 86 cells/mm3. Later that year, she began experiencing frequent episodes of bloody diarrhea, with up to 20 stools daily, with cramping, rectal bleeding and elevated C-reactive protein (CRP). Stool was repeatedly negative for Clostridium difficile and ova and parasites. Colonoscopy demonstrated severe pancolitis and biopsies consistent with active UC with acute cryptitis, crypt abcesses with lymphoid hyperplasia, focal erosions, acute inflammatory exudate with architectural disortion. Hematoxylin and eosin stains for cytomegalovirus and histochemical exams for Herpes Simplex Virus I/II were negative. Despite high doses of oral prednisone (40–60 mg daily) and several emergency room visits to receive intravenous (IV) methylprednisolone for flares, she was deemed steroid-refractory.
Later that year, she received maximum doses of oral mesalamine and 6-mercaptopurine, as well as mesalamine suppositories and enemas. She then received infliximab (2012–2013), an antitumor necrois fator-α (anti-TNFα) monoclonal antibody, until antibody formation. Despite maximum doses of adalimumab (2014), her UC remained refractory although no antibodies were detected using a drug-tolerant assay and medication levels were therapeutic (>12 μg/ml, the highest limit of detection). Attempts to taper her steroids resulted in flare-ups and a cushingoid feature. She declined colectomy as she felt this would interfere with her lifestyle, especially since she was getting married, and concerns about her future fertility.
One of the options explored was the use of vedolizumab, a monoclonal antibody against α4β7 integrin, via a clinical trial. However, due to the patient’s HIV infection she was not eligible to participate in any of the recruiting trials at the centre as HIV infection is frequently an exclusion criteria. Colonoscopy in 2015 revealed severe inflammation with ulcerations and friability consistent with Mayo 3 colitis, despite high-dose steroids and adalimumab, an anti-TNFα monoclonal antibody, at a dose of 80 mg weekly. By December 2015, vedolizumab was obtained through standard of care and initiated at 300 mg IV at weeks 0 and 2, 6 (loading dose) and then every 8 weeks thereafter as a maintenance dose. She was still bleeding from the rectum and had decreased weight, therefore daily prednisone 10 mg orally was maintained. She achieved clinical remission by March 2016 and steroids were stopped. Two months later, she developed right foot cellulitis following a minor trauma during a pedicure and required 48 hours of IV followed by oral antibiotics.
Colonoscopy in June 2016, 3 months after stopping steroids, showed worsening condition with Mayo 3 colitis, so she was changed to vedolizumab 300 mg IV q 4 weeks and prednisone increased to 40 mg orally (po) daily. Anti-α4β7 antibodies were not detected. She was passing bright red blood per rectum 12 times in 24 hours and having five stools per 24 hours with lower abdominal cramping and rectal pain. Janus kinase (JAK) inhibitor, tofacitinab 10 mg po twice daily, was initiated October 2016 and prednisone 40 mg po daily maintained. Symptoms persisted requiring admission for IV prednisolone, but she continued to decline surgical colectomy. She also developed a bacterial vaginitis treated with metronidazole cream and later a skin furuncle, treated with oral antibiotics.
Following tofacitinib, she received interleukin 12/23 inhibitor ustekinumab March–September 2017. She gained 30 pounds in 1 year (body mass index 37), increased abdominal fat and bilateral cataracts due to cortisone. Attempts to decrease prednisone below 30 mg daily led to bloody diarrhea (12–17 bowel movements daily). She eventually accepted to undergo subtotal abdominal colectomy (pathology shown in Fig. 1) with rectal stump and temporary end ileostomy by June 2018. She improved and was seen for follow-up a month post-op, at which time she was having increasing right lower quadrant pain and rising CRP. A computed tomography scan demonstrated collections in the subcutaneous fat surrounding the ostomy and a second collection centimeter with rim enhancement and fat stranding. These were drained and cultures grew E. coli and B. fragilis. She responded to IV antibiotics for 3 days followed by oral step-down antibiotics to complete 2 weeks. Eight months following her colectomy, she developed polyarthralgia in her interphalangeal joints, wrists, shoulders, knees and feet with a normal CRP and a negative Rheumatoid Factor while off prednisone, thought to be either inflammatory or mechanical polyarthralgia. Pathology on surveillance sigmoidoscopy March 2019 demonstrated chronic active proctitis with ulceration consistent with chronic idiopathic IBD. Throughout this entire time, her CD4 range was between 400 and 900 cells/mm3, with CD4/CD8 ratio of 0.41:1.12, and HIV viral load remained suppressed since November 2012.
Figure 1 Colonic resection histology. The colonic mucosa shows characteristic features of chronic ulcerative colitis including crypt architecture alteration, cryptitis, crypt abscess and focal mucosa ulceration. There is no evidence of dysplasia.
DISCUSSION
Due to repeated decline of surgery in order to preserve her quality of life and fertility, this woman with HIV and refractory UC received all available conventional therapies including mesalamine, glucocorticoids, thiopurines, antagonists to TNF- α, IL-12/23 blockers and anti-α4 β7 integrin. She also received a small-molecule JAK inhibitor. TNF-α inhibitors and α4β7 integrin blockers are used with extreme caution in PLWH due to concerns of additional immunosuppression and subsequent infection risk. However, during her 6 years of being on immunosuppressants, the patient only experienced one episode of cellulitis, bacterial vaginosis, a skin furuncle and peristomal abscesses, all of which were easily managed with traditional therapies. Another concern with the use of integrin receptor antagonists in PLWH, although rare, is the possibility of Progressive Multifocal Leukoencephalopathy due to John Cunningham (JC) virus [1]. Our patient underwent blood plasma JC virus testing prior to vedolizumab initiation and this polymerase chain reaction testing was negative. She also denied any neurological signs or symptoms throughout treatment.
This woman’s case demonstrates that the spectrum of drug classes available and sequential use of biologics for treatment of UC were safe in this patient with well-controlled HIV infection ART, including an TNF-α blocker, JK inhibitor, IL-12/23 blocker and the α4β7 integrin blocker vedolizumab. Our patient did not incur any significant changes in her CD4 count nor CD4/CD8 ratio during the course of her treatments and infections were relatively minor. Although we did not use combination biologics in this patient, their efficacy and safety for IBD and other and other inflammatory diseases associated was explored in a systematic review of observational studies which did not find any differences related to improvements in disease condition, adverse effects or infection rates in patients receiving combined treatment compared to placebo groups [2]. A clinical trial (NCT02764762) examining efficacy and safety of combined vedolizumab, adalimumab and oral methotrexate in patients with Crohn’s Disease is in progress [3]. Until evidence from clinical trials is available on efficacy and safety of biologics and combination therapy in PLWH, case reports and case series provide a channel for dissemination of these experiences within the medical community.
ACKNOWLEDGMENTS
The authors thank Pathologist, Dr Zu-hua Gao, for provision of the histology image. No funding was received for the preparation of this manuscript.
CONFLICTS OF INTEREST STATEMENT
None declared.
FUNDING
No funding was received for the preparation of this manuscript.
ETHICS APPROVAL
The authors received ethical approval for publication of the case report.
CONSENT TO PUBLISH
The patient provided informed written consent for the preparation of this case report and publication of data and pathological image in an open access journal. The participant understood that the details/images would be freely available on the internet and may be seen by the general public. A copy of the written consent is available for review by the editor of the journal.
GUARANTOR
Dr Costiniuk is the guarantor of the case report. | 300 MG/200 MG | DrugDosageText | CC BY-NC | 33542833 | 19,710,764 | 2021-01 |
What was the outcome of reaction 'Colitis ulcerative'? | Use of various immunotherapies for refractory ulcerative colitis in a person living with HIV: a case report.
Cancer therapies include several immune checkpoint or anticytokine therapies whereas ulcerative colitis treatments consist of anticytokine therapies. The development of tolerance and immunogical effects of these agents in people living with HIV are not well assessed as these persons are often excluded from clinical trials. Herein, we report a case of a Caucasian woman who received multiple sequential immunotherapies for severe ulcerative colitis. Due to steroid-refractory disease, receipt of maximal doses of mesalamine and initial repeated decline of surgical intervention, she went on to receive biologic immune inhibitors like tumor necrosis fator-α blockers infliximab and adalimumab, the α4β7integrin blocker vedolizumab, anti-interleukin 12/23 blocker ustekinumab and Janus Kinase inihibitor tofacitinib without achieving remission. Only minor infectious complications were encountered and no significant changes in CD4 count nor CD4/CD8 ratio occurred. This case provides support for the safety and tolerability of the above immunotherapies in people living with HIV with suppressed viral load on antiretroviral therapy.
INTRODUCTION
In the management of ulcerative colitis (UC), one provides immunosuppressive therapy with the hope of tempering excessive inflammation while preserving immune function. However, if the proper balance between immunosuppression and immune preservation is not achieved, an individual will be tipped into immunodeficiency with increased infection risk. People living with HIV (PLWH) are often excluding from clinical trials involving biologics based on concerns of additive immunosuppression and infection risk. Consequently, little data are available to guide clinicians in managing PLWH who suffer from advanced inflammatory bowel disease (IBD). Herein, we present the case of young woman with HIV infection and extensive UC refractory to many therapies. Following repeated decline of surgical intervention, she was treated with multiple sequential immunomodulators and did not experience any major adverse effects.
CASE REPORT
A 36-year-old, Canadian-born Caucasian woman was diagnosed with HIV in 2008. She began antiretroviral therapy with tenofovir disoproxil 300 mg/emtracitabine 200 mg orally once daily and raltegravir 400 mg orally twice daily in 2012, when her CD4 count rapidly dropped to 86 cells/mm3. Later that year, she began experiencing frequent episodes of bloody diarrhea, with up to 20 stools daily, with cramping, rectal bleeding and elevated C-reactive protein (CRP). Stool was repeatedly negative for Clostridium difficile and ova and parasites. Colonoscopy demonstrated severe pancolitis and biopsies consistent with active UC with acute cryptitis, crypt abcesses with lymphoid hyperplasia, focal erosions, acute inflammatory exudate with architectural disortion. Hematoxylin and eosin stains for cytomegalovirus and histochemical exams for Herpes Simplex Virus I/II were negative. Despite high doses of oral prednisone (40–60 mg daily) and several emergency room visits to receive intravenous (IV) methylprednisolone for flares, she was deemed steroid-refractory.
Later that year, she received maximum doses of oral mesalamine and 6-mercaptopurine, as well as mesalamine suppositories and enemas. She then received infliximab (2012–2013), an antitumor necrois fator-α (anti-TNFα) monoclonal antibody, until antibody formation. Despite maximum doses of adalimumab (2014), her UC remained refractory although no antibodies were detected using a drug-tolerant assay and medication levels were therapeutic (>12 μg/ml, the highest limit of detection). Attempts to taper her steroids resulted in flare-ups and a cushingoid feature. She declined colectomy as she felt this would interfere with her lifestyle, especially since she was getting married, and concerns about her future fertility.
One of the options explored was the use of vedolizumab, a monoclonal antibody against α4β7 integrin, via a clinical trial. However, due to the patient’s HIV infection she was not eligible to participate in any of the recruiting trials at the centre as HIV infection is frequently an exclusion criteria. Colonoscopy in 2015 revealed severe inflammation with ulcerations and friability consistent with Mayo 3 colitis, despite high-dose steroids and adalimumab, an anti-TNFα monoclonal antibody, at a dose of 80 mg weekly. By December 2015, vedolizumab was obtained through standard of care and initiated at 300 mg IV at weeks 0 and 2, 6 (loading dose) and then every 8 weeks thereafter as a maintenance dose. She was still bleeding from the rectum and had decreased weight, therefore daily prednisone 10 mg orally was maintained. She achieved clinical remission by March 2016 and steroids were stopped. Two months later, she developed right foot cellulitis following a minor trauma during a pedicure and required 48 hours of IV followed by oral antibiotics.
Colonoscopy in June 2016, 3 months after stopping steroids, showed worsening condition with Mayo 3 colitis, so she was changed to vedolizumab 300 mg IV q 4 weeks and prednisone increased to 40 mg orally (po) daily. Anti-α4β7 antibodies were not detected. She was passing bright red blood per rectum 12 times in 24 hours and having five stools per 24 hours with lower abdominal cramping and rectal pain. Janus kinase (JAK) inhibitor, tofacitinab 10 mg po twice daily, was initiated October 2016 and prednisone 40 mg po daily maintained. Symptoms persisted requiring admission for IV prednisolone, but she continued to decline surgical colectomy. She also developed a bacterial vaginitis treated with metronidazole cream and later a skin furuncle, treated with oral antibiotics.
Following tofacitinib, she received interleukin 12/23 inhibitor ustekinumab March–September 2017. She gained 30 pounds in 1 year (body mass index 37), increased abdominal fat and bilateral cataracts due to cortisone. Attempts to decrease prednisone below 30 mg daily led to bloody diarrhea (12–17 bowel movements daily). She eventually accepted to undergo subtotal abdominal colectomy (pathology shown in Fig. 1) with rectal stump and temporary end ileostomy by June 2018. She improved and was seen for follow-up a month post-op, at which time she was having increasing right lower quadrant pain and rising CRP. A computed tomography scan demonstrated collections in the subcutaneous fat surrounding the ostomy and a second collection centimeter with rim enhancement and fat stranding. These were drained and cultures grew E. coli and B. fragilis. She responded to IV antibiotics for 3 days followed by oral step-down antibiotics to complete 2 weeks. Eight months following her colectomy, she developed polyarthralgia in her interphalangeal joints, wrists, shoulders, knees and feet with a normal CRP and a negative Rheumatoid Factor while off prednisone, thought to be either inflammatory or mechanical polyarthralgia. Pathology on surveillance sigmoidoscopy March 2019 demonstrated chronic active proctitis with ulceration consistent with chronic idiopathic IBD. Throughout this entire time, her CD4 range was between 400 and 900 cells/mm3, with CD4/CD8 ratio of 0.41:1.12, and HIV viral load remained suppressed since November 2012.
Figure 1 Colonic resection histology. The colonic mucosa shows characteristic features of chronic ulcerative colitis including crypt architecture alteration, cryptitis, crypt abscess and focal mucosa ulceration. There is no evidence of dysplasia.
DISCUSSION
Due to repeated decline of surgery in order to preserve her quality of life and fertility, this woman with HIV and refractory UC received all available conventional therapies including mesalamine, glucocorticoids, thiopurines, antagonists to TNF- α, IL-12/23 blockers and anti-α4 β7 integrin. She also received a small-molecule JAK inhibitor. TNF-α inhibitors and α4β7 integrin blockers are used with extreme caution in PLWH due to concerns of additional immunosuppression and subsequent infection risk. However, during her 6 years of being on immunosuppressants, the patient only experienced one episode of cellulitis, bacterial vaginosis, a skin furuncle and peristomal abscesses, all of which were easily managed with traditional therapies. Another concern with the use of integrin receptor antagonists in PLWH, although rare, is the possibility of Progressive Multifocal Leukoencephalopathy due to John Cunningham (JC) virus [1]. Our patient underwent blood plasma JC virus testing prior to vedolizumab initiation and this polymerase chain reaction testing was negative. She also denied any neurological signs or symptoms throughout treatment.
This woman’s case demonstrates that the spectrum of drug classes available and sequential use of biologics for treatment of UC were safe in this patient with well-controlled HIV infection ART, including an TNF-α blocker, JK inhibitor, IL-12/23 blocker and the α4β7 integrin blocker vedolizumab. Our patient did not incur any significant changes in her CD4 count nor CD4/CD8 ratio during the course of her treatments and infections were relatively minor. Although we did not use combination biologics in this patient, their efficacy and safety for IBD and other and other inflammatory diseases associated was explored in a systematic review of observational studies which did not find any differences related to improvements in disease condition, adverse effects or infection rates in patients receiving combined treatment compared to placebo groups [2]. A clinical trial (NCT02764762) examining efficacy and safety of combined vedolizumab, adalimumab and oral methotrexate in patients with Crohn’s Disease is in progress [3]. Until evidence from clinical trials is available on efficacy and safety of biologics and combination therapy in PLWH, case reports and case series provide a channel for dissemination of these experiences within the medical community.
ACKNOWLEDGMENTS
The authors thank Pathologist, Dr Zu-hua Gao, for provision of the histology image. No funding was received for the preparation of this manuscript.
CONFLICTS OF INTEREST STATEMENT
None declared.
FUNDING
No funding was received for the preparation of this manuscript.
ETHICS APPROVAL
The authors received ethical approval for publication of the case report.
CONSENT TO PUBLISH
The patient provided informed written consent for the preparation of this case report and publication of data and pathological image in an open access journal. The participant understood that the details/images would be freely available on the internet and may be seen by the general public. A copy of the written consent is available for review by the editor of the journal.
GUARANTOR
Dr Costiniuk is the guarantor of the case report. | Recovering | ReactionOutcome | CC BY-NC | 33542833 | 19,114,036 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug resistance'. | Use of Infliximab to Treat Paradoxical Tuberculous Meningitis Reactions.
We documented dramatic responses to infliximab in 4 tuberculous meningitis cases with severe paradoxical reactions after effective antibacterial treatment, despite high-dose steroids. In every instance, infliximab was used as a last resort after all other options were exhausted, resulting in delayed initiation that may have adversely affected patient outcomes.
Tuberculous meningitis frequently results in permanent neurological sequelae [1, 2]. The characteristic inflammatory exudate at the base of the brain may block cerebrospinal fluid (CSF) flow with resultant hydrocephalus or cause cerebral ischemia and stroke secondary to vasculitis [1, 2]. Mass effects associated with localized inflammation may also compromise critical structures, such as the optic chiasm [3]. These effects may occur with natural disease progression or as a paradoxical reaction, generally defined as clinical worsening after initial improvement on appropriate antibacterial treatment.
Tumor necrosis factor (TNFα) is critical for effective host defense against mycobacteria, and monoclonal antibodies that inhibit TNFα, such as infliximab, greatly increase tuberculosis vulnerability [4]. On the other hand, deterioration of tuberculosis patients after infliximab cessation suggests that TNFα may also contribute to disease pathology [5]. The use of infliximab to control paradoxical reactions in a patient with tuberculous meningitis was first demonstrated in 2008 [6]. Subsequent case reports support the initial observations [7–10], but awareness of infliximab benefit in select cases is low and completely overshadowed by the perception of risk. Most clinicians remain highly reluctant to consider infliximab use in any tuberculosis patient.
We present a series of tuberculous meningitis cases with likely paradoxical reactions in whom infliximab was used with good effect. The Table 1 provides an overview of the case presentation, treatment, clinical progress, and outcome, with a focus on the administration and clinical effect of infliximab.
Case 1
A 36-year-old male bus driver who migrated to Australia from India 15 months prior was diagnosed with miliary tuberculosis and cerebral tuberculomas. Sputum, bronchoalveolar lavage (BAL), cerebrospinal fluid (CSF), and blood were all culture negative at the time. He was discharged home on isoniazid, rifampicin, pyrazinamide, ethambutol, and oral prednisolone. Interim brain magnetic resonance imaging (MRI) showed improvement of tuberculomas before readmission 6 weeks later with new-onset ataxia and drowsiness. Findings on the repeat MRI included hydrocephalus and cerebritis, with the patient experiencing rapid progression to coma requiring intubation and ventilation.
A brain biopsy was performed, and an external ventricular drain was inserted. The brain biopsy tested Xpert MTB/Rif positive, with rifampicin resistance detected. Empiric MDR treatment was commenced with moxifloxacin, amikacin, prothionamide, and linezolid added, awaiting culture results. Phenotypic drug susceptibility testing (DST) identified resistance to all first-line drugs with additional low-level resistance to moxifloxacin; line probe assays identified katG, rpoB, and gyrA mutations. First-line treatment, except pyrazinamide, was stopped, and the patient was continued on high-dose moxifloxacin with the addition of bedaquiline and clofazimine. On this regimen, the patient slowly improved and became more responsive, before deteriorating a second time with new midbrain tuberculomas, multiple infarcts, and increasing leptomeningeal enhancement on MRI.
In the absence of a clinical response to high-dose intravenous (IV) dexamethasone, a “trial dose” of infliximab was given. Fever and C-reactive protein (CRP) settled promptly, and the patient’s sensorium improved within days, allowing him to be weaned off the ventilator. Symptoms recrudesced 3 weeks later, with new parenchymal foci and increased enhancement around existing tuberculomas seen on MRI. A second dose of infliximab induced another prompt response, and the patient continued to make a slow recovery, receiving a total of 3 monthly doses. Linezolid (after 6 months) and amikacin (after 12 months) were ceased due to bone marrow suppression and sensorineural hearing loss, respectively. In total, the patient completed 24 months of treatment and was discharged to a disability home, where he lives independently with minimal caregiver help.
Case 2
A 32-year-old woman (on TB treatment) presented with a 7-day history of bilateral thigh pain and paraesthesia, gait disturbance, and urinary retention. Spinal MRI revealed compressive lesions at T5 and T11/12, occurring 4 months after commencing treatment for culture-confirmed miliary tuberculosis; CSF was not assessed at the time. Tuberculosis treatment consisted of isoniazid, rifampicin, pyrazinamide, ethambutol (isoniazid discontinued after documented high-level resistance), and moxifloxacin, with excellent treatment adherence and no vomiting or clinical indication of malabsorption, such as diarrhea. High-dose IV dexamethasone was initiated, and an urgent T4-6 and T11-12 laminectomy was performed, which was complicated by dense pachymeningeal adhesions. With new-onset fecal incontinence, further debulking of the T11/12 lesion was performed, but distressing symptoms persisted.
Histopathology from both lesions showed necrotizing granulomas that were negative for acid fast bacilli and mycobacterial growth. In the absence of live bacilli or any documented steroid response, infliximab was started, with rapid clinical improvement. Full bowel and bladder control, as well as mobility, was regained within 2 weeks. In the absence of raised inflammatory markers, serial positron emission tomography (PET) scans were used to track treatment response with significant reduction in glucose uptake at 2 months and no ongoing activity detected at 4 months, when infliximab treatment was stopped.
Case 3
A 53-year-old woman visiting from Indonesia presented with paraplegia, fecal incontinence, and urinary retention, as well as headache and a third cranial nerve palsy. Extensive intracranial and intraspinal leptomeningeal and pachymeningeal enhancement was demonstrated on MRI. Her CSF grew a fully susceptible strain of Mycobacterium tuberculosis. Therapy with isoniazid, rifampicin, pyrazinamide, and moxifloxacin together with high-dose steroids led to initial improvement with resolution of headaches and the third nerve palsy, but after 7 weeks of treatment and while still on high-dose steroids, the patient experienced worsening headaches and new-onset vomiting. Repeat MRI demonstrated increased leptomeningeal inflammation with multiple new intracranial and intraspinal tuberculomas (Figures 1 and 2).
Figure 1. T1-weighted postgadolinium MRI brain images demonstrating evolution of brain tuberculomas in Case 3; pre– and post–infliximab use. MRI of the brain at (A) time of presentation, (B) week 7 post–commencement of TB therapy with formation of multiple tuberculomas (pre-infliximab), and (C) week 21 post–commencement of TB therapy and after 3 doses of infliximab, demonstrating complete resolution of brain tuberculomas. Abbreviations: MRI, magnetic resonance imaging; TB, tuberculosis.
Figure 2. T1-weighted postgadolinium MRI brain images demonstrating evolution of spinal tuberculomas in Case 3; pre– and post–infliximab use. MRI of the spine at (A) time of presentation, (B) week 7 post–commencement of TB therapy with formation of spinal cord tuberculoma (pre-infliximab), and (C) week 21 post–commencement of TB therapy and after 3 doses of infliximab, demonstrating incomplete resolution of spinal cord tuberculoma. Abbreviations: MRI, magnetic resonance imaging; TB, tuberculosis.
Treatment with infliximab resulted in rapid clinical improvement. Fever and headaches briefly recurred before the second monthly dose, with a total of 3 monthly doses administered. High-dose oral steroids were continued for 4 months before slow tapering. Thalidomide and lenalidomide were trialed for longer-term inflammatory suppression, but both resulted in an extensive generalized rash and were discontinued. A progress MRI demonstrated significant improvement in leptomeningeal enhancement and ring-enhancing tuberculomas after 6 months of therapy. The patient returned to Indonesia 8 months after treatment initiation, having regained muscle strength, but sphincter function remained compromised.
Case 4
A 26-year-old male student from India was admitted with cough, weight loss, and lethargy. There were multiple lung cavities on chest computed tomography (CT), but he had no neurological signs and a noncontrast CT scan of the brain detected no intracranial pathology. He commenced treatment on standard first-line therapy without corticosteroids. Within days of treatment initiation, he developed headache, vomiting, and disorientation, with bilateral lower limb weakness and urinary retention. An MRI of the brain and spine demonstrated communicating hydrocephalus with extensive leptomeningeal enhancement involving the spine, as well as multilevel spondylodiscitis with paravertebral abscesses. A lumbar drain was inserted, and high-dose IV dexamethasone was commenced. The rifampicin dose was increased to 900 mg/d, and levofloxacin 750 mg/d was added. M. tuberculosis grown from sputum was subsequently shown to be fully drug susceptible.
Six weeks later, while still on IV dexamethasone, the patient developed new fever, worsening leg weakness, and diplopia. MRI of the brain and spine demonstrated increased basal meningeal enhancement, a new left occipital tuberculoma, and evidence of compressive myelopathy with progression of the spondylodiscitis. Fever and neurological symptoms improved rapidly after a dose of infliximab. Following symptom recrudescence, repeat infliximab doses were given 3, 7, and 17 weeks later, each time followed by prompt improvement. Repeat MRI at 6 months demonstrated resolution of the meningitis, hydrocephalus, tuberculomas, and spondylodiscitis with improvement of the paravertebral abscesses, now regarded as too small for drainage. The antibacterial treatment was rationalized to rifampicin and isoniazid with a plan to treat for 12 months in total.
DISCUSSION
All 4 cases experienced clinical deterioration despite adequate antibacterial treatment and high-dose corticosteroids. In every instance, infliximab therapy was followed by rapid clinical improvement; no adverse effects were reported. The pronounced and consistent temporal association in clinical improvement, as well as MRI and/or PET changes, suggests a strong therapeutic effect. Our findings support the observation that TNFα is a key driver of inflammation in TB meningitis [11], consistent with the therapeutic effect observed in previous reports [6–10], including those using other TNFα inhibitors, such as adalimumab [12] and thalidomide [3]. Monoclonal antibodies do not usually cross the blood–brain barrier but may do so in the presence of meningeal inflammation and barrier disruption. In rats with hepatic encephalopathy, infliximab significantly reduced neuroinflammation, as demonstrated on immunohistochemistry [13]. In all reported cases, infliximab was only considered after other treatment options were exhausted, but earlier commencement may have prevented some of the invasive procedures and permanent sequelae. It should be emphasized that anti-TNFα treatment should only be contemplated in the presence of effective antibacterial therapy with adequate CSF penetration [14].
The optimal timing and duration of anti-TNFα treatment, as well as the value of corticosteroid co-administration, remains unclear. Symptomatic improvement, inflammatory markers (if raised to begin with), and MRI or PET changes may guide treatment duration; 3–4 doses of infliximab led to significant and durable clinical improvement in all patients. Although optimal dosing and timing of delivery remain uncertain, a rational approach may be to give 5 mg/kg at 0, 2, and 6 weeks (similar to induction dosing recommended for patients with active psoriatic arthritis), with consideration of additional doses at 10–14 weeks guided by the treatment response. This is based on 3 monthly doses provided in the first description of infliximab use in TB meningitis [6] and the fact that our patients experienced “breakthrough symptoms” before the second monthly dose. Therapeutic drug monitoring would be useful to inform dosing schedules [15] but is rarely available and was not performed in our patients. The added value of high-dose corticosteroids is uncertain and requires further evaluation; in reported cases, deterioration occurred under “steroid cover.”
Randomized controlled trials to assess the benefit of infliximab use in tuberculous meningitis, in conjunction with effective antibacterial treatment, would be highly informative and might be considered in the following situations: (1) in immune-competent (HIV-uninfected) patients with paradoxical reactions, (2) in TB/HIV-coinfected patients who experience immune reconstitution inflammatory syndrome (IRIS) affecting the central nervous system, and (3) as part of routine care to prevent severe and irreversible sequelae. Multicenter recruitment using standardized methods is preferred [16], although the numbers required to detect a pronounced therapeutic effect, which is the key clinical need, would be relatively small.
Table 1. Tuberculous Meningitis Cases With Paradoxical Reactions Treated With Infliximab
Case Diagnosis at Presentation Site of Paradoxical Reaction TB Treatment Regimen Other Treatment Before and After Infliximab Infliximab Dose Outcome
Case 1:
Flinders Hospital, Adelaide,
36 y, male
HIV uninfected,
Indiaa Miliary TB with TBM Multiple brain tuberculomas and obstructed CSF flow with raised ICP Empiric HRZE,
thenc
high-dose mfx, amk, lzdd, pto, Z, bdq, cfz Before: High-dose steroidsb for 3 mo
After: High-dose steroids for 4 mo; tapered over 2 mo 10 mg/kg
monthly x3
Rapid fever resolution with CRP decline; improved sensorium allowing weaning off the ventilator within days;
long term—mild cognitive deficit, require assistance with activities of daily living
Case 2:
Concord Hospital, Sydney,
32 y, female
HIV uninfected,
Chinaa Miliary TB with TBM Multiple spinal tuberculomas with edema and local mass effect Empiric HRZE,
thene
RZE + mfx Before: High-dose steroids for 2 mo; decompressive spinal surgery
After: High-dose steroids for 2 mo; tapered over 1 mo 5 mg/kg
0, 2, 6, and 14 wk Rapid restoration of bladder function (2 wk) and mobility (3–4 wk);
long term—full neurological recovery
Case 3:
Royal North Shore Hospital, Sydney,
55 y, female
HIV uninfected,
Indonesiaa TBM and necrotic lymph-adenitis Multiple brain and spinal cord tuberculomas with cauda equina syndrome HRZ + mfx Before: High-dose steroids for 2 mo
After: High-dose steroids for 4 mo; tapered over 2 mo; failed trial of thalidomide 5 mg/kg
monthly x3
Rapid resolution of fever and meningism; improvement in lower limb power;
long term—incomplete recovery with compromised sphincter function at discharge; regained mobility with ongoing improvement in lower limb power
Case 4:
Westmead Hospital, Sydney,
26 y, male
HIV uninfected,
Indiaa
PTB with CNS and bone involvement Multiple brain and spinal tuberculomas with raised ICP, compressive spinal myelopathy, and cold abscesses Empiric HRZE,
then
HR (900 mg) Z + lfx
Before: High-dose steroids for 6 wk with unsuccessful weaning
After: High-dose steroids for 2 mo; tapered over 1 mo 10 mg/kg
(0, 3 wk)
5 mg/kg
(7, 17 wk) Rapid resolution of fever and neurological improvement (reduced pressure effects);
long term—regained sphincter function and mobility with ongoing improvement on rehabilitation
Abbreviations: amk, amikacin; bdq, edaquiline; cfz, clofazimine; CNS, central nervous system; E, ethambutol; H, isoniazid; ICP, intracranial pressure; lfx, levofloxacin; lzd, linezolid; mfx, moxifloxacin; PTB, pulmonary TB; pto, prothionamide; R, rifampicin; TB, tuberculosis; TBM, TB meningitis; Z, pyrazinamide.
aCountry of origin.
bHigh-dose steroids included intravenous dexamethasone (4–8 mg 3–4x/d) and/or oral prednisone (1–2 mg/kg/d - maximum 60 mg/d).
cAfter identification of pan-resistance to all first-line drugs, including high-level isoniazid and low-level moxifloxacin resistance.
dLinezolid (6 months) and amikacin (12 months) stopped after demonstrated toxicity.
eIsoniazid replaced by moxifloxacin given high-level isoniazid monoresistance.
Acknowledgments
Financial support. None.
Potential conflicts of interest. None of the authors have financial relationships relevant to this article. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
Patient consent. Patients were treated at 4 different hospitals with different case report requirements. All institutional requirements and local ethical standards were met. Written patient consent was provided in all instances, except 1 patient who left Australia. No patient identifiers were disclosed, and all patients/families indicated agreement that relevant clinical information could be shared for academic purposes in order for other patients to benefit from the knowledge gained. | ISONIAZID | DrugsGivenReaction | CC BY-NC-ND | 33542942 | 20,099,828 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Myelosuppression'. | Use of Infliximab to Treat Paradoxical Tuberculous Meningitis Reactions.
We documented dramatic responses to infliximab in 4 tuberculous meningitis cases with severe paradoxical reactions after effective antibacterial treatment, despite high-dose steroids. In every instance, infliximab was used as a last resort after all other options were exhausted, resulting in delayed initiation that may have adversely affected patient outcomes.
Tuberculous meningitis frequently results in permanent neurological sequelae [1, 2]. The characteristic inflammatory exudate at the base of the brain may block cerebrospinal fluid (CSF) flow with resultant hydrocephalus or cause cerebral ischemia and stroke secondary to vasculitis [1, 2]. Mass effects associated with localized inflammation may also compromise critical structures, such as the optic chiasm [3]. These effects may occur with natural disease progression or as a paradoxical reaction, generally defined as clinical worsening after initial improvement on appropriate antibacterial treatment.
Tumor necrosis factor (TNFα) is critical for effective host defense against mycobacteria, and monoclonal antibodies that inhibit TNFα, such as infliximab, greatly increase tuberculosis vulnerability [4]. On the other hand, deterioration of tuberculosis patients after infliximab cessation suggests that TNFα may also contribute to disease pathology [5]. The use of infliximab to control paradoxical reactions in a patient with tuberculous meningitis was first demonstrated in 2008 [6]. Subsequent case reports support the initial observations [7–10], but awareness of infliximab benefit in select cases is low and completely overshadowed by the perception of risk. Most clinicians remain highly reluctant to consider infliximab use in any tuberculosis patient.
We present a series of tuberculous meningitis cases with likely paradoxical reactions in whom infliximab was used with good effect. The Table 1 provides an overview of the case presentation, treatment, clinical progress, and outcome, with a focus on the administration and clinical effect of infliximab.
Case 1
A 36-year-old male bus driver who migrated to Australia from India 15 months prior was diagnosed with miliary tuberculosis and cerebral tuberculomas. Sputum, bronchoalveolar lavage (BAL), cerebrospinal fluid (CSF), and blood were all culture negative at the time. He was discharged home on isoniazid, rifampicin, pyrazinamide, ethambutol, and oral prednisolone. Interim brain magnetic resonance imaging (MRI) showed improvement of tuberculomas before readmission 6 weeks later with new-onset ataxia and drowsiness. Findings on the repeat MRI included hydrocephalus and cerebritis, with the patient experiencing rapid progression to coma requiring intubation and ventilation.
A brain biopsy was performed, and an external ventricular drain was inserted. The brain biopsy tested Xpert MTB/Rif positive, with rifampicin resistance detected. Empiric MDR treatment was commenced with moxifloxacin, amikacin, prothionamide, and linezolid added, awaiting culture results. Phenotypic drug susceptibility testing (DST) identified resistance to all first-line drugs with additional low-level resistance to moxifloxacin; line probe assays identified katG, rpoB, and gyrA mutations. First-line treatment, except pyrazinamide, was stopped, and the patient was continued on high-dose moxifloxacin with the addition of bedaquiline and clofazimine. On this regimen, the patient slowly improved and became more responsive, before deteriorating a second time with new midbrain tuberculomas, multiple infarcts, and increasing leptomeningeal enhancement on MRI.
In the absence of a clinical response to high-dose intravenous (IV) dexamethasone, a “trial dose” of infliximab was given. Fever and C-reactive protein (CRP) settled promptly, and the patient’s sensorium improved within days, allowing him to be weaned off the ventilator. Symptoms recrudesced 3 weeks later, with new parenchymal foci and increased enhancement around existing tuberculomas seen on MRI. A second dose of infliximab induced another prompt response, and the patient continued to make a slow recovery, receiving a total of 3 monthly doses. Linezolid (after 6 months) and amikacin (after 12 months) were ceased due to bone marrow suppression and sensorineural hearing loss, respectively. In total, the patient completed 24 months of treatment and was discharged to a disability home, where he lives independently with minimal caregiver help.
Case 2
A 32-year-old woman (on TB treatment) presented with a 7-day history of bilateral thigh pain and paraesthesia, gait disturbance, and urinary retention. Spinal MRI revealed compressive lesions at T5 and T11/12, occurring 4 months after commencing treatment for culture-confirmed miliary tuberculosis; CSF was not assessed at the time. Tuberculosis treatment consisted of isoniazid, rifampicin, pyrazinamide, ethambutol (isoniazid discontinued after documented high-level resistance), and moxifloxacin, with excellent treatment adherence and no vomiting or clinical indication of malabsorption, such as diarrhea. High-dose IV dexamethasone was initiated, and an urgent T4-6 and T11-12 laminectomy was performed, which was complicated by dense pachymeningeal adhesions. With new-onset fecal incontinence, further debulking of the T11/12 lesion was performed, but distressing symptoms persisted.
Histopathology from both lesions showed necrotizing granulomas that were negative for acid fast bacilli and mycobacterial growth. In the absence of live bacilli or any documented steroid response, infliximab was started, with rapid clinical improvement. Full bowel and bladder control, as well as mobility, was regained within 2 weeks. In the absence of raised inflammatory markers, serial positron emission tomography (PET) scans were used to track treatment response with significant reduction in glucose uptake at 2 months and no ongoing activity detected at 4 months, when infliximab treatment was stopped.
Case 3
A 53-year-old woman visiting from Indonesia presented with paraplegia, fecal incontinence, and urinary retention, as well as headache and a third cranial nerve palsy. Extensive intracranial and intraspinal leptomeningeal and pachymeningeal enhancement was demonstrated on MRI. Her CSF grew a fully susceptible strain of Mycobacterium tuberculosis. Therapy with isoniazid, rifampicin, pyrazinamide, and moxifloxacin together with high-dose steroids led to initial improvement with resolution of headaches and the third nerve palsy, but after 7 weeks of treatment and while still on high-dose steroids, the patient experienced worsening headaches and new-onset vomiting. Repeat MRI demonstrated increased leptomeningeal inflammation with multiple new intracranial and intraspinal tuberculomas (Figures 1 and 2).
Figure 1. T1-weighted postgadolinium MRI brain images demonstrating evolution of brain tuberculomas in Case 3; pre– and post–infliximab use. MRI of the brain at (A) time of presentation, (B) week 7 post–commencement of TB therapy with formation of multiple tuberculomas (pre-infliximab), and (C) week 21 post–commencement of TB therapy and after 3 doses of infliximab, demonstrating complete resolution of brain tuberculomas. Abbreviations: MRI, magnetic resonance imaging; TB, tuberculosis.
Figure 2. T1-weighted postgadolinium MRI brain images demonstrating evolution of spinal tuberculomas in Case 3; pre– and post–infliximab use. MRI of the spine at (A) time of presentation, (B) week 7 post–commencement of TB therapy with formation of spinal cord tuberculoma (pre-infliximab), and (C) week 21 post–commencement of TB therapy and after 3 doses of infliximab, demonstrating incomplete resolution of spinal cord tuberculoma. Abbreviations: MRI, magnetic resonance imaging; TB, tuberculosis.
Treatment with infliximab resulted in rapid clinical improvement. Fever and headaches briefly recurred before the second monthly dose, with a total of 3 monthly doses administered. High-dose oral steroids were continued for 4 months before slow tapering. Thalidomide and lenalidomide were trialed for longer-term inflammatory suppression, but both resulted in an extensive generalized rash and were discontinued. A progress MRI demonstrated significant improvement in leptomeningeal enhancement and ring-enhancing tuberculomas after 6 months of therapy. The patient returned to Indonesia 8 months after treatment initiation, having regained muscle strength, but sphincter function remained compromised.
Case 4
A 26-year-old male student from India was admitted with cough, weight loss, and lethargy. There were multiple lung cavities on chest computed tomography (CT), but he had no neurological signs and a noncontrast CT scan of the brain detected no intracranial pathology. He commenced treatment on standard first-line therapy without corticosteroids. Within days of treatment initiation, he developed headache, vomiting, and disorientation, with bilateral lower limb weakness and urinary retention. An MRI of the brain and spine demonstrated communicating hydrocephalus with extensive leptomeningeal enhancement involving the spine, as well as multilevel spondylodiscitis with paravertebral abscesses. A lumbar drain was inserted, and high-dose IV dexamethasone was commenced. The rifampicin dose was increased to 900 mg/d, and levofloxacin 750 mg/d was added. M. tuberculosis grown from sputum was subsequently shown to be fully drug susceptible.
Six weeks later, while still on IV dexamethasone, the patient developed new fever, worsening leg weakness, and diplopia. MRI of the brain and spine demonstrated increased basal meningeal enhancement, a new left occipital tuberculoma, and evidence of compressive myelopathy with progression of the spondylodiscitis. Fever and neurological symptoms improved rapidly after a dose of infliximab. Following symptom recrudescence, repeat infliximab doses were given 3, 7, and 17 weeks later, each time followed by prompt improvement. Repeat MRI at 6 months demonstrated resolution of the meningitis, hydrocephalus, tuberculomas, and spondylodiscitis with improvement of the paravertebral abscesses, now regarded as too small for drainage. The antibacterial treatment was rationalized to rifampicin and isoniazid with a plan to treat for 12 months in total.
DISCUSSION
All 4 cases experienced clinical deterioration despite adequate antibacterial treatment and high-dose corticosteroids. In every instance, infliximab therapy was followed by rapid clinical improvement; no adverse effects were reported. The pronounced and consistent temporal association in clinical improvement, as well as MRI and/or PET changes, suggests a strong therapeutic effect. Our findings support the observation that TNFα is a key driver of inflammation in TB meningitis [11], consistent with the therapeutic effect observed in previous reports [6–10], including those using other TNFα inhibitors, such as adalimumab [12] and thalidomide [3]. Monoclonal antibodies do not usually cross the blood–brain barrier but may do so in the presence of meningeal inflammation and barrier disruption. In rats with hepatic encephalopathy, infliximab significantly reduced neuroinflammation, as demonstrated on immunohistochemistry [13]. In all reported cases, infliximab was only considered after other treatment options were exhausted, but earlier commencement may have prevented some of the invasive procedures and permanent sequelae. It should be emphasized that anti-TNFα treatment should only be contemplated in the presence of effective antibacterial therapy with adequate CSF penetration [14].
The optimal timing and duration of anti-TNFα treatment, as well as the value of corticosteroid co-administration, remains unclear. Symptomatic improvement, inflammatory markers (if raised to begin with), and MRI or PET changes may guide treatment duration; 3–4 doses of infliximab led to significant and durable clinical improvement in all patients. Although optimal dosing and timing of delivery remain uncertain, a rational approach may be to give 5 mg/kg at 0, 2, and 6 weeks (similar to induction dosing recommended for patients with active psoriatic arthritis), with consideration of additional doses at 10–14 weeks guided by the treatment response. This is based on 3 monthly doses provided in the first description of infliximab use in TB meningitis [6] and the fact that our patients experienced “breakthrough symptoms” before the second monthly dose. Therapeutic drug monitoring would be useful to inform dosing schedules [15] but is rarely available and was not performed in our patients. The added value of high-dose corticosteroids is uncertain and requires further evaluation; in reported cases, deterioration occurred under “steroid cover.”
Randomized controlled trials to assess the benefit of infliximab use in tuberculous meningitis, in conjunction with effective antibacterial treatment, would be highly informative and might be considered in the following situations: (1) in immune-competent (HIV-uninfected) patients with paradoxical reactions, (2) in TB/HIV-coinfected patients who experience immune reconstitution inflammatory syndrome (IRIS) affecting the central nervous system, and (3) as part of routine care to prevent severe and irreversible sequelae. Multicenter recruitment using standardized methods is preferred [16], although the numbers required to detect a pronounced therapeutic effect, which is the key clinical need, would be relatively small.
Table 1. Tuberculous Meningitis Cases With Paradoxical Reactions Treated With Infliximab
Case Diagnosis at Presentation Site of Paradoxical Reaction TB Treatment Regimen Other Treatment Before and After Infliximab Infliximab Dose Outcome
Case 1:
Flinders Hospital, Adelaide,
36 y, male
HIV uninfected,
Indiaa Miliary TB with TBM Multiple brain tuberculomas and obstructed CSF flow with raised ICP Empiric HRZE,
thenc
high-dose mfx, amk, lzdd, pto, Z, bdq, cfz Before: High-dose steroidsb for 3 mo
After: High-dose steroids for 4 mo; tapered over 2 mo 10 mg/kg
monthly x3
Rapid fever resolution with CRP decline; improved sensorium allowing weaning off the ventilator within days;
long term—mild cognitive deficit, require assistance with activities of daily living
Case 2:
Concord Hospital, Sydney,
32 y, female
HIV uninfected,
Chinaa Miliary TB with TBM Multiple spinal tuberculomas with edema and local mass effect Empiric HRZE,
thene
RZE + mfx Before: High-dose steroids for 2 mo; decompressive spinal surgery
After: High-dose steroids for 2 mo; tapered over 1 mo 5 mg/kg
0, 2, 6, and 14 wk Rapid restoration of bladder function (2 wk) and mobility (3–4 wk);
long term—full neurological recovery
Case 3:
Royal North Shore Hospital, Sydney,
55 y, female
HIV uninfected,
Indonesiaa TBM and necrotic lymph-adenitis Multiple brain and spinal cord tuberculomas with cauda equina syndrome HRZ + mfx Before: High-dose steroids for 2 mo
After: High-dose steroids for 4 mo; tapered over 2 mo; failed trial of thalidomide 5 mg/kg
monthly x3
Rapid resolution of fever and meningism; improvement in lower limb power;
long term—incomplete recovery with compromised sphincter function at discharge; regained mobility with ongoing improvement in lower limb power
Case 4:
Westmead Hospital, Sydney,
26 y, male
HIV uninfected,
Indiaa
PTB with CNS and bone involvement Multiple brain and spinal tuberculomas with raised ICP, compressive spinal myelopathy, and cold abscesses Empiric HRZE,
then
HR (900 mg) Z + lfx
Before: High-dose steroids for 6 wk with unsuccessful weaning
After: High-dose steroids for 2 mo; tapered over 1 mo 10 mg/kg
(0, 3 wk)
5 mg/kg
(7, 17 wk) Rapid resolution of fever and neurological improvement (reduced pressure effects);
long term—regained sphincter function and mobility with ongoing improvement on rehabilitation
Abbreviations: amk, amikacin; bdq, edaquiline; cfz, clofazimine; CNS, central nervous system; E, ethambutol; H, isoniazid; ICP, intracranial pressure; lfx, levofloxacin; lzd, linezolid; mfx, moxifloxacin; PTB, pulmonary TB; pto, prothionamide; R, rifampicin; TB, tuberculosis; TBM, TB meningitis; Z, pyrazinamide.
aCountry of origin.
bHigh-dose steroids included intravenous dexamethasone (4–8 mg 3–4x/d) and/or oral prednisone (1–2 mg/kg/d - maximum 60 mg/d).
cAfter identification of pan-resistance to all first-line drugs, including high-level isoniazid and low-level moxifloxacin resistance.
dLinezolid (6 months) and amikacin (12 months) stopped after demonstrated toxicity.
eIsoniazid replaced by moxifloxacin given high-level isoniazid monoresistance.
Acknowledgments
Financial support. None.
Potential conflicts of interest. None of the authors have financial relationships relevant to this article. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
Patient consent. Patients were treated at 4 different hospitals with different case report requirements. All institutional requirements and local ethical standards were met. Written patient consent was provided in all instances, except 1 patient who left Australia. No patient identifiers were disclosed, and all patients/families indicated agreement that relevant clinical information could be shared for academic purposes in order for other patients to benefit from the knowledge gained. | AMIKACIN, BEDAQUILINE, CLOFAZIMINE, INFLIXIMAB, LINEZOLID, MOXIFLOXACIN, PROTIONAMIDE, PYRAZINAMIDE | DrugsGivenReaction | CC BY-NC-ND | 33542942 | 20,453,576 | 2021-01 |
What was the dosage of drug 'INFLIXIMAB'? | Use of Infliximab to Treat Paradoxical Tuberculous Meningitis Reactions.
We documented dramatic responses to infliximab in 4 tuberculous meningitis cases with severe paradoxical reactions after effective antibacterial treatment, despite high-dose steroids. In every instance, infliximab was used as a last resort after all other options were exhausted, resulting in delayed initiation that may have adversely affected patient outcomes.
Tuberculous meningitis frequently results in permanent neurological sequelae [1, 2]. The characteristic inflammatory exudate at the base of the brain may block cerebrospinal fluid (CSF) flow with resultant hydrocephalus or cause cerebral ischemia and stroke secondary to vasculitis [1, 2]. Mass effects associated with localized inflammation may also compromise critical structures, such as the optic chiasm [3]. These effects may occur with natural disease progression or as a paradoxical reaction, generally defined as clinical worsening after initial improvement on appropriate antibacterial treatment.
Tumor necrosis factor (TNFα) is critical for effective host defense against mycobacteria, and monoclonal antibodies that inhibit TNFα, such as infliximab, greatly increase tuberculosis vulnerability [4]. On the other hand, deterioration of tuberculosis patients after infliximab cessation suggests that TNFα may also contribute to disease pathology [5]. The use of infliximab to control paradoxical reactions in a patient with tuberculous meningitis was first demonstrated in 2008 [6]. Subsequent case reports support the initial observations [7–10], but awareness of infliximab benefit in select cases is low and completely overshadowed by the perception of risk. Most clinicians remain highly reluctant to consider infliximab use in any tuberculosis patient.
We present a series of tuberculous meningitis cases with likely paradoxical reactions in whom infliximab was used with good effect. The Table 1 provides an overview of the case presentation, treatment, clinical progress, and outcome, with a focus on the administration and clinical effect of infliximab.
Case 1
A 36-year-old male bus driver who migrated to Australia from India 15 months prior was diagnosed with miliary tuberculosis and cerebral tuberculomas. Sputum, bronchoalveolar lavage (BAL), cerebrospinal fluid (CSF), and blood were all culture negative at the time. He was discharged home on isoniazid, rifampicin, pyrazinamide, ethambutol, and oral prednisolone. Interim brain magnetic resonance imaging (MRI) showed improvement of tuberculomas before readmission 6 weeks later with new-onset ataxia and drowsiness. Findings on the repeat MRI included hydrocephalus and cerebritis, with the patient experiencing rapid progression to coma requiring intubation and ventilation.
A brain biopsy was performed, and an external ventricular drain was inserted. The brain biopsy tested Xpert MTB/Rif positive, with rifampicin resistance detected. Empiric MDR treatment was commenced with moxifloxacin, amikacin, prothionamide, and linezolid added, awaiting culture results. Phenotypic drug susceptibility testing (DST) identified resistance to all first-line drugs with additional low-level resistance to moxifloxacin; line probe assays identified katG, rpoB, and gyrA mutations. First-line treatment, except pyrazinamide, was stopped, and the patient was continued on high-dose moxifloxacin with the addition of bedaquiline and clofazimine. On this regimen, the patient slowly improved and became more responsive, before deteriorating a second time with new midbrain tuberculomas, multiple infarcts, and increasing leptomeningeal enhancement on MRI.
In the absence of a clinical response to high-dose intravenous (IV) dexamethasone, a “trial dose” of infliximab was given. Fever and C-reactive protein (CRP) settled promptly, and the patient’s sensorium improved within days, allowing him to be weaned off the ventilator. Symptoms recrudesced 3 weeks later, with new parenchymal foci and increased enhancement around existing tuberculomas seen on MRI. A second dose of infliximab induced another prompt response, and the patient continued to make a slow recovery, receiving a total of 3 monthly doses. Linezolid (after 6 months) and amikacin (after 12 months) were ceased due to bone marrow suppression and sensorineural hearing loss, respectively. In total, the patient completed 24 months of treatment and was discharged to a disability home, where he lives independently with minimal caregiver help.
Case 2
A 32-year-old woman (on TB treatment) presented with a 7-day history of bilateral thigh pain and paraesthesia, gait disturbance, and urinary retention. Spinal MRI revealed compressive lesions at T5 and T11/12, occurring 4 months after commencing treatment for culture-confirmed miliary tuberculosis; CSF was not assessed at the time. Tuberculosis treatment consisted of isoniazid, rifampicin, pyrazinamide, ethambutol (isoniazid discontinued after documented high-level resistance), and moxifloxacin, with excellent treatment adherence and no vomiting or clinical indication of malabsorption, such as diarrhea. High-dose IV dexamethasone was initiated, and an urgent T4-6 and T11-12 laminectomy was performed, which was complicated by dense pachymeningeal adhesions. With new-onset fecal incontinence, further debulking of the T11/12 lesion was performed, but distressing symptoms persisted.
Histopathology from both lesions showed necrotizing granulomas that were negative for acid fast bacilli and mycobacterial growth. In the absence of live bacilli or any documented steroid response, infliximab was started, with rapid clinical improvement. Full bowel and bladder control, as well as mobility, was regained within 2 weeks. In the absence of raised inflammatory markers, serial positron emission tomography (PET) scans were used to track treatment response with significant reduction in glucose uptake at 2 months and no ongoing activity detected at 4 months, when infliximab treatment was stopped.
Case 3
A 53-year-old woman visiting from Indonesia presented with paraplegia, fecal incontinence, and urinary retention, as well as headache and a third cranial nerve palsy. Extensive intracranial and intraspinal leptomeningeal and pachymeningeal enhancement was demonstrated on MRI. Her CSF grew a fully susceptible strain of Mycobacterium tuberculosis. Therapy with isoniazid, rifampicin, pyrazinamide, and moxifloxacin together with high-dose steroids led to initial improvement with resolution of headaches and the third nerve palsy, but after 7 weeks of treatment and while still on high-dose steroids, the patient experienced worsening headaches and new-onset vomiting. Repeat MRI demonstrated increased leptomeningeal inflammation with multiple new intracranial and intraspinal tuberculomas (Figures 1 and 2).
Figure 1. T1-weighted postgadolinium MRI brain images demonstrating evolution of brain tuberculomas in Case 3; pre– and post–infliximab use. MRI of the brain at (A) time of presentation, (B) week 7 post–commencement of TB therapy with formation of multiple tuberculomas (pre-infliximab), and (C) week 21 post–commencement of TB therapy and after 3 doses of infliximab, demonstrating complete resolution of brain tuberculomas. Abbreviations: MRI, magnetic resonance imaging; TB, tuberculosis.
Figure 2. T1-weighted postgadolinium MRI brain images demonstrating evolution of spinal tuberculomas in Case 3; pre– and post–infliximab use. MRI of the spine at (A) time of presentation, (B) week 7 post–commencement of TB therapy with formation of spinal cord tuberculoma (pre-infliximab), and (C) week 21 post–commencement of TB therapy and after 3 doses of infliximab, demonstrating incomplete resolution of spinal cord tuberculoma. Abbreviations: MRI, magnetic resonance imaging; TB, tuberculosis.
Treatment with infliximab resulted in rapid clinical improvement. Fever and headaches briefly recurred before the second monthly dose, with a total of 3 monthly doses administered. High-dose oral steroids were continued for 4 months before slow tapering. Thalidomide and lenalidomide were trialed for longer-term inflammatory suppression, but both resulted in an extensive generalized rash and were discontinued. A progress MRI demonstrated significant improvement in leptomeningeal enhancement and ring-enhancing tuberculomas after 6 months of therapy. The patient returned to Indonesia 8 months after treatment initiation, having regained muscle strength, but sphincter function remained compromised.
Case 4
A 26-year-old male student from India was admitted with cough, weight loss, and lethargy. There were multiple lung cavities on chest computed tomography (CT), but he had no neurological signs and a noncontrast CT scan of the brain detected no intracranial pathology. He commenced treatment on standard first-line therapy without corticosteroids. Within days of treatment initiation, he developed headache, vomiting, and disorientation, with bilateral lower limb weakness and urinary retention. An MRI of the brain and spine demonstrated communicating hydrocephalus with extensive leptomeningeal enhancement involving the spine, as well as multilevel spondylodiscitis with paravertebral abscesses. A lumbar drain was inserted, and high-dose IV dexamethasone was commenced. The rifampicin dose was increased to 900 mg/d, and levofloxacin 750 mg/d was added. M. tuberculosis grown from sputum was subsequently shown to be fully drug susceptible.
Six weeks later, while still on IV dexamethasone, the patient developed new fever, worsening leg weakness, and diplopia. MRI of the brain and spine demonstrated increased basal meningeal enhancement, a new left occipital tuberculoma, and evidence of compressive myelopathy with progression of the spondylodiscitis. Fever and neurological symptoms improved rapidly after a dose of infliximab. Following symptom recrudescence, repeat infliximab doses were given 3, 7, and 17 weeks later, each time followed by prompt improvement. Repeat MRI at 6 months demonstrated resolution of the meningitis, hydrocephalus, tuberculomas, and spondylodiscitis with improvement of the paravertebral abscesses, now regarded as too small for drainage. The antibacterial treatment was rationalized to rifampicin and isoniazid with a plan to treat for 12 months in total.
DISCUSSION
All 4 cases experienced clinical deterioration despite adequate antibacterial treatment and high-dose corticosteroids. In every instance, infliximab therapy was followed by rapid clinical improvement; no adverse effects were reported. The pronounced and consistent temporal association in clinical improvement, as well as MRI and/or PET changes, suggests a strong therapeutic effect. Our findings support the observation that TNFα is a key driver of inflammation in TB meningitis [11], consistent with the therapeutic effect observed in previous reports [6–10], including those using other TNFα inhibitors, such as adalimumab [12] and thalidomide [3]. Monoclonal antibodies do not usually cross the blood–brain barrier but may do so in the presence of meningeal inflammation and barrier disruption. In rats with hepatic encephalopathy, infliximab significantly reduced neuroinflammation, as demonstrated on immunohistochemistry [13]. In all reported cases, infliximab was only considered after other treatment options were exhausted, but earlier commencement may have prevented some of the invasive procedures and permanent sequelae. It should be emphasized that anti-TNFα treatment should only be contemplated in the presence of effective antibacterial therapy with adequate CSF penetration [14].
The optimal timing and duration of anti-TNFα treatment, as well as the value of corticosteroid co-administration, remains unclear. Symptomatic improvement, inflammatory markers (if raised to begin with), and MRI or PET changes may guide treatment duration; 3–4 doses of infliximab led to significant and durable clinical improvement in all patients. Although optimal dosing and timing of delivery remain uncertain, a rational approach may be to give 5 mg/kg at 0, 2, and 6 weeks (similar to induction dosing recommended for patients with active psoriatic arthritis), with consideration of additional doses at 10–14 weeks guided by the treatment response. This is based on 3 monthly doses provided in the first description of infliximab use in TB meningitis [6] and the fact that our patients experienced “breakthrough symptoms” before the second monthly dose. Therapeutic drug monitoring would be useful to inform dosing schedules [15] but is rarely available and was not performed in our patients. The added value of high-dose corticosteroids is uncertain and requires further evaluation; in reported cases, deterioration occurred under “steroid cover.”
Randomized controlled trials to assess the benefit of infliximab use in tuberculous meningitis, in conjunction with effective antibacterial treatment, would be highly informative and might be considered in the following situations: (1) in immune-competent (HIV-uninfected) patients with paradoxical reactions, (2) in TB/HIV-coinfected patients who experience immune reconstitution inflammatory syndrome (IRIS) affecting the central nervous system, and (3) as part of routine care to prevent severe and irreversible sequelae. Multicenter recruitment using standardized methods is preferred [16], although the numbers required to detect a pronounced therapeutic effect, which is the key clinical need, would be relatively small.
Table 1. Tuberculous Meningitis Cases With Paradoxical Reactions Treated With Infliximab
Case Diagnosis at Presentation Site of Paradoxical Reaction TB Treatment Regimen Other Treatment Before and After Infliximab Infliximab Dose Outcome
Case 1:
Flinders Hospital, Adelaide,
36 y, male
HIV uninfected,
Indiaa Miliary TB with TBM Multiple brain tuberculomas and obstructed CSF flow with raised ICP Empiric HRZE,
thenc
high-dose mfx, amk, lzdd, pto, Z, bdq, cfz Before: High-dose steroidsb for 3 mo
After: High-dose steroids for 4 mo; tapered over 2 mo 10 mg/kg
monthly x3
Rapid fever resolution with CRP decline; improved sensorium allowing weaning off the ventilator within days;
long term—mild cognitive deficit, require assistance with activities of daily living
Case 2:
Concord Hospital, Sydney,
32 y, female
HIV uninfected,
Chinaa Miliary TB with TBM Multiple spinal tuberculomas with edema and local mass effect Empiric HRZE,
thene
RZE + mfx Before: High-dose steroids for 2 mo; decompressive spinal surgery
After: High-dose steroids for 2 mo; tapered over 1 mo 5 mg/kg
0, 2, 6, and 14 wk Rapid restoration of bladder function (2 wk) and mobility (3–4 wk);
long term—full neurological recovery
Case 3:
Royal North Shore Hospital, Sydney,
55 y, female
HIV uninfected,
Indonesiaa TBM and necrotic lymph-adenitis Multiple brain and spinal cord tuberculomas with cauda equina syndrome HRZ + mfx Before: High-dose steroids for 2 mo
After: High-dose steroids for 4 mo; tapered over 2 mo; failed trial of thalidomide 5 mg/kg
monthly x3
Rapid resolution of fever and meningism; improvement in lower limb power;
long term—incomplete recovery with compromised sphincter function at discharge; regained mobility with ongoing improvement in lower limb power
Case 4:
Westmead Hospital, Sydney,
26 y, male
HIV uninfected,
Indiaa
PTB with CNS and bone involvement Multiple brain and spinal tuberculomas with raised ICP, compressive spinal myelopathy, and cold abscesses Empiric HRZE,
then
HR (900 mg) Z + lfx
Before: High-dose steroids for 6 wk with unsuccessful weaning
After: High-dose steroids for 2 mo; tapered over 1 mo 10 mg/kg
(0, 3 wk)
5 mg/kg
(7, 17 wk) Rapid resolution of fever and neurological improvement (reduced pressure effects);
long term—regained sphincter function and mobility with ongoing improvement on rehabilitation
Abbreviations: amk, amikacin; bdq, edaquiline; cfz, clofazimine; CNS, central nervous system; E, ethambutol; H, isoniazid; ICP, intracranial pressure; lfx, levofloxacin; lzd, linezolid; mfx, moxifloxacin; PTB, pulmonary TB; pto, prothionamide; R, rifampicin; TB, tuberculosis; TBM, TB meningitis; Z, pyrazinamide.
aCountry of origin.
bHigh-dose steroids included intravenous dexamethasone (4–8 mg 3–4x/d) and/or oral prednisone (1–2 mg/kg/d - maximum 60 mg/d).
cAfter identification of pan-resistance to all first-line drugs, including high-level isoniazid and low-level moxifloxacin resistance.
dLinezolid (6 months) and amikacin (12 months) stopped after demonstrated toxicity.
eIsoniazid replaced by moxifloxacin given high-level isoniazid monoresistance.
Acknowledgments
Financial support. None.
Potential conflicts of interest. None of the authors have financial relationships relevant to this article. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
Patient consent. Patients were treated at 4 different hospitals with different case report requirements. All institutional requirements and local ethical standards were met. Written patient consent was provided in all instances, except 1 patient who left Australia. No patient identifiers were disclosed, and all patients/families indicated agreement that relevant clinical information could be shared for academic purposes in order for other patients to benefit from the knowledge gained. | 30 MG/KG, EVERY ONE MONTH | DrugDosageText | CC BY-NC-ND | 33542942 | 20,453,576 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Condition aggravated'. | Clinical spectrum of ischaemic arterial diseases associated with COVID-19: a series of four illustrative cases.
Severe coronavirus-induced disease 2019 (COVID-19) leads to acute respiratory distress syndrome with an increased risk of venous thrombo-embolic events. To a much lesser extent, arterial thrombo-embolic events have also been reported in this setting.
Here, we describe four different cases of COVID-19 infection with ischaemic arterial events, such as a myocardial infarction with high thrombus load, ischaemic stroke on spontaneous thrombosis of the aortic valve, floating thrombus with mesenteric, splenic and renal infarction, and acute limb ischaemia.
Cardiovascular risk factors such as hypertension, obesity, and diabetes are comorbidities most frequently found in patients with a severe COVID-19 infection and are associated with a higher death rate. Our goal is to provide an overview of the clinical spectrum of ischaemic arterial events that may either reveal or complicate COVID-19. Several suspected pathophysiological mechanisms could explain the association between cardiovascular events and COVID-19 (role of systemic inflammatory response syndrome, endothelial dysfunction, activation of coagulation cascade leading to a hypercoagulability state, virus-induced secondary antiphospholipid syndrome). We need additional studies of larger size, to estimate the incidence of these arterial events and to assess the efficacy of anticoagulation therapy.
Learning points
Cardiovascular risk factors are comorbidities most frequently found in patients with a severe coronavirus-induced disease 2019 (COVID-19) infection and are associated with higher death rate.
Arterial thrombo-embolic event in COVID-19 infection may affect multiple territories such as myocardial infarction or ischaemic stroke and may either reveal or complicate COVID-19.
Endothelial dysfunction, sepsis-induced coagulopathy, virus-induced antiphospholipid syndrome, and systemic inflammatory response syndrome are the main pathophysiological mechanisms that could explain the association between arterial thrombo-embolic events and COVID-19.
Introduction
Adult patients with coronavirus-induced disease 2019 (COVID-19) can remain asymptomatic, present with fever and mild respiratory symptoms or show extensive pneumonia, which can lead to a life-threatening acute respiratory distress syndrome. Clinicians have already reported that infection with COVID-19 can be associated with various cardiac manifestations,1 venous thromboembolic events (VTEs),2,3 and sepsis-induced coagulopathy (SIC).4 The presence of cardiac involvement is associated with poor prognosis.5 COVID-19-associated arterial manifestations seem less frequent than VTE and their characteristics are still poorly known.
Here, we report four cases from our institution, encompassing the spectrum of arterial thrombo-embolic events in the context of COVID-19.
Timeline
Patient 1 Patient 2 Patient 3 Patient 4
Age (years) 57 57 50 36
Gender Male Male Male Male
Ethnicity African Caucasian African African
Cardiovascular risk factors Hypertension, obesity Type 2 diabetes, obesity Obesity None
First symptoms of COVID-19 March 15
Fever, cough, and asthenia
March 16
Fever, cough, asthenia, and dyspnoea
March 21
Fever, cough, asthenia, and dyspnoea
March 27
Fever, cough, diarrhoea, ageusia, and dyspnoea
Diagnostic evidence for COVID-19 (diagnosis of COVID-19 infection was based on positivity of reverse transcription polymerase chain reaction (RT-PCR) or serology or computed tomography (CT) scan showing typical lesions) April 5
Pulmonary CT
March 26
RT-PCR and pulmonary CT
March 25
RT-PCR
April 10
Pulmonary CT
Serology
Arterial event April 5
Floating thrombus within the aortic arch: left subclavian artery thrombosis
April 30
Intra-aortic thrombi: mesenteric, splenic, and renal infarction, ischaemia of the lower limbs
March 25
Myocardial infarction: occlusion of the proximal left circumflex artery
April 13
Spontaneous thrombosis of the aortic valve: occlusion of the M2 segment of the middle cerebral artery
D-dimer (µg/L)
Reference range (RR) < 500
NA 1169 2804 1971
Fibrinogen (g/L)
RR 2–4
6.3 NA 8.0 5.2
Activated partial thromboplastin time (s)
RR < 1.2 s
29.6 NA NA 31.8
Prothrombin time (s)
RR 10–13 s
13.2 12.8 13.5 13.4
C-reactive protein (mg/L)
RR <5 mg/l
26 139 100 19
Antiphospholipid serology Lupus anticoagulant doubtful Anti-cardiolipin IgM 21 NA Negative
Treatment Thrombectomy and intravenous (IV) unfractionated heparin (UFH) Low-dose aspirin and IV UFH Dual antiplatelet therapy, thrombectomy and stent implantation, anti-GPIIb/IIIa and IV UFH Thrombolysis, mechanical thrombectomy and IV UFH
Follow-up and outcome Successful treatment, discharge at Day 5 Critical limb ischaemia, planned revascularization surgery, discharge at Day 15 Successful treatment, discharge at Day 4 Successful thrombectomy, discharge at Day 17
Case presentation
Case 1
A non-smoker 57-year-old man, with a history of hypertension, was referred to the emergency care unit (ECU) of Henri Mondor University Hospital, in Créteil, France, on 5 April 2020, for syncope and severe pain in the left arm, suggestive of acute ischaemia and/or acute dissection. He had previously consulted his general practitioner for fever and asthenia, symptoms had spontaneously resolved.
Upon admission, his temperature was 36.2°C, blood pressure measured at the right arm was 150/85 mmHg, and heart rate was 84 b.p.m. Body mass index (BMI) 30.3 kg/m2. Oxygen saturation was 98% (room air), respiratory rate was normal. There was a left upper-limb motor deficit (grade 1/5) and an abolition of the pulses of the left upper limb. Lung auscultation was unremarkable.
The computed tomography (CT) angiography (CTA) scan of the thoracic aorta showed left subclavian artery thrombosis and ulcerated plaques with floating thrombus within the aortic arch (Figure 1). Chest CT revealed the presence of ground-glass opacities in both lungs with mild extension, typical of COVID-19. Laboratory results on admission showed elevated C-reactive protein (CRP) 26.0 mg/L [reference range (RR) < 5 mg/L]. The electrocardiogram (EKG) was normal.
Figure 1 Computed tomography scan showing floating thrombus of the thoracic aorta.
An arteriography with thrombectomy was performed and the patient was later treated with intravenous (IV) unfractionated heparin (UFH).
Transthoracic echography (TTE) was normal. There was a prolongation of the activated partial thromboplastin time and the search for lupus anticoagulant (LA) was inconclusive. The outcome was favourable after 4 days of IV UFH, the patient was discharged on April 10 on vitamin K antagonist (VKA) therapy.
Case 2
A 57-year-old man, with a previous history of uncomplicated type 2 diabetes, was admitted to the ECU on 26 March 2020, for dyspnoea and fever.
Upon admission, his temperature was 37.2°C, blood pressure was 132/87 mmHg, and heart rate was 107 b.p.m. BMI 27.8 kg/m2. Oxygen saturation was 86% (room air) and respiratory rate was 20/per min. Lung auscultation was normal.
Laboratory results showed: elevated CRP (52.4 mg/L) and lymphocytopenia. Results for the reverse transcription polymerase chain reaction (RT-PCR) for COVID-19 were positive. Chest CT showed ground-glass opacities and peripheral condensations in both lungs with severe extension (over 50%), typical of COVID-19.
On Day 1, the patient was provided with oxygen therapy at 4 L/min, anti-viral treatment with hydroxychloroquine and antibiotic therapy, given the suspicion of a concomitant bacterial infection, and a prophylactic dose of low-molecular-weight heparin (LMWH). On Day 2, respiratory parameters declined and oxygen therapy was increased at 9 L/min. I.V Tocilizumab was administered off-label at 800 mg, allowing stabilization of the respiratory state. On April 30, the patient complained of a pain in the right leg, associated with a cyanotic appearance. The arterial Doppler ultrasound revealed features of acute ischaemia of the right leg, with occlusion of the right superficial femoral artery. The CTA of the abdominal aorta and lower limbs showed multiple intra-aortic thrombi, occlusion of the distal superior mesenteric artery, splenic and renal ischaemic lesions, occlusion of the right superficial femoral artery at the canal of Hunter and occlusion of the left supra-articular popliteal artery (Figure 2). EKG was normal.
Figure 2 Computed tomography scan showing left subclavian artery occlusion.
The patient was given low-dose aspirin and IV UFH. Thrombectomy or thrombolysis could not be performed, as his respiratory state did not allow general anaesthesia.
TTE showed physiological mitral regurgitation. Immunoglobulin (IgM) M anti-cardiolipin antibodies (aCls) were slightly positive at 21 Units Isotype M Phospholipid (UMPL, RR <20 UMPL), IgG aCl were negative, as well as anti-β2GP1 antibodies.
The patient’s ischaemic manifestations improved under anticoagulation first by IV UFH and then VKA, repeat investigations by CTA and new assessment of aCl were scheduled a month later to discuss a revascularization surgery. The patient was transferred to a rehabilitation unit on April 10.
Case 3
A 50-year-old man with a history of obesity presented to the ECU for an ongoing chest pain for 3 h. He had been suffering from a flu-like syndrome for the past 4 days and intermittent chest pain for 48 h. Clinical examination revealed fever (38.1°C) and low oxygen saturation (90%) without acute respiratory failure. Initial EKG showed lateral ST-elevation. The patient was treated with dual antiplatelet and anticoagulant therapies and immediately transferred for coronary angiogram. The coronary angiogram revealed an acute occlusion of the proximal left circumflex artery with a high thrombus load, successfully treated through thrombectomy and followed by stent implantation (Figure 3). Given the high thrombus load, treatment with anti-GPIIb/IIIa antibody and UFH was added for 24 and 48 h, respectively. After treatment, the chest pain and ST-segment deviation resolved but dyspnoea sustained, with an oxygen requirement of 5 L/min. Lung auscultation showed bilateral crackles. TTE showed a normal ejection fraction without increase in left ventricular filling pressure. Results from the RT-PCR for COVID-19 came back positive. Evolution was good without any dedicated treatment for COVID-19 and the patient was transferred to a cardiac rehabilitation unit on Day 4.
Figure 3 Computed tomography scan of floating thrombus (left arrow) with splenic (right arrow) and renal infarction.
Case 4
A 36-year-old man presented to the ECU with intermittent chest pain and dyspnoea for the last 24 h. He described an influenza-like illness with cough and ageusia for the past 2 weeks. His wife had previously been tested positive for COVID-19. Clinical examination revealed fever (37.9°C) and a 100% oxygen saturation. Lung auscultation showed bilateral crackles. EKG was normal. Laboratory results showed a high sensitive troponin of 402 ng/L (RR < 14 ng/L) and a CRP of 19 mg/L.
A CT scan revealed areas of ground-glass opacities, suggestive of COVID-19. TTE showed a normal left ejection fraction but with an antero-apical hypokinesia. Coronary angiogram was normal. The cardiac magnetic resonance imaging was inconclusive for a myocarditis associated with COVID-19. He was given a prophylactic dose of LMWH.
Thirty-six hours later, neurological defect including motor aphasia, confusion and right hemiparesis with an NIHSS of 13 appeared. A brain CT scan showed an acute occlusion of the M2 segment of the middle cerebral artery (Figure 3). The patient was treated with thrombolysis and mechanical thrombectomy with complete recovery. The evolution was favourable without recurrence or bleeding. Regarding the aetiology of this stroke, there was no cardiovascular risk factor. TTE was normal, except for a suspicion of patent foramen ovale, without evidence for a pulmonary embolism. Duplex ultrasound found no evidence of deep-vein thrombosis, ruling out the diagnosis of paradoxical embolism. The RT-PCR for COVID-19 was negative, but the clinic and CT scan were sufficient to confirm the infection. Besides COVID-19, there was no other infection (negatives blood cultures). LA was weakly positive. Transoesophageal echocardiography (TOE) was performed and showed vegetation on the aortic valve, suggestive of infective endocarditis, valvular fibroelastoma, or spontaneous thrombosis of the aortic valve (Figure 4). At Day 13, bacterial serology and blood cultures remained negative in the absence of any previous antibiotic therapy. The patient was given IV UFH. A check of TOE at 7 days from the start of heparin shows a complete regression of the thrombus. In the end, the patient was found seropositive for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As such, the most probable scenario was a thrombosis of the aortic valve, following a COVID-19 infection.
Figure 4 Coronary angiogram, the arrow revealing an acute occlusion of the proximal left circumflex artery.
Figure 5 Coronary angiogram, the arrowrevealing an acute occlusion of the proximal left circumflex artery with a high thrombus load.
Figure 6 Computed tomography angiography scan of the cerebral arteries, the arrow showing occlusion of the M2 segment of the middle cerebral artery.
Figure 7 Two-dimensional transoesophageal echocardiography, the arrow showing vegetation appended to a cups of the aortic valve before anticoagulant treatment.
Discussion
There is a high prevalence of cardiovascular risk factors among symptomatic adults patients admitted to hospital for COVID-19.6,7 These comorbidities are associated with a high risk of developing a severe and life-threatening form of the infection.5–8 Whereas an increased incidence of VTE in the context of COVID-19 has been recognized and reported,2,3 data upon COVID-19-associated arterial manifestations remain scarce.
A previous study in China showed that the incidence of stroke among hospitalized patients with Covid-19 was approximately 5%. Patients with stroke had more often biological markers of coagulopathy and a more severe form of the disease with poorer prognosis.9 Similarly, the study by Klok et al.3 found 3.7% of arterial thrombotic events among 184 patients with COVID-19 in intensive care unit (ICU).
Colleagues from Argenteuil, France, recently published a series of seven patients with severe arterial thrombotic events associated with COVID-19. The majority of these were lower limb ischaemia or floating thrombus of the aorta.10
There are several suspected pathophysiological mechanisms to explain the association between cardiovascular events and COVID-19 including:
Endothelial dysfunction: the receptor for viral adhesion is an angiotensin-converting enzyme 2 receptor on endothelial cells,11 with viral replication causing inflammatory cell infiltration, endothelial cell apoptosis, and microvascular prothrombotic effects.12
Activation of coagulation cascade leading to a hypercoagulability state called SIC,13 a precursor state to disseminated intravascular coagulation, associated with elevated prothrombin time, elevated D-dimer, and thrombocytopenia, but without hypofibrinogenemia. It is related to an infection-induced systemic inflammatory response with endothelial dysfunction and microthrombosis with organ failure and usually no bleeding.12 SIC in patients with COVID-19 is associated with an increased risk of death.13
Virus-induced secondary antiphospholipid syndrome has been described in COVID-19 infection,4 although a transient positivity of aCl and/or LA is known in various viral infections.14 These antibodies are usually considered as non-pathogenic and reflect only B cell activation, but their role in promoting venous or arterial thrombotic events during COVID-19 cannot be ruled out at this stage.15
Role of systemic inflammatory response syndrome. Significant inflammation is present in patients with severe COVID-19 infection, based on elevated levels of tumour necrosis factor-α, interleukins (ILs), including IL-1 and IL-6, increased CRP, erythrocyte sedimentation rate and fibrinogen at presentation. These biological disturbances are higher in ICU patients than non-ICU patients. Those cytokines can initiates coagulation activation and thrombin generation via tissue factor expression and suppression of endogenous anticoagulant pathways.12
In order to reduce the incidence of VTE and arterial thrombosis, we need additional studies of larger size, to estimate the incidence of these arterial events and to assess the efficacy of prophylactic or full anticoagulation therapy, as the study by Tang could suggest.16 Another perspective of antithrombotic therapy could be Tissue plasminogen activator treatment.17 The use of active treatments on endothelium such as renin–angiotensin system inhibitors or statin is being considered. Immunosuppressive treatments have shown promising results, dexamethasone reduce deaths by one-third in ventilated patient and by one-fifth in other patients receiving oxygen only.18 Finally, IL blocade seem to be effective in retrospective cohort studies,19 results of randomized trials and impact on thrombotic complications are still pending.
Our study presents an overview of the different arterial thrombo-embolic events encountered in COVID-19. To our surprise, as described in Case 1 and 3, the arterial thrombo-embolic event may reveal the COVID-19 infection. This was also reported in the study of Kashi et al.,10 where arterial ischaemia revealed COVID-19 infection for three out of seven patients.
Unfortunately, in our work, not all cases were proven by RT-PCR, but clinical presentation and CT scan were typical for Patient 1 and SARS-CoV-2 serology was finally positive for Patient 4. CT scan sensitivity is probably overestimated but seems correct in a high prevalence of COVID-19 area like Ile de France.20
Conclusion
Cardiovascular risk factors are comorbidities most frequently found in patients with a severe COVID-19 infection and are associated with a higher death rate. In this report, we have described the clinical spectrum of various ischaemic arterial manifestations associated with COVID-19 infection. Similar to the occurrence of VTE, ischaemic arterial events appear to be more frequently associated during the course of COVID-19 and may also reveal COVID-19. Given the seriousness of these complications, clinicians will have to pay particular attention to any signs suggestive of stroke, myocardial infarction or another sign of peripheral artery disease, for as long as this virus circulates.
Lead author biography
Dr Guillet Henri graduated University School of Medicine of Paris Est Créteil in 2012 and began his medical training at the Henri Mondor University Hospital. He then continued his practical training in the field of internal medicine, haematology, and vascular medicine and is currently working in the Sickle Cell Disease centre in Henri Mondor University Hospital.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The author/s confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patients in line with COPE guidance.
Conflict of interest: none declared.
Funding: none declared.
Figure 8 Two-dimensional transoesophageal echocardiography showing regression of vegetation appended to a cups of the aortic valve after anticoagulant treatment.
Supplementary Material
ytaa488_Supplementary_Data Click here for additional data file. | HYDROXYCHLOROQUINE | DrugsGivenReaction | CC BY-NC | 33542975 | 19,435,942 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Anaphylactic reaction'. | PEG That Reaction: A Case Series of Allergy to Polyethylene Glycol.
Polyethylene glycol (PEG), also known as macrogol, is an excipient in numerous medications, health care products, cosmetics, and foods. It acts as an inert bulking, or stabilizing, agent. Despite its ubiquity, including in 2 of the newly launched vaccines against SARS-CoV-2, awareness of PEG allergy remains low. We present 6 cases of acute hypersensitivity to PEG. Accurate diagnoses in these cases posed a challenge, and although the triggering agents differed, PEG was demonstrated as the common culprit. All cases were female, with a mean age of 36.4 years. Four patients were originally suspected to have nonsteroid anti-inflammatory drug allergy, and 2 had a history of chronic spontaneous urticaria and angioedema. Biphasic allergic reactions featured prominently in this case series. Diagnosis relies on a high index of suspicion leading to a focused clinical history, supported by skin tests with PEG solutions to demonstrate sensitization. This case series highlights important clinical features of this rare, potentially serious, and increasingly recognized excipient allergy.
pmcPolyethylene glycol (PEG), also known as macrogol or E1521, is a commonly used bulking and stabilizing agent. It is an excipient in a wide variety of medications and also encountered in cosmetics and processed foods. Notably, both Pfizer BioNTech and Moderna mRNA vaccines against SARS‐CoV‐2, which are being internationally deployed to combat the current pandemic, contain polyethylene glycol. Allergy to PEG is rare but is increasingly recognized and can be severe. We present a case series to highlight features of this unusual excipient allergy. A high index of suspicion with early referral for expert diagnostic workup is required to implement appropriate risk management strategies.
The incident case experienced anaphylaxis after intramuscular Depo‐Provera administered by her general practitioner. She developed rapid‐onset sneezing, rhinorrhea, urticaria, profound hypotension, and chest tightness. She was managed with 2 doses of intramuscular adrenaline, steroids, and nebulized salbutamol. Symptoms improved; however, 6 hours following initial treatment she experienced further urticaria. The patient had recently tolerated similar progesterone in the oral contraceptive pill. Allergy to an excipient ingredient was suspected. The specific intramuscular formulation contained PEG‐3350 (Table 1). Skin‐prick testing (SPT) was positive and avoidance advised.
Table 1 Patient Case Summary With Triggering Agents and Associated PEG Compounds, Allergic Symptoms Experienced, Outcome of Skin Prick Testing, and Results of Supervised Provocation Challenges Detailed for Each Patient
Case Allergic Disease Trigger Symptoms Negative Provocation Challenge Positive Investigation
Case 1
Female, 35 years
None Depo‐Provera: medroxyprogesterone PEG‐3350 Sneezing, ocular irritation, rhinorrhea, urticaria, hypotension, chest tightness, respiratory compromise.
Biphasic urticaria.
None SPT PEG‐3350:
positive, 7 x 7 mm
Case 2
Female, 25 years
None Nexium: esomeprazole "Macrogols"
MoviPrep: osmotic laxative PEG‐3350
Cosmetics: PEG‐100
Urticaria, angioedema,
Respiratory compromise.
Pruritus, urticaria, angioedema, hypotension, swelling of hands and feet.
Biphasic urticaria.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free
"Teva”:
pantoprazole
PEG‐free
SPT PEG‐3350:
positive, 10 x 11 mm
Case 3
Female, 40 years
None Effervescent vitamin C: HMW‐PEG
Klean Prep: osmotic laxative PEG‐3350.
Vimovo: esomeprazole,
naproxen.
PEG‐8000.
EMLA topical anesthetic:
lidocaine, prilocaine.
HMW‐PEG.
Urticaria, syncope.
Urticaria, angioedema.
Urticaria, presyncopal.
Generalized pruritus.
Cerazette:
desogestrel
PEG‐400
“Teva”:
pantoprazole
PEG‐free
SPT PEG‐400, 3350:
Inconclusive because of dermographism.
Movicol challenge, PEG‐3350: positive
Case 4
Female, 44 years
None Klean Prep: osmotic laxative,
PEG‐3350.
Phosphate Sandoz: effervescent phosphate,
PEG‐4000.
Cosmetics: LMW‐ and HMW‐PEG.
Perioral paresthesia, angioedema, dyspnea, stridor, visual disturbance, syncope.
Angioedema, dyspnea, presyncope.
Urticaria
None SPT PEG‐3350:
positive
Case 5
Female, 36 years
CSUA Motilium Suppository: domperidone,
PEG‐400 and 1000.
Nurofen: ibuprofen,
PEG‐6000.
Angioedema, paresthesia,
throat tightness.
Angioedema, paresthesia,
throat tightness.
Motilium oral tablet:
PEG‐free
Nurofen syrup:
PEG‐free
SPT PEG‐3350:
positive
Case 6
Female, 38 years
CSUA
Physical urticaria
Betadine: wound dressing, povidone‐iodine,
PEG‐400, 6000.
Voltorol Oral: diclofenac
PEG‐8000.
Diclofenac IM:
HMW‐PEG.
Shaving foam: LMW‐ and HMW‐PEG.
Cosmetics: LMW‐ and HMW‐PEG.
Urticaria, presyncopal.
Urticaria.
Urticaria.
Urticaria, angioedema,
respiratory distress, hypotension.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free.
Ibuprofen tablet:
PEG‐free
SPT PEG‐3350:
10 × 10 mm
John Wiley & Sons, Ltd.
The second patient experienced acute urticaria and angioedema following concomitant ibuprofen and esomeprazole ingestion. Nonsteroidal anti‐inflammatory drug (NSAID) sensitivity was initially suspected (Table 1). While awaiting further investigation, she developed urticaria, angioedema, and hypotension following minimal ingestion of the PEG‐containing osmotic laxative Movi‐Prep. Symptoms settled with steroids and antihistamine; however, she experienced further urticaria 6 hours later. In addition, the patient described contact urticaria with certain cosmetics. PEG was suspected as a common trigger, and SPT was supportive (Table 1).
Case 3 had urticaria and syncope within minutes of effervescent vitamin C and separately developed urticaria, angioedema, and throat tightness with difficulty swallowing after the osmotic laxative Klean‐Prep. She gave a history of urticaria associated with Vimovo (esomeprazole and naproxen) and similar symptoms during a dental procedure (Table 1). All identified agents contained high‐molecular‐weight (HMW)‐PEG (Table 1). Unfortunately, SPT was inconclusive because of dermographism (negative control inciting a wheal). A provocation challenge to HMW‐PEG (Movicol) was objectively positive. The patient has remained completely symptom‐free with a PEG avoidance strategy. She has tolerated challenges with PEG‐free medications.
Anaphylaxis to Klean‐Prep was also a presenting feature of the fourth case. A PEG‐3350 allergy was suspected and avoidance advised until formal review at an allergy clinic. In the following months, while awaiting assessment and as a hospital inpatient for an unrelated condition, she had a second anaphylaxis within minutes of taking a PEG‐containing effervescent phosphate replacement preparation. SPT was subsequently positive to PEG‐3350, which has been avoided since.
The fifth patient was referred for assessment of multiple allergic drug reactions, on a background of chronic spontaneous urticaria and angioedema (CSUA). The first episode occurred within minutes of a Motilium suppository and was managed with intramuscular adrenaline, hydrocortisone, chlorphenamine, and fluid resuscitation. The second episode was precipitated by oral ibuprofen, again requiring adrenaline. PEG was considered a likely trigger, SPT was supportive. The patient subsequently tolerated PEG‐free domperidone and ibuprofen (Table 1).
The final case similarly had multiple adverse drug reactions, including anaphylaxis, on a background of CSUA. The initial allergic episode occurred following a Betadine dressing to a wound. She had systemic symptoms with oral and intramuscular diclofenac, oral Solpadeine (paracetamol and codeine), and contact urticaria with various cosmetics (Table 1). The patient subsequently tolerated PEG‐free forms of NSAIDs and codeine. PEG was suspected as a common inciting agent, SPT was supportive and strict avoidance recommended. After diagnosis, the patient experienced anaphylaxis while shaving with a product containing PEG requiring self‐administration of an adrenaline autoinjector.
This case series illustrates the diverse presentations of PEG allergy. Patients experienced an average of 3 allergic episodes before a formal diagnosis consistent with other case series. 1 Reactions were distressing for patients and objectively severe. Media reports of a case of fatal anaphylaxis in a patient with an established diagnosis of PEG allergy highlight the significance of this emerging problem. 2 The true incidence of PEG allergy is difficult to determine and may be underestimated. 3
It is hypothesized that initial PEG‐sensitization could be via cutaneous exposure from cosmetics and hygiene products or absorption of low‐molecular‐weight (LMW)‐PEG in pharmaceuticals. 3 The role of LMW‐PEG exposure prior to hypersensitivity has not been explored and may merit investigation. A female predominance was noted in our case series, but has not been universally observed. 1 , 4 Overall, the literature reports equal incidence between sexes. Interestingly, more recent case reports demonstrate a younger median age of diagnosis compared with older publications. 1 , 5 This is likely multifactorial and may be influenced by improved awareness of drug, and specifically PEG allergy, improved access to specialist allergy services, and potentially earlier or greater opportunity for sensitization. This is something that can only be speculated on because of limited clinical data.
Four of the 6 cases were suspected to have an NSAID allergy that was subsequently ruled out with negative provocation tests (Table 1). This emphasizes the prevalence of understandable misdiagnosis and unnecessary drug restrictions in this cohort. A review published in 2016 identified 37 cases labeled as “PEG‐allergy,” totaling 74 reactions. 4 More than half were associated with laxatives, also prominent allergens in this series. PEG‐3350 has been listed in more than 1000 approved medications. 3 Despite this ubiquity, reported incidence of hypersensitivity appears low. However we demonstrate that reactions can be severe and are diagnostically challenging.
NSAIDs are one of the most common inducers of drug‐related hypersensitivity reactions. 6 PEG sensitivity does not need to be considered in all NSAID‐related reactions. However, there are features that can be divined from an allergy history that offer pointers toward the need for PEG sensitization assessment. Patients with multiple episodes of “unexplained” anaphylaxis or tolerance of individual brands of the same drug merit closer investigation. Reactions to laxatives or bowel preparations, “depo” medications, and mucosal absorption from lubricants, gels, and dressings are red flags that should have PEG hypersensitivity in the differential. Bruusgaard‐Mouritsen et al (2021) similarly highlighted analgesics, depo injections, and laxatives as common triggers in their cohort, as well noting antacids and antibiotics as culprits. 1
We recommend that an adrenaline autoinjector be prescribed to those with PEG allergy because of an ongoing risk of accidental exposure. Unfortunately, comprehensive avoidance list cannot be provided, as medical preparations frequently change; thus, awareness is key. We advise patient empowerment with education, supported by step‐by‐step instructions on how to interrogate summary of product characteristics (SPC) for the variety of terms that indicate a PEG excipient. Patients are advised to engage with pharmacists and inform all health care professionals encountered of the disorder. In addition they should wear alert jewelry and only take a medication when they and their health care professional are satisfied that it does not contain PEG. Effective use of an electronic patient record can assist with communicating this issue, but as with all drug allergy, effective communication among disparate health care providers is a challenge. In addition, the cases presented here suggest a higher rate of biphasic allergic reactions than might be expected. 7 Based on these observations, we recommend extended monitoring for 12 hours after resolution of symptoms following a PEG‐related reaction. Although biphasic symptoms are usually mild, they can be distressing, especially to patients who have had a history of unexplained adverse events.
The identification of PEG allergy is increasing. These cases offer insight into the variety of ways this allergy can present. We report characteristics that flag PEG as a potential trigger and highlight the need for extended observation after resolution of symptoms because of the risk of biphasic reactions. Reports of immediate hypersensitivity in 2 health care workers on the first day of mass COVID‐19 vaccination in the United Kingdom are concerning. 8 It remains unknown if PEG‐2000 is involved in these reactions. Leaders in allergy have already engaged with regulatory authorities to highlight PEG as a possible allergen in mRNA vaccines and to support the objective investigation of reported reactions. 9
PEG allergy is now well known among allergy professionals. However, increased awareness of this allergen among the wider medical community is needed. Early recognition through a thorough clinical history and rapid referral to allergy diagnostic centers is required to confirm the diagnosis and effectively manage this high‐risk drug allergy.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Funding
We did not receive funding for this study.
Data‐Sharing Statement
Please contact the corresponding author, Dr Fionnuala Cox, on coxff@tcd.ie, if you wish to request further information on study data.
Author Contributions
F.C. conceived the study and interpreted data. F.C., N.C., and K.K. diagnosed and managed patients. All authors contributed to the writing and approval of the article.
Acknowledgments
We thank the patients and Clinical Immunology Teams in St James's Hospital and Beaumont Hospital, Dublin. | MEDROXYPROGESTERONE ACETATE, POLYETHYLENE GLYCOL 3350 | DrugsGivenReaction | CC BY-NC-ND | 33543766 | 19,443,824 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Chronic spontaneous urticaria'. | PEG That Reaction: A Case Series of Allergy to Polyethylene Glycol.
Polyethylene glycol (PEG), also known as macrogol, is an excipient in numerous medications, health care products, cosmetics, and foods. It acts as an inert bulking, or stabilizing, agent. Despite its ubiquity, including in 2 of the newly launched vaccines against SARS-CoV-2, awareness of PEG allergy remains low. We present 6 cases of acute hypersensitivity to PEG. Accurate diagnoses in these cases posed a challenge, and although the triggering agents differed, PEG was demonstrated as the common culprit. All cases were female, with a mean age of 36.4 years. Four patients were originally suspected to have nonsteroid anti-inflammatory drug allergy, and 2 had a history of chronic spontaneous urticaria and angioedema. Biphasic allergic reactions featured prominently in this case series. Diagnosis relies on a high index of suspicion leading to a focused clinical history, supported by skin tests with PEG solutions to demonstrate sensitization. This case series highlights important clinical features of this rare, potentially serious, and increasingly recognized excipient allergy.
pmcPolyethylene glycol (PEG), also known as macrogol or E1521, is a commonly used bulking and stabilizing agent. It is an excipient in a wide variety of medications and also encountered in cosmetics and processed foods. Notably, both Pfizer BioNTech and Moderna mRNA vaccines against SARS‐CoV‐2, which are being internationally deployed to combat the current pandemic, contain polyethylene glycol. Allergy to PEG is rare but is increasingly recognized and can be severe. We present a case series to highlight features of this unusual excipient allergy. A high index of suspicion with early referral for expert diagnostic workup is required to implement appropriate risk management strategies.
The incident case experienced anaphylaxis after intramuscular Depo‐Provera administered by her general practitioner. She developed rapid‐onset sneezing, rhinorrhea, urticaria, profound hypotension, and chest tightness. She was managed with 2 doses of intramuscular adrenaline, steroids, and nebulized salbutamol. Symptoms improved; however, 6 hours following initial treatment she experienced further urticaria. The patient had recently tolerated similar progesterone in the oral contraceptive pill. Allergy to an excipient ingredient was suspected. The specific intramuscular formulation contained PEG‐3350 (Table 1). Skin‐prick testing (SPT) was positive and avoidance advised.
Table 1 Patient Case Summary With Triggering Agents and Associated PEG Compounds, Allergic Symptoms Experienced, Outcome of Skin Prick Testing, and Results of Supervised Provocation Challenges Detailed for Each Patient
Case Allergic Disease Trigger Symptoms Negative Provocation Challenge Positive Investigation
Case 1
Female, 35 years
None Depo‐Provera: medroxyprogesterone PEG‐3350 Sneezing, ocular irritation, rhinorrhea, urticaria, hypotension, chest tightness, respiratory compromise.
Biphasic urticaria.
None SPT PEG‐3350:
positive, 7 x 7 mm
Case 2
Female, 25 years
None Nexium: esomeprazole "Macrogols"
MoviPrep: osmotic laxative PEG‐3350
Cosmetics: PEG‐100
Urticaria, angioedema,
Respiratory compromise.
Pruritus, urticaria, angioedema, hypotension, swelling of hands and feet.
Biphasic urticaria.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free
"Teva”:
pantoprazole
PEG‐free
SPT PEG‐3350:
positive, 10 x 11 mm
Case 3
Female, 40 years
None Effervescent vitamin C: HMW‐PEG
Klean Prep: osmotic laxative PEG‐3350.
Vimovo: esomeprazole,
naproxen.
PEG‐8000.
EMLA topical anesthetic:
lidocaine, prilocaine.
HMW‐PEG.
Urticaria, syncope.
Urticaria, angioedema.
Urticaria, presyncopal.
Generalized pruritus.
Cerazette:
desogestrel
PEG‐400
“Teva”:
pantoprazole
PEG‐free
SPT PEG‐400, 3350:
Inconclusive because of dermographism.
Movicol challenge, PEG‐3350: positive
Case 4
Female, 44 years
None Klean Prep: osmotic laxative,
PEG‐3350.
Phosphate Sandoz: effervescent phosphate,
PEG‐4000.
Cosmetics: LMW‐ and HMW‐PEG.
Perioral paresthesia, angioedema, dyspnea, stridor, visual disturbance, syncope.
Angioedema, dyspnea, presyncope.
Urticaria
None SPT PEG‐3350:
positive
Case 5
Female, 36 years
CSUA Motilium Suppository: domperidone,
PEG‐400 and 1000.
Nurofen: ibuprofen,
PEG‐6000.
Angioedema, paresthesia,
throat tightness.
Angioedema, paresthesia,
throat tightness.
Motilium oral tablet:
PEG‐free
Nurofen syrup:
PEG‐free
SPT PEG‐3350:
positive
Case 6
Female, 38 years
CSUA
Physical urticaria
Betadine: wound dressing, povidone‐iodine,
PEG‐400, 6000.
Voltorol Oral: diclofenac
PEG‐8000.
Diclofenac IM:
HMW‐PEG.
Shaving foam: LMW‐ and HMW‐PEG.
Cosmetics: LMW‐ and HMW‐PEG.
Urticaria, presyncopal.
Urticaria.
Urticaria.
Urticaria, angioedema,
respiratory distress, hypotension.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free.
Ibuprofen tablet:
PEG‐free
SPT PEG‐3350:
10 × 10 mm
John Wiley & Sons, Ltd.
The second patient experienced acute urticaria and angioedema following concomitant ibuprofen and esomeprazole ingestion. Nonsteroidal anti‐inflammatory drug (NSAID) sensitivity was initially suspected (Table 1). While awaiting further investigation, she developed urticaria, angioedema, and hypotension following minimal ingestion of the PEG‐containing osmotic laxative Movi‐Prep. Symptoms settled with steroids and antihistamine; however, she experienced further urticaria 6 hours later. In addition, the patient described contact urticaria with certain cosmetics. PEG was suspected as a common trigger, and SPT was supportive (Table 1).
Case 3 had urticaria and syncope within minutes of effervescent vitamin C and separately developed urticaria, angioedema, and throat tightness with difficulty swallowing after the osmotic laxative Klean‐Prep. She gave a history of urticaria associated with Vimovo (esomeprazole and naproxen) and similar symptoms during a dental procedure (Table 1). All identified agents contained high‐molecular‐weight (HMW)‐PEG (Table 1). Unfortunately, SPT was inconclusive because of dermographism (negative control inciting a wheal). A provocation challenge to HMW‐PEG (Movicol) was objectively positive. The patient has remained completely symptom‐free with a PEG avoidance strategy. She has tolerated challenges with PEG‐free medications.
Anaphylaxis to Klean‐Prep was also a presenting feature of the fourth case. A PEG‐3350 allergy was suspected and avoidance advised until formal review at an allergy clinic. In the following months, while awaiting assessment and as a hospital inpatient for an unrelated condition, she had a second anaphylaxis within minutes of taking a PEG‐containing effervescent phosphate replacement preparation. SPT was subsequently positive to PEG‐3350, which has been avoided since.
The fifth patient was referred for assessment of multiple allergic drug reactions, on a background of chronic spontaneous urticaria and angioedema (CSUA). The first episode occurred within minutes of a Motilium suppository and was managed with intramuscular adrenaline, hydrocortisone, chlorphenamine, and fluid resuscitation. The second episode was precipitated by oral ibuprofen, again requiring adrenaline. PEG was considered a likely trigger, SPT was supportive. The patient subsequently tolerated PEG‐free domperidone and ibuprofen (Table 1).
The final case similarly had multiple adverse drug reactions, including anaphylaxis, on a background of CSUA. The initial allergic episode occurred following a Betadine dressing to a wound. She had systemic symptoms with oral and intramuscular diclofenac, oral Solpadeine (paracetamol and codeine), and contact urticaria with various cosmetics (Table 1). The patient subsequently tolerated PEG‐free forms of NSAIDs and codeine. PEG was suspected as a common inciting agent, SPT was supportive and strict avoidance recommended. After diagnosis, the patient experienced anaphylaxis while shaving with a product containing PEG requiring self‐administration of an adrenaline autoinjector.
This case series illustrates the diverse presentations of PEG allergy. Patients experienced an average of 3 allergic episodes before a formal diagnosis consistent with other case series. 1 Reactions were distressing for patients and objectively severe. Media reports of a case of fatal anaphylaxis in a patient with an established diagnosis of PEG allergy highlight the significance of this emerging problem. 2 The true incidence of PEG allergy is difficult to determine and may be underestimated. 3
It is hypothesized that initial PEG‐sensitization could be via cutaneous exposure from cosmetics and hygiene products or absorption of low‐molecular‐weight (LMW)‐PEG in pharmaceuticals. 3 The role of LMW‐PEG exposure prior to hypersensitivity has not been explored and may merit investigation. A female predominance was noted in our case series, but has not been universally observed. 1 , 4 Overall, the literature reports equal incidence between sexes. Interestingly, more recent case reports demonstrate a younger median age of diagnosis compared with older publications. 1 , 5 This is likely multifactorial and may be influenced by improved awareness of drug, and specifically PEG allergy, improved access to specialist allergy services, and potentially earlier or greater opportunity for sensitization. This is something that can only be speculated on because of limited clinical data.
Four of the 6 cases were suspected to have an NSAID allergy that was subsequently ruled out with negative provocation tests (Table 1). This emphasizes the prevalence of understandable misdiagnosis and unnecessary drug restrictions in this cohort. A review published in 2016 identified 37 cases labeled as “PEG‐allergy,” totaling 74 reactions. 4 More than half were associated with laxatives, also prominent allergens in this series. PEG‐3350 has been listed in more than 1000 approved medications. 3 Despite this ubiquity, reported incidence of hypersensitivity appears low. However we demonstrate that reactions can be severe and are diagnostically challenging.
NSAIDs are one of the most common inducers of drug‐related hypersensitivity reactions. 6 PEG sensitivity does not need to be considered in all NSAID‐related reactions. However, there are features that can be divined from an allergy history that offer pointers toward the need for PEG sensitization assessment. Patients with multiple episodes of “unexplained” anaphylaxis or tolerance of individual brands of the same drug merit closer investigation. Reactions to laxatives or bowel preparations, “depo” medications, and mucosal absorption from lubricants, gels, and dressings are red flags that should have PEG hypersensitivity in the differential. Bruusgaard‐Mouritsen et al (2021) similarly highlighted analgesics, depo injections, and laxatives as common triggers in their cohort, as well noting antacids and antibiotics as culprits. 1
We recommend that an adrenaline autoinjector be prescribed to those with PEG allergy because of an ongoing risk of accidental exposure. Unfortunately, comprehensive avoidance list cannot be provided, as medical preparations frequently change; thus, awareness is key. We advise patient empowerment with education, supported by step‐by‐step instructions on how to interrogate summary of product characteristics (SPC) for the variety of terms that indicate a PEG excipient. Patients are advised to engage with pharmacists and inform all health care professionals encountered of the disorder. In addition they should wear alert jewelry and only take a medication when they and their health care professional are satisfied that it does not contain PEG. Effective use of an electronic patient record can assist with communicating this issue, but as with all drug allergy, effective communication among disparate health care providers is a challenge. In addition, the cases presented here suggest a higher rate of biphasic allergic reactions than might be expected. 7 Based on these observations, we recommend extended monitoring for 12 hours after resolution of symptoms following a PEG‐related reaction. Although biphasic symptoms are usually mild, they can be distressing, especially to patients who have had a history of unexplained adverse events.
The identification of PEG allergy is increasing. These cases offer insight into the variety of ways this allergy can present. We report characteristics that flag PEG as a potential trigger and highlight the need for extended observation after resolution of symptoms because of the risk of biphasic reactions. Reports of immediate hypersensitivity in 2 health care workers on the first day of mass COVID‐19 vaccination in the United Kingdom are concerning. 8 It remains unknown if PEG‐2000 is involved in these reactions. Leaders in allergy have already engaged with regulatory authorities to highlight PEG as a possible allergen in mRNA vaccines and to support the objective investigation of reported reactions. 9
PEG allergy is now well known among allergy professionals. However, increased awareness of this allergen among the wider medical community is needed. Early recognition through a thorough clinical history and rapid referral to allergy diagnostic centers is required to confirm the diagnosis and effectively manage this high‐risk drug allergy.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Funding
We did not receive funding for this study.
Data‐Sharing Statement
Please contact the corresponding author, Dr Fionnuala Cox, on coxff@tcd.ie, if you wish to request further information on study data.
Author Contributions
F.C. conceived the study and interpreted data. F.C., N.C., and K.K. diagnosed and managed patients. All authors contributed to the writing and approval of the article.
Acknowledgments
We thank the patients and Clinical Immunology Teams in St James's Hospital and Beaumont Hospital, Dublin. | IBUPROFEN | DrugsGivenReaction | CC BY-NC-ND | 33543766 | 19,047,609 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Paraesthesia'. | PEG That Reaction: A Case Series of Allergy to Polyethylene Glycol.
Polyethylene glycol (PEG), also known as macrogol, is an excipient in numerous medications, health care products, cosmetics, and foods. It acts as an inert bulking, or stabilizing, agent. Despite its ubiquity, including in 2 of the newly launched vaccines against SARS-CoV-2, awareness of PEG allergy remains low. We present 6 cases of acute hypersensitivity to PEG. Accurate diagnoses in these cases posed a challenge, and although the triggering agents differed, PEG was demonstrated as the common culprit. All cases were female, with a mean age of 36.4 years. Four patients were originally suspected to have nonsteroid anti-inflammatory drug allergy, and 2 had a history of chronic spontaneous urticaria and angioedema. Biphasic allergic reactions featured prominently in this case series. Diagnosis relies on a high index of suspicion leading to a focused clinical history, supported by skin tests with PEG solutions to demonstrate sensitization. This case series highlights important clinical features of this rare, potentially serious, and increasingly recognized excipient allergy.
pmcPolyethylene glycol (PEG), also known as macrogol or E1521, is a commonly used bulking and stabilizing agent. It is an excipient in a wide variety of medications and also encountered in cosmetics and processed foods. Notably, both Pfizer BioNTech and Moderna mRNA vaccines against SARS‐CoV‐2, which are being internationally deployed to combat the current pandemic, contain polyethylene glycol. Allergy to PEG is rare but is increasingly recognized and can be severe. We present a case series to highlight features of this unusual excipient allergy. A high index of suspicion with early referral for expert diagnostic workup is required to implement appropriate risk management strategies.
The incident case experienced anaphylaxis after intramuscular Depo‐Provera administered by her general practitioner. She developed rapid‐onset sneezing, rhinorrhea, urticaria, profound hypotension, and chest tightness. She was managed with 2 doses of intramuscular adrenaline, steroids, and nebulized salbutamol. Symptoms improved; however, 6 hours following initial treatment she experienced further urticaria. The patient had recently tolerated similar progesterone in the oral contraceptive pill. Allergy to an excipient ingredient was suspected. The specific intramuscular formulation contained PEG‐3350 (Table 1). Skin‐prick testing (SPT) was positive and avoidance advised.
Table 1 Patient Case Summary With Triggering Agents and Associated PEG Compounds, Allergic Symptoms Experienced, Outcome of Skin Prick Testing, and Results of Supervised Provocation Challenges Detailed for Each Patient
Case Allergic Disease Trigger Symptoms Negative Provocation Challenge Positive Investigation
Case 1
Female, 35 years
None Depo‐Provera: medroxyprogesterone PEG‐3350 Sneezing, ocular irritation, rhinorrhea, urticaria, hypotension, chest tightness, respiratory compromise.
Biphasic urticaria.
None SPT PEG‐3350:
positive, 7 x 7 mm
Case 2
Female, 25 years
None Nexium: esomeprazole "Macrogols"
MoviPrep: osmotic laxative PEG‐3350
Cosmetics: PEG‐100
Urticaria, angioedema,
Respiratory compromise.
Pruritus, urticaria, angioedema, hypotension, swelling of hands and feet.
Biphasic urticaria.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free
"Teva”:
pantoprazole
PEG‐free
SPT PEG‐3350:
positive, 10 x 11 mm
Case 3
Female, 40 years
None Effervescent vitamin C: HMW‐PEG
Klean Prep: osmotic laxative PEG‐3350.
Vimovo: esomeprazole,
naproxen.
PEG‐8000.
EMLA topical anesthetic:
lidocaine, prilocaine.
HMW‐PEG.
Urticaria, syncope.
Urticaria, angioedema.
Urticaria, presyncopal.
Generalized pruritus.
Cerazette:
desogestrel
PEG‐400
“Teva”:
pantoprazole
PEG‐free
SPT PEG‐400, 3350:
Inconclusive because of dermographism.
Movicol challenge, PEG‐3350: positive
Case 4
Female, 44 years
None Klean Prep: osmotic laxative,
PEG‐3350.
Phosphate Sandoz: effervescent phosphate,
PEG‐4000.
Cosmetics: LMW‐ and HMW‐PEG.
Perioral paresthesia, angioedema, dyspnea, stridor, visual disturbance, syncope.
Angioedema, dyspnea, presyncope.
Urticaria
None SPT PEG‐3350:
positive
Case 5
Female, 36 years
CSUA Motilium Suppository: domperidone,
PEG‐400 and 1000.
Nurofen: ibuprofen,
PEG‐6000.
Angioedema, paresthesia,
throat tightness.
Angioedema, paresthesia,
throat tightness.
Motilium oral tablet:
PEG‐free
Nurofen syrup:
PEG‐free
SPT PEG‐3350:
positive
Case 6
Female, 38 years
CSUA
Physical urticaria
Betadine: wound dressing, povidone‐iodine,
PEG‐400, 6000.
Voltorol Oral: diclofenac
PEG‐8000.
Diclofenac IM:
HMW‐PEG.
Shaving foam: LMW‐ and HMW‐PEG.
Cosmetics: LMW‐ and HMW‐PEG.
Urticaria, presyncopal.
Urticaria.
Urticaria.
Urticaria, angioedema,
respiratory distress, hypotension.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free.
Ibuprofen tablet:
PEG‐free
SPT PEG‐3350:
10 × 10 mm
John Wiley & Sons, Ltd.
The second patient experienced acute urticaria and angioedema following concomitant ibuprofen and esomeprazole ingestion. Nonsteroidal anti‐inflammatory drug (NSAID) sensitivity was initially suspected (Table 1). While awaiting further investigation, she developed urticaria, angioedema, and hypotension following minimal ingestion of the PEG‐containing osmotic laxative Movi‐Prep. Symptoms settled with steroids and antihistamine; however, she experienced further urticaria 6 hours later. In addition, the patient described contact urticaria with certain cosmetics. PEG was suspected as a common trigger, and SPT was supportive (Table 1).
Case 3 had urticaria and syncope within minutes of effervescent vitamin C and separately developed urticaria, angioedema, and throat tightness with difficulty swallowing after the osmotic laxative Klean‐Prep. She gave a history of urticaria associated with Vimovo (esomeprazole and naproxen) and similar symptoms during a dental procedure (Table 1). All identified agents contained high‐molecular‐weight (HMW)‐PEG (Table 1). Unfortunately, SPT was inconclusive because of dermographism (negative control inciting a wheal). A provocation challenge to HMW‐PEG (Movicol) was objectively positive. The patient has remained completely symptom‐free with a PEG avoidance strategy. She has tolerated challenges with PEG‐free medications.
Anaphylaxis to Klean‐Prep was also a presenting feature of the fourth case. A PEG‐3350 allergy was suspected and avoidance advised until formal review at an allergy clinic. In the following months, while awaiting assessment and as a hospital inpatient for an unrelated condition, she had a second anaphylaxis within minutes of taking a PEG‐containing effervescent phosphate replacement preparation. SPT was subsequently positive to PEG‐3350, which has been avoided since.
The fifth patient was referred for assessment of multiple allergic drug reactions, on a background of chronic spontaneous urticaria and angioedema (CSUA). The first episode occurred within minutes of a Motilium suppository and was managed with intramuscular adrenaline, hydrocortisone, chlorphenamine, and fluid resuscitation. The second episode was precipitated by oral ibuprofen, again requiring adrenaline. PEG was considered a likely trigger, SPT was supportive. The patient subsequently tolerated PEG‐free domperidone and ibuprofen (Table 1).
The final case similarly had multiple adverse drug reactions, including anaphylaxis, on a background of CSUA. The initial allergic episode occurred following a Betadine dressing to a wound. She had systemic symptoms with oral and intramuscular diclofenac, oral Solpadeine (paracetamol and codeine), and contact urticaria with various cosmetics (Table 1). The patient subsequently tolerated PEG‐free forms of NSAIDs and codeine. PEG was suspected as a common inciting agent, SPT was supportive and strict avoidance recommended. After diagnosis, the patient experienced anaphylaxis while shaving with a product containing PEG requiring self‐administration of an adrenaline autoinjector.
This case series illustrates the diverse presentations of PEG allergy. Patients experienced an average of 3 allergic episodes before a formal diagnosis consistent with other case series. 1 Reactions were distressing for patients and objectively severe. Media reports of a case of fatal anaphylaxis in a patient with an established diagnosis of PEG allergy highlight the significance of this emerging problem. 2 The true incidence of PEG allergy is difficult to determine and may be underestimated. 3
It is hypothesized that initial PEG‐sensitization could be via cutaneous exposure from cosmetics and hygiene products or absorption of low‐molecular‐weight (LMW)‐PEG in pharmaceuticals. 3 The role of LMW‐PEG exposure prior to hypersensitivity has not been explored and may merit investigation. A female predominance was noted in our case series, but has not been universally observed. 1 , 4 Overall, the literature reports equal incidence between sexes. Interestingly, more recent case reports demonstrate a younger median age of diagnosis compared with older publications. 1 , 5 This is likely multifactorial and may be influenced by improved awareness of drug, and specifically PEG allergy, improved access to specialist allergy services, and potentially earlier or greater opportunity for sensitization. This is something that can only be speculated on because of limited clinical data.
Four of the 6 cases were suspected to have an NSAID allergy that was subsequently ruled out with negative provocation tests (Table 1). This emphasizes the prevalence of understandable misdiagnosis and unnecessary drug restrictions in this cohort. A review published in 2016 identified 37 cases labeled as “PEG‐allergy,” totaling 74 reactions. 4 More than half were associated with laxatives, also prominent allergens in this series. PEG‐3350 has been listed in more than 1000 approved medications. 3 Despite this ubiquity, reported incidence of hypersensitivity appears low. However we demonstrate that reactions can be severe and are diagnostically challenging.
NSAIDs are one of the most common inducers of drug‐related hypersensitivity reactions. 6 PEG sensitivity does not need to be considered in all NSAID‐related reactions. However, there are features that can be divined from an allergy history that offer pointers toward the need for PEG sensitization assessment. Patients with multiple episodes of “unexplained” anaphylaxis or tolerance of individual brands of the same drug merit closer investigation. Reactions to laxatives or bowel preparations, “depo” medications, and mucosal absorption from lubricants, gels, and dressings are red flags that should have PEG hypersensitivity in the differential. Bruusgaard‐Mouritsen et al (2021) similarly highlighted analgesics, depo injections, and laxatives as common triggers in their cohort, as well noting antacids and antibiotics as culprits. 1
We recommend that an adrenaline autoinjector be prescribed to those with PEG allergy because of an ongoing risk of accidental exposure. Unfortunately, comprehensive avoidance list cannot be provided, as medical preparations frequently change; thus, awareness is key. We advise patient empowerment with education, supported by step‐by‐step instructions on how to interrogate summary of product characteristics (SPC) for the variety of terms that indicate a PEG excipient. Patients are advised to engage with pharmacists and inform all health care professionals encountered of the disorder. In addition they should wear alert jewelry and only take a medication when they and their health care professional are satisfied that it does not contain PEG. Effective use of an electronic patient record can assist with communicating this issue, but as with all drug allergy, effective communication among disparate health care providers is a challenge. In addition, the cases presented here suggest a higher rate of biphasic allergic reactions than might be expected. 7 Based on these observations, we recommend extended monitoring for 12 hours after resolution of symptoms following a PEG‐related reaction. Although biphasic symptoms are usually mild, they can be distressing, especially to patients who have had a history of unexplained adverse events.
The identification of PEG allergy is increasing. These cases offer insight into the variety of ways this allergy can present. We report characteristics that flag PEG as a potential trigger and highlight the need for extended observation after resolution of symptoms because of the risk of biphasic reactions. Reports of immediate hypersensitivity in 2 health care workers on the first day of mass COVID‐19 vaccination in the United Kingdom are concerning. 8 It remains unknown if PEG‐2000 is involved in these reactions. Leaders in allergy have already engaged with regulatory authorities to highlight PEG as a possible allergen in mRNA vaccines and to support the objective investigation of reported reactions. 9
PEG allergy is now well known among allergy professionals. However, increased awareness of this allergen among the wider medical community is needed. Early recognition through a thorough clinical history and rapid referral to allergy diagnostic centers is required to confirm the diagnosis and effectively manage this high‐risk drug allergy.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Funding
We did not receive funding for this study.
Data‐Sharing Statement
Please contact the corresponding author, Dr Fionnuala Cox, on coxff@tcd.ie, if you wish to request further information on study data.
Author Contributions
F.C. conceived the study and interpreted data. F.C., N.C., and K.K. diagnosed and managed patients. All authors contributed to the writing and approval of the article.
Acknowledgments
We thank the patients and Clinical Immunology Teams in St James's Hospital and Beaumont Hospital, Dublin. | DOMPERIDONE, IBUPROFEN | DrugsGivenReaction | CC BY-NC-ND | 33543766 | 19,417,536 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Peripheral swelling'. | PEG That Reaction: A Case Series of Allergy to Polyethylene Glycol.
Polyethylene glycol (PEG), also known as macrogol, is an excipient in numerous medications, health care products, cosmetics, and foods. It acts as an inert bulking, or stabilizing, agent. Despite its ubiquity, including in 2 of the newly launched vaccines against SARS-CoV-2, awareness of PEG allergy remains low. We present 6 cases of acute hypersensitivity to PEG. Accurate diagnoses in these cases posed a challenge, and although the triggering agents differed, PEG was demonstrated as the common culprit. All cases were female, with a mean age of 36.4 years. Four patients were originally suspected to have nonsteroid anti-inflammatory drug allergy, and 2 had a history of chronic spontaneous urticaria and angioedema. Biphasic allergic reactions featured prominently in this case series. Diagnosis relies on a high index of suspicion leading to a focused clinical history, supported by skin tests with PEG solutions to demonstrate sensitization. This case series highlights important clinical features of this rare, potentially serious, and increasingly recognized excipient allergy.
pmcPolyethylene glycol (PEG), also known as macrogol or E1521, is a commonly used bulking and stabilizing agent. It is an excipient in a wide variety of medications and also encountered in cosmetics and processed foods. Notably, both Pfizer BioNTech and Moderna mRNA vaccines against SARS‐CoV‐2, which are being internationally deployed to combat the current pandemic, contain polyethylene glycol. Allergy to PEG is rare but is increasingly recognized and can be severe. We present a case series to highlight features of this unusual excipient allergy. A high index of suspicion with early referral for expert diagnostic workup is required to implement appropriate risk management strategies.
The incident case experienced anaphylaxis after intramuscular Depo‐Provera administered by her general practitioner. She developed rapid‐onset sneezing, rhinorrhea, urticaria, profound hypotension, and chest tightness. She was managed with 2 doses of intramuscular adrenaline, steroids, and nebulized salbutamol. Symptoms improved; however, 6 hours following initial treatment she experienced further urticaria. The patient had recently tolerated similar progesterone in the oral contraceptive pill. Allergy to an excipient ingredient was suspected. The specific intramuscular formulation contained PEG‐3350 (Table 1). Skin‐prick testing (SPT) was positive and avoidance advised.
Table 1 Patient Case Summary With Triggering Agents and Associated PEG Compounds, Allergic Symptoms Experienced, Outcome of Skin Prick Testing, and Results of Supervised Provocation Challenges Detailed for Each Patient
Case Allergic Disease Trigger Symptoms Negative Provocation Challenge Positive Investigation
Case 1
Female, 35 years
None Depo‐Provera: medroxyprogesterone PEG‐3350 Sneezing, ocular irritation, rhinorrhea, urticaria, hypotension, chest tightness, respiratory compromise.
Biphasic urticaria.
None SPT PEG‐3350:
positive, 7 x 7 mm
Case 2
Female, 25 years
None Nexium: esomeprazole "Macrogols"
MoviPrep: osmotic laxative PEG‐3350
Cosmetics: PEG‐100
Urticaria, angioedema,
Respiratory compromise.
Pruritus, urticaria, angioedema, hypotension, swelling of hands and feet.
Biphasic urticaria.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free
"Teva”:
pantoprazole
PEG‐free
SPT PEG‐3350:
positive, 10 x 11 mm
Case 3
Female, 40 years
None Effervescent vitamin C: HMW‐PEG
Klean Prep: osmotic laxative PEG‐3350.
Vimovo: esomeprazole,
naproxen.
PEG‐8000.
EMLA topical anesthetic:
lidocaine, prilocaine.
HMW‐PEG.
Urticaria, syncope.
Urticaria, angioedema.
Urticaria, presyncopal.
Generalized pruritus.
Cerazette:
desogestrel
PEG‐400
“Teva”:
pantoprazole
PEG‐free
SPT PEG‐400, 3350:
Inconclusive because of dermographism.
Movicol challenge, PEG‐3350: positive
Case 4
Female, 44 years
None Klean Prep: osmotic laxative,
PEG‐3350.
Phosphate Sandoz: effervescent phosphate,
PEG‐4000.
Cosmetics: LMW‐ and HMW‐PEG.
Perioral paresthesia, angioedema, dyspnea, stridor, visual disturbance, syncope.
Angioedema, dyspnea, presyncope.
Urticaria
None SPT PEG‐3350:
positive
Case 5
Female, 36 years
CSUA Motilium Suppository: domperidone,
PEG‐400 and 1000.
Nurofen: ibuprofen,
PEG‐6000.
Angioedema, paresthesia,
throat tightness.
Angioedema, paresthesia,
throat tightness.
Motilium oral tablet:
PEG‐free
Nurofen syrup:
PEG‐free
SPT PEG‐3350:
positive
Case 6
Female, 38 years
CSUA
Physical urticaria
Betadine: wound dressing, povidone‐iodine,
PEG‐400, 6000.
Voltorol Oral: diclofenac
PEG‐8000.
Diclofenac IM:
HMW‐PEG.
Shaving foam: LMW‐ and HMW‐PEG.
Cosmetics: LMW‐ and HMW‐PEG.
Urticaria, presyncopal.
Urticaria.
Urticaria.
Urticaria, angioedema,
respiratory distress, hypotension.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free.
Ibuprofen tablet:
PEG‐free
SPT PEG‐3350:
10 × 10 mm
John Wiley & Sons, Ltd.
The second patient experienced acute urticaria and angioedema following concomitant ibuprofen and esomeprazole ingestion. Nonsteroidal anti‐inflammatory drug (NSAID) sensitivity was initially suspected (Table 1). While awaiting further investigation, she developed urticaria, angioedema, and hypotension following minimal ingestion of the PEG‐containing osmotic laxative Movi‐Prep. Symptoms settled with steroids and antihistamine; however, she experienced further urticaria 6 hours later. In addition, the patient described contact urticaria with certain cosmetics. PEG was suspected as a common trigger, and SPT was supportive (Table 1).
Case 3 had urticaria and syncope within minutes of effervescent vitamin C and separately developed urticaria, angioedema, and throat tightness with difficulty swallowing after the osmotic laxative Klean‐Prep. She gave a history of urticaria associated with Vimovo (esomeprazole and naproxen) and similar symptoms during a dental procedure (Table 1). All identified agents contained high‐molecular‐weight (HMW)‐PEG (Table 1). Unfortunately, SPT was inconclusive because of dermographism (negative control inciting a wheal). A provocation challenge to HMW‐PEG (Movicol) was objectively positive. The patient has remained completely symptom‐free with a PEG avoidance strategy. She has tolerated challenges with PEG‐free medications.
Anaphylaxis to Klean‐Prep was also a presenting feature of the fourth case. A PEG‐3350 allergy was suspected and avoidance advised until formal review at an allergy clinic. In the following months, while awaiting assessment and as a hospital inpatient for an unrelated condition, she had a second anaphylaxis within minutes of taking a PEG‐containing effervescent phosphate replacement preparation. SPT was subsequently positive to PEG‐3350, which has been avoided since.
The fifth patient was referred for assessment of multiple allergic drug reactions, on a background of chronic spontaneous urticaria and angioedema (CSUA). The first episode occurred within minutes of a Motilium suppository and was managed with intramuscular adrenaline, hydrocortisone, chlorphenamine, and fluid resuscitation. The second episode was precipitated by oral ibuprofen, again requiring adrenaline. PEG was considered a likely trigger, SPT was supportive. The patient subsequently tolerated PEG‐free domperidone and ibuprofen (Table 1).
The final case similarly had multiple adverse drug reactions, including anaphylaxis, on a background of CSUA. The initial allergic episode occurred following a Betadine dressing to a wound. She had systemic symptoms with oral and intramuscular diclofenac, oral Solpadeine (paracetamol and codeine), and contact urticaria with various cosmetics (Table 1). The patient subsequently tolerated PEG‐free forms of NSAIDs and codeine. PEG was suspected as a common inciting agent, SPT was supportive and strict avoidance recommended. After diagnosis, the patient experienced anaphylaxis while shaving with a product containing PEG requiring self‐administration of an adrenaline autoinjector.
This case series illustrates the diverse presentations of PEG allergy. Patients experienced an average of 3 allergic episodes before a formal diagnosis consistent with other case series. 1 Reactions were distressing for patients and objectively severe. Media reports of a case of fatal anaphylaxis in a patient with an established diagnosis of PEG allergy highlight the significance of this emerging problem. 2 The true incidence of PEG allergy is difficult to determine and may be underestimated. 3
It is hypothesized that initial PEG‐sensitization could be via cutaneous exposure from cosmetics and hygiene products or absorption of low‐molecular‐weight (LMW)‐PEG in pharmaceuticals. 3 The role of LMW‐PEG exposure prior to hypersensitivity has not been explored and may merit investigation. A female predominance was noted in our case series, but has not been universally observed. 1 , 4 Overall, the literature reports equal incidence between sexes. Interestingly, more recent case reports demonstrate a younger median age of diagnosis compared with older publications. 1 , 5 This is likely multifactorial and may be influenced by improved awareness of drug, and specifically PEG allergy, improved access to specialist allergy services, and potentially earlier or greater opportunity for sensitization. This is something that can only be speculated on because of limited clinical data.
Four of the 6 cases were suspected to have an NSAID allergy that was subsequently ruled out with negative provocation tests (Table 1). This emphasizes the prevalence of understandable misdiagnosis and unnecessary drug restrictions in this cohort. A review published in 2016 identified 37 cases labeled as “PEG‐allergy,” totaling 74 reactions. 4 More than half were associated with laxatives, also prominent allergens in this series. PEG‐3350 has been listed in more than 1000 approved medications. 3 Despite this ubiquity, reported incidence of hypersensitivity appears low. However we demonstrate that reactions can be severe and are diagnostically challenging.
NSAIDs are one of the most common inducers of drug‐related hypersensitivity reactions. 6 PEG sensitivity does not need to be considered in all NSAID‐related reactions. However, there are features that can be divined from an allergy history that offer pointers toward the need for PEG sensitization assessment. Patients with multiple episodes of “unexplained” anaphylaxis or tolerance of individual brands of the same drug merit closer investigation. Reactions to laxatives or bowel preparations, “depo” medications, and mucosal absorption from lubricants, gels, and dressings are red flags that should have PEG hypersensitivity in the differential. Bruusgaard‐Mouritsen et al (2021) similarly highlighted analgesics, depo injections, and laxatives as common triggers in their cohort, as well noting antacids and antibiotics as culprits. 1
We recommend that an adrenaline autoinjector be prescribed to those with PEG allergy because of an ongoing risk of accidental exposure. Unfortunately, comprehensive avoidance list cannot be provided, as medical preparations frequently change; thus, awareness is key. We advise patient empowerment with education, supported by step‐by‐step instructions on how to interrogate summary of product characteristics (SPC) for the variety of terms that indicate a PEG excipient. Patients are advised to engage with pharmacists and inform all health care professionals encountered of the disorder. In addition they should wear alert jewelry and only take a medication when they and their health care professional are satisfied that it does not contain PEG. Effective use of an electronic patient record can assist with communicating this issue, but as with all drug allergy, effective communication among disparate health care providers is a challenge. In addition, the cases presented here suggest a higher rate of biphasic allergic reactions than might be expected. 7 Based on these observations, we recommend extended monitoring for 12 hours after resolution of symptoms following a PEG‐related reaction. Although biphasic symptoms are usually mild, they can be distressing, especially to patients who have had a history of unexplained adverse events.
The identification of PEG allergy is increasing. These cases offer insight into the variety of ways this allergy can present. We report characteristics that flag PEG as a potential trigger and highlight the need for extended observation after resolution of symptoms because of the risk of biphasic reactions. Reports of immediate hypersensitivity in 2 health care workers on the first day of mass COVID‐19 vaccination in the United Kingdom are concerning. 8 It remains unknown if PEG‐2000 is involved in these reactions. Leaders in allergy have already engaged with regulatory authorities to highlight PEG as a possible allergen in mRNA vaccines and to support the objective investigation of reported reactions. 9
PEG allergy is now well known among allergy professionals. However, increased awareness of this allergen among the wider medical community is needed. Early recognition through a thorough clinical history and rapid referral to allergy diagnostic centers is required to confirm the diagnosis and effectively manage this high‐risk drug allergy.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Funding
We did not receive funding for this study.
Data‐Sharing Statement
Please contact the corresponding author, Dr Fionnuala Cox, on coxff@tcd.ie, if you wish to request further information on study data.
Author Contributions
F.C. conceived the study and interpreted data. F.C., N.C., and K.K. diagnosed and managed patients. All authors contributed to the writing and approval of the article.
Acknowledgments
We thank the patients and Clinical Immunology Teams in St James's Hospital and Beaumont Hospital, Dublin. | ASCORBIC ACID\POLYETHYLENE GLYCOL 3350\POTASSIUM CHLORIDE\SODIUM ASCORBATE\SODIUM CHLORIDE\SODIUM SULFATE, ESOMEPRAZOLE MAGNESIUM, IBUPROFEN | DrugsGivenReaction | CC BY-NC-ND | 33543766 | 19,417,483 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Reaction to excipient'. | PEG That Reaction: A Case Series of Allergy to Polyethylene Glycol.
Polyethylene glycol (PEG), also known as macrogol, is an excipient in numerous medications, health care products, cosmetics, and foods. It acts as an inert bulking, or stabilizing, agent. Despite its ubiquity, including in 2 of the newly launched vaccines against SARS-CoV-2, awareness of PEG allergy remains low. We present 6 cases of acute hypersensitivity to PEG. Accurate diagnoses in these cases posed a challenge, and although the triggering agents differed, PEG was demonstrated as the common culprit. All cases were female, with a mean age of 36.4 years. Four patients were originally suspected to have nonsteroid anti-inflammatory drug allergy, and 2 had a history of chronic spontaneous urticaria and angioedema. Biphasic allergic reactions featured prominently in this case series. Diagnosis relies on a high index of suspicion leading to a focused clinical history, supported by skin tests with PEG solutions to demonstrate sensitization. This case series highlights important clinical features of this rare, potentially serious, and increasingly recognized excipient allergy.
pmcPolyethylene glycol (PEG), also known as macrogol or E1521, is a commonly used bulking and stabilizing agent. It is an excipient in a wide variety of medications and also encountered in cosmetics and processed foods. Notably, both Pfizer BioNTech and Moderna mRNA vaccines against SARS‐CoV‐2, which are being internationally deployed to combat the current pandemic, contain polyethylene glycol. Allergy to PEG is rare but is increasingly recognized and can be severe. We present a case series to highlight features of this unusual excipient allergy. A high index of suspicion with early referral for expert diagnostic workup is required to implement appropriate risk management strategies.
The incident case experienced anaphylaxis after intramuscular Depo‐Provera administered by her general practitioner. She developed rapid‐onset sneezing, rhinorrhea, urticaria, profound hypotension, and chest tightness. She was managed with 2 doses of intramuscular adrenaline, steroids, and nebulized salbutamol. Symptoms improved; however, 6 hours following initial treatment she experienced further urticaria. The patient had recently tolerated similar progesterone in the oral contraceptive pill. Allergy to an excipient ingredient was suspected. The specific intramuscular formulation contained PEG‐3350 (Table 1). Skin‐prick testing (SPT) was positive and avoidance advised.
Table 1 Patient Case Summary With Triggering Agents and Associated PEG Compounds, Allergic Symptoms Experienced, Outcome of Skin Prick Testing, and Results of Supervised Provocation Challenges Detailed for Each Patient
Case Allergic Disease Trigger Symptoms Negative Provocation Challenge Positive Investigation
Case 1
Female, 35 years
None Depo‐Provera: medroxyprogesterone PEG‐3350 Sneezing, ocular irritation, rhinorrhea, urticaria, hypotension, chest tightness, respiratory compromise.
Biphasic urticaria.
None SPT PEG‐3350:
positive, 7 x 7 mm
Case 2
Female, 25 years
None Nexium: esomeprazole "Macrogols"
MoviPrep: osmotic laxative PEG‐3350
Cosmetics: PEG‐100
Urticaria, angioedema,
Respiratory compromise.
Pruritus, urticaria, angioedema, hypotension, swelling of hands and feet.
Biphasic urticaria.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free
"Teva”:
pantoprazole
PEG‐free
SPT PEG‐3350:
positive, 10 x 11 mm
Case 3
Female, 40 years
None Effervescent vitamin C: HMW‐PEG
Klean Prep: osmotic laxative PEG‐3350.
Vimovo: esomeprazole,
naproxen.
PEG‐8000.
EMLA topical anesthetic:
lidocaine, prilocaine.
HMW‐PEG.
Urticaria, syncope.
Urticaria, angioedema.
Urticaria, presyncopal.
Generalized pruritus.
Cerazette:
desogestrel
PEG‐400
“Teva”:
pantoprazole
PEG‐free
SPT PEG‐400, 3350:
Inconclusive because of dermographism.
Movicol challenge, PEG‐3350: positive
Case 4
Female, 44 years
None Klean Prep: osmotic laxative,
PEG‐3350.
Phosphate Sandoz: effervescent phosphate,
PEG‐4000.
Cosmetics: LMW‐ and HMW‐PEG.
Perioral paresthesia, angioedema, dyspnea, stridor, visual disturbance, syncope.
Angioedema, dyspnea, presyncope.
Urticaria
None SPT PEG‐3350:
positive
Case 5
Female, 36 years
CSUA Motilium Suppository: domperidone,
PEG‐400 and 1000.
Nurofen: ibuprofen,
PEG‐6000.
Angioedema, paresthesia,
throat tightness.
Angioedema, paresthesia,
throat tightness.
Motilium oral tablet:
PEG‐free
Nurofen syrup:
PEG‐free
SPT PEG‐3350:
positive
Case 6
Female, 38 years
CSUA
Physical urticaria
Betadine: wound dressing, povidone‐iodine,
PEG‐400, 6000.
Voltorol Oral: diclofenac
PEG‐8000.
Diclofenac IM:
HMW‐PEG.
Shaving foam: LMW‐ and HMW‐PEG.
Cosmetics: LMW‐ and HMW‐PEG.
Urticaria, presyncopal.
Urticaria.
Urticaria.
Urticaria, angioedema,
respiratory distress, hypotension.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free.
Ibuprofen tablet:
PEG‐free
SPT PEG‐3350:
10 × 10 mm
John Wiley & Sons, Ltd.
The second patient experienced acute urticaria and angioedema following concomitant ibuprofen and esomeprazole ingestion. Nonsteroidal anti‐inflammatory drug (NSAID) sensitivity was initially suspected (Table 1). While awaiting further investigation, she developed urticaria, angioedema, and hypotension following minimal ingestion of the PEG‐containing osmotic laxative Movi‐Prep. Symptoms settled with steroids and antihistamine; however, she experienced further urticaria 6 hours later. In addition, the patient described contact urticaria with certain cosmetics. PEG was suspected as a common trigger, and SPT was supportive (Table 1).
Case 3 had urticaria and syncope within minutes of effervescent vitamin C and separately developed urticaria, angioedema, and throat tightness with difficulty swallowing after the osmotic laxative Klean‐Prep. She gave a history of urticaria associated with Vimovo (esomeprazole and naproxen) and similar symptoms during a dental procedure (Table 1). All identified agents contained high‐molecular‐weight (HMW)‐PEG (Table 1). Unfortunately, SPT was inconclusive because of dermographism (negative control inciting a wheal). A provocation challenge to HMW‐PEG (Movicol) was objectively positive. The patient has remained completely symptom‐free with a PEG avoidance strategy. She has tolerated challenges with PEG‐free medications.
Anaphylaxis to Klean‐Prep was also a presenting feature of the fourth case. A PEG‐3350 allergy was suspected and avoidance advised until formal review at an allergy clinic. In the following months, while awaiting assessment and as a hospital inpatient for an unrelated condition, she had a second anaphylaxis within minutes of taking a PEG‐containing effervescent phosphate replacement preparation. SPT was subsequently positive to PEG‐3350, which has been avoided since.
The fifth patient was referred for assessment of multiple allergic drug reactions, on a background of chronic spontaneous urticaria and angioedema (CSUA). The first episode occurred within minutes of a Motilium suppository and was managed with intramuscular adrenaline, hydrocortisone, chlorphenamine, and fluid resuscitation. The second episode was precipitated by oral ibuprofen, again requiring adrenaline. PEG was considered a likely trigger, SPT was supportive. The patient subsequently tolerated PEG‐free domperidone and ibuprofen (Table 1).
The final case similarly had multiple adverse drug reactions, including anaphylaxis, on a background of CSUA. The initial allergic episode occurred following a Betadine dressing to a wound. She had systemic symptoms with oral and intramuscular diclofenac, oral Solpadeine (paracetamol and codeine), and contact urticaria with various cosmetics (Table 1). The patient subsequently tolerated PEG‐free forms of NSAIDs and codeine. PEG was suspected as a common inciting agent, SPT was supportive and strict avoidance recommended. After diagnosis, the patient experienced anaphylaxis while shaving with a product containing PEG requiring self‐administration of an adrenaline autoinjector.
This case series illustrates the diverse presentations of PEG allergy. Patients experienced an average of 3 allergic episodes before a formal diagnosis consistent with other case series. 1 Reactions were distressing for patients and objectively severe. Media reports of a case of fatal anaphylaxis in a patient with an established diagnosis of PEG allergy highlight the significance of this emerging problem. 2 The true incidence of PEG allergy is difficult to determine and may be underestimated. 3
It is hypothesized that initial PEG‐sensitization could be via cutaneous exposure from cosmetics and hygiene products or absorption of low‐molecular‐weight (LMW)‐PEG in pharmaceuticals. 3 The role of LMW‐PEG exposure prior to hypersensitivity has not been explored and may merit investigation. A female predominance was noted in our case series, but has not been universally observed. 1 , 4 Overall, the literature reports equal incidence between sexes. Interestingly, more recent case reports demonstrate a younger median age of diagnosis compared with older publications. 1 , 5 This is likely multifactorial and may be influenced by improved awareness of drug, and specifically PEG allergy, improved access to specialist allergy services, and potentially earlier or greater opportunity for sensitization. This is something that can only be speculated on because of limited clinical data.
Four of the 6 cases were suspected to have an NSAID allergy that was subsequently ruled out with negative provocation tests (Table 1). This emphasizes the prevalence of understandable misdiagnosis and unnecessary drug restrictions in this cohort. A review published in 2016 identified 37 cases labeled as “PEG‐allergy,” totaling 74 reactions. 4 More than half were associated with laxatives, also prominent allergens in this series. PEG‐3350 has been listed in more than 1000 approved medications. 3 Despite this ubiquity, reported incidence of hypersensitivity appears low. However we demonstrate that reactions can be severe and are diagnostically challenging.
NSAIDs are one of the most common inducers of drug‐related hypersensitivity reactions. 6 PEG sensitivity does not need to be considered in all NSAID‐related reactions. However, there are features that can be divined from an allergy history that offer pointers toward the need for PEG sensitization assessment. Patients with multiple episodes of “unexplained” anaphylaxis or tolerance of individual brands of the same drug merit closer investigation. Reactions to laxatives or bowel preparations, “depo” medications, and mucosal absorption from lubricants, gels, and dressings are red flags that should have PEG hypersensitivity in the differential. Bruusgaard‐Mouritsen et al (2021) similarly highlighted analgesics, depo injections, and laxatives as common triggers in their cohort, as well noting antacids and antibiotics as culprits. 1
We recommend that an adrenaline autoinjector be prescribed to those with PEG allergy because of an ongoing risk of accidental exposure. Unfortunately, comprehensive avoidance list cannot be provided, as medical preparations frequently change; thus, awareness is key. We advise patient empowerment with education, supported by step‐by‐step instructions on how to interrogate summary of product characteristics (SPC) for the variety of terms that indicate a PEG excipient. Patients are advised to engage with pharmacists and inform all health care professionals encountered of the disorder. In addition they should wear alert jewelry and only take a medication when they and their health care professional are satisfied that it does not contain PEG. Effective use of an electronic patient record can assist with communicating this issue, but as with all drug allergy, effective communication among disparate health care providers is a challenge. In addition, the cases presented here suggest a higher rate of biphasic allergic reactions than might be expected. 7 Based on these observations, we recommend extended monitoring for 12 hours after resolution of symptoms following a PEG‐related reaction. Although biphasic symptoms are usually mild, they can be distressing, especially to patients who have had a history of unexplained adverse events.
The identification of PEG allergy is increasing. These cases offer insight into the variety of ways this allergy can present. We report characteristics that flag PEG as a potential trigger and highlight the need for extended observation after resolution of symptoms because of the risk of biphasic reactions. Reports of immediate hypersensitivity in 2 health care workers on the first day of mass COVID‐19 vaccination in the United Kingdom are concerning. 8 It remains unknown if PEG‐2000 is involved in these reactions. Leaders in allergy have already engaged with regulatory authorities to highlight PEG as a possible allergen in mRNA vaccines and to support the objective investigation of reported reactions. 9
PEG allergy is now well known among allergy professionals. However, increased awareness of this allergen among the wider medical community is needed. Early recognition through a thorough clinical history and rapid referral to allergy diagnostic centers is required to confirm the diagnosis and effectively manage this high‐risk drug allergy.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Funding
We did not receive funding for this study.
Data‐Sharing Statement
Please contact the corresponding author, Dr Fionnuala Cox, on coxff@tcd.ie, if you wish to request further information on study data.
Author Contributions
F.C. conceived the study and interpreted data. F.C., N.C., and K.K. diagnosed and managed patients. All authors contributed to the writing and approval of the article.
Acknowledgments
We thank the patients and Clinical Immunology Teams in St James's Hospital and Beaumont Hospital, Dublin. | MEDROXYPROGESTERONE ACETATE, POLYETHYLENE GLYCOL 3350 | DrugsGivenReaction | CC BY-NC-ND | 33543766 | 19,443,824 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Respiratory disorder'. | PEG That Reaction: A Case Series of Allergy to Polyethylene Glycol.
Polyethylene glycol (PEG), also known as macrogol, is an excipient in numerous medications, health care products, cosmetics, and foods. It acts as an inert bulking, or stabilizing, agent. Despite its ubiquity, including in 2 of the newly launched vaccines against SARS-CoV-2, awareness of PEG allergy remains low. We present 6 cases of acute hypersensitivity to PEG. Accurate diagnoses in these cases posed a challenge, and although the triggering agents differed, PEG was demonstrated as the common culprit. All cases were female, with a mean age of 36.4 years. Four patients were originally suspected to have nonsteroid anti-inflammatory drug allergy, and 2 had a history of chronic spontaneous urticaria and angioedema. Biphasic allergic reactions featured prominently in this case series. Diagnosis relies on a high index of suspicion leading to a focused clinical history, supported by skin tests with PEG solutions to demonstrate sensitization. This case series highlights important clinical features of this rare, potentially serious, and increasingly recognized excipient allergy.
pmcPolyethylene glycol (PEG), also known as macrogol or E1521, is a commonly used bulking and stabilizing agent. It is an excipient in a wide variety of medications and also encountered in cosmetics and processed foods. Notably, both Pfizer BioNTech and Moderna mRNA vaccines against SARS‐CoV‐2, which are being internationally deployed to combat the current pandemic, contain polyethylene glycol. Allergy to PEG is rare but is increasingly recognized and can be severe. We present a case series to highlight features of this unusual excipient allergy. A high index of suspicion with early referral for expert diagnostic workup is required to implement appropriate risk management strategies.
The incident case experienced anaphylaxis after intramuscular Depo‐Provera administered by her general practitioner. She developed rapid‐onset sneezing, rhinorrhea, urticaria, profound hypotension, and chest tightness. She was managed with 2 doses of intramuscular adrenaline, steroids, and nebulized salbutamol. Symptoms improved; however, 6 hours following initial treatment she experienced further urticaria. The patient had recently tolerated similar progesterone in the oral contraceptive pill. Allergy to an excipient ingredient was suspected. The specific intramuscular formulation contained PEG‐3350 (Table 1). Skin‐prick testing (SPT) was positive and avoidance advised.
Table 1 Patient Case Summary With Triggering Agents and Associated PEG Compounds, Allergic Symptoms Experienced, Outcome of Skin Prick Testing, and Results of Supervised Provocation Challenges Detailed for Each Patient
Case Allergic Disease Trigger Symptoms Negative Provocation Challenge Positive Investigation
Case 1
Female, 35 years
None Depo‐Provera: medroxyprogesterone PEG‐3350 Sneezing, ocular irritation, rhinorrhea, urticaria, hypotension, chest tightness, respiratory compromise.
Biphasic urticaria.
None SPT PEG‐3350:
positive, 7 x 7 mm
Case 2
Female, 25 years
None Nexium: esomeprazole "Macrogols"
MoviPrep: osmotic laxative PEG‐3350
Cosmetics: PEG‐100
Urticaria, angioedema,
Respiratory compromise.
Pruritus, urticaria, angioedema, hypotension, swelling of hands and feet.
Biphasic urticaria.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free
"Teva”:
pantoprazole
PEG‐free
SPT PEG‐3350:
positive, 10 x 11 mm
Case 3
Female, 40 years
None Effervescent vitamin C: HMW‐PEG
Klean Prep: osmotic laxative PEG‐3350.
Vimovo: esomeprazole,
naproxen.
PEG‐8000.
EMLA topical anesthetic:
lidocaine, prilocaine.
HMW‐PEG.
Urticaria, syncope.
Urticaria, angioedema.
Urticaria, presyncopal.
Generalized pruritus.
Cerazette:
desogestrel
PEG‐400
“Teva”:
pantoprazole
PEG‐free
SPT PEG‐400, 3350:
Inconclusive because of dermographism.
Movicol challenge, PEG‐3350: positive
Case 4
Female, 44 years
None Klean Prep: osmotic laxative,
PEG‐3350.
Phosphate Sandoz: effervescent phosphate,
PEG‐4000.
Cosmetics: LMW‐ and HMW‐PEG.
Perioral paresthesia, angioedema, dyspnea, stridor, visual disturbance, syncope.
Angioedema, dyspnea, presyncope.
Urticaria
None SPT PEG‐3350:
positive
Case 5
Female, 36 years
CSUA Motilium Suppository: domperidone,
PEG‐400 and 1000.
Nurofen: ibuprofen,
PEG‐6000.
Angioedema, paresthesia,
throat tightness.
Angioedema, paresthesia,
throat tightness.
Motilium oral tablet:
PEG‐free
Nurofen syrup:
PEG‐free
SPT PEG‐3350:
positive
Case 6
Female, 38 years
CSUA
Physical urticaria
Betadine: wound dressing, povidone‐iodine,
PEG‐400, 6000.
Voltorol Oral: diclofenac
PEG‐8000.
Diclofenac IM:
HMW‐PEG.
Shaving foam: LMW‐ and HMW‐PEG.
Cosmetics: LMW‐ and HMW‐PEG.
Urticaria, presyncopal.
Urticaria.
Urticaria.
Urticaria, angioedema,
respiratory distress, hypotension.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free.
Ibuprofen tablet:
PEG‐free
SPT PEG‐3350:
10 × 10 mm
John Wiley & Sons, Ltd.
The second patient experienced acute urticaria and angioedema following concomitant ibuprofen and esomeprazole ingestion. Nonsteroidal anti‐inflammatory drug (NSAID) sensitivity was initially suspected (Table 1). While awaiting further investigation, she developed urticaria, angioedema, and hypotension following minimal ingestion of the PEG‐containing osmotic laxative Movi‐Prep. Symptoms settled with steroids and antihistamine; however, she experienced further urticaria 6 hours later. In addition, the patient described contact urticaria with certain cosmetics. PEG was suspected as a common trigger, and SPT was supportive (Table 1).
Case 3 had urticaria and syncope within minutes of effervescent vitamin C and separately developed urticaria, angioedema, and throat tightness with difficulty swallowing after the osmotic laxative Klean‐Prep. She gave a history of urticaria associated with Vimovo (esomeprazole and naproxen) and similar symptoms during a dental procedure (Table 1). All identified agents contained high‐molecular‐weight (HMW)‐PEG (Table 1). Unfortunately, SPT was inconclusive because of dermographism (negative control inciting a wheal). A provocation challenge to HMW‐PEG (Movicol) was objectively positive. The patient has remained completely symptom‐free with a PEG avoidance strategy. She has tolerated challenges with PEG‐free medications.
Anaphylaxis to Klean‐Prep was also a presenting feature of the fourth case. A PEG‐3350 allergy was suspected and avoidance advised until formal review at an allergy clinic. In the following months, while awaiting assessment and as a hospital inpatient for an unrelated condition, she had a second anaphylaxis within minutes of taking a PEG‐containing effervescent phosphate replacement preparation. SPT was subsequently positive to PEG‐3350, which has been avoided since.
The fifth patient was referred for assessment of multiple allergic drug reactions, on a background of chronic spontaneous urticaria and angioedema (CSUA). The first episode occurred within minutes of a Motilium suppository and was managed with intramuscular adrenaline, hydrocortisone, chlorphenamine, and fluid resuscitation. The second episode was precipitated by oral ibuprofen, again requiring adrenaline. PEG was considered a likely trigger, SPT was supportive. The patient subsequently tolerated PEG‐free domperidone and ibuprofen (Table 1).
The final case similarly had multiple adverse drug reactions, including anaphylaxis, on a background of CSUA. The initial allergic episode occurred following a Betadine dressing to a wound. She had systemic symptoms with oral and intramuscular diclofenac, oral Solpadeine (paracetamol and codeine), and contact urticaria with various cosmetics (Table 1). The patient subsequently tolerated PEG‐free forms of NSAIDs and codeine. PEG was suspected as a common inciting agent, SPT was supportive and strict avoidance recommended. After diagnosis, the patient experienced anaphylaxis while shaving with a product containing PEG requiring self‐administration of an adrenaline autoinjector.
This case series illustrates the diverse presentations of PEG allergy. Patients experienced an average of 3 allergic episodes before a formal diagnosis consistent with other case series. 1 Reactions were distressing for patients and objectively severe. Media reports of a case of fatal anaphylaxis in a patient with an established diagnosis of PEG allergy highlight the significance of this emerging problem. 2 The true incidence of PEG allergy is difficult to determine and may be underestimated. 3
It is hypothesized that initial PEG‐sensitization could be via cutaneous exposure from cosmetics and hygiene products or absorption of low‐molecular‐weight (LMW)‐PEG in pharmaceuticals. 3 The role of LMW‐PEG exposure prior to hypersensitivity has not been explored and may merit investigation. A female predominance was noted in our case series, but has not been universally observed. 1 , 4 Overall, the literature reports equal incidence between sexes. Interestingly, more recent case reports demonstrate a younger median age of diagnosis compared with older publications. 1 , 5 This is likely multifactorial and may be influenced by improved awareness of drug, and specifically PEG allergy, improved access to specialist allergy services, and potentially earlier or greater opportunity for sensitization. This is something that can only be speculated on because of limited clinical data.
Four of the 6 cases were suspected to have an NSAID allergy that was subsequently ruled out with negative provocation tests (Table 1). This emphasizes the prevalence of understandable misdiagnosis and unnecessary drug restrictions in this cohort. A review published in 2016 identified 37 cases labeled as “PEG‐allergy,” totaling 74 reactions. 4 More than half were associated with laxatives, also prominent allergens in this series. PEG‐3350 has been listed in more than 1000 approved medications. 3 Despite this ubiquity, reported incidence of hypersensitivity appears low. However we demonstrate that reactions can be severe and are diagnostically challenging.
NSAIDs are one of the most common inducers of drug‐related hypersensitivity reactions. 6 PEG sensitivity does not need to be considered in all NSAID‐related reactions. However, there are features that can be divined from an allergy history that offer pointers toward the need for PEG sensitization assessment. Patients with multiple episodes of “unexplained” anaphylaxis or tolerance of individual brands of the same drug merit closer investigation. Reactions to laxatives or bowel preparations, “depo” medications, and mucosal absorption from lubricants, gels, and dressings are red flags that should have PEG hypersensitivity in the differential. Bruusgaard‐Mouritsen et al (2021) similarly highlighted analgesics, depo injections, and laxatives as common triggers in their cohort, as well noting antacids and antibiotics as culprits. 1
We recommend that an adrenaline autoinjector be prescribed to those with PEG allergy because of an ongoing risk of accidental exposure. Unfortunately, comprehensive avoidance list cannot be provided, as medical preparations frequently change; thus, awareness is key. We advise patient empowerment with education, supported by step‐by‐step instructions on how to interrogate summary of product characteristics (SPC) for the variety of terms that indicate a PEG excipient. Patients are advised to engage with pharmacists and inform all health care professionals encountered of the disorder. In addition they should wear alert jewelry and only take a medication when they and their health care professional are satisfied that it does not contain PEG. Effective use of an electronic patient record can assist with communicating this issue, but as with all drug allergy, effective communication among disparate health care providers is a challenge. In addition, the cases presented here suggest a higher rate of biphasic allergic reactions than might be expected. 7 Based on these observations, we recommend extended monitoring for 12 hours after resolution of symptoms following a PEG‐related reaction. Although biphasic symptoms are usually mild, they can be distressing, especially to patients who have had a history of unexplained adverse events.
The identification of PEG allergy is increasing. These cases offer insight into the variety of ways this allergy can present. We report characteristics that flag PEG as a potential trigger and highlight the need for extended observation after resolution of symptoms because of the risk of biphasic reactions. Reports of immediate hypersensitivity in 2 health care workers on the first day of mass COVID‐19 vaccination in the United Kingdom are concerning. 8 It remains unknown if PEG‐2000 is involved in these reactions. Leaders in allergy have already engaged with regulatory authorities to highlight PEG as a possible allergen in mRNA vaccines and to support the objective investigation of reported reactions. 9
PEG allergy is now well known among allergy professionals. However, increased awareness of this allergen among the wider medical community is needed. Early recognition through a thorough clinical history and rapid referral to allergy diagnostic centers is required to confirm the diagnosis and effectively manage this high‐risk drug allergy.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Funding
We did not receive funding for this study.
Data‐Sharing Statement
Please contact the corresponding author, Dr Fionnuala Cox, on coxff@tcd.ie, if you wish to request further information on study data.
Author Contributions
F.C. conceived the study and interpreted data. F.C., N.C., and K.K. diagnosed and managed patients. All authors contributed to the writing and approval of the article.
Acknowledgments
We thank the patients and Clinical Immunology Teams in St James's Hospital and Beaumont Hospital, Dublin. | ASCORBIC ACID\POLYETHYLENE GLYCOL 3350\POTASSIUM CHLORIDE\SODIUM ASCORBATE\SODIUM CHLORIDE\SODIUM SULFATE, ESOMEPRAZOLE MAGNESIUM, IBUPROFEN | DrugsGivenReaction | CC BY-NC-ND | 33543766 | 19,415,712 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Respiratory distress'. | PEG That Reaction: A Case Series of Allergy to Polyethylene Glycol.
Polyethylene glycol (PEG), also known as macrogol, is an excipient in numerous medications, health care products, cosmetics, and foods. It acts as an inert bulking, or stabilizing, agent. Despite its ubiquity, including in 2 of the newly launched vaccines against SARS-CoV-2, awareness of PEG allergy remains low. We present 6 cases of acute hypersensitivity to PEG. Accurate diagnoses in these cases posed a challenge, and although the triggering agents differed, PEG was demonstrated as the common culprit. All cases were female, with a mean age of 36.4 years. Four patients were originally suspected to have nonsteroid anti-inflammatory drug allergy, and 2 had a history of chronic spontaneous urticaria and angioedema. Biphasic allergic reactions featured prominently in this case series. Diagnosis relies on a high index of suspicion leading to a focused clinical history, supported by skin tests with PEG solutions to demonstrate sensitization. This case series highlights important clinical features of this rare, potentially serious, and increasingly recognized excipient allergy.
pmcPolyethylene glycol (PEG), also known as macrogol or E1521, is a commonly used bulking and stabilizing agent. It is an excipient in a wide variety of medications and also encountered in cosmetics and processed foods. Notably, both Pfizer BioNTech and Moderna mRNA vaccines against SARS‐CoV‐2, which are being internationally deployed to combat the current pandemic, contain polyethylene glycol. Allergy to PEG is rare but is increasingly recognized and can be severe. We present a case series to highlight features of this unusual excipient allergy. A high index of suspicion with early referral for expert diagnostic workup is required to implement appropriate risk management strategies.
The incident case experienced anaphylaxis after intramuscular Depo‐Provera administered by her general practitioner. She developed rapid‐onset sneezing, rhinorrhea, urticaria, profound hypotension, and chest tightness. She was managed with 2 doses of intramuscular adrenaline, steroids, and nebulized salbutamol. Symptoms improved; however, 6 hours following initial treatment she experienced further urticaria. The patient had recently tolerated similar progesterone in the oral contraceptive pill. Allergy to an excipient ingredient was suspected. The specific intramuscular formulation contained PEG‐3350 (Table 1). Skin‐prick testing (SPT) was positive and avoidance advised.
Table 1 Patient Case Summary With Triggering Agents and Associated PEG Compounds, Allergic Symptoms Experienced, Outcome of Skin Prick Testing, and Results of Supervised Provocation Challenges Detailed for Each Patient
Case Allergic Disease Trigger Symptoms Negative Provocation Challenge Positive Investigation
Case 1
Female, 35 years
None Depo‐Provera: medroxyprogesterone PEG‐3350 Sneezing, ocular irritation, rhinorrhea, urticaria, hypotension, chest tightness, respiratory compromise.
Biphasic urticaria.
None SPT PEG‐3350:
positive, 7 x 7 mm
Case 2
Female, 25 years
None Nexium: esomeprazole "Macrogols"
MoviPrep: osmotic laxative PEG‐3350
Cosmetics: PEG‐100
Urticaria, angioedema,
Respiratory compromise.
Pruritus, urticaria, angioedema, hypotension, swelling of hands and feet.
Biphasic urticaria.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free
"Teva”:
pantoprazole
PEG‐free
SPT PEG‐3350:
positive, 10 x 11 mm
Case 3
Female, 40 years
None Effervescent vitamin C: HMW‐PEG
Klean Prep: osmotic laxative PEG‐3350.
Vimovo: esomeprazole,
naproxen.
PEG‐8000.
EMLA topical anesthetic:
lidocaine, prilocaine.
HMW‐PEG.
Urticaria, syncope.
Urticaria, angioedema.
Urticaria, presyncopal.
Generalized pruritus.
Cerazette:
desogestrel
PEG‐400
“Teva”:
pantoprazole
PEG‐free
SPT PEG‐400, 3350:
Inconclusive because of dermographism.
Movicol challenge, PEG‐3350: positive
Case 4
Female, 44 years
None Klean Prep: osmotic laxative,
PEG‐3350.
Phosphate Sandoz: effervescent phosphate,
PEG‐4000.
Cosmetics: LMW‐ and HMW‐PEG.
Perioral paresthesia, angioedema, dyspnea, stridor, visual disturbance, syncope.
Angioedema, dyspnea, presyncope.
Urticaria
None SPT PEG‐3350:
positive
Case 5
Female, 36 years
CSUA Motilium Suppository: domperidone,
PEG‐400 and 1000.
Nurofen: ibuprofen,
PEG‐6000.
Angioedema, paresthesia,
throat tightness.
Angioedema, paresthesia,
throat tightness.
Motilium oral tablet:
PEG‐free
Nurofen syrup:
PEG‐free
SPT PEG‐3350:
positive
Case 6
Female, 38 years
CSUA
Physical urticaria
Betadine: wound dressing, povidone‐iodine,
PEG‐400, 6000.
Voltorol Oral: diclofenac
PEG‐8000.
Diclofenac IM:
HMW‐PEG.
Shaving foam: LMW‐ and HMW‐PEG.
Cosmetics: LMW‐ and HMW‐PEG.
Urticaria, presyncopal.
Urticaria.
Urticaria.
Urticaria, angioedema,
respiratory distress, hypotension.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free.
Ibuprofen tablet:
PEG‐free
SPT PEG‐3350:
10 × 10 mm
John Wiley & Sons, Ltd.
The second patient experienced acute urticaria and angioedema following concomitant ibuprofen and esomeprazole ingestion. Nonsteroidal anti‐inflammatory drug (NSAID) sensitivity was initially suspected (Table 1). While awaiting further investigation, she developed urticaria, angioedema, and hypotension following minimal ingestion of the PEG‐containing osmotic laxative Movi‐Prep. Symptoms settled with steroids and antihistamine; however, she experienced further urticaria 6 hours later. In addition, the patient described contact urticaria with certain cosmetics. PEG was suspected as a common trigger, and SPT was supportive (Table 1).
Case 3 had urticaria and syncope within minutes of effervescent vitamin C and separately developed urticaria, angioedema, and throat tightness with difficulty swallowing after the osmotic laxative Klean‐Prep. She gave a history of urticaria associated with Vimovo (esomeprazole and naproxen) and similar symptoms during a dental procedure (Table 1). All identified agents contained high‐molecular‐weight (HMW)‐PEG (Table 1). Unfortunately, SPT was inconclusive because of dermographism (negative control inciting a wheal). A provocation challenge to HMW‐PEG (Movicol) was objectively positive. The patient has remained completely symptom‐free with a PEG avoidance strategy. She has tolerated challenges with PEG‐free medications.
Anaphylaxis to Klean‐Prep was also a presenting feature of the fourth case. A PEG‐3350 allergy was suspected and avoidance advised until formal review at an allergy clinic. In the following months, while awaiting assessment and as a hospital inpatient for an unrelated condition, she had a second anaphylaxis within minutes of taking a PEG‐containing effervescent phosphate replacement preparation. SPT was subsequently positive to PEG‐3350, which has been avoided since.
The fifth patient was referred for assessment of multiple allergic drug reactions, on a background of chronic spontaneous urticaria and angioedema (CSUA). The first episode occurred within minutes of a Motilium suppository and was managed with intramuscular adrenaline, hydrocortisone, chlorphenamine, and fluid resuscitation. The second episode was precipitated by oral ibuprofen, again requiring adrenaline. PEG was considered a likely trigger, SPT was supportive. The patient subsequently tolerated PEG‐free domperidone and ibuprofen (Table 1).
The final case similarly had multiple adverse drug reactions, including anaphylaxis, on a background of CSUA. The initial allergic episode occurred following a Betadine dressing to a wound. She had systemic symptoms with oral and intramuscular diclofenac, oral Solpadeine (paracetamol and codeine), and contact urticaria with various cosmetics (Table 1). The patient subsequently tolerated PEG‐free forms of NSAIDs and codeine. PEG was suspected as a common inciting agent, SPT was supportive and strict avoidance recommended. After diagnosis, the patient experienced anaphylaxis while shaving with a product containing PEG requiring self‐administration of an adrenaline autoinjector.
This case series illustrates the diverse presentations of PEG allergy. Patients experienced an average of 3 allergic episodes before a formal diagnosis consistent with other case series. 1 Reactions were distressing for patients and objectively severe. Media reports of a case of fatal anaphylaxis in a patient with an established diagnosis of PEG allergy highlight the significance of this emerging problem. 2 The true incidence of PEG allergy is difficult to determine and may be underestimated. 3
It is hypothesized that initial PEG‐sensitization could be via cutaneous exposure from cosmetics and hygiene products or absorption of low‐molecular‐weight (LMW)‐PEG in pharmaceuticals. 3 The role of LMW‐PEG exposure prior to hypersensitivity has not been explored and may merit investigation. A female predominance was noted in our case series, but has not been universally observed. 1 , 4 Overall, the literature reports equal incidence between sexes. Interestingly, more recent case reports demonstrate a younger median age of diagnosis compared with older publications. 1 , 5 This is likely multifactorial and may be influenced by improved awareness of drug, and specifically PEG allergy, improved access to specialist allergy services, and potentially earlier or greater opportunity for sensitization. This is something that can only be speculated on because of limited clinical data.
Four of the 6 cases were suspected to have an NSAID allergy that was subsequently ruled out with negative provocation tests (Table 1). This emphasizes the prevalence of understandable misdiagnosis and unnecessary drug restrictions in this cohort. A review published in 2016 identified 37 cases labeled as “PEG‐allergy,” totaling 74 reactions. 4 More than half were associated with laxatives, also prominent allergens in this series. PEG‐3350 has been listed in more than 1000 approved medications. 3 Despite this ubiquity, reported incidence of hypersensitivity appears low. However we demonstrate that reactions can be severe and are diagnostically challenging.
NSAIDs are one of the most common inducers of drug‐related hypersensitivity reactions. 6 PEG sensitivity does not need to be considered in all NSAID‐related reactions. However, there are features that can be divined from an allergy history that offer pointers toward the need for PEG sensitization assessment. Patients with multiple episodes of “unexplained” anaphylaxis or tolerance of individual brands of the same drug merit closer investigation. Reactions to laxatives or bowel preparations, “depo” medications, and mucosal absorption from lubricants, gels, and dressings are red flags that should have PEG hypersensitivity in the differential. Bruusgaard‐Mouritsen et al (2021) similarly highlighted analgesics, depo injections, and laxatives as common triggers in their cohort, as well noting antacids and antibiotics as culprits. 1
We recommend that an adrenaline autoinjector be prescribed to those with PEG allergy because of an ongoing risk of accidental exposure. Unfortunately, comprehensive avoidance list cannot be provided, as medical preparations frequently change; thus, awareness is key. We advise patient empowerment with education, supported by step‐by‐step instructions on how to interrogate summary of product characteristics (SPC) for the variety of terms that indicate a PEG excipient. Patients are advised to engage with pharmacists and inform all health care professionals encountered of the disorder. In addition they should wear alert jewelry and only take a medication when they and their health care professional are satisfied that it does not contain PEG. Effective use of an electronic patient record can assist with communicating this issue, but as with all drug allergy, effective communication among disparate health care providers is a challenge. In addition, the cases presented here suggest a higher rate of biphasic allergic reactions than might be expected. 7 Based on these observations, we recommend extended monitoring for 12 hours after resolution of symptoms following a PEG‐related reaction. Although biphasic symptoms are usually mild, they can be distressing, especially to patients who have had a history of unexplained adverse events.
The identification of PEG allergy is increasing. These cases offer insight into the variety of ways this allergy can present. We report characteristics that flag PEG as a potential trigger and highlight the need for extended observation after resolution of symptoms because of the risk of biphasic reactions. Reports of immediate hypersensitivity in 2 health care workers on the first day of mass COVID‐19 vaccination in the United Kingdom are concerning. 8 It remains unknown if PEG‐2000 is involved in these reactions. Leaders in allergy have already engaged with regulatory authorities to highlight PEG as a possible allergen in mRNA vaccines and to support the objective investigation of reported reactions. 9
PEG allergy is now well known among allergy professionals. However, increased awareness of this allergen among the wider medical community is needed. Early recognition through a thorough clinical history and rapid referral to allergy diagnostic centers is required to confirm the diagnosis and effectively manage this high‐risk drug allergy.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Funding
We did not receive funding for this study.
Data‐Sharing Statement
Please contact the corresponding author, Dr Fionnuala Cox, on coxff@tcd.ie, if you wish to request further information on study data.
Author Contributions
F.C. conceived the study and interpreted data. F.C., N.C., and K.K. diagnosed and managed patients. All authors contributed to the writing and approval of the article.
Acknowledgments
We thank the patients and Clinical Immunology Teams in St James's Hospital and Beaumont Hospital, Dublin. | DICLOFENAC | DrugsGivenReaction | CC BY-NC-ND | 33543766 | 19,414,913 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Throat tightness'. | PEG That Reaction: A Case Series of Allergy to Polyethylene Glycol.
Polyethylene glycol (PEG), also known as macrogol, is an excipient in numerous medications, health care products, cosmetics, and foods. It acts as an inert bulking, or stabilizing, agent. Despite its ubiquity, including in 2 of the newly launched vaccines against SARS-CoV-2, awareness of PEG allergy remains low. We present 6 cases of acute hypersensitivity to PEG. Accurate diagnoses in these cases posed a challenge, and although the triggering agents differed, PEG was demonstrated as the common culprit. All cases were female, with a mean age of 36.4 years. Four patients were originally suspected to have nonsteroid anti-inflammatory drug allergy, and 2 had a history of chronic spontaneous urticaria and angioedema. Biphasic allergic reactions featured prominently in this case series. Diagnosis relies on a high index of suspicion leading to a focused clinical history, supported by skin tests with PEG solutions to demonstrate sensitization. This case series highlights important clinical features of this rare, potentially serious, and increasingly recognized excipient allergy.
pmcPolyethylene glycol (PEG), also known as macrogol or E1521, is a commonly used bulking and stabilizing agent. It is an excipient in a wide variety of medications and also encountered in cosmetics and processed foods. Notably, both Pfizer BioNTech and Moderna mRNA vaccines against SARS‐CoV‐2, which are being internationally deployed to combat the current pandemic, contain polyethylene glycol. Allergy to PEG is rare but is increasingly recognized and can be severe. We present a case series to highlight features of this unusual excipient allergy. A high index of suspicion with early referral for expert diagnostic workup is required to implement appropriate risk management strategies.
The incident case experienced anaphylaxis after intramuscular Depo‐Provera administered by her general practitioner. She developed rapid‐onset sneezing, rhinorrhea, urticaria, profound hypotension, and chest tightness. She was managed with 2 doses of intramuscular adrenaline, steroids, and nebulized salbutamol. Symptoms improved; however, 6 hours following initial treatment she experienced further urticaria. The patient had recently tolerated similar progesterone in the oral contraceptive pill. Allergy to an excipient ingredient was suspected. The specific intramuscular formulation contained PEG‐3350 (Table 1). Skin‐prick testing (SPT) was positive and avoidance advised.
Table 1 Patient Case Summary With Triggering Agents and Associated PEG Compounds, Allergic Symptoms Experienced, Outcome of Skin Prick Testing, and Results of Supervised Provocation Challenges Detailed for Each Patient
Case Allergic Disease Trigger Symptoms Negative Provocation Challenge Positive Investigation
Case 1
Female, 35 years
None Depo‐Provera: medroxyprogesterone PEG‐3350 Sneezing, ocular irritation, rhinorrhea, urticaria, hypotension, chest tightness, respiratory compromise.
Biphasic urticaria.
None SPT PEG‐3350:
positive, 7 x 7 mm
Case 2
Female, 25 years
None Nexium: esomeprazole "Macrogols"
MoviPrep: osmotic laxative PEG‐3350
Cosmetics: PEG‐100
Urticaria, angioedema,
Respiratory compromise.
Pruritus, urticaria, angioedema, hypotension, swelling of hands and feet.
Biphasic urticaria.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free
"Teva”:
pantoprazole
PEG‐free
SPT PEG‐3350:
positive, 10 x 11 mm
Case 3
Female, 40 years
None Effervescent vitamin C: HMW‐PEG
Klean Prep: osmotic laxative PEG‐3350.
Vimovo: esomeprazole,
naproxen.
PEG‐8000.
EMLA topical anesthetic:
lidocaine, prilocaine.
HMW‐PEG.
Urticaria, syncope.
Urticaria, angioedema.
Urticaria, presyncopal.
Generalized pruritus.
Cerazette:
desogestrel
PEG‐400
“Teva”:
pantoprazole
PEG‐free
SPT PEG‐400, 3350:
Inconclusive because of dermographism.
Movicol challenge, PEG‐3350: positive
Case 4
Female, 44 years
None Klean Prep: osmotic laxative,
PEG‐3350.
Phosphate Sandoz: effervescent phosphate,
PEG‐4000.
Cosmetics: LMW‐ and HMW‐PEG.
Perioral paresthesia, angioedema, dyspnea, stridor, visual disturbance, syncope.
Angioedema, dyspnea, presyncope.
Urticaria
None SPT PEG‐3350:
positive
Case 5
Female, 36 years
CSUA Motilium Suppository: domperidone,
PEG‐400 and 1000.
Nurofen: ibuprofen,
PEG‐6000.
Angioedema, paresthesia,
throat tightness.
Angioedema, paresthesia,
throat tightness.
Motilium oral tablet:
PEG‐free
Nurofen syrup:
PEG‐free
SPT PEG‐3350:
positive
Case 6
Female, 38 years
CSUA
Physical urticaria
Betadine: wound dressing, povidone‐iodine,
PEG‐400, 6000.
Voltorol Oral: diclofenac
PEG‐8000.
Diclofenac IM:
HMW‐PEG.
Shaving foam: LMW‐ and HMW‐PEG.
Cosmetics: LMW‐ and HMW‐PEG.
Urticaria, presyncopal.
Urticaria.
Urticaria.
Urticaria, angioedema,
respiratory distress, hypotension.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free.
Ibuprofen tablet:
PEG‐free
SPT PEG‐3350:
10 × 10 mm
John Wiley & Sons, Ltd.
The second patient experienced acute urticaria and angioedema following concomitant ibuprofen and esomeprazole ingestion. Nonsteroidal anti‐inflammatory drug (NSAID) sensitivity was initially suspected (Table 1). While awaiting further investigation, she developed urticaria, angioedema, and hypotension following minimal ingestion of the PEG‐containing osmotic laxative Movi‐Prep. Symptoms settled with steroids and antihistamine; however, she experienced further urticaria 6 hours later. In addition, the patient described contact urticaria with certain cosmetics. PEG was suspected as a common trigger, and SPT was supportive (Table 1).
Case 3 had urticaria and syncope within minutes of effervescent vitamin C and separately developed urticaria, angioedema, and throat tightness with difficulty swallowing after the osmotic laxative Klean‐Prep. She gave a history of urticaria associated with Vimovo (esomeprazole and naproxen) and similar symptoms during a dental procedure (Table 1). All identified agents contained high‐molecular‐weight (HMW)‐PEG (Table 1). Unfortunately, SPT was inconclusive because of dermographism (negative control inciting a wheal). A provocation challenge to HMW‐PEG (Movicol) was objectively positive. The patient has remained completely symptom‐free with a PEG avoidance strategy. She has tolerated challenges with PEG‐free medications.
Anaphylaxis to Klean‐Prep was also a presenting feature of the fourth case. A PEG‐3350 allergy was suspected and avoidance advised until formal review at an allergy clinic. In the following months, while awaiting assessment and as a hospital inpatient for an unrelated condition, she had a second anaphylaxis within minutes of taking a PEG‐containing effervescent phosphate replacement preparation. SPT was subsequently positive to PEG‐3350, which has been avoided since.
The fifth patient was referred for assessment of multiple allergic drug reactions, on a background of chronic spontaneous urticaria and angioedema (CSUA). The first episode occurred within minutes of a Motilium suppository and was managed with intramuscular adrenaline, hydrocortisone, chlorphenamine, and fluid resuscitation. The second episode was precipitated by oral ibuprofen, again requiring adrenaline. PEG was considered a likely trigger, SPT was supportive. The patient subsequently tolerated PEG‐free domperidone and ibuprofen (Table 1).
The final case similarly had multiple adverse drug reactions, including anaphylaxis, on a background of CSUA. The initial allergic episode occurred following a Betadine dressing to a wound. She had systemic symptoms with oral and intramuscular diclofenac, oral Solpadeine (paracetamol and codeine), and contact urticaria with various cosmetics (Table 1). The patient subsequently tolerated PEG‐free forms of NSAIDs and codeine. PEG was suspected as a common inciting agent, SPT was supportive and strict avoidance recommended. After diagnosis, the patient experienced anaphylaxis while shaving with a product containing PEG requiring self‐administration of an adrenaline autoinjector.
This case series illustrates the diverse presentations of PEG allergy. Patients experienced an average of 3 allergic episodes before a formal diagnosis consistent with other case series. 1 Reactions were distressing for patients and objectively severe. Media reports of a case of fatal anaphylaxis in a patient with an established diagnosis of PEG allergy highlight the significance of this emerging problem. 2 The true incidence of PEG allergy is difficult to determine and may be underestimated. 3
It is hypothesized that initial PEG‐sensitization could be via cutaneous exposure from cosmetics and hygiene products or absorption of low‐molecular‐weight (LMW)‐PEG in pharmaceuticals. 3 The role of LMW‐PEG exposure prior to hypersensitivity has not been explored and may merit investigation. A female predominance was noted in our case series, but has not been universally observed. 1 , 4 Overall, the literature reports equal incidence between sexes. Interestingly, more recent case reports demonstrate a younger median age of diagnosis compared with older publications. 1 , 5 This is likely multifactorial and may be influenced by improved awareness of drug, and specifically PEG allergy, improved access to specialist allergy services, and potentially earlier or greater opportunity for sensitization. This is something that can only be speculated on because of limited clinical data.
Four of the 6 cases were suspected to have an NSAID allergy that was subsequently ruled out with negative provocation tests (Table 1). This emphasizes the prevalence of understandable misdiagnosis and unnecessary drug restrictions in this cohort. A review published in 2016 identified 37 cases labeled as “PEG‐allergy,” totaling 74 reactions. 4 More than half were associated with laxatives, also prominent allergens in this series. PEG‐3350 has been listed in more than 1000 approved medications. 3 Despite this ubiquity, reported incidence of hypersensitivity appears low. However we demonstrate that reactions can be severe and are diagnostically challenging.
NSAIDs are one of the most common inducers of drug‐related hypersensitivity reactions. 6 PEG sensitivity does not need to be considered in all NSAID‐related reactions. However, there are features that can be divined from an allergy history that offer pointers toward the need for PEG sensitization assessment. Patients with multiple episodes of “unexplained” anaphylaxis or tolerance of individual brands of the same drug merit closer investigation. Reactions to laxatives or bowel preparations, “depo” medications, and mucosal absorption from lubricants, gels, and dressings are red flags that should have PEG hypersensitivity in the differential. Bruusgaard‐Mouritsen et al (2021) similarly highlighted analgesics, depo injections, and laxatives as common triggers in their cohort, as well noting antacids and antibiotics as culprits. 1
We recommend that an adrenaline autoinjector be prescribed to those with PEG allergy because of an ongoing risk of accidental exposure. Unfortunately, comprehensive avoidance list cannot be provided, as medical preparations frequently change; thus, awareness is key. We advise patient empowerment with education, supported by step‐by‐step instructions on how to interrogate summary of product characteristics (SPC) for the variety of terms that indicate a PEG excipient. Patients are advised to engage with pharmacists and inform all health care professionals encountered of the disorder. In addition they should wear alert jewelry and only take a medication when they and their health care professional are satisfied that it does not contain PEG. Effective use of an electronic patient record can assist with communicating this issue, but as with all drug allergy, effective communication among disparate health care providers is a challenge. In addition, the cases presented here suggest a higher rate of biphasic allergic reactions than might be expected. 7 Based on these observations, we recommend extended monitoring for 12 hours after resolution of symptoms following a PEG‐related reaction. Although biphasic symptoms are usually mild, they can be distressing, especially to patients who have had a history of unexplained adverse events.
The identification of PEG allergy is increasing. These cases offer insight into the variety of ways this allergy can present. We report characteristics that flag PEG as a potential trigger and highlight the need for extended observation after resolution of symptoms because of the risk of biphasic reactions. Reports of immediate hypersensitivity in 2 health care workers on the first day of mass COVID‐19 vaccination in the United Kingdom are concerning. 8 It remains unknown if PEG‐2000 is involved in these reactions. Leaders in allergy have already engaged with regulatory authorities to highlight PEG as a possible allergen in mRNA vaccines and to support the objective investigation of reported reactions. 9
PEG allergy is now well known among allergy professionals. However, increased awareness of this allergen among the wider medical community is needed. Early recognition through a thorough clinical history and rapid referral to allergy diagnostic centers is required to confirm the diagnosis and effectively manage this high‐risk drug allergy.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Funding
We did not receive funding for this study.
Data‐Sharing Statement
Please contact the corresponding author, Dr Fionnuala Cox, on coxff@tcd.ie, if you wish to request further information on study data.
Author Contributions
F.C. conceived the study and interpreted data. F.C., N.C., and K.K. diagnosed and managed patients. All authors contributed to the writing and approval of the article.
Acknowledgments
We thank the patients and Clinical Immunology Teams in St James's Hospital and Beaumont Hospital, Dublin. | DOMPERIDONE, IBUPROFEN | DrugsGivenReaction | CC BY-NC-ND | 33543766 | 19,417,536 | 2021-06 |
What was the administration route of drug 'ASCORBIC ACID\POLYETHYLENE GLYCOL 3350\POTASSIUM CHLORIDE\SODIUM ASCORBATE\SODIUM CHLORIDE\SODIUM SULFATE'? | PEG That Reaction: A Case Series of Allergy to Polyethylene Glycol.
Polyethylene glycol (PEG), also known as macrogol, is an excipient in numerous medications, health care products, cosmetics, and foods. It acts as an inert bulking, or stabilizing, agent. Despite its ubiquity, including in 2 of the newly launched vaccines against SARS-CoV-2, awareness of PEG allergy remains low. We present 6 cases of acute hypersensitivity to PEG. Accurate diagnoses in these cases posed a challenge, and although the triggering agents differed, PEG was demonstrated as the common culprit. All cases were female, with a mean age of 36.4 years. Four patients were originally suspected to have nonsteroid anti-inflammatory drug allergy, and 2 had a history of chronic spontaneous urticaria and angioedema. Biphasic allergic reactions featured prominently in this case series. Diagnosis relies on a high index of suspicion leading to a focused clinical history, supported by skin tests with PEG solutions to demonstrate sensitization. This case series highlights important clinical features of this rare, potentially serious, and increasingly recognized excipient allergy.
pmcPolyethylene glycol (PEG), also known as macrogol or E1521, is a commonly used bulking and stabilizing agent. It is an excipient in a wide variety of medications and also encountered in cosmetics and processed foods. Notably, both Pfizer BioNTech and Moderna mRNA vaccines against SARS‐CoV‐2, which are being internationally deployed to combat the current pandemic, contain polyethylene glycol. Allergy to PEG is rare but is increasingly recognized and can be severe. We present a case series to highlight features of this unusual excipient allergy. A high index of suspicion with early referral for expert diagnostic workup is required to implement appropriate risk management strategies.
The incident case experienced anaphylaxis after intramuscular Depo‐Provera administered by her general practitioner. She developed rapid‐onset sneezing, rhinorrhea, urticaria, profound hypotension, and chest tightness. She was managed with 2 doses of intramuscular adrenaline, steroids, and nebulized salbutamol. Symptoms improved; however, 6 hours following initial treatment she experienced further urticaria. The patient had recently tolerated similar progesterone in the oral contraceptive pill. Allergy to an excipient ingredient was suspected. The specific intramuscular formulation contained PEG‐3350 (Table 1). Skin‐prick testing (SPT) was positive and avoidance advised.
Table 1 Patient Case Summary With Triggering Agents and Associated PEG Compounds, Allergic Symptoms Experienced, Outcome of Skin Prick Testing, and Results of Supervised Provocation Challenges Detailed for Each Patient
Case Allergic Disease Trigger Symptoms Negative Provocation Challenge Positive Investigation
Case 1
Female, 35 years
None Depo‐Provera: medroxyprogesterone PEG‐3350 Sneezing, ocular irritation, rhinorrhea, urticaria, hypotension, chest tightness, respiratory compromise.
Biphasic urticaria.
None SPT PEG‐3350:
positive, 7 x 7 mm
Case 2
Female, 25 years
None Nexium: esomeprazole "Macrogols"
MoviPrep: osmotic laxative PEG‐3350
Cosmetics: PEG‐100
Urticaria, angioedema,
Respiratory compromise.
Pruritus, urticaria, angioedema, hypotension, swelling of hands and feet.
Biphasic urticaria.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free
"Teva”:
pantoprazole
PEG‐free
SPT PEG‐3350:
positive, 10 x 11 mm
Case 3
Female, 40 years
None Effervescent vitamin C: HMW‐PEG
Klean Prep: osmotic laxative PEG‐3350.
Vimovo: esomeprazole,
naproxen.
PEG‐8000.
EMLA topical anesthetic:
lidocaine, prilocaine.
HMW‐PEG.
Urticaria, syncope.
Urticaria, angioedema.
Urticaria, presyncopal.
Generalized pruritus.
Cerazette:
desogestrel
PEG‐400
“Teva”:
pantoprazole
PEG‐free
SPT PEG‐400, 3350:
Inconclusive because of dermographism.
Movicol challenge, PEG‐3350: positive
Case 4
Female, 44 years
None Klean Prep: osmotic laxative,
PEG‐3350.
Phosphate Sandoz: effervescent phosphate,
PEG‐4000.
Cosmetics: LMW‐ and HMW‐PEG.
Perioral paresthesia, angioedema, dyspnea, stridor, visual disturbance, syncope.
Angioedema, dyspnea, presyncope.
Urticaria
None SPT PEG‐3350:
positive
Case 5
Female, 36 years
CSUA Motilium Suppository: domperidone,
PEG‐400 and 1000.
Nurofen: ibuprofen,
PEG‐6000.
Angioedema, paresthesia,
throat tightness.
Angioedema, paresthesia,
throat tightness.
Motilium oral tablet:
PEG‐free
Nurofen syrup:
PEG‐free
SPT PEG‐3350:
positive
Case 6
Female, 38 years
CSUA
Physical urticaria
Betadine: wound dressing, povidone‐iodine,
PEG‐400, 6000.
Voltorol Oral: diclofenac
PEG‐8000.
Diclofenac IM:
HMW‐PEG.
Shaving foam: LMW‐ and HMW‐PEG.
Cosmetics: LMW‐ and HMW‐PEG.
Urticaria, presyncopal.
Urticaria.
Urticaria.
Urticaria, angioedema,
respiratory distress, hypotension.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free.
Ibuprofen tablet:
PEG‐free
SPT PEG‐3350:
10 × 10 mm
John Wiley & Sons, Ltd.
The second patient experienced acute urticaria and angioedema following concomitant ibuprofen and esomeprazole ingestion. Nonsteroidal anti‐inflammatory drug (NSAID) sensitivity was initially suspected (Table 1). While awaiting further investigation, she developed urticaria, angioedema, and hypotension following minimal ingestion of the PEG‐containing osmotic laxative Movi‐Prep. Symptoms settled with steroids and antihistamine; however, she experienced further urticaria 6 hours later. In addition, the patient described contact urticaria with certain cosmetics. PEG was suspected as a common trigger, and SPT was supportive (Table 1).
Case 3 had urticaria and syncope within minutes of effervescent vitamin C and separately developed urticaria, angioedema, and throat tightness with difficulty swallowing after the osmotic laxative Klean‐Prep. She gave a history of urticaria associated with Vimovo (esomeprazole and naproxen) and similar symptoms during a dental procedure (Table 1). All identified agents contained high‐molecular‐weight (HMW)‐PEG (Table 1). Unfortunately, SPT was inconclusive because of dermographism (negative control inciting a wheal). A provocation challenge to HMW‐PEG (Movicol) was objectively positive. The patient has remained completely symptom‐free with a PEG avoidance strategy. She has tolerated challenges with PEG‐free medications.
Anaphylaxis to Klean‐Prep was also a presenting feature of the fourth case. A PEG‐3350 allergy was suspected and avoidance advised until formal review at an allergy clinic. In the following months, while awaiting assessment and as a hospital inpatient for an unrelated condition, she had a second anaphylaxis within minutes of taking a PEG‐containing effervescent phosphate replacement preparation. SPT was subsequently positive to PEG‐3350, which has been avoided since.
The fifth patient was referred for assessment of multiple allergic drug reactions, on a background of chronic spontaneous urticaria and angioedema (CSUA). The first episode occurred within minutes of a Motilium suppository and was managed with intramuscular adrenaline, hydrocortisone, chlorphenamine, and fluid resuscitation. The second episode was precipitated by oral ibuprofen, again requiring adrenaline. PEG was considered a likely trigger, SPT was supportive. The patient subsequently tolerated PEG‐free domperidone and ibuprofen (Table 1).
The final case similarly had multiple adverse drug reactions, including anaphylaxis, on a background of CSUA. The initial allergic episode occurred following a Betadine dressing to a wound. She had systemic symptoms with oral and intramuscular diclofenac, oral Solpadeine (paracetamol and codeine), and contact urticaria with various cosmetics (Table 1). The patient subsequently tolerated PEG‐free forms of NSAIDs and codeine. PEG was suspected as a common inciting agent, SPT was supportive and strict avoidance recommended. After diagnosis, the patient experienced anaphylaxis while shaving with a product containing PEG requiring self‐administration of an adrenaline autoinjector.
This case series illustrates the diverse presentations of PEG allergy. Patients experienced an average of 3 allergic episodes before a formal diagnosis consistent with other case series. 1 Reactions were distressing for patients and objectively severe. Media reports of a case of fatal anaphylaxis in a patient with an established diagnosis of PEG allergy highlight the significance of this emerging problem. 2 The true incidence of PEG allergy is difficult to determine and may be underestimated. 3
It is hypothesized that initial PEG‐sensitization could be via cutaneous exposure from cosmetics and hygiene products or absorption of low‐molecular‐weight (LMW)‐PEG in pharmaceuticals. 3 The role of LMW‐PEG exposure prior to hypersensitivity has not been explored and may merit investigation. A female predominance was noted in our case series, but has not been universally observed. 1 , 4 Overall, the literature reports equal incidence between sexes. Interestingly, more recent case reports demonstrate a younger median age of diagnosis compared with older publications. 1 , 5 This is likely multifactorial and may be influenced by improved awareness of drug, and specifically PEG allergy, improved access to specialist allergy services, and potentially earlier or greater opportunity for sensitization. This is something that can only be speculated on because of limited clinical data.
Four of the 6 cases were suspected to have an NSAID allergy that was subsequently ruled out with negative provocation tests (Table 1). This emphasizes the prevalence of understandable misdiagnosis and unnecessary drug restrictions in this cohort. A review published in 2016 identified 37 cases labeled as “PEG‐allergy,” totaling 74 reactions. 4 More than half were associated with laxatives, also prominent allergens in this series. PEG‐3350 has been listed in more than 1000 approved medications. 3 Despite this ubiquity, reported incidence of hypersensitivity appears low. However we demonstrate that reactions can be severe and are diagnostically challenging.
NSAIDs are one of the most common inducers of drug‐related hypersensitivity reactions. 6 PEG sensitivity does not need to be considered in all NSAID‐related reactions. However, there are features that can be divined from an allergy history that offer pointers toward the need for PEG sensitization assessment. Patients with multiple episodes of “unexplained” anaphylaxis or tolerance of individual brands of the same drug merit closer investigation. Reactions to laxatives or bowel preparations, “depo” medications, and mucosal absorption from lubricants, gels, and dressings are red flags that should have PEG hypersensitivity in the differential. Bruusgaard‐Mouritsen et al (2021) similarly highlighted analgesics, depo injections, and laxatives as common triggers in their cohort, as well noting antacids and antibiotics as culprits. 1
We recommend that an adrenaline autoinjector be prescribed to those with PEG allergy because of an ongoing risk of accidental exposure. Unfortunately, comprehensive avoidance list cannot be provided, as medical preparations frequently change; thus, awareness is key. We advise patient empowerment with education, supported by step‐by‐step instructions on how to interrogate summary of product characteristics (SPC) for the variety of terms that indicate a PEG excipient. Patients are advised to engage with pharmacists and inform all health care professionals encountered of the disorder. In addition they should wear alert jewelry and only take a medication when they and their health care professional are satisfied that it does not contain PEG. Effective use of an electronic patient record can assist with communicating this issue, but as with all drug allergy, effective communication among disparate health care providers is a challenge. In addition, the cases presented here suggest a higher rate of biphasic allergic reactions than might be expected. 7 Based on these observations, we recommend extended monitoring for 12 hours after resolution of symptoms following a PEG‐related reaction. Although biphasic symptoms are usually mild, they can be distressing, especially to patients who have had a history of unexplained adverse events.
The identification of PEG allergy is increasing. These cases offer insight into the variety of ways this allergy can present. We report characteristics that flag PEG as a potential trigger and highlight the need for extended observation after resolution of symptoms because of the risk of biphasic reactions. Reports of immediate hypersensitivity in 2 health care workers on the first day of mass COVID‐19 vaccination in the United Kingdom are concerning. 8 It remains unknown if PEG‐2000 is involved in these reactions. Leaders in allergy have already engaged with regulatory authorities to highlight PEG as a possible allergen in mRNA vaccines and to support the objective investigation of reported reactions. 9
PEG allergy is now well known among allergy professionals. However, increased awareness of this allergen among the wider medical community is needed. Early recognition through a thorough clinical history and rapid referral to allergy diagnostic centers is required to confirm the diagnosis and effectively manage this high‐risk drug allergy.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Funding
We did not receive funding for this study.
Data‐Sharing Statement
Please contact the corresponding author, Dr Fionnuala Cox, on coxff@tcd.ie, if you wish to request further information on study data.
Author Contributions
F.C. conceived the study and interpreted data. F.C., N.C., and K.K. diagnosed and managed patients. All authors contributed to the writing and approval of the article.
Acknowledgments
We thank the patients and Clinical Immunology Teams in St James's Hospital and Beaumont Hospital, Dublin. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33543766 | 19,415,712 | 2021-06 |
What was the administration route of drug 'ESOMEPRAZOLE MAGNESIUM'? | PEG That Reaction: A Case Series of Allergy to Polyethylene Glycol.
Polyethylene glycol (PEG), also known as macrogol, is an excipient in numerous medications, health care products, cosmetics, and foods. It acts as an inert bulking, or stabilizing, agent. Despite its ubiquity, including in 2 of the newly launched vaccines against SARS-CoV-2, awareness of PEG allergy remains low. We present 6 cases of acute hypersensitivity to PEG. Accurate diagnoses in these cases posed a challenge, and although the triggering agents differed, PEG was demonstrated as the common culprit. All cases were female, with a mean age of 36.4 years. Four patients were originally suspected to have nonsteroid anti-inflammatory drug allergy, and 2 had a history of chronic spontaneous urticaria and angioedema. Biphasic allergic reactions featured prominently in this case series. Diagnosis relies on a high index of suspicion leading to a focused clinical history, supported by skin tests with PEG solutions to demonstrate sensitization. This case series highlights important clinical features of this rare, potentially serious, and increasingly recognized excipient allergy.
pmcPolyethylene glycol (PEG), also known as macrogol or E1521, is a commonly used bulking and stabilizing agent. It is an excipient in a wide variety of medications and also encountered in cosmetics and processed foods. Notably, both Pfizer BioNTech and Moderna mRNA vaccines against SARS‐CoV‐2, which are being internationally deployed to combat the current pandemic, contain polyethylene glycol. Allergy to PEG is rare but is increasingly recognized and can be severe. We present a case series to highlight features of this unusual excipient allergy. A high index of suspicion with early referral for expert diagnostic workup is required to implement appropriate risk management strategies.
The incident case experienced anaphylaxis after intramuscular Depo‐Provera administered by her general practitioner. She developed rapid‐onset sneezing, rhinorrhea, urticaria, profound hypotension, and chest tightness. She was managed with 2 doses of intramuscular adrenaline, steroids, and nebulized salbutamol. Symptoms improved; however, 6 hours following initial treatment she experienced further urticaria. The patient had recently tolerated similar progesterone in the oral contraceptive pill. Allergy to an excipient ingredient was suspected. The specific intramuscular formulation contained PEG‐3350 (Table 1). Skin‐prick testing (SPT) was positive and avoidance advised.
Table 1 Patient Case Summary With Triggering Agents and Associated PEG Compounds, Allergic Symptoms Experienced, Outcome of Skin Prick Testing, and Results of Supervised Provocation Challenges Detailed for Each Patient
Case Allergic Disease Trigger Symptoms Negative Provocation Challenge Positive Investigation
Case 1
Female, 35 years
None Depo‐Provera: medroxyprogesterone PEG‐3350 Sneezing, ocular irritation, rhinorrhea, urticaria, hypotension, chest tightness, respiratory compromise.
Biphasic urticaria.
None SPT PEG‐3350:
positive, 7 x 7 mm
Case 2
Female, 25 years
None Nexium: esomeprazole "Macrogols"
MoviPrep: osmotic laxative PEG‐3350
Cosmetics: PEG‐100
Urticaria, angioedema,
Respiratory compromise.
Pruritus, urticaria, angioedema, hypotension, swelling of hands and feet.
Biphasic urticaria.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free
"Teva”:
pantoprazole
PEG‐free
SPT PEG‐3350:
positive, 10 x 11 mm
Case 3
Female, 40 years
None Effervescent vitamin C: HMW‐PEG
Klean Prep: osmotic laxative PEG‐3350.
Vimovo: esomeprazole,
naproxen.
PEG‐8000.
EMLA topical anesthetic:
lidocaine, prilocaine.
HMW‐PEG.
Urticaria, syncope.
Urticaria, angioedema.
Urticaria, presyncopal.
Generalized pruritus.
Cerazette:
desogestrel
PEG‐400
“Teva”:
pantoprazole
PEG‐free
SPT PEG‐400, 3350:
Inconclusive because of dermographism.
Movicol challenge, PEG‐3350: positive
Case 4
Female, 44 years
None Klean Prep: osmotic laxative,
PEG‐3350.
Phosphate Sandoz: effervescent phosphate,
PEG‐4000.
Cosmetics: LMW‐ and HMW‐PEG.
Perioral paresthesia, angioedema, dyspnea, stridor, visual disturbance, syncope.
Angioedema, dyspnea, presyncope.
Urticaria
None SPT PEG‐3350:
positive
Case 5
Female, 36 years
CSUA Motilium Suppository: domperidone,
PEG‐400 and 1000.
Nurofen: ibuprofen,
PEG‐6000.
Angioedema, paresthesia,
throat tightness.
Angioedema, paresthesia,
throat tightness.
Motilium oral tablet:
PEG‐free
Nurofen syrup:
PEG‐free
SPT PEG‐3350:
positive
Case 6
Female, 38 years
CSUA
Physical urticaria
Betadine: wound dressing, povidone‐iodine,
PEG‐400, 6000.
Voltorol Oral: diclofenac
PEG‐8000.
Diclofenac IM:
HMW‐PEG.
Shaving foam: LMW‐ and HMW‐PEG.
Cosmetics: LMW‐ and HMW‐PEG.
Urticaria, presyncopal.
Urticaria.
Urticaria.
Urticaria, angioedema,
respiratory distress, hypotension.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free.
Ibuprofen tablet:
PEG‐free
SPT PEG‐3350:
10 × 10 mm
John Wiley & Sons, Ltd.
The second patient experienced acute urticaria and angioedema following concomitant ibuprofen and esomeprazole ingestion. Nonsteroidal anti‐inflammatory drug (NSAID) sensitivity was initially suspected (Table 1). While awaiting further investigation, she developed urticaria, angioedema, and hypotension following minimal ingestion of the PEG‐containing osmotic laxative Movi‐Prep. Symptoms settled with steroids and antihistamine; however, she experienced further urticaria 6 hours later. In addition, the patient described contact urticaria with certain cosmetics. PEG was suspected as a common trigger, and SPT was supportive (Table 1).
Case 3 had urticaria and syncope within minutes of effervescent vitamin C and separately developed urticaria, angioedema, and throat tightness with difficulty swallowing after the osmotic laxative Klean‐Prep. She gave a history of urticaria associated with Vimovo (esomeprazole and naproxen) and similar symptoms during a dental procedure (Table 1). All identified agents contained high‐molecular‐weight (HMW)‐PEG (Table 1). Unfortunately, SPT was inconclusive because of dermographism (negative control inciting a wheal). A provocation challenge to HMW‐PEG (Movicol) was objectively positive. The patient has remained completely symptom‐free with a PEG avoidance strategy. She has tolerated challenges with PEG‐free medications.
Anaphylaxis to Klean‐Prep was also a presenting feature of the fourth case. A PEG‐3350 allergy was suspected and avoidance advised until formal review at an allergy clinic. In the following months, while awaiting assessment and as a hospital inpatient for an unrelated condition, she had a second anaphylaxis within minutes of taking a PEG‐containing effervescent phosphate replacement preparation. SPT was subsequently positive to PEG‐3350, which has been avoided since.
The fifth patient was referred for assessment of multiple allergic drug reactions, on a background of chronic spontaneous urticaria and angioedema (CSUA). The first episode occurred within minutes of a Motilium suppository and was managed with intramuscular adrenaline, hydrocortisone, chlorphenamine, and fluid resuscitation. The second episode was precipitated by oral ibuprofen, again requiring adrenaline. PEG was considered a likely trigger, SPT was supportive. The patient subsequently tolerated PEG‐free domperidone and ibuprofen (Table 1).
The final case similarly had multiple adverse drug reactions, including anaphylaxis, on a background of CSUA. The initial allergic episode occurred following a Betadine dressing to a wound. She had systemic symptoms with oral and intramuscular diclofenac, oral Solpadeine (paracetamol and codeine), and contact urticaria with various cosmetics (Table 1). The patient subsequently tolerated PEG‐free forms of NSAIDs and codeine. PEG was suspected as a common inciting agent, SPT was supportive and strict avoidance recommended. After diagnosis, the patient experienced anaphylaxis while shaving with a product containing PEG requiring self‐administration of an adrenaline autoinjector.
This case series illustrates the diverse presentations of PEG allergy. Patients experienced an average of 3 allergic episodes before a formal diagnosis consistent with other case series. 1 Reactions were distressing for patients and objectively severe. Media reports of a case of fatal anaphylaxis in a patient with an established diagnosis of PEG allergy highlight the significance of this emerging problem. 2 The true incidence of PEG allergy is difficult to determine and may be underestimated. 3
It is hypothesized that initial PEG‐sensitization could be via cutaneous exposure from cosmetics and hygiene products or absorption of low‐molecular‐weight (LMW)‐PEG in pharmaceuticals. 3 The role of LMW‐PEG exposure prior to hypersensitivity has not been explored and may merit investigation. A female predominance was noted in our case series, but has not been universally observed. 1 , 4 Overall, the literature reports equal incidence between sexes. Interestingly, more recent case reports demonstrate a younger median age of diagnosis compared with older publications. 1 , 5 This is likely multifactorial and may be influenced by improved awareness of drug, and specifically PEG allergy, improved access to specialist allergy services, and potentially earlier or greater opportunity for sensitization. This is something that can only be speculated on because of limited clinical data.
Four of the 6 cases were suspected to have an NSAID allergy that was subsequently ruled out with negative provocation tests (Table 1). This emphasizes the prevalence of understandable misdiagnosis and unnecessary drug restrictions in this cohort. A review published in 2016 identified 37 cases labeled as “PEG‐allergy,” totaling 74 reactions. 4 More than half were associated with laxatives, also prominent allergens in this series. PEG‐3350 has been listed in more than 1000 approved medications. 3 Despite this ubiquity, reported incidence of hypersensitivity appears low. However we demonstrate that reactions can be severe and are diagnostically challenging.
NSAIDs are one of the most common inducers of drug‐related hypersensitivity reactions. 6 PEG sensitivity does not need to be considered in all NSAID‐related reactions. However, there are features that can be divined from an allergy history that offer pointers toward the need for PEG sensitization assessment. Patients with multiple episodes of “unexplained” anaphylaxis or tolerance of individual brands of the same drug merit closer investigation. Reactions to laxatives or bowel preparations, “depo” medications, and mucosal absorption from lubricants, gels, and dressings are red flags that should have PEG hypersensitivity in the differential. Bruusgaard‐Mouritsen et al (2021) similarly highlighted analgesics, depo injections, and laxatives as common triggers in their cohort, as well noting antacids and antibiotics as culprits. 1
We recommend that an adrenaline autoinjector be prescribed to those with PEG allergy because of an ongoing risk of accidental exposure. Unfortunately, comprehensive avoidance list cannot be provided, as medical preparations frequently change; thus, awareness is key. We advise patient empowerment with education, supported by step‐by‐step instructions on how to interrogate summary of product characteristics (SPC) for the variety of terms that indicate a PEG excipient. Patients are advised to engage with pharmacists and inform all health care professionals encountered of the disorder. In addition they should wear alert jewelry and only take a medication when they and their health care professional are satisfied that it does not contain PEG. Effective use of an electronic patient record can assist with communicating this issue, but as with all drug allergy, effective communication among disparate health care providers is a challenge. In addition, the cases presented here suggest a higher rate of biphasic allergic reactions than might be expected. 7 Based on these observations, we recommend extended monitoring for 12 hours after resolution of symptoms following a PEG‐related reaction. Although biphasic symptoms are usually mild, they can be distressing, especially to patients who have had a history of unexplained adverse events.
The identification of PEG allergy is increasing. These cases offer insight into the variety of ways this allergy can present. We report characteristics that flag PEG as a potential trigger and highlight the need for extended observation after resolution of symptoms because of the risk of biphasic reactions. Reports of immediate hypersensitivity in 2 health care workers on the first day of mass COVID‐19 vaccination in the United Kingdom are concerning. 8 It remains unknown if PEG‐2000 is involved in these reactions. Leaders in allergy have already engaged with regulatory authorities to highlight PEG as a possible allergen in mRNA vaccines and to support the objective investigation of reported reactions. 9
PEG allergy is now well known among allergy professionals. However, increased awareness of this allergen among the wider medical community is needed. Early recognition through a thorough clinical history and rapid referral to allergy diagnostic centers is required to confirm the diagnosis and effectively manage this high‐risk drug allergy.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Funding
We did not receive funding for this study.
Data‐Sharing Statement
Please contact the corresponding author, Dr Fionnuala Cox, on coxff@tcd.ie, if you wish to request further information on study data.
Author Contributions
F.C. conceived the study and interpreted data. F.C., N.C., and K.K. diagnosed and managed patients. All authors contributed to the writing and approval of the article.
Acknowledgments
We thank the patients and Clinical Immunology Teams in St James's Hospital and Beaumont Hospital, Dublin. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33543766 | 19,048,029 | 2021-06 |
What was the administration route of drug 'IBUPROFEN'? | PEG That Reaction: A Case Series of Allergy to Polyethylene Glycol.
Polyethylene glycol (PEG), also known as macrogol, is an excipient in numerous medications, health care products, cosmetics, and foods. It acts as an inert bulking, or stabilizing, agent. Despite its ubiquity, including in 2 of the newly launched vaccines against SARS-CoV-2, awareness of PEG allergy remains low. We present 6 cases of acute hypersensitivity to PEG. Accurate diagnoses in these cases posed a challenge, and although the triggering agents differed, PEG was demonstrated as the common culprit. All cases were female, with a mean age of 36.4 years. Four patients were originally suspected to have nonsteroid anti-inflammatory drug allergy, and 2 had a history of chronic spontaneous urticaria and angioedema. Biphasic allergic reactions featured prominently in this case series. Diagnosis relies on a high index of suspicion leading to a focused clinical history, supported by skin tests with PEG solutions to demonstrate sensitization. This case series highlights important clinical features of this rare, potentially serious, and increasingly recognized excipient allergy.
pmcPolyethylene glycol (PEG), also known as macrogol or E1521, is a commonly used bulking and stabilizing agent. It is an excipient in a wide variety of medications and also encountered in cosmetics and processed foods. Notably, both Pfizer BioNTech and Moderna mRNA vaccines against SARS‐CoV‐2, which are being internationally deployed to combat the current pandemic, contain polyethylene glycol. Allergy to PEG is rare but is increasingly recognized and can be severe. We present a case series to highlight features of this unusual excipient allergy. A high index of suspicion with early referral for expert diagnostic workup is required to implement appropriate risk management strategies.
The incident case experienced anaphylaxis after intramuscular Depo‐Provera administered by her general practitioner. She developed rapid‐onset sneezing, rhinorrhea, urticaria, profound hypotension, and chest tightness. She was managed with 2 doses of intramuscular adrenaline, steroids, and nebulized salbutamol. Symptoms improved; however, 6 hours following initial treatment she experienced further urticaria. The patient had recently tolerated similar progesterone in the oral contraceptive pill. Allergy to an excipient ingredient was suspected. The specific intramuscular formulation contained PEG‐3350 (Table 1). Skin‐prick testing (SPT) was positive and avoidance advised.
Table 1 Patient Case Summary With Triggering Agents and Associated PEG Compounds, Allergic Symptoms Experienced, Outcome of Skin Prick Testing, and Results of Supervised Provocation Challenges Detailed for Each Patient
Case Allergic Disease Trigger Symptoms Negative Provocation Challenge Positive Investigation
Case 1
Female, 35 years
None Depo‐Provera: medroxyprogesterone PEG‐3350 Sneezing, ocular irritation, rhinorrhea, urticaria, hypotension, chest tightness, respiratory compromise.
Biphasic urticaria.
None SPT PEG‐3350:
positive, 7 x 7 mm
Case 2
Female, 25 years
None Nexium: esomeprazole "Macrogols"
MoviPrep: osmotic laxative PEG‐3350
Cosmetics: PEG‐100
Urticaria, angioedema,
Respiratory compromise.
Pruritus, urticaria, angioedema, hypotension, swelling of hands and feet.
Biphasic urticaria.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free
"Teva”:
pantoprazole
PEG‐free
SPT PEG‐3350:
positive, 10 x 11 mm
Case 3
Female, 40 years
None Effervescent vitamin C: HMW‐PEG
Klean Prep: osmotic laxative PEG‐3350.
Vimovo: esomeprazole,
naproxen.
PEG‐8000.
EMLA topical anesthetic:
lidocaine, prilocaine.
HMW‐PEG.
Urticaria, syncope.
Urticaria, angioedema.
Urticaria, presyncopal.
Generalized pruritus.
Cerazette:
desogestrel
PEG‐400
“Teva”:
pantoprazole
PEG‐free
SPT PEG‐400, 3350:
Inconclusive because of dermographism.
Movicol challenge, PEG‐3350: positive
Case 4
Female, 44 years
None Klean Prep: osmotic laxative,
PEG‐3350.
Phosphate Sandoz: effervescent phosphate,
PEG‐4000.
Cosmetics: LMW‐ and HMW‐PEG.
Perioral paresthesia, angioedema, dyspnea, stridor, visual disturbance, syncope.
Angioedema, dyspnea, presyncope.
Urticaria
None SPT PEG‐3350:
positive
Case 5
Female, 36 years
CSUA Motilium Suppository: domperidone,
PEG‐400 and 1000.
Nurofen: ibuprofen,
PEG‐6000.
Angioedema, paresthesia,
throat tightness.
Angioedema, paresthesia,
throat tightness.
Motilium oral tablet:
PEG‐free
Nurofen syrup:
PEG‐free
SPT PEG‐3350:
positive
Case 6
Female, 38 years
CSUA
Physical urticaria
Betadine: wound dressing, povidone‐iodine,
PEG‐400, 6000.
Voltorol Oral: diclofenac
PEG‐8000.
Diclofenac IM:
HMW‐PEG.
Shaving foam: LMW‐ and HMW‐PEG.
Cosmetics: LMW‐ and HMW‐PEG.
Urticaria, presyncopal.
Urticaria.
Urticaria.
Urticaria, angioedema,
respiratory distress, hypotension.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free.
Ibuprofen tablet:
PEG‐free
SPT PEG‐3350:
10 × 10 mm
John Wiley & Sons, Ltd.
The second patient experienced acute urticaria and angioedema following concomitant ibuprofen and esomeprazole ingestion. Nonsteroidal anti‐inflammatory drug (NSAID) sensitivity was initially suspected (Table 1). While awaiting further investigation, she developed urticaria, angioedema, and hypotension following minimal ingestion of the PEG‐containing osmotic laxative Movi‐Prep. Symptoms settled with steroids and antihistamine; however, she experienced further urticaria 6 hours later. In addition, the patient described contact urticaria with certain cosmetics. PEG was suspected as a common trigger, and SPT was supportive (Table 1).
Case 3 had urticaria and syncope within minutes of effervescent vitamin C and separately developed urticaria, angioedema, and throat tightness with difficulty swallowing after the osmotic laxative Klean‐Prep. She gave a history of urticaria associated with Vimovo (esomeprazole and naproxen) and similar symptoms during a dental procedure (Table 1). All identified agents contained high‐molecular‐weight (HMW)‐PEG (Table 1). Unfortunately, SPT was inconclusive because of dermographism (negative control inciting a wheal). A provocation challenge to HMW‐PEG (Movicol) was objectively positive. The patient has remained completely symptom‐free with a PEG avoidance strategy. She has tolerated challenges with PEG‐free medications.
Anaphylaxis to Klean‐Prep was also a presenting feature of the fourth case. A PEG‐3350 allergy was suspected and avoidance advised until formal review at an allergy clinic. In the following months, while awaiting assessment and as a hospital inpatient for an unrelated condition, she had a second anaphylaxis within minutes of taking a PEG‐containing effervescent phosphate replacement preparation. SPT was subsequently positive to PEG‐3350, which has been avoided since.
The fifth patient was referred for assessment of multiple allergic drug reactions, on a background of chronic spontaneous urticaria and angioedema (CSUA). The first episode occurred within minutes of a Motilium suppository and was managed with intramuscular adrenaline, hydrocortisone, chlorphenamine, and fluid resuscitation. The second episode was precipitated by oral ibuprofen, again requiring adrenaline. PEG was considered a likely trigger, SPT was supportive. The patient subsequently tolerated PEG‐free domperidone and ibuprofen (Table 1).
The final case similarly had multiple adverse drug reactions, including anaphylaxis, on a background of CSUA. The initial allergic episode occurred following a Betadine dressing to a wound. She had systemic symptoms with oral and intramuscular diclofenac, oral Solpadeine (paracetamol and codeine), and contact urticaria with various cosmetics (Table 1). The patient subsequently tolerated PEG‐free forms of NSAIDs and codeine. PEG was suspected as a common inciting agent, SPT was supportive and strict avoidance recommended. After diagnosis, the patient experienced anaphylaxis while shaving with a product containing PEG requiring self‐administration of an adrenaline autoinjector.
This case series illustrates the diverse presentations of PEG allergy. Patients experienced an average of 3 allergic episodes before a formal diagnosis consistent with other case series. 1 Reactions were distressing for patients and objectively severe. Media reports of a case of fatal anaphylaxis in a patient with an established diagnosis of PEG allergy highlight the significance of this emerging problem. 2 The true incidence of PEG allergy is difficult to determine and may be underestimated. 3
It is hypothesized that initial PEG‐sensitization could be via cutaneous exposure from cosmetics and hygiene products or absorption of low‐molecular‐weight (LMW)‐PEG in pharmaceuticals. 3 The role of LMW‐PEG exposure prior to hypersensitivity has not been explored and may merit investigation. A female predominance was noted in our case series, but has not been universally observed. 1 , 4 Overall, the literature reports equal incidence between sexes. Interestingly, more recent case reports demonstrate a younger median age of diagnosis compared with older publications. 1 , 5 This is likely multifactorial and may be influenced by improved awareness of drug, and specifically PEG allergy, improved access to specialist allergy services, and potentially earlier or greater opportunity for sensitization. This is something that can only be speculated on because of limited clinical data.
Four of the 6 cases were suspected to have an NSAID allergy that was subsequently ruled out with negative provocation tests (Table 1). This emphasizes the prevalence of understandable misdiagnosis and unnecessary drug restrictions in this cohort. A review published in 2016 identified 37 cases labeled as “PEG‐allergy,” totaling 74 reactions. 4 More than half were associated with laxatives, also prominent allergens in this series. PEG‐3350 has been listed in more than 1000 approved medications. 3 Despite this ubiquity, reported incidence of hypersensitivity appears low. However we demonstrate that reactions can be severe and are diagnostically challenging.
NSAIDs are one of the most common inducers of drug‐related hypersensitivity reactions. 6 PEG sensitivity does not need to be considered in all NSAID‐related reactions. However, there are features that can be divined from an allergy history that offer pointers toward the need for PEG sensitization assessment. Patients with multiple episodes of “unexplained” anaphylaxis or tolerance of individual brands of the same drug merit closer investigation. Reactions to laxatives or bowel preparations, “depo” medications, and mucosal absorption from lubricants, gels, and dressings are red flags that should have PEG hypersensitivity in the differential. Bruusgaard‐Mouritsen et al (2021) similarly highlighted analgesics, depo injections, and laxatives as common triggers in their cohort, as well noting antacids and antibiotics as culprits. 1
We recommend that an adrenaline autoinjector be prescribed to those with PEG allergy because of an ongoing risk of accidental exposure. Unfortunately, comprehensive avoidance list cannot be provided, as medical preparations frequently change; thus, awareness is key. We advise patient empowerment with education, supported by step‐by‐step instructions on how to interrogate summary of product characteristics (SPC) for the variety of terms that indicate a PEG excipient. Patients are advised to engage with pharmacists and inform all health care professionals encountered of the disorder. In addition they should wear alert jewelry and only take a medication when they and their health care professional are satisfied that it does not contain PEG. Effective use of an electronic patient record can assist with communicating this issue, but as with all drug allergy, effective communication among disparate health care providers is a challenge. In addition, the cases presented here suggest a higher rate of biphasic allergic reactions than might be expected. 7 Based on these observations, we recommend extended monitoring for 12 hours after resolution of symptoms following a PEG‐related reaction. Although biphasic symptoms are usually mild, they can be distressing, especially to patients who have had a history of unexplained adverse events.
The identification of PEG allergy is increasing. These cases offer insight into the variety of ways this allergy can present. We report characteristics that flag PEG as a potential trigger and highlight the need for extended observation after resolution of symptoms because of the risk of biphasic reactions. Reports of immediate hypersensitivity in 2 health care workers on the first day of mass COVID‐19 vaccination in the United Kingdom are concerning. 8 It remains unknown if PEG‐2000 is involved in these reactions. Leaders in allergy have already engaged with regulatory authorities to highlight PEG as a possible allergen in mRNA vaccines and to support the objective investigation of reported reactions. 9
PEG allergy is now well known among allergy professionals. However, increased awareness of this allergen among the wider medical community is needed. Early recognition through a thorough clinical history and rapid referral to allergy diagnostic centers is required to confirm the diagnosis and effectively manage this high‐risk drug allergy.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Funding
We did not receive funding for this study.
Data‐Sharing Statement
Please contact the corresponding author, Dr Fionnuala Cox, on coxff@tcd.ie, if you wish to request further information on study data.
Author Contributions
F.C. conceived the study and interpreted data. F.C., N.C., and K.K. diagnosed and managed patients. All authors contributed to the writing and approval of the article.
Acknowledgments
We thank the patients and Clinical Immunology Teams in St James's Hospital and Beaumont Hospital, Dublin. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33543766 | 19,048,029 | 2021-06 |
What was the administration route of drug 'LIDOCAINE\PRILOCAINE'? | PEG That Reaction: A Case Series of Allergy to Polyethylene Glycol.
Polyethylene glycol (PEG), also known as macrogol, is an excipient in numerous medications, health care products, cosmetics, and foods. It acts as an inert bulking, or stabilizing, agent. Despite its ubiquity, including in 2 of the newly launched vaccines against SARS-CoV-2, awareness of PEG allergy remains low. We present 6 cases of acute hypersensitivity to PEG. Accurate diagnoses in these cases posed a challenge, and although the triggering agents differed, PEG was demonstrated as the common culprit. All cases were female, with a mean age of 36.4 years. Four patients were originally suspected to have nonsteroid anti-inflammatory drug allergy, and 2 had a history of chronic spontaneous urticaria and angioedema. Biphasic allergic reactions featured prominently in this case series. Diagnosis relies on a high index of suspicion leading to a focused clinical history, supported by skin tests with PEG solutions to demonstrate sensitization. This case series highlights important clinical features of this rare, potentially serious, and increasingly recognized excipient allergy.
pmcPolyethylene glycol (PEG), also known as macrogol or E1521, is a commonly used bulking and stabilizing agent. It is an excipient in a wide variety of medications and also encountered in cosmetics and processed foods. Notably, both Pfizer BioNTech and Moderna mRNA vaccines against SARS‐CoV‐2, which are being internationally deployed to combat the current pandemic, contain polyethylene glycol. Allergy to PEG is rare but is increasingly recognized and can be severe. We present a case series to highlight features of this unusual excipient allergy. A high index of suspicion with early referral for expert diagnostic workup is required to implement appropriate risk management strategies.
The incident case experienced anaphylaxis after intramuscular Depo‐Provera administered by her general practitioner. She developed rapid‐onset sneezing, rhinorrhea, urticaria, profound hypotension, and chest tightness. She was managed with 2 doses of intramuscular adrenaline, steroids, and nebulized salbutamol. Symptoms improved; however, 6 hours following initial treatment she experienced further urticaria. The patient had recently tolerated similar progesterone in the oral contraceptive pill. Allergy to an excipient ingredient was suspected. The specific intramuscular formulation contained PEG‐3350 (Table 1). Skin‐prick testing (SPT) was positive and avoidance advised.
Table 1 Patient Case Summary With Triggering Agents and Associated PEG Compounds, Allergic Symptoms Experienced, Outcome of Skin Prick Testing, and Results of Supervised Provocation Challenges Detailed for Each Patient
Case Allergic Disease Trigger Symptoms Negative Provocation Challenge Positive Investigation
Case 1
Female, 35 years
None Depo‐Provera: medroxyprogesterone PEG‐3350 Sneezing, ocular irritation, rhinorrhea, urticaria, hypotension, chest tightness, respiratory compromise.
Biphasic urticaria.
None SPT PEG‐3350:
positive, 7 x 7 mm
Case 2
Female, 25 years
None Nexium: esomeprazole "Macrogols"
MoviPrep: osmotic laxative PEG‐3350
Cosmetics: PEG‐100
Urticaria, angioedema,
Respiratory compromise.
Pruritus, urticaria, angioedema, hypotension, swelling of hands and feet.
Biphasic urticaria.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free
"Teva”:
pantoprazole
PEG‐free
SPT PEG‐3350:
positive, 10 x 11 mm
Case 3
Female, 40 years
None Effervescent vitamin C: HMW‐PEG
Klean Prep: osmotic laxative PEG‐3350.
Vimovo: esomeprazole,
naproxen.
PEG‐8000.
EMLA topical anesthetic:
lidocaine, prilocaine.
HMW‐PEG.
Urticaria, syncope.
Urticaria, angioedema.
Urticaria, presyncopal.
Generalized pruritus.
Cerazette:
desogestrel
PEG‐400
“Teva”:
pantoprazole
PEG‐free
SPT PEG‐400, 3350:
Inconclusive because of dermographism.
Movicol challenge, PEG‐3350: positive
Case 4
Female, 44 years
None Klean Prep: osmotic laxative,
PEG‐3350.
Phosphate Sandoz: effervescent phosphate,
PEG‐4000.
Cosmetics: LMW‐ and HMW‐PEG.
Perioral paresthesia, angioedema, dyspnea, stridor, visual disturbance, syncope.
Angioedema, dyspnea, presyncope.
Urticaria
None SPT PEG‐3350:
positive
Case 5
Female, 36 years
CSUA Motilium Suppository: domperidone,
PEG‐400 and 1000.
Nurofen: ibuprofen,
PEG‐6000.
Angioedema, paresthesia,
throat tightness.
Angioedema, paresthesia,
throat tightness.
Motilium oral tablet:
PEG‐free
Nurofen syrup:
PEG‐free
SPT PEG‐3350:
positive
Case 6
Female, 38 years
CSUA
Physical urticaria
Betadine: wound dressing, povidone‐iodine,
PEG‐400, 6000.
Voltorol Oral: diclofenac
PEG‐8000.
Diclofenac IM:
HMW‐PEG.
Shaving foam: LMW‐ and HMW‐PEG.
Cosmetics: LMW‐ and HMW‐PEG.
Urticaria, presyncopal.
Urticaria.
Urticaria.
Urticaria, angioedema,
respiratory distress, hypotension.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free.
Ibuprofen tablet:
PEG‐free
SPT PEG‐3350:
10 × 10 mm
John Wiley & Sons, Ltd.
The second patient experienced acute urticaria and angioedema following concomitant ibuprofen and esomeprazole ingestion. Nonsteroidal anti‐inflammatory drug (NSAID) sensitivity was initially suspected (Table 1). While awaiting further investigation, she developed urticaria, angioedema, and hypotension following minimal ingestion of the PEG‐containing osmotic laxative Movi‐Prep. Symptoms settled with steroids and antihistamine; however, she experienced further urticaria 6 hours later. In addition, the patient described contact urticaria with certain cosmetics. PEG was suspected as a common trigger, and SPT was supportive (Table 1).
Case 3 had urticaria and syncope within minutes of effervescent vitamin C and separately developed urticaria, angioedema, and throat tightness with difficulty swallowing after the osmotic laxative Klean‐Prep. She gave a history of urticaria associated with Vimovo (esomeprazole and naproxen) and similar symptoms during a dental procedure (Table 1). All identified agents contained high‐molecular‐weight (HMW)‐PEG (Table 1). Unfortunately, SPT was inconclusive because of dermographism (negative control inciting a wheal). A provocation challenge to HMW‐PEG (Movicol) was objectively positive. The patient has remained completely symptom‐free with a PEG avoidance strategy. She has tolerated challenges with PEG‐free medications.
Anaphylaxis to Klean‐Prep was also a presenting feature of the fourth case. A PEG‐3350 allergy was suspected and avoidance advised until formal review at an allergy clinic. In the following months, while awaiting assessment and as a hospital inpatient for an unrelated condition, she had a second anaphylaxis within minutes of taking a PEG‐containing effervescent phosphate replacement preparation. SPT was subsequently positive to PEG‐3350, which has been avoided since.
The fifth patient was referred for assessment of multiple allergic drug reactions, on a background of chronic spontaneous urticaria and angioedema (CSUA). The first episode occurred within minutes of a Motilium suppository and was managed with intramuscular adrenaline, hydrocortisone, chlorphenamine, and fluid resuscitation. The second episode was precipitated by oral ibuprofen, again requiring adrenaline. PEG was considered a likely trigger, SPT was supportive. The patient subsequently tolerated PEG‐free domperidone and ibuprofen (Table 1).
The final case similarly had multiple adverse drug reactions, including anaphylaxis, on a background of CSUA. The initial allergic episode occurred following a Betadine dressing to a wound. She had systemic symptoms with oral and intramuscular diclofenac, oral Solpadeine (paracetamol and codeine), and contact urticaria with various cosmetics (Table 1). The patient subsequently tolerated PEG‐free forms of NSAIDs and codeine. PEG was suspected as a common inciting agent, SPT was supportive and strict avoidance recommended. After diagnosis, the patient experienced anaphylaxis while shaving with a product containing PEG requiring self‐administration of an adrenaline autoinjector.
This case series illustrates the diverse presentations of PEG allergy. Patients experienced an average of 3 allergic episodes before a formal diagnosis consistent with other case series. 1 Reactions were distressing for patients and objectively severe. Media reports of a case of fatal anaphylaxis in a patient with an established diagnosis of PEG allergy highlight the significance of this emerging problem. 2 The true incidence of PEG allergy is difficult to determine and may be underestimated. 3
It is hypothesized that initial PEG‐sensitization could be via cutaneous exposure from cosmetics and hygiene products or absorption of low‐molecular‐weight (LMW)‐PEG in pharmaceuticals. 3 The role of LMW‐PEG exposure prior to hypersensitivity has not been explored and may merit investigation. A female predominance was noted in our case series, but has not been universally observed. 1 , 4 Overall, the literature reports equal incidence between sexes. Interestingly, more recent case reports demonstrate a younger median age of diagnosis compared with older publications. 1 , 5 This is likely multifactorial and may be influenced by improved awareness of drug, and specifically PEG allergy, improved access to specialist allergy services, and potentially earlier or greater opportunity for sensitization. This is something that can only be speculated on because of limited clinical data.
Four of the 6 cases were suspected to have an NSAID allergy that was subsequently ruled out with negative provocation tests (Table 1). This emphasizes the prevalence of understandable misdiagnosis and unnecessary drug restrictions in this cohort. A review published in 2016 identified 37 cases labeled as “PEG‐allergy,” totaling 74 reactions. 4 More than half were associated with laxatives, also prominent allergens in this series. PEG‐3350 has been listed in more than 1000 approved medications. 3 Despite this ubiquity, reported incidence of hypersensitivity appears low. However we demonstrate that reactions can be severe and are diagnostically challenging.
NSAIDs are one of the most common inducers of drug‐related hypersensitivity reactions. 6 PEG sensitivity does not need to be considered in all NSAID‐related reactions. However, there are features that can be divined from an allergy history that offer pointers toward the need for PEG sensitization assessment. Patients with multiple episodes of “unexplained” anaphylaxis or tolerance of individual brands of the same drug merit closer investigation. Reactions to laxatives or bowel preparations, “depo” medications, and mucosal absorption from lubricants, gels, and dressings are red flags that should have PEG hypersensitivity in the differential. Bruusgaard‐Mouritsen et al (2021) similarly highlighted analgesics, depo injections, and laxatives as common triggers in their cohort, as well noting antacids and antibiotics as culprits. 1
We recommend that an adrenaline autoinjector be prescribed to those with PEG allergy because of an ongoing risk of accidental exposure. Unfortunately, comprehensive avoidance list cannot be provided, as medical preparations frequently change; thus, awareness is key. We advise patient empowerment with education, supported by step‐by‐step instructions on how to interrogate summary of product characteristics (SPC) for the variety of terms that indicate a PEG excipient. Patients are advised to engage with pharmacists and inform all health care professionals encountered of the disorder. In addition they should wear alert jewelry and only take a medication when they and their health care professional are satisfied that it does not contain PEG. Effective use of an electronic patient record can assist with communicating this issue, but as with all drug allergy, effective communication among disparate health care providers is a challenge. In addition, the cases presented here suggest a higher rate of biphasic allergic reactions than might be expected. 7 Based on these observations, we recommend extended monitoring for 12 hours after resolution of symptoms following a PEG‐related reaction. Although biphasic symptoms are usually mild, they can be distressing, especially to patients who have had a history of unexplained adverse events.
The identification of PEG allergy is increasing. These cases offer insight into the variety of ways this allergy can present. We report characteristics that flag PEG as a potential trigger and highlight the need for extended observation after resolution of symptoms because of the risk of biphasic reactions. Reports of immediate hypersensitivity in 2 health care workers on the first day of mass COVID‐19 vaccination in the United Kingdom are concerning. 8 It remains unknown if PEG‐2000 is involved in these reactions. Leaders in allergy have already engaged with regulatory authorities to highlight PEG as a possible allergen in mRNA vaccines and to support the objective investigation of reported reactions. 9
PEG allergy is now well known among allergy professionals. However, increased awareness of this allergen among the wider medical community is needed. Early recognition through a thorough clinical history and rapid referral to allergy diagnostic centers is required to confirm the diagnosis and effectively manage this high‐risk drug allergy.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Funding
We did not receive funding for this study.
Data‐Sharing Statement
Please contact the corresponding author, Dr Fionnuala Cox, on coxff@tcd.ie, if you wish to request further information on study data.
Author Contributions
F.C. conceived the study and interpreted data. F.C., N.C., and K.K. diagnosed and managed patients. All authors contributed to the writing and approval of the article.
Acknowledgments
We thank the patients and Clinical Immunology Teams in St James's Hospital and Beaumont Hospital, Dublin. | Topical | DrugAdministrationRoute | CC BY-NC-ND | 33543766 | 19,399,217 | 2021-06 |
What was the administration route of drug 'MEDROXYPROGESTERONE ACETATE'? | PEG That Reaction: A Case Series of Allergy to Polyethylene Glycol.
Polyethylene glycol (PEG), also known as macrogol, is an excipient in numerous medications, health care products, cosmetics, and foods. It acts as an inert bulking, or stabilizing, agent. Despite its ubiquity, including in 2 of the newly launched vaccines against SARS-CoV-2, awareness of PEG allergy remains low. We present 6 cases of acute hypersensitivity to PEG. Accurate diagnoses in these cases posed a challenge, and although the triggering agents differed, PEG was demonstrated as the common culprit. All cases were female, with a mean age of 36.4 years. Four patients were originally suspected to have nonsteroid anti-inflammatory drug allergy, and 2 had a history of chronic spontaneous urticaria and angioedema. Biphasic allergic reactions featured prominently in this case series. Diagnosis relies on a high index of suspicion leading to a focused clinical history, supported by skin tests with PEG solutions to demonstrate sensitization. This case series highlights important clinical features of this rare, potentially serious, and increasingly recognized excipient allergy.
pmcPolyethylene glycol (PEG), also known as macrogol or E1521, is a commonly used bulking and stabilizing agent. It is an excipient in a wide variety of medications and also encountered in cosmetics and processed foods. Notably, both Pfizer BioNTech and Moderna mRNA vaccines against SARS‐CoV‐2, which are being internationally deployed to combat the current pandemic, contain polyethylene glycol. Allergy to PEG is rare but is increasingly recognized and can be severe. We present a case series to highlight features of this unusual excipient allergy. A high index of suspicion with early referral for expert diagnostic workup is required to implement appropriate risk management strategies.
The incident case experienced anaphylaxis after intramuscular Depo‐Provera administered by her general practitioner. She developed rapid‐onset sneezing, rhinorrhea, urticaria, profound hypotension, and chest tightness. She was managed with 2 doses of intramuscular adrenaline, steroids, and nebulized salbutamol. Symptoms improved; however, 6 hours following initial treatment she experienced further urticaria. The patient had recently tolerated similar progesterone in the oral contraceptive pill. Allergy to an excipient ingredient was suspected. The specific intramuscular formulation contained PEG‐3350 (Table 1). Skin‐prick testing (SPT) was positive and avoidance advised.
Table 1 Patient Case Summary With Triggering Agents and Associated PEG Compounds, Allergic Symptoms Experienced, Outcome of Skin Prick Testing, and Results of Supervised Provocation Challenges Detailed for Each Patient
Case Allergic Disease Trigger Symptoms Negative Provocation Challenge Positive Investigation
Case 1
Female, 35 years
None Depo‐Provera: medroxyprogesterone PEG‐3350 Sneezing, ocular irritation, rhinorrhea, urticaria, hypotension, chest tightness, respiratory compromise.
Biphasic urticaria.
None SPT PEG‐3350:
positive, 7 x 7 mm
Case 2
Female, 25 years
None Nexium: esomeprazole "Macrogols"
MoviPrep: osmotic laxative PEG‐3350
Cosmetics: PEG‐100
Urticaria, angioedema,
Respiratory compromise.
Pruritus, urticaria, angioedema, hypotension, swelling of hands and feet.
Biphasic urticaria.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free
"Teva”:
pantoprazole
PEG‐free
SPT PEG‐3350:
positive, 10 x 11 mm
Case 3
Female, 40 years
None Effervescent vitamin C: HMW‐PEG
Klean Prep: osmotic laxative PEG‐3350.
Vimovo: esomeprazole,
naproxen.
PEG‐8000.
EMLA topical anesthetic:
lidocaine, prilocaine.
HMW‐PEG.
Urticaria, syncope.
Urticaria, angioedema.
Urticaria, presyncopal.
Generalized pruritus.
Cerazette:
desogestrel
PEG‐400
“Teva”:
pantoprazole
PEG‐free
SPT PEG‐400, 3350:
Inconclusive because of dermographism.
Movicol challenge, PEG‐3350: positive
Case 4
Female, 44 years
None Klean Prep: osmotic laxative,
PEG‐3350.
Phosphate Sandoz: effervescent phosphate,
PEG‐4000.
Cosmetics: LMW‐ and HMW‐PEG.
Perioral paresthesia, angioedema, dyspnea, stridor, visual disturbance, syncope.
Angioedema, dyspnea, presyncope.
Urticaria
None SPT PEG‐3350:
positive
Case 5
Female, 36 years
CSUA Motilium Suppository: domperidone,
PEG‐400 and 1000.
Nurofen: ibuprofen,
PEG‐6000.
Angioedema, paresthesia,
throat tightness.
Angioedema, paresthesia,
throat tightness.
Motilium oral tablet:
PEG‐free
Nurofen syrup:
PEG‐free
SPT PEG‐3350:
positive
Case 6
Female, 38 years
CSUA
Physical urticaria
Betadine: wound dressing, povidone‐iodine,
PEG‐400, 6000.
Voltorol Oral: diclofenac
PEG‐8000.
Diclofenac IM:
HMW‐PEG.
Shaving foam: LMW‐ and HMW‐PEG.
Cosmetics: LMW‐ and HMW‐PEG.
Urticaria, presyncopal.
Urticaria.
Urticaria.
Urticaria, angioedema,
respiratory distress, hypotension.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free.
Ibuprofen tablet:
PEG‐free
SPT PEG‐3350:
10 × 10 mm
John Wiley & Sons, Ltd.
The second patient experienced acute urticaria and angioedema following concomitant ibuprofen and esomeprazole ingestion. Nonsteroidal anti‐inflammatory drug (NSAID) sensitivity was initially suspected (Table 1). While awaiting further investigation, she developed urticaria, angioedema, and hypotension following minimal ingestion of the PEG‐containing osmotic laxative Movi‐Prep. Symptoms settled with steroids and antihistamine; however, she experienced further urticaria 6 hours later. In addition, the patient described contact urticaria with certain cosmetics. PEG was suspected as a common trigger, and SPT was supportive (Table 1).
Case 3 had urticaria and syncope within minutes of effervescent vitamin C and separately developed urticaria, angioedema, and throat tightness with difficulty swallowing after the osmotic laxative Klean‐Prep. She gave a history of urticaria associated with Vimovo (esomeprazole and naproxen) and similar symptoms during a dental procedure (Table 1). All identified agents contained high‐molecular‐weight (HMW)‐PEG (Table 1). Unfortunately, SPT was inconclusive because of dermographism (negative control inciting a wheal). A provocation challenge to HMW‐PEG (Movicol) was objectively positive. The patient has remained completely symptom‐free with a PEG avoidance strategy. She has tolerated challenges with PEG‐free medications.
Anaphylaxis to Klean‐Prep was also a presenting feature of the fourth case. A PEG‐3350 allergy was suspected and avoidance advised until formal review at an allergy clinic. In the following months, while awaiting assessment and as a hospital inpatient for an unrelated condition, she had a second anaphylaxis within minutes of taking a PEG‐containing effervescent phosphate replacement preparation. SPT was subsequently positive to PEG‐3350, which has been avoided since.
The fifth patient was referred for assessment of multiple allergic drug reactions, on a background of chronic spontaneous urticaria and angioedema (CSUA). The first episode occurred within minutes of a Motilium suppository and was managed with intramuscular adrenaline, hydrocortisone, chlorphenamine, and fluid resuscitation. The second episode was precipitated by oral ibuprofen, again requiring adrenaline. PEG was considered a likely trigger, SPT was supportive. The patient subsequently tolerated PEG‐free domperidone and ibuprofen (Table 1).
The final case similarly had multiple adverse drug reactions, including anaphylaxis, on a background of CSUA. The initial allergic episode occurred following a Betadine dressing to a wound. She had systemic symptoms with oral and intramuscular diclofenac, oral Solpadeine (paracetamol and codeine), and contact urticaria with various cosmetics (Table 1). The patient subsequently tolerated PEG‐free forms of NSAIDs and codeine. PEG was suspected as a common inciting agent, SPT was supportive and strict avoidance recommended. After diagnosis, the patient experienced anaphylaxis while shaving with a product containing PEG requiring self‐administration of an adrenaline autoinjector.
This case series illustrates the diverse presentations of PEG allergy. Patients experienced an average of 3 allergic episodes before a formal diagnosis consistent with other case series. 1 Reactions were distressing for patients and objectively severe. Media reports of a case of fatal anaphylaxis in a patient with an established diagnosis of PEG allergy highlight the significance of this emerging problem. 2 The true incidence of PEG allergy is difficult to determine and may be underestimated. 3
It is hypothesized that initial PEG‐sensitization could be via cutaneous exposure from cosmetics and hygiene products or absorption of low‐molecular‐weight (LMW)‐PEG in pharmaceuticals. 3 The role of LMW‐PEG exposure prior to hypersensitivity has not been explored and may merit investigation. A female predominance was noted in our case series, but has not been universally observed. 1 , 4 Overall, the literature reports equal incidence between sexes. Interestingly, more recent case reports demonstrate a younger median age of diagnosis compared with older publications. 1 , 5 This is likely multifactorial and may be influenced by improved awareness of drug, and specifically PEG allergy, improved access to specialist allergy services, and potentially earlier or greater opportunity for sensitization. This is something that can only be speculated on because of limited clinical data.
Four of the 6 cases were suspected to have an NSAID allergy that was subsequently ruled out with negative provocation tests (Table 1). This emphasizes the prevalence of understandable misdiagnosis and unnecessary drug restrictions in this cohort. A review published in 2016 identified 37 cases labeled as “PEG‐allergy,” totaling 74 reactions. 4 More than half were associated with laxatives, also prominent allergens in this series. PEG‐3350 has been listed in more than 1000 approved medications. 3 Despite this ubiquity, reported incidence of hypersensitivity appears low. However we demonstrate that reactions can be severe and are diagnostically challenging.
NSAIDs are one of the most common inducers of drug‐related hypersensitivity reactions. 6 PEG sensitivity does not need to be considered in all NSAID‐related reactions. However, there are features that can be divined from an allergy history that offer pointers toward the need for PEG sensitization assessment. Patients with multiple episodes of “unexplained” anaphylaxis or tolerance of individual brands of the same drug merit closer investigation. Reactions to laxatives or bowel preparations, “depo” medications, and mucosal absorption from lubricants, gels, and dressings are red flags that should have PEG hypersensitivity in the differential. Bruusgaard‐Mouritsen et al (2021) similarly highlighted analgesics, depo injections, and laxatives as common triggers in their cohort, as well noting antacids and antibiotics as culprits. 1
We recommend that an adrenaline autoinjector be prescribed to those with PEG allergy because of an ongoing risk of accidental exposure. Unfortunately, comprehensive avoidance list cannot be provided, as medical preparations frequently change; thus, awareness is key. We advise patient empowerment with education, supported by step‐by‐step instructions on how to interrogate summary of product characteristics (SPC) for the variety of terms that indicate a PEG excipient. Patients are advised to engage with pharmacists and inform all health care professionals encountered of the disorder. In addition they should wear alert jewelry and only take a medication when they and their health care professional are satisfied that it does not contain PEG. Effective use of an electronic patient record can assist with communicating this issue, but as with all drug allergy, effective communication among disparate health care providers is a challenge. In addition, the cases presented here suggest a higher rate of biphasic allergic reactions than might be expected. 7 Based on these observations, we recommend extended monitoring for 12 hours after resolution of symptoms following a PEG‐related reaction. Although biphasic symptoms are usually mild, they can be distressing, especially to patients who have had a history of unexplained adverse events.
The identification of PEG allergy is increasing. These cases offer insight into the variety of ways this allergy can present. We report characteristics that flag PEG as a potential trigger and highlight the need for extended observation after resolution of symptoms because of the risk of biphasic reactions. Reports of immediate hypersensitivity in 2 health care workers on the first day of mass COVID‐19 vaccination in the United Kingdom are concerning. 8 It remains unknown if PEG‐2000 is involved in these reactions. Leaders in allergy have already engaged with regulatory authorities to highlight PEG as a possible allergen in mRNA vaccines and to support the objective investigation of reported reactions. 9
PEG allergy is now well known among allergy professionals. However, increased awareness of this allergen among the wider medical community is needed. Early recognition through a thorough clinical history and rapid referral to allergy diagnostic centers is required to confirm the diagnosis and effectively manage this high‐risk drug allergy.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Funding
We did not receive funding for this study.
Data‐Sharing Statement
Please contact the corresponding author, Dr Fionnuala Cox, on coxff@tcd.ie, if you wish to request further information on study data.
Author Contributions
F.C. conceived the study and interpreted data. F.C., N.C., and K.K. diagnosed and managed patients. All authors contributed to the writing and approval of the article.
Acknowledgments
We thank the patients and Clinical Immunology Teams in St James's Hospital and Beaumont Hospital, Dublin. | Intramuscular | DrugAdministrationRoute | CC BY-NC-ND | 33543766 | 19,443,824 | 2021-06 |
What was the administration route of drug 'POLYETHYLENE GLYCOL 3350'? | PEG That Reaction: A Case Series of Allergy to Polyethylene Glycol.
Polyethylene glycol (PEG), also known as macrogol, is an excipient in numerous medications, health care products, cosmetics, and foods. It acts as an inert bulking, or stabilizing, agent. Despite its ubiquity, including in 2 of the newly launched vaccines against SARS-CoV-2, awareness of PEG allergy remains low. We present 6 cases of acute hypersensitivity to PEG. Accurate diagnoses in these cases posed a challenge, and although the triggering agents differed, PEG was demonstrated as the common culprit. All cases were female, with a mean age of 36.4 years. Four patients were originally suspected to have nonsteroid anti-inflammatory drug allergy, and 2 had a history of chronic spontaneous urticaria and angioedema. Biphasic allergic reactions featured prominently in this case series. Diagnosis relies on a high index of suspicion leading to a focused clinical history, supported by skin tests with PEG solutions to demonstrate sensitization. This case series highlights important clinical features of this rare, potentially serious, and increasingly recognized excipient allergy.
pmcPolyethylene glycol (PEG), also known as macrogol or E1521, is a commonly used bulking and stabilizing agent. It is an excipient in a wide variety of medications and also encountered in cosmetics and processed foods. Notably, both Pfizer BioNTech and Moderna mRNA vaccines against SARS‐CoV‐2, which are being internationally deployed to combat the current pandemic, contain polyethylene glycol. Allergy to PEG is rare but is increasingly recognized and can be severe. We present a case series to highlight features of this unusual excipient allergy. A high index of suspicion with early referral for expert diagnostic workup is required to implement appropriate risk management strategies.
The incident case experienced anaphylaxis after intramuscular Depo‐Provera administered by her general practitioner. She developed rapid‐onset sneezing, rhinorrhea, urticaria, profound hypotension, and chest tightness. She was managed with 2 doses of intramuscular adrenaline, steroids, and nebulized salbutamol. Symptoms improved; however, 6 hours following initial treatment she experienced further urticaria. The patient had recently tolerated similar progesterone in the oral contraceptive pill. Allergy to an excipient ingredient was suspected. The specific intramuscular formulation contained PEG‐3350 (Table 1). Skin‐prick testing (SPT) was positive and avoidance advised.
Table 1 Patient Case Summary With Triggering Agents and Associated PEG Compounds, Allergic Symptoms Experienced, Outcome of Skin Prick Testing, and Results of Supervised Provocation Challenges Detailed for Each Patient
Case Allergic Disease Trigger Symptoms Negative Provocation Challenge Positive Investigation
Case 1
Female, 35 years
None Depo‐Provera: medroxyprogesterone PEG‐3350 Sneezing, ocular irritation, rhinorrhea, urticaria, hypotension, chest tightness, respiratory compromise.
Biphasic urticaria.
None SPT PEG‐3350:
positive, 7 x 7 mm
Case 2
Female, 25 years
None Nexium: esomeprazole "Macrogols"
MoviPrep: osmotic laxative PEG‐3350
Cosmetics: PEG‐100
Urticaria, angioedema,
Respiratory compromise.
Pruritus, urticaria, angioedema, hypotension, swelling of hands and feet.
Biphasic urticaria.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free
"Teva”:
pantoprazole
PEG‐free
SPT PEG‐3350:
positive, 10 x 11 mm
Case 3
Female, 40 years
None Effervescent vitamin C: HMW‐PEG
Klean Prep: osmotic laxative PEG‐3350.
Vimovo: esomeprazole,
naproxen.
PEG‐8000.
EMLA topical anesthetic:
lidocaine, prilocaine.
HMW‐PEG.
Urticaria, syncope.
Urticaria, angioedema.
Urticaria, presyncopal.
Generalized pruritus.
Cerazette:
desogestrel
PEG‐400
“Teva”:
pantoprazole
PEG‐free
SPT PEG‐400, 3350:
Inconclusive because of dermographism.
Movicol challenge, PEG‐3350: positive
Case 4
Female, 44 years
None Klean Prep: osmotic laxative,
PEG‐3350.
Phosphate Sandoz: effervescent phosphate,
PEG‐4000.
Cosmetics: LMW‐ and HMW‐PEG.
Perioral paresthesia, angioedema, dyspnea, stridor, visual disturbance, syncope.
Angioedema, dyspnea, presyncope.
Urticaria
None SPT PEG‐3350:
positive
Case 5
Female, 36 years
CSUA Motilium Suppository: domperidone,
PEG‐400 and 1000.
Nurofen: ibuprofen,
PEG‐6000.
Angioedema, paresthesia,
throat tightness.
Angioedema, paresthesia,
throat tightness.
Motilium oral tablet:
PEG‐free
Nurofen syrup:
PEG‐free
SPT PEG‐3350:
positive
Case 6
Female, 38 years
CSUA
Physical urticaria
Betadine: wound dressing, povidone‐iodine,
PEG‐400, 6000.
Voltorol Oral: diclofenac
PEG‐8000.
Diclofenac IM:
HMW‐PEG.
Shaving foam: LMW‐ and HMW‐PEG.
Cosmetics: LMW‐ and HMW‐PEG.
Urticaria, presyncopal.
Urticaria.
Urticaria.
Urticaria, angioedema,
respiratory distress, hypotension.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free.
Ibuprofen tablet:
PEG‐free
SPT PEG‐3350:
10 × 10 mm
John Wiley & Sons, Ltd.
The second patient experienced acute urticaria and angioedema following concomitant ibuprofen and esomeprazole ingestion. Nonsteroidal anti‐inflammatory drug (NSAID) sensitivity was initially suspected (Table 1). While awaiting further investigation, she developed urticaria, angioedema, and hypotension following minimal ingestion of the PEG‐containing osmotic laxative Movi‐Prep. Symptoms settled with steroids and antihistamine; however, she experienced further urticaria 6 hours later. In addition, the patient described contact urticaria with certain cosmetics. PEG was suspected as a common trigger, and SPT was supportive (Table 1).
Case 3 had urticaria and syncope within minutes of effervescent vitamin C and separately developed urticaria, angioedema, and throat tightness with difficulty swallowing after the osmotic laxative Klean‐Prep. She gave a history of urticaria associated with Vimovo (esomeprazole and naproxen) and similar symptoms during a dental procedure (Table 1). All identified agents contained high‐molecular‐weight (HMW)‐PEG (Table 1). Unfortunately, SPT was inconclusive because of dermographism (negative control inciting a wheal). A provocation challenge to HMW‐PEG (Movicol) was objectively positive. The patient has remained completely symptom‐free with a PEG avoidance strategy. She has tolerated challenges with PEG‐free medications.
Anaphylaxis to Klean‐Prep was also a presenting feature of the fourth case. A PEG‐3350 allergy was suspected and avoidance advised until formal review at an allergy clinic. In the following months, while awaiting assessment and as a hospital inpatient for an unrelated condition, she had a second anaphylaxis within minutes of taking a PEG‐containing effervescent phosphate replacement preparation. SPT was subsequently positive to PEG‐3350, which has been avoided since.
The fifth patient was referred for assessment of multiple allergic drug reactions, on a background of chronic spontaneous urticaria and angioedema (CSUA). The first episode occurred within minutes of a Motilium suppository and was managed with intramuscular adrenaline, hydrocortisone, chlorphenamine, and fluid resuscitation. The second episode was precipitated by oral ibuprofen, again requiring adrenaline. PEG was considered a likely trigger, SPT was supportive. The patient subsequently tolerated PEG‐free domperidone and ibuprofen (Table 1).
The final case similarly had multiple adverse drug reactions, including anaphylaxis, on a background of CSUA. The initial allergic episode occurred following a Betadine dressing to a wound. She had systemic symptoms with oral and intramuscular diclofenac, oral Solpadeine (paracetamol and codeine), and contact urticaria with various cosmetics (Table 1). The patient subsequently tolerated PEG‐free forms of NSAIDs and codeine. PEG was suspected as a common inciting agent, SPT was supportive and strict avoidance recommended. After diagnosis, the patient experienced anaphylaxis while shaving with a product containing PEG requiring self‐administration of an adrenaline autoinjector.
This case series illustrates the diverse presentations of PEG allergy. Patients experienced an average of 3 allergic episodes before a formal diagnosis consistent with other case series. 1 Reactions were distressing for patients and objectively severe. Media reports of a case of fatal anaphylaxis in a patient with an established diagnosis of PEG allergy highlight the significance of this emerging problem. 2 The true incidence of PEG allergy is difficult to determine and may be underestimated. 3
It is hypothesized that initial PEG‐sensitization could be via cutaneous exposure from cosmetics and hygiene products or absorption of low‐molecular‐weight (LMW)‐PEG in pharmaceuticals. 3 The role of LMW‐PEG exposure prior to hypersensitivity has not been explored and may merit investigation. A female predominance was noted in our case series, but has not been universally observed. 1 , 4 Overall, the literature reports equal incidence between sexes. Interestingly, more recent case reports demonstrate a younger median age of diagnosis compared with older publications. 1 , 5 This is likely multifactorial and may be influenced by improved awareness of drug, and specifically PEG allergy, improved access to specialist allergy services, and potentially earlier or greater opportunity for sensitization. This is something that can only be speculated on because of limited clinical data.
Four of the 6 cases were suspected to have an NSAID allergy that was subsequently ruled out with negative provocation tests (Table 1). This emphasizes the prevalence of understandable misdiagnosis and unnecessary drug restrictions in this cohort. A review published in 2016 identified 37 cases labeled as “PEG‐allergy,” totaling 74 reactions. 4 More than half were associated with laxatives, also prominent allergens in this series. PEG‐3350 has been listed in more than 1000 approved medications. 3 Despite this ubiquity, reported incidence of hypersensitivity appears low. However we demonstrate that reactions can be severe and are diagnostically challenging.
NSAIDs are one of the most common inducers of drug‐related hypersensitivity reactions. 6 PEG sensitivity does not need to be considered in all NSAID‐related reactions. However, there are features that can be divined from an allergy history that offer pointers toward the need for PEG sensitization assessment. Patients with multiple episodes of “unexplained” anaphylaxis or tolerance of individual brands of the same drug merit closer investigation. Reactions to laxatives or bowel preparations, “depo” medications, and mucosal absorption from lubricants, gels, and dressings are red flags that should have PEG hypersensitivity in the differential. Bruusgaard‐Mouritsen et al (2021) similarly highlighted analgesics, depo injections, and laxatives as common triggers in their cohort, as well noting antacids and antibiotics as culprits. 1
We recommend that an adrenaline autoinjector be prescribed to those with PEG allergy because of an ongoing risk of accidental exposure. Unfortunately, comprehensive avoidance list cannot be provided, as medical preparations frequently change; thus, awareness is key. We advise patient empowerment with education, supported by step‐by‐step instructions on how to interrogate summary of product characteristics (SPC) for the variety of terms that indicate a PEG excipient. Patients are advised to engage with pharmacists and inform all health care professionals encountered of the disorder. In addition they should wear alert jewelry and only take a medication when they and their health care professional are satisfied that it does not contain PEG. Effective use of an electronic patient record can assist with communicating this issue, but as with all drug allergy, effective communication among disparate health care providers is a challenge. In addition, the cases presented here suggest a higher rate of biphasic allergic reactions than might be expected. 7 Based on these observations, we recommend extended monitoring for 12 hours after resolution of symptoms following a PEG‐related reaction. Although biphasic symptoms are usually mild, they can be distressing, especially to patients who have had a history of unexplained adverse events.
The identification of PEG allergy is increasing. These cases offer insight into the variety of ways this allergy can present. We report characteristics that flag PEG as a potential trigger and highlight the need for extended observation after resolution of symptoms because of the risk of biphasic reactions. Reports of immediate hypersensitivity in 2 health care workers on the first day of mass COVID‐19 vaccination in the United Kingdom are concerning. 8 It remains unknown if PEG‐2000 is involved in these reactions. Leaders in allergy have already engaged with regulatory authorities to highlight PEG as a possible allergen in mRNA vaccines and to support the objective investigation of reported reactions. 9
PEG allergy is now well known among allergy professionals. However, increased awareness of this allergen among the wider medical community is needed. Early recognition through a thorough clinical history and rapid referral to allergy diagnostic centers is required to confirm the diagnosis and effectively manage this high‐risk drug allergy.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Funding
We did not receive funding for this study.
Data‐Sharing Statement
Please contact the corresponding author, Dr Fionnuala Cox, on coxff@tcd.ie, if you wish to request further information on study data.
Author Contributions
F.C. conceived the study and interpreted data. F.C., N.C., and K.K. diagnosed and managed patients. All authors contributed to the writing and approval of the article.
Acknowledgments
We thank the patients and Clinical Immunology Teams in St James's Hospital and Beaumont Hospital, Dublin. | Intramuscular | DrugAdministrationRoute | CC BY-NC-ND | 33543766 | 19,443,824 | 2021-06 |
What was the dosage of drug 'ASCORBIC ACID'? | PEG That Reaction: A Case Series of Allergy to Polyethylene Glycol.
Polyethylene glycol (PEG), also known as macrogol, is an excipient in numerous medications, health care products, cosmetics, and foods. It acts as an inert bulking, or stabilizing, agent. Despite its ubiquity, including in 2 of the newly launched vaccines against SARS-CoV-2, awareness of PEG allergy remains low. We present 6 cases of acute hypersensitivity to PEG. Accurate diagnoses in these cases posed a challenge, and although the triggering agents differed, PEG was demonstrated as the common culprit. All cases were female, with a mean age of 36.4 years. Four patients were originally suspected to have nonsteroid anti-inflammatory drug allergy, and 2 had a history of chronic spontaneous urticaria and angioedema. Biphasic allergic reactions featured prominently in this case series. Diagnosis relies on a high index of suspicion leading to a focused clinical history, supported by skin tests with PEG solutions to demonstrate sensitization. This case series highlights important clinical features of this rare, potentially serious, and increasingly recognized excipient allergy.
pmcPolyethylene glycol (PEG), also known as macrogol or E1521, is a commonly used bulking and stabilizing agent. It is an excipient in a wide variety of medications and also encountered in cosmetics and processed foods. Notably, both Pfizer BioNTech and Moderna mRNA vaccines against SARS‐CoV‐2, which are being internationally deployed to combat the current pandemic, contain polyethylene glycol. Allergy to PEG is rare but is increasingly recognized and can be severe. We present a case series to highlight features of this unusual excipient allergy. A high index of suspicion with early referral for expert diagnostic workup is required to implement appropriate risk management strategies.
The incident case experienced anaphylaxis after intramuscular Depo‐Provera administered by her general practitioner. She developed rapid‐onset sneezing, rhinorrhea, urticaria, profound hypotension, and chest tightness. She was managed with 2 doses of intramuscular adrenaline, steroids, and nebulized salbutamol. Symptoms improved; however, 6 hours following initial treatment she experienced further urticaria. The patient had recently tolerated similar progesterone in the oral contraceptive pill. Allergy to an excipient ingredient was suspected. The specific intramuscular formulation contained PEG‐3350 (Table 1). Skin‐prick testing (SPT) was positive and avoidance advised.
Table 1 Patient Case Summary With Triggering Agents and Associated PEG Compounds, Allergic Symptoms Experienced, Outcome of Skin Prick Testing, and Results of Supervised Provocation Challenges Detailed for Each Patient
Case Allergic Disease Trigger Symptoms Negative Provocation Challenge Positive Investigation
Case 1
Female, 35 years
None Depo‐Provera: medroxyprogesterone PEG‐3350 Sneezing, ocular irritation, rhinorrhea, urticaria, hypotension, chest tightness, respiratory compromise.
Biphasic urticaria.
None SPT PEG‐3350:
positive, 7 x 7 mm
Case 2
Female, 25 years
None Nexium: esomeprazole "Macrogols"
MoviPrep: osmotic laxative PEG‐3350
Cosmetics: PEG‐100
Urticaria, angioedema,
Respiratory compromise.
Pruritus, urticaria, angioedema, hypotension, swelling of hands and feet.
Biphasic urticaria.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free
"Teva”:
pantoprazole
PEG‐free
SPT PEG‐3350:
positive, 10 x 11 mm
Case 3
Female, 40 years
None Effervescent vitamin C: HMW‐PEG
Klean Prep: osmotic laxative PEG‐3350.
Vimovo: esomeprazole,
naproxen.
PEG‐8000.
EMLA topical anesthetic:
lidocaine, prilocaine.
HMW‐PEG.
Urticaria, syncope.
Urticaria, angioedema.
Urticaria, presyncopal.
Generalized pruritus.
Cerazette:
desogestrel
PEG‐400
“Teva”:
pantoprazole
PEG‐free
SPT PEG‐400, 3350:
Inconclusive because of dermographism.
Movicol challenge, PEG‐3350: positive
Case 4
Female, 44 years
None Klean Prep: osmotic laxative,
PEG‐3350.
Phosphate Sandoz: effervescent phosphate,
PEG‐4000.
Cosmetics: LMW‐ and HMW‐PEG.
Perioral paresthesia, angioedema, dyspnea, stridor, visual disturbance, syncope.
Angioedema, dyspnea, presyncope.
Urticaria
None SPT PEG‐3350:
positive
Case 5
Female, 36 years
CSUA Motilium Suppository: domperidone,
PEG‐400 and 1000.
Nurofen: ibuprofen,
PEG‐6000.
Angioedema, paresthesia,
throat tightness.
Angioedema, paresthesia,
throat tightness.
Motilium oral tablet:
PEG‐free
Nurofen syrup:
PEG‐free
SPT PEG‐3350:
positive
Case 6
Female, 38 years
CSUA
Physical urticaria
Betadine: wound dressing, povidone‐iodine,
PEG‐400, 6000.
Voltorol Oral: diclofenac
PEG‐8000.
Diclofenac IM:
HMW‐PEG.
Shaving foam: LMW‐ and HMW‐PEG.
Cosmetics: LMW‐ and HMW‐PEG.
Urticaria, presyncopal.
Urticaria.
Urticaria.
Urticaria, angioedema,
respiratory distress, hypotension.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free.
Ibuprofen tablet:
PEG‐free
SPT PEG‐3350:
10 × 10 mm
John Wiley & Sons, Ltd.
The second patient experienced acute urticaria and angioedema following concomitant ibuprofen and esomeprazole ingestion. Nonsteroidal anti‐inflammatory drug (NSAID) sensitivity was initially suspected (Table 1). While awaiting further investigation, she developed urticaria, angioedema, and hypotension following minimal ingestion of the PEG‐containing osmotic laxative Movi‐Prep. Symptoms settled with steroids and antihistamine; however, she experienced further urticaria 6 hours later. In addition, the patient described contact urticaria with certain cosmetics. PEG was suspected as a common trigger, and SPT was supportive (Table 1).
Case 3 had urticaria and syncope within minutes of effervescent vitamin C and separately developed urticaria, angioedema, and throat tightness with difficulty swallowing after the osmotic laxative Klean‐Prep. She gave a history of urticaria associated with Vimovo (esomeprazole and naproxen) and similar symptoms during a dental procedure (Table 1). All identified agents contained high‐molecular‐weight (HMW)‐PEG (Table 1). Unfortunately, SPT was inconclusive because of dermographism (negative control inciting a wheal). A provocation challenge to HMW‐PEG (Movicol) was objectively positive. The patient has remained completely symptom‐free with a PEG avoidance strategy. She has tolerated challenges with PEG‐free medications.
Anaphylaxis to Klean‐Prep was also a presenting feature of the fourth case. A PEG‐3350 allergy was suspected and avoidance advised until formal review at an allergy clinic. In the following months, while awaiting assessment and as a hospital inpatient for an unrelated condition, she had a second anaphylaxis within minutes of taking a PEG‐containing effervescent phosphate replacement preparation. SPT was subsequently positive to PEG‐3350, which has been avoided since.
The fifth patient was referred for assessment of multiple allergic drug reactions, on a background of chronic spontaneous urticaria and angioedema (CSUA). The first episode occurred within minutes of a Motilium suppository and was managed with intramuscular adrenaline, hydrocortisone, chlorphenamine, and fluid resuscitation. The second episode was precipitated by oral ibuprofen, again requiring adrenaline. PEG was considered a likely trigger, SPT was supportive. The patient subsequently tolerated PEG‐free domperidone and ibuprofen (Table 1).
The final case similarly had multiple adverse drug reactions, including anaphylaxis, on a background of CSUA. The initial allergic episode occurred following a Betadine dressing to a wound. She had systemic symptoms with oral and intramuscular diclofenac, oral Solpadeine (paracetamol and codeine), and contact urticaria with various cosmetics (Table 1). The patient subsequently tolerated PEG‐free forms of NSAIDs and codeine. PEG was suspected as a common inciting agent, SPT was supportive and strict avoidance recommended. After diagnosis, the patient experienced anaphylaxis while shaving with a product containing PEG requiring self‐administration of an adrenaline autoinjector.
This case series illustrates the diverse presentations of PEG allergy. Patients experienced an average of 3 allergic episodes before a formal diagnosis consistent with other case series. 1 Reactions were distressing for patients and objectively severe. Media reports of a case of fatal anaphylaxis in a patient with an established diagnosis of PEG allergy highlight the significance of this emerging problem. 2 The true incidence of PEG allergy is difficult to determine and may be underestimated. 3
It is hypothesized that initial PEG‐sensitization could be via cutaneous exposure from cosmetics and hygiene products or absorption of low‐molecular‐weight (LMW)‐PEG in pharmaceuticals. 3 The role of LMW‐PEG exposure prior to hypersensitivity has not been explored and may merit investigation. A female predominance was noted in our case series, but has not been universally observed. 1 , 4 Overall, the literature reports equal incidence between sexes. Interestingly, more recent case reports demonstrate a younger median age of diagnosis compared with older publications. 1 , 5 This is likely multifactorial and may be influenced by improved awareness of drug, and specifically PEG allergy, improved access to specialist allergy services, and potentially earlier or greater opportunity for sensitization. This is something that can only be speculated on because of limited clinical data.
Four of the 6 cases were suspected to have an NSAID allergy that was subsequently ruled out with negative provocation tests (Table 1). This emphasizes the prevalence of understandable misdiagnosis and unnecessary drug restrictions in this cohort. A review published in 2016 identified 37 cases labeled as “PEG‐allergy,” totaling 74 reactions. 4 More than half were associated with laxatives, also prominent allergens in this series. PEG‐3350 has been listed in more than 1000 approved medications. 3 Despite this ubiquity, reported incidence of hypersensitivity appears low. However we demonstrate that reactions can be severe and are diagnostically challenging.
NSAIDs are one of the most common inducers of drug‐related hypersensitivity reactions. 6 PEG sensitivity does not need to be considered in all NSAID‐related reactions. However, there are features that can be divined from an allergy history that offer pointers toward the need for PEG sensitization assessment. Patients with multiple episodes of “unexplained” anaphylaxis or tolerance of individual brands of the same drug merit closer investigation. Reactions to laxatives or bowel preparations, “depo” medications, and mucosal absorption from lubricants, gels, and dressings are red flags that should have PEG hypersensitivity in the differential. Bruusgaard‐Mouritsen et al (2021) similarly highlighted analgesics, depo injections, and laxatives as common triggers in their cohort, as well noting antacids and antibiotics as culprits. 1
We recommend that an adrenaline autoinjector be prescribed to those with PEG allergy because of an ongoing risk of accidental exposure. Unfortunately, comprehensive avoidance list cannot be provided, as medical preparations frequently change; thus, awareness is key. We advise patient empowerment with education, supported by step‐by‐step instructions on how to interrogate summary of product characteristics (SPC) for the variety of terms that indicate a PEG excipient. Patients are advised to engage with pharmacists and inform all health care professionals encountered of the disorder. In addition they should wear alert jewelry and only take a medication when they and their health care professional are satisfied that it does not contain PEG. Effective use of an electronic patient record can assist with communicating this issue, but as with all drug allergy, effective communication among disparate health care providers is a challenge. In addition, the cases presented here suggest a higher rate of biphasic allergic reactions than might be expected. 7 Based on these observations, we recommend extended monitoring for 12 hours after resolution of symptoms following a PEG‐related reaction. Although biphasic symptoms are usually mild, they can be distressing, especially to patients who have had a history of unexplained adverse events.
The identification of PEG allergy is increasing. These cases offer insight into the variety of ways this allergy can present. We report characteristics that flag PEG as a potential trigger and highlight the need for extended observation after resolution of symptoms because of the risk of biphasic reactions. Reports of immediate hypersensitivity in 2 health care workers on the first day of mass COVID‐19 vaccination in the United Kingdom are concerning. 8 It remains unknown if PEG‐2000 is involved in these reactions. Leaders in allergy have already engaged with regulatory authorities to highlight PEG as a possible allergen in mRNA vaccines and to support the objective investigation of reported reactions. 9
PEG allergy is now well known among allergy professionals. However, increased awareness of this allergen among the wider medical community is needed. Early recognition through a thorough clinical history and rapid referral to allergy diagnostic centers is required to confirm the diagnosis and effectively manage this high‐risk drug allergy.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Funding
We did not receive funding for this study.
Data‐Sharing Statement
Please contact the corresponding author, Dr Fionnuala Cox, on coxff@tcd.ie, if you wish to request further information on study data.
Author Contributions
F.C. conceived the study and interpreted data. F.C., N.C., and K.K. diagnosed and managed patients. All authors contributed to the writing and approval of the article.
Acknowledgments
We thank the patients and Clinical Immunology Teams in St James's Hospital and Beaumont Hospital, Dublin. | CONTAINED HMW?PEG AS EXCIPIENT | DrugDosageText | CC BY-NC-ND | 33543766 | 19,399,217 | 2021-06 |
What was the dosage of drug 'ASCORBIC ACID\POLYETHYLENE GLYCOL 3350\POTASSIUM CHLORIDE\SODIUM ASCORBATE\SODIUM CHLORIDE\SODIUM SULFATE'? | PEG That Reaction: A Case Series of Allergy to Polyethylene Glycol.
Polyethylene glycol (PEG), also known as macrogol, is an excipient in numerous medications, health care products, cosmetics, and foods. It acts as an inert bulking, or stabilizing, agent. Despite its ubiquity, including in 2 of the newly launched vaccines against SARS-CoV-2, awareness of PEG allergy remains low. We present 6 cases of acute hypersensitivity to PEG. Accurate diagnoses in these cases posed a challenge, and although the triggering agents differed, PEG was demonstrated as the common culprit. All cases were female, with a mean age of 36.4 years. Four patients were originally suspected to have nonsteroid anti-inflammatory drug allergy, and 2 had a history of chronic spontaneous urticaria and angioedema. Biphasic allergic reactions featured prominently in this case series. Diagnosis relies on a high index of suspicion leading to a focused clinical history, supported by skin tests with PEG solutions to demonstrate sensitization. This case series highlights important clinical features of this rare, potentially serious, and increasingly recognized excipient allergy.
pmcPolyethylene glycol (PEG), also known as macrogol or E1521, is a commonly used bulking and stabilizing agent. It is an excipient in a wide variety of medications and also encountered in cosmetics and processed foods. Notably, both Pfizer BioNTech and Moderna mRNA vaccines against SARS‐CoV‐2, which are being internationally deployed to combat the current pandemic, contain polyethylene glycol. Allergy to PEG is rare but is increasingly recognized and can be severe. We present a case series to highlight features of this unusual excipient allergy. A high index of suspicion with early referral for expert diagnostic workup is required to implement appropriate risk management strategies.
The incident case experienced anaphylaxis after intramuscular Depo‐Provera administered by her general practitioner. She developed rapid‐onset sneezing, rhinorrhea, urticaria, profound hypotension, and chest tightness. She was managed with 2 doses of intramuscular adrenaline, steroids, and nebulized salbutamol. Symptoms improved; however, 6 hours following initial treatment she experienced further urticaria. The patient had recently tolerated similar progesterone in the oral contraceptive pill. Allergy to an excipient ingredient was suspected. The specific intramuscular formulation contained PEG‐3350 (Table 1). Skin‐prick testing (SPT) was positive and avoidance advised.
Table 1 Patient Case Summary With Triggering Agents and Associated PEG Compounds, Allergic Symptoms Experienced, Outcome of Skin Prick Testing, and Results of Supervised Provocation Challenges Detailed for Each Patient
Case Allergic Disease Trigger Symptoms Negative Provocation Challenge Positive Investigation
Case 1
Female, 35 years
None Depo‐Provera: medroxyprogesterone PEG‐3350 Sneezing, ocular irritation, rhinorrhea, urticaria, hypotension, chest tightness, respiratory compromise.
Biphasic urticaria.
None SPT PEG‐3350:
positive, 7 x 7 mm
Case 2
Female, 25 years
None Nexium: esomeprazole "Macrogols"
MoviPrep: osmotic laxative PEG‐3350
Cosmetics: PEG‐100
Urticaria, angioedema,
Respiratory compromise.
Pruritus, urticaria, angioedema, hypotension, swelling of hands and feet.
Biphasic urticaria.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free
"Teva”:
pantoprazole
PEG‐free
SPT PEG‐3350:
positive, 10 x 11 mm
Case 3
Female, 40 years
None Effervescent vitamin C: HMW‐PEG
Klean Prep: osmotic laxative PEG‐3350.
Vimovo: esomeprazole,
naproxen.
PEG‐8000.
EMLA topical anesthetic:
lidocaine, prilocaine.
HMW‐PEG.
Urticaria, syncope.
Urticaria, angioedema.
Urticaria, presyncopal.
Generalized pruritus.
Cerazette:
desogestrel
PEG‐400
“Teva”:
pantoprazole
PEG‐free
SPT PEG‐400, 3350:
Inconclusive because of dermographism.
Movicol challenge, PEG‐3350: positive
Case 4
Female, 44 years
None Klean Prep: osmotic laxative,
PEG‐3350.
Phosphate Sandoz: effervescent phosphate,
PEG‐4000.
Cosmetics: LMW‐ and HMW‐PEG.
Perioral paresthesia, angioedema, dyspnea, stridor, visual disturbance, syncope.
Angioedema, dyspnea, presyncope.
Urticaria
None SPT PEG‐3350:
positive
Case 5
Female, 36 years
CSUA Motilium Suppository: domperidone,
PEG‐400 and 1000.
Nurofen: ibuprofen,
PEG‐6000.
Angioedema, paresthesia,
throat tightness.
Angioedema, paresthesia,
throat tightness.
Motilium oral tablet:
PEG‐free
Nurofen syrup:
PEG‐free
SPT PEG‐3350:
positive
Case 6
Female, 38 years
CSUA
Physical urticaria
Betadine: wound dressing, povidone‐iodine,
PEG‐400, 6000.
Voltorol Oral: diclofenac
PEG‐8000.
Diclofenac IM:
HMW‐PEG.
Shaving foam: LMW‐ and HMW‐PEG.
Cosmetics: LMW‐ and HMW‐PEG.
Urticaria, presyncopal.
Urticaria.
Urticaria.
Urticaria, angioedema,
respiratory distress, hypotension.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free.
Ibuprofen tablet:
PEG‐free
SPT PEG‐3350:
10 × 10 mm
John Wiley & Sons, Ltd.
The second patient experienced acute urticaria and angioedema following concomitant ibuprofen and esomeprazole ingestion. Nonsteroidal anti‐inflammatory drug (NSAID) sensitivity was initially suspected (Table 1). While awaiting further investigation, she developed urticaria, angioedema, and hypotension following minimal ingestion of the PEG‐containing osmotic laxative Movi‐Prep. Symptoms settled with steroids and antihistamine; however, she experienced further urticaria 6 hours later. In addition, the patient described contact urticaria with certain cosmetics. PEG was suspected as a common trigger, and SPT was supportive (Table 1).
Case 3 had urticaria and syncope within minutes of effervescent vitamin C and separately developed urticaria, angioedema, and throat tightness with difficulty swallowing after the osmotic laxative Klean‐Prep. She gave a history of urticaria associated with Vimovo (esomeprazole and naproxen) and similar symptoms during a dental procedure (Table 1). All identified agents contained high‐molecular‐weight (HMW)‐PEG (Table 1). Unfortunately, SPT was inconclusive because of dermographism (negative control inciting a wheal). A provocation challenge to HMW‐PEG (Movicol) was objectively positive. The patient has remained completely symptom‐free with a PEG avoidance strategy. She has tolerated challenges with PEG‐free medications.
Anaphylaxis to Klean‐Prep was also a presenting feature of the fourth case. A PEG‐3350 allergy was suspected and avoidance advised until formal review at an allergy clinic. In the following months, while awaiting assessment and as a hospital inpatient for an unrelated condition, she had a second anaphylaxis within minutes of taking a PEG‐containing effervescent phosphate replacement preparation. SPT was subsequently positive to PEG‐3350, which has been avoided since.
The fifth patient was referred for assessment of multiple allergic drug reactions, on a background of chronic spontaneous urticaria and angioedema (CSUA). The first episode occurred within minutes of a Motilium suppository and was managed with intramuscular adrenaline, hydrocortisone, chlorphenamine, and fluid resuscitation. The second episode was precipitated by oral ibuprofen, again requiring adrenaline. PEG was considered a likely trigger, SPT was supportive. The patient subsequently tolerated PEG‐free domperidone and ibuprofen (Table 1).
The final case similarly had multiple adverse drug reactions, including anaphylaxis, on a background of CSUA. The initial allergic episode occurred following a Betadine dressing to a wound. She had systemic symptoms with oral and intramuscular diclofenac, oral Solpadeine (paracetamol and codeine), and contact urticaria with various cosmetics (Table 1). The patient subsequently tolerated PEG‐free forms of NSAIDs and codeine. PEG was suspected as a common inciting agent, SPT was supportive and strict avoidance recommended. After diagnosis, the patient experienced anaphylaxis while shaving with a product containing PEG requiring self‐administration of an adrenaline autoinjector.
This case series illustrates the diverse presentations of PEG allergy. Patients experienced an average of 3 allergic episodes before a formal diagnosis consistent with other case series. 1 Reactions were distressing for patients and objectively severe. Media reports of a case of fatal anaphylaxis in a patient with an established diagnosis of PEG allergy highlight the significance of this emerging problem. 2 The true incidence of PEG allergy is difficult to determine and may be underestimated. 3
It is hypothesized that initial PEG‐sensitization could be via cutaneous exposure from cosmetics and hygiene products or absorption of low‐molecular‐weight (LMW)‐PEG in pharmaceuticals. 3 The role of LMW‐PEG exposure prior to hypersensitivity has not been explored and may merit investigation. A female predominance was noted in our case series, but has not been universally observed. 1 , 4 Overall, the literature reports equal incidence between sexes. Interestingly, more recent case reports demonstrate a younger median age of diagnosis compared with older publications. 1 , 5 This is likely multifactorial and may be influenced by improved awareness of drug, and specifically PEG allergy, improved access to specialist allergy services, and potentially earlier or greater opportunity for sensitization. This is something that can only be speculated on because of limited clinical data.
Four of the 6 cases were suspected to have an NSAID allergy that was subsequently ruled out with negative provocation tests (Table 1). This emphasizes the prevalence of understandable misdiagnosis and unnecessary drug restrictions in this cohort. A review published in 2016 identified 37 cases labeled as “PEG‐allergy,” totaling 74 reactions. 4 More than half were associated with laxatives, also prominent allergens in this series. PEG‐3350 has been listed in more than 1000 approved medications. 3 Despite this ubiquity, reported incidence of hypersensitivity appears low. However we demonstrate that reactions can be severe and are diagnostically challenging.
NSAIDs are one of the most common inducers of drug‐related hypersensitivity reactions. 6 PEG sensitivity does not need to be considered in all NSAID‐related reactions. However, there are features that can be divined from an allergy history that offer pointers toward the need for PEG sensitization assessment. Patients with multiple episodes of “unexplained” anaphylaxis or tolerance of individual brands of the same drug merit closer investigation. Reactions to laxatives or bowel preparations, “depo” medications, and mucosal absorption from lubricants, gels, and dressings are red flags that should have PEG hypersensitivity in the differential. Bruusgaard‐Mouritsen et al (2021) similarly highlighted analgesics, depo injections, and laxatives as common triggers in their cohort, as well noting antacids and antibiotics as culprits. 1
We recommend that an adrenaline autoinjector be prescribed to those with PEG allergy because of an ongoing risk of accidental exposure. Unfortunately, comprehensive avoidance list cannot be provided, as medical preparations frequently change; thus, awareness is key. We advise patient empowerment with education, supported by step‐by‐step instructions on how to interrogate summary of product characteristics (SPC) for the variety of terms that indicate a PEG excipient. Patients are advised to engage with pharmacists and inform all health care professionals encountered of the disorder. In addition they should wear alert jewelry and only take a medication when they and their health care professional are satisfied that it does not contain PEG. Effective use of an electronic patient record can assist with communicating this issue, but as with all drug allergy, effective communication among disparate health care providers is a challenge. In addition, the cases presented here suggest a higher rate of biphasic allergic reactions than might be expected. 7 Based on these observations, we recommend extended monitoring for 12 hours after resolution of symptoms following a PEG‐related reaction. Although biphasic symptoms are usually mild, they can be distressing, especially to patients who have had a history of unexplained adverse events.
The identification of PEG allergy is increasing. These cases offer insight into the variety of ways this allergy can present. We report characteristics that flag PEG as a potential trigger and highlight the need for extended observation after resolution of symptoms because of the risk of biphasic reactions. Reports of immediate hypersensitivity in 2 health care workers on the first day of mass COVID‐19 vaccination in the United Kingdom are concerning. 8 It remains unknown if PEG‐2000 is involved in these reactions. Leaders in allergy have already engaged with regulatory authorities to highlight PEG as a possible allergen in mRNA vaccines and to support the objective investigation of reported reactions. 9
PEG allergy is now well known among allergy professionals. However, increased awareness of this allergen among the wider medical community is needed. Early recognition through a thorough clinical history and rapid referral to allergy diagnostic centers is required to confirm the diagnosis and effectively manage this high‐risk drug allergy.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Funding
We did not receive funding for this study.
Data‐Sharing Statement
Please contact the corresponding author, Dr Fionnuala Cox, on coxff@tcd.ie, if you wish to request further information on study data.
Author Contributions
F.C. conceived the study and interpreted data. F.C., N.C., and K.K. diagnosed and managed patients. All authors contributed to the writing and approval of the article.
Acknowledgments
We thank the patients and Clinical Immunology Teams in St James's Hospital and Beaumont Hospital, Dublin. | CONTAINED PEG?3350 AS EXCIPIENT?MOVI?PREP | DrugDosageText | CC BY-NC-ND | 33543766 | 19,415,712 | 2021-06 |
What was the dosage of drug 'ELECTROLYTES NOS\POLYETHYLENE GLYCOL 3350'? | PEG That Reaction: A Case Series of Allergy to Polyethylene Glycol.
Polyethylene glycol (PEG), also known as macrogol, is an excipient in numerous medications, health care products, cosmetics, and foods. It acts as an inert bulking, or stabilizing, agent. Despite its ubiquity, including in 2 of the newly launched vaccines against SARS-CoV-2, awareness of PEG allergy remains low. We present 6 cases of acute hypersensitivity to PEG. Accurate diagnoses in these cases posed a challenge, and although the triggering agents differed, PEG was demonstrated as the common culprit. All cases were female, with a mean age of 36.4 years. Four patients were originally suspected to have nonsteroid anti-inflammatory drug allergy, and 2 had a history of chronic spontaneous urticaria and angioedema. Biphasic allergic reactions featured prominently in this case series. Diagnosis relies on a high index of suspicion leading to a focused clinical history, supported by skin tests with PEG solutions to demonstrate sensitization. This case series highlights important clinical features of this rare, potentially serious, and increasingly recognized excipient allergy.
pmcPolyethylene glycol (PEG), also known as macrogol or E1521, is a commonly used bulking and stabilizing agent. It is an excipient in a wide variety of medications and also encountered in cosmetics and processed foods. Notably, both Pfizer BioNTech and Moderna mRNA vaccines against SARS‐CoV‐2, which are being internationally deployed to combat the current pandemic, contain polyethylene glycol. Allergy to PEG is rare but is increasingly recognized and can be severe. We present a case series to highlight features of this unusual excipient allergy. A high index of suspicion with early referral for expert diagnostic workup is required to implement appropriate risk management strategies.
The incident case experienced anaphylaxis after intramuscular Depo‐Provera administered by her general practitioner. She developed rapid‐onset sneezing, rhinorrhea, urticaria, profound hypotension, and chest tightness. She was managed with 2 doses of intramuscular adrenaline, steroids, and nebulized salbutamol. Symptoms improved; however, 6 hours following initial treatment she experienced further urticaria. The patient had recently tolerated similar progesterone in the oral contraceptive pill. Allergy to an excipient ingredient was suspected. The specific intramuscular formulation contained PEG‐3350 (Table 1). Skin‐prick testing (SPT) was positive and avoidance advised.
Table 1 Patient Case Summary With Triggering Agents and Associated PEG Compounds, Allergic Symptoms Experienced, Outcome of Skin Prick Testing, and Results of Supervised Provocation Challenges Detailed for Each Patient
Case Allergic Disease Trigger Symptoms Negative Provocation Challenge Positive Investigation
Case 1
Female, 35 years
None Depo‐Provera: medroxyprogesterone PEG‐3350 Sneezing, ocular irritation, rhinorrhea, urticaria, hypotension, chest tightness, respiratory compromise.
Biphasic urticaria.
None SPT PEG‐3350:
positive, 7 x 7 mm
Case 2
Female, 25 years
None Nexium: esomeprazole "Macrogols"
MoviPrep: osmotic laxative PEG‐3350
Cosmetics: PEG‐100
Urticaria, angioedema,
Respiratory compromise.
Pruritus, urticaria, angioedema, hypotension, swelling of hands and feet.
Biphasic urticaria.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free
"Teva”:
pantoprazole
PEG‐free
SPT PEG‐3350:
positive, 10 x 11 mm
Case 3
Female, 40 years
None Effervescent vitamin C: HMW‐PEG
Klean Prep: osmotic laxative PEG‐3350.
Vimovo: esomeprazole,
naproxen.
PEG‐8000.
EMLA topical anesthetic:
lidocaine, prilocaine.
HMW‐PEG.
Urticaria, syncope.
Urticaria, angioedema.
Urticaria, presyncopal.
Generalized pruritus.
Cerazette:
desogestrel
PEG‐400
“Teva”:
pantoprazole
PEG‐free
SPT PEG‐400, 3350:
Inconclusive because of dermographism.
Movicol challenge, PEG‐3350: positive
Case 4
Female, 44 years
None Klean Prep: osmotic laxative,
PEG‐3350.
Phosphate Sandoz: effervescent phosphate,
PEG‐4000.
Cosmetics: LMW‐ and HMW‐PEG.
Perioral paresthesia, angioedema, dyspnea, stridor, visual disturbance, syncope.
Angioedema, dyspnea, presyncope.
Urticaria
None SPT PEG‐3350:
positive
Case 5
Female, 36 years
CSUA Motilium Suppository: domperidone,
PEG‐400 and 1000.
Nurofen: ibuprofen,
PEG‐6000.
Angioedema, paresthesia,
throat tightness.
Angioedema, paresthesia,
throat tightness.
Motilium oral tablet:
PEG‐free
Nurofen syrup:
PEG‐free
SPT PEG‐3350:
positive
Case 6
Female, 38 years
CSUA
Physical urticaria
Betadine: wound dressing, povidone‐iodine,
PEG‐400, 6000.
Voltorol Oral: diclofenac
PEG‐8000.
Diclofenac IM:
HMW‐PEG.
Shaving foam: LMW‐ and HMW‐PEG.
Cosmetics: LMW‐ and HMW‐PEG.
Urticaria, presyncopal.
Urticaria.
Urticaria.
Urticaria, angioedema,
respiratory distress, hypotension.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free.
Ibuprofen tablet:
PEG‐free
SPT PEG‐3350:
10 × 10 mm
John Wiley & Sons, Ltd.
The second patient experienced acute urticaria and angioedema following concomitant ibuprofen and esomeprazole ingestion. Nonsteroidal anti‐inflammatory drug (NSAID) sensitivity was initially suspected (Table 1). While awaiting further investigation, she developed urticaria, angioedema, and hypotension following minimal ingestion of the PEG‐containing osmotic laxative Movi‐Prep. Symptoms settled with steroids and antihistamine; however, she experienced further urticaria 6 hours later. In addition, the patient described contact urticaria with certain cosmetics. PEG was suspected as a common trigger, and SPT was supportive (Table 1).
Case 3 had urticaria and syncope within minutes of effervescent vitamin C and separately developed urticaria, angioedema, and throat tightness with difficulty swallowing after the osmotic laxative Klean‐Prep. She gave a history of urticaria associated with Vimovo (esomeprazole and naproxen) and similar symptoms during a dental procedure (Table 1). All identified agents contained high‐molecular‐weight (HMW)‐PEG (Table 1). Unfortunately, SPT was inconclusive because of dermographism (negative control inciting a wheal). A provocation challenge to HMW‐PEG (Movicol) was objectively positive. The patient has remained completely symptom‐free with a PEG avoidance strategy. She has tolerated challenges with PEG‐free medications.
Anaphylaxis to Klean‐Prep was also a presenting feature of the fourth case. A PEG‐3350 allergy was suspected and avoidance advised until formal review at an allergy clinic. In the following months, while awaiting assessment and as a hospital inpatient for an unrelated condition, she had a second anaphylaxis within minutes of taking a PEG‐containing effervescent phosphate replacement preparation. SPT was subsequently positive to PEG‐3350, which has been avoided since.
The fifth patient was referred for assessment of multiple allergic drug reactions, on a background of chronic spontaneous urticaria and angioedema (CSUA). The first episode occurred within minutes of a Motilium suppository and was managed with intramuscular adrenaline, hydrocortisone, chlorphenamine, and fluid resuscitation. The second episode was precipitated by oral ibuprofen, again requiring adrenaline. PEG was considered a likely trigger, SPT was supportive. The patient subsequently tolerated PEG‐free domperidone and ibuprofen (Table 1).
The final case similarly had multiple adverse drug reactions, including anaphylaxis, on a background of CSUA. The initial allergic episode occurred following a Betadine dressing to a wound. She had systemic symptoms with oral and intramuscular diclofenac, oral Solpadeine (paracetamol and codeine), and contact urticaria with various cosmetics (Table 1). The patient subsequently tolerated PEG‐free forms of NSAIDs and codeine. PEG was suspected as a common inciting agent, SPT was supportive and strict avoidance recommended. After diagnosis, the patient experienced anaphylaxis while shaving with a product containing PEG requiring self‐administration of an adrenaline autoinjector.
This case series illustrates the diverse presentations of PEG allergy. Patients experienced an average of 3 allergic episodes before a formal diagnosis consistent with other case series. 1 Reactions were distressing for patients and objectively severe. Media reports of a case of fatal anaphylaxis in a patient with an established diagnosis of PEG allergy highlight the significance of this emerging problem. 2 The true incidence of PEG allergy is difficult to determine and may be underestimated. 3
It is hypothesized that initial PEG‐sensitization could be via cutaneous exposure from cosmetics and hygiene products or absorption of low‐molecular‐weight (LMW)‐PEG in pharmaceuticals. 3 The role of LMW‐PEG exposure prior to hypersensitivity has not been explored and may merit investigation. A female predominance was noted in our case series, but has not been universally observed. 1 , 4 Overall, the literature reports equal incidence between sexes. Interestingly, more recent case reports demonstrate a younger median age of diagnosis compared with older publications. 1 , 5 This is likely multifactorial and may be influenced by improved awareness of drug, and specifically PEG allergy, improved access to specialist allergy services, and potentially earlier or greater opportunity for sensitization. This is something that can only be speculated on because of limited clinical data.
Four of the 6 cases were suspected to have an NSAID allergy that was subsequently ruled out with negative provocation tests (Table 1). This emphasizes the prevalence of understandable misdiagnosis and unnecessary drug restrictions in this cohort. A review published in 2016 identified 37 cases labeled as “PEG‐allergy,” totaling 74 reactions. 4 More than half were associated with laxatives, also prominent allergens in this series. PEG‐3350 has been listed in more than 1000 approved medications. 3 Despite this ubiquity, reported incidence of hypersensitivity appears low. However we demonstrate that reactions can be severe and are diagnostically challenging.
NSAIDs are one of the most common inducers of drug‐related hypersensitivity reactions. 6 PEG sensitivity does not need to be considered in all NSAID‐related reactions. However, there are features that can be divined from an allergy history that offer pointers toward the need for PEG sensitization assessment. Patients with multiple episodes of “unexplained” anaphylaxis or tolerance of individual brands of the same drug merit closer investigation. Reactions to laxatives or bowel preparations, “depo” medications, and mucosal absorption from lubricants, gels, and dressings are red flags that should have PEG hypersensitivity in the differential. Bruusgaard‐Mouritsen et al (2021) similarly highlighted analgesics, depo injections, and laxatives as common triggers in their cohort, as well noting antacids and antibiotics as culprits. 1
We recommend that an adrenaline autoinjector be prescribed to those with PEG allergy because of an ongoing risk of accidental exposure. Unfortunately, comprehensive avoidance list cannot be provided, as medical preparations frequently change; thus, awareness is key. We advise patient empowerment with education, supported by step‐by‐step instructions on how to interrogate summary of product characteristics (SPC) for the variety of terms that indicate a PEG excipient. Patients are advised to engage with pharmacists and inform all health care professionals encountered of the disorder. In addition they should wear alert jewelry and only take a medication when they and their health care professional are satisfied that it does not contain PEG. Effective use of an electronic patient record can assist with communicating this issue, but as with all drug allergy, effective communication among disparate health care providers is a challenge. In addition, the cases presented here suggest a higher rate of biphasic allergic reactions than might be expected. 7 Based on these observations, we recommend extended monitoring for 12 hours after resolution of symptoms following a PEG‐related reaction. Although biphasic symptoms are usually mild, they can be distressing, especially to patients who have had a history of unexplained adverse events.
The identification of PEG allergy is increasing. These cases offer insight into the variety of ways this allergy can present. We report characteristics that flag PEG as a potential trigger and highlight the need for extended observation after resolution of symptoms because of the risk of biphasic reactions. Reports of immediate hypersensitivity in 2 health care workers on the first day of mass COVID‐19 vaccination in the United Kingdom are concerning. 8 It remains unknown if PEG‐2000 is involved in these reactions. Leaders in allergy have already engaged with regulatory authorities to highlight PEG as a possible allergen in mRNA vaccines and to support the objective investigation of reported reactions. 9
PEG allergy is now well known among allergy professionals. However, increased awareness of this allergen among the wider medical community is needed. Early recognition through a thorough clinical history and rapid referral to allergy diagnostic centers is required to confirm the diagnosis and effectively manage this high‐risk drug allergy.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Funding
We did not receive funding for this study.
Data‐Sharing Statement
Please contact the corresponding author, Dr Fionnuala Cox, on coxff@tcd.ie, if you wish to request further information on study data.
Author Contributions
F.C. conceived the study and interpreted data. F.C., N.C., and K.K. diagnosed and managed patients. All authors contributed to the writing and approval of the article.
Acknowledgments
We thank the patients and Clinical Immunology Teams in St James's Hospital and Beaumont Hospital, Dublin. | CONTAINED PEG?3350 AS EXCIPIENT | DrugDosageText | CC BY-NC-ND | 33543766 | 19,399,217 | 2021-06 |
What was the dosage of drug 'ESOMEPRAZOLE MAGNESIUM'? | PEG That Reaction: A Case Series of Allergy to Polyethylene Glycol.
Polyethylene glycol (PEG), also known as macrogol, is an excipient in numerous medications, health care products, cosmetics, and foods. It acts as an inert bulking, or stabilizing, agent. Despite its ubiquity, including in 2 of the newly launched vaccines against SARS-CoV-2, awareness of PEG allergy remains low. We present 6 cases of acute hypersensitivity to PEG. Accurate diagnoses in these cases posed a challenge, and although the triggering agents differed, PEG was demonstrated as the common culprit. All cases were female, with a mean age of 36.4 years. Four patients were originally suspected to have nonsteroid anti-inflammatory drug allergy, and 2 had a history of chronic spontaneous urticaria and angioedema. Biphasic allergic reactions featured prominently in this case series. Diagnosis relies on a high index of suspicion leading to a focused clinical history, supported by skin tests with PEG solutions to demonstrate sensitization. This case series highlights important clinical features of this rare, potentially serious, and increasingly recognized excipient allergy.
pmcPolyethylene glycol (PEG), also known as macrogol or E1521, is a commonly used bulking and stabilizing agent. It is an excipient in a wide variety of medications and also encountered in cosmetics and processed foods. Notably, both Pfizer BioNTech and Moderna mRNA vaccines against SARS‐CoV‐2, which are being internationally deployed to combat the current pandemic, contain polyethylene glycol. Allergy to PEG is rare but is increasingly recognized and can be severe. We present a case series to highlight features of this unusual excipient allergy. A high index of suspicion with early referral for expert diagnostic workup is required to implement appropriate risk management strategies.
The incident case experienced anaphylaxis after intramuscular Depo‐Provera administered by her general practitioner. She developed rapid‐onset sneezing, rhinorrhea, urticaria, profound hypotension, and chest tightness. She was managed with 2 doses of intramuscular adrenaline, steroids, and nebulized salbutamol. Symptoms improved; however, 6 hours following initial treatment she experienced further urticaria. The patient had recently tolerated similar progesterone in the oral contraceptive pill. Allergy to an excipient ingredient was suspected. The specific intramuscular formulation contained PEG‐3350 (Table 1). Skin‐prick testing (SPT) was positive and avoidance advised.
Table 1 Patient Case Summary With Triggering Agents and Associated PEG Compounds, Allergic Symptoms Experienced, Outcome of Skin Prick Testing, and Results of Supervised Provocation Challenges Detailed for Each Patient
Case Allergic Disease Trigger Symptoms Negative Provocation Challenge Positive Investigation
Case 1
Female, 35 years
None Depo‐Provera: medroxyprogesterone PEG‐3350 Sneezing, ocular irritation, rhinorrhea, urticaria, hypotension, chest tightness, respiratory compromise.
Biphasic urticaria.
None SPT PEG‐3350:
positive, 7 x 7 mm
Case 2
Female, 25 years
None Nexium: esomeprazole "Macrogols"
MoviPrep: osmotic laxative PEG‐3350
Cosmetics: PEG‐100
Urticaria, angioedema,
Respiratory compromise.
Pruritus, urticaria, angioedema, hypotension, swelling of hands and feet.
Biphasic urticaria.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free
"Teva”:
pantoprazole
PEG‐free
SPT PEG‐3350:
positive, 10 x 11 mm
Case 3
Female, 40 years
None Effervescent vitamin C: HMW‐PEG
Klean Prep: osmotic laxative PEG‐3350.
Vimovo: esomeprazole,
naproxen.
PEG‐8000.
EMLA topical anesthetic:
lidocaine, prilocaine.
HMW‐PEG.
Urticaria, syncope.
Urticaria, angioedema.
Urticaria, presyncopal.
Generalized pruritus.
Cerazette:
desogestrel
PEG‐400
“Teva”:
pantoprazole
PEG‐free
SPT PEG‐400, 3350:
Inconclusive because of dermographism.
Movicol challenge, PEG‐3350: positive
Case 4
Female, 44 years
None Klean Prep: osmotic laxative,
PEG‐3350.
Phosphate Sandoz: effervescent phosphate,
PEG‐4000.
Cosmetics: LMW‐ and HMW‐PEG.
Perioral paresthesia, angioedema, dyspnea, stridor, visual disturbance, syncope.
Angioedema, dyspnea, presyncope.
Urticaria
None SPT PEG‐3350:
positive
Case 5
Female, 36 years
CSUA Motilium Suppository: domperidone,
PEG‐400 and 1000.
Nurofen: ibuprofen,
PEG‐6000.
Angioedema, paresthesia,
throat tightness.
Angioedema, paresthesia,
throat tightness.
Motilium oral tablet:
PEG‐free
Nurofen syrup:
PEG‐free
SPT PEG‐3350:
positive
Case 6
Female, 38 years
CSUA
Physical urticaria
Betadine: wound dressing, povidone‐iodine,
PEG‐400, 6000.
Voltorol Oral: diclofenac
PEG‐8000.
Diclofenac IM:
HMW‐PEG.
Shaving foam: LMW‐ and HMW‐PEG.
Cosmetics: LMW‐ and HMW‐PEG.
Urticaria, presyncopal.
Urticaria.
Urticaria.
Urticaria, angioedema,
respiratory distress, hypotension.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free.
Ibuprofen tablet:
PEG‐free
SPT PEG‐3350:
10 × 10 mm
John Wiley & Sons, Ltd.
The second patient experienced acute urticaria and angioedema following concomitant ibuprofen and esomeprazole ingestion. Nonsteroidal anti‐inflammatory drug (NSAID) sensitivity was initially suspected (Table 1). While awaiting further investigation, she developed urticaria, angioedema, and hypotension following minimal ingestion of the PEG‐containing osmotic laxative Movi‐Prep. Symptoms settled with steroids and antihistamine; however, she experienced further urticaria 6 hours later. In addition, the patient described contact urticaria with certain cosmetics. PEG was suspected as a common trigger, and SPT was supportive (Table 1).
Case 3 had urticaria and syncope within minutes of effervescent vitamin C and separately developed urticaria, angioedema, and throat tightness with difficulty swallowing after the osmotic laxative Klean‐Prep. She gave a history of urticaria associated with Vimovo (esomeprazole and naproxen) and similar symptoms during a dental procedure (Table 1). All identified agents contained high‐molecular‐weight (HMW)‐PEG (Table 1). Unfortunately, SPT was inconclusive because of dermographism (negative control inciting a wheal). A provocation challenge to HMW‐PEG (Movicol) was objectively positive. The patient has remained completely symptom‐free with a PEG avoidance strategy. She has tolerated challenges with PEG‐free medications.
Anaphylaxis to Klean‐Prep was also a presenting feature of the fourth case. A PEG‐3350 allergy was suspected and avoidance advised until formal review at an allergy clinic. In the following months, while awaiting assessment and as a hospital inpatient for an unrelated condition, she had a second anaphylaxis within minutes of taking a PEG‐containing effervescent phosphate replacement preparation. SPT was subsequently positive to PEG‐3350, which has been avoided since.
The fifth patient was referred for assessment of multiple allergic drug reactions, on a background of chronic spontaneous urticaria and angioedema (CSUA). The first episode occurred within minutes of a Motilium suppository and was managed with intramuscular adrenaline, hydrocortisone, chlorphenamine, and fluid resuscitation. The second episode was precipitated by oral ibuprofen, again requiring adrenaline. PEG was considered a likely trigger, SPT was supportive. The patient subsequently tolerated PEG‐free domperidone and ibuprofen (Table 1).
The final case similarly had multiple adverse drug reactions, including anaphylaxis, on a background of CSUA. The initial allergic episode occurred following a Betadine dressing to a wound. She had systemic symptoms with oral and intramuscular diclofenac, oral Solpadeine (paracetamol and codeine), and contact urticaria with various cosmetics (Table 1). The patient subsequently tolerated PEG‐free forms of NSAIDs and codeine. PEG was suspected as a common inciting agent, SPT was supportive and strict avoidance recommended. After diagnosis, the patient experienced anaphylaxis while shaving with a product containing PEG requiring self‐administration of an adrenaline autoinjector.
This case series illustrates the diverse presentations of PEG allergy. Patients experienced an average of 3 allergic episodes before a formal diagnosis consistent with other case series. 1 Reactions were distressing for patients and objectively severe. Media reports of a case of fatal anaphylaxis in a patient with an established diagnosis of PEG allergy highlight the significance of this emerging problem. 2 The true incidence of PEG allergy is difficult to determine and may be underestimated. 3
It is hypothesized that initial PEG‐sensitization could be via cutaneous exposure from cosmetics and hygiene products or absorption of low‐molecular‐weight (LMW)‐PEG in pharmaceuticals. 3 The role of LMW‐PEG exposure prior to hypersensitivity has not been explored and may merit investigation. A female predominance was noted in our case series, but has not been universally observed. 1 , 4 Overall, the literature reports equal incidence between sexes. Interestingly, more recent case reports demonstrate a younger median age of diagnosis compared with older publications. 1 , 5 This is likely multifactorial and may be influenced by improved awareness of drug, and specifically PEG allergy, improved access to specialist allergy services, and potentially earlier or greater opportunity for sensitization. This is something that can only be speculated on because of limited clinical data.
Four of the 6 cases were suspected to have an NSAID allergy that was subsequently ruled out with negative provocation tests (Table 1). This emphasizes the prevalence of understandable misdiagnosis and unnecessary drug restrictions in this cohort. A review published in 2016 identified 37 cases labeled as “PEG‐allergy,” totaling 74 reactions. 4 More than half were associated with laxatives, also prominent allergens in this series. PEG‐3350 has been listed in more than 1000 approved medications. 3 Despite this ubiquity, reported incidence of hypersensitivity appears low. However we demonstrate that reactions can be severe and are diagnostically challenging.
NSAIDs are one of the most common inducers of drug‐related hypersensitivity reactions. 6 PEG sensitivity does not need to be considered in all NSAID‐related reactions. However, there are features that can be divined from an allergy history that offer pointers toward the need for PEG sensitization assessment. Patients with multiple episodes of “unexplained” anaphylaxis or tolerance of individual brands of the same drug merit closer investigation. Reactions to laxatives or bowel preparations, “depo” medications, and mucosal absorption from lubricants, gels, and dressings are red flags that should have PEG hypersensitivity in the differential. Bruusgaard‐Mouritsen et al (2021) similarly highlighted analgesics, depo injections, and laxatives as common triggers in their cohort, as well noting antacids and antibiotics as culprits. 1
We recommend that an adrenaline autoinjector be prescribed to those with PEG allergy because of an ongoing risk of accidental exposure. Unfortunately, comprehensive avoidance list cannot be provided, as medical preparations frequently change; thus, awareness is key. We advise patient empowerment with education, supported by step‐by‐step instructions on how to interrogate summary of product characteristics (SPC) for the variety of terms that indicate a PEG excipient. Patients are advised to engage with pharmacists and inform all health care professionals encountered of the disorder. In addition they should wear alert jewelry and only take a medication when they and their health care professional are satisfied that it does not contain PEG. Effective use of an electronic patient record can assist with communicating this issue, but as with all drug allergy, effective communication among disparate health care providers is a challenge. In addition, the cases presented here suggest a higher rate of biphasic allergic reactions than might be expected. 7 Based on these observations, we recommend extended monitoring for 12 hours after resolution of symptoms following a PEG‐related reaction. Although biphasic symptoms are usually mild, they can be distressing, especially to patients who have had a history of unexplained adverse events.
The identification of PEG allergy is increasing. These cases offer insight into the variety of ways this allergy can present. We report characteristics that flag PEG as a potential trigger and highlight the need for extended observation after resolution of symptoms because of the risk of biphasic reactions. Reports of immediate hypersensitivity in 2 health care workers on the first day of mass COVID‐19 vaccination in the United Kingdom are concerning. 8 It remains unknown if PEG‐2000 is involved in these reactions. Leaders in allergy have already engaged with regulatory authorities to highlight PEG as a possible allergen in mRNA vaccines and to support the objective investigation of reported reactions. 9
PEG allergy is now well known among allergy professionals. However, increased awareness of this allergen among the wider medical community is needed. Early recognition through a thorough clinical history and rapid referral to allergy diagnostic centers is required to confirm the diagnosis and effectively manage this high‐risk drug allergy.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Funding
We did not receive funding for this study.
Data‐Sharing Statement
Please contact the corresponding author, Dr Fionnuala Cox, on coxff@tcd.ie, if you wish to request further information on study data.
Author Contributions
F.C. conceived the study and interpreted data. F.C., N.C., and K.K. diagnosed and managed patients. All authors contributed to the writing and approval of the article.
Acknowledgments
We thank the patients and Clinical Immunology Teams in St James's Hospital and Beaumont Hospital, Dublin. | CONTAINED MACROGOLS (PEG) AS EXCIPIENT | DrugDosageText | CC BY-NC-ND | 33543766 | 19,415,712 | 2021-06 |
What was the dosage of drug 'ESOMEPRAZOLE MAGNESIUM\NAPROXEN'? | PEG That Reaction: A Case Series of Allergy to Polyethylene Glycol.
Polyethylene glycol (PEG), also known as macrogol, is an excipient in numerous medications, health care products, cosmetics, and foods. It acts as an inert bulking, or stabilizing, agent. Despite its ubiquity, including in 2 of the newly launched vaccines against SARS-CoV-2, awareness of PEG allergy remains low. We present 6 cases of acute hypersensitivity to PEG. Accurate diagnoses in these cases posed a challenge, and although the triggering agents differed, PEG was demonstrated as the common culprit. All cases were female, with a mean age of 36.4 years. Four patients were originally suspected to have nonsteroid anti-inflammatory drug allergy, and 2 had a history of chronic spontaneous urticaria and angioedema. Biphasic allergic reactions featured prominently in this case series. Diagnosis relies on a high index of suspicion leading to a focused clinical history, supported by skin tests with PEG solutions to demonstrate sensitization. This case series highlights important clinical features of this rare, potentially serious, and increasingly recognized excipient allergy.
pmcPolyethylene glycol (PEG), also known as macrogol or E1521, is a commonly used bulking and stabilizing agent. It is an excipient in a wide variety of medications and also encountered in cosmetics and processed foods. Notably, both Pfizer BioNTech and Moderna mRNA vaccines against SARS‐CoV‐2, which are being internationally deployed to combat the current pandemic, contain polyethylene glycol. Allergy to PEG is rare but is increasingly recognized and can be severe. We present a case series to highlight features of this unusual excipient allergy. A high index of suspicion with early referral for expert diagnostic workup is required to implement appropriate risk management strategies.
The incident case experienced anaphylaxis after intramuscular Depo‐Provera administered by her general practitioner. She developed rapid‐onset sneezing, rhinorrhea, urticaria, profound hypotension, and chest tightness. She was managed with 2 doses of intramuscular adrenaline, steroids, and nebulized salbutamol. Symptoms improved; however, 6 hours following initial treatment she experienced further urticaria. The patient had recently tolerated similar progesterone in the oral contraceptive pill. Allergy to an excipient ingredient was suspected. The specific intramuscular formulation contained PEG‐3350 (Table 1). Skin‐prick testing (SPT) was positive and avoidance advised.
Table 1 Patient Case Summary With Triggering Agents and Associated PEG Compounds, Allergic Symptoms Experienced, Outcome of Skin Prick Testing, and Results of Supervised Provocation Challenges Detailed for Each Patient
Case Allergic Disease Trigger Symptoms Negative Provocation Challenge Positive Investigation
Case 1
Female, 35 years
None Depo‐Provera: medroxyprogesterone PEG‐3350 Sneezing, ocular irritation, rhinorrhea, urticaria, hypotension, chest tightness, respiratory compromise.
Biphasic urticaria.
None SPT PEG‐3350:
positive, 7 x 7 mm
Case 2
Female, 25 years
None Nexium: esomeprazole "Macrogols"
MoviPrep: osmotic laxative PEG‐3350
Cosmetics: PEG‐100
Urticaria, angioedema,
Respiratory compromise.
Pruritus, urticaria, angioedema, hypotension, swelling of hands and feet.
Biphasic urticaria.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free
"Teva”:
pantoprazole
PEG‐free
SPT PEG‐3350:
positive, 10 x 11 mm
Case 3
Female, 40 years
None Effervescent vitamin C: HMW‐PEG
Klean Prep: osmotic laxative PEG‐3350.
Vimovo: esomeprazole,
naproxen.
PEG‐8000.
EMLA topical anesthetic:
lidocaine, prilocaine.
HMW‐PEG.
Urticaria, syncope.
Urticaria, angioedema.
Urticaria, presyncopal.
Generalized pruritus.
Cerazette:
desogestrel
PEG‐400
“Teva”:
pantoprazole
PEG‐free
SPT PEG‐400, 3350:
Inconclusive because of dermographism.
Movicol challenge, PEG‐3350: positive
Case 4
Female, 44 years
None Klean Prep: osmotic laxative,
PEG‐3350.
Phosphate Sandoz: effervescent phosphate,
PEG‐4000.
Cosmetics: LMW‐ and HMW‐PEG.
Perioral paresthesia, angioedema, dyspnea, stridor, visual disturbance, syncope.
Angioedema, dyspnea, presyncope.
Urticaria
None SPT PEG‐3350:
positive
Case 5
Female, 36 years
CSUA Motilium Suppository: domperidone,
PEG‐400 and 1000.
Nurofen: ibuprofen,
PEG‐6000.
Angioedema, paresthesia,
throat tightness.
Angioedema, paresthesia,
throat tightness.
Motilium oral tablet:
PEG‐free
Nurofen syrup:
PEG‐free
SPT PEG‐3350:
positive
Case 6
Female, 38 years
CSUA
Physical urticaria
Betadine: wound dressing, povidone‐iodine,
PEG‐400, 6000.
Voltorol Oral: diclofenac
PEG‐8000.
Diclofenac IM:
HMW‐PEG.
Shaving foam: LMW‐ and HMW‐PEG.
Cosmetics: LMW‐ and HMW‐PEG.
Urticaria, presyncopal.
Urticaria.
Urticaria.
Urticaria, angioedema,
respiratory distress, hypotension.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free.
Ibuprofen tablet:
PEG‐free
SPT PEG‐3350:
10 × 10 mm
John Wiley & Sons, Ltd.
The second patient experienced acute urticaria and angioedema following concomitant ibuprofen and esomeprazole ingestion. Nonsteroidal anti‐inflammatory drug (NSAID) sensitivity was initially suspected (Table 1). While awaiting further investigation, she developed urticaria, angioedema, and hypotension following minimal ingestion of the PEG‐containing osmotic laxative Movi‐Prep. Symptoms settled with steroids and antihistamine; however, she experienced further urticaria 6 hours later. In addition, the patient described contact urticaria with certain cosmetics. PEG was suspected as a common trigger, and SPT was supportive (Table 1).
Case 3 had urticaria and syncope within minutes of effervescent vitamin C and separately developed urticaria, angioedema, and throat tightness with difficulty swallowing after the osmotic laxative Klean‐Prep. She gave a history of urticaria associated with Vimovo (esomeprazole and naproxen) and similar symptoms during a dental procedure (Table 1). All identified agents contained high‐molecular‐weight (HMW)‐PEG (Table 1). Unfortunately, SPT was inconclusive because of dermographism (negative control inciting a wheal). A provocation challenge to HMW‐PEG (Movicol) was objectively positive. The patient has remained completely symptom‐free with a PEG avoidance strategy. She has tolerated challenges with PEG‐free medications.
Anaphylaxis to Klean‐Prep was also a presenting feature of the fourth case. A PEG‐3350 allergy was suspected and avoidance advised until formal review at an allergy clinic. In the following months, while awaiting assessment and as a hospital inpatient for an unrelated condition, she had a second anaphylaxis within minutes of taking a PEG‐containing effervescent phosphate replacement preparation. SPT was subsequently positive to PEG‐3350, which has been avoided since.
The fifth patient was referred for assessment of multiple allergic drug reactions, on a background of chronic spontaneous urticaria and angioedema (CSUA). The first episode occurred within minutes of a Motilium suppository and was managed with intramuscular adrenaline, hydrocortisone, chlorphenamine, and fluid resuscitation. The second episode was precipitated by oral ibuprofen, again requiring adrenaline. PEG was considered a likely trigger, SPT was supportive. The patient subsequently tolerated PEG‐free domperidone and ibuprofen (Table 1).
The final case similarly had multiple adverse drug reactions, including anaphylaxis, on a background of CSUA. The initial allergic episode occurred following a Betadine dressing to a wound. She had systemic symptoms with oral and intramuscular diclofenac, oral Solpadeine (paracetamol and codeine), and contact urticaria with various cosmetics (Table 1). The patient subsequently tolerated PEG‐free forms of NSAIDs and codeine. PEG was suspected as a common inciting agent, SPT was supportive and strict avoidance recommended. After diagnosis, the patient experienced anaphylaxis while shaving with a product containing PEG requiring self‐administration of an adrenaline autoinjector.
This case series illustrates the diverse presentations of PEG allergy. Patients experienced an average of 3 allergic episodes before a formal diagnosis consistent with other case series. 1 Reactions were distressing for patients and objectively severe. Media reports of a case of fatal anaphylaxis in a patient with an established diagnosis of PEG allergy highlight the significance of this emerging problem. 2 The true incidence of PEG allergy is difficult to determine and may be underestimated. 3
It is hypothesized that initial PEG‐sensitization could be via cutaneous exposure from cosmetics and hygiene products or absorption of low‐molecular‐weight (LMW)‐PEG in pharmaceuticals. 3 The role of LMW‐PEG exposure prior to hypersensitivity has not been explored and may merit investigation. A female predominance was noted in our case series, but has not been universally observed. 1 , 4 Overall, the literature reports equal incidence between sexes. Interestingly, more recent case reports demonstrate a younger median age of diagnosis compared with older publications. 1 , 5 This is likely multifactorial and may be influenced by improved awareness of drug, and specifically PEG allergy, improved access to specialist allergy services, and potentially earlier or greater opportunity for sensitization. This is something that can only be speculated on because of limited clinical data.
Four of the 6 cases were suspected to have an NSAID allergy that was subsequently ruled out with negative provocation tests (Table 1). This emphasizes the prevalence of understandable misdiagnosis and unnecessary drug restrictions in this cohort. A review published in 2016 identified 37 cases labeled as “PEG‐allergy,” totaling 74 reactions. 4 More than half were associated with laxatives, also prominent allergens in this series. PEG‐3350 has been listed in more than 1000 approved medications. 3 Despite this ubiquity, reported incidence of hypersensitivity appears low. However we demonstrate that reactions can be severe and are diagnostically challenging.
NSAIDs are one of the most common inducers of drug‐related hypersensitivity reactions. 6 PEG sensitivity does not need to be considered in all NSAID‐related reactions. However, there are features that can be divined from an allergy history that offer pointers toward the need for PEG sensitization assessment. Patients with multiple episodes of “unexplained” anaphylaxis or tolerance of individual brands of the same drug merit closer investigation. Reactions to laxatives or bowel preparations, “depo” medications, and mucosal absorption from lubricants, gels, and dressings are red flags that should have PEG hypersensitivity in the differential. Bruusgaard‐Mouritsen et al (2021) similarly highlighted analgesics, depo injections, and laxatives as common triggers in their cohort, as well noting antacids and antibiotics as culprits. 1
We recommend that an adrenaline autoinjector be prescribed to those with PEG allergy because of an ongoing risk of accidental exposure. Unfortunately, comprehensive avoidance list cannot be provided, as medical preparations frequently change; thus, awareness is key. We advise patient empowerment with education, supported by step‐by‐step instructions on how to interrogate summary of product characteristics (SPC) for the variety of terms that indicate a PEG excipient. Patients are advised to engage with pharmacists and inform all health care professionals encountered of the disorder. In addition they should wear alert jewelry and only take a medication when they and their health care professional are satisfied that it does not contain PEG. Effective use of an electronic patient record can assist with communicating this issue, but as with all drug allergy, effective communication among disparate health care providers is a challenge. In addition, the cases presented here suggest a higher rate of biphasic allergic reactions than might be expected. 7 Based on these observations, we recommend extended monitoring for 12 hours after resolution of symptoms following a PEG‐related reaction. Although biphasic symptoms are usually mild, they can be distressing, especially to patients who have had a history of unexplained adverse events.
The identification of PEG allergy is increasing. These cases offer insight into the variety of ways this allergy can present. We report characteristics that flag PEG as a potential trigger and highlight the need for extended observation after resolution of symptoms because of the risk of biphasic reactions. Reports of immediate hypersensitivity in 2 health care workers on the first day of mass COVID‐19 vaccination in the United Kingdom are concerning. 8 It remains unknown if PEG‐2000 is involved in these reactions. Leaders in allergy have already engaged with regulatory authorities to highlight PEG as a possible allergen in mRNA vaccines and to support the objective investigation of reported reactions. 9
PEG allergy is now well known among allergy professionals. However, increased awareness of this allergen among the wider medical community is needed. Early recognition through a thorough clinical history and rapid referral to allergy diagnostic centers is required to confirm the diagnosis and effectively manage this high‐risk drug allergy.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Funding
We did not receive funding for this study.
Data‐Sharing Statement
Please contact the corresponding author, Dr Fionnuala Cox, on coxff@tcd.ie, if you wish to request further information on study data.
Author Contributions
F.C. conceived the study and interpreted data. F.C., N.C., and K.K. diagnosed and managed patients. All authors contributed to the writing and approval of the article.
Acknowledgments
We thank the patients and Clinical Immunology Teams in St James's Hospital and Beaumont Hospital, Dublin. | CONTAINED PEG?8000 AS EXCIPIENT | DrugDosageText | CC BY-NC-ND | 33543766 | 19,399,217 | 2021-06 |
What was the dosage of drug 'IBUPROFEN'? | PEG That Reaction: A Case Series of Allergy to Polyethylene Glycol.
Polyethylene glycol (PEG), also known as macrogol, is an excipient in numerous medications, health care products, cosmetics, and foods. It acts as an inert bulking, or stabilizing, agent. Despite its ubiquity, including in 2 of the newly launched vaccines against SARS-CoV-2, awareness of PEG allergy remains low. We present 6 cases of acute hypersensitivity to PEG. Accurate diagnoses in these cases posed a challenge, and although the triggering agents differed, PEG was demonstrated as the common culprit. All cases were female, with a mean age of 36.4 years. Four patients were originally suspected to have nonsteroid anti-inflammatory drug allergy, and 2 had a history of chronic spontaneous urticaria and angioedema. Biphasic allergic reactions featured prominently in this case series. Diagnosis relies on a high index of suspicion leading to a focused clinical history, supported by skin tests with PEG solutions to demonstrate sensitization. This case series highlights important clinical features of this rare, potentially serious, and increasingly recognized excipient allergy.
pmcPolyethylene glycol (PEG), also known as macrogol or E1521, is a commonly used bulking and stabilizing agent. It is an excipient in a wide variety of medications and also encountered in cosmetics and processed foods. Notably, both Pfizer BioNTech and Moderna mRNA vaccines against SARS‐CoV‐2, which are being internationally deployed to combat the current pandemic, contain polyethylene glycol. Allergy to PEG is rare but is increasingly recognized and can be severe. We present a case series to highlight features of this unusual excipient allergy. A high index of suspicion with early referral for expert diagnostic workup is required to implement appropriate risk management strategies.
The incident case experienced anaphylaxis after intramuscular Depo‐Provera administered by her general practitioner. She developed rapid‐onset sneezing, rhinorrhea, urticaria, profound hypotension, and chest tightness. She was managed with 2 doses of intramuscular adrenaline, steroids, and nebulized salbutamol. Symptoms improved; however, 6 hours following initial treatment she experienced further urticaria. The patient had recently tolerated similar progesterone in the oral contraceptive pill. Allergy to an excipient ingredient was suspected. The specific intramuscular formulation contained PEG‐3350 (Table 1). Skin‐prick testing (SPT) was positive and avoidance advised.
Table 1 Patient Case Summary With Triggering Agents and Associated PEG Compounds, Allergic Symptoms Experienced, Outcome of Skin Prick Testing, and Results of Supervised Provocation Challenges Detailed for Each Patient
Case Allergic Disease Trigger Symptoms Negative Provocation Challenge Positive Investigation
Case 1
Female, 35 years
None Depo‐Provera: medroxyprogesterone PEG‐3350 Sneezing, ocular irritation, rhinorrhea, urticaria, hypotension, chest tightness, respiratory compromise.
Biphasic urticaria.
None SPT PEG‐3350:
positive, 7 x 7 mm
Case 2
Female, 25 years
None Nexium: esomeprazole "Macrogols"
MoviPrep: osmotic laxative PEG‐3350
Cosmetics: PEG‐100
Urticaria, angioedema,
Respiratory compromise.
Pruritus, urticaria, angioedema, hypotension, swelling of hands and feet.
Biphasic urticaria.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free
"Teva”:
pantoprazole
PEG‐free
SPT PEG‐3350:
positive, 10 x 11 mm
Case 3
Female, 40 years
None Effervescent vitamin C: HMW‐PEG
Klean Prep: osmotic laxative PEG‐3350.
Vimovo: esomeprazole,
naproxen.
PEG‐8000.
EMLA topical anesthetic:
lidocaine, prilocaine.
HMW‐PEG.
Urticaria, syncope.
Urticaria, angioedema.
Urticaria, presyncopal.
Generalized pruritus.
Cerazette:
desogestrel
PEG‐400
“Teva”:
pantoprazole
PEG‐free
SPT PEG‐400, 3350:
Inconclusive because of dermographism.
Movicol challenge, PEG‐3350: positive
Case 4
Female, 44 years
None Klean Prep: osmotic laxative,
PEG‐3350.
Phosphate Sandoz: effervescent phosphate,
PEG‐4000.
Cosmetics: LMW‐ and HMW‐PEG.
Perioral paresthesia, angioedema, dyspnea, stridor, visual disturbance, syncope.
Angioedema, dyspnea, presyncope.
Urticaria
None SPT PEG‐3350:
positive
Case 5
Female, 36 years
CSUA Motilium Suppository: domperidone,
PEG‐400 and 1000.
Nurofen: ibuprofen,
PEG‐6000.
Angioedema, paresthesia,
throat tightness.
Angioedema, paresthesia,
throat tightness.
Motilium oral tablet:
PEG‐free
Nurofen syrup:
PEG‐free
SPT PEG‐3350:
positive
Case 6
Female, 38 years
CSUA
Physical urticaria
Betadine: wound dressing, povidone‐iodine,
PEG‐400, 6000.
Voltorol Oral: diclofenac
PEG‐8000.
Diclofenac IM:
HMW‐PEG.
Shaving foam: LMW‐ and HMW‐PEG.
Cosmetics: LMW‐ and HMW‐PEG.
Urticaria, presyncopal.
Urticaria.
Urticaria.
Urticaria, angioedema,
respiratory distress, hypotension.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free.
Ibuprofen tablet:
PEG‐free
SPT PEG‐3350:
10 × 10 mm
John Wiley & Sons, Ltd.
The second patient experienced acute urticaria and angioedema following concomitant ibuprofen and esomeprazole ingestion. Nonsteroidal anti‐inflammatory drug (NSAID) sensitivity was initially suspected (Table 1). While awaiting further investigation, she developed urticaria, angioedema, and hypotension following minimal ingestion of the PEG‐containing osmotic laxative Movi‐Prep. Symptoms settled with steroids and antihistamine; however, she experienced further urticaria 6 hours later. In addition, the patient described contact urticaria with certain cosmetics. PEG was suspected as a common trigger, and SPT was supportive (Table 1).
Case 3 had urticaria and syncope within minutes of effervescent vitamin C and separately developed urticaria, angioedema, and throat tightness with difficulty swallowing after the osmotic laxative Klean‐Prep. She gave a history of urticaria associated with Vimovo (esomeprazole and naproxen) and similar symptoms during a dental procedure (Table 1). All identified agents contained high‐molecular‐weight (HMW)‐PEG (Table 1). Unfortunately, SPT was inconclusive because of dermographism (negative control inciting a wheal). A provocation challenge to HMW‐PEG (Movicol) was objectively positive. The patient has remained completely symptom‐free with a PEG avoidance strategy. She has tolerated challenges with PEG‐free medications.
Anaphylaxis to Klean‐Prep was also a presenting feature of the fourth case. A PEG‐3350 allergy was suspected and avoidance advised until formal review at an allergy clinic. In the following months, while awaiting assessment and as a hospital inpatient for an unrelated condition, she had a second anaphylaxis within minutes of taking a PEG‐containing effervescent phosphate replacement preparation. SPT was subsequently positive to PEG‐3350, which has been avoided since.
The fifth patient was referred for assessment of multiple allergic drug reactions, on a background of chronic spontaneous urticaria and angioedema (CSUA). The first episode occurred within minutes of a Motilium suppository and was managed with intramuscular adrenaline, hydrocortisone, chlorphenamine, and fluid resuscitation. The second episode was precipitated by oral ibuprofen, again requiring adrenaline. PEG was considered a likely trigger, SPT was supportive. The patient subsequently tolerated PEG‐free domperidone and ibuprofen (Table 1).
The final case similarly had multiple adverse drug reactions, including anaphylaxis, on a background of CSUA. The initial allergic episode occurred following a Betadine dressing to a wound. She had systemic symptoms with oral and intramuscular diclofenac, oral Solpadeine (paracetamol and codeine), and contact urticaria with various cosmetics (Table 1). The patient subsequently tolerated PEG‐free forms of NSAIDs and codeine. PEG was suspected as a common inciting agent, SPT was supportive and strict avoidance recommended. After diagnosis, the patient experienced anaphylaxis while shaving with a product containing PEG requiring self‐administration of an adrenaline autoinjector.
This case series illustrates the diverse presentations of PEG allergy. Patients experienced an average of 3 allergic episodes before a formal diagnosis consistent with other case series. 1 Reactions were distressing for patients and objectively severe. Media reports of a case of fatal anaphylaxis in a patient with an established diagnosis of PEG allergy highlight the significance of this emerging problem. 2 The true incidence of PEG allergy is difficult to determine and may be underestimated. 3
It is hypothesized that initial PEG‐sensitization could be via cutaneous exposure from cosmetics and hygiene products or absorption of low‐molecular‐weight (LMW)‐PEG in pharmaceuticals. 3 The role of LMW‐PEG exposure prior to hypersensitivity has not been explored and may merit investigation. A female predominance was noted in our case series, but has not been universally observed. 1 , 4 Overall, the literature reports equal incidence between sexes. Interestingly, more recent case reports demonstrate a younger median age of diagnosis compared with older publications. 1 , 5 This is likely multifactorial and may be influenced by improved awareness of drug, and specifically PEG allergy, improved access to specialist allergy services, and potentially earlier or greater opportunity for sensitization. This is something that can only be speculated on because of limited clinical data.
Four of the 6 cases were suspected to have an NSAID allergy that was subsequently ruled out with negative provocation tests (Table 1). This emphasizes the prevalence of understandable misdiagnosis and unnecessary drug restrictions in this cohort. A review published in 2016 identified 37 cases labeled as “PEG‐allergy,” totaling 74 reactions. 4 More than half were associated with laxatives, also prominent allergens in this series. PEG‐3350 has been listed in more than 1000 approved medications. 3 Despite this ubiquity, reported incidence of hypersensitivity appears low. However we demonstrate that reactions can be severe and are diagnostically challenging.
NSAIDs are one of the most common inducers of drug‐related hypersensitivity reactions. 6 PEG sensitivity does not need to be considered in all NSAID‐related reactions. However, there are features that can be divined from an allergy history that offer pointers toward the need for PEG sensitization assessment. Patients with multiple episodes of “unexplained” anaphylaxis or tolerance of individual brands of the same drug merit closer investigation. Reactions to laxatives or bowel preparations, “depo” medications, and mucosal absorption from lubricants, gels, and dressings are red flags that should have PEG hypersensitivity in the differential. Bruusgaard‐Mouritsen et al (2021) similarly highlighted analgesics, depo injections, and laxatives as common triggers in their cohort, as well noting antacids and antibiotics as culprits. 1
We recommend that an adrenaline autoinjector be prescribed to those with PEG allergy because of an ongoing risk of accidental exposure. Unfortunately, comprehensive avoidance list cannot be provided, as medical preparations frequently change; thus, awareness is key. We advise patient empowerment with education, supported by step‐by‐step instructions on how to interrogate summary of product characteristics (SPC) for the variety of terms that indicate a PEG excipient. Patients are advised to engage with pharmacists and inform all health care professionals encountered of the disorder. In addition they should wear alert jewelry and only take a medication when they and their health care professional are satisfied that it does not contain PEG. Effective use of an electronic patient record can assist with communicating this issue, but as with all drug allergy, effective communication among disparate health care providers is a challenge. In addition, the cases presented here suggest a higher rate of biphasic allergic reactions than might be expected. 7 Based on these observations, we recommend extended monitoring for 12 hours after resolution of symptoms following a PEG‐related reaction. Although biphasic symptoms are usually mild, they can be distressing, especially to patients who have had a history of unexplained adverse events.
The identification of PEG allergy is increasing. These cases offer insight into the variety of ways this allergy can present. We report characteristics that flag PEG as a potential trigger and highlight the need for extended observation after resolution of symptoms because of the risk of biphasic reactions. Reports of immediate hypersensitivity in 2 health care workers on the first day of mass COVID‐19 vaccination in the United Kingdom are concerning. 8 It remains unknown if PEG‐2000 is involved in these reactions. Leaders in allergy have already engaged with regulatory authorities to highlight PEG as a possible allergen in mRNA vaccines and to support the objective investigation of reported reactions. 9
PEG allergy is now well known among allergy professionals. However, increased awareness of this allergen among the wider medical community is needed. Early recognition through a thorough clinical history and rapid referral to allergy diagnostic centers is required to confirm the diagnosis and effectively manage this high‐risk drug allergy.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Funding
We did not receive funding for this study.
Data‐Sharing Statement
Please contact the corresponding author, Dr Fionnuala Cox, on coxff@tcd.ie, if you wish to request further information on study data.
Author Contributions
F.C. conceived the study and interpreted data. F.C., N.C., and K.K. diagnosed and managed patients. All authors contributed to the writing and approval of the article.
Acknowledgments
We thank the patients and Clinical Immunology Teams in St James's Hospital and Beaumont Hospital, Dublin. | CONTAINED MACROGOLS (PEG) AS EXCIPIENT | DrugDosageText | CC BY-NC-ND | 33543766 | 19,415,712 | 2021-06 |
What was the dosage of drug 'LIDOCAINE\PRILOCAINE'? | PEG That Reaction: A Case Series of Allergy to Polyethylene Glycol.
Polyethylene glycol (PEG), also known as macrogol, is an excipient in numerous medications, health care products, cosmetics, and foods. It acts as an inert bulking, or stabilizing, agent. Despite its ubiquity, including in 2 of the newly launched vaccines against SARS-CoV-2, awareness of PEG allergy remains low. We present 6 cases of acute hypersensitivity to PEG. Accurate diagnoses in these cases posed a challenge, and although the triggering agents differed, PEG was demonstrated as the common culprit. All cases were female, with a mean age of 36.4 years. Four patients were originally suspected to have nonsteroid anti-inflammatory drug allergy, and 2 had a history of chronic spontaneous urticaria and angioedema. Biphasic allergic reactions featured prominently in this case series. Diagnosis relies on a high index of suspicion leading to a focused clinical history, supported by skin tests with PEG solutions to demonstrate sensitization. This case series highlights important clinical features of this rare, potentially serious, and increasingly recognized excipient allergy.
pmcPolyethylene glycol (PEG), also known as macrogol or E1521, is a commonly used bulking and stabilizing agent. It is an excipient in a wide variety of medications and also encountered in cosmetics and processed foods. Notably, both Pfizer BioNTech and Moderna mRNA vaccines against SARS‐CoV‐2, which are being internationally deployed to combat the current pandemic, contain polyethylene glycol. Allergy to PEG is rare but is increasingly recognized and can be severe. We present a case series to highlight features of this unusual excipient allergy. A high index of suspicion with early referral for expert diagnostic workup is required to implement appropriate risk management strategies.
The incident case experienced anaphylaxis after intramuscular Depo‐Provera administered by her general practitioner. She developed rapid‐onset sneezing, rhinorrhea, urticaria, profound hypotension, and chest tightness. She was managed with 2 doses of intramuscular adrenaline, steroids, and nebulized salbutamol. Symptoms improved; however, 6 hours following initial treatment she experienced further urticaria. The patient had recently tolerated similar progesterone in the oral contraceptive pill. Allergy to an excipient ingredient was suspected. The specific intramuscular formulation contained PEG‐3350 (Table 1). Skin‐prick testing (SPT) was positive and avoidance advised.
Table 1 Patient Case Summary With Triggering Agents and Associated PEG Compounds, Allergic Symptoms Experienced, Outcome of Skin Prick Testing, and Results of Supervised Provocation Challenges Detailed for Each Patient
Case Allergic Disease Trigger Symptoms Negative Provocation Challenge Positive Investigation
Case 1
Female, 35 years
None Depo‐Provera: medroxyprogesterone PEG‐3350 Sneezing, ocular irritation, rhinorrhea, urticaria, hypotension, chest tightness, respiratory compromise.
Biphasic urticaria.
None SPT PEG‐3350:
positive, 7 x 7 mm
Case 2
Female, 25 years
None Nexium: esomeprazole "Macrogols"
MoviPrep: osmotic laxative PEG‐3350
Cosmetics: PEG‐100
Urticaria, angioedema,
Respiratory compromise.
Pruritus, urticaria, angioedema, hypotension, swelling of hands and feet.
Biphasic urticaria.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free
"Teva”:
pantoprazole
PEG‐free
SPT PEG‐3350:
positive, 10 x 11 mm
Case 3
Female, 40 years
None Effervescent vitamin C: HMW‐PEG
Klean Prep: osmotic laxative PEG‐3350.
Vimovo: esomeprazole,
naproxen.
PEG‐8000.
EMLA topical anesthetic:
lidocaine, prilocaine.
HMW‐PEG.
Urticaria, syncope.
Urticaria, angioedema.
Urticaria, presyncopal.
Generalized pruritus.
Cerazette:
desogestrel
PEG‐400
“Teva”:
pantoprazole
PEG‐free
SPT PEG‐400, 3350:
Inconclusive because of dermographism.
Movicol challenge, PEG‐3350: positive
Case 4
Female, 44 years
None Klean Prep: osmotic laxative,
PEG‐3350.
Phosphate Sandoz: effervescent phosphate,
PEG‐4000.
Cosmetics: LMW‐ and HMW‐PEG.
Perioral paresthesia, angioedema, dyspnea, stridor, visual disturbance, syncope.
Angioedema, dyspnea, presyncope.
Urticaria
None SPT PEG‐3350:
positive
Case 5
Female, 36 years
CSUA Motilium Suppository: domperidone,
PEG‐400 and 1000.
Nurofen: ibuprofen,
PEG‐6000.
Angioedema, paresthesia,
throat tightness.
Angioedema, paresthesia,
throat tightness.
Motilium oral tablet:
PEG‐free
Nurofen syrup:
PEG‐free
SPT PEG‐3350:
positive
Case 6
Female, 38 years
CSUA
Physical urticaria
Betadine: wound dressing, povidone‐iodine,
PEG‐400, 6000.
Voltorol Oral: diclofenac
PEG‐8000.
Diclofenac IM:
HMW‐PEG.
Shaving foam: LMW‐ and HMW‐PEG.
Cosmetics: LMW‐ and HMW‐PEG.
Urticaria, presyncopal.
Urticaria.
Urticaria.
Urticaria, angioedema,
respiratory distress, hypotension.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free.
Ibuprofen tablet:
PEG‐free
SPT PEG‐3350:
10 × 10 mm
John Wiley & Sons, Ltd.
The second patient experienced acute urticaria and angioedema following concomitant ibuprofen and esomeprazole ingestion. Nonsteroidal anti‐inflammatory drug (NSAID) sensitivity was initially suspected (Table 1). While awaiting further investigation, she developed urticaria, angioedema, and hypotension following minimal ingestion of the PEG‐containing osmotic laxative Movi‐Prep. Symptoms settled with steroids and antihistamine; however, she experienced further urticaria 6 hours later. In addition, the patient described contact urticaria with certain cosmetics. PEG was suspected as a common trigger, and SPT was supportive (Table 1).
Case 3 had urticaria and syncope within minutes of effervescent vitamin C and separately developed urticaria, angioedema, and throat tightness with difficulty swallowing after the osmotic laxative Klean‐Prep. She gave a history of urticaria associated with Vimovo (esomeprazole and naproxen) and similar symptoms during a dental procedure (Table 1). All identified agents contained high‐molecular‐weight (HMW)‐PEG (Table 1). Unfortunately, SPT was inconclusive because of dermographism (negative control inciting a wheal). A provocation challenge to HMW‐PEG (Movicol) was objectively positive. The patient has remained completely symptom‐free with a PEG avoidance strategy. She has tolerated challenges with PEG‐free medications.
Anaphylaxis to Klean‐Prep was also a presenting feature of the fourth case. A PEG‐3350 allergy was suspected and avoidance advised until formal review at an allergy clinic. In the following months, while awaiting assessment and as a hospital inpatient for an unrelated condition, she had a second anaphylaxis within minutes of taking a PEG‐containing effervescent phosphate replacement preparation. SPT was subsequently positive to PEG‐3350, which has been avoided since.
The fifth patient was referred for assessment of multiple allergic drug reactions, on a background of chronic spontaneous urticaria and angioedema (CSUA). The first episode occurred within minutes of a Motilium suppository and was managed with intramuscular adrenaline, hydrocortisone, chlorphenamine, and fluid resuscitation. The second episode was precipitated by oral ibuprofen, again requiring adrenaline. PEG was considered a likely trigger, SPT was supportive. The patient subsequently tolerated PEG‐free domperidone and ibuprofen (Table 1).
The final case similarly had multiple adverse drug reactions, including anaphylaxis, on a background of CSUA. The initial allergic episode occurred following a Betadine dressing to a wound. She had systemic symptoms with oral and intramuscular diclofenac, oral Solpadeine (paracetamol and codeine), and contact urticaria with various cosmetics (Table 1). The patient subsequently tolerated PEG‐free forms of NSAIDs and codeine. PEG was suspected as a common inciting agent, SPT was supportive and strict avoidance recommended. After diagnosis, the patient experienced anaphylaxis while shaving with a product containing PEG requiring self‐administration of an adrenaline autoinjector.
This case series illustrates the diverse presentations of PEG allergy. Patients experienced an average of 3 allergic episodes before a formal diagnosis consistent with other case series. 1 Reactions were distressing for patients and objectively severe. Media reports of a case of fatal anaphylaxis in a patient with an established diagnosis of PEG allergy highlight the significance of this emerging problem. 2 The true incidence of PEG allergy is difficult to determine and may be underestimated. 3
It is hypothesized that initial PEG‐sensitization could be via cutaneous exposure from cosmetics and hygiene products or absorption of low‐molecular‐weight (LMW)‐PEG in pharmaceuticals. 3 The role of LMW‐PEG exposure prior to hypersensitivity has not been explored and may merit investigation. A female predominance was noted in our case series, but has not been universally observed. 1 , 4 Overall, the literature reports equal incidence between sexes. Interestingly, more recent case reports demonstrate a younger median age of diagnosis compared with older publications. 1 , 5 This is likely multifactorial and may be influenced by improved awareness of drug, and specifically PEG allergy, improved access to specialist allergy services, and potentially earlier or greater opportunity for sensitization. This is something that can only be speculated on because of limited clinical data.
Four of the 6 cases were suspected to have an NSAID allergy that was subsequently ruled out with negative provocation tests (Table 1). This emphasizes the prevalence of understandable misdiagnosis and unnecessary drug restrictions in this cohort. A review published in 2016 identified 37 cases labeled as “PEG‐allergy,” totaling 74 reactions. 4 More than half were associated with laxatives, also prominent allergens in this series. PEG‐3350 has been listed in more than 1000 approved medications. 3 Despite this ubiquity, reported incidence of hypersensitivity appears low. However we demonstrate that reactions can be severe and are diagnostically challenging.
NSAIDs are one of the most common inducers of drug‐related hypersensitivity reactions. 6 PEG sensitivity does not need to be considered in all NSAID‐related reactions. However, there are features that can be divined from an allergy history that offer pointers toward the need for PEG sensitization assessment. Patients with multiple episodes of “unexplained” anaphylaxis or tolerance of individual brands of the same drug merit closer investigation. Reactions to laxatives or bowel preparations, “depo” medications, and mucosal absorption from lubricants, gels, and dressings are red flags that should have PEG hypersensitivity in the differential. Bruusgaard‐Mouritsen et al (2021) similarly highlighted analgesics, depo injections, and laxatives as common triggers in their cohort, as well noting antacids and antibiotics as culprits. 1
We recommend that an adrenaline autoinjector be prescribed to those with PEG allergy because of an ongoing risk of accidental exposure. Unfortunately, comprehensive avoidance list cannot be provided, as medical preparations frequently change; thus, awareness is key. We advise patient empowerment with education, supported by step‐by‐step instructions on how to interrogate summary of product characteristics (SPC) for the variety of terms that indicate a PEG excipient. Patients are advised to engage with pharmacists and inform all health care professionals encountered of the disorder. In addition they should wear alert jewelry and only take a medication when they and their health care professional are satisfied that it does not contain PEG. Effective use of an electronic patient record can assist with communicating this issue, but as with all drug allergy, effective communication among disparate health care providers is a challenge. In addition, the cases presented here suggest a higher rate of biphasic allergic reactions than might be expected. 7 Based on these observations, we recommend extended monitoring for 12 hours after resolution of symptoms following a PEG‐related reaction. Although biphasic symptoms are usually mild, they can be distressing, especially to patients who have had a history of unexplained adverse events.
The identification of PEG allergy is increasing. These cases offer insight into the variety of ways this allergy can present. We report characteristics that flag PEG as a potential trigger and highlight the need for extended observation after resolution of symptoms because of the risk of biphasic reactions. Reports of immediate hypersensitivity in 2 health care workers on the first day of mass COVID‐19 vaccination in the United Kingdom are concerning. 8 It remains unknown if PEG‐2000 is involved in these reactions. Leaders in allergy have already engaged with regulatory authorities to highlight PEG as a possible allergen in mRNA vaccines and to support the objective investigation of reported reactions. 9
PEG allergy is now well known among allergy professionals. However, increased awareness of this allergen among the wider medical community is needed. Early recognition through a thorough clinical history and rapid referral to allergy diagnostic centers is required to confirm the diagnosis and effectively manage this high‐risk drug allergy.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Funding
We did not receive funding for this study.
Data‐Sharing Statement
Please contact the corresponding author, Dr Fionnuala Cox, on coxff@tcd.ie, if you wish to request further information on study data.
Author Contributions
F.C. conceived the study and interpreted data. F.C., N.C., and K.K. diagnosed and managed patients. All authors contributed to the writing and approval of the article.
Acknowledgments
We thank the patients and Clinical Immunology Teams in St James's Hospital and Beaumont Hospital, Dublin. | CONTAINED HMW?PEG AS EXCIPIENT | DrugDosageText | CC BY-NC-ND | 33543766 | 19,399,217 | 2021-06 |
What was the outcome of reaction 'Anaphylactic reaction'? | PEG That Reaction: A Case Series of Allergy to Polyethylene Glycol.
Polyethylene glycol (PEG), also known as macrogol, is an excipient in numerous medications, health care products, cosmetics, and foods. It acts as an inert bulking, or stabilizing, agent. Despite its ubiquity, including in 2 of the newly launched vaccines against SARS-CoV-2, awareness of PEG allergy remains low. We present 6 cases of acute hypersensitivity to PEG. Accurate diagnoses in these cases posed a challenge, and although the triggering agents differed, PEG was demonstrated as the common culprit. All cases were female, with a mean age of 36.4 years. Four patients were originally suspected to have nonsteroid anti-inflammatory drug allergy, and 2 had a history of chronic spontaneous urticaria and angioedema. Biphasic allergic reactions featured prominently in this case series. Diagnosis relies on a high index of suspicion leading to a focused clinical history, supported by skin tests with PEG solutions to demonstrate sensitization. This case series highlights important clinical features of this rare, potentially serious, and increasingly recognized excipient allergy.
pmcPolyethylene glycol (PEG), also known as macrogol or E1521, is a commonly used bulking and stabilizing agent. It is an excipient in a wide variety of medications and also encountered in cosmetics and processed foods. Notably, both Pfizer BioNTech and Moderna mRNA vaccines against SARS‐CoV‐2, which are being internationally deployed to combat the current pandemic, contain polyethylene glycol. Allergy to PEG is rare but is increasingly recognized and can be severe. We present a case series to highlight features of this unusual excipient allergy. A high index of suspicion with early referral for expert diagnostic workup is required to implement appropriate risk management strategies.
The incident case experienced anaphylaxis after intramuscular Depo‐Provera administered by her general practitioner. She developed rapid‐onset sneezing, rhinorrhea, urticaria, profound hypotension, and chest tightness. She was managed with 2 doses of intramuscular adrenaline, steroids, and nebulized salbutamol. Symptoms improved; however, 6 hours following initial treatment she experienced further urticaria. The patient had recently tolerated similar progesterone in the oral contraceptive pill. Allergy to an excipient ingredient was suspected. The specific intramuscular formulation contained PEG‐3350 (Table 1). Skin‐prick testing (SPT) was positive and avoidance advised.
Table 1 Patient Case Summary With Triggering Agents and Associated PEG Compounds, Allergic Symptoms Experienced, Outcome of Skin Prick Testing, and Results of Supervised Provocation Challenges Detailed for Each Patient
Case Allergic Disease Trigger Symptoms Negative Provocation Challenge Positive Investigation
Case 1
Female, 35 years
None Depo‐Provera: medroxyprogesterone PEG‐3350 Sneezing, ocular irritation, rhinorrhea, urticaria, hypotension, chest tightness, respiratory compromise.
Biphasic urticaria.
None SPT PEG‐3350:
positive, 7 x 7 mm
Case 2
Female, 25 years
None Nexium: esomeprazole "Macrogols"
MoviPrep: osmotic laxative PEG‐3350
Cosmetics: PEG‐100
Urticaria, angioedema,
Respiratory compromise.
Pruritus, urticaria, angioedema, hypotension, swelling of hands and feet.
Biphasic urticaria.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free
"Teva”:
pantoprazole
PEG‐free
SPT PEG‐3350:
positive, 10 x 11 mm
Case 3
Female, 40 years
None Effervescent vitamin C: HMW‐PEG
Klean Prep: osmotic laxative PEG‐3350.
Vimovo: esomeprazole,
naproxen.
PEG‐8000.
EMLA topical anesthetic:
lidocaine, prilocaine.
HMW‐PEG.
Urticaria, syncope.
Urticaria, angioedema.
Urticaria, presyncopal.
Generalized pruritus.
Cerazette:
desogestrel
PEG‐400
“Teva”:
pantoprazole
PEG‐free
SPT PEG‐400, 3350:
Inconclusive because of dermographism.
Movicol challenge, PEG‐3350: positive
Case 4
Female, 44 years
None Klean Prep: osmotic laxative,
PEG‐3350.
Phosphate Sandoz: effervescent phosphate,
PEG‐4000.
Cosmetics: LMW‐ and HMW‐PEG.
Perioral paresthesia, angioedema, dyspnea, stridor, visual disturbance, syncope.
Angioedema, dyspnea, presyncope.
Urticaria
None SPT PEG‐3350:
positive
Case 5
Female, 36 years
CSUA Motilium Suppository: domperidone,
PEG‐400 and 1000.
Nurofen: ibuprofen,
PEG‐6000.
Angioedema, paresthesia,
throat tightness.
Angioedema, paresthesia,
throat tightness.
Motilium oral tablet:
PEG‐free
Nurofen syrup:
PEG‐free
SPT PEG‐3350:
positive
Case 6
Female, 38 years
CSUA
Physical urticaria
Betadine: wound dressing, povidone‐iodine,
PEG‐400, 6000.
Voltorol Oral: diclofenac
PEG‐8000.
Diclofenac IM:
HMW‐PEG.
Shaving foam: LMW‐ and HMW‐PEG.
Cosmetics: LMW‐ and HMW‐PEG.
Urticaria, presyncopal.
Urticaria.
Urticaria.
Urticaria, angioedema,
respiratory distress, hypotension.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free.
Ibuprofen tablet:
PEG‐free
SPT PEG‐3350:
10 × 10 mm
John Wiley & Sons, Ltd.
The second patient experienced acute urticaria and angioedema following concomitant ibuprofen and esomeprazole ingestion. Nonsteroidal anti‐inflammatory drug (NSAID) sensitivity was initially suspected (Table 1). While awaiting further investigation, she developed urticaria, angioedema, and hypotension following minimal ingestion of the PEG‐containing osmotic laxative Movi‐Prep. Symptoms settled with steroids and antihistamine; however, she experienced further urticaria 6 hours later. In addition, the patient described contact urticaria with certain cosmetics. PEG was suspected as a common trigger, and SPT was supportive (Table 1).
Case 3 had urticaria and syncope within minutes of effervescent vitamin C and separately developed urticaria, angioedema, and throat tightness with difficulty swallowing after the osmotic laxative Klean‐Prep. She gave a history of urticaria associated with Vimovo (esomeprazole and naproxen) and similar symptoms during a dental procedure (Table 1). All identified agents contained high‐molecular‐weight (HMW)‐PEG (Table 1). Unfortunately, SPT was inconclusive because of dermographism (negative control inciting a wheal). A provocation challenge to HMW‐PEG (Movicol) was objectively positive. The patient has remained completely symptom‐free with a PEG avoidance strategy. She has tolerated challenges with PEG‐free medications.
Anaphylaxis to Klean‐Prep was also a presenting feature of the fourth case. A PEG‐3350 allergy was suspected and avoidance advised until formal review at an allergy clinic. In the following months, while awaiting assessment and as a hospital inpatient for an unrelated condition, she had a second anaphylaxis within minutes of taking a PEG‐containing effervescent phosphate replacement preparation. SPT was subsequently positive to PEG‐3350, which has been avoided since.
The fifth patient was referred for assessment of multiple allergic drug reactions, on a background of chronic spontaneous urticaria and angioedema (CSUA). The first episode occurred within minutes of a Motilium suppository and was managed with intramuscular adrenaline, hydrocortisone, chlorphenamine, and fluid resuscitation. The second episode was precipitated by oral ibuprofen, again requiring adrenaline. PEG was considered a likely trigger, SPT was supportive. The patient subsequently tolerated PEG‐free domperidone and ibuprofen (Table 1).
The final case similarly had multiple adverse drug reactions, including anaphylaxis, on a background of CSUA. The initial allergic episode occurred following a Betadine dressing to a wound. She had systemic symptoms with oral and intramuscular diclofenac, oral Solpadeine (paracetamol and codeine), and contact urticaria with various cosmetics (Table 1). The patient subsequently tolerated PEG‐free forms of NSAIDs and codeine. PEG was suspected as a common inciting agent, SPT was supportive and strict avoidance recommended. After diagnosis, the patient experienced anaphylaxis while shaving with a product containing PEG requiring self‐administration of an adrenaline autoinjector.
This case series illustrates the diverse presentations of PEG allergy. Patients experienced an average of 3 allergic episodes before a formal diagnosis consistent with other case series. 1 Reactions were distressing for patients and objectively severe. Media reports of a case of fatal anaphylaxis in a patient with an established diagnosis of PEG allergy highlight the significance of this emerging problem. 2 The true incidence of PEG allergy is difficult to determine and may be underestimated. 3
It is hypothesized that initial PEG‐sensitization could be via cutaneous exposure from cosmetics and hygiene products or absorption of low‐molecular‐weight (LMW)‐PEG in pharmaceuticals. 3 The role of LMW‐PEG exposure prior to hypersensitivity has not been explored and may merit investigation. A female predominance was noted in our case series, but has not been universally observed. 1 , 4 Overall, the literature reports equal incidence between sexes. Interestingly, more recent case reports demonstrate a younger median age of diagnosis compared with older publications. 1 , 5 This is likely multifactorial and may be influenced by improved awareness of drug, and specifically PEG allergy, improved access to specialist allergy services, and potentially earlier or greater opportunity for sensitization. This is something that can only be speculated on because of limited clinical data.
Four of the 6 cases were suspected to have an NSAID allergy that was subsequently ruled out with negative provocation tests (Table 1). This emphasizes the prevalence of understandable misdiagnosis and unnecessary drug restrictions in this cohort. A review published in 2016 identified 37 cases labeled as “PEG‐allergy,” totaling 74 reactions. 4 More than half were associated with laxatives, also prominent allergens in this series. PEG‐3350 has been listed in more than 1000 approved medications. 3 Despite this ubiquity, reported incidence of hypersensitivity appears low. However we demonstrate that reactions can be severe and are diagnostically challenging.
NSAIDs are one of the most common inducers of drug‐related hypersensitivity reactions. 6 PEG sensitivity does not need to be considered in all NSAID‐related reactions. However, there are features that can be divined from an allergy history that offer pointers toward the need for PEG sensitization assessment. Patients with multiple episodes of “unexplained” anaphylaxis or tolerance of individual brands of the same drug merit closer investigation. Reactions to laxatives or bowel preparations, “depo” medications, and mucosal absorption from lubricants, gels, and dressings are red flags that should have PEG hypersensitivity in the differential. Bruusgaard‐Mouritsen et al (2021) similarly highlighted analgesics, depo injections, and laxatives as common triggers in their cohort, as well noting antacids and antibiotics as culprits. 1
We recommend that an adrenaline autoinjector be prescribed to those with PEG allergy because of an ongoing risk of accidental exposure. Unfortunately, comprehensive avoidance list cannot be provided, as medical preparations frequently change; thus, awareness is key. We advise patient empowerment with education, supported by step‐by‐step instructions on how to interrogate summary of product characteristics (SPC) for the variety of terms that indicate a PEG excipient. Patients are advised to engage with pharmacists and inform all health care professionals encountered of the disorder. In addition they should wear alert jewelry and only take a medication when they and their health care professional are satisfied that it does not contain PEG. Effective use of an electronic patient record can assist with communicating this issue, but as with all drug allergy, effective communication among disparate health care providers is a challenge. In addition, the cases presented here suggest a higher rate of biphasic allergic reactions than might be expected. 7 Based on these observations, we recommend extended monitoring for 12 hours after resolution of symptoms following a PEG‐related reaction. Although biphasic symptoms are usually mild, they can be distressing, especially to patients who have had a history of unexplained adverse events.
The identification of PEG allergy is increasing. These cases offer insight into the variety of ways this allergy can present. We report characteristics that flag PEG as a potential trigger and highlight the need for extended observation after resolution of symptoms because of the risk of biphasic reactions. Reports of immediate hypersensitivity in 2 health care workers on the first day of mass COVID‐19 vaccination in the United Kingdom are concerning. 8 It remains unknown if PEG‐2000 is involved in these reactions. Leaders in allergy have already engaged with regulatory authorities to highlight PEG as a possible allergen in mRNA vaccines and to support the objective investigation of reported reactions. 9
PEG allergy is now well known among allergy professionals. However, increased awareness of this allergen among the wider medical community is needed. Early recognition through a thorough clinical history and rapid referral to allergy diagnostic centers is required to confirm the diagnosis and effectively manage this high‐risk drug allergy.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Funding
We did not receive funding for this study.
Data‐Sharing Statement
Please contact the corresponding author, Dr Fionnuala Cox, on coxff@tcd.ie, if you wish to request further information on study data.
Author Contributions
F.C. conceived the study and interpreted data. F.C., N.C., and K.K. diagnosed and managed patients. All authors contributed to the writing and approval of the article.
Acknowledgments
We thank the patients and Clinical Immunology Teams in St James's Hospital and Beaumont Hospital, Dublin. | Recovering | ReactionOutcome | CC BY-NC-ND | 33543766 | 19,443,824 | 2021-06 |
What was the outcome of reaction 'Reaction to excipient'? | PEG That Reaction: A Case Series of Allergy to Polyethylene Glycol.
Polyethylene glycol (PEG), also known as macrogol, is an excipient in numerous medications, health care products, cosmetics, and foods. It acts as an inert bulking, or stabilizing, agent. Despite its ubiquity, including in 2 of the newly launched vaccines against SARS-CoV-2, awareness of PEG allergy remains low. We present 6 cases of acute hypersensitivity to PEG. Accurate diagnoses in these cases posed a challenge, and although the triggering agents differed, PEG was demonstrated as the common culprit. All cases were female, with a mean age of 36.4 years. Four patients were originally suspected to have nonsteroid anti-inflammatory drug allergy, and 2 had a history of chronic spontaneous urticaria and angioedema. Biphasic allergic reactions featured prominently in this case series. Diagnosis relies on a high index of suspicion leading to a focused clinical history, supported by skin tests with PEG solutions to demonstrate sensitization. This case series highlights important clinical features of this rare, potentially serious, and increasingly recognized excipient allergy.
pmcPolyethylene glycol (PEG), also known as macrogol or E1521, is a commonly used bulking and stabilizing agent. It is an excipient in a wide variety of medications and also encountered in cosmetics and processed foods. Notably, both Pfizer BioNTech and Moderna mRNA vaccines against SARS‐CoV‐2, which are being internationally deployed to combat the current pandemic, contain polyethylene glycol. Allergy to PEG is rare but is increasingly recognized and can be severe. We present a case series to highlight features of this unusual excipient allergy. A high index of suspicion with early referral for expert diagnostic workup is required to implement appropriate risk management strategies.
The incident case experienced anaphylaxis after intramuscular Depo‐Provera administered by her general practitioner. She developed rapid‐onset sneezing, rhinorrhea, urticaria, profound hypotension, and chest tightness. She was managed with 2 doses of intramuscular adrenaline, steroids, and nebulized salbutamol. Symptoms improved; however, 6 hours following initial treatment she experienced further urticaria. The patient had recently tolerated similar progesterone in the oral contraceptive pill. Allergy to an excipient ingredient was suspected. The specific intramuscular formulation contained PEG‐3350 (Table 1). Skin‐prick testing (SPT) was positive and avoidance advised.
Table 1 Patient Case Summary With Triggering Agents and Associated PEG Compounds, Allergic Symptoms Experienced, Outcome of Skin Prick Testing, and Results of Supervised Provocation Challenges Detailed for Each Patient
Case Allergic Disease Trigger Symptoms Negative Provocation Challenge Positive Investigation
Case 1
Female, 35 years
None Depo‐Provera: medroxyprogesterone PEG‐3350 Sneezing, ocular irritation, rhinorrhea, urticaria, hypotension, chest tightness, respiratory compromise.
Biphasic urticaria.
None SPT PEG‐3350:
positive, 7 x 7 mm
Case 2
Female, 25 years
None Nexium: esomeprazole "Macrogols"
MoviPrep: osmotic laxative PEG‐3350
Cosmetics: PEG‐100
Urticaria, angioedema,
Respiratory compromise.
Pruritus, urticaria, angioedema, hypotension, swelling of hands and feet.
Biphasic urticaria.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free
"Teva”:
pantoprazole
PEG‐free
SPT PEG‐3350:
positive, 10 x 11 mm
Case 3
Female, 40 years
None Effervescent vitamin C: HMW‐PEG
Klean Prep: osmotic laxative PEG‐3350.
Vimovo: esomeprazole,
naproxen.
PEG‐8000.
EMLA topical anesthetic:
lidocaine, prilocaine.
HMW‐PEG.
Urticaria, syncope.
Urticaria, angioedema.
Urticaria, presyncopal.
Generalized pruritus.
Cerazette:
desogestrel
PEG‐400
“Teva”:
pantoprazole
PEG‐free
SPT PEG‐400, 3350:
Inconclusive because of dermographism.
Movicol challenge, PEG‐3350: positive
Case 4
Female, 44 years
None Klean Prep: osmotic laxative,
PEG‐3350.
Phosphate Sandoz: effervescent phosphate,
PEG‐4000.
Cosmetics: LMW‐ and HMW‐PEG.
Perioral paresthesia, angioedema, dyspnea, stridor, visual disturbance, syncope.
Angioedema, dyspnea, presyncope.
Urticaria
None SPT PEG‐3350:
positive
Case 5
Female, 36 years
CSUA Motilium Suppository: domperidone,
PEG‐400 and 1000.
Nurofen: ibuprofen,
PEG‐6000.
Angioedema, paresthesia,
throat tightness.
Angioedema, paresthesia,
throat tightness.
Motilium oral tablet:
PEG‐free
Nurofen syrup:
PEG‐free
SPT PEG‐3350:
positive
Case 6
Female, 38 years
CSUA
Physical urticaria
Betadine: wound dressing, povidone‐iodine,
PEG‐400, 6000.
Voltorol Oral: diclofenac
PEG‐8000.
Diclofenac IM:
HMW‐PEG.
Shaving foam: LMW‐ and HMW‐PEG.
Cosmetics: LMW‐ and HMW‐PEG.
Urticaria, presyncopal.
Urticaria.
Urticaria.
Urticaria, angioedema,
respiratory distress, hypotension.
Contact urticaria.
Celebrex:
Celecoxib
PEG‐free.
Ibuprofen tablet:
PEG‐free
SPT PEG‐3350:
10 × 10 mm
John Wiley & Sons, Ltd.
The second patient experienced acute urticaria and angioedema following concomitant ibuprofen and esomeprazole ingestion. Nonsteroidal anti‐inflammatory drug (NSAID) sensitivity was initially suspected (Table 1). While awaiting further investigation, she developed urticaria, angioedema, and hypotension following minimal ingestion of the PEG‐containing osmotic laxative Movi‐Prep. Symptoms settled with steroids and antihistamine; however, she experienced further urticaria 6 hours later. In addition, the patient described contact urticaria with certain cosmetics. PEG was suspected as a common trigger, and SPT was supportive (Table 1).
Case 3 had urticaria and syncope within minutes of effervescent vitamin C and separately developed urticaria, angioedema, and throat tightness with difficulty swallowing after the osmotic laxative Klean‐Prep. She gave a history of urticaria associated with Vimovo (esomeprazole and naproxen) and similar symptoms during a dental procedure (Table 1). All identified agents contained high‐molecular‐weight (HMW)‐PEG (Table 1). Unfortunately, SPT was inconclusive because of dermographism (negative control inciting a wheal). A provocation challenge to HMW‐PEG (Movicol) was objectively positive. The patient has remained completely symptom‐free with a PEG avoidance strategy. She has tolerated challenges with PEG‐free medications.
Anaphylaxis to Klean‐Prep was also a presenting feature of the fourth case. A PEG‐3350 allergy was suspected and avoidance advised until formal review at an allergy clinic. In the following months, while awaiting assessment and as a hospital inpatient for an unrelated condition, she had a second anaphylaxis within minutes of taking a PEG‐containing effervescent phosphate replacement preparation. SPT was subsequently positive to PEG‐3350, which has been avoided since.
The fifth patient was referred for assessment of multiple allergic drug reactions, on a background of chronic spontaneous urticaria and angioedema (CSUA). The first episode occurred within minutes of a Motilium suppository and was managed with intramuscular adrenaline, hydrocortisone, chlorphenamine, and fluid resuscitation. The second episode was precipitated by oral ibuprofen, again requiring adrenaline. PEG was considered a likely trigger, SPT was supportive. The patient subsequently tolerated PEG‐free domperidone and ibuprofen (Table 1).
The final case similarly had multiple adverse drug reactions, including anaphylaxis, on a background of CSUA. The initial allergic episode occurred following a Betadine dressing to a wound. She had systemic symptoms with oral and intramuscular diclofenac, oral Solpadeine (paracetamol and codeine), and contact urticaria with various cosmetics (Table 1). The patient subsequently tolerated PEG‐free forms of NSAIDs and codeine. PEG was suspected as a common inciting agent, SPT was supportive and strict avoidance recommended. After diagnosis, the patient experienced anaphylaxis while shaving with a product containing PEG requiring self‐administration of an adrenaline autoinjector.
This case series illustrates the diverse presentations of PEG allergy. Patients experienced an average of 3 allergic episodes before a formal diagnosis consistent with other case series. 1 Reactions were distressing for patients and objectively severe. Media reports of a case of fatal anaphylaxis in a patient with an established diagnosis of PEG allergy highlight the significance of this emerging problem. 2 The true incidence of PEG allergy is difficult to determine and may be underestimated. 3
It is hypothesized that initial PEG‐sensitization could be via cutaneous exposure from cosmetics and hygiene products or absorption of low‐molecular‐weight (LMW)‐PEG in pharmaceuticals. 3 The role of LMW‐PEG exposure prior to hypersensitivity has not been explored and may merit investigation. A female predominance was noted in our case series, but has not been universally observed. 1 , 4 Overall, the literature reports equal incidence between sexes. Interestingly, more recent case reports demonstrate a younger median age of diagnosis compared with older publications. 1 , 5 This is likely multifactorial and may be influenced by improved awareness of drug, and specifically PEG allergy, improved access to specialist allergy services, and potentially earlier or greater opportunity for sensitization. This is something that can only be speculated on because of limited clinical data.
Four of the 6 cases were suspected to have an NSAID allergy that was subsequently ruled out with negative provocation tests (Table 1). This emphasizes the prevalence of understandable misdiagnosis and unnecessary drug restrictions in this cohort. A review published in 2016 identified 37 cases labeled as “PEG‐allergy,” totaling 74 reactions. 4 More than half were associated with laxatives, also prominent allergens in this series. PEG‐3350 has been listed in more than 1000 approved medications. 3 Despite this ubiquity, reported incidence of hypersensitivity appears low. However we demonstrate that reactions can be severe and are diagnostically challenging.
NSAIDs are one of the most common inducers of drug‐related hypersensitivity reactions. 6 PEG sensitivity does not need to be considered in all NSAID‐related reactions. However, there are features that can be divined from an allergy history that offer pointers toward the need for PEG sensitization assessment. Patients with multiple episodes of “unexplained” anaphylaxis or tolerance of individual brands of the same drug merit closer investigation. Reactions to laxatives or bowel preparations, “depo” medications, and mucosal absorption from lubricants, gels, and dressings are red flags that should have PEG hypersensitivity in the differential. Bruusgaard‐Mouritsen et al (2021) similarly highlighted analgesics, depo injections, and laxatives as common triggers in their cohort, as well noting antacids and antibiotics as culprits. 1
We recommend that an adrenaline autoinjector be prescribed to those with PEG allergy because of an ongoing risk of accidental exposure. Unfortunately, comprehensive avoidance list cannot be provided, as medical preparations frequently change; thus, awareness is key. We advise patient empowerment with education, supported by step‐by‐step instructions on how to interrogate summary of product characteristics (SPC) for the variety of terms that indicate a PEG excipient. Patients are advised to engage with pharmacists and inform all health care professionals encountered of the disorder. In addition they should wear alert jewelry and only take a medication when they and their health care professional are satisfied that it does not contain PEG. Effective use of an electronic patient record can assist with communicating this issue, but as with all drug allergy, effective communication among disparate health care providers is a challenge. In addition, the cases presented here suggest a higher rate of biphasic allergic reactions than might be expected. 7 Based on these observations, we recommend extended monitoring for 12 hours after resolution of symptoms following a PEG‐related reaction. Although biphasic symptoms are usually mild, they can be distressing, especially to patients who have had a history of unexplained adverse events.
The identification of PEG allergy is increasing. These cases offer insight into the variety of ways this allergy can present. We report characteristics that flag PEG as a potential trigger and highlight the need for extended observation after resolution of symptoms because of the risk of biphasic reactions. Reports of immediate hypersensitivity in 2 health care workers on the first day of mass COVID‐19 vaccination in the United Kingdom are concerning. 8 It remains unknown if PEG‐2000 is involved in these reactions. Leaders in allergy have already engaged with regulatory authorities to highlight PEG as a possible allergen in mRNA vaccines and to support the objective investigation of reported reactions. 9
PEG allergy is now well known among allergy professionals. However, increased awareness of this allergen among the wider medical community is needed. Early recognition through a thorough clinical history and rapid referral to allergy diagnostic centers is required to confirm the diagnosis and effectively manage this high‐risk drug allergy.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Funding
We did not receive funding for this study.
Data‐Sharing Statement
Please contact the corresponding author, Dr Fionnuala Cox, on coxff@tcd.ie, if you wish to request further information on study data.
Author Contributions
F.C. conceived the study and interpreted data. F.C., N.C., and K.K. diagnosed and managed patients. All authors contributed to the writing and approval of the article.
Acknowledgments
We thank the patients and Clinical Immunology Teams in St James's Hospital and Beaumont Hospital, Dublin. | Recovering | ReactionOutcome | CC BY-NC-ND | 33543766 | 19,443,824 | 2021-06 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Deep vein thrombosis'. | Hypercalcemia during pregnancy: management and outcomes for mother and child.
Diagnosing and treating hypercalcemia during pregnancy can be challenging due to both the physiological changes in calcium homeostasis and the underlying cause for the hypercalcemia. During pregnancy and lactation there is increased mobilization of calcium in the mother to meet the fetus' calcium requirements. Here we discuss the diagnostic challenges, management, and patient perspective of hypercalcemia during pregnancy in two particular cases and in other rare conditions causing hypercalcemia.
Introduction
Hypercalcemia in pregnancy is rare and in >90% of cases caused by a newly diagnosed primary hyperparathyroidism (PHPT). Hypercalcemia during pregnancy due to other disorders of calcium metabolism is even more rare and literature regarding the maternal management and fetal outcomes is lacking. Diagnosing hypercalcemia is challenging during pregnancy, as symptoms such as fatigue or nausea mimic those in early pregnancy. However, longstanding hypercalcemia might induce nephrolithiasis, pancreatitis, and preeclampsia in the mother [1]. Therefore, the occurrence of these diseases during pregnancy should push the physicians to screen for hypercalcemia. In the fetus, maternal hypercalcemia can result in fetal growth restriction [2]. Following birth, further complications may arise such as severe neonatal hypocalcemia, tetany, and even death due to fetal hypoparathyroidism [3, 4]. In rare calcium-related disorders, the diagnosis is often known before the pregnancy and patients and partners can be counseled by the treating endocrinologist, obstetrician, pediatrician, and geneticist when required, taking into account the possible physical and mental maternal adverse effects, but also the eventual consequences for the newborn. Here we would like to discuss the diagnostic challenges and management of hypercalcemia during pregnancy in two particular cases as example of rare conditions causing hypercalcemia complicating pregnancy.
Case 1
A 34-year-old woman was referred with severe hypercalcemia and a pregnancy wish. At the age of 24 she was diagnosed with PHPT, without underlying genetic causes. During parathyroidectomy (PTX) there was spill of the adenoma, histologically confirmed, which led to chronic hypercalcemia for which she underwent several re-operations in various hospitals including a thyroidectomy in 2 tempi with resection of surrounding fat-tissue and a bilateral modified lymph node resection. However, she remained dependent on cinacalcet and bisphosphonates in various dosages. At referral, albumin-corrected serum calcium was 2.89 mmol/L (ref 2.15–2.55 mmol/L) with PTH 10.7 (ref 1–8 pmol/L) while on cinacalcet 60 mg/day, and 3.16 mmol/L with PTH of 29 without cinacalcet. She and her partner were counselled by a team consisting of gynecologists, pediatricians, and endocrinologists on several aspects of the disease and potential consequences for a pregnancy. Prophylactic surgery was not possible at that time. Bisphosphonates were stopped and she became pregnant after 12 months. Cinacalcet was stopped and a fluid intake of 4 L was advised. However, she was admitted with a symptomatic hypercalcemia, 3.4 mmol/L, within 2 weeks. Hyperhydration and cinacalcet, up to 90 mg/day, were started in combination with furosemide 40 mg and acetylsalicylic acid 80 mg daily as preeclampsia prophylaxis. She suffered from severe hyperemesis gravidarum and due to persistent hypercalcemia, she received saline infusions of 5 L/day in a homecare setting with a peripheral intravasal central catheter (PICC). During follow up the PICC caused deep vein thrombosis for which nadroparin injections were started but with this treatment serum calcium remained stable around 2.7–2.9 mmol/L. At 38 weeks of gestation she developed hypertension with a rapidly developing HELLP syndrome and an emergency cesarean section was performed. A healthy baby boy, weight 3305 g, was delivered; he only received active vitamin D supplementation for a few days and two years after delivery; no calcium disturbances or skeletal abnormalities have been observed. The mother did not breastfeed. After delivery, the mother experienced a post-traumatic stress syndrome (PTSS) with depression for which she started Eye Movement Desensitization and Reprocessing (EMDR). The depression and PTSS was related to the latter part of the pregnancy and delivery, but most likely exacerbated due to a postpartum rise in calcium to 3.3 mmol/L. Surgery was successfully performed after which her mental complaints improved.
Case 2
A 38-year-old female was diagnosed with PHPT at a non-university hospital, based on a modest hypercalcemia, and elevated PTH of 9.2 pmol/L and high to normal urinary calcium excretion of 8.5 g/L and calcium-to-creatinine clearance above 0.02. Despite her young age, it was decided not to perform PTX because of an increased risk for venous thromboembolism and obesity. Five years later, she had an unexpected pregnancy and was referred for PTX in the second trimester. During that time serum calcium had increased from 2.63 mmol/L to 2.83 mmol/L with a non-suppressed PTH of 3.8 pmol/L. The patient and her partner were counseled by a team consisting of endocrinologists, anesthesiologists, endocrine surgeons, pediatricians, and obstetricians. Imaging studies did not reveal a clear-cut adenoma and considering the progressive rise in calcium to 2.93 mmol/L, urinary calcium excretion of 12 g/L in 24 h and proceeding into the end of the second trimester an elective neck exploration was performed at gestational age of 24 + 2 weeks, showing four gland hyperplasia. During surgery, it was decided to remove only the two right-sided glands in order not to risk hypoparathyroidism. After surgery hypercalcemia persisted with calcium levels between 2.60 mmol/L and 2.65 mmol/L and PTH between 2.1 pmol/L and 3.6 pmol/L. Considering the marked hyperplasia the patient was discussed in the clinical patient management system (CPMS) panel of main thematic group two, calcium and phosphate disorders of the European Reference Network for rare endocrine diseases (ENDO-ERN). The advice of this panel was to perform genetic testing for familial hypocalciuric calciuria (FHH), which came back positive for a mutation in the CASR-gen, c.653A>G p.(Tyr218Cys), establishing a diagnosis of FHH type one. At 39 + 3 weeks she delivered a healthy baby girl of 4150 g without any calcium disturbances. Post-partum the calcium levels of the mother remained at 2.6 mmol and PTH rose again to 10.3 pmol/L, which has been stable since.
Patient perspective
Patient one had an active pregnancy wish for 5 years, with a negative counselling in several centers. At the Leiden University Medical Center (LUMC) it was again made clear that this would not be without risks for mother and child but if desired we would do our best to monitor the pregnancy as good as possible, which was much appreciated as this was not discussed before. Although she was well prepared and extensively counseled, the intensity of the pregnancy was overwhelming. Both the high calcium levels, frequent investigations and the continuous hyperhydration were extremely demanding and resulted, together with the further rise in calcium, in a pre- and post-natal depression for which EMDR and psychotherapy were needed. Looking back, she would advise other patients to realize that it will be extremely tough, but absolutely worth it. The fact that caretakers were so involved in her well-being and their clear communication was helpful and appreciated. The health care system structure with various doctors during hospital admission remains unfortunate from her point of view, which was in contrast to the outpatient clinic care with one regular healthcare provider.
Despite living with, a supposed, PHPT for many years, patient 2 had never been counseled about PHPT in terms of treatment and follow up. In the initial phase of her referral to LUMC this was done rapidly as time was ticking for a safe window of surgery as the second trimester is the preferred trimester for surgery for maternal and fetal reasons. In addition, due to her increased risk for venous thromboembolism and obesity, emergency surgery in case of severe hypercalcemia was considered to be a high risk for the mother. The patient found the amount of information overwhelming. However, it was appreciated as it made the patient and her partner feel part of the team. After surgery, when she had postoperative pains, this induced more stress being pregnant. Caregivers should be aware that in pregnant patients’ complaints that might be considered as normal after surgery can induce a stressful trigger in patients who are already in a stressful situation. The doubts about the original diagnosis of PHPT were shared including the desire of the treating physicians to discuss her case with other experts. Although providing more insecurity, the patient did feel comfortable that this meant that no other surgery was likely to be needed. After the pregnancy she reported that the physical part of the pregnancy did not give her many discomforts but the uncertainty about the well-being of the baby was very stressful. But overall, she was very satisfied with the care given.
In collaboration with these patients we produced a checklist for women in the same position or with a recent diagnosis of PHPT, which might be of help, see Table 1.Table 1 Questions for women in the childbearing age to ask their doctor when diagnosed with a high calcium level
1. What is the most likely diagnosis causing this high calcium level?
2. What tests do I need to make the diagnosis more likely? And are these tests influenced by pregnancy?
3. How will this affect pregnancy?
What will be the risks for my unborn child?
What will be the risks for me?
Which interventions are possible/necessary before, during and after pregnancy?
4. What can I do to minimalize complaints during and after the pregnancy?
5. How can we decrease my risk for preeclampsia?
6. Which drugs might be used during the pregnancy and what are their side effects?
7. How can you monitor my child?
8. How will my disease affect me after delivery?
9. How will this affect my child directly after delivery?
10. Can I breastfeed?
11. Who is in my multidisciplinary team and how can I reach them?
12. What can be done by my general practitioner?
13. What would be the risk of getting pregnant and to whom can I speak to for counseling?
In both cases patients and partners experienced the pregnancy as a rollercoaster with lot of uncertainties. Whereas both patients were diagnosed with hypercalcemia before pregnancy, patient 1 was counseled extensively in the pre-pregnancy period and even repeatedly got the advice not to become pregnant while patient 2 was never counseled. Also, in patient 2 the diagnosis was changed from PHPT to FHH, the finding of the marked hyperplasia triggered doubts about the original diagnosis of PHPT. In patient 1, the initial decision for surgery would still be made as her calcium values were rising and she did develop nausea and in FHH hyperplasia is also often described.
Physiological changes during pregnancy (Fig. 1a)
During pregnancy and lactation there is increased mobilization of calcium in the mother to meet the fetus’ calcium requirements [5, 6]. This is done by increasing intestinal calcium absorption through increasing 1.25 vitamin D production and PTH-related peptide (PTHrP), which is released from placenta and breasts in response to estradiol, placental lactogen, and prolactin [6, 7]. Despite the overlapping modes of action, PTH and PTHrP are produced by different genes on different chromosomes and the gene encoding PTHrP is more complex than for PTH. PTHrP is undetectable in the circulating blood of non-pregnant women, but is produced in a paracrine/autocrine fashion during pregnancy. Lessons from PTHrP or PTH1R gene knockout mice, which die at birth or in utero, emphasize the critical role of PTHrP for normal life [8, 9]. In addition, nascent PTHrP isoforms are processed by members of the prohormone convertase family to at least three fragments: N-terminal PTHrP [1–36], structurally related to PTH; a mid-region PTHrP (38–94); and a C-terminal PTHrP(107–139) with distinct biological properties and receptors. PTHrP is able to act not only via the classical autocrine/paracrine pathways, but also through a so-called intracrine pathway, which involves the translocation of the protein into the nucleus, where it can directly regulate proliferation and apoptosis [10, 11]. PTHrP has multiple activities including control of fetal development, trans-epithelial calcium transfer, lactation, smooth muscle relaxation, and cell growth. The mid-molecular region of PTHrP stimulates placental calcium transport in the fetus, while the COOH terminal region may also affect osteoclast activity. Thus, although PTHrP was discovered as a tumor-derived hypercalcemic factor, its primary physiological role is as a local regulator of many physiological processes especially in early life [12, 13].Fig. 1 a *Intravascular fluid expansion causes gestational hypoalbuminemia. The dilutional hypoalbuminemia of pregnancy leads to a decline in total calcium concentration. Ionized calcium on the other hand, remains stable and may provide more accurate information. ** The increase in 1.25 vitamin D production leads to an increase in intestinal calcium absorption. ***“Absorptive hypercalciuria of pregnancy”. Postprandial and 24-h urinary calcium excretion increase after 12 weeks, due to increased intestinal calcium absorption supposedly unrelated to increased formation of 1.25 vitamin D in early pregnancy. Fasting urine samples will not be affected by this phenomenon [45]. b *Prednison to reduce 1.25OH formation and thus intestinal calcium absorption. ** Reducing PTH-rp production mammae. *** No clinical data during pregnancy, only case reports. In animal studies no abnormalities observed, but it does pass the placenta [31, 46]. Breastfeeding: in animal studies (rat), cinacalcet is found in milk [46].
Maternal causes and consequences of hypercalcemia (Fig. 1b)
Hypercalcemia due to hyperparathyroidism is the most described cause of hypercalcemia during pregnancy. As most reviews focus on maternal and fetal outcomes in PHPT we will not cover this topic in the current paper [14, 15]. Hyperparathyroidism due to diffusely spread hyperthyroid nodules, parathyromatosis, post-parathyroidectomy, in the context of malignancy, MEN syndromes, or in chronic renal disease has been rarely described [15, 16]. Literature data on parathyromatosis is limited to around 20 cases published so far with only one report on a woman diagnosed and treated during pregnancy [17, 18].
FHH is a rare autosomal dominant disorder, with a prevalence of ~1:78.000 though this might likely be higher, as many cases remain asymptomatic lifelong and no causal treatment is available [19–21]. According to the genetic defect causing the pathology, three types of FHH have been defined [21–24]. FHH1 is the most common type and is found in about 65% of all FHH cases [21]. Patients with FHH present with mild to moderate hypercalcaemia, low urinary excretion, and PTH serum levels that are either normal or slightly elevated. Many patients with FHH are misdiagnosed as suffering from PHPT as in the case of our patient. Data on FHH manifested during pregnancy, literature data are sparse. Only four cases were published so far. Walker et al. reported the case of a pregnant patient, initially diagnosed with PHPT, who showed no improvement after PTX. The newborn presented with asymptomatic hypercalcemia; the genetic analysis confirmed the diagnosis of FHH [25]. The newborn presented elevated serum calcium levels with no clinical symptoms, while the genetic analysis confirmed the diagnosis of FHH. Others reported hypercalcemic profiles for which they underwent surgery during pregnancy [26, 27].
PTHrP-induced hypercalcemia during pregnancy or lactation has also been reported, either with or without gigantomastia [28–33]. In the reported cases, associating gigantomastia and increased PTHrP serum values, hypercalcaemia was diagnosed during gestation and resolved only after mastectomy, bromocriptin administration, or termination of pregnancy [29, 31, 32].
After delivery, there is a risk of severe hypercalcemia in women with PHPT who are lactating as PTH-rp production will increase [6, 34]. Especially women with gestational hypercalcemia with gigantomastia should be advised against breastfeeding as this will keep PTHrp levels high. The rise in PTHrp during pregnancy was not seen in patient 1 in whom PTHrp production was fully suppressed during entire pregnancy. The observed rise in calcium levels in patient 2 might in retrospect be due to her different setpoint and PTHrp production. Mental consequences of hypercalcemia are well known and include depression and anxiety [35, 36]. During pregnancy mothers might have additional stress which might be exaggerated by the hypercalcemia.
Fetal consequences of hypercalcemia
In the fetus, maternal PHPT can result in fetal growth restriction, severe neonatal hypocalcemia, tetany, and death [36]. In maternal FHH potential fetal complications include mild hypercalcemia, severe hypocalcemia, or neonatal severe hyperparathyroidism, depending on the genotype of the fetus. Because FHH is an autosomal dominant condition, three genetic situations might be encountered by the newborns of FHH mothers: the unaffected and the heterozygous neonates might present with hypocalcaemia induced by the in utero suppression of the parathyroid, the latter being at risk of developing hypercalcemia with hypocalcaemia in the first year of life. The homozygous form of FHH results in a severe neonatal hyperparathyroidism, which requires the surgical removal of the glands during the neonatal phase [37, 38].
Most outcomes on the fetal consequences of hypercalcemia were described in reports on patients with PHPT. Untreated hypercalcemia was associated with fetal or neonatal complications in the majority of cases [3, 36, 39, 40]. However, these findings are based on early literature of PHPT patients when hypercalcemia was often diagnosed in an advanced stage and more recent literature has shown that, compared to age-matched controls, women with PHPT had no difference in most pregnancy outcomes, including stillbirths [39]. That same study also showed that Apgar scores and anthropometric measurements were similar to babies born in uncomplicated pregnancies. However, this recent study did not report on maternal outcomes of preeclampsia. Other recent studies also report lower complications rates and good treatment outcomes when the hypercalcemia is moderate and not severe [1, 41].
Elevated maternal serum calcium leads to hypercalcemia in the fetus, which causes fetal parathyroid gland suppression. After delivery, these glands are still suppressed causing fetal hypocalcemia, which is usually transient (lasting 3–5 months after birth), but permanent hypoparathyroidism has anecdotally been described [42].
In the case of parathyromatosis diagnosed during pregnancy, Edling et al. reported that the infant presented initially with high calcium and low PTH levels, which normalized rapidly, with no further complications [18]. Newborns of mothers presenting with humoral hypercalcemia of pregnancy were having normal calcium levels at birth [29, 30, 33].
Diagnosing hypercalcemia during pregnancy might be challenging due to both physiological changes in calcium homeostasis, as well as due to the underlying cause for the hypercalcemia; changes in urinary calcium excretion vary during daytime, introducing difficulty in using urinary calcium indices as a diagnostic tool. In non-pregnant population, the measurement of calcium/creatinine clearance ratio can be useful in distinguishing between PHPT(>0.02 mmol/mmol) and FHH(<0.01 mmol/mmol). However, it is known that almost 20% of FHH patients might present with a calcium/creatinine ratio >0.01, and individuals with PPHT and simultaneous vitamin D deficiency might show lower than expected calcium excretion [43]. Genetic testing, when available, should be considered for confirming the clinical suspicion of FHH. More than 130 CaSR mutations have been reported so far in relation to FHH1, fact that explains the phenotypical variations in relation to the observed differences in serum calcium and PTH levels [21, 44].
During pregnancy, the distinction between FHH and PHPT is further complicated by the physiological changes in maternal calcium metabolism: increased breast and placental production of PTHrP, that together with the placental lactogen, leads to an increase in 1,25-(OH)2- vitamin D and a reduction of the PTH levels. As a result, the intestinal calcium absorption and the urine calcium excretion are physiologically increased [5, 45]. Treatment is depending on the underlying cause and might be invasive or conservative, but all decisions need good counseling, as it concerns not only the mother, but also the fetus and partner as well. Also we, as physicians, need to be aware that the treatment does not stop with the deliverance of a healthy baby and that the postpartum period might actually be the period with the highest risk for the mother due to the risk of sudden rises in calcium level and to excessive mental stress caused by possible events during pregnancy or delivery.
But foremost, irrespective of the underlying cause of hypercalcemia, patients and partners need to be closely involved in the decision processes in order to ensure overall good outcomes for mother and child.
Acknowledgements
We would like to acknowledge the European Reference Network for Rare Endocrine diseases, specifically main thematic group two calcium and phosphate disorders. We would like to thank both C.W.M. Janssen and S. Mourits for their agreement on publication of their medical history and contribution to the content of the manuscript.
Authors contributions
Conceptualization, writing original draft preparation, reviewing and editing: N.M.A-D. Reviewing and editing, critically revising the manuscript: D-A.E, M.C.Z, L.R, and E.M.W.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CINACALCET HYDROCHLORIDE, UNSPECIFIED INGREDIENT | DrugsGivenReaction | CC BY | 33544354 | 20,513,294 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Depression'. | Hypercalcemia during pregnancy: management and outcomes for mother and child.
Diagnosing and treating hypercalcemia during pregnancy can be challenging due to both the physiological changes in calcium homeostasis and the underlying cause for the hypercalcemia. During pregnancy and lactation there is increased mobilization of calcium in the mother to meet the fetus' calcium requirements. Here we discuss the diagnostic challenges, management, and patient perspective of hypercalcemia during pregnancy in two particular cases and in other rare conditions causing hypercalcemia.
Introduction
Hypercalcemia in pregnancy is rare and in >90% of cases caused by a newly diagnosed primary hyperparathyroidism (PHPT). Hypercalcemia during pregnancy due to other disorders of calcium metabolism is even more rare and literature regarding the maternal management and fetal outcomes is lacking. Diagnosing hypercalcemia is challenging during pregnancy, as symptoms such as fatigue or nausea mimic those in early pregnancy. However, longstanding hypercalcemia might induce nephrolithiasis, pancreatitis, and preeclampsia in the mother [1]. Therefore, the occurrence of these diseases during pregnancy should push the physicians to screen for hypercalcemia. In the fetus, maternal hypercalcemia can result in fetal growth restriction [2]. Following birth, further complications may arise such as severe neonatal hypocalcemia, tetany, and even death due to fetal hypoparathyroidism [3, 4]. In rare calcium-related disorders, the diagnosis is often known before the pregnancy and patients and partners can be counseled by the treating endocrinologist, obstetrician, pediatrician, and geneticist when required, taking into account the possible physical and mental maternal adverse effects, but also the eventual consequences for the newborn. Here we would like to discuss the diagnostic challenges and management of hypercalcemia during pregnancy in two particular cases as example of rare conditions causing hypercalcemia complicating pregnancy.
Case 1
A 34-year-old woman was referred with severe hypercalcemia and a pregnancy wish. At the age of 24 she was diagnosed with PHPT, without underlying genetic causes. During parathyroidectomy (PTX) there was spill of the adenoma, histologically confirmed, which led to chronic hypercalcemia for which she underwent several re-operations in various hospitals including a thyroidectomy in 2 tempi with resection of surrounding fat-tissue and a bilateral modified lymph node resection. However, she remained dependent on cinacalcet and bisphosphonates in various dosages. At referral, albumin-corrected serum calcium was 2.89 mmol/L (ref 2.15–2.55 mmol/L) with PTH 10.7 (ref 1–8 pmol/L) while on cinacalcet 60 mg/day, and 3.16 mmol/L with PTH of 29 without cinacalcet. She and her partner were counselled by a team consisting of gynecologists, pediatricians, and endocrinologists on several aspects of the disease and potential consequences for a pregnancy. Prophylactic surgery was not possible at that time. Bisphosphonates were stopped and she became pregnant after 12 months. Cinacalcet was stopped and a fluid intake of 4 L was advised. However, she was admitted with a symptomatic hypercalcemia, 3.4 mmol/L, within 2 weeks. Hyperhydration and cinacalcet, up to 90 mg/day, were started in combination with furosemide 40 mg and acetylsalicylic acid 80 mg daily as preeclampsia prophylaxis. She suffered from severe hyperemesis gravidarum and due to persistent hypercalcemia, she received saline infusions of 5 L/day in a homecare setting with a peripheral intravasal central catheter (PICC). During follow up the PICC caused deep vein thrombosis for which nadroparin injections were started but with this treatment serum calcium remained stable around 2.7–2.9 mmol/L. At 38 weeks of gestation she developed hypertension with a rapidly developing HELLP syndrome and an emergency cesarean section was performed. A healthy baby boy, weight 3305 g, was delivered; he only received active vitamin D supplementation for a few days and two years after delivery; no calcium disturbances or skeletal abnormalities have been observed. The mother did not breastfeed. After delivery, the mother experienced a post-traumatic stress syndrome (PTSS) with depression for which she started Eye Movement Desensitization and Reprocessing (EMDR). The depression and PTSS was related to the latter part of the pregnancy and delivery, but most likely exacerbated due to a postpartum rise in calcium to 3.3 mmol/L. Surgery was successfully performed after which her mental complaints improved.
Case 2
A 38-year-old female was diagnosed with PHPT at a non-university hospital, based on a modest hypercalcemia, and elevated PTH of 9.2 pmol/L and high to normal urinary calcium excretion of 8.5 g/L and calcium-to-creatinine clearance above 0.02. Despite her young age, it was decided not to perform PTX because of an increased risk for venous thromboembolism and obesity. Five years later, she had an unexpected pregnancy and was referred for PTX in the second trimester. During that time serum calcium had increased from 2.63 mmol/L to 2.83 mmol/L with a non-suppressed PTH of 3.8 pmol/L. The patient and her partner were counseled by a team consisting of endocrinologists, anesthesiologists, endocrine surgeons, pediatricians, and obstetricians. Imaging studies did not reveal a clear-cut adenoma and considering the progressive rise in calcium to 2.93 mmol/L, urinary calcium excretion of 12 g/L in 24 h and proceeding into the end of the second trimester an elective neck exploration was performed at gestational age of 24 + 2 weeks, showing four gland hyperplasia. During surgery, it was decided to remove only the two right-sided glands in order not to risk hypoparathyroidism. After surgery hypercalcemia persisted with calcium levels between 2.60 mmol/L and 2.65 mmol/L and PTH between 2.1 pmol/L and 3.6 pmol/L. Considering the marked hyperplasia the patient was discussed in the clinical patient management system (CPMS) panel of main thematic group two, calcium and phosphate disorders of the European Reference Network for rare endocrine diseases (ENDO-ERN). The advice of this panel was to perform genetic testing for familial hypocalciuric calciuria (FHH), which came back positive for a mutation in the CASR-gen, c.653A>G p.(Tyr218Cys), establishing a diagnosis of FHH type one. At 39 + 3 weeks she delivered a healthy baby girl of 4150 g without any calcium disturbances. Post-partum the calcium levels of the mother remained at 2.6 mmol and PTH rose again to 10.3 pmol/L, which has been stable since.
Patient perspective
Patient one had an active pregnancy wish for 5 years, with a negative counselling in several centers. At the Leiden University Medical Center (LUMC) it was again made clear that this would not be without risks for mother and child but if desired we would do our best to monitor the pregnancy as good as possible, which was much appreciated as this was not discussed before. Although she was well prepared and extensively counseled, the intensity of the pregnancy was overwhelming. Both the high calcium levels, frequent investigations and the continuous hyperhydration were extremely demanding and resulted, together with the further rise in calcium, in a pre- and post-natal depression for which EMDR and psychotherapy were needed. Looking back, she would advise other patients to realize that it will be extremely tough, but absolutely worth it. The fact that caretakers were so involved in her well-being and their clear communication was helpful and appreciated. The health care system structure with various doctors during hospital admission remains unfortunate from her point of view, which was in contrast to the outpatient clinic care with one regular healthcare provider.
Despite living with, a supposed, PHPT for many years, patient 2 had never been counseled about PHPT in terms of treatment and follow up. In the initial phase of her referral to LUMC this was done rapidly as time was ticking for a safe window of surgery as the second trimester is the preferred trimester for surgery for maternal and fetal reasons. In addition, due to her increased risk for venous thromboembolism and obesity, emergency surgery in case of severe hypercalcemia was considered to be a high risk for the mother. The patient found the amount of information overwhelming. However, it was appreciated as it made the patient and her partner feel part of the team. After surgery, when she had postoperative pains, this induced more stress being pregnant. Caregivers should be aware that in pregnant patients’ complaints that might be considered as normal after surgery can induce a stressful trigger in patients who are already in a stressful situation. The doubts about the original diagnosis of PHPT were shared including the desire of the treating physicians to discuss her case with other experts. Although providing more insecurity, the patient did feel comfortable that this meant that no other surgery was likely to be needed. After the pregnancy she reported that the physical part of the pregnancy did not give her many discomforts but the uncertainty about the well-being of the baby was very stressful. But overall, she was very satisfied with the care given.
In collaboration with these patients we produced a checklist for women in the same position or with a recent diagnosis of PHPT, which might be of help, see Table 1.Table 1 Questions for women in the childbearing age to ask their doctor when diagnosed with a high calcium level
1. What is the most likely diagnosis causing this high calcium level?
2. What tests do I need to make the diagnosis more likely? And are these tests influenced by pregnancy?
3. How will this affect pregnancy?
What will be the risks for my unborn child?
What will be the risks for me?
Which interventions are possible/necessary before, during and after pregnancy?
4. What can I do to minimalize complaints during and after the pregnancy?
5. How can we decrease my risk for preeclampsia?
6. Which drugs might be used during the pregnancy and what are their side effects?
7. How can you monitor my child?
8. How will my disease affect me after delivery?
9. How will this affect my child directly after delivery?
10. Can I breastfeed?
11. Who is in my multidisciplinary team and how can I reach them?
12. What can be done by my general practitioner?
13. What would be the risk of getting pregnant and to whom can I speak to for counseling?
In both cases patients and partners experienced the pregnancy as a rollercoaster with lot of uncertainties. Whereas both patients were diagnosed with hypercalcemia before pregnancy, patient 1 was counseled extensively in the pre-pregnancy period and even repeatedly got the advice not to become pregnant while patient 2 was never counseled. Also, in patient 2 the diagnosis was changed from PHPT to FHH, the finding of the marked hyperplasia triggered doubts about the original diagnosis of PHPT. In patient 1, the initial decision for surgery would still be made as her calcium values were rising and she did develop nausea and in FHH hyperplasia is also often described.
Physiological changes during pregnancy (Fig. 1a)
During pregnancy and lactation there is increased mobilization of calcium in the mother to meet the fetus’ calcium requirements [5, 6]. This is done by increasing intestinal calcium absorption through increasing 1.25 vitamin D production and PTH-related peptide (PTHrP), which is released from placenta and breasts in response to estradiol, placental lactogen, and prolactin [6, 7]. Despite the overlapping modes of action, PTH and PTHrP are produced by different genes on different chromosomes and the gene encoding PTHrP is more complex than for PTH. PTHrP is undetectable in the circulating blood of non-pregnant women, but is produced in a paracrine/autocrine fashion during pregnancy. Lessons from PTHrP or PTH1R gene knockout mice, which die at birth or in utero, emphasize the critical role of PTHrP for normal life [8, 9]. In addition, nascent PTHrP isoforms are processed by members of the prohormone convertase family to at least three fragments: N-terminal PTHrP [1–36], structurally related to PTH; a mid-region PTHrP (38–94); and a C-terminal PTHrP(107–139) with distinct biological properties and receptors. PTHrP is able to act not only via the classical autocrine/paracrine pathways, but also through a so-called intracrine pathway, which involves the translocation of the protein into the nucleus, where it can directly regulate proliferation and apoptosis [10, 11]. PTHrP has multiple activities including control of fetal development, trans-epithelial calcium transfer, lactation, smooth muscle relaxation, and cell growth. The mid-molecular region of PTHrP stimulates placental calcium transport in the fetus, while the COOH terminal region may also affect osteoclast activity. Thus, although PTHrP was discovered as a tumor-derived hypercalcemic factor, its primary physiological role is as a local regulator of many physiological processes especially in early life [12, 13].Fig. 1 a *Intravascular fluid expansion causes gestational hypoalbuminemia. The dilutional hypoalbuminemia of pregnancy leads to a decline in total calcium concentration. Ionized calcium on the other hand, remains stable and may provide more accurate information. ** The increase in 1.25 vitamin D production leads to an increase in intestinal calcium absorption. ***“Absorptive hypercalciuria of pregnancy”. Postprandial and 24-h urinary calcium excretion increase after 12 weeks, due to increased intestinal calcium absorption supposedly unrelated to increased formation of 1.25 vitamin D in early pregnancy. Fasting urine samples will not be affected by this phenomenon [45]. b *Prednison to reduce 1.25OH formation and thus intestinal calcium absorption. ** Reducing PTH-rp production mammae. *** No clinical data during pregnancy, only case reports. In animal studies no abnormalities observed, but it does pass the placenta [31, 46]. Breastfeeding: in animal studies (rat), cinacalcet is found in milk [46].
Maternal causes and consequences of hypercalcemia (Fig. 1b)
Hypercalcemia due to hyperparathyroidism is the most described cause of hypercalcemia during pregnancy. As most reviews focus on maternal and fetal outcomes in PHPT we will not cover this topic in the current paper [14, 15]. Hyperparathyroidism due to diffusely spread hyperthyroid nodules, parathyromatosis, post-parathyroidectomy, in the context of malignancy, MEN syndromes, or in chronic renal disease has been rarely described [15, 16]. Literature data on parathyromatosis is limited to around 20 cases published so far with only one report on a woman diagnosed and treated during pregnancy [17, 18].
FHH is a rare autosomal dominant disorder, with a prevalence of ~1:78.000 though this might likely be higher, as many cases remain asymptomatic lifelong and no causal treatment is available [19–21]. According to the genetic defect causing the pathology, three types of FHH have been defined [21–24]. FHH1 is the most common type and is found in about 65% of all FHH cases [21]. Patients with FHH present with mild to moderate hypercalcaemia, low urinary excretion, and PTH serum levels that are either normal or slightly elevated. Many patients with FHH are misdiagnosed as suffering from PHPT as in the case of our patient. Data on FHH manifested during pregnancy, literature data are sparse. Only four cases were published so far. Walker et al. reported the case of a pregnant patient, initially diagnosed with PHPT, who showed no improvement after PTX. The newborn presented with asymptomatic hypercalcemia; the genetic analysis confirmed the diagnosis of FHH [25]. The newborn presented elevated serum calcium levels with no clinical symptoms, while the genetic analysis confirmed the diagnosis of FHH. Others reported hypercalcemic profiles for which they underwent surgery during pregnancy [26, 27].
PTHrP-induced hypercalcemia during pregnancy or lactation has also been reported, either with or without gigantomastia [28–33]. In the reported cases, associating gigantomastia and increased PTHrP serum values, hypercalcaemia was diagnosed during gestation and resolved only after mastectomy, bromocriptin administration, or termination of pregnancy [29, 31, 32].
After delivery, there is a risk of severe hypercalcemia in women with PHPT who are lactating as PTH-rp production will increase [6, 34]. Especially women with gestational hypercalcemia with gigantomastia should be advised against breastfeeding as this will keep PTHrp levels high. The rise in PTHrp during pregnancy was not seen in patient 1 in whom PTHrp production was fully suppressed during entire pregnancy. The observed rise in calcium levels in patient 2 might in retrospect be due to her different setpoint and PTHrp production. Mental consequences of hypercalcemia are well known and include depression and anxiety [35, 36]. During pregnancy mothers might have additional stress which might be exaggerated by the hypercalcemia.
Fetal consequences of hypercalcemia
In the fetus, maternal PHPT can result in fetal growth restriction, severe neonatal hypocalcemia, tetany, and death [36]. In maternal FHH potential fetal complications include mild hypercalcemia, severe hypocalcemia, or neonatal severe hyperparathyroidism, depending on the genotype of the fetus. Because FHH is an autosomal dominant condition, three genetic situations might be encountered by the newborns of FHH mothers: the unaffected and the heterozygous neonates might present with hypocalcaemia induced by the in utero suppression of the parathyroid, the latter being at risk of developing hypercalcemia with hypocalcaemia in the first year of life. The homozygous form of FHH results in a severe neonatal hyperparathyroidism, which requires the surgical removal of the glands during the neonatal phase [37, 38].
Most outcomes on the fetal consequences of hypercalcemia were described in reports on patients with PHPT. Untreated hypercalcemia was associated with fetal or neonatal complications in the majority of cases [3, 36, 39, 40]. However, these findings are based on early literature of PHPT patients when hypercalcemia was often diagnosed in an advanced stage and more recent literature has shown that, compared to age-matched controls, women with PHPT had no difference in most pregnancy outcomes, including stillbirths [39]. That same study also showed that Apgar scores and anthropometric measurements were similar to babies born in uncomplicated pregnancies. However, this recent study did not report on maternal outcomes of preeclampsia. Other recent studies also report lower complications rates and good treatment outcomes when the hypercalcemia is moderate and not severe [1, 41].
Elevated maternal serum calcium leads to hypercalcemia in the fetus, which causes fetal parathyroid gland suppression. After delivery, these glands are still suppressed causing fetal hypocalcemia, which is usually transient (lasting 3–5 months after birth), but permanent hypoparathyroidism has anecdotally been described [42].
In the case of parathyromatosis diagnosed during pregnancy, Edling et al. reported that the infant presented initially with high calcium and low PTH levels, which normalized rapidly, with no further complications [18]. Newborns of mothers presenting with humoral hypercalcemia of pregnancy were having normal calcium levels at birth [29, 30, 33].
Diagnosing hypercalcemia during pregnancy might be challenging due to both physiological changes in calcium homeostasis, as well as due to the underlying cause for the hypercalcemia; changes in urinary calcium excretion vary during daytime, introducing difficulty in using urinary calcium indices as a diagnostic tool. In non-pregnant population, the measurement of calcium/creatinine clearance ratio can be useful in distinguishing between PHPT(>0.02 mmol/mmol) and FHH(<0.01 mmol/mmol). However, it is known that almost 20% of FHH patients might present with a calcium/creatinine ratio >0.01, and individuals with PPHT and simultaneous vitamin D deficiency might show lower than expected calcium excretion [43]. Genetic testing, when available, should be considered for confirming the clinical suspicion of FHH. More than 130 CaSR mutations have been reported so far in relation to FHH1, fact that explains the phenotypical variations in relation to the observed differences in serum calcium and PTH levels [21, 44].
During pregnancy, the distinction between FHH and PHPT is further complicated by the physiological changes in maternal calcium metabolism: increased breast and placental production of PTHrP, that together with the placental lactogen, leads to an increase in 1,25-(OH)2- vitamin D and a reduction of the PTH levels. As a result, the intestinal calcium absorption and the urine calcium excretion are physiologically increased [5, 45]. Treatment is depending on the underlying cause and might be invasive or conservative, but all decisions need good counseling, as it concerns not only the mother, but also the fetus and partner as well. Also we, as physicians, need to be aware that the treatment does not stop with the deliverance of a healthy baby and that the postpartum period might actually be the period with the highest risk for the mother due to the risk of sudden rises in calcium level and to excessive mental stress caused by possible events during pregnancy or delivery.
But foremost, irrespective of the underlying cause of hypercalcemia, patients and partners need to be closely involved in the decision processes in order to ensure overall good outcomes for mother and child.
Acknowledgements
We would like to acknowledge the European Reference Network for Rare Endocrine diseases, specifically main thematic group two calcium and phosphate disorders. We would like to thank both C.W.M. Janssen and S. Mourits for their agreement on publication of their medical history and contribution to the content of the manuscript.
Authors contributions
Conceptualization, writing original draft preparation, reviewing and editing: N.M.A-D. Reviewing and editing, critically revising the manuscript: D-A.E, M.C.Z, L.R, and E.M.W.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CINACALCET HYDROCHLORIDE, UNSPECIFIED INGREDIENT | DrugsGivenReaction | CC BY | 33544354 | 20,513,294 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug dose titration not performed'. | Hypercalcemia during pregnancy: management and outcomes for mother and child.
Diagnosing and treating hypercalcemia during pregnancy can be challenging due to both the physiological changes in calcium homeostasis and the underlying cause for the hypercalcemia. During pregnancy and lactation there is increased mobilization of calcium in the mother to meet the fetus' calcium requirements. Here we discuss the diagnostic challenges, management, and patient perspective of hypercalcemia during pregnancy in two particular cases and in other rare conditions causing hypercalcemia.
Introduction
Hypercalcemia in pregnancy is rare and in >90% of cases caused by a newly diagnosed primary hyperparathyroidism (PHPT). Hypercalcemia during pregnancy due to other disorders of calcium metabolism is even more rare and literature regarding the maternal management and fetal outcomes is lacking. Diagnosing hypercalcemia is challenging during pregnancy, as symptoms such as fatigue or nausea mimic those in early pregnancy. However, longstanding hypercalcemia might induce nephrolithiasis, pancreatitis, and preeclampsia in the mother [1]. Therefore, the occurrence of these diseases during pregnancy should push the physicians to screen for hypercalcemia. In the fetus, maternal hypercalcemia can result in fetal growth restriction [2]. Following birth, further complications may arise such as severe neonatal hypocalcemia, tetany, and even death due to fetal hypoparathyroidism [3, 4]. In rare calcium-related disorders, the diagnosis is often known before the pregnancy and patients and partners can be counseled by the treating endocrinologist, obstetrician, pediatrician, and geneticist when required, taking into account the possible physical and mental maternal adverse effects, but also the eventual consequences for the newborn. Here we would like to discuss the diagnostic challenges and management of hypercalcemia during pregnancy in two particular cases as example of rare conditions causing hypercalcemia complicating pregnancy.
Case 1
A 34-year-old woman was referred with severe hypercalcemia and a pregnancy wish. At the age of 24 she was diagnosed with PHPT, without underlying genetic causes. During parathyroidectomy (PTX) there was spill of the adenoma, histologically confirmed, which led to chronic hypercalcemia for which she underwent several re-operations in various hospitals including a thyroidectomy in 2 tempi with resection of surrounding fat-tissue and a bilateral modified lymph node resection. However, she remained dependent on cinacalcet and bisphosphonates in various dosages. At referral, albumin-corrected serum calcium was 2.89 mmol/L (ref 2.15–2.55 mmol/L) with PTH 10.7 (ref 1–8 pmol/L) while on cinacalcet 60 mg/day, and 3.16 mmol/L with PTH of 29 without cinacalcet. She and her partner were counselled by a team consisting of gynecologists, pediatricians, and endocrinologists on several aspects of the disease and potential consequences for a pregnancy. Prophylactic surgery was not possible at that time. Bisphosphonates were stopped and she became pregnant after 12 months. Cinacalcet was stopped and a fluid intake of 4 L was advised. However, she was admitted with a symptomatic hypercalcemia, 3.4 mmol/L, within 2 weeks. Hyperhydration and cinacalcet, up to 90 mg/day, were started in combination with furosemide 40 mg and acetylsalicylic acid 80 mg daily as preeclampsia prophylaxis. She suffered from severe hyperemesis gravidarum and due to persistent hypercalcemia, she received saline infusions of 5 L/day in a homecare setting with a peripheral intravasal central catheter (PICC). During follow up the PICC caused deep vein thrombosis for which nadroparin injections were started but with this treatment serum calcium remained stable around 2.7–2.9 mmol/L. At 38 weeks of gestation she developed hypertension with a rapidly developing HELLP syndrome and an emergency cesarean section was performed. A healthy baby boy, weight 3305 g, was delivered; he only received active vitamin D supplementation for a few days and two years after delivery; no calcium disturbances or skeletal abnormalities have been observed. The mother did not breastfeed. After delivery, the mother experienced a post-traumatic stress syndrome (PTSS) with depression for which she started Eye Movement Desensitization and Reprocessing (EMDR). The depression and PTSS was related to the latter part of the pregnancy and delivery, but most likely exacerbated due to a postpartum rise in calcium to 3.3 mmol/L. Surgery was successfully performed after which her mental complaints improved.
Case 2
A 38-year-old female was diagnosed with PHPT at a non-university hospital, based on a modest hypercalcemia, and elevated PTH of 9.2 pmol/L and high to normal urinary calcium excretion of 8.5 g/L and calcium-to-creatinine clearance above 0.02. Despite her young age, it was decided not to perform PTX because of an increased risk for venous thromboembolism and obesity. Five years later, she had an unexpected pregnancy and was referred for PTX in the second trimester. During that time serum calcium had increased from 2.63 mmol/L to 2.83 mmol/L with a non-suppressed PTH of 3.8 pmol/L. The patient and her partner were counseled by a team consisting of endocrinologists, anesthesiologists, endocrine surgeons, pediatricians, and obstetricians. Imaging studies did not reveal a clear-cut adenoma and considering the progressive rise in calcium to 2.93 mmol/L, urinary calcium excretion of 12 g/L in 24 h and proceeding into the end of the second trimester an elective neck exploration was performed at gestational age of 24 + 2 weeks, showing four gland hyperplasia. During surgery, it was decided to remove only the two right-sided glands in order not to risk hypoparathyroidism. After surgery hypercalcemia persisted with calcium levels between 2.60 mmol/L and 2.65 mmol/L and PTH between 2.1 pmol/L and 3.6 pmol/L. Considering the marked hyperplasia the patient was discussed in the clinical patient management system (CPMS) panel of main thematic group two, calcium and phosphate disorders of the European Reference Network for rare endocrine diseases (ENDO-ERN). The advice of this panel was to perform genetic testing for familial hypocalciuric calciuria (FHH), which came back positive for a mutation in the CASR-gen, c.653A>G p.(Tyr218Cys), establishing a diagnosis of FHH type one. At 39 + 3 weeks she delivered a healthy baby girl of 4150 g without any calcium disturbances. Post-partum the calcium levels of the mother remained at 2.6 mmol and PTH rose again to 10.3 pmol/L, which has been stable since.
Patient perspective
Patient one had an active pregnancy wish for 5 years, with a negative counselling in several centers. At the Leiden University Medical Center (LUMC) it was again made clear that this would not be without risks for mother and child but if desired we would do our best to monitor the pregnancy as good as possible, which was much appreciated as this was not discussed before. Although she was well prepared and extensively counseled, the intensity of the pregnancy was overwhelming. Both the high calcium levels, frequent investigations and the continuous hyperhydration were extremely demanding and resulted, together with the further rise in calcium, in a pre- and post-natal depression for which EMDR and psychotherapy were needed. Looking back, she would advise other patients to realize that it will be extremely tough, but absolutely worth it. The fact that caretakers were so involved in her well-being and their clear communication was helpful and appreciated. The health care system structure with various doctors during hospital admission remains unfortunate from her point of view, which was in contrast to the outpatient clinic care with one regular healthcare provider.
Despite living with, a supposed, PHPT for many years, patient 2 had never been counseled about PHPT in terms of treatment and follow up. In the initial phase of her referral to LUMC this was done rapidly as time was ticking for a safe window of surgery as the second trimester is the preferred trimester for surgery for maternal and fetal reasons. In addition, due to her increased risk for venous thromboembolism and obesity, emergency surgery in case of severe hypercalcemia was considered to be a high risk for the mother. The patient found the amount of information overwhelming. However, it was appreciated as it made the patient and her partner feel part of the team. After surgery, when she had postoperative pains, this induced more stress being pregnant. Caregivers should be aware that in pregnant patients’ complaints that might be considered as normal after surgery can induce a stressful trigger in patients who are already in a stressful situation. The doubts about the original diagnosis of PHPT were shared including the desire of the treating physicians to discuss her case with other experts. Although providing more insecurity, the patient did feel comfortable that this meant that no other surgery was likely to be needed. After the pregnancy she reported that the physical part of the pregnancy did not give her many discomforts but the uncertainty about the well-being of the baby was very stressful. But overall, she was very satisfied with the care given.
In collaboration with these patients we produced a checklist for women in the same position or with a recent diagnosis of PHPT, which might be of help, see Table 1.Table 1 Questions for women in the childbearing age to ask their doctor when diagnosed with a high calcium level
1. What is the most likely diagnosis causing this high calcium level?
2. What tests do I need to make the diagnosis more likely? And are these tests influenced by pregnancy?
3. How will this affect pregnancy?
What will be the risks for my unborn child?
What will be the risks for me?
Which interventions are possible/necessary before, during and after pregnancy?
4. What can I do to minimalize complaints during and after the pregnancy?
5. How can we decrease my risk for preeclampsia?
6. Which drugs might be used during the pregnancy and what are their side effects?
7. How can you monitor my child?
8. How will my disease affect me after delivery?
9. How will this affect my child directly after delivery?
10. Can I breastfeed?
11. Who is in my multidisciplinary team and how can I reach them?
12. What can be done by my general practitioner?
13. What would be the risk of getting pregnant and to whom can I speak to for counseling?
In both cases patients and partners experienced the pregnancy as a rollercoaster with lot of uncertainties. Whereas both patients were diagnosed with hypercalcemia before pregnancy, patient 1 was counseled extensively in the pre-pregnancy period and even repeatedly got the advice not to become pregnant while patient 2 was never counseled. Also, in patient 2 the diagnosis was changed from PHPT to FHH, the finding of the marked hyperplasia triggered doubts about the original diagnosis of PHPT. In patient 1, the initial decision for surgery would still be made as her calcium values were rising and she did develop nausea and in FHH hyperplasia is also often described.
Physiological changes during pregnancy (Fig. 1a)
During pregnancy and lactation there is increased mobilization of calcium in the mother to meet the fetus’ calcium requirements [5, 6]. This is done by increasing intestinal calcium absorption through increasing 1.25 vitamin D production and PTH-related peptide (PTHrP), which is released from placenta and breasts in response to estradiol, placental lactogen, and prolactin [6, 7]. Despite the overlapping modes of action, PTH and PTHrP are produced by different genes on different chromosomes and the gene encoding PTHrP is more complex than for PTH. PTHrP is undetectable in the circulating blood of non-pregnant women, but is produced in a paracrine/autocrine fashion during pregnancy. Lessons from PTHrP or PTH1R gene knockout mice, which die at birth or in utero, emphasize the critical role of PTHrP for normal life [8, 9]. In addition, nascent PTHrP isoforms are processed by members of the prohormone convertase family to at least three fragments: N-terminal PTHrP [1–36], structurally related to PTH; a mid-region PTHrP (38–94); and a C-terminal PTHrP(107–139) with distinct biological properties and receptors. PTHrP is able to act not only via the classical autocrine/paracrine pathways, but also through a so-called intracrine pathway, which involves the translocation of the protein into the nucleus, where it can directly regulate proliferation and apoptosis [10, 11]. PTHrP has multiple activities including control of fetal development, trans-epithelial calcium transfer, lactation, smooth muscle relaxation, and cell growth. The mid-molecular region of PTHrP stimulates placental calcium transport in the fetus, while the COOH terminal region may also affect osteoclast activity. Thus, although PTHrP was discovered as a tumor-derived hypercalcemic factor, its primary physiological role is as a local regulator of many physiological processes especially in early life [12, 13].Fig. 1 a *Intravascular fluid expansion causes gestational hypoalbuminemia. The dilutional hypoalbuminemia of pregnancy leads to a decline in total calcium concentration. Ionized calcium on the other hand, remains stable and may provide more accurate information. ** The increase in 1.25 vitamin D production leads to an increase in intestinal calcium absorption. ***“Absorptive hypercalciuria of pregnancy”. Postprandial and 24-h urinary calcium excretion increase after 12 weeks, due to increased intestinal calcium absorption supposedly unrelated to increased formation of 1.25 vitamin D in early pregnancy. Fasting urine samples will not be affected by this phenomenon [45]. b *Prednison to reduce 1.25OH formation and thus intestinal calcium absorption. ** Reducing PTH-rp production mammae. *** No clinical data during pregnancy, only case reports. In animal studies no abnormalities observed, but it does pass the placenta [31, 46]. Breastfeeding: in animal studies (rat), cinacalcet is found in milk [46].
Maternal causes and consequences of hypercalcemia (Fig. 1b)
Hypercalcemia due to hyperparathyroidism is the most described cause of hypercalcemia during pregnancy. As most reviews focus on maternal and fetal outcomes in PHPT we will not cover this topic in the current paper [14, 15]. Hyperparathyroidism due to diffusely spread hyperthyroid nodules, parathyromatosis, post-parathyroidectomy, in the context of malignancy, MEN syndromes, or in chronic renal disease has been rarely described [15, 16]. Literature data on parathyromatosis is limited to around 20 cases published so far with only one report on a woman diagnosed and treated during pregnancy [17, 18].
FHH is a rare autosomal dominant disorder, with a prevalence of ~1:78.000 though this might likely be higher, as many cases remain asymptomatic lifelong and no causal treatment is available [19–21]. According to the genetic defect causing the pathology, three types of FHH have been defined [21–24]. FHH1 is the most common type and is found in about 65% of all FHH cases [21]. Patients with FHH present with mild to moderate hypercalcaemia, low urinary excretion, and PTH serum levels that are either normal or slightly elevated. Many patients with FHH are misdiagnosed as suffering from PHPT as in the case of our patient. Data on FHH manifested during pregnancy, literature data are sparse. Only four cases were published so far. Walker et al. reported the case of a pregnant patient, initially diagnosed with PHPT, who showed no improvement after PTX. The newborn presented with asymptomatic hypercalcemia; the genetic analysis confirmed the diagnosis of FHH [25]. The newborn presented elevated serum calcium levels with no clinical symptoms, while the genetic analysis confirmed the diagnosis of FHH. Others reported hypercalcemic profiles for which they underwent surgery during pregnancy [26, 27].
PTHrP-induced hypercalcemia during pregnancy or lactation has also been reported, either with or without gigantomastia [28–33]. In the reported cases, associating gigantomastia and increased PTHrP serum values, hypercalcaemia was diagnosed during gestation and resolved only after mastectomy, bromocriptin administration, or termination of pregnancy [29, 31, 32].
After delivery, there is a risk of severe hypercalcemia in women with PHPT who are lactating as PTH-rp production will increase [6, 34]. Especially women with gestational hypercalcemia with gigantomastia should be advised against breastfeeding as this will keep PTHrp levels high. The rise in PTHrp during pregnancy was not seen in patient 1 in whom PTHrp production was fully suppressed during entire pregnancy. The observed rise in calcium levels in patient 2 might in retrospect be due to her different setpoint and PTHrp production. Mental consequences of hypercalcemia are well known and include depression and anxiety [35, 36]. During pregnancy mothers might have additional stress which might be exaggerated by the hypercalcemia.
Fetal consequences of hypercalcemia
In the fetus, maternal PHPT can result in fetal growth restriction, severe neonatal hypocalcemia, tetany, and death [36]. In maternal FHH potential fetal complications include mild hypercalcemia, severe hypocalcemia, or neonatal severe hyperparathyroidism, depending on the genotype of the fetus. Because FHH is an autosomal dominant condition, three genetic situations might be encountered by the newborns of FHH mothers: the unaffected and the heterozygous neonates might present with hypocalcaemia induced by the in utero suppression of the parathyroid, the latter being at risk of developing hypercalcemia with hypocalcaemia in the first year of life. The homozygous form of FHH results in a severe neonatal hyperparathyroidism, which requires the surgical removal of the glands during the neonatal phase [37, 38].
Most outcomes on the fetal consequences of hypercalcemia were described in reports on patients with PHPT. Untreated hypercalcemia was associated with fetal or neonatal complications in the majority of cases [3, 36, 39, 40]. However, these findings are based on early literature of PHPT patients when hypercalcemia was often diagnosed in an advanced stage and more recent literature has shown that, compared to age-matched controls, women with PHPT had no difference in most pregnancy outcomes, including stillbirths [39]. That same study also showed that Apgar scores and anthropometric measurements were similar to babies born in uncomplicated pregnancies. However, this recent study did not report on maternal outcomes of preeclampsia. Other recent studies also report lower complications rates and good treatment outcomes when the hypercalcemia is moderate and not severe [1, 41].
Elevated maternal serum calcium leads to hypercalcemia in the fetus, which causes fetal parathyroid gland suppression. After delivery, these glands are still suppressed causing fetal hypocalcemia, which is usually transient (lasting 3–5 months after birth), but permanent hypoparathyroidism has anecdotally been described [42].
In the case of parathyromatosis diagnosed during pregnancy, Edling et al. reported that the infant presented initially with high calcium and low PTH levels, which normalized rapidly, with no further complications [18]. Newborns of mothers presenting with humoral hypercalcemia of pregnancy were having normal calcium levels at birth [29, 30, 33].
Diagnosing hypercalcemia during pregnancy might be challenging due to both physiological changes in calcium homeostasis, as well as due to the underlying cause for the hypercalcemia; changes in urinary calcium excretion vary during daytime, introducing difficulty in using urinary calcium indices as a diagnostic tool. In non-pregnant population, the measurement of calcium/creatinine clearance ratio can be useful in distinguishing between PHPT(>0.02 mmol/mmol) and FHH(<0.01 mmol/mmol). However, it is known that almost 20% of FHH patients might present with a calcium/creatinine ratio >0.01, and individuals with PPHT and simultaneous vitamin D deficiency might show lower than expected calcium excretion [43]. Genetic testing, when available, should be considered for confirming the clinical suspicion of FHH. More than 130 CaSR mutations have been reported so far in relation to FHH1, fact that explains the phenotypical variations in relation to the observed differences in serum calcium and PTH levels [21, 44].
During pregnancy, the distinction between FHH and PHPT is further complicated by the physiological changes in maternal calcium metabolism: increased breast and placental production of PTHrP, that together with the placental lactogen, leads to an increase in 1,25-(OH)2- vitamin D and a reduction of the PTH levels. As a result, the intestinal calcium absorption and the urine calcium excretion are physiologically increased [5, 45]. Treatment is depending on the underlying cause and might be invasive or conservative, but all decisions need good counseling, as it concerns not only the mother, but also the fetus and partner as well. Also we, as physicians, need to be aware that the treatment does not stop with the deliverance of a healthy baby and that the postpartum period might actually be the period with the highest risk for the mother due to the risk of sudden rises in calcium level and to excessive mental stress caused by possible events during pregnancy or delivery.
But foremost, irrespective of the underlying cause of hypercalcemia, patients and partners need to be closely involved in the decision processes in order to ensure overall good outcomes for mother and child.
Acknowledgements
We would like to acknowledge the European Reference Network for Rare Endocrine diseases, specifically main thematic group two calcium and phosphate disorders. We would like to thank both C.W.M. Janssen and S. Mourits for their agreement on publication of their medical history and contribution to the content of the manuscript.
Authors contributions
Conceptualization, writing original draft preparation, reviewing and editing: N.M.A-D. Reviewing and editing, critically revising the manuscript: D-A.E, M.C.Z, L.R, and E.M.W.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CINACALCET HYDROCHLORIDE, UNSPECIFIED INGREDIENT | DrugsGivenReaction | CC BY | 33544354 | 20,513,294 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Exposure during pregnancy'. | Hypercalcemia during pregnancy: management and outcomes for mother and child.
Diagnosing and treating hypercalcemia during pregnancy can be challenging due to both the physiological changes in calcium homeostasis and the underlying cause for the hypercalcemia. During pregnancy and lactation there is increased mobilization of calcium in the mother to meet the fetus' calcium requirements. Here we discuss the diagnostic challenges, management, and patient perspective of hypercalcemia during pregnancy in two particular cases and in other rare conditions causing hypercalcemia.
Introduction
Hypercalcemia in pregnancy is rare and in >90% of cases caused by a newly diagnosed primary hyperparathyroidism (PHPT). Hypercalcemia during pregnancy due to other disorders of calcium metabolism is even more rare and literature regarding the maternal management and fetal outcomes is lacking. Diagnosing hypercalcemia is challenging during pregnancy, as symptoms such as fatigue or nausea mimic those in early pregnancy. However, longstanding hypercalcemia might induce nephrolithiasis, pancreatitis, and preeclampsia in the mother [1]. Therefore, the occurrence of these diseases during pregnancy should push the physicians to screen for hypercalcemia. In the fetus, maternal hypercalcemia can result in fetal growth restriction [2]. Following birth, further complications may arise such as severe neonatal hypocalcemia, tetany, and even death due to fetal hypoparathyroidism [3, 4]. In rare calcium-related disorders, the diagnosis is often known before the pregnancy and patients and partners can be counseled by the treating endocrinologist, obstetrician, pediatrician, and geneticist when required, taking into account the possible physical and mental maternal adverse effects, but also the eventual consequences for the newborn. Here we would like to discuss the diagnostic challenges and management of hypercalcemia during pregnancy in two particular cases as example of rare conditions causing hypercalcemia complicating pregnancy.
Case 1
A 34-year-old woman was referred with severe hypercalcemia and a pregnancy wish. At the age of 24 she was diagnosed with PHPT, without underlying genetic causes. During parathyroidectomy (PTX) there was spill of the adenoma, histologically confirmed, which led to chronic hypercalcemia for which she underwent several re-operations in various hospitals including a thyroidectomy in 2 tempi with resection of surrounding fat-tissue and a bilateral modified lymph node resection. However, she remained dependent on cinacalcet and bisphosphonates in various dosages. At referral, albumin-corrected serum calcium was 2.89 mmol/L (ref 2.15–2.55 mmol/L) with PTH 10.7 (ref 1–8 pmol/L) while on cinacalcet 60 mg/day, and 3.16 mmol/L with PTH of 29 without cinacalcet. She and her partner were counselled by a team consisting of gynecologists, pediatricians, and endocrinologists on several aspects of the disease and potential consequences for a pregnancy. Prophylactic surgery was not possible at that time. Bisphosphonates were stopped and she became pregnant after 12 months. Cinacalcet was stopped and a fluid intake of 4 L was advised. However, she was admitted with a symptomatic hypercalcemia, 3.4 mmol/L, within 2 weeks. Hyperhydration and cinacalcet, up to 90 mg/day, were started in combination with furosemide 40 mg and acetylsalicylic acid 80 mg daily as preeclampsia prophylaxis. She suffered from severe hyperemesis gravidarum and due to persistent hypercalcemia, she received saline infusions of 5 L/day in a homecare setting with a peripheral intravasal central catheter (PICC). During follow up the PICC caused deep vein thrombosis for which nadroparin injections were started but with this treatment serum calcium remained stable around 2.7–2.9 mmol/L. At 38 weeks of gestation she developed hypertension with a rapidly developing HELLP syndrome and an emergency cesarean section was performed. A healthy baby boy, weight 3305 g, was delivered; he only received active vitamin D supplementation for a few days and two years after delivery; no calcium disturbances or skeletal abnormalities have been observed. The mother did not breastfeed. After delivery, the mother experienced a post-traumatic stress syndrome (PTSS) with depression for which she started Eye Movement Desensitization and Reprocessing (EMDR). The depression and PTSS was related to the latter part of the pregnancy and delivery, but most likely exacerbated due to a postpartum rise in calcium to 3.3 mmol/L. Surgery was successfully performed after which her mental complaints improved.
Case 2
A 38-year-old female was diagnosed with PHPT at a non-university hospital, based on a modest hypercalcemia, and elevated PTH of 9.2 pmol/L and high to normal urinary calcium excretion of 8.5 g/L and calcium-to-creatinine clearance above 0.02. Despite her young age, it was decided not to perform PTX because of an increased risk for venous thromboembolism and obesity. Five years later, she had an unexpected pregnancy and was referred for PTX in the second trimester. During that time serum calcium had increased from 2.63 mmol/L to 2.83 mmol/L with a non-suppressed PTH of 3.8 pmol/L. The patient and her partner were counseled by a team consisting of endocrinologists, anesthesiologists, endocrine surgeons, pediatricians, and obstetricians. Imaging studies did not reveal a clear-cut adenoma and considering the progressive rise in calcium to 2.93 mmol/L, urinary calcium excretion of 12 g/L in 24 h and proceeding into the end of the second trimester an elective neck exploration was performed at gestational age of 24 + 2 weeks, showing four gland hyperplasia. During surgery, it was decided to remove only the two right-sided glands in order not to risk hypoparathyroidism. After surgery hypercalcemia persisted with calcium levels between 2.60 mmol/L and 2.65 mmol/L and PTH between 2.1 pmol/L and 3.6 pmol/L. Considering the marked hyperplasia the patient was discussed in the clinical patient management system (CPMS) panel of main thematic group two, calcium and phosphate disorders of the European Reference Network for rare endocrine diseases (ENDO-ERN). The advice of this panel was to perform genetic testing for familial hypocalciuric calciuria (FHH), which came back positive for a mutation in the CASR-gen, c.653A>G p.(Tyr218Cys), establishing a diagnosis of FHH type one. At 39 + 3 weeks she delivered a healthy baby girl of 4150 g without any calcium disturbances. Post-partum the calcium levels of the mother remained at 2.6 mmol and PTH rose again to 10.3 pmol/L, which has been stable since.
Patient perspective
Patient one had an active pregnancy wish for 5 years, with a negative counselling in several centers. At the Leiden University Medical Center (LUMC) it was again made clear that this would not be without risks for mother and child but if desired we would do our best to monitor the pregnancy as good as possible, which was much appreciated as this was not discussed before. Although she was well prepared and extensively counseled, the intensity of the pregnancy was overwhelming. Both the high calcium levels, frequent investigations and the continuous hyperhydration were extremely demanding and resulted, together with the further rise in calcium, in a pre- and post-natal depression for which EMDR and psychotherapy were needed. Looking back, she would advise other patients to realize that it will be extremely tough, but absolutely worth it. The fact that caretakers were so involved in her well-being and their clear communication was helpful and appreciated. The health care system structure with various doctors during hospital admission remains unfortunate from her point of view, which was in contrast to the outpatient clinic care with one regular healthcare provider.
Despite living with, a supposed, PHPT for many years, patient 2 had never been counseled about PHPT in terms of treatment and follow up. In the initial phase of her referral to LUMC this was done rapidly as time was ticking for a safe window of surgery as the second trimester is the preferred trimester for surgery for maternal and fetal reasons. In addition, due to her increased risk for venous thromboembolism and obesity, emergency surgery in case of severe hypercalcemia was considered to be a high risk for the mother. The patient found the amount of information overwhelming. However, it was appreciated as it made the patient and her partner feel part of the team. After surgery, when she had postoperative pains, this induced more stress being pregnant. Caregivers should be aware that in pregnant patients’ complaints that might be considered as normal after surgery can induce a stressful trigger in patients who are already in a stressful situation. The doubts about the original diagnosis of PHPT were shared including the desire of the treating physicians to discuss her case with other experts. Although providing more insecurity, the patient did feel comfortable that this meant that no other surgery was likely to be needed. After the pregnancy she reported that the physical part of the pregnancy did not give her many discomforts but the uncertainty about the well-being of the baby was very stressful. But overall, she was very satisfied with the care given.
In collaboration with these patients we produced a checklist for women in the same position or with a recent diagnosis of PHPT, which might be of help, see Table 1.Table 1 Questions for women in the childbearing age to ask their doctor when diagnosed with a high calcium level
1. What is the most likely diagnosis causing this high calcium level?
2. What tests do I need to make the diagnosis more likely? And are these tests influenced by pregnancy?
3. How will this affect pregnancy?
What will be the risks for my unborn child?
What will be the risks for me?
Which interventions are possible/necessary before, during and after pregnancy?
4. What can I do to minimalize complaints during and after the pregnancy?
5. How can we decrease my risk for preeclampsia?
6. Which drugs might be used during the pregnancy and what are their side effects?
7. How can you monitor my child?
8. How will my disease affect me after delivery?
9. How will this affect my child directly after delivery?
10. Can I breastfeed?
11. Who is in my multidisciplinary team and how can I reach them?
12. What can be done by my general practitioner?
13. What would be the risk of getting pregnant and to whom can I speak to for counseling?
In both cases patients and partners experienced the pregnancy as a rollercoaster with lot of uncertainties. Whereas both patients were diagnosed with hypercalcemia before pregnancy, patient 1 was counseled extensively in the pre-pregnancy period and even repeatedly got the advice not to become pregnant while patient 2 was never counseled. Also, in patient 2 the diagnosis was changed from PHPT to FHH, the finding of the marked hyperplasia triggered doubts about the original diagnosis of PHPT. In patient 1, the initial decision for surgery would still be made as her calcium values were rising and she did develop nausea and in FHH hyperplasia is also often described.
Physiological changes during pregnancy (Fig. 1a)
During pregnancy and lactation there is increased mobilization of calcium in the mother to meet the fetus’ calcium requirements [5, 6]. This is done by increasing intestinal calcium absorption through increasing 1.25 vitamin D production and PTH-related peptide (PTHrP), which is released from placenta and breasts in response to estradiol, placental lactogen, and prolactin [6, 7]. Despite the overlapping modes of action, PTH and PTHrP are produced by different genes on different chromosomes and the gene encoding PTHrP is more complex than for PTH. PTHrP is undetectable in the circulating blood of non-pregnant women, but is produced in a paracrine/autocrine fashion during pregnancy. Lessons from PTHrP or PTH1R gene knockout mice, which die at birth or in utero, emphasize the critical role of PTHrP for normal life [8, 9]. In addition, nascent PTHrP isoforms are processed by members of the prohormone convertase family to at least three fragments: N-terminal PTHrP [1–36], structurally related to PTH; a mid-region PTHrP (38–94); and a C-terminal PTHrP(107–139) with distinct biological properties and receptors. PTHrP is able to act not only via the classical autocrine/paracrine pathways, but also through a so-called intracrine pathway, which involves the translocation of the protein into the nucleus, where it can directly regulate proliferation and apoptosis [10, 11]. PTHrP has multiple activities including control of fetal development, trans-epithelial calcium transfer, lactation, smooth muscle relaxation, and cell growth. The mid-molecular region of PTHrP stimulates placental calcium transport in the fetus, while the COOH terminal region may also affect osteoclast activity. Thus, although PTHrP was discovered as a tumor-derived hypercalcemic factor, its primary physiological role is as a local regulator of many physiological processes especially in early life [12, 13].Fig. 1 a *Intravascular fluid expansion causes gestational hypoalbuminemia. The dilutional hypoalbuminemia of pregnancy leads to a decline in total calcium concentration. Ionized calcium on the other hand, remains stable and may provide more accurate information. ** The increase in 1.25 vitamin D production leads to an increase in intestinal calcium absorption. ***“Absorptive hypercalciuria of pregnancy”. Postprandial and 24-h urinary calcium excretion increase after 12 weeks, due to increased intestinal calcium absorption supposedly unrelated to increased formation of 1.25 vitamin D in early pregnancy. Fasting urine samples will not be affected by this phenomenon [45]. b *Prednison to reduce 1.25OH formation and thus intestinal calcium absorption. ** Reducing PTH-rp production mammae. *** No clinical data during pregnancy, only case reports. In animal studies no abnormalities observed, but it does pass the placenta [31, 46]. Breastfeeding: in animal studies (rat), cinacalcet is found in milk [46].
Maternal causes and consequences of hypercalcemia (Fig. 1b)
Hypercalcemia due to hyperparathyroidism is the most described cause of hypercalcemia during pregnancy. As most reviews focus on maternal and fetal outcomes in PHPT we will not cover this topic in the current paper [14, 15]. Hyperparathyroidism due to diffusely spread hyperthyroid nodules, parathyromatosis, post-parathyroidectomy, in the context of malignancy, MEN syndromes, or in chronic renal disease has been rarely described [15, 16]. Literature data on parathyromatosis is limited to around 20 cases published so far with only one report on a woman diagnosed and treated during pregnancy [17, 18].
FHH is a rare autosomal dominant disorder, with a prevalence of ~1:78.000 though this might likely be higher, as many cases remain asymptomatic lifelong and no causal treatment is available [19–21]. According to the genetic defect causing the pathology, three types of FHH have been defined [21–24]. FHH1 is the most common type and is found in about 65% of all FHH cases [21]. Patients with FHH present with mild to moderate hypercalcaemia, low urinary excretion, and PTH serum levels that are either normal or slightly elevated. Many patients with FHH are misdiagnosed as suffering from PHPT as in the case of our patient. Data on FHH manifested during pregnancy, literature data are sparse. Only four cases were published so far. Walker et al. reported the case of a pregnant patient, initially diagnosed with PHPT, who showed no improvement after PTX. The newborn presented with asymptomatic hypercalcemia; the genetic analysis confirmed the diagnosis of FHH [25]. The newborn presented elevated serum calcium levels with no clinical symptoms, while the genetic analysis confirmed the diagnosis of FHH. Others reported hypercalcemic profiles for which they underwent surgery during pregnancy [26, 27].
PTHrP-induced hypercalcemia during pregnancy or lactation has also been reported, either with or without gigantomastia [28–33]. In the reported cases, associating gigantomastia and increased PTHrP serum values, hypercalcaemia was diagnosed during gestation and resolved only after mastectomy, bromocriptin administration, or termination of pregnancy [29, 31, 32].
After delivery, there is a risk of severe hypercalcemia in women with PHPT who are lactating as PTH-rp production will increase [6, 34]. Especially women with gestational hypercalcemia with gigantomastia should be advised against breastfeeding as this will keep PTHrp levels high. The rise in PTHrp during pregnancy was not seen in patient 1 in whom PTHrp production was fully suppressed during entire pregnancy. The observed rise in calcium levels in patient 2 might in retrospect be due to her different setpoint and PTHrp production. Mental consequences of hypercalcemia are well known and include depression and anxiety [35, 36]. During pregnancy mothers might have additional stress which might be exaggerated by the hypercalcemia.
Fetal consequences of hypercalcemia
In the fetus, maternal PHPT can result in fetal growth restriction, severe neonatal hypocalcemia, tetany, and death [36]. In maternal FHH potential fetal complications include mild hypercalcemia, severe hypocalcemia, or neonatal severe hyperparathyroidism, depending on the genotype of the fetus. Because FHH is an autosomal dominant condition, three genetic situations might be encountered by the newborns of FHH mothers: the unaffected and the heterozygous neonates might present with hypocalcaemia induced by the in utero suppression of the parathyroid, the latter being at risk of developing hypercalcemia with hypocalcaemia in the first year of life. The homozygous form of FHH results in a severe neonatal hyperparathyroidism, which requires the surgical removal of the glands during the neonatal phase [37, 38].
Most outcomes on the fetal consequences of hypercalcemia were described in reports on patients with PHPT. Untreated hypercalcemia was associated with fetal or neonatal complications in the majority of cases [3, 36, 39, 40]. However, these findings are based on early literature of PHPT patients when hypercalcemia was often diagnosed in an advanced stage and more recent literature has shown that, compared to age-matched controls, women with PHPT had no difference in most pregnancy outcomes, including stillbirths [39]. That same study also showed that Apgar scores and anthropometric measurements were similar to babies born in uncomplicated pregnancies. However, this recent study did not report on maternal outcomes of preeclampsia. Other recent studies also report lower complications rates and good treatment outcomes when the hypercalcemia is moderate and not severe [1, 41].
Elevated maternal serum calcium leads to hypercalcemia in the fetus, which causes fetal parathyroid gland suppression. After delivery, these glands are still suppressed causing fetal hypocalcemia, which is usually transient (lasting 3–5 months after birth), but permanent hypoparathyroidism has anecdotally been described [42].
In the case of parathyromatosis diagnosed during pregnancy, Edling et al. reported that the infant presented initially with high calcium and low PTH levels, which normalized rapidly, with no further complications [18]. Newborns of mothers presenting with humoral hypercalcemia of pregnancy were having normal calcium levels at birth [29, 30, 33].
Diagnosing hypercalcemia during pregnancy might be challenging due to both physiological changes in calcium homeostasis, as well as due to the underlying cause for the hypercalcemia; changes in urinary calcium excretion vary during daytime, introducing difficulty in using urinary calcium indices as a diagnostic tool. In non-pregnant population, the measurement of calcium/creatinine clearance ratio can be useful in distinguishing between PHPT(>0.02 mmol/mmol) and FHH(<0.01 mmol/mmol). However, it is known that almost 20% of FHH patients might present with a calcium/creatinine ratio >0.01, and individuals with PPHT and simultaneous vitamin D deficiency might show lower than expected calcium excretion [43]. Genetic testing, when available, should be considered for confirming the clinical suspicion of FHH. More than 130 CaSR mutations have been reported so far in relation to FHH1, fact that explains the phenotypical variations in relation to the observed differences in serum calcium and PTH levels [21, 44].
During pregnancy, the distinction between FHH and PHPT is further complicated by the physiological changes in maternal calcium metabolism: increased breast and placental production of PTHrP, that together with the placental lactogen, leads to an increase in 1,25-(OH)2- vitamin D and a reduction of the PTH levels. As a result, the intestinal calcium absorption and the urine calcium excretion are physiologically increased [5, 45]. Treatment is depending on the underlying cause and might be invasive or conservative, but all decisions need good counseling, as it concerns not only the mother, but also the fetus and partner as well. Also we, as physicians, need to be aware that the treatment does not stop with the deliverance of a healthy baby and that the postpartum period might actually be the period with the highest risk for the mother due to the risk of sudden rises in calcium level and to excessive mental stress caused by possible events during pregnancy or delivery.
But foremost, irrespective of the underlying cause of hypercalcemia, patients and partners need to be closely involved in the decision processes in order to ensure overall good outcomes for mother and child.
Acknowledgements
We would like to acknowledge the European Reference Network for Rare Endocrine diseases, specifically main thematic group two calcium and phosphate disorders. We would like to thank both C.W.M. Janssen and S. Mourits for their agreement on publication of their medical history and contribution to the content of the manuscript.
Authors contributions
Conceptualization, writing original draft preparation, reviewing and editing: N.M.A-D. Reviewing and editing, critically revising the manuscript: D-A.E, M.C.Z, L.R, and E.M.W.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ASPIRIN, CINACALCET, FUROSEMIDE, NADROPARIN | DrugsGivenReaction | CC BY | 33544354 | 19,563,598 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'HELLP syndrome'. | Hypercalcemia during pregnancy: management and outcomes for mother and child.
Diagnosing and treating hypercalcemia during pregnancy can be challenging due to both the physiological changes in calcium homeostasis and the underlying cause for the hypercalcemia. During pregnancy and lactation there is increased mobilization of calcium in the mother to meet the fetus' calcium requirements. Here we discuss the diagnostic challenges, management, and patient perspective of hypercalcemia during pregnancy in two particular cases and in other rare conditions causing hypercalcemia.
Introduction
Hypercalcemia in pregnancy is rare and in >90% of cases caused by a newly diagnosed primary hyperparathyroidism (PHPT). Hypercalcemia during pregnancy due to other disorders of calcium metabolism is even more rare and literature regarding the maternal management and fetal outcomes is lacking. Diagnosing hypercalcemia is challenging during pregnancy, as symptoms such as fatigue or nausea mimic those in early pregnancy. However, longstanding hypercalcemia might induce nephrolithiasis, pancreatitis, and preeclampsia in the mother [1]. Therefore, the occurrence of these diseases during pregnancy should push the physicians to screen for hypercalcemia. In the fetus, maternal hypercalcemia can result in fetal growth restriction [2]. Following birth, further complications may arise such as severe neonatal hypocalcemia, tetany, and even death due to fetal hypoparathyroidism [3, 4]. In rare calcium-related disorders, the diagnosis is often known before the pregnancy and patients and partners can be counseled by the treating endocrinologist, obstetrician, pediatrician, and geneticist when required, taking into account the possible physical and mental maternal adverse effects, but also the eventual consequences for the newborn. Here we would like to discuss the diagnostic challenges and management of hypercalcemia during pregnancy in two particular cases as example of rare conditions causing hypercalcemia complicating pregnancy.
Case 1
A 34-year-old woman was referred with severe hypercalcemia and a pregnancy wish. At the age of 24 she was diagnosed with PHPT, without underlying genetic causes. During parathyroidectomy (PTX) there was spill of the adenoma, histologically confirmed, which led to chronic hypercalcemia for which she underwent several re-operations in various hospitals including a thyroidectomy in 2 tempi with resection of surrounding fat-tissue and a bilateral modified lymph node resection. However, she remained dependent on cinacalcet and bisphosphonates in various dosages. At referral, albumin-corrected serum calcium was 2.89 mmol/L (ref 2.15–2.55 mmol/L) with PTH 10.7 (ref 1–8 pmol/L) while on cinacalcet 60 mg/day, and 3.16 mmol/L with PTH of 29 without cinacalcet. She and her partner were counselled by a team consisting of gynecologists, pediatricians, and endocrinologists on several aspects of the disease and potential consequences for a pregnancy. Prophylactic surgery was not possible at that time. Bisphosphonates were stopped and she became pregnant after 12 months. Cinacalcet was stopped and a fluid intake of 4 L was advised. However, she was admitted with a symptomatic hypercalcemia, 3.4 mmol/L, within 2 weeks. Hyperhydration and cinacalcet, up to 90 mg/day, were started in combination with furosemide 40 mg and acetylsalicylic acid 80 mg daily as preeclampsia prophylaxis. She suffered from severe hyperemesis gravidarum and due to persistent hypercalcemia, she received saline infusions of 5 L/day in a homecare setting with a peripheral intravasal central catheter (PICC). During follow up the PICC caused deep vein thrombosis for which nadroparin injections were started but with this treatment serum calcium remained stable around 2.7–2.9 mmol/L. At 38 weeks of gestation she developed hypertension with a rapidly developing HELLP syndrome and an emergency cesarean section was performed. A healthy baby boy, weight 3305 g, was delivered; he only received active vitamin D supplementation for a few days and two years after delivery; no calcium disturbances or skeletal abnormalities have been observed. The mother did not breastfeed. After delivery, the mother experienced a post-traumatic stress syndrome (PTSS) with depression for which she started Eye Movement Desensitization and Reprocessing (EMDR). The depression and PTSS was related to the latter part of the pregnancy and delivery, but most likely exacerbated due to a postpartum rise in calcium to 3.3 mmol/L. Surgery was successfully performed after which her mental complaints improved.
Case 2
A 38-year-old female was diagnosed with PHPT at a non-university hospital, based on a modest hypercalcemia, and elevated PTH of 9.2 pmol/L and high to normal urinary calcium excretion of 8.5 g/L and calcium-to-creatinine clearance above 0.02. Despite her young age, it was decided not to perform PTX because of an increased risk for venous thromboembolism and obesity. Five years later, she had an unexpected pregnancy and was referred for PTX in the second trimester. During that time serum calcium had increased from 2.63 mmol/L to 2.83 mmol/L with a non-suppressed PTH of 3.8 pmol/L. The patient and her partner were counseled by a team consisting of endocrinologists, anesthesiologists, endocrine surgeons, pediatricians, and obstetricians. Imaging studies did not reveal a clear-cut adenoma and considering the progressive rise in calcium to 2.93 mmol/L, urinary calcium excretion of 12 g/L in 24 h and proceeding into the end of the second trimester an elective neck exploration was performed at gestational age of 24 + 2 weeks, showing four gland hyperplasia. During surgery, it was decided to remove only the two right-sided glands in order not to risk hypoparathyroidism. After surgery hypercalcemia persisted with calcium levels between 2.60 mmol/L and 2.65 mmol/L and PTH between 2.1 pmol/L and 3.6 pmol/L. Considering the marked hyperplasia the patient was discussed in the clinical patient management system (CPMS) panel of main thematic group two, calcium and phosphate disorders of the European Reference Network for rare endocrine diseases (ENDO-ERN). The advice of this panel was to perform genetic testing for familial hypocalciuric calciuria (FHH), which came back positive for a mutation in the CASR-gen, c.653A>G p.(Tyr218Cys), establishing a diagnosis of FHH type one. At 39 + 3 weeks she delivered a healthy baby girl of 4150 g without any calcium disturbances. Post-partum the calcium levels of the mother remained at 2.6 mmol and PTH rose again to 10.3 pmol/L, which has been stable since.
Patient perspective
Patient one had an active pregnancy wish for 5 years, with a negative counselling in several centers. At the Leiden University Medical Center (LUMC) it was again made clear that this would not be without risks for mother and child but if desired we would do our best to monitor the pregnancy as good as possible, which was much appreciated as this was not discussed before. Although she was well prepared and extensively counseled, the intensity of the pregnancy was overwhelming. Both the high calcium levels, frequent investigations and the continuous hyperhydration were extremely demanding and resulted, together with the further rise in calcium, in a pre- and post-natal depression for which EMDR and psychotherapy were needed. Looking back, she would advise other patients to realize that it will be extremely tough, but absolutely worth it. The fact that caretakers were so involved in her well-being and their clear communication was helpful and appreciated. The health care system structure with various doctors during hospital admission remains unfortunate from her point of view, which was in contrast to the outpatient clinic care with one regular healthcare provider.
Despite living with, a supposed, PHPT for many years, patient 2 had never been counseled about PHPT in terms of treatment and follow up. In the initial phase of her referral to LUMC this was done rapidly as time was ticking for a safe window of surgery as the second trimester is the preferred trimester for surgery for maternal and fetal reasons. In addition, due to her increased risk for venous thromboembolism and obesity, emergency surgery in case of severe hypercalcemia was considered to be a high risk for the mother. The patient found the amount of information overwhelming. However, it was appreciated as it made the patient and her partner feel part of the team. After surgery, when she had postoperative pains, this induced more stress being pregnant. Caregivers should be aware that in pregnant patients’ complaints that might be considered as normal after surgery can induce a stressful trigger in patients who are already in a stressful situation. The doubts about the original diagnosis of PHPT were shared including the desire of the treating physicians to discuss her case with other experts. Although providing more insecurity, the patient did feel comfortable that this meant that no other surgery was likely to be needed. After the pregnancy she reported that the physical part of the pregnancy did not give her many discomforts but the uncertainty about the well-being of the baby was very stressful. But overall, she was very satisfied with the care given.
In collaboration with these patients we produced a checklist for women in the same position or with a recent diagnosis of PHPT, which might be of help, see Table 1.Table 1 Questions for women in the childbearing age to ask their doctor when diagnosed with a high calcium level
1. What is the most likely diagnosis causing this high calcium level?
2. What tests do I need to make the diagnosis more likely? And are these tests influenced by pregnancy?
3. How will this affect pregnancy?
What will be the risks for my unborn child?
What will be the risks for me?
Which interventions are possible/necessary before, during and after pregnancy?
4. What can I do to minimalize complaints during and after the pregnancy?
5. How can we decrease my risk for preeclampsia?
6. Which drugs might be used during the pregnancy and what are their side effects?
7. How can you monitor my child?
8. How will my disease affect me after delivery?
9. How will this affect my child directly after delivery?
10. Can I breastfeed?
11. Who is in my multidisciplinary team and how can I reach them?
12. What can be done by my general practitioner?
13. What would be the risk of getting pregnant and to whom can I speak to for counseling?
In both cases patients and partners experienced the pregnancy as a rollercoaster with lot of uncertainties. Whereas both patients were diagnosed with hypercalcemia before pregnancy, patient 1 was counseled extensively in the pre-pregnancy period and even repeatedly got the advice not to become pregnant while patient 2 was never counseled. Also, in patient 2 the diagnosis was changed from PHPT to FHH, the finding of the marked hyperplasia triggered doubts about the original diagnosis of PHPT. In patient 1, the initial decision for surgery would still be made as her calcium values were rising and she did develop nausea and in FHH hyperplasia is also often described.
Physiological changes during pregnancy (Fig. 1a)
During pregnancy and lactation there is increased mobilization of calcium in the mother to meet the fetus’ calcium requirements [5, 6]. This is done by increasing intestinal calcium absorption through increasing 1.25 vitamin D production and PTH-related peptide (PTHrP), which is released from placenta and breasts in response to estradiol, placental lactogen, and prolactin [6, 7]. Despite the overlapping modes of action, PTH and PTHrP are produced by different genes on different chromosomes and the gene encoding PTHrP is more complex than for PTH. PTHrP is undetectable in the circulating blood of non-pregnant women, but is produced in a paracrine/autocrine fashion during pregnancy. Lessons from PTHrP or PTH1R gene knockout mice, which die at birth or in utero, emphasize the critical role of PTHrP for normal life [8, 9]. In addition, nascent PTHrP isoforms are processed by members of the prohormone convertase family to at least three fragments: N-terminal PTHrP [1–36], structurally related to PTH; a mid-region PTHrP (38–94); and a C-terminal PTHrP(107–139) with distinct biological properties and receptors. PTHrP is able to act not only via the classical autocrine/paracrine pathways, but also through a so-called intracrine pathway, which involves the translocation of the protein into the nucleus, where it can directly regulate proliferation and apoptosis [10, 11]. PTHrP has multiple activities including control of fetal development, trans-epithelial calcium transfer, lactation, smooth muscle relaxation, and cell growth. The mid-molecular region of PTHrP stimulates placental calcium transport in the fetus, while the COOH terminal region may also affect osteoclast activity. Thus, although PTHrP was discovered as a tumor-derived hypercalcemic factor, its primary physiological role is as a local regulator of many physiological processes especially in early life [12, 13].Fig. 1 a *Intravascular fluid expansion causes gestational hypoalbuminemia. The dilutional hypoalbuminemia of pregnancy leads to a decline in total calcium concentration. Ionized calcium on the other hand, remains stable and may provide more accurate information. ** The increase in 1.25 vitamin D production leads to an increase in intestinal calcium absorption. ***“Absorptive hypercalciuria of pregnancy”. Postprandial and 24-h urinary calcium excretion increase after 12 weeks, due to increased intestinal calcium absorption supposedly unrelated to increased formation of 1.25 vitamin D in early pregnancy. Fasting urine samples will not be affected by this phenomenon [45]. b *Prednison to reduce 1.25OH formation and thus intestinal calcium absorption. ** Reducing PTH-rp production mammae. *** No clinical data during pregnancy, only case reports. In animal studies no abnormalities observed, but it does pass the placenta [31, 46]. Breastfeeding: in animal studies (rat), cinacalcet is found in milk [46].
Maternal causes and consequences of hypercalcemia (Fig. 1b)
Hypercalcemia due to hyperparathyroidism is the most described cause of hypercalcemia during pregnancy. As most reviews focus on maternal and fetal outcomes in PHPT we will not cover this topic in the current paper [14, 15]. Hyperparathyroidism due to diffusely spread hyperthyroid nodules, parathyromatosis, post-parathyroidectomy, in the context of malignancy, MEN syndromes, or in chronic renal disease has been rarely described [15, 16]. Literature data on parathyromatosis is limited to around 20 cases published so far with only one report on a woman diagnosed and treated during pregnancy [17, 18].
FHH is a rare autosomal dominant disorder, with a prevalence of ~1:78.000 though this might likely be higher, as many cases remain asymptomatic lifelong and no causal treatment is available [19–21]. According to the genetic defect causing the pathology, three types of FHH have been defined [21–24]. FHH1 is the most common type and is found in about 65% of all FHH cases [21]. Patients with FHH present with mild to moderate hypercalcaemia, low urinary excretion, and PTH serum levels that are either normal or slightly elevated. Many patients with FHH are misdiagnosed as suffering from PHPT as in the case of our patient. Data on FHH manifested during pregnancy, literature data are sparse. Only four cases were published so far. Walker et al. reported the case of a pregnant patient, initially diagnosed with PHPT, who showed no improvement after PTX. The newborn presented with asymptomatic hypercalcemia; the genetic analysis confirmed the diagnosis of FHH [25]. The newborn presented elevated serum calcium levels with no clinical symptoms, while the genetic analysis confirmed the diagnosis of FHH. Others reported hypercalcemic profiles for which they underwent surgery during pregnancy [26, 27].
PTHrP-induced hypercalcemia during pregnancy or lactation has also been reported, either with or without gigantomastia [28–33]. In the reported cases, associating gigantomastia and increased PTHrP serum values, hypercalcaemia was diagnosed during gestation and resolved only after mastectomy, bromocriptin administration, or termination of pregnancy [29, 31, 32].
After delivery, there is a risk of severe hypercalcemia in women with PHPT who are lactating as PTH-rp production will increase [6, 34]. Especially women with gestational hypercalcemia with gigantomastia should be advised against breastfeeding as this will keep PTHrp levels high. The rise in PTHrp during pregnancy was not seen in patient 1 in whom PTHrp production was fully suppressed during entire pregnancy. The observed rise in calcium levels in patient 2 might in retrospect be due to her different setpoint and PTHrp production. Mental consequences of hypercalcemia are well known and include depression and anxiety [35, 36]. During pregnancy mothers might have additional stress which might be exaggerated by the hypercalcemia.
Fetal consequences of hypercalcemia
In the fetus, maternal PHPT can result in fetal growth restriction, severe neonatal hypocalcemia, tetany, and death [36]. In maternal FHH potential fetal complications include mild hypercalcemia, severe hypocalcemia, or neonatal severe hyperparathyroidism, depending on the genotype of the fetus. Because FHH is an autosomal dominant condition, three genetic situations might be encountered by the newborns of FHH mothers: the unaffected and the heterozygous neonates might present with hypocalcaemia induced by the in utero suppression of the parathyroid, the latter being at risk of developing hypercalcemia with hypocalcaemia in the first year of life. The homozygous form of FHH results in a severe neonatal hyperparathyroidism, which requires the surgical removal of the glands during the neonatal phase [37, 38].
Most outcomes on the fetal consequences of hypercalcemia were described in reports on patients with PHPT. Untreated hypercalcemia was associated with fetal or neonatal complications in the majority of cases [3, 36, 39, 40]. However, these findings are based on early literature of PHPT patients when hypercalcemia was often diagnosed in an advanced stage and more recent literature has shown that, compared to age-matched controls, women with PHPT had no difference in most pregnancy outcomes, including stillbirths [39]. That same study also showed that Apgar scores and anthropometric measurements were similar to babies born in uncomplicated pregnancies. However, this recent study did not report on maternal outcomes of preeclampsia. Other recent studies also report lower complications rates and good treatment outcomes when the hypercalcemia is moderate and not severe [1, 41].
Elevated maternal serum calcium leads to hypercalcemia in the fetus, which causes fetal parathyroid gland suppression. After delivery, these glands are still suppressed causing fetal hypocalcemia, which is usually transient (lasting 3–5 months after birth), but permanent hypoparathyroidism has anecdotally been described [42].
In the case of parathyromatosis diagnosed during pregnancy, Edling et al. reported that the infant presented initially with high calcium and low PTH levels, which normalized rapidly, with no further complications [18]. Newborns of mothers presenting with humoral hypercalcemia of pregnancy were having normal calcium levels at birth [29, 30, 33].
Diagnosing hypercalcemia during pregnancy might be challenging due to both physiological changes in calcium homeostasis, as well as due to the underlying cause for the hypercalcemia; changes in urinary calcium excretion vary during daytime, introducing difficulty in using urinary calcium indices as a diagnostic tool. In non-pregnant population, the measurement of calcium/creatinine clearance ratio can be useful in distinguishing between PHPT(>0.02 mmol/mmol) and FHH(<0.01 mmol/mmol). However, it is known that almost 20% of FHH patients might present with a calcium/creatinine ratio >0.01, and individuals with PPHT and simultaneous vitamin D deficiency might show lower than expected calcium excretion [43]. Genetic testing, when available, should be considered for confirming the clinical suspicion of FHH. More than 130 CaSR mutations have been reported so far in relation to FHH1, fact that explains the phenotypical variations in relation to the observed differences in serum calcium and PTH levels [21, 44].
During pregnancy, the distinction between FHH and PHPT is further complicated by the physiological changes in maternal calcium metabolism: increased breast and placental production of PTHrP, that together with the placental lactogen, leads to an increase in 1,25-(OH)2- vitamin D and a reduction of the PTH levels. As a result, the intestinal calcium absorption and the urine calcium excretion are physiologically increased [5, 45]. Treatment is depending on the underlying cause and might be invasive or conservative, but all decisions need good counseling, as it concerns not only the mother, but also the fetus and partner as well. Also we, as physicians, need to be aware that the treatment does not stop with the deliverance of a healthy baby and that the postpartum period might actually be the period with the highest risk for the mother due to the risk of sudden rises in calcium level and to excessive mental stress caused by possible events during pregnancy or delivery.
But foremost, irrespective of the underlying cause of hypercalcemia, patients and partners need to be closely involved in the decision processes in order to ensure overall good outcomes for mother and child.
Acknowledgements
We would like to acknowledge the European Reference Network for Rare Endocrine diseases, specifically main thematic group two calcium and phosphate disorders. We would like to thank both C.W.M. Janssen and S. Mourits for their agreement on publication of their medical history and contribution to the content of the manuscript.
Authors contributions
Conceptualization, writing original draft preparation, reviewing and editing: N.M.A-D. Reviewing and editing, critically revising the manuscript: D-A.E, M.C.Z, L.R, and E.M.W.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CINACALCET HYDROCHLORIDE, UNSPECIFIED INGREDIENT | DrugsGivenReaction | CC BY | 33544354 | 20,513,294 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypercalcaemia'. | Hypercalcemia during pregnancy: management and outcomes for mother and child.
Diagnosing and treating hypercalcemia during pregnancy can be challenging due to both the physiological changes in calcium homeostasis and the underlying cause for the hypercalcemia. During pregnancy and lactation there is increased mobilization of calcium in the mother to meet the fetus' calcium requirements. Here we discuss the diagnostic challenges, management, and patient perspective of hypercalcemia during pregnancy in two particular cases and in other rare conditions causing hypercalcemia.
Introduction
Hypercalcemia in pregnancy is rare and in >90% of cases caused by a newly diagnosed primary hyperparathyroidism (PHPT). Hypercalcemia during pregnancy due to other disorders of calcium metabolism is even more rare and literature regarding the maternal management and fetal outcomes is lacking. Diagnosing hypercalcemia is challenging during pregnancy, as symptoms such as fatigue or nausea mimic those in early pregnancy. However, longstanding hypercalcemia might induce nephrolithiasis, pancreatitis, and preeclampsia in the mother [1]. Therefore, the occurrence of these diseases during pregnancy should push the physicians to screen for hypercalcemia. In the fetus, maternal hypercalcemia can result in fetal growth restriction [2]. Following birth, further complications may arise such as severe neonatal hypocalcemia, tetany, and even death due to fetal hypoparathyroidism [3, 4]. In rare calcium-related disorders, the diagnosis is often known before the pregnancy and patients and partners can be counseled by the treating endocrinologist, obstetrician, pediatrician, and geneticist when required, taking into account the possible physical and mental maternal adverse effects, but also the eventual consequences for the newborn. Here we would like to discuss the diagnostic challenges and management of hypercalcemia during pregnancy in two particular cases as example of rare conditions causing hypercalcemia complicating pregnancy.
Case 1
A 34-year-old woman was referred with severe hypercalcemia and a pregnancy wish. At the age of 24 she was diagnosed with PHPT, without underlying genetic causes. During parathyroidectomy (PTX) there was spill of the adenoma, histologically confirmed, which led to chronic hypercalcemia for which she underwent several re-operations in various hospitals including a thyroidectomy in 2 tempi with resection of surrounding fat-tissue and a bilateral modified lymph node resection. However, she remained dependent on cinacalcet and bisphosphonates in various dosages. At referral, albumin-corrected serum calcium was 2.89 mmol/L (ref 2.15–2.55 mmol/L) with PTH 10.7 (ref 1–8 pmol/L) while on cinacalcet 60 mg/day, and 3.16 mmol/L with PTH of 29 without cinacalcet. She and her partner were counselled by a team consisting of gynecologists, pediatricians, and endocrinologists on several aspects of the disease and potential consequences for a pregnancy. Prophylactic surgery was not possible at that time. Bisphosphonates were stopped and she became pregnant after 12 months. Cinacalcet was stopped and a fluid intake of 4 L was advised. However, she was admitted with a symptomatic hypercalcemia, 3.4 mmol/L, within 2 weeks. Hyperhydration and cinacalcet, up to 90 mg/day, were started in combination with furosemide 40 mg and acetylsalicylic acid 80 mg daily as preeclampsia prophylaxis. She suffered from severe hyperemesis gravidarum and due to persistent hypercalcemia, she received saline infusions of 5 L/day in a homecare setting with a peripheral intravasal central catheter (PICC). During follow up the PICC caused deep vein thrombosis for which nadroparin injections were started but with this treatment serum calcium remained stable around 2.7–2.9 mmol/L. At 38 weeks of gestation she developed hypertension with a rapidly developing HELLP syndrome and an emergency cesarean section was performed. A healthy baby boy, weight 3305 g, was delivered; he only received active vitamin D supplementation for a few days and two years after delivery; no calcium disturbances or skeletal abnormalities have been observed. The mother did not breastfeed. After delivery, the mother experienced a post-traumatic stress syndrome (PTSS) with depression for which she started Eye Movement Desensitization and Reprocessing (EMDR). The depression and PTSS was related to the latter part of the pregnancy and delivery, but most likely exacerbated due to a postpartum rise in calcium to 3.3 mmol/L. Surgery was successfully performed after which her mental complaints improved.
Case 2
A 38-year-old female was diagnosed with PHPT at a non-university hospital, based on a modest hypercalcemia, and elevated PTH of 9.2 pmol/L and high to normal urinary calcium excretion of 8.5 g/L and calcium-to-creatinine clearance above 0.02. Despite her young age, it was decided not to perform PTX because of an increased risk for venous thromboembolism and obesity. Five years later, she had an unexpected pregnancy and was referred for PTX in the second trimester. During that time serum calcium had increased from 2.63 mmol/L to 2.83 mmol/L with a non-suppressed PTH of 3.8 pmol/L. The patient and her partner were counseled by a team consisting of endocrinologists, anesthesiologists, endocrine surgeons, pediatricians, and obstetricians. Imaging studies did not reveal a clear-cut adenoma and considering the progressive rise in calcium to 2.93 mmol/L, urinary calcium excretion of 12 g/L in 24 h and proceeding into the end of the second trimester an elective neck exploration was performed at gestational age of 24 + 2 weeks, showing four gland hyperplasia. During surgery, it was decided to remove only the two right-sided glands in order not to risk hypoparathyroidism. After surgery hypercalcemia persisted with calcium levels between 2.60 mmol/L and 2.65 mmol/L and PTH between 2.1 pmol/L and 3.6 pmol/L. Considering the marked hyperplasia the patient was discussed in the clinical patient management system (CPMS) panel of main thematic group two, calcium and phosphate disorders of the European Reference Network for rare endocrine diseases (ENDO-ERN). The advice of this panel was to perform genetic testing for familial hypocalciuric calciuria (FHH), which came back positive for a mutation in the CASR-gen, c.653A>G p.(Tyr218Cys), establishing a diagnosis of FHH type one. At 39 + 3 weeks she delivered a healthy baby girl of 4150 g without any calcium disturbances. Post-partum the calcium levels of the mother remained at 2.6 mmol and PTH rose again to 10.3 pmol/L, which has been stable since.
Patient perspective
Patient one had an active pregnancy wish for 5 years, with a negative counselling in several centers. At the Leiden University Medical Center (LUMC) it was again made clear that this would not be without risks for mother and child but if desired we would do our best to monitor the pregnancy as good as possible, which was much appreciated as this was not discussed before. Although she was well prepared and extensively counseled, the intensity of the pregnancy was overwhelming. Both the high calcium levels, frequent investigations and the continuous hyperhydration were extremely demanding and resulted, together with the further rise in calcium, in a pre- and post-natal depression for which EMDR and psychotherapy were needed. Looking back, she would advise other patients to realize that it will be extremely tough, but absolutely worth it. The fact that caretakers were so involved in her well-being and their clear communication was helpful and appreciated. The health care system structure with various doctors during hospital admission remains unfortunate from her point of view, which was in contrast to the outpatient clinic care with one regular healthcare provider.
Despite living with, a supposed, PHPT for many years, patient 2 had never been counseled about PHPT in terms of treatment and follow up. In the initial phase of her referral to LUMC this was done rapidly as time was ticking for a safe window of surgery as the second trimester is the preferred trimester for surgery for maternal and fetal reasons. In addition, due to her increased risk for venous thromboembolism and obesity, emergency surgery in case of severe hypercalcemia was considered to be a high risk for the mother. The patient found the amount of information overwhelming. However, it was appreciated as it made the patient and her partner feel part of the team. After surgery, when she had postoperative pains, this induced more stress being pregnant. Caregivers should be aware that in pregnant patients’ complaints that might be considered as normal after surgery can induce a stressful trigger in patients who are already in a stressful situation. The doubts about the original diagnosis of PHPT were shared including the desire of the treating physicians to discuss her case with other experts. Although providing more insecurity, the patient did feel comfortable that this meant that no other surgery was likely to be needed. After the pregnancy she reported that the physical part of the pregnancy did not give her many discomforts but the uncertainty about the well-being of the baby was very stressful. But overall, she was very satisfied with the care given.
In collaboration with these patients we produced a checklist for women in the same position or with a recent diagnosis of PHPT, which might be of help, see Table 1.Table 1 Questions for women in the childbearing age to ask their doctor when diagnosed with a high calcium level
1. What is the most likely diagnosis causing this high calcium level?
2. What tests do I need to make the diagnosis more likely? And are these tests influenced by pregnancy?
3. How will this affect pregnancy?
What will be the risks for my unborn child?
What will be the risks for me?
Which interventions are possible/necessary before, during and after pregnancy?
4. What can I do to minimalize complaints during and after the pregnancy?
5. How can we decrease my risk for preeclampsia?
6. Which drugs might be used during the pregnancy and what are their side effects?
7. How can you monitor my child?
8. How will my disease affect me after delivery?
9. How will this affect my child directly after delivery?
10. Can I breastfeed?
11. Who is in my multidisciplinary team and how can I reach them?
12. What can be done by my general practitioner?
13. What would be the risk of getting pregnant and to whom can I speak to for counseling?
In both cases patients and partners experienced the pregnancy as a rollercoaster with lot of uncertainties. Whereas both patients were diagnosed with hypercalcemia before pregnancy, patient 1 was counseled extensively in the pre-pregnancy period and even repeatedly got the advice not to become pregnant while patient 2 was never counseled. Also, in patient 2 the diagnosis was changed from PHPT to FHH, the finding of the marked hyperplasia triggered doubts about the original diagnosis of PHPT. In patient 1, the initial decision for surgery would still be made as her calcium values were rising and she did develop nausea and in FHH hyperplasia is also often described.
Physiological changes during pregnancy (Fig. 1a)
During pregnancy and lactation there is increased mobilization of calcium in the mother to meet the fetus’ calcium requirements [5, 6]. This is done by increasing intestinal calcium absorption through increasing 1.25 vitamin D production and PTH-related peptide (PTHrP), which is released from placenta and breasts in response to estradiol, placental lactogen, and prolactin [6, 7]. Despite the overlapping modes of action, PTH and PTHrP are produced by different genes on different chromosomes and the gene encoding PTHrP is more complex than for PTH. PTHrP is undetectable in the circulating blood of non-pregnant women, but is produced in a paracrine/autocrine fashion during pregnancy. Lessons from PTHrP or PTH1R gene knockout mice, which die at birth or in utero, emphasize the critical role of PTHrP for normal life [8, 9]. In addition, nascent PTHrP isoforms are processed by members of the prohormone convertase family to at least three fragments: N-terminal PTHrP [1–36], structurally related to PTH; a mid-region PTHrP (38–94); and a C-terminal PTHrP(107–139) with distinct biological properties and receptors. PTHrP is able to act not only via the classical autocrine/paracrine pathways, but also through a so-called intracrine pathway, which involves the translocation of the protein into the nucleus, where it can directly regulate proliferation and apoptosis [10, 11]. PTHrP has multiple activities including control of fetal development, trans-epithelial calcium transfer, lactation, smooth muscle relaxation, and cell growth. The mid-molecular region of PTHrP stimulates placental calcium transport in the fetus, while the COOH terminal region may also affect osteoclast activity. Thus, although PTHrP was discovered as a tumor-derived hypercalcemic factor, its primary physiological role is as a local regulator of many physiological processes especially in early life [12, 13].Fig. 1 a *Intravascular fluid expansion causes gestational hypoalbuminemia. The dilutional hypoalbuminemia of pregnancy leads to a decline in total calcium concentration. Ionized calcium on the other hand, remains stable and may provide more accurate information. ** The increase in 1.25 vitamin D production leads to an increase in intestinal calcium absorption. ***“Absorptive hypercalciuria of pregnancy”. Postprandial and 24-h urinary calcium excretion increase after 12 weeks, due to increased intestinal calcium absorption supposedly unrelated to increased formation of 1.25 vitamin D in early pregnancy. Fasting urine samples will not be affected by this phenomenon [45]. b *Prednison to reduce 1.25OH formation and thus intestinal calcium absorption. ** Reducing PTH-rp production mammae. *** No clinical data during pregnancy, only case reports. In animal studies no abnormalities observed, but it does pass the placenta [31, 46]. Breastfeeding: in animal studies (rat), cinacalcet is found in milk [46].
Maternal causes and consequences of hypercalcemia (Fig. 1b)
Hypercalcemia due to hyperparathyroidism is the most described cause of hypercalcemia during pregnancy. As most reviews focus on maternal and fetal outcomes in PHPT we will not cover this topic in the current paper [14, 15]. Hyperparathyroidism due to diffusely spread hyperthyroid nodules, parathyromatosis, post-parathyroidectomy, in the context of malignancy, MEN syndromes, or in chronic renal disease has been rarely described [15, 16]. Literature data on parathyromatosis is limited to around 20 cases published so far with only one report on a woman diagnosed and treated during pregnancy [17, 18].
FHH is a rare autosomal dominant disorder, with a prevalence of ~1:78.000 though this might likely be higher, as many cases remain asymptomatic lifelong and no causal treatment is available [19–21]. According to the genetic defect causing the pathology, three types of FHH have been defined [21–24]. FHH1 is the most common type and is found in about 65% of all FHH cases [21]. Patients with FHH present with mild to moderate hypercalcaemia, low urinary excretion, and PTH serum levels that are either normal or slightly elevated. Many patients with FHH are misdiagnosed as suffering from PHPT as in the case of our patient. Data on FHH manifested during pregnancy, literature data are sparse. Only four cases were published so far. Walker et al. reported the case of a pregnant patient, initially diagnosed with PHPT, who showed no improvement after PTX. The newborn presented with asymptomatic hypercalcemia; the genetic analysis confirmed the diagnosis of FHH [25]. The newborn presented elevated serum calcium levels with no clinical symptoms, while the genetic analysis confirmed the diagnosis of FHH. Others reported hypercalcemic profiles for which they underwent surgery during pregnancy [26, 27].
PTHrP-induced hypercalcemia during pregnancy or lactation has also been reported, either with or without gigantomastia [28–33]. In the reported cases, associating gigantomastia and increased PTHrP serum values, hypercalcaemia was diagnosed during gestation and resolved only after mastectomy, bromocriptin administration, or termination of pregnancy [29, 31, 32].
After delivery, there is a risk of severe hypercalcemia in women with PHPT who are lactating as PTH-rp production will increase [6, 34]. Especially women with gestational hypercalcemia with gigantomastia should be advised against breastfeeding as this will keep PTHrp levels high. The rise in PTHrp during pregnancy was not seen in patient 1 in whom PTHrp production was fully suppressed during entire pregnancy. The observed rise in calcium levels in patient 2 might in retrospect be due to her different setpoint and PTHrp production. Mental consequences of hypercalcemia are well known and include depression and anxiety [35, 36]. During pregnancy mothers might have additional stress which might be exaggerated by the hypercalcemia.
Fetal consequences of hypercalcemia
In the fetus, maternal PHPT can result in fetal growth restriction, severe neonatal hypocalcemia, tetany, and death [36]. In maternal FHH potential fetal complications include mild hypercalcemia, severe hypocalcemia, or neonatal severe hyperparathyroidism, depending on the genotype of the fetus. Because FHH is an autosomal dominant condition, three genetic situations might be encountered by the newborns of FHH mothers: the unaffected and the heterozygous neonates might present with hypocalcaemia induced by the in utero suppression of the parathyroid, the latter being at risk of developing hypercalcemia with hypocalcaemia in the first year of life. The homozygous form of FHH results in a severe neonatal hyperparathyroidism, which requires the surgical removal of the glands during the neonatal phase [37, 38].
Most outcomes on the fetal consequences of hypercalcemia were described in reports on patients with PHPT. Untreated hypercalcemia was associated with fetal or neonatal complications in the majority of cases [3, 36, 39, 40]. However, these findings are based on early literature of PHPT patients when hypercalcemia was often diagnosed in an advanced stage and more recent literature has shown that, compared to age-matched controls, women with PHPT had no difference in most pregnancy outcomes, including stillbirths [39]. That same study also showed that Apgar scores and anthropometric measurements were similar to babies born in uncomplicated pregnancies. However, this recent study did not report on maternal outcomes of preeclampsia. Other recent studies also report lower complications rates and good treatment outcomes when the hypercalcemia is moderate and not severe [1, 41].
Elevated maternal serum calcium leads to hypercalcemia in the fetus, which causes fetal parathyroid gland suppression. After delivery, these glands are still suppressed causing fetal hypocalcemia, which is usually transient (lasting 3–5 months after birth), but permanent hypoparathyroidism has anecdotally been described [42].
In the case of parathyromatosis diagnosed during pregnancy, Edling et al. reported that the infant presented initially with high calcium and low PTH levels, which normalized rapidly, with no further complications [18]. Newborns of mothers presenting with humoral hypercalcemia of pregnancy were having normal calcium levels at birth [29, 30, 33].
Diagnosing hypercalcemia during pregnancy might be challenging due to both physiological changes in calcium homeostasis, as well as due to the underlying cause for the hypercalcemia; changes in urinary calcium excretion vary during daytime, introducing difficulty in using urinary calcium indices as a diagnostic tool. In non-pregnant population, the measurement of calcium/creatinine clearance ratio can be useful in distinguishing between PHPT(>0.02 mmol/mmol) and FHH(<0.01 mmol/mmol). However, it is known that almost 20% of FHH patients might present with a calcium/creatinine ratio >0.01, and individuals with PPHT and simultaneous vitamin D deficiency might show lower than expected calcium excretion [43]. Genetic testing, when available, should be considered for confirming the clinical suspicion of FHH. More than 130 CaSR mutations have been reported so far in relation to FHH1, fact that explains the phenotypical variations in relation to the observed differences in serum calcium and PTH levels [21, 44].
During pregnancy, the distinction between FHH and PHPT is further complicated by the physiological changes in maternal calcium metabolism: increased breast and placental production of PTHrP, that together with the placental lactogen, leads to an increase in 1,25-(OH)2- vitamin D and a reduction of the PTH levels. As a result, the intestinal calcium absorption and the urine calcium excretion are physiologically increased [5, 45]. Treatment is depending on the underlying cause and might be invasive or conservative, but all decisions need good counseling, as it concerns not only the mother, but also the fetus and partner as well. Also we, as physicians, need to be aware that the treatment does not stop with the deliverance of a healthy baby and that the postpartum period might actually be the period with the highest risk for the mother due to the risk of sudden rises in calcium level and to excessive mental stress caused by possible events during pregnancy or delivery.
But foremost, irrespective of the underlying cause of hypercalcemia, patients and partners need to be closely involved in the decision processes in order to ensure overall good outcomes for mother and child.
Acknowledgements
We would like to acknowledge the European Reference Network for Rare Endocrine diseases, specifically main thematic group two calcium and phosphate disorders. We would like to thank both C.W.M. Janssen and S. Mourits for their agreement on publication of their medical history and contribution to the content of the manuscript.
Authors contributions
Conceptualization, writing original draft preparation, reviewing and editing: N.M.A-D. Reviewing and editing, critically revising the manuscript: D-A.E, M.C.Z, L.R, and E.M.W.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CINACALCET HYDROCHLORIDE, UNSPECIFIED INGREDIENT | DrugsGivenReaction | CC BY | 33544354 | 20,513,294 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hyperemesis gravidarum'. | Hypercalcemia during pregnancy: management and outcomes for mother and child.
Diagnosing and treating hypercalcemia during pregnancy can be challenging due to both the physiological changes in calcium homeostasis and the underlying cause for the hypercalcemia. During pregnancy and lactation there is increased mobilization of calcium in the mother to meet the fetus' calcium requirements. Here we discuss the diagnostic challenges, management, and patient perspective of hypercalcemia during pregnancy in two particular cases and in other rare conditions causing hypercalcemia.
Introduction
Hypercalcemia in pregnancy is rare and in >90% of cases caused by a newly diagnosed primary hyperparathyroidism (PHPT). Hypercalcemia during pregnancy due to other disorders of calcium metabolism is even more rare and literature regarding the maternal management and fetal outcomes is lacking. Diagnosing hypercalcemia is challenging during pregnancy, as symptoms such as fatigue or nausea mimic those in early pregnancy. However, longstanding hypercalcemia might induce nephrolithiasis, pancreatitis, and preeclampsia in the mother [1]. Therefore, the occurrence of these diseases during pregnancy should push the physicians to screen for hypercalcemia. In the fetus, maternal hypercalcemia can result in fetal growth restriction [2]. Following birth, further complications may arise such as severe neonatal hypocalcemia, tetany, and even death due to fetal hypoparathyroidism [3, 4]. In rare calcium-related disorders, the diagnosis is often known before the pregnancy and patients and partners can be counseled by the treating endocrinologist, obstetrician, pediatrician, and geneticist when required, taking into account the possible physical and mental maternal adverse effects, but also the eventual consequences for the newborn. Here we would like to discuss the diagnostic challenges and management of hypercalcemia during pregnancy in two particular cases as example of rare conditions causing hypercalcemia complicating pregnancy.
Case 1
A 34-year-old woman was referred with severe hypercalcemia and a pregnancy wish. At the age of 24 she was diagnosed with PHPT, without underlying genetic causes. During parathyroidectomy (PTX) there was spill of the adenoma, histologically confirmed, which led to chronic hypercalcemia for which she underwent several re-operations in various hospitals including a thyroidectomy in 2 tempi with resection of surrounding fat-tissue and a bilateral modified lymph node resection. However, she remained dependent on cinacalcet and bisphosphonates in various dosages. At referral, albumin-corrected serum calcium was 2.89 mmol/L (ref 2.15–2.55 mmol/L) with PTH 10.7 (ref 1–8 pmol/L) while on cinacalcet 60 mg/day, and 3.16 mmol/L with PTH of 29 without cinacalcet. She and her partner were counselled by a team consisting of gynecologists, pediatricians, and endocrinologists on several aspects of the disease and potential consequences for a pregnancy. Prophylactic surgery was not possible at that time. Bisphosphonates were stopped and she became pregnant after 12 months. Cinacalcet was stopped and a fluid intake of 4 L was advised. However, she was admitted with a symptomatic hypercalcemia, 3.4 mmol/L, within 2 weeks. Hyperhydration and cinacalcet, up to 90 mg/day, were started in combination with furosemide 40 mg and acetylsalicylic acid 80 mg daily as preeclampsia prophylaxis. She suffered from severe hyperemesis gravidarum and due to persistent hypercalcemia, she received saline infusions of 5 L/day in a homecare setting with a peripheral intravasal central catheter (PICC). During follow up the PICC caused deep vein thrombosis for which nadroparin injections were started but with this treatment serum calcium remained stable around 2.7–2.9 mmol/L. At 38 weeks of gestation she developed hypertension with a rapidly developing HELLP syndrome and an emergency cesarean section was performed. A healthy baby boy, weight 3305 g, was delivered; he only received active vitamin D supplementation for a few days and two years after delivery; no calcium disturbances or skeletal abnormalities have been observed. The mother did not breastfeed. After delivery, the mother experienced a post-traumatic stress syndrome (PTSS) with depression for which she started Eye Movement Desensitization and Reprocessing (EMDR). The depression and PTSS was related to the latter part of the pregnancy and delivery, but most likely exacerbated due to a postpartum rise in calcium to 3.3 mmol/L. Surgery was successfully performed after which her mental complaints improved.
Case 2
A 38-year-old female was diagnosed with PHPT at a non-university hospital, based on a modest hypercalcemia, and elevated PTH of 9.2 pmol/L and high to normal urinary calcium excretion of 8.5 g/L and calcium-to-creatinine clearance above 0.02. Despite her young age, it was decided not to perform PTX because of an increased risk for venous thromboembolism and obesity. Five years later, she had an unexpected pregnancy and was referred for PTX in the second trimester. During that time serum calcium had increased from 2.63 mmol/L to 2.83 mmol/L with a non-suppressed PTH of 3.8 pmol/L. The patient and her partner were counseled by a team consisting of endocrinologists, anesthesiologists, endocrine surgeons, pediatricians, and obstetricians. Imaging studies did not reveal a clear-cut adenoma and considering the progressive rise in calcium to 2.93 mmol/L, urinary calcium excretion of 12 g/L in 24 h and proceeding into the end of the second trimester an elective neck exploration was performed at gestational age of 24 + 2 weeks, showing four gland hyperplasia. During surgery, it was decided to remove only the two right-sided glands in order not to risk hypoparathyroidism. After surgery hypercalcemia persisted with calcium levels between 2.60 mmol/L and 2.65 mmol/L and PTH between 2.1 pmol/L and 3.6 pmol/L. Considering the marked hyperplasia the patient was discussed in the clinical patient management system (CPMS) panel of main thematic group two, calcium and phosphate disorders of the European Reference Network for rare endocrine diseases (ENDO-ERN). The advice of this panel was to perform genetic testing for familial hypocalciuric calciuria (FHH), which came back positive for a mutation in the CASR-gen, c.653A>G p.(Tyr218Cys), establishing a diagnosis of FHH type one. At 39 + 3 weeks she delivered a healthy baby girl of 4150 g without any calcium disturbances. Post-partum the calcium levels of the mother remained at 2.6 mmol and PTH rose again to 10.3 pmol/L, which has been stable since.
Patient perspective
Patient one had an active pregnancy wish for 5 years, with a negative counselling in several centers. At the Leiden University Medical Center (LUMC) it was again made clear that this would not be without risks for mother and child but if desired we would do our best to monitor the pregnancy as good as possible, which was much appreciated as this was not discussed before. Although she was well prepared and extensively counseled, the intensity of the pregnancy was overwhelming. Both the high calcium levels, frequent investigations and the continuous hyperhydration were extremely demanding and resulted, together with the further rise in calcium, in a pre- and post-natal depression for which EMDR and psychotherapy were needed. Looking back, she would advise other patients to realize that it will be extremely tough, but absolutely worth it. The fact that caretakers were so involved in her well-being and their clear communication was helpful and appreciated. The health care system structure with various doctors during hospital admission remains unfortunate from her point of view, which was in contrast to the outpatient clinic care with one regular healthcare provider.
Despite living with, a supposed, PHPT for many years, patient 2 had never been counseled about PHPT in terms of treatment and follow up. In the initial phase of her referral to LUMC this was done rapidly as time was ticking for a safe window of surgery as the second trimester is the preferred trimester for surgery for maternal and fetal reasons. In addition, due to her increased risk for venous thromboembolism and obesity, emergency surgery in case of severe hypercalcemia was considered to be a high risk for the mother. The patient found the amount of information overwhelming. However, it was appreciated as it made the patient and her partner feel part of the team. After surgery, when she had postoperative pains, this induced more stress being pregnant. Caregivers should be aware that in pregnant patients’ complaints that might be considered as normal after surgery can induce a stressful trigger in patients who are already in a stressful situation. The doubts about the original diagnosis of PHPT were shared including the desire of the treating physicians to discuss her case with other experts. Although providing more insecurity, the patient did feel comfortable that this meant that no other surgery was likely to be needed. After the pregnancy she reported that the physical part of the pregnancy did not give her many discomforts but the uncertainty about the well-being of the baby was very stressful. But overall, she was very satisfied with the care given.
In collaboration with these patients we produced a checklist for women in the same position or with a recent diagnosis of PHPT, which might be of help, see Table 1.Table 1 Questions for women in the childbearing age to ask their doctor when diagnosed with a high calcium level
1. What is the most likely diagnosis causing this high calcium level?
2. What tests do I need to make the diagnosis more likely? And are these tests influenced by pregnancy?
3. How will this affect pregnancy?
What will be the risks for my unborn child?
What will be the risks for me?
Which interventions are possible/necessary before, during and after pregnancy?
4. What can I do to minimalize complaints during and after the pregnancy?
5. How can we decrease my risk for preeclampsia?
6. Which drugs might be used during the pregnancy and what are their side effects?
7. How can you monitor my child?
8. How will my disease affect me after delivery?
9. How will this affect my child directly after delivery?
10. Can I breastfeed?
11. Who is in my multidisciplinary team and how can I reach them?
12. What can be done by my general practitioner?
13. What would be the risk of getting pregnant and to whom can I speak to for counseling?
In both cases patients and partners experienced the pregnancy as a rollercoaster with lot of uncertainties. Whereas both patients were diagnosed with hypercalcemia before pregnancy, patient 1 was counseled extensively in the pre-pregnancy period and even repeatedly got the advice not to become pregnant while patient 2 was never counseled. Also, in patient 2 the diagnosis was changed from PHPT to FHH, the finding of the marked hyperplasia triggered doubts about the original diagnosis of PHPT. In patient 1, the initial decision for surgery would still be made as her calcium values were rising and she did develop nausea and in FHH hyperplasia is also often described.
Physiological changes during pregnancy (Fig. 1a)
During pregnancy and lactation there is increased mobilization of calcium in the mother to meet the fetus’ calcium requirements [5, 6]. This is done by increasing intestinal calcium absorption through increasing 1.25 vitamin D production and PTH-related peptide (PTHrP), which is released from placenta and breasts in response to estradiol, placental lactogen, and prolactin [6, 7]. Despite the overlapping modes of action, PTH and PTHrP are produced by different genes on different chromosomes and the gene encoding PTHrP is more complex than for PTH. PTHrP is undetectable in the circulating blood of non-pregnant women, but is produced in a paracrine/autocrine fashion during pregnancy. Lessons from PTHrP or PTH1R gene knockout mice, which die at birth or in utero, emphasize the critical role of PTHrP for normal life [8, 9]. In addition, nascent PTHrP isoforms are processed by members of the prohormone convertase family to at least three fragments: N-terminal PTHrP [1–36], structurally related to PTH; a mid-region PTHrP (38–94); and a C-terminal PTHrP(107–139) with distinct biological properties and receptors. PTHrP is able to act not only via the classical autocrine/paracrine pathways, but also through a so-called intracrine pathway, which involves the translocation of the protein into the nucleus, where it can directly regulate proliferation and apoptosis [10, 11]. PTHrP has multiple activities including control of fetal development, trans-epithelial calcium transfer, lactation, smooth muscle relaxation, and cell growth. The mid-molecular region of PTHrP stimulates placental calcium transport in the fetus, while the COOH terminal region may also affect osteoclast activity. Thus, although PTHrP was discovered as a tumor-derived hypercalcemic factor, its primary physiological role is as a local regulator of many physiological processes especially in early life [12, 13].Fig. 1 a *Intravascular fluid expansion causes gestational hypoalbuminemia. The dilutional hypoalbuminemia of pregnancy leads to a decline in total calcium concentration. Ionized calcium on the other hand, remains stable and may provide more accurate information. ** The increase in 1.25 vitamin D production leads to an increase in intestinal calcium absorption. ***“Absorptive hypercalciuria of pregnancy”. Postprandial and 24-h urinary calcium excretion increase after 12 weeks, due to increased intestinal calcium absorption supposedly unrelated to increased formation of 1.25 vitamin D in early pregnancy. Fasting urine samples will not be affected by this phenomenon [45]. b *Prednison to reduce 1.25OH formation and thus intestinal calcium absorption. ** Reducing PTH-rp production mammae. *** No clinical data during pregnancy, only case reports. In animal studies no abnormalities observed, but it does pass the placenta [31, 46]. Breastfeeding: in animal studies (rat), cinacalcet is found in milk [46].
Maternal causes and consequences of hypercalcemia (Fig. 1b)
Hypercalcemia due to hyperparathyroidism is the most described cause of hypercalcemia during pregnancy. As most reviews focus on maternal and fetal outcomes in PHPT we will not cover this topic in the current paper [14, 15]. Hyperparathyroidism due to diffusely spread hyperthyroid nodules, parathyromatosis, post-parathyroidectomy, in the context of malignancy, MEN syndromes, or in chronic renal disease has been rarely described [15, 16]. Literature data on parathyromatosis is limited to around 20 cases published so far with only one report on a woman diagnosed and treated during pregnancy [17, 18].
FHH is a rare autosomal dominant disorder, with a prevalence of ~1:78.000 though this might likely be higher, as many cases remain asymptomatic lifelong and no causal treatment is available [19–21]. According to the genetic defect causing the pathology, three types of FHH have been defined [21–24]. FHH1 is the most common type and is found in about 65% of all FHH cases [21]. Patients with FHH present with mild to moderate hypercalcaemia, low urinary excretion, and PTH serum levels that are either normal or slightly elevated. Many patients with FHH are misdiagnosed as suffering from PHPT as in the case of our patient. Data on FHH manifested during pregnancy, literature data are sparse. Only four cases were published so far. Walker et al. reported the case of a pregnant patient, initially diagnosed with PHPT, who showed no improvement after PTX. The newborn presented with asymptomatic hypercalcemia; the genetic analysis confirmed the diagnosis of FHH [25]. The newborn presented elevated serum calcium levels with no clinical symptoms, while the genetic analysis confirmed the diagnosis of FHH. Others reported hypercalcemic profiles for which they underwent surgery during pregnancy [26, 27].
PTHrP-induced hypercalcemia during pregnancy or lactation has also been reported, either with or without gigantomastia [28–33]. In the reported cases, associating gigantomastia and increased PTHrP serum values, hypercalcaemia was diagnosed during gestation and resolved only after mastectomy, bromocriptin administration, or termination of pregnancy [29, 31, 32].
After delivery, there is a risk of severe hypercalcemia in women with PHPT who are lactating as PTH-rp production will increase [6, 34]. Especially women with gestational hypercalcemia with gigantomastia should be advised against breastfeeding as this will keep PTHrp levels high. The rise in PTHrp during pregnancy was not seen in patient 1 in whom PTHrp production was fully suppressed during entire pregnancy. The observed rise in calcium levels in patient 2 might in retrospect be due to her different setpoint and PTHrp production. Mental consequences of hypercalcemia are well known and include depression and anxiety [35, 36]. During pregnancy mothers might have additional stress which might be exaggerated by the hypercalcemia.
Fetal consequences of hypercalcemia
In the fetus, maternal PHPT can result in fetal growth restriction, severe neonatal hypocalcemia, tetany, and death [36]. In maternal FHH potential fetal complications include mild hypercalcemia, severe hypocalcemia, or neonatal severe hyperparathyroidism, depending on the genotype of the fetus. Because FHH is an autosomal dominant condition, three genetic situations might be encountered by the newborns of FHH mothers: the unaffected and the heterozygous neonates might present with hypocalcaemia induced by the in utero suppression of the parathyroid, the latter being at risk of developing hypercalcemia with hypocalcaemia in the first year of life. The homozygous form of FHH results in a severe neonatal hyperparathyroidism, which requires the surgical removal of the glands during the neonatal phase [37, 38].
Most outcomes on the fetal consequences of hypercalcemia were described in reports on patients with PHPT. Untreated hypercalcemia was associated with fetal or neonatal complications in the majority of cases [3, 36, 39, 40]. However, these findings are based on early literature of PHPT patients when hypercalcemia was often diagnosed in an advanced stage and more recent literature has shown that, compared to age-matched controls, women with PHPT had no difference in most pregnancy outcomes, including stillbirths [39]. That same study also showed that Apgar scores and anthropometric measurements were similar to babies born in uncomplicated pregnancies. However, this recent study did not report on maternal outcomes of preeclampsia. Other recent studies also report lower complications rates and good treatment outcomes when the hypercalcemia is moderate and not severe [1, 41].
Elevated maternal serum calcium leads to hypercalcemia in the fetus, which causes fetal parathyroid gland suppression. After delivery, these glands are still suppressed causing fetal hypocalcemia, which is usually transient (lasting 3–5 months after birth), but permanent hypoparathyroidism has anecdotally been described [42].
In the case of parathyromatosis diagnosed during pregnancy, Edling et al. reported that the infant presented initially with high calcium and low PTH levels, which normalized rapidly, with no further complications [18]. Newborns of mothers presenting with humoral hypercalcemia of pregnancy were having normal calcium levels at birth [29, 30, 33].
Diagnosing hypercalcemia during pregnancy might be challenging due to both physiological changes in calcium homeostasis, as well as due to the underlying cause for the hypercalcemia; changes in urinary calcium excretion vary during daytime, introducing difficulty in using urinary calcium indices as a diagnostic tool. In non-pregnant population, the measurement of calcium/creatinine clearance ratio can be useful in distinguishing between PHPT(>0.02 mmol/mmol) and FHH(<0.01 mmol/mmol). However, it is known that almost 20% of FHH patients might present with a calcium/creatinine ratio >0.01, and individuals with PPHT and simultaneous vitamin D deficiency might show lower than expected calcium excretion [43]. Genetic testing, when available, should be considered for confirming the clinical suspicion of FHH. More than 130 CaSR mutations have been reported so far in relation to FHH1, fact that explains the phenotypical variations in relation to the observed differences in serum calcium and PTH levels [21, 44].
During pregnancy, the distinction between FHH and PHPT is further complicated by the physiological changes in maternal calcium metabolism: increased breast and placental production of PTHrP, that together with the placental lactogen, leads to an increase in 1,25-(OH)2- vitamin D and a reduction of the PTH levels. As a result, the intestinal calcium absorption and the urine calcium excretion are physiologically increased [5, 45]. Treatment is depending on the underlying cause and might be invasive or conservative, but all decisions need good counseling, as it concerns not only the mother, but also the fetus and partner as well. Also we, as physicians, need to be aware that the treatment does not stop with the deliverance of a healthy baby and that the postpartum period might actually be the period with the highest risk for the mother due to the risk of sudden rises in calcium level and to excessive mental stress caused by possible events during pregnancy or delivery.
But foremost, irrespective of the underlying cause of hypercalcemia, patients and partners need to be closely involved in the decision processes in order to ensure overall good outcomes for mother and child.
Acknowledgements
We would like to acknowledge the European Reference Network for Rare Endocrine diseases, specifically main thematic group two calcium and phosphate disorders. We would like to thank both C.W.M. Janssen and S. Mourits for their agreement on publication of their medical history and contribution to the content of the manuscript.
Authors contributions
Conceptualization, writing original draft preparation, reviewing and editing: N.M.A-D. Reviewing and editing, critically revising the manuscript: D-A.E, M.C.Z, L.R, and E.M.W.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CINACALCET HYDROCHLORIDE, UNSPECIFIED INGREDIENT | DrugsGivenReaction | CC BY | 33544354 | 20,513,294 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypertension'. | Hypercalcemia during pregnancy: management and outcomes for mother and child.
Diagnosing and treating hypercalcemia during pregnancy can be challenging due to both the physiological changes in calcium homeostasis and the underlying cause for the hypercalcemia. During pregnancy and lactation there is increased mobilization of calcium in the mother to meet the fetus' calcium requirements. Here we discuss the diagnostic challenges, management, and patient perspective of hypercalcemia during pregnancy in two particular cases and in other rare conditions causing hypercalcemia.
Introduction
Hypercalcemia in pregnancy is rare and in >90% of cases caused by a newly diagnosed primary hyperparathyroidism (PHPT). Hypercalcemia during pregnancy due to other disorders of calcium metabolism is even more rare and literature regarding the maternal management and fetal outcomes is lacking. Diagnosing hypercalcemia is challenging during pregnancy, as symptoms such as fatigue or nausea mimic those in early pregnancy. However, longstanding hypercalcemia might induce nephrolithiasis, pancreatitis, and preeclampsia in the mother [1]. Therefore, the occurrence of these diseases during pregnancy should push the physicians to screen for hypercalcemia. In the fetus, maternal hypercalcemia can result in fetal growth restriction [2]. Following birth, further complications may arise such as severe neonatal hypocalcemia, tetany, and even death due to fetal hypoparathyroidism [3, 4]. In rare calcium-related disorders, the diagnosis is often known before the pregnancy and patients and partners can be counseled by the treating endocrinologist, obstetrician, pediatrician, and geneticist when required, taking into account the possible physical and mental maternal adverse effects, but also the eventual consequences for the newborn. Here we would like to discuss the diagnostic challenges and management of hypercalcemia during pregnancy in two particular cases as example of rare conditions causing hypercalcemia complicating pregnancy.
Case 1
A 34-year-old woman was referred with severe hypercalcemia and a pregnancy wish. At the age of 24 she was diagnosed with PHPT, without underlying genetic causes. During parathyroidectomy (PTX) there was spill of the adenoma, histologically confirmed, which led to chronic hypercalcemia for which she underwent several re-operations in various hospitals including a thyroidectomy in 2 tempi with resection of surrounding fat-tissue and a bilateral modified lymph node resection. However, she remained dependent on cinacalcet and bisphosphonates in various dosages. At referral, albumin-corrected serum calcium was 2.89 mmol/L (ref 2.15–2.55 mmol/L) with PTH 10.7 (ref 1–8 pmol/L) while on cinacalcet 60 mg/day, and 3.16 mmol/L with PTH of 29 without cinacalcet. She and her partner were counselled by a team consisting of gynecologists, pediatricians, and endocrinologists on several aspects of the disease and potential consequences for a pregnancy. Prophylactic surgery was not possible at that time. Bisphosphonates were stopped and she became pregnant after 12 months. Cinacalcet was stopped and a fluid intake of 4 L was advised. However, she was admitted with a symptomatic hypercalcemia, 3.4 mmol/L, within 2 weeks. Hyperhydration and cinacalcet, up to 90 mg/day, were started in combination with furosemide 40 mg and acetylsalicylic acid 80 mg daily as preeclampsia prophylaxis. She suffered from severe hyperemesis gravidarum and due to persistent hypercalcemia, she received saline infusions of 5 L/day in a homecare setting with a peripheral intravasal central catheter (PICC). During follow up the PICC caused deep vein thrombosis for which nadroparin injections were started but with this treatment serum calcium remained stable around 2.7–2.9 mmol/L. At 38 weeks of gestation she developed hypertension with a rapidly developing HELLP syndrome and an emergency cesarean section was performed. A healthy baby boy, weight 3305 g, was delivered; he only received active vitamin D supplementation for a few days and two years after delivery; no calcium disturbances or skeletal abnormalities have been observed. The mother did not breastfeed. After delivery, the mother experienced a post-traumatic stress syndrome (PTSS) with depression for which she started Eye Movement Desensitization and Reprocessing (EMDR). The depression and PTSS was related to the latter part of the pregnancy and delivery, but most likely exacerbated due to a postpartum rise in calcium to 3.3 mmol/L. Surgery was successfully performed after which her mental complaints improved.
Case 2
A 38-year-old female was diagnosed with PHPT at a non-university hospital, based on a modest hypercalcemia, and elevated PTH of 9.2 pmol/L and high to normal urinary calcium excretion of 8.5 g/L and calcium-to-creatinine clearance above 0.02. Despite her young age, it was decided not to perform PTX because of an increased risk for venous thromboembolism and obesity. Five years later, she had an unexpected pregnancy and was referred for PTX in the second trimester. During that time serum calcium had increased from 2.63 mmol/L to 2.83 mmol/L with a non-suppressed PTH of 3.8 pmol/L. The patient and her partner were counseled by a team consisting of endocrinologists, anesthesiologists, endocrine surgeons, pediatricians, and obstetricians. Imaging studies did not reveal a clear-cut adenoma and considering the progressive rise in calcium to 2.93 mmol/L, urinary calcium excretion of 12 g/L in 24 h and proceeding into the end of the second trimester an elective neck exploration was performed at gestational age of 24 + 2 weeks, showing four gland hyperplasia. During surgery, it was decided to remove only the two right-sided glands in order not to risk hypoparathyroidism. After surgery hypercalcemia persisted with calcium levels between 2.60 mmol/L and 2.65 mmol/L and PTH between 2.1 pmol/L and 3.6 pmol/L. Considering the marked hyperplasia the patient was discussed in the clinical patient management system (CPMS) panel of main thematic group two, calcium and phosphate disorders of the European Reference Network for rare endocrine diseases (ENDO-ERN). The advice of this panel was to perform genetic testing for familial hypocalciuric calciuria (FHH), which came back positive for a mutation in the CASR-gen, c.653A>G p.(Tyr218Cys), establishing a diagnosis of FHH type one. At 39 + 3 weeks she delivered a healthy baby girl of 4150 g without any calcium disturbances. Post-partum the calcium levels of the mother remained at 2.6 mmol and PTH rose again to 10.3 pmol/L, which has been stable since.
Patient perspective
Patient one had an active pregnancy wish for 5 years, with a negative counselling in several centers. At the Leiden University Medical Center (LUMC) it was again made clear that this would not be without risks for mother and child but if desired we would do our best to monitor the pregnancy as good as possible, which was much appreciated as this was not discussed before. Although she was well prepared and extensively counseled, the intensity of the pregnancy was overwhelming. Both the high calcium levels, frequent investigations and the continuous hyperhydration were extremely demanding and resulted, together with the further rise in calcium, in a pre- and post-natal depression for which EMDR and psychotherapy were needed. Looking back, she would advise other patients to realize that it will be extremely tough, but absolutely worth it. The fact that caretakers were so involved in her well-being and their clear communication was helpful and appreciated. The health care system structure with various doctors during hospital admission remains unfortunate from her point of view, which was in contrast to the outpatient clinic care with one regular healthcare provider.
Despite living with, a supposed, PHPT for many years, patient 2 had never been counseled about PHPT in terms of treatment and follow up. In the initial phase of her referral to LUMC this was done rapidly as time was ticking for a safe window of surgery as the second trimester is the preferred trimester for surgery for maternal and fetal reasons. In addition, due to her increased risk for venous thromboembolism and obesity, emergency surgery in case of severe hypercalcemia was considered to be a high risk for the mother. The patient found the amount of information overwhelming. However, it was appreciated as it made the patient and her partner feel part of the team. After surgery, when she had postoperative pains, this induced more stress being pregnant. Caregivers should be aware that in pregnant patients’ complaints that might be considered as normal after surgery can induce a stressful trigger in patients who are already in a stressful situation. The doubts about the original diagnosis of PHPT were shared including the desire of the treating physicians to discuss her case with other experts. Although providing more insecurity, the patient did feel comfortable that this meant that no other surgery was likely to be needed. After the pregnancy she reported that the physical part of the pregnancy did not give her many discomforts but the uncertainty about the well-being of the baby was very stressful. But overall, she was very satisfied with the care given.
In collaboration with these patients we produced a checklist for women in the same position or with a recent diagnosis of PHPT, which might be of help, see Table 1.Table 1 Questions for women in the childbearing age to ask their doctor when diagnosed with a high calcium level
1. What is the most likely diagnosis causing this high calcium level?
2. What tests do I need to make the diagnosis more likely? And are these tests influenced by pregnancy?
3. How will this affect pregnancy?
What will be the risks for my unborn child?
What will be the risks for me?
Which interventions are possible/necessary before, during and after pregnancy?
4. What can I do to minimalize complaints during and after the pregnancy?
5. How can we decrease my risk for preeclampsia?
6. Which drugs might be used during the pregnancy and what are their side effects?
7. How can you monitor my child?
8. How will my disease affect me after delivery?
9. How will this affect my child directly after delivery?
10. Can I breastfeed?
11. Who is in my multidisciplinary team and how can I reach them?
12. What can be done by my general practitioner?
13. What would be the risk of getting pregnant and to whom can I speak to for counseling?
In both cases patients and partners experienced the pregnancy as a rollercoaster with lot of uncertainties. Whereas both patients were diagnosed with hypercalcemia before pregnancy, patient 1 was counseled extensively in the pre-pregnancy period and even repeatedly got the advice not to become pregnant while patient 2 was never counseled. Also, in patient 2 the diagnosis was changed from PHPT to FHH, the finding of the marked hyperplasia triggered doubts about the original diagnosis of PHPT. In patient 1, the initial decision for surgery would still be made as her calcium values were rising and she did develop nausea and in FHH hyperplasia is also often described.
Physiological changes during pregnancy (Fig. 1a)
During pregnancy and lactation there is increased mobilization of calcium in the mother to meet the fetus’ calcium requirements [5, 6]. This is done by increasing intestinal calcium absorption through increasing 1.25 vitamin D production and PTH-related peptide (PTHrP), which is released from placenta and breasts in response to estradiol, placental lactogen, and prolactin [6, 7]. Despite the overlapping modes of action, PTH and PTHrP are produced by different genes on different chromosomes and the gene encoding PTHrP is more complex than for PTH. PTHrP is undetectable in the circulating blood of non-pregnant women, but is produced in a paracrine/autocrine fashion during pregnancy. Lessons from PTHrP or PTH1R gene knockout mice, which die at birth or in utero, emphasize the critical role of PTHrP for normal life [8, 9]. In addition, nascent PTHrP isoforms are processed by members of the prohormone convertase family to at least three fragments: N-terminal PTHrP [1–36], structurally related to PTH; a mid-region PTHrP (38–94); and a C-terminal PTHrP(107–139) with distinct biological properties and receptors. PTHrP is able to act not only via the classical autocrine/paracrine pathways, but also through a so-called intracrine pathway, which involves the translocation of the protein into the nucleus, where it can directly regulate proliferation and apoptosis [10, 11]. PTHrP has multiple activities including control of fetal development, trans-epithelial calcium transfer, lactation, smooth muscle relaxation, and cell growth. The mid-molecular region of PTHrP stimulates placental calcium transport in the fetus, while the COOH terminal region may also affect osteoclast activity. Thus, although PTHrP was discovered as a tumor-derived hypercalcemic factor, its primary physiological role is as a local regulator of many physiological processes especially in early life [12, 13].Fig. 1 a *Intravascular fluid expansion causes gestational hypoalbuminemia. The dilutional hypoalbuminemia of pregnancy leads to a decline in total calcium concentration. Ionized calcium on the other hand, remains stable and may provide more accurate information. ** The increase in 1.25 vitamin D production leads to an increase in intestinal calcium absorption. ***“Absorptive hypercalciuria of pregnancy”. Postprandial and 24-h urinary calcium excretion increase after 12 weeks, due to increased intestinal calcium absorption supposedly unrelated to increased formation of 1.25 vitamin D in early pregnancy. Fasting urine samples will not be affected by this phenomenon [45]. b *Prednison to reduce 1.25OH formation and thus intestinal calcium absorption. ** Reducing PTH-rp production mammae. *** No clinical data during pregnancy, only case reports. In animal studies no abnormalities observed, but it does pass the placenta [31, 46]. Breastfeeding: in animal studies (rat), cinacalcet is found in milk [46].
Maternal causes and consequences of hypercalcemia (Fig. 1b)
Hypercalcemia due to hyperparathyroidism is the most described cause of hypercalcemia during pregnancy. As most reviews focus on maternal and fetal outcomes in PHPT we will not cover this topic in the current paper [14, 15]. Hyperparathyroidism due to diffusely spread hyperthyroid nodules, parathyromatosis, post-parathyroidectomy, in the context of malignancy, MEN syndromes, or in chronic renal disease has been rarely described [15, 16]. Literature data on parathyromatosis is limited to around 20 cases published so far with only one report on a woman diagnosed and treated during pregnancy [17, 18].
FHH is a rare autosomal dominant disorder, with a prevalence of ~1:78.000 though this might likely be higher, as many cases remain asymptomatic lifelong and no causal treatment is available [19–21]. According to the genetic defect causing the pathology, three types of FHH have been defined [21–24]. FHH1 is the most common type and is found in about 65% of all FHH cases [21]. Patients with FHH present with mild to moderate hypercalcaemia, low urinary excretion, and PTH serum levels that are either normal or slightly elevated. Many patients with FHH are misdiagnosed as suffering from PHPT as in the case of our patient. Data on FHH manifested during pregnancy, literature data are sparse. Only four cases were published so far. Walker et al. reported the case of a pregnant patient, initially diagnosed with PHPT, who showed no improvement after PTX. The newborn presented with asymptomatic hypercalcemia; the genetic analysis confirmed the diagnosis of FHH [25]. The newborn presented elevated serum calcium levels with no clinical symptoms, while the genetic analysis confirmed the diagnosis of FHH. Others reported hypercalcemic profiles for which they underwent surgery during pregnancy [26, 27].
PTHrP-induced hypercalcemia during pregnancy or lactation has also been reported, either with or without gigantomastia [28–33]. In the reported cases, associating gigantomastia and increased PTHrP serum values, hypercalcaemia was diagnosed during gestation and resolved only after mastectomy, bromocriptin administration, or termination of pregnancy [29, 31, 32].
After delivery, there is a risk of severe hypercalcemia in women with PHPT who are lactating as PTH-rp production will increase [6, 34]. Especially women with gestational hypercalcemia with gigantomastia should be advised against breastfeeding as this will keep PTHrp levels high. The rise in PTHrp during pregnancy was not seen in patient 1 in whom PTHrp production was fully suppressed during entire pregnancy. The observed rise in calcium levels in patient 2 might in retrospect be due to her different setpoint and PTHrp production. Mental consequences of hypercalcemia are well known and include depression and anxiety [35, 36]. During pregnancy mothers might have additional stress which might be exaggerated by the hypercalcemia.
Fetal consequences of hypercalcemia
In the fetus, maternal PHPT can result in fetal growth restriction, severe neonatal hypocalcemia, tetany, and death [36]. In maternal FHH potential fetal complications include mild hypercalcemia, severe hypocalcemia, or neonatal severe hyperparathyroidism, depending on the genotype of the fetus. Because FHH is an autosomal dominant condition, three genetic situations might be encountered by the newborns of FHH mothers: the unaffected and the heterozygous neonates might present with hypocalcaemia induced by the in utero suppression of the parathyroid, the latter being at risk of developing hypercalcemia with hypocalcaemia in the first year of life. The homozygous form of FHH results in a severe neonatal hyperparathyroidism, which requires the surgical removal of the glands during the neonatal phase [37, 38].
Most outcomes on the fetal consequences of hypercalcemia were described in reports on patients with PHPT. Untreated hypercalcemia was associated with fetal or neonatal complications in the majority of cases [3, 36, 39, 40]. However, these findings are based on early literature of PHPT patients when hypercalcemia was often diagnosed in an advanced stage and more recent literature has shown that, compared to age-matched controls, women with PHPT had no difference in most pregnancy outcomes, including stillbirths [39]. That same study also showed that Apgar scores and anthropometric measurements were similar to babies born in uncomplicated pregnancies. However, this recent study did not report on maternal outcomes of preeclampsia. Other recent studies also report lower complications rates and good treatment outcomes when the hypercalcemia is moderate and not severe [1, 41].
Elevated maternal serum calcium leads to hypercalcemia in the fetus, which causes fetal parathyroid gland suppression. After delivery, these glands are still suppressed causing fetal hypocalcemia, which is usually transient (lasting 3–5 months after birth), but permanent hypoparathyroidism has anecdotally been described [42].
In the case of parathyromatosis diagnosed during pregnancy, Edling et al. reported that the infant presented initially with high calcium and low PTH levels, which normalized rapidly, with no further complications [18]. Newborns of mothers presenting with humoral hypercalcemia of pregnancy were having normal calcium levels at birth [29, 30, 33].
Diagnosing hypercalcemia during pregnancy might be challenging due to both physiological changes in calcium homeostasis, as well as due to the underlying cause for the hypercalcemia; changes in urinary calcium excretion vary during daytime, introducing difficulty in using urinary calcium indices as a diagnostic tool. In non-pregnant population, the measurement of calcium/creatinine clearance ratio can be useful in distinguishing between PHPT(>0.02 mmol/mmol) and FHH(<0.01 mmol/mmol). However, it is known that almost 20% of FHH patients might present with a calcium/creatinine ratio >0.01, and individuals with PPHT and simultaneous vitamin D deficiency might show lower than expected calcium excretion [43]. Genetic testing, when available, should be considered for confirming the clinical suspicion of FHH. More than 130 CaSR mutations have been reported so far in relation to FHH1, fact that explains the phenotypical variations in relation to the observed differences in serum calcium and PTH levels [21, 44].
During pregnancy, the distinction between FHH and PHPT is further complicated by the physiological changes in maternal calcium metabolism: increased breast and placental production of PTHrP, that together with the placental lactogen, leads to an increase in 1,25-(OH)2- vitamin D and a reduction of the PTH levels. As a result, the intestinal calcium absorption and the urine calcium excretion are physiologically increased [5, 45]. Treatment is depending on the underlying cause and might be invasive or conservative, but all decisions need good counseling, as it concerns not only the mother, but also the fetus and partner as well. Also we, as physicians, need to be aware that the treatment does not stop with the deliverance of a healthy baby and that the postpartum period might actually be the period with the highest risk for the mother due to the risk of sudden rises in calcium level and to excessive mental stress caused by possible events during pregnancy or delivery.
But foremost, irrespective of the underlying cause of hypercalcemia, patients and partners need to be closely involved in the decision processes in order to ensure overall good outcomes for mother and child.
Acknowledgements
We would like to acknowledge the European Reference Network for Rare Endocrine diseases, specifically main thematic group two calcium and phosphate disorders. We would like to thank both C.W.M. Janssen and S. Mourits for their agreement on publication of their medical history and contribution to the content of the manuscript.
Authors contributions
Conceptualization, writing original draft preparation, reviewing and editing: N.M.A-D. Reviewing and editing, critically revising the manuscript: D-A.E, M.C.Z, L.R, and E.M.W.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CINACALCET HYDROCHLORIDE, UNSPECIFIED INGREDIENT | DrugsGivenReaction | CC BY | 33544354 | 20,513,294 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Live birth'. | Hypercalcemia during pregnancy: management and outcomes for mother and child.
Diagnosing and treating hypercalcemia during pregnancy can be challenging due to both the physiological changes in calcium homeostasis and the underlying cause for the hypercalcemia. During pregnancy and lactation there is increased mobilization of calcium in the mother to meet the fetus' calcium requirements. Here we discuss the diagnostic challenges, management, and patient perspective of hypercalcemia during pregnancy in two particular cases and in other rare conditions causing hypercalcemia.
Introduction
Hypercalcemia in pregnancy is rare and in >90% of cases caused by a newly diagnosed primary hyperparathyroidism (PHPT). Hypercalcemia during pregnancy due to other disorders of calcium metabolism is even more rare and literature regarding the maternal management and fetal outcomes is lacking. Diagnosing hypercalcemia is challenging during pregnancy, as symptoms such as fatigue or nausea mimic those in early pregnancy. However, longstanding hypercalcemia might induce nephrolithiasis, pancreatitis, and preeclampsia in the mother [1]. Therefore, the occurrence of these diseases during pregnancy should push the physicians to screen for hypercalcemia. In the fetus, maternal hypercalcemia can result in fetal growth restriction [2]. Following birth, further complications may arise such as severe neonatal hypocalcemia, tetany, and even death due to fetal hypoparathyroidism [3, 4]. In rare calcium-related disorders, the diagnosis is often known before the pregnancy and patients and partners can be counseled by the treating endocrinologist, obstetrician, pediatrician, and geneticist when required, taking into account the possible physical and mental maternal adverse effects, but also the eventual consequences for the newborn. Here we would like to discuss the diagnostic challenges and management of hypercalcemia during pregnancy in two particular cases as example of rare conditions causing hypercalcemia complicating pregnancy.
Case 1
A 34-year-old woman was referred with severe hypercalcemia and a pregnancy wish. At the age of 24 she was diagnosed with PHPT, without underlying genetic causes. During parathyroidectomy (PTX) there was spill of the adenoma, histologically confirmed, which led to chronic hypercalcemia for which she underwent several re-operations in various hospitals including a thyroidectomy in 2 tempi with resection of surrounding fat-tissue and a bilateral modified lymph node resection. However, she remained dependent on cinacalcet and bisphosphonates in various dosages. At referral, albumin-corrected serum calcium was 2.89 mmol/L (ref 2.15–2.55 mmol/L) with PTH 10.7 (ref 1–8 pmol/L) while on cinacalcet 60 mg/day, and 3.16 mmol/L with PTH of 29 without cinacalcet. She and her partner were counselled by a team consisting of gynecologists, pediatricians, and endocrinologists on several aspects of the disease and potential consequences for a pregnancy. Prophylactic surgery was not possible at that time. Bisphosphonates were stopped and she became pregnant after 12 months. Cinacalcet was stopped and a fluid intake of 4 L was advised. However, she was admitted with a symptomatic hypercalcemia, 3.4 mmol/L, within 2 weeks. Hyperhydration and cinacalcet, up to 90 mg/day, were started in combination with furosemide 40 mg and acetylsalicylic acid 80 mg daily as preeclampsia prophylaxis. She suffered from severe hyperemesis gravidarum and due to persistent hypercalcemia, she received saline infusions of 5 L/day in a homecare setting with a peripheral intravasal central catheter (PICC). During follow up the PICC caused deep vein thrombosis for which nadroparin injections were started but with this treatment serum calcium remained stable around 2.7–2.9 mmol/L. At 38 weeks of gestation she developed hypertension with a rapidly developing HELLP syndrome and an emergency cesarean section was performed. A healthy baby boy, weight 3305 g, was delivered; he only received active vitamin D supplementation for a few days and two years after delivery; no calcium disturbances or skeletal abnormalities have been observed. The mother did not breastfeed. After delivery, the mother experienced a post-traumatic stress syndrome (PTSS) with depression for which she started Eye Movement Desensitization and Reprocessing (EMDR). The depression and PTSS was related to the latter part of the pregnancy and delivery, but most likely exacerbated due to a postpartum rise in calcium to 3.3 mmol/L. Surgery was successfully performed after which her mental complaints improved.
Case 2
A 38-year-old female was diagnosed with PHPT at a non-university hospital, based on a modest hypercalcemia, and elevated PTH of 9.2 pmol/L and high to normal urinary calcium excretion of 8.5 g/L and calcium-to-creatinine clearance above 0.02. Despite her young age, it was decided not to perform PTX because of an increased risk for venous thromboembolism and obesity. Five years later, she had an unexpected pregnancy and was referred for PTX in the second trimester. During that time serum calcium had increased from 2.63 mmol/L to 2.83 mmol/L with a non-suppressed PTH of 3.8 pmol/L. The patient and her partner were counseled by a team consisting of endocrinologists, anesthesiologists, endocrine surgeons, pediatricians, and obstetricians. Imaging studies did not reveal a clear-cut adenoma and considering the progressive rise in calcium to 2.93 mmol/L, urinary calcium excretion of 12 g/L in 24 h and proceeding into the end of the second trimester an elective neck exploration was performed at gestational age of 24 + 2 weeks, showing four gland hyperplasia. During surgery, it was decided to remove only the two right-sided glands in order not to risk hypoparathyroidism. After surgery hypercalcemia persisted with calcium levels between 2.60 mmol/L and 2.65 mmol/L and PTH between 2.1 pmol/L and 3.6 pmol/L. Considering the marked hyperplasia the patient was discussed in the clinical patient management system (CPMS) panel of main thematic group two, calcium and phosphate disorders of the European Reference Network for rare endocrine diseases (ENDO-ERN). The advice of this panel was to perform genetic testing for familial hypocalciuric calciuria (FHH), which came back positive for a mutation in the CASR-gen, c.653A>G p.(Tyr218Cys), establishing a diagnosis of FHH type one. At 39 + 3 weeks she delivered a healthy baby girl of 4150 g without any calcium disturbances. Post-partum the calcium levels of the mother remained at 2.6 mmol and PTH rose again to 10.3 pmol/L, which has been stable since.
Patient perspective
Patient one had an active pregnancy wish for 5 years, with a negative counselling in several centers. At the Leiden University Medical Center (LUMC) it was again made clear that this would not be without risks for mother and child but if desired we would do our best to monitor the pregnancy as good as possible, which was much appreciated as this was not discussed before. Although she was well prepared and extensively counseled, the intensity of the pregnancy was overwhelming. Both the high calcium levels, frequent investigations and the continuous hyperhydration were extremely demanding and resulted, together with the further rise in calcium, in a pre- and post-natal depression for which EMDR and psychotherapy were needed. Looking back, she would advise other patients to realize that it will be extremely tough, but absolutely worth it. The fact that caretakers were so involved in her well-being and their clear communication was helpful and appreciated. The health care system structure with various doctors during hospital admission remains unfortunate from her point of view, which was in contrast to the outpatient clinic care with one regular healthcare provider.
Despite living with, a supposed, PHPT for many years, patient 2 had never been counseled about PHPT in terms of treatment and follow up. In the initial phase of her referral to LUMC this was done rapidly as time was ticking for a safe window of surgery as the second trimester is the preferred trimester for surgery for maternal and fetal reasons. In addition, due to her increased risk for venous thromboembolism and obesity, emergency surgery in case of severe hypercalcemia was considered to be a high risk for the mother. The patient found the amount of information overwhelming. However, it was appreciated as it made the patient and her partner feel part of the team. After surgery, when she had postoperative pains, this induced more stress being pregnant. Caregivers should be aware that in pregnant patients’ complaints that might be considered as normal after surgery can induce a stressful trigger in patients who are already in a stressful situation. The doubts about the original diagnosis of PHPT were shared including the desire of the treating physicians to discuss her case with other experts. Although providing more insecurity, the patient did feel comfortable that this meant that no other surgery was likely to be needed. After the pregnancy she reported that the physical part of the pregnancy did not give her many discomforts but the uncertainty about the well-being of the baby was very stressful. But overall, she was very satisfied with the care given.
In collaboration with these patients we produced a checklist for women in the same position or with a recent diagnosis of PHPT, which might be of help, see Table 1.Table 1 Questions for women in the childbearing age to ask their doctor when diagnosed with a high calcium level
1. What is the most likely diagnosis causing this high calcium level?
2. What tests do I need to make the diagnosis more likely? And are these tests influenced by pregnancy?
3. How will this affect pregnancy?
What will be the risks for my unborn child?
What will be the risks for me?
Which interventions are possible/necessary before, during and after pregnancy?
4. What can I do to minimalize complaints during and after the pregnancy?
5. How can we decrease my risk for preeclampsia?
6. Which drugs might be used during the pregnancy and what are their side effects?
7. How can you monitor my child?
8. How will my disease affect me after delivery?
9. How will this affect my child directly after delivery?
10. Can I breastfeed?
11. Who is in my multidisciplinary team and how can I reach them?
12. What can be done by my general practitioner?
13. What would be the risk of getting pregnant and to whom can I speak to for counseling?
In both cases patients and partners experienced the pregnancy as a rollercoaster with lot of uncertainties. Whereas both patients were diagnosed with hypercalcemia before pregnancy, patient 1 was counseled extensively in the pre-pregnancy period and even repeatedly got the advice not to become pregnant while patient 2 was never counseled. Also, in patient 2 the diagnosis was changed from PHPT to FHH, the finding of the marked hyperplasia triggered doubts about the original diagnosis of PHPT. In patient 1, the initial decision for surgery would still be made as her calcium values were rising and she did develop nausea and in FHH hyperplasia is also often described.
Physiological changes during pregnancy (Fig. 1a)
During pregnancy and lactation there is increased mobilization of calcium in the mother to meet the fetus’ calcium requirements [5, 6]. This is done by increasing intestinal calcium absorption through increasing 1.25 vitamin D production and PTH-related peptide (PTHrP), which is released from placenta and breasts in response to estradiol, placental lactogen, and prolactin [6, 7]. Despite the overlapping modes of action, PTH and PTHrP are produced by different genes on different chromosomes and the gene encoding PTHrP is more complex than for PTH. PTHrP is undetectable in the circulating blood of non-pregnant women, but is produced in a paracrine/autocrine fashion during pregnancy. Lessons from PTHrP or PTH1R gene knockout mice, which die at birth or in utero, emphasize the critical role of PTHrP for normal life [8, 9]. In addition, nascent PTHrP isoforms are processed by members of the prohormone convertase family to at least three fragments: N-terminal PTHrP [1–36], structurally related to PTH; a mid-region PTHrP (38–94); and a C-terminal PTHrP(107–139) with distinct biological properties and receptors. PTHrP is able to act not only via the classical autocrine/paracrine pathways, but also through a so-called intracrine pathway, which involves the translocation of the protein into the nucleus, where it can directly regulate proliferation and apoptosis [10, 11]. PTHrP has multiple activities including control of fetal development, trans-epithelial calcium transfer, lactation, smooth muscle relaxation, and cell growth. The mid-molecular region of PTHrP stimulates placental calcium transport in the fetus, while the COOH terminal region may also affect osteoclast activity. Thus, although PTHrP was discovered as a tumor-derived hypercalcemic factor, its primary physiological role is as a local regulator of many physiological processes especially in early life [12, 13].Fig. 1 a *Intravascular fluid expansion causes gestational hypoalbuminemia. The dilutional hypoalbuminemia of pregnancy leads to a decline in total calcium concentration. Ionized calcium on the other hand, remains stable and may provide more accurate information. ** The increase in 1.25 vitamin D production leads to an increase in intestinal calcium absorption. ***“Absorptive hypercalciuria of pregnancy”. Postprandial and 24-h urinary calcium excretion increase after 12 weeks, due to increased intestinal calcium absorption supposedly unrelated to increased formation of 1.25 vitamin D in early pregnancy. Fasting urine samples will not be affected by this phenomenon [45]. b *Prednison to reduce 1.25OH formation and thus intestinal calcium absorption. ** Reducing PTH-rp production mammae. *** No clinical data during pregnancy, only case reports. In animal studies no abnormalities observed, but it does pass the placenta [31, 46]. Breastfeeding: in animal studies (rat), cinacalcet is found in milk [46].
Maternal causes and consequences of hypercalcemia (Fig. 1b)
Hypercalcemia due to hyperparathyroidism is the most described cause of hypercalcemia during pregnancy. As most reviews focus on maternal and fetal outcomes in PHPT we will not cover this topic in the current paper [14, 15]. Hyperparathyroidism due to diffusely spread hyperthyroid nodules, parathyromatosis, post-parathyroidectomy, in the context of malignancy, MEN syndromes, or in chronic renal disease has been rarely described [15, 16]. Literature data on parathyromatosis is limited to around 20 cases published so far with only one report on a woman diagnosed and treated during pregnancy [17, 18].
FHH is a rare autosomal dominant disorder, with a prevalence of ~1:78.000 though this might likely be higher, as many cases remain asymptomatic lifelong and no causal treatment is available [19–21]. According to the genetic defect causing the pathology, three types of FHH have been defined [21–24]. FHH1 is the most common type and is found in about 65% of all FHH cases [21]. Patients with FHH present with mild to moderate hypercalcaemia, low urinary excretion, and PTH serum levels that are either normal or slightly elevated. Many patients with FHH are misdiagnosed as suffering from PHPT as in the case of our patient. Data on FHH manifested during pregnancy, literature data are sparse. Only four cases were published so far. Walker et al. reported the case of a pregnant patient, initially diagnosed with PHPT, who showed no improvement after PTX. The newborn presented with asymptomatic hypercalcemia; the genetic analysis confirmed the diagnosis of FHH [25]. The newborn presented elevated serum calcium levels with no clinical symptoms, while the genetic analysis confirmed the diagnosis of FHH. Others reported hypercalcemic profiles for which they underwent surgery during pregnancy [26, 27].
PTHrP-induced hypercalcemia during pregnancy or lactation has also been reported, either with or without gigantomastia [28–33]. In the reported cases, associating gigantomastia and increased PTHrP serum values, hypercalcaemia was diagnosed during gestation and resolved only after mastectomy, bromocriptin administration, or termination of pregnancy [29, 31, 32].
After delivery, there is a risk of severe hypercalcemia in women with PHPT who are lactating as PTH-rp production will increase [6, 34]. Especially women with gestational hypercalcemia with gigantomastia should be advised against breastfeeding as this will keep PTHrp levels high. The rise in PTHrp during pregnancy was not seen in patient 1 in whom PTHrp production was fully suppressed during entire pregnancy. The observed rise in calcium levels in patient 2 might in retrospect be due to her different setpoint and PTHrp production. Mental consequences of hypercalcemia are well known and include depression and anxiety [35, 36]. During pregnancy mothers might have additional stress which might be exaggerated by the hypercalcemia.
Fetal consequences of hypercalcemia
In the fetus, maternal PHPT can result in fetal growth restriction, severe neonatal hypocalcemia, tetany, and death [36]. In maternal FHH potential fetal complications include mild hypercalcemia, severe hypocalcemia, or neonatal severe hyperparathyroidism, depending on the genotype of the fetus. Because FHH is an autosomal dominant condition, three genetic situations might be encountered by the newborns of FHH mothers: the unaffected and the heterozygous neonates might present with hypocalcaemia induced by the in utero suppression of the parathyroid, the latter being at risk of developing hypercalcemia with hypocalcaemia in the first year of life. The homozygous form of FHH results in a severe neonatal hyperparathyroidism, which requires the surgical removal of the glands during the neonatal phase [37, 38].
Most outcomes on the fetal consequences of hypercalcemia were described in reports on patients with PHPT. Untreated hypercalcemia was associated with fetal or neonatal complications in the majority of cases [3, 36, 39, 40]. However, these findings are based on early literature of PHPT patients when hypercalcemia was often diagnosed in an advanced stage and more recent literature has shown that, compared to age-matched controls, women with PHPT had no difference in most pregnancy outcomes, including stillbirths [39]. That same study also showed that Apgar scores and anthropometric measurements were similar to babies born in uncomplicated pregnancies. However, this recent study did not report on maternal outcomes of preeclampsia. Other recent studies also report lower complications rates and good treatment outcomes when the hypercalcemia is moderate and not severe [1, 41].
Elevated maternal serum calcium leads to hypercalcemia in the fetus, which causes fetal parathyroid gland suppression. After delivery, these glands are still suppressed causing fetal hypocalcemia, which is usually transient (lasting 3–5 months after birth), but permanent hypoparathyroidism has anecdotally been described [42].
In the case of parathyromatosis diagnosed during pregnancy, Edling et al. reported that the infant presented initially with high calcium and low PTH levels, which normalized rapidly, with no further complications [18]. Newborns of mothers presenting with humoral hypercalcemia of pregnancy were having normal calcium levels at birth [29, 30, 33].
Diagnosing hypercalcemia during pregnancy might be challenging due to both physiological changes in calcium homeostasis, as well as due to the underlying cause for the hypercalcemia; changes in urinary calcium excretion vary during daytime, introducing difficulty in using urinary calcium indices as a diagnostic tool. In non-pregnant population, the measurement of calcium/creatinine clearance ratio can be useful in distinguishing between PHPT(>0.02 mmol/mmol) and FHH(<0.01 mmol/mmol). However, it is known that almost 20% of FHH patients might present with a calcium/creatinine ratio >0.01, and individuals with PPHT and simultaneous vitamin D deficiency might show lower than expected calcium excretion [43]. Genetic testing, when available, should be considered for confirming the clinical suspicion of FHH. More than 130 CaSR mutations have been reported so far in relation to FHH1, fact that explains the phenotypical variations in relation to the observed differences in serum calcium and PTH levels [21, 44].
During pregnancy, the distinction between FHH and PHPT is further complicated by the physiological changes in maternal calcium metabolism: increased breast and placental production of PTHrP, that together with the placental lactogen, leads to an increase in 1,25-(OH)2- vitamin D and a reduction of the PTH levels. As a result, the intestinal calcium absorption and the urine calcium excretion are physiologically increased [5, 45]. Treatment is depending on the underlying cause and might be invasive or conservative, but all decisions need good counseling, as it concerns not only the mother, but also the fetus and partner as well. Also we, as physicians, need to be aware that the treatment does not stop with the deliverance of a healthy baby and that the postpartum period might actually be the period with the highest risk for the mother due to the risk of sudden rises in calcium level and to excessive mental stress caused by possible events during pregnancy or delivery.
But foremost, irrespective of the underlying cause of hypercalcemia, patients and partners need to be closely involved in the decision processes in order to ensure overall good outcomes for mother and child.
Acknowledgements
We would like to acknowledge the European Reference Network for Rare Endocrine diseases, specifically main thematic group two calcium and phosphate disorders. We would like to thank both C.W.M. Janssen and S. Mourits for their agreement on publication of their medical history and contribution to the content of the manuscript.
Authors contributions
Conceptualization, writing original draft preparation, reviewing and editing: N.M.A-D. Reviewing and editing, critically revising the manuscript: D-A.E, M.C.Z, L.R, and E.M.W.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ASPIRIN, CINACALCET, FUROSEMIDE, NADROPARIN | DrugsGivenReaction | CC BY | 33544354 | 19,563,598 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Maternal exposure during pregnancy'. | Hypercalcemia during pregnancy: management and outcomes for mother and child.
Diagnosing and treating hypercalcemia during pregnancy can be challenging due to both the physiological changes in calcium homeostasis and the underlying cause for the hypercalcemia. During pregnancy and lactation there is increased mobilization of calcium in the mother to meet the fetus' calcium requirements. Here we discuss the diagnostic challenges, management, and patient perspective of hypercalcemia during pregnancy in two particular cases and in other rare conditions causing hypercalcemia.
Introduction
Hypercalcemia in pregnancy is rare and in >90% of cases caused by a newly diagnosed primary hyperparathyroidism (PHPT). Hypercalcemia during pregnancy due to other disorders of calcium metabolism is even more rare and literature regarding the maternal management and fetal outcomes is lacking. Diagnosing hypercalcemia is challenging during pregnancy, as symptoms such as fatigue or nausea mimic those in early pregnancy. However, longstanding hypercalcemia might induce nephrolithiasis, pancreatitis, and preeclampsia in the mother [1]. Therefore, the occurrence of these diseases during pregnancy should push the physicians to screen for hypercalcemia. In the fetus, maternal hypercalcemia can result in fetal growth restriction [2]. Following birth, further complications may arise such as severe neonatal hypocalcemia, tetany, and even death due to fetal hypoparathyroidism [3, 4]. In rare calcium-related disorders, the diagnosis is often known before the pregnancy and patients and partners can be counseled by the treating endocrinologist, obstetrician, pediatrician, and geneticist when required, taking into account the possible physical and mental maternal adverse effects, but also the eventual consequences for the newborn. Here we would like to discuss the diagnostic challenges and management of hypercalcemia during pregnancy in two particular cases as example of rare conditions causing hypercalcemia complicating pregnancy.
Case 1
A 34-year-old woman was referred with severe hypercalcemia and a pregnancy wish. At the age of 24 she was diagnosed with PHPT, without underlying genetic causes. During parathyroidectomy (PTX) there was spill of the adenoma, histologically confirmed, which led to chronic hypercalcemia for which she underwent several re-operations in various hospitals including a thyroidectomy in 2 tempi with resection of surrounding fat-tissue and a bilateral modified lymph node resection. However, she remained dependent on cinacalcet and bisphosphonates in various dosages. At referral, albumin-corrected serum calcium was 2.89 mmol/L (ref 2.15–2.55 mmol/L) with PTH 10.7 (ref 1–8 pmol/L) while on cinacalcet 60 mg/day, and 3.16 mmol/L with PTH of 29 without cinacalcet. She and her partner were counselled by a team consisting of gynecologists, pediatricians, and endocrinologists on several aspects of the disease and potential consequences for a pregnancy. Prophylactic surgery was not possible at that time. Bisphosphonates were stopped and she became pregnant after 12 months. Cinacalcet was stopped and a fluid intake of 4 L was advised. However, she was admitted with a symptomatic hypercalcemia, 3.4 mmol/L, within 2 weeks. Hyperhydration and cinacalcet, up to 90 mg/day, were started in combination with furosemide 40 mg and acetylsalicylic acid 80 mg daily as preeclampsia prophylaxis. She suffered from severe hyperemesis gravidarum and due to persistent hypercalcemia, she received saline infusions of 5 L/day in a homecare setting with a peripheral intravasal central catheter (PICC). During follow up the PICC caused deep vein thrombosis for which nadroparin injections were started but with this treatment serum calcium remained stable around 2.7–2.9 mmol/L. At 38 weeks of gestation she developed hypertension with a rapidly developing HELLP syndrome and an emergency cesarean section was performed. A healthy baby boy, weight 3305 g, was delivered; he only received active vitamin D supplementation for a few days and two years after delivery; no calcium disturbances or skeletal abnormalities have been observed. The mother did not breastfeed. After delivery, the mother experienced a post-traumatic stress syndrome (PTSS) with depression for which she started Eye Movement Desensitization and Reprocessing (EMDR). The depression and PTSS was related to the latter part of the pregnancy and delivery, but most likely exacerbated due to a postpartum rise in calcium to 3.3 mmol/L. Surgery was successfully performed after which her mental complaints improved.
Case 2
A 38-year-old female was diagnosed with PHPT at a non-university hospital, based on a modest hypercalcemia, and elevated PTH of 9.2 pmol/L and high to normal urinary calcium excretion of 8.5 g/L and calcium-to-creatinine clearance above 0.02. Despite her young age, it was decided not to perform PTX because of an increased risk for venous thromboembolism and obesity. Five years later, she had an unexpected pregnancy and was referred for PTX in the second trimester. During that time serum calcium had increased from 2.63 mmol/L to 2.83 mmol/L with a non-suppressed PTH of 3.8 pmol/L. The patient and her partner were counseled by a team consisting of endocrinologists, anesthesiologists, endocrine surgeons, pediatricians, and obstetricians. Imaging studies did not reveal a clear-cut adenoma and considering the progressive rise in calcium to 2.93 mmol/L, urinary calcium excretion of 12 g/L in 24 h and proceeding into the end of the second trimester an elective neck exploration was performed at gestational age of 24 + 2 weeks, showing four gland hyperplasia. During surgery, it was decided to remove only the two right-sided glands in order not to risk hypoparathyroidism. After surgery hypercalcemia persisted with calcium levels between 2.60 mmol/L and 2.65 mmol/L and PTH between 2.1 pmol/L and 3.6 pmol/L. Considering the marked hyperplasia the patient was discussed in the clinical patient management system (CPMS) panel of main thematic group two, calcium and phosphate disorders of the European Reference Network for rare endocrine diseases (ENDO-ERN). The advice of this panel was to perform genetic testing for familial hypocalciuric calciuria (FHH), which came back positive for a mutation in the CASR-gen, c.653A>G p.(Tyr218Cys), establishing a diagnosis of FHH type one. At 39 + 3 weeks she delivered a healthy baby girl of 4150 g without any calcium disturbances. Post-partum the calcium levels of the mother remained at 2.6 mmol and PTH rose again to 10.3 pmol/L, which has been stable since.
Patient perspective
Patient one had an active pregnancy wish for 5 years, with a negative counselling in several centers. At the Leiden University Medical Center (LUMC) it was again made clear that this would not be without risks for mother and child but if desired we would do our best to monitor the pregnancy as good as possible, which was much appreciated as this was not discussed before. Although she was well prepared and extensively counseled, the intensity of the pregnancy was overwhelming. Both the high calcium levels, frequent investigations and the continuous hyperhydration were extremely demanding and resulted, together with the further rise in calcium, in a pre- and post-natal depression for which EMDR and psychotherapy were needed. Looking back, she would advise other patients to realize that it will be extremely tough, but absolutely worth it. The fact that caretakers were so involved in her well-being and their clear communication was helpful and appreciated. The health care system structure with various doctors during hospital admission remains unfortunate from her point of view, which was in contrast to the outpatient clinic care with one regular healthcare provider.
Despite living with, a supposed, PHPT for many years, patient 2 had never been counseled about PHPT in terms of treatment and follow up. In the initial phase of her referral to LUMC this was done rapidly as time was ticking for a safe window of surgery as the second trimester is the preferred trimester for surgery for maternal and fetal reasons. In addition, due to her increased risk for venous thromboembolism and obesity, emergency surgery in case of severe hypercalcemia was considered to be a high risk for the mother. The patient found the amount of information overwhelming. However, it was appreciated as it made the patient and her partner feel part of the team. After surgery, when she had postoperative pains, this induced more stress being pregnant. Caregivers should be aware that in pregnant patients’ complaints that might be considered as normal after surgery can induce a stressful trigger in patients who are already in a stressful situation. The doubts about the original diagnosis of PHPT were shared including the desire of the treating physicians to discuss her case with other experts. Although providing more insecurity, the patient did feel comfortable that this meant that no other surgery was likely to be needed. After the pregnancy she reported that the physical part of the pregnancy did not give her many discomforts but the uncertainty about the well-being of the baby was very stressful. But overall, she was very satisfied with the care given.
In collaboration with these patients we produced a checklist for women in the same position or with a recent diagnosis of PHPT, which might be of help, see Table 1.Table 1 Questions for women in the childbearing age to ask their doctor when diagnosed with a high calcium level
1. What is the most likely diagnosis causing this high calcium level?
2. What tests do I need to make the diagnosis more likely? And are these tests influenced by pregnancy?
3. How will this affect pregnancy?
What will be the risks for my unborn child?
What will be the risks for me?
Which interventions are possible/necessary before, during and after pregnancy?
4. What can I do to minimalize complaints during and after the pregnancy?
5. How can we decrease my risk for preeclampsia?
6. Which drugs might be used during the pregnancy and what are their side effects?
7. How can you monitor my child?
8. How will my disease affect me after delivery?
9. How will this affect my child directly after delivery?
10. Can I breastfeed?
11. Who is in my multidisciplinary team and how can I reach them?
12. What can be done by my general practitioner?
13. What would be the risk of getting pregnant and to whom can I speak to for counseling?
In both cases patients and partners experienced the pregnancy as a rollercoaster with lot of uncertainties. Whereas both patients were diagnosed with hypercalcemia before pregnancy, patient 1 was counseled extensively in the pre-pregnancy period and even repeatedly got the advice not to become pregnant while patient 2 was never counseled. Also, in patient 2 the diagnosis was changed from PHPT to FHH, the finding of the marked hyperplasia triggered doubts about the original diagnosis of PHPT. In patient 1, the initial decision for surgery would still be made as her calcium values were rising and she did develop nausea and in FHH hyperplasia is also often described.
Physiological changes during pregnancy (Fig. 1a)
During pregnancy and lactation there is increased mobilization of calcium in the mother to meet the fetus’ calcium requirements [5, 6]. This is done by increasing intestinal calcium absorption through increasing 1.25 vitamin D production and PTH-related peptide (PTHrP), which is released from placenta and breasts in response to estradiol, placental lactogen, and prolactin [6, 7]. Despite the overlapping modes of action, PTH and PTHrP are produced by different genes on different chromosomes and the gene encoding PTHrP is more complex than for PTH. PTHrP is undetectable in the circulating blood of non-pregnant women, but is produced in a paracrine/autocrine fashion during pregnancy. Lessons from PTHrP or PTH1R gene knockout mice, which die at birth or in utero, emphasize the critical role of PTHrP for normal life [8, 9]. In addition, nascent PTHrP isoforms are processed by members of the prohormone convertase family to at least three fragments: N-terminal PTHrP [1–36], structurally related to PTH; a mid-region PTHrP (38–94); and a C-terminal PTHrP(107–139) with distinct biological properties and receptors. PTHrP is able to act not only via the classical autocrine/paracrine pathways, but also through a so-called intracrine pathway, which involves the translocation of the protein into the nucleus, where it can directly regulate proliferation and apoptosis [10, 11]. PTHrP has multiple activities including control of fetal development, trans-epithelial calcium transfer, lactation, smooth muscle relaxation, and cell growth. The mid-molecular region of PTHrP stimulates placental calcium transport in the fetus, while the COOH terminal region may also affect osteoclast activity. Thus, although PTHrP was discovered as a tumor-derived hypercalcemic factor, its primary physiological role is as a local regulator of many physiological processes especially in early life [12, 13].Fig. 1 a *Intravascular fluid expansion causes gestational hypoalbuminemia. The dilutional hypoalbuminemia of pregnancy leads to a decline in total calcium concentration. Ionized calcium on the other hand, remains stable and may provide more accurate information. ** The increase in 1.25 vitamin D production leads to an increase in intestinal calcium absorption. ***“Absorptive hypercalciuria of pregnancy”. Postprandial and 24-h urinary calcium excretion increase after 12 weeks, due to increased intestinal calcium absorption supposedly unrelated to increased formation of 1.25 vitamin D in early pregnancy. Fasting urine samples will not be affected by this phenomenon [45]. b *Prednison to reduce 1.25OH formation and thus intestinal calcium absorption. ** Reducing PTH-rp production mammae. *** No clinical data during pregnancy, only case reports. In animal studies no abnormalities observed, but it does pass the placenta [31, 46]. Breastfeeding: in animal studies (rat), cinacalcet is found in milk [46].
Maternal causes and consequences of hypercalcemia (Fig. 1b)
Hypercalcemia due to hyperparathyroidism is the most described cause of hypercalcemia during pregnancy. As most reviews focus on maternal and fetal outcomes in PHPT we will not cover this topic in the current paper [14, 15]. Hyperparathyroidism due to diffusely spread hyperthyroid nodules, parathyromatosis, post-parathyroidectomy, in the context of malignancy, MEN syndromes, or in chronic renal disease has been rarely described [15, 16]. Literature data on parathyromatosis is limited to around 20 cases published so far with only one report on a woman diagnosed and treated during pregnancy [17, 18].
FHH is a rare autosomal dominant disorder, with a prevalence of ~1:78.000 though this might likely be higher, as many cases remain asymptomatic lifelong and no causal treatment is available [19–21]. According to the genetic defect causing the pathology, three types of FHH have been defined [21–24]. FHH1 is the most common type and is found in about 65% of all FHH cases [21]. Patients with FHH present with mild to moderate hypercalcaemia, low urinary excretion, and PTH serum levels that are either normal or slightly elevated. Many patients with FHH are misdiagnosed as suffering from PHPT as in the case of our patient. Data on FHH manifested during pregnancy, literature data are sparse. Only four cases were published so far. Walker et al. reported the case of a pregnant patient, initially diagnosed with PHPT, who showed no improvement after PTX. The newborn presented with asymptomatic hypercalcemia; the genetic analysis confirmed the diagnosis of FHH [25]. The newborn presented elevated serum calcium levels with no clinical symptoms, while the genetic analysis confirmed the diagnosis of FHH. Others reported hypercalcemic profiles for which they underwent surgery during pregnancy [26, 27].
PTHrP-induced hypercalcemia during pregnancy or lactation has also been reported, either with or without gigantomastia [28–33]. In the reported cases, associating gigantomastia and increased PTHrP serum values, hypercalcaemia was diagnosed during gestation and resolved only after mastectomy, bromocriptin administration, or termination of pregnancy [29, 31, 32].
After delivery, there is a risk of severe hypercalcemia in women with PHPT who are lactating as PTH-rp production will increase [6, 34]. Especially women with gestational hypercalcemia with gigantomastia should be advised against breastfeeding as this will keep PTHrp levels high. The rise in PTHrp during pregnancy was not seen in patient 1 in whom PTHrp production was fully suppressed during entire pregnancy. The observed rise in calcium levels in patient 2 might in retrospect be due to her different setpoint and PTHrp production. Mental consequences of hypercalcemia are well known and include depression and anxiety [35, 36]. During pregnancy mothers might have additional stress which might be exaggerated by the hypercalcemia.
Fetal consequences of hypercalcemia
In the fetus, maternal PHPT can result in fetal growth restriction, severe neonatal hypocalcemia, tetany, and death [36]. In maternal FHH potential fetal complications include mild hypercalcemia, severe hypocalcemia, or neonatal severe hyperparathyroidism, depending on the genotype of the fetus. Because FHH is an autosomal dominant condition, three genetic situations might be encountered by the newborns of FHH mothers: the unaffected and the heterozygous neonates might present with hypocalcaemia induced by the in utero suppression of the parathyroid, the latter being at risk of developing hypercalcemia with hypocalcaemia in the first year of life. The homozygous form of FHH results in a severe neonatal hyperparathyroidism, which requires the surgical removal of the glands during the neonatal phase [37, 38].
Most outcomes on the fetal consequences of hypercalcemia were described in reports on patients with PHPT. Untreated hypercalcemia was associated with fetal or neonatal complications in the majority of cases [3, 36, 39, 40]. However, these findings are based on early literature of PHPT patients when hypercalcemia was often diagnosed in an advanced stage and more recent literature has shown that, compared to age-matched controls, women with PHPT had no difference in most pregnancy outcomes, including stillbirths [39]. That same study also showed that Apgar scores and anthropometric measurements were similar to babies born in uncomplicated pregnancies. However, this recent study did not report on maternal outcomes of preeclampsia. Other recent studies also report lower complications rates and good treatment outcomes when the hypercalcemia is moderate and not severe [1, 41].
Elevated maternal serum calcium leads to hypercalcemia in the fetus, which causes fetal parathyroid gland suppression. After delivery, these glands are still suppressed causing fetal hypocalcemia, which is usually transient (lasting 3–5 months after birth), but permanent hypoparathyroidism has anecdotally been described [42].
In the case of parathyromatosis diagnosed during pregnancy, Edling et al. reported that the infant presented initially with high calcium and low PTH levels, which normalized rapidly, with no further complications [18]. Newborns of mothers presenting with humoral hypercalcemia of pregnancy were having normal calcium levels at birth [29, 30, 33].
Diagnosing hypercalcemia during pregnancy might be challenging due to both physiological changes in calcium homeostasis, as well as due to the underlying cause for the hypercalcemia; changes in urinary calcium excretion vary during daytime, introducing difficulty in using urinary calcium indices as a diagnostic tool. In non-pregnant population, the measurement of calcium/creatinine clearance ratio can be useful in distinguishing between PHPT(>0.02 mmol/mmol) and FHH(<0.01 mmol/mmol). However, it is known that almost 20% of FHH patients might present with a calcium/creatinine ratio >0.01, and individuals with PPHT and simultaneous vitamin D deficiency might show lower than expected calcium excretion [43]. Genetic testing, when available, should be considered for confirming the clinical suspicion of FHH. More than 130 CaSR mutations have been reported so far in relation to FHH1, fact that explains the phenotypical variations in relation to the observed differences in serum calcium and PTH levels [21, 44].
During pregnancy, the distinction between FHH and PHPT is further complicated by the physiological changes in maternal calcium metabolism: increased breast and placental production of PTHrP, that together with the placental lactogen, leads to an increase in 1,25-(OH)2- vitamin D and a reduction of the PTH levels. As a result, the intestinal calcium absorption and the urine calcium excretion are physiologically increased [5, 45]. Treatment is depending on the underlying cause and might be invasive or conservative, but all decisions need good counseling, as it concerns not only the mother, but also the fetus and partner as well. Also we, as physicians, need to be aware that the treatment does not stop with the deliverance of a healthy baby and that the postpartum period might actually be the period with the highest risk for the mother due to the risk of sudden rises in calcium level and to excessive mental stress caused by possible events during pregnancy or delivery.
But foremost, irrespective of the underlying cause of hypercalcemia, patients and partners need to be closely involved in the decision processes in order to ensure overall good outcomes for mother and child.
Acknowledgements
We would like to acknowledge the European Reference Network for Rare Endocrine diseases, specifically main thematic group two calcium and phosphate disorders. We would like to thank both C.W.M. Janssen and S. Mourits for their agreement on publication of their medical history and contribution to the content of the manuscript.
Authors contributions
Conceptualization, writing original draft preparation, reviewing and editing: N.M.A-D. Reviewing and editing, critically revising the manuscript: D-A.E, M.C.Z, L.R, and E.M.W.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CINACALCET HYDROCHLORIDE, UNSPECIFIED INGREDIENT | DrugsGivenReaction | CC BY | 33544354 | 20,513,294 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Post-traumatic stress disorder'. | Hypercalcemia during pregnancy: management and outcomes for mother and child.
Diagnosing and treating hypercalcemia during pregnancy can be challenging due to both the physiological changes in calcium homeostasis and the underlying cause for the hypercalcemia. During pregnancy and lactation there is increased mobilization of calcium in the mother to meet the fetus' calcium requirements. Here we discuss the diagnostic challenges, management, and patient perspective of hypercalcemia during pregnancy in two particular cases and in other rare conditions causing hypercalcemia.
Introduction
Hypercalcemia in pregnancy is rare and in >90% of cases caused by a newly diagnosed primary hyperparathyroidism (PHPT). Hypercalcemia during pregnancy due to other disorders of calcium metabolism is even more rare and literature regarding the maternal management and fetal outcomes is lacking. Diagnosing hypercalcemia is challenging during pregnancy, as symptoms such as fatigue or nausea mimic those in early pregnancy. However, longstanding hypercalcemia might induce nephrolithiasis, pancreatitis, and preeclampsia in the mother [1]. Therefore, the occurrence of these diseases during pregnancy should push the physicians to screen for hypercalcemia. In the fetus, maternal hypercalcemia can result in fetal growth restriction [2]. Following birth, further complications may arise such as severe neonatal hypocalcemia, tetany, and even death due to fetal hypoparathyroidism [3, 4]. In rare calcium-related disorders, the diagnosis is often known before the pregnancy and patients and partners can be counseled by the treating endocrinologist, obstetrician, pediatrician, and geneticist when required, taking into account the possible physical and mental maternal adverse effects, but also the eventual consequences for the newborn. Here we would like to discuss the diagnostic challenges and management of hypercalcemia during pregnancy in two particular cases as example of rare conditions causing hypercalcemia complicating pregnancy.
Case 1
A 34-year-old woman was referred with severe hypercalcemia and a pregnancy wish. At the age of 24 she was diagnosed with PHPT, without underlying genetic causes. During parathyroidectomy (PTX) there was spill of the adenoma, histologically confirmed, which led to chronic hypercalcemia for which she underwent several re-operations in various hospitals including a thyroidectomy in 2 tempi with resection of surrounding fat-tissue and a bilateral modified lymph node resection. However, she remained dependent on cinacalcet and bisphosphonates in various dosages. At referral, albumin-corrected serum calcium was 2.89 mmol/L (ref 2.15–2.55 mmol/L) with PTH 10.7 (ref 1–8 pmol/L) while on cinacalcet 60 mg/day, and 3.16 mmol/L with PTH of 29 without cinacalcet. She and her partner were counselled by a team consisting of gynecologists, pediatricians, and endocrinologists on several aspects of the disease and potential consequences for a pregnancy. Prophylactic surgery was not possible at that time. Bisphosphonates were stopped and she became pregnant after 12 months. Cinacalcet was stopped and a fluid intake of 4 L was advised. However, she was admitted with a symptomatic hypercalcemia, 3.4 mmol/L, within 2 weeks. Hyperhydration and cinacalcet, up to 90 mg/day, were started in combination with furosemide 40 mg and acetylsalicylic acid 80 mg daily as preeclampsia prophylaxis. She suffered from severe hyperemesis gravidarum and due to persistent hypercalcemia, she received saline infusions of 5 L/day in a homecare setting with a peripheral intravasal central catheter (PICC). During follow up the PICC caused deep vein thrombosis for which nadroparin injections were started but with this treatment serum calcium remained stable around 2.7–2.9 mmol/L. At 38 weeks of gestation she developed hypertension with a rapidly developing HELLP syndrome and an emergency cesarean section was performed. A healthy baby boy, weight 3305 g, was delivered; he only received active vitamin D supplementation for a few days and two years after delivery; no calcium disturbances or skeletal abnormalities have been observed. The mother did not breastfeed. After delivery, the mother experienced a post-traumatic stress syndrome (PTSS) with depression for which she started Eye Movement Desensitization and Reprocessing (EMDR). The depression and PTSS was related to the latter part of the pregnancy and delivery, but most likely exacerbated due to a postpartum rise in calcium to 3.3 mmol/L. Surgery was successfully performed after which her mental complaints improved.
Case 2
A 38-year-old female was diagnosed with PHPT at a non-university hospital, based on a modest hypercalcemia, and elevated PTH of 9.2 pmol/L and high to normal urinary calcium excretion of 8.5 g/L and calcium-to-creatinine clearance above 0.02. Despite her young age, it was decided not to perform PTX because of an increased risk for venous thromboembolism and obesity. Five years later, she had an unexpected pregnancy and was referred for PTX in the second trimester. During that time serum calcium had increased from 2.63 mmol/L to 2.83 mmol/L with a non-suppressed PTH of 3.8 pmol/L. The patient and her partner were counseled by a team consisting of endocrinologists, anesthesiologists, endocrine surgeons, pediatricians, and obstetricians. Imaging studies did not reveal a clear-cut adenoma and considering the progressive rise in calcium to 2.93 mmol/L, urinary calcium excretion of 12 g/L in 24 h and proceeding into the end of the second trimester an elective neck exploration was performed at gestational age of 24 + 2 weeks, showing four gland hyperplasia. During surgery, it was decided to remove only the two right-sided glands in order not to risk hypoparathyroidism. After surgery hypercalcemia persisted with calcium levels between 2.60 mmol/L and 2.65 mmol/L and PTH between 2.1 pmol/L and 3.6 pmol/L. Considering the marked hyperplasia the patient was discussed in the clinical patient management system (CPMS) panel of main thematic group two, calcium and phosphate disorders of the European Reference Network for rare endocrine diseases (ENDO-ERN). The advice of this panel was to perform genetic testing for familial hypocalciuric calciuria (FHH), which came back positive for a mutation in the CASR-gen, c.653A>G p.(Tyr218Cys), establishing a diagnosis of FHH type one. At 39 + 3 weeks she delivered a healthy baby girl of 4150 g without any calcium disturbances. Post-partum the calcium levels of the mother remained at 2.6 mmol and PTH rose again to 10.3 pmol/L, which has been stable since.
Patient perspective
Patient one had an active pregnancy wish for 5 years, with a negative counselling in several centers. At the Leiden University Medical Center (LUMC) it was again made clear that this would not be without risks for mother and child but if desired we would do our best to monitor the pregnancy as good as possible, which was much appreciated as this was not discussed before. Although she was well prepared and extensively counseled, the intensity of the pregnancy was overwhelming. Both the high calcium levels, frequent investigations and the continuous hyperhydration were extremely demanding and resulted, together with the further rise in calcium, in a pre- and post-natal depression for which EMDR and psychotherapy were needed. Looking back, she would advise other patients to realize that it will be extremely tough, but absolutely worth it. The fact that caretakers were so involved in her well-being and their clear communication was helpful and appreciated. The health care system structure with various doctors during hospital admission remains unfortunate from her point of view, which was in contrast to the outpatient clinic care with one regular healthcare provider.
Despite living with, a supposed, PHPT for many years, patient 2 had never been counseled about PHPT in terms of treatment and follow up. In the initial phase of her referral to LUMC this was done rapidly as time was ticking for a safe window of surgery as the second trimester is the preferred trimester for surgery for maternal and fetal reasons. In addition, due to her increased risk for venous thromboembolism and obesity, emergency surgery in case of severe hypercalcemia was considered to be a high risk for the mother. The patient found the amount of information overwhelming. However, it was appreciated as it made the patient and her partner feel part of the team. After surgery, when she had postoperative pains, this induced more stress being pregnant. Caregivers should be aware that in pregnant patients’ complaints that might be considered as normal after surgery can induce a stressful trigger in patients who are already in a stressful situation. The doubts about the original diagnosis of PHPT were shared including the desire of the treating physicians to discuss her case with other experts. Although providing more insecurity, the patient did feel comfortable that this meant that no other surgery was likely to be needed. After the pregnancy she reported that the physical part of the pregnancy did not give her many discomforts but the uncertainty about the well-being of the baby was very stressful. But overall, she was very satisfied with the care given.
In collaboration with these patients we produced a checklist for women in the same position or with a recent diagnosis of PHPT, which might be of help, see Table 1.Table 1 Questions for women in the childbearing age to ask their doctor when diagnosed with a high calcium level
1. What is the most likely diagnosis causing this high calcium level?
2. What tests do I need to make the diagnosis more likely? And are these tests influenced by pregnancy?
3. How will this affect pregnancy?
What will be the risks for my unborn child?
What will be the risks for me?
Which interventions are possible/necessary before, during and after pregnancy?
4. What can I do to minimalize complaints during and after the pregnancy?
5. How can we decrease my risk for preeclampsia?
6. Which drugs might be used during the pregnancy and what are their side effects?
7. How can you monitor my child?
8. How will my disease affect me after delivery?
9. How will this affect my child directly after delivery?
10. Can I breastfeed?
11. Who is in my multidisciplinary team and how can I reach them?
12. What can be done by my general practitioner?
13. What would be the risk of getting pregnant and to whom can I speak to for counseling?
In both cases patients and partners experienced the pregnancy as a rollercoaster with lot of uncertainties. Whereas both patients were diagnosed with hypercalcemia before pregnancy, patient 1 was counseled extensively in the pre-pregnancy period and even repeatedly got the advice not to become pregnant while patient 2 was never counseled. Also, in patient 2 the diagnosis was changed from PHPT to FHH, the finding of the marked hyperplasia triggered doubts about the original diagnosis of PHPT. In patient 1, the initial decision for surgery would still be made as her calcium values were rising and she did develop nausea and in FHH hyperplasia is also often described.
Physiological changes during pregnancy (Fig. 1a)
During pregnancy and lactation there is increased mobilization of calcium in the mother to meet the fetus’ calcium requirements [5, 6]. This is done by increasing intestinal calcium absorption through increasing 1.25 vitamin D production and PTH-related peptide (PTHrP), which is released from placenta and breasts in response to estradiol, placental lactogen, and prolactin [6, 7]. Despite the overlapping modes of action, PTH and PTHrP are produced by different genes on different chromosomes and the gene encoding PTHrP is more complex than for PTH. PTHrP is undetectable in the circulating blood of non-pregnant women, but is produced in a paracrine/autocrine fashion during pregnancy. Lessons from PTHrP or PTH1R gene knockout mice, which die at birth or in utero, emphasize the critical role of PTHrP for normal life [8, 9]. In addition, nascent PTHrP isoforms are processed by members of the prohormone convertase family to at least three fragments: N-terminal PTHrP [1–36], structurally related to PTH; a mid-region PTHrP (38–94); and a C-terminal PTHrP(107–139) with distinct biological properties and receptors. PTHrP is able to act not only via the classical autocrine/paracrine pathways, but also through a so-called intracrine pathway, which involves the translocation of the protein into the nucleus, where it can directly regulate proliferation and apoptosis [10, 11]. PTHrP has multiple activities including control of fetal development, trans-epithelial calcium transfer, lactation, smooth muscle relaxation, and cell growth. The mid-molecular region of PTHrP stimulates placental calcium transport in the fetus, while the COOH terminal region may also affect osteoclast activity. Thus, although PTHrP was discovered as a tumor-derived hypercalcemic factor, its primary physiological role is as a local regulator of many physiological processes especially in early life [12, 13].Fig. 1 a *Intravascular fluid expansion causes gestational hypoalbuminemia. The dilutional hypoalbuminemia of pregnancy leads to a decline in total calcium concentration. Ionized calcium on the other hand, remains stable and may provide more accurate information. ** The increase in 1.25 vitamin D production leads to an increase in intestinal calcium absorption. ***“Absorptive hypercalciuria of pregnancy”. Postprandial and 24-h urinary calcium excretion increase after 12 weeks, due to increased intestinal calcium absorption supposedly unrelated to increased formation of 1.25 vitamin D in early pregnancy. Fasting urine samples will not be affected by this phenomenon [45]. b *Prednison to reduce 1.25OH formation and thus intestinal calcium absorption. ** Reducing PTH-rp production mammae. *** No clinical data during pregnancy, only case reports. In animal studies no abnormalities observed, but it does pass the placenta [31, 46]. Breastfeeding: in animal studies (rat), cinacalcet is found in milk [46].
Maternal causes and consequences of hypercalcemia (Fig. 1b)
Hypercalcemia due to hyperparathyroidism is the most described cause of hypercalcemia during pregnancy. As most reviews focus on maternal and fetal outcomes in PHPT we will not cover this topic in the current paper [14, 15]. Hyperparathyroidism due to diffusely spread hyperthyroid nodules, parathyromatosis, post-parathyroidectomy, in the context of malignancy, MEN syndromes, or in chronic renal disease has been rarely described [15, 16]. Literature data on parathyromatosis is limited to around 20 cases published so far with only one report on a woman diagnosed and treated during pregnancy [17, 18].
FHH is a rare autosomal dominant disorder, with a prevalence of ~1:78.000 though this might likely be higher, as many cases remain asymptomatic lifelong and no causal treatment is available [19–21]. According to the genetic defect causing the pathology, three types of FHH have been defined [21–24]. FHH1 is the most common type and is found in about 65% of all FHH cases [21]. Patients with FHH present with mild to moderate hypercalcaemia, low urinary excretion, and PTH serum levels that are either normal or slightly elevated. Many patients with FHH are misdiagnosed as suffering from PHPT as in the case of our patient. Data on FHH manifested during pregnancy, literature data are sparse. Only four cases were published so far. Walker et al. reported the case of a pregnant patient, initially diagnosed with PHPT, who showed no improvement after PTX. The newborn presented with asymptomatic hypercalcemia; the genetic analysis confirmed the diagnosis of FHH [25]. The newborn presented elevated serum calcium levels with no clinical symptoms, while the genetic analysis confirmed the diagnosis of FHH. Others reported hypercalcemic profiles for which they underwent surgery during pregnancy [26, 27].
PTHrP-induced hypercalcemia during pregnancy or lactation has also been reported, either with or without gigantomastia [28–33]. In the reported cases, associating gigantomastia and increased PTHrP serum values, hypercalcaemia was diagnosed during gestation and resolved only after mastectomy, bromocriptin administration, or termination of pregnancy [29, 31, 32].
After delivery, there is a risk of severe hypercalcemia in women with PHPT who are lactating as PTH-rp production will increase [6, 34]. Especially women with gestational hypercalcemia with gigantomastia should be advised against breastfeeding as this will keep PTHrp levels high. The rise in PTHrp during pregnancy was not seen in patient 1 in whom PTHrp production was fully suppressed during entire pregnancy. The observed rise in calcium levels in patient 2 might in retrospect be due to her different setpoint and PTHrp production. Mental consequences of hypercalcemia are well known and include depression and anxiety [35, 36]. During pregnancy mothers might have additional stress which might be exaggerated by the hypercalcemia.
Fetal consequences of hypercalcemia
In the fetus, maternal PHPT can result in fetal growth restriction, severe neonatal hypocalcemia, tetany, and death [36]. In maternal FHH potential fetal complications include mild hypercalcemia, severe hypocalcemia, or neonatal severe hyperparathyroidism, depending on the genotype of the fetus. Because FHH is an autosomal dominant condition, three genetic situations might be encountered by the newborns of FHH mothers: the unaffected and the heterozygous neonates might present with hypocalcaemia induced by the in utero suppression of the parathyroid, the latter being at risk of developing hypercalcemia with hypocalcaemia in the first year of life. The homozygous form of FHH results in a severe neonatal hyperparathyroidism, which requires the surgical removal of the glands during the neonatal phase [37, 38].
Most outcomes on the fetal consequences of hypercalcemia were described in reports on patients with PHPT. Untreated hypercalcemia was associated with fetal or neonatal complications in the majority of cases [3, 36, 39, 40]. However, these findings are based on early literature of PHPT patients when hypercalcemia was often diagnosed in an advanced stage and more recent literature has shown that, compared to age-matched controls, women with PHPT had no difference in most pregnancy outcomes, including stillbirths [39]. That same study also showed that Apgar scores and anthropometric measurements were similar to babies born in uncomplicated pregnancies. However, this recent study did not report on maternal outcomes of preeclampsia. Other recent studies also report lower complications rates and good treatment outcomes when the hypercalcemia is moderate and not severe [1, 41].
Elevated maternal serum calcium leads to hypercalcemia in the fetus, which causes fetal parathyroid gland suppression. After delivery, these glands are still suppressed causing fetal hypocalcemia, which is usually transient (lasting 3–5 months after birth), but permanent hypoparathyroidism has anecdotally been described [42].
In the case of parathyromatosis diagnosed during pregnancy, Edling et al. reported that the infant presented initially with high calcium and low PTH levels, which normalized rapidly, with no further complications [18]. Newborns of mothers presenting with humoral hypercalcemia of pregnancy were having normal calcium levels at birth [29, 30, 33].
Diagnosing hypercalcemia during pregnancy might be challenging due to both physiological changes in calcium homeostasis, as well as due to the underlying cause for the hypercalcemia; changes in urinary calcium excretion vary during daytime, introducing difficulty in using urinary calcium indices as a diagnostic tool. In non-pregnant population, the measurement of calcium/creatinine clearance ratio can be useful in distinguishing between PHPT(>0.02 mmol/mmol) and FHH(<0.01 mmol/mmol). However, it is known that almost 20% of FHH patients might present with a calcium/creatinine ratio >0.01, and individuals with PPHT and simultaneous vitamin D deficiency might show lower than expected calcium excretion [43]. Genetic testing, when available, should be considered for confirming the clinical suspicion of FHH. More than 130 CaSR mutations have been reported so far in relation to FHH1, fact that explains the phenotypical variations in relation to the observed differences in serum calcium and PTH levels [21, 44].
During pregnancy, the distinction between FHH and PHPT is further complicated by the physiological changes in maternal calcium metabolism: increased breast and placental production of PTHrP, that together with the placental lactogen, leads to an increase in 1,25-(OH)2- vitamin D and a reduction of the PTH levels. As a result, the intestinal calcium absorption and the urine calcium excretion are physiologically increased [5, 45]. Treatment is depending on the underlying cause and might be invasive or conservative, but all decisions need good counseling, as it concerns not only the mother, but also the fetus and partner as well. Also we, as physicians, need to be aware that the treatment does not stop with the deliverance of a healthy baby and that the postpartum period might actually be the period with the highest risk for the mother due to the risk of sudden rises in calcium level and to excessive mental stress caused by possible events during pregnancy or delivery.
But foremost, irrespective of the underlying cause of hypercalcemia, patients and partners need to be closely involved in the decision processes in order to ensure overall good outcomes for mother and child.
Acknowledgements
We would like to acknowledge the European Reference Network for Rare Endocrine diseases, specifically main thematic group two calcium and phosphate disorders. We would like to thank both C.W.M. Janssen and S. Mourits for their agreement on publication of their medical history and contribution to the content of the manuscript.
Authors contributions
Conceptualization, writing original draft preparation, reviewing and editing: N.M.A-D. Reviewing and editing, critically revising the manuscript: D-A.E, M.C.Z, L.R, and E.M.W.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CINACALCET HYDROCHLORIDE, UNSPECIFIED INGREDIENT | DrugsGivenReaction | CC BY | 33544354 | 20,513,294 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use issue'. | Hypercalcemia during pregnancy: management and outcomes for mother and child.
Diagnosing and treating hypercalcemia during pregnancy can be challenging due to both the physiological changes in calcium homeostasis and the underlying cause for the hypercalcemia. During pregnancy and lactation there is increased mobilization of calcium in the mother to meet the fetus' calcium requirements. Here we discuss the diagnostic challenges, management, and patient perspective of hypercalcemia during pregnancy in two particular cases and in other rare conditions causing hypercalcemia.
Introduction
Hypercalcemia in pregnancy is rare and in >90% of cases caused by a newly diagnosed primary hyperparathyroidism (PHPT). Hypercalcemia during pregnancy due to other disorders of calcium metabolism is even more rare and literature regarding the maternal management and fetal outcomes is lacking. Diagnosing hypercalcemia is challenging during pregnancy, as symptoms such as fatigue or nausea mimic those in early pregnancy. However, longstanding hypercalcemia might induce nephrolithiasis, pancreatitis, and preeclampsia in the mother [1]. Therefore, the occurrence of these diseases during pregnancy should push the physicians to screen for hypercalcemia. In the fetus, maternal hypercalcemia can result in fetal growth restriction [2]. Following birth, further complications may arise such as severe neonatal hypocalcemia, tetany, and even death due to fetal hypoparathyroidism [3, 4]. In rare calcium-related disorders, the diagnosis is often known before the pregnancy and patients and partners can be counseled by the treating endocrinologist, obstetrician, pediatrician, and geneticist when required, taking into account the possible physical and mental maternal adverse effects, but also the eventual consequences for the newborn. Here we would like to discuss the diagnostic challenges and management of hypercalcemia during pregnancy in two particular cases as example of rare conditions causing hypercalcemia complicating pregnancy.
Case 1
A 34-year-old woman was referred with severe hypercalcemia and a pregnancy wish. At the age of 24 she was diagnosed with PHPT, without underlying genetic causes. During parathyroidectomy (PTX) there was spill of the adenoma, histologically confirmed, which led to chronic hypercalcemia for which she underwent several re-operations in various hospitals including a thyroidectomy in 2 tempi with resection of surrounding fat-tissue and a bilateral modified lymph node resection. However, she remained dependent on cinacalcet and bisphosphonates in various dosages. At referral, albumin-corrected serum calcium was 2.89 mmol/L (ref 2.15–2.55 mmol/L) with PTH 10.7 (ref 1–8 pmol/L) while on cinacalcet 60 mg/day, and 3.16 mmol/L with PTH of 29 without cinacalcet. She and her partner were counselled by a team consisting of gynecologists, pediatricians, and endocrinologists on several aspects of the disease and potential consequences for a pregnancy. Prophylactic surgery was not possible at that time. Bisphosphonates were stopped and she became pregnant after 12 months. Cinacalcet was stopped and a fluid intake of 4 L was advised. However, she was admitted with a symptomatic hypercalcemia, 3.4 mmol/L, within 2 weeks. Hyperhydration and cinacalcet, up to 90 mg/day, were started in combination with furosemide 40 mg and acetylsalicylic acid 80 mg daily as preeclampsia prophylaxis. She suffered from severe hyperemesis gravidarum and due to persistent hypercalcemia, she received saline infusions of 5 L/day in a homecare setting with a peripheral intravasal central catheter (PICC). During follow up the PICC caused deep vein thrombosis for which nadroparin injections were started but with this treatment serum calcium remained stable around 2.7–2.9 mmol/L. At 38 weeks of gestation she developed hypertension with a rapidly developing HELLP syndrome and an emergency cesarean section was performed. A healthy baby boy, weight 3305 g, was delivered; he only received active vitamin D supplementation for a few days and two years after delivery; no calcium disturbances or skeletal abnormalities have been observed. The mother did not breastfeed. After delivery, the mother experienced a post-traumatic stress syndrome (PTSS) with depression for which she started Eye Movement Desensitization and Reprocessing (EMDR). The depression and PTSS was related to the latter part of the pregnancy and delivery, but most likely exacerbated due to a postpartum rise in calcium to 3.3 mmol/L. Surgery was successfully performed after which her mental complaints improved.
Case 2
A 38-year-old female was diagnosed with PHPT at a non-university hospital, based on a modest hypercalcemia, and elevated PTH of 9.2 pmol/L and high to normal urinary calcium excretion of 8.5 g/L and calcium-to-creatinine clearance above 0.02. Despite her young age, it was decided not to perform PTX because of an increased risk for venous thromboembolism and obesity. Five years later, she had an unexpected pregnancy and was referred for PTX in the second trimester. During that time serum calcium had increased from 2.63 mmol/L to 2.83 mmol/L with a non-suppressed PTH of 3.8 pmol/L. The patient and her partner were counseled by a team consisting of endocrinologists, anesthesiologists, endocrine surgeons, pediatricians, and obstetricians. Imaging studies did not reveal a clear-cut adenoma and considering the progressive rise in calcium to 2.93 mmol/L, urinary calcium excretion of 12 g/L in 24 h and proceeding into the end of the second trimester an elective neck exploration was performed at gestational age of 24 + 2 weeks, showing four gland hyperplasia. During surgery, it was decided to remove only the two right-sided glands in order not to risk hypoparathyroidism. After surgery hypercalcemia persisted with calcium levels between 2.60 mmol/L and 2.65 mmol/L and PTH between 2.1 pmol/L and 3.6 pmol/L. Considering the marked hyperplasia the patient was discussed in the clinical patient management system (CPMS) panel of main thematic group two, calcium and phosphate disorders of the European Reference Network for rare endocrine diseases (ENDO-ERN). The advice of this panel was to perform genetic testing for familial hypocalciuric calciuria (FHH), which came back positive for a mutation in the CASR-gen, c.653A>G p.(Tyr218Cys), establishing a diagnosis of FHH type one. At 39 + 3 weeks she delivered a healthy baby girl of 4150 g without any calcium disturbances. Post-partum the calcium levels of the mother remained at 2.6 mmol and PTH rose again to 10.3 pmol/L, which has been stable since.
Patient perspective
Patient one had an active pregnancy wish for 5 years, with a negative counselling in several centers. At the Leiden University Medical Center (LUMC) it was again made clear that this would not be without risks for mother and child but if desired we would do our best to monitor the pregnancy as good as possible, which was much appreciated as this was not discussed before. Although she was well prepared and extensively counseled, the intensity of the pregnancy was overwhelming. Both the high calcium levels, frequent investigations and the continuous hyperhydration were extremely demanding and resulted, together with the further rise in calcium, in a pre- and post-natal depression for which EMDR and psychotherapy were needed. Looking back, she would advise other patients to realize that it will be extremely tough, but absolutely worth it. The fact that caretakers were so involved in her well-being and their clear communication was helpful and appreciated. The health care system structure with various doctors during hospital admission remains unfortunate from her point of view, which was in contrast to the outpatient clinic care with one regular healthcare provider.
Despite living with, a supposed, PHPT for many years, patient 2 had never been counseled about PHPT in terms of treatment and follow up. In the initial phase of her referral to LUMC this was done rapidly as time was ticking for a safe window of surgery as the second trimester is the preferred trimester for surgery for maternal and fetal reasons. In addition, due to her increased risk for venous thromboembolism and obesity, emergency surgery in case of severe hypercalcemia was considered to be a high risk for the mother. The patient found the amount of information overwhelming. However, it was appreciated as it made the patient and her partner feel part of the team. After surgery, when she had postoperative pains, this induced more stress being pregnant. Caregivers should be aware that in pregnant patients’ complaints that might be considered as normal after surgery can induce a stressful trigger in patients who are already in a stressful situation. The doubts about the original diagnosis of PHPT were shared including the desire of the treating physicians to discuss her case with other experts. Although providing more insecurity, the patient did feel comfortable that this meant that no other surgery was likely to be needed. After the pregnancy she reported that the physical part of the pregnancy did not give her many discomforts but the uncertainty about the well-being of the baby was very stressful. But overall, she was very satisfied with the care given.
In collaboration with these patients we produced a checklist for women in the same position or with a recent diagnosis of PHPT, which might be of help, see Table 1.Table 1 Questions for women in the childbearing age to ask their doctor when diagnosed with a high calcium level
1. What is the most likely diagnosis causing this high calcium level?
2. What tests do I need to make the diagnosis more likely? And are these tests influenced by pregnancy?
3. How will this affect pregnancy?
What will be the risks for my unborn child?
What will be the risks for me?
Which interventions are possible/necessary before, during and after pregnancy?
4. What can I do to minimalize complaints during and after the pregnancy?
5. How can we decrease my risk for preeclampsia?
6. Which drugs might be used during the pregnancy and what are their side effects?
7. How can you monitor my child?
8. How will my disease affect me after delivery?
9. How will this affect my child directly after delivery?
10. Can I breastfeed?
11. Who is in my multidisciplinary team and how can I reach them?
12. What can be done by my general practitioner?
13. What would be the risk of getting pregnant and to whom can I speak to for counseling?
In both cases patients and partners experienced the pregnancy as a rollercoaster with lot of uncertainties. Whereas both patients were diagnosed with hypercalcemia before pregnancy, patient 1 was counseled extensively in the pre-pregnancy period and even repeatedly got the advice not to become pregnant while patient 2 was never counseled. Also, in patient 2 the diagnosis was changed from PHPT to FHH, the finding of the marked hyperplasia triggered doubts about the original diagnosis of PHPT. In patient 1, the initial decision for surgery would still be made as her calcium values were rising and she did develop nausea and in FHH hyperplasia is also often described.
Physiological changes during pregnancy (Fig. 1a)
During pregnancy and lactation there is increased mobilization of calcium in the mother to meet the fetus’ calcium requirements [5, 6]. This is done by increasing intestinal calcium absorption through increasing 1.25 vitamin D production and PTH-related peptide (PTHrP), which is released from placenta and breasts in response to estradiol, placental lactogen, and prolactin [6, 7]. Despite the overlapping modes of action, PTH and PTHrP are produced by different genes on different chromosomes and the gene encoding PTHrP is more complex than for PTH. PTHrP is undetectable in the circulating blood of non-pregnant women, but is produced in a paracrine/autocrine fashion during pregnancy. Lessons from PTHrP or PTH1R gene knockout mice, which die at birth or in utero, emphasize the critical role of PTHrP for normal life [8, 9]. In addition, nascent PTHrP isoforms are processed by members of the prohormone convertase family to at least three fragments: N-terminal PTHrP [1–36], structurally related to PTH; a mid-region PTHrP (38–94); and a C-terminal PTHrP(107–139) with distinct biological properties and receptors. PTHrP is able to act not only via the classical autocrine/paracrine pathways, but also through a so-called intracrine pathway, which involves the translocation of the protein into the nucleus, where it can directly regulate proliferation and apoptosis [10, 11]. PTHrP has multiple activities including control of fetal development, trans-epithelial calcium transfer, lactation, smooth muscle relaxation, and cell growth. The mid-molecular region of PTHrP stimulates placental calcium transport in the fetus, while the COOH terminal region may also affect osteoclast activity. Thus, although PTHrP was discovered as a tumor-derived hypercalcemic factor, its primary physiological role is as a local regulator of many physiological processes especially in early life [12, 13].Fig. 1 a *Intravascular fluid expansion causes gestational hypoalbuminemia. The dilutional hypoalbuminemia of pregnancy leads to a decline in total calcium concentration. Ionized calcium on the other hand, remains stable and may provide more accurate information. ** The increase in 1.25 vitamin D production leads to an increase in intestinal calcium absorption. ***“Absorptive hypercalciuria of pregnancy”. Postprandial and 24-h urinary calcium excretion increase after 12 weeks, due to increased intestinal calcium absorption supposedly unrelated to increased formation of 1.25 vitamin D in early pregnancy. Fasting urine samples will not be affected by this phenomenon [45]. b *Prednison to reduce 1.25OH formation and thus intestinal calcium absorption. ** Reducing PTH-rp production mammae. *** No clinical data during pregnancy, only case reports. In animal studies no abnormalities observed, but it does pass the placenta [31, 46]. Breastfeeding: in animal studies (rat), cinacalcet is found in milk [46].
Maternal causes and consequences of hypercalcemia (Fig. 1b)
Hypercalcemia due to hyperparathyroidism is the most described cause of hypercalcemia during pregnancy. As most reviews focus on maternal and fetal outcomes in PHPT we will not cover this topic in the current paper [14, 15]. Hyperparathyroidism due to diffusely spread hyperthyroid nodules, parathyromatosis, post-parathyroidectomy, in the context of malignancy, MEN syndromes, or in chronic renal disease has been rarely described [15, 16]. Literature data on parathyromatosis is limited to around 20 cases published so far with only one report on a woman diagnosed and treated during pregnancy [17, 18].
FHH is a rare autosomal dominant disorder, with a prevalence of ~1:78.000 though this might likely be higher, as many cases remain asymptomatic lifelong and no causal treatment is available [19–21]. According to the genetic defect causing the pathology, three types of FHH have been defined [21–24]. FHH1 is the most common type and is found in about 65% of all FHH cases [21]. Patients with FHH present with mild to moderate hypercalcaemia, low urinary excretion, and PTH serum levels that are either normal or slightly elevated. Many patients with FHH are misdiagnosed as suffering from PHPT as in the case of our patient. Data on FHH manifested during pregnancy, literature data are sparse. Only four cases were published so far. Walker et al. reported the case of a pregnant patient, initially diagnosed with PHPT, who showed no improvement after PTX. The newborn presented with asymptomatic hypercalcemia; the genetic analysis confirmed the diagnosis of FHH [25]. The newborn presented elevated serum calcium levels with no clinical symptoms, while the genetic analysis confirmed the diagnosis of FHH. Others reported hypercalcemic profiles for which they underwent surgery during pregnancy [26, 27].
PTHrP-induced hypercalcemia during pregnancy or lactation has also been reported, either with or without gigantomastia [28–33]. In the reported cases, associating gigantomastia and increased PTHrP serum values, hypercalcaemia was diagnosed during gestation and resolved only after mastectomy, bromocriptin administration, or termination of pregnancy [29, 31, 32].
After delivery, there is a risk of severe hypercalcemia in women with PHPT who are lactating as PTH-rp production will increase [6, 34]. Especially women with gestational hypercalcemia with gigantomastia should be advised against breastfeeding as this will keep PTHrp levels high. The rise in PTHrp during pregnancy was not seen in patient 1 in whom PTHrp production was fully suppressed during entire pregnancy. The observed rise in calcium levels in patient 2 might in retrospect be due to her different setpoint and PTHrp production. Mental consequences of hypercalcemia are well known and include depression and anxiety [35, 36]. During pregnancy mothers might have additional stress which might be exaggerated by the hypercalcemia.
Fetal consequences of hypercalcemia
In the fetus, maternal PHPT can result in fetal growth restriction, severe neonatal hypocalcemia, tetany, and death [36]. In maternal FHH potential fetal complications include mild hypercalcemia, severe hypocalcemia, or neonatal severe hyperparathyroidism, depending on the genotype of the fetus. Because FHH is an autosomal dominant condition, three genetic situations might be encountered by the newborns of FHH mothers: the unaffected and the heterozygous neonates might present with hypocalcaemia induced by the in utero suppression of the parathyroid, the latter being at risk of developing hypercalcemia with hypocalcaemia in the first year of life. The homozygous form of FHH results in a severe neonatal hyperparathyroidism, which requires the surgical removal of the glands during the neonatal phase [37, 38].
Most outcomes on the fetal consequences of hypercalcemia were described in reports on patients with PHPT. Untreated hypercalcemia was associated with fetal or neonatal complications in the majority of cases [3, 36, 39, 40]. However, these findings are based on early literature of PHPT patients when hypercalcemia was often diagnosed in an advanced stage and more recent literature has shown that, compared to age-matched controls, women with PHPT had no difference in most pregnancy outcomes, including stillbirths [39]. That same study also showed that Apgar scores and anthropometric measurements were similar to babies born in uncomplicated pregnancies. However, this recent study did not report on maternal outcomes of preeclampsia. Other recent studies also report lower complications rates and good treatment outcomes when the hypercalcemia is moderate and not severe [1, 41].
Elevated maternal serum calcium leads to hypercalcemia in the fetus, which causes fetal parathyroid gland suppression. After delivery, these glands are still suppressed causing fetal hypocalcemia, which is usually transient (lasting 3–5 months after birth), but permanent hypoparathyroidism has anecdotally been described [42].
In the case of parathyromatosis diagnosed during pregnancy, Edling et al. reported that the infant presented initially with high calcium and low PTH levels, which normalized rapidly, with no further complications [18]. Newborns of mothers presenting with humoral hypercalcemia of pregnancy were having normal calcium levels at birth [29, 30, 33].
Diagnosing hypercalcemia during pregnancy might be challenging due to both physiological changes in calcium homeostasis, as well as due to the underlying cause for the hypercalcemia; changes in urinary calcium excretion vary during daytime, introducing difficulty in using urinary calcium indices as a diagnostic tool. In non-pregnant population, the measurement of calcium/creatinine clearance ratio can be useful in distinguishing between PHPT(>0.02 mmol/mmol) and FHH(<0.01 mmol/mmol). However, it is known that almost 20% of FHH patients might present with a calcium/creatinine ratio >0.01, and individuals with PPHT and simultaneous vitamin D deficiency might show lower than expected calcium excretion [43]. Genetic testing, when available, should be considered for confirming the clinical suspicion of FHH. More than 130 CaSR mutations have been reported so far in relation to FHH1, fact that explains the phenotypical variations in relation to the observed differences in serum calcium and PTH levels [21, 44].
During pregnancy, the distinction between FHH and PHPT is further complicated by the physiological changes in maternal calcium metabolism: increased breast and placental production of PTHrP, that together with the placental lactogen, leads to an increase in 1,25-(OH)2- vitamin D and a reduction of the PTH levels. As a result, the intestinal calcium absorption and the urine calcium excretion are physiologically increased [5, 45]. Treatment is depending on the underlying cause and might be invasive or conservative, but all decisions need good counseling, as it concerns not only the mother, but also the fetus and partner as well. Also we, as physicians, need to be aware that the treatment does not stop with the deliverance of a healthy baby and that the postpartum period might actually be the period with the highest risk for the mother due to the risk of sudden rises in calcium level and to excessive mental stress caused by possible events during pregnancy or delivery.
But foremost, irrespective of the underlying cause of hypercalcemia, patients and partners need to be closely involved in the decision processes in order to ensure overall good outcomes for mother and child.
Acknowledgements
We would like to acknowledge the European Reference Network for Rare Endocrine diseases, specifically main thematic group two calcium and phosphate disorders. We would like to thank both C.W.M. Janssen and S. Mourits for their agreement on publication of their medical history and contribution to the content of the manuscript.
Authors contributions
Conceptualization, writing original draft preparation, reviewing and editing: N.M.A-D. Reviewing and editing, critically revising the manuscript: D-A.E, M.C.Z, L.R, and E.M.W.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CINACALCET HYDROCHLORIDE, UNSPECIFIED INGREDIENT | DrugsGivenReaction | CC BY | 33544354 | 20,513,294 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Treatment failure'. | Hypercalcemia during pregnancy: management and outcomes for mother and child.
Diagnosing and treating hypercalcemia during pregnancy can be challenging due to both the physiological changes in calcium homeostasis and the underlying cause for the hypercalcemia. During pregnancy and lactation there is increased mobilization of calcium in the mother to meet the fetus' calcium requirements. Here we discuss the diagnostic challenges, management, and patient perspective of hypercalcemia during pregnancy in two particular cases and in other rare conditions causing hypercalcemia.
Introduction
Hypercalcemia in pregnancy is rare and in >90% of cases caused by a newly diagnosed primary hyperparathyroidism (PHPT). Hypercalcemia during pregnancy due to other disorders of calcium metabolism is even more rare and literature regarding the maternal management and fetal outcomes is lacking. Diagnosing hypercalcemia is challenging during pregnancy, as symptoms such as fatigue or nausea mimic those in early pregnancy. However, longstanding hypercalcemia might induce nephrolithiasis, pancreatitis, and preeclampsia in the mother [1]. Therefore, the occurrence of these diseases during pregnancy should push the physicians to screen for hypercalcemia. In the fetus, maternal hypercalcemia can result in fetal growth restriction [2]. Following birth, further complications may arise such as severe neonatal hypocalcemia, tetany, and even death due to fetal hypoparathyroidism [3, 4]. In rare calcium-related disorders, the diagnosis is often known before the pregnancy and patients and partners can be counseled by the treating endocrinologist, obstetrician, pediatrician, and geneticist when required, taking into account the possible physical and mental maternal adverse effects, but also the eventual consequences for the newborn. Here we would like to discuss the diagnostic challenges and management of hypercalcemia during pregnancy in two particular cases as example of rare conditions causing hypercalcemia complicating pregnancy.
Case 1
A 34-year-old woman was referred with severe hypercalcemia and a pregnancy wish. At the age of 24 she was diagnosed with PHPT, without underlying genetic causes. During parathyroidectomy (PTX) there was spill of the adenoma, histologically confirmed, which led to chronic hypercalcemia for which she underwent several re-operations in various hospitals including a thyroidectomy in 2 tempi with resection of surrounding fat-tissue and a bilateral modified lymph node resection. However, she remained dependent on cinacalcet and bisphosphonates in various dosages. At referral, albumin-corrected serum calcium was 2.89 mmol/L (ref 2.15–2.55 mmol/L) with PTH 10.7 (ref 1–8 pmol/L) while on cinacalcet 60 mg/day, and 3.16 mmol/L with PTH of 29 without cinacalcet. She and her partner were counselled by a team consisting of gynecologists, pediatricians, and endocrinologists on several aspects of the disease and potential consequences for a pregnancy. Prophylactic surgery was not possible at that time. Bisphosphonates were stopped and she became pregnant after 12 months. Cinacalcet was stopped and a fluid intake of 4 L was advised. However, she was admitted with a symptomatic hypercalcemia, 3.4 mmol/L, within 2 weeks. Hyperhydration and cinacalcet, up to 90 mg/day, were started in combination with furosemide 40 mg and acetylsalicylic acid 80 mg daily as preeclampsia prophylaxis. She suffered from severe hyperemesis gravidarum and due to persistent hypercalcemia, she received saline infusions of 5 L/day in a homecare setting with a peripheral intravasal central catheter (PICC). During follow up the PICC caused deep vein thrombosis for which nadroparin injections were started but with this treatment serum calcium remained stable around 2.7–2.9 mmol/L. At 38 weeks of gestation she developed hypertension with a rapidly developing HELLP syndrome and an emergency cesarean section was performed. A healthy baby boy, weight 3305 g, was delivered; he only received active vitamin D supplementation for a few days and two years after delivery; no calcium disturbances or skeletal abnormalities have been observed. The mother did not breastfeed. After delivery, the mother experienced a post-traumatic stress syndrome (PTSS) with depression for which she started Eye Movement Desensitization and Reprocessing (EMDR). The depression and PTSS was related to the latter part of the pregnancy and delivery, but most likely exacerbated due to a postpartum rise in calcium to 3.3 mmol/L. Surgery was successfully performed after which her mental complaints improved.
Case 2
A 38-year-old female was diagnosed with PHPT at a non-university hospital, based on a modest hypercalcemia, and elevated PTH of 9.2 pmol/L and high to normal urinary calcium excretion of 8.5 g/L and calcium-to-creatinine clearance above 0.02. Despite her young age, it was decided not to perform PTX because of an increased risk for venous thromboembolism and obesity. Five years later, she had an unexpected pregnancy and was referred for PTX in the second trimester. During that time serum calcium had increased from 2.63 mmol/L to 2.83 mmol/L with a non-suppressed PTH of 3.8 pmol/L. The patient and her partner were counseled by a team consisting of endocrinologists, anesthesiologists, endocrine surgeons, pediatricians, and obstetricians. Imaging studies did not reveal a clear-cut adenoma and considering the progressive rise in calcium to 2.93 mmol/L, urinary calcium excretion of 12 g/L in 24 h and proceeding into the end of the second trimester an elective neck exploration was performed at gestational age of 24 + 2 weeks, showing four gland hyperplasia. During surgery, it was decided to remove only the two right-sided glands in order not to risk hypoparathyroidism. After surgery hypercalcemia persisted with calcium levels between 2.60 mmol/L and 2.65 mmol/L and PTH between 2.1 pmol/L and 3.6 pmol/L. Considering the marked hyperplasia the patient was discussed in the clinical patient management system (CPMS) panel of main thematic group two, calcium and phosphate disorders of the European Reference Network for rare endocrine diseases (ENDO-ERN). The advice of this panel was to perform genetic testing for familial hypocalciuric calciuria (FHH), which came back positive for a mutation in the CASR-gen, c.653A>G p.(Tyr218Cys), establishing a diagnosis of FHH type one. At 39 + 3 weeks she delivered a healthy baby girl of 4150 g without any calcium disturbances. Post-partum the calcium levels of the mother remained at 2.6 mmol and PTH rose again to 10.3 pmol/L, which has been stable since.
Patient perspective
Patient one had an active pregnancy wish for 5 years, with a negative counselling in several centers. At the Leiden University Medical Center (LUMC) it was again made clear that this would not be without risks for mother and child but if desired we would do our best to monitor the pregnancy as good as possible, which was much appreciated as this was not discussed before. Although she was well prepared and extensively counseled, the intensity of the pregnancy was overwhelming. Both the high calcium levels, frequent investigations and the continuous hyperhydration were extremely demanding and resulted, together with the further rise in calcium, in a pre- and post-natal depression for which EMDR and psychotherapy were needed. Looking back, she would advise other patients to realize that it will be extremely tough, but absolutely worth it. The fact that caretakers were so involved in her well-being and their clear communication was helpful and appreciated. The health care system structure with various doctors during hospital admission remains unfortunate from her point of view, which was in contrast to the outpatient clinic care with one regular healthcare provider.
Despite living with, a supposed, PHPT for many years, patient 2 had never been counseled about PHPT in terms of treatment and follow up. In the initial phase of her referral to LUMC this was done rapidly as time was ticking for a safe window of surgery as the second trimester is the preferred trimester for surgery for maternal and fetal reasons. In addition, due to her increased risk for venous thromboembolism and obesity, emergency surgery in case of severe hypercalcemia was considered to be a high risk for the mother. The patient found the amount of information overwhelming. However, it was appreciated as it made the patient and her partner feel part of the team. After surgery, when she had postoperative pains, this induced more stress being pregnant. Caregivers should be aware that in pregnant patients’ complaints that might be considered as normal after surgery can induce a stressful trigger in patients who are already in a stressful situation. The doubts about the original diagnosis of PHPT were shared including the desire of the treating physicians to discuss her case with other experts. Although providing more insecurity, the patient did feel comfortable that this meant that no other surgery was likely to be needed. After the pregnancy she reported that the physical part of the pregnancy did not give her many discomforts but the uncertainty about the well-being of the baby was very stressful. But overall, she was very satisfied with the care given.
In collaboration with these patients we produced a checklist for women in the same position or with a recent diagnosis of PHPT, which might be of help, see Table 1.Table 1 Questions for women in the childbearing age to ask their doctor when diagnosed with a high calcium level
1. What is the most likely diagnosis causing this high calcium level?
2. What tests do I need to make the diagnosis more likely? And are these tests influenced by pregnancy?
3. How will this affect pregnancy?
What will be the risks for my unborn child?
What will be the risks for me?
Which interventions are possible/necessary before, during and after pregnancy?
4. What can I do to minimalize complaints during and after the pregnancy?
5. How can we decrease my risk for preeclampsia?
6. Which drugs might be used during the pregnancy and what are their side effects?
7. How can you monitor my child?
8. How will my disease affect me after delivery?
9. How will this affect my child directly after delivery?
10. Can I breastfeed?
11. Who is in my multidisciplinary team and how can I reach them?
12. What can be done by my general practitioner?
13. What would be the risk of getting pregnant and to whom can I speak to for counseling?
In both cases patients and partners experienced the pregnancy as a rollercoaster with lot of uncertainties. Whereas both patients were diagnosed with hypercalcemia before pregnancy, patient 1 was counseled extensively in the pre-pregnancy period and even repeatedly got the advice not to become pregnant while patient 2 was never counseled. Also, in patient 2 the diagnosis was changed from PHPT to FHH, the finding of the marked hyperplasia triggered doubts about the original diagnosis of PHPT. In patient 1, the initial decision for surgery would still be made as her calcium values were rising and she did develop nausea and in FHH hyperplasia is also often described.
Physiological changes during pregnancy (Fig. 1a)
During pregnancy and lactation there is increased mobilization of calcium in the mother to meet the fetus’ calcium requirements [5, 6]. This is done by increasing intestinal calcium absorption through increasing 1.25 vitamin D production and PTH-related peptide (PTHrP), which is released from placenta and breasts in response to estradiol, placental lactogen, and prolactin [6, 7]. Despite the overlapping modes of action, PTH and PTHrP are produced by different genes on different chromosomes and the gene encoding PTHrP is more complex than for PTH. PTHrP is undetectable in the circulating blood of non-pregnant women, but is produced in a paracrine/autocrine fashion during pregnancy. Lessons from PTHrP or PTH1R gene knockout mice, which die at birth or in utero, emphasize the critical role of PTHrP for normal life [8, 9]. In addition, nascent PTHrP isoforms are processed by members of the prohormone convertase family to at least three fragments: N-terminal PTHrP [1–36], structurally related to PTH; a mid-region PTHrP (38–94); and a C-terminal PTHrP(107–139) with distinct biological properties and receptors. PTHrP is able to act not only via the classical autocrine/paracrine pathways, but also through a so-called intracrine pathway, which involves the translocation of the protein into the nucleus, where it can directly regulate proliferation and apoptosis [10, 11]. PTHrP has multiple activities including control of fetal development, trans-epithelial calcium transfer, lactation, smooth muscle relaxation, and cell growth. The mid-molecular region of PTHrP stimulates placental calcium transport in the fetus, while the COOH terminal region may also affect osteoclast activity. Thus, although PTHrP was discovered as a tumor-derived hypercalcemic factor, its primary physiological role is as a local regulator of many physiological processes especially in early life [12, 13].Fig. 1 a *Intravascular fluid expansion causes gestational hypoalbuminemia. The dilutional hypoalbuminemia of pregnancy leads to a decline in total calcium concentration. Ionized calcium on the other hand, remains stable and may provide more accurate information. ** The increase in 1.25 vitamin D production leads to an increase in intestinal calcium absorption. ***“Absorptive hypercalciuria of pregnancy”. Postprandial and 24-h urinary calcium excretion increase after 12 weeks, due to increased intestinal calcium absorption supposedly unrelated to increased formation of 1.25 vitamin D in early pregnancy. Fasting urine samples will not be affected by this phenomenon [45]. b *Prednison to reduce 1.25OH formation and thus intestinal calcium absorption. ** Reducing PTH-rp production mammae. *** No clinical data during pregnancy, only case reports. In animal studies no abnormalities observed, but it does pass the placenta [31, 46]. Breastfeeding: in animal studies (rat), cinacalcet is found in milk [46].
Maternal causes and consequences of hypercalcemia (Fig. 1b)
Hypercalcemia due to hyperparathyroidism is the most described cause of hypercalcemia during pregnancy. As most reviews focus on maternal and fetal outcomes in PHPT we will not cover this topic in the current paper [14, 15]. Hyperparathyroidism due to diffusely spread hyperthyroid nodules, parathyromatosis, post-parathyroidectomy, in the context of malignancy, MEN syndromes, or in chronic renal disease has been rarely described [15, 16]. Literature data on parathyromatosis is limited to around 20 cases published so far with only one report on a woman diagnosed and treated during pregnancy [17, 18].
FHH is a rare autosomal dominant disorder, with a prevalence of ~1:78.000 though this might likely be higher, as many cases remain asymptomatic lifelong and no causal treatment is available [19–21]. According to the genetic defect causing the pathology, three types of FHH have been defined [21–24]. FHH1 is the most common type and is found in about 65% of all FHH cases [21]. Patients with FHH present with mild to moderate hypercalcaemia, low urinary excretion, and PTH serum levels that are either normal or slightly elevated. Many patients with FHH are misdiagnosed as suffering from PHPT as in the case of our patient. Data on FHH manifested during pregnancy, literature data are sparse. Only four cases were published so far. Walker et al. reported the case of a pregnant patient, initially diagnosed with PHPT, who showed no improvement after PTX. The newborn presented with asymptomatic hypercalcemia; the genetic analysis confirmed the diagnosis of FHH [25]. The newborn presented elevated serum calcium levels with no clinical symptoms, while the genetic analysis confirmed the diagnosis of FHH. Others reported hypercalcemic profiles for which they underwent surgery during pregnancy [26, 27].
PTHrP-induced hypercalcemia during pregnancy or lactation has also been reported, either with or without gigantomastia [28–33]. In the reported cases, associating gigantomastia and increased PTHrP serum values, hypercalcaemia was diagnosed during gestation and resolved only after mastectomy, bromocriptin administration, or termination of pregnancy [29, 31, 32].
After delivery, there is a risk of severe hypercalcemia in women with PHPT who are lactating as PTH-rp production will increase [6, 34]. Especially women with gestational hypercalcemia with gigantomastia should be advised against breastfeeding as this will keep PTHrp levels high. The rise in PTHrp during pregnancy was not seen in patient 1 in whom PTHrp production was fully suppressed during entire pregnancy. The observed rise in calcium levels in patient 2 might in retrospect be due to her different setpoint and PTHrp production. Mental consequences of hypercalcemia are well known and include depression and anxiety [35, 36]. During pregnancy mothers might have additional stress which might be exaggerated by the hypercalcemia.
Fetal consequences of hypercalcemia
In the fetus, maternal PHPT can result in fetal growth restriction, severe neonatal hypocalcemia, tetany, and death [36]. In maternal FHH potential fetal complications include mild hypercalcemia, severe hypocalcemia, or neonatal severe hyperparathyroidism, depending on the genotype of the fetus. Because FHH is an autosomal dominant condition, three genetic situations might be encountered by the newborns of FHH mothers: the unaffected and the heterozygous neonates might present with hypocalcaemia induced by the in utero suppression of the parathyroid, the latter being at risk of developing hypercalcemia with hypocalcaemia in the first year of life. The homozygous form of FHH results in a severe neonatal hyperparathyroidism, which requires the surgical removal of the glands during the neonatal phase [37, 38].
Most outcomes on the fetal consequences of hypercalcemia were described in reports on patients with PHPT. Untreated hypercalcemia was associated with fetal or neonatal complications in the majority of cases [3, 36, 39, 40]. However, these findings are based on early literature of PHPT patients when hypercalcemia was often diagnosed in an advanced stage and more recent literature has shown that, compared to age-matched controls, women with PHPT had no difference in most pregnancy outcomes, including stillbirths [39]. That same study also showed that Apgar scores and anthropometric measurements were similar to babies born in uncomplicated pregnancies. However, this recent study did not report on maternal outcomes of preeclampsia. Other recent studies also report lower complications rates and good treatment outcomes when the hypercalcemia is moderate and not severe [1, 41].
Elevated maternal serum calcium leads to hypercalcemia in the fetus, which causes fetal parathyroid gland suppression. After delivery, these glands are still suppressed causing fetal hypocalcemia, which is usually transient (lasting 3–5 months after birth), but permanent hypoparathyroidism has anecdotally been described [42].
In the case of parathyromatosis diagnosed during pregnancy, Edling et al. reported that the infant presented initially with high calcium and low PTH levels, which normalized rapidly, with no further complications [18]. Newborns of mothers presenting with humoral hypercalcemia of pregnancy were having normal calcium levels at birth [29, 30, 33].
Diagnosing hypercalcemia during pregnancy might be challenging due to both physiological changes in calcium homeostasis, as well as due to the underlying cause for the hypercalcemia; changes in urinary calcium excretion vary during daytime, introducing difficulty in using urinary calcium indices as a diagnostic tool. In non-pregnant population, the measurement of calcium/creatinine clearance ratio can be useful in distinguishing between PHPT(>0.02 mmol/mmol) and FHH(<0.01 mmol/mmol). However, it is known that almost 20% of FHH patients might present with a calcium/creatinine ratio >0.01, and individuals with PPHT and simultaneous vitamin D deficiency might show lower than expected calcium excretion [43]. Genetic testing, when available, should be considered for confirming the clinical suspicion of FHH. More than 130 CaSR mutations have been reported so far in relation to FHH1, fact that explains the phenotypical variations in relation to the observed differences in serum calcium and PTH levels [21, 44].
During pregnancy, the distinction between FHH and PHPT is further complicated by the physiological changes in maternal calcium metabolism: increased breast and placental production of PTHrP, that together with the placental lactogen, leads to an increase in 1,25-(OH)2- vitamin D and a reduction of the PTH levels. As a result, the intestinal calcium absorption and the urine calcium excretion are physiologically increased [5, 45]. Treatment is depending on the underlying cause and might be invasive or conservative, but all decisions need good counseling, as it concerns not only the mother, but also the fetus and partner as well. Also we, as physicians, need to be aware that the treatment does not stop with the deliverance of a healthy baby and that the postpartum period might actually be the period with the highest risk for the mother due to the risk of sudden rises in calcium level and to excessive mental stress caused by possible events during pregnancy or delivery.
But foremost, irrespective of the underlying cause of hypercalcemia, patients and partners need to be closely involved in the decision processes in order to ensure overall good outcomes for mother and child.
Acknowledgements
We would like to acknowledge the European Reference Network for Rare Endocrine diseases, specifically main thematic group two calcium and phosphate disorders. We would like to thank both C.W.M. Janssen and S. Mourits for their agreement on publication of their medical history and contribution to the content of the manuscript.
Authors contributions
Conceptualization, writing original draft preparation, reviewing and editing: N.M.A-D. Reviewing and editing, critically revising the manuscript: D-A.E, M.C.Z, L.R, and E.M.W.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | CINACALCET HYDROCHLORIDE, UNSPECIFIED INGREDIENT | DrugsGivenReaction | CC BY | 33544354 | 20,513,294 | 2021-03 |
What was the outcome of reaction 'Depression'? | Hypercalcemia during pregnancy: management and outcomes for mother and child.
Diagnosing and treating hypercalcemia during pregnancy can be challenging due to both the physiological changes in calcium homeostasis and the underlying cause for the hypercalcemia. During pregnancy and lactation there is increased mobilization of calcium in the mother to meet the fetus' calcium requirements. Here we discuss the diagnostic challenges, management, and patient perspective of hypercalcemia during pregnancy in two particular cases and in other rare conditions causing hypercalcemia.
Introduction
Hypercalcemia in pregnancy is rare and in >90% of cases caused by a newly diagnosed primary hyperparathyroidism (PHPT). Hypercalcemia during pregnancy due to other disorders of calcium metabolism is even more rare and literature regarding the maternal management and fetal outcomes is lacking. Diagnosing hypercalcemia is challenging during pregnancy, as symptoms such as fatigue or nausea mimic those in early pregnancy. However, longstanding hypercalcemia might induce nephrolithiasis, pancreatitis, and preeclampsia in the mother [1]. Therefore, the occurrence of these diseases during pregnancy should push the physicians to screen for hypercalcemia. In the fetus, maternal hypercalcemia can result in fetal growth restriction [2]. Following birth, further complications may arise such as severe neonatal hypocalcemia, tetany, and even death due to fetal hypoparathyroidism [3, 4]. In rare calcium-related disorders, the diagnosis is often known before the pregnancy and patients and partners can be counseled by the treating endocrinologist, obstetrician, pediatrician, and geneticist when required, taking into account the possible physical and mental maternal adverse effects, but also the eventual consequences for the newborn. Here we would like to discuss the diagnostic challenges and management of hypercalcemia during pregnancy in two particular cases as example of rare conditions causing hypercalcemia complicating pregnancy.
Case 1
A 34-year-old woman was referred with severe hypercalcemia and a pregnancy wish. At the age of 24 she was diagnosed with PHPT, without underlying genetic causes. During parathyroidectomy (PTX) there was spill of the adenoma, histologically confirmed, which led to chronic hypercalcemia for which she underwent several re-operations in various hospitals including a thyroidectomy in 2 tempi with resection of surrounding fat-tissue and a bilateral modified lymph node resection. However, she remained dependent on cinacalcet and bisphosphonates in various dosages. At referral, albumin-corrected serum calcium was 2.89 mmol/L (ref 2.15–2.55 mmol/L) with PTH 10.7 (ref 1–8 pmol/L) while on cinacalcet 60 mg/day, and 3.16 mmol/L with PTH of 29 without cinacalcet. She and her partner were counselled by a team consisting of gynecologists, pediatricians, and endocrinologists on several aspects of the disease and potential consequences for a pregnancy. Prophylactic surgery was not possible at that time. Bisphosphonates were stopped and she became pregnant after 12 months. Cinacalcet was stopped and a fluid intake of 4 L was advised. However, she was admitted with a symptomatic hypercalcemia, 3.4 mmol/L, within 2 weeks. Hyperhydration and cinacalcet, up to 90 mg/day, were started in combination with furosemide 40 mg and acetylsalicylic acid 80 mg daily as preeclampsia prophylaxis. She suffered from severe hyperemesis gravidarum and due to persistent hypercalcemia, she received saline infusions of 5 L/day in a homecare setting with a peripheral intravasal central catheter (PICC). During follow up the PICC caused deep vein thrombosis for which nadroparin injections were started but with this treatment serum calcium remained stable around 2.7–2.9 mmol/L. At 38 weeks of gestation she developed hypertension with a rapidly developing HELLP syndrome and an emergency cesarean section was performed. A healthy baby boy, weight 3305 g, was delivered; he only received active vitamin D supplementation for a few days and two years after delivery; no calcium disturbances or skeletal abnormalities have been observed. The mother did not breastfeed. After delivery, the mother experienced a post-traumatic stress syndrome (PTSS) with depression for which she started Eye Movement Desensitization and Reprocessing (EMDR). The depression and PTSS was related to the latter part of the pregnancy and delivery, but most likely exacerbated due to a postpartum rise in calcium to 3.3 mmol/L. Surgery was successfully performed after which her mental complaints improved.
Case 2
A 38-year-old female was diagnosed with PHPT at a non-university hospital, based on a modest hypercalcemia, and elevated PTH of 9.2 pmol/L and high to normal urinary calcium excretion of 8.5 g/L and calcium-to-creatinine clearance above 0.02. Despite her young age, it was decided not to perform PTX because of an increased risk for venous thromboembolism and obesity. Five years later, she had an unexpected pregnancy and was referred for PTX in the second trimester. During that time serum calcium had increased from 2.63 mmol/L to 2.83 mmol/L with a non-suppressed PTH of 3.8 pmol/L. The patient and her partner were counseled by a team consisting of endocrinologists, anesthesiologists, endocrine surgeons, pediatricians, and obstetricians. Imaging studies did not reveal a clear-cut adenoma and considering the progressive rise in calcium to 2.93 mmol/L, urinary calcium excretion of 12 g/L in 24 h and proceeding into the end of the second trimester an elective neck exploration was performed at gestational age of 24 + 2 weeks, showing four gland hyperplasia. During surgery, it was decided to remove only the two right-sided glands in order not to risk hypoparathyroidism. After surgery hypercalcemia persisted with calcium levels between 2.60 mmol/L and 2.65 mmol/L and PTH between 2.1 pmol/L and 3.6 pmol/L. Considering the marked hyperplasia the patient was discussed in the clinical patient management system (CPMS) panel of main thematic group two, calcium and phosphate disorders of the European Reference Network for rare endocrine diseases (ENDO-ERN). The advice of this panel was to perform genetic testing for familial hypocalciuric calciuria (FHH), which came back positive for a mutation in the CASR-gen, c.653A>G p.(Tyr218Cys), establishing a diagnosis of FHH type one. At 39 + 3 weeks she delivered a healthy baby girl of 4150 g without any calcium disturbances. Post-partum the calcium levels of the mother remained at 2.6 mmol and PTH rose again to 10.3 pmol/L, which has been stable since.
Patient perspective
Patient one had an active pregnancy wish for 5 years, with a negative counselling in several centers. At the Leiden University Medical Center (LUMC) it was again made clear that this would not be without risks for mother and child but if desired we would do our best to monitor the pregnancy as good as possible, which was much appreciated as this was not discussed before. Although she was well prepared and extensively counseled, the intensity of the pregnancy was overwhelming. Both the high calcium levels, frequent investigations and the continuous hyperhydration were extremely demanding and resulted, together with the further rise in calcium, in a pre- and post-natal depression for which EMDR and psychotherapy were needed. Looking back, she would advise other patients to realize that it will be extremely tough, but absolutely worth it. The fact that caretakers were so involved in her well-being and their clear communication was helpful and appreciated. The health care system structure with various doctors during hospital admission remains unfortunate from her point of view, which was in contrast to the outpatient clinic care with one regular healthcare provider.
Despite living with, a supposed, PHPT for many years, patient 2 had never been counseled about PHPT in terms of treatment and follow up. In the initial phase of her referral to LUMC this was done rapidly as time was ticking for a safe window of surgery as the second trimester is the preferred trimester for surgery for maternal and fetal reasons. In addition, due to her increased risk for venous thromboembolism and obesity, emergency surgery in case of severe hypercalcemia was considered to be a high risk for the mother. The patient found the amount of information overwhelming. However, it was appreciated as it made the patient and her partner feel part of the team. After surgery, when she had postoperative pains, this induced more stress being pregnant. Caregivers should be aware that in pregnant patients’ complaints that might be considered as normal after surgery can induce a stressful trigger in patients who are already in a stressful situation. The doubts about the original diagnosis of PHPT were shared including the desire of the treating physicians to discuss her case with other experts. Although providing more insecurity, the patient did feel comfortable that this meant that no other surgery was likely to be needed. After the pregnancy she reported that the physical part of the pregnancy did not give her many discomforts but the uncertainty about the well-being of the baby was very stressful. But overall, she was very satisfied with the care given.
In collaboration with these patients we produced a checklist for women in the same position or with a recent diagnosis of PHPT, which might be of help, see Table 1.Table 1 Questions for women in the childbearing age to ask their doctor when diagnosed with a high calcium level
1. What is the most likely diagnosis causing this high calcium level?
2. What tests do I need to make the diagnosis more likely? And are these tests influenced by pregnancy?
3. How will this affect pregnancy?
What will be the risks for my unborn child?
What will be the risks for me?
Which interventions are possible/necessary before, during and after pregnancy?
4. What can I do to minimalize complaints during and after the pregnancy?
5. How can we decrease my risk for preeclampsia?
6. Which drugs might be used during the pregnancy and what are their side effects?
7. How can you monitor my child?
8. How will my disease affect me after delivery?
9. How will this affect my child directly after delivery?
10. Can I breastfeed?
11. Who is in my multidisciplinary team and how can I reach them?
12. What can be done by my general practitioner?
13. What would be the risk of getting pregnant and to whom can I speak to for counseling?
In both cases patients and partners experienced the pregnancy as a rollercoaster with lot of uncertainties. Whereas both patients were diagnosed with hypercalcemia before pregnancy, patient 1 was counseled extensively in the pre-pregnancy period and even repeatedly got the advice not to become pregnant while patient 2 was never counseled. Also, in patient 2 the diagnosis was changed from PHPT to FHH, the finding of the marked hyperplasia triggered doubts about the original diagnosis of PHPT. In patient 1, the initial decision for surgery would still be made as her calcium values were rising and she did develop nausea and in FHH hyperplasia is also often described.
Physiological changes during pregnancy (Fig. 1a)
During pregnancy and lactation there is increased mobilization of calcium in the mother to meet the fetus’ calcium requirements [5, 6]. This is done by increasing intestinal calcium absorption through increasing 1.25 vitamin D production and PTH-related peptide (PTHrP), which is released from placenta and breasts in response to estradiol, placental lactogen, and prolactin [6, 7]. Despite the overlapping modes of action, PTH and PTHrP are produced by different genes on different chromosomes and the gene encoding PTHrP is more complex than for PTH. PTHrP is undetectable in the circulating blood of non-pregnant women, but is produced in a paracrine/autocrine fashion during pregnancy. Lessons from PTHrP or PTH1R gene knockout mice, which die at birth or in utero, emphasize the critical role of PTHrP for normal life [8, 9]. In addition, nascent PTHrP isoforms are processed by members of the prohormone convertase family to at least three fragments: N-terminal PTHrP [1–36], structurally related to PTH; a mid-region PTHrP (38–94); and a C-terminal PTHrP(107–139) with distinct biological properties and receptors. PTHrP is able to act not only via the classical autocrine/paracrine pathways, but also through a so-called intracrine pathway, which involves the translocation of the protein into the nucleus, where it can directly regulate proliferation and apoptosis [10, 11]. PTHrP has multiple activities including control of fetal development, trans-epithelial calcium transfer, lactation, smooth muscle relaxation, and cell growth. The mid-molecular region of PTHrP stimulates placental calcium transport in the fetus, while the COOH terminal region may also affect osteoclast activity. Thus, although PTHrP was discovered as a tumor-derived hypercalcemic factor, its primary physiological role is as a local regulator of many physiological processes especially in early life [12, 13].Fig. 1 a *Intravascular fluid expansion causes gestational hypoalbuminemia. The dilutional hypoalbuminemia of pregnancy leads to a decline in total calcium concentration. Ionized calcium on the other hand, remains stable and may provide more accurate information. ** The increase in 1.25 vitamin D production leads to an increase in intestinal calcium absorption. ***“Absorptive hypercalciuria of pregnancy”. Postprandial and 24-h urinary calcium excretion increase after 12 weeks, due to increased intestinal calcium absorption supposedly unrelated to increased formation of 1.25 vitamin D in early pregnancy. Fasting urine samples will not be affected by this phenomenon [45]. b *Prednison to reduce 1.25OH formation and thus intestinal calcium absorption. ** Reducing PTH-rp production mammae. *** No clinical data during pregnancy, only case reports. In animal studies no abnormalities observed, but it does pass the placenta [31, 46]. Breastfeeding: in animal studies (rat), cinacalcet is found in milk [46].
Maternal causes and consequences of hypercalcemia (Fig. 1b)
Hypercalcemia due to hyperparathyroidism is the most described cause of hypercalcemia during pregnancy. As most reviews focus on maternal and fetal outcomes in PHPT we will not cover this topic in the current paper [14, 15]. Hyperparathyroidism due to diffusely spread hyperthyroid nodules, parathyromatosis, post-parathyroidectomy, in the context of malignancy, MEN syndromes, or in chronic renal disease has been rarely described [15, 16]. Literature data on parathyromatosis is limited to around 20 cases published so far with only one report on a woman diagnosed and treated during pregnancy [17, 18].
FHH is a rare autosomal dominant disorder, with a prevalence of ~1:78.000 though this might likely be higher, as many cases remain asymptomatic lifelong and no causal treatment is available [19–21]. According to the genetic defect causing the pathology, three types of FHH have been defined [21–24]. FHH1 is the most common type and is found in about 65% of all FHH cases [21]. Patients with FHH present with mild to moderate hypercalcaemia, low urinary excretion, and PTH serum levels that are either normal or slightly elevated. Many patients with FHH are misdiagnosed as suffering from PHPT as in the case of our patient. Data on FHH manifested during pregnancy, literature data are sparse. Only four cases were published so far. Walker et al. reported the case of a pregnant patient, initially diagnosed with PHPT, who showed no improvement after PTX. The newborn presented with asymptomatic hypercalcemia; the genetic analysis confirmed the diagnosis of FHH [25]. The newborn presented elevated serum calcium levels with no clinical symptoms, while the genetic analysis confirmed the diagnosis of FHH. Others reported hypercalcemic profiles for which they underwent surgery during pregnancy [26, 27].
PTHrP-induced hypercalcemia during pregnancy or lactation has also been reported, either with or without gigantomastia [28–33]. In the reported cases, associating gigantomastia and increased PTHrP serum values, hypercalcaemia was diagnosed during gestation and resolved only after mastectomy, bromocriptin administration, or termination of pregnancy [29, 31, 32].
After delivery, there is a risk of severe hypercalcemia in women with PHPT who are lactating as PTH-rp production will increase [6, 34]. Especially women with gestational hypercalcemia with gigantomastia should be advised against breastfeeding as this will keep PTHrp levels high. The rise in PTHrp during pregnancy was not seen in patient 1 in whom PTHrp production was fully suppressed during entire pregnancy. The observed rise in calcium levels in patient 2 might in retrospect be due to her different setpoint and PTHrp production. Mental consequences of hypercalcemia are well known and include depression and anxiety [35, 36]. During pregnancy mothers might have additional stress which might be exaggerated by the hypercalcemia.
Fetal consequences of hypercalcemia
In the fetus, maternal PHPT can result in fetal growth restriction, severe neonatal hypocalcemia, tetany, and death [36]. In maternal FHH potential fetal complications include mild hypercalcemia, severe hypocalcemia, or neonatal severe hyperparathyroidism, depending on the genotype of the fetus. Because FHH is an autosomal dominant condition, three genetic situations might be encountered by the newborns of FHH mothers: the unaffected and the heterozygous neonates might present with hypocalcaemia induced by the in utero suppression of the parathyroid, the latter being at risk of developing hypercalcemia with hypocalcaemia in the first year of life. The homozygous form of FHH results in a severe neonatal hyperparathyroidism, which requires the surgical removal of the glands during the neonatal phase [37, 38].
Most outcomes on the fetal consequences of hypercalcemia were described in reports on patients with PHPT. Untreated hypercalcemia was associated with fetal or neonatal complications in the majority of cases [3, 36, 39, 40]. However, these findings are based on early literature of PHPT patients when hypercalcemia was often diagnosed in an advanced stage and more recent literature has shown that, compared to age-matched controls, women with PHPT had no difference in most pregnancy outcomes, including stillbirths [39]. That same study also showed that Apgar scores and anthropometric measurements were similar to babies born in uncomplicated pregnancies. However, this recent study did not report on maternal outcomes of preeclampsia. Other recent studies also report lower complications rates and good treatment outcomes when the hypercalcemia is moderate and not severe [1, 41].
Elevated maternal serum calcium leads to hypercalcemia in the fetus, which causes fetal parathyroid gland suppression. After delivery, these glands are still suppressed causing fetal hypocalcemia, which is usually transient (lasting 3–5 months after birth), but permanent hypoparathyroidism has anecdotally been described [42].
In the case of parathyromatosis diagnosed during pregnancy, Edling et al. reported that the infant presented initially with high calcium and low PTH levels, which normalized rapidly, with no further complications [18]. Newborns of mothers presenting with humoral hypercalcemia of pregnancy were having normal calcium levels at birth [29, 30, 33].
Diagnosing hypercalcemia during pregnancy might be challenging due to both physiological changes in calcium homeostasis, as well as due to the underlying cause for the hypercalcemia; changes in urinary calcium excretion vary during daytime, introducing difficulty in using urinary calcium indices as a diagnostic tool. In non-pregnant population, the measurement of calcium/creatinine clearance ratio can be useful in distinguishing between PHPT(>0.02 mmol/mmol) and FHH(<0.01 mmol/mmol). However, it is known that almost 20% of FHH patients might present with a calcium/creatinine ratio >0.01, and individuals with PPHT and simultaneous vitamin D deficiency might show lower than expected calcium excretion [43]. Genetic testing, when available, should be considered for confirming the clinical suspicion of FHH. More than 130 CaSR mutations have been reported so far in relation to FHH1, fact that explains the phenotypical variations in relation to the observed differences in serum calcium and PTH levels [21, 44].
During pregnancy, the distinction between FHH and PHPT is further complicated by the physiological changes in maternal calcium metabolism: increased breast and placental production of PTHrP, that together with the placental lactogen, leads to an increase in 1,25-(OH)2- vitamin D and a reduction of the PTH levels. As a result, the intestinal calcium absorption and the urine calcium excretion are physiologically increased [5, 45]. Treatment is depending on the underlying cause and might be invasive or conservative, but all decisions need good counseling, as it concerns not only the mother, but also the fetus and partner as well. Also we, as physicians, need to be aware that the treatment does not stop with the deliverance of a healthy baby and that the postpartum period might actually be the period with the highest risk for the mother due to the risk of sudden rises in calcium level and to excessive mental stress caused by possible events during pregnancy or delivery.
But foremost, irrespective of the underlying cause of hypercalcemia, patients and partners need to be closely involved in the decision processes in order to ensure overall good outcomes for mother and child.
Acknowledgements
We would like to acknowledge the European Reference Network for Rare Endocrine diseases, specifically main thematic group two calcium and phosphate disorders. We would like to thank both C.W.M. Janssen and S. Mourits for their agreement on publication of their medical history and contribution to the content of the manuscript.
Authors contributions
Conceptualization, writing original draft preparation, reviewing and editing: N.M.A-D. Reviewing and editing, critically revising the manuscript: D-A.E, M.C.Z, L.R, and E.M.W.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovering | ReactionOutcome | CC BY | 33544354 | 20,513,294 | 2021-03 |
What was the outcome of reaction 'Maternal exposure during pregnancy'? | Hypercalcemia during pregnancy: management and outcomes for mother and child.
Diagnosing and treating hypercalcemia during pregnancy can be challenging due to both the physiological changes in calcium homeostasis and the underlying cause for the hypercalcemia. During pregnancy and lactation there is increased mobilization of calcium in the mother to meet the fetus' calcium requirements. Here we discuss the diagnostic challenges, management, and patient perspective of hypercalcemia during pregnancy in two particular cases and in other rare conditions causing hypercalcemia.
Introduction
Hypercalcemia in pregnancy is rare and in >90% of cases caused by a newly diagnosed primary hyperparathyroidism (PHPT). Hypercalcemia during pregnancy due to other disorders of calcium metabolism is even more rare and literature regarding the maternal management and fetal outcomes is lacking. Diagnosing hypercalcemia is challenging during pregnancy, as symptoms such as fatigue or nausea mimic those in early pregnancy. However, longstanding hypercalcemia might induce nephrolithiasis, pancreatitis, and preeclampsia in the mother [1]. Therefore, the occurrence of these diseases during pregnancy should push the physicians to screen for hypercalcemia. In the fetus, maternal hypercalcemia can result in fetal growth restriction [2]. Following birth, further complications may arise such as severe neonatal hypocalcemia, tetany, and even death due to fetal hypoparathyroidism [3, 4]. In rare calcium-related disorders, the diagnosis is often known before the pregnancy and patients and partners can be counseled by the treating endocrinologist, obstetrician, pediatrician, and geneticist when required, taking into account the possible physical and mental maternal adverse effects, but also the eventual consequences for the newborn. Here we would like to discuss the diagnostic challenges and management of hypercalcemia during pregnancy in two particular cases as example of rare conditions causing hypercalcemia complicating pregnancy.
Case 1
A 34-year-old woman was referred with severe hypercalcemia and a pregnancy wish. At the age of 24 she was diagnosed with PHPT, without underlying genetic causes. During parathyroidectomy (PTX) there was spill of the adenoma, histologically confirmed, which led to chronic hypercalcemia for which she underwent several re-operations in various hospitals including a thyroidectomy in 2 tempi with resection of surrounding fat-tissue and a bilateral modified lymph node resection. However, she remained dependent on cinacalcet and bisphosphonates in various dosages. At referral, albumin-corrected serum calcium was 2.89 mmol/L (ref 2.15–2.55 mmol/L) with PTH 10.7 (ref 1–8 pmol/L) while on cinacalcet 60 mg/day, and 3.16 mmol/L with PTH of 29 without cinacalcet. She and her partner were counselled by a team consisting of gynecologists, pediatricians, and endocrinologists on several aspects of the disease and potential consequences for a pregnancy. Prophylactic surgery was not possible at that time. Bisphosphonates were stopped and she became pregnant after 12 months. Cinacalcet was stopped and a fluid intake of 4 L was advised. However, she was admitted with a symptomatic hypercalcemia, 3.4 mmol/L, within 2 weeks. Hyperhydration and cinacalcet, up to 90 mg/day, were started in combination with furosemide 40 mg and acetylsalicylic acid 80 mg daily as preeclampsia prophylaxis. She suffered from severe hyperemesis gravidarum and due to persistent hypercalcemia, she received saline infusions of 5 L/day in a homecare setting with a peripheral intravasal central catheter (PICC). During follow up the PICC caused deep vein thrombosis for which nadroparin injections were started but with this treatment serum calcium remained stable around 2.7–2.9 mmol/L. At 38 weeks of gestation she developed hypertension with a rapidly developing HELLP syndrome and an emergency cesarean section was performed. A healthy baby boy, weight 3305 g, was delivered; he only received active vitamin D supplementation for a few days and two years after delivery; no calcium disturbances or skeletal abnormalities have been observed. The mother did not breastfeed. After delivery, the mother experienced a post-traumatic stress syndrome (PTSS) with depression for which she started Eye Movement Desensitization and Reprocessing (EMDR). The depression and PTSS was related to the latter part of the pregnancy and delivery, but most likely exacerbated due to a postpartum rise in calcium to 3.3 mmol/L. Surgery was successfully performed after which her mental complaints improved.
Case 2
A 38-year-old female was diagnosed with PHPT at a non-university hospital, based on a modest hypercalcemia, and elevated PTH of 9.2 pmol/L and high to normal urinary calcium excretion of 8.5 g/L and calcium-to-creatinine clearance above 0.02. Despite her young age, it was decided not to perform PTX because of an increased risk for venous thromboembolism and obesity. Five years later, she had an unexpected pregnancy and was referred for PTX in the second trimester. During that time serum calcium had increased from 2.63 mmol/L to 2.83 mmol/L with a non-suppressed PTH of 3.8 pmol/L. The patient and her partner were counseled by a team consisting of endocrinologists, anesthesiologists, endocrine surgeons, pediatricians, and obstetricians. Imaging studies did not reveal a clear-cut adenoma and considering the progressive rise in calcium to 2.93 mmol/L, urinary calcium excretion of 12 g/L in 24 h and proceeding into the end of the second trimester an elective neck exploration was performed at gestational age of 24 + 2 weeks, showing four gland hyperplasia. During surgery, it was decided to remove only the two right-sided glands in order not to risk hypoparathyroidism. After surgery hypercalcemia persisted with calcium levels between 2.60 mmol/L and 2.65 mmol/L and PTH between 2.1 pmol/L and 3.6 pmol/L. Considering the marked hyperplasia the patient was discussed in the clinical patient management system (CPMS) panel of main thematic group two, calcium and phosphate disorders of the European Reference Network for rare endocrine diseases (ENDO-ERN). The advice of this panel was to perform genetic testing for familial hypocalciuric calciuria (FHH), which came back positive for a mutation in the CASR-gen, c.653A>G p.(Tyr218Cys), establishing a diagnosis of FHH type one. At 39 + 3 weeks she delivered a healthy baby girl of 4150 g without any calcium disturbances. Post-partum the calcium levels of the mother remained at 2.6 mmol and PTH rose again to 10.3 pmol/L, which has been stable since.
Patient perspective
Patient one had an active pregnancy wish for 5 years, with a negative counselling in several centers. At the Leiden University Medical Center (LUMC) it was again made clear that this would not be without risks for mother and child but if desired we would do our best to monitor the pregnancy as good as possible, which was much appreciated as this was not discussed before. Although she was well prepared and extensively counseled, the intensity of the pregnancy was overwhelming. Both the high calcium levels, frequent investigations and the continuous hyperhydration were extremely demanding and resulted, together with the further rise in calcium, in a pre- and post-natal depression for which EMDR and psychotherapy were needed. Looking back, she would advise other patients to realize that it will be extremely tough, but absolutely worth it. The fact that caretakers were so involved in her well-being and their clear communication was helpful and appreciated. The health care system structure with various doctors during hospital admission remains unfortunate from her point of view, which was in contrast to the outpatient clinic care with one regular healthcare provider.
Despite living with, a supposed, PHPT for many years, patient 2 had never been counseled about PHPT in terms of treatment and follow up. In the initial phase of her referral to LUMC this was done rapidly as time was ticking for a safe window of surgery as the second trimester is the preferred trimester for surgery for maternal and fetal reasons. In addition, due to her increased risk for venous thromboembolism and obesity, emergency surgery in case of severe hypercalcemia was considered to be a high risk for the mother. The patient found the amount of information overwhelming. However, it was appreciated as it made the patient and her partner feel part of the team. After surgery, when she had postoperative pains, this induced more stress being pregnant. Caregivers should be aware that in pregnant patients’ complaints that might be considered as normal after surgery can induce a stressful trigger in patients who are already in a stressful situation. The doubts about the original diagnosis of PHPT were shared including the desire of the treating physicians to discuss her case with other experts. Although providing more insecurity, the patient did feel comfortable that this meant that no other surgery was likely to be needed. After the pregnancy she reported that the physical part of the pregnancy did not give her many discomforts but the uncertainty about the well-being of the baby was very stressful. But overall, she was very satisfied with the care given.
In collaboration with these patients we produced a checklist for women in the same position or with a recent diagnosis of PHPT, which might be of help, see Table 1.Table 1 Questions for women in the childbearing age to ask their doctor when diagnosed with a high calcium level
1. What is the most likely diagnosis causing this high calcium level?
2. What tests do I need to make the diagnosis more likely? And are these tests influenced by pregnancy?
3. How will this affect pregnancy?
What will be the risks for my unborn child?
What will be the risks for me?
Which interventions are possible/necessary before, during and after pregnancy?
4. What can I do to minimalize complaints during and after the pregnancy?
5. How can we decrease my risk for preeclampsia?
6. Which drugs might be used during the pregnancy and what are their side effects?
7. How can you monitor my child?
8. How will my disease affect me after delivery?
9. How will this affect my child directly after delivery?
10. Can I breastfeed?
11. Who is in my multidisciplinary team and how can I reach them?
12. What can be done by my general practitioner?
13. What would be the risk of getting pregnant and to whom can I speak to for counseling?
In both cases patients and partners experienced the pregnancy as a rollercoaster with lot of uncertainties. Whereas both patients were diagnosed with hypercalcemia before pregnancy, patient 1 was counseled extensively in the pre-pregnancy period and even repeatedly got the advice not to become pregnant while patient 2 was never counseled. Also, in patient 2 the diagnosis was changed from PHPT to FHH, the finding of the marked hyperplasia triggered doubts about the original diagnosis of PHPT. In patient 1, the initial decision for surgery would still be made as her calcium values were rising and she did develop nausea and in FHH hyperplasia is also often described.
Physiological changes during pregnancy (Fig. 1a)
During pregnancy and lactation there is increased mobilization of calcium in the mother to meet the fetus’ calcium requirements [5, 6]. This is done by increasing intestinal calcium absorption through increasing 1.25 vitamin D production and PTH-related peptide (PTHrP), which is released from placenta and breasts in response to estradiol, placental lactogen, and prolactin [6, 7]. Despite the overlapping modes of action, PTH and PTHrP are produced by different genes on different chromosomes and the gene encoding PTHrP is more complex than for PTH. PTHrP is undetectable in the circulating blood of non-pregnant women, but is produced in a paracrine/autocrine fashion during pregnancy. Lessons from PTHrP or PTH1R gene knockout mice, which die at birth or in utero, emphasize the critical role of PTHrP for normal life [8, 9]. In addition, nascent PTHrP isoforms are processed by members of the prohormone convertase family to at least three fragments: N-terminal PTHrP [1–36], structurally related to PTH; a mid-region PTHrP (38–94); and a C-terminal PTHrP(107–139) with distinct biological properties and receptors. PTHrP is able to act not only via the classical autocrine/paracrine pathways, but also through a so-called intracrine pathway, which involves the translocation of the protein into the nucleus, where it can directly regulate proliferation and apoptosis [10, 11]. PTHrP has multiple activities including control of fetal development, trans-epithelial calcium transfer, lactation, smooth muscle relaxation, and cell growth. The mid-molecular region of PTHrP stimulates placental calcium transport in the fetus, while the COOH terminal region may also affect osteoclast activity. Thus, although PTHrP was discovered as a tumor-derived hypercalcemic factor, its primary physiological role is as a local regulator of many physiological processes especially in early life [12, 13].Fig. 1 a *Intravascular fluid expansion causes gestational hypoalbuminemia. The dilutional hypoalbuminemia of pregnancy leads to a decline in total calcium concentration. Ionized calcium on the other hand, remains stable and may provide more accurate information. ** The increase in 1.25 vitamin D production leads to an increase in intestinal calcium absorption. ***“Absorptive hypercalciuria of pregnancy”. Postprandial and 24-h urinary calcium excretion increase after 12 weeks, due to increased intestinal calcium absorption supposedly unrelated to increased formation of 1.25 vitamin D in early pregnancy. Fasting urine samples will not be affected by this phenomenon [45]. b *Prednison to reduce 1.25OH formation and thus intestinal calcium absorption. ** Reducing PTH-rp production mammae. *** No clinical data during pregnancy, only case reports. In animal studies no abnormalities observed, but it does pass the placenta [31, 46]. Breastfeeding: in animal studies (rat), cinacalcet is found in milk [46].
Maternal causes and consequences of hypercalcemia (Fig. 1b)
Hypercalcemia due to hyperparathyroidism is the most described cause of hypercalcemia during pregnancy. As most reviews focus on maternal and fetal outcomes in PHPT we will not cover this topic in the current paper [14, 15]. Hyperparathyroidism due to diffusely spread hyperthyroid nodules, parathyromatosis, post-parathyroidectomy, in the context of malignancy, MEN syndromes, or in chronic renal disease has been rarely described [15, 16]. Literature data on parathyromatosis is limited to around 20 cases published so far with only one report on a woman diagnosed and treated during pregnancy [17, 18].
FHH is a rare autosomal dominant disorder, with a prevalence of ~1:78.000 though this might likely be higher, as many cases remain asymptomatic lifelong and no causal treatment is available [19–21]. According to the genetic defect causing the pathology, three types of FHH have been defined [21–24]. FHH1 is the most common type and is found in about 65% of all FHH cases [21]. Patients with FHH present with mild to moderate hypercalcaemia, low urinary excretion, and PTH serum levels that are either normal or slightly elevated. Many patients with FHH are misdiagnosed as suffering from PHPT as in the case of our patient. Data on FHH manifested during pregnancy, literature data are sparse. Only four cases were published so far. Walker et al. reported the case of a pregnant patient, initially diagnosed with PHPT, who showed no improvement after PTX. The newborn presented with asymptomatic hypercalcemia; the genetic analysis confirmed the diagnosis of FHH [25]. The newborn presented elevated serum calcium levels with no clinical symptoms, while the genetic analysis confirmed the diagnosis of FHH. Others reported hypercalcemic profiles for which they underwent surgery during pregnancy [26, 27].
PTHrP-induced hypercalcemia during pregnancy or lactation has also been reported, either with or without gigantomastia [28–33]. In the reported cases, associating gigantomastia and increased PTHrP serum values, hypercalcaemia was diagnosed during gestation and resolved only after mastectomy, bromocriptin administration, or termination of pregnancy [29, 31, 32].
After delivery, there is a risk of severe hypercalcemia in women with PHPT who are lactating as PTH-rp production will increase [6, 34]. Especially women with gestational hypercalcemia with gigantomastia should be advised against breastfeeding as this will keep PTHrp levels high. The rise in PTHrp during pregnancy was not seen in patient 1 in whom PTHrp production was fully suppressed during entire pregnancy. The observed rise in calcium levels in patient 2 might in retrospect be due to her different setpoint and PTHrp production. Mental consequences of hypercalcemia are well known and include depression and anxiety [35, 36]. During pregnancy mothers might have additional stress which might be exaggerated by the hypercalcemia.
Fetal consequences of hypercalcemia
In the fetus, maternal PHPT can result in fetal growth restriction, severe neonatal hypocalcemia, tetany, and death [36]. In maternal FHH potential fetal complications include mild hypercalcemia, severe hypocalcemia, or neonatal severe hyperparathyroidism, depending on the genotype of the fetus. Because FHH is an autosomal dominant condition, three genetic situations might be encountered by the newborns of FHH mothers: the unaffected and the heterozygous neonates might present with hypocalcaemia induced by the in utero suppression of the parathyroid, the latter being at risk of developing hypercalcemia with hypocalcaemia in the first year of life. The homozygous form of FHH results in a severe neonatal hyperparathyroidism, which requires the surgical removal of the glands during the neonatal phase [37, 38].
Most outcomes on the fetal consequences of hypercalcemia were described in reports on patients with PHPT. Untreated hypercalcemia was associated with fetal or neonatal complications in the majority of cases [3, 36, 39, 40]. However, these findings are based on early literature of PHPT patients when hypercalcemia was often diagnosed in an advanced stage and more recent literature has shown that, compared to age-matched controls, women with PHPT had no difference in most pregnancy outcomes, including stillbirths [39]. That same study also showed that Apgar scores and anthropometric measurements were similar to babies born in uncomplicated pregnancies. However, this recent study did not report on maternal outcomes of preeclampsia. Other recent studies also report lower complications rates and good treatment outcomes when the hypercalcemia is moderate and not severe [1, 41].
Elevated maternal serum calcium leads to hypercalcemia in the fetus, which causes fetal parathyroid gland suppression. After delivery, these glands are still suppressed causing fetal hypocalcemia, which is usually transient (lasting 3–5 months after birth), but permanent hypoparathyroidism has anecdotally been described [42].
In the case of parathyromatosis diagnosed during pregnancy, Edling et al. reported that the infant presented initially with high calcium and low PTH levels, which normalized rapidly, with no further complications [18]. Newborns of mothers presenting with humoral hypercalcemia of pregnancy were having normal calcium levels at birth [29, 30, 33].
Diagnosing hypercalcemia during pregnancy might be challenging due to both physiological changes in calcium homeostasis, as well as due to the underlying cause for the hypercalcemia; changes in urinary calcium excretion vary during daytime, introducing difficulty in using urinary calcium indices as a diagnostic tool. In non-pregnant population, the measurement of calcium/creatinine clearance ratio can be useful in distinguishing between PHPT(>0.02 mmol/mmol) and FHH(<0.01 mmol/mmol). However, it is known that almost 20% of FHH patients might present with a calcium/creatinine ratio >0.01, and individuals with PPHT and simultaneous vitamin D deficiency might show lower than expected calcium excretion [43]. Genetic testing, when available, should be considered for confirming the clinical suspicion of FHH. More than 130 CaSR mutations have been reported so far in relation to FHH1, fact that explains the phenotypical variations in relation to the observed differences in serum calcium and PTH levels [21, 44].
During pregnancy, the distinction between FHH and PHPT is further complicated by the physiological changes in maternal calcium metabolism: increased breast and placental production of PTHrP, that together with the placental lactogen, leads to an increase in 1,25-(OH)2- vitamin D and a reduction of the PTH levels. As a result, the intestinal calcium absorption and the urine calcium excretion are physiologically increased [5, 45]. Treatment is depending on the underlying cause and might be invasive or conservative, but all decisions need good counseling, as it concerns not only the mother, but also the fetus and partner as well. Also we, as physicians, need to be aware that the treatment does not stop with the deliverance of a healthy baby and that the postpartum period might actually be the period with the highest risk for the mother due to the risk of sudden rises in calcium level and to excessive mental stress caused by possible events during pregnancy or delivery.
But foremost, irrespective of the underlying cause of hypercalcemia, patients and partners need to be closely involved in the decision processes in order to ensure overall good outcomes for mother and child.
Acknowledgements
We would like to acknowledge the European Reference Network for Rare Endocrine diseases, specifically main thematic group two calcium and phosphate disorders. We would like to thank both C.W.M. Janssen and S. Mourits for their agreement on publication of their medical history and contribution to the content of the manuscript.
Authors contributions
Conceptualization, writing original draft preparation, reviewing and editing: N.M.A-D. Reviewing and editing, critically revising the manuscript: D-A.E, M.C.Z, L.R, and E.M.W.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovered | ReactionOutcome | CC BY | 33544354 | 20,513,294 | 2021-03 |
What was the outcome of reaction 'Post-traumatic stress disorder'? | Hypercalcemia during pregnancy: management and outcomes for mother and child.
Diagnosing and treating hypercalcemia during pregnancy can be challenging due to both the physiological changes in calcium homeostasis and the underlying cause for the hypercalcemia. During pregnancy and lactation there is increased mobilization of calcium in the mother to meet the fetus' calcium requirements. Here we discuss the diagnostic challenges, management, and patient perspective of hypercalcemia during pregnancy in two particular cases and in other rare conditions causing hypercalcemia.
Introduction
Hypercalcemia in pregnancy is rare and in >90% of cases caused by a newly diagnosed primary hyperparathyroidism (PHPT). Hypercalcemia during pregnancy due to other disorders of calcium metabolism is even more rare and literature regarding the maternal management and fetal outcomes is lacking. Diagnosing hypercalcemia is challenging during pregnancy, as symptoms such as fatigue or nausea mimic those in early pregnancy. However, longstanding hypercalcemia might induce nephrolithiasis, pancreatitis, and preeclampsia in the mother [1]. Therefore, the occurrence of these diseases during pregnancy should push the physicians to screen for hypercalcemia. In the fetus, maternal hypercalcemia can result in fetal growth restriction [2]. Following birth, further complications may arise such as severe neonatal hypocalcemia, tetany, and even death due to fetal hypoparathyroidism [3, 4]. In rare calcium-related disorders, the diagnosis is often known before the pregnancy and patients and partners can be counseled by the treating endocrinologist, obstetrician, pediatrician, and geneticist when required, taking into account the possible physical and mental maternal adverse effects, but also the eventual consequences for the newborn. Here we would like to discuss the diagnostic challenges and management of hypercalcemia during pregnancy in two particular cases as example of rare conditions causing hypercalcemia complicating pregnancy.
Case 1
A 34-year-old woman was referred with severe hypercalcemia and a pregnancy wish. At the age of 24 she was diagnosed with PHPT, without underlying genetic causes. During parathyroidectomy (PTX) there was spill of the adenoma, histologically confirmed, which led to chronic hypercalcemia for which she underwent several re-operations in various hospitals including a thyroidectomy in 2 tempi with resection of surrounding fat-tissue and a bilateral modified lymph node resection. However, she remained dependent on cinacalcet and bisphosphonates in various dosages. At referral, albumin-corrected serum calcium was 2.89 mmol/L (ref 2.15–2.55 mmol/L) with PTH 10.7 (ref 1–8 pmol/L) while on cinacalcet 60 mg/day, and 3.16 mmol/L with PTH of 29 without cinacalcet. She and her partner were counselled by a team consisting of gynecologists, pediatricians, and endocrinologists on several aspects of the disease and potential consequences for a pregnancy. Prophylactic surgery was not possible at that time. Bisphosphonates were stopped and she became pregnant after 12 months. Cinacalcet was stopped and a fluid intake of 4 L was advised. However, she was admitted with a symptomatic hypercalcemia, 3.4 mmol/L, within 2 weeks. Hyperhydration and cinacalcet, up to 90 mg/day, were started in combination with furosemide 40 mg and acetylsalicylic acid 80 mg daily as preeclampsia prophylaxis. She suffered from severe hyperemesis gravidarum and due to persistent hypercalcemia, she received saline infusions of 5 L/day in a homecare setting with a peripheral intravasal central catheter (PICC). During follow up the PICC caused deep vein thrombosis for which nadroparin injections were started but with this treatment serum calcium remained stable around 2.7–2.9 mmol/L. At 38 weeks of gestation she developed hypertension with a rapidly developing HELLP syndrome and an emergency cesarean section was performed. A healthy baby boy, weight 3305 g, was delivered; he only received active vitamin D supplementation for a few days and two years after delivery; no calcium disturbances or skeletal abnormalities have been observed. The mother did not breastfeed. After delivery, the mother experienced a post-traumatic stress syndrome (PTSS) with depression for which she started Eye Movement Desensitization and Reprocessing (EMDR). The depression and PTSS was related to the latter part of the pregnancy and delivery, but most likely exacerbated due to a postpartum rise in calcium to 3.3 mmol/L. Surgery was successfully performed after which her mental complaints improved.
Case 2
A 38-year-old female was diagnosed with PHPT at a non-university hospital, based on a modest hypercalcemia, and elevated PTH of 9.2 pmol/L and high to normal urinary calcium excretion of 8.5 g/L and calcium-to-creatinine clearance above 0.02. Despite her young age, it was decided not to perform PTX because of an increased risk for venous thromboembolism and obesity. Five years later, she had an unexpected pregnancy and was referred for PTX in the second trimester. During that time serum calcium had increased from 2.63 mmol/L to 2.83 mmol/L with a non-suppressed PTH of 3.8 pmol/L. The patient and her partner were counseled by a team consisting of endocrinologists, anesthesiologists, endocrine surgeons, pediatricians, and obstetricians. Imaging studies did not reveal a clear-cut adenoma and considering the progressive rise in calcium to 2.93 mmol/L, urinary calcium excretion of 12 g/L in 24 h and proceeding into the end of the second trimester an elective neck exploration was performed at gestational age of 24 + 2 weeks, showing four gland hyperplasia. During surgery, it was decided to remove only the two right-sided glands in order not to risk hypoparathyroidism. After surgery hypercalcemia persisted with calcium levels between 2.60 mmol/L and 2.65 mmol/L and PTH between 2.1 pmol/L and 3.6 pmol/L. Considering the marked hyperplasia the patient was discussed in the clinical patient management system (CPMS) panel of main thematic group two, calcium and phosphate disorders of the European Reference Network for rare endocrine diseases (ENDO-ERN). The advice of this panel was to perform genetic testing for familial hypocalciuric calciuria (FHH), which came back positive for a mutation in the CASR-gen, c.653A>G p.(Tyr218Cys), establishing a diagnosis of FHH type one. At 39 + 3 weeks she delivered a healthy baby girl of 4150 g without any calcium disturbances. Post-partum the calcium levels of the mother remained at 2.6 mmol and PTH rose again to 10.3 pmol/L, which has been stable since.
Patient perspective
Patient one had an active pregnancy wish for 5 years, with a negative counselling in several centers. At the Leiden University Medical Center (LUMC) it was again made clear that this would not be without risks for mother and child but if desired we would do our best to monitor the pregnancy as good as possible, which was much appreciated as this was not discussed before. Although she was well prepared and extensively counseled, the intensity of the pregnancy was overwhelming. Both the high calcium levels, frequent investigations and the continuous hyperhydration were extremely demanding and resulted, together with the further rise in calcium, in a pre- and post-natal depression for which EMDR and psychotherapy were needed. Looking back, she would advise other patients to realize that it will be extremely tough, but absolutely worth it. The fact that caretakers were so involved in her well-being and their clear communication was helpful and appreciated. The health care system structure with various doctors during hospital admission remains unfortunate from her point of view, which was in contrast to the outpatient clinic care with one regular healthcare provider.
Despite living with, a supposed, PHPT for many years, patient 2 had never been counseled about PHPT in terms of treatment and follow up. In the initial phase of her referral to LUMC this was done rapidly as time was ticking for a safe window of surgery as the second trimester is the preferred trimester for surgery for maternal and fetal reasons. In addition, due to her increased risk for venous thromboembolism and obesity, emergency surgery in case of severe hypercalcemia was considered to be a high risk for the mother. The patient found the amount of information overwhelming. However, it was appreciated as it made the patient and her partner feel part of the team. After surgery, when she had postoperative pains, this induced more stress being pregnant. Caregivers should be aware that in pregnant patients’ complaints that might be considered as normal after surgery can induce a stressful trigger in patients who are already in a stressful situation. The doubts about the original diagnosis of PHPT were shared including the desire of the treating physicians to discuss her case with other experts. Although providing more insecurity, the patient did feel comfortable that this meant that no other surgery was likely to be needed. After the pregnancy she reported that the physical part of the pregnancy did not give her many discomforts but the uncertainty about the well-being of the baby was very stressful. But overall, she was very satisfied with the care given.
In collaboration with these patients we produced a checklist for women in the same position or with a recent diagnosis of PHPT, which might be of help, see Table 1.Table 1 Questions for women in the childbearing age to ask their doctor when diagnosed with a high calcium level
1. What is the most likely diagnosis causing this high calcium level?
2. What tests do I need to make the diagnosis more likely? And are these tests influenced by pregnancy?
3. How will this affect pregnancy?
What will be the risks for my unborn child?
What will be the risks for me?
Which interventions are possible/necessary before, during and after pregnancy?
4. What can I do to minimalize complaints during and after the pregnancy?
5. How can we decrease my risk for preeclampsia?
6. Which drugs might be used during the pregnancy and what are their side effects?
7. How can you monitor my child?
8. How will my disease affect me after delivery?
9. How will this affect my child directly after delivery?
10. Can I breastfeed?
11. Who is in my multidisciplinary team and how can I reach them?
12. What can be done by my general practitioner?
13. What would be the risk of getting pregnant and to whom can I speak to for counseling?
In both cases patients and partners experienced the pregnancy as a rollercoaster with lot of uncertainties. Whereas both patients were diagnosed with hypercalcemia before pregnancy, patient 1 was counseled extensively in the pre-pregnancy period and even repeatedly got the advice not to become pregnant while patient 2 was never counseled. Also, in patient 2 the diagnosis was changed from PHPT to FHH, the finding of the marked hyperplasia triggered doubts about the original diagnosis of PHPT. In patient 1, the initial decision for surgery would still be made as her calcium values were rising and she did develop nausea and in FHH hyperplasia is also often described.
Physiological changes during pregnancy (Fig. 1a)
During pregnancy and lactation there is increased mobilization of calcium in the mother to meet the fetus’ calcium requirements [5, 6]. This is done by increasing intestinal calcium absorption through increasing 1.25 vitamin D production and PTH-related peptide (PTHrP), which is released from placenta and breasts in response to estradiol, placental lactogen, and prolactin [6, 7]. Despite the overlapping modes of action, PTH and PTHrP are produced by different genes on different chromosomes and the gene encoding PTHrP is more complex than for PTH. PTHrP is undetectable in the circulating blood of non-pregnant women, but is produced in a paracrine/autocrine fashion during pregnancy. Lessons from PTHrP or PTH1R gene knockout mice, which die at birth or in utero, emphasize the critical role of PTHrP for normal life [8, 9]. In addition, nascent PTHrP isoforms are processed by members of the prohormone convertase family to at least three fragments: N-terminal PTHrP [1–36], structurally related to PTH; a mid-region PTHrP (38–94); and a C-terminal PTHrP(107–139) with distinct biological properties and receptors. PTHrP is able to act not only via the classical autocrine/paracrine pathways, but also through a so-called intracrine pathway, which involves the translocation of the protein into the nucleus, where it can directly regulate proliferation and apoptosis [10, 11]. PTHrP has multiple activities including control of fetal development, trans-epithelial calcium transfer, lactation, smooth muscle relaxation, and cell growth. The mid-molecular region of PTHrP stimulates placental calcium transport in the fetus, while the COOH terminal region may also affect osteoclast activity. Thus, although PTHrP was discovered as a tumor-derived hypercalcemic factor, its primary physiological role is as a local regulator of many physiological processes especially in early life [12, 13].Fig. 1 a *Intravascular fluid expansion causes gestational hypoalbuminemia. The dilutional hypoalbuminemia of pregnancy leads to a decline in total calcium concentration. Ionized calcium on the other hand, remains stable and may provide more accurate information. ** The increase in 1.25 vitamin D production leads to an increase in intestinal calcium absorption. ***“Absorptive hypercalciuria of pregnancy”. Postprandial and 24-h urinary calcium excretion increase after 12 weeks, due to increased intestinal calcium absorption supposedly unrelated to increased formation of 1.25 vitamin D in early pregnancy. Fasting urine samples will not be affected by this phenomenon [45]. b *Prednison to reduce 1.25OH formation and thus intestinal calcium absorption. ** Reducing PTH-rp production mammae. *** No clinical data during pregnancy, only case reports. In animal studies no abnormalities observed, but it does pass the placenta [31, 46]. Breastfeeding: in animal studies (rat), cinacalcet is found in milk [46].
Maternal causes and consequences of hypercalcemia (Fig. 1b)
Hypercalcemia due to hyperparathyroidism is the most described cause of hypercalcemia during pregnancy. As most reviews focus on maternal and fetal outcomes in PHPT we will not cover this topic in the current paper [14, 15]. Hyperparathyroidism due to diffusely spread hyperthyroid nodules, parathyromatosis, post-parathyroidectomy, in the context of malignancy, MEN syndromes, or in chronic renal disease has been rarely described [15, 16]. Literature data on parathyromatosis is limited to around 20 cases published so far with only one report on a woman diagnosed and treated during pregnancy [17, 18].
FHH is a rare autosomal dominant disorder, with a prevalence of ~1:78.000 though this might likely be higher, as many cases remain asymptomatic lifelong and no causal treatment is available [19–21]. According to the genetic defect causing the pathology, three types of FHH have been defined [21–24]. FHH1 is the most common type and is found in about 65% of all FHH cases [21]. Patients with FHH present with mild to moderate hypercalcaemia, low urinary excretion, and PTH serum levels that are either normal or slightly elevated. Many patients with FHH are misdiagnosed as suffering from PHPT as in the case of our patient. Data on FHH manifested during pregnancy, literature data are sparse. Only four cases were published so far. Walker et al. reported the case of a pregnant patient, initially diagnosed with PHPT, who showed no improvement after PTX. The newborn presented with asymptomatic hypercalcemia; the genetic analysis confirmed the diagnosis of FHH [25]. The newborn presented elevated serum calcium levels with no clinical symptoms, while the genetic analysis confirmed the diagnosis of FHH. Others reported hypercalcemic profiles for which they underwent surgery during pregnancy [26, 27].
PTHrP-induced hypercalcemia during pregnancy or lactation has also been reported, either with or without gigantomastia [28–33]. In the reported cases, associating gigantomastia and increased PTHrP serum values, hypercalcaemia was diagnosed during gestation and resolved only after mastectomy, bromocriptin administration, or termination of pregnancy [29, 31, 32].
After delivery, there is a risk of severe hypercalcemia in women with PHPT who are lactating as PTH-rp production will increase [6, 34]. Especially women with gestational hypercalcemia with gigantomastia should be advised against breastfeeding as this will keep PTHrp levels high. The rise in PTHrp during pregnancy was not seen in patient 1 in whom PTHrp production was fully suppressed during entire pregnancy. The observed rise in calcium levels in patient 2 might in retrospect be due to her different setpoint and PTHrp production. Mental consequences of hypercalcemia are well known and include depression and anxiety [35, 36]. During pregnancy mothers might have additional stress which might be exaggerated by the hypercalcemia.
Fetal consequences of hypercalcemia
In the fetus, maternal PHPT can result in fetal growth restriction, severe neonatal hypocalcemia, tetany, and death [36]. In maternal FHH potential fetal complications include mild hypercalcemia, severe hypocalcemia, or neonatal severe hyperparathyroidism, depending on the genotype of the fetus. Because FHH is an autosomal dominant condition, three genetic situations might be encountered by the newborns of FHH mothers: the unaffected and the heterozygous neonates might present with hypocalcaemia induced by the in utero suppression of the parathyroid, the latter being at risk of developing hypercalcemia with hypocalcaemia in the first year of life. The homozygous form of FHH results in a severe neonatal hyperparathyroidism, which requires the surgical removal of the glands during the neonatal phase [37, 38].
Most outcomes on the fetal consequences of hypercalcemia were described in reports on patients with PHPT. Untreated hypercalcemia was associated with fetal or neonatal complications in the majority of cases [3, 36, 39, 40]. However, these findings are based on early literature of PHPT patients when hypercalcemia was often diagnosed in an advanced stage and more recent literature has shown that, compared to age-matched controls, women with PHPT had no difference in most pregnancy outcomes, including stillbirths [39]. That same study also showed that Apgar scores and anthropometric measurements were similar to babies born in uncomplicated pregnancies. However, this recent study did not report on maternal outcomes of preeclampsia. Other recent studies also report lower complications rates and good treatment outcomes when the hypercalcemia is moderate and not severe [1, 41].
Elevated maternal serum calcium leads to hypercalcemia in the fetus, which causes fetal parathyroid gland suppression. After delivery, these glands are still suppressed causing fetal hypocalcemia, which is usually transient (lasting 3–5 months after birth), but permanent hypoparathyroidism has anecdotally been described [42].
In the case of parathyromatosis diagnosed during pregnancy, Edling et al. reported that the infant presented initially with high calcium and low PTH levels, which normalized rapidly, with no further complications [18]. Newborns of mothers presenting with humoral hypercalcemia of pregnancy were having normal calcium levels at birth [29, 30, 33].
Diagnosing hypercalcemia during pregnancy might be challenging due to both physiological changes in calcium homeostasis, as well as due to the underlying cause for the hypercalcemia; changes in urinary calcium excretion vary during daytime, introducing difficulty in using urinary calcium indices as a diagnostic tool. In non-pregnant population, the measurement of calcium/creatinine clearance ratio can be useful in distinguishing between PHPT(>0.02 mmol/mmol) and FHH(<0.01 mmol/mmol). However, it is known that almost 20% of FHH patients might present with a calcium/creatinine ratio >0.01, and individuals with PPHT and simultaneous vitamin D deficiency might show lower than expected calcium excretion [43]. Genetic testing, when available, should be considered for confirming the clinical suspicion of FHH. More than 130 CaSR mutations have been reported so far in relation to FHH1, fact that explains the phenotypical variations in relation to the observed differences in serum calcium and PTH levels [21, 44].
During pregnancy, the distinction between FHH and PHPT is further complicated by the physiological changes in maternal calcium metabolism: increased breast and placental production of PTHrP, that together with the placental lactogen, leads to an increase in 1,25-(OH)2- vitamin D and a reduction of the PTH levels. As a result, the intestinal calcium absorption and the urine calcium excretion are physiologically increased [5, 45]. Treatment is depending on the underlying cause and might be invasive or conservative, but all decisions need good counseling, as it concerns not only the mother, but also the fetus and partner as well. Also we, as physicians, need to be aware that the treatment does not stop with the deliverance of a healthy baby and that the postpartum period might actually be the period with the highest risk for the mother due to the risk of sudden rises in calcium level and to excessive mental stress caused by possible events during pregnancy or delivery.
But foremost, irrespective of the underlying cause of hypercalcemia, patients and partners need to be closely involved in the decision processes in order to ensure overall good outcomes for mother and child.
Acknowledgements
We would like to acknowledge the European Reference Network for Rare Endocrine diseases, specifically main thematic group two calcium and phosphate disorders. We would like to thank both C.W.M. Janssen and S. Mourits for their agreement on publication of their medical history and contribution to the content of the manuscript.
Authors contributions
Conceptualization, writing original draft preparation, reviewing and editing: N.M.A-D. Reviewing and editing, critically revising the manuscript: D-A.E, M.C.Z, L.R, and E.M.W.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovering | ReactionOutcome | CC BY | 33544354 | 20,513,294 | 2021-03 |
What was the outcome of reaction 'Product use issue'? | Hypercalcemia during pregnancy: management and outcomes for mother and child.
Diagnosing and treating hypercalcemia during pregnancy can be challenging due to both the physiological changes in calcium homeostasis and the underlying cause for the hypercalcemia. During pregnancy and lactation there is increased mobilization of calcium in the mother to meet the fetus' calcium requirements. Here we discuss the diagnostic challenges, management, and patient perspective of hypercalcemia during pregnancy in two particular cases and in other rare conditions causing hypercalcemia.
Introduction
Hypercalcemia in pregnancy is rare and in >90% of cases caused by a newly diagnosed primary hyperparathyroidism (PHPT). Hypercalcemia during pregnancy due to other disorders of calcium metabolism is even more rare and literature regarding the maternal management and fetal outcomes is lacking. Diagnosing hypercalcemia is challenging during pregnancy, as symptoms such as fatigue or nausea mimic those in early pregnancy. However, longstanding hypercalcemia might induce nephrolithiasis, pancreatitis, and preeclampsia in the mother [1]. Therefore, the occurrence of these diseases during pregnancy should push the physicians to screen for hypercalcemia. In the fetus, maternal hypercalcemia can result in fetal growth restriction [2]. Following birth, further complications may arise such as severe neonatal hypocalcemia, tetany, and even death due to fetal hypoparathyroidism [3, 4]. In rare calcium-related disorders, the diagnosis is often known before the pregnancy and patients and partners can be counseled by the treating endocrinologist, obstetrician, pediatrician, and geneticist when required, taking into account the possible physical and mental maternal adverse effects, but also the eventual consequences for the newborn. Here we would like to discuss the diagnostic challenges and management of hypercalcemia during pregnancy in two particular cases as example of rare conditions causing hypercalcemia complicating pregnancy.
Case 1
A 34-year-old woman was referred with severe hypercalcemia and a pregnancy wish. At the age of 24 she was diagnosed with PHPT, without underlying genetic causes. During parathyroidectomy (PTX) there was spill of the adenoma, histologically confirmed, which led to chronic hypercalcemia for which she underwent several re-operations in various hospitals including a thyroidectomy in 2 tempi with resection of surrounding fat-tissue and a bilateral modified lymph node resection. However, she remained dependent on cinacalcet and bisphosphonates in various dosages. At referral, albumin-corrected serum calcium was 2.89 mmol/L (ref 2.15–2.55 mmol/L) with PTH 10.7 (ref 1–8 pmol/L) while on cinacalcet 60 mg/day, and 3.16 mmol/L with PTH of 29 without cinacalcet. She and her partner were counselled by a team consisting of gynecologists, pediatricians, and endocrinologists on several aspects of the disease and potential consequences for a pregnancy. Prophylactic surgery was not possible at that time. Bisphosphonates were stopped and she became pregnant after 12 months. Cinacalcet was stopped and a fluid intake of 4 L was advised. However, she was admitted with a symptomatic hypercalcemia, 3.4 mmol/L, within 2 weeks. Hyperhydration and cinacalcet, up to 90 mg/day, were started in combination with furosemide 40 mg and acetylsalicylic acid 80 mg daily as preeclampsia prophylaxis. She suffered from severe hyperemesis gravidarum and due to persistent hypercalcemia, she received saline infusions of 5 L/day in a homecare setting with a peripheral intravasal central catheter (PICC). During follow up the PICC caused deep vein thrombosis for which nadroparin injections were started but with this treatment serum calcium remained stable around 2.7–2.9 mmol/L. At 38 weeks of gestation she developed hypertension with a rapidly developing HELLP syndrome and an emergency cesarean section was performed. A healthy baby boy, weight 3305 g, was delivered; he only received active vitamin D supplementation for a few days and two years after delivery; no calcium disturbances or skeletal abnormalities have been observed. The mother did not breastfeed. After delivery, the mother experienced a post-traumatic stress syndrome (PTSS) with depression for which she started Eye Movement Desensitization and Reprocessing (EMDR). The depression and PTSS was related to the latter part of the pregnancy and delivery, but most likely exacerbated due to a postpartum rise in calcium to 3.3 mmol/L. Surgery was successfully performed after which her mental complaints improved.
Case 2
A 38-year-old female was diagnosed with PHPT at a non-university hospital, based on a modest hypercalcemia, and elevated PTH of 9.2 pmol/L and high to normal urinary calcium excretion of 8.5 g/L and calcium-to-creatinine clearance above 0.02. Despite her young age, it was decided not to perform PTX because of an increased risk for venous thromboembolism and obesity. Five years later, she had an unexpected pregnancy and was referred for PTX in the second trimester. During that time serum calcium had increased from 2.63 mmol/L to 2.83 mmol/L with a non-suppressed PTH of 3.8 pmol/L. The patient and her partner were counseled by a team consisting of endocrinologists, anesthesiologists, endocrine surgeons, pediatricians, and obstetricians. Imaging studies did not reveal a clear-cut adenoma and considering the progressive rise in calcium to 2.93 mmol/L, urinary calcium excretion of 12 g/L in 24 h and proceeding into the end of the second trimester an elective neck exploration was performed at gestational age of 24 + 2 weeks, showing four gland hyperplasia. During surgery, it was decided to remove only the two right-sided glands in order not to risk hypoparathyroidism. After surgery hypercalcemia persisted with calcium levels between 2.60 mmol/L and 2.65 mmol/L and PTH between 2.1 pmol/L and 3.6 pmol/L. Considering the marked hyperplasia the patient was discussed in the clinical patient management system (CPMS) panel of main thematic group two, calcium and phosphate disorders of the European Reference Network for rare endocrine diseases (ENDO-ERN). The advice of this panel was to perform genetic testing for familial hypocalciuric calciuria (FHH), which came back positive for a mutation in the CASR-gen, c.653A>G p.(Tyr218Cys), establishing a diagnosis of FHH type one. At 39 + 3 weeks she delivered a healthy baby girl of 4150 g without any calcium disturbances. Post-partum the calcium levels of the mother remained at 2.6 mmol and PTH rose again to 10.3 pmol/L, which has been stable since.
Patient perspective
Patient one had an active pregnancy wish for 5 years, with a negative counselling in several centers. At the Leiden University Medical Center (LUMC) it was again made clear that this would not be without risks for mother and child but if desired we would do our best to monitor the pregnancy as good as possible, which was much appreciated as this was not discussed before. Although she was well prepared and extensively counseled, the intensity of the pregnancy was overwhelming. Both the high calcium levels, frequent investigations and the continuous hyperhydration were extremely demanding and resulted, together with the further rise in calcium, in a pre- and post-natal depression for which EMDR and psychotherapy were needed. Looking back, she would advise other patients to realize that it will be extremely tough, but absolutely worth it. The fact that caretakers were so involved in her well-being and their clear communication was helpful and appreciated. The health care system structure with various doctors during hospital admission remains unfortunate from her point of view, which was in contrast to the outpatient clinic care with one regular healthcare provider.
Despite living with, a supposed, PHPT for many years, patient 2 had never been counseled about PHPT in terms of treatment and follow up. In the initial phase of her referral to LUMC this was done rapidly as time was ticking for a safe window of surgery as the second trimester is the preferred trimester for surgery for maternal and fetal reasons. In addition, due to her increased risk for venous thromboembolism and obesity, emergency surgery in case of severe hypercalcemia was considered to be a high risk for the mother. The patient found the amount of information overwhelming. However, it was appreciated as it made the patient and her partner feel part of the team. After surgery, when she had postoperative pains, this induced more stress being pregnant. Caregivers should be aware that in pregnant patients’ complaints that might be considered as normal after surgery can induce a stressful trigger in patients who are already in a stressful situation. The doubts about the original diagnosis of PHPT were shared including the desire of the treating physicians to discuss her case with other experts. Although providing more insecurity, the patient did feel comfortable that this meant that no other surgery was likely to be needed. After the pregnancy she reported that the physical part of the pregnancy did not give her many discomforts but the uncertainty about the well-being of the baby was very stressful. But overall, she was very satisfied with the care given.
In collaboration with these patients we produced a checklist for women in the same position or with a recent diagnosis of PHPT, which might be of help, see Table 1.Table 1 Questions for women in the childbearing age to ask their doctor when diagnosed with a high calcium level
1. What is the most likely diagnosis causing this high calcium level?
2. What tests do I need to make the diagnosis more likely? And are these tests influenced by pregnancy?
3. How will this affect pregnancy?
What will be the risks for my unborn child?
What will be the risks for me?
Which interventions are possible/necessary before, during and after pregnancy?
4. What can I do to minimalize complaints during and after the pregnancy?
5. How can we decrease my risk for preeclampsia?
6. Which drugs might be used during the pregnancy and what are their side effects?
7. How can you monitor my child?
8. How will my disease affect me after delivery?
9. How will this affect my child directly after delivery?
10. Can I breastfeed?
11. Who is in my multidisciplinary team and how can I reach them?
12. What can be done by my general practitioner?
13. What would be the risk of getting pregnant and to whom can I speak to for counseling?
In both cases patients and partners experienced the pregnancy as a rollercoaster with lot of uncertainties. Whereas both patients were diagnosed with hypercalcemia before pregnancy, patient 1 was counseled extensively in the pre-pregnancy period and even repeatedly got the advice not to become pregnant while patient 2 was never counseled. Also, in patient 2 the diagnosis was changed from PHPT to FHH, the finding of the marked hyperplasia triggered doubts about the original diagnosis of PHPT. In patient 1, the initial decision for surgery would still be made as her calcium values were rising and she did develop nausea and in FHH hyperplasia is also often described.
Physiological changes during pregnancy (Fig. 1a)
During pregnancy and lactation there is increased mobilization of calcium in the mother to meet the fetus’ calcium requirements [5, 6]. This is done by increasing intestinal calcium absorption through increasing 1.25 vitamin D production and PTH-related peptide (PTHrP), which is released from placenta and breasts in response to estradiol, placental lactogen, and prolactin [6, 7]. Despite the overlapping modes of action, PTH and PTHrP are produced by different genes on different chromosomes and the gene encoding PTHrP is more complex than for PTH. PTHrP is undetectable in the circulating blood of non-pregnant women, but is produced in a paracrine/autocrine fashion during pregnancy. Lessons from PTHrP or PTH1R gene knockout mice, which die at birth or in utero, emphasize the critical role of PTHrP for normal life [8, 9]. In addition, nascent PTHrP isoforms are processed by members of the prohormone convertase family to at least three fragments: N-terminal PTHrP [1–36], structurally related to PTH; a mid-region PTHrP (38–94); and a C-terminal PTHrP(107–139) with distinct biological properties and receptors. PTHrP is able to act not only via the classical autocrine/paracrine pathways, but also through a so-called intracrine pathway, which involves the translocation of the protein into the nucleus, where it can directly regulate proliferation and apoptosis [10, 11]. PTHrP has multiple activities including control of fetal development, trans-epithelial calcium transfer, lactation, smooth muscle relaxation, and cell growth. The mid-molecular region of PTHrP stimulates placental calcium transport in the fetus, while the COOH terminal region may also affect osteoclast activity. Thus, although PTHrP was discovered as a tumor-derived hypercalcemic factor, its primary physiological role is as a local regulator of many physiological processes especially in early life [12, 13].Fig. 1 a *Intravascular fluid expansion causes gestational hypoalbuminemia. The dilutional hypoalbuminemia of pregnancy leads to a decline in total calcium concentration. Ionized calcium on the other hand, remains stable and may provide more accurate information. ** The increase in 1.25 vitamin D production leads to an increase in intestinal calcium absorption. ***“Absorptive hypercalciuria of pregnancy”. Postprandial and 24-h urinary calcium excretion increase after 12 weeks, due to increased intestinal calcium absorption supposedly unrelated to increased formation of 1.25 vitamin D in early pregnancy. Fasting urine samples will not be affected by this phenomenon [45]. b *Prednison to reduce 1.25OH formation and thus intestinal calcium absorption. ** Reducing PTH-rp production mammae. *** No clinical data during pregnancy, only case reports. In animal studies no abnormalities observed, but it does pass the placenta [31, 46]. Breastfeeding: in animal studies (rat), cinacalcet is found in milk [46].
Maternal causes and consequences of hypercalcemia (Fig. 1b)
Hypercalcemia due to hyperparathyroidism is the most described cause of hypercalcemia during pregnancy. As most reviews focus on maternal and fetal outcomes in PHPT we will not cover this topic in the current paper [14, 15]. Hyperparathyroidism due to diffusely spread hyperthyroid nodules, parathyromatosis, post-parathyroidectomy, in the context of malignancy, MEN syndromes, or in chronic renal disease has been rarely described [15, 16]. Literature data on parathyromatosis is limited to around 20 cases published so far with only one report on a woman diagnosed and treated during pregnancy [17, 18].
FHH is a rare autosomal dominant disorder, with a prevalence of ~1:78.000 though this might likely be higher, as many cases remain asymptomatic lifelong and no causal treatment is available [19–21]. According to the genetic defect causing the pathology, three types of FHH have been defined [21–24]. FHH1 is the most common type and is found in about 65% of all FHH cases [21]. Patients with FHH present with mild to moderate hypercalcaemia, low urinary excretion, and PTH serum levels that are either normal or slightly elevated. Many patients with FHH are misdiagnosed as suffering from PHPT as in the case of our patient. Data on FHH manifested during pregnancy, literature data are sparse. Only four cases were published so far. Walker et al. reported the case of a pregnant patient, initially diagnosed with PHPT, who showed no improvement after PTX. The newborn presented with asymptomatic hypercalcemia; the genetic analysis confirmed the diagnosis of FHH [25]. The newborn presented elevated serum calcium levels with no clinical symptoms, while the genetic analysis confirmed the diagnosis of FHH. Others reported hypercalcemic profiles for which they underwent surgery during pregnancy [26, 27].
PTHrP-induced hypercalcemia during pregnancy or lactation has also been reported, either with or without gigantomastia [28–33]. In the reported cases, associating gigantomastia and increased PTHrP serum values, hypercalcaemia was diagnosed during gestation and resolved only after mastectomy, bromocriptin administration, or termination of pregnancy [29, 31, 32].
After delivery, there is a risk of severe hypercalcemia in women with PHPT who are lactating as PTH-rp production will increase [6, 34]. Especially women with gestational hypercalcemia with gigantomastia should be advised against breastfeeding as this will keep PTHrp levels high. The rise in PTHrp during pregnancy was not seen in patient 1 in whom PTHrp production was fully suppressed during entire pregnancy. The observed rise in calcium levels in patient 2 might in retrospect be due to her different setpoint and PTHrp production. Mental consequences of hypercalcemia are well known and include depression and anxiety [35, 36]. During pregnancy mothers might have additional stress which might be exaggerated by the hypercalcemia.
Fetal consequences of hypercalcemia
In the fetus, maternal PHPT can result in fetal growth restriction, severe neonatal hypocalcemia, tetany, and death [36]. In maternal FHH potential fetal complications include mild hypercalcemia, severe hypocalcemia, or neonatal severe hyperparathyroidism, depending on the genotype of the fetus. Because FHH is an autosomal dominant condition, three genetic situations might be encountered by the newborns of FHH mothers: the unaffected and the heterozygous neonates might present with hypocalcaemia induced by the in utero suppression of the parathyroid, the latter being at risk of developing hypercalcemia with hypocalcaemia in the first year of life. The homozygous form of FHH results in a severe neonatal hyperparathyroidism, which requires the surgical removal of the glands during the neonatal phase [37, 38].
Most outcomes on the fetal consequences of hypercalcemia were described in reports on patients with PHPT. Untreated hypercalcemia was associated with fetal or neonatal complications in the majority of cases [3, 36, 39, 40]. However, these findings are based on early literature of PHPT patients when hypercalcemia was often diagnosed in an advanced stage and more recent literature has shown that, compared to age-matched controls, women with PHPT had no difference in most pregnancy outcomes, including stillbirths [39]. That same study also showed that Apgar scores and anthropometric measurements were similar to babies born in uncomplicated pregnancies. However, this recent study did not report on maternal outcomes of preeclampsia. Other recent studies also report lower complications rates and good treatment outcomes when the hypercalcemia is moderate and not severe [1, 41].
Elevated maternal serum calcium leads to hypercalcemia in the fetus, which causes fetal parathyroid gland suppression. After delivery, these glands are still suppressed causing fetal hypocalcemia, which is usually transient (lasting 3–5 months after birth), but permanent hypoparathyroidism has anecdotally been described [42].
In the case of parathyromatosis diagnosed during pregnancy, Edling et al. reported that the infant presented initially with high calcium and low PTH levels, which normalized rapidly, with no further complications [18]. Newborns of mothers presenting with humoral hypercalcemia of pregnancy were having normal calcium levels at birth [29, 30, 33].
Diagnosing hypercalcemia during pregnancy might be challenging due to both physiological changes in calcium homeostasis, as well as due to the underlying cause for the hypercalcemia; changes in urinary calcium excretion vary during daytime, introducing difficulty in using urinary calcium indices as a diagnostic tool. In non-pregnant population, the measurement of calcium/creatinine clearance ratio can be useful in distinguishing between PHPT(>0.02 mmol/mmol) and FHH(<0.01 mmol/mmol). However, it is known that almost 20% of FHH patients might present with a calcium/creatinine ratio >0.01, and individuals with PPHT and simultaneous vitamin D deficiency might show lower than expected calcium excretion [43]. Genetic testing, when available, should be considered for confirming the clinical suspicion of FHH. More than 130 CaSR mutations have been reported so far in relation to FHH1, fact that explains the phenotypical variations in relation to the observed differences in serum calcium and PTH levels [21, 44].
During pregnancy, the distinction between FHH and PHPT is further complicated by the physiological changes in maternal calcium metabolism: increased breast and placental production of PTHrP, that together with the placental lactogen, leads to an increase in 1,25-(OH)2- vitamin D and a reduction of the PTH levels. As a result, the intestinal calcium absorption and the urine calcium excretion are physiologically increased [5, 45]. Treatment is depending on the underlying cause and might be invasive or conservative, but all decisions need good counseling, as it concerns not only the mother, but also the fetus and partner as well. Also we, as physicians, need to be aware that the treatment does not stop with the deliverance of a healthy baby and that the postpartum period might actually be the period with the highest risk for the mother due to the risk of sudden rises in calcium level and to excessive mental stress caused by possible events during pregnancy or delivery.
But foremost, irrespective of the underlying cause of hypercalcemia, patients and partners need to be closely involved in the decision processes in order to ensure overall good outcomes for mother and child.
Acknowledgements
We would like to acknowledge the European Reference Network for Rare Endocrine diseases, specifically main thematic group two calcium and phosphate disorders. We would like to thank both C.W.M. Janssen and S. Mourits for their agreement on publication of their medical history and contribution to the content of the manuscript.
Authors contributions
Conceptualization, writing original draft preparation, reviewing and editing: N.M.A-D. Reviewing and editing, critically revising the manuscript: D-A.E, M.C.Z, L.R, and E.M.W.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Recovered | ReactionOutcome | CC BY | 33544354 | 20,513,294 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypotension'. | Vocal fold paralysis and cauda equina syndrome following spinal-epidural anesthesia: A case report.
BACKGROUND
Vocal fold paralysis and cauda equina syndrome are very rare neurologic deficits. This report describes the case of a patient who simultaneously developed both after uneventful spinal-epidural anesthesia with 0.5% hyperbaric bupivacaine.
We report the case of a 45-year-old female, who underwent surgery for bilateral hallux valgus developed cauda equina syndrome and unilateral vocal fold paralysis after uneventful spinal-epidural anesthesia was administered. There was no pain or paresthesia during needle placement or drug injection. Surgery was performed uneventfully.
Right vocal fold paralysis was diagnosed with flexible laryngoscopy.
METHODS
Patient was started on the treatment with a surgery for bilateral hallux valgus, who developed cauda equina syndrome and unilateral vocal fold paralysis after uneventful spinal-epidural anesthesia was administered.
RESULTS
Postoperatively, she had difficulty in urination and defecation. In addition, she developed unilateral vocal fold paralysis characterized by hoarseness, effortful voice production, and choking with liquids. Magnetic resonance imaging performed on the lumbosacral area and computed tomography of the neck, the chest, and the skull revealed entirely normal results. However, flexible laryngoscopy revealed a right vocal fold paralysis. Although cauda equina syndrome can occur due to neurotoxicity of local anesthetics, the exact etiology of vocal fold paralysis is uncertain.
CONCLUSIONS
The case highlights that 2 rare and serious complications of spinal-epidural anesthesia can even occur in the same patient after uneventful surgery and block performance.
1 Introduction
Regional anesthesia for lower limb surgeries is generally held to be inherently safe. Spinal and epidural blocks are therefore used widely, with the more recently introduced combined spinal and epidural technique gaining popularity. Serious neurologic deficits such as cauda equine syndrome and vocal fold paralysis after spinal anesthesia are relatively rare.[1–4] Cauda equina syndrome is a serious neurologic disorder that is caused by damage of the lumbosacral and coccygeal nerve roots which include the ascending and descending nerve roots from L2 through the coccygeal segments. These nerves control lower limb movement (L2-S2), lower limb sensation (L2-S3), bladder control (S2-S4), external analsphincter control (S2-S4), external genitalia and perianal sensation (S2-S4), and coccygeal sensation (S4, S5, and the coccygeal nerve).[5] Cauda equina syndrome is associated with varying degrees of signs and symptoms including loss of bowel and bladder function, insensate perineal areas and lower extremity muscle weakness.[6,7] In addition to cauda equina syndrome, cranial nerve palsy is also a rare complication of spinal anesthesia. The most commonly affected cranial nerve is the abducent nerve because of its long intracranial course.[8] Palsies of the oculomotor, facial, trigeminal, and trochlear nerves, as well as transient hypoacusis and Horner syndrome, have also been reported.[9–13] Vagal neuropathy, following spinal anesthesia was first described recently.[2–4] These cranial palsies are typically transient and resolve within weeks to months, but complete neurological recovery after cauda equina syndrome is unusual. The simultaneous occurrence of these 2 rare complications in the same patient has not been previously reported. This report describes the case of a patient who simultaneously developed both after uneventful spinal-epidural anesthesia with 0.5% hyperbaric bupivacaine. With early diagnosis and appropriate treatment, the patient recovered eventually.
2 Case presentation
A previously healthy 45-year-old female, with no preexisting neurologic deficits, was subjected to surgery because of bilateral hallux valgus. The patient's routine preoperative test results were within normal ranges. Spinal anesthesia was administered at the L3–4 interspace by using a 27-gauge Quincke point spinal needle through an 18-G Tuohy needle. Afterward, 3 ml of 0.5% hyperbaric bupivacaine was injected intrathecally in approximately 15 seconds after the clear cerebrospinal fluid (CSF) without any blood was aspirated. After bupivacaine was injected, an epidural catheter was inserted 4 cm into the epidural space in the cephalad direction via the Tuohy needle. Paraesthesia, back pain or any other signs of nerve irritation was not experienced during needle placement or drug injection. A urinary catheter was inserted before the surgery. The sensory level block was bilateral, symmetric, and caudal to T10 15 minutes after bupivacaine was administered, as assessed via the pinprick method; a complete lower extremity motor block was achieved. The patient's blood pressure decreased transiently from 140/85 mm Hg to 85/60 mm Hg; afterward, 4 mg of ephedrine was provided with hypotension resolution. The patient's arterial pressure remained normal throughout the procedure. Surgical blood loss was not significant. The 90 minutes operation was performed uneventfully. She was discharged to the ward after the operation. Ropivacaine was injected through the epidural catheter to reduce postoperative pain. After a 5 ml bolus of 0.5% ropivacaine was administered, the mixed solution composed of 0.2% ropivacaine and 4 mg/L fentanyl was infused at a basal rate of 2 ml/hour. In addition, patient-controlled epidural analgesia was maintained for almost 2 days (4 ml for 1 push, 30 minutes lockout) by using a disposable pump. The surgical procedure was conducted uneventfully with the patient in the supine position. The final sensory level achieved was T12 bilaterally by pinprick.
After surgery, the patient complained of mild headache. Thereafter, neck stiffness and pain, photophobia, nausea and vomiting also occurred. The next day of the operation, she felt a sudden weakness in her left leg but still able to walk with an assistive device. Then, the weakness increased as well as the right leg. Unexpectedly, she complained of numbness in the gluteal and perianal region. The epidural catheter was removed immediately. According to the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI), which developed by the American Spinal Injury Association (ASIA) and endorsed by the International Spinal Cord Society, is a well-accepted classification of neurologic deficit after Spinal Cord Injury (SCI),[14,15] the examination used dermatomal light touch and pin prick sensation and motor strength of selected muscle groups of the lower extremities to determine the neurologic level of the injury. In the patient, physical examination at that time revealed bilateral lower extremity weakness with 3/5 for left hip flexors and knee extensors; 2/5 for left ankle dorsiflexors and plantar flexors, 1/5 for left extensor hallucis longus; 4/5 for the right hip flexors and knee extensors; 3/5 for right ankle dorsiflexors and plantar flexors, 2/5 for right extensor hallucis longus. Motor scores of the 2 lower limbs were 27 points. Neurological examination documented lower extremity and perianal hypoesthesia and lower extremity hyporeflexia. We defined lower extremity pin prick and light touch scores as the sum of L2 to S5 dermatomes bilaterally (maximum score of 32 points). Pinprick sensation of the left L4-S1 segment, right L4-L5 segment and perianal area in the S3–5 segment was diminished. Pin prick and light touch scores of the left and right lower limbs were 22 and 24 points respectively. The Achilles and patellar reflexes were obviously reduced, and the anal wink reflex was absent in this patient. The anal sphincter tone was decreased. The abdominal reflexes and strength of abdominal wall muscles were bilaterally normal. Three days after surgery, the symptom of headache faded away gradually. The patient was unable to micturate when the urinary catheter was removed on the third postoperative day; as a result, urinary retention (on the third day) and rectal incontinence (on the fourth day) occurred. The bladder was recatheterized because of the urinary retention. Seven days after surgery, Magnetic resonance imaging (MRI) was performed on the lumbosacral area to obtain further information. The MRI revealed no tumor, hematoma, abscess, infarction, spinal stenosis, or cauda equina nerve root compression. Based on the patient's symptoms and MRI findings, cauda equina syndrome was diagnosed. In addition to cauda equina syndrome, she noted onset of hoarseness, effortful voice production and chocking with liquids on postoperative day 5; she believed that her voice had been normal before and immediately after surgery. She subsequently underwent flexible laryngoscopy, which revealed a right vocal fold paralysis. Computed tomography (CT) of the neck and chest was performed 10 days after surgery, which did not reveal any lesions along the recurrent laryngeal nerve. The brain MRI findings showed: diffuse dural enhancement, downward displacement of the brainstem, and diminution of cerebral ventricles, which are typical features of intracranial hypotension (ICH). Stroboscopy performed 15 days after surgery confirmed the finding of an immobile right vocal fold.
The patient was managed conservatively on heavy doses of steroids:[16] methylprednisolone 500 mg intravenously guttae daily for 5 days, then reduced to 80 mg intravenously guttae daily for 10 days. She also underwent a rehabilitation program including traditional Chinese medicine and acupuncture 3 days per week, which aimed to normalize movement patterns. Physical therapy for cauda equine syndrome included static and dynamic control of position, neurophysiologic exercises, progressive ambulation, balance skills, and activities of daily living. Clean intermittent self-catheterization 3 times a day was started for neurogenic bladder. Vocal therapy in unilateral vocal fold paralysis consisted of electrotherapy, hard glottal attacks and pushing exercises, half-swallow boom, accent method, lip and tongue trills. After 2 months, her lower extremity motor strength significantly improved and the sensation of the 2 lower limbs recovered gradually except hypoesthesia in the S3–5 segment. Motor scores of the 2 lower limbs were 45 points; pin prick and light touch scores of the left and right lower limbs were 26 and 28 points, respectively. At the 3-month follow-up, the patient had regained 5/5 strength in all motor groups, could walk normally without any assistive devices and perianal sensation somehow returned. At the 11-month follow-up, the patient recovered from urinary retention and fecal incontinence. In addition, a laryngeal electromyography, performed at 3 months following surgery, showed evidence of denervation of the right thyroarytenoid (innervated by the recurrent laryngeal nerve) and cricothyroid muscle (innervated by the superior laryngeal nerve), consistent with a right vagal neuropathy; at 7-month follow-up, the patient reported that her voice quality improved to near normal and only mild residual paresis was noted on stroboscopy.
3 Discussion and conclusions
The patient developed cauda equina syndrome characterized by urinary retention and fecal incontinence, perianal sensory loss, and lower extremity weakness after uneventful routine spinal-epidural anesthesia. She simultaneously developed a right vocal fold paralysis. Although these major complications rarely occur after spinal-epidural anesthesia, the described patient developed both.
Various possible causes achieved vocal fold paralysis. It may be infectious, neoplastic, or idiopathic in origin. There was no evidence of infection in this case. The CT ruled out the possibility of neoplasm. At first glance, this case of vocal fold paralysis may be classified as idiopathic because spinal anesthesia is generally not considered in the differential diagnosis of vocal fold paralysis. However, a causal relationship may be considered according to the documented occurrence of upper cranial neuropathy as a result of spinal anesthesia, especially in the absence of other important contributing factors. The onset of symptoms is consistent with previously reported cases of cranial neuropathy following spinal anesthesia. Guardiani et al[2] reported 4 cases of vocal fold paralysis after spinal anesthesia. Cranial nerve palsy following subarachnoid block or unintentional dural puncture has been attributed to CSF depletion and ICH, which appears to be the cause of vocal fold palsy.[13] ICH is a clinical syndrome characterized by postural headache and low CSF opening pressure. Symptoms may include nausea, vomiting, nuchal pain, dizziness, tinnitus, nystagmus, and blurred vision.[3] The MRI findings of ICH are diffuse pachymeningeal enhancement, subdural effusion, engorgement of venous sinuses, pituitary enlargement, and herniation of the cerebellar tonsils.[17] It has been explained on the basis of CSF loss causing sagging of the brain and stretching of the nerve.[18] The brain descends caudally to a vertical position, which may harm the cranial nerves that anchor the brain to the skull. In the described patient, laryngeal electromyography suggested a vagal lesion, in light of the evidence of denervation of both the cricothyroid and thyroarytenoid muscle, rather than an isolated neuropathy of the recurrent laryngeal nerve; this supports the hypothesis of traction on the vagal nerve rather than an idiopathic palsy, the majority of which are recurrent nerve phenomena. Therefore, the decrease in intracranial CSF pressure may have contributed to the presentation, which may induce stretching of the vagal nerve bilaterally. In this case, only the right vocal fold was immobile, therefore, the vagal nerve could be stretched with 1 side more affected than the other. Hypotension during surgery may also serve as a contributing factor to this complication because vascular perfusion of nerve fibers might be compromised. Thus the explanation for vocal fold paralysis is uncertain and consequently speculative.
Cauda equina syndrome is a rare but an extremely distressing complication of spinal-epidural anesthesia.[19–21] Most neurological complications are caused by epidural hematoma, abscess, catheter trauma, infection, and anesthetic toxicity. In the patient, the MRI revealed no hematoma, abscess, infarction, spinal stenosis, or lumbar disc herniation. Direct nerve damage may contribute to the onset of neurological symptoms; disposable needle tips are very sharp, nerve fibers can easily be injured by them. Most neural injuries are associated with either paraesthesia or pain upon injection.[22] However, direct damage to the spinal cord via dural puncture is unlikely the cause of the condition observed in the patient because neurologic pain or paraesthesia was not experienced during needle insertion.[23,24] Spinal cord compression caused by an expanding hematoma was excluded through MRI. Infection was not observed because the patient did not manifest clinical signs or laboratory abnormality corresponding to infection. Dural blood flow is significantly reduced in animals once epinephrine is added to local anesthetic solutions.[25] However, spinal cord ischemia was unlikely observed in this case because epinephrine that can induce vascular contraction was not administered, the patient did not suffer from microvascular disease and was hemodynamically stable perioperatively.[26] Rigler et al[27] postulated that a combination of trauma, maldistribution, and relatively high dose of local anesthetic resulted in neurotoxic injury. Most cauda equina syndrome cases following spinal anesthesia are reportedly associated with toxicity of local anesthetics, especially lidocaine. Limited cephalad extension of sensory blocks suggests restricted diffuse of lidocaine in the cerebrospinal fluid and is likely to induce anesthetic neurotoxicity. Several cases of cauda equina syndrome following spinal anesthesia with bupivacaine have been reported. Kato et al[28] reported a cauda equina syndrome case following spinal anesthesia with bupivacaine and epidural anesthesia with ropivacaine, which took 10 months to recover. Similarly, Chabbou et al[29] reported a cauda equina syndrome case following spinal anesthesia with 0.5% hyperbaric bupivacaine without any causative factors in the genesis of the syndrome. Therefore, based on the patient's symptoms and MRI findings, the outcome was probably caused by the neurotoxicity of bupivacaine alone or in combination with ropivacaine. In contrast to other patients, the patient in this report recovered almost completely. This may be the result of the early detection and therapy of the neurologic complication.
In summary, the case highlights that 2 rare and serious complications of spinal-epidural anesthesia can even occur in the same patient after uneventful surgery and block performance. The neurotoxicity of local anesthetics, even with normal dose, is suggested as the most likely cause of cauda equina syndrome, and ICH caused by leakage of CSF serves as a potential factor in causing vocal fold paralysis. Therefore, detailed physical examination, and monitoring recovery of sensory and motor functions following spinal-epidural anesthesia are significant for early detection and therapy of neurologic complications. Notably, practitioners should detect and deal with these rare types of neurologic complications as early as possible, the patient should be investigated thoroughly, and appropriate treatment and rehabilitation program should be initiated promptly. In this patient, early diagnosis and intervention of vocal fold paralysis is crucial to manage it; otherwise, permanent injuries may likely occur.
Author contributions
Conceptualization: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Data curation: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Formal analysis: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Investigation: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Methodology: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Project administration: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Resources: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Software: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Supervision: Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Validation: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Visualization: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Writing – original draft: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Writing – review & editing: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Abbreviations: ASIA = American Spinal Injury Association, CSF = cerebrospinal fluid, CT = computed tomography, ICH = intracranial hypotension, ISNCSCI = the International Standards for Neurological Classification of Spinal Cord Injury, MRI = magnetic resonance imaging, SCI = spinal cord injury.
How to cite this article: Xiang Y, Wang W, Jing S, Zhang Z, Wang D. Vocal fold paralysis and cauda equina syndrome following spinal-epidural anesthesia: a case report. Medicine. 2021;100:3(e24374).
Written consent was obtained from the patient for the purpose of publication of case details and images.
The authors have no conflicts of interests to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. | BUPIVACAINE, FENTANYL, ROPIVACAINE | DrugsGivenReaction | CC BY | 33546075 | 18,981,348 | 2021-01-22 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Intracranial hypotension'. | Vocal fold paralysis and cauda equina syndrome following spinal-epidural anesthesia: A case report.
BACKGROUND
Vocal fold paralysis and cauda equina syndrome are very rare neurologic deficits. This report describes the case of a patient who simultaneously developed both after uneventful spinal-epidural anesthesia with 0.5% hyperbaric bupivacaine.
We report the case of a 45-year-old female, who underwent surgery for bilateral hallux valgus developed cauda equina syndrome and unilateral vocal fold paralysis after uneventful spinal-epidural anesthesia was administered. There was no pain or paresthesia during needle placement or drug injection. Surgery was performed uneventfully.
Right vocal fold paralysis was diagnosed with flexible laryngoscopy.
METHODS
Patient was started on the treatment with a surgery for bilateral hallux valgus, who developed cauda equina syndrome and unilateral vocal fold paralysis after uneventful spinal-epidural anesthesia was administered.
RESULTS
Postoperatively, she had difficulty in urination and defecation. In addition, she developed unilateral vocal fold paralysis characterized by hoarseness, effortful voice production, and choking with liquids. Magnetic resonance imaging performed on the lumbosacral area and computed tomography of the neck, the chest, and the skull revealed entirely normal results. However, flexible laryngoscopy revealed a right vocal fold paralysis. Although cauda equina syndrome can occur due to neurotoxicity of local anesthetics, the exact etiology of vocal fold paralysis is uncertain.
CONCLUSIONS
The case highlights that 2 rare and serious complications of spinal-epidural anesthesia can even occur in the same patient after uneventful surgery and block performance.
1 Introduction
Regional anesthesia for lower limb surgeries is generally held to be inherently safe. Spinal and epidural blocks are therefore used widely, with the more recently introduced combined spinal and epidural technique gaining popularity. Serious neurologic deficits such as cauda equine syndrome and vocal fold paralysis after spinal anesthesia are relatively rare.[1–4] Cauda equina syndrome is a serious neurologic disorder that is caused by damage of the lumbosacral and coccygeal nerve roots which include the ascending and descending nerve roots from L2 through the coccygeal segments. These nerves control lower limb movement (L2-S2), lower limb sensation (L2-S3), bladder control (S2-S4), external analsphincter control (S2-S4), external genitalia and perianal sensation (S2-S4), and coccygeal sensation (S4, S5, and the coccygeal nerve).[5] Cauda equina syndrome is associated with varying degrees of signs and symptoms including loss of bowel and bladder function, insensate perineal areas and lower extremity muscle weakness.[6,7] In addition to cauda equina syndrome, cranial nerve palsy is also a rare complication of spinal anesthesia. The most commonly affected cranial nerve is the abducent nerve because of its long intracranial course.[8] Palsies of the oculomotor, facial, trigeminal, and trochlear nerves, as well as transient hypoacusis and Horner syndrome, have also been reported.[9–13] Vagal neuropathy, following spinal anesthesia was first described recently.[2–4] These cranial palsies are typically transient and resolve within weeks to months, but complete neurological recovery after cauda equina syndrome is unusual. The simultaneous occurrence of these 2 rare complications in the same patient has not been previously reported. This report describes the case of a patient who simultaneously developed both after uneventful spinal-epidural anesthesia with 0.5% hyperbaric bupivacaine. With early diagnosis and appropriate treatment, the patient recovered eventually.
2 Case presentation
A previously healthy 45-year-old female, with no preexisting neurologic deficits, was subjected to surgery because of bilateral hallux valgus. The patient's routine preoperative test results were within normal ranges. Spinal anesthesia was administered at the L3–4 interspace by using a 27-gauge Quincke point spinal needle through an 18-G Tuohy needle. Afterward, 3 ml of 0.5% hyperbaric bupivacaine was injected intrathecally in approximately 15 seconds after the clear cerebrospinal fluid (CSF) without any blood was aspirated. After bupivacaine was injected, an epidural catheter was inserted 4 cm into the epidural space in the cephalad direction via the Tuohy needle. Paraesthesia, back pain or any other signs of nerve irritation was not experienced during needle placement or drug injection. A urinary catheter was inserted before the surgery. The sensory level block was bilateral, symmetric, and caudal to T10 15 minutes after bupivacaine was administered, as assessed via the pinprick method; a complete lower extremity motor block was achieved. The patient's blood pressure decreased transiently from 140/85 mm Hg to 85/60 mm Hg; afterward, 4 mg of ephedrine was provided with hypotension resolution. The patient's arterial pressure remained normal throughout the procedure. Surgical blood loss was not significant. The 90 minutes operation was performed uneventfully. She was discharged to the ward after the operation. Ropivacaine was injected through the epidural catheter to reduce postoperative pain. After a 5 ml bolus of 0.5% ropivacaine was administered, the mixed solution composed of 0.2% ropivacaine and 4 mg/L fentanyl was infused at a basal rate of 2 ml/hour. In addition, patient-controlled epidural analgesia was maintained for almost 2 days (4 ml for 1 push, 30 minutes lockout) by using a disposable pump. The surgical procedure was conducted uneventfully with the patient in the supine position. The final sensory level achieved was T12 bilaterally by pinprick.
After surgery, the patient complained of mild headache. Thereafter, neck stiffness and pain, photophobia, nausea and vomiting also occurred. The next day of the operation, she felt a sudden weakness in her left leg but still able to walk with an assistive device. Then, the weakness increased as well as the right leg. Unexpectedly, she complained of numbness in the gluteal and perianal region. The epidural catheter was removed immediately. According to the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI), which developed by the American Spinal Injury Association (ASIA) and endorsed by the International Spinal Cord Society, is a well-accepted classification of neurologic deficit after Spinal Cord Injury (SCI),[14,15] the examination used dermatomal light touch and pin prick sensation and motor strength of selected muscle groups of the lower extremities to determine the neurologic level of the injury. In the patient, physical examination at that time revealed bilateral lower extremity weakness with 3/5 for left hip flexors and knee extensors; 2/5 for left ankle dorsiflexors and plantar flexors, 1/5 for left extensor hallucis longus; 4/5 for the right hip flexors and knee extensors; 3/5 for right ankle dorsiflexors and plantar flexors, 2/5 for right extensor hallucis longus. Motor scores of the 2 lower limbs were 27 points. Neurological examination documented lower extremity and perianal hypoesthesia and lower extremity hyporeflexia. We defined lower extremity pin prick and light touch scores as the sum of L2 to S5 dermatomes bilaterally (maximum score of 32 points). Pinprick sensation of the left L4-S1 segment, right L4-L5 segment and perianal area in the S3–5 segment was diminished. Pin prick and light touch scores of the left and right lower limbs were 22 and 24 points respectively. The Achilles and patellar reflexes were obviously reduced, and the anal wink reflex was absent in this patient. The anal sphincter tone was decreased. The abdominal reflexes and strength of abdominal wall muscles were bilaterally normal. Three days after surgery, the symptom of headache faded away gradually. The patient was unable to micturate when the urinary catheter was removed on the third postoperative day; as a result, urinary retention (on the third day) and rectal incontinence (on the fourth day) occurred. The bladder was recatheterized because of the urinary retention. Seven days after surgery, Magnetic resonance imaging (MRI) was performed on the lumbosacral area to obtain further information. The MRI revealed no tumor, hematoma, abscess, infarction, spinal stenosis, or cauda equina nerve root compression. Based on the patient's symptoms and MRI findings, cauda equina syndrome was diagnosed. In addition to cauda equina syndrome, she noted onset of hoarseness, effortful voice production and chocking with liquids on postoperative day 5; she believed that her voice had been normal before and immediately after surgery. She subsequently underwent flexible laryngoscopy, which revealed a right vocal fold paralysis. Computed tomography (CT) of the neck and chest was performed 10 days after surgery, which did not reveal any lesions along the recurrent laryngeal nerve. The brain MRI findings showed: diffuse dural enhancement, downward displacement of the brainstem, and diminution of cerebral ventricles, which are typical features of intracranial hypotension (ICH). Stroboscopy performed 15 days after surgery confirmed the finding of an immobile right vocal fold.
The patient was managed conservatively on heavy doses of steroids:[16] methylprednisolone 500 mg intravenously guttae daily for 5 days, then reduced to 80 mg intravenously guttae daily for 10 days. She also underwent a rehabilitation program including traditional Chinese medicine and acupuncture 3 days per week, which aimed to normalize movement patterns. Physical therapy for cauda equine syndrome included static and dynamic control of position, neurophysiologic exercises, progressive ambulation, balance skills, and activities of daily living. Clean intermittent self-catheterization 3 times a day was started for neurogenic bladder. Vocal therapy in unilateral vocal fold paralysis consisted of electrotherapy, hard glottal attacks and pushing exercises, half-swallow boom, accent method, lip and tongue trills. After 2 months, her lower extremity motor strength significantly improved and the sensation of the 2 lower limbs recovered gradually except hypoesthesia in the S3–5 segment. Motor scores of the 2 lower limbs were 45 points; pin prick and light touch scores of the left and right lower limbs were 26 and 28 points, respectively. At the 3-month follow-up, the patient had regained 5/5 strength in all motor groups, could walk normally without any assistive devices and perianal sensation somehow returned. At the 11-month follow-up, the patient recovered from urinary retention and fecal incontinence. In addition, a laryngeal electromyography, performed at 3 months following surgery, showed evidence of denervation of the right thyroarytenoid (innervated by the recurrent laryngeal nerve) and cricothyroid muscle (innervated by the superior laryngeal nerve), consistent with a right vagal neuropathy; at 7-month follow-up, the patient reported that her voice quality improved to near normal and only mild residual paresis was noted on stroboscopy.
3 Discussion and conclusions
The patient developed cauda equina syndrome characterized by urinary retention and fecal incontinence, perianal sensory loss, and lower extremity weakness after uneventful routine spinal-epidural anesthesia. She simultaneously developed a right vocal fold paralysis. Although these major complications rarely occur after spinal-epidural anesthesia, the described patient developed both.
Various possible causes achieved vocal fold paralysis. It may be infectious, neoplastic, or idiopathic in origin. There was no evidence of infection in this case. The CT ruled out the possibility of neoplasm. At first glance, this case of vocal fold paralysis may be classified as idiopathic because spinal anesthesia is generally not considered in the differential diagnosis of vocal fold paralysis. However, a causal relationship may be considered according to the documented occurrence of upper cranial neuropathy as a result of spinal anesthesia, especially in the absence of other important contributing factors. The onset of symptoms is consistent with previously reported cases of cranial neuropathy following spinal anesthesia. Guardiani et al[2] reported 4 cases of vocal fold paralysis after spinal anesthesia. Cranial nerve palsy following subarachnoid block or unintentional dural puncture has been attributed to CSF depletion and ICH, which appears to be the cause of vocal fold palsy.[13] ICH is a clinical syndrome characterized by postural headache and low CSF opening pressure. Symptoms may include nausea, vomiting, nuchal pain, dizziness, tinnitus, nystagmus, and blurred vision.[3] The MRI findings of ICH are diffuse pachymeningeal enhancement, subdural effusion, engorgement of venous sinuses, pituitary enlargement, and herniation of the cerebellar tonsils.[17] It has been explained on the basis of CSF loss causing sagging of the brain and stretching of the nerve.[18] The brain descends caudally to a vertical position, which may harm the cranial nerves that anchor the brain to the skull. In the described patient, laryngeal electromyography suggested a vagal lesion, in light of the evidence of denervation of both the cricothyroid and thyroarytenoid muscle, rather than an isolated neuropathy of the recurrent laryngeal nerve; this supports the hypothesis of traction on the vagal nerve rather than an idiopathic palsy, the majority of which are recurrent nerve phenomena. Therefore, the decrease in intracranial CSF pressure may have contributed to the presentation, which may induce stretching of the vagal nerve bilaterally. In this case, only the right vocal fold was immobile, therefore, the vagal nerve could be stretched with 1 side more affected than the other. Hypotension during surgery may also serve as a contributing factor to this complication because vascular perfusion of nerve fibers might be compromised. Thus the explanation for vocal fold paralysis is uncertain and consequently speculative.
Cauda equina syndrome is a rare but an extremely distressing complication of spinal-epidural anesthesia.[19–21] Most neurological complications are caused by epidural hematoma, abscess, catheter trauma, infection, and anesthetic toxicity. In the patient, the MRI revealed no hematoma, abscess, infarction, spinal stenosis, or lumbar disc herniation. Direct nerve damage may contribute to the onset of neurological symptoms; disposable needle tips are very sharp, nerve fibers can easily be injured by them. Most neural injuries are associated with either paraesthesia or pain upon injection.[22] However, direct damage to the spinal cord via dural puncture is unlikely the cause of the condition observed in the patient because neurologic pain or paraesthesia was not experienced during needle insertion.[23,24] Spinal cord compression caused by an expanding hematoma was excluded through MRI. Infection was not observed because the patient did not manifest clinical signs or laboratory abnormality corresponding to infection. Dural blood flow is significantly reduced in animals once epinephrine is added to local anesthetic solutions.[25] However, spinal cord ischemia was unlikely observed in this case because epinephrine that can induce vascular contraction was not administered, the patient did not suffer from microvascular disease and was hemodynamically stable perioperatively.[26] Rigler et al[27] postulated that a combination of trauma, maldistribution, and relatively high dose of local anesthetic resulted in neurotoxic injury. Most cauda equina syndrome cases following spinal anesthesia are reportedly associated with toxicity of local anesthetics, especially lidocaine. Limited cephalad extension of sensory blocks suggests restricted diffuse of lidocaine in the cerebrospinal fluid and is likely to induce anesthetic neurotoxicity. Several cases of cauda equina syndrome following spinal anesthesia with bupivacaine have been reported. Kato et al[28] reported a cauda equina syndrome case following spinal anesthesia with bupivacaine and epidural anesthesia with ropivacaine, which took 10 months to recover. Similarly, Chabbou et al[29] reported a cauda equina syndrome case following spinal anesthesia with 0.5% hyperbaric bupivacaine without any causative factors in the genesis of the syndrome. Therefore, based on the patient's symptoms and MRI findings, the outcome was probably caused by the neurotoxicity of bupivacaine alone or in combination with ropivacaine. In contrast to other patients, the patient in this report recovered almost completely. This may be the result of the early detection and therapy of the neurologic complication.
In summary, the case highlights that 2 rare and serious complications of spinal-epidural anesthesia can even occur in the same patient after uneventful surgery and block performance. The neurotoxicity of local anesthetics, even with normal dose, is suggested as the most likely cause of cauda equina syndrome, and ICH caused by leakage of CSF serves as a potential factor in causing vocal fold paralysis. Therefore, detailed physical examination, and monitoring recovery of sensory and motor functions following spinal-epidural anesthesia are significant for early detection and therapy of neurologic complications. Notably, practitioners should detect and deal with these rare types of neurologic complications as early as possible, the patient should be investigated thoroughly, and appropriate treatment and rehabilitation program should be initiated promptly. In this patient, early diagnosis and intervention of vocal fold paralysis is crucial to manage it; otherwise, permanent injuries may likely occur.
Author contributions
Conceptualization: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Data curation: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Formal analysis: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Investigation: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Methodology: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Project administration: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Resources: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Software: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Supervision: Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Validation: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Visualization: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Writing – original draft: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Writing – review & editing: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Abbreviations: ASIA = American Spinal Injury Association, CSF = cerebrospinal fluid, CT = computed tomography, ICH = intracranial hypotension, ISNCSCI = the International Standards for Neurological Classification of Spinal Cord Injury, MRI = magnetic resonance imaging, SCI = spinal cord injury.
How to cite this article: Xiang Y, Wang W, Jing S, Zhang Z, Wang D. Vocal fold paralysis and cauda equina syndrome following spinal-epidural anesthesia: a case report. Medicine. 2021;100:3(e24374).
Written consent was obtained from the patient for the purpose of publication of case details and images.
The authors have no conflicts of interests to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. | BUPIVACAINE, FENTANYL, ROPIVACAINE | DrugsGivenReaction | CC BY | 33546075 | 18,981,348 | 2021-01-22 |
What was the administration route of drug 'BUPIVACAINE HYDROCHLORIDE'? | Vocal fold paralysis and cauda equina syndrome following spinal-epidural anesthesia: A case report.
BACKGROUND
Vocal fold paralysis and cauda equina syndrome are very rare neurologic deficits. This report describes the case of a patient who simultaneously developed both after uneventful spinal-epidural anesthesia with 0.5% hyperbaric bupivacaine.
We report the case of a 45-year-old female, who underwent surgery for bilateral hallux valgus developed cauda equina syndrome and unilateral vocal fold paralysis after uneventful spinal-epidural anesthesia was administered. There was no pain or paresthesia during needle placement or drug injection. Surgery was performed uneventfully.
Right vocal fold paralysis was diagnosed with flexible laryngoscopy.
METHODS
Patient was started on the treatment with a surgery for bilateral hallux valgus, who developed cauda equina syndrome and unilateral vocal fold paralysis after uneventful spinal-epidural anesthesia was administered.
RESULTS
Postoperatively, she had difficulty in urination and defecation. In addition, she developed unilateral vocal fold paralysis characterized by hoarseness, effortful voice production, and choking with liquids. Magnetic resonance imaging performed on the lumbosacral area and computed tomography of the neck, the chest, and the skull revealed entirely normal results. However, flexible laryngoscopy revealed a right vocal fold paralysis. Although cauda equina syndrome can occur due to neurotoxicity of local anesthetics, the exact etiology of vocal fold paralysis is uncertain.
CONCLUSIONS
The case highlights that 2 rare and serious complications of spinal-epidural anesthesia can even occur in the same patient after uneventful surgery and block performance.
1 Introduction
Regional anesthesia for lower limb surgeries is generally held to be inherently safe. Spinal and epidural blocks are therefore used widely, with the more recently introduced combined spinal and epidural technique gaining popularity. Serious neurologic deficits such as cauda equine syndrome and vocal fold paralysis after spinal anesthesia are relatively rare.[1–4] Cauda equina syndrome is a serious neurologic disorder that is caused by damage of the lumbosacral and coccygeal nerve roots which include the ascending and descending nerve roots from L2 through the coccygeal segments. These nerves control lower limb movement (L2-S2), lower limb sensation (L2-S3), bladder control (S2-S4), external analsphincter control (S2-S4), external genitalia and perianal sensation (S2-S4), and coccygeal sensation (S4, S5, and the coccygeal nerve).[5] Cauda equina syndrome is associated with varying degrees of signs and symptoms including loss of bowel and bladder function, insensate perineal areas and lower extremity muscle weakness.[6,7] In addition to cauda equina syndrome, cranial nerve palsy is also a rare complication of spinal anesthesia. The most commonly affected cranial nerve is the abducent nerve because of its long intracranial course.[8] Palsies of the oculomotor, facial, trigeminal, and trochlear nerves, as well as transient hypoacusis and Horner syndrome, have also been reported.[9–13] Vagal neuropathy, following spinal anesthesia was first described recently.[2–4] These cranial palsies are typically transient and resolve within weeks to months, but complete neurological recovery after cauda equina syndrome is unusual. The simultaneous occurrence of these 2 rare complications in the same patient has not been previously reported. This report describes the case of a patient who simultaneously developed both after uneventful spinal-epidural anesthesia with 0.5% hyperbaric bupivacaine. With early diagnosis and appropriate treatment, the patient recovered eventually.
2 Case presentation
A previously healthy 45-year-old female, with no preexisting neurologic deficits, was subjected to surgery because of bilateral hallux valgus. The patient's routine preoperative test results were within normal ranges. Spinal anesthesia was administered at the L3–4 interspace by using a 27-gauge Quincke point spinal needle through an 18-G Tuohy needle. Afterward, 3 ml of 0.5% hyperbaric bupivacaine was injected intrathecally in approximately 15 seconds after the clear cerebrospinal fluid (CSF) without any blood was aspirated. After bupivacaine was injected, an epidural catheter was inserted 4 cm into the epidural space in the cephalad direction via the Tuohy needle. Paraesthesia, back pain or any other signs of nerve irritation was not experienced during needle placement or drug injection. A urinary catheter was inserted before the surgery. The sensory level block was bilateral, symmetric, and caudal to T10 15 minutes after bupivacaine was administered, as assessed via the pinprick method; a complete lower extremity motor block was achieved. The patient's blood pressure decreased transiently from 140/85 mm Hg to 85/60 mm Hg; afterward, 4 mg of ephedrine was provided with hypotension resolution. The patient's arterial pressure remained normal throughout the procedure. Surgical blood loss was not significant. The 90 minutes operation was performed uneventfully. She was discharged to the ward after the operation. Ropivacaine was injected through the epidural catheter to reduce postoperative pain. After a 5 ml bolus of 0.5% ropivacaine was administered, the mixed solution composed of 0.2% ropivacaine and 4 mg/L fentanyl was infused at a basal rate of 2 ml/hour. In addition, patient-controlled epidural analgesia was maintained for almost 2 days (4 ml for 1 push, 30 minutes lockout) by using a disposable pump. The surgical procedure was conducted uneventfully with the patient in the supine position. The final sensory level achieved was T12 bilaterally by pinprick.
After surgery, the patient complained of mild headache. Thereafter, neck stiffness and pain, photophobia, nausea and vomiting also occurred. The next day of the operation, she felt a sudden weakness in her left leg but still able to walk with an assistive device. Then, the weakness increased as well as the right leg. Unexpectedly, she complained of numbness in the gluteal and perianal region. The epidural catheter was removed immediately. According to the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI), which developed by the American Spinal Injury Association (ASIA) and endorsed by the International Spinal Cord Society, is a well-accepted classification of neurologic deficit after Spinal Cord Injury (SCI),[14,15] the examination used dermatomal light touch and pin prick sensation and motor strength of selected muscle groups of the lower extremities to determine the neurologic level of the injury. In the patient, physical examination at that time revealed bilateral lower extremity weakness with 3/5 for left hip flexors and knee extensors; 2/5 for left ankle dorsiflexors and plantar flexors, 1/5 for left extensor hallucis longus; 4/5 for the right hip flexors and knee extensors; 3/5 for right ankle dorsiflexors and plantar flexors, 2/5 for right extensor hallucis longus. Motor scores of the 2 lower limbs were 27 points. Neurological examination documented lower extremity and perianal hypoesthesia and lower extremity hyporeflexia. We defined lower extremity pin prick and light touch scores as the sum of L2 to S5 dermatomes bilaterally (maximum score of 32 points). Pinprick sensation of the left L4-S1 segment, right L4-L5 segment and perianal area in the S3–5 segment was diminished. Pin prick and light touch scores of the left and right lower limbs were 22 and 24 points respectively. The Achilles and patellar reflexes were obviously reduced, and the anal wink reflex was absent in this patient. The anal sphincter tone was decreased. The abdominal reflexes and strength of abdominal wall muscles were bilaterally normal. Three days after surgery, the symptom of headache faded away gradually. The patient was unable to micturate when the urinary catheter was removed on the third postoperative day; as a result, urinary retention (on the third day) and rectal incontinence (on the fourth day) occurred. The bladder was recatheterized because of the urinary retention. Seven days after surgery, Magnetic resonance imaging (MRI) was performed on the lumbosacral area to obtain further information. The MRI revealed no tumor, hematoma, abscess, infarction, spinal stenosis, or cauda equina nerve root compression. Based on the patient's symptoms and MRI findings, cauda equina syndrome was diagnosed. In addition to cauda equina syndrome, she noted onset of hoarseness, effortful voice production and chocking with liquids on postoperative day 5; she believed that her voice had been normal before and immediately after surgery. She subsequently underwent flexible laryngoscopy, which revealed a right vocal fold paralysis. Computed tomography (CT) of the neck and chest was performed 10 days after surgery, which did not reveal any lesions along the recurrent laryngeal nerve. The brain MRI findings showed: diffuse dural enhancement, downward displacement of the brainstem, and diminution of cerebral ventricles, which are typical features of intracranial hypotension (ICH). Stroboscopy performed 15 days after surgery confirmed the finding of an immobile right vocal fold.
The patient was managed conservatively on heavy doses of steroids:[16] methylprednisolone 500 mg intravenously guttae daily for 5 days, then reduced to 80 mg intravenously guttae daily for 10 days. She also underwent a rehabilitation program including traditional Chinese medicine and acupuncture 3 days per week, which aimed to normalize movement patterns. Physical therapy for cauda equine syndrome included static and dynamic control of position, neurophysiologic exercises, progressive ambulation, balance skills, and activities of daily living. Clean intermittent self-catheterization 3 times a day was started for neurogenic bladder. Vocal therapy in unilateral vocal fold paralysis consisted of electrotherapy, hard glottal attacks and pushing exercises, half-swallow boom, accent method, lip and tongue trills. After 2 months, her lower extremity motor strength significantly improved and the sensation of the 2 lower limbs recovered gradually except hypoesthesia in the S3–5 segment. Motor scores of the 2 lower limbs were 45 points; pin prick and light touch scores of the left and right lower limbs were 26 and 28 points, respectively. At the 3-month follow-up, the patient had regained 5/5 strength in all motor groups, could walk normally without any assistive devices and perianal sensation somehow returned. At the 11-month follow-up, the patient recovered from urinary retention and fecal incontinence. In addition, a laryngeal electromyography, performed at 3 months following surgery, showed evidence of denervation of the right thyroarytenoid (innervated by the recurrent laryngeal nerve) and cricothyroid muscle (innervated by the superior laryngeal nerve), consistent with a right vagal neuropathy; at 7-month follow-up, the patient reported that her voice quality improved to near normal and only mild residual paresis was noted on stroboscopy.
3 Discussion and conclusions
The patient developed cauda equina syndrome characterized by urinary retention and fecal incontinence, perianal sensory loss, and lower extremity weakness after uneventful routine spinal-epidural anesthesia. She simultaneously developed a right vocal fold paralysis. Although these major complications rarely occur after spinal-epidural anesthesia, the described patient developed both.
Various possible causes achieved vocal fold paralysis. It may be infectious, neoplastic, or idiopathic in origin. There was no evidence of infection in this case. The CT ruled out the possibility of neoplasm. At first glance, this case of vocal fold paralysis may be classified as idiopathic because spinal anesthesia is generally not considered in the differential diagnosis of vocal fold paralysis. However, a causal relationship may be considered according to the documented occurrence of upper cranial neuropathy as a result of spinal anesthesia, especially in the absence of other important contributing factors. The onset of symptoms is consistent with previously reported cases of cranial neuropathy following spinal anesthesia. Guardiani et al[2] reported 4 cases of vocal fold paralysis after spinal anesthesia. Cranial nerve palsy following subarachnoid block or unintentional dural puncture has been attributed to CSF depletion and ICH, which appears to be the cause of vocal fold palsy.[13] ICH is a clinical syndrome characterized by postural headache and low CSF opening pressure. Symptoms may include nausea, vomiting, nuchal pain, dizziness, tinnitus, nystagmus, and blurred vision.[3] The MRI findings of ICH are diffuse pachymeningeal enhancement, subdural effusion, engorgement of venous sinuses, pituitary enlargement, and herniation of the cerebellar tonsils.[17] It has been explained on the basis of CSF loss causing sagging of the brain and stretching of the nerve.[18] The brain descends caudally to a vertical position, which may harm the cranial nerves that anchor the brain to the skull. In the described patient, laryngeal electromyography suggested a vagal lesion, in light of the evidence of denervation of both the cricothyroid and thyroarytenoid muscle, rather than an isolated neuropathy of the recurrent laryngeal nerve; this supports the hypothesis of traction on the vagal nerve rather than an idiopathic palsy, the majority of which are recurrent nerve phenomena. Therefore, the decrease in intracranial CSF pressure may have contributed to the presentation, which may induce stretching of the vagal nerve bilaterally. In this case, only the right vocal fold was immobile, therefore, the vagal nerve could be stretched with 1 side more affected than the other. Hypotension during surgery may also serve as a contributing factor to this complication because vascular perfusion of nerve fibers might be compromised. Thus the explanation for vocal fold paralysis is uncertain and consequently speculative.
Cauda equina syndrome is a rare but an extremely distressing complication of spinal-epidural anesthesia.[19–21] Most neurological complications are caused by epidural hematoma, abscess, catheter trauma, infection, and anesthetic toxicity. In the patient, the MRI revealed no hematoma, abscess, infarction, spinal stenosis, or lumbar disc herniation. Direct nerve damage may contribute to the onset of neurological symptoms; disposable needle tips are very sharp, nerve fibers can easily be injured by them. Most neural injuries are associated with either paraesthesia or pain upon injection.[22] However, direct damage to the spinal cord via dural puncture is unlikely the cause of the condition observed in the patient because neurologic pain or paraesthesia was not experienced during needle insertion.[23,24] Spinal cord compression caused by an expanding hematoma was excluded through MRI. Infection was not observed because the patient did not manifest clinical signs or laboratory abnormality corresponding to infection. Dural blood flow is significantly reduced in animals once epinephrine is added to local anesthetic solutions.[25] However, spinal cord ischemia was unlikely observed in this case because epinephrine that can induce vascular contraction was not administered, the patient did not suffer from microvascular disease and was hemodynamically stable perioperatively.[26] Rigler et al[27] postulated that a combination of trauma, maldistribution, and relatively high dose of local anesthetic resulted in neurotoxic injury. Most cauda equina syndrome cases following spinal anesthesia are reportedly associated with toxicity of local anesthetics, especially lidocaine. Limited cephalad extension of sensory blocks suggests restricted diffuse of lidocaine in the cerebrospinal fluid and is likely to induce anesthetic neurotoxicity. Several cases of cauda equina syndrome following spinal anesthesia with bupivacaine have been reported. Kato et al[28] reported a cauda equina syndrome case following spinal anesthesia with bupivacaine and epidural anesthesia with ropivacaine, which took 10 months to recover. Similarly, Chabbou et al[29] reported a cauda equina syndrome case following spinal anesthesia with 0.5% hyperbaric bupivacaine without any causative factors in the genesis of the syndrome. Therefore, based on the patient's symptoms and MRI findings, the outcome was probably caused by the neurotoxicity of bupivacaine alone or in combination with ropivacaine. In contrast to other patients, the patient in this report recovered almost completely. This may be the result of the early detection and therapy of the neurologic complication.
In summary, the case highlights that 2 rare and serious complications of spinal-epidural anesthesia can even occur in the same patient after uneventful surgery and block performance. The neurotoxicity of local anesthetics, even with normal dose, is suggested as the most likely cause of cauda equina syndrome, and ICH caused by leakage of CSF serves as a potential factor in causing vocal fold paralysis. Therefore, detailed physical examination, and monitoring recovery of sensory and motor functions following spinal-epidural anesthesia are significant for early detection and therapy of neurologic complications. Notably, practitioners should detect and deal with these rare types of neurologic complications as early as possible, the patient should be investigated thoroughly, and appropriate treatment and rehabilitation program should be initiated promptly. In this patient, early diagnosis and intervention of vocal fold paralysis is crucial to manage it; otherwise, permanent injuries may likely occur.
Author contributions
Conceptualization: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Data curation: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Formal analysis: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Investigation: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Methodology: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Project administration: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Resources: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Software: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Supervision: Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Validation: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Visualization: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Writing – original draft: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Writing – review & editing: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Abbreviations: ASIA = American Spinal Injury Association, CSF = cerebrospinal fluid, CT = computed tomography, ICH = intracranial hypotension, ISNCSCI = the International Standards for Neurological Classification of Spinal Cord Injury, MRI = magnetic resonance imaging, SCI = spinal cord injury.
How to cite this article: Xiang Y, Wang W, Jing S, Zhang Z, Wang D. Vocal fold paralysis and cauda equina syndrome following spinal-epidural anesthesia: a case report. Medicine. 2021;100:3(e24374).
Written consent was obtained from the patient for the purpose of publication of case details and images.
The authors have no conflicts of interests to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. | Intrathecal | DrugAdministrationRoute | CC BY | 33546075 | 19,033,943 | 2021-01-22 |
What was the administration route of drug 'BUPIVACAINE'? | Vocal fold paralysis and cauda equina syndrome following spinal-epidural anesthesia: A case report.
BACKGROUND
Vocal fold paralysis and cauda equina syndrome are very rare neurologic deficits. This report describes the case of a patient who simultaneously developed both after uneventful spinal-epidural anesthesia with 0.5% hyperbaric bupivacaine.
We report the case of a 45-year-old female, who underwent surgery for bilateral hallux valgus developed cauda equina syndrome and unilateral vocal fold paralysis after uneventful spinal-epidural anesthesia was administered. There was no pain or paresthesia during needle placement or drug injection. Surgery was performed uneventfully.
Right vocal fold paralysis was diagnosed with flexible laryngoscopy.
METHODS
Patient was started on the treatment with a surgery for bilateral hallux valgus, who developed cauda equina syndrome and unilateral vocal fold paralysis after uneventful spinal-epidural anesthesia was administered.
RESULTS
Postoperatively, she had difficulty in urination and defecation. In addition, she developed unilateral vocal fold paralysis characterized by hoarseness, effortful voice production, and choking with liquids. Magnetic resonance imaging performed on the lumbosacral area and computed tomography of the neck, the chest, and the skull revealed entirely normal results. However, flexible laryngoscopy revealed a right vocal fold paralysis. Although cauda equina syndrome can occur due to neurotoxicity of local anesthetics, the exact etiology of vocal fold paralysis is uncertain.
CONCLUSIONS
The case highlights that 2 rare and serious complications of spinal-epidural anesthesia can even occur in the same patient after uneventful surgery and block performance.
1 Introduction
Regional anesthesia for lower limb surgeries is generally held to be inherently safe. Spinal and epidural blocks are therefore used widely, with the more recently introduced combined spinal and epidural technique gaining popularity. Serious neurologic deficits such as cauda equine syndrome and vocal fold paralysis after spinal anesthesia are relatively rare.[1–4] Cauda equina syndrome is a serious neurologic disorder that is caused by damage of the lumbosacral and coccygeal nerve roots which include the ascending and descending nerve roots from L2 through the coccygeal segments. These nerves control lower limb movement (L2-S2), lower limb sensation (L2-S3), bladder control (S2-S4), external analsphincter control (S2-S4), external genitalia and perianal sensation (S2-S4), and coccygeal sensation (S4, S5, and the coccygeal nerve).[5] Cauda equina syndrome is associated with varying degrees of signs and symptoms including loss of bowel and bladder function, insensate perineal areas and lower extremity muscle weakness.[6,7] In addition to cauda equina syndrome, cranial nerve palsy is also a rare complication of spinal anesthesia. The most commonly affected cranial nerve is the abducent nerve because of its long intracranial course.[8] Palsies of the oculomotor, facial, trigeminal, and trochlear nerves, as well as transient hypoacusis and Horner syndrome, have also been reported.[9–13] Vagal neuropathy, following spinal anesthesia was first described recently.[2–4] These cranial palsies are typically transient and resolve within weeks to months, but complete neurological recovery after cauda equina syndrome is unusual. The simultaneous occurrence of these 2 rare complications in the same patient has not been previously reported. This report describes the case of a patient who simultaneously developed both after uneventful spinal-epidural anesthesia with 0.5% hyperbaric bupivacaine. With early diagnosis and appropriate treatment, the patient recovered eventually.
2 Case presentation
A previously healthy 45-year-old female, with no preexisting neurologic deficits, was subjected to surgery because of bilateral hallux valgus. The patient's routine preoperative test results were within normal ranges. Spinal anesthesia was administered at the L3–4 interspace by using a 27-gauge Quincke point spinal needle through an 18-G Tuohy needle. Afterward, 3 ml of 0.5% hyperbaric bupivacaine was injected intrathecally in approximately 15 seconds after the clear cerebrospinal fluid (CSF) without any blood was aspirated. After bupivacaine was injected, an epidural catheter was inserted 4 cm into the epidural space in the cephalad direction via the Tuohy needle. Paraesthesia, back pain or any other signs of nerve irritation was not experienced during needle placement or drug injection. A urinary catheter was inserted before the surgery. The sensory level block was bilateral, symmetric, and caudal to T10 15 minutes after bupivacaine was administered, as assessed via the pinprick method; a complete lower extremity motor block was achieved. The patient's blood pressure decreased transiently from 140/85 mm Hg to 85/60 mm Hg; afterward, 4 mg of ephedrine was provided with hypotension resolution. The patient's arterial pressure remained normal throughout the procedure. Surgical blood loss was not significant. The 90 minutes operation was performed uneventfully. She was discharged to the ward after the operation. Ropivacaine was injected through the epidural catheter to reduce postoperative pain. After a 5 ml bolus of 0.5% ropivacaine was administered, the mixed solution composed of 0.2% ropivacaine and 4 mg/L fentanyl was infused at a basal rate of 2 ml/hour. In addition, patient-controlled epidural analgesia was maintained for almost 2 days (4 ml for 1 push, 30 minutes lockout) by using a disposable pump. The surgical procedure was conducted uneventfully with the patient in the supine position. The final sensory level achieved was T12 bilaterally by pinprick.
After surgery, the patient complained of mild headache. Thereafter, neck stiffness and pain, photophobia, nausea and vomiting also occurred. The next day of the operation, she felt a sudden weakness in her left leg but still able to walk with an assistive device. Then, the weakness increased as well as the right leg. Unexpectedly, she complained of numbness in the gluteal and perianal region. The epidural catheter was removed immediately. According to the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI), which developed by the American Spinal Injury Association (ASIA) and endorsed by the International Spinal Cord Society, is a well-accepted classification of neurologic deficit after Spinal Cord Injury (SCI),[14,15] the examination used dermatomal light touch and pin prick sensation and motor strength of selected muscle groups of the lower extremities to determine the neurologic level of the injury. In the patient, physical examination at that time revealed bilateral lower extremity weakness with 3/5 for left hip flexors and knee extensors; 2/5 for left ankle dorsiflexors and plantar flexors, 1/5 for left extensor hallucis longus; 4/5 for the right hip flexors and knee extensors; 3/5 for right ankle dorsiflexors and plantar flexors, 2/5 for right extensor hallucis longus. Motor scores of the 2 lower limbs were 27 points. Neurological examination documented lower extremity and perianal hypoesthesia and lower extremity hyporeflexia. We defined lower extremity pin prick and light touch scores as the sum of L2 to S5 dermatomes bilaterally (maximum score of 32 points). Pinprick sensation of the left L4-S1 segment, right L4-L5 segment and perianal area in the S3–5 segment was diminished. Pin prick and light touch scores of the left and right lower limbs were 22 and 24 points respectively. The Achilles and patellar reflexes were obviously reduced, and the anal wink reflex was absent in this patient. The anal sphincter tone was decreased. The abdominal reflexes and strength of abdominal wall muscles were bilaterally normal. Three days after surgery, the symptom of headache faded away gradually. The patient was unable to micturate when the urinary catheter was removed on the third postoperative day; as a result, urinary retention (on the third day) and rectal incontinence (on the fourth day) occurred. The bladder was recatheterized because of the urinary retention. Seven days after surgery, Magnetic resonance imaging (MRI) was performed on the lumbosacral area to obtain further information. The MRI revealed no tumor, hematoma, abscess, infarction, spinal stenosis, or cauda equina nerve root compression. Based on the patient's symptoms and MRI findings, cauda equina syndrome was diagnosed. In addition to cauda equina syndrome, she noted onset of hoarseness, effortful voice production and chocking with liquids on postoperative day 5; she believed that her voice had been normal before and immediately after surgery. She subsequently underwent flexible laryngoscopy, which revealed a right vocal fold paralysis. Computed tomography (CT) of the neck and chest was performed 10 days after surgery, which did not reveal any lesions along the recurrent laryngeal nerve. The brain MRI findings showed: diffuse dural enhancement, downward displacement of the brainstem, and diminution of cerebral ventricles, which are typical features of intracranial hypotension (ICH). Stroboscopy performed 15 days after surgery confirmed the finding of an immobile right vocal fold.
The patient was managed conservatively on heavy doses of steroids:[16] methylprednisolone 500 mg intravenously guttae daily for 5 days, then reduced to 80 mg intravenously guttae daily for 10 days. She also underwent a rehabilitation program including traditional Chinese medicine and acupuncture 3 days per week, which aimed to normalize movement patterns. Physical therapy for cauda equine syndrome included static and dynamic control of position, neurophysiologic exercises, progressive ambulation, balance skills, and activities of daily living. Clean intermittent self-catheterization 3 times a day was started for neurogenic bladder. Vocal therapy in unilateral vocal fold paralysis consisted of electrotherapy, hard glottal attacks and pushing exercises, half-swallow boom, accent method, lip and tongue trills. After 2 months, her lower extremity motor strength significantly improved and the sensation of the 2 lower limbs recovered gradually except hypoesthesia in the S3–5 segment. Motor scores of the 2 lower limbs were 45 points; pin prick and light touch scores of the left and right lower limbs were 26 and 28 points, respectively. At the 3-month follow-up, the patient had regained 5/5 strength in all motor groups, could walk normally without any assistive devices and perianal sensation somehow returned. At the 11-month follow-up, the patient recovered from urinary retention and fecal incontinence. In addition, a laryngeal electromyography, performed at 3 months following surgery, showed evidence of denervation of the right thyroarytenoid (innervated by the recurrent laryngeal nerve) and cricothyroid muscle (innervated by the superior laryngeal nerve), consistent with a right vagal neuropathy; at 7-month follow-up, the patient reported that her voice quality improved to near normal and only mild residual paresis was noted on stroboscopy.
3 Discussion and conclusions
The patient developed cauda equina syndrome characterized by urinary retention and fecal incontinence, perianal sensory loss, and lower extremity weakness after uneventful routine spinal-epidural anesthesia. She simultaneously developed a right vocal fold paralysis. Although these major complications rarely occur after spinal-epidural anesthesia, the described patient developed both.
Various possible causes achieved vocal fold paralysis. It may be infectious, neoplastic, or idiopathic in origin. There was no evidence of infection in this case. The CT ruled out the possibility of neoplasm. At first glance, this case of vocal fold paralysis may be classified as idiopathic because spinal anesthesia is generally not considered in the differential diagnosis of vocal fold paralysis. However, a causal relationship may be considered according to the documented occurrence of upper cranial neuropathy as a result of spinal anesthesia, especially in the absence of other important contributing factors. The onset of symptoms is consistent with previously reported cases of cranial neuropathy following spinal anesthesia. Guardiani et al[2] reported 4 cases of vocal fold paralysis after spinal anesthesia. Cranial nerve palsy following subarachnoid block or unintentional dural puncture has been attributed to CSF depletion and ICH, which appears to be the cause of vocal fold palsy.[13] ICH is a clinical syndrome characterized by postural headache and low CSF opening pressure. Symptoms may include nausea, vomiting, nuchal pain, dizziness, tinnitus, nystagmus, and blurred vision.[3] The MRI findings of ICH are diffuse pachymeningeal enhancement, subdural effusion, engorgement of venous sinuses, pituitary enlargement, and herniation of the cerebellar tonsils.[17] It has been explained on the basis of CSF loss causing sagging of the brain and stretching of the nerve.[18] The brain descends caudally to a vertical position, which may harm the cranial nerves that anchor the brain to the skull. In the described patient, laryngeal electromyography suggested a vagal lesion, in light of the evidence of denervation of both the cricothyroid and thyroarytenoid muscle, rather than an isolated neuropathy of the recurrent laryngeal nerve; this supports the hypothesis of traction on the vagal nerve rather than an idiopathic palsy, the majority of which are recurrent nerve phenomena. Therefore, the decrease in intracranial CSF pressure may have contributed to the presentation, which may induce stretching of the vagal nerve bilaterally. In this case, only the right vocal fold was immobile, therefore, the vagal nerve could be stretched with 1 side more affected than the other. Hypotension during surgery may also serve as a contributing factor to this complication because vascular perfusion of nerve fibers might be compromised. Thus the explanation for vocal fold paralysis is uncertain and consequently speculative.
Cauda equina syndrome is a rare but an extremely distressing complication of spinal-epidural anesthesia.[19–21] Most neurological complications are caused by epidural hematoma, abscess, catheter trauma, infection, and anesthetic toxicity. In the patient, the MRI revealed no hematoma, abscess, infarction, spinal stenosis, or lumbar disc herniation. Direct nerve damage may contribute to the onset of neurological symptoms; disposable needle tips are very sharp, nerve fibers can easily be injured by them. Most neural injuries are associated with either paraesthesia or pain upon injection.[22] However, direct damage to the spinal cord via dural puncture is unlikely the cause of the condition observed in the patient because neurologic pain or paraesthesia was not experienced during needle insertion.[23,24] Spinal cord compression caused by an expanding hematoma was excluded through MRI. Infection was not observed because the patient did not manifest clinical signs or laboratory abnormality corresponding to infection. Dural blood flow is significantly reduced in animals once epinephrine is added to local anesthetic solutions.[25] However, spinal cord ischemia was unlikely observed in this case because epinephrine that can induce vascular contraction was not administered, the patient did not suffer from microvascular disease and was hemodynamically stable perioperatively.[26] Rigler et al[27] postulated that a combination of trauma, maldistribution, and relatively high dose of local anesthetic resulted in neurotoxic injury. Most cauda equina syndrome cases following spinal anesthesia are reportedly associated with toxicity of local anesthetics, especially lidocaine. Limited cephalad extension of sensory blocks suggests restricted diffuse of lidocaine in the cerebrospinal fluid and is likely to induce anesthetic neurotoxicity. Several cases of cauda equina syndrome following spinal anesthesia with bupivacaine have been reported. Kato et al[28] reported a cauda equina syndrome case following spinal anesthesia with bupivacaine and epidural anesthesia with ropivacaine, which took 10 months to recover. Similarly, Chabbou et al[29] reported a cauda equina syndrome case following spinal anesthesia with 0.5% hyperbaric bupivacaine without any causative factors in the genesis of the syndrome. Therefore, based on the patient's symptoms and MRI findings, the outcome was probably caused by the neurotoxicity of bupivacaine alone or in combination with ropivacaine. In contrast to other patients, the patient in this report recovered almost completely. This may be the result of the early detection and therapy of the neurologic complication.
In summary, the case highlights that 2 rare and serious complications of spinal-epidural anesthesia can even occur in the same patient after uneventful surgery and block performance. The neurotoxicity of local anesthetics, even with normal dose, is suggested as the most likely cause of cauda equina syndrome, and ICH caused by leakage of CSF serves as a potential factor in causing vocal fold paralysis. Therefore, detailed physical examination, and monitoring recovery of sensory and motor functions following spinal-epidural anesthesia are significant for early detection and therapy of neurologic complications. Notably, practitioners should detect and deal with these rare types of neurologic complications as early as possible, the patient should be investigated thoroughly, and appropriate treatment and rehabilitation program should be initiated promptly. In this patient, early diagnosis and intervention of vocal fold paralysis is crucial to manage it; otherwise, permanent injuries may likely occur.
Author contributions
Conceptualization: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Data curation: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Formal analysis: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Investigation: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Methodology: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Project administration: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Resources: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Software: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Supervision: Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Validation: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Visualization: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Writing – original draft: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Writing – review & editing: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Abbreviations: ASIA = American Spinal Injury Association, CSF = cerebrospinal fluid, CT = computed tomography, ICH = intracranial hypotension, ISNCSCI = the International Standards for Neurological Classification of Spinal Cord Injury, MRI = magnetic resonance imaging, SCI = spinal cord injury.
How to cite this article: Xiang Y, Wang W, Jing S, Zhang Z, Wang D. Vocal fold paralysis and cauda equina syndrome following spinal-epidural anesthesia: a case report. Medicine. 2021;100:3(e24374).
Written consent was obtained from the patient for the purpose of publication of case details and images.
The authors have no conflicts of interests to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. | Intrathecal | DrugAdministrationRoute | CC BY | 33546075 | 19,046,254 | 2021-01-22 |
What was the administration route of drug 'FENTANYL'? | Vocal fold paralysis and cauda equina syndrome following spinal-epidural anesthesia: A case report.
BACKGROUND
Vocal fold paralysis and cauda equina syndrome are very rare neurologic deficits. This report describes the case of a patient who simultaneously developed both after uneventful spinal-epidural anesthesia with 0.5% hyperbaric bupivacaine.
We report the case of a 45-year-old female, who underwent surgery for bilateral hallux valgus developed cauda equina syndrome and unilateral vocal fold paralysis after uneventful spinal-epidural anesthesia was administered. There was no pain or paresthesia during needle placement or drug injection. Surgery was performed uneventfully.
Right vocal fold paralysis was diagnosed with flexible laryngoscopy.
METHODS
Patient was started on the treatment with a surgery for bilateral hallux valgus, who developed cauda equina syndrome and unilateral vocal fold paralysis after uneventful spinal-epidural anesthesia was administered.
RESULTS
Postoperatively, she had difficulty in urination and defecation. In addition, she developed unilateral vocal fold paralysis characterized by hoarseness, effortful voice production, and choking with liquids. Magnetic resonance imaging performed on the lumbosacral area and computed tomography of the neck, the chest, and the skull revealed entirely normal results. However, flexible laryngoscopy revealed a right vocal fold paralysis. Although cauda equina syndrome can occur due to neurotoxicity of local anesthetics, the exact etiology of vocal fold paralysis is uncertain.
CONCLUSIONS
The case highlights that 2 rare and serious complications of spinal-epidural anesthesia can even occur in the same patient after uneventful surgery and block performance.
1 Introduction
Regional anesthesia for lower limb surgeries is generally held to be inherently safe. Spinal and epidural blocks are therefore used widely, with the more recently introduced combined spinal and epidural technique gaining popularity. Serious neurologic deficits such as cauda equine syndrome and vocal fold paralysis after spinal anesthesia are relatively rare.[1–4] Cauda equina syndrome is a serious neurologic disorder that is caused by damage of the lumbosacral and coccygeal nerve roots which include the ascending and descending nerve roots from L2 through the coccygeal segments. These nerves control lower limb movement (L2-S2), lower limb sensation (L2-S3), bladder control (S2-S4), external analsphincter control (S2-S4), external genitalia and perianal sensation (S2-S4), and coccygeal sensation (S4, S5, and the coccygeal nerve).[5] Cauda equina syndrome is associated with varying degrees of signs and symptoms including loss of bowel and bladder function, insensate perineal areas and lower extremity muscle weakness.[6,7] In addition to cauda equina syndrome, cranial nerve palsy is also a rare complication of spinal anesthesia. The most commonly affected cranial nerve is the abducent nerve because of its long intracranial course.[8] Palsies of the oculomotor, facial, trigeminal, and trochlear nerves, as well as transient hypoacusis and Horner syndrome, have also been reported.[9–13] Vagal neuropathy, following spinal anesthesia was first described recently.[2–4] These cranial palsies are typically transient and resolve within weeks to months, but complete neurological recovery after cauda equina syndrome is unusual. The simultaneous occurrence of these 2 rare complications in the same patient has not been previously reported. This report describes the case of a patient who simultaneously developed both after uneventful spinal-epidural anesthesia with 0.5% hyperbaric bupivacaine. With early diagnosis and appropriate treatment, the patient recovered eventually.
2 Case presentation
A previously healthy 45-year-old female, with no preexisting neurologic deficits, was subjected to surgery because of bilateral hallux valgus. The patient's routine preoperative test results were within normal ranges. Spinal anesthesia was administered at the L3–4 interspace by using a 27-gauge Quincke point spinal needle through an 18-G Tuohy needle. Afterward, 3 ml of 0.5% hyperbaric bupivacaine was injected intrathecally in approximately 15 seconds after the clear cerebrospinal fluid (CSF) without any blood was aspirated. After bupivacaine was injected, an epidural catheter was inserted 4 cm into the epidural space in the cephalad direction via the Tuohy needle. Paraesthesia, back pain or any other signs of nerve irritation was not experienced during needle placement or drug injection. A urinary catheter was inserted before the surgery. The sensory level block was bilateral, symmetric, and caudal to T10 15 minutes after bupivacaine was administered, as assessed via the pinprick method; a complete lower extremity motor block was achieved. The patient's blood pressure decreased transiently from 140/85 mm Hg to 85/60 mm Hg; afterward, 4 mg of ephedrine was provided with hypotension resolution. The patient's arterial pressure remained normal throughout the procedure. Surgical blood loss was not significant. The 90 minutes operation was performed uneventfully. She was discharged to the ward after the operation. Ropivacaine was injected through the epidural catheter to reduce postoperative pain. After a 5 ml bolus of 0.5% ropivacaine was administered, the mixed solution composed of 0.2% ropivacaine and 4 mg/L fentanyl was infused at a basal rate of 2 ml/hour. In addition, patient-controlled epidural analgesia was maintained for almost 2 days (4 ml for 1 push, 30 minutes lockout) by using a disposable pump. The surgical procedure was conducted uneventfully with the patient in the supine position. The final sensory level achieved was T12 bilaterally by pinprick.
After surgery, the patient complained of mild headache. Thereafter, neck stiffness and pain, photophobia, nausea and vomiting also occurred. The next day of the operation, she felt a sudden weakness in her left leg but still able to walk with an assistive device. Then, the weakness increased as well as the right leg. Unexpectedly, she complained of numbness in the gluteal and perianal region. The epidural catheter was removed immediately. According to the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI), which developed by the American Spinal Injury Association (ASIA) and endorsed by the International Spinal Cord Society, is a well-accepted classification of neurologic deficit after Spinal Cord Injury (SCI),[14,15] the examination used dermatomal light touch and pin prick sensation and motor strength of selected muscle groups of the lower extremities to determine the neurologic level of the injury. In the patient, physical examination at that time revealed bilateral lower extremity weakness with 3/5 for left hip flexors and knee extensors; 2/5 for left ankle dorsiflexors and plantar flexors, 1/5 for left extensor hallucis longus; 4/5 for the right hip flexors and knee extensors; 3/5 for right ankle dorsiflexors and plantar flexors, 2/5 for right extensor hallucis longus. Motor scores of the 2 lower limbs were 27 points. Neurological examination documented lower extremity and perianal hypoesthesia and lower extremity hyporeflexia. We defined lower extremity pin prick and light touch scores as the sum of L2 to S5 dermatomes bilaterally (maximum score of 32 points). Pinprick sensation of the left L4-S1 segment, right L4-L5 segment and perianal area in the S3–5 segment was diminished. Pin prick and light touch scores of the left and right lower limbs were 22 and 24 points respectively. The Achilles and patellar reflexes were obviously reduced, and the anal wink reflex was absent in this patient. The anal sphincter tone was decreased. The abdominal reflexes and strength of abdominal wall muscles were bilaterally normal. Three days after surgery, the symptom of headache faded away gradually. The patient was unable to micturate when the urinary catheter was removed on the third postoperative day; as a result, urinary retention (on the third day) and rectal incontinence (on the fourth day) occurred. The bladder was recatheterized because of the urinary retention. Seven days after surgery, Magnetic resonance imaging (MRI) was performed on the lumbosacral area to obtain further information. The MRI revealed no tumor, hematoma, abscess, infarction, spinal stenosis, or cauda equina nerve root compression. Based on the patient's symptoms and MRI findings, cauda equina syndrome was diagnosed. In addition to cauda equina syndrome, she noted onset of hoarseness, effortful voice production and chocking with liquids on postoperative day 5; she believed that her voice had been normal before and immediately after surgery. She subsequently underwent flexible laryngoscopy, which revealed a right vocal fold paralysis. Computed tomography (CT) of the neck and chest was performed 10 days after surgery, which did not reveal any lesions along the recurrent laryngeal nerve. The brain MRI findings showed: diffuse dural enhancement, downward displacement of the brainstem, and diminution of cerebral ventricles, which are typical features of intracranial hypotension (ICH). Stroboscopy performed 15 days after surgery confirmed the finding of an immobile right vocal fold.
The patient was managed conservatively on heavy doses of steroids:[16] methylprednisolone 500 mg intravenously guttae daily for 5 days, then reduced to 80 mg intravenously guttae daily for 10 days. She also underwent a rehabilitation program including traditional Chinese medicine and acupuncture 3 days per week, which aimed to normalize movement patterns. Physical therapy for cauda equine syndrome included static and dynamic control of position, neurophysiologic exercises, progressive ambulation, balance skills, and activities of daily living. Clean intermittent self-catheterization 3 times a day was started for neurogenic bladder. Vocal therapy in unilateral vocal fold paralysis consisted of electrotherapy, hard glottal attacks and pushing exercises, half-swallow boom, accent method, lip and tongue trills. After 2 months, her lower extremity motor strength significantly improved and the sensation of the 2 lower limbs recovered gradually except hypoesthesia in the S3–5 segment. Motor scores of the 2 lower limbs were 45 points; pin prick and light touch scores of the left and right lower limbs were 26 and 28 points, respectively. At the 3-month follow-up, the patient had regained 5/5 strength in all motor groups, could walk normally without any assistive devices and perianal sensation somehow returned. At the 11-month follow-up, the patient recovered from urinary retention and fecal incontinence. In addition, a laryngeal electromyography, performed at 3 months following surgery, showed evidence of denervation of the right thyroarytenoid (innervated by the recurrent laryngeal nerve) and cricothyroid muscle (innervated by the superior laryngeal nerve), consistent with a right vagal neuropathy; at 7-month follow-up, the patient reported that her voice quality improved to near normal and only mild residual paresis was noted on stroboscopy.
3 Discussion and conclusions
The patient developed cauda equina syndrome characterized by urinary retention and fecal incontinence, perianal sensory loss, and lower extremity weakness after uneventful routine spinal-epidural anesthesia. She simultaneously developed a right vocal fold paralysis. Although these major complications rarely occur after spinal-epidural anesthesia, the described patient developed both.
Various possible causes achieved vocal fold paralysis. It may be infectious, neoplastic, or idiopathic in origin. There was no evidence of infection in this case. The CT ruled out the possibility of neoplasm. At first glance, this case of vocal fold paralysis may be classified as idiopathic because spinal anesthesia is generally not considered in the differential diagnosis of vocal fold paralysis. However, a causal relationship may be considered according to the documented occurrence of upper cranial neuropathy as a result of spinal anesthesia, especially in the absence of other important contributing factors. The onset of symptoms is consistent with previously reported cases of cranial neuropathy following spinal anesthesia. Guardiani et al[2] reported 4 cases of vocal fold paralysis after spinal anesthesia. Cranial nerve palsy following subarachnoid block or unintentional dural puncture has been attributed to CSF depletion and ICH, which appears to be the cause of vocal fold palsy.[13] ICH is a clinical syndrome characterized by postural headache and low CSF opening pressure. Symptoms may include nausea, vomiting, nuchal pain, dizziness, tinnitus, nystagmus, and blurred vision.[3] The MRI findings of ICH are diffuse pachymeningeal enhancement, subdural effusion, engorgement of venous sinuses, pituitary enlargement, and herniation of the cerebellar tonsils.[17] It has been explained on the basis of CSF loss causing sagging of the brain and stretching of the nerve.[18] The brain descends caudally to a vertical position, which may harm the cranial nerves that anchor the brain to the skull. In the described patient, laryngeal electromyography suggested a vagal lesion, in light of the evidence of denervation of both the cricothyroid and thyroarytenoid muscle, rather than an isolated neuropathy of the recurrent laryngeal nerve; this supports the hypothesis of traction on the vagal nerve rather than an idiopathic palsy, the majority of which are recurrent nerve phenomena. Therefore, the decrease in intracranial CSF pressure may have contributed to the presentation, which may induce stretching of the vagal nerve bilaterally. In this case, only the right vocal fold was immobile, therefore, the vagal nerve could be stretched with 1 side more affected than the other. Hypotension during surgery may also serve as a contributing factor to this complication because vascular perfusion of nerve fibers might be compromised. Thus the explanation for vocal fold paralysis is uncertain and consequently speculative.
Cauda equina syndrome is a rare but an extremely distressing complication of spinal-epidural anesthesia.[19–21] Most neurological complications are caused by epidural hematoma, abscess, catheter trauma, infection, and anesthetic toxicity. In the patient, the MRI revealed no hematoma, abscess, infarction, spinal stenosis, or lumbar disc herniation. Direct nerve damage may contribute to the onset of neurological symptoms; disposable needle tips are very sharp, nerve fibers can easily be injured by them. Most neural injuries are associated with either paraesthesia or pain upon injection.[22] However, direct damage to the spinal cord via dural puncture is unlikely the cause of the condition observed in the patient because neurologic pain or paraesthesia was not experienced during needle insertion.[23,24] Spinal cord compression caused by an expanding hematoma was excluded through MRI. Infection was not observed because the patient did not manifest clinical signs or laboratory abnormality corresponding to infection. Dural blood flow is significantly reduced in animals once epinephrine is added to local anesthetic solutions.[25] However, spinal cord ischemia was unlikely observed in this case because epinephrine that can induce vascular contraction was not administered, the patient did not suffer from microvascular disease and was hemodynamically stable perioperatively.[26] Rigler et al[27] postulated that a combination of trauma, maldistribution, and relatively high dose of local anesthetic resulted in neurotoxic injury. Most cauda equina syndrome cases following spinal anesthesia are reportedly associated with toxicity of local anesthetics, especially lidocaine. Limited cephalad extension of sensory blocks suggests restricted diffuse of lidocaine in the cerebrospinal fluid and is likely to induce anesthetic neurotoxicity. Several cases of cauda equina syndrome following spinal anesthesia with bupivacaine have been reported. Kato et al[28] reported a cauda equina syndrome case following spinal anesthesia with bupivacaine and epidural anesthesia with ropivacaine, which took 10 months to recover. Similarly, Chabbou et al[29] reported a cauda equina syndrome case following spinal anesthesia with 0.5% hyperbaric bupivacaine without any causative factors in the genesis of the syndrome. Therefore, based on the patient's symptoms and MRI findings, the outcome was probably caused by the neurotoxicity of bupivacaine alone or in combination with ropivacaine. In contrast to other patients, the patient in this report recovered almost completely. This may be the result of the early detection and therapy of the neurologic complication.
In summary, the case highlights that 2 rare and serious complications of spinal-epidural anesthesia can even occur in the same patient after uneventful surgery and block performance. The neurotoxicity of local anesthetics, even with normal dose, is suggested as the most likely cause of cauda equina syndrome, and ICH caused by leakage of CSF serves as a potential factor in causing vocal fold paralysis. Therefore, detailed physical examination, and monitoring recovery of sensory and motor functions following spinal-epidural anesthesia are significant for early detection and therapy of neurologic complications. Notably, practitioners should detect and deal with these rare types of neurologic complications as early as possible, the patient should be investigated thoroughly, and appropriate treatment and rehabilitation program should be initiated promptly. In this patient, early diagnosis and intervention of vocal fold paralysis is crucial to manage it; otherwise, permanent injuries may likely occur.
Author contributions
Conceptualization: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Data curation: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Formal analysis: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Investigation: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Methodology: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Project administration: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Resources: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Software: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Supervision: Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Validation: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Visualization: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Writing – original draft: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Writing – review & editing: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Abbreviations: ASIA = American Spinal Injury Association, CSF = cerebrospinal fluid, CT = computed tomography, ICH = intracranial hypotension, ISNCSCI = the International Standards for Neurological Classification of Spinal Cord Injury, MRI = magnetic resonance imaging, SCI = spinal cord injury.
How to cite this article: Xiang Y, Wang W, Jing S, Zhang Z, Wang D. Vocal fold paralysis and cauda equina syndrome following spinal-epidural anesthesia: a case report. Medicine. 2021;100:3(e24374).
Written consent was obtained from the patient for the purpose of publication of case details and images.
The authors have no conflicts of interests to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. | Epidural | DrugAdministrationRoute | CC BY | 33546075 | 19,046,254 | 2021-01-22 |
What was the administration route of drug 'ROPIVACAINE HYDROCHLORIDE'? | Vocal fold paralysis and cauda equina syndrome following spinal-epidural anesthesia: A case report.
BACKGROUND
Vocal fold paralysis and cauda equina syndrome are very rare neurologic deficits. This report describes the case of a patient who simultaneously developed both after uneventful spinal-epidural anesthesia with 0.5% hyperbaric bupivacaine.
We report the case of a 45-year-old female, who underwent surgery for bilateral hallux valgus developed cauda equina syndrome and unilateral vocal fold paralysis after uneventful spinal-epidural anesthesia was administered. There was no pain or paresthesia during needle placement or drug injection. Surgery was performed uneventfully.
Right vocal fold paralysis was diagnosed with flexible laryngoscopy.
METHODS
Patient was started on the treatment with a surgery for bilateral hallux valgus, who developed cauda equina syndrome and unilateral vocal fold paralysis after uneventful spinal-epidural anesthesia was administered.
RESULTS
Postoperatively, she had difficulty in urination and defecation. In addition, she developed unilateral vocal fold paralysis characterized by hoarseness, effortful voice production, and choking with liquids. Magnetic resonance imaging performed on the lumbosacral area and computed tomography of the neck, the chest, and the skull revealed entirely normal results. However, flexible laryngoscopy revealed a right vocal fold paralysis. Although cauda equina syndrome can occur due to neurotoxicity of local anesthetics, the exact etiology of vocal fold paralysis is uncertain.
CONCLUSIONS
The case highlights that 2 rare and serious complications of spinal-epidural anesthesia can even occur in the same patient after uneventful surgery and block performance.
1 Introduction
Regional anesthesia for lower limb surgeries is generally held to be inherently safe. Spinal and epidural blocks are therefore used widely, with the more recently introduced combined spinal and epidural technique gaining popularity. Serious neurologic deficits such as cauda equine syndrome and vocal fold paralysis after spinal anesthesia are relatively rare.[1–4] Cauda equina syndrome is a serious neurologic disorder that is caused by damage of the lumbosacral and coccygeal nerve roots which include the ascending and descending nerve roots from L2 through the coccygeal segments. These nerves control lower limb movement (L2-S2), lower limb sensation (L2-S3), bladder control (S2-S4), external analsphincter control (S2-S4), external genitalia and perianal sensation (S2-S4), and coccygeal sensation (S4, S5, and the coccygeal nerve).[5] Cauda equina syndrome is associated with varying degrees of signs and symptoms including loss of bowel and bladder function, insensate perineal areas and lower extremity muscle weakness.[6,7] In addition to cauda equina syndrome, cranial nerve palsy is also a rare complication of spinal anesthesia. The most commonly affected cranial nerve is the abducent nerve because of its long intracranial course.[8] Palsies of the oculomotor, facial, trigeminal, and trochlear nerves, as well as transient hypoacusis and Horner syndrome, have also been reported.[9–13] Vagal neuropathy, following spinal anesthesia was first described recently.[2–4] These cranial palsies are typically transient and resolve within weeks to months, but complete neurological recovery after cauda equina syndrome is unusual. The simultaneous occurrence of these 2 rare complications in the same patient has not been previously reported. This report describes the case of a patient who simultaneously developed both after uneventful spinal-epidural anesthesia with 0.5% hyperbaric bupivacaine. With early diagnosis and appropriate treatment, the patient recovered eventually.
2 Case presentation
A previously healthy 45-year-old female, with no preexisting neurologic deficits, was subjected to surgery because of bilateral hallux valgus. The patient's routine preoperative test results were within normal ranges. Spinal anesthesia was administered at the L3–4 interspace by using a 27-gauge Quincke point spinal needle through an 18-G Tuohy needle. Afterward, 3 ml of 0.5% hyperbaric bupivacaine was injected intrathecally in approximately 15 seconds after the clear cerebrospinal fluid (CSF) without any blood was aspirated. After bupivacaine was injected, an epidural catheter was inserted 4 cm into the epidural space in the cephalad direction via the Tuohy needle. Paraesthesia, back pain or any other signs of nerve irritation was not experienced during needle placement or drug injection. A urinary catheter was inserted before the surgery. The sensory level block was bilateral, symmetric, and caudal to T10 15 minutes after bupivacaine was administered, as assessed via the pinprick method; a complete lower extremity motor block was achieved. The patient's blood pressure decreased transiently from 140/85 mm Hg to 85/60 mm Hg; afterward, 4 mg of ephedrine was provided with hypotension resolution. The patient's arterial pressure remained normal throughout the procedure. Surgical blood loss was not significant. The 90 minutes operation was performed uneventfully. She was discharged to the ward after the operation. Ropivacaine was injected through the epidural catheter to reduce postoperative pain. After a 5 ml bolus of 0.5% ropivacaine was administered, the mixed solution composed of 0.2% ropivacaine and 4 mg/L fentanyl was infused at a basal rate of 2 ml/hour. In addition, patient-controlled epidural analgesia was maintained for almost 2 days (4 ml for 1 push, 30 minutes lockout) by using a disposable pump. The surgical procedure was conducted uneventfully with the patient in the supine position. The final sensory level achieved was T12 bilaterally by pinprick.
After surgery, the patient complained of mild headache. Thereafter, neck stiffness and pain, photophobia, nausea and vomiting also occurred. The next day of the operation, she felt a sudden weakness in her left leg but still able to walk with an assistive device. Then, the weakness increased as well as the right leg. Unexpectedly, she complained of numbness in the gluteal and perianal region. The epidural catheter was removed immediately. According to the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI), which developed by the American Spinal Injury Association (ASIA) and endorsed by the International Spinal Cord Society, is a well-accepted classification of neurologic deficit after Spinal Cord Injury (SCI),[14,15] the examination used dermatomal light touch and pin prick sensation and motor strength of selected muscle groups of the lower extremities to determine the neurologic level of the injury. In the patient, physical examination at that time revealed bilateral lower extremity weakness with 3/5 for left hip flexors and knee extensors; 2/5 for left ankle dorsiflexors and plantar flexors, 1/5 for left extensor hallucis longus; 4/5 for the right hip flexors and knee extensors; 3/5 for right ankle dorsiflexors and plantar flexors, 2/5 for right extensor hallucis longus. Motor scores of the 2 lower limbs were 27 points. Neurological examination documented lower extremity and perianal hypoesthesia and lower extremity hyporeflexia. We defined lower extremity pin prick and light touch scores as the sum of L2 to S5 dermatomes bilaterally (maximum score of 32 points). Pinprick sensation of the left L4-S1 segment, right L4-L5 segment and perianal area in the S3–5 segment was diminished. Pin prick and light touch scores of the left and right lower limbs were 22 and 24 points respectively. The Achilles and patellar reflexes were obviously reduced, and the anal wink reflex was absent in this patient. The anal sphincter tone was decreased. The abdominal reflexes and strength of abdominal wall muscles were bilaterally normal. Three days after surgery, the symptom of headache faded away gradually. The patient was unable to micturate when the urinary catheter was removed on the third postoperative day; as a result, urinary retention (on the third day) and rectal incontinence (on the fourth day) occurred. The bladder was recatheterized because of the urinary retention. Seven days after surgery, Magnetic resonance imaging (MRI) was performed on the lumbosacral area to obtain further information. The MRI revealed no tumor, hematoma, abscess, infarction, spinal stenosis, or cauda equina nerve root compression. Based on the patient's symptoms and MRI findings, cauda equina syndrome was diagnosed. In addition to cauda equina syndrome, she noted onset of hoarseness, effortful voice production and chocking with liquids on postoperative day 5; she believed that her voice had been normal before and immediately after surgery. She subsequently underwent flexible laryngoscopy, which revealed a right vocal fold paralysis. Computed tomography (CT) of the neck and chest was performed 10 days after surgery, which did not reveal any lesions along the recurrent laryngeal nerve. The brain MRI findings showed: diffuse dural enhancement, downward displacement of the brainstem, and diminution of cerebral ventricles, which are typical features of intracranial hypotension (ICH). Stroboscopy performed 15 days after surgery confirmed the finding of an immobile right vocal fold.
The patient was managed conservatively on heavy doses of steroids:[16] methylprednisolone 500 mg intravenously guttae daily for 5 days, then reduced to 80 mg intravenously guttae daily for 10 days. She also underwent a rehabilitation program including traditional Chinese medicine and acupuncture 3 days per week, which aimed to normalize movement patterns. Physical therapy for cauda equine syndrome included static and dynamic control of position, neurophysiologic exercises, progressive ambulation, balance skills, and activities of daily living. Clean intermittent self-catheterization 3 times a day was started for neurogenic bladder. Vocal therapy in unilateral vocal fold paralysis consisted of electrotherapy, hard glottal attacks and pushing exercises, half-swallow boom, accent method, lip and tongue trills. After 2 months, her lower extremity motor strength significantly improved and the sensation of the 2 lower limbs recovered gradually except hypoesthesia in the S3–5 segment. Motor scores of the 2 lower limbs were 45 points; pin prick and light touch scores of the left and right lower limbs were 26 and 28 points, respectively. At the 3-month follow-up, the patient had regained 5/5 strength in all motor groups, could walk normally without any assistive devices and perianal sensation somehow returned. At the 11-month follow-up, the patient recovered from urinary retention and fecal incontinence. In addition, a laryngeal electromyography, performed at 3 months following surgery, showed evidence of denervation of the right thyroarytenoid (innervated by the recurrent laryngeal nerve) and cricothyroid muscle (innervated by the superior laryngeal nerve), consistent with a right vagal neuropathy; at 7-month follow-up, the patient reported that her voice quality improved to near normal and only mild residual paresis was noted on stroboscopy.
3 Discussion and conclusions
The patient developed cauda equina syndrome characterized by urinary retention and fecal incontinence, perianal sensory loss, and lower extremity weakness after uneventful routine spinal-epidural anesthesia. She simultaneously developed a right vocal fold paralysis. Although these major complications rarely occur after spinal-epidural anesthesia, the described patient developed both.
Various possible causes achieved vocal fold paralysis. It may be infectious, neoplastic, or idiopathic in origin. There was no evidence of infection in this case. The CT ruled out the possibility of neoplasm. At first glance, this case of vocal fold paralysis may be classified as idiopathic because spinal anesthesia is generally not considered in the differential diagnosis of vocal fold paralysis. However, a causal relationship may be considered according to the documented occurrence of upper cranial neuropathy as a result of spinal anesthesia, especially in the absence of other important contributing factors. The onset of symptoms is consistent with previously reported cases of cranial neuropathy following spinal anesthesia. Guardiani et al[2] reported 4 cases of vocal fold paralysis after spinal anesthesia. Cranial nerve palsy following subarachnoid block or unintentional dural puncture has been attributed to CSF depletion and ICH, which appears to be the cause of vocal fold palsy.[13] ICH is a clinical syndrome characterized by postural headache and low CSF opening pressure. Symptoms may include nausea, vomiting, nuchal pain, dizziness, tinnitus, nystagmus, and blurred vision.[3] The MRI findings of ICH are diffuse pachymeningeal enhancement, subdural effusion, engorgement of venous sinuses, pituitary enlargement, and herniation of the cerebellar tonsils.[17] It has been explained on the basis of CSF loss causing sagging of the brain and stretching of the nerve.[18] The brain descends caudally to a vertical position, which may harm the cranial nerves that anchor the brain to the skull. In the described patient, laryngeal electromyography suggested a vagal lesion, in light of the evidence of denervation of both the cricothyroid and thyroarytenoid muscle, rather than an isolated neuropathy of the recurrent laryngeal nerve; this supports the hypothesis of traction on the vagal nerve rather than an idiopathic palsy, the majority of which are recurrent nerve phenomena. Therefore, the decrease in intracranial CSF pressure may have contributed to the presentation, which may induce stretching of the vagal nerve bilaterally. In this case, only the right vocal fold was immobile, therefore, the vagal nerve could be stretched with 1 side more affected than the other. Hypotension during surgery may also serve as a contributing factor to this complication because vascular perfusion of nerve fibers might be compromised. Thus the explanation for vocal fold paralysis is uncertain and consequently speculative.
Cauda equina syndrome is a rare but an extremely distressing complication of spinal-epidural anesthesia.[19–21] Most neurological complications are caused by epidural hematoma, abscess, catheter trauma, infection, and anesthetic toxicity. In the patient, the MRI revealed no hematoma, abscess, infarction, spinal stenosis, or lumbar disc herniation. Direct nerve damage may contribute to the onset of neurological symptoms; disposable needle tips are very sharp, nerve fibers can easily be injured by them. Most neural injuries are associated with either paraesthesia or pain upon injection.[22] However, direct damage to the spinal cord via dural puncture is unlikely the cause of the condition observed in the patient because neurologic pain or paraesthesia was not experienced during needle insertion.[23,24] Spinal cord compression caused by an expanding hematoma was excluded through MRI. Infection was not observed because the patient did not manifest clinical signs or laboratory abnormality corresponding to infection. Dural blood flow is significantly reduced in animals once epinephrine is added to local anesthetic solutions.[25] However, spinal cord ischemia was unlikely observed in this case because epinephrine that can induce vascular contraction was not administered, the patient did not suffer from microvascular disease and was hemodynamically stable perioperatively.[26] Rigler et al[27] postulated that a combination of trauma, maldistribution, and relatively high dose of local anesthetic resulted in neurotoxic injury. Most cauda equina syndrome cases following spinal anesthesia are reportedly associated with toxicity of local anesthetics, especially lidocaine. Limited cephalad extension of sensory blocks suggests restricted diffuse of lidocaine in the cerebrospinal fluid and is likely to induce anesthetic neurotoxicity. Several cases of cauda equina syndrome following spinal anesthesia with bupivacaine have been reported. Kato et al[28] reported a cauda equina syndrome case following spinal anesthesia with bupivacaine and epidural anesthesia with ropivacaine, which took 10 months to recover. Similarly, Chabbou et al[29] reported a cauda equina syndrome case following spinal anesthesia with 0.5% hyperbaric bupivacaine without any causative factors in the genesis of the syndrome. Therefore, based on the patient's symptoms and MRI findings, the outcome was probably caused by the neurotoxicity of bupivacaine alone or in combination with ropivacaine. In contrast to other patients, the patient in this report recovered almost completely. This may be the result of the early detection and therapy of the neurologic complication.
In summary, the case highlights that 2 rare and serious complications of spinal-epidural anesthesia can even occur in the same patient after uneventful surgery and block performance. The neurotoxicity of local anesthetics, even with normal dose, is suggested as the most likely cause of cauda equina syndrome, and ICH caused by leakage of CSF serves as a potential factor in causing vocal fold paralysis. Therefore, detailed physical examination, and monitoring recovery of sensory and motor functions following spinal-epidural anesthesia are significant for early detection and therapy of neurologic complications. Notably, practitioners should detect and deal with these rare types of neurologic complications as early as possible, the patient should be investigated thoroughly, and appropriate treatment and rehabilitation program should be initiated promptly. In this patient, early diagnosis and intervention of vocal fold paralysis is crucial to manage it; otherwise, permanent injuries may likely occur.
Author contributions
Conceptualization: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Data curation: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Formal analysis: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Investigation: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Methodology: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Project administration: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Resources: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Software: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Supervision: Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Validation: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Visualization: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Writing – original draft: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Writing – review & editing: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Abbreviations: ASIA = American Spinal Injury Association, CSF = cerebrospinal fluid, CT = computed tomography, ICH = intracranial hypotension, ISNCSCI = the International Standards for Neurological Classification of Spinal Cord Injury, MRI = magnetic resonance imaging, SCI = spinal cord injury.
How to cite this article: Xiang Y, Wang W, Jing S, Zhang Z, Wang D. Vocal fold paralysis and cauda equina syndrome following spinal-epidural anesthesia: a case report. Medicine. 2021;100:3(e24374).
Written consent was obtained from the patient for the purpose of publication of case details and images.
The authors have no conflicts of interests to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. | Epidural | DrugAdministrationRoute | CC BY | 33546075 | 19,046,254 | 2021-01-22 |
What was the administration route of drug 'ROPIVACAINE'? | Vocal fold paralysis and cauda equina syndrome following spinal-epidural anesthesia: A case report.
BACKGROUND
Vocal fold paralysis and cauda equina syndrome are very rare neurologic deficits. This report describes the case of a patient who simultaneously developed both after uneventful spinal-epidural anesthesia with 0.5% hyperbaric bupivacaine.
We report the case of a 45-year-old female, who underwent surgery for bilateral hallux valgus developed cauda equina syndrome and unilateral vocal fold paralysis after uneventful spinal-epidural anesthesia was administered. There was no pain or paresthesia during needle placement or drug injection. Surgery was performed uneventfully.
Right vocal fold paralysis was diagnosed with flexible laryngoscopy.
METHODS
Patient was started on the treatment with a surgery for bilateral hallux valgus, who developed cauda equina syndrome and unilateral vocal fold paralysis after uneventful spinal-epidural anesthesia was administered.
RESULTS
Postoperatively, she had difficulty in urination and defecation. In addition, she developed unilateral vocal fold paralysis characterized by hoarseness, effortful voice production, and choking with liquids. Magnetic resonance imaging performed on the lumbosacral area and computed tomography of the neck, the chest, and the skull revealed entirely normal results. However, flexible laryngoscopy revealed a right vocal fold paralysis. Although cauda equina syndrome can occur due to neurotoxicity of local anesthetics, the exact etiology of vocal fold paralysis is uncertain.
CONCLUSIONS
The case highlights that 2 rare and serious complications of spinal-epidural anesthesia can even occur in the same patient after uneventful surgery and block performance.
1 Introduction
Regional anesthesia for lower limb surgeries is generally held to be inherently safe. Spinal and epidural blocks are therefore used widely, with the more recently introduced combined spinal and epidural technique gaining popularity. Serious neurologic deficits such as cauda equine syndrome and vocal fold paralysis after spinal anesthesia are relatively rare.[1–4] Cauda equina syndrome is a serious neurologic disorder that is caused by damage of the lumbosacral and coccygeal nerve roots which include the ascending and descending nerve roots from L2 through the coccygeal segments. These nerves control lower limb movement (L2-S2), lower limb sensation (L2-S3), bladder control (S2-S4), external analsphincter control (S2-S4), external genitalia and perianal sensation (S2-S4), and coccygeal sensation (S4, S5, and the coccygeal nerve).[5] Cauda equina syndrome is associated with varying degrees of signs and symptoms including loss of bowel and bladder function, insensate perineal areas and lower extremity muscle weakness.[6,7] In addition to cauda equina syndrome, cranial nerve palsy is also a rare complication of spinal anesthesia. The most commonly affected cranial nerve is the abducent nerve because of its long intracranial course.[8] Palsies of the oculomotor, facial, trigeminal, and trochlear nerves, as well as transient hypoacusis and Horner syndrome, have also been reported.[9–13] Vagal neuropathy, following spinal anesthesia was first described recently.[2–4] These cranial palsies are typically transient and resolve within weeks to months, but complete neurological recovery after cauda equina syndrome is unusual. The simultaneous occurrence of these 2 rare complications in the same patient has not been previously reported. This report describes the case of a patient who simultaneously developed both after uneventful spinal-epidural anesthesia with 0.5% hyperbaric bupivacaine. With early diagnosis and appropriate treatment, the patient recovered eventually.
2 Case presentation
A previously healthy 45-year-old female, with no preexisting neurologic deficits, was subjected to surgery because of bilateral hallux valgus. The patient's routine preoperative test results were within normal ranges. Spinal anesthesia was administered at the L3–4 interspace by using a 27-gauge Quincke point spinal needle through an 18-G Tuohy needle. Afterward, 3 ml of 0.5% hyperbaric bupivacaine was injected intrathecally in approximately 15 seconds after the clear cerebrospinal fluid (CSF) without any blood was aspirated. After bupivacaine was injected, an epidural catheter was inserted 4 cm into the epidural space in the cephalad direction via the Tuohy needle. Paraesthesia, back pain or any other signs of nerve irritation was not experienced during needle placement or drug injection. A urinary catheter was inserted before the surgery. The sensory level block was bilateral, symmetric, and caudal to T10 15 minutes after bupivacaine was administered, as assessed via the pinprick method; a complete lower extremity motor block was achieved. The patient's blood pressure decreased transiently from 140/85 mm Hg to 85/60 mm Hg; afterward, 4 mg of ephedrine was provided with hypotension resolution. The patient's arterial pressure remained normal throughout the procedure. Surgical blood loss was not significant. The 90 minutes operation was performed uneventfully. She was discharged to the ward after the operation. Ropivacaine was injected through the epidural catheter to reduce postoperative pain. After a 5 ml bolus of 0.5% ropivacaine was administered, the mixed solution composed of 0.2% ropivacaine and 4 mg/L fentanyl was infused at a basal rate of 2 ml/hour. In addition, patient-controlled epidural analgesia was maintained for almost 2 days (4 ml for 1 push, 30 minutes lockout) by using a disposable pump. The surgical procedure was conducted uneventfully with the patient in the supine position. The final sensory level achieved was T12 bilaterally by pinprick.
After surgery, the patient complained of mild headache. Thereafter, neck stiffness and pain, photophobia, nausea and vomiting also occurred. The next day of the operation, she felt a sudden weakness in her left leg but still able to walk with an assistive device. Then, the weakness increased as well as the right leg. Unexpectedly, she complained of numbness in the gluteal and perianal region. The epidural catheter was removed immediately. According to the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI), which developed by the American Spinal Injury Association (ASIA) and endorsed by the International Spinal Cord Society, is a well-accepted classification of neurologic deficit after Spinal Cord Injury (SCI),[14,15] the examination used dermatomal light touch and pin prick sensation and motor strength of selected muscle groups of the lower extremities to determine the neurologic level of the injury. In the patient, physical examination at that time revealed bilateral lower extremity weakness with 3/5 for left hip flexors and knee extensors; 2/5 for left ankle dorsiflexors and plantar flexors, 1/5 for left extensor hallucis longus; 4/5 for the right hip flexors and knee extensors; 3/5 for right ankle dorsiflexors and plantar flexors, 2/5 for right extensor hallucis longus. Motor scores of the 2 lower limbs were 27 points. Neurological examination documented lower extremity and perianal hypoesthesia and lower extremity hyporeflexia. We defined lower extremity pin prick and light touch scores as the sum of L2 to S5 dermatomes bilaterally (maximum score of 32 points). Pinprick sensation of the left L4-S1 segment, right L4-L5 segment and perianal area in the S3–5 segment was diminished. Pin prick and light touch scores of the left and right lower limbs were 22 and 24 points respectively. The Achilles and patellar reflexes were obviously reduced, and the anal wink reflex was absent in this patient. The anal sphincter tone was decreased. The abdominal reflexes and strength of abdominal wall muscles were bilaterally normal. Three days after surgery, the symptom of headache faded away gradually. The patient was unable to micturate when the urinary catheter was removed on the third postoperative day; as a result, urinary retention (on the third day) and rectal incontinence (on the fourth day) occurred. The bladder was recatheterized because of the urinary retention. Seven days after surgery, Magnetic resonance imaging (MRI) was performed on the lumbosacral area to obtain further information. The MRI revealed no tumor, hematoma, abscess, infarction, spinal stenosis, or cauda equina nerve root compression. Based on the patient's symptoms and MRI findings, cauda equina syndrome was diagnosed. In addition to cauda equina syndrome, she noted onset of hoarseness, effortful voice production and chocking with liquids on postoperative day 5; she believed that her voice had been normal before and immediately after surgery. She subsequently underwent flexible laryngoscopy, which revealed a right vocal fold paralysis. Computed tomography (CT) of the neck and chest was performed 10 days after surgery, which did not reveal any lesions along the recurrent laryngeal nerve. The brain MRI findings showed: diffuse dural enhancement, downward displacement of the brainstem, and diminution of cerebral ventricles, which are typical features of intracranial hypotension (ICH). Stroboscopy performed 15 days after surgery confirmed the finding of an immobile right vocal fold.
The patient was managed conservatively on heavy doses of steroids:[16] methylprednisolone 500 mg intravenously guttae daily for 5 days, then reduced to 80 mg intravenously guttae daily for 10 days. She also underwent a rehabilitation program including traditional Chinese medicine and acupuncture 3 days per week, which aimed to normalize movement patterns. Physical therapy for cauda equine syndrome included static and dynamic control of position, neurophysiologic exercises, progressive ambulation, balance skills, and activities of daily living. Clean intermittent self-catheterization 3 times a day was started for neurogenic bladder. Vocal therapy in unilateral vocal fold paralysis consisted of electrotherapy, hard glottal attacks and pushing exercises, half-swallow boom, accent method, lip and tongue trills. After 2 months, her lower extremity motor strength significantly improved and the sensation of the 2 lower limbs recovered gradually except hypoesthesia in the S3–5 segment. Motor scores of the 2 lower limbs were 45 points; pin prick and light touch scores of the left and right lower limbs were 26 and 28 points, respectively. At the 3-month follow-up, the patient had regained 5/5 strength in all motor groups, could walk normally without any assistive devices and perianal sensation somehow returned. At the 11-month follow-up, the patient recovered from urinary retention and fecal incontinence. In addition, a laryngeal electromyography, performed at 3 months following surgery, showed evidence of denervation of the right thyroarytenoid (innervated by the recurrent laryngeal nerve) and cricothyroid muscle (innervated by the superior laryngeal nerve), consistent with a right vagal neuropathy; at 7-month follow-up, the patient reported that her voice quality improved to near normal and only mild residual paresis was noted on stroboscopy.
3 Discussion and conclusions
The patient developed cauda equina syndrome characterized by urinary retention and fecal incontinence, perianal sensory loss, and lower extremity weakness after uneventful routine spinal-epidural anesthesia. She simultaneously developed a right vocal fold paralysis. Although these major complications rarely occur after spinal-epidural anesthesia, the described patient developed both.
Various possible causes achieved vocal fold paralysis. It may be infectious, neoplastic, or idiopathic in origin. There was no evidence of infection in this case. The CT ruled out the possibility of neoplasm. At first glance, this case of vocal fold paralysis may be classified as idiopathic because spinal anesthesia is generally not considered in the differential diagnosis of vocal fold paralysis. However, a causal relationship may be considered according to the documented occurrence of upper cranial neuropathy as a result of spinal anesthesia, especially in the absence of other important contributing factors. The onset of symptoms is consistent with previously reported cases of cranial neuropathy following spinal anesthesia. Guardiani et al[2] reported 4 cases of vocal fold paralysis after spinal anesthesia. Cranial nerve palsy following subarachnoid block or unintentional dural puncture has been attributed to CSF depletion and ICH, which appears to be the cause of vocal fold palsy.[13] ICH is a clinical syndrome characterized by postural headache and low CSF opening pressure. Symptoms may include nausea, vomiting, nuchal pain, dizziness, tinnitus, nystagmus, and blurred vision.[3] The MRI findings of ICH are diffuse pachymeningeal enhancement, subdural effusion, engorgement of venous sinuses, pituitary enlargement, and herniation of the cerebellar tonsils.[17] It has been explained on the basis of CSF loss causing sagging of the brain and stretching of the nerve.[18] The brain descends caudally to a vertical position, which may harm the cranial nerves that anchor the brain to the skull. In the described patient, laryngeal electromyography suggested a vagal lesion, in light of the evidence of denervation of both the cricothyroid and thyroarytenoid muscle, rather than an isolated neuropathy of the recurrent laryngeal nerve; this supports the hypothesis of traction on the vagal nerve rather than an idiopathic palsy, the majority of which are recurrent nerve phenomena. Therefore, the decrease in intracranial CSF pressure may have contributed to the presentation, which may induce stretching of the vagal nerve bilaterally. In this case, only the right vocal fold was immobile, therefore, the vagal nerve could be stretched with 1 side more affected than the other. Hypotension during surgery may also serve as a contributing factor to this complication because vascular perfusion of nerve fibers might be compromised. Thus the explanation for vocal fold paralysis is uncertain and consequently speculative.
Cauda equina syndrome is a rare but an extremely distressing complication of spinal-epidural anesthesia.[19–21] Most neurological complications are caused by epidural hematoma, abscess, catheter trauma, infection, and anesthetic toxicity. In the patient, the MRI revealed no hematoma, abscess, infarction, spinal stenosis, or lumbar disc herniation. Direct nerve damage may contribute to the onset of neurological symptoms; disposable needle tips are very sharp, nerve fibers can easily be injured by them. Most neural injuries are associated with either paraesthesia or pain upon injection.[22] However, direct damage to the spinal cord via dural puncture is unlikely the cause of the condition observed in the patient because neurologic pain or paraesthesia was not experienced during needle insertion.[23,24] Spinal cord compression caused by an expanding hematoma was excluded through MRI. Infection was not observed because the patient did not manifest clinical signs or laboratory abnormality corresponding to infection. Dural blood flow is significantly reduced in animals once epinephrine is added to local anesthetic solutions.[25] However, spinal cord ischemia was unlikely observed in this case because epinephrine that can induce vascular contraction was not administered, the patient did not suffer from microvascular disease and was hemodynamically stable perioperatively.[26] Rigler et al[27] postulated that a combination of trauma, maldistribution, and relatively high dose of local anesthetic resulted in neurotoxic injury. Most cauda equina syndrome cases following spinal anesthesia are reportedly associated with toxicity of local anesthetics, especially lidocaine. Limited cephalad extension of sensory blocks suggests restricted diffuse of lidocaine in the cerebrospinal fluid and is likely to induce anesthetic neurotoxicity. Several cases of cauda equina syndrome following spinal anesthesia with bupivacaine have been reported. Kato et al[28] reported a cauda equina syndrome case following spinal anesthesia with bupivacaine and epidural anesthesia with ropivacaine, which took 10 months to recover. Similarly, Chabbou et al[29] reported a cauda equina syndrome case following spinal anesthesia with 0.5% hyperbaric bupivacaine without any causative factors in the genesis of the syndrome. Therefore, based on the patient's symptoms and MRI findings, the outcome was probably caused by the neurotoxicity of bupivacaine alone or in combination with ropivacaine. In contrast to other patients, the patient in this report recovered almost completely. This may be the result of the early detection and therapy of the neurologic complication.
In summary, the case highlights that 2 rare and serious complications of spinal-epidural anesthesia can even occur in the same patient after uneventful surgery and block performance. The neurotoxicity of local anesthetics, even with normal dose, is suggested as the most likely cause of cauda equina syndrome, and ICH caused by leakage of CSF serves as a potential factor in causing vocal fold paralysis. Therefore, detailed physical examination, and monitoring recovery of sensory and motor functions following spinal-epidural anesthesia are significant for early detection and therapy of neurologic complications. Notably, practitioners should detect and deal with these rare types of neurologic complications as early as possible, the patient should be investigated thoroughly, and appropriate treatment and rehabilitation program should be initiated promptly. In this patient, early diagnosis and intervention of vocal fold paralysis is crucial to manage it; otherwise, permanent injuries may likely occur.
Author contributions
Conceptualization: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Data curation: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Formal analysis: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Investigation: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Methodology: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Project administration: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Resources: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Software: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Supervision: Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Validation: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Visualization: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Writing – original draft: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Writing – review & editing: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Abbreviations: ASIA = American Spinal Injury Association, CSF = cerebrospinal fluid, CT = computed tomography, ICH = intracranial hypotension, ISNCSCI = the International Standards for Neurological Classification of Spinal Cord Injury, MRI = magnetic resonance imaging, SCI = spinal cord injury.
How to cite this article: Xiang Y, Wang W, Jing S, Zhang Z, Wang D. Vocal fold paralysis and cauda equina syndrome following spinal-epidural anesthesia: a case report. Medicine. 2021;100:3(e24374).
Written consent was obtained from the patient for the purpose of publication of case details and images.
The authors have no conflicts of interests to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. | Epidural | DrugAdministrationRoute | CC BY | 33546075 | 18,981,348 | 2021-01-22 |
What was the dosage of drug 'ROPIVACAINE'? | Vocal fold paralysis and cauda equina syndrome following spinal-epidural anesthesia: A case report.
BACKGROUND
Vocal fold paralysis and cauda equina syndrome are very rare neurologic deficits. This report describes the case of a patient who simultaneously developed both after uneventful spinal-epidural anesthesia with 0.5% hyperbaric bupivacaine.
We report the case of a 45-year-old female, who underwent surgery for bilateral hallux valgus developed cauda equina syndrome and unilateral vocal fold paralysis after uneventful spinal-epidural anesthesia was administered. There was no pain or paresthesia during needle placement or drug injection. Surgery was performed uneventfully.
Right vocal fold paralysis was diagnosed with flexible laryngoscopy.
METHODS
Patient was started on the treatment with a surgery for bilateral hallux valgus, who developed cauda equina syndrome and unilateral vocal fold paralysis after uneventful spinal-epidural anesthesia was administered.
RESULTS
Postoperatively, she had difficulty in urination and defecation. In addition, she developed unilateral vocal fold paralysis characterized by hoarseness, effortful voice production, and choking with liquids. Magnetic resonance imaging performed on the lumbosacral area and computed tomography of the neck, the chest, and the skull revealed entirely normal results. However, flexible laryngoscopy revealed a right vocal fold paralysis. Although cauda equina syndrome can occur due to neurotoxicity of local anesthetics, the exact etiology of vocal fold paralysis is uncertain.
CONCLUSIONS
The case highlights that 2 rare and serious complications of spinal-epidural anesthesia can even occur in the same patient after uneventful surgery and block performance.
1 Introduction
Regional anesthesia for lower limb surgeries is generally held to be inherently safe. Spinal and epidural blocks are therefore used widely, with the more recently introduced combined spinal and epidural technique gaining popularity. Serious neurologic deficits such as cauda equine syndrome and vocal fold paralysis after spinal anesthesia are relatively rare.[1–4] Cauda equina syndrome is a serious neurologic disorder that is caused by damage of the lumbosacral and coccygeal nerve roots which include the ascending and descending nerve roots from L2 through the coccygeal segments. These nerves control lower limb movement (L2-S2), lower limb sensation (L2-S3), bladder control (S2-S4), external analsphincter control (S2-S4), external genitalia and perianal sensation (S2-S4), and coccygeal sensation (S4, S5, and the coccygeal nerve).[5] Cauda equina syndrome is associated with varying degrees of signs and symptoms including loss of bowel and bladder function, insensate perineal areas and lower extremity muscle weakness.[6,7] In addition to cauda equina syndrome, cranial nerve palsy is also a rare complication of spinal anesthesia. The most commonly affected cranial nerve is the abducent nerve because of its long intracranial course.[8] Palsies of the oculomotor, facial, trigeminal, and trochlear nerves, as well as transient hypoacusis and Horner syndrome, have also been reported.[9–13] Vagal neuropathy, following spinal anesthesia was first described recently.[2–4] These cranial palsies are typically transient and resolve within weeks to months, but complete neurological recovery after cauda equina syndrome is unusual. The simultaneous occurrence of these 2 rare complications in the same patient has not been previously reported. This report describes the case of a patient who simultaneously developed both after uneventful spinal-epidural anesthesia with 0.5% hyperbaric bupivacaine. With early diagnosis and appropriate treatment, the patient recovered eventually.
2 Case presentation
A previously healthy 45-year-old female, with no preexisting neurologic deficits, was subjected to surgery because of bilateral hallux valgus. The patient's routine preoperative test results were within normal ranges. Spinal anesthesia was administered at the L3–4 interspace by using a 27-gauge Quincke point spinal needle through an 18-G Tuohy needle. Afterward, 3 ml of 0.5% hyperbaric bupivacaine was injected intrathecally in approximately 15 seconds after the clear cerebrospinal fluid (CSF) without any blood was aspirated. After bupivacaine was injected, an epidural catheter was inserted 4 cm into the epidural space in the cephalad direction via the Tuohy needle. Paraesthesia, back pain or any other signs of nerve irritation was not experienced during needle placement or drug injection. A urinary catheter was inserted before the surgery. The sensory level block was bilateral, symmetric, and caudal to T10 15 minutes after bupivacaine was administered, as assessed via the pinprick method; a complete lower extremity motor block was achieved. The patient's blood pressure decreased transiently from 140/85 mm Hg to 85/60 mm Hg; afterward, 4 mg of ephedrine was provided with hypotension resolution. The patient's arterial pressure remained normal throughout the procedure. Surgical blood loss was not significant. The 90 minutes operation was performed uneventfully. She was discharged to the ward after the operation. Ropivacaine was injected through the epidural catheter to reduce postoperative pain. After a 5 ml bolus of 0.5% ropivacaine was administered, the mixed solution composed of 0.2% ropivacaine and 4 mg/L fentanyl was infused at a basal rate of 2 ml/hour. In addition, patient-controlled epidural analgesia was maintained for almost 2 days (4 ml for 1 push, 30 minutes lockout) by using a disposable pump. The surgical procedure was conducted uneventfully with the patient in the supine position. The final sensory level achieved was T12 bilaterally by pinprick.
After surgery, the patient complained of mild headache. Thereafter, neck stiffness and pain, photophobia, nausea and vomiting also occurred. The next day of the operation, she felt a sudden weakness in her left leg but still able to walk with an assistive device. Then, the weakness increased as well as the right leg. Unexpectedly, she complained of numbness in the gluteal and perianal region. The epidural catheter was removed immediately. According to the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI), which developed by the American Spinal Injury Association (ASIA) and endorsed by the International Spinal Cord Society, is a well-accepted classification of neurologic deficit after Spinal Cord Injury (SCI),[14,15] the examination used dermatomal light touch and pin prick sensation and motor strength of selected muscle groups of the lower extremities to determine the neurologic level of the injury. In the patient, physical examination at that time revealed bilateral lower extremity weakness with 3/5 for left hip flexors and knee extensors; 2/5 for left ankle dorsiflexors and plantar flexors, 1/5 for left extensor hallucis longus; 4/5 for the right hip flexors and knee extensors; 3/5 for right ankle dorsiflexors and plantar flexors, 2/5 for right extensor hallucis longus. Motor scores of the 2 lower limbs were 27 points. Neurological examination documented lower extremity and perianal hypoesthesia and lower extremity hyporeflexia. We defined lower extremity pin prick and light touch scores as the sum of L2 to S5 dermatomes bilaterally (maximum score of 32 points). Pinprick sensation of the left L4-S1 segment, right L4-L5 segment and perianal area in the S3–5 segment was diminished. Pin prick and light touch scores of the left and right lower limbs were 22 and 24 points respectively. The Achilles and patellar reflexes were obviously reduced, and the anal wink reflex was absent in this patient. The anal sphincter tone was decreased. The abdominal reflexes and strength of abdominal wall muscles were bilaterally normal. Three days after surgery, the symptom of headache faded away gradually. The patient was unable to micturate when the urinary catheter was removed on the third postoperative day; as a result, urinary retention (on the third day) and rectal incontinence (on the fourth day) occurred. The bladder was recatheterized because of the urinary retention. Seven days after surgery, Magnetic resonance imaging (MRI) was performed on the lumbosacral area to obtain further information. The MRI revealed no tumor, hematoma, abscess, infarction, spinal stenosis, or cauda equina nerve root compression. Based on the patient's symptoms and MRI findings, cauda equina syndrome was diagnosed. In addition to cauda equina syndrome, she noted onset of hoarseness, effortful voice production and chocking with liquids on postoperative day 5; she believed that her voice had been normal before and immediately after surgery. She subsequently underwent flexible laryngoscopy, which revealed a right vocal fold paralysis. Computed tomography (CT) of the neck and chest was performed 10 days after surgery, which did not reveal any lesions along the recurrent laryngeal nerve. The brain MRI findings showed: diffuse dural enhancement, downward displacement of the brainstem, and diminution of cerebral ventricles, which are typical features of intracranial hypotension (ICH). Stroboscopy performed 15 days after surgery confirmed the finding of an immobile right vocal fold.
The patient was managed conservatively on heavy doses of steroids:[16] methylprednisolone 500 mg intravenously guttae daily for 5 days, then reduced to 80 mg intravenously guttae daily for 10 days. She also underwent a rehabilitation program including traditional Chinese medicine and acupuncture 3 days per week, which aimed to normalize movement patterns. Physical therapy for cauda equine syndrome included static and dynamic control of position, neurophysiologic exercises, progressive ambulation, balance skills, and activities of daily living. Clean intermittent self-catheterization 3 times a day was started for neurogenic bladder. Vocal therapy in unilateral vocal fold paralysis consisted of electrotherapy, hard glottal attacks and pushing exercises, half-swallow boom, accent method, lip and tongue trills. After 2 months, her lower extremity motor strength significantly improved and the sensation of the 2 lower limbs recovered gradually except hypoesthesia in the S3–5 segment. Motor scores of the 2 lower limbs were 45 points; pin prick and light touch scores of the left and right lower limbs were 26 and 28 points, respectively. At the 3-month follow-up, the patient had regained 5/5 strength in all motor groups, could walk normally without any assistive devices and perianal sensation somehow returned. At the 11-month follow-up, the patient recovered from urinary retention and fecal incontinence. In addition, a laryngeal electromyography, performed at 3 months following surgery, showed evidence of denervation of the right thyroarytenoid (innervated by the recurrent laryngeal nerve) and cricothyroid muscle (innervated by the superior laryngeal nerve), consistent with a right vagal neuropathy; at 7-month follow-up, the patient reported that her voice quality improved to near normal and only mild residual paresis was noted on stroboscopy.
3 Discussion and conclusions
The patient developed cauda equina syndrome characterized by urinary retention and fecal incontinence, perianal sensory loss, and lower extremity weakness after uneventful routine spinal-epidural anesthesia. She simultaneously developed a right vocal fold paralysis. Although these major complications rarely occur after spinal-epidural anesthesia, the described patient developed both.
Various possible causes achieved vocal fold paralysis. It may be infectious, neoplastic, or idiopathic in origin. There was no evidence of infection in this case. The CT ruled out the possibility of neoplasm. At first glance, this case of vocal fold paralysis may be classified as idiopathic because spinal anesthesia is generally not considered in the differential diagnosis of vocal fold paralysis. However, a causal relationship may be considered according to the documented occurrence of upper cranial neuropathy as a result of spinal anesthesia, especially in the absence of other important contributing factors. The onset of symptoms is consistent with previously reported cases of cranial neuropathy following spinal anesthesia. Guardiani et al[2] reported 4 cases of vocal fold paralysis after spinal anesthesia. Cranial nerve palsy following subarachnoid block or unintentional dural puncture has been attributed to CSF depletion and ICH, which appears to be the cause of vocal fold palsy.[13] ICH is a clinical syndrome characterized by postural headache and low CSF opening pressure. Symptoms may include nausea, vomiting, nuchal pain, dizziness, tinnitus, nystagmus, and blurred vision.[3] The MRI findings of ICH are diffuse pachymeningeal enhancement, subdural effusion, engorgement of venous sinuses, pituitary enlargement, and herniation of the cerebellar tonsils.[17] It has been explained on the basis of CSF loss causing sagging of the brain and stretching of the nerve.[18] The brain descends caudally to a vertical position, which may harm the cranial nerves that anchor the brain to the skull. In the described patient, laryngeal electromyography suggested a vagal lesion, in light of the evidence of denervation of both the cricothyroid and thyroarytenoid muscle, rather than an isolated neuropathy of the recurrent laryngeal nerve; this supports the hypothesis of traction on the vagal nerve rather than an idiopathic palsy, the majority of which are recurrent nerve phenomena. Therefore, the decrease in intracranial CSF pressure may have contributed to the presentation, which may induce stretching of the vagal nerve bilaterally. In this case, only the right vocal fold was immobile, therefore, the vagal nerve could be stretched with 1 side more affected than the other. Hypotension during surgery may also serve as a contributing factor to this complication because vascular perfusion of nerve fibers might be compromised. Thus the explanation for vocal fold paralysis is uncertain and consequently speculative.
Cauda equina syndrome is a rare but an extremely distressing complication of spinal-epidural anesthesia.[19–21] Most neurological complications are caused by epidural hematoma, abscess, catheter trauma, infection, and anesthetic toxicity. In the patient, the MRI revealed no hematoma, abscess, infarction, spinal stenosis, or lumbar disc herniation. Direct nerve damage may contribute to the onset of neurological symptoms; disposable needle tips are very sharp, nerve fibers can easily be injured by them. Most neural injuries are associated with either paraesthesia or pain upon injection.[22] However, direct damage to the spinal cord via dural puncture is unlikely the cause of the condition observed in the patient because neurologic pain or paraesthesia was not experienced during needle insertion.[23,24] Spinal cord compression caused by an expanding hematoma was excluded through MRI. Infection was not observed because the patient did not manifest clinical signs or laboratory abnormality corresponding to infection. Dural blood flow is significantly reduced in animals once epinephrine is added to local anesthetic solutions.[25] However, spinal cord ischemia was unlikely observed in this case because epinephrine that can induce vascular contraction was not administered, the patient did not suffer from microvascular disease and was hemodynamically stable perioperatively.[26] Rigler et al[27] postulated that a combination of trauma, maldistribution, and relatively high dose of local anesthetic resulted in neurotoxic injury. Most cauda equina syndrome cases following spinal anesthesia are reportedly associated with toxicity of local anesthetics, especially lidocaine. Limited cephalad extension of sensory blocks suggests restricted diffuse of lidocaine in the cerebrospinal fluid and is likely to induce anesthetic neurotoxicity. Several cases of cauda equina syndrome following spinal anesthesia with bupivacaine have been reported. Kato et al[28] reported a cauda equina syndrome case following spinal anesthesia with bupivacaine and epidural anesthesia with ropivacaine, which took 10 months to recover. Similarly, Chabbou et al[29] reported a cauda equina syndrome case following spinal anesthesia with 0.5% hyperbaric bupivacaine without any causative factors in the genesis of the syndrome. Therefore, based on the patient's symptoms and MRI findings, the outcome was probably caused by the neurotoxicity of bupivacaine alone or in combination with ropivacaine. In contrast to other patients, the patient in this report recovered almost completely. This may be the result of the early detection and therapy of the neurologic complication.
In summary, the case highlights that 2 rare and serious complications of spinal-epidural anesthesia can even occur in the same patient after uneventful surgery and block performance. The neurotoxicity of local anesthetics, even with normal dose, is suggested as the most likely cause of cauda equina syndrome, and ICH caused by leakage of CSF serves as a potential factor in causing vocal fold paralysis. Therefore, detailed physical examination, and monitoring recovery of sensory and motor functions following spinal-epidural anesthesia are significant for early detection and therapy of neurologic complications. Notably, practitioners should detect and deal with these rare types of neurologic complications as early as possible, the patient should be investigated thoroughly, and appropriate treatment and rehabilitation program should be initiated promptly. In this patient, early diagnosis and intervention of vocal fold paralysis is crucial to manage it; otherwise, permanent injuries may likely occur.
Author contributions
Conceptualization: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Data curation: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Formal analysis: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Investigation: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Methodology: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Project administration: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Resources: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Software: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Supervision: Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Validation: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Visualization: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Writing – original draft: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Writing – review & editing: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Abbreviations: ASIA = American Spinal Injury Association, CSF = cerebrospinal fluid, CT = computed tomography, ICH = intracranial hypotension, ISNCSCI = the International Standards for Neurological Classification of Spinal Cord Injury, MRI = magnetic resonance imaging, SCI = spinal cord injury.
How to cite this article: Xiang Y, Wang W, Jing S, Zhang Z, Wang D. Vocal fold paralysis and cauda equina syndrome following spinal-epidural anesthesia: a case report. Medicine. 2021;100:3(e24374).
Written consent was obtained from the patient for the purpose of publication of case details and images.
The authors have no conflicts of interests to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. | MIXED SOLUTION WITH 4MG/L FENTANYL AT A BASAL RATE OF 2ML/HOUR | DrugDosageText | CC BY | 33546075 | 18,981,348 | 2021-01-22 |
What was the outcome of reaction 'Hypotension'? | Vocal fold paralysis and cauda equina syndrome following spinal-epidural anesthesia: A case report.
BACKGROUND
Vocal fold paralysis and cauda equina syndrome are very rare neurologic deficits. This report describes the case of a patient who simultaneously developed both after uneventful spinal-epidural anesthesia with 0.5% hyperbaric bupivacaine.
We report the case of a 45-year-old female, who underwent surgery for bilateral hallux valgus developed cauda equina syndrome and unilateral vocal fold paralysis after uneventful spinal-epidural anesthesia was administered. There was no pain or paresthesia during needle placement or drug injection. Surgery was performed uneventfully.
Right vocal fold paralysis was diagnosed with flexible laryngoscopy.
METHODS
Patient was started on the treatment with a surgery for bilateral hallux valgus, who developed cauda equina syndrome and unilateral vocal fold paralysis after uneventful spinal-epidural anesthesia was administered.
RESULTS
Postoperatively, she had difficulty in urination and defecation. In addition, she developed unilateral vocal fold paralysis characterized by hoarseness, effortful voice production, and choking with liquids. Magnetic resonance imaging performed on the lumbosacral area and computed tomography of the neck, the chest, and the skull revealed entirely normal results. However, flexible laryngoscopy revealed a right vocal fold paralysis. Although cauda equina syndrome can occur due to neurotoxicity of local anesthetics, the exact etiology of vocal fold paralysis is uncertain.
CONCLUSIONS
The case highlights that 2 rare and serious complications of spinal-epidural anesthesia can even occur in the same patient after uneventful surgery and block performance.
1 Introduction
Regional anesthesia for lower limb surgeries is generally held to be inherently safe. Spinal and epidural blocks are therefore used widely, with the more recently introduced combined spinal and epidural technique gaining popularity. Serious neurologic deficits such as cauda equine syndrome and vocal fold paralysis after spinal anesthesia are relatively rare.[1–4] Cauda equina syndrome is a serious neurologic disorder that is caused by damage of the lumbosacral and coccygeal nerve roots which include the ascending and descending nerve roots from L2 through the coccygeal segments. These nerves control lower limb movement (L2-S2), lower limb sensation (L2-S3), bladder control (S2-S4), external analsphincter control (S2-S4), external genitalia and perianal sensation (S2-S4), and coccygeal sensation (S4, S5, and the coccygeal nerve).[5] Cauda equina syndrome is associated with varying degrees of signs and symptoms including loss of bowel and bladder function, insensate perineal areas and lower extremity muscle weakness.[6,7] In addition to cauda equina syndrome, cranial nerve palsy is also a rare complication of spinal anesthesia. The most commonly affected cranial nerve is the abducent nerve because of its long intracranial course.[8] Palsies of the oculomotor, facial, trigeminal, and trochlear nerves, as well as transient hypoacusis and Horner syndrome, have also been reported.[9–13] Vagal neuropathy, following spinal anesthesia was first described recently.[2–4] These cranial palsies are typically transient and resolve within weeks to months, but complete neurological recovery after cauda equina syndrome is unusual. The simultaneous occurrence of these 2 rare complications in the same patient has not been previously reported. This report describes the case of a patient who simultaneously developed both after uneventful spinal-epidural anesthesia with 0.5% hyperbaric bupivacaine. With early diagnosis and appropriate treatment, the patient recovered eventually.
2 Case presentation
A previously healthy 45-year-old female, with no preexisting neurologic deficits, was subjected to surgery because of bilateral hallux valgus. The patient's routine preoperative test results were within normal ranges. Spinal anesthesia was administered at the L3–4 interspace by using a 27-gauge Quincke point spinal needle through an 18-G Tuohy needle. Afterward, 3 ml of 0.5% hyperbaric bupivacaine was injected intrathecally in approximately 15 seconds after the clear cerebrospinal fluid (CSF) without any blood was aspirated. After bupivacaine was injected, an epidural catheter was inserted 4 cm into the epidural space in the cephalad direction via the Tuohy needle. Paraesthesia, back pain or any other signs of nerve irritation was not experienced during needle placement or drug injection. A urinary catheter was inserted before the surgery. The sensory level block was bilateral, symmetric, and caudal to T10 15 minutes after bupivacaine was administered, as assessed via the pinprick method; a complete lower extremity motor block was achieved. The patient's blood pressure decreased transiently from 140/85 mm Hg to 85/60 mm Hg; afterward, 4 mg of ephedrine was provided with hypotension resolution. The patient's arterial pressure remained normal throughout the procedure. Surgical blood loss was not significant. The 90 minutes operation was performed uneventfully. She was discharged to the ward after the operation. Ropivacaine was injected through the epidural catheter to reduce postoperative pain. After a 5 ml bolus of 0.5% ropivacaine was administered, the mixed solution composed of 0.2% ropivacaine and 4 mg/L fentanyl was infused at a basal rate of 2 ml/hour. In addition, patient-controlled epidural analgesia was maintained for almost 2 days (4 ml for 1 push, 30 minutes lockout) by using a disposable pump. The surgical procedure was conducted uneventfully with the patient in the supine position. The final sensory level achieved was T12 bilaterally by pinprick.
After surgery, the patient complained of mild headache. Thereafter, neck stiffness and pain, photophobia, nausea and vomiting also occurred. The next day of the operation, she felt a sudden weakness in her left leg but still able to walk with an assistive device. Then, the weakness increased as well as the right leg. Unexpectedly, she complained of numbness in the gluteal and perianal region. The epidural catheter was removed immediately. According to the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI), which developed by the American Spinal Injury Association (ASIA) and endorsed by the International Spinal Cord Society, is a well-accepted classification of neurologic deficit after Spinal Cord Injury (SCI),[14,15] the examination used dermatomal light touch and pin prick sensation and motor strength of selected muscle groups of the lower extremities to determine the neurologic level of the injury. In the patient, physical examination at that time revealed bilateral lower extremity weakness with 3/5 for left hip flexors and knee extensors; 2/5 for left ankle dorsiflexors and plantar flexors, 1/5 for left extensor hallucis longus; 4/5 for the right hip flexors and knee extensors; 3/5 for right ankle dorsiflexors and plantar flexors, 2/5 for right extensor hallucis longus. Motor scores of the 2 lower limbs were 27 points. Neurological examination documented lower extremity and perianal hypoesthesia and lower extremity hyporeflexia. We defined lower extremity pin prick and light touch scores as the sum of L2 to S5 dermatomes bilaterally (maximum score of 32 points). Pinprick sensation of the left L4-S1 segment, right L4-L5 segment and perianal area in the S3–5 segment was diminished. Pin prick and light touch scores of the left and right lower limbs were 22 and 24 points respectively. The Achilles and patellar reflexes were obviously reduced, and the anal wink reflex was absent in this patient. The anal sphincter tone was decreased. The abdominal reflexes and strength of abdominal wall muscles were bilaterally normal. Three days after surgery, the symptom of headache faded away gradually. The patient was unable to micturate when the urinary catheter was removed on the third postoperative day; as a result, urinary retention (on the third day) and rectal incontinence (on the fourth day) occurred. The bladder was recatheterized because of the urinary retention. Seven days after surgery, Magnetic resonance imaging (MRI) was performed on the lumbosacral area to obtain further information. The MRI revealed no tumor, hematoma, abscess, infarction, spinal stenosis, or cauda equina nerve root compression. Based on the patient's symptoms and MRI findings, cauda equina syndrome was diagnosed. In addition to cauda equina syndrome, she noted onset of hoarseness, effortful voice production and chocking with liquids on postoperative day 5; she believed that her voice had been normal before and immediately after surgery. She subsequently underwent flexible laryngoscopy, which revealed a right vocal fold paralysis. Computed tomography (CT) of the neck and chest was performed 10 days after surgery, which did not reveal any lesions along the recurrent laryngeal nerve. The brain MRI findings showed: diffuse dural enhancement, downward displacement of the brainstem, and diminution of cerebral ventricles, which are typical features of intracranial hypotension (ICH). Stroboscopy performed 15 days after surgery confirmed the finding of an immobile right vocal fold.
The patient was managed conservatively on heavy doses of steroids:[16] methylprednisolone 500 mg intravenously guttae daily for 5 days, then reduced to 80 mg intravenously guttae daily for 10 days. She also underwent a rehabilitation program including traditional Chinese medicine and acupuncture 3 days per week, which aimed to normalize movement patterns. Physical therapy for cauda equine syndrome included static and dynamic control of position, neurophysiologic exercises, progressive ambulation, balance skills, and activities of daily living. Clean intermittent self-catheterization 3 times a day was started for neurogenic bladder. Vocal therapy in unilateral vocal fold paralysis consisted of electrotherapy, hard glottal attacks and pushing exercises, half-swallow boom, accent method, lip and tongue trills. After 2 months, her lower extremity motor strength significantly improved and the sensation of the 2 lower limbs recovered gradually except hypoesthesia in the S3–5 segment. Motor scores of the 2 lower limbs were 45 points; pin prick and light touch scores of the left and right lower limbs were 26 and 28 points, respectively. At the 3-month follow-up, the patient had regained 5/5 strength in all motor groups, could walk normally without any assistive devices and perianal sensation somehow returned. At the 11-month follow-up, the patient recovered from urinary retention and fecal incontinence. In addition, a laryngeal electromyography, performed at 3 months following surgery, showed evidence of denervation of the right thyroarytenoid (innervated by the recurrent laryngeal nerve) and cricothyroid muscle (innervated by the superior laryngeal nerve), consistent with a right vagal neuropathy; at 7-month follow-up, the patient reported that her voice quality improved to near normal and only mild residual paresis was noted on stroboscopy.
3 Discussion and conclusions
The patient developed cauda equina syndrome characterized by urinary retention and fecal incontinence, perianal sensory loss, and lower extremity weakness after uneventful routine spinal-epidural anesthesia. She simultaneously developed a right vocal fold paralysis. Although these major complications rarely occur after spinal-epidural anesthesia, the described patient developed both.
Various possible causes achieved vocal fold paralysis. It may be infectious, neoplastic, or idiopathic in origin. There was no evidence of infection in this case. The CT ruled out the possibility of neoplasm. At first glance, this case of vocal fold paralysis may be classified as idiopathic because spinal anesthesia is generally not considered in the differential diagnosis of vocal fold paralysis. However, a causal relationship may be considered according to the documented occurrence of upper cranial neuropathy as a result of spinal anesthesia, especially in the absence of other important contributing factors. The onset of symptoms is consistent with previously reported cases of cranial neuropathy following spinal anesthesia. Guardiani et al[2] reported 4 cases of vocal fold paralysis after spinal anesthesia. Cranial nerve palsy following subarachnoid block or unintentional dural puncture has been attributed to CSF depletion and ICH, which appears to be the cause of vocal fold palsy.[13] ICH is a clinical syndrome characterized by postural headache and low CSF opening pressure. Symptoms may include nausea, vomiting, nuchal pain, dizziness, tinnitus, nystagmus, and blurred vision.[3] The MRI findings of ICH are diffuse pachymeningeal enhancement, subdural effusion, engorgement of venous sinuses, pituitary enlargement, and herniation of the cerebellar tonsils.[17] It has been explained on the basis of CSF loss causing sagging of the brain and stretching of the nerve.[18] The brain descends caudally to a vertical position, which may harm the cranial nerves that anchor the brain to the skull. In the described patient, laryngeal electromyography suggested a vagal lesion, in light of the evidence of denervation of both the cricothyroid and thyroarytenoid muscle, rather than an isolated neuropathy of the recurrent laryngeal nerve; this supports the hypothesis of traction on the vagal nerve rather than an idiopathic palsy, the majority of which are recurrent nerve phenomena. Therefore, the decrease in intracranial CSF pressure may have contributed to the presentation, which may induce stretching of the vagal nerve bilaterally. In this case, only the right vocal fold was immobile, therefore, the vagal nerve could be stretched with 1 side more affected than the other. Hypotension during surgery may also serve as a contributing factor to this complication because vascular perfusion of nerve fibers might be compromised. Thus the explanation for vocal fold paralysis is uncertain and consequently speculative.
Cauda equina syndrome is a rare but an extremely distressing complication of spinal-epidural anesthesia.[19–21] Most neurological complications are caused by epidural hematoma, abscess, catheter trauma, infection, and anesthetic toxicity. In the patient, the MRI revealed no hematoma, abscess, infarction, spinal stenosis, or lumbar disc herniation. Direct nerve damage may contribute to the onset of neurological symptoms; disposable needle tips are very sharp, nerve fibers can easily be injured by them. Most neural injuries are associated with either paraesthesia or pain upon injection.[22] However, direct damage to the spinal cord via dural puncture is unlikely the cause of the condition observed in the patient because neurologic pain or paraesthesia was not experienced during needle insertion.[23,24] Spinal cord compression caused by an expanding hematoma was excluded through MRI. Infection was not observed because the patient did not manifest clinical signs or laboratory abnormality corresponding to infection. Dural blood flow is significantly reduced in animals once epinephrine is added to local anesthetic solutions.[25] However, spinal cord ischemia was unlikely observed in this case because epinephrine that can induce vascular contraction was not administered, the patient did not suffer from microvascular disease and was hemodynamically stable perioperatively.[26] Rigler et al[27] postulated that a combination of trauma, maldistribution, and relatively high dose of local anesthetic resulted in neurotoxic injury. Most cauda equina syndrome cases following spinal anesthesia are reportedly associated with toxicity of local anesthetics, especially lidocaine. Limited cephalad extension of sensory blocks suggests restricted diffuse of lidocaine in the cerebrospinal fluid and is likely to induce anesthetic neurotoxicity. Several cases of cauda equina syndrome following spinal anesthesia with bupivacaine have been reported. Kato et al[28] reported a cauda equina syndrome case following spinal anesthesia with bupivacaine and epidural anesthesia with ropivacaine, which took 10 months to recover. Similarly, Chabbou et al[29] reported a cauda equina syndrome case following spinal anesthesia with 0.5% hyperbaric bupivacaine without any causative factors in the genesis of the syndrome. Therefore, based on the patient's symptoms and MRI findings, the outcome was probably caused by the neurotoxicity of bupivacaine alone or in combination with ropivacaine. In contrast to other patients, the patient in this report recovered almost completely. This may be the result of the early detection and therapy of the neurologic complication.
In summary, the case highlights that 2 rare and serious complications of spinal-epidural anesthesia can even occur in the same patient after uneventful surgery and block performance. The neurotoxicity of local anesthetics, even with normal dose, is suggested as the most likely cause of cauda equina syndrome, and ICH caused by leakage of CSF serves as a potential factor in causing vocal fold paralysis. Therefore, detailed physical examination, and monitoring recovery of sensory and motor functions following spinal-epidural anesthesia are significant for early detection and therapy of neurologic complications. Notably, practitioners should detect and deal with these rare types of neurologic complications as early as possible, the patient should be investigated thoroughly, and appropriate treatment and rehabilitation program should be initiated promptly. In this patient, early diagnosis and intervention of vocal fold paralysis is crucial to manage it; otherwise, permanent injuries may likely occur.
Author contributions
Conceptualization: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Data curation: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Formal analysis: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Investigation: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Methodology: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Project administration: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Resources: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Software: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Supervision: Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Validation: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Visualization: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Writing – original draft: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Writing – review & editing: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Abbreviations: ASIA = American Spinal Injury Association, CSF = cerebrospinal fluid, CT = computed tomography, ICH = intracranial hypotension, ISNCSCI = the International Standards for Neurological Classification of Spinal Cord Injury, MRI = magnetic resonance imaging, SCI = spinal cord injury.
How to cite this article: Xiang Y, Wang W, Jing S, Zhang Z, Wang D. Vocal fold paralysis and cauda equina syndrome following spinal-epidural anesthesia: a case report. Medicine. 2021;100:3(e24374).
Written consent was obtained from the patient for the purpose of publication of case details and images.
The authors have no conflicts of interests to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. | Recovered | ReactionOutcome | CC BY | 33546075 | 18,981,348 | 2021-01-22 |
What was the outcome of reaction 'Intracranial hypotension'? | Vocal fold paralysis and cauda equina syndrome following spinal-epidural anesthesia: A case report.
BACKGROUND
Vocal fold paralysis and cauda equina syndrome are very rare neurologic deficits. This report describes the case of a patient who simultaneously developed both after uneventful spinal-epidural anesthesia with 0.5% hyperbaric bupivacaine.
We report the case of a 45-year-old female, who underwent surgery for bilateral hallux valgus developed cauda equina syndrome and unilateral vocal fold paralysis after uneventful spinal-epidural anesthesia was administered. There was no pain or paresthesia during needle placement or drug injection. Surgery was performed uneventfully.
Right vocal fold paralysis was diagnosed with flexible laryngoscopy.
METHODS
Patient was started on the treatment with a surgery for bilateral hallux valgus, who developed cauda equina syndrome and unilateral vocal fold paralysis after uneventful spinal-epidural anesthesia was administered.
RESULTS
Postoperatively, she had difficulty in urination and defecation. In addition, she developed unilateral vocal fold paralysis characterized by hoarseness, effortful voice production, and choking with liquids. Magnetic resonance imaging performed on the lumbosacral area and computed tomography of the neck, the chest, and the skull revealed entirely normal results. However, flexible laryngoscopy revealed a right vocal fold paralysis. Although cauda equina syndrome can occur due to neurotoxicity of local anesthetics, the exact etiology of vocal fold paralysis is uncertain.
CONCLUSIONS
The case highlights that 2 rare and serious complications of spinal-epidural anesthesia can even occur in the same patient after uneventful surgery and block performance.
1 Introduction
Regional anesthesia for lower limb surgeries is generally held to be inherently safe. Spinal and epidural blocks are therefore used widely, with the more recently introduced combined spinal and epidural technique gaining popularity. Serious neurologic deficits such as cauda equine syndrome and vocal fold paralysis after spinal anesthesia are relatively rare.[1–4] Cauda equina syndrome is a serious neurologic disorder that is caused by damage of the lumbosacral and coccygeal nerve roots which include the ascending and descending nerve roots from L2 through the coccygeal segments. These nerves control lower limb movement (L2-S2), lower limb sensation (L2-S3), bladder control (S2-S4), external analsphincter control (S2-S4), external genitalia and perianal sensation (S2-S4), and coccygeal sensation (S4, S5, and the coccygeal nerve).[5] Cauda equina syndrome is associated with varying degrees of signs and symptoms including loss of bowel and bladder function, insensate perineal areas and lower extremity muscle weakness.[6,7] In addition to cauda equina syndrome, cranial nerve palsy is also a rare complication of spinal anesthesia. The most commonly affected cranial nerve is the abducent nerve because of its long intracranial course.[8] Palsies of the oculomotor, facial, trigeminal, and trochlear nerves, as well as transient hypoacusis and Horner syndrome, have also been reported.[9–13] Vagal neuropathy, following spinal anesthesia was first described recently.[2–4] These cranial palsies are typically transient and resolve within weeks to months, but complete neurological recovery after cauda equina syndrome is unusual. The simultaneous occurrence of these 2 rare complications in the same patient has not been previously reported. This report describes the case of a patient who simultaneously developed both after uneventful spinal-epidural anesthesia with 0.5% hyperbaric bupivacaine. With early diagnosis and appropriate treatment, the patient recovered eventually.
2 Case presentation
A previously healthy 45-year-old female, with no preexisting neurologic deficits, was subjected to surgery because of bilateral hallux valgus. The patient's routine preoperative test results were within normal ranges. Spinal anesthesia was administered at the L3–4 interspace by using a 27-gauge Quincke point spinal needle through an 18-G Tuohy needle. Afterward, 3 ml of 0.5% hyperbaric bupivacaine was injected intrathecally in approximately 15 seconds after the clear cerebrospinal fluid (CSF) without any blood was aspirated. After bupivacaine was injected, an epidural catheter was inserted 4 cm into the epidural space in the cephalad direction via the Tuohy needle. Paraesthesia, back pain or any other signs of nerve irritation was not experienced during needle placement or drug injection. A urinary catheter was inserted before the surgery. The sensory level block was bilateral, symmetric, and caudal to T10 15 minutes after bupivacaine was administered, as assessed via the pinprick method; a complete lower extremity motor block was achieved. The patient's blood pressure decreased transiently from 140/85 mm Hg to 85/60 mm Hg; afterward, 4 mg of ephedrine was provided with hypotension resolution. The patient's arterial pressure remained normal throughout the procedure. Surgical blood loss was not significant. The 90 minutes operation was performed uneventfully. She was discharged to the ward after the operation. Ropivacaine was injected through the epidural catheter to reduce postoperative pain. After a 5 ml bolus of 0.5% ropivacaine was administered, the mixed solution composed of 0.2% ropivacaine and 4 mg/L fentanyl was infused at a basal rate of 2 ml/hour. In addition, patient-controlled epidural analgesia was maintained for almost 2 days (4 ml for 1 push, 30 minutes lockout) by using a disposable pump. The surgical procedure was conducted uneventfully with the patient in the supine position. The final sensory level achieved was T12 bilaterally by pinprick.
After surgery, the patient complained of mild headache. Thereafter, neck stiffness and pain, photophobia, nausea and vomiting also occurred. The next day of the operation, she felt a sudden weakness in her left leg but still able to walk with an assistive device. Then, the weakness increased as well as the right leg. Unexpectedly, she complained of numbness in the gluteal and perianal region. The epidural catheter was removed immediately. According to the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI), which developed by the American Spinal Injury Association (ASIA) and endorsed by the International Spinal Cord Society, is a well-accepted classification of neurologic deficit after Spinal Cord Injury (SCI),[14,15] the examination used dermatomal light touch and pin prick sensation and motor strength of selected muscle groups of the lower extremities to determine the neurologic level of the injury. In the patient, physical examination at that time revealed bilateral lower extremity weakness with 3/5 for left hip flexors and knee extensors; 2/5 for left ankle dorsiflexors and plantar flexors, 1/5 for left extensor hallucis longus; 4/5 for the right hip flexors and knee extensors; 3/5 for right ankle dorsiflexors and plantar flexors, 2/5 for right extensor hallucis longus. Motor scores of the 2 lower limbs were 27 points. Neurological examination documented lower extremity and perianal hypoesthesia and lower extremity hyporeflexia. We defined lower extremity pin prick and light touch scores as the sum of L2 to S5 dermatomes bilaterally (maximum score of 32 points). Pinprick sensation of the left L4-S1 segment, right L4-L5 segment and perianal area in the S3–5 segment was diminished. Pin prick and light touch scores of the left and right lower limbs were 22 and 24 points respectively. The Achilles and patellar reflexes were obviously reduced, and the anal wink reflex was absent in this patient. The anal sphincter tone was decreased. The abdominal reflexes and strength of abdominal wall muscles were bilaterally normal. Three days after surgery, the symptom of headache faded away gradually. The patient was unable to micturate when the urinary catheter was removed on the third postoperative day; as a result, urinary retention (on the third day) and rectal incontinence (on the fourth day) occurred. The bladder was recatheterized because of the urinary retention. Seven days after surgery, Magnetic resonance imaging (MRI) was performed on the lumbosacral area to obtain further information. The MRI revealed no tumor, hematoma, abscess, infarction, spinal stenosis, or cauda equina nerve root compression. Based on the patient's symptoms and MRI findings, cauda equina syndrome was diagnosed. In addition to cauda equina syndrome, she noted onset of hoarseness, effortful voice production and chocking with liquids on postoperative day 5; she believed that her voice had been normal before and immediately after surgery. She subsequently underwent flexible laryngoscopy, which revealed a right vocal fold paralysis. Computed tomography (CT) of the neck and chest was performed 10 days after surgery, which did not reveal any lesions along the recurrent laryngeal nerve. The brain MRI findings showed: diffuse dural enhancement, downward displacement of the brainstem, and diminution of cerebral ventricles, which are typical features of intracranial hypotension (ICH). Stroboscopy performed 15 days after surgery confirmed the finding of an immobile right vocal fold.
The patient was managed conservatively on heavy doses of steroids:[16] methylprednisolone 500 mg intravenously guttae daily for 5 days, then reduced to 80 mg intravenously guttae daily for 10 days. She also underwent a rehabilitation program including traditional Chinese medicine and acupuncture 3 days per week, which aimed to normalize movement patterns. Physical therapy for cauda equine syndrome included static and dynamic control of position, neurophysiologic exercises, progressive ambulation, balance skills, and activities of daily living. Clean intermittent self-catheterization 3 times a day was started for neurogenic bladder. Vocal therapy in unilateral vocal fold paralysis consisted of electrotherapy, hard glottal attacks and pushing exercises, half-swallow boom, accent method, lip and tongue trills. After 2 months, her lower extremity motor strength significantly improved and the sensation of the 2 lower limbs recovered gradually except hypoesthesia in the S3–5 segment. Motor scores of the 2 lower limbs were 45 points; pin prick and light touch scores of the left and right lower limbs were 26 and 28 points, respectively. At the 3-month follow-up, the patient had regained 5/5 strength in all motor groups, could walk normally without any assistive devices and perianal sensation somehow returned. At the 11-month follow-up, the patient recovered from urinary retention and fecal incontinence. In addition, a laryngeal electromyography, performed at 3 months following surgery, showed evidence of denervation of the right thyroarytenoid (innervated by the recurrent laryngeal nerve) and cricothyroid muscle (innervated by the superior laryngeal nerve), consistent with a right vagal neuropathy; at 7-month follow-up, the patient reported that her voice quality improved to near normal and only mild residual paresis was noted on stroboscopy.
3 Discussion and conclusions
The patient developed cauda equina syndrome characterized by urinary retention and fecal incontinence, perianal sensory loss, and lower extremity weakness after uneventful routine spinal-epidural anesthesia. She simultaneously developed a right vocal fold paralysis. Although these major complications rarely occur after spinal-epidural anesthesia, the described patient developed both.
Various possible causes achieved vocal fold paralysis. It may be infectious, neoplastic, or idiopathic in origin. There was no evidence of infection in this case. The CT ruled out the possibility of neoplasm. At first glance, this case of vocal fold paralysis may be classified as idiopathic because spinal anesthesia is generally not considered in the differential diagnosis of vocal fold paralysis. However, a causal relationship may be considered according to the documented occurrence of upper cranial neuropathy as a result of spinal anesthesia, especially in the absence of other important contributing factors. The onset of symptoms is consistent with previously reported cases of cranial neuropathy following spinal anesthesia. Guardiani et al[2] reported 4 cases of vocal fold paralysis after spinal anesthesia. Cranial nerve palsy following subarachnoid block or unintentional dural puncture has been attributed to CSF depletion and ICH, which appears to be the cause of vocal fold palsy.[13] ICH is a clinical syndrome characterized by postural headache and low CSF opening pressure. Symptoms may include nausea, vomiting, nuchal pain, dizziness, tinnitus, nystagmus, and blurred vision.[3] The MRI findings of ICH are diffuse pachymeningeal enhancement, subdural effusion, engorgement of venous sinuses, pituitary enlargement, and herniation of the cerebellar tonsils.[17] It has been explained on the basis of CSF loss causing sagging of the brain and stretching of the nerve.[18] The brain descends caudally to a vertical position, which may harm the cranial nerves that anchor the brain to the skull. In the described patient, laryngeal electromyography suggested a vagal lesion, in light of the evidence of denervation of both the cricothyroid and thyroarytenoid muscle, rather than an isolated neuropathy of the recurrent laryngeal nerve; this supports the hypothesis of traction on the vagal nerve rather than an idiopathic palsy, the majority of which are recurrent nerve phenomena. Therefore, the decrease in intracranial CSF pressure may have contributed to the presentation, which may induce stretching of the vagal nerve bilaterally. In this case, only the right vocal fold was immobile, therefore, the vagal nerve could be stretched with 1 side more affected than the other. Hypotension during surgery may also serve as a contributing factor to this complication because vascular perfusion of nerve fibers might be compromised. Thus the explanation for vocal fold paralysis is uncertain and consequently speculative.
Cauda equina syndrome is a rare but an extremely distressing complication of spinal-epidural anesthesia.[19–21] Most neurological complications are caused by epidural hematoma, abscess, catheter trauma, infection, and anesthetic toxicity. In the patient, the MRI revealed no hematoma, abscess, infarction, spinal stenosis, or lumbar disc herniation. Direct nerve damage may contribute to the onset of neurological symptoms; disposable needle tips are very sharp, nerve fibers can easily be injured by them. Most neural injuries are associated with either paraesthesia or pain upon injection.[22] However, direct damage to the spinal cord via dural puncture is unlikely the cause of the condition observed in the patient because neurologic pain or paraesthesia was not experienced during needle insertion.[23,24] Spinal cord compression caused by an expanding hematoma was excluded through MRI. Infection was not observed because the patient did not manifest clinical signs or laboratory abnormality corresponding to infection. Dural blood flow is significantly reduced in animals once epinephrine is added to local anesthetic solutions.[25] However, spinal cord ischemia was unlikely observed in this case because epinephrine that can induce vascular contraction was not administered, the patient did not suffer from microvascular disease and was hemodynamically stable perioperatively.[26] Rigler et al[27] postulated that a combination of trauma, maldistribution, and relatively high dose of local anesthetic resulted in neurotoxic injury. Most cauda equina syndrome cases following spinal anesthesia are reportedly associated with toxicity of local anesthetics, especially lidocaine. Limited cephalad extension of sensory blocks suggests restricted diffuse of lidocaine in the cerebrospinal fluid and is likely to induce anesthetic neurotoxicity. Several cases of cauda equina syndrome following spinal anesthesia with bupivacaine have been reported. Kato et al[28] reported a cauda equina syndrome case following spinal anesthesia with bupivacaine and epidural anesthesia with ropivacaine, which took 10 months to recover. Similarly, Chabbou et al[29] reported a cauda equina syndrome case following spinal anesthesia with 0.5% hyperbaric bupivacaine without any causative factors in the genesis of the syndrome. Therefore, based on the patient's symptoms and MRI findings, the outcome was probably caused by the neurotoxicity of bupivacaine alone or in combination with ropivacaine. In contrast to other patients, the patient in this report recovered almost completely. This may be the result of the early detection and therapy of the neurologic complication.
In summary, the case highlights that 2 rare and serious complications of spinal-epidural anesthesia can even occur in the same patient after uneventful surgery and block performance. The neurotoxicity of local anesthetics, even with normal dose, is suggested as the most likely cause of cauda equina syndrome, and ICH caused by leakage of CSF serves as a potential factor in causing vocal fold paralysis. Therefore, detailed physical examination, and monitoring recovery of sensory and motor functions following spinal-epidural anesthesia are significant for early detection and therapy of neurologic complications. Notably, practitioners should detect and deal with these rare types of neurologic complications as early as possible, the patient should be investigated thoroughly, and appropriate treatment and rehabilitation program should be initiated promptly. In this patient, early diagnosis and intervention of vocal fold paralysis is crucial to manage it; otherwise, permanent injuries may likely occur.
Author contributions
Conceptualization: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Data curation: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Formal analysis: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Investigation: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Methodology: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Project administration: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Resources: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Software: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Supervision: Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Validation: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Visualization: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Writing – original draft: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Writing – review & editing: Yuanling Xiang, Weifeng Wang, Shenfeng Jing, Zhong Zhang, Dezhang Wang.
Abbreviations: ASIA = American Spinal Injury Association, CSF = cerebrospinal fluid, CT = computed tomography, ICH = intracranial hypotension, ISNCSCI = the International Standards for Neurological Classification of Spinal Cord Injury, MRI = magnetic resonance imaging, SCI = spinal cord injury.
How to cite this article: Xiang Y, Wang W, Jing S, Zhang Z, Wang D. Vocal fold paralysis and cauda equina syndrome following spinal-epidural anesthesia: a case report. Medicine. 2021;100:3(e24374).
Written consent was obtained from the patient for the purpose of publication of case details and images.
The authors have no conflicts of interests to disclose.
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. | Recovered | ReactionOutcome | CC BY | 33546075 | 18,981,348 | 2021-01-22 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Toxic epidermal necrolysis'. | Toxic epidermal necrolysis in a patient on atorvastatin therapy expressing human leukocyte antigen alleles: A case report.
BACKGROUND
Toxic epidermal necrolysis (TEN) is a rare, severe mucosal response of the skin associated with a high mortality rate. TEN is most commonly caused by drugs, and is characterized by extensive skin epidermal exfoliation.
A 68-year-old woman presented with a rash that had persisted for four days. The patient who had undergone a mitral valve replacement 1 month prior and was taking atorvastatin at the time of admission.
The patient exhibited more than 30% exfoliation surfaces and the severe drug eruption was considered to be TEN. According to human leukocyte antigen (HLA) allele detection and ALDEN score, HLA alleles which found in this case report may be an cause of TEN induced by atorvastatin.
METHODS
All drugs used prior to admission were discontinued and the patient was given antiallergic drugs.
RESULTS
After 3 weeks following Antiallergic treatment, the rash on patient's calf had subsided, the edema was relieved, and the patient was no longer experiencing pain. After 60 days following discharge, the patient's skin has regrown.
CONCLUSIONS
This is the first report describing the induction of TEN by atorvastatin in a HLA alleles carrier. For HLA alleles carrier, atorvastatin may need to be used with caution to avoid TEN. Future systematic research is also required to confirm this finding and avoid similar serious skin adverse reactions.
1 Introduction
Toxic epidermal necrolysis (TEN) is an acute, life-threatening, severe dermatosis characterized by epidermal loss and multi-site mucositis, and is accompanied by systemic disturbance.[1] It is rare but very serious forms of drug-induced cutaneous adverse reaction. The morbidity of TEN is approximately 2 cases per million individuals each year.[2] The average mortality rate of TEN is over 30%, and the mortality rate of critically ill patients (SCORTEN > 3) is as high as 60% to 90%.[3]
Approximately 85% of TEN cases are induced by drugs.[4] The primary sensitizing drugs associated with TEN include antibiotics, anticonvulsants, antiviral drugs, and traditional Chinese medicine.[3] Recent studies have found that the occurrence of TEN is related to the individual human leukocyte antigen (HLA) allele genotype.[5,6,7] The HLA complex consists more than 200 genes on chromosome 6 can be categorized into 3 subgroups: Class I HLA, being recognized by CD8+ T cells, consists of 3 main genes, that is HLA-A, HLA-B, and HLA-C. Class II HLA, being recognized by CD4+ T cells, consists of 6 maingenes, that is, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLADQB1, HLA-DRA, and HLA-DRB1. HLA class I molecules are expressed in almost all the cells and are responsible for presenting peptides to immune cells.[5] Studies have shown that certain drugs that cause TEN are associated with HLA alleles; for example, carbamazepine-induced TEN and the HLA-B∗ 15:02 allele are highly correlated. Moreover, TEN induced by abacavir is correlated with individuals positive for the HLA-B∗57:01 allele.[5]
2 Case report
A 68-year-old woman presented with a rash that had persisted for 4 days. She had undergone a mitral valve replacement 1 month prior. Four days before admission, the patient developed a red rash on her face, chest, and back, accompanied by itching and a fever. At the time of admission, she presented with a burgundy rash that was distributed diffusely throughout her entire body. Moreover, some of the lesions were fused together, with a few blisters, itching, tolerability, fever, without skin breakage, subcutaneous nodules, bleeding, and ulcers (Fig. 1A). The laboratory test results revealed: albumin, 34.6 g/L; gamma glutamyl transpeptidase, 45 U/L; glucose, 13.24 mmol/L; creatine kinase MB subtype, 18.0 U/L; creatine kinase, 20 U/L; lactic dehydrogenase, 398 U/L; sodium, 135.9 mmol/L; leukocyte count, 5.19∗109/L; hemoglobin, 98.0 g/L; platelet count, 267 g/L; procalcitonin, 0.130 ng/mL; and fibrinogen, 4.35 g/L. The patient was taking the following medications at the time of admission: 0.125 mg qd po digoxin; 20 mg bid po furosemide; 1 g bid po potassium chloride; 0.625 mg qn po warfarin; and 20 mg qn po atorvastatin.
Figure 1 (A) At the time of admission, a burgundy rash was distributed diffusely throughout the patient's entire body. (B) On the fifth day of admission, the patient's facial skin began to peel, and blisters on her trunk began to rupture and peel. (C) After 60 days following discharge, the patient's skin has regrown.
On Day 1 post-admission, all drugs used prior to admission were discontinued and the patient was given antiallergic drugs, including 10 mg qd po loratadine, 10 mg qd po cetirizine, 100 mg tid po vitamin C, 120 mg q12 h po methylprednisolone, 40 mg q12 h ivgtt omeprazole acid, calamine and ethacridine for external use. The following day, the patient developed a large number of blisters that began to rupture over a large area of skin, and was accompanied by a fever. On Day 4, human immunoglobulin was intravenously administered. On Day 5, the patient's facial skin began to peel, and blisters on her trunk began to rupture and peel, which was associated with obvious pain. Mupirocin ointment was applied externally as treatment (Fig. 1B). On Day 11, the patient developed a new red patchy rash on both of her lower extremities accompanied by mild edema, as well as moderate blister formation near the thigh (Fig. 2). On Day 17, after developing erythema, blisters, rupture and peeling, the face and trunk skin were basically healed. On Day 22, the rash on her calf had subsided, the edema was relieved, and she was no longer experiencing pain. Then he was discharged from hospital. After 60 days following discharge, the patient's skin has regrown (Fig. 1C). During hospitalization, the location and exfoliation site of the rash were observed (Fig. 3); since the patient exhibited more than 30% exfoliation surfaces, the severe drug eruption was considered to be TEN rather than Stevens-Johnson Syndrome (SJS).
Figure 2 On Day 11 of admission, the patient developed a new red patchy rash on both lower extremities, which was accompanied by mild edema, and moderate blister formation near the thigh.
Figure 3 The location and exfoliation site of the rash were observed during hospitalization.
3 Investigations
Since more than 80% of TEN cases are caused by a drug allergy, timely cessation of the sensitizing drugs is the first step in treatment. Screening for suspected drug allergies relies primarily on medical history and previous reports of adverse drug reactions, however, for patients who have used multiple drugs before the onset of TEN, it is often difficult to identify the sensitizing drug.[4] The 2016 British Adult Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis Symptoms Management Guide recommends using the ALDEN score (drug causality algorithm for epidermal necrolysis) to retrospectively evaluate sensitizing drugs for TEN.[8] The ALDEN score was designed based on the results of the Severe Cutaneous Adverse Reaction case-control study conducted from 1989 to 1993. Therefore, we analyzed all of the drugs used in this patient according to the ALDEN score in order to identify those that induce TEN (Table 1). Atorvastatin had an ALDEN score of 4 (the highest score of all drugs taken; Table 1) and was judged to be “probable” for sensitization. Furthermore, the patient had taken warfarin for venous thrombosis of lower extremities 2 years ago and did not induce TEN. Thus, the patient's TEN was most likely caused by atorvastatin.
Table 1 Possible sensitizing drugs ALDEN score.
Values
Drugs the duration of use Criterion1 Criterion2 Criterion3 Criterion 4 Criterion 5 Final score Sensitization possibility∗
Aspirin 9/15–9/30 2a −3c 0e 0g −1i −2 Very unlikely
Atorvastatin calcium 9/20–10/16 3b 0d 0e 0g 1j 4 probable
Cefazolin sodium 9/14–9/15 2b −3c 0e 0g 1j 0 unlikely
Compound ammonia barbital 9/15–9/16 2a −3c 0e 0g 0k −1 Very unlikely
Furosemide 9/11–9/15,9/20–9/30, 10/1–10/16 3b 0d −2f −2h 0k −1 Very unlikely
Isosorbide mononitrate 9/20–10/16 3b 0d −2f 0g 1j 2 possible
Nitroglycerin 9/15–9/22 2a −3c 0e 0g 0k −1 Very unlikely
Cefoperazone Sulbactam Sodium 9/16–9/30 3b −3c −2f 0g 1j −1 Very unlikely
Warfarin 9/20–10/16 3b 0d −2f 0g 1j 2 possible
Tramadol 9/20–9/30 3b −3c 0e 0g 0k 0 unlikely
3.1 HLA allele detection
A 2-mL sample of peripheral venous blood was collected from the patient. Genomic DNA was extracted using a DNA extraction kit (Shanghai Baio Co., Ltd.) in accordance with the manufacturer's protocol. The exons of the HLA-A, -B, and-C loci were sequenced using sanger.[5] The results showed that the patient carried the HLA-A∗02:07, HLA-A∗11:01, HLA-B∗15:02, HLA-B∗40:01, HLA-C∗03:04, and HLA-C∗08:01 alleles.
4 Discussion
TEN is a serious skin mucosal disease characterized by large areas of erythema, blisters, epidermal exfoliation, and multi-site mucositis, that is often accompanied by systemic dysfunction.[1] The onset is urgent, progresses rapidly, and is associated with a high mortality rate. Thus, there is an urgent need to identify drugs that induce TEN. By using ALDEN to score all the drugs the patient had used, we were able to determine that atorvastatin was most likely associated with TEN in this patient. There have been 6 reports of statin-induced exfoliative dermatitis in the literature, including TEN, but none of the studies tested for HLA-related genes.[9,10,11,12,13,14] In addition, it is mentioned on the atorvastatin drug label that it may cause TEN in extremely rare cases.[15]
Genetic factors are also closely related to the occurrence of SJS/TEN. In this study, the patient's HLA exon was sequenced and found to carry multiple mutant HLA genotypes, that may have the correlation with SJS and TEN. A thorough review of the literature reveals that, among these alleles, HLA-B∗15:02, HLA-A∗02:07 and TEN may have the correlation.[16,17,18] The correlation between other alleles and TEN has not been reported, but their association cannot be ruled out, it need to be further investigated. HLA alleles have been proposed as markers of SJS/TEN. Studies revealed a high prevalence of pharmacogenetic markers of drug-induced SJS/TEN e.g., B∗13:01 for dapsone; B∗15:02 for carbamazepine and oxcarbazepine; B∗58:01, A∗33:03 and C∗03:02 for allopurinol; C∗08:01, C∗14:02 and DRB1∗12:02 for co-trimoxazole.[18] HLA alleles which found in this case report may be an cause of TEN induced by atorvastatin. Previous studies have found that HLA-B∗15:02 is an cause of serious adverse reactions in the skin induced by anti-epileptic drugs.[16] Carbamazepine non-covalently bind to proteins or peptides and are presented by MHC molecules after cellular processing, resulting in the HLA–restricted T cell activation.[17,19] Perhaps the mechanism of atorvastatin-induced TEN could be studied in the light of this study.
Atorvastatin is the most common drug for lipid lowering in patients with dyslipidemia, and the proportion of dyslipidemia in Chinese population is as high as 40.40%.[20] Therefore, the population of atorvastatin is very large, but SJS/TEN is very rare, HLA alleles may be a genetic factor. This is the first report describing the induction of TEN by atorvastatin in a HLA alleles carrier. Future systematic research is required to confirm this finding and avoid similar serious skin adverse reactions.
Author contributions
Conceptualization: Meina Lv, Yuxin Liu, Jinhua Zhang.
Data curation: Shaojun Jiang, Jinglan Fu.
Formal analysis: Yuxin Liu, Siheng Lian.
Project administration: Meina Lv, Jinhua Zhang.
Writing – original draft: Meina Lv.
Writing – review & editing: Shaojun Jiang, Jinglan Fu, Yuxin Liu, Siheng Lian, Jinhua Zhang.
Abbreviations: HLA = human leukocyte antigen, SJS = stevens-johnson syndrome, TEN = toxic epidermal necrolysis.
How to cite this article: Lv M, Jiang S, Fu J, Liu Y, Lian S, Zhang J. Toxic epidermal necrolysis in a patient on atorvastatin therapy expressing human leukocyte antigen alleles: a case report. Medicine. 2021;100:3(e24392).
This study was supported by the Natural Science Foundation of Fujian Province of China [grant number 2018Y0037].
Informed consent was obtained from the patient for publication of this case report. Approval of the study by our hospital's ethics committee was not required because it was a case report.
The authors have no conflicts of interest to disclose.
All data generated or analyzed during this study are included in this published article [and its supplementary information files].
∗ < 0, very unlikely; 0 – 1, unlikely; 2 – 3, possible; 4 – 5, probable; ≥ 6, very probable.
a Delay from initial drug component intake to onset of reaction: from 29 to 56 days.
b Delay from initial drug component intake to onset of reaction: from 5 to 28 days.
c Drug present in the body on index day: drug stopped at a time point prior to the index day by more than 5 times the elimination half-life, without liver or kidney function alterations or suspected drug interactions.
d Drug present in the body on index day: drug continued up to index day or stopped at a time point less than 5 times the elimination half-life before the index day.
e Prechallenge/rechanllenge: no known previous exposure to this drug.
f Prechallenge/rechanllenge: Exposure to this drug without any reaction (before or after reaction).
g Dechallenge: Drug stopped (or unknown).
h Dechallenge: Drug continued without harm.
i Type of drug (notoriety):No evidence of association from previous epidemiology study with sufficient number of exposed control.
j Type of drug (notoriety): Several previous reports, ambiguous epidemiology results (drug “under surveillance”).
k Type of drug (notoriety): All other drugs including newly released ones. | ASPIRIN, ATORVASTATIN CALCIUM, BARBITAL, CEFAZOLIN, CEFOPERAZONE\SULBACTAM, DIGOXIN, FUROSEMIDE, ISOSORBIDE, NITROGLYCERIN, POTASSIUM CHLORIDE, TRAMADOL, WARFARIN | DrugsGivenReaction | CC BY | 33546081 | 18,901,737 | 2021-01-22 |
What was the administration route of drug 'ATORVASTATIN CALCIUM'? | Toxic epidermal necrolysis in a patient on atorvastatin therapy expressing human leukocyte antigen alleles: A case report.
BACKGROUND
Toxic epidermal necrolysis (TEN) is a rare, severe mucosal response of the skin associated with a high mortality rate. TEN is most commonly caused by drugs, and is characterized by extensive skin epidermal exfoliation.
A 68-year-old woman presented with a rash that had persisted for four days. The patient who had undergone a mitral valve replacement 1 month prior and was taking atorvastatin at the time of admission.
The patient exhibited more than 30% exfoliation surfaces and the severe drug eruption was considered to be TEN. According to human leukocyte antigen (HLA) allele detection and ALDEN score, HLA alleles which found in this case report may be an cause of TEN induced by atorvastatin.
METHODS
All drugs used prior to admission were discontinued and the patient was given antiallergic drugs.
RESULTS
After 3 weeks following Antiallergic treatment, the rash on patient's calf had subsided, the edema was relieved, and the patient was no longer experiencing pain. After 60 days following discharge, the patient's skin has regrown.
CONCLUSIONS
This is the first report describing the induction of TEN by atorvastatin in a HLA alleles carrier. For HLA alleles carrier, atorvastatin may need to be used with caution to avoid TEN. Future systematic research is also required to confirm this finding and avoid similar serious skin adverse reactions.
1 Introduction
Toxic epidermal necrolysis (TEN) is an acute, life-threatening, severe dermatosis characterized by epidermal loss and multi-site mucositis, and is accompanied by systemic disturbance.[1] It is rare but very serious forms of drug-induced cutaneous adverse reaction. The morbidity of TEN is approximately 2 cases per million individuals each year.[2] The average mortality rate of TEN is over 30%, and the mortality rate of critically ill patients (SCORTEN > 3) is as high as 60% to 90%.[3]
Approximately 85% of TEN cases are induced by drugs.[4] The primary sensitizing drugs associated with TEN include antibiotics, anticonvulsants, antiviral drugs, and traditional Chinese medicine.[3] Recent studies have found that the occurrence of TEN is related to the individual human leukocyte antigen (HLA) allele genotype.[5,6,7] The HLA complex consists more than 200 genes on chromosome 6 can be categorized into 3 subgroups: Class I HLA, being recognized by CD8+ T cells, consists of 3 main genes, that is HLA-A, HLA-B, and HLA-C. Class II HLA, being recognized by CD4+ T cells, consists of 6 maingenes, that is, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLADQB1, HLA-DRA, and HLA-DRB1. HLA class I molecules are expressed in almost all the cells and are responsible for presenting peptides to immune cells.[5] Studies have shown that certain drugs that cause TEN are associated with HLA alleles; for example, carbamazepine-induced TEN and the HLA-B∗ 15:02 allele are highly correlated. Moreover, TEN induced by abacavir is correlated with individuals positive for the HLA-B∗57:01 allele.[5]
2 Case report
A 68-year-old woman presented with a rash that had persisted for 4 days. She had undergone a mitral valve replacement 1 month prior. Four days before admission, the patient developed a red rash on her face, chest, and back, accompanied by itching and a fever. At the time of admission, she presented with a burgundy rash that was distributed diffusely throughout her entire body. Moreover, some of the lesions were fused together, with a few blisters, itching, tolerability, fever, without skin breakage, subcutaneous nodules, bleeding, and ulcers (Fig. 1A). The laboratory test results revealed: albumin, 34.6 g/L; gamma glutamyl transpeptidase, 45 U/L; glucose, 13.24 mmol/L; creatine kinase MB subtype, 18.0 U/L; creatine kinase, 20 U/L; lactic dehydrogenase, 398 U/L; sodium, 135.9 mmol/L; leukocyte count, 5.19∗109/L; hemoglobin, 98.0 g/L; platelet count, 267 g/L; procalcitonin, 0.130 ng/mL; and fibrinogen, 4.35 g/L. The patient was taking the following medications at the time of admission: 0.125 mg qd po digoxin; 20 mg bid po furosemide; 1 g bid po potassium chloride; 0.625 mg qn po warfarin; and 20 mg qn po atorvastatin.
Figure 1 (A) At the time of admission, a burgundy rash was distributed diffusely throughout the patient's entire body. (B) On the fifth day of admission, the patient's facial skin began to peel, and blisters on her trunk began to rupture and peel. (C) After 60 days following discharge, the patient's skin has regrown.
On Day 1 post-admission, all drugs used prior to admission were discontinued and the patient was given antiallergic drugs, including 10 mg qd po loratadine, 10 mg qd po cetirizine, 100 mg tid po vitamin C, 120 mg q12 h po methylprednisolone, 40 mg q12 h ivgtt omeprazole acid, calamine and ethacridine for external use. The following day, the patient developed a large number of blisters that began to rupture over a large area of skin, and was accompanied by a fever. On Day 4, human immunoglobulin was intravenously administered. On Day 5, the patient's facial skin began to peel, and blisters on her trunk began to rupture and peel, which was associated with obvious pain. Mupirocin ointment was applied externally as treatment (Fig. 1B). On Day 11, the patient developed a new red patchy rash on both of her lower extremities accompanied by mild edema, as well as moderate blister formation near the thigh (Fig. 2). On Day 17, after developing erythema, blisters, rupture and peeling, the face and trunk skin were basically healed. On Day 22, the rash on her calf had subsided, the edema was relieved, and she was no longer experiencing pain. Then he was discharged from hospital. After 60 days following discharge, the patient's skin has regrown (Fig. 1C). During hospitalization, the location and exfoliation site of the rash were observed (Fig. 3); since the patient exhibited more than 30% exfoliation surfaces, the severe drug eruption was considered to be TEN rather than Stevens-Johnson Syndrome (SJS).
Figure 2 On Day 11 of admission, the patient developed a new red patchy rash on both lower extremities, which was accompanied by mild edema, and moderate blister formation near the thigh.
Figure 3 The location and exfoliation site of the rash were observed during hospitalization.
3 Investigations
Since more than 80% of TEN cases are caused by a drug allergy, timely cessation of the sensitizing drugs is the first step in treatment. Screening for suspected drug allergies relies primarily on medical history and previous reports of adverse drug reactions, however, for patients who have used multiple drugs before the onset of TEN, it is often difficult to identify the sensitizing drug.[4] The 2016 British Adult Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis Symptoms Management Guide recommends using the ALDEN score (drug causality algorithm for epidermal necrolysis) to retrospectively evaluate sensitizing drugs for TEN.[8] The ALDEN score was designed based on the results of the Severe Cutaneous Adverse Reaction case-control study conducted from 1989 to 1993. Therefore, we analyzed all of the drugs used in this patient according to the ALDEN score in order to identify those that induce TEN (Table 1). Atorvastatin had an ALDEN score of 4 (the highest score of all drugs taken; Table 1) and was judged to be “probable” for sensitization. Furthermore, the patient had taken warfarin for venous thrombosis of lower extremities 2 years ago and did not induce TEN. Thus, the patient's TEN was most likely caused by atorvastatin.
Table 1 Possible sensitizing drugs ALDEN score.
Values
Drugs the duration of use Criterion1 Criterion2 Criterion3 Criterion 4 Criterion 5 Final score Sensitization possibility∗
Aspirin 9/15–9/30 2a −3c 0e 0g −1i −2 Very unlikely
Atorvastatin calcium 9/20–10/16 3b 0d 0e 0g 1j 4 probable
Cefazolin sodium 9/14–9/15 2b −3c 0e 0g 1j 0 unlikely
Compound ammonia barbital 9/15–9/16 2a −3c 0e 0g 0k −1 Very unlikely
Furosemide 9/11–9/15,9/20–9/30, 10/1–10/16 3b 0d −2f −2h 0k −1 Very unlikely
Isosorbide mononitrate 9/20–10/16 3b 0d −2f 0g 1j 2 possible
Nitroglycerin 9/15–9/22 2a −3c 0e 0g 0k −1 Very unlikely
Cefoperazone Sulbactam Sodium 9/16–9/30 3b −3c −2f 0g 1j −1 Very unlikely
Warfarin 9/20–10/16 3b 0d −2f 0g 1j 2 possible
Tramadol 9/20–9/30 3b −3c 0e 0g 0k 0 unlikely
3.1 HLA allele detection
A 2-mL sample of peripheral venous blood was collected from the patient. Genomic DNA was extracted using a DNA extraction kit (Shanghai Baio Co., Ltd.) in accordance with the manufacturer's protocol. The exons of the HLA-A, -B, and-C loci were sequenced using sanger.[5] The results showed that the patient carried the HLA-A∗02:07, HLA-A∗11:01, HLA-B∗15:02, HLA-B∗40:01, HLA-C∗03:04, and HLA-C∗08:01 alleles.
4 Discussion
TEN is a serious skin mucosal disease characterized by large areas of erythema, blisters, epidermal exfoliation, and multi-site mucositis, that is often accompanied by systemic dysfunction.[1] The onset is urgent, progresses rapidly, and is associated with a high mortality rate. Thus, there is an urgent need to identify drugs that induce TEN. By using ALDEN to score all the drugs the patient had used, we were able to determine that atorvastatin was most likely associated with TEN in this patient. There have been 6 reports of statin-induced exfoliative dermatitis in the literature, including TEN, but none of the studies tested for HLA-related genes.[9,10,11,12,13,14] In addition, it is mentioned on the atorvastatin drug label that it may cause TEN in extremely rare cases.[15]
Genetic factors are also closely related to the occurrence of SJS/TEN. In this study, the patient's HLA exon was sequenced and found to carry multiple mutant HLA genotypes, that may have the correlation with SJS and TEN. A thorough review of the literature reveals that, among these alleles, HLA-B∗15:02, HLA-A∗02:07 and TEN may have the correlation.[16,17,18] The correlation between other alleles and TEN has not been reported, but their association cannot be ruled out, it need to be further investigated. HLA alleles have been proposed as markers of SJS/TEN. Studies revealed a high prevalence of pharmacogenetic markers of drug-induced SJS/TEN e.g., B∗13:01 for dapsone; B∗15:02 for carbamazepine and oxcarbazepine; B∗58:01, A∗33:03 and C∗03:02 for allopurinol; C∗08:01, C∗14:02 and DRB1∗12:02 for co-trimoxazole.[18] HLA alleles which found in this case report may be an cause of TEN induced by atorvastatin. Previous studies have found that HLA-B∗15:02 is an cause of serious adverse reactions in the skin induced by anti-epileptic drugs.[16] Carbamazepine non-covalently bind to proteins or peptides and are presented by MHC molecules after cellular processing, resulting in the HLA–restricted T cell activation.[17,19] Perhaps the mechanism of atorvastatin-induced TEN could be studied in the light of this study.
Atorvastatin is the most common drug for lipid lowering in patients with dyslipidemia, and the proportion of dyslipidemia in Chinese population is as high as 40.40%.[20] Therefore, the population of atorvastatin is very large, but SJS/TEN is very rare, HLA alleles may be a genetic factor. This is the first report describing the induction of TEN by atorvastatin in a HLA alleles carrier. Future systematic research is required to confirm this finding and avoid similar serious skin adverse reactions.
Author contributions
Conceptualization: Meina Lv, Yuxin Liu, Jinhua Zhang.
Data curation: Shaojun Jiang, Jinglan Fu.
Formal analysis: Yuxin Liu, Siheng Lian.
Project administration: Meina Lv, Jinhua Zhang.
Writing – original draft: Meina Lv.
Writing – review & editing: Shaojun Jiang, Jinglan Fu, Yuxin Liu, Siheng Lian, Jinhua Zhang.
Abbreviations: HLA = human leukocyte antigen, SJS = stevens-johnson syndrome, TEN = toxic epidermal necrolysis.
How to cite this article: Lv M, Jiang S, Fu J, Liu Y, Lian S, Zhang J. Toxic epidermal necrolysis in a patient on atorvastatin therapy expressing human leukocyte antigen alleles: a case report. Medicine. 2021;100:3(e24392).
This study was supported by the Natural Science Foundation of Fujian Province of China [grant number 2018Y0037].
Informed consent was obtained from the patient for publication of this case report. Approval of the study by our hospital's ethics committee was not required because it was a case report.
The authors have no conflicts of interest to disclose.
All data generated or analyzed during this study are included in this published article [and its supplementary information files].
∗ < 0, very unlikely; 0 – 1, unlikely; 2 – 3, possible; 4 – 5, probable; ≥ 6, very probable.
a Delay from initial drug component intake to onset of reaction: from 29 to 56 days.
b Delay from initial drug component intake to onset of reaction: from 5 to 28 days.
c Drug present in the body on index day: drug stopped at a time point prior to the index day by more than 5 times the elimination half-life, without liver or kidney function alterations or suspected drug interactions.
d Drug present in the body on index day: drug continued up to index day or stopped at a time point less than 5 times the elimination half-life before the index day.
e Prechallenge/rechanllenge: no known previous exposure to this drug.
f Prechallenge/rechanllenge: Exposure to this drug without any reaction (before or after reaction).
g Dechallenge: Drug stopped (or unknown).
h Dechallenge: Drug continued without harm.
i Type of drug (notoriety):No evidence of association from previous epidemiology study with sufficient number of exposed control.
j Type of drug (notoriety): Several previous reports, ambiguous epidemiology results (drug “under surveillance”).
k Type of drug (notoriety): All other drugs including newly released ones. | Oral | DrugAdministrationRoute | CC BY | 33546081 | 18,901,737 | 2021-01-22 |
What was the administration route of drug 'DIGOXIN'? | Toxic epidermal necrolysis in a patient on atorvastatin therapy expressing human leukocyte antigen alleles: A case report.
BACKGROUND
Toxic epidermal necrolysis (TEN) is a rare, severe mucosal response of the skin associated with a high mortality rate. TEN is most commonly caused by drugs, and is characterized by extensive skin epidermal exfoliation.
A 68-year-old woman presented with a rash that had persisted for four days. The patient who had undergone a mitral valve replacement 1 month prior and was taking atorvastatin at the time of admission.
The patient exhibited more than 30% exfoliation surfaces and the severe drug eruption was considered to be TEN. According to human leukocyte antigen (HLA) allele detection and ALDEN score, HLA alleles which found in this case report may be an cause of TEN induced by atorvastatin.
METHODS
All drugs used prior to admission were discontinued and the patient was given antiallergic drugs.
RESULTS
After 3 weeks following Antiallergic treatment, the rash on patient's calf had subsided, the edema was relieved, and the patient was no longer experiencing pain. After 60 days following discharge, the patient's skin has regrown.
CONCLUSIONS
This is the first report describing the induction of TEN by atorvastatin in a HLA alleles carrier. For HLA alleles carrier, atorvastatin may need to be used with caution to avoid TEN. Future systematic research is also required to confirm this finding and avoid similar serious skin adverse reactions.
1 Introduction
Toxic epidermal necrolysis (TEN) is an acute, life-threatening, severe dermatosis characterized by epidermal loss and multi-site mucositis, and is accompanied by systemic disturbance.[1] It is rare but very serious forms of drug-induced cutaneous adverse reaction. The morbidity of TEN is approximately 2 cases per million individuals each year.[2] The average mortality rate of TEN is over 30%, and the mortality rate of critically ill patients (SCORTEN > 3) is as high as 60% to 90%.[3]
Approximately 85% of TEN cases are induced by drugs.[4] The primary sensitizing drugs associated with TEN include antibiotics, anticonvulsants, antiviral drugs, and traditional Chinese medicine.[3] Recent studies have found that the occurrence of TEN is related to the individual human leukocyte antigen (HLA) allele genotype.[5,6,7] The HLA complex consists more than 200 genes on chromosome 6 can be categorized into 3 subgroups: Class I HLA, being recognized by CD8+ T cells, consists of 3 main genes, that is HLA-A, HLA-B, and HLA-C. Class II HLA, being recognized by CD4+ T cells, consists of 6 maingenes, that is, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLADQB1, HLA-DRA, and HLA-DRB1. HLA class I molecules are expressed in almost all the cells and are responsible for presenting peptides to immune cells.[5] Studies have shown that certain drugs that cause TEN are associated with HLA alleles; for example, carbamazepine-induced TEN and the HLA-B∗ 15:02 allele are highly correlated. Moreover, TEN induced by abacavir is correlated with individuals positive for the HLA-B∗57:01 allele.[5]
2 Case report
A 68-year-old woman presented with a rash that had persisted for 4 days. She had undergone a mitral valve replacement 1 month prior. Four days before admission, the patient developed a red rash on her face, chest, and back, accompanied by itching and a fever. At the time of admission, she presented with a burgundy rash that was distributed diffusely throughout her entire body. Moreover, some of the lesions were fused together, with a few blisters, itching, tolerability, fever, without skin breakage, subcutaneous nodules, bleeding, and ulcers (Fig. 1A). The laboratory test results revealed: albumin, 34.6 g/L; gamma glutamyl transpeptidase, 45 U/L; glucose, 13.24 mmol/L; creatine kinase MB subtype, 18.0 U/L; creatine kinase, 20 U/L; lactic dehydrogenase, 398 U/L; sodium, 135.9 mmol/L; leukocyte count, 5.19∗109/L; hemoglobin, 98.0 g/L; platelet count, 267 g/L; procalcitonin, 0.130 ng/mL; and fibrinogen, 4.35 g/L. The patient was taking the following medications at the time of admission: 0.125 mg qd po digoxin; 20 mg bid po furosemide; 1 g bid po potassium chloride; 0.625 mg qn po warfarin; and 20 mg qn po atorvastatin.
Figure 1 (A) At the time of admission, a burgundy rash was distributed diffusely throughout the patient's entire body. (B) On the fifth day of admission, the patient's facial skin began to peel, and blisters on her trunk began to rupture and peel. (C) After 60 days following discharge, the patient's skin has regrown.
On Day 1 post-admission, all drugs used prior to admission were discontinued and the patient was given antiallergic drugs, including 10 mg qd po loratadine, 10 mg qd po cetirizine, 100 mg tid po vitamin C, 120 mg q12 h po methylprednisolone, 40 mg q12 h ivgtt omeprazole acid, calamine and ethacridine for external use. The following day, the patient developed a large number of blisters that began to rupture over a large area of skin, and was accompanied by a fever. On Day 4, human immunoglobulin was intravenously administered. On Day 5, the patient's facial skin began to peel, and blisters on her trunk began to rupture and peel, which was associated with obvious pain. Mupirocin ointment was applied externally as treatment (Fig. 1B). On Day 11, the patient developed a new red patchy rash on both of her lower extremities accompanied by mild edema, as well as moderate blister formation near the thigh (Fig. 2). On Day 17, after developing erythema, blisters, rupture and peeling, the face and trunk skin were basically healed. On Day 22, the rash on her calf had subsided, the edema was relieved, and she was no longer experiencing pain. Then he was discharged from hospital. After 60 days following discharge, the patient's skin has regrown (Fig. 1C). During hospitalization, the location and exfoliation site of the rash were observed (Fig. 3); since the patient exhibited more than 30% exfoliation surfaces, the severe drug eruption was considered to be TEN rather than Stevens-Johnson Syndrome (SJS).
Figure 2 On Day 11 of admission, the patient developed a new red patchy rash on both lower extremities, which was accompanied by mild edema, and moderate blister formation near the thigh.
Figure 3 The location and exfoliation site of the rash were observed during hospitalization.
3 Investigations
Since more than 80% of TEN cases are caused by a drug allergy, timely cessation of the sensitizing drugs is the first step in treatment. Screening for suspected drug allergies relies primarily on medical history and previous reports of adverse drug reactions, however, for patients who have used multiple drugs before the onset of TEN, it is often difficult to identify the sensitizing drug.[4] The 2016 British Adult Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis Symptoms Management Guide recommends using the ALDEN score (drug causality algorithm for epidermal necrolysis) to retrospectively evaluate sensitizing drugs for TEN.[8] The ALDEN score was designed based on the results of the Severe Cutaneous Adverse Reaction case-control study conducted from 1989 to 1993. Therefore, we analyzed all of the drugs used in this patient according to the ALDEN score in order to identify those that induce TEN (Table 1). Atorvastatin had an ALDEN score of 4 (the highest score of all drugs taken; Table 1) and was judged to be “probable” for sensitization. Furthermore, the patient had taken warfarin for venous thrombosis of lower extremities 2 years ago and did not induce TEN. Thus, the patient's TEN was most likely caused by atorvastatin.
Table 1 Possible sensitizing drugs ALDEN score.
Values
Drugs the duration of use Criterion1 Criterion2 Criterion3 Criterion 4 Criterion 5 Final score Sensitization possibility∗
Aspirin 9/15–9/30 2a −3c 0e 0g −1i −2 Very unlikely
Atorvastatin calcium 9/20–10/16 3b 0d 0e 0g 1j 4 probable
Cefazolin sodium 9/14–9/15 2b −3c 0e 0g 1j 0 unlikely
Compound ammonia barbital 9/15–9/16 2a −3c 0e 0g 0k −1 Very unlikely
Furosemide 9/11–9/15,9/20–9/30, 10/1–10/16 3b 0d −2f −2h 0k −1 Very unlikely
Isosorbide mononitrate 9/20–10/16 3b 0d −2f 0g 1j 2 possible
Nitroglycerin 9/15–9/22 2a −3c 0e 0g 0k −1 Very unlikely
Cefoperazone Sulbactam Sodium 9/16–9/30 3b −3c −2f 0g 1j −1 Very unlikely
Warfarin 9/20–10/16 3b 0d −2f 0g 1j 2 possible
Tramadol 9/20–9/30 3b −3c 0e 0g 0k 0 unlikely
3.1 HLA allele detection
A 2-mL sample of peripheral venous blood was collected from the patient. Genomic DNA was extracted using a DNA extraction kit (Shanghai Baio Co., Ltd.) in accordance with the manufacturer's protocol. The exons of the HLA-A, -B, and-C loci were sequenced using sanger.[5] The results showed that the patient carried the HLA-A∗02:07, HLA-A∗11:01, HLA-B∗15:02, HLA-B∗40:01, HLA-C∗03:04, and HLA-C∗08:01 alleles.
4 Discussion
TEN is a serious skin mucosal disease characterized by large areas of erythema, blisters, epidermal exfoliation, and multi-site mucositis, that is often accompanied by systemic dysfunction.[1] The onset is urgent, progresses rapidly, and is associated with a high mortality rate. Thus, there is an urgent need to identify drugs that induce TEN. By using ALDEN to score all the drugs the patient had used, we were able to determine that atorvastatin was most likely associated with TEN in this patient. There have been 6 reports of statin-induced exfoliative dermatitis in the literature, including TEN, but none of the studies tested for HLA-related genes.[9,10,11,12,13,14] In addition, it is mentioned on the atorvastatin drug label that it may cause TEN in extremely rare cases.[15]
Genetic factors are also closely related to the occurrence of SJS/TEN. In this study, the patient's HLA exon was sequenced and found to carry multiple mutant HLA genotypes, that may have the correlation with SJS and TEN. A thorough review of the literature reveals that, among these alleles, HLA-B∗15:02, HLA-A∗02:07 and TEN may have the correlation.[16,17,18] The correlation between other alleles and TEN has not been reported, but their association cannot be ruled out, it need to be further investigated. HLA alleles have been proposed as markers of SJS/TEN. Studies revealed a high prevalence of pharmacogenetic markers of drug-induced SJS/TEN e.g., B∗13:01 for dapsone; B∗15:02 for carbamazepine and oxcarbazepine; B∗58:01, A∗33:03 and C∗03:02 for allopurinol; C∗08:01, C∗14:02 and DRB1∗12:02 for co-trimoxazole.[18] HLA alleles which found in this case report may be an cause of TEN induced by atorvastatin. Previous studies have found that HLA-B∗15:02 is an cause of serious adverse reactions in the skin induced by anti-epileptic drugs.[16] Carbamazepine non-covalently bind to proteins or peptides and are presented by MHC molecules after cellular processing, resulting in the HLA–restricted T cell activation.[17,19] Perhaps the mechanism of atorvastatin-induced TEN could be studied in the light of this study.
Atorvastatin is the most common drug for lipid lowering in patients with dyslipidemia, and the proportion of dyslipidemia in Chinese population is as high as 40.40%.[20] Therefore, the population of atorvastatin is very large, but SJS/TEN is very rare, HLA alleles may be a genetic factor. This is the first report describing the induction of TEN by atorvastatin in a HLA alleles carrier. Future systematic research is required to confirm this finding and avoid similar serious skin adverse reactions.
Author contributions
Conceptualization: Meina Lv, Yuxin Liu, Jinhua Zhang.
Data curation: Shaojun Jiang, Jinglan Fu.
Formal analysis: Yuxin Liu, Siheng Lian.
Project administration: Meina Lv, Jinhua Zhang.
Writing – original draft: Meina Lv.
Writing – review & editing: Shaojun Jiang, Jinglan Fu, Yuxin Liu, Siheng Lian, Jinhua Zhang.
Abbreviations: HLA = human leukocyte antigen, SJS = stevens-johnson syndrome, TEN = toxic epidermal necrolysis.
How to cite this article: Lv M, Jiang S, Fu J, Liu Y, Lian S, Zhang J. Toxic epidermal necrolysis in a patient on atorvastatin therapy expressing human leukocyte antigen alleles: a case report. Medicine. 2021;100:3(e24392).
This study was supported by the Natural Science Foundation of Fujian Province of China [grant number 2018Y0037].
Informed consent was obtained from the patient for publication of this case report. Approval of the study by our hospital's ethics committee was not required because it was a case report.
The authors have no conflicts of interest to disclose.
All data generated or analyzed during this study are included in this published article [and its supplementary information files].
∗ < 0, very unlikely; 0 – 1, unlikely; 2 – 3, possible; 4 – 5, probable; ≥ 6, very probable.
a Delay from initial drug component intake to onset of reaction: from 29 to 56 days.
b Delay from initial drug component intake to onset of reaction: from 5 to 28 days.
c Drug present in the body on index day: drug stopped at a time point prior to the index day by more than 5 times the elimination half-life, without liver or kidney function alterations or suspected drug interactions.
d Drug present in the body on index day: drug continued up to index day or stopped at a time point less than 5 times the elimination half-life before the index day.
e Prechallenge/rechanllenge: no known previous exposure to this drug.
f Prechallenge/rechanllenge: Exposure to this drug without any reaction (before or after reaction).
g Dechallenge: Drug stopped (or unknown).
h Dechallenge: Drug continued without harm.
i Type of drug (notoriety):No evidence of association from previous epidemiology study with sufficient number of exposed control.
j Type of drug (notoriety): Several previous reports, ambiguous epidemiology results (drug “under surveillance”).
k Type of drug (notoriety): All other drugs including newly released ones. | Oral | DrugAdministrationRoute | CC BY | 33546081 | 18,901,737 | 2021-01-22 |
What was the administration route of drug 'FUROSEMIDE'? | Toxic epidermal necrolysis in a patient on atorvastatin therapy expressing human leukocyte antigen alleles: A case report.
BACKGROUND
Toxic epidermal necrolysis (TEN) is a rare, severe mucosal response of the skin associated with a high mortality rate. TEN is most commonly caused by drugs, and is characterized by extensive skin epidermal exfoliation.
A 68-year-old woman presented with a rash that had persisted for four days. The patient who had undergone a mitral valve replacement 1 month prior and was taking atorvastatin at the time of admission.
The patient exhibited more than 30% exfoliation surfaces and the severe drug eruption was considered to be TEN. According to human leukocyte antigen (HLA) allele detection and ALDEN score, HLA alleles which found in this case report may be an cause of TEN induced by atorvastatin.
METHODS
All drugs used prior to admission were discontinued and the patient was given antiallergic drugs.
RESULTS
After 3 weeks following Antiallergic treatment, the rash on patient's calf had subsided, the edema was relieved, and the patient was no longer experiencing pain. After 60 days following discharge, the patient's skin has regrown.
CONCLUSIONS
This is the first report describing the induction of TEN by atorvastatin in a HLA alleles carrier. For HLA alleles carrier, atorvastatin may need to be used with caution to avoid TEN. Future systematic research is also required to confirm this finding and avoid similar serious skin adverse reactions.
1 Introduction
Toxic epidermal necrolysis (TEN) is an acute, life-threatening, severe dermatosis characterized by epidermal loss and multi-site mucositis, and is accompanied by systemic disturbance.[1] It is rare but very serious forms of drug-induced cutaneous adverse reaction. The morbidity of TEN is approximately 2 cases per million individuals each year.[2] The average mortality rate of TEN is over 30%, and the mortality rate of critically ill patients (SCORTEN > 3) is as high as 60% to 90%.[3]
Approximately 85% of TEN cases are induced by drugs.[4] The primary sensitizing drugs associated with TEN include antibiotics, anticonvulsants, antiviral drugs, and traditional Chinese medicine.[3] Recent studies have found that the occurrence of TEN is related to the individual human leukocyte antigen (HLA) allele genotype.[5,6,7] The HLA complex consists more than 200 genes on chromosome 6 can be categorized into 3 subgroups: Class I HLA, being recognized by CD8+ T cells, consists of 3 main genes, that is HLA-A, HLA-B, and HLA-C. Class II HLA, being recognized by CD4+ T cells, consists of 6 maingenes, that is, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLADQB1, HLA-DRA, and HLA-DRB1. HLA class I molecules are expressed in almost all the cells and are responsible for presenting peptides to immune cells.[5] Studies have shown that certain drugs that cause TEN are associated with HLA alleles; for example, carbamazepine-induced TEN and the HLA-B∗ 15:02 allele are highly correlated. Moreover, TEN induced by abacavir is correlated with individuals positive for the HLA-B∗57:01 allele.[5]
2 Case report
A 68-year-old woman presented with a rash that had persisted for 4 days. She had undergone a mitral valve replacement 1 month prior. Four days before admission, the patient developed a red rash on her face, chest, and back, accompanied by itching and a fever. At the time of admission, she presented with a burgundy rash that was distributed diffusely throughout her entire body. Moreover, some of the lesions were fused together, with a few blisters, itching, tolerability, fever, without skin breakage, subcutaneous nodules, bleeding, and ulcers (Fig. 1A). The laboratory test results revealed: albumin, 34.6 g/L; gamma glutamyl transpeptidase, 45 U/L; glucose, 13.24 mmol/L; creatine kinase MB subtype, 18.0 U/L; creatine kinase, 20 U/L; lactic dehydrogenase, 398 U/L; sodium, 135.9 mmol/L; leukocyte count, 5.19∗109/L; hemoglobin, 98.0 g/L; platelet count, 267 g/L; procalcitonin, 0.130 ng/mL; and fibrinogen, 4.35 g/L. The patient was taking the following medications at the time of admission: 0.125 mg qd po digoxin; 20 mg bid po furosemide; 1 g bid po potassium chloride; 0.625 mg qn po warfarin; and 20 mg qn po atorvastatin.
Figure 1 (A) At the time of admission, a burgundy rash was distributed diffusely throughout the patient's entire body. (B) On the fifth day of admission, the patient's facial skin began to peel, and blisters on her trunk began to rupture and peel. (C) After 60 days following discharge, the patient's skin has regrown.
On Day 1 post-admission, all drugs used prior to admission were discontinued and the patient was given antiallergic drugs, including 10 mg qd po loratadine, 10 mg qd po cetirizine, 100 mg tid po vitamin C, 120 mg q12 h po methylprednisolone, 40 mg q12 h ivgtt omeprazole acid, calamine and ethacridine for external use. The following day, the patient developed a large number of blisters that began to rupture over a large area of skin, and was accompanied by a fever. On Day 4, human immunoglobulin was intravenously administered. On Day 5, the patient's facial skin began to peel, and blisters on her trunk began to rupture and peel, which was associated with obvious pain. Mupirocin ointment was applied externally as treatment (Fig. 1B). On Day 11, the patient developed a new red patchy rash on both of her lower extremities accompanied by mild edema, as well as moderate blister formation near the thigh (Fig. 2). On Day 17, after developing erythema, blisters, rupture and peeling, the face and trunk skin were basically healed. On Day 22, the rash on her calf had subsided, the edema was relieved, and she was no longer experiencing pain. Then he was discharged from hospital. After 60 days following discharge, the patient's skin has regrown (Fig. 1C). During hospitalization, the location and exfoliation site of the rash were observed (Fig. 3); since the patient exhibited more than 30% exfoliation surfaces, the severe drug eruption was considered to be TEN rather than Stevens-Johnson Syndrome (SJS).
Figure 2 On Day 11 of admission, the patient developed a new red patchy rash on both lower extremities, which was accompanied by mild edema, and moderate blister formation near the thigh.
Figure 3 The location and exfoliation site of the rash were observed during hospitalization.
3 Investigations
Since more than 80% of TEN cases are caused by a drug allergy, timely cessation of the sensitizing drugs is the first step in treatment. Screening for suspected drug allergies relies primarily on medical history and previous reports of adverse drug reactions, however, for patients who have used multiple drugs before the onset of TEN, it is often difficult to identify the sensitizing drug.[4] The 2016 British Adult Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis Symptoms Management Guide recommends using the ALDEN score (drug causality algorithm for epidermal necrolysis) to retrospectively evaluate sensitizing drugs for TEN.[8] The ALDEN score was designed based on the results of the Severe Cutaneous Adverse Reaction case-control study conducted from 1989 to 1993. Therefore, we analyzed all of the drugs used in this patient according to the ALDEN score in order to identify those that induce TEN (Table 1). Atorvastatin had an ALDEN score of 4 (the highest score of all drugs taken; Table 1) and was judged to be “probable” for sensitization. Furthermore, the patient had taken warfarin for venous thrombosis of lower extremities 2 years ago and did not induce TEN. Thus, the patient's TEN was most likely caused by atorvastatin.
Table 1 Possible sensitizing drugs ALDEN score.
Values
Drugs the duration of use Criterion1 Criterion2 Criterion3 Criterion 4 Criterion 5 Final score Sensitization possibility∗
Aspirin 9/15–9/30 2a −3c 0e 0g −1i −2 Very unlikely
Atorvastatin calcium 9/20–10/16 3b 0d 0e 0g 1j 4 probable
Cefazolin sodium 9/14–9/15 2b −3c 0e 0g 1j 0 unlikely
Compound ammonia barbital 9/15–9/16 2a −3c 0e 0g 0k −1 Very unlikely
Furosemide 9/11–9/15,9/20–9/30, 10/1–10/16 3b 0d −2f −2h 0k −1 Very unlikely
Isosorbide mononitrate 9/20–10/16 3b 0d −2f 0g 1j 2 possible
Nitroglycerin 9/15–9/22 2a −3c 0e 0g 0k −1 Very unlikely
Cefoperazone Sulbactam Sodium 9/16–9/30 3b −3c −2f 0g 1j −1 Very unlikely
Warfarin 9/20–10/16 3b 0d −2f 0g 1j 2 possible
Tramadol 9/20–9/30 3b −3c 0e 0g 0k 0 unlikely
3.1 HLA allele detection
A 2-mL sample of peripheral venous blood was collected from the patient. Genomic DNA was extracted using a DNA extraction kit (Shanghai Baio Co., Ltd.) in accordance with the manufacturer's protocol. The exons of the HLA-A, -B, and-C loci were sequenced using sanger.[5] The results showed that the patient carried the HLA-A∗02:07, HLA-A∗11:01, HLA-B∗15:02, HLA-B∗40:01, HLA-C∗03:04, and HLA-C∗08:01 alleles.
4 Discussion
TEN is a serious skin mucosal disease characterized by large areas of erythema, blisters, epidermal exfoliation, and multi-site mucositis, that is often accompanied by systemic dysfunction.[1] The onset is urgent, progresses rapidly, and is associated with a high mortality rate. Thus, there is an urgent need to identify drugs that induce TEN. By using ALDEN to score all the drugs the patient had used, we were able to determine that atorvastatin was most likely associated with TEN in this patient. There have been 6 reports of statin-induced exfoliative dermatitis in the literature, including TEN, but none of the studies tested for HLA-related genes.[9,10,11,12,13,14] In addition, it is mentioned on the atorvastatin drug label that it may cause TEN in extremely rare cases.[15]
Genetic factors are also closely related to the occurrence of SJS/TEN. In this study, the patient's HLA exon was sequenced and found to carry multiple mutant HLA genotypes, that may have the correlation with SJS and TEN. A thorough review of the literature reveals that, among these alleles, HLA-B∗15:02, HLA-A∗02:07 and TEN may have the correlation.[16,17,18] The correlation between other alleles and TEN has not been reported, but their association cannot be ruled out, it need to be further investigated. HLA alleles have been proposed as markers of SJS/TEN. Studies revealed a high prevalence of pharmacogenetic markers of drug-induced SJS/TEN e.g., B∗13:01 for dapsone; B∗15:02 for carbamazepine and oxcarbazepine; B∗58:01, A∗33:03 and C∗03:02 for allopurinol; C∗08:01, C∗14:02 and DRB1∗12:02 for co-trimoxazole.[18] HLA alleles which found in this case report may be an cause of TEN induced by atorvastatin. Previous studies have found that HLA-B∗15:02 is an cause of serious adverse reactions in the skin induced by anti-epileptic drugs.[16] Carbamazepine non-covalently bind to proteins or peptides and are presented by MHC molecules after cellular processing, resulting in the HLA–restricted T cell activation.[17,19] Perhaps the mechanism of atorvastatin-induced TEN could be studied in the light of this study.
Atorvastatin is the most common drug for lipid lowering in patients with dyslipidemia, and the proportion of dyslipidemia in Chinese population is as high as 40.40%.[20] Therefore, the population of atorvastatin is very large, but SJS/TEN is very rare, HLA alleles may be a genetic factor. This is the first report describing the induction of TEN by atorvastatin in a HLA alleles carrier. Future systematic research is required to confirm this finding and avoid similar serious skin adverse reactions.
Author contributions
Conceptualization: Meina Lv, Yuxin Liu, Jinhua Zhang.
Data curation: Shaojun Jiang, Jinglan Fu.
Formal analysis: Yuxin Liu, Siheng Lian.
Project administration: Meina Lv, Jinhua Zhang.
Writing – original draft: Meina Lv.
Writing – review & editing: Shaojun Jiang, Jinglan Fu, Yuxin Liu, Siheng Lian, Jinhua Zhang.
Abbreviations: HLA = human leukocyte antigen, SJS = stevens-johnson syndrome, TEN = toxic epidermal necrolysis.
How to cite this article: Lv M, Jiang S, Fu J, Liu Y, Lian S, Zhang J. Toxic epidermal necrolysis in a patient on atorvastatin therapy expressing human leukocyte antigen alleles: a case report. Medicine. 2021;100:3(e24392).
This study was supported by the Natural Science Foundation of Fujian Province of China [grant number 2018Y0037].
Informed consent was obtained from the patient for publication of this case report. Approval of the study by our hospital's ethics committee was not required because it was a case report.
The authors have no conflicts of interest to disclose.
All data generated or analyzed during this study are included in this published article [and its supplementary information files].
∗ < 0, very unlikely; 0 – 1, unlikely; 2 – 3, possible; 4 – 5, probable; ≥ 6, very probable.
a Delay from initial drug component intake to onset of reaction: from 29 to 56 days.
b Delay from initial drug component intake to onset of reaction: from 5 to 28 days.
c Drug present in the body on index day: drug stopped at a time point prior to the index day by more than 5 times the elimination half-life, without liver or kidney function alterations or suspected drug interactions.
d Drug present in the body on index day: drug continued up to index day or stopped at a time point less than 5 times the elimination half-life before the index day.
e Prechallenge/rechanllenge: no known previous exposure to this drug.
f Prechallenge/rechanllenge: Exposure to this drug without any reaction (before or after reaction).
g Dechallenge: Drug stopped (or unknown).
h Dechallenge: Drug continued without harm.
i Type of drug (notoriety):No evidence of association from previous epidemiology study with sufficient number of exposed control.
j Type of drug (notoriety): Several previous reports, ambiguous epidemiology results (drug “under surveillance”).
k Type of drug (notoriety): All other drugs including newly released ones. | Oral | DrugAdministrationRoute | CC BY | 33546081 | 18,901,737 | 2021-01-22 |
What was the administration route of drug 'POTASSIUM CHLORIDE'? | Toxic epidermal necrolysis in a patient on atorvastatin therapy expressing human leukocyte antigen alleles: A case report.
BACKGROUND
Toxic epidermal necrolysis (TEN) is a rare, severe mucosal response of the skin associated with a high mortality rate. TEN is most commonly caused by drugs, and is characterized by extensive skin epidermal exfoliation.
A 68-year-old woman presented with a rash that had persisted for four days. The patient who had undergone a mitral valve replacement 1 month prior and was taking atorvastatin at the time of admission.
The patient exhibited more than 30% exfoliation surfaces and the severe drug eruption was considered to be TEN. According to human leukocyte antigen (HLA) allele detection and ALDEN score, HLA alleles which found in this case report may be an cause of TEN induced by atorvastatin.
METHODS
All drugs used prior to admission were discontinued and the patient was given antiallergic drugs.
RESULTS
After 3 weeks following Antiallergic treatment, the rash on patient's calf had subsided, the edema was relieved, and the patient was no longer experiencing pain. After 60 days following discharge, the patient's skin has regrown.
CONCLUSIONS
This is the first report describing the induction of TEN by atorvastatin in a HLA alleles carrier. For HLA alleles carrier, atorvastatin may need to be used with caution to avoid TEN. Future systematic research is also required to confirm this finding and avoid similar serious skin adverse reactions.
1 Introduction
Toxic epidermal necrolysis (TEN) is an acute, life-threatening, severe dermatosis characterized by epidermal loss and multi-site mucositis, and is accompanied by systemic disturbance.[1] It is rare but very serious forms of drug-induced cutaneous adverse reaction. The morbidity of TEN is approximately 2 cases per million individuals each year.[2] The average mortality rate of TEN is over 30%, and the mortality rate of critically ill patients (SCORTEN > 3) is as high as 60% to 90%.[3]
Approximately 85% of TEN cases are induced by drugs.[4] The primary sensitizing drugs associated with TEN include antibiotics, anticonvulsants, antiviral drugs, and traditional Chinese medicine.[3] Recent studies have found that the occurrence of TEN is related to the individual human leukocyte antigen (HLA) allele genotype.[5,6,7] The HLA complex consists more than 200 genes on chromosome 6 can be categorized into 3 subgroups: Class I HLA, being recognized by CD8+ T cells, consists of 3 main genes, that is HLA-A, HLA-B, and HLA-C. Class II HLA, being recognized by CD4+ T cells, consists of 6 maingenes, that is, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLADQB1, HLA-DRA, and HLA-DRB1. HLA class I molecules are expressed in almost all the cells and are responsible for presenting peptides to immune cells.[5] Studies have shown that certain drugs that cause TEN are associated with HLA alleles; for example, carbamazepine-induced TEN and the HLA-B∗ 15:02 allele are highly correlated. Moreover, TEN induced by abacavir is correlated with individuals positive for the HLA-B∗57:01 allele.[5]
2 Case report
A 68-year-old woman presented with a rash that had persisted for 4 days. She had undergone a mitral valve replacement 1 month prior. Four days before admission, the patient developed a red rash on her face, chest, and back, accompanied by itching and a fever. At the time of admission, she presented with a burgundy rash that was distributed diffusely throughout her entire body. Moreover, some of the lesions were fused together, with a few blisters, itching, tolerability, fever, without skin breakage, subcutaneous nodules, bleeding, and ulcers (Fig. 1A). The laboratory test results revealed: albumin, 34.6 g/L; gamma glutamyl transpeptidase, 45 U/L; glucose, 13.24 mmol/L; creatine kinase MB subtype, 18.0 U/L; creatine kinase, 20 U/L; lactic dehydrogenase, 398 U/L; sodium, 135.9 mmol/L; leukocyte count, 5.19∗109/L; hemoglobin, 98.0 g/L; platelet count, 267 g/L; procalcitonin, 0.130 ng/mL; and fibrinogen, 4.35 g/L. The patient was taking the following medications at the time of admission: 0.125 mg qd po digoxin; 20 mg bid po furosemide; 1 g bid po potassium chloride; 0.625 mg qn po warfarin; and 20 mg qn po atorvastatin.
Figure 1 (A) At the time of admission, a burgundy rash was distributed diffusely throughout the patient's entire body. (B) On the fifth day of admission, the patient's facial skin began to peel, and blisters on her trunk began to rupture and peel. (C) After 60 days following discharge, the patient's skin has regrown.
On Day 1 post-admission, all drugs used prior to admission were discontinued and the patient was given antiallergic drugs, including 10 mg qd po loratadine, 10 mg qd po cetirizine, 100 mg tid po vitamin C, 120 mg q12 h po methylprednisolone, 40 mg q12 h ivgtt omeprazole acid, calamine and ethacridine for external use. The following day, the patient developed a large number of blisters that began to rupture over a large area of skin, and was accompanied by a fever. On Day 4, human immunoglobulin was intravenously administered. On Day 5, the patient's facial skin began to peel, and blisters on her trunk began to rupture and peel, which was associated with obvious pain. Mupirocin ointment was applied externally as treatment (Fig. 1B). On Day 11, the patient developed a new red patchy rash on both of her lower extremities accompanied by mild edema, as well as moderate blister formation near the thigh (Fig. 2). On Day 17, after developing erythema, blisters, rupture and peeling, the face and trunk skin were basically healed. On Day 22, the rash on her calf had subsided, the edema was relieved, and she was no longer experiencing pain. Then he was discharged from hospital. After 60 days following discharge, the patient's skin has regrown (Fig. 1C). During hospitalization, the location and exfoliation site of the rash were observed (Fig. 3); since the patient exhibited more than 30% exfoliation surfaces, the severe drug eruption was considered to be TEN rather than Stevens-Johnson Syndrome (SJS).
Figure 2 On Day 11 of admission, the patient developed a new red patchy rash on both lower extremities, which was accompanied by mild edema, and moderate blister formation near the thigh.
Figure 3 The location and exfoliation site of the rash were observed during hospitalization.
3 Investigations
Since more than 80% of TEN cases are caused by a drug allergy, timely cessation of the sensitizing drugs is the first step in treatment. Screening for suspected drug allergies relies primarily on medical history and previous reports of adverse drug reactions, however, for patients who have used multiple drugs before the onset of TEN, it is often difficult to identify the sensitizing drug.[4] The 2016 British Adult Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis Symptoms Management Guide recommends using the ALDEN score (drug causality algorithm for epidermal necrolysis) to retrospectively evaluate sensitizing drugs for TEN.[8] The ALDEN score was designed based on the results of the Severe Cutaneous Adverse Reaction case-control study conducted from 1989 to 1993. Therefore, we analyzed all of the drugs used in this patient according to the ALDEN score in order to identify those that induce TEN (Table 1). Atorvastatin had an ALDEN score of 4 (the highest score of all drugs taken; Table 1) and was judged to be “probable” for sensitization. Furthermore, the patient had taken warfarin for venous thrombosis of lower extremities 2 years ago and did not induce TEN. Thus, the patient's TEN was most likely caused by atorvastatin.
Table 1 Possible sensitizing drugs ALDEN score.
Values
Drugs the duration of use Criterion1 Criterion2 Criterion3 Criterion 4 Criterion 5 Final score Sensitization possibility∗
Aspirin 9/15–9/30 2a −3c 0e 0g −1i −2 Very unlikely
Atorvastatin calcium 9/20–10/16 3b 0d 0e 0g 1j 4 probable
Cefazolin sodium 9/14–9/15 2b −3c 0e 0g 1j 0 unlikely
Compound ammonia barbital 9/15–9/16 2a −3c 0e 0g 0k −1 Very unlikely
Furosemide 9/11–9/15,9/20–9/30, 10/1–10/16 3b 0d −2f −2h 0k −1 Very unlikely
Isosorbide mononitrate 9/20–10/16 3b 0d −2f 0g 1j 2 possible
Nitroglycerin 9/15–9/22 2a −3c 0e 0g 0k −1 Very unlikely
Cefoperazone Sulbactam Sodium 9/16–9/30 3b −3c −2f 0g 1j −1 Very unlikely
Warfarin 9/20–10/16 3b 0d −2f 0g 1j 2 possible
Tramadol 9/20–9/30 3b −3c 0e 0g 0k 0 unlikely
3.1 HLA allele detection
A 2-mL sample of peripheral venous blood was collected from the patient. Genomic DNA was extracted using a DNA extraction kit (Shanghai Baio Co., Ltd.) in accordance with the manufacturer's protocol. The exons of the HLA-A, -B, and-C loci were sequenced using sanger.[5] The results showed that the patient carried the HLA-A∗02:07, HLA-A∗11:01, HLA-B∗15:02, HLA-B∗40:01, HLA-C∗03:04, and HLA-C∗08:01 alleles.
4 Discussion
TEN is a serious skin mucosal disease characterized by large areas of erythema, blisters, epidermal exfoliation, and multi-site mucositis, that is often accompanied by systemic dysfunction.[1] The onset is urgent, progresses rapidly, and is associated with a high mortality rate. Thus, there is an urgent need to identify drugs that induce TEN. By using ALDEN to score all the drugs the patient had used, we were able to determine that atorvastatin was most likely associated with TEN in this patient. There have been 6 reports of statin-induced exfoliative dermatitis in the literature, including TEN, but none of the studies tested for HLA-related genes.[9,10,11,12,13,14] In addition, it is mentioned on the atorvastatin drug label that it may cause TEN in extremely rare cases.[15]
Genetic factors are also closely related to the occurrence of SJS/TEN. In this study, the patient's HLA exon was sequenced and found to carry multiple mutant HLA genotypes, that may have the correlation with SJS and TEN. A thorough review of the literature reveals that, among these alleles, HLA-B∗15:02, HLA-A∗02:07 and TEN may have the correlation.[16,17,18] The correlation between other alleles and TEN has not been reported, but their association cannot be ruled out, it need to be further investigated. HLA alleles have been proposed as markers of SJS/TEN. Studies revealed a high prevalence of pharmacogenetic markers of drug-induced SJS/TEN e.g., B∗13:01 for dapsone; B∗15:02 for carbamazepine and oxcarbazepine; B∗58:01, A∗33:03 and C∗03:02 for allopurinol; C∗08:01, C∗14:02 and DRB1∗12:02 for co-trimoxazole.[18] HLA alleles which found in this case report may be an cause of TEN induced by atorvastatin. Previous studies have found that HLA-B∗15:02 is an cause of serious adverse reactions in the skin induced by anti-epileptic drugs.[16] Carbamazepine non-covalently bind to proteins or peptides and are presented by MHC molecules after cellular processing, resulting in the HLA–restricted T cell activation.[17,19] Perhaps the mechanism of atorvastatin-induced TEN could be studied in the light of this study.
Atorvastatin is the most common drug for lipid lowering in patients with dyslipidemia, and the proportion of dyslipidemia in Chinese population is as high as 40.40%.[20] Therefore, the population of atorvastatin is very large, but SJS/TEN is very rare, HLA alleles may be a genetic factor. This is the first report describing the induction of TEN by atorvastatin in a HLA alleles carrier. Future systematic research is required to confirm this finding and avoid similar serious skin adverse reactions.
Author contributions
Conceptualization: Meina Lv, Yuxin Liu, Jinhua Zhang.
Data curation: Shaojun Jiang, Jinglan Fu.
Formal analysis: Yuxin Liu, Siheng Lian.
Project administration: Meina Lv, Jinhua Zhang.
Writing – original draft: Meina Lv.
Writing – review & editing: Shaojun Jiang, Jinglan Fu, Yuxin Liu, Siheng Lian, Jinhua Zhang.
Abbreviations: HLA = human leukocyte antigen, SJS = stevens-johnson syndrome, TEN = toxic epidermal necrolysis.
How to cite this article: Lv M, Jiang S, Fu J, Liu Y, Lian S, Zhang J. Toxic epidermal necrolysis in a patient on atorvastatin therapy expressing human leukocyte antigen alleles: a case report. Medicine. 2021;100:3(e24392).
This study was supported by the Natural Science Foundation of Fujian Province of China [grant number 2018Y0037].
Informed consent was obtained from the patient for publication of this case report. Approval of the study by our hospital's ethics committee was not required because it was a case report.
The authors have no conflicts of interest to disclose.
All data generated or analyzed during this study are included in this published article [and its supplementary information files].
∗ < 0, very unlikely; 0 – 1, unlikely; 2 – 3, possible; 4 – 5, probable; ≥ 6, very probable.
a Delay from initial drug component intake to onset of reaction: from 29 to 56 days.
b Delay from initial drug component intake to onset of reaction: from 5 to 28 days.
c Drug present in the body on index day: drug stopped at a time point prior to the index day by more than 5 times the elimination half-life, without liver or kidney function alterations or suspected drug interactions.
d Drug present in the body on index day: drug continued up to index day or stopped at a time point less than 5 times the elimination half-life before the index day.
e Prechallenge/rechanllenge: no known previous exposure to this drug.
f Prechallenge/rechanllenge: Exposure to this drug without any reaction (before or after reaction).
g Dechallenge: Drug stopped (or unknown).
h Dechallenge: Drug continued without harm.
i Type of drug (notoriety):No evidence of association from previous epidemiology study with sufficient number of exposed control.
j Type of drug (notoriety): Several previous reports, ambiguous epidemiology results (drug “under surveillance”).
k Type of drug (notoriety): All other drugs including newly released ones. | Oral | DrugAdministrationRoute | CC BY | 33546081 | 18,901,737 | 2021-01-22 |
What was the administration route of drug 'WARFARIN'? | Toxic epidermal necrolysis in a patient on atorvastatin therapy expressing human leukocyte antigen alleles: A case report.
BACKGROUND
Toxic epidermal necrolysis (TEN) is a rare, severe mucosal response of the skin associated with a high mortality rate. TEN is most commonly caused by drugs, and is characterized by extensive skin epidermal exfoliation.
A 68-year-old woman presented with a rash that had persisted for four days. The patient who had undergone a mitral valve replacement 1 month prior and was taking atorvastatin at the time of admission.
The patient exhibited more than 30% exfoliation surfaces and the severe drug eruption was considered to be TEN. According to human leukocyte antigen (HLA) allele detection and ALDEN score, HLA alleles which found in this case report may be an cause of TEN induced by atorvastatin.
METHODS
All drugs used prior to admission were discontinued and the patient was given antiallergic drugs.
RESULTS
After 3 weeks following Antiallergic treatment, the rash on patient's calf had subsided, the edema was relieved, and the patient was no longer experiencing pain. After 60 days following discharge, the patient's skin has regrown.
CONCLUSIONS
This is the first report describing the induction of TEN by atorvastatin in a HLA alleles carrier. For HLA alleles carrier, atorvastatin may need to be used with caution to avoid TEN. Future systematic research is also required to confirm this finding and avoid similar serious skin adverse reactions.
1 Introduction
Toxic epidermal necrolysis (TEN) is an acute, life-threatening, severe dermatosis characterized by epidermal loss and multi-site mucositis, and is accompanied by systemic disturbance.[1] It is rare but very serious forms of drug-induced cutaneous adverse reaction. The morbidity of TEN is approximately 2 cases per million individuals each year.[2] The average mortality rate of TEN is over 30%, and the mortality rate of critically ill patients (SCORTEN > 3) is as high as 60% to 90%.[3]
Approximately 85% of TEN cases are induced by drugs.[4] The primary sensitizing drugs associated with TEN include antibiotics, anticonvulsants, antiviral drugs, and traditional Chinese medicine.[3] Recent studies have found that the occurrence of TEN is related to the individual human leukocyte antigen (HLA) allele genotype.[5,6,7] The HLA complex consists more than 200 genes on chromosome 6 can be categorized into 3 subgroups: Class I HLA, being recognized by CD8+ T cells, consists of 3 main genes, that is HLA-A, HLA-B, and HLA-C. Class II HLA, being recognized by CD4+ T cells, consists of 6 maingenes, that is, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLADQB1, HLA-DRA, and HLA-DRB1. HLA class I molecules are expressed in almost all the cells and are responsible for presenting peptides to immune cells.[5] Studies have shown that certain drugs that cause TEN are associated with HLA alleles; for example, carbamazepine-induced TEN and the HLA-B∗ 15:02 allele are highly correlated. Moreover, TEN induced by abacavir is correlated with individuals positive for the HLA-B∗57:01 allele.[5]
2 Case report
A 68-year-old woman presented with a rash that had persisted for 4 days. She had undergone a mitral valve replacement 1 month prior. Four days before admission, the patient developed a red rash on her face, chest, and back, accompanied by itching and a fever. At the time of admission, she presented with a burgundy rash that was distributed diffusely throughout her entire body. Moreover, some of the lesions were fused together, with a few blisters, itching, tolerability, fever, without skin breakage, subcutaneous nodules, bleeding, and ulcers (Fig. 1A). The laboratory test results revealed: albumin, 34.6 g/L; gamma glutamyl transpeptidase, 45 U/L; glucose, 13.24 mmol/L; creatine kinase MB subtype, 18.0 U/L; creatine kinase, 20 U/L; lactic dehydrogenase, 398 U/L; sodium, 135.9 mmol/L; leukocyte count, 5.19∗109/L; hemoglobin, 98.0 g/L; platelet count, 267 g/L; procalcitonin, 0.130 ng/mL; and fibrinogen, 4.35 g/L. The patient was taking the following medications at the time of admission: 0.125 mg qd po digoxin; 20 mg bid po furosemide; 1 g bid po potassium chloride; 0.625 mg qn po warfarin; and 20 mg qn po atorvastatin.
Figure 1 (A) At the time of admission, a burgundy rash was distributed diffusely throughout the patient's entire body. (B) On the fifth day of admission, the patient's facial skin began to peel, and blisters on her trunk began to rupture and peel. (C) After 60 days following discharge, the patient's skin has regrown.
On Day 1 post-admission, all drugs used prior to admission were discontinued and the patient was given antiallergic drugs, including 10 mg qd po loratadine, 10 mg qd po cetirizine, 100 mg tid po vitamin C, 120 mg q12 h po methylprednisolone, 40 mg q12 h ivgtt omeprazole acid, calamine and ethacridine for external use. The following day, the patient developed a large number of blisters that began to rupture over a large area of skin, and was accompanied by a fever. On Day 4, human immunoglobulin was intravenously administered. On Day 5, the patient's facial skin began to peel, and blisters on her trunk began to rupture and peel, which was associated with obvious pain. Mupirocin ointment was applied externally as treatment (Fig. 1B). On Day 11, the patient developed a new red patchy rash on both of her lower extremities accompanied by mild edema, as well as moderate blister formation near the thigh (Fig. 2). On Day 17, after developing erythema, blisters, rupture and peeling, the face and trunk skin were basically healed. On Day 22, the rash on her calf had subsided, the edema was relieved, and she was no longer experiencing pain. Then he was discharged from hospital. After 60 days following discharge, the patient's skin has regrown (Fig. 1C). During hospitalization, the location and exfoliation site of the rash were observed (Fig. 3); since the patient exhibited more than 30% exfoliation surfaces, the severe drug eruption was considered to be TEN rather than Stevens-Johnson Syndrome (SJS).
Figure 2 On Day 11 of admission, the patient developed a new red patchy rash on both lower extremities, which was accompanied by mild edema, and moderate blister formation near the thigh.
Figure 3 The location and exfoliation site of the rash were observed during hospitalization.
3 Investigations
Since more than 80% of TEN cases are caused by a drug allergy, timely cessation of the sensitizing drugs is the first step in treatment. Screening for suspected drug allergies relies primarily on medical history and previous reports of adverse drug reactions, however, for patients who have used multiple drugs before the onset of TEN, it is often difficult to identify the sensitizing drug.[4] The 2016 British Adult Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis Symptoms Management Guide recommends using the ALDEN score (drug causality algorithm for epidermal necrolysis) to retrospectively evaluate sensitizing drugs for TEN.[8] The ALDEN score was designed based on the results of the Severe Cutaneous Adverse Reaction case-control study conducted from 1989 to 1993. Therefore, we analyzed all of the drugs used in this patient according to the ALDEN score in order to identify those that induce TEN (Table 1). Atorvastatin had an ALDEN score of 4 (the highest score of all drugs taken; Table 1) and was judged to be “probable” for sensitization. Furthermore, the patient had taken warfarin for venous thrombosis of lower extremities 2 years ago and did not induce TEN. Thus, the patient's TEN was most likely caused by atorvastatin.
Table 1 Possible sensitizing drugs ALDEN score.
Values
Drugs the duration of use Criterion1 Criterion2 Criterion3 Criterion 4 Criterion 5 Final score Sensitization possibility∗
Aspirin 9/15–9/30 2a −3c 0e 0g −1i −2 Very unlikely
Atorvastatin calcium 9/20–10/16 3b 0d 0e 0g 1j 4 probable
Cefazolin sodium 9/14–9/15 2b −3c 0e 0g 1j 0 unlikely
Compound ammonia barbital 9/15–9/16 2a −3c 0e 0g 0k −1 Very unlikely
Furosemide 9/11–9/15,9/20–9/30, 10/1–10/16 3b 0d −2f −2h 0k −1 Very unlikely
Isosorbide mononitrate 9/20–10/16 3b 0d −2f 0g 1j 2 possible
Nitroglycerin 9/15–9/22 2a −3c 0e 0g 0k −1 Very unlikely
Cefoperazone Sulbactam Sodium 9/16–9/30 3b −3c −2f 0g 1j −1 Very unlikely
Warfarin 9/20–10/16 3b 0d −2f 0g 1j 2 possible
Tramadol 9/20–9/30 3b −3c 0e 0g 0k 0 unlikely
3.1 HLA allele detection
A 2-mL sample of peripheral venous blood was collected from the patient. Genomic DNA was extracted using a DNA extraction kit (Shanghai Baio Co., Ltd.) in accordance with the manufacturer's protocol. The exons of the HLA-A, -B, and-C loci were sequenced using sanger.[5] The results showed that the patient carried the HLA-A∗02:07, HLA-A∗11:01, HLA-B∗15:02, HLA-B∗40:01, HLA-C∗03:04, and HLA-C∗08:01 alleles.
4 Discussion
TEN is a serious skin mucosal disease characterized by large areas of erythema, blisters, epidermal exfoliation, and multi-site mucositis, that is often accompanied by systemic dysfunction.[1] The onset is urgent, progresses rapidly, and is associated with a high mortality rate. Thus, there is an urgent need to identify drugs that induce TEN. By using ALDEN to score all the drugs the patient had used, we were able to determine that atorvastatin was most likely associated with TEN in this patient. There have been 6 reports of statin-induced exfoliative dermatitis in the literature, including TEN, but none of the studies tested for HLA-related genes.[9,10,11,12,13,14] In addition, it is mentioned on the atorvastatin drug label that it may cause TEN in extremely rare cases.[15]
Genetic factors are also closely related to the occurrence of SJS/TEN. In this study, the patient's HLA exon was sequenced and found to carry multiple mutant HLA genotypes, that may have the correlation with SJS and TEN. A thorough review of the literature reveals that, among these alleles, HLA-B∗15:02, HLA-A∗02:07 and TEN may have the correlation.[16,17,18] The correlation between other alleles and TEN has not been reported, but their association cannot be ruled out, it need to be further investigated. HLA alleles have been proposed as markers of SJS/TEN. Studies revealed a high prevalence of pharmacogenetic markers of drug-induced SJS/TEN e.g., B∗13:01 for dapsone; B∗15:02 for carbamazepine and oxcarbazepine; B∗58:01, A∗33:03 and C∗03:02 for allopurinol; C∗08:01, C∗14:02 and DRB1∗12:02 for co-trimoxazole.[18] HLA alleles which found in this case report may be an cause of TEN induced by atorvastatin. Previous studies have found that HLA-B∗15:02 is an cause of serious adverse reactions in the skin induced by anti-epileptic drugs.[16] Carbamazepine non-covalently bind to proteins or peptides and are presented by MHC molecules after cellular processing, resulting in the HLA–restricted T cell activation.[17,19] Perhaps the mechanism of atorvastatin-induced TEN could be studied in the light of this study.
Atorvastatin is the most common drug for lipid lowering in patients with dyslipidemia, and the proportion of dyslipidemia in Chinese population is as high as 40.40%.[20] Therefore, the population of atorvastatin is very large, but SJS/TEN is very rare, HLA alleles may be a genetic factor. This is the first report describing the induction of TEN by atorvastatin in a HLA alleles carrier. Future systematic research is required to confirm this finding and avoid similar serious skin adverse reactions.
Author contributions
Conceptualization: Meina Lv, Yuxin Liu, Jinhua Zhang.
Data curation: Shaojun Jiang, Jinglan Fu.
Formal analysis: Yuxin Liu, Siheng Lian.
Project administration: Meina Lv, Jinhua Zhang.
Writing – original draft: Meina Lv.
Writing – review & editing: Shaojun Jiang, Jinglan Fu, Yuxin Liu, Siheng Lian, Jinhua Zhang.
Abbreviations: HLA = human leukocyte antigen, SJS = stevens-johnson syndrome, TEN = toxic epidermal necrolysis.
How to cite this article: Lv M, Jiang S, Fu J, Liu Y, Lian S, Zhang J. Toxic epidermal necrolysis in a patient on atorvastatin therapy expressing human leukocyte antigen alleles: a case report. Medicine. 2021;100:3(e24392).
This study was supported by the Natural Science Foundation of Fujian Province of China [grant number 2018Y0037].
Informed consent was obtained from the patient for publication of this case report. Approval of the study by our hospital's ethics committee was not required because it was a case report.
The authors have no conflicts of interest to disclose.
All data generated or analyzed during this study are included in this published article [and its supplementary information files].
∗ < 0, very unlikely; 0 – 1, unlikely; 2 – 3, possible; 4 – 5, probable; ≥ 6, very probable.
a Delay from initial drug component intake to onset of reaction: from 29 to 56 days.
b Delay from initial drug component intake to onset of reaction: from 5 to 28 days.
c Drug present in the body on index day: drug stopped at a time point prior to the index day by more than 5 times the elimination half-life, without liver or kidney function alterations or suspected drug interactions.
d Drug present in the body on index day: drug continued up to index day or stopped at a time point less than 5 times the elimination half-life before the index day.
e Prechallenge/rechanllenge: no known previous exposure to this drug.
f Prechallenge/rechanllenge: Exposure to this drug without any reaction (before or after reaction).
g Dechallenge: Drug stopped (or unknown).
h Dechallenge: Drug continued without harm.
i Type of drug (notoriety):No evidence of association from previous epidemiology study with sufficient number of exposed control.
j Type of drug (notoriety): Several previous reports, ambiguous epidemiology results (drug “under surveillance”).
k Type of drug (notoriety): All other drugs including newly released ones. | Oral | DrugAdministrationRoute | CC BY | 33546081 | 18,901,737 | 2021-01-22 |
What was the dosage of drug 'ASPIRIN'? | Toxic epidermal necrolysis in a patient on atorvastatin therapy expressing human leukocyte antigen alleles: A case report.
BACKGROUND
Toxic epidermal necrolysis (TEN) is a rare, severe mucosal response of the skin associated with a high mortality rate. TEN is most commonly caused by drugs, and is characterized by extensive skin epidermal exfoliation.
A 68-year-old woman presented with a rash that had persisted for four days. The patient who had undergone a mitral valve replacement 1 month prior and was taking atorvastatin at the time of admission.
The patient exhibited more than 30% exfoliation surfaces and the severe drug eruption was considered to be TEN. According to human leukocyte antigen (HLA) allele detection and ALDEN score, HLA alleles which found in this case report may be an cause of TEN induced by atorvastatin.
METHODS
All drugs used prior to admission were discontinued and the patient was given antiallergic drugs.
RESULTS
After 3 weeks following Antiallergic treatment, the rash on patient's calf had subsided, the edema was relieved, and the patient was no longer experiencing pain. After 60 days following discharge, the patient's skin has regrown.
CONCLUSIONS
This is the first report describing the induction of TEN by atorvastatin in a HLA alleles carrier. For HLA alleles carrier, atorvastatin may need to be used with caution to avoid TEN. Future systematic research is also required to confirm this finding and avoid similar serious skin adverse reactions.
1 Introduction
Toxic epidermal necrolysis (TEN) is an acute, life-threatening, severe dermatosis characterized by epidermal loss and multi-site mucositis, and is accompanied by systemic disturbance.[1] It is rare but very serious forms of drug-induced cutaneous adverse reaction. The morbidity of TEN is approximately 2 cases per million individuals each year.[2] The average mortality rate of TEN is over 30%, and the mortality rate of critically ill patients (SCORTEN > 3) is as high as 60% to 90%.[3]
Approximately 85% of TEN cases are induced by drugs.[4] The primary sensitizing drugs associated with TEN include antibiotics, anticonvulsants, antiviral drugs, and traditional Chinese medicine.[3] Recent studies have found that the occurrence of TEN is related to the individual human leukocyte antigen (HLA) allele genotype.[5,6,7] The HLA complex consists more than 200 genes on chromosome 6 can be categorized into 3 subgroups: Class I HLA, being recognized by CD8+ T cells, consists of 3 main genes, that is HLA-A, HLA-B, and HLA-C. Class II HLA, being recognized by CD4+ T cells, consists of 6 maingenes, that is, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLADQB1, HLA-DRA, and HLA-DRB1. HLA class I molecules are expressed in almost all the cells and are responsible for presenting peptides to immune cells.[5] Studies have shown that certain drugs that cause TEN are associated with HLA alleles; for example, carbamazepine-induced TEN and the HLA-B∗ 15:02 allele are highly correlated. Moreover, TEN induced by abacavir is correlated with individuals positive for the HLA-B∗57:01 allele.[5]
2 Case report
A 68-year-old woman presented with a rash that had persisted for 4 days. She had undergone a mitral valve replacement 1 month prior. Four days before admission, the patient developed a red rash on her face, chest, and back, accompanied by itching and a fever. At the time of admission, she presented with a burgundy rash that was distributed diffusely throughout her entire body. Moreover, some of the lesions were fused together, with a few blisters, itching, tolerability, fever, without skin breakage, subcutaneous nodules, bleeding, and ulcers (Fig. 1A). The laboratory test results revealed: albumin, 34.6 g/L; gamma glutamyl transpeptidase, 45 U/L; glucose, 13.24 mmol/L; creatine kinase MB subtype, 18.0 U/L; creatine kinase, 20 U/L; lactic dehydrogenase, 398 U/L; sodium, 135.9 mmol/L; leukocyte count, 5.19∗109/L; hemoglobin, 98.0 g/L; platelet count, 267 g/L; procalcitonin, 0.130 ng/mL; and fibrinogen, 4.35 g/L. The patient was taking the following medications at the time of admission: 0.125 mg qd po digoxin; 20 mg bid po furosemide; 1 g bid po potassium chloride; 0.625 mg qn po warfarin; and 20 mg qn po atorvastatin.
Figure 1 (A) At the time of admission, a burgundy rash was distributed diffusely throughout the patient's entire body. (B) On the fifth day of admission, the patient's facial skin began to peel, and blisters on her trunk began to rupture and peel. (C) After 60 days following discharge, the patient's skin has regrown.
On Day 1 post-admission, all drugs used prior to admission were discontinued and the patient was given antiallergic drugs, including 10 mg qd po loratadine, 10 mg qd po cetirizine, 100 mg tid po vitamin C, 120 mg q12 h po methylprednisolone, 40 mg q12 h ivgtt omeprazole acid, calamine and ethacridine for external use. The following day, the patient developed a large number of blisters that began to rupture over a large area of skin, and was accompanied by a fever. On Day 4, human immunoglobulin was intravenously administered. On Day 5, the patient's facial skin began to peel, and blisters on her trunk began to rupture and peel, which was associated with obvious pain. Mupirocin ointment was applied externally as treatment (Fig. 1B). On Day 11, the patient developed a new red patchy rash on both of her lower extremities accompanied by mild edema, as well as moderate blister formation near the thigh (Fig. 2). On Day 17, after developing erythema, blisters, rupture and peeling, the face and trunk skin were basically healed. On Day 22, the rash on her calf had subsided, the edema was relieved, and she was no longer experiencing pain. Then he was discharged from hospital. After 60 days following discharge, the patient's skin has regrown (Fig. 1C). During hospitalization, the location and exfoliation site of the rash were observed (Fig. 3); since the patient exhibited more than 30% exfoliation surfaces, the severe drug eruption was considered to be TEN rather than Stevens-Johnson Syndrome (SJS).
Figure 2 On Day 11 of admission, the patient developed a new red patchy rash on both lower extremities, which was accompanied by mild edema, and moderate blister formation near the thigh.
Figure 3 The location and exfoliation site of the rash were observed during hospitalization.
3 Investigations
Since more than 80% of TEN cases are caused by a drug allergy, timely cessation of the sensitizing drugs is the first step in treatment. Screening for suspected drug allergies relies primarily on medical history and previous reports of adverse drug reactions, however, for patients who have used multiple drugs before the onset of TEN, it is often difficult to identify the sensitizing drug.[4] The 2016 British Adult Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis Symptoms Management Guide recommends using the ALDEN score (drug causality algorithm for epidermal necrolysis) to retrospectively evaluate sensitizing drugs for TEN.[8] The ALDEN score was designed based on the results of the Severe Cutaneous Adverse Reaction case-control study conducted from 1989 to 1993. Therefore, we analyzed all of the drugs used in this patient according to the ALDEN score in order to identify those that induce TEN (Table 1). Atorvastatin had an ALDEN score of 4 (the highest score of all drugs taken; Table 1) and was judged to be “probable” for sensitization. Furthermore, the patient had taken warfarin for venous thrombosis of lower extremities 2 years ago and did not induce TEN. Thus, the patient's TEN was most likely caused by atorvastatin.
Table 1 Possible sensitizing drugs ALDEN score.
Values
Drugs the duration of use Criterion1 Criterion2 Criterion3 Criterion 4 Criterion 5 Final score Sensitization possibility∗
Aspirin 9/15–9/30 2a −3c 0e 0g −1i −2 Very unlikely
Atorvastatin calcium 9/20–10/16 3b 0d 0e 0g 1j 4 probable
Cefazolin sodium 9/14–9/15 2b −3c 0e 0g 1j 0 unlikely
Compound ammonia barbital 9/15–9/16 2a −3c 0e 0g 0k −1 Very unlikely
Furosemide 9/11–9/15,9/20–9/30, 10/1–10/16 3b 0d −2f −2h 0k −1 Very unlikely
Isosorbide mononitrate 9/20–10/16 3b 0d −2f 0g 1j 2 possible
Nitroglycerin 9/15–9/22 2a −3c 0e 0g 0k −1 Very unlikely
Cefoperazone Sulbactam Sodium 9/16–9/30 3b −3c −2f 0g 1j −1 Very unlikely
Warfarin 9/20–10/16 3b 0d −2f 0g 1j 2 possible
Tramadol 9/20–9/30 3b −3c 0e 0g 0k 0 unlikely
3.1 HLA allele detection
A 2-mL sample of peripheral venous blood was collected from the patient. Genomic DNA was extracted using a DNA extraction kit (Shanghai Baio Co., Ltd.) in accordance with the manufacturer's protocol. The exons of the HLA-A, -B, and-C loci were sequenced using sanger.[5] The results showed that the patient carried the HLA-A∗02:07, HLA-A∗11:01, HLA-B∗15:02, HLA-B∗40:01, HLA-C∗03:04, and HLA-C∗08:01 alleles.
4 Discussion
TEN is a serious skin mucosal disease characterized by large areas of erythema, blisters, epidermal exfoliation, and multi-site mucositis, that is often accompanied by systemic dysfunction.[1] The onset is urgent, progresses rapidly, and is associated with a high mortality rate. Thus, there is an urgent need to identify drugs that induce TEN. By using ALDEN to score all the drugs the patient had used, we were able to determine that atorvastatin was most likely associated with TEN in this patient. There have been 6 reports of statin-induced exfoliative dermatitis in the literature, including TEN, but none of the studies tested for HLA-related genes.[9,10,11,12,13,14] In addition, it is mentioned on the atorvastatin drug label that it may cause TEN in extremely rare cases.[15]
Genetic factors are also closely related to the occurrence of SJS/TEN. In this study, the patient's HLA exon was sequenced and found to carry multiple mutant HLA genotypes, that may have the correlation with SJS and TEN. A thorough review of the literature reveals that, among these alleles, HLA-B∗15:02, HLA-A∗02:07 and TEN may have the correlation.[16,17,18] The correlation between other alleles and TEN has not been reported, but their association cannot be ruled out, it need to be further investigated. HLA alleles have been proposed as markers of SJS/TEN. Studies revealed a high prevalence of pharmacogenetic markers of drug-induced SJS/TEN e.g., B∗13:01 for dapsone; B∗15:02 for carbamazepine and oxcarbazepine; B∗58:01, A∗33:03 and C∗03:02 for allopurinol; C∗08:01, C∗14:02 and DRB1∗12:02 for co-trimoxazole.[18] HLA alleles which found in this case report may be an cause of TEN induced by atorvastatin. Previous studies have found that HLA-B∗15:02 is an cause of serious adverse reactions in the skin induced by anti-epileptic drugs.[16] Carbamazepine non-covalently bind to proteins or peptides and are presented by MHC molecules after cellular processing, resulting in the HLA–restricted T cell activation.[17,19] Perhaps the mechanism of atorvastatin-induced TEN could be studied in the light of this study.
Atorvastatin is the most common drug for lipid lowering in patients with dyslipidemia, and the proportion of dyslipidemia in Chinese population is as high as 40.40%.[20] Therefore, the population of atorvastatin is very large, but SJS/TEN is very rare, HLA alleles may be a genetic factor. This is the first report describing the induction of TEN by atorvastatin in a HLA alleles carrier. Future systematic research is required to confirm this finding and avoid similar serious skin adverse reactions.
Author contributions
Conceptualization: Meina Lv, Yuxin Liu, Jinhua Zhang.
Data curation: Shaojun Jiang, Jinglan Fu.
Formal analysis: Yuxin Liu, Siheng Lian.
Project administration: Meina Lv, Jinhua Zhang.
Writing – original draft: Meina Lv.
Writing – review & editing: Shaojun Jiang, Jinglan Fu, Yuxin Liu, Siheng Lian, Jinhua Zhang.
Abbreviations: HLA = human leukocyte antigen, SJS = stevens-johnson syndrome, TEN = toxic epidermal necrolysis.
How to cite this article: Lv M, Jiang S, Fu J, Liu Y, Lian S, Zhang J. Toxic epidermal necrolysis in a patient on atorvastatin therapy expressing human leukocyte antigen alleles: a case report. Medicine. 2021;100:3(e24392).
This study was supported by the Natural Science Foundation of Fujian Province of China [grant number 2018Y0037].
Informed consent was obtained from the patient for publication of this case report. Approval of the study by our hospital's ethics committee was not required because it was a case report.
The authors have no conflicts of interest to disclose.
All data generated or analyzed during this study are included in this published article [and its supplementary information files].
∗ < 0, very unlikely; 0 – 1, unlikely; 2 – 3, possible; 4 – 5, probable; ≥ 6, very probable.
a Delay from initial drug component intake to onset of reaction: from 29 to 56 days.
b Delay from initial drug component intake to onset of reaction: from 5 to 28 days.
c Drug present in the body on index day: drug stopped at a time point prior to the index day by more than 5 times the elimination half-life, without liver or kidney function alterations or suspected drug interactions.
d Drug present in the body on index day: drug continued up to index day or stopped at a time point less than 5 times the elimination half-life before the index day.
e Prechallenge/rechanllenge: no known previous exposure to this drug.
f Prechallenge/rechanllenge: Exposure to this drug without any reaction (before or after reaction).
g Dechallenge: Drug stopped (or unknown).
h Dechallenge: Drug continued without harm.
i Type of drug (notoriety):No evidence of association from previous epidemiology study with sufficient number of exposed control.
j Type of drug (notoriety): Several previous reports, ambiguous epidemiology results (drug “under surveillance”).
k Type of drug (notoriety): All other drugs including newly released ones. | DURATION OF USE: 9/15?9/30 | DrugDosageText | CC BY | 33546081 | 18,901,737 | 2021-01-22 |
What was the dosage of drug 'BARBITAL'? | Toxic epidermal necrolysis in a patient on atorvastatin therapy expressing human leukocyte antigen alleles: A case report.
BACKGROUND
Toxic epidermal necrolysis (TEN) is a rare, severe mucosal response of the skin associated with a high mortality rate. TEN is most commonly caused by drugs, and is characterized by extensive skin epidermal exfoliation.
A 68-year-old woman presented with a rash that had persisted for four days. The patient who had undergone a mitral valve replacement 1 month prior and was taking atorvastatin at the time of admission.
The patient exhibited more than 30% exfoliation surfaces and the severe drug eruption was considered to be TEN. According to human leukocyte antigen (HLA) allele detection and ALDEN score, HLA alleles which found in this case report may be an cause of TEN induced by atorvastatin.
METHODS
All drugs used prior to admission were discontinued and the patient was given antiallergic drugs.
RESULTS
After 3 weeks following Antiallergic treatment, the rash on patient's calf had subsided, the edema was relieved, and the patient was no longer experiencing pain. After 60 days following discharge, the patient's skin has regrown.
CONCLUSIONS
This is the first report describing the induction of TEN by atorvastatin in a HLA alleles carrier. For HLA alleles carrier, atorvastatin may need to be used with caution to avoid TEN. Future systematic research is also required to confirm this finding and avoid similar serious skin adverse reactions.
1 Introduction
Toxic epidermal necrolysis (TEN) is an acute, life-threatening, severe dermatosis characterized by epidermal loss and multi-site mucositis, and is accompanied by systemic disturbance.[1] It is rare but very serious forms of drug-induced cutaneous adverse reaction. The morbidity of TEN is approximately 2 cases per million individuals each year.[2] The average mortality rate of TEN is over 30%, and the mortality rate of critically ill patients (SCORTEN > 3) is as high as 60% to 90%.[3]
Approximately 85% of TEN cases are induced by drugs.[4] The primary sensitizing drugs associated with TEN include antibiotics, anticonvulsants, antiviral drugs, and traditional Chinese medicine.[3] Recent studies have found that the occurrence of TEN is related to the individual human leukocyte antigen (HLA) allele genotype.[5,6,7] The HLA complex consists more than 200 genes on chromosome 6 can be categorized into 3 subgroups: Class I HLA, being recognized by CD8+ T cells, consists of 3 main genes, that is HLA-A, HLA-B, and HLA-C. Class II HLA, being recognized by CD4+ T cells, consists of 6 maingenes, that is, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLADQB1, HLA-DRA, and HLA-DRB1. HLA class I molecules are expressed in almost all the cells and are responsible for presenting peptides to immune cells.[5] Studies have shown that certain drugs that cause TEN are associated with HLA alleles; for example, carbamazepine-induced TEN and the HLA-B∗ 15:02 allele are highly correlated. Moreover, TEN induced by abacavir is correlated with individuals positive for the HLA-B∗57:01 allele.[5]
2 Case report
A 68-year-old woman presented with a rash that had persisted for 4 days. She had undergone a mitral valve replacement 1 month prior. Four days before admission, the patient developed a red rash on her face, chest, and back, accompanied by itching and a fever. At the time of admission, she presented with a burgundy rash that was distributed diffusely throughout her entire body. Moreover, some of the lesions were fused together, with a few blisters, itching, tolerability, fever, without skin breakage, subcutaneous nodules, bleeding, and ulcers (Fig. 1A). The laboratory test results revealed: albumin, 34.6 g/L; gamma glutamyl transpeptidase, 45 U/L; glucose, 13.24 mmol/L; creatine kinase MB subtype, 18.0 U/L; creatine kinase, 20 U/L; lactic dehydrogenase, 398 U/L; sodium, 135.9 mmol/L; leukocyte count, 5.19∗109/L; hemoglobin, 98.0 g/L; platelet count, 267 g/L; procalcitonin, 0.130 ng/mL; and fibrinogen, 4.35 g/L. The patient was taking the following medications at the time of admission: 0.125 mg qd po digoxin; 20 mg bid po furosemide; 1 g bid po potassium chloride; 0.625 mg qn po warfarin; and 20 mg qn po atorvastatin.
Figure 1 (A) At the time of admission, a burgundy rash was distributed diffusely throughout the patient's entire body. (B) On the fifth day of admission, the patient's facial skin began to peel, and blisters on her trunk began to rupture and peel. (C) After 60 days following discharge, the patient's skin has regrown.
On Day 1 post-admission, all drugs used prior to admission were discontinued and the patient was given antiallergic drugs, including 10 mg qd po loratadine, 10 mg qd po cetirizine, 100 mg tid po vitamin C, 120 mg q12 h po methylprednisolone, 40 mg q12 h ivgtt omeprazole acid, calamine and ethacridine for external use. The following day, the patient developed a large number of blisters that began to rupture over a large area of skin, and was accompanied by a fever. On Day 4, human immunoglobulin was intravenously administered. On Day 5, the patient's facial skin began to peel, and blisters on her trunk began to rupture and peel, which was associated with obvious pain. Mupirocin ointment was applied externally as treatment (Fig. 1B). On Day 11, the patient developed a new red patchy rash on both of her lower extremities accompanied by mild edema, as well as moderate blister formation near the thigh (Fig. 2). On Day 17, after developing erythema, blisters, rupture and peeling, the face and trunk skin were basically healed. On Day 22, the rash on her calf had subsided, the edema was relieved, and she was no longer experiencing pain. Then he was discharged from hospital. After 60 days following discharge, the patient's skin has regrown (Fig. 1C). During hospitalization, the location and exfoliation site of the rash were observed (Fig. 3); since the patient exhibited more than 30% exfoliation surfaces, the severe drug eruption was considered to be TEN rather than Stevens-Johnson Syndrome (SJS).
Figure 2 On Day 11 of admission, the patient developed a new red patchy rash on both lower extremities, which was accompanied by mild edema, and moderate blister formation near the thigh.
Figure 3 The location and exfoliation site of the rash were observed during hospitalization.
3 Investigations
Since more than 80% of TEN cases are caused by a drug allergy, timely cessation of the sensitizing drugs is the first step in treatment. Screening for suspected drug allergies relies primarily on medical history and previous reports of adverse drug reactions, however, for patients who have used multiple drugs before the onset of TEN, it is often difficult to identify the sensitizing drug.[4] The 2016 British Adult Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis Symptoms Management Guide recommends using the ALDEN score (drug causality algorithm for epidermal necrolysis) to retrospectively evaluate sensitizing drugs for TEN.[8] The ALDEN score was designed based on the results of the Severe Cutaneous Adverse Reaction case-control study conducted from 1989 to 1993. Therefore, we analyzed all of the drugs used in this patient according to the ALDEN score in order to identify those that induce TEN (Table 1). Atorvastatin had an ALDEN score of 4 (the highest score of all drugs taken; Table 1) and was judged to be “probable” for sensitization. Furthermore, the patient had taken warfarin for venous thrombosis of lower extremities 2 years ago and did not induce TEN. Thus, the patient's TEN was most likely caused by atorvastatin.
Table 1 Possible sensitizing drugs ALDEN score.
Values
Drugs the duration of use Criterion1 Criterion2 Criterion3 Criterion 4 Criterion 5 Final score Sensitization possibility∗
Aspirin 9/15–9/30 2a −3c 0e 0g −1i −2 Very unlikely
Atorvastatin calcium 9/20–10/16 3b 0d 0e 0g 1j 4 probable
Cefazolin sodium 9/14–9/15 2b −3c 0e 0g 1j 0 unlikely
Compound ammonia barbital 9/15–9/16 2a −3c 0e 0g 0k −1 Very unlikely
Furosemide 9/11–9/15,9/20–9/30, 10/1–10/16 3b 0d −2f −2h 0k −1 Very unlikely
Isosorbide mononitrate 9/20–10/16 3b 0d −2f 0g 1j 2 possible
Nitroglycerin 9/15–9/22 2a −3c 0e 0g 0k −1 Very unlikely
Cefoperazone Sulbactam Sodium 9/16–9/30 3b −3c −2f 0g 1j −1 Very unlikely
Warfarin 9/20–10/16 3b 0d −2f 0g 1j 2 possible
Tramadol 9/20–9/30 3b −3c 0e 0g 0k 0 unlikely
3.1 HLA allele detection
A 2-mL sample of peripheral venous blood was collected from the patient. Genomic DNA was extracted using a DNA extraction kit (Shanghai Baio Co., Ltd.) in accordance with the manufacturer's protocol. The exons of the HLA-A, -B, and-C loci were sequenced using sanger.[5] The results showed that the patient carried the HLA-A∗02:07, HLA-A∗11:01, HLA-B∗15:02, HLA-B∗40:01, HLA-C∗03:04, and HLA-C∗08:01 alleles.
4 Discussion
TEN is a serious skin mucosal disease characterized by large areas of erythema, blisters, epidermal exfoliation, and multi-site mucositis, that is often accompanied by systemic dysfunction.[1] The onset is urgent, progresses rapidly, and is associated with a high mortality rate. Thus, there is an urgent need to identify drugs that induce TEN. By using ALDEN to score all the drugs the patient had used, we were able to determine that atorvastatin was most likely associated with TEN in this patient. There have been 6 reports of statin-induced exfoliative dermatitis in the literature, including TEN, but none of the studies tested for HLA-related genes.[9,10,11,12,13,14] In addition, it is mentioned on the atorvastatin drug label that it may cause TEN in extremely rare cases.[15]
Genetic factors are also closely related to the occurrence of SJS/TEN. In this study, the patient's HLA exon was sequenced and found to carry multiple mutant HLA genotypes, that may have the correlation with SJS and TEN. A thorough review of the literature reveals that, among these alleles, HLA-B∗15:02, HLA-A∗02:07 and TEN may have the correlation.[16,17,18] The correlation between other alleles and TEN has not been reported, but their association cannot be ruled out, it need to be further investigated. HLA alleles have been proposed as markers of SJS/TEN. Studies revealed a high prevalence of pharmacogenetic markers of drug-induced SJS/TEN e.g., B∗13:01 for dapsone; B∗15:02 for carbamazepine and oxcarbazepine; B∗58:01, A∗33:03 and C∗03:02 for allopurinol; C∗08:01, C∗14:02 and DRB1∗12:02 for co-trimoxazole.[18] HLA alleles which found in this case report may be an cause of TEN induced by atorvastatin. Previous studies have found that HLA-B∗15:02 is an cause of serious adverse reactions in the skin induced by anti-epileptic drugs.[16] Carbamazepine non-covalently bind to proteins or peptides and are presented by MHC molecules after cellular processing, resulting in the HLA–restricted T cell activation.[17,19] Perhaps the mechanism of atorvastatin-induced TEN could be studied in the light of this study.
Atorvastatin is the most common drug for lipid lowering in patients with dyslipidemia, and the proportion of dyslipidemia in Chinese population is as high as 40.40%.[20] Therefore, the population of atorvastatin is very large, but SJS/TEN is very rare, HLA alleles may be a genetic factor. This is the first report describing the induction of TEN by atorvastatin in a HLA alleles carrier. Future systematic research is required to confirm this finding and avoid similar serious skin adverse reactions.
Author contributions
Conceptualization: Meina Lv, Yuxin Liu, Jinhua Zhang.
Data curation: Shaojun Jiang, Jinglan Fu.
Formal analysis: Yuxin Liu, Siheng Lian.
Project administration: Meina Lv, Jinhua Zhang.
Writing – original draft: Meina Lv.
Writing – review & editing: Shaojun Jiang, Jinglan Fu, Yuxin Liu, Siheng Lian, Jinhua Zhang.
Abbreviations: HLA = human leukocyte antigen, SJS = stevens-johnson syndrome, TEN = toxic epidermal necrolysis.
How to cite this article: Lv M, Jiang S, Fu J, Liu Y, Lian S, Zhang J. Toxic epidermal necrolysis in a patient on atorvastatin therapy expressing human leukocyte antigen alleles: a case report. Medicine. 2021;100:3(e24392).
This study was supported by the Natural Science Foundation of Fujian Province of China [grant number 2018Y0037].
Informed consent was obtained from the patient for publication of this case report. Approval of the study by our hospital's ethics committee was not required because it was a case report.
The authors have no conflicts of interest to disclose.
All data generated or analyzed during this study are included in this published article [and its supplementary information files].
∗ < 0, very unlikely; 0 – 1, unlikely; 2 – 3, possible; 4 – 5, probable; ≥ 6, very probable.
a Delay from initial drug component intake to onset of reaction: from 29 to 56 days.
b Delay from initial drug component intake to onset of reaction: from 5 to 28 days.
c Drug present in the body on index day: drug stopped at a time point prior to the index day by more than 5 times the elimination half-life, without liver or kidney function alterations or suspected drug interactions.
d Drug present in the body on index day: drug continued up to index day or stopped at a time point less than 5 times the elimination half-life before the index day.
e Prechallenge/rechanllenge: no known previous exposure to this drug.
f Prechallenge/rechanllenge: Exposure to this drug without any reaction (before or after reaction).
g Dechallenge: Drug stopped (or unknown).
h Dechallenge: Drug continued without harm.
i Type of drug (notoriety):No evidence of association from previous epidemiology study with sufficient number of exposed control.
j Type of drug (notoriety): Several previous reports, ambiguous epidemiology results (drug “under surveillance”).
k Type of drug (notoriety): All other drugs including newly released ones. | DURATION OF USE: 9/15?9/16 | DrugDosageText | CC BY | 33546081 | 18,901,737 | 2021-01-22 |
What was the dosage of drug 'CEFAZOLIN'? | Toxic epidermal necrolysis in a patient on atorvastatin therapy expressing human leukocyte antigen alleles: A case report.
BACKGROUND
Toxic epidermal necrolysis (TEN) is a rare, severe mucosal response of the skin associated with a high mortality rate. TEN is most commonly caused by drugs, and is characterized by extensive skin epidermal exfoliation.
A 68-year-old woman presented with a rash that had persisted for four days. The patient who had undergone a mitral valve replacement 1 month prior and was taking atorvastatin at the time of admission.
The patient exhibited more than 30% exfoliation surfaces and the severe drug eruption was considered to be TEN. According to human leukocyte antigen (HLA) allele detection and ALDEN score, HLA alleles which found in this case report may be an cause of TEN induced by atorvastatin.
METHODS
All drugs used prior to admission were discontinued and the patient was given antiallergic drugs.
RESULTS
After 3 weeks following Antiallergic treatment, the rash on patient's calf had subsided, the edema was relieved, and the patient was no longer experiencing pain. After 60 days following discharge, the patient's skin has regrown.
CONCLUSIONS
This is the first report describing the induction of TEN by atorvastatin in a HLA alleles carrier. For HLA alleles carrier, atorvastatin may need to be used with caution to avoid TEN. Future systematic research is also required to confirm this finding and avoid similar serious skin adverse reactions.
1 Introduction
Toxic epidermal necrolysis (TEN) is an acute, life-threatening, severe dermatosis characterized by epidermal loss and multi-site mucositis, and is accompanied by systemic disturbance.[1] It is rare but very serious forms of drug-induced cutaneous adverse reaction. The morbidity of TEN is approximately 2 cases per million individuals each year.[2] The average mortality rate of TEN is over 30%, and the mortality rate of critically ill patients (SCORTEN > 3) is as high as 60% to 90%.[3]
Approximately 85% of TEN cases are induced by drugs.[4] The primary sensitizing drugs associated with TEN include antibiotics, anticonvulsants, antiviral drugs, and traditional Chinese medicine.[3] Recent studies have found that the occurrence of TEN is related to the individual human leukocyte antigen (HLA) allele genotype.[5,6,7] The HLA complex consists more than 200 genes on chromosome 6 can be categorized into 3 subgroups: Class I HLA, being recognized by CD8+ T cells, consists of 3 main genes, that is HLA-A, HLA-B, and HLA-C. Class II HLA, being recognized by CD4+ T cells, consists of 6 maingenes, that is, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLADQB1, HLA-DRA, and HLA-DRB1. HLA class I molecules are expressed in almost all the cells and are responsible for presenting peptides to immune cells.[5] Studies have shown that certain drugs that cause TEN are associated with HLA alleles; for example, carbamazepine-induced TEN and the HLA-B∗ 15:02 allele are highly correlated. Moreover, TEN induced by abacavir is correlated with individuals positive for the HLA-B∗57:01 allele.[5]
2 Case report
A 68-year-old woman presented with a rash that had persisted for 4 days. She had undergone a mitral valve replacement 1 month prior. Four days before admission, the patient developed a red rash on her face, chest, and back, accompanied by itching and a fever. At the time of admission, she presented with a burgundy rash that was distributed diffusely throughout her entire body. Moreover, some of the lesions were fused together, with a few blisters, itching, tolerability, fever, without skin breakage, subcutaneous nodules, bleeding, and ulcers (Fig. 1A). The laboratory test results revealed: albumin, 34.6 g/L; gamma glutamyl transpeptidase, 45 U/L; glucose, 13.24 mmol/L; creatine kinase MB subtype, 18.0 U/L; creatine kinase, 20 U/L; lactic dehydrogenase, 398 U/L; sodium, 135.9 mmol/L; leukocyte count, 5.19∗109/L; hemoglobin, 98.0 g/L; platelet count, 267 g/L; procalcitonin, 0.130 ng/mL; and fibrinogen, 4.35 g/L. The patient was taking the following medications at the time of admission: 0.125 mg qd po digoxin; 20 mg bid po furosemide; 1 g bid po potassium chloride; 0.625 mg qn po warfarin; and 20 mg qn po atorvastatin.
Figure 1 (A) At the time of admission, a burgundy rash was distributed diffusely throughout the patient's entire body. (B) On the fifth day of admission, the patient's facial skin began to peel, and blisters on her trunk began to rupture and peel. (C) After 60 days following discharge, the patient's skin has regrown.
On Day 1 post-admission, all drugs used prior to admission were discontinued and the patient was given antiallergic drugs, including 10 mg qd po loratadine, 10 mg qd po cetirizine, 100 mg tid po vitamin C, 120 mg q12 h po methylprednisolone, 40 mg q12 h ivgtt omeprazole acid, calamine and ethacridine for external use. The following day, the patient developed a large number of blisters that began to rupture over a large area of skin, and was accompanied by a fever. On Day 4, human immunoglobulin was intravenously administered. On Day 5, the patient's facial skin began to peel, and blisters on her trunk began to rupture and peel, which was associated with obvious pain. Mupirocin ointment was applied externally as treatment (Fig. 1B). On Day 11, the patient developed a new red patchy rash on both of her lower extremities accompanied by mild edema, as well as moderate blister formation near the thigh (Fig. 2). On Day 17, after developing erythema, blisters, rupture and peeling, the face and trunk skin were basically healed. On Day 22, the rash on her calf had subsided, the edema was relieved, and she was no longer experiencing pain. Then he was discharged from hospital. After 60 days following discharge, the patient's skin has regrown (Fig. 1C). During hospitalization, the location and exfoliation site of the rash were observed (Fig. 3); since the patient exhibited more than 30% exfoliation surfaces, the severe drug eruption was considered to be TEN rather than Stevens-Johnson Syndrome (SJS).
Figure 2 On Day 11 of admission, the patient developed a new red patchy rash on both lower extremities, which was accompanied by mild edema, and moderate blister formation near the thigh.
Figure 3 The location and exfoliation site of the rash were observed during hospitalization.
3 Investigations
Since more than 80% of TEN cases are caused by a drug allergy, timely cessation of the sensitizing drugs is the first step in treatment. Screening for suspected drug allergies relies primarily on medical history and previous reports of adverse drug reactions, however, for patients who have used multiple drugs before the onset of TEN, it is often difficult to identify the sensitizing drug.[4] The 2016 British Adult Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis Symptoms Management Guide recommends using the ALDEN score (drug causality algorithm for epidermal necrolysis) to retrospectively evaluate sensitizing drugs for TEN.[8] The ALDEN score was designed based on the results of the Severe Cutaneous Adverse Reaction case-control study conducted from 1989 to 1993. Therefore, we analyzed all of the drugs used in this patient according to the ALDEN score in order to identify those that induce TEN (Table 1). Atorvastatin had an ALDEN score of 4 (the highest score of all drugs taken; Table 1) and was judged to be “probable” for sensitization. Furthermore, the patient had taken warfarin for venous thrombosis of lower extremities 2 years ago and did not induce TEN. Thus, the patient's TEN was most likely caused by atorvastatin.
Table 1 Possible sensitizing drugs ALDEN score.
Values
Drugs the duration of use Criterion1 Criterion2 Criterion3 Criterion 4 Criterion 5 Final score Sensitization possibility∗
Aspirin 9/15–9/30 2a −3c 0e 0g −1i −2 Very unlikely
Atorvastatin calcium 9/20–10/16 3b 0d 0e 0g 1j 4 probable
Cefazolin sodium 9/14–9/15 2b −3c 0e 0g 1j 0 unlikely
Compound ammonia barbital 9/15–9/16 2a −3c 0e 0g 0k −1 Very unlikely
Furosemide 9/11–9/15,9/20–9/30, 10/1–10/16 3b 0d −2f −2h 0k −1 Very unlikely
Isosorbide mononitrate 9/20–10/16 3b 0d −2f 0g 1j 2 possible
Nitroglycerin 9/15–9/22 2a −3c 0e 0g 0k −1 Very unlikely
Cefoperazone Sulbactam Sodium 9/16–9/30 3b −3c −2f 0g 1j −1 Very unlikely
Warfarin 9/20–10/16 3b 0d −2f 0g 1j 2 possible
Tramadol 9/20–9/30 3b −3c 0e 0g 0k 0 unlikely
3.1 HLA allele detection
A 2-mL sample of peripheral venous blood was collected from the patient. Genomic DNA was extracted using a DNA extraction kit (Shanghai Baio Co., Ltd.) in accordance with the manufacturer's protocol. The exons of the HLA-A, -B, and-C loci were sequenced using sanger.[5] The results showed that the patient carried the HLA-A∗02:07, HLA-A∗11:01, HLA-B∗15:02, HLA-B∗40:01, HLA-C∗03:04, and HLA-C∗08:01 alleles.
4 Discussion
TEN is a serious skin mucosal disease characterized by large areas of erythema, blisters, epidermal exfoliation, and multi-site mucositis, that is often accompanied by systemic dysfunction.[1] The onset is urgent, progresses rapidly, and is associated with a high mortality rate. Thus, there is an urgent need to identify drugs that induce TEN. By using ALDEN to score all the drugs the patient had used, we were able to determine that atorvastatin was most likely associated with TEN in this patient. There have been 6 reports of statin-induced exfoliative dermatitis in the literature, including TEN, but none of the studies tested for HLA-related genes.[9,10,11,12,13,14] In addition, it is mentioned on the atorvastatin drug label that it may cause TEN in extremely rare cases.[15]
Genetic factors are also closely related to the occurrence of SJS/TEN. In this study, the patient's HLA exon was sequenced and found to carry multiple mutant HLA genotypes, that may have the correlation with SJS and TEN. A thorough review of the literature reveals that, among these alleles, HLA-B∗15:02, HLA-A∗02:07 and TEN may have the correlation.[16,17,18] The correlation between other alleles and TEN has not been reported, but their association cannot be ruled out, it need to be further investigated. HLA alleles have been proposed as markers of SJS/TEN. Studies revealed a high prevalence of pharmacogenetic markers of drug-induced SJS/TEN e.g., B∗13:01 for dapsone; B∗15:02 for carbamazepine and oxcarbazepine; B∗58:01, A∗33:03 and C∗03:02 for allopurinol; C∗08:01, C∗14:02 and DRB1∗12:02 for co-trimoxazole.[18] HLA alleles which found in this case report may be an cause of TEN induced by atorvastatin. Previous studies have found that HLA-B∗15:02 is an cause of serious adverse reactions in the skin induced by anti-epileptic drugs.[16] Carbamazepine non-covalently bind to proteins or peptides and are presented by MHC molecules after cellular processing, resulting in the HLA–restricted T cell activation.[17,19] Perhaps the mechanism of atorvastatin-induced TEN could be studied in the light of this study.
Atorvastatin is the most common drug for lipid lowering in patients with dyslipidemia, and the proportion of dyslipidemia in Chinese population is as high as 40.40%.[20] Therefore, the population of atorvastatin is very large, but SJS/TEN is very rare, HLA alleles may be a genetic factor. This is the first report describing the induction of TEN by atorvastatin in a HLA alleles carrier. Future systematic research is required to confirm this finding and avoid similar serious skin adverse reactions.
Author contributions
Conceptualization: Meina Lv, Yuxin Liu, Jinhua Zhang.
Data curation: Shaojun Jiang, Jinglan Fu.
Formal analysis: Yuxin Liu, Siheng Lian.
Project administration: Meina Lv, Jinhua Zhang.
Writing – original draft: Meina Lv.
Writing – review & editing: Shaojun Jiang, Jinglan Fu, Yuxin Liu, Siheng Lian, Jinhua Zhang.
Abbreviations: HLA = human leukocyte antigen, SJS = stevens-johnson syndrome, TEN = toxic epidermal necrolysis.
How to cite this article: Lv M, Jiang S, Fu J, Liu Y, Lian S, Zhang J. Toxic epidermal necrolysis in a patient on atorvastatin therapy expressing human leukocyte antigen alleles: a case report. Medicine. 2021;100:3(e24392).
This study was supported by the Natural Science Foundation of Fujian Province of China [grant number 2018Y0037].
Informed consent was obtained from the patient for publication of this case report. Approval of the study by our hospital's ethics committee was not required because it was a case report.
The authors have no conflicts of interest to disclose.
All data generated or analyzed during this study are included in this published article [and its supplementary information files].
∗ < 0, very unlikely; 0 – 1, unlikely; 2 – 3, possible; 4 – 5, probable; ≥ 6, very probable.
a Delay from initial drug component intake to onset of reaction: from 29 to 56 days.
b Delay from initial drug component intake to onset of reaction: from 5 to 28 days.
c Drug present in the body on index day: drug stopped at a time point prior to the index day by more than 5 times the elimination half-life, without liver or kidney function alterations or suspected drug interactions.
d Drug present in the body on index day: drug continued up to index day or stopped at a time point less than 5 times the elimination half-life before the index day.
e Prechallenge/rechanllenge: no known previous exposure to this drug.
f Prechallenge/rechanllenge: Exposure to this drug without any reaction (before or after reaction).
g Dechallenge: Drug stopped (or unknown).
h Dechallenge: Drug continued without harm.
i Type of drug (notoriety):No evidence of association from previous epidemiology study with sufficient number of exposed control.
j Type of drug (notoriety): Several previous reports, ambiguous epidemiology results (drug “under surveillance”).
k Type of drug (notoriety): All other drugs including newly released ones. | DURATION OF USE: 9/14?9/15 | DrugDosageText | CC BY | 33546081 | 18,901,737 | 2021-01-22 |
What was the dosage of drug 'CEFOPERAZONE\SULBACTAM'? | Toxic epidermal necrolysis in a patient on atorvastatin therapy expressing human leukocyte antigen alleles: A case report.
BACKGROUND
Toxic epidermal necrolysis (TEN) is a rare, severe mucosal response of the skin associated with a high mortality rate. TEN is most commonly caused by drugs, and is characterized by extensive skin epidermal exfoliation.
A 68-year-old woman presented with a rash that had persisted for four days. The patient who had undergone a mitral valve replacement 1 month prior and was taking atorvastatin at the time of admission.
The patient exhibited more than 30% exfoliation surfaces and the severe drug eruption was considered to be TEN. According to human leukocyte antigen (HLA) allele detection and ALDEN score, HLA alleles which found in this case report may be an cause of TEN induced by atorvastatin.
METHODS
All drugs used prior to admission were discontinued and the patient was given antiallergic drugs.
RESULTS
After 3 weeks following Antiallergic treatment, the rash on patient's calf had subsided, the edema was relieved, and the patient was no longer experiencing pain. After 60 days following discharge, the patient's skin has regrown.
CONCLUSIONS
This is the first report describing the induction of TEN by atorvastatin in a HLA alleles carrier. For HLA alleles carrier, atorvastatin may need to be used with caution to avoid TEN. Future systematic research is also required to confirm this finding and avoid similar serious skin adverse reactions.
1 Introduction
Toxic epidermal necrolysis (TEN) is an acute, life-threatening, severe dermatosis characterized by epidermal loss and multi-site mucositis, and is accompanied by systemic disturbance.[1] It is rare but very serious forms of drug-induced cutaneous adverse reaction. The morbidity of TEN is approximately 2 cases per million individuals each year.[2] The average mortality rate of TEN is over 30%, and the mortality rate of critically ill patients (SCORTEN > 3) is as high as 60% to 90%.[3]
Approximately 85% of TEN cases are induced by drugs.[4] The primary sensitizing drugs associated with TEN include antibiotics, anticonvulsants, antiviral drugs, and traditional Chinese medicine.[3] Recent studies have found that the occurrence of TEN is related to the individual human leukocyte antigen (HLA) allele genotype.[5,6,7] The HLA complex consists more than 200 genes on chromosome 6 can be categorized into 3 subgroups: Class I HLA, being recognized by CD8+ T cells, consists of 3 main genes, that is HLA-A, HLA-B, and HLA-C. Class II HLA, being recognized by CD4+ T cells, consists of 6 maingenes, that is, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLADQB1, HLA-DRA, and HLA-DRB1. HLA class I molecules are expressed in almost all the cells and are responsible for presenting peptides to immune cells.[5] Studies have shown that certain drugs that cause TEN are associated with HLA alleles; for example, carbamazepine-induced TEN and the HLA-B∗ 15:02 allele are highly correlated. Moreover, TEN induced by abacavir is correlated with individuals positive for the HLA-B∗57:01 allele.[5]
2 Case report
A 68-year-old woman presented with a rash that had persisted for 4 days. She had undergone a mitral valve replacement 1 month prior. Four days before admission, the patient developed a red rash on her face, chest, and back, accompanied by itching and a fever. At the time of admission, she presented with a burgundy rash that was distributed diffusely throughout her entire body. Moreover, some of the lesions were fused together, with a few blisters, itching, tolerability, fever, without skin breakage, subcutaneous nodules, bleeding, and ulcers (Fig. 1A). The laboratory test results revealed: albumin, 34.6 g/L; gamma glutamyl transpeptidase, 45 U/L; glucose, 13.24 mmol/L; creatine kinase MB subtype, 18.0 U/L; creatine kinase, 20 U/L; lactic dehydrogenase, 398 U/L; sodium, 135.9 mmol/L; leukocyte count, 5.19∗109/L; hemoglobin, 98.0 g/L; platelet count, 267 g/L; procalcitonin, 0.130 ng/mL; and fibrinogen, 4.35 g/L. The patient was taking the following medications at the time of admission: 0.125 mg qd po digoxin; 20 mg bid po furosemide; 1 g bid po potassium chloride; 0.625 mg qn po warfarin; and 20 mg qn po atorvastatin.
Figure 1 (A) At the time of admission, a burgundy rash was distributed diffusely throughout the patient's entire body. (B) On the fifth day of admission, the patient's facial skin began to peel, and blisters on her trunk began to rupture and peel. (C) After 60 days following discharge, the patient's skin has regrown.
On Day 1 post-admission, all drugs used prior to admission were discontinued and the patient was given antiallergic drugs, including 10 mg qd po loratadine, 10 mg qd po cetirizine, 100 mg tid po vitamin C, 120 mg q12 h po methylprednisolone, 40 mg q12 h ivgtt omeprazole acid, calamine and ethacridine for external use. The following day, the patient developed a large number of blisters that began to rupture over a large area of skin, and was accompanied by a fever. On Day 4, human immunoglobulin was intravenously administered. On Day 5, the patient's facial skin began to peel, and blisters on her trunk began to rupture and peel, which was associated with obvious pain. Mupirocin ointment was applied externally as treatment (Fig. 1B). On Day 11, the patient developed a new red patchy rash on both of her lower extremities accompanied by mild edema, as well as moderate blister formation near the thigh (Fig. 2). On Day 17, after developing erythema, blisters, rupture and peeling, the face and trunk skin were basically healed. On Day 22, the rash on her calf had subsided, the edema was relieved, and she was no longer experiencing pain. Then he was discharged from hospital. After 60 days following discharge, the patient's skin has regrown (Fig. 1C). During hospitalization, the location and exfoliation site of the rash were observed (Fig. 3); since the patient exhibited more than 30% exfoliation surfaces, the severe drug eruption was considered to be TEN rather than Stevens-Johnson Syndrome (SJS).
Figure 2 On Day 11 of admission, the patient developed a new red patchy rash on both lower extremities, which was accompanied by mild edema, and moderate blister formation near the thigh.
Figure 3 The location and exfoliation site of the rash were observed during hospitalization.
3 Investigations
Since more than 80% of TEN cases are caused by a drug allergy, timely cessation of the sensitizing drugs is the first step in treatment. Screening for suspected drug allergies relies primarily on medical history and previous reports of adverse drug reactions, however, for patients who have used multiple drugs before the onset of TEN, it is often difficult to identify the sensitizing drug.[4] The 2016 British Adult Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis Symptoms Management Guide recommends using the ALDEN score (drug causality algorithm for epidermal necrolysis) to retrospectively evaluate sensitizing drugs for TEN.[8] The ALDEN score was designed based on the results of the Severe Cutaneous Adverse Reaction case-control study conducted from 1989 to 1993. Therefore, we analyzed all of the drugs used in this patient according to the ALDEN score in order to identify those that induce TEN (Table 1). Atorvastatin had an ALDEN score of 4 (the highest score of all drugs taken; Table 1) and was judged to be “probable” for sensitization. Furthermore, the patient had taken warfarin for venous thrombosis of lower extremities 2 years ago and did not induce TEN. Thus, the patient's TEN was most likely caused by atorvastatin.
Table 1 Possible sensitizing drugs ALDEN score.
Values
Drugs the duration of use Criterion1 Criterion2 Criterion3 Criterion 4 Criterion 5 Final score Sensitization possibility∗
Aspirin 9/15–9/30 2a −3c 0e 0g −1i −2 Very unlikely
Atorvastatin calcium 9/20–10/16 3b 0d 0e 0g 1j 4 probable
Cefazolin sodium 9/14–9/15 2b −3c 0e 0g 1j 0 unlikely
Compound ammonia barbital 9/15–9/16 2a −3c 0e 0g 0k −1 Very unlikely
Furosemide 9/11–9/15,9/20–9/30, 10/1–10/16 3b 0d −2f −2h 0k −1 Very unlikely
Isosorbide mononitrate 9/20–10/16 3b 0d −2f 0g 1j 2 possible
Nitroglycerin 9/15–9/22 2a −3c 0e 0g 0k −1 Very unlikely
Cefoperazone Sulbactam Sodium 9/16–9/30 3b −3c −2f 0g 1j −1 Very unlikely
Warfarin 9/20–10/16 3b 0d −2f 0g 1j 2 possible
Tramadol 9/20–9/30 3b −3c 0e 0g 0k 0 unlikely
3.1 HLA allele detection
A 2-mL sample of peripheral venous blood was collected from the patient. Genomic DNA was extracted using a DNA extraction kit (Shanghai Baio Co., Ltd.) in accordance with the manufacturer's protocol. The exons of the HLA-A, -B, and-C loci were sequenced using sanger.[5] The results showed that the patient carried the HLA-A∗02:07, HLA-A∗11:01, HLA-B∗15:02, HLA-B∗40:01, HLA-C∗03:04, and HLA-C∗08:01 alleles.
4 Discussion
TEN is a serious skin mucosal disease characterized by large areas of erythema, blisters, epidermal exfoliation, and multi-site mucositis, that is often accompanied by systemic dysfunction.[1] The onset is urgent, progresses rapidly, and is associated with a high mortality rate. Thus, there is an urgent need to identify drugs that induce TEN. By using ALDEN to score all the drugs the patient had used, we were able to determine that atorvastatin was most likely associated with TEN in this patient. There have been 6 reports of statin-induced exfoliative dermatitis in the literature, including TEN, but none of the studies tested for HLA-related genes.[9,10,11,12,13,14] In addition, it is mentioned on the atorvastatin drug label that it may cause TEN in extremely rare cases.[15]
Genetic factors are also closely related to the occurrence of SJS/TEN. In this study, the patient's HLA exon was sequenced and found to carry multiple mutant HLA genotypes, that may have the correlation with SJS and TEN. A thorough review of the literature reveals that, among these alleles, HLA-B∗15:02, HLA-A∗02:07 and TEN may have the correlation.[16,17,18] The correlation between other alleles and TEN has not been reported, but their association cannot be ruled out, it need to be further investigated. HLA alleles have been proposed as markers of SJS/TEN. Studies revealed a high prevalence of pharmacogenetic markers of drug-induced SJS/TEN e.g., B∗13:01 for dapsone; B∗15:02 for carbamazepine and oxcarbazepine; B∗58:01, A∗33:03 and C∗03:02 for allopurinol; C∗08:01, C∗14:02 and DRB1∗12:02 for co-trimoxazole.[18] HLA alleles which found in this case report may be an cause of TEN induced by atorvastatin. Previous studies have found that HLA-B∗15:02 is an cause of serious adverse reactions in the skin induced by anti-epileptic drugs.[16] Carbamazepine non-covalently bind to proteins or peptides and are presented by MHC molecules after cellular processing, resulting in the HLA–restricted T cell activation.[17,19] Perhaps the mechanism of atorvastatin-induced TEN could be studied in the light of this study.
Atorvastatin is the most common drug for lipid lowering in patients with dyslipidemia, and the proportion of dyslipidemia in Chinese population is as high as 40.40%.[20] Therefore, the population of atorvastatin is very large, but SJS/TEN is very rare, HLA alleles may be a genetic factor. This is the first report describing the induction of TEN by atorvastatin in a HLA alleles carrier. Future systematic research is required to confirm this finding and avoid similar serious skin adverse reactions.
Author contributions
Conceptualization: Meina Lv, Yuxin Liu, Jinhua Zhang.
Data curation: Shaojun Jiang, Jinglan Fu.
Formal analysis: Yuxin Liu, Siheng Lian.
Project administration: Meina Lv, Jinhua Zhang.
Writing – original draft: Meina Lv.
Writing – review & editing: Shaojun Jiang, Jinglan Fu, Yuxin Liu, Siheng Lian, Jinhua Zhang.
Abbreviations: HLA = human leukocyte antigen, SJS = stevens-johnson syndrome, TEN = toxic epidermal necrolysis.
How to cite this article: Lv M, Jiang S, Fu J, Liu Y, Lian S, Zhang J. Toxic epidermal necrolysis in a patient on atorvastatin therapy expressing human leukocyte antigen alleles: a case report. Medicine. 2021;100:3(e24392).
This study was supported by the Natural Science Foundation of Fujian Province of China [grant number 2018Y0037].
Informed consent was obtained from the patient for publication of this case report. Approval of the study by our hospital's ethics committee was not required because it was a case report.
The authors have no conflicts of interest to disclose.
All data generated or analyzed during this study are included in this published article [and its supplementary information files].
∗ < 0, very unlikely; 0 – 1, unlikely; 2 – 3, possible; 4 – 5, probable; ≥ 6, very probable.
a Delay from initial drug component intake to onset of reaction: from 29 to 56 days.
b Delay from initial drug component intake to onset of reaction: from 5 to 28 days.
c Drug present in the body on index day: drug stopped at a time point prior to the index day by more than 5 times the elimination half-life, without liver or kidney function alterations or suspected drug interactions.
d Drug present in the body on index day: drug continued up to index day or stopped at a time point less than 5 times the elimination half-life before the index day.
e Prechallenge/rechanllenge: no known previous exposure to this drug.
f Prechallenge/rechanllenge: Exposure to this drug without any reaction (before or after reaction).
g Dechallenge: Drug stopped (or unknown).
h Dechallenge: Drug continued without harm.
i Type of drug (notoriety):No evidence of association from previous epidemiology study with sufficient number of exposed control.
j Type of drug (notoriety): Several previous reports, ambiguous epidemiology results (drug “under surveillance”).
k Type of drug (notoriety): All other drugs including newly released ones. | DURATION OF USE: 9/16?9/30 | DrugDosageText | CC BY | 33546081 | 18,901,737 | 2021-01-22 |
What was the dosage of drug 'ISOSORBIDE'? | Toxic epidermal necrolysis in a patient on atorvastatin therapy expressing human leukocyte antigen alleles: A case report.
BACKGROUND
Toxic epidermal necrolysis (TEN) is a rare, severe mucosal response of the skin associated with a high mortality rate. TEN is most commonly caused by drugs, and is characterized by extensive skin epidermal exfoliation.
A 68-year-old woman presented with a rash that had persisted for four days. The patient who had undergone a mitral valve replacement 1 month prior and was taking atorvastatin at the time of admission.
The patient exhibited more than 30% exfoliation surfaces and the severe drug eruption was considered to be TEN. According to human leukocyte antigen (HLA) allele detection and ALDEN score, HLA alleles which found in this case report may be an cause of TEN induced by atorvastatin.
METHODS
All drugs used prior to admission were discontinued and the patient was given antiallergic drugs.
RESULTS
After 3 weeks following Antiallergic treatment, the rash on patient's calf had subsided, the edema was relieved, and the patient was no longer experiencing pain. After 60 days following discharge, the patient's skin has regrown.
CONCLUSIONS
This is the first report describing the induction of TEN by atorvastatin in a HLA alleles carrier. For HLA alleles carrier, atorvastatin may need to be used with caution to avoid TEN. Future systematic research is also required to confirm this finding and avoid similar serious skin adverse reactions.
1 Introduction
Toxic epidermal necrolysis (TEN) is an acute, life-threatening, severe dermatosis characterized by epidermal loss and multi-site mucositis, and is accompanied by systemic disturbance.[1] It is rare but very serious forms of drug-induced cutaneous adverse reaction. The morbidity of TEN is approximately 2 cases per million individuals each year.[2] The average mortality rate of TEN is over 30%, and the mortality rate of critically ill patients (SCORTEN > 3) is as high as 60% to 90%.[3]
Approximately 85% of TEN cases are induced by drugs.[4] The primary sensitizing drugs associated with TEN include antibiotics, anticonvulsants, antiviral drugs, and traditional Chinese medicine.[3] Recent studies have found that the occurrence of TEN is related to the individual human leukocyte antigen (HLA) allele genotype.[5,6,7] The HLA complex consists more than 200 genes on chromosome 6 can be categorized into 3 subgroups: Class I HLA, being recognized by CD8+ T cells, consists of 3 main genes, that is HLA-A, HLA-B, and HLA-C. Class II HLA, being recognized by CD4+ T cells, consists of 6 maingenes, that is, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLADQB1, HLA-DRA, and HLA-DRB1. HLA class I molecules are expressed in almost all the cells and are responsible for presenting peptides to immune cells.[5] Studies have shown that certain drugs that cause TEN are associated with HLA alleles; for example, carbamazepine-induced TEN and the HLA-B∗ 15:02 allele are highly correlated. Moreover, TEN induced by abacavir is correlated with individuals positive for the HLA-B∗57:01 allele.[5]
2 Case report
A 68-year-old woman presented with a rash that had persisted for 4 days. She had undergone a mitral valve replacement 1 month prior. Four days before admission, the patient developed a red rash on her face, chest, and back, accompanied by itching and a fever. At the time of admission, she presented with a burgundy rash that was distributed diffusely throughout her entire body. Moreover, some of the lesions were fused together, with a few blisters, itching, tolerability, fever, without skin breakage, subcutaneous nodules, bleeding, and ulcers (Fig. 1A). The laboratory test results revealed: albumin, 34.6 g/L; gamma glutamyl transpeptidase, 45 U/L; glucose, 13.24 mmol/L; creatine kinase MB subtype, 18.0 U/L; creatine kinase, 20 U/L; lactic dehydrogenase, 398 U/L; sodium, 135.9 mmol/L; leukocyte count, 5.19∗109/L; hemoglobin, 98.0 g/L; platelet count, 267 g/L; procalcitonin, 0.130 ng/mL; and fibrinogen, 4.35 g/L. The patient was taking the following medications at the time of admission: 0.125 mg qd po digoxin; 20 mg bid po furosemide; 1 g bid po potassium chloride; 0.625 mg qn po warfarin; and 20 mg qn po atorvastatin.
Figure 1 (A) At the time of admission, a burgundy rash was distributed diffusely throughout the patient's entire body. (B) On the fifth day of admission, the patient's facial skin began to peel, and blisters on her trunk began to rupture and peel. (C) After 60 days following discharge, the patient's skin has regrown.
On Day 1 post-admission, all drugs used prior to admission were discontinued and the patient was given antiallergic drugs, including 10 mg qd po loratadine, 10 mg qd po cetirizine, 100 mg tid po vitamin C, 120 mg q12 h po methylprednisolone, 40 mg q12 h ivgtt omeprazole acid, calamine and ethacridine for external use. The following day, the patient developed a large number of blisters that began to rupture over a large area of skin, and was accompanied by a fever. On Day 4, human immunoglobulin was intravenously administered. On Day 5, the patient's facial skin began to peel, and blisters on her trunk began to rupture and peel, which was associated with obvious pain. Mupirocin ointment was applied externally as treatment (Fig. 1B). On Day 11, the patient developed a new red patchy rash on both of her lower extremities accompanied by mild edema, as well as moderate blister formation near the thigh (Fig. 2). On Day 17, after developing erythema, blisters, rupture and peeling, the face and trunk skin were basically healed. On Day 22, the rash on her calf had subsided, the edema was relieved, and she was no longer experiencing pain. Then he was discharged from hospital. After 60 days following discharge, the patient's skin has regrown (Fig. 1C). During hospitalization, the location and exfoliation site of the rash were observed (Fig. 3); since the patient exhibited more than 30% exfoliation surfaces, the severe drug eruption was considered to be TEN rather than Stevens-Johnson Syndrome (SJS).
Figure 2 On Day 11 of admission, the patient developed a new red patchy rash on both lower extremities, which was accompanied by mild edema, and moderate blister formation near the thigh.
Figure 3 The location and exfoliation site of the rash were observed during hospitalization.
3 Investigations
Since more than 80% of TEN cases are caused by a drug allergy, timely cessation of the sensitizing drugs is the first step in treatment. Screening for suspected drug allergies relies primarily on medical history and previous reports of adverse drug reactions, however, for patients who have used multiple drugs before the onset of TEN, it is often difficult to identify the sensitizing drug.[4] The 2016 British Adult Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis Symptoms Management Guide recommends using the ALDEN score (drug causality algorithm for epidermal necrolysis) to retrospectively evaluate sensitizing drugs for TEN.[8] The ALDEN score was designed based on the results of the Severe Cutaneous Adverse Reaction case-control study conducted from 1989 to 1993. Therefore, we analyzed all of the drugs used in this patient according to the ALDEN score in order to identify those that induce TEN (Table 1). Atorvastatin had an ALDEN score of 4 (the highest score of all drugs taken; Table 1) and was judged to be “probable” for sensitization. Furthermore, the patient had taken warfarin for venous thrombosis of lower extremities 2 years ago and did not induce TEN. Thus, the patient's TEN was most likely caused by atorvastatin.
Table 1 Possible sensitizing drugs ALDEN score.
Values
Drugs the duration of use Criterion1 Criterion2 Criterion3 Criterion 4 Criterion 5 Final score Sensitization possibility∗
Aspirin 9/15–9/30 2a −3c 0e 0g −1i −2 Very unlikely
Atorvastatin calcium 9/20–10/16 3b 0d 0e 0g 1j 4 probable
Cefazolin sodium 9/14–9/15 2b −3c 0e 0g 1j 0 unlikely
Compound ammonia barbital 9/15–9/16 2a −3c 0e 0g 0k −1 Very unlikely
Furosemide 9/11–9/15,9/20–9/30, 10/1–10/16 3b 0d −2f −2h 0k −1 Very unlikely
Isosorbide mononitrate 9/20–10/16 3b 0d −2f 0g 1j 2 possible
Nitroglycerin 9/15–9/22 2a −3c 0e 0g 0k −1 Very unlikely
Cefoperazone Sulbactam Sodium 9/16–9/30 3b −3c −2f 0g 1j −1 Very unlikely
Warfarin 9/20–10/16 3b 0d −2f 0g 1j 2 possible
Tramadol 9/20–9/30 3b −3c 0e 0g 0k 0 unlikely
3.1 HLA allele detection
A 2-mL sample of peripheral venous blood was collected from the patient. Genomic DNA was extracted using a DNA extraction kit (Shanghai Baio Co., Ltd.) in accordance with the manufacturer's protocol. The exons of the HLA-A, -B, and-C loci were sequenced using sanger.[5] The results showed that the patient carried the HLA-A∗02:07, HLA-A∗11:01, HLA-B∗15:02, HLA-B∗40:01, HLA-C∗03:04, and HLA-C∗08:01 alleles.
4 Discussion
TEN is a serious skin mucosal disease characterized by large areas of erythema, blisters, epidermal exfoliation, and multi-site mucositis, that is often accompanied by systemic dysfunction.[1] The onset is urgent, progresses rapidly, and is associated with a high mortality rate. Thus, there is an urgent need to identify drugs that induce TEN. By using ALDEN to score all the drugs the patient had used, we were able to determine that atorvastatin was most likely associated with TEN in this patient. There have been 6 reports of statin-induced exfoliative dermatitis in the literature, including TEN, but none of the studies tested for HLA-related genes.[9,10,11,12,13,14] In addition, it is mentioned on the atorvastatin drug label that it may cause TEN in extremely rare cases.[15]
Genetic factors are also closely related to the occurrence of SJS/TEN. In this study, the patient's HLA exon was sequenced and found to carry multiple mutant HLA genotypes, that may have the correlation with SJS and TEN. A thorough review of the literature reveals that, among these alleles, HLA-B∗15:02, HLA-A∗02:07 and TEN may have the correlation.[16,17,18] The correlation between other alleles and TEN has not been reported, but their association cannot be ruled out, it need to be further investigated. HLA alleles have been proposed as markers of SJS/TEN. Studies revealed a high prevalence of pharmacogenetic markers of drug-induced SJS/TEN e.g., B∗13:01 for dapsone; B∗15:02 for carbamazepine and oxcarbazepine; B∗58:01, A∗33:03 and C∗03:02 for allopurinol; C∗08:01, C∗14:02 and DRB1∗12:02 for co-trimoxazole.[18] HLA alleles which found in this case report may be an cause of TEN induced by atorvastatin. Previous studies have found that HLA-B∗15:02 is an cause of serious adverse reactions in the skin induced by anti-epileptic drugs.[16] Carbamazepine non-covalently bind to proteins or peptides and are presented by MHC molecules after cellular processing, resulting in the HLA–restricted T cell activation.[17,19] Perhaps the mechanism of atorvastatin-induced TEN could be studied in the light of this study.
Atorvastatin is the most common drug for lipid lowering in patients with dyslipidemia, and the proportion of dyslipidemia in Chinese population is as high as 40.40%.[20] Therefore, the population of atorvastatin is very large, but SJS/TEN is very rare, HLA alleles may be a genetic factor. This is the first report describing the induction of TEN by atorvastatin in a HLA alleles carrier. Future systematic research is required to confirm this finding and avoid similar serious skin adverse reactions.
Author contributions
Conceptualization: Meina Lv, Yuxin Liu, Jinhua Zhang.
Data curation: Shaojun Jiang, Jinglan Fu.
Formal analysis: Yuxin Liu, Siheng Lian.
Project administration: Meina Lv, Jinhua Zhang.
Writing – original draft: Meina Lv.
Writing – review & editing: Shaojun Jiang, Jinglan Fu, Yuxin Liu, Siheng Lian, Jinhua Zhang.
Abbreviations: HLA = human leukocyte antigen, SJS = stevens-johnson syndrome, TEN = toxic epidermal necrolysis.
How to cite this article: Lv M, Jiang S, Fu J, Liu Y, Lian S, Zhang J. Toxic epidermal necrolysis in a patient on atorvastatin therapy expressing human leukocyte antigen alleles: a case report. Medicine. 2021;100:3(e24392).
This study was supported by the Natural Science Foundation of Fujian Province of China [grant number 2018Y0037].
Informed consent was obtained from the patient for publication of this case report. Approval of the study by our hospital's ethics committee was not required because it was a case report.
The authors have no conflicts of interest to disclose.
All data generated or analyzed during this study are included in this published article [and its supplementary information files].
∗ < 0, very unlikely; 0 – 1, unlikely; 2 – 3, possible; 4 – 5, probable; ≥ 6, very probable.
a Delay from initial drug component intake to onset of reaction: from 29 to 56 days.
b Delay from initial drug component intake to onset of reaction: from 5 to 28 days.
c Drug present in the body on index day: drug stopped at a time point prior to the index day by more than 5 times the elimination half-life, without liver or kidney function alterations or suspected drug interactions.
d Drug present in the body on index day: drug continued up to index day or stopped at a time point less than 5 times the elimination half-life before the index day.
e Prechallenge/rechanllenge: no known previous exposure to this drug.
f Prechallenge/rechanllenge: Exposure to this drug without any reaction (before or after reaction).
g Dechallenge: Drug stopped (or unknown).
h Dechallenge: Drug continued without harm.
i Type of drug (notoriety):No evidence of association from previous epidemiology study with sufficient number of exposed control.
j Type of drug (notoriety): Several previous reports, ambiguous epidemiology results (drug “under surveillance”).
k Type of drug (notoriety): All other drugs including newly released ones. | DURATION OF USE: 9/20?10/16 (27 DAYS ) | DrugDosageText | CC BY | 33546081 | 18,901,737 | 2021-01-22 |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.