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What was the administration route of drug 'DOXORUBICIN'? | Delayed Bladder Perforation Related to Immediate Single Dose Intravesical Doxorubicin Instillation After TURBT: A Case Report and Literature Review.
Intravesical chemotherapy instillation immediately after tumor resection is a well-known practice in the management of non-muscle invasive bladder cancer. Despite being largely well tolerated in most cases, it is not devoid of severe and life-threatening complications.
We present an unusual case of bladder perforation that happened 2 weeks after bladder tumor resection. The patient had received single dose intra-vesical instillation of doxorubicin after TUR-BT. Conservative managements failed to achieve bladder healing; as a result, open surgical repair was performed. To the best of our knowledge, this is the first reported case of bladder perforation after intra-vesical doxorubicin instillation.
The occurrence of such a rare serious complication in a mostly safe intervention must be taken into consideration. A high index of suspicion, timely management, and proceeding to more invasive surgical treatments when necessary are cornerstones in the management and preserving the bladder.
Introduction
Bladder cancer (BC) is the seventh most commonly diagnosed cancer in men worldwide. About 75% of the cases are Non-muscle invasive (NMIBC).1 Transurethral resection of the bladder tumor (TURBT) remains the gold standard of therapy for diagnosing and treating NMIBC. To decrease the recurrence rate of low-risk tumors, a single, immediate, post-operative intravesical instillation of chemotherapy is recommended.1
The most commonly used chemotherapeutic agent is Mitomycin C (MMC), which is an alkylating agent that inhibits DNA synthesis and causes single-strand breakage of DNA and chromosomal breaks.2
Immediate single instillation (SI) is largely well-tolerated. However, severe complications and even death have been reported in the literature. Here we present a case wherein the patient had an extraperitoneal bladder perforation that occurred 2 weeks after TUT-BT and immediate postoperative instillation of doxorubicin.
Case Presentation
A 63-Year-old male, a heavy smoker, with no other co-morbidities, was referred to urology clinic for evaluation and management of a lesion on the left bladder wall that was incidentally detected on a CT scan. He did not have any urinary symptoms on initial presentation.
Cystourethroscopy revealed 2 papillary growths on the left lateral bladder wall, which were resected completely and smoothly by a resectoscope using a monopolar energy. Complete resection of the tumor was achieved without any intra-operative complication or perforation. Hemostasis was secured, and a urethral catheter was inserted.
In accordance of the EAU guidelines, the patient received an intravesical instillation of 50 ml of doxorubicin diluted in 100 cc of saline 6 hours after the TURBT. During the instillation, his vital signs were stable and he had neither hematuria nor abdominal pain. One hour after the instillation, the catheter was unclamped and was attached to continuous bladder irrigation.
Two days after the surgery and in the absence of hematuria, the indwelling catheter was removed, and the patient was discharged home the next day.
When seen in the clinic 1 week later the patient was fine with no alarming symptoms. The pathology report showed a low-grade Ta Papillary urothelial carcinoma. Based on the pathological diagnosis and according to the EAU guidelines, adjuvant chemotherapy instillations were planned.
Two weeks later, the patient presented with, dysuria, frequency, urgency, as well as pelvic and perineal pain. Physical examination was unremarkable. Urine analysis showed numerous WBC’s, RBC’s, and bacteria. An empirical antibiotics course was commenced.
In view of the worsening symptoms and the past history of anal fistula, a contrast enhanced pelvic MRI was performed. It showed a diffusely thickened urinary bladder wall, with evidence of a focal wall defect at its left aspect (the site of the resected tumor). The active urine leak into the perivesical space confirmed the diagnosis of retroperitoneal bladder perforation (Figure 1).
Figure. 1. Pelvic MRI (axial view) showing extraperitoneal bladder perforation at the left lateral wall (arrow points to extravasated contrast).
The patient was managed conservatively with antibiotics and an indwelling catheter for 3 weeks.
A follow-up retrograde CT cystogram showed no improvement and a gross contrast leak from the same site was identified. The catheter was kept for 6 more weeks and the CT cystogram was repeated showing the same results with no evidence of improvement. The patient refused to keep the catheter for a longer period so the option of open surgical repair was discussed with him.
Extraperitoneal laparotomy was performed, a perivesical small abscess was drained and cultured, necrotic tissues were debrided, and the bladder wall defect was rimed and closed in 3 layers. Tissue biopsies from the pelvic wall and bladder wall were harvested. A urethral catheter and pelvic drain were kept in place. The postoperative course was uneventful, the drain was removed on the third-day postoperatively, and the patient was discharged home with the urethral catheter in.
Histopathological evaluation of the pelvic wall and the bladder biopsies verified acute and chronic inflammation as well as granulation tissue formation. However, both were negative for malignancy. The urinary bladder biopsy also showed extensive foci of dystrophic calcification while the pelvic wall biopsy revealed fat necrosis (Figures 2 and 3).
Figure 2. The histologic examination revealed fragments of soft tissue with fat necrosis in the lower left area, mixed acute and chronic inflammatory cell infiltrate and hemorrhage in the upper right area (Hematoxylin & Eosin, 200X).
Figure 3. The histologic examination revealed multiple areas of calcifications embedded deep in the tissue with associated crystal-like material suggestive of calcium-oxalate or talc powder crystals (Hematoxylin & Eosin, 200X).
A follow up CT cystogram was done 3 weeks after the bladder repair. Although it showed a considerable regression in the size of the bladder defect, interestingly it also showed persistent extra-peritoneal contrast leak from the bladder along it’s left lateral aspect (Figure 4).
Figure 4. Retrograde Ct cystogram showing persistent contrast leak from the left lateral aspect after surgical repair.
Due to this slow healing, the catheter was kept in. Six weeks later, a follow up CT cystogram showed healing with no extraperitoneal contrast leak (Figure 5). And hence the catheter was removed.
Figure 5. Retrograde Ct cystogram showing a healed bladder wall with no contrast leak.
Two follow up cystoscopies and bladder biopsy (from an erythematous area on the left lateral wall) with 3 months intervals showed good healing of the bladder wall and no recurrence of the tumor.
Discussion
Single intravesical instillation with mitomycin C (MMC), epirubicin, or pirarubicin, have shown a beneficial effect in reducing recurrence rate compared to TURBT alone. However, randomized comparisons of individual drugs have not been conducted.3
The high recurrence rate of NMIBC may be attributed to the seeding of floating tumor cells. Immediate chemotherapy instillation has been shown to act by destroying these circulating tumor cells after TURBT. Hence the EAU guidelines recommend initiating the instillation within the first few hours after TURBT.1
Most of the complications of intravesical chemotherapy instillation are minor and can be managed medically. Dysuria and urinary frequency and urgency were the most common complications.4
On the other hand, reporting major complications such as bladder perforation, perirectal abscesses, eosinophilic cystitis, and ureteral stenosis is limited to case reports.5-14
In this case, we described our experience with bladder perforation after immediate intravesical instillation of doxorubicin.
One can argue that the perforation has occurred intraoperatively and gone unnoticed. However, in view of the absence of endoscopic evidence of perforation, late presentation of symptoms, and the absence of symptoms during and after the instillation we assume that the Single Dose Intravesical Doxorubicin Instillation caused the perforation rather than complicating an existing one.
To explain the mechanism of perforation, Lim et al7 and Cliff et al8 hypothesized that perforation is caused when attenuated muscularis propria gets necrosed after MMC instillation.
The presenting complaints of our patient were perineal and pelvic pain as well as urinary irritative symptoms. This is similar to Elmamoun et al9 cohort in which all the 6 patients presented with perineal and pelvic pain. Other symptoms such as fever, urine retention, and recurrent UTI were variably reported by others. Table 1 summarizes the clinical presentation and management of bladder perforation in the previously published case reports.
Table1. A summary of the presentation and management of bladder perforation after immediate chemotheraputic agent intravesical instillation.
Ref. number The instilled drug Number of patients Initial presentation Management outline
Lim et al7 MMC 1 Pelvic and suprapubic pain Exploratry laparotomy and bladder repair after failed conservative management
Elmamoun et al9 MMC 6 3 patients presented with pelvic pain Conservative management and urethral catheterization for 2, 26, and 52 weeks
Pelvic pain Recurrent UTIs Left ureteric obstruction Partial cystectomy + left to right trans-ureteroureterostomy
Pelvic pain, Persistent urinary leak
Left ureteric obstruction Augmentation cystoplasty + leftUreteric reimplantationThe patient ended with persistent leak, so a long-term catheter was used
Pelvic painSevere LUTS Bilateral ureteric obstruction Urinary diversion (ileal conduit)
Penna et al10 MMC 1 Lower abdominal pain and inability to void Analgesia, antibiotics and urethral catheter for 4 weeks
Tyritzis et al11 EPI 2 Fever and retropubic pain Conservative: Antibiotics and urethral catheter
Fever, lower abdominal pain and cellulitis Exploratry laparotomy and bladder repair after failed conservative management
Nieuwenhuijzen et al12 MMC Pelvic pain and fever Exploratry laparotomy and bladder repair after failed conservative management for 1 month
Racioppi et al13 MMC Pelvic pain, fever and pancytopenia Exploratry laparotomy and bladder repair after failed conservative management for 3 weeks
Hatem and Leifeld14 MMC Pelvic pain
Fever and positive blood culture for ecoli as well as purulent discharge from the drain site after the first expolratory laparatomy Conservative management for 10 daysExploratory laparatomy that revealed edematous anterior bladder wall without defectRenewed laparotomy, drainage of the abscess, debridement of the necrotic tissue, mono-J ureteral stents and nephrostomyRadical cystectomy with a urinary diversion through ureterocutaneostomy
Shenaq et al15 EPI 3 Strong urge and pain in the lower left abdomen Conservative management with antibiotics and urethral catheterization
Abdominal pain and intestinal obstruction Conservative management for 12 daysExploratory laparotomy that revealed infiltrative mass on the top of the bladder causing IO, so colostomy was done.The patient died due to multi organ failure
Progressive pain in the lower abdomen Conservative management with antibiotics and urethral catheterization
Abbreviations: Ep, epirubicin; MMC, mitomycin C.
Concerning the management, almost all the reported cases were initially managed conservatively by urethral catheterization, anticholinergics, and antibiotics. However, this was insufficient to heal the bladder in some cases which needed open repair. Moreover, some ended with cystectomy.
In our case, the patient has an extraperitoneal extravasation that failed the conservative management and needed open surgical repair.
A striking feature of the healing process that was seen in many cases including ours is the poor and slow healing. In our case, the patient needed 9 weeks for complete healing after proper open 3 layers bladder wall repair.7-9,13,14
While Lim et al attributed the slow healing in their case to the patient’s pre-existing peripheral vascular disease and suboptimal tissue oxygenation, no risk factors were identified in the other cases including our patient who was free of any comorbidities. We suppose that the poor healing is linked to the chemotherapeutic agent inflammatory effect rather than to patient factor.
This assumption is backed by the reported characteristic of mitomycin induced skin ulcer in cases of extravasation after intravenous administration. These ulcers are well known for their chronicity and the low tendency of spontaneous healing. Moreover, debridement and soft-tissue reconstruction following extravasation of MMC are recommended for patients with persistent ulceration and pain.15
Another common finding in the cases that mandate open repair was the presence of perivesical soft tissue necrosis and extensive inflammation. Doherty et al observed that more extensive bladder wall and fat necrosis of extravesical tissue in cystectomy specimens occurred when either epirubicin or mitomycin instillation was administered than in that seen following TURBT alone.16
This cytotoxic effect was also reported by Tyritzis et al11 after epirubicin instillation, and by Cliff et al,8 Nieuwenhuijzen et al,12 and Hatem and Leifeld14 after MMC instillation. This cytotoxic effect was recognized herein for the doxorubicin instillation, which is the first time to be reported as a complication of doxorubicin.
It is worth to mention that the perforation had no adverse oncological effect on our patient as no tumor recurrence was detected during follow up.
Conclusion
Immediate intravesical instillations of chemotherapy are not devoid from risk and serious complications as bladder perforation can occur. Whether it’s value in decreasing the recurrence justify the risk of bladder perforation is not our argument in this case report. Nevertheless, this severe complication should be kept in mind, and high index of suspicion will aid in timely management. If perforation is suspected, urethral catheterization and contrasted imaging are mandatory. In the case of failed conservative management surgical repair is warranted even in extraperitoneal leak.
Funding:The author(s) received no financial support for the research, authorship, and/or publication of this article.
Declaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Author Contributions: Concept: AA, SAD. Design: MA, SA. Supervision: AA, SAD, MAA. Resources: MA, HM, NB. Materials: AA, MA, NB. Writing manuscript: AA, MA, HM. Critical review: AA, SAD, MAA.
Informed Consent: The patient has given his written informed consent to publish his case including publication of images. The study follows the guidelines for human studies and is conducted in accordance with the World Medical Association Declaration of Helsinki.
ORCID iD: Hammam Mansi
https://orcid.org/0000-0002-4571-4336 | Intravesical | DrugAdministrationRoute | CC BY-NC | 33473244 | 18,858,074 | 2021 |
What was the dosage of drug 'SODIUM CHLORIDE'? | Delayed Bladder Perforation Related to Immediate Single Dose Intravesical Doxorubicin Instillation After TURBT: A Case Report and Literature Review.
Intravesical chemotherapy instillation immediately after tumor resection is a well-known practice in the management of non-muscle invasive bladder cancer. Despite being largely well tolerated in most cases, it is not devoid of severe and life-threatening complications.
We present an unusual case of bladder perforation that happened 2 weeks after bladder tumor resection. The patient had received single dose intra-vesical instillation of doxorubicin after TUR-BT. Conservative managements failed to achieve bladder healing; as a result, open surgical repair was performed. To the best of our knowledge, this is the first reported case of bladder perforation after intra-vesical doxorubicin instillation.
The occurrence of such a rare serious complication in a mostly safe intervention must be taken into consideration. A high index of suspicion, timely management, and proceeding to more invasive surgical treatments when necessary are cornerstones in the management and preserving the bladder.
Introduction
Bladder cancer (BC) is the seventh most commonly diagnosed cancer in men worldwide. About 75% of the cases are Non-muscle invasive (NMIBC).1 Transurethral resection of the bladder tumor (TURBT) remains the gold standard of therapy for diagnosing and treating NMIBC. To decrease the recurrence rate of low-risk tumors, a single, immediate, post-operative intravesical instillation of chemotherapy is recommended.1
The most commonly used chemotherapeutic agent is Mitomycin C (MMC), which is an alkylating agent that inhibits DNA synthesis and causes single-strand breakage of DNA and chromosomal breaks.2
Immediate single instillation (SI) is largely well-tolerated. However, severe complications and even death have been reported in the literature. Here we present a case wherein the patient had an extraperitoneal bladder perforation that occurred 2 weeks after TUT-BT and immediate postoperative instillation of doxorubicin.
Case Presentation
A 63-Year-old male, a heavy smoker, with no other co-morbidities, was referred to urology clinic for evaluation and management of a lesion on the left bladder wall that was incidentally detected on a CT scan. He did not have any urinary symptoms on initial presentation.
Cystourethroscopy revealed 2 papillary growths on the left lateral bladder wall, which were resected completely and smoothly by a resectoscope using a monopolar energy. Complete resection of the tumor was achieved without any intra-operative complication or perforation. Hemostasis was secured, and a urethral catheter was inserted.
In accordance of the EAU guidelines, the patient received an intravesical instillation of 50 ml of doxorubicin diluted in 100 cc of saline 6 hours after the TURBT. During the instillation, his vital signs were stable and he had neither hematuria nor abdominal pain. One hour after the instillation, the catheter was unclamped and was attached to continuous bladder irrigation.
Two days after the surgery and in the absence of hematuria, the indwelling catheter was removed, and the patient was discharged home the next day.
When seen in the clinic 1 week later the patient was fine with no alarming symptoms. The pathology report showed a low-grade Ta Papillary urothelial carcinoma. Based on the pathological diagnosis and according to the EAU guidelines, adjuvant chemotherapy instillations were planned.
Two weeks later, the patient presented with, dysuria, frequency, urgency, as well as pelvic and perineal pain. Physical examination was unremarkable. Urine analysis showed numerous WBC’s, RBC’s, and bacteria. An empirical antibiotics course was commenced.
In view of the worsening symptoms and the past history of anal fistula, a contrast enhanced pelvic MRI was performed. It showed a diffusely thickened urinary bladder wall, with evidence of a focal wall defect at its left aspect (the site of the resected tumor). The active urine leak into the perivesical space confirmed the diagnosis of retroperitoneal bladder perforation (Figure 1).
Figure. 1. Pelvic MRI (axial view) showing extraperitoneal bladder perforation at the left lateral wall (arrow points to extravasated contrast).
The patient was managed conservatively with antibiotics and an indwelling catheter for 3 weeks.
A follow-up retrograde CT cystogram showed no improvement and a gross contrast leak from the same site was identified. The catheter was kept for 6 more weeks and the CT cystogram was repeated showing the same results with no evidence of improvement. The patient refused to keep the catheter for a longer period so the option of open surgical repair was discussed with him.
Extraperitoneal laparotomy was performed, a perivesical small abscess was drained and cultured, necrotic tissues were debrided, and the bladder wall defect was rimed and closed in 3 layers. Tissue biopsies from the pelvic wall and bladder wall were harvested. A urethral catheter and pelvic drain were kept in place. The postoperative course was uneventful, the drain was removed on the third-day postoperatively, and the patient was discharged home with the urethral catheter in.
Histopathological evaluation of the pelvic wall and the bladder biopsies verified acute and chronic inflammation as well as granulation tissue formation. However, both were negative for malignancy. The urinary bladder biopsy also showed extensive foci of dystrophic calcification while the pelvic wall biopsy revealed fat necrosis (Figures 2 and 3).
Figure 2. The histologic examination revealed fragments of soft tissue with fat necrosis in the lower left area, mixed acute and chronic inflammatory cell infiltrate and hemorrhage in the upper right area (Hematoxylin & Eosin, 200X).
Figure 3. The histologic examination revealed multiple areas of calcifications embedded deep in the tissue with associated crystal-like material suggestive of calcium-oxalate or talc powder crystals (Hematoxylin & Eosin, 200X).
A follow up CT cystogram was done 3 weeks after the bladder repair. Although it showed a considerable regression in the size of the bladder defect, interestingly it also showed persistent extra-peritoneal contrast leak from the bladder along it’s left lateral aspect (Figure 4).
Figure 4. Retrograde Ct cystogram showing persistent contrast leak from the left lateral aspect after surgical repair.
Due to this slow healing, the catheter was kept in. Six weeks later, a follow up CT cystogram showed healing with no extraperitoneal contrast leak (Figure 5). And hence the catheter was removed.
Figure 5. Retrograde Ct cystogram showing a healed bladder wall with no contrast leak.
Two follow up cystoscopies and bladder biopsy (from an erythematous area on the left lateral wall) with 3 months intervals showed good healing of the bladder wall and no recurrence of the tumor.
Discussion
Single intravesical instillation with mitomycin C (MMC), epirubicin, or pirarubicin, have shown a beneficial effect in reducing recurrence rate compared to TURBT alone. However, randomized comparisons of individual drugs have not been conducted.3
The high recurrence rate of NMIBC may be attributed to the seeding of floating tumor cells. Immediate chemotherapy instillation has been shown to act by destroying these circulating tumor cells after TURBT. Hence the EAU guidelines recommend initiating the instillation within the first few hours after TURBT.1
Most of the complications of intravesical chemotherapy instillation are minor and can be managed medically. Dysuria and urinary frequency and urgency were the most common complications.4
On the other hand, reporting major complications such as bladder perforation, perirectal abscesses, eosinophilic cystitis, and ureteral stenosis is limited to case reports.5-14
In this case, we described our experience with bladder perforation after immediate intravesical instillation of doxorubicin.
One can argue that the perforation has occurred intraoperatively and gone unnoticed. However, in view of the absence of endoscopic evidence of perforation, late presentation of symptoms, and the absence of symptoms during and after the instillation we assume that the Single Dose Intravesical Doxorubicin Instillation caused the perforation rather than complicating an existing one.
To explain the mechanism of perforation, Lim et al7 and Cliff et al8 hypothesized that perforation is caused when attenuated muscularis propria gets necrosed after MMC instillation.
The presenting complaints of our patient were perineal and pelvic pain as well as urinary irritative symptoms. This is similar to Elmamoun et al9 cohort in which all the 6 patients presented with perineal and pelvic pain. Other symptoms such as fever, urine retention, and recurrent UTI were variably reported by others. Table 1 summarizes the clinical presentation and management of bladder perforation in the previously published case reports.
Table1. A summary of the presentation and management of bladder perforation after immediate chemotheraputic agent intravesical instillation.
Ref. number The instilled drug Number of patients Initial presentation Management outline
Lim et al7 MMC 1 Pelvic and suprapubic pain Exploratry laparotomy and bladder repair after failed conservative management
Elmamoun et al9 MMC 6 3 patients presented with pelvic pain Conservative management and urethral catheterization for 2, 26, and 52 weeks
Pelvic pain Recurrent UTIs Left ureteric obstruction Partial cystectomy + left to right trans-ureteroureterostomy
Pelvic pain, Persistent urinary leak
Left ureteric obstruction Augmentation cystoplasty + leftUreteric reimplantationThe patient ended with persistent leak, so a long-term catheter was used
Pelvic painSevere LUTS Bilateral ureteric obstruction Urinary diversion (ileal conduit)
Penna et al10 MMC 1 Lower abdominal pain and inability to void Analgesia, antibiotics and urethral catheter for 4 weeks
Tyritzis et al11 EPI 2 Fever and retropubic pain Conservative: Antibiotics and urethral catheter
Fever, lower abdominal pain and cellulitis Exploratry laparotomy and bladder repair after failed conservative management
Nieuwenhuijzen et al12 MMC Pelvic pain and fever Exploratry laparotomy and bladder repair after failed conservative management for 1 month
Racioppi et al13 MMC Pelvic pain, fever and pancytopenia Exploratry laparotomy and bladder repair after failed conservative management for 3 weeks
Hatem and Leifeld14 MMC Pelvic pain
Fever and positive blood culture for ecoli as well as purulent discharge from the drain site after the first expolratory laparatomy Conservative management for 10 daysExploratory laparatomy that revealed edematous anterior bladder wall without defectRenewed laparotomy, drainage of the abscess, debridement of the necrotic tissue, mono-J ureteral stents and nephrostomyRadical cystectomy with a urinary diversion through ureterocutaneostomy
Shenaq et al15 EPI 3 Strong urge and pain in the lower left abdomen Conservative management with antibiotics and urethral catheterization
Abdominal pain and intestinal obstruction Conservative management for 12 daysExploratory laparotomy that revealed infiltrative mass on the top of the bladder causing IO, so colostomy was done.The patient died due to multi organ failure
Progressive pain in the lower abdomen Conservative management with antibiotics and urethral catheterization
Abbreviations: Ep, epirubicin; MMC, mitomycin C.
Concerning the management, almost all the reported cases were initially managed conservatively by urethral catheterization, anticholinergics, and antibiotics. However, this was insufficient to heal the bladder in some cases which needed open repair. Moreover, some ended with cystectomy.
In our case, the patient has an extraperitoneal extravasation that failed the conservative management and needed open surgical repair.
A striking feature of the healing process that was seen in many cases including ours is the poor and slow healing. In our case, the patient needed 9 weeks for complete healing after proper open 3 layers bladder wall repair.7-9,13,14
While Lim et al attributed the slow healing in their case to the patient’s pre-existing peripheral vascular disease and suboptimal tissue oxygenation, no risk factors were identified in the other cases including our patient who was free of any comorbidities. We suppose that the poor healing is linked to the chemotherapeutic agent inflammatory effect rather than to patient factor.
This assumption is backed by the reported characteristic of mitomycin induced skin ulcer in cases of extravasation after intravenous administration. These ulcers are well known for their chronicity and the low tendency of spontaneous healing. Moreover, debridement and soft-tissue reconstruction following extravasation of MMC are recommended for patients with persistent ulceration and pain.15
Another common finding in the cases that mandate open repair was the presence of perivesical soft tissue necrosis and extensive inflammation. Doherty et al observed that more extensive bladder wall and fat necrosis of extravesical tissue in cystectomy specimens occurred when either epirubicin or mitomycin instillation was administered than in that seen following TURBT alone.16
This cytotoxic effect was also reported by Tyritzis et al11 after epirubicin instillation, and by Cliff et al,8 Nieuwenhuijzen et al,12 and Hatem and Leifeld14 after MMC instillation. This cytotoxic effect was recognized herein for the doxorubicin instillation, which is the first time to be reported as a complication of doxorubicin.
It is worth to mention that the perforation had no adverse oncological effect on our patient as no tumor recurrence was detected during follow up.
Conclusion
Immediate intravesical instillations of chemotherapy are not devoid from risk and serious complications as bladder perforation can occur. Whether it’s value in decreasing the recurrence justify the risk of bladder perforation is not our argument in this case report. Nevertheless, this severe complication should be kept in mind, and high index of suspicion will aid in timely management. If perforation is suspected, urethral catheterization and contrasted imaging are mandatory. In the case of failed conservative management surgical repair is warranted even in extraperitoneal leak.
Funding:The author(s) received no financial support for the research, authorship, and/or publication of this article.
Declaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Author Contributions: Concept: AA, SAD. Design: MA, SA. Supervision: AA, SAD, MAA. Resources: MA, HM, NB. Materials: AA, MA, NB. Writing manuscript: AA, MA, HM. Critical review: AA, SAD, MAA.
Informed Consent: The patient has given his written informed consent to publish his case including publication of images. The study follows the guidelines for human studies and is conducted in accordance with the World Medical Association Declaration of Helsinki.
ORCID iD: Hammam Mansi
https://orcid.org/0000-0002-4571-4336 | 50 ML DILUTED IN 100 CC OF SALINE | DrugDosageText | CC BY-NC | 33473244 | 18,846,152 | 2021 |
What was the outcome of reaction 'Dystrophic calcification'? | Delayed Bladder Perforation Related to Immediate Single Dose Intravesical Doxorubicin Instillation After TURBT: A Case Report and Literature Review.
Intravesical chemotherapy instillation immediately after tumor resection is a well-known practice in the management of non-muscle invasive bladder cancer. Despite being largely well tolerated in most cases, it is not devoid of severe and life-threatening complications.
We present an unusual case of bladder perforation that happened 2 weeks after bladder tumor resection. The patient had received single dose intra-vesical instillation of doxorubicin after TUR-BT. Conservative managements failed to achieve bladder healing; as a result, open surgical repair was performed. To the best of our knowledge, this is the first reported case of bladder perforation after intra-vesical doxorubicin instillation.
The occurrence of such a rare serious complication in a mostly safe intervention must be taken into consideration. A high index of suspicion, timely management, and proceeding to more invasive surgical treatments when necessary are cornerstones in the management and preserving the bladder.
Introduction
Bladder cancer (BC) is the seventh most commonly diagnosed cancer in men worldwide. About 75% of the cases are Non-muscle invasive (NMIBC).1 Transurethral resection of the bladder tumor (TURBT) remains the gold standard of therapy for diagnosing and treating NMIBC. To decrease the recurrence rate of low-risk tumors, a single, immediate, post-operative intravesical instillation of chemotherapy is recommended.1
The most commonly used chemotherapeutic agent is Mitomycin C (MMC), which is an alkylating agent that inhibits DNA synthesis and causes single-strand breakage of DNA and chromosomal breaks.2
Immediate single instillation (SI) is largely well-tolerated. However, severe complications and even death have been reported in the literature. Here we present a case wherein the patient had an extraperitoneal bladder perforation that occurred 2 weeks after TUT-BT and immediate postoperative instillation of doxorubicin.
Case Presentation
A 63-Year-old male, a heavy smoker, with no other co-morbidities, was referred to urology clinic for evaluation and management of a lesion on the left bladder wall that was incidentally detected on a CT scan. He did not have any urinary symptoms on initial presentation.
Cystourethroscopy revealed 2 papillary growths on the left lateral bladder wall, which were resected completely and smoothly by a resectoscope using a monopolar energy. Complete resection of the tumor was achieved without any intra-operative complication or perforation. Hemostasis was secured, and a urethral catheter was inserted.
In accordance of the EAU guidelines, the patient received an intravesical instillation of 50 ml of doxorubicin diluted in 100 cc of saline 6 hours after the TURBT. During the instillation, his vital signs were stable and he had neither hematuria nor abdominal pain. One hour after the instillation, the catheter was unclamped and was attached to continuous bladder irrigation.
Two days after the surgery and in the absence of hematuria, the indwelling catheter was removed, and the patient was discharged home the next day.
When seen in the clinic 1 week later the patient was fine with no alarming symptoms. The pathology report showed a low-grade Ta Papillary urothelial carcinoma. Based on the pathological diagnosis and according to the EAU guidelines, adjuvant chemotherapy instillations were planned.
Two weeks later, the patient presented with, dysuria, frequency, urgency, as well as pelvic and perineal pain. Physical examination was unremarkable. Urine analysis showed numerous WBC’s, RBC’s, and bacteria. An empirical antibiotics course was commenced.
In view of the worsening symptoms and the past history of anal fistula, a contrast enhanced pelvic MRI was performed. It showed a diffusely thickened urinary bladder wall, with evidence of a focal wall defect at its left aspect (the site of the resected tumor). The active urine leak into the perivesical space confirmed the diagnosis of retroperitoneal bladder perforation (Figure 1).
Figure. 1. Pelvic MRI (axial view) showing extraperitoneal bladder perforation at the left lateral wall (arrow points to extravasated contrast).
The patient was managed conservatively with antibiotics and an indwelling catheter for 3 weeks.
A follow-up retrograde CT cystogram showed no improvement and a gross contrast leak from the same site was identified. The catheter was kept for 6 more weeks and the CT cystogram was repeated showing the same results with no evidence of improvement. The patient refused to keep the catheter for a longer period so the option of open surgical repair was discussed with him.
Extraperitoneal laparotomy was performed, a perivesical small abscess was drained and cultured, necrotic tissues were debrided, and the bladder wall defect was rimed and closed in 3 layers. Tissue biopsies from the pelvic wall and bladder wall were harvested. A urethral catheter and pelvic drain were kept in place. The postoperative course was uneventful, the drain was removed on the third-day postoperatively, and the patient was discharged home with the urethral catheter in.
Histopathological evaluation of the pelvic wall and the bladder biopsies verified acute and chronic inflammation as well as granulation tissue formation. However, both were negative for malignancy. The urinary bladder biopsy also showed extensive foci of dystrophic calcification while the pelvic wall biopsy revealed fat necrosis (Figures 2 and 3).
Figure 2. The histologic examination revealed fragments of soft tissue with fat necrosis in the lower left area, mixed acute and chronic inflammatory cell infiltrate and hemorrhage in the upper right area (Hematoxylin & Eosin, 200X).
Figure 3. The histologic examination revealed multiple areas of calcifications embedded deep in the tissue with associated crystal-like material suggestive of calcium-oxalate or talc powder crystals (Hematoxylin & Eosin, 200X).
A follow up CT cystogram was done 3 weeks after the bladder repair. Although it showed a considerable regression in the size of the bladder defect, interestingly it also showed persistent extra-peritoneal contrast leak from the bladder along it’s left lateral aspect (Figure 4).
Figure 4. Retrograde Ct cystogram showing persistent contrast leak from the left lateral aspect after surgical repair.
Due to this slow healing, the catheter was kept in. Six weeks later, a follow up CT cystogram showed healing with no extraperitoneal contrast leak (Figure 5). And hence the catheter was removed.
Figure 5. Retrograde Ct cystogram showing a healed bladder wall with no contrast leak.
Two follow up cystoscopies and bladder biopsy (from an erythematous area on the left lateral wall) with 3 months intervals showed good healing of the bladder wall and no recurrence of the tumor.
Discussion
Single intravesical instillation with mitomycin C (MMC), epirubicin, or pirarubicin, have shown a beneficial effect in reducing recurrence rate compared to TURBT alone. However, randomized comparisons of individual drugs have not been conducted.3
The high recurrence rate of NMIBC may be attributed to the seeding of floating tumor cells. Immediate chemotherapy instillation has been shown to act by destroying these circulating tumor cells after TURBT. Hence the EAU guidelines recommend initiating the instillation within the first few hours after TURBT.1
Most of the complications of intravesical chemotherapy instillation are minor and can be managed medically. Dysuria and urinary frequency and urgency were the most common complications.4
On the other hand, reporting major complications such as bladder perforation, perirectal abscesses, eosinophilic cystitis, and ureteral stenosis is limited to case reports.5-14
In this case, we described our experience with bladder perforation after immediate intravesical instillation of doxorubicin.
One can argue that the perforation has occurred intraoperatively and gone unnoticed. However, in view of the absence of endoscopic evidence of perforation, late presentation of symptoms, and the absence of symptoms during and after the instillation we assume that the Single Dose Intravesical Doxorubicin Instillation caused the perforation rather than complicating an existing one.
To explain the mechanism of perforation, Lim et al7 and Cliff et al8 hypothesized that perforation is caused when attenuated muscularis propria gets necrosed after MMC instillation.
The presenting complaints of our patient were perineal and pelvic pain as well as urinary irritative symptoms. This is similar to Elmamoun et al9 cohort in which all the 6 patients presented with perineal and pelvic pain. Other symptoms such as fever, urine retention, and recurrent UTI were variably reported by others. Table 1 summarizes the clinical presentation and management of bladder perforation in the previously published case reports.
Table1. A summary of the presentation and management of bladder perforation after immediate chemotheraputic agent intravesical instillation.
Ref. number The instilled drug Number of patients Initial presentation Management outline
Lim et al7 MMC 1 Pelvic and suprapubic pain Exploratry laparotomy and bladder repair after failed conservative management
Elmamoun et al9 MMC 6 3 patients presented with pelvic pain Conservative management and urethral catheterization for 2, 26, and 52 weeks
Pelvic pain Recurrent UTIs Left ureteric obstruction Partial cystectomy + left to right trans-ureteroureterostomy
Pelvic pain, Persistent urinary leak
Left ureteric obstruction Augmentation cystoplasty + leftUreteric reimplantationThe patient ended with persistent leak, so a long-term catheter was used
Pelvic painSevere LUTS Bilateral ureteric obstruction Urinary diversion (ileal conduit)
Penna et al10 MMC 1 Lower abdominal pain and inability to void Analgesia, antibiotics and urethral catheter for 4 weeks
Tyritzis et al11 EPI 2 Fever and retropubic pain Conservative: Antibiotics and urethral catheter
Fever, lower abdominal pain and cellulitis Exploratry laparotomy and bladder repair after failed conservative management
Nieuwenhuijzen et al12 MMC Pelvic pain and fever Exploratry laparotomy and bladder repair after failed conservative management for 1 month
Racioppi et al13 MMC Pelvic pain, fever and pancytopenia Exploratry laparotomy and bladder repair after failed conservative management for 3 weeks
Hatem and Leifeld14 MMC Pelvic pain
Fever and positive blood culture for ecoli as well as purulent discharge from the drain site after the first expolratory laparatomy Conservative management for 10 daysExploratory laparatomy that revealed edematous anterior bladder wall without defectRenewed laparotomy, drainage of the abscess, debridement of the necrotic tissue, mono-J ureteral stents and nephrostomyRadical cystectomy with a urinary diversion through ureterocutaneostomy
Shenaq et al15 EPI 3 Strong urge and pain in the lower left abdomen Conservative management with antibiotics and urethral catheterization
Abdominal pain and intestinal obstruction Conservative management for 12 daysExploratory laparotomy that revealed infiltrative mass on the top of the bladder causing IO, so colostomy was done.The patient died due to multi organ failure
Progressive pain in the lower abdomen Conservative management with antibiotics and urethral catheterization
Abbreviations: Ep, epirubicin; MMC, mitomycin C.
Concerning the management, almost all the reported cases were initially managed conservatively by urethral catheterization, anticholinergics, and antibiotics. However, this was insufficient to heal the bladder in some cases which needed open repair. Moreover, some ended with cystectomy.
In our case, the patient has an extraperitoneal extravasation that failed the conservative management and needed open surgical repair.
A striking feature of the healing process that was seen in many cases including ours is the poor and slow healing. In our case, the patient needed 9 weeks for complete healing after proper open 3 layers bladder wall repair.7-9,13,14
While Lim et al attributed the slow healing in their case to the patient’s pre-existing peripheral vascular disease and suboptimal tissue oxygenation, no risk factors were identified in the other cases including our patient who was free of any comorbidities. We suppose that the poor healing is linked to the chemotherapeutic agent inflammatory effect rather than to patient factor.
This assumption is backed by the reported characteristic of mitomycin induced skin ulcer in cases of extravasation after intravenous administration. These ulcers are well known for their chronicity and the low tendency of spontaneous healing. Moreover, debridement and soft-tissue reconstruction following extravasation of MMC are recommended for patients with persistent ulceration and pain.15
Another common finding in the cases that mandate open repair was the presence of perivesical soft tissue necrosis and extensive inflammation. Doherty et al observed that more extensive bladder wall and fat necrosis of extravesical tissue in cystectomy specimens occurred when either epirubicin or mitomycin instillation was administered than in that seen following TURBT alone.16
This cytotoxic effect was also reported by Tyritzis et al11 after epirubicin instillation, and by Cliff et al,8 Nieuwenhuijzen et al,12 and Hatem and Leifeld14 after MMC instillation. This cytotoxic effect was recognized herein for the doxorubicin instillation, which is the first time to be reported as a complication of doxorubicin.
It is worth to mention that the perforation had no adverse oncological effect on our patient as no tumor recurrence was detected during follow up.
Conclusion
Immediate intravesical instillations of chemotherapy are not devoid from risk and serious complications as bladder perforation can occur. Whether it’s value in decreasing the recurrence justify the risk of bladder perforation is not our argument in this case report. Nevertheless, this severe complication should be kept in mind, and high index of suspicion will aid in timely management. If perforation is suspected, urethral catheterization and contrasted imaging are mandatory. In the case of failed conservative management surgical repair is warranted even in extraperitoneal leak.
Funding:The author(s) received no financial support for the research, authorship, and/or publication of this article.
Declaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Author Contributions: Concept: AA, SAD. Design: MA, SA. Supervision: AA, SAD, MAA. Resources: MA, HM, NB. Materials: AA, MA, NB. Writing manuscript: AA, MA, HM. Critical review: AA, SAD, MAA.
Informed Consent: The patient has given his written informed consent to publish his case including publication of images. The study follows the guidelines for human studies and is conducted in accordance with the World Medical Association Declaration of Helsinki.
ORCID iD: Hammam Mansi
https://orcid.org/0000-0002-4571-4336 | Recovered | ReactionOutcome | CC BY-NC | 33473244 | 18,858,074 | 2021 |
What was the outcome of reaction 'Extravasation of urine'? | Delayed Bladder Perforation Related to Immediate Single Dose Intravesical Doxorubicin Instillation After TURBT: A Case Report and Literature Review.
Intravesical chemotherapy instillation immediately after tumor resection is a well-known practice in the management of non-muscle invasive bladder cancer. Despite being largely well tolerated in most cases, it is not devoid of severe and life-threatening complications.
We present an unusual case of bladder perforation that happened 2 weeks after bladder tumor resection. The patient had received single dose intra-vesical instillation of doxorubicin after TUR-BT. Conservative managements failed to achieve bladder healing; as a result, open surgical repair was performed. To the best of our knowledge, this is the first reported case of bladder perforation after intra-vesical doxorubicin instillation.
The occurrence of such a rare serious complication in a mostly safe intervention must be taken into consideration. A high index of suspicion, timely management, and proceeding to more invasive surgical treatments when necessary are cornerstones in the management and preserving the bladder.
Introduction
Bladder cancer (BC) is the seventh most commonly diagnosed cancer in men worldwide. About 75% of the cases are Non-muscle invasive (NMIBC).1 Transurethral resection of the bladder tumor (TURBT) remains the gold standard of therapy for diagnosing and treating NMIBC. To decrease the recurrence rate of low-risk tumors, a single, immediate, post-operative intravesical instillation of chemotherapy is recommended.1
The most commonly used chemotherapeutic agent is Mitomycin C (MMC), which is an alkylating agent that inhibits DNA synthesis and causes single-strand breakage of DNA and chromosomal breaks.2
Immediate single instillation (SI) is largely well-tolerated. However, severe complications and even death have been reported in the literature. Here we present a case wherein the patient had an extraperitoneal bladder perforation that occurred 2 weeks after TUT-BT and immediate postoperative instillation of doxorubicin.
Case Presentation
A 63-Year-old male, a heavy smoker, with no other co-morbidities, was referred to urology clinic for evaluation and management of a lesion on the left bladder wall that was incidentally detected on a CT scan. He did not have any urinary symptoms on initial presentation.
Cystourethroscopy revealed 2 papillary growths on the left lateral bladder wall, which were resected completely and smoothly by a resectoscope using a monopolar energy. Complete resection of the tumor was achieved without any intra-operative complication or perforation. Hemostasis was secured, and a urethral catheter was inserted.
In accordance of the EAU guidelines, the patient received an intravesical instillation of 50 ml of doxorubicin diluted in 100 cc of saline 6 hours after the TURBT. During the instillation, his vital signs were stable and he had neither hematuria nor abdominal pain. One hour after the instillation, the catheter was unclamped and was attached to continuous bladder irrigation.
Two days after the surgery and in the absence of hematuria, the indwelling catheter was removed, and the patient was discharged home the next day.
When seen in the clinic 1 week later the patient was fine with no alarming symptoms. The pathology report showed a low-grade Ta Papillary urothelial carcinoma. Based on the pathological diagnosis and according to the EAU guidelines, adjuvant chemotherapy instillations were planned.
Two weeks later, the patient presented with, dysuria, frequency, urgency, as well as pelvic and perineal pain. Physical examination was unremarkable. Urine analysis showed numerous WBC’s, RBC’s, and bacteria. An empirical antibiotics course was commenced.
In view of the worsening symptoms and the past history of anal fistula, a contrast enhanced pelvic MRI was performed. It showed a diffusely thickened urinary bladder wall, with evidence of a focal wall defect at its left aspect (the site of the resected tumor). The active urine leak into the perivesical space confirmed the diagnosis of retroperitoneal bladder perforation (Figure 1).
Figure. 1. Pelvic MRI (axial view) showing extraperitoneal bladder perforation at the left lateral wall (arrow points to extravasated contrast).
The patient was managed conservatively with antibiotics and an indwelling catheter for 3 weeks.
A follow-up retrograde CT cystogram showed no improvement and a gross contrast leak from the same site was identified. The catheter was kept for 6 more weeks and the CT cystogram was repeated showing the same results with no evidence of improvement. The patient refused to keep the catheter for a longer period so the option of open surgical repair was discussed with him.
Extraperitoneal laparotomy was performed, a perivesical small abscess was drained and cultured, necrotic tissues were debrided, and the bladder wall defect was rimed and closed in 3 layers. Tissue biopsies from the pelvic wall and bladder wall were harvested. A urethral catheter and pelvic drain were kept in place. The postoperative course was uneventful, the drain was removed on the third-day postoperatively, and the patient was discharged home with the urethral catheter in.
Histopathological evaluation of the pelvic wall and the bladder biopsies verified acute and chronic inflammation as well as granulation tissue formation. However, both were negative for malignancy. The urinary bladder biopsy also showed extensive foci of dystrophic calcification while the pelvic wall biopsy revealed fat necrosis (Figures 2 and 3).
Figure 2. The histologic examination revealed fragments of soft tissue with fat necrosis in the lower left area, mixed acute and chronic inflammatory cell infiltrate and hemorrhage in the upper right area (Hematoxylin & Eosin, 200X).
Figure 3. The histologic examination revealed multiple areas of calcifications embedded deep in the tissue with associated crystal-like material suggestive of calcium-oxalate or talc powder crystals (Hematoxylin & Eosin, 200X).
A follow up CT cystogram was done 3 weeks after the bladder repair. Although it showed a considerable regression in the size of the bladder defect, interestingly it also showed persistent extra-peritoneal contrast leak from the bladder along it’s left lateral aspect (Figure 4).
Figure 4. Retrograde Ct cystogram showing persistent contrast leak from the left lateral aspect after surgical repair.
Due to this slow healing, the catheter was kept in. Six weeks later, a follow up CT cystogram showed healing with no extraperitoneal contrast leak (Figure 5). And hence the catheter was removed.
Figure 5. Retrograde Ct cystogram showing a healed bladder wall with no contrast leak.
Two follow up cystoscopies and bladder biopsy (from an erythematous area on the left lateral wall) with 3 months intervals showed good healing of the bladder wall and no recurrence of the tumor.
Discussion
Single intravesical instillation with mitomycin C (MMC), epirubicin, or pirarubicin, have shown a beneficial effect in reducing recurrence rate compared to TURBT alone. However, randomized comparisons of individual drugs have not been conducted.3
The high recurrence rate of NMIBC may be attributed to the seeding of floating tumor cells. Immediate chemotherapy instillation has been shown to act by destroying these circulating tumor cells after TURBT. Hence the EAU guidelines recommend initiating the instillation within the first few hours after TURBT.1
Most of the complications of intravesical chemotherapy instillation are minor and can be managed medically. Dysuria and urinary frequency and urgency were the most common complications.4
On the other hand, reporting major complications such as bladder perforation, perirectal abscesses, eosinophilic cystitis, and ureteral stenosis is limited to case reports.5-14
In this case, we described our experience with bladder perforation after immediate intravesical instillation of doxorubicin.
One can argue that the perforation has occurred intraoperatively and gone unnoticed. However, in view of the absence of endoscopic evidence of perforation, late presentation of symptoms, and the absence of symptoms during and after the instillation we assume that the Single Dose Intravesical Doxorubicin Instillation caused the perforation rather than complicating an existing one.
To explain the mechanism of perforation, Lim et al7 and Cliff et al8 hypothesized that perforation is caused when attenuated muscularis propria gets necrosed after MMC instillation.
The presenting complaints of our patient were perineal and pelvic pain as well as urinary irritative symptoms. This is similar to Elmamoun et al9 cohort in which all the 6 patients presented with perineal and pelvic pain. Other symptoms such as fever, urine retention, and recurrent UTI were variably reported by others. Table 1 summarizes the clinical presentation and management of bladder perforation in the previously published case reports.
Table1. A summary of the presentation and management of bladder perforation after immediate chemotheraputic agent intravesical instillation.
Ref. number The instilled drug Number of patients Initial presentation Management outline
Lim et al7 MMC 1 Pelvic and suprapubic pain Exploratry laparotomy and bladder repair after failed conservative management
Elmamoun et al9 MMC 6 3 patients presented with pelvic pain Conservative management and urethral catheterization for 2, 26, and 52 weeks
Pelvic pain Recurrent UTIs Left ureteric obstruction Partial cystectomy + left to right trans-ureteroureterostomy
Pelvic pain, Persistent urinary leak
Left ureteric obstruction Augmentation cystoplasty + leftUreteric reimplantationThe patient ended with persistent leak, so a long-term catheter was used
Pelvic painSevere LUTS Bilateral ureteric obstruction Urinary diversion (ileal conduit)
Penna et al10 MMC 1 Lower abdominal pain and inability to void Analgesia, antibiotics and urethral catheter for 4 weeks
Tyritzis et al11 EPI 2 Fever and retropubic pain Conservative: Antibiotics and urethral catheter
Fever, lower abdominal pain and cellulitis Exploratry laparotomy and bladder repair after failed conservative management
Nieuwenhuijzen et al12 MMC Pelvic pain and fever Exploratry laparotomy and bladder repair after failed conservative management for 1 month
Racioppi et al13 MMC Pelvic pain, fever and pancytopenia Exploratry laparotomy and bladder repair after failed conservative management for 3 weeks
Hatem and Leifeld14 MMC Pelvic pain
Fever and positive blood culture for ecoli as well as purulent discharge from the drain site after the first expolratory laparatomy Conservative management for 10 daysExploratory laparatomy that revealed edematous anterior bladder wall without defectRenewed laparotomy, drainage of the abscess, debridement of the necrotic tissue, mono-J ureteral stents and nephrostomyRadical cystectomy with a urinary diversion through ureterocutaneostomy
Shenaq et al15 EPI 3 Strong urge and pain in the lower left abdomen Conservative management with antibiotics and urethral catheterization
Abdominal pain and intestinal obstruction Conservative management for 12 daysExploratory laparotomy that revealed infiltrative mass on the top of the bladder causing IO, so colostomy was done.The patient died due to multi organ failure
Progressive pain in the lower abdomen Conservative management with antibiotics and urethral catheterization
Abbreviations: Ep, epirubicin; MMC, mitomycin C.
Concerning the management, almost all the reported cases were initially managed conservatively by urethral catheterization, anticholinergics, and antibiotics. However, this was insufficient to heal the bladder in some cases which needed open repair. Moreover, some ended with cystectomy.
In our case, the patient has an extraperitoneal extravasation that failed the conservative management and needed open surgical repair.
A striking feature of the healing process that was seen in many cases including ours is the poor and slow healing. In our case, the patient needed 9 weeks for complete healing after proper open 3 layers bladder wall repair.7-9,13,14
While Lim et al attributed the slow healing in their case to the patient’s pre-existing peripheral vascular disease and suboptimal tissue oxygenation, no risk factors were identified in the other cases including our patient who was free of any comorbidities. We suppose that the poor healing is linked to the chemotherapeutic agent inflammatory effect rather than to patient factor.
This assumption is backed by the reported characteristic of mitomycin induced skin ulcer in cases of extravasation after intravenous administration. These ulcers are well known for their chronicity and the low tendency of spontaneous healing. Moreover, debridement and soft-tissue reconstruction following extravasation of MMC are recommended for patients with persistent ulceration and pain.15
Another common finding in the cases that mandate open repair was the presence of perivesical soft tissue necrosis and extensive inflammation. Doherty et al observed that more extensive bladder wall and fat necrosis of extravesical tissue in cystectomy specimens occurred when either epirubicin or mitomycin instillation was administered than in that seen following TURBT alone.16
This cytotoxic effect was also reported by Tyritzis et al11 after epirubicin instillation, and by Cliff et al,8 Nieuwenhuijzen et al,12 and Hatem and Leifeld14 after MMC instillation. This cytotoxic effect was recognized herein for the doxorubicin instillation, which is the first time to be reported as a complication of doxorubicin.
It is worth to mention that the perforation had no adverse oncological effect on our patient as no tumor recurrence was detected during follow up.
Conclusion
Immediate intravesical instillations of chemotherapy are not devoid from risk and serious complications as bladder perforation can occur. Whether it’s value in decreasing the recurrence justify the risk of bladder perforation is not our argument in this case report. Nevertheless, this severe complication should be kept in mind, and high index of suspicion will aid in timely management. If perforation is suspected, urethral catheterization and contrasted imaging are mandatory. In the case of failed conservative management surgical repair is warranted even in extraperitoneal leak.
Funding:The author(s) received no financial support for the research, authorship, and/or publication of this article.
Declaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Author Contributions: Concept: AA, SAD. Design: MA, SA. Supervision: AA, SAD, MAA. Resources: MA, HM, NB. Materials: AA, MA, NB. Writing manuscript: AA, MA, HM. Critical review: AA, SAD, MAA.
Informed Consent: The patient has given his written informed consent to publish his case including publication of images. The study follows the guidelines for human studies and is conducted in accordance with the World Medical Association Declaration of Helsinki.
ORCID iD: Hammam Mansi
https://orcid.org/0000-0002-4571-4336 | Recovered | ReactionOutcome | CC BY-NC | 33473244 | 18,858,074 | 2021 |
What was the outcome of reaction 'Fat necrosis'? | Delayed Bladder Perforation Related to Immediate Single Dose Intravesical Doxorubicin Instillation After TURBT: A Case Report and Literature Review.
Intravesical chemotherapy instillation immediately after tumor resection is a well-known practice in the management of non-muscle invasive bladder cancer. Despite being largely well tolerated in most cases, it is not devoid of severe and life-threatening complications.
We present an unusual case of bladder perforation that happened 2 weeks after bladder tumor resection. The patient had received single dose intra-vesical instillation of doxorubicin after TUR-BT. Conservative managements failed to achieve bladder healing; as a result, open surgical repair was performed. To the best of our knowledge, this is the first reported case of bladder perforation after intra-vesical doxorubicin instillation.
The occurrence of such a rare serious complication in a mostly safe intervention must be taken into consideration. A high index of suspicion, timely management, and proceeding to more invasive surgical treatments when necessary are cornerstones in the management and preserving the bladder.
Introduction
Bladder cancer (BC) is the seventh most commonly diagnosed cancer in men worldwide. About 75% of the cases are Non-muscle invasive (NMIBC).1 Transurethral resection of the bladder tumor (TURBT) remains the gold standard of therapy for diagnosing and treating NMIBC. To decrease the recurrence rate of low-risk tumors, a single, immediate, post-operative intravesical instillation of chemotherapy is recommended.1
The most commonly used chemotherapeutic agent is Mitomycin C (MMC), which is an alkylating agent that inhibits DNA synthesis and causes single-strand breakage of DNA and chromosomal breaks.2
Immediate single instillation (SI) is largely well-tolerated. However, severe complications and even death have been reported in the literature. Here we present a case wherein the patient had an extraperitoneal bladder perforation that occurred 2 weeks after TUT-BT and immediate postoperative instillation of doxorubicin.
Case Presentation
A 63-Year-old male, a heavy smoker, with no other co-morbidities, was referred to urology clinic for evaluation and management of a lesion on the left bladder wall that was incidentally detected on a CT scan. He did not have any urinary symptoms on initial presentation.
Cystourethroscopy revealed 2 papillary growths on the left lateral bladder wall, which were resected completely and smoothly by a resectoscope using a monopolar energy. Complete resection of the tumor was achieved without any intra-operative complication or perforation. Hemostasis was secured, and a urethral catheter was inserted.
In accordance of the EAU guidelines, the patient received an intravesical instillation of 50 ml of doxorubicin diluted in 100 cc of saline 6 hours after the TURBT. During the instillation, his vital signs were stable and he had neither hematuria nor abdominal pain. One hour after the instillation, the catheter was unclamped and was attached to continuous bladder irrigation.
Two days after the surgery and in the absence of hematuria, the indwelling catheter was removed, and the patient was discharged home the next day.
When seen in the clinic 1 week later the patient was fine with no alarming symptoms. The pathology report showed a low-grade Ta Papillary urothelial carcinoma. Based on the pathological diagnosis and according to the EAU guidelines, adjuvant chemotherapy instillations were planned.
Two weeks later, the patient presented with, dysuria, frequency, urgency, as well as pelvic and perineal pain. Physical examination was unremarkable. Urine analysis showed numerous WBC’s, RBC’s, and bacteria. An empirical antibiotics course was commenced.
In view of the worsening symptoms and the past history of anal fistula, a contrast enhanced pelvic MRI was performed. It showed a diffusely thickened urinary bladder wall, with evidence of a focal wall defect at its left aspect (the site of the resected tumor). The active urine leak into the perivesical space confirmed the diagnosis of retroperitoneal bladder perforation (Figure 1).
Figure. 1. Pelvic MRI (axial view) showing extraperitoneal bladder perforation at the left lateral wall (arrow points to extravasated contrast).
The patient was managed conservatively with antibiotics and an indwelling catheter for 3 weeks.
A follow-up retrograde CT cystogram showed no improvement and a gross contrast leak from the same site was identified. The catheter was kept for 6 more weeks and the CT cystogram was repeated showing the same results with no evidence of improvement. The patient refused to keep the catheter for a longer period so the option of open surgical repair was discussed with him.
Extraperitoneal laparotomy was performed, a perivesical small abscess was drained and cultured, necrotic tissues were debrided, and the bladder wall defect was rimed and closed in 3 layers. Tissue biopsies from the pelvic wall and bladder wall were harvested. A urethral catheter and pelvic drain were kept in place. The postoperative course was uneventful, the drain was removed on the third-day postoperatively, and the patient was discharged home with the urethral catheter in.
Histopathological evaluation of the pelvic wall and the bladder biopsies verified acute and chronic inflammation as well as granulation tissue formation. However, both were negative for malignancy. The urinary bladder biopsy also showed extensive foci of dystrophic calcification while the pelvic wall biopsy revealed fat necrosis (Figures 2 and 3).
Figure 2. The histologic examination revealed fragments of soft tissue with fat necrosis in the lower left area, mixed acute and chronic inflammatory cell infiltrate and hemorrhage in the upper right area (Hematoxylin & Eosin, 200X).
Figure 3. The histologic examination revealed multiple areas of calcifications embedded deep in the tissue with associated crystal-like material suggestive of calcium-oxalate or talc powder crystals (Hematoxylin & Eosin, 200X).
A follow up CT cystogram was done 3 weeks after the bladder repair. Although it showed a considerable regression in the size of the bladder defect, interestingly it also showed persistent extra-peritoneal contrast leak from the bladder along it’s left lateral aspect (Figure 4).
Figure 4. Retrograde Ct cystogram showing persistent contrast leak from the left lateral aspect after surgical repair.
Due to this slow healing, the catheter was kept in. Six weeks later, a follow up CT cystogram showed healing with no extraperitoneal contrast leak (Figure 5). And hence the catheter was removed.
Figure 5. Retrograde Ct cystogram showing a healed bladder wall with no contrast leak.
Two follow up cystoscopies and bladder biopsy (from an erythematous area on the left lateral wall) with 3 months intervals showed good healing of the bladder wall and no recurrence of the tumor.
Discussion
Single intravesical instillation with mitomycin C (MMC), epirubicin, or pirarubicin, have shown a beneficial effect in reducing recurrence rate compared to TURBT alone. However, randomized comparisons of individual drugs have not been conducted.3
The high recurrence rate of NMIBC may be attributed to the seeding of floating tumor cells. Immediate chemotherapy instillation has been shown to act by destroying these circulating tumor cells after TURBT. Hence the EAU guidelines recommend initiating the instillation within the first few hours after TURBT.1
Most of the complications of intravesical chemotherapy instillation are minor and can be managed medically. Dysuria and urinary frequency and urgency were the most common complications.4
On the other hand, reporting major complications such as bladder perforation, perirectal abscesses, eosinophilic cystitis, and ureteral stenosis is limited to case reports.5-14
In this case, we described our experience with bladder perforation after immediate intravesical instillation of doxorubicin.
One can argue that the perforation has occurred intraoperatively and gone unnoticed. However, in view of the absence of endoscopic evidence of perforation, late presentation of symptoms, and the absence of symptoms during and after the instillation we assume that the Single Dose Intravesical Doxorubicin Instillation caused the perforation rather than complicating an existing one.
To explain the mechanism of perforation, Lim et al7 and Cliff et al8 hypothesized that perforation is caused when attenuated muscularis propria gets necrosed after MMC instillation.
The presenting complaints of our patient were perineal and pelvic pain as well as urinary irritative symptoms. This is similar to Elmamoun et al9 cohort in which all the 6 patients presented with perineal and pelvic pain. Other symptoms such as fever, urine retention, and recurrent UTI were variably reported by others. Table 1 summarizes the clinical presentation and management of bladder perforation in the previously published case reports.
Table1. A summary of the presentation and management of bladder perforation after immediate chemotheraputic agent intravesical instillation.
Ref. number The instilled drug Number of patients Initial presentation Management outline
Lim et al7 MMC 1 Pelvic and suprapubic pain Exploratry laparotomy and bladder repair after failed conservative management
Elmamoun et al9 MMC 6 3 patients presented with pelvic pain Conservative management and urethral catheterization for 2, 26, and 52 weeks
Pelvic pain Recurrent UTIs Left ureteric obstruction Partial cystectomy + left to right trans-ureteroureterostomy
Pelvic pain, Persistent urinary leak
Left ureteric obstruction Augmentation cystoplasty + leftUreteric reimplantationThe patient ended with persistent leak, so a long-term catheter was used
Pelvic painSevere LUTS Bilateral ureteric obstruction Urinary diversion (ileal conduit)
Penna et al10 MMC 1 Lower abdominal pain and inability to void Analgesia, antibiotics and urethral catheter for 4 weeks
Tyritzis et al11 EPI 2 Fever and retropubic pain Conservative: Antibiotics and urethral catheter
Fever, lower abdominal pain and cellulitis Exploratry laparotomy and bladder repair after failed conservative management
Nieuwenhuijzen et al12 MMC Pelvic pain and fever Exploratry laparotomy and bladder repair after failed conservative management for 1 month
Racioppi et al13 MMC Pelvic pain, fever and pancytopenia Exploratry laparotomy and bladder repair after failed conservative management for 3 weeks
Hatem and Leifeld14 MMC Pelvic pain
Fever and positive blood culture for ecoli as well as purulent discharge from the drain site after the first expolratory laparatomy Conservative management for 10 daysExploratory laparatomy that revealed edematous anterior bladder wall without defectRenewed laparotomy, drainage of the abscess, debridement of the necrotic tissue, mono-J ureteral stents and nephrostomyRadical cystectomy with a urinary diversion through ureterocutaneostomy
Shenaq et al15 EPI 3 Strong urge and pain in the lower left abdomen Conservative management with antibiotics and urethral catheterization
Abdominal pain and intestinal obstruction Conservative management for 12 daysExploratory laparotomy that revealed infiltrative mass on the top of the bladder causing IO, so colostomy was done.The patient died due to multi organ failure
Progressive pain in the lower abdomen Conservative management with antibiotics and urethral catheterization
Abbreviations: Ep, epirubicin; MMC, mitomycin C.
Concerning the management, almost all the reported cases were initially managed conservatively by urethral catheterization, anticholinergics, and antibiotics. However, this was insufficient to heal the bladder in some cases which needed open repair. Moreover, some ended with cystectomy.
In our case, the patient has an extraperitoneal extravasation that failed the conservative management and needed open surgical repair.
A striking feature of the healing process that was seen in many cases including ours is the poor and slow healing. In our case, the patient needed 9 weeks for complete healing after proper open 3 layers bladder wall repair.7-9,13,14
While Lim et al attributed the slow healing in their case to the patient’s pre-existing peripheral vascular disease and suboptimal tissue oxygenation, no risk factors were identified in the other cases including our patient who was free of any comorbidities. We suppose that the poor healing is linked to the chemotherapeutic agent inflammatory effect rather than to patient factor.
This assumption is backed by the reported characteristic of mitomycin induced skin ulcer in cases of extravasation after intravenous administration. These ulcers are well known for their chronicity and the low tendency of spontaneous healing. Moreover, debridement and soft-tissue reconstruction following extravasation of MMC are recommended for patients with persistent ulceration and pain.15
Another common finding in the cases that mandate open repair was the presence of perivesical soft tissue necrosis and extensive inflammation. Doherty et al observed that more extensive bladder wall and fat necrosis of extravesical tissue in cystectomy specimens occurred when either epirubicin or mitomycin instillation was administered than in that seen following TURBT alone.16
This cytotoxic effect was also reported by Tyritzis et al11 after epirubicin instillation, and by Cliff et al,8 Nieuwenhuijzen et al,12 and Hatem and Leifeld14 after MMC instillation. This cytotoxic effect was recognized herein for the doxorubicin instillation, which is the first time to be reported as a complication of doxorubicin.
It is worth to mention that the perforation had no adverse oncological effect on our patient as no tumor recurrence was detected during follow up.
Conclusion
Immediate intravesical instillations of chemotherapy are not devoid from risk and serious complications as bladder perforation can occur. Whether it’s value in decreasing the recurrence justify the risk of bladder perforation is not our argument in this case report. Nevertheless, this severe complication should be kept in mind, and high index of suspicion will aid in timely management. If perforation is suspected, urethral catheterization and contrasted imaging are mandatory. In the case of failed conservative management surgical repair is warranted even in extraperitoneal leak.
Funding:The author(s) received no financial support for the research, authorship, and/or publication of this article.
Declaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Author Contributions: Concept: AA, SAD. Design: MA, SA. Supervision: AA, SAD, MAA. Resources: MA, HM, NB. Materials: AA, MA, NB. Writing manuscript: AA, MA, HM. Critical review: AA, SAD, MAA.
Informed Consent: The patient has given his written informed consent to publish his case including publication of images. The study follows the guidelines for human studies and is conducted in accordance with the World Medical Association Declaration of Helsinki.
ORCID iD: Hammam Mansi
https://orcid.org/0000-0002-4571-4336 | Recovered | ReactionOutcome | CC BY-NC | 33473244 | 18,858,074 | 2021 |
What was the outcome of reaction 'Impaired healing'? | Delayed Bladder Perforation Related to Immediate Single Dose Intravesical Doxorubicin Instillation After TURBT: A Case Report and Literature Review.
Intravesical chemotherapy instillation immediately after tumor resection is a well-known practice in the management of non-muscle invasive bladder cancer. Despite being largely well tolerated in most cases, it is not devoid of severe and life-threatening complications.
We present an unusual case of bladder perforation that happened 2 weeks after bladder tumor resection. The patient had received single dose intra-vesical instillation of doxorubicin after TUR-BT. Conservative managements failed to achieve bladder healing; as a result, open surgical repair was performed. To the best of our knowledge, this is the first reported case of bladder perforation after intra-vesical doxorubicin instillation.
The occurrence of such a rare serious complication in a mostly safe intervention must be taken into consideration. A high index of suspicion, timely management, and proceeding to more invasive surgical treatments when necessary are cornerstones in the management and preserving the bladder.
Introduction
Bladder cancer (BC) is the seventh most commonly diagnosed cancer in men worldwide. About 75% of the cases are Non-muscle invasive (NMIBC).1 Transurethral resection of the bladder tumor (TURBT) remains the gold standard of therapy for diagnosing and treating NMIBC. To decrease the recurrence rate of low-risk tumors, a single, immediate, post-operative intravesical instillation of chemotherapy is recommended.1
The most commonly used chemotherapeutic agent is Mitomycin C (MMC), which is an alkylating agent that inhibits DNA synthesis and causes single-strand breakage of DNA and chromosomal breaks.2
Immediate single instillation (SI) is largely well-tolerated. However, severe complications and even death have been reported in the literature. Here we present a case wherein the patient had an extraperitoneal bladder perforation that occurred 2 weeks after TUT-BT and immediate postoperative instillation of doxorubicin.
Case Presentation
A 63-Year-old male, a heavy smoker, with no other co-morbidities, was referred to urology clinic for evaluation and management of a lesion on the left bladder wall that was incidentally detected on a CT scan. He did not have any urinary symptoms on initial presentation.
Cystourethroscopy revealed 2 papillary growths on the left lateral bladder wall, which were resected completely and smoothly by a resectoscope using a monopolar energy. Complete resection of the tumor was achieved without any intra-operative complication or perforation. Hemostasis was secured, and a urethral catheter was inserted.
In accordance of the EAU guidelines, the patient received an intravesical instillation of 50 ml of doxorubicin diluted in 100 cc of saline 6 hours after the TURBT. During the instillation, his vital signs were stable and he had neither hematuria nor abdominal pain. One hour after the instillation, the catheter was unclamped and was attached to continuous bladder irrigation.
Two days after the surgery and in the absence of hematuria, the indwelling catheter was removed, and the patient was discharged home the next day.
When seen in the clinic 1 week later the patient was fine with no alarming symptoms. The pathology report showed a low-grade Ta Papillary urothelial carcinoma. Based on the pathological diagnosis and according to the EAU guidelines, adjuvant chemotherapy instillations were planned.
Two weeks later, the patient presented with, dysuria, frequency, urgency, as well as pelvic and perineal pain. Physical examination was unremarkable. Urine analysis showed numerous WBC’s, RBC’s, and bacteria. An empirical antibiotics course was commenced.
In view of the worsening symptoms and the past history of anal fistula, a contrast enhanced pelvic MRI was performed. It showed a diffusely thickened urinary bladder wall, with evidence of a focal wall defect at its left aspect (the site of the resected tumor). The active urine leak into the perivesical space confirmed the diagnosis of retroperitoneal bladder perforation (Figure 1).
Figure. 1. Pelvic MRI (axial view) showing extraperitoneal bladder perforation at the left lateral wall (arrow points to extravasated contrast).
The patient was managed conservatively with antibiotics and an indwelling catheter for 3 weeks.
A follow-up retrograde CT cystogram showed no improvement and a gross contrast leak from the same site was identified. The catheter was kept for 6 more weeks and the CT cystogram was repeated showing the same results with no evidence of improvement. The patient refused to keep the catheter for a longer period so the option of open surgical repair was discussed with him.
Extraperitoneal laparotomy was performed, a perivesical small abscess was drained and cultured, necrotic tissues were debrided, and the bladder wall defect was rimed and closed in 3 layers. Tissue biopsies from the pelvic wall and bladder wall were harvested. A urethral catheter and pelvic drain were kept in place. The postoperative course was uneventful, the drain was removed on the third-day postoperatively, and the patient was discharged home with the urethral catheter in.
Histopathological evaluation of the pelvic wall and the bladder biopsies verified acute and chronic inflammation as well as granulation tissue formation. However, both were negative for malignancy. The urinary bladder biopsy also showed extensive foci of dystrophic calcification while the pelvic wall biopsy revealed fat necrosis (Figures 2 and 3).
Figure 2. The histologic examination revealed fragments of soft tissue with fat necrosis in the lower left area, mixed acute and chronic inflammatory cell infiltrate and hemorrhage in the upper right area (Hematoxylin & Eosin, 200X).
Figure 3. The histologic examination revealed multiple areas of calcifications embedded deep in the tissue with associated crystal-like material suggestive of calcium-oxalate or talc powder crystals (Hematoxylin & Eosin, 200X).
A follow up CT cystogram was done 3 weeks after the bladder repair. Although it showed a considerable regression in the size of the bladder defect, interestingly it also showed persistent extra-peritoneal contrast leak from the bladder along it’s left lateral aspect (Figure 4).
Figure 4. Retrograde Ct cystogram showing persistent contrast leak from the left lateral aspect after surgical repair.
Due to this slow healing, the catheter was kept in. Six weeks later, a follow up CT cystogram showed healing with no extraperitoneal contrast leak (Figure 5). And hence the catheter was removed.
Figure 5. Retrograde Ct cystogram showing a healed bladder wall with no contrast leak.
Two follow up cystoscopies and bladder biopsy (from an erythematous area on the left lateral wall) with 3 months intervals showed good healing of the bladder wall and no recurrence of the tumor.
Discussion
Single intravesical instillation with mitomycin C (MMC), epirubicin, or pirarubicin, have shown a beneficial effect in reducing recurrence rate compared to TURBT alone. However, randomized comparisons of individual drugs have not been conducted.3
The high recurrence rate of NMIBC may be attributed to the seeding of floating tumor cells. Immediate chemotherapy instillation has been shown to act by destroying these circulating tumor cells after TURBT. Hence the EAU guidelines recommend initiating the instillation within the first few hours after TURBT.1
Most of the complications of intravesical chemotherapy instillation are minor and can be managed medically. Dysuria and urinary frequency and urgency were the most common complications.4
On the other hand, reporting major complications such as bladder perforation, perirectal abscesses, eosinophilic cystitis, and ureteral stenosis is limited to case reports.5-14
In this case, we described our experience with bladder perforation after immediate intravesical instillation of doxorubicin.
One can argue that the perforation has occurred intraoperatively and gone unnoticed. However, in view of the absence of endoscopic evidence of perforation, late presentation of symptoms, and the absence of symptoms during and after the instillation we assume that the Single Dose Intravesical Doxorubicin Instillation caused the perforation rather than complicating an existing one.
To explain the mechanism of perforation, Lim et al7 and Cliff et al8 hypothesized that perforation is caused when attenuated muscularis propria gets necrosed after MMC instillation.
The presenting complaints of our patient were perineal and pelvic pain as well as urinary irritative symptoms. This is similar to Elmamoun et al9 cohort in which all the 6 patients presented with perineal and pelvic pain. Other symptoms such as fever, urine retention, and recurrent UTI were variably reported by others. Table 1 summarizes the clinical presentation and management of bladder perforation in the previously published case reports.
Table1. A summary of the presentation and management of bladder perforation after immediate chemotheraputic agent intravesical instillation.
Ref. number The instilled drug Number of patients Initial presentation Management outline
Lim et al7 MMC 1 Pelvic and suprapubic pain Exploratry laparotomy and bladder repair after failed conservative management
Elmamoun et al9 MMC 6 3 patients presented with pelvic pain Conservative management and urethral catheterization for 2, 26, and 52 weeks
Pelvic pain Recurrent UTIs Left ureteric obstruction Partial cystectomy + left to right trans-ureteroureterostomy
Pelvic pain, Persistent urinary leak
Left ureteric obstruction Augmentation cystoplasty + leftUreteric reimplantationThe patient ended with persistent leak, so a long-term catheter was used
Pelvic painSevere LUTS Bilateral ureteric obstruction Urinary diversion (ileal conduit)
Penna et al10 MMC 1 Lower abdominal pain and inability to void Analgesia, antibiotics and urethral catheter for 4 weeks
Tyritzis et al11 EPI 2 Fever and retropubic pain Conservative: Antibiotics and urethral catheter
Fever, lower abdominal pain and cellulitis Exploratry laparotomy and bladder repair after failed conservative management
Nieuwenhuijzen et al12 MMC Pelvic pain and fever Exploratry laparotomy and bladder repair after failed conservative management for 1 month
Racioppi et al13 MMC Pelvic pain, fever and pancytopenia Exploratry laparotomy and bladder repair after failed conservative management for 3 weeks
Hatem and Leifeld14 MMC Pelvic pain
Fever and positive blood culture for ecoli as well as purulent discharge from the drain site after the first expolratory laparatomy Conservative management for 10 daysExploratory laparatomy that revealed edematous anterior bladder wall without defectRenewed laparotomy, drainage of the abscess, debridement of the necrotic tissue, mono-J ureteral stents and nephrostomyRadical cystectomy with a urinary diversion through ureterocutaneostomy
Shenaq et al15 EPI 3 Strong urge and pain in the lower left abdomen Conservative management with antibiotics and urethral catheterization
Abdominal pain and intestinal obstruction Conservative management for 12 daysExploratory laparotomy that revealed infiltrative mass on the top of the bladder causing IO, so colostomy was done.The patient died due to multi organ failure
Progressive pain in the lower abdomen Conservative management with antibiotics and urethral catheterization
Abbreviations: Ep, epirubicin; MMC, mitomycin C.
Concerning the management, almost all the reported cases were initially managed conservatively by urethral catheterization, anticholinergics, and antibiotics. However, this was insufficient to heal the bladder in some cases which needed open repair. Moreover, some ended with cystectomy.
In our case, the patient has an extraperitoneal extravasation that failed the conservative management and needed open surgical repair.
A striking feature of the healing process that was seen in many cases including ours is the poor and slow healing. In our case, the patient needed 9 weeks for complete healing after proper open 3 layers bladder wall repair.7-9,13,14
While Lim et al attributed the slow healing in their case to the patient’s pre-existing peripheral vascular disease and suboptimal tissue oxygenation, no risk factors were identified in the other cases including our patient who was free of any comorbidities. We suppose that the poor healing is linked to the chemotherapeutic agent inflammatory effect rather than to patient factor.
This assumption is backed by the reported characteristic of mitomycin induced skin ulcer in cases of extravasation after intravenous administration. These ulcers are well known for their chronicity and the low tendency of spontaneous healing. Moreover, debridement and soft-tissue reconstruction following extravasation of MMC are recommended for patients with persistent ulceration and pain.15
Another common finding in the cases that mandate open repair was the presence of perivesical soft tissue necrosis and extensive inflammation. Doherty et al observed that more extensive bladder wall and fat necrosis of extravesical tissue in cystectomy specimens occurred when either epirubicin or mitomycin instillation was administered than in that seen following TURBT alone.16
This cytotoxic effect was also reported by Tyritzis et al11 after epirubicin instillation, and by Cliff et al,8 Nieuwenhuijzen et al,12 and Hatem and Leifeld14 after MMC instillation. This cytotoxic effect was recognized herein for the doxorubicin instillation, which is the first time to be reported as a complication of doxorubicin.
It is worth to mention that the perforation had no adverse oncological effect on our patient as no tumor recurrence was detected during follow up.
Conclusion
Immediate intravesical instillations of chemotherapy are not devoid from risk and serious complications as bladder perforation can occur. Whether it’s value in decreasing the recurrence justify the risk of bladder perforation is not our argument in this case report. Nevertheless, this severe complication should be kept in mind, and high index of suspicion will aid in timely management. If perforation is suspected, urethral catheterization and contrasted imaging are mandatory. In the case of failed conservative management surgical repair is warranted even in extraperitoneal leak.
Funding:The author(s) received no financial support for the research, authorship, and/or publication of this article.
Declaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Author Contributions: Concept: AA, SAD. Design: MA, SA. Supervision: AA, SAD, MAA. Resources: MA, HM, NB. Materials: AA, MA, NB. Writing manuscript: AA, MA, HM. Critical review: AA, SAD, MAA.
Informed Consent: The patient has given his written informed consent to publish his case including publication of images. The study follows the guidelines for human studies and is conducted in accordance with the World Medical Association Declaration of Helsinki.
ORCID iD: Hammam Mansi
https://orcid.org/0000-0002-4571-4336 | Recovered | ReactionOutcome | CC BY-NC | 33473244 | 18,858,074 | 2021 |
What was the outcome of reaction 'Micturition urgency'? | Delayed Bladder Perforation Related to Immediate Single Dose Intravesical Doxorubicin Instillation After TURBT: A Case Report and Literature Review.
Intravesical chemotherapy instillation immediately after tumor resection is a well-known practice in the management of non-muscle invasive bladder cancer. Despite being largely well tolerated in most cases, it is not devoid of severe and life-threatening complications.
We present an unusual case of bladder perforation that happened 2 weeks after bladder tumor resection. The patient had received single dose intra-vesical instillation of doxorubicin after TUR-BT. Conservative managements failed to achieve bladder healing; as a result, open surgical repair was performed. To the best of our knowledge, this is the first reported case of bladder perforation after intra-vesical doxorubicin instillation.
The occurrence of such a rare serious complication in a mostly safe intervention must be taken into consideration. A high index of suspicion, timely management, and proceeding to more invasive surgical treatments when necessary are cornerstones in the management and preserving the bladder.
Introduction
Bladder cancer (BC) is the seventh most commonly diagnosed cancer in men worldwide. About 75% of the cases are Non-muscle invasive (NMIBC).1 Transurethral resection of the bladder tumor (TURBT) remains the gold standard of therapy for diagnosing and treating NMIBC. To decrease the recurrence rate of low-risk tumors, a single, immediate, post-operative intravesical instillation of chemotherapy is recommended.1
The most commonly used chemotherapeutic agent is Mitomycin C (MMC), which is an alkylating agent that inhibits DNA synthesis and causes single-strand breakage of DNA and chromosomal breaks.2
Immediate single instillation (SI) is largely well-tolerated. However, severe complications and even death have been reported in the literature. Here we present a case wherein the patient had an extraperitoneal bladder perforation that occurred 2 weeks after TUT-BT and immediate postoperative instillation of doxorubicin.
Case Presentation
A 63-Year-old male, a heavy smoker, with no other co-morbidities, was referred to urology clinic for evaluation and management of a lesion on the left bladder wall that was incidentally detected on a CT scan. He did not have any urinary symptoms on initial presentation.
Cystourethroscopy revealed 2 papillary growths on the left lateral bladder wall, which were resected completely and smoothly by a resectoscope using a monopolar energy. Complete resection of the tumor was achieved without any intra-operative complication or perforation. Hemostasis was secured, and a urethral catheter was inserted.
In accordance of the EAU guidelines, the patient received an intravesical instillation of 50 ml of doxorubicin diluted in 100 cc of saline 6 hours after the TURBT. During the instillation, his vital signs were stable and he had neither hematuria nor abdominal pain. One hour after the instillation, the catheter was unclamped and was attached to continuous bladder irrigation.
Two days after the surgery and in the absence of hematuria, the indwelling catheter was removed, and the patient was discharged home the next day.
When seen in the clinic 1 week later the patient was fine with no alarming symptoms. The pathology report showed a low-grade Ta Papillary urothelial carcinoma. Based on the pathological diagnosis and according to the EAU guidelines, adjuvant chemotherapy instillations were planned.
Two weeks later, the patient presented with, dysuria, frequency, urgency, as well as pelvic and perineal pain. Physical examination was unremarkable. Urine analysis showed numerous WBC’s, RBC’s, and bacteria. An empirical antibiotics course was commenced.
In view of the worsening symptoms and the past history of anal fistula, a contrast enhanced pelvic MRI was performed. It showed a diffusely thickened urinary bladder wall, with evidence of a focal wall defect at its left aspect (the site of the resected tumor). The active urine leak into the perivesical space confirmed the diagnosis of retroperitoneal bladder perforation (Figure 1).
Figure. 1. Pelvic MRI (axial view) showing extraperitoneal bladder perforation at the left lateral wall (arrow points to extravasated contrast).
The patient was managed conservatively with antibiotics and an indwelling catheter for 3 weeks.
A follow-up retrograde CT cystogram showed no improvement and a gross contrast leak from the same site was identified. The catheter was kept for 6 more weeks and the CT cystogram was repeated showing the same results with no evidence of improvement. The patient refused to keep the catheter for a longer period so the option of open surgical repair was discussed with him.
Extraperitoneal laparotomy was performed, a perivesical small abscess was drained and cultured, necrotic tissues were debrided, and the bladder wall defect was rimed and closed in 3 layers. Tissue biopsies from the pelvic wall and bladder wall were harvested. A urethral catheter and pelvic drain were kept in place. The postoperative course was uneventful, the drain was removed on the third-day postoperatively, and the patient was discharged home with the urethral catheter in.
Histopathological evaluation of the pelvic wall and the bladder biopsies verified acute and chronic inflammation as well as granulation tissue formation. However, both were negative for malignancy. The urinary bladder biopsy also showed extensive foci of dystrophic calcification while the pelvic wall biopsy revealed fat necrosis (Figures 2 and 3).
Figure 2. The histologic examination revealed fragments of soft tissue with fat necrosis in the lower left area, mixed acute and chronic inflammatory cell infiltrate and hemorrhage in the upper right area (Hematoxylin & Eosin, 200X).
Figure 3. The histologic examination revealed multiple areas of calcifications embedded deep in the tissue with associated crystal-like material suggestive of calcium-oxalate or talc powder crystals (Hematoxylin & Eosin, 200X).
A follow up CT cystogram was done 3 weeks after the bladder repair. Although it showed a considerable regression in the size of the bladder defect, interestingly it also showed persistent extra-peritoneal contrast leak from the bladder along it’s left lateral aspect (Figure 4).
Figure 4. Retrograde Ct cystogram showing persistent contrast leak from the left lateral aspect after surgical repair.
Due to this slow healing, the catheter was kept in. Six weeks later, a follow up CT cystogram showed healing with no extraperitoneal contrast leak (Figure 5). And hence the catheter was removed.
Figure 5. Retrograde Ct cystogram showing a healed bladder wall with no contrast leak.
Two follow up cystoscopies and bladder biopsy (from an erythematous area on the left lateral wall) with 3 months intervals showed good healing of the bladder wall and no recurrence of the tumor.
Discussion
Single intravesical instillation with mitomycin C (MMC), epirubicin, or pirarubicin, have shown a beneficial effect in reducing recurrence rate compared to TURBT alone. However, randomized comparisons of individual drugs have not been conducted.3
The high recurrence rate of NMIBC may be attributed to the seeding of floating tumor cells. Immediate chemotherapy instillation has been shown to act by destroying these circulating tumor cells after TURBT. Hence the EAU guidelines recommend initiating the instillation within the first few hours after TURBT.1
Most of the complications of intravesical chemotherapy instillation are minor and can be managed medically. Dysuria and urinary frequency and urgency were the most common complications.4
On the other hand, reporting major complications such as bladder perforation, perirectal abscesses, eosinophilic cystitis, and ureteral stenosis is limited to case reports.5-14
In this case, we described our experience with bladder perforation after immediate intravesical instillation of doxorubicin.
One can argue that the perforation has occurred intraoperatively and gone unnoticed. However, in view of the absence of endoscopic evidence of perforation, late presentation of symptoms, and the absence of symptoms during and after the instillation we assume that the Single Dose Intravesical Doxorubicin Instillation caused the perforation rather than complicating an existing one.
To explain the mechanism of perforation, Lim et al7 and Cliff et al8 hypothesized that perforation is caused when attenuated muscularis propria gets necrosed after MMC instillation.
The presenting complaints of our patient were perineal and pelvic pain as well as urinary irritative symptoms. This is similar to Elmamoun et al9 cohort in which all the 6 patients presented with perineal and pelvic pain. Other symptoms such as fever, urine retention, and recurrent UTI were variably reported by others. Table 1 summarizes the clinical presentation and management of bladder perforation in the previously published case reports.
Table1. A summary of the presentation and management of bladder perforation after immediate chemotheraputic agent intravesical instillation.
Ref. number The instilled drug Number of patients Initial presentation Management outline
Lim et al7 MMC 1 Pelvic and suprapubic pain Exploratry laparotomy and bladder repair after failed conservative management
Elmamoun et al9 MMC 6 3 patients presented with pelvic pain Conservative management and urethral catheterization for 2, 26, and 52 weeks
Pelvic pain Recurrent UTIs Left ureteric obstruction Partial cystectomy + left to right trans-ureteroureterostomy
Pelvic pain, Persistent urinary leak
Left ureteric obstruction Augmentation cystoplasty + leftUreteric reimplantationThe patient ended with persistent leak, so a long-term catheter was used
Pelvic painSevere LUTS Bilateral ureteric obstruction Urinary diversion (ileal conduit)
Penna et al10 MMC 1 Lower abdominal pain and inability to void Analgesia, antibiotics and urethral catheter for 4 weeks
Tyritzis et al11 EPI 2 Fever and retropubic pain Conservative: Antibiotics and urethral catheter
Fever, lower abdominal pain and cellulitis Exploratry laparotomy and bladder repair after failed conservative management
Nieuwenhuijzen et al12 MMC Pelvic pain and fever Exploratry laparotomy and bladder repair after failed conservative management for 1 month
Racioppi et al13 MMC Pelvic pain, fever and pancytopenia Exploratry laparotomy and bladder repair after failed conservative management for 3 weeks
Hatem and Leifeld14 MMC Pelvic pain
Fever and positive blood culture for ecoli as well as purulent discharge from the drain site after the first expolratory laparatomy Conservative management for 10 daysExploratory laparatomy that revealed edematous anterior bladder wall without defectRenewed laparotomy, drainage of the abscess, debridement of the necrotic tissue, mono-J ureteral stents and nephrostomyRadical cystectomy with a urinary diversion through ureterocutaneostomy
Shenaq et al15 EPI 3 Strong urge and pain in the lower left abdomen Conservative management with antibiotics and urethral catheterization
Abdominal pain and intestinal obstruction Conservative management for 12 daysExploratory laparotomy that revealed infiltrative mass on the top of the bladder causing IO, so colostomy was done.The patient died due to multi organ failure
Progressive pain in the lower abdomen Conservative management with antibiotics and urethral catheterization
Abbreviations: Ep, epirubicin; MMC, mitomycin C.
Concerning the management, almost all the reported cases were initially managed conservatively by urethral catheterization, anticholinergics, and antibiotics. However, this was insufficient to heal the bladder in some cases which needed open repair. Moreover, some ended with cystectomy.
In our case, the patient has an extraperitoneal extravasation that failed the conservative management and needed open surgical repair.
A striking feature of the healing process that was seen in many cases including ours is the poor and slow healing. In our case, the patient needed 9 weeks for complete healing after proper open 3 layers bladder wall repair.7-9,13,14
While Lim et al attributed the slow healing in their case to the patient’s pre-existing peripheral vascular disease and suboptimal tissue oxygenation, no risk factors were identified in the other cases including our patient who was free of any comorbidities. We suppose that the poor healing is linked to the chemotherapeutic agent inflammatory effect rather than to patient factor.
This assumption is backed by the reported characteristic of mitomycin induced skin ulcer in cases of extravasation after intravenous administration. These ulcers are well known for their chronicity and the low tendency of spontaneous healing. Moreover, debridement and soft-tissue reconstruction following extravasation of MMC are recommended for patients with persistent ulceration and pain.15
Another common finding in the cases that mandate open repair was the presence of perivesical soft tissue necrosis and extensive inflammation. Doherty et al observed that more extensive bladder wall and fat necrosis of extravesical tissue in cystectomy specimens occurred when either epirubicin or mitomycin instillation was administered than in that seen following TURBT alone.16
This cytotoxic effect was also reported by Tyritzis et al11 after epirubicin instillation, and by Cliff et al,8 Nieuwenhuijzen et al,12 and Hatem and Leifeld14 after MMC instillation. This cytotoxic effect was recognized herein for the doxorubicin instillation, which is the first time to be reported as a complication of doxorubicin.
It is worth to mention that the perforation had no adverse oncological effect on our patient as no tumor recurrence was detected during follow up.
Conclusion
Immediate intravesical instillations of chemotherapy are not devoid from risk and serious complications as bladder perforation can occur. Whether it’s value in decreasing the recurrence justify the risk of bladder perforation is not our argument in this case report. Nevertheless, this severe complication should be kept in mind, and high index of suspicion will aid in timely management. If perforation is suspected, urethral catheterization and contrasted imaging are mandatory. In the case of failed conservative management surgical repair is warranted even in extraperitoneal leak.
Funding:The author(s) received no financial support for the research, authorship, and/or publication of this article.
Declaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Author Contributions: Concept: AA, SAD. Design: MA, SA. Supervision: AA, SAD, MAA. Resources: MA, HM, NB. Materials: AA, MA, NB. Writing manuscript: AA, MA, HM. Critical review: AA, SAD, MAA.
Informed Consent: The patient has given his written informed consent to publish his case including publication of images. The study follows the guidelines for human studies and is conducted in accordance with the World Medical Association Declaration of Helsinki.
ORCID iD: Hammam Mansi
https://orcid.org/0000-0002-4571-4336 | Recovered | ReactionOutcome | CC BY-NC | 33473244 | 18,858,074 | 2021 |
What was the outcome of reaction 'Pelvic pain'? | Delayed Bladder Perforation Related to Immediate Single Dose Intravesical Doxorubicin Instillation After TURBT: A Case Report and Literature Review.
Intravesical chemotherapy instillation immediately after tumor resection is a well-known practice in the management of non-muscle invasive bladder cancer. Despite being largely well tolerated in most cases, it is not devoid of severe and life-threatening complications.
We present an unusual case of bladder perforation that happened 2 weeks after bladder tumor resection. The patient had received single dose intra-vesical instillation of doxorubicin after TUR-BT. Conservative managements failed to achieve bladder healing; as a result, open surgical repair was performed. To the best of our knowledge, this is the first reported case of bladder perforation after intra-vesical doxorubicin instillation.
The occurrence of such a rare serious complication in a mostly safe intervention must be taken into consideration. A high index of suspicion, timely management, and proceeding to more invasive surgical treatments when necessary are cornerstones in the management and preserving the bladder.
Introduction
Bladder cancer (BC) is the seventh most commonly diagnosed cancer in men worldwide. About 75% of the cases are Non-muscle invasive (NMIBC).1 Transurethral resection of the bladder tumor (TURBT) remains the gold standard of therapy for diagnosing and treating NMIBC. To decrease the recurrence rate of low-risk tumors, a single, immediate, post-operative intravesical instillation of chemotherapy is recommended.1
The most commonly used chemotherapeutic agent is Mitomycin C (MMC), which is an alkylating agent that inhibits DNA synthesis and causes single-strand breakage of DNA and chromosomal breaks.2
Immediate single instillation (SI) is largely well-tolerated. However, severe complications and even death have been reported in the literature. Here we present a case wherein the patient had an extraperitoneal bladder perforation that occurred 2 weeks after TUT-BT and immediate postoperative instillation of doxorubicin.
Case Presentation
A 63-Year-old male, a heavy smoker, with no other co-morbidities, was referred to urology clinic for evaluation and management of a lesion on the left bladder wall that was incidentally detected on a CT scan. He did not have any urinary symptoms on initial presentation.
Cystourethroscopy revealed 2 papillary growths on the left lateral bladder wall, which were resected completely and smoothly by a resectoscope using a monopolar energy. Complete resection of the tumor was achieved without any intra-operative complication or perforation. Hemostasis was secured, and a urethral catheter was inserted.
In accordance of the EAU guidelines, the patient received an intravesical instillation of 50 ml of doxorubicin diluted in 100 cc of saline 6 hours after the TURBT. During the instillation, his vital signs were stable and he had neither hematuria nor abdominal pain. One hour after the instillation, the catheter was unclamped and was attached to continuous bladder irrigation.
Two days after the surgery and in the absence of hematuria, the indwelling catheter was removed, and the patient was discharged home the next day.
When seen in the clinic 1 week later the patient was fine with no alarming symptoms. The pathology report showed a low-grade Ta Papillary urothelial carcinoma. Based on the pathological diagnosis and according to the EAU guidelines, adjuvant chemotherapy instillations were planned.
Two weeks later, the patient presented with, dysuria, frequency, urgency, as well as pelvic and perineal pain. Physical examination was unremarkable. Urine analysis showed numerous WBC’s, RBC’s, and bacteria. An empirical antibiotics course was commenced.
In view of the worsening symptoms and the past history of anal fistula, a contrast enhanced pelvic MRI was performed. It showed a diffusely thickened urinary bladder wall, with evidence of a focal wall defect at its left aspect (the site of the resected tumor). The active urine leak into the perivesical space confirmed the diagnosis of retroperitoneal bladder perforation (Figure 1).
Figure. 1. Pelvic MRI (axial view) showing extraperitoneal bladder perforation at the left lateral wall (arrow points to extravasated contrast).
The patient was managed conservatively with antibiotics and an indwelling catheter for 3 weeks.
A follow-up retrograde CT cystogram showed no improvement and a gross contrast leak from the same site was identified. The catheter was kept for 6 more weeks and the CT cystogram was repeated showing the same results with no evidence of improvement. The patient refused to keep the catheter for a longer period so the option of open surgical repair was discussed with him.
Extraperitoneal laparotomy was performed, a perivesical small abscess was drained and cultured, necrotic tissues were debrided, and the bladder wall defect was rimed and closed in 3 layers. Tissue biopsies from the pelvic wall and bladder wall were harvested. A urethral catheter and pelvic drain were kept in place. The postoperative course was uneventful, the drain was removed on the third-day postoperatively, and the patient was discharged home with the urethral catheter in.
Histopathological evaluation of the pelvic wall and the bladder biopsies verified acute and chronic inflammation as well as granulation tissue formation. However, both were negative for malignancy. The urinary bladder biopsy also showed extensive foci of dystrophic calcification while the pelvic wall biopsy revealed fat necrosis (Figures 2 and 3).
Figure 2. The histologic examination revealed fragments of soft tissue with fat necrosis in the lower left area, mixed acute and chronic inflammatory cell infiltrate and hemorrhage in the upper right area (Hematoxylin & Eosin, 200X).
Figure 3. The histologic examination revealed multiple areas of calcifications embedded deep in the tissue with associated crystal-like material suggestive of calcium-oxalate or talc powder crystals (Hematoxylin & Eosin, 200X).
A follow up CT cystogram was done 3 weeks after the bladder repair. Although it showed a considerable regression in the size of the bladder defect, interestingly it also showed persistent extra-peritoneal contrast leak from the bladder along it’s left lateral aspect (Figure 4).
Figure 4. Retrograde Ct cystogram showing persistent contrast leak from the left lateral aspect after surgical repair.
Due to this slow healing, the catheter was kept in. Six weeks later, a follow up CT cystogram showed healing with no extraperitoneal contrast leak (Figure 5). And hence the catheter was removed.
Figure 5. Retrograde Ct cystogram showing a healed bladder wall with no contrast leak.
Two follow up cystoscopies and bladder biopsy (from an erythematous area on the left lateral wall) with 3 months intervals showed good healing of the bladder wall and no recurrence of the tumor.
Discussion
Single intravesical instillation with mitomycin C (MMC), epirubicin, or pirarubicin, have shown a beneficial effect in reducing recurrence rate compared to TURBT alone. However, randomized comparisons of individual drugs have not been conducted.3
The high recurrence rate of NMIBC may be attributed to the seeding of floating tumor cells. Immediate chemotherapy instillation has been shown to act by destroying these circulating tumor cells after TURBT. Hence the EAU guidelines recommend initiating the instillation within the first few hours after TURBT.1
Most of the complications of intravesical chemotherapy instillation are minor and can be managed medically. Dysuria and urinary frequency and urgency were the most common complications.4
On the other hand, reporting major complications such as bladder perforation, perirectal abscesses, eosinophilic cystitis, and ureteral stenosis is limited to case reports.5-14
In this case, we described our experience with bladder perforation after immediate intravesical instillation of doxorubicin.
One can argue that the perforation has occurred intraoperatively and gone unnoticed. However, in view of the absence of endoscopic evidence of perforation, late presentation of symptoms, and the absence of symptoms during and after the instillation we assume that the Single Dose Intravesical Doxorubicin Instillation caused the perforation rather than complicating an existing one.
To explain the mechanism of perforation, Lim et al7 and Cliff et al8 hypothesized that perforation is caused when attenuated muscularis propria gets necrosed after MMC instillation.
The presenting complaints of our patient were perineal and pelvic pain as well as urinary irritative symptoms. This is similar to Elmamoun et al9 cohort in which all the 6 patients presented with perineal and pelvic pain. Other symptoms such as fever, urine retention, and recurrent UTI were variably reported by others. Table 1 summarizes the clinical presentation and management of bladder perforation in the previously published case reports.
Table1. A summary of the presentation and management of bladder perforation after immediate chemotheraputic agent intravesical instillation.
Ref. number The instilled drug Number of patients Initial presentation Management outline
Lim et al7 MMC 1 Pelvic and suprapubic pain Exploratry laparotomy and bladder repair after failed conservative management
Elmamoun et al9 MMC 6 3 patients presented with pelvic pain Conservative management and urethral catheterization for 2, 26, and 52 weeks
Pelvic pain Recurrent UTIs Left ureteric obstruction Partial cystectomy + left to right trans-ureteroureterostomy
Pelvic pain, Persistent urinary leak
Left ureteric obstruction Augmentation cystoplasty + leftUreteric reimplantationThe patient ended with persistent leak, so a long-term catheter was used
Pelvic painSevere LUTS Bilateral ureteric obstruction Urinary diversion (ileal conduit)
Penna et al10 MMC 1 Lower abdominal pain and inability to void Analgesia, antibiotics and urethral catheter for 4 weeks
Tyritzis et al11 EPI 2 Fever and retropubic pain Conservative: Antibiotics and urethral catheter
Fever, lower abdominal pain and cellulitis Exploratry laparotomy and bladder repair after failed conservative management
Nieuwenhuijzen et al12 MMC Pelvic pain and fever Exploratry laparotomy and bladder repair after failed conservative management for 1 month
Racioppi et al13 MMC Pelvic pain, fever and pancytopenia Exploratry laparotomy and bladder repair after failed conservative management for 3 weeks
Hatem and Leifeld14 MMC Pelvic pain
Fever and positive blood culture for ecoli as well as purulent discharge from the drain site after the first expolratory laparatomy Conservative management for 10 daysExploratory laparatomy that revealed edematous anterior bladder wall without defectRenewed laparotomy, drainage of the abscess, debridement of the necrotic tissue, mono-J ureteral stents and nephrostomyRadical cystectomy with a urinary diversion through ureterocutaneostomy
Shenaq et al15 EPI 3 Strong urge and pain in the lower left abdomen Conservative management with antibiotics and urethral catheterization
Abdominal pain and intestinal obstruction Conservative management for 12 daysExploratory laparotomy that revealed infiltrative mass on the top of the bladder causing IO, so colostomy was done.The patient died due to multi organ failure
Progressive pain in the lower abdomen Conservative management with antibiotics and urethral catheterization
Abbreviations: Ep, epirubicin; MMC, mitomycin C.
Concerning the management, almost all the reported cases were initially managed conservatively by urethral catheterization, anticholinergics, and antibiotics. However, this was insufficient to heal the bladder in some cases which needed open repair. Moreover, some ended with cystectomy.
In our case, the patient has an extraperitoneal extravasation that failed the conservative management and needed open surgical repair.
A striking feature of the healing process that was seen in many cases including ours is the poor and slow healing. In our case, the patient needed 9 weeks for complete healing after proper open 3 layers bladder wall repair.7-9,13,14
While Lim et al attributed the slow healing in their case to the patient’s pre-existing peripheral vascular disease and suboptimal tissue oxygenation, no risk factors were identified in the other cases including our patient who was free of any comorbidities. We suppose that the poor healing is linked to the chemotherapeutic agent inflammatory effect rather than to patient factor.
This assumption is backed by the reported characteristic of mitomycin induced skin ulcer in cases of extravasation after intravenous administration. These ulcers are well known for their chronicity and the low tendency of spontaneous healing. Moreover, debridement and soft-tissue reconstruction following extravasation of MMC are recommended for patients with persistent ulceration and pain.15
Another common finding in the cases that mandate open repair was the presence of perivesical soft tissue necrosis and extensive inflammation. Doherty et al observed that more extensive bladder wall and fat necrosis of extravesical tissue in cystectomy specimens occurred when either epirubicin or mitomycin instillation was administered than in that seen following TURBT alone.16
This cytotoxic effect was also reported by Tyritzis et al11 after epirubicin instillation, and by Cliff et al,8 Nieuwenhuijzen et al,12 and Hatem and Leifeld14 after MMC instillation. This cytotoxic effect was recognized herein for the doxorubicin instillation, which is the first time to be reported as a complication of doxorubicin.
It is worth to mention that the perforation had no adverse oncological effect on our patient as no tumor recurrence was detected during follow up.
Conclusion
Immediate intravesical instillations of chemotherapy are not devoid from risk and serious complications as bladder perforation can occur. Whether it’s value in decreasing the recurrence justify the risk of bladder perforation is not our argument in this case report. Nevertheless, this severe complication should be kept in mind, and high index of suspicion will aid in timely management. If perforation is suspected, urethral catheterization and contrasted imaging are mandatory. In the case of failed conservative management surgical repair is warranted even in extraperitoneal leak.
Funding:The author(s) received no financial support for the research, authorship, and/or publication of this article.
Declaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Author Contributions: Concept: AA, SAD. Design: MA, SA. Supervision: AA, SAD, MAA. Resources: MA, HM, NB. Materials: AA, MA, NB. Writing manuscript: AA, MA, HM. Critical review: AA, SAD, MAA.
Informed Consent: The patient has given his written informed consent to publish his case including publication of images. The study follows the guidelines for human studies and is conducted in accordance with the World Medical Association Declaration of Helsinki.
ORCID iD: Hammam Mansi
https://orcid.org/0000-0002-4571-4336 | Recovering | ReactionOutcome | CC BY-NC | 33473244 | 18,870,263 | 2021 |
What was the outcome of reaction 'Perineal pain'? | Delayed Bladder Perforation Related to Immediate Single Dose Intravesical Doxorubicin Instillation After TURBT: A Case Report and Literature Review.
Intravesical chemotherapy instillation immediately after tumor resection is a well-known practice in the management of non-muscle invasive bladder cancer. Despite being largely well tolerated in most cases, it is not devoid of severe and life-threatening complications.
We present an unusual case of bladder perforation that happened 2 weeks after bladder tumor resection. The patient had received single dose intra-vesical instillation of doxorubicin after TUR-BT. Conservative managements failed to achieve bladder healing; as a result, open surgical repair was performed. To the best of our knowledge, this is the first reported case of bladder perforation after intra-vesical doxorubicin instillation.
The occurrence of such a rare serious complication in a mostly safe intervention must be taken into consideration. A high index of suspicion, timely management, and proceeding to more invasive surgical treatments when necessary are cornerstones in the management and preserving the bladder.
Introduction
Bladder cancer (BC) is the seventh most commonly diagnosed cancer in men worldwide. About 75% of the cases are Non-muscle invasive (NMIBC).1 Transurethral resection of the bladder tumor (TURBT) remains the gold standard of therapy for diagnosing and treating NMIBC. To decrease the recurrence rate of low-risk tumors, a single, immediate, post-operative intravesical instillation of chemotherapy is recommended.1
The most commonly used chemotherapeutic agent is Mitomycin C (MMC), which is an alkylating agent that inhibits DNA synthesis and causes single-strand breakage of DNA and chromosomal breaks.2
Immediate single instillation (SI) is largely well-tolerated. However, severe complications and even death have been reported in the literature. Here we present a case wherein the patient had an extraperitoneal bladder perforation that occurred 2 weeks after TUT-BT and immediate postoperative instillation of doxorubicin.
Case Presentation
A 63-Year-old male, a heavy smoker, with no other co-morbidities, was referred to urology clinic for evaluation and management of a lesion on the left bladder wall that was incidentally detected on a CT scan. He did not have any urinary symptoms on initial presentation.
Cystourethroscopy revealed 2 papillary growths on the left lateral bladder wall, which were resected completely and smoothly by a resectoscope using a monopolar energy. Complete resection of the tumor was achieved without any intra-operative complication or perforation. Hemostasis was secured, and a urethral catheter was inserted.
In accordance of the EAU guidelines, the patient received an intravesical instillation of 50 ml of doxorubicin diluted in 100 cc of saline 6 hours after the TURBT. During the instillation, his vital signs were stable and he had neither hematuria nor abdominal pain. One hour after the instillation, the catheter was unclamped and was attached to continuous bladder irrigation.
Two days after the surgery and in the absence of hematuria, the indwelling catheter was removed, and the patient was discharged home the next day.
When seen in the clinic 1 week later the patient was fine with no alarming symptoms. The pathology report showed a low-grade Ta Papillary urothelial carcinoma. Based on the pathological diagnosis and according to the EAU guidelines, adjuvant chemotherapy instillations were planned.
Two weeks later, the patient presented with, dysuria, frequency, urgency, as well as pelvic and perineal pain. Physical examination was unremarkable. Urine analysis showed numerous WBC’s, RBC’s, and bacteria. An empirical antibiotics course was commenced.
In view of the worsening symptoms and the past history of anal fistula, a contrast enhanced pelvic MRI was performed. It showed a diffusely thickened urinary bladder wall, with evidence of a focal wall defect at its left aspect (the site of the resected tumor). The active urine leak into the perivesical space confirmed the diagnosis of retroperitoneal bladder perforation (Figure 1).
Figure. 1. Pelvic MRI (axial view) showing extraperitoneal bladder perforation at the left lateral wall (arrow points to extravasated contrast).
The patient was managed conservatively with antibiotics and an indwelling catheter for 3 weeks.
A follow-up retrograde CT cystogram showed no improvement and a gross contrast leak from the same site was identified. The catheter was kept for 6 more weeks and the CT cystogram was repeated showing the same results with no evidence of improvement. The patient refused to keep the catheter for a longer period so the option of open surgical repair was discussed with him.
Extraperitoneal laparotomy was performed, a perivesical small abscess was drained and cultured, necrotic tissues were debrided, and the bladder wall defect was rimed and closed in 3 layers. Tissue biopsies from the pelvic wall and bladder wall were harvested. A urethral catheter and pelvic drain were kept in place. The postoperative course was uneventful, the drain was removed on the third-day postoperatively, and the patient was discharged home with the urethral catheter in.
Histopathological evaluation of the pelvic wall and the bladder biopsies verified acute and chronic inflammation as well as granulation tissue formation. However, both were negative for malignancy. The urinary bladder biopsy also showed extensive foci of dystrophic calcification while the pelvic wall biopsy revealed fat necrosis (Figures 2 and 3).
Figure 2. The histologic examination revealed fragments of soft tissue with fat necrosis in the lower left area, mixed acute and chronic inflammatory cell infiltrate and hemorrhage in the upper right area (Hematoxylin & Eosin, 200X).
Figure 3. The histologic examination revealed multiple areas of calcifications embedded deep in the tissue with associated crystal-like material suggestive of calcium-oxalate or talc powder crystals (Hematoxylin & Eosin, 200X).
A follow up CT cystogram was done 3 weeks after the bladder repair. Although it showed a considerable regression in the size of the bladder defect, interestingly it also showed persistent extra-peritoneal contrast leak from the bladder along it’s left lateral aspect (Figure 4).
Figure 4. Retrograde Ct cystogram showing persistent contrast leak from the left lateral aspect after surgical repair.
Due to this slow healing, the catheter was kept in. Six weeks later, a follow up CT cystogram showed healing with no extraperitoneal contrast leak (Figure 5). And hence the catheter was removed.
Figure 5. Retrograde Ct cystogram showing a healed bladder wall with no contrast leak.
Two follow up cystoscopies and bladder biopsy (from an erythematous area on the left lateral wall) with 3 months intervals showed good healing of the bladder wall and no recurrence of the tumor.
Discussion
Single intravesical instillation with mitomycin C (MMC), epirubicin, or pirarubicin, have shown a beneficial effect in reducing recurrence rate compared to TURBT alone. However, randomized comparisons of individual drugs have not been conducted.3
The high recurrence rate of NMIBC may be attributed to the seeding of floating tumor cells. Immediate chemotherapy instillation has been shown to act by destroying these circulating tumor cells after TURBT. Hence the EAU guidelines recommend initiating the instillation within the first few hours after TURBT.1
Most of the complications of intravesical chemotherapy instillation are minor and can be managed medically. Dysuria and urinary frequency and urgency were the most common complications.4
On the other hand, reporting major complications such as bladder perforation, perirectal abscesses, eosinophilic cystitis, and ureteral stenosis is limited to case reports.5-14
In this case, we described our experience with bladder perforation after immediate intravesical instillation of doxorubicin.
One can argue that the perforation has occurred intraoperatively and gone unnoticed. However, in view of the absence of endoscopic evidence of perforation, late presentation of symptoms, and the absence of symptoms during and after the instillation we assume that the Single Dose Intravesical Doxorubicin Instillation caused the perforation rather than complicating an existing one.
To explain the mechanism of perforation, Lim et al7 and Cliff et al8 hypothesized that perforation is caused when attenuated muscularis propria gets necrosed after MMC instillation.
The presenting complaints of our patient were perineal and pelvic pain as well as urinary irritative symptoms. This is similar to Elmamoun et al9 cohort in which all the 6 patients presented with perineal and pelvic pain. Other symptoms such as fever, urine retention, and recurrent UTI were variably reported by others. Table 1 summarizes the clinical presentation and management of bladder perforation in the previously published case reports.
Table1. A summary of the presentation and management of bladder perforation after immediate chemotheraputic agent intravesical instillation.
Ref. number The instilled drug Number of patients Initial presentation Management outline
Lim et al7 MMC 1 Pelvic and suprapubic pain Exploratry laparotomy and bladder repair after failed conservative management
Elmamoun et al9 MMC 6 3 patients presented with pelvic pain Conservative management and urethral catheterization for 2, 26, and 52 weeks
Pelvic pain Recurrent UTIs Left ureteric obstruction Partial cystectomy + left to right trans-ureteroureterostomy
Pelvic pain, Persistent urinary leak
Left ureteric obstruction Augmentation cystoplasty + leftUreteric reimplantationThe patient ended with persistent leak, so a long-term catheter was used
Pelvic painSevere LUTS Bilateral ureteric obstruction Urinary diversion (ileal conduit)
Penna et al10 MMC 1 Lower abdominal pain and inability to void Analgesia, antibiotics and urethral catheter for 4 weeks
Tyritzis et al11 EPI 2 Fever and retropubic pain Conservative: Antibiotics and urethral catheter
Fever, lower abdominal pain and cellulitis Exploratry laparotomy and bladder repair after failed conservative management
Nieuwenhuijzen et al12 MMC Pelvic pain and fever Exploratry laparotomy and bladder repair after failed conservative management for 1 month
Racioppi et al13 MMC Pelvic pain, fever and pancytopenia Exploratry laparotomy and bladder repair after failed conservative management for 3 weeks
Hatem and Leifeld14 MMC Pelvic pain
Fever and positive blood culture for ecoli as well as purulent discharge from the drain site after the first expolratory laparatomy Conservative management for 10 daysExploratory laparatomy that revealed edematous anterior bladder wall without defectRenewed laparotomy, drainage of the abscess, debridement of the necrotic tissue, mono-J ureteral stents and nephrostomyRadical cystectomy with a urinary diversion through ureterocutaneostomy
Shenaq et al15 EPI 3 Strong urge and pain in the lower left abdomen Conservative management with antibiotics and urethral catheterization
Abdominal pain and intestinal obstruction Conservative management for 12 daysExploratory laparotomy that revealed infiltrative mass on the top of the bladder causing IO, so colostomy was done.The patient died due to multi organ failure
Progressive pain in the lower abdomen Conservative management with antibiotics and urethral catheterization
Abbreviations: Ep, epirubicin; MMC, mitomycin C.
Concerning the management, almost all the reported cases were initially managed conservatively by urethral catheterization, anticholinergics, and antibiotics. However, this was insufficient to heal the bladder in some cases which needed open repair. Moreover, some ended with cystectomy.
In our case, the patient has an extraperitoneal extravasation that failed the conservative management and needed open surgical repair.
A striking feature of the healing process that was seen in many cases including ours is the poor and slow healing. In our case, the patient needed 9 weeks for complete healing after proper open 3 layers bladder wall repair.7-9,13,14
While Lim et al attributed the slow healing in their case to the patient’s pre-existing peripheral vascular disease and suboptimal tissue oxygenation, no risk factors were identified in the other cases including our patient who was free of any comorbidities. We suppose that the poor healing is linked to the chemotherapeutic agent inflammatory effect rather than to patient factor.
This assumption is backed by the reported characteristic of mitomycin induced skin ulcer in cases of extravasation after intravenous administration. These ulcers are well known for their chronicity and the low tendency of spontaneous healing. Moreover, debridement and soft-tissue reconstruction following extravasation of MMC are recommended for patients with persistent ulceration and pain.15
Another common finding in the cases that mandate open repair was the presence of perivesical soft tissue necrosis and extensive inflammation. Doherty et al observed that more extensive bladder wall and fat necrosis of extravesical tissue in cystectomy specimens occurred when either epirubicin or mitomycin instillation was administered than in that seen following TURBT alone.16
This cytotoxic effect was also reported by Tyritzis et al11 after epirubicin instillation, and by Cliff et al,8 Nieuwenhuijzen et al,12 and Hatem and Leifeld14 after MMC instillation. This cytotoxic effect was recognized herein for the doxorubicin instillation, which is the first time to be reported as a complication of doxorubicin.
It is worth to mention that the perforation had no adverse oncological effect on our patient as no tumor recurrence was detected during follow up.
Conclusion
Immediate intravesical instillations of chemotherapy are not devoid from risk and serious complications as bladder perforation can occur. Whether it’s value in decreasing the recurrence justify the risk of bladder perforation is not our argument in this case report. Nevertheless, this severe complication should be kept in mind, and high index of suspicion will aid in timely management. If perforation is suspected, urethral catheterization and contrasted imaging are mandatory. In the case of failed conservative management surgical repair is warranted even in extraperitoneal leak.
Funding:The author(s) received no financial support for the research, authorship, and/or publication of this article.
Declaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Author Contributions: Concept: AA, SAD. Design: MA, SA. Supervision: AA, SAD, MAA. Resources: MA, HM, NB. Materials: AA, MA, NB. Writing manuscript: AA, MA, HM. Critical review: AA, SAD, MAA.
Informed Consent: The patient has given his written informed consent to publish his case including publication of images. The study follows the guidelines for human studies and is conducted in accordance with the World Medical Association Declaration of Helsinki.
ORCID iD: Hammam Mansi
https://orcid.org/0000-0002-4571-4336 | Recovering | ReactionOutcome | CC BY-NC | 33473244 | 18,870,263 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Mediastinitis'. | Staphylococcus aureus mediastinitis due to subclavian vein perforation and catheter-related-infection.
In rare cases the implantation or use of a port-a-cath can be complicated by venous perforation or catheter-related infection. We describe a patient with these two complications resulting in Staphylococcus aureus mediastinitis. Removal of the device and prolonged antibiotic therapy cured the infection.
Introduction
Central venous catheters are widely used. To deliver chemotherapy, the use of a port-a-cath (PAC) is recommended. Complications such as venous perforation or catheter-related infection (CRI) may occur in this context; however, the combination of these two events is exceptional.
We describe a patient undergoing treatment for metastatic cancer of the left breast who presented with acute infectious mediastinitis secondary to left subclavian vein perforation and Staphylococcus aureus CRI.
Case presentation
A 58-year-old woman presented to the emergency department with a three-day history of fever and chills. She had a history of cancer of the left breast with metastatic recurrence. Three weeks prior, chemotherapy had been initiated with targeted therapy combining paclitaxel, pertuzumab and trastuzumab. A positron emission tomography (PET) was performed before initiation of treatment (Fig. 1A) as well as a contrast-enhanced scan of the chest, abdomen and pelvis (Fig. 2A). A PAC had been implanted at the left subclavian vein. Two weekly courses of chemotherapy had been administered with no significant adverse reactions. Due to PAC rotation and malposition, operative surgical revision had been performed one week prior and chemotherapy was held.Fig. 1 PET scan.
A) Before the infectious episode.
B) At the time of the infection, showing the anterior mediastinal uptake (red arrow).
C) At the end of the antibiotic treatment.
Fig. 1Fig. 2 Contrast-enhanced chest scans.
A: scan before the start of the oncology treatment.
B: scan performed at the time of the infection, showing anterior mediastinal infiltration (red arrow).
C: disappearance of anterior mediastinal uptake, persistence of adenopathies in the paratracheal area.
Fig. 2
On admission the patient complained of chest pain and dyspnea that had progressed over three days. Clinical examination revealed a temperature of 39 °C and tachycardia (110 beats). The skin at the port-a-cath chest wall site was erythematous and tender. Laboratory evaluation revealed a normal complete blood count and an elevated C-reactive protein (CRP) of 97.2 mg/L. Two blood cultures were collected from the PAC and two from a peripheral site. Empiric therapy with intravenous daptomycin 10 mg/kg daily was initiated.
On the second day of hospitalization, methicillin-susceptible S. aureus (MSSA) was recovered from all blood cultures. Blood cultures drawn from the peripheral site became positive two hours after those drawn from the PAC, indicating a CRI. The PAC was surgically removed and sent for culture, pus was noted in the area at the time of removal. Antibiotic therapy was changed to continuous infusion cloxacillin at a dose of 12 g every 24 h due to the possibility of infective endocarditis. However, no signs of endocarditis were observed on a transthoracic cardiac ultrasound. The culture of the PAC also grew MSSA, with the same antibiogram. A transoesophageal ultrasound performed one week after admission revealed no evidence of endocarditis. The patient's blood cultures were rapidly sterilized. However, despite ten days of antibiotic therapy, a persistent inflammatory syndrome was observed with fever and elevated CRP reaching a plateau of 50 mg/L. There were no focal findings on clinical examination to suggest uncontrolled infection. A contrast-enhanced scan of the chest, abdomen and pelvis (Fig. 2B) identified a thrombosis in the left subclavian vein associated with anterior mediastinal infiltration suggestive of mediastinitis. Myocardial PET scan (Fig. 1B) revealed thrombophlebitis. There was no evidence of endocarditis.
Given these findings, a second reading of radiographs following the surgical revision of the PAC, demonstrated that the tip of the catheter was located outside of the left subclavian vein in the mediastinum, a finding not noted on the prior reading (Fig. 3).Fig. 3 Frontal and profile chest x-rays showing the extremity of the intra-mediastinal and extra-vascular PAC (red arrows) (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article).
Fig. 3
Expert opinion was sought from a regional referral center for infectious diseases. The case was reviewed by a multidisciplinary panel and the consensus was that the patient had acute S. aureus mediastinitis due to procedure-related venous perforation and CRI. A decision was taken to continue the high-dose intravenous cloxacillin for a total of six weeks in combination with oral levofloxacin (750 mg/24 h) for six weeks. Her inflammatory improved rapidly with this regimen. Six weeks after starting the treatment, the patient was changed to oral levofloxacin and clindamycin to provide coverage for possible mediastinal osteomyelitis.
Targeted therapies were resumed after completion of intravenous cloxacillin therapy given peripherally. Follow-up PET CT showed absence of residual infectious focus (Fig. 1C). Regression of the mediastinitis was observed on follow-up chest CT (Fig. 2C). Paclitaxel therapy was resumed after placement of a right subclavian PAC and the completion of the oral clindamycin and levofloxacin.
Discussion
Acute mediastinitis is a rare and fatal infection. The condition is frequently described following heart surgery where it can trigger anterior infections. It can also be caused directly by injury, sternal osteomyelitis, oesophageal wound, or indirectly but by propagation where it triggers posterior necrotising mediastinitis. Rarely, mediastinitis can be spontaneously spread by hematogenous dissemination. In the literature, one similar case of acute infectious mediastinitis secondary to the implantation of a central venous catheter, the perforation of the superior vena cava and a CRI has been described [1].
Our patient was diagnosed with treatment-related acute infectious mediastinitis secondary to a CRI following traumatic perforation of the left subclavian vein. The combination of these two complications is very unusual. The frequency of jugular venous puncture as a complication of implanting a central venous catheter using ultrasound guidance is report at 1 % [2]. In a meta-analysis of more than 200 prospective studies, the risk of catheter-associated with bacteremia in patients with PACs is 0.1/1000 catheter days [3].
Our patient had received adjuvant radiation therapy to the left breast and axilla, five years prior to metastatic recurrence. Although arterial complications secondary to radiation therapy are widely described in the literature [4], little is known of the impact of radiation on the venous system. However, venous thrombosis in the radiated area has been reported [5]. In addition, radiation-induced fibrosis of healthy tissues is one of the potential late-onset complications of radiation therapy [6]. Despite involving a large vessel and the administration of very low doses, the left brachiocephalic venous trunk was located in the area of radiation. It is thus hypothesised that this adjuvant radiotherapy may have triggered changes to the vessel enhancing the likelihood of venous perforation and thrombosis.
Rare cases of mediastinitis caused by chemotherapy extravasation have been reported in the literature [7]. In these cases, the origin of the mediastinitis was chemical, irritative and non-infectious. Blood cultures from periphery and PAC were sterile.
When infectious acute mediastinitis is diagnosed based on the criteria of the Centers for Disease Control and Prevention [8], the collection of a mediastinal sample for culture is not necessary for diagnosis. In our patient, her mediastinal infection was almost certainly due to MSSA in view of the clinical and microbiological findings.
The role and utility of PET scans in the diagnosis of mediastinitis is unknown. In one case of descending necrotising mediastinitis [9] the uptake of the mediastinal infiltrate on the PET scan was intense. However, in our patient, the mediastinal infiltration was absent. We can hypothesize that the lack of uptake was related to ten days of effective antibiotic therapy in our patient.
Empiric broad-spectrum antibiotic therapy of mediastinitis should be initiated as soon as possible while awaiting blood or mediastinal culture results. Therapy is prolonged initially at least three weeks of intravenous therapy followed by oral therapy for three weeks [10].
These recommendations also apply to mediastinitis following heart surgery. In our patient, empiric daptomycin that provided coverage for S. aureus (the most likely pathogen) was initiated in the setting of CRI, followed by a change to cloxacillin when susceptibility results were available. High dose cloxacillin was used due to the concern for endocarditis. There is no consensus on the length of antibiotic therapy. It is possible that a shorter course of therapy would have been equally effective in our patient.
While infectious mediastinitis was the reason for suspending targeted cancer therapy for six weeks and chemotherapy for 12 weeks, it did not appear to have any clinical consequences. Six months after this complication, our patient continues to receive targeted maintenance therapies and her response is still complete.
Conclusion
We describe the second case of infectious mediastinitis secondary to venous perforation and CRI. The combined complications of venous perforation and CRI leading to mediastinitis are extremely rare but should be given consideration and investigated based on clinical presentation.
Funding
Authors did not have any funding source.
These informations have not been presented in a meeting.
Author agreement statement
All authors declare that this manuscript is original, has not been published before and is not currently being considered for publication elsewhere.
We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed.
We further confirm that the order of authors listed in the manuscript has been approved by all of us.
We understand that the Corresponding Author is the sole contact for the Editorial process. He is responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs.
Declaration of Competing Interest
The authors declare that they have no conflict of interest.
Acknowledgements
PR suggested this clinical case. He was involved in the bibliographic research, the drafting, proofreading and submission of the article.
JB was involved in the bibliographic research and proofreading of the article.
FH was involved in the bibliographic research and proofreading of the article.
NR provided a radiological opinion and reviewed the various images.
AN was involved in the proofreading of this article.
AT was involved in the proofreading of this article and provided a radiotherapist opinion.
SD was involved in the proofreading of this article and provided a radiotherapist opinion.
GM was involved in the bibliographic research, the drafting, proofreading and correction of the article. | PACLITAXEL, PERTUZUMAB, TRASTUZUMAB | DrugsGivenReaction | CC BY-NC-ND | 33473350 | 18,991,130 | 2021 |
What was the administration route of drug 'PACLITAXEL'? | Staphylococcus aureus mediastinitis due to subclavian vein perforation and catheter-related-infection.
In rare cases the implantation or use of a port-a-cath can be complicated by venous perforation or catheter-related infection. We describe a patient with these two complications resulting in Staphylococcus aureus mediastinitis. Removal of the device and prolonged antibiotic therapy cured the infection.
Introduction
Central venous catheters are widely used. To deliver chemotherapy, the use of a port-a-cath (PAC) is recommended. Complications such as venous perforation or catheter-related infection (CRI) may occur in this context; however, the combination of these two events is exceptional.
We describe a patient undergoing treatment for metastatic cancer of the left breast who presented with acute infectious mediastinitis secondary to left subclavian vein perforation and Staphylococcus aureus CRI.
Case presentation
A 58-year-old woman presented to the emergency department with a three-day history of fever and chills. She had a history of cancer of the left breast with metastatic recurrence. Three weeks prior, chemotherapy had been initiated with targeted therapy combining paclitaxel, pertuzumab and trastuzumab. A positron emission tomography (PET) was performed before initiation of treatment (Fig. 1A) as well as a contrast-enhanced scan of the chest, abdomen and pelvis (Fig. 2A). A PAC had been implanted at the left subclavian vein. Two weekly courses of chemotherapy had been administered with no significant adverse reactions. Due to PAC rotation and malposition, operative surgical revision had been performed one week prior and chemotherapy was held.Fig. 1 PET scan.
A) Before the infectious episode.
B) At the time of the infection, showing the anterior mediastinal uptake (red arrow).
C) At the end of the antibiotic treatment.
Fig. 1Fig. 2 Contrast-enhanced chest scans.
A: scan before the start of the oncology treatment.
B: scan performed at the time of the infection, showing anterior mediastinal infiltration (red arrow).
C: disappearance of anterior mediastinal uptake, persistence of adenopathies in the paratracheal area.
Fig. 2
On admission the patient complained of chest pain and dyspnea that had progressed over three days. Clinical examination revealed a temperature of 39 °C and tachycardia (110 beats). The skin at the port-a-cath chest wall site was erythematous and tender. Laboratory evaluation revealed a normal complete blood count and an elevated C-reactive protein (CRP) of 97.2 mg/L. Two blood cultures were collected from the PAC and two from a peripheral site. Empiric therapy with intravenous daptomycin 10 mg/kg daily was initiated.
On the second day of hospitalization, methicillin-susceptible S. aureus (MSSA) was recovered from all blood cultures. Blood cultures drawn from the peripheral site became positive two hours after those drawn from the PAC, indicating a CRI. The PAC was surgically removed and sent for culture, pus was noted in the area at the time of removal. Antibiotic therapy was changed to continuous infusion cloxacillin at a dose of 12 g every 24 h due to the possibility of infective endocarditis. However, no signs of endocarditis were observed on a transthoracic cardiac ultrasound. The culture of the PAC also grew MSSA, with the same antibiogram. A transoesophageal ultrasound performed one week after admission revealed no evidence of endocarditis. The patient's blood cultures were rapidly sterilized. However, despite ten days of antibiotic therapy, a persistent inflammatory syndrome was observed with fever and elevated CRP reaching a plateau of 50 mg/L. There were no focal findings on clinical examination to suggest uncontrolled infection. A contrast-enhanced scan of the chest, abdomen and pelvis (Fig. 2B) identified a thrombosis in the left subclavian vein associated with anterior mediastinal infiltration suggestive of mediastinitis. Myocardial PET scan (Fig. 1B) revealed thrombophlebitis. There was no evidence of endocarditis.
Given these findings, a second reading of radiographs following the surgical revision of the PAC, demonstrated that the tip of the catheter was located outside of the left subclavian vein in the mediastinum, a finding not noted on the prior reading (Fig. 3).Fig. 3 Frontal and profile chest x-rays showing the extremity of the intra-mediastinal and extra-vascular PAC (red arrows) (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article).
Fig. 3
Expert opinion was sought from a regional referral center for infectious diseases. The case was reviewed by a multidisciplinary panel and the consensus was that the patient had acute S. aureus mediastinitis due to procedure-related venous perforation and CRI. A decision was taken to continue the high-dose intravenous cloxacillin for a total of six weeks in combination with oral levofloxacin (750 mg/24 h) for six weeks. Her inflammatory improved rapidly with this regimen. Six weeks after starting the treatment, the patient was changed to oral levofloxacin and clindamycin to provide coverage for possible mediastinal osteomyelitis.
Targeted therapies were resumed after completion of intravenous cloxacillin therapy given peripherally. Follow-up PET CT showed absence of residual infectious focus (Fig. 1C). Regression of the mediastinitis was observed on follow-up chest CT (Fig. 2C). Paclitaxel therapy was resumed after placement of a right subclavian PAC and the completion of the oral clindamycin and levofloxacin.
Discussion
Acute mediastinitis is a rare and fatal infection. The condition is frequently described following heart surgery where it can trigger anterior infections. It can also be caused directly by injury, sternal osteomyelitis, oesophageal wound, or indirectly but by propagation where it triggers posterior necrotising mediastinitis. Rarely, mediastinitis can be spontaneously spread by hematogenous dissemination. In the literature, one similar case of acute infectious mediastinitis secondary to the implantation of a central venous catheter, the perforation of the superior vena cava and a CRI has been described [1].
Our patient was diagnosed with treatment-related acute infectious mediastinitis secondary to a CRI following traumatic perforation of the left subclavian vein. The combination of these two complications is very unusual. The frequency of jugular venous puncture as a complication of implanting a central venous catheter using ultrasound guidance is report at 1 % [2]. In a meta-analysis of more than 200 prospective studies, the risk of catheter-associated with bacteremia in patients with PACs is 0.1/1000 catheter days [3].
Our patient had received adjuvant radiation therapy to the left breast and axilla, five years prior to metastatic recurrence. Although arterial complications secondary to radiation therapy are widely described in the literature [4], little is known of the impact of radiation on the venous system. However, venous thrombosis in the radiated area has been reported [5]. In addition, radiation-induced fibrosis of healthy tissues is one of the potential late-onset complications of radiation therapy [6]. Despite involving a large vessel and the administration of very low doses, the left brachiocephalic venous trunk was located in the area of radiation. It is thus hypothesised that this adjuvant radiotherapy may have triggered changes to the vessel enhancing the likelihood of venous perforation and thrombosis.
Rare cases of mediastinitis caused by chemotherapy extravasation have been reported in the literature [7]. In these cases, the origin of the mediastinitis was chemical, irritative and non-infectious. Blood cultures from periphery and PAC were sterile.
When infectious acute mediastinitis is diagnosed based on the criteria of the Centers for Disease Control and Prevention [8], the collection of a mediastinal sample for culture is not necessary for diagnosis. In our patient, her mediastinal infection was almost certainly due to MSSA in view of the clinical and microbiological findings.
The role and utility of PET scans in the diagnosis of mediastinitis is unknown. In one case of descending necrotising mediastinitis [9] the uptake of the mediastinal infiltrate on the PET scan was intense. However, in our patient, the mediastinal infiltration was absent. We can hypothesize that the lack of uptake was related to ten days of effective antibiotic therapy in our patient.
Empiric broad-spectrum antibiotic therapy of mediastinitis should be initiated as soon as possible while awaiting blood or mediastinal culture results. Therapy is prolonged initially at least three weeks of intravenous therapy followed by oral therapy for three weeks [10].
These recommendations also apply to mediastinitis following heart surgery. In our patient, empiric daptomycin that provided coverage for S. aureus (the most likely pathogen) was initiated in the setting of CRI, followed by a change to cloxacillin when susceptibility results were available. High dose cloxacillin was used due to the concern for endocarditis. There is no consensus on the length of antibiotic therapy. It is possible that a shorter course of therapy would have been equally effective in our patient.
While infectious mediastinitis was the reason for suspending targeted cancer therapy for six weeks and chemotherapy for 12 weeks, it did not appear to have any clinical consequences. Six months after this complication, our patient continues to receive targeted maintenance therapies and her response is still complete.
Conclusion
We describe the second case of infectious mediastinitis secondary to venous perforation and CRI. The combined complications of venous perforation and CRI leading to mediastinitis are extremely rare but should be given consideration and investigated based on clinical presentation.
Funding
Authors did not have any funding source.
These informations have not been presented in a meeting.
Author agreement statement
All authors declare that this manuscript is original, has not been published before and is not currently being considered for publication elsewhere.
We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed.
We further confirm that the order of authors listed in the manuscript has been approved by all of us.
We understand that the Corresponding Author is the sole contact for the Editorial process. He is responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs.
Declaration of Competing Interest
The authors declare that they have no conflict of interest.
Acknowledgements
PR suggested this clinical case. He was involved in the bibliographic research, the drafting, proofreading and submission of the article.
JB was involved in the bibliographic research and proofreading of the article.
FH was involved in the bibliographic research and proofreading of the article.
NR provided a radiological opinion and reviewed the various images.
AN was involved in the proofreading of this article.
AT was involved in the proofreading of this article and provided a radiotherapist opinion.
SD was involved in the proofreading of this article and provided a radiotherapist opinion.
GM was involved in the bibliographic research, the drafting, proofreading and correction of the article. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33473350 | 18,991,130 | 2021 |
What was the administration route of drug 'PERTUZUMAB'? | Staphylococcus aureus mediastinitis due to subclavian vein perforation and catheter-related-infection.
In rare cases the implantation or use of a port-a-cath can be complicated by venous perforation or catheter-related infection. We describe a patient with these two complications resulting in Staphylococcus aureus mediastinitis. Removal of the device and prolonged antibiotic therapy cured the infection.
Introduction
Central venous catheters are widely used. To deliver chemotherapy, the use of a port-a-cath (PAC) is recommended. Complications such as venous perforation or catheter-related infection (CRI) may occur in this context; however, the combination of these two events is exceptional.
We describe a patient undergoing treatment for metastatic cancer of the left breast who presented with acute infectious mediastinitis secondary to left subclavian vein perforation and Staphylococcus aureus CRI.
Case presentation
A 58-year-old woman presented to the emergency department with a three-day history of fever and chills. She had a history of cancer of the left breast with metastatic recurrence. Three weeks prior, chemotherapy had been initiated with targeted therapy combining paclitaxel, pertuzumab and trastuzumab. A positron emission tomography (PET) was performed before initiation of treatment (Fig. 1A) as well as a contrast-enhanced scan of the chest, abdomen and pelvis (Fig. 2A). A PAC had been implanted at the left subclavian vein. Two weekly courses of chemotherapy had been administered with no significant adverse reactions. Due to PAC rotation and malposition, operative surgical revision had been performed one week prior and chemotherapy was held.Fig. 1 PET scan.
A) Before the infectious episode.
B) At the time of the infection, showing the anterior mediastinal uptake (red arrow).
C) At the end of the antibiotic treatment.
Fig. 1Fig. 2 Contrast-enhanced chest scans.
A: scan before the start of the oncology treatment.
B: scan performed at the time of the infection, showing anterior mediastinal infiltration (red arrow).
C: disappearance of anterior mediastinal uptake, persistence of adenopathies in the paratracheal area.
Fig. 2
On admission the patient complained of chest pain and dyspnea that had progressed over three days. Clinical examination revealed a temperature of 39 °C and tachycardia (110 beats). The skin at the port-a-cath chest wall site was erythematous and tender. Laboratory evaluation revealed a normal complete blood count and an elevated C-reactive protein (CRP) of 97.2 mg/L. Two blood cultures were collected from the PAC and two from a peripheral site. Empiric therapy with intravenous daptomycin 10 mg/kg daily was initiated.
On the second day of hospitalization, methicillin-susceptible S. aureus (MSSA) was recovered from all blood cultures. Blood cultures drawn from the peripheral site became positive two hours after those drawn from the PAC, indicating a CRI. The PAC was surgically removed and sent for culture, pus was noted in the area at the time of removal. Antibiotic therapy was changed to continuous infusion cloxacillin at a dose of 12 g every 24 h due to the possibility of infective endocarditis. However, no signs of endocarditis were observed on a transthoracic cardiac ultrasound. The culture of the PAC also grew MSSA, with the same antibiogram. A transoesophageal ultrasound performed one week after admission revealed no evidence of endocarditis. The patient's blood cultures were rapidly sterilized. However, despite ten days of antibiotic therapy, a persistent inflammatory syndrome was observed with fever and elevated CRP reaching a plateau of 50 mg/L. There were no focal findings on clinical examination to suggest uncontrolled infection. A contrast-enhanced scan of the chest, abdomen and pelvis (Fig. 2B) identified a thrombosis in the left subclavian vein associated with anterior mediastinal infiltration suggestive of mediastinitis. Myocardial PET scan (Fig. 1B) revealed thrombophlebitis. There was no evidence of endocarditis.
Given these findings, a second reading of radiographs following the surgical revision of the PAC, demonstrated that the tip of the catheter was located outside of the left subclavian vein in the mediastinum, a finding not noted on the prior reading (Fig. 3).Fig. 3 Frontal and profile chest x-rays showing the extremity of the intra-mediastinal and extra-vascular PAC (red arrows) (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article).
Fig. 3
Expert opinion was sought from a regional referral center for infectious diseases. The case was reviewed by a multidisciplinary panel and the consensus was that the patient had acute S. aureus mediastinitis due to procedure-related venous perforation and CRI. A decision was taken to continue the high-dose intravenous cloxacillin for a total of six weeks in combination with oral levofloxacin (750 mg/24 h) for six weeks. Her inflammatory improved rapidly with this regimen. Six weeks after starting the treatment, the patient was changed to oral levofloxacin and clindamycin to provide coverage for possible mediastinal osteomyelitis.
Targeted therapies were resumed after completion of intravenous cloxacillin therapy given peripherally. Follow-up PET CT showed absence of residual infectious focus (Fig. 1C). Regression of the mediastinitis was observed on follow-up chest CT (Fig. 2C). Paclitaxel therapy was resumed after placement of a right subclavian PAC and the completion of the oral clindamycin and levofloxacin.
Discussion
Acute mediastinitis is a rare and fatal infection. The condition is frequently described following heart surgery where it can trigger anterior infections. It can also be caused directly by injury, sternal osteomyelitis, oesophageal wound, or indirectly but by propagation where it triggers posterior necrotising mediastinitis. Rarely, mediastinitis can be spontaneously spread by hematogenous dissemination. In the literature, one similar case of acute infectious mediastinitis secondary to the implantation of a central venous catheter, the perforation of the superior vena cava and a CRI has been described [1].
Our patient was diagnosed with treatment-related acute infectious mediastinitis secondary to a CRI following traumatic perforation of the left subclavian vein. The combination of these two complications is very unusual. The frequency of jugular venous puncture as a complication of implanting a central venous catheter using ultrasound guidance is report at 1 % [2]. In a meta-analysis of more than 200 prospective studies, the risk of catheter-associated with bacteremia in patients with PACs is 0.1/1000 catheter days [3].
Our patient had received adjuvant radiation therapy to the left breast and axilla, five years prior to metastatic recurrence. Although arterial complications secondary to radiation therapy are widely described in the literature [4], little is known of the impact of radiation on the venous system. However, venous thrombosis in the radiated area has been reported [5]. In addition, radiation-induced fibrosis of healthy tissues is one of the potential late-onset complications of radiation therapy [6]. Despite involving a large vessel and the administration of very low doses, the left brachiocephalic venous trunk was located in the area of radiation. It is thus hypothesised that this adjuvant radiotherapy may have triggered changes to the vessel enhancing the likelihood of venous perforation and thrombosis.
Rare cases of mediastinitis caused by chemotherapy extravasation have been reported in the literature [7]. In these cases, the origin of the mediastinitis was chemical, irritative and non-infectious. Blood cultures from periphery and PAC were sterile.
When infectious acute mediastinitis is diagnosed based on the criteria of the Centers for Disease Control and Prevention [8], the collection of a mediastinal sample for culture is not necessary for diagnosis. In our patient, her mediastinal infection was almost certainly due to MSSA in view of the clinical and microbiological findings.
The role and utility of PET scans in the diagnosis of mediastinitis is unknown. In one case of descending necrotising mediastinitis [9] the uptake of the mediastinal infiltrate on the PET scan was intense. However, in our patient, the mediastinal infiltration was absent. We can hypothesize that the lack of uptake was related to ten days of effective antibiotic therapy in our patient.
Empiric broad-spectrum antibiotic therapy of mediastinitis should be initiated as soon as possible while awaiting blood or mediastinal culture results. Therapy is prolonged initially at least three weeks of intravenous therapy followed by oral therapy for three weeks [10].
These recommendations also apply to mediastinitis following heart surgery. In our patient, empiric daptomycin that provided coverage for S. aureus (the most likely pathogen) was initiated in the setting of CRI, followed by a change to cloxacillin when susceptibility results were available. High dose cloxacillin was used due to the concern for endocarditis. There is no consensus on the length of antibiotic therapy. It is possible that a shorter course of therapy would have been equally effective in our patient.
While infectious mediastinitis was the reason for suspending targeted cancer therapy for six weeks and chemotherapy for 12 weeks, it did not appear to have any clinical consequences. Six months after this complication, our patient continues to receive targeted maintenance therapies and her response is still complete.
Conclusion
We describe the second case of infectious mediastinitis secondary to venous perforation and CRI. The combined complications of venous perforation and CRI leading to mediastinitis are extremely rare but should be given consideration and investigated based on clinical presentation.
Funding
Authors did not have any funding source.
These informations have not been presented in a meeting.
Author agreement statement
All authors declare that this manuscript is original, has not been published before and is not currently being considered for publication elsewhere.
We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed.
We further confirm that the order of authors listed in the manuscript has been approved by all of us.
We understand that the Corresponding Author is the sole contact for the Editorial process. He is responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs.
Declaration of Competing Interest
The authors declare that they have no conflict of interest.
Acknowledgements
PR suggested this clinical case. He was involved in the bibliographic research, the drafting, proofreading and submission of the article.
JB was involved in the bibliographic research and proofreading of the article.
FH was involved in the bibliographic research and proofreading of the article.
NR provided a radiological opinion and reviewed the various images.
AN was involved in the proofreading of this article.
AT was involved in the proofreading of this article and provided a radiotherapist opinion.
SD was involved in the proofreading of this article and provided a radiotherapist opinion.
GM was involved in the bibliographic research, the drafting, proofreading and correction of the article. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33473350 | 18,991,130 | 2021 |
What was the administration route of drug 'TRASTUZUMAB'? | Staphylococcus aureus mediastinitis due to subclavian vein perforation and catheter-related-infection.
In rare cases the implantation or use of a port-a-cath can be complicated by venous perforation or catheter-related infection. We describe a patient with these two complications resulting in Staphylococcus aureus mediastinitis. Removal of the device and prolonged antibiotic therapy cured the infection.
Introduction
Central venous catheters are widely used. To deliver chemotherapy, the use of a port-a-cath (PAC) is recommended. Complications such as venous perforation or catheter-related infection (CRI) may occur in this context; however, the combination of these two events is exceptional.
We describe a patient undergoing treatment for metastatic cancer of the left breast who presented with acute infectious mediastinitis secondary to left subclavian vein perforation and Staphylococcus aureus CRI.
Case presentation
A 58-year-old woman presented to the emergency department with a three-day history of fever and chills. She had a history of cancer of the left breast with metastatic recurrence. Three weeks prior, chemotherapy had been initiated with targeted therapy combining paclitaxel, pertuzumab and trastuzumab. A positron emission tomography (PET) was performed before initiation of treatment (Fig. 1A) as well as a contrast-enhanced scan of the chest, abdomen and pelvis (Fig. 2A). A PAC had been implanted at the left subclavian vein. Two weekly courses of chemotherapy had been administered with no significant adverse reactions. Due to PAC rotation and malposition, operative surgical revision had been performed one week prior and chemotherapy was held.Fig. 1 PET scan.
A) Before the infectious episode.
B) At the time of the infection, showing the anterior mediastinal uptake (red arrow).
C) At the end of the antibiotic treatment.
Fig. 1Fig. 2 Contrast-enhanced chest scans.
A: scan before the start of the oncology treatment.
B: scan performed at the time of the infection, showing anterior mediastinal infiltration (red arrow).
C: disappearance of anterior mediastinal uptake, persistence of adenopathies in the paratracheal area.
Fig. 2
On admission the patient complained of chest pain and dyspnea that had progressed over three days. Clinical examination revealed a temperature of 39 °C and tachycardia (110 beats). The skin at the port-a-cath chest wall site was erythematous and tender. Laboratory evaluation revealed a normal complete blood count and an elevated C-reactive protein (CRP) of 97.2 mg/L. Two blood cultures were collected from the PAC and two from a peripheral site. Empiric therapy with intravenous daptomycin 10 mg/kg daily was initiated.
On the second day of hospitalization, methicillin-susceptible S. aureus (MSSA) was recovered from all blood cultures. Blood cultures drawn from the peripheral site became positive two hours after those drawn from the PAC, indicating a CRI. The PAC was surgically removed and sent for culture, pus was noted in the area at the time of removal. Antibiotic therapy was changed to continuous infusion cloxacillin at a dose of 12 g every 24 h due to the possibility of infective endocarditis. However, no signs of endocarditis were observed on a transthoracic cardiac ultrasound. The culture of the PAC also grew MSSA, with the same antibiogram. A transoesophageal ultrasound performed one week after admission revealed no evidence of endocarditis. The patient's blood cultures were rapidly sterilized. However, despite ten days of antibiotic therapy, a persistent inflammatory syndrome was observed with fever and elevated CRP reaching a plateau of 50 mg/L. There were no focal findings on clinical examination to suggest uncontrolled infection. A contrast-enhanced scan of the chest, abdomen and pelvis (Fig. 2B) identified a thrombosis in the left subclavian vein associated with anterior mediastinal infiltration suggestive of mediastinitis. Myocardial PET scan (Fig. 1B) revealed thrombophlebitis. There was no evidence of endocarditis.
Given these findings, a second reading of radiographs following the surgical revision of the PAC, demonstrated that the tip of the catheter was located outside of the left subclavian vein in the mediastinum, a finding not noted on the prior reading (Fig. 3).Fig. 3 Frontal and profile chest x-rays showing the extremity of the intra-mediastinal and extra-vascular PAC (red arrows) (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article).
Fig. 3
Expert opinion was sought from a regional referral center for infectious diseases. The case was reviewed by a multidisciplinary panel and the consensus was that the patient had acute S. aureus mediastinitis due to procedure-related venous perforation and CRI. A decision was taken to continue the high-dose intravenous cloxacillin for a total of six weeks in combination with oral levofloxacin (750 mg/24 h) for six weeks. Her inflammatory improved rapidly with this regimen. Six weeks after starting the treatment, the patient was changed to oral levofloxacin and clindamycin to provide coverage for possible mediastinal osteomyelitis.
Targeted therapies were resumed after completion of intravenous cloxacillin therapy given peripherally. Follow-up PET CT showed absence of residual infectious focus (Fig. 1C). Regression of the mediastinitis was observed on follow-up chest CT (Fig. 2C). Paclitaxel therapy was resumed after placement of a right subclavian PAC and the completion of the oral clindamycin and levofloxacin.
Discussion
Acute mediastinitis is a rare and fatal infection. The condition is frequently described following heart surgery where it can trigger anterior infections. It can also be caused directly by injury, sternal osteomyelitis, oesophageal wound, or indirectly but by propagation where it triggers posterior necrotising mediastinitis. Rarely, mediastinitis can be spontaneously spread by hematogenous dissemination. In the literature, one similar case of acute infectious mediastinitis secondary to the implantation of a central venous catheter, the perforation of the superior vena cava and a CRI has been described [1].
Our patient was diagnosed with treatment-related acute infectious mediastinitis secondary to a CRI following traumatic perforation of the left subclavian vein. The combination of these two complications is very unusual. The frequency of jugular venous puncture as a complication of implanting a central venous catheter using ultrasound guidance is report at 1 % [2]. In a meta-analysis of more than 200 prospective studies, the risk of catheter-associated with bacteremia in patients with PACs is 0.1/1000 catheter days [3].
Our patient had received adjuvant radiation therapy to the left breast and axilla, five years prior to metastatic recurrence. Although arterial complications secondary to radiation therapy are widely described in the literature [4], little is known of the impact of radiation on the venous system. However, venous thrombosis in the radiated area has been reported [5]. In addition, radiation-induced fibrosis of healthy tissues is one of the potential late-onset complications of radiation therapy [6]. Despite involving a large vessel and the administration of very low doses, the left brachiocephalic venous trunk was located in the area of radiation. It is thus hypothesised that this adjuvant radiotherapy may have triggered changes to the vessel enhancing the likelihood of venous perforation and thrombosis.
Rare cases of mediastinitis caused by chemotherapy extravasation have been reported in the literature [7]. In these cases, the origin of the mediastinitis was chemical, irritative and non-infectious. Blood cultures from periphery and PAC were sterile.
When infectious acute mediastinitis is diagnosed based on the criteria of the Centers for Disease Control and Prevention [8], the collection of a mediastinal sample for culture is not necessary for diagnosis. In our patient, her mediastinal infection was almost certainly due to MSSA in view of the clinical and microbiological findings.
The role and utility of PET scans in the diagnosis of mediastinitis is unknown. In one case of descending necrotising mediastinitis [9] the uptake of the mediastinal infiltrate on the PET scan was intense. However, in our patient, the mediastinal infiltration was absent. We can hypothesize that the lack of uptake was related to ten days of effective antibiotic therapy in our patient.
Empiric broad-spectrum antibiotic therapy of mediastinitis should be initiated as soon as possible while awaiting blood or mediastinal culture results. Therapy is prolonged initially at least three weeks of intravenous therapy followed by oral therapy for three weeks [10].
These recommendations also apply to mediastinitis following heart surgery. In our patient, empiric daptomycin that provided coverage for S. aureus (the most likely pathogen) was initiated in the setting of CRI, followed by a change to cloxacillin when susceptibility results were available. High dose cloxacillin was used due to the concern for endocarditis. There is no consensus on the length of antibiotic therapy. It is possible that a shorter course of therapy would have been equally effective in our patient.
While infectious mediastinitis was the reason for suspending targeted cancer therapy for six weeks and chemotherapy for 12 weeks, it did not appear to have any clinical consequences. Six months after this complication, our patient continues to receive targeted maintenance therapies and her response is still complete.
Conclusion
We describe the second case of infectious mediastinitis secondary to venous perforation and CRI. The combined complications of venous perforation and CRI leading to mediastinitis are extremely rare but should be given consideration and investigated based on clinical presentation.
Funding
Authors did not have any funding source.
These informations have not been presented in a meeting.
Author agreement statement
All authors declare that this manuscript is original, has not been published before and is not currently being considered for publication elsewhere.
We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed.
We further confirm that the order of authors listed in the manuscript has been approved by all of us.
We understand that the Corresponding Author is the sole contact for the Editorial process. He is responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs.
Declaration of Competing Interest
The authors declare that they have no conflict of interest.
Acknowledgements
PR suggested this clinical case. He was involved in the bibliographic research, the drafting, proofreading and submission of the article.
JB was involved in the bibliographic research and proofreading of the article.
FH was involved in the bibliographic research and proofreading of the article.
NR provided a radiological opinion and reviewed the various images.
AN was involved in the proofreading of this article.
AT was involved in the proofreading of this article and provided a radiotherapist opinion.
SD was involved in the proofreading of this article and provided a radiotherapist opinion.
GM was involved in the bibliographic research, the drafting, proofreading and correction of the article. | Intravenous drip | DrugAdministrationRoute | CC BY-NC-ND | 33473350 | 18,991,130 | 2021 |
What was the outcome of reaction 'Mediastinitis'? | Staphylococcus aureus mediastinitis due to subclavian vein perforation and catheter-related-infection.
In rare cases the implantation or use of a port-a-cath can be complicated by venous perforation or catheter-related infection. We describe a patient with these two complications resulting in Staphylococcus aureus mediastinitis. Removal of the device and prolonged antibiotic therapy cured the infection.
Introduction
Central venous catheters are widely used. To deliver chemotherapy, the use of a port-a-cath (PAC) is recommended. Complications such as venous perforation or catheter-related infection (CRI) may occur in this context; however, the combination of these two events is exceptional.
We describe a patient undergoing treatment for metastatic cancer of the left breast who presented with acute infectious mediastinitis secondary to left subclavian vein perforation and Staphylococcus aureus CRI.
Case presentation
A 58-year-old woman presented to the emergency department with a three-day history of fever and chills. She had a history of cancer of the left breast with metastatic recurrence. Three weeks prior, chemotherapy had been initiated with targeted therapy combining paclitaxel, pertuzumab and trastuzumab. A positron emission tomography (PET) was performed before initiation of treatment (Fig. 1A) as well as a contrast-enhanced scan of the chest, abdomen and pelvis (Fig. 2A). A PAC had been implanted at the left subclavian vein. Two weekly courses of chemotherapy had been administered with no significant adverse reactions. Due to PAC rotation and malposition, operative surgical revision had been performed one week prior and chemotherapy was held.Fig. 1 PET scan.
A) Before the infectious episode.
B) At the time of the infection, showing the anterior mediastinal uptake (red arrow).
C) At the end of the antibiotic treatment.
Fig. 1Fig. 2 Contrast-enhanced chest scans.
A: scan before the start of the oncology treatment.
B: scan performed at the time of the infection, showing anterior mediastinal infiltration (red arrow).
C: disappearance of anterior mediastinal uptake, persistence of adenopathies in the paratracheal area.
Fig. 2
On admission the patient complained of chest pain and dyspnea that had progressed over three days. Clinical examination revealed a temperature of 39 °C and tachycardia (110 beats). The skin at the port-a-cath chest wall site was erythematous and tender. Laboratory evaluation revealed a normal complete blood count and an elevated C-reactive protein (CRP) of 97.2 mg/L. Two blood cultures were collected from the PAC and two from a peripheral site. Empiric therapy with intravenous daptomycin 10 mg/kg daily was initiated.
On the second day of hospitalization, methicillin-susceptible S. aureus (MSSA) was recovered from all blood cultures. Blood cultures drawn from the peripheral site became positive two hours after those drawn from the PAC, indicating a CRI. The PAC was surgically removed and sent for culture, pus was noted in the area at the time of removal. Antibiotic therapy was changed to continuous infusion cloxacillin at a dose of 12 g every 24 h due to the possibility of infective endocarditis. However, no signs of endocarditis were observed on a transthoracic cardiac ultrasound. The culture of the PAC also grew MSSA, with the same antibiogram. A transoesophageal ultrasound performed one week after admission revealed no evidence of endocarditis. The patient's blood cultures were rapidly sterilized. However, despite ten days of antibiotic therapy, a persistent inflammatory syndrome was observed with fever and elevated CRP reaching a plateau of 50 mg/L. There were no focal findings on clinical examination to suggest uncontrolled infection. A contrast-enhanced scan of the chest, abdomen and pelvis (Fig. 2B) identified a thrombosis in the left subclavian vein associated with anterior mediastinal infiltration suggestive of mediastinitis. Myocardial PET scan (Fig. 1B) revealed thrombophlebitis. There was no evidence of endocarditis.
Given these findings, a second reading of radiographs following the surgical revision of the PAC, demonstrated that the tip of the catheter was located outside of the left subclavian vein in the mediastinum, a finding not noted on the prior reading (Fig. 3).Fig. 3 Frontal and profile chest x-rays showing the extremity of the intra-mediastinal and extra-vascular PAC (red arrows) (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article).
Fig. 3
Expert opinion was sought from a regional referral center for infectious diseases. The case was reviewed by a multidisciplinary panel and the consensus was that the patient had acute S. aureus mediastinitis due to procedure-related venous perforation and CRI. A decision was taken to continue the high-dose intravenous cloxacillin for a total of six weeks in combination with oral levofloxacin (750 mg/24 h) for six weeks. Her inflammatory improved rapidly with this regimen. Six weeks after starting the treatment, the patient was changed to oral levofloxacin and clindamycin to provide coverage for possible mediastinal osteomyelitis.
Targeted therapies were resumed after completion of intravenous cloxacillin therapy given peripherally. Follow-up PET CT showed absence of residual infectious focus (Fig. 1C). Regression of the mediastinitis was observed on follow-up chest CT (Fig. 2C). Paclitaxel therapy was resumed after placement of a right subclavian PAC and the completion of the oral clindamycin and levofloxacin.
Discussion
Acute mediastinitis is a rare and fatal infection. The condition is frequently described following heart surgery where it can trigger anterior infections. It can also be caused directly by injury, sternal osteomyelitis, oesophageal wound, or indirectly but by propagation where it triggers posterior necrotising mediastinitis. Rarely, mediastinitis can be spontaneously spread by hematogenous dissemination. In the literature, one similar case of acute infectious mediastinitis secondary to the implantation of a central venous catheter, the perforation of the superior vena cava and a CRI has been described [1].
Our patient was diagnosed with treatment-related acute infectious mediastinitis secondary to a CRI following traumatic perforation of the left subclavian vein. The combination of these two complications is very unusual. The frequency of jugular venous puncture as a complication of implanting a central venous catheter using ultrasound guidance is report at 1 % [2]. In a meta-analysis of more than 200 prospective studies, the risk of catheter-associated with bacteremia in patients with PACs is 0.1/1000 catheter days [3].
Our patient had received adjuvant radiation therapy to the left breast and axilla, five years prior to metastatic recurrence. Although arterial complications secondary to radiation therapy are widely described in the literature [4], little is known of the impact of radiation on the venous system. However, venous thrombosis in the radiated area has been reported [5]. In addition, radiation-induced fibrosis of healthy tissues is one of the potential late-onset complications of radiation therapy [6]. Despite involving a large vessel and the administration of very low doses, the left brachiocephalic venous trunk was located in the area of radiation. It is thus hypothesised that this adjuvant radiotherapy may have triggered changes to the vessel enhancing the likelihood of venous perforation and thrombosis.
Rare cases of mediastinitis caused by chemotherapy extravasation have been reported in the literature [7]. In these cases, the origin of the mediastinitis was chemical, irritative and non-infectious. Blood cultures from periphery and PAC were sterile.
When infectious acute mediastinitis is diagnosed based on the criteria of the Centers for Disease Control and Prevention [8], the collection of a mediastinal sample for culture is not necessary for diagnosis. In our patient, her mediastinal infection was almost certainly due to MSSA in view of the clinical and microbiological findings.
The role and utility of PET scans in the diagnosis of mediastinitis is unknown. In one case of descending necrotising mediastinitis [9] the uptake of the mediastinal infiltrate on the PET scan was intense. However, in our patient, the mediastinal infiltration was absent. We can hypothesize that the lack of uptake was related to ten days of effective antibiotic therapy in our patient.
Empiric broad-spectrum antibiotic therapy of mediastinitis should be initiated as soon as possible while awaiting blood or mediastinal culture results. Therapy is prolonged initially at least three weeks of intravenous therapy followed by oral therapy for three weeks [10].
These recommendations also apply to mediastinitis following heart surgery. In our patient, empiric daptomycin that provided coverage for S. aureus (the most likely pathogen) was initiated in the setting of CRI, followed by a change to cloxacillin when susceptibility results were available. High dose cloxacillin was used due to the concern for endocarditis. There is no consensus on the length of antibiotic therapy. It is possible that a shorter course of therapy would have been equally effective in our patient.
While infectious mediastinitis was the reason for suspending targeted cancer therapy for six weeks and chemotherapy for 12 weeks, it did not appear to have any clinical consequences. Six months after this complication, our patient continues to receive targeted maintenance therapies and her response is still complete.
Conclusion
We describe the second case of infectious mediastinitis secondary to venous perforation and CRI. The combined complications of venous perforation and CRI leading to mediastinitis are extremely rare but should be given consideration and investigated based on clinical presentation.
Funding
Authors did not have any funding source.
These informations have not been presented in a meeting.
Author agreement statement
All authors declare that this manuscript is original, has not been published before and is not currently being considered for publication elsewhere.
We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed.
We further confirm that the order of authors listed in the manuscript has been approved by all of us.
We understand that the Corresponding Author is the sole contact for the Editorial process. He is responsible for communicating with the other authors about progress, submissions of revisions and final approval of proofs.
Declaration of Competing Interest
The authors declare that they have no conflict of interest.
Acknowledgements
PR suggested this clinical case. He was involved in the bibliographic research, the drafting, proofreading and submission of the article.
JB was involved in the bibliographic research and proofreading of the article.
FH was involved in the bibliographic research and proofreading of the article.
NR provided a radiological opinion and reviewed the various images.
AN was involved in the proofreading of this article.
AT was involved in the proofreading of this article and provided a radiotherapist opinion.
SD was involved in the proofreading of this article and provided a radiotherapist opinion.
GM was involved in the bibliographic research, the drafting, proofreading and correction of the article. | Recovered | ReactionOutcome | CC BY-NC-ND | 33473350 | 18,991,130 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Abdominal pain upper'. | Clinical Characteristics, Urinary Leukotriene E4 Levels, and Aspirin Desensitization Results in Patients With NSAID-Induced Blended Reactions.
OBJECTIVE
Data on non-steroidal anti-inflammatory drug (NSAID) hypersensitivity in Southeast Asia are scarce. Increased urinary leukotriene E4 (uLTE4) levels have been suggested as a biomarker of NSAID-exacerbated respiratory disease (NERD). This study investigated clinical patterns of NSAID sensitivity in Thailand and the diagnostic roles of uLTE4 measurement in various phenotypes.
METHODS
The clinical phenotypes in 92 Thai adults with cross-reactive NSAID hypersensitivity were characterized based on the clinical history and drug provocation. The uLTE4 levels were measured at baseline, after aspirin provocation and after desensitization.
RESULTS
More than half of the patients (56.5%) presented with cutaneous symptoms (NSAID-exacerbated cutaneous disease), while one-third (33.7%) developed symptoms in at least 2 systems (NSAID-induced blended reactions; NIBR). Fifty-two patients underwent drug provocation and 59.6% of them yielded positive results. After drug provocation, a significant number of patients with confirmed NSAID cross-reactivity experienced clinical symptoms in more than one organ system. The uLTE4 levels at baseline were comparable between the NSAID-tolerant and NSAID-sensitive groups, but were substantially increased after aspirin provocation predominantly in NERD (983.4 pg/mg creatinine) and NIBR (501.0 pg/mg creatinine) compared to NSAID-tolerant subjects (122.1 pg/mg creatinine, P < 0.01 and 0.05, respectively). The uLTE4 levels were elevated after aspirin desensitization, although nasal polyposis and asthma were under control in 3 NERD and 3 NIBR subjects.
CONCLUSIONS
NIBR is not uncommon among NSAID-sensitive patients in Thailand. The diagnostic value of basal uLTE4 levels was limited, but increased uLTE4 levels upon aspirin provocation suggest NSAID cross-reactivity with respiratory components. This study indicates that aspirin desensitization, if necessary, might be effective in both NERD and NIBR.
BACKGROUND
ClinicalTrials.gov Identifier: NCT03849625.
INTRODUCTION
Hypersensitivity reactions to aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most common drug allergic reactions in clinical practice. They are generally categorized into 5 major phenotypes: NSAID-exacerbated respiratory disease (NERD), NSAID-exacerbated cutaneous (urticaria/angioedema) disease (NECD) in patients with underlying chronic urticaria, NSAID-induced urticaria/angioedema (NIUA) in patients without underlying chronic urticaria, single NSAID-induced urticaria/angioedema or anaphylaxis, and single NSAID-induced delayed hypersensitivity reactions.1 The first 3 phenotypes are non-immunologically mediated, and patients can develop cross-reactive hypersensitivity to chemically unrelated NSAIDs, while the latter 2 are selective NSAID sensitivities associated with drug-specific immunoglobulin E (IgE) and T-cell response, respectively.
Genetic and epigenetic variations play significant roles in the development of NERD.2 The proposed underlying mechanism is that the disturbance in arachidonic acid synthesis pathways leads to overproduction of cysteinyl leukotrienes (cysLT) and persistent airway inflammation.3 Mast cells are believed to be the major source of cysLT, but platelet-adherent leukocytes may be responsible for cysLT overproduction in NERD as well.4 The consumption of drugs inhibiting the cyclooxygenase-1 (COX-1) enzyme, such as aspirin and conventional NSAIDs, aggravates respiratory symptoms by enhancing cysLT production in NSAID-sensitive subjects, while the administration of specific COX-2 inhibitors, such as celecoxib, is generally safe.56 Besides aspirin/NSAID avoidance, aspirin desensitization has also been proven to be helpful for long term management in NERD subjects. Beneficial effects of aspirin desensitization in preventing nasal polyp recurrence and control symptoms of chronic rhinosinusitis and asthma have been well documented.7 Rapid aspirin desensitization has shown to be effective for the treatment of coronary artery disease in patients with a history of aspirin/NSAID-induced urticaria/angioedema, but it is not indicated for the treatment of chronic urticaria.8
Worldwide epidemiological data on clinical characteristics of NSAID hypersensitivity are limited. Most studies on NERD were performed in the United States and northern European countries.9101112 However, the predominant manifestation in Latin Americans and southern Europeans is the cutaneous phenotype (NIUA, NECD, and NSAID-induced isolated periorbital angioedema).1314 Studies in Asian populations have suggested that the prevalence of the NERD phenotype is not common in this region of the world. A study performed in China indicated that the prevalence of NSAID hypersensitivity in Chinese patients with chronic rhinosinusitis is very low (0.57%) compared to their European counterparts.15 It was also noted that NSAID-induced blended reactions (NIBR) are common in young Asian, atopic children in Singapore.16 Reports from Singapore and Thailand indicated that aspirin/NSAID-induced angioedema/urticaria is probably the prominent phenotype in Southeast Asia, with acetaminophen hypersensitivity being frequent.1718
In clinical practice, the current classification of cross-reactive NSAID hypersensitivity into 3 distinct phenotypes has some limitations. Clinical characteristics in NSAID-sensitive patients may not be well defined, and a combination of respiratory and cutaneous or other symptoms, such as gastrointestinal symptoms (mixed or blended reactions), is frequently observed.19 A previous report stated that aspirin nasal provocation is potentially useful for diagnosing patients with the blended reaction as well.20 However, the role of aspirin desensitization in other phenotypes of NSAID hypersensitivity, besides NERD, for long-term management of inflammatory airway diseases has not yet been established. Whether aspirin desensitization would be effective in controlling asthma and the recurrence of nasal polyposis after sinus surgery in NIBR is currently unknown.
At present, cross-reactive types of NSAID hypersensitivity can only be diagnosed by careful history taking and controlled-provocation testing, since there is no reliable in vitro method to confirm the diagnosis.21 There is evidence that basal urinary levels of leukotriene E4 (uLTE4), a stable product of the cysLT synthesis pathway, are elevated in NERD patients and could be a potential biomarker for differentiating between NSAID-sensitive and NSAID-tolerant asthmatics. However, these data are still controversial.222324 There have also been preliminary studies showing that uLTE4 levels might be increased in NECD.2526 Whether the measurement of basal uLTE4 levels could be a diagnostic marker for any phenotype of NSAID hypersensitivity is yet to be explored.
The purpose of this study was to analyze the clinical characteristics of patients diagnosed with NSAID-induced immediate reactions in Thailand and to explore whether the measurement of uLTE4 levels would be helpful in identifying NSAID-sensitive subjects or in differentiating among different phenotypes of cross-reactive NSAID hypersensitivities.
MATERIALS AND METHODS
Patient recruitment
Adult patients (18 years of age and older) with a suggestive history of NSAID-induced hypersensitivity reaction visiting the allergy clinic at King Chulalongkorn University Hospital between June 2014 and July 2018 were recruited into this study. Those with a history compatible with drug-induced non-immediate reactions (maculopapular rash, fixed drug eruption, acute generalized exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms, Stevens-Johnson syndrome/toxic epidermal necrolysis) or NSAID-related side effects were excluded. The status of NSAID-induced immediate hypersensitivity was diagnosed in patients with a well-documented drug allergy history or in patients with a suggestive history of NSAID sensitivity who yielded a positive drug provocation test as follows.
Clinical diagnosis of NSAID hypersensitivity
The diagnosis of cross-reactive NSAID hypersensitivity was clinically made in patients with a well-documented history of multiple episodes of respiratory, cutaneous, and/or gastrointestinal reactions within 2 hours after exposure to at least 2 different NSAID classes.1212728 Patient demographic data were collected, including the underlying diseases, atopic family history, and details on drug allergy history as well as the presenting symptoms and types of the culprit NSAIDs.
Aspirin provocation test
Oral aspirin provocation was performed in patients with a suggestive medical history or in those who had a history of an immediate reaction to a single NSAID to confirm the diagnosis of cross-reactive NSAID hypersensitivity according to the EAACI/GA2LEN guidelines, with some modifications.293031 Four increasing doses of aspirin (40.5, 81, 150, and 300 mg) were administered at 90-minute intervals until a positive reaction occurred. Clinical symptoms, fractional exhaled nitric oxide (FeNO), and the forced expiratory volume in 1 second (FEV1) were monitored to evaluate the reaction. A positive provocation test was defined if any of the following reactions developed: lower respiratory/bronchial reaction (a 15% decrease in FEV1 plus naso-ocular reaction or a 20% decrease in FEV1 alone), upper respiratory/naso-ocular reaction (nasal congestion and rhinorrhea; conjunctival injection), cutaneous reactions (urticaria/angioedema, periorbital edema), and/or other reactions (gastrointestinal symptoms such as nausea/vomiting, stomach cramps, and diarrhea). The test was considered negative if a patient tolerated the final dose (300 mg of aspirin) without any significant symptoms mentioned above.
Oral provocation test (OPT) with other NSAIDs, acetaminophen, or celecoxib
Patients with a history of an immediate reaction to only aspirin were challenged with escalating doses of ibuprofen to confirm the diagnosis of cross-reactive NSAID sensitivity. Patients with a history of an immediate reaction to a single NSAID were provoked with the suspected drug to verify the status of single NSAID hypersensitivity after a negative aspirin provocation test. Escalating doses of ibuprofen, diclofenac, and acetaminophen were administered, if applicable, as follows: ibuprofen (50, 100, and 200 mg), diclofenac (6.25, 12.5, and 25 mg), and acetaminophen (125, 250, and 500 mg). Celecoxib was also provoked in 3 doses (50, 100, and 200 mg) in patients with confirmed hypersensitivity to multiple NSAIDs who were willing to identify a safe alternative drug. The provocation test for each drug was performed on separate days at least 7 days apart. Each dose of drug provocation was provided at 90-minute intervals until the final dose was reached.
Classification of NSAID hypersensitivity according to drug provocation test results
Patients with cross-reactive NSAID phenotypes were classified according to the results of the drug provocation test as 1) NECD/NIUA if they developed cutaneous symptoms alone; 2) NERD if they developed respiratory symptoms alone; and 3) NIBR if they developed a combination of symptoms involving more than one organ system (respiratory, cutaneous, and/or gastrointestinal symptoms). Single NSAID hypersensitivity was diagnosed in patients with a positive provocation test to the suspected NSAID, but a negative aspirin provocation test. Patients who had negative provocations to both aspirin and the suspected culprit drug were labeled as NSAID-tolerant subjects. NECD/NIUA were purposely categorized together in our study to compare the differences and similarities between patients diagnosed with NSAID-induced cutaneous reactions and -respiratory reactions. Moreover, NECD and NIUA share similar background characteristics from a clinical point of view and some patients diagnosed with NIUA eventually evolve to NECD over time.32
Skin prick tests with common aeroallergens in Thailand (mixed dust mites, mixed cockroaches, mixed mold, cat dander, dog hair, and southern grass mix; ALK-Abello, Hørsholm, Denmark) were also examined in tested patients to identify atopic status. Wheal size ≥ 3 mm was considered a positive test.
Measurement of FeNO and the FEV1 in patients who underwent drug provocation test
FeNO was measured in all participants at baseline and after drug provocation by using a portable electrochemical analyzer (NObreath®; Bedfont Scientific Ltd, Maidstone, UK) according to the ATS/ERS recommendations.33 Measurements of FEV1 were also performed using a Vitalograph spirometer (Vitalograph®, Buckingham, UK). The best of 3 repeated attempts was recorded.
The uLTE4 measurement
The uLTE4 levels were measured by a leukotriene E4 ELISA kit (Cayman Chemical, Ann Arbor, MI, USA) at baseline and 90 minutes after the final dose of drug provocation, as well as at the follow-up visits after aspirin desensitization and reported after adjustment to urine creatinine levels.
Aspirin desensitization
Outpatient aspirin desensitization was performed in NSAID-sensitive patients who were referred from otolaryngologists to prevent the recurrence of nasal polyposis. The procedure was carried out according to the intranasal ketorolac and modified aspirin challenge 2-day protocol.34 Aspirin desensitization was completed after patients were able to tolerate a 325-mg dose of aspirin by the end of day 2 and experience no symptoms, changes in nasal flow rates, or decrease in FEV1 values. The prescribed maintenance dose of aspirin was 325 mg twice a day.
Statistical analysis
Patient characteristics are reported as means ± standard deviation for quantitative analysis, and median and interquartile range (IQR) are used to describe non-parametric data. The Mann-Whitney U test and Kruskal-Wallis test with Dunn's multiple comparisons were used to analyze the differences between 2 groups and more than 2 groups, respectively. Statistical analyses were performed using GraphPad Prism 8.3 software (GraphPad Software Inc., San Diego, CA, USA). P values < 0.05 were considered statistically significant.
Ethical considerations
Patients enrolled in this study were those who recruited in the study entitled “Characteristics of Patients Diagnosed With NSAID Sensitivity in Thailand” registered at ClinicalTrials.gov (NCT03849625). The study was approved by the Ethics and Research Committee of the Faculty of Medicine, Chulalongkorn University, Approval Number: COA No. 659/2012 and informed consent was obtained from all participants.
RESULTS
A total of 158 adult patients with a suspected history of NSAID hypersensitivity between 2015 and 2018 at King Chulalongkorn Memorial Hospital were initially recruited into this study as shown in Fig. 1. Thirty-five patients with a history compatible with a non-immediate hypersensitivity reaction and 4 subjects with clinical symptoms compatible with NSAID-related side effects were later excluded.
Fig. 1 Schematic diagram of patient selection for this study.
A total of 158 patients with a suspected history of NSAID hypersensitivity were initially recruited into this study. Cross-reactive NSAID hypersensitivity was clinically diagnosed in 67 patients with a well-documented drug allergy history and verified by a positive drug provocation test in 25 patients with a suggestive history of NSAID reactions.
NSAID, non-steroidal anti-inflammatory drug.
Cross-reactive NSAID hypersensitivity was clinically diagnosed in 67 patients with a convincing drug allergy history as defined in the methods section. The remaining 52 patients with a suggestive history of NSAID hypersensitivity underwent an OPT to confirm NSAID cross-reactivity status. Fifteen out of 25 patients with confirmed NSAID cross-reactivity were subsequently provoked with celecoxib to find a safe alternative NSAID. Single NSAID/acetaminophen hypersensitivity was verified in 6 patients who tolerated aspirin provocation but developed an allergic reaction upon re-challenge with acetaminophen or diclofenac.
Demographic data of adult patients with cross-reactive NSAID hypersensitivity
The clinical characteristics of adult patients with cross-reactive NSAID hypersensitivity are shown in Table 1 (n = 92). Most patients were females (77.2%) with an average age of 45.7 ± 13.4 years. The average age of onset was 32.2 ± 13.3 years and about half of them had atopic family history. The majority of them (56.5%) reported only cutaneous symptoms such as facial angioedema and/or acute urticarial rash, after NSAID exposure, while 9.8% of them developed only respiratory symptoms. Interestingly, about 33.7% of the patients experienced a combination of symptoms in multiple organ systems as shown in Fig. 2. The groups of NSAIDs frequently responsible for hypersensitivity reactions were propionic acid derivatives and acetic acid derivatives. Although inflammatory airway diseases (chronic sinusitis, nasal polyposis, and asthma) were significantly more common in patients who experienced only respiratory reactions after exposure to an NSAID compared to the other phenotypes, a significant portion of the patients reporting blended reactions had underlying airway diseases and chronic urticaria as well. Acetaminophen intolerance was also reported in about one-third (35.9%) of NSAID-sensitive subjects.
Table 1 Clinical characteristics among different phenotypes of patients with cross-reactive NSAID hypersensitivity (n = 92)
Phenotypes NECD/NIUA (n = 52) NERD (n = 9) NIBR (n = 31) Total (n = 92)
Gender (female/male) 37/15 6/3 28/3 71/21
Age (yr) 43.6 ± 12.3 47.3 ± 11.9 48.7 ± 15.3 45.7 ± 13.4
Age of onset (yr) 31.3 ± 13.8 34.6 ± 11.0 33.1 ± 13.3 32.2 ± 13.3
Underlying disease (%)
Chronic urticaria 13.5 11.1 29.0 18.5
Chronic sinusitis* 13.5 55.6 32.3 23.9
Nasal polyposis* 7.7 66.7 16.1 16.3
Asthma* 17.3 88.9 35.5 30.4
Atopic family history (%) 42.3 55.6 61.3 50.0
Drug exposure time to symptom onset (min) 58.8 ± 31.9 48.3 ± 34.3 47.6 ± 29.9 54.0 ± 31.6
Presenting symptoms (%)*
Facial/periorbital angioedema 71.2 0.0 74.2 65.2
Acute urticaria 73.1 0.0 61.3 62.0
Naso-ocular reaction 0.0 33.3 61.3 23.9
Acute asthma 0.0 88.9 67.7 31.5
Gastrointestinal symptoms 0.0 0.0 16.1 5.4
Implicated NSAIDs (%)†
Salicylic acids 23.1 55.6 35.5 30.4
Propionic acids 44.2 22.2 54.8 45.7
Acetic acids 23.1 22.2 48.4 31.5
Enolic acids 7.7 0.0 6.5 6.5
Anthranilic/fenamic acids 28.8 11.1 29.0 27.2
Acetaminophen intolerance (%)§ 28.8 22.2 51.6 35.9
Values are presented as number (%) or mean ± standard deviation. Each patient could present with multiple symptoms and from more than one implicated drug.
NSAID, non-steroidal anti-inflammatory drug; NECD, non-steroidal anti-inflammatory drug-exacerbated cutaneous (urticaria/angioedema) disease in patients with underlying chronic urticaria; NIUA, non-steroidal anti-inflammatory drug-induced urticaria/angioedema in patients without underlying chronic urticaria; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
*P < 0.05 among different phenotypes. †Examples of commonly implicated drugs in this study based on NSAID classification: 1) Salicylic acids: acetylsalicylic acid (aspirin), salicylic acid, diflunisal, salsalate; 2) Propionic acids: ibuprofen, naproxen, ketoprofen, fenoprofen, flurbiprofen; 3) Acetic acids: indomethacin, ketorolac, diclofenac, sulindac; 4) Enolic acids: piroxicam, meloxicam, tenoxicam; 5) Anthranilic/fenamic acids: mefenamic acid, flufenamic acid. §Acetaminophen intolerance: cannot tolerate acetaminophen higher than 500 mg.
Fig. 2 Clinical presentations in patients with cross-reactive NSAID hypersensitivity.
A proportional Venn diagram shows that about half of patients with cross-reactive NSAID hypersensitivity in Thailand reported only cutaneous symptoms after NSAID exposure, while one-third of them experienced NSAID-induced blended reactions.
NSAID, non-steroidal anti-inflammatory drug.
Clinical respiratory parameters and uLTE4 levels in different phenotypes of patients with cross-reactive NSAID hypersensitivity confirmed by positive OPT
NSAID hypersensitivity was confirmed in 59.6% (31/52) of the tested patients with a history of NSAID-induced immediate reactions. The majority of patients with cross-reactive NSAID hypersensitivity (17/25) according to OPT results were atopic individuals. The common phenotypes of patients with confirmed cross-reactive NSAID sensitivity were NECD/NIUA, NIBR, and NERD, respectively, as shown in Supplementary Table S1.
The average FeNO, %predicted FEV1, and uLTE4 levels were measured at baseline and after provocation with aspirin/NSAID in 25 NSAID cross-reactive and 21 NSAID-tolerant subjects as shown in Table 2. At baseline, patients with confirmed NSAID cross-reactivity (NSAID-sensitive group) had higher FeNO (P < 0.01) and slightly less %predicted FEV1 compared to the NSAID-tolerant subjects, while basal uLTE4 levels between NSAID-sensitive and NSAID-tolerant groups were comparable. After provocation, %predicted FEV1 was substantially reduced in NSAID-sensitive subjects, whereas uLTE4 levels were significantly elevated compared to the NSAID-tolerant group (P < 0.01). Celecoxib provocation was well tolerated in all NSAID-sensitive subjects. No statistical differences in the average FeNO, %predicted FEV1, or uLTE4 levels in 15 NSAID-sensitive patients (7 NECD/NIUA, 4 NIBR, 4 NERD) after celecoxib provocation were observed compared to those in NSAID-tolerant subjects.
Table 2 Respiratory parameters and uLTE4 levels in NSAID-sensitive subjects upon provocation with aspirin or celecoxib compared to NSAID-tolerant subjects
Characteristics Baseline After aspirin (OPT) P value*
NSAID tolerant (n = 21)
FeNO (ppb) 13.0 (8.5–19.5) 10.2 (7.0–16.8) 0.03
%predicted FEV1 100.8 (82.8–115.9) 99.0 (75.2–118.2) 0.90
uLTE4 (pg/mg creatinine) 116.3 (66.5–305.4) 122.1 (63.5–173.8) 0.17
NSAID sensitive (n = 25)
FeNO (ppb) 27.0 (17.8–40.9)† 18.0 (10.5–31.0) <0.01
%predicted FEV1 86.7 (63.3–104.9) 74.6 (52.4–89.8)† <0.01
uLTE4 (pg/mg creatinine) 118.3 (93.2–407.2) 204.9 (90.6–817.8)† <0.01
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; OPT, oral provocation test; ppb, parts per billion; FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in 1 second.
*P values before vs. after provocation test, Wilcoxon signed-rank test; †P < 0.01 compared to the NSAID-tolerant subjects.
According to the subgroup analysis, 10 NECD/NIUA, 9 NIBR, and 6 NERD were categorized as shown in Fig. 3. At baseline, %predicted FEV1 was not significantly different among different types of cross-reactive NSAID hypersensitivity, although those in patients with confirmed NIBR were lowest (64.9%, IQR 56.9–97.3). The significant differences in basal FeNO levels (P < 0.01) among the 3 different phenotypes were observed. The basal FeNO levels were significantly higher in NIBR (36.9%, IQR 27.0–95.4) than in NSAID-tolerant subjects (P < 0.01). After aspirin OPT, the reduction of %FEV1 was considerably higher in patients with confirmed NERD (22.0%, IQR 16.0-28.8), followed by NIBR (13.3%, IQR 7.6–28.0), compared to those in NSAID-tolerant groups (P < 0.01). Basal uLTE4 levels were not significantly different among the 3 phenotypes. Interestingly, uLTE4 levels after aspirin provocation were significantly higher in NERD and NIBR patients than in the NECD/NIUA and NSAID-tolerant groups (P < 0.05 and < 0.01, respectively).
Fig. 3 Respiratory parameters and uLTE4 levels in different phenotypes of NSAID-sensitive subjects compared to NSAID-tolerant subjects.
Baseline FeNO in NIBR and NERD were higher than those in the NSAID-tolerant group. After aspirin provocation, % predicted FEV1 in NERD and NIBR were significantly reduced from the baseline while uLTE4 levels were much higher than those in NSAID-tolerant subjects.
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; FEV1, forced expiratory volume in 1 second.
*P values < 0.05, †P values < 0.01.
Effects of aspirin desensitization on uLTE4 levels in patients diagnosed with NERD and NIBR
Aspirin desensitization was performed in selected patients (3 NERD and 3 NIBR) who had pre-existing inflammatory airway diseases and a history of recurrent nasal polyposis after surgery as shown in Table 3. The maintenance dose of aspirin was 650 mg/day during the first 6 months and reduced to 325 mg/day afterward. Levels of uLTE4 were measured at baseline after aspirin desensitization and serially followed up for 2–3 years as demonstrated in Fig. 4. Other than respiratory symptoms, acute urticarial rash and gastrointestinal symptoms (abdominal cramp/nausea/diarrhea) were also aggravated in NIBR subjects during aspirin desensitization as shown in Supplementary Fig. S1, but gradually relieved with supportive treatment. No sinus surgery was required for nasal polyp recurrence, and asthma symptoms were under control after aspirin desensitization in all 6 cases. Up to 3 years after aspirin desensitization, however, uLTE4 levels were significantly increased and remained elevated throughout the follow-up period, although urticarial rash and gastrointestinal symptoms were no longer observed while taking aspirin.
Table 3 Details of patients with cross-reactive NSAID hypersensitivity undergoing aspirin desensitization in this study
Patients (sex/year) Underlying diseases History of adverse drug reactions Indication for aspirin desensitization Follow-up duration (months) Asthma control before/after aspirin desensitization Recurrent nasal polyposis after aspirin desensitization Skin symptoms after aspirin desensitization Gastrointestinal symptoms after aspirin desensitization
1. NERD (M/46) Chronic sinusitis, nasal polyposis, asthma Acute asthma 20 min after taking aspirin 2 recurrent nasal polyps 74 Partly controlled with high dose ICS-LABA and add-on LTRA/well controlled with low dose ICS None NA NA
2. NERD (M/54) Chronic rhinitis, nasal polyposis, asthma Acute asthma, blocked nose 1 hr after taking aspirin 3 recurrent nasal polyps 24 Uncontrolled with high dose ICS-LABA and add-on LTRA/well controlled with medium dose ICS-LABA None NA NA
3. NERD (M/56) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked nose 1 hr after taking ibuprofen 6 recurrent nasal polyps 32 Partly controlled asthma with high dose ICS-LABA and add-on LTRA/well controlled with medium dose ICS-LABA None NA NA
4. NIBR (M/48) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked nose, conjunctival injection, urticarial rash 2 hr after taking aspirin 3 recurrent nasal polyps 72 Partly controlled with medium dose ICS-LABA/well controlled with low dose ICS-LABA None No rash after taking aspirin NA
5. NIBR (F/65) Chronic sinusitis, nasal polyposis, chronic urticaria, asthma (history of cardiac arrest from severe asthma) Urticarial rash, periorbital angioedema, blocked nose, conjunctival injection, rhinorrhea, bronchospasm/wheezing, hoarseness of voice 1 hr after taking aspirin, ibuprofen, mefenamic acid, acetaminophen 2 recurrent nasal polyps 48 Uncontrolled with high dose ICS-LABA and add-on LTRA/well controlled with low dose ICS-LABA None No rash after taking aspirin, chronic urticaria resolved NA
6. NIBR (F/38) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked/running nose, stomach cramp, diarrhea, periorbital angioedema, urticaria 30 min after taking ibuprofen, indomethacin, mefenamic acid 2 recurrent nasal polyps 21 Partly controlled with medium dose ICS-LABA/well controlled, with medium dose ICS-LABA None No rash after taking aspirin No gastrointestinal symptoms after taking aspirin
NSAID, non-steroidal anti-inflammatory drug; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; ICS, inhaled corticosteroid; LABA, long-acting beta-agonist; LTRA, leukotriene receptor antagonist; NA, not applicable (no symptoms prior to aspirin desensitization); NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
Fig. 4 uLTE4 levels in NSAID-sensitive subjects after aspirin desensitization.
Our study demonstrated that uLTE4 levels (pg/mg creatinine) in 3 NERD and 3 NIBR patients were increased and remained elevated up to 3 years after aspirin desensitization even though recurrent nasal polyposis was successfully prevented in all cases.
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
DISCUSSION
Most studies on NSAID hypersensitivity have focused on NERD, although worldwide epidemiological data suggest that NECD/NIUA might be more common. Recent data have demonstrated that some patients cannot be categorized into the current classification of NSAID hypersensitivity, for example those with NSAID-induced periorbital angioedema and NIBR.1419 These patients may also have underlying chronic airway diseases; however, the role of aspirin desensitization in the prevention of recurrent nasal polyposis and control of airway inflammation in NSAID-sensitive subjects other than the NERD phenotype has never been reported.
The leading presentations in NSAID-sensitive subjects in this study were periorbital angioedema, acute urticaria, bronchial symptoms, and naso-ocular reactions, respectively. Even those confirmed with NSAID exposure, a significant number of patients in our cohort also showed clinical responses in more than 1 organ system, indicating that the prevalence of NIBR was higher than previously thought. Although patients with IgE-mediated anaphylaxis might also present with multiple organ involvement, the fact that most of the reactions took about 1–2 hours to occur and the ability to react to multiple NSAIDs with dissimilar chemical structures made them more compatible with the non-immunologic effect of the drugs.
Facial angioedema around the periorbital area was the most common presenting symptom in Thai patients. Upon NSAID provocation, however, the predominant periorbital angioedema often accompanied by blocked nose, running nose, and itchy/red eyes. After a thorough examination, small urticarial rash on the trunk and extremities, and expiratory wheezing were occasionally detected, although frequently asymptomatic. It is noteworthy that periorbital angioedema may persist for hours or days while urticarial rash and respiratory symptoms are quickly resolved after treatment. As a result, NIBR could be underdiagnosed if history taking is not thoroughly reviewed, since symptoms with lesser severity in other organ systems may be unnoticed. In addition, the COX-1 inhibitor properties of the exposed NSAIDs could affect the phenotype of NSAID sensitivity reported by patients as some patients experienced both asthmatic attack and periorbital angioedema/generalized urticaria after taking aspirin but reported only periorbital edema after taking acetaminophen.
It is practically difficult to clearly distinguish between NSAID-induced periorbital angioedema and NSAID-induced naso-ocular reactions (upper airway manifestations of NERD), since patients occasionally experienced periorbital swelling, red/swollen eyes with tearing, and nasal congestion at the same time. In our opinion, the majority of NSAID hypersensitivity in the Thai population would be described as “NSAID-induced blended reaction with predominant periorbital angioedema” and probably related to “NSAID-induced isolated periorbital angioedema” phenotype as proposed by the Spanish group. It is interesting to note that the prevalence of atopic disease was high in this patient group. We speculate that the increased leukotriene production after NSAID consumption could lead to the worsening of pre-existing mucosal inflammation around the nose and eyes in patients who already suffered from the late-phase reaction of persistent allergic rhinitis.
Our study did not find any difference in terms of basal uLTE4 levels between NSAID-sensitive and NSAID-tolerant subjects. However, uLTE4 levels were higher in NSAID-sensitive patients, particularly in NERD and NIBR subjects, after the NSAID challenge compared to those in the NSAID-tolerant group. Though basal uLTE4 levels may not be a suitable marker to screen NSAID sensitivity status, elevated uLTE4 levels after aspirin OPT could be the supporting evidence for the diagnosis of cross-reactive NSAID hypersensitivity in cases where the clinical response is equivocal. Our study demonstrated that the degree of defective leukotriene homeostasis after exposure to drugs affecting the cyclo-oxygenase pathway might be related to the severity of respiratory involvement upon NSAID exposure.35 The fact that uLTE4 levels were barely changed after celecoxib provocation in patients with NSAID cross-reactivity confirms that celecoxib is a safe alternative NSAID in these patient groups.
According to our study, the patterns of NSAID hypersensitivity in southeast Asians are similar to those in southern Europeans and Latin Americans, and somewhat different from those reported in patients of northern European descent. Previous data suggested that aspirin nasal provocation could potentially diagnose some NSAID-sensitive patients presenting with predominant cutaneous reactions.3637 Retrospectively, some of these patients might be re-classified as the NIBR phenotype, since a decreased nasal volume was also observed. In other words, patients diagnosed with an NSAID-induced cutaneous reaction who positively reacted to NSAID nasal provocation, especially those with a periorbital reaction, might be NIBR subjects with subclinical airway involvement.
The novelties of this study were the findings that NIBR accounted for about one-third of adult patients with cross-reactive NSAID hypersensitivity and that aspirin desensitization could successfully prevent the recurrence of nasal polyposis and alleviate respiratory symptoms not only in NERD, but also in NIBR, even though urine LTE4 levels remained elevated. However, since the reactions in some NIBR patients could lead to serious adverse events, aspirin desensitization in NIBR subjects should be performed only when it is strongly indicated in selected patients with no previous severe reactions to NSAIDs. In NIBR subjects who experienced previous severe reactions in multiple organ systems, the procedure of aspirin desensitization, if necessary, should be carefully monitored and the administration of biological agents such as dupilumab, if available, should be considered a safer therapeutic option in these cases.
Interestingly, uLTE4 levels were increased after aspirin desensitization and remained elevated throughout the follow-up period. It should be emphasized that urticarial rash and stomach-ache in NIBR patients also disappeared while patients were taking daily aspirin. These data suggest that the pathogenesis of nasal polyposis cannot be explained by cysLT overproduction alone and that aspirin desensitization could be useful to alleviate both respiratory and non-respiratory symptoms in NIBR subjects.
Interestingly, a recent study also found that the clinical benefit of high-dose aspirin desensitization in NERD was independent of a reduction of mast cell activation and cysLT production. They reported paradoxically increased uLTE4 levels 8 weeks after aspirin desensitization compared to the baseline levels and concluded that high-dose aspirin therapy did not restore the impaired eicosanoid pathway.38 According to their study findings and ours, the therapeutic effect of aspirin desensitization was not directly correlated with a change of arachidonic acid metabolism.
There are some limitations to this study. Aspirin desensitization was performed in only 6 patients in our cohort; therefore, the comparative success rates and potential adverse reactions of aspirin desensitization between NERD and NIBR patients could not be analyzed. Further studies with a larger sample size are needed to compare the long-term prognosis between NERD and NIBR, to understand the mechanism of aspirin desensitization for the improvement of respiratory and extra-respiratory symptoms and to evaluate its risk-benefit ratio of aspirin desensitization in NIBR subjects.
In conclusion, NIBR is not uncommon among patients diagnosed with NSAID hypersensitivity in Thailand. Increased uLTE4 levels upon aspirin provocation suggested a diagnosis of NSAID cross-reactivity, while baseline uLTE4 levels were not distinguishable between NSAID-tolerant and NSAID-sensitive subjects. Our study indicates that aspirin desensitization is effective not only in NERD but also in NIBR. The persistently high levels of uLTE4 in spite of clinical improvement in NSAID-sensitive patients after successful aspirin desensitization suggest that elevated leukotrienes alone cannot explain the pathogenesis of NSAID hypersensitivity reactions.
ACKNOWLEDGMENTS
This study was supported by the Ratchadaphiseksomphot fund, Faculty of Medicine, Chulalongkorn University, grant No. RA55/19 and the Skin and Allergy Research Unit, Chulalongkorn University, Bangkok, Thailand. Study data were collected and managed using Research Electronic Data Capture (REDCap) hosted at HIV Netherlands Australia Thailand Research Collaboration. The authors thank Thitima Kantachatvanich, MD for providing patient information.
Disclosure: There are no financial or other issues that might lead to conflict of interest.
SUPPLEMENTARY MATERIALS
Supplementary Table S1
Clinical characteristics of patients with confirmed NSAID-induced immediate reactions
Supplementary Fig. S1
Representative photos of skin rash demonstrated during aspirin desensitization in NIBR patients. | IBUPROFEN, INDOMETHACIN, MEFENAMIC ACID | DrugsGivenReaction | CC BY-NC | 33474858 | 18,863,279 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Aspirin-exacerbated respiratory disease'. | Clinical Characteristics, Urinary Leukotriene E4 Levels, and Aspirin Desensitization Results in Patients With NSAID-Induced Blended Reactions.
OBJECTIVE
Data on non-steroidal anti-inflammatory drug (NSAID) hypersensitivity in Southeast Asia are scarce. Increased urinary leukotriene E4 (uLTE4) levels have been suggested as a biomarker of NSAID-exacerbated respiratory disease (NERD). This study investigated clinical patterns of NSAID sensitivity in Thailand and the diagnostic roles of uLTE4 measurement in various phenotypes.
METHODS
The clinical phenotypes in 92 Thai adults with cross-reactive NSAID hypersensitivity were characterized based on the clinical history and drug provocation. The uLTE4 levels were measured at baseline, after aspirin provocation and after desensitization.
RESULTS
More than half of the patients (56.5%) presented with cutaneous symptoms (NSAID-exacerbated cutaneous disease), while one-third (33.7%) developed symptoms in at least 2 systems (NSAID-induced blended reactions; NIBR). Fifty-two patients underwent drug provocation and 59.6% of them yielded positive results. After drug provocation, a significant number of patients with confirmed NSAID cross-reactivity experienced clinical symptoms in more than one organ system. The uLTE4 levels at baseline were comparable between the NSAID-tolerant and NSAID-sensitive groups, but were substantially increased after aspirin provocation predominantly in NERD (983.4 pg/mg creatinine) and NIBR (501.0 pg/mg creatinine) compared to NSAID-tolerant subjects (122.1 pg/mg creatinine, P < 0.01 and 0.05, respectively). The uLTE4 levels were elevated after aspirin desensitization, although nasal polyposis and asthma were under control in 3 NERD and 3 NIBR subjects.
CONCLUSIONS
NIBR is not uncommon among NSAID-sensitive patients in Thailand. The diagnostic value of basal uLTE4 levels was limited, but increased uLTE4 levels upon aspirin provocation suggest NSAID cross-reactivity with respiratory components. This study indicates that aspirin desensitization, if necessary, might be effective in both NERD and NIBR.
BACKGROUND
ClinicalTrials.gov Identifier: NCT03849625.
INTRODUCTION
Hypersensitivity reactions to aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most common drug allergic reactions in clinical practice. They are generally categorized into 5 major phenotypes: NSAID-exacerbated respiratory disease (NERD), NSAID-exacerbated cutaneous (urticaria/angioedema) disease (NECD) in patients with underlying chronic urticaria, NSAID-induced urticaria/angioedema (NIUA) in patients without underlying chronic urticaria, single NSAID-induced urticaria/angioedema or anaphylaxis, and single NSAID-induced delayed hypersensitivity reactions.1 The first 3 phenotypes are non-immunologically mediated, and patients can develop cross-reactive hypersensitivity to chemically unrelated NSAIDs, while the latter 2 are selective NSAID sensitivities associated with drug-specific immunoglobulin E (IgE) and T-cell response, respectively.
Genetic and epigenetic variations play significant roles in the development of NERD.2 The proposed underlying mechanism is that the disturbance in arachidonic acid synthesis pathways leads to overproduction of cysteinyl leukotrienes (cysLT) and persistent airway inflammation.3 Mast cells are believed to be the major source of cysLT, but platelet-adherent leukocytes may be responsible for cysLT overproduction in NERD as well.4 The consumption of drugs inhibiting the cyclooxygenase-1 (COX-1) enzyme, such as aspirin and conventional NSAIDs, aggravates respiratory symptoms by enhancing cysLT production in NSAID-sensitive subjects, while the administration of specific COX-2 inhibitors, such as celecoxib, is generally safe.56 Besides aspirin/NSAID avoidance, aspirin desensitization has also been proven to be helpful for long term management in NERD subjects. Beneficial effects of aspirin desensitization in preventing nasal polyp recurrence and control symptoms of chronic rhinosinusitis and asthma have been well documented.7 Rapid aspirin desensitization has shown to be effective for the treatment of coronary artery disease in patients with a history of aspirin/NSAID-induced urticaria/angioedema, but it is not indicated for the treatment of chronic urticaria.8
Worldwide epidemiological data on clinical characteristics of NSAID hypersensitivity are limited. Most studies on NERD were performed in the United States and northern European countries.9101112 However, the predominant manifestation in Latin Americans and southern Europeans is the cutaneous phenotype (NIUA, NECD, and NSAID-induced isolated periorbital angioedema).1314 Studies in Asian populations have suggested that the prevalence of the NERD phenotype is not common in this region of the world. A study performed in China indicated that the prevalence of NSAID hypersensitivity in Chinese patients with chronic rhinosinusitis is very low (0.57%) compared to their European counterparts.15 It was also noted that NSAID-induced blended reactions (NIBR) are common in young Asian, atopic children in Singapore.16 Reports from Singapore and Thailand indicated that aspirin/NSAID-induced angioedema/urticaria is probably the prominent phenotype in Southeast Asia, with acetaminophen hypersensitivity being frequent.1718
In clinical practice, the current classification of cross-reactive NSAID hypersensitivity into 3 distinct phenotypes has some limitations. Clinical characteristics in NSAID-sensitive patients may not be well defined, and a combination of respiratory and cutaneous or other symptoms, such as gastrointestinal symptoms (mixed or blended reactions), is frequently observed.19 A previous report stated that aspirin nasal provocation is potentially useful for diagnosing patients with the blended reaction as well.20 However, the role of aspirin desensitization in other phenotypes of NSAID hypersensitivity, besides NERD, for long-term management of inflammatory airway diseases has not yet been established. Whether aspirin desensitization would be effective in controlling asthma and the recurrence of nasal polyposis after sinus surgery in NIBR is currently unknown.
At present, cross-reactive types of NSAID hypersensitivity can only be diagnosed by careful history taking and controlled-provocation testing, since there is no reliable in vitro method to confirm the diagnosis.21 There is evidence that basal urinary levels of leukotriene E4 (uLTE4), a stable product of the cysLT synthesis pathway, are elevated in NERD patients and could be a potential biomarker for differentiating between NSAID-sensitive and NSAID-tolerant asthmatics. However, these data are still controversial.222324 There have also been preliminary studies showing that uLTE4 levels might be increased in NECD.2526 Whether the measurement of basal uLTE4 levels could be a diagnostic marker for any phenotype of NSAID hypersensitivity is yet to be explored.
The purpose of this study was to analyze the clinical characteristics of patients diagnosed with NSAID-induced immediate reactions in Thailand and to explore whether the measurement of uLTE4 levels would be helpful in identifying NSAID-sensitive subjects or in differentiating among different phenotypes of cross-reactive NSAID hypersensitivities.
MATERIALS AND METHODS
Patient recruitment
Adult patients (18 years of age and older) with a suggestive history of NSAID-induced hypersensitivity reaction visiting the allergy clinic at King Chulalongkorn University Hospital between June 2014 and July 2018 were recruited into this study. Those with a history compatible with drug-induced non-immediate reactions (maculopapular rash, fixed drug eruption, acute generalized exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms, Stevens-Johnson syndrome/toxic epidermal necrolysis) or NSAID-related side effects were excluded. The status of NSAID-induced immediate hypersensitivity was diagnosed in patients with a well-documented drug allergy history or in patients with a suggestive history of NSAID sensitivity who yielded a positive drug provocation test as follows.
Clinical diagnosis of NSAID hypersensitivity
The diagnosis of cross-reactive NSAID hypersensitivity was clinically made in patients with a well-documented history of multiple episodes of respiratory, cutaneous, and/or gastrointestinal reactions within 2 hours after exposure to at least 2 different NSAID classes.1212728 Patient demographic data were collected, including the underlying diseases, atopic family history, and details on drug allergy history as well as the presenting symptoms and types of the culprit NSAIDs.
Aspirin provocation test
Oral aspirin provocation was performed in patients with a suggestive medical history or in those who had a history of an immediate reaction to a single NSAID to confirm the diagnosis of cross-reactive NSAID hypersensitivity according to the EAACI/GA2LEN guidelines, with some modifications.293031 Four increasing doses of aspirin (40.5, 81, 150, and 300 mg) were administered at 90-minute intervals until a positive reaction occurred. Clinical symptoms, fractional exhaled nitric oxide (FeNO), and the forced expiratory volume in 1 second (FEV1) were monitored to evaluate the reaction. A positive provocation test was defined if any of the following reactions developed: lower respiratory/bronchial reaction (a 15% decrease in FEV1 plus naso-ocular reaction or a 20% decrease in FEV1 alone), upper respiratory/naso-ocular reaction (nasal congestion and rhinorrhea; conjunctival injection), cutaneous reactions (urticaria/angioedema, periorbital edema), and/or other reactions (gastrointestinal symptoms such as nausea/vomiting, stomach cramps, and diarrhea). The test was considered negative if a patient tolerated the final dose (300 mg of aspirin) without any significant symptoms mentioned above.
Oral provocation test (OPT) with other NSAIDs, acetaminophen, or celecoxib
Patients with a history of an immediate reaction to only aspirin were challenged with escalating doses of ibuprofen to confirm the diagnosis of cross-reactive NSAID sensitivity. Patients with a history of an immediate reaction to a single NSAID were provoked with the suspected drug to verify the status of single NSAID hypersensitivity after a negative aspirin provocation test. Escalating doses of ibuprofen, diclofenac, and acetaminophen were administered, if applicable, as follows: ibuprofen (50, 100, and 200 mg), diclofenac (6.25, 12.5, and 25 mg), and acetaminophen (125, 250, and 500 mg). Celecoxib was also provoked in 3 doses (50, 100, and 200 mg) in patients with confirmed hypersensitivity to multiple NSAIDs who were willing to identify a safe alternative drug. The provocation test for each drug was performed on separate days at least 7 days apart. Each dose of drug provocation was provided at 90-minute intervals until the final dose was reached.
Classification of NSAID hypersensitivity according to drug provocation test results
Patients with cross-reactive NSAID phenotypes were classified according to the results of the drug provocation test as 1) NECD/NIUA if they developed cutaneous symptoms alone; 2) NERD if they developed respiratory symptoms alone; and 3) NIBR if they developed a combination of symptoms involving more than one organ system (respiratory, cutaneous, and/or gastrointestinal symptoms). Single NSAID hypersensitivity was diagnosed in patients with a positive provocation test to the suspected NSAID, but a negative aspirin provocation test. Patients who had negative provocations to both aspirin and the suspected culprit drug were labeled as NSAID-tolerant subjects. NECD/NIUA were purposely categorized together in our study to compare the differences and similarities between patients diagnosed with NSAID-induced cutaneous reactions and -respiratory reactions. Moreover, NECD and NIUA share similar background characteristics from a clinical point of view and some patients diagnosed with NIUA eventually evolve to NECD over time.32
Skin prick tests with common aeroallergens in Thailand (mixed dust mites, mixed cockroaches, mixed mold, cat dander, dog hair, and southern grass mix; ALK-Abello, Hørsholm, Denmark) were also examined in tested patients to identify atopic status. Wheal size ≥ 3 mm was considered a positive test.
Measurement of FeNO and the FEV1 in patients who underwent drug provocation test
FeNO was measured in all participants at baseline and after drug provocation by using a portable electrochemical analyzer (NObreath®; Bedfont Scientific Ltd, Maidstone, UK) according to the ATS/ERS recommendations.33 Measurements of FEV1 were also performed using a Vitalograph spirometer (Vitalograph®, Buckingham, UK). The best of 3 repeated attempts was recorded.
The uLTE4 measurement
The uLTE4 levels were measured by a leukotriene E4 ELISA kit (Cayman Chemical, Ann Arbor, MI, USA) at baseline and 90 minutes after the final dose of drug provocation, as well as at the follow-up visits after aspirin desensitization and reported after adjustment to urine creatinine levels.
Aspirin desensitization
Outpatient aspirin desensitization was performed in NSAID-sensitive patients who were referred from otolaryngologists to prevent the recurrence of nasal polyposis. The procedure was carried out according to the intranasal ketorolac and modified aspirin challenge 2-day protocol.34 Aspirin desensitization was completed after patients were able to tolerate a 325-mg dose of aspirin by the end of day 2 and experience no symptoms, changes in nasal flow rates, or decrease in FEV1 values. The prescribed maintenance dose of aspirin was 325 mg twice a day.
Statistical analysis
Patient characteristics are reported as means ± standard deviation for quantitative analysis, and median and interquartile range (IQR) are used to describe non-parametric data. The Mann-Whitney U test and Kruskal-Wallis test with Dunn's multiple comparisons were used to analyze the differences between 2 groups and more than 2 groups, respectively. Statistical analyses were performed using GraphPad Prism 8.3 software (GraphPad Software Inc., San Diego, CA, USA). P values < 0.05 were considered statistically significant.
Ethical considerations
Patients enrolled in this study were those who recruited in the study entitled “Characteristics of Patients Diagnosed With NSAID Sensitivity in Thailand” registered at ClinicalTrials.gov (NCT03849625). The study was approved by the Ethics and Research Committee of the Faculty of Medicine, Chulalongkorn University, Approval Number: COA No. 659/2012 and informed consent was obtained from all participants.
RESULTS
A total of 158 adult patients with a suspected history of NSAID hypersensitivity between 2015 and 2018 at King Chulalongkorn Memorial Hospital were initially recruited into this study as shown in Fig. 1. Thirty-five patients with a history compatible with a non-immediate hypersensitivity reaction and 4 subjects with clinical symptoms compatible with NSAID-related side effects were later excluded.
Fig. 1 Schematic diagram of patient selection for this study.
A total of 158 patients with a suspected history of NSAID hypersensitivity were initially recruited into this study. Cross-reactive NSAID hypersensitivity was clinically diagnosed in 67 patients with a well-documented drug allergy history and verified by a positive drug provocation test in 25 patients with a suggestive history of NSAID reactions.
NSAID, non-steroidal anti-inflammatory drug.
Cross-reactive NSAID hypersensitivity was clinically diagnosed in 67 patients with a convincing drug allergy history as defined in the methods section. The remaining 52 patients with a suggestive history of NSAID hypersensitivity underwent an OPT to confirm NSAID cross-reactivity status. Fifteen out of 25 patients with confirmed NSAID cross-reactivity were subsequently provoked with celecoxib to find a safe alternative NSAID. Single NSAID/acetaminophen hypersensitivity was verified in 6 patients who tolerated aspirin provocation but developed an allergic reaction upon re-challenge with acetaminophen or diclofenac.
Demographic data of adult patients with cross-reactive NSAID hypersensitivity
The clinical characteristics of adult patients with cross-reactive NSAID hypersensitivity are shown in Table 1 (n = 92). Most patients were females (77.2%) with an average age of 45.7 ± 13.4 years. The average age of onset was 32.2 ± 13.3 years and about half of them had atopic family history. The majority of them (56.5%) reported only cutaneous symptoms such as facial angioedema and/or acute urticarial rash, after NSAID exposure, while 9.8% of them developed only respiratory symptoms. Interestingly, about 33.7% of the patients experienced a combination of symptoms in multiple organ systems as shown in Fig. 2. The groups of NSAIDs frequently responsible for hypersensitivity reactions were propionic acid derivatives and acetic acid derivatives. Although inflammatory airway diseases (chronic sinusitis, nasal polyposis, and asthma) were significantly more common in patients who experienced only respiratory reactions after exposure to an NSAID compared to the other phenotypes, a significant portion of the patients reporting blended reactions had underlying airway diseases and chronic urticaria as well. Acetaminophen intolerance was also reported in about one-third (35.9%) of NSAID-sensitive subjects.
Table 1 Clinical characteristics among different phenotypes of patients with cross-reactive NSAID hypersensitivity (n = 92)
Phenotypes NECD/NIUA (n = 52) NERD (n = 9) NIBR (n = 31) Total (n = 92)
Gender (female/male) 37/15 6/3 28/3 71/21
Age (yr) 43.6 ± 12.3 47.3 ± 11.9 48.7 ± 15.3 45.7 ± 13.4
Age of onset (yr) 31.3 ± 13.8 34.6 ± 11.0 33.1 ± 13.3 32.2 ± 13.3
Underlying disease (%)
Chronic urticaria 13.5 11.1 29.0 18.5
Chronic sinusitis* 13.5 55.6 32.3 23.9
Nasal polyposis* 7.7 66.7 16.1 16.3
Asthma* 17.3 88.9 35.5 30.4
Atopic family history (%) 42.3 55.6 61.3 50.0
Drug exposure time to symptom onset (min) 58.8 ± 31.9 48.3 ± 34.3 47.6 ± 29.9 54.0 ± 31.6
Presenting symptoms (%)*
Facial/periorbital angioedema 71.2 0.0 74.2 65.2
Acute urticaria 73.1 0.0 61.3 62.0
Naso-ocular reaction 0.0 33.3 61.3 23.9
Acute asthma 0.0 88.9 67.7 31.5
Gastrointestinal symptoms 0.0 0.0 16.1 5.4
Implicated NSAIDs (%)†
Salicylic acids 23.1 55.6 35.5 30.4
Propionic acids 44.2 22.2 54.8 45.7
Acetic acids 23.1 22.2 48.4 31.5
Enolic acids 7.7 0.0 6.5 6.5
Anthranilic/fenamic acids 28.8 11.1 29.0 27.2
Acetaminophen intolerance (%)§ 28.8 22.2 51.6 35.9
Values are presented as number (%) or mean ± standard deviation. Each patient could present with multiple symptoms and from more than one implicated drug.
NSAID, non-steroidal anti-inflammatory drug; NECD, non-steroidal anti-inflammatory drug-exacerbated cutaneous (urticaria/angioedema) disease in patients with underlying chronic urticaria; NIUA, non-steroidal anti-inflammatory drug-induced urticaria/angioedema in patients without underlying chronic urticaria; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
*P < 0.05 among different phenotypes. †Examples of commonly implicated drugs in this study based on NSAID classification: 1) Salicylic acids: acetylsalicylic acid (aspirin), salicylic acid, diflunisal, salsalate; 2) Propionic acids: ibuprofen, naproxen, ketoprofen, fenoprofen, flurbiprofen; 3) Acetic acids: indomethacin, ketorolac, diclofenac, sulindac; 4) Enolic acids: piroxicam, meloxicam, tenoxicam; 5) Anthranilic/fenamic acids: mefenamic acid, flufenamic acid. §Acetaminophen intolerance: cannot tolerate acetaminophen higher than 500 mg.
Fig. 2 Clinical presentations in patients with cross-reactive NSAID hypersensitivity.
A proportional Venn diagram shows that about half of patients with cross-reactive NSAID hypersensitivity in Thailand reported only cutaneous symptoms after NSAID exposure, while one-third of them experienced NSAID-induced blended reactions.
NSAID, non-steroidal anti-inflammatory drug.
Clinical respiratory parameters and uLTE4 levels in different phenotypes of patients with cross-reactive NSAID hypersensitivity confirmed by positive OPT
NSAID hypersensitivity was confirmed in 59.6% (31/52) of the tested patients with a history of NSAID-induced immediate reactions. The majority of patients with cross-reactive NSAID hypersensitivity (17/25) according to OPT results were atopic individuals. The common phenotypes of patients with confirmed cross-reactive NSAID sensitivity were NECD/NIUA, NIBR, and NERD, respectively, as shown in Supplementary Table S1.
The average FeNO, %predicted FEV1, and uLTE4 levels were measured at baseline and after provocation with aspirin/NSAID in 25 NSAID cross-reactive and 21 NSAID-tolerant subjects as shown in Table 2. At baseline, patients with confirmed NSAID cross-reactivity (NSAID-sensitive group) had higher FeNO (P < 0.01) and slightly less %predicted FEV1 compared to the NSAID-tolerant subjects, while basal uLTE4 levels between NSAID-sensitive and NSAID-tolerant groups were comparable. After provocation, %predicted FEV1 was substantially reduced in NSAID-sensitive subjects, whereas uLTE4 levels were significantly elevated compared to the NSAID-tolerant group (P < 0.01). Celecoxib provocation was well tolerated in all NSAID-sensitive subjects. No statistical differences in the average FeNO, %predicted FEV1, or uLTE4 levels in 15 NSAID-sensitive patients (7 NECD/NIUA, 4 NIBR, 4 NERD) after celecoxib provocation were observed compared to those in NSAID-tolerant subjects.
Table 2 Respiratory parameters and uLTE4 levels in NSAID-sensitive subjects upon provocation with aspirin or celecoxib compared to NSAID-tolerant subjects
Characteristics Baseline After aspirin (OPT) P value*
NSAID tolerant (n = 21)
FeNO (ppb) 13.0 (8.5–19.5) 10.2 (7.0–16.8) 0.03
%predicted FEV1 100.8 (82.8–115.9) 99.0 (75.2–118.2) 0.90
uLTE4 (pg/mg creatinine) 116.3 (66.5–305.4) 122.1 (63.5–173.8) 0.17
NSAID sensitive (n = 25)
FeNO (ppb) 27.0 (17.8–40.9)† 18.0 (10.5–31.0) <0.01
%predicted FEV1 86.7 (63.3–104.9) 74.6 (52.4–89.8)† <0.01
uLTE4 (pg/mg creatinine) 118.3 (93.2–407.2) 204.9 (90.6–817.8)† <0.01
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; OPT, oral provocation test; ppb, parts per billion; FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in 1 second.
*P values before vs. after provocation test, Wilcoxon signed-rank test; †P < 0.01 compared to the NSAID-tolerant subjects.
According to the subgroup analysis, 10 NECD/NIUA, 9 NIBR, and 6 NERD were categorized as shown in Fig. 3. At baseline, %predicted FEV1 was not significantly different among different types of cross-reactive NSAID hypersensitivity, although those in patients with confirmed NIBR were lowest (64.9%, IQR 56.9–97.3). The significant differences in basal FeNO levels (P < 0.01) among the 3 different phenotypes were observed. The basal FeNO levels were significantly higher in NIBR (36.9%, IQR 27.0–95.4) than in NSAID-tolerant subjects (P < 0.01). After aspirin OPT, the reduction of %FEV1 was considerably higher in patients with confirmed NERD (22.0%, IQR 16.0-28.8), followed by NIBR (13.3%, IQR 7.6–28.0), compared to those in NSAID-tolerant groups (P < 0.01). Basal uLTE4 levels were not significantly different among the 3 phenotypes. Interestingly, uLTE4 levels after aspirin provocation were significantly higher in NERD and NIBR patients than in the NECD/NIUA and NSAID-tolerant groups (P < 0.05 and < 0.01, respectively).
Fig. 3 Respiratory parameters and uLTE4 levels in different phenotypes of NSAID-sensitive subjects compared to NSAID-tolerant subjects.
Baseline FeNO in NIBR and NERD were higher than those in the NSAID-tolerant group. After aspirin provocation, % predicted FEV1 in NERD and NIBR were significantly reduced from the baseline while uLTE4 levels were much higher than those in NSAID-tolerant subjects.
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; FEV1, forced expiratory volume in 1 second.
*P values < 0.05, †P values < 0.01.
Effects of aspirin desensitization on uLTE4 levels in patients diagnosed with NERD and NIBR
Aspirin desensitization was performed in selected patients (3 NERD and 3 NIBR) who had pre-existing inflammatory airway diseases and a history of recurrent nasal polyposis after surgery as shown in Table 3. The maintenance dose of aspirin was 650 mg/day during the first 6 months and reduced to 325 mg/day afterward. Levels of uLTE4 were measured at baseline after aspirin desensitization and serially followed up for 2–3 years as demonstrated in Fig. 4. Other than respiratory symptoms, acute urticarial rash and gastrointestinal symptoms (abdominal cramp/nausea/diarrhea) were also aggravated in NIBR subjects during aspirin desensitization as shown in Supplementary Fig. S1, but gradually relieved with supportive treatment. No sinus surgery was required for nasal polyp recurrence, and asthma symptoms were under control after aspirin desensitization in all 6 cases. Up to 3 years after aspirin desensitization, however, uLTE4 levels were significantly increased and remained elevated throughout the follow-up period, although urticarial rash and gastrointestinal symptoms were no longer observed while taking aspirin.
Table 3 Details of patients with cross-reactive NSAID hypersensitivity undergoing aspirin desensitization in this study
Patients (sex/year) Underlying diseases History of adverse drug reactions Indication for aspirin desensitization Follow-up duration (months) Asthma control before/after aspirin desensitization Recurrent nasal polyposis after aspirin desensitization Skin symptoms after aspirin desensitization Gastrointestinal symptoms after aspirin desensitization
1. NERD (M/46) Chronic sinusitis, nasal polyposis, asthma Acute asthma 20 min after taking aspirin 2 recurrent nasal polyps 74 Partly controlled with high dose ICS-LABA and add-on LTRA/well controlled with low dose ICS None NA NA
2. NERD (M/54) Chronic rhinitis, nasal polyposis, asthma Acute asthma, blocked nose 1 hr after taking aspirin 3 recurrent nasal polyps 24 Uncontrolled with high dose ICS-LABA and add-on LTRA/well controlled with medium dose ICS-LABA None NA NA
3. NERD (M/56) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked nose 1 hr after taking ibuprofen 6 recurrent nasal polyps 32 Partly controlled asthma with high dose ICS-LABA and add-on LTRA/well controlled with medium dose ICS-LABA None NA NA
4. NIBR (M/48) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked nose, conjunctival injection, urticarial rash 2 hr after taking aspirin 3 recurrent nasal polyps 72 Partly controlled with medium dose ICS-LABA/well controlled with low dose ICS-LABA None No rash after taking aspirin NA
5. NIBR (F/65) Chronic sinusitis, nasal polyposis, chronic urticaria, asthma (history of cardiac arrest from severe asthma) Urticarial rash, periorbital angioedema, blocked nose, conjunctival injection, rhinorrhea, bronchospasm/wheezing, hoarseness of voice 1 hr after taking aspirin, ibuprofen, mefenamic acid, acetaminophen 2 recurrent nasal polyps 48 Uncontrolled with high dose ICS-LABA and add-on LTRA/well controlled with low dose ICS-LABA None No rash after taking aspirin, chronic urticaria resolved NA
6. NIBR (F/38) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked/running nose, stomach cramp, diarrhea, periorbital angioedema, urticaria 30 min after taking ibuprofen, indomethacin, mefenamic acid 2 recurrent nasal polyps 21 Partly controlled with medium dose ICS-LABA/well controlled, with medium dose ICS-LABA None No rash after taking aspirin No gastrointestinal symptoms after taking aspirin
NSAID, non-steroidal anti-inflammatory drug; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; ICS, inhaled corticosteroid; LABA, long-acting beta-agonist; LTRA, leukotriene receptor antagonist; NA, not applicable (no symptoms prior to aspirin desensitization); NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
Fig. 4 uLTE4 levels in NSAID-sensitive subjects after aspirin desensitization.
Our study demonstrated that uLTE4 levels (pg/mg creatinine) in 3 NERD and 3 NIBR patients were increased and remained elevated up to 3 years after aspirin desensitization even though recurrent nasal polyposis was successfully prevented in all cases.
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
DISCUSSION
Most studies on NSAID hypersensitivity have focused on NERD, although worldwide epidemiological data suggest that NECD/NIUA might be more common. Recent data have demonstrated that some patients cannot be categorized into the current classification of NSAID hypersensitivity, for example those with NSAID-induced periorbital angioedema and NIBR.1419 These patients may also have underlying chronic airway diseases; however, the role of aspirin desensitization in the prevention of recurrent nasal polyposis and control of airway inflammation in NSAID-sensitive subjects other than the NERD phenotype has never been reported.
The leading presentations in NSAID-sensitive subjects in this study were periorbital angioedema, acute urticaria, bronchial symptoms, and naso-ocular reactions, respectively. Even those confirmed with NSAID exposure, a significant number of patients in our cohort also showed clinical responses in more than 1 organ system, indicating that the prevalence of NIBR was higher than previously thought. Although patients with IgE-mediated anaphylaxis might also present with multiple organ involvement, the fact that most of the reactions took about 1–2 hours to occur and the ability to react to multiple NSAIDs with dissimilar chemical structures made them more compatible with the non-immunologic effect of the drugs.
Facial angioedema around the periorbital area was the most common presenting symptom in Thai patients. Upon NSAID provocation, however, the predominant periorbital angioedema often accompanied by blocked nose, running nose, and itchy/red eyes. After a thorough examination, small urticarial rash on the trunk and extremities, and expiratory wheezing were occasionally detected, although frequently asymptomatic. It is noteworthy that periorbital angioedema may persist for hours or days while urticarial rash and respiratory symptoms are quickly resolved after treatment. As a result, NIBR could be underdiagnosed if history taking is not thoroughly reviewed, since symptoms with lesser severity in other organ systems may be unnoticed. In addition, the COX-1 inhibitor properties of the exposed NSAIDs could affect the phenotype of NSAID sensitivity reported by patients as some patients experienced both asthmatic attack and periorbital angioedema/generalized urticaria after taking aspirin but reported only periorbital edema after taking acetaminophen.
It is practically difficult to clearly distinguish between NSAID-induced periorbital angioedema and NSAID-induced naso-ocular reactions (upper airway manifestations of NERD), since patients occasionally experienced periorbital swelling, red/swollen eyes with tearing, and nasal congestion at the same time. In our opinion, the majority of NSAID hypersensitivity in the Thai population would be described as “NSAID-induced blended reaction with predominant periorbital angioedema” and probably related to “NSAID-induced isolated periorbital angioedema” phenotype as proposed by the Spanish group. It is interesting to note that the prevalence of atopic disease was high in this patient group. We speculate that the increased leukotriene production after NSAID consumption could lead to the worsening of pre-existing mucosal inflammation around the nose and eyes in patients who already suffered from the late-phase reaction of persistent allergic rhinitis.
Our study did not find any difference in terms of basal uLTE4 levels between NSAID-sensitive and NSAID-tolerant subjects. However, uLTE4 levels were higher in NSAID-sensitive patients, particularly in NERD and NIBR subjects, after the NSAID challenge compared to those in the NSAID-tolerant group. Though basal uLTE4 levels may not be a suitable marker to screen NSAID sensitivity status, elevated uLTE4 levels after aspirin OPT could be the supporting evidence for the diagnosis of cross-reactive NSAID hypersensitivity in cases where the clinical response is equivocal. Our study demonstrated that the degree of defective leukotriene homeostasis after exposure to drugs affecting the cyclo-oxygenase pathway might be related to the severity of respiratory involvement upon NSAID exposure.35 The fact that uLTE4 levels were barely changed after celecoxib provocation in patients with NSAID cross-reactivity confirms that celecoxib is a safe alternative NSAID in these patient groups.
According to our study, the patterns of NSAID hypersensitivity in southeast Asians are similar to those in southern Europeans and Latin Americans, and somewhat different from those reported in patients of northern European descent. Previous data suggested that aspirin nasal provocation could potentially diagnose some NSAID-sensitive patients presenting with predominant cutaneous reactions.3637 Retrospectively, some of these patients might be re-classified as the NIBR phenotype, since a decreased nasal volume was also observed. In other words, patients diagnosed with an NSAID-induced cutaneous reaction who positively reacted to NSAID nasal provocation, especially those with a periorbital reaction, might be NIBR subjects with subclinical airway involvement.
The novelties of this study were the findings that NIBR accounted for about one-third of adult patients with cross-reactive NSAID hypersensitivity and that aspirin desensitization could successfully prevent the recurrence of nasal polyposis and alleviate respiratory symptoms not only in NERD, but also in NIBR, even though urine LTE4 levels remained elevated. However, since the reactions in some NIBR patients could lead to serious adverse events, aspirin desensitization in NIBR subjects should be performed only when it is strongly indicated in selected patients with no previous severe reactions to NSAIDs. In NIBR subjects who experienced previous severe reactions in multiple organ systems, the procedure of aspirin desensitization, if necessary, should be carefully monitored and the administration of biological agents such as dupilumab, if available, should be considered a safer therapeutic option in these cases.
Interestingly, uLTE4 levels were increased after aspirin desensitization and remained elevated throughout the follow-up period. It should be emphasized that urticarial rash and stomach-ache in NIBR patients also disappeared while patients were taking daily aspirin. These data suggest that the pathogenesis of nasal polyposis cannot be explained by cysLT overproduction alone and that aspirin desensitization could be useful to alleviate both respiratory and non-respiratory symptoms in NIBR subjects.
Interestingly, a recent study also found that the clinical benefit of high-dose aspirin desensitization in NERD was independent of a reduction of mast cell activation and cysLT production. They reported paradoxically increased uLTE4 levels 8 weeks after aspirin desensitization compared to the baseline levels and concluded that high-dose aspirin therapy did not restore the impaired eicosanoid pathway.38 According to their study findings and ours, the therapeutic effect of aspirin desensitization was not directly correlated with a change of arachidonic acid metabolism.
There are some limitations to this study. Aspirin desensitization was performed in only 6 patients in our cohort; therefore, the comparative success rates and potential adverse reactions of aspirin desensitization between NERD and NIBR patients could not be analyzed. Further studies with a larger sample size are needed to compare the long-term prognosis between NERD and NIBR, to understand the mechanism of aspirin desensitization for the improvement of respiratory and extra-respiratory symptoms and to evaluate its risk-benefit ratio of aspirin desensitization in NIBR subjects.
In conclusion, NIBR is not uncommon among patients diagnosed with NSAID hypersensitivity in Thailand. Increased uLTE4 levels upon aspirin provocation suggested a diagnosis of NSAID cross-reactivity, while baseline uLTE4 levels were not distinguishable between NSAID-tolerant and NSAID-sensitive subjects. Our study indicates that aspirin desensitization is effective not only in NERD but also in NIBR. The persistently high levels of uLTE4 in spite of clinical improvement in NSAID-sensitive patients after successful aspirin desensitization suggest that elevated leukotrienes alone cannot explain the pathogenesis of NSAID hypersensitivity reactions.
ACKNOWLEDGMENTS
This study was supported by the Ratchadaphiseksomphot fund, Faculty of Medicine, Chulalongkorn University, grant No. RA55/19 and the Skin and Allergy Research Unit, Chulalongkorn University, Bangkok, Thailand. Study data were collected and managed using Research Electronic Data Capture (REDCap) hosted at HIV Netherlands Australia Thailand Research Collaboration. The authors thank Thitima Kantachatvanich, MD for providing patient information.
Disclosure: There are no financial or other issues that might lead to conflict of interest.
SUPPLEMENTARY MATERIALS
Supplementary Table S1
Clinical characteristics of patients with confirmed NSAID-induced immediate reactions
Supplementary Fig. S1
Representative photos of skin rash demonstrated during aspirin desensitization in NIBR patients. | IBUPROFEN, INDOMETHACIN, MEFENAMIC ACID | DrugsGivenReaction | CC BY-NC | 33474858 | 18,863,279 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Asthma'. | Clinical Characteristics, Urinary Leukotriene E4 Levels, and Aspirin Desensitization Results in Patients With NSAID-Induced Blended Reactions.
OBJECTIVE
Data on non-steroidal anti-inflammatory drug (NSAID) hypersensitivity in Southeast Asia are scarce. Increased urinary leukotriene E4 (uLTE4) levels have been suggested as a biomarker of NSAID-exacerbated respiratory disease (NERD). This study investigated clinical patterns of NSAID sensitivity in Thailand and the diagnostic roles of uLTE4 measurement in various phenotypes.
METHODS
The clinical phenotypes in 92 Thai adults with cross-reactive NSAID hypersensitivity were characterized based on the clinical history and drug provocation. The uLTE4 levels were measured at baseline, after aspirin provocation and after desensitization.
RESULTS
More than half of the patients (56.5%) presented with cutaneous symptoms (NSAID-exacerbated cutaneous disease), while one-third (33.7%) developed symptoms in at least 2 systems (NSAID-induced blended reactions; NIBR). Fifty-two patients underwent drug provocation and 59.6% of them yielded positive results. After drug provocation, a significant number of patients with confirmed NSAID cross-reactivity experienced clinical symptoms in more than one organ system. The uLTE4 levels at baseline were comparable between the NSAID-tolerant and NSAID-sensitive groups, but were substantially increased after aspirin provocation predominantly in NERD (983.4 pg/mg creatinine) and NIBR (501.0 pg/mg creatinine) compared to NSAID-tolerant subjects (122.1 pg/mg creatinine, P < 0.01 and 0.05, respectively). The uLTE4 levels were elevated after aspirin desensitization, although nasal polyposis and asthma were under control in 3 NERD and 3 NIBR subjects.
CONCLUSIONS
NIBR is not uncommon among NSAID-sensitive patients in Thailand. The diagnostic value of basal uLTE4 levels was limited, but increased uLTE4 levels upon aspirin provocation suggest NSAID cross-reactivity with respiratory components. This study indicates that aspirin desensitization, if necessary, might be effective in both NERD and NIBR.
BACKGROUND
ClinicalTrials.gov Identifier: NCT03849625.
INTRODUCTION
Hypersensitivity reactions to aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most common drug allergic reactions in clinical practice. They are generally categorized into 5 major phenotypes: NSAID-exacerbated respiratory disease (NERD), NSAID-exacerbated cutaneous (urticaria/angioedema) disease (NECD) in patients with underlying chronic urticaria, NSAID-induced urticaria/angioedema (NIUA) in patients without underlying chronic urticaria, single NSAID-induced urticaria/angioedema or anaphylaxis, and single NSAID-induced delayed hypersensitivity reactions.1 The first 3 phenotypes are non-immunologically mediated, and patients can develop cross-reactive hypersensitivity to chemically unrelated NSAIDs, while the latter 2 are selective NSAID sensitivities associated with drug-specific immunoglobulin E (IgE) and T-cell response, respectively.
Genetic and epigenetic variations play significant roles in the development of NERD.2 The proposed underlying mechanism is that the disturbance in arachidonic acid synthesis pathways leads to overproduction of cysteinyl leukotrienes (cysLT) and persistent airway inflammation.3 Mast cells are believed to be the major source of cysLT, but platelet-adherent leukocytes may be responsible for cysLT overproduction in NERD as well.4 The consumption of drugs inhibiting the cyclooxygenase-1 (COX-1) enzyme, such as aspirin and conventional NSAIDs, aggravates respiratory symptoms by enhancing cysLT production in NSAID-sensitive subjects, while the administration of specific COX-2 inhibitors, such as celecoxib, is generally safe.56 Besides aspirin/NSAID avoidance, aspirin desensitization has also been proven to be helpful for long term management in NERD subjects. Beneficial effects of aspirin desensitization in preventing nasal polyp recurrence and control symptoms of chronic rhinosinusitis and asthma have been well documented.7 Rapid aspirin desensitization has shown to be effective for the treatment of coronary artery disease in patients with a history of aspirin/NSAID-induced urticaria/angioedema, but it is not indicated for the treatment of chronic urticaria.8
Worldwide epidemiological data on clinical characteristics of NSAID hypersensitivity are limited. Most studies on NERD were performed in the United States and northern European countries.9101112 However, the predominant manifestation in Latin Americans and southern Europeans is the cutaneous phenotype (NIUA, NECD, and NSAID-induced isolated periorbital angioedema).1314 Studies in Asian populations have suggested that the prevalence of the NERD phenotype is not common in this region of the world. A study performed in China indicated that the prevalence of NSAID hypersensitivity in Chinese patients with chronic rhinosinusitis is very low (0.57%) compared to their European counterparts.15 It was also noted that NSAID-induced blended reactions (NIBR) are common in young Asian, atopic children in Singapore.16 Reports from Singapore and Thailand indicated that aspirin/NSAID-induced angioedema/urticaria is probably the prominent phenotype in Southeast Asia, with acetaminophen hypersensitivity being frequent.1718
In clinical practice, the current classification of cross-reactive NSAID hypersensitivity into 3 distinct phenotypes has some limitations. Clinical characteristics in NSAID-sensitive patients may not be well defined, and a combination of respiratory and cutaneous or other symptoms, such as gastrointestinal symptoms (mixed or blended reactions), is frequently observed.19 A previous report stated that aspirin nasal provocation is potentially useful for diagnosing patients with the blended reaction as well.20 However, the role of aspirin desensitization in other phenotypes of NSAID hypersensitivity, besides NERD, for long-term management of inflammatory airway diseases has not yet been established. Whether aspirin desensitization would be effective in controlling asthma and the recurrence of nasal polyposis after sinus surgery in NIBR is currently unknown.
At present, cross-reactive types of NSAID hypersensitivity can only be diagnosed by careful history taking and controlled-provocation testing, since there is no reliable in vitro method to confirm the diagnosis.21 There is evidence that basal urinary levels of leukotriene E4 (uLTE4), a stable product of the cysLT synthesis pathway, are elevated in NERD patients and could be a potential biomarker for differentiating between NSAID-sensitive and NSAID-tolerant asthmatics. However, these data are still controversial.222324 There have also been preliminary studies showing that uLTE4 levels might be increased in NECD.2526 Whether the measurement of basal uLTE4 levels could be a diagnostic marker for any phenotype of NSAID hypersensitivity is yet to be explored.
The purpose of this study was to analyze the clinical characteristics of patients diagnosed with NSAID-induced immediate reactions in Thailand and to explore whether the measurement of uLTE4 levels would be helpful in identifying NSAID-sensitive subjects or in differentiating among different phenotypes of cross-reactive NSAID hypersensitivities.
MATERIALS AND METHODS
Patient recruitment
Adult patients (18 years of age and older) with a suggestive history of NSAID-induced hypersensitivity reaction visiting the allergy clinic at King Chulalongkorn University Hospital between June 2014 and July 2018 were recruited into this study. Those with a history compatible with drug-induced non-immediate reactions (maculopapular rash, fixed drug eruption, acute generalized exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms, Stevens-Johnson syndrome/toxic epidermal necrolysis) or NSAID-related side effects were excluded. The status of NSAID-induced immediate hypersensitivity was diagnosed in patients with a well-documented drug allergy history or in patients with a suggestive history of NSAID sensitivity who yielded a positive drug provocation test as follows.
Clinical diagnosis of NSAID hypersensitivity
The diagnosis of cross-reactive NSAID hypersensitivity was clinically made in patients with a well-documented history of multiple episodes of respiratory, cutaneous, and/or gastrointestinal reactions within 2 hours after exposure to at least 2 different NSAID classes.1212728 Patient demographic data were collected, including the underlying diseases, atopic family history, and details on drug allergy history as well as the presenting symptoms and types of the culprit NSAIDs.
Aspirin provocation test
Oral aspirin provocation was performed in patients with a suggestive medical history or in those who had a history of an immediate reaction to a single NSAID to confirm the diagnosis of cross-reactive NSAID hypersensitivity according to the EAACI/GA2LEN guidelines, with some modifications.293031 Four increasing doses of aspirin (40.5, 81, 150, and 300 mg) were administered at 90-minute intervals until a positive reaction occurred. Clinical symptoms, fractional exhaled nitric oxide (FeNO), and the forced expiratory volume in 1 second (FEV1) were monitored to evaluate the reaction. A positive provocation test was defined if any of the following reactions developed: lower respiratory/bronchial reaction (a 15% decrease in FEV1 plus naso-ocular reaction or a 20% decrease in FEV1 alone), upper respiratory/naso-ocular reaction (nasal congestion and rhinorrhea; conjunctival injection), cutaneous reactions (urticaria/angioedema, periorbital edema), and/or other reactions (gastrointestinal symptoms such as nausea/vomiting, stomach cramps, and diarrhea). The test was considered negative if a patient tolerated the final dose (300 mg of aspirin) without any significant symptoms mentioned above.
Oral provocation test (OPT) with other NSAIDs, acetaminophen, or celecoxib
Patients with a history of an immediate reaction to only aspirin were challenged with escalating doses of ibuprofen to confirm the diagnosis of cross-reactive NSAID sensitivity. Patients with a history of an immediate reaction to a single NSAID were provoked with the suspected drug to verify the status of single NSAID hypersensitivity after a negative aspirin provocation test. Escalating doses of ibuprofen, diclofenac, and acetaminophen were administered, if applicable, as follows: ibuprofen (50, 100, and 200 mg), diclofenac (6.25, 12.5, and 25 mg), and acetaminophen (125, 250, and 500 mg). Celecoxib was also provoked in 3 doses (50, 100, and 200 mg) in patients with confirmed hypersensitivity to multiple NSAIDs who were willing to identify a safe alternative drug. The provocation test for each drug was performed on separate days at least 7 days apart. Each dose of drug provocation was provided at 90-minute intervals until the final dose was reached.
Classification of NSAID hypersensitivity according to drug provocation test results
Patients with cross-reactive NSAID phenotypes were classified according to the results of the drug provocation test as 1) NECD/NIUA if they developed cutaneous symptoms alone; 2) NERD if they developed respiratory symptoms alone; and 3) NIBR if they developed a combination of symptoms involving more than one organ system (respiratory, cutaneous, and/or gastrointestinal symptoms). Single NSAID hypersensitivity was diagnosed in patients with a positive provocation test to the suspected NSAID, but a negative aspirin provocation test. Patients who had negative provocations to both aspirin and the suspected culprit drug were labeled as NSAID-tolerant subjects. NECD/NIUA were purposely categorized together in our study to compare the differences and similarities between patients diagnosed with NSAID-induced cutaneous reactions and -respiratory reactions. Moreover, NECD and NIUA share similar background characteristics from a clinical point of view and some patients diagnosed with NIUA eventually evolve to NECD over time.32
Skin prick tests with common aeroallergens in Thailand (mixed dust mites, mixed cockroaches, mixed mold, cat dander, dog hair, and southern grass mix; ALK-Abello, Hørsholm, Denmark) were also examined in tested patients to identify atopic status. Wheal size ≥ 3 mm was considered a positive test.
Measurement of FeNO and the FEV1 in patients who underwent drug provocation test
FeNO was measured in all participants at baseline and after drug provocation by using a portable electrochemical analyzer (NObreath®; Bedfont Scientific Ltd, Maidstone, UK) according to the ATS/ERS recommendations.33 Measurements of FEV1 were also performed using a Vitalograph spirometer (Vitalograph®, Buckingham, UK). The best of 3 repeated attempts was recorded.
The uLTE4 measurement
The uLTE4 levels were measured by a leukotriene E4 ELISA kit (Cayman Chemical, Ann Arbor, MI, USA) at baseline and 90 minutes after the final dose of drug provocation, as well as at the follow-up visits after aspirin desensitization and reported after adjustment to urine creatinine levels.
Aspirin desensitization
Outpatient aspirin desensitization was performed in NSAID-sensitive patients who were referred from otolaryngologists to prevent the recurrence of nasal polyposis. The procedure was carried out according to the intranasal ketorolac and modified aspirin challenge 2-day protocol.34 Aspirin desensitization was completed after patients were able to tolerate a 325-mg dose of aspirin by the end of day 2 and experience no symptoms, changes in nasal flow rates, or decrease in FEV1 values. The prescribed maintenance dose of aspirin was 325 mg twice a day.
Statistical analysis
Patient characteristics are reported as means ± standard deviation for quantitative analysis, and median and interquartile range (IQR) are used to describe non-parametric data. The Mann-Whitney U test and Kruskal-Wallis test with Dunn's multiple comparisons were used to analyze the differences between 2 groups and more than 2 groups, respectively. Statistical analyses were performed using GraphPad Prism 8.3 software (GraphPad Software Inc., San Diego, CA, USA). P values < 0.05 were considered statistically significant.
Ethical considerations
Patients enrolled in this study were those who recruited in the study entitled “Characteristics of Patients Diagnosed With NSAID Sensitivity in Thailand” registered at ClinicalTrials.gov (NCT03849625). The study was approved by the Ethics and Research Committee of the Faculty of Medicine, Chulalongkorn University, Approval Number: COA No. 659/2012 and informed consent was obtained from all participants.
RESULTS
A total of 158 adult patients with a suspected history of NSAID hypersensitivity between 2015 and 2018 at King Chulalongkorn Memorial Hospital were initially recruited into this study as shown in Fig. 1. Thirty-five patients with a history compatible with a non-immediate hypersensitivity reaction and 4 subjects with clinical symptoms compatible with NSAID-related side effects were later excluded.
Fig. 1 Schematic diagram of patient selection for this study.
A total of 158 patients with a suspected history of NSAID hypersensitivity were initially recruited into this study. Cross-reactive NSAID hypersensitivity was clinically diagnosed in 67 patients with a well-documented drug allergy history and verified by a positive drug provocation test in 25 patients with a suggestive history of NSAID reactions.
NSAID, non-steroidal anti-inflammatory drug.
Cross-reactive NSAID hypersensitivity was clinically diagnosed in 67 patients with a convincing drug allergy history as defined in the methods section. The remaining 52 patients with a suggestive history of NSAID hypersensitivity underwent an OPT to confirm NSAID cross-reactivity status. Fifteen out of 25 patients with confirmed NSAID cross-reactivity were subsequently provoked with celecoxib to find a safe alternative NSAID. Single NSAID/acetaminophen hypersensitivity was verified in 6 patients who tolerated aspirin provocation but developed an allergic reaction upon re-challenge with acetaminophen or diclofenac.
Demographic data of adult patients with cross-reactive NSAID hypersensitivity
The clinical characteristics of adult patients with cross-reactive NSAID hypersensitivity are shown in Table 1 (n = 92). Most patients were females (77.2%) with an average age of 45.7 ± 13.4 years. The average age of onset was 32.2 ± 13.3 years and about half of them had atopic family history. The majority of them (56.5%) reported only cutaneous symptoms such as facial angioedema and/or acute urticarial rash, after NSAID exposure, while 9.8% of them developed only respiratory symptoms. Interestingly, about 33.7% of the patients experienced a combination of symptoms in multiple organ systems as shown in Fig. 2. The groups of NSAIDs frequently responsible for hypersensitivity reactions were propionic acid derivatives and acetic acid derivatives. Although inflammatory airway diseases (chronic sinusitis, nasal polyposis, and asthma) were significantly more common in patients who experienced only respiratory reactions after exposure to an NSAID compared to the other phenotypes, a significant portion of the patients reporting blended reactions had underlying airway diseases and chronic urticaria as well. Acetaminophen intolerance was also reported in about one-third (35.9%) of NSAID-sensitive subjects.
Table 1 Clinical characteristics among different phenotypes of patients with cross-reactive NSAID hypersensitivity (n = 92)
Phenotypes NECD/NIUA (n = 52) NERD (n = 9) NIBR (n = 31) Total (n = 92)
Gender (female/male) 37/15 6/3 28/3 71/21
Age (yr) 43.6 ± 12.3 47.3 ± 11.9 48.7 ± 15.3 45.7 ± 13.4
Age of onset (yr) 31.3 ± 13.8 34.6 ± 11.0 33.1 ± 13.3 32.2 ± 13.3
Underlying disease (%)
Chronic urticaria 13.5 11.1 29.0 18.5
Chronic sinusitis* 13.5 55.6 32.3 23.9
Nasal polyposis* 7.7 66.7 16.1 16.3
Asthma* 17.3 88.9 35.5 30.4
Atopic family history (%) 42.3 55.6 61.3 50.0
Drug exposure time to symptom onset (min) 58.8 ± 31.9 48.3 ± 34.3 47.6 ± 29.9 54.0 ± 31.6
Presenting symptoms (%)*
Facial/periorbital angioedema 71.2 0.0 74.2 65.2
Acute urticaria 73.1 0.0 61.3 62.0
Naso-ocular reaction 0.0 33.3 61.3 23.9
Acute asthma 0.0 88.9 67.7 31.5
Gastrointestinal symptoms 0.0 0.0 16.1 5.4
Implicated NSAIDs (%)†
Salicylic acids 23.1 55.6 35.5 30.4
Propionic acids 44.2 22.2 54.8 45.7
Acetic acids 23.1 22.2 48.4 31.5
Enolic acids 7.7 0.0 6.5 6.5
Anthranilic/fenamic acids 28.8 11.1 29.0 27.2
Acetaminophen intolerance (%)§ 28.8 22.2 51.6 35.9
Values are presented as number (%) or mean ± standard deviation. Each patient could present with multiple symptoms and from more than one implicated drug.
NSAID, non-steroidal anti-inflammatory drug; NECD, non-steroidal anti-inflammatory drug-exacerbated cutaneous (urticaria/angioedema) disease in patients with underlying chronic urticaria; NIUA, non-steroidal anti-inflammatory drug-induced urticaria/angioedema in patients without underlying chronic urticaria; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
*P < 0.05 among different phenotypes. †Examples of commonly implicated drugs in this study based on NSAID classification: 1) Salicylic acids: acetylsalicylic acid (aspirin), salicylic acid, diflunisal, salsalate; 2) Propionic acids: ibuprofen, naproxen, ketoprofen, fenoprofen, flurbiprofen; 3) Acetic acids: indomethacin, ketorolac, diclofenac, sulindac; 4) Enolic acids: piroxicam, meloxicam, tenoxicam; 5) Anthranilic/fenamic acids: mefenamic acid, flufenamic acid. §Acetaminophen intolerance: cannot tolerate acetaminophen higher than 500 mg.
Fig. 2 Clinical presentations in patients with cross-reactive NSAID hypersensitivity.
A proportional Venn diagram shows that about half of patients with cross-reactive NSAID hypersensitivity in Thailand reported only cutaneous symptoms after NSAID exposure, while one-third of them experienced NSAID-induced blended reactions.
NSAID, non-steroidal anti-inflammatory drug.
Clinical respiratory parameters and uLTE4 levels in different phenotypes of patients with cross-reactive NSAID hypersensitivity confirmed by positive OPT
NSAID hypersensitivity was confirmed in 59.6% (31/52) of the tested patients with a history of NSAID-induced immediate reactions. The majority of patients with cross-reactive NSAID hypersensitivity (17/25) according to OPT results were atopic individuals. The common phenotypes of patients with confirmed cross-reactive NSAID sensitivity were NECD/NIUA, NIBR, and NERD, respectively, as shown in Supplementary Table S1.
The average FeNO, %predicted FEV1, and uLTE4 levels were measured at baseline and after provocation with aspirin/NSAID in 25 NSAID cross-reactive and 21 NSAID-tolerant subjects as shown in Table 2. At baseline, patients with confirmed NSAID cross-reactivity (NSAID-sensitive group) had higher FeNO (P < 0.01) and slightly less %predicted FEV1 compared to the NSAID-tolerant subjects, while basal uLTE4 levels between NSAID-sensitive and NSAID-tolerant groups were comparable. After provocation, %predicted FEV1 was substantially reduced in NSAID-sensitive subjects, whereas uLTE4 levels were significantly elevated compared to the NSAID-tolerant group (P < 0.01). Celecoxib provocation was well tolerated in all NSAID-sensitive subjects. No statistical differences in the average FeNO, %predicted FEV1, or uLTE4 levels in 15 NSAID-sensitive patients (7 NECD/NIUA, 4 NIBR, 4 NERD) after celecoxib provocation were observed compared to those in NSAID-tolerant subjects.
Table 2 Respiratory parameters and uLTE4 levels in NSAID-sensitive subjects upon provocation with aspirin or celecoxib compared to NSAID-tolerant subjects
Characteristics Baseline After aspirin (OPT) P value*
NSAID tolerant (n = 21)
FeNO (ppb) 13.0 (8.5–19.5) 10.2 (7.0–16.8) 0.03
%predicted FEV1 100.8 (82.8–115.9) 99.0 (75.2–118.2) 0.90
uLTE4 (pg/mg creatinine) 116.3 (66.5–305.4) 122.1 (63.5–173.8) 0.17
NSAID sensitive (n = 25)
FeNO (ppb) 27.0 (17.8–40.9)† 18.0 (10.5–31.0) <0.01
%predicted FEV1 86.7 (63.3–104.9) 74.6 (52.4–89.8)† <0.01
uLTE4 (pg/mg creatinine) 118.3 (93.2–407.2) 204.9 (90.6–817.8)† <0.01
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; OPT, oral provocation test; ppb, parts per billion; FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in 1 second.
*P values before vs. after provocation test, Wilcoxon signed-rank test; †P < 0.01 compared to the NSAID-tolerant subjects.
According to the subgroup analysis, 10 NECD/NIUA, 9 NIBR, and 6 NERD were categorized as shown in Fig. 3. At baseline, %predicted FEV1 was not significantly different among different types of cross-reactive NSAID hypersensitivity, although those in patients with confirmed NIBR were lowest (64.9%, IQR 56.9–97.3). The significant differences in basal FeNO levels (P < 0.01) among the 3 different phenotypes were observed. The basal FeNO levels were significantly higher in NIBR (36.9%, IQR 27.0–95.4) than in NSAID-tolerant subjects (P < 0.01). After aspirin OPT, the reduction of %FEV1 was considerably higher in patients with confirmed NERD (22.0%, IQR 16.0-28.8), followed by NIBR (13.3%, IQR 7.6–28.0), compared to those in NSAID-tolerant groups (P < 0.01). Basal uLTE4 levels were not significantly different among the 3 phenotypes. Interestingly, uLTE4 levels after aspirin provocation were significantly higher in NERD and NIBR patients than in the NECD/NIUA and NSAID-tolerant groups (P < 0.05 and < 0.01, respectively).
Fig. 3 Respiratory parameters and uLTE4 levels in different phenotypes of NSAID-sensitive subjects compared to NSAID-tolerant subjects.
Baseline FeNO in NIBR and NERD were higher than those in the NSAID-tolerant group. After aspirin provocation, % predicted FEV1 in NERD and NIBR were significantly reduced from the baseline while uLTE4 levels were much higher than those in NSAID-tolerant subjects.
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; FEV1, forced expiratory volume in 1 second.
*P values < 0.05, †P values < 0.01.
Effects of aspirin desensitization on uLTE4 levels in patients diagnosed with NERD and NIBR
Aspirin desensitization was performed in selected patients (3 NERD and 3 NIBR) who had pre-existing inflammatory airway diseases and a history of recurrent nasal polyposis after surgery as shown in Table 3. The maintenance dose of aspirin was 650 mg/day during the first 6 months and reduced to 325 mg/day afterward. Levels of uLTE4 were measured at baseline after aspirin desensitization and serially followed up for 2–3 years as demonstrated in Fig. 4. Other than respiratory symptoms, acute urticarial rash and gastrointestinal symptoms (abdominal cramp/nausea/diarrhea) were also aggravated in NIBR subjects during aspirin desensitization as shown in Supplementary Fig. S1, but gradually relieved with supportive treatment. No sinus surgery was required for nasal polyp recurrence, and asthma symptoms were under control after aspirin desensitization in all 6 cases. Up to 3 years after aspirin desensitization, however, uLTE4 levels were significantly increased and remained elevated throughout the follow-up period, although urticarial rash and gastrointestinal symptoms were no longer observed while taking aspirin.
Table 3 Details of patients with cross-reactive NSAID hypersensitivity undergoing aspirin desensitization in this study
Patients (sex/year) Underlying diseases History of adverse drug reactions Indication for aspirin desensitization Follow-up duration (months) Asthma control before/after aspirin desensitization Recurrent nasal polyposis after aspirin desensitization Skin symptoms after aspirin desensitization Gastrointestinal symptoms after aspirin desensitization
1. NERD (M/46) Chronic sinusitis, nasal polyposis, asthma Acute asthma 20 min after taking aspirin 2 recurrent nasal polyps 74 Partly controlled with high dose ICS-LABA and add-on LTRA/well controlled with low dose ICS None NA NA
2. NERD (M/54) Chronic rhinitis, nasal polyposis, asthma Acute asthma, blocked nose 1 hr after taking aspirin 3 recurrent nasal polyps 24 Uncontrolled with high dose ICS-LABA and add-on LTRA/well controlled with medium dose ICS-LABA None NA NA
3. NERD (M/56) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked nose 1 hr after taking ibuprofen 6 recurrent nasal polyps 32 Partly controlled asthma with high dose ICS-LABA and add-on LTRA/well controlled with medium dose ICS-LABA None NA NA
4. NIBR (M/48) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked nose, conjunctival injection, urticarial rash 2 hr after taking aspirin 3 recurrent nasal polyps 72 Partly controlled with medium dose ICS-LABA/well controlled with low dose ICS-LABA None No rash after taking aspirin NA
5. NIBR (F/65) Chronic sinusitis, nasal polyposis, chronic urticaria, asthma (history of cardiac arrest from severe asthma) Urticarial rash, periorbital angioedema, blocked nose, conjunctival injection, rhinorrhea, bronchospasm/wheezing, hoarseness of voice 1 hr after taking aspirin, ibuprofen, mefenamic acid, acetaminophen 2 recurrent nasal polyps 48 Uncontrolled with high dose ICS-LABA and add-on LTRA/well controlled with low dose ICS-LABA None No rash after taking aspirin, chronic urticaria resolved NA
6. NIBR (F/38) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked/running nose, stomach cramp, diarrhea, periorbital angioedema, urticaria 30 min after taking ibuprofen, indomethacin, mefenamic acid 2 recurrent nasal polyps 21 Partly controlled with medium dose ICS-LABA/well controlled, with medium dose ICS-LABA None No rash after taking aspirin No gastrointestinal symptoms after taking aspirin
NSAID, non-steroidal anti-inflammatory drug; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; ICS, inhaled corticosteroid; LABA, long-acting beta-agonist; LTRA, leukotriene receptor antagonist; NA, not applicable (no symptoms prior to aspirin desensitization); NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
Fig. 4 uLTE4 levels in NSAID-sensitive subjects after aspirin desensitization.
Our study demonstrated that uLTE4 levels (pg/mg creatinine) in 3 NERD and 3 NIBR patients were increased and remained elevated up to 3 years after aspirin desensitization even though recurrent nasal polyposis was successfully prevented in all cases.
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
DISCUSSION
Most studies on NSAID hypersensitivity have focused on NERD, although worldwide epidemiological data suggest that NECD/NIUA might be more common. Recent data have demonstrated that some patients cannot be categorized into the current classification of NSAID hypersensitivity, for example those with NSAID-induced periorbital angioedema and NIBR.1419 These patients may also have underlying chronic airway diseases; however, the role of aspirin desensitization in the prevention of recurrent nasal polyposis and control of airway inflammation in NSAID-sensitive subjects other than the NERD phenotype has never been reported.
The leading presentations in NSAID-sensitive subjects in this study were periorbital angioedema, acute urticaria, bronchial symptoms, and naso-ocular reactions, respectively. Even those confirmed with NSAID exposure, a significant number of patients in our cohort also showed clinical responses in more than 1 organ system, indicating that the prevalence of NIBR was higher than previously thought. Although patients with IgE-mediated anaphylaxis might also present with multiple organ involvement, the fact that most of the reactions took about 1–2 hours to occur and the ability to react to multiple NSAIDs with dissimilar chemical structures made them more compatible with the non-immunologic effect of the drugs.
Facial angioedema around the periorbital area was the most common presenting symptom in Thai patients. Upon NSAID provocation, however, the predominant periorbital angioedema often accompanied by blocked nose, running nose, and itchy/red eyes. After a thorough examination, small urticarial rash on the trunk and extremities, and expiratory wheezing were occasionally detected, although frequently asymptomatic. It is noteworthy that periorbital angioedema may persist for hours or days while urticarial rash and respiratory symptoms are quickly resolved after treatment. As a result, NIBR could be underdiagnosed if history taking is not thoroughly reviewed, since symptoms with lesser severity in other organ systems may be unnoticed. In addition, the COX-1 inhibitor properties of the exposed NSAIDs could affect the phenotype of NSAID sensitivity reported by patients as some patients experienced both asthmatic attack and periorbital angioedema/generalized urticaria after taking aspirin but reported only periorbital edema after taking acetaminophen.
It is practically difficult to clearly distinguish between NSAID-induced periorbital angioedema and NSAID-induced naso-ocular reactions (upper airway manifestations of NERD), since patients occasionally experienced periorbital swelling, red/swollen eyes with tearing, and nasal congestion at the same time. In our opinion, the majority of NSAID hypersensitivity in the Thai population would be described as “NSAID-induced blended reaction with predominant periorbital angioedema” and probably related to “NSAID-induced isolated periorbital angioedema” phenotype as proposed by the Spanish group. It is interesting to note that the prevalence of atopic disease was high in this patient group. We speculate that the increased leukotriene production after NSAID consumption could lead to the worsening of pre-existing mucosal inflammation around the nose and eyes in patients who already suffered from the late-phase reaction of persistent allergic rhinitis.
Our study did not find any difference in terms of basal uLTE4 levels between NSAID-sensitive and NSAID-tolerant subjects. However, uLTE4 levels were higher in NSAID-sensitive patients, particularly in NERD and NIBR subjects, after the NSAID challenge compared to those in the NSAID-tolerant group. Though basal uLTE4 levels may not be a suitable marker to screen NSAID sensitivity status, elevated uLTE4 levels after aspirin OPT could be the supporting evidence for the diagnosis of cross-reactive NSAID hypersensitivity in cases where the clinical response is equivocal. Our study demonstrated that the degree of defective leukotriene homeostasis after exposure to drugs affecting the cyclo-oxygenase pathway might be related to the severity of respiratory involvement upon NSAID exposure.35 The fact that uLTE4 levels were barely changed after celecoxib provocation in patients with NSAID cross-reactivity confirms that celecoxib is a safe alternative NSAID in these patient groups.
According to our study, the patterns of NSAID hypersensitivity in southeast Asians are similar to those in southern Europeans and Latin Americans, and somewhat different from those reported in patients of northern European descent. Previous data suggested that aspirin nasal provocation could potentially diagnose some NSAID-sensitive patients presenting with predominant cutaneous reactions.3637 Retrospectively, some of these patients might be re-classified as the NIBR phenotype, since a decreased nasal volume was also observed. In other words, patients diagnosed with an NSAID-induced cutaneous reaction who positively reacted to NSAID nasal provocation, especially those with a periorbital reaction, might be NIBR subjects with subclinical airway involvement.
The novelties of this study were the findings that NIBR accounted for about one-third of adult patients with cross-reactive NSAID hypersensitivity and that aspirin desensitization could successfully prevent the recurrence of nasal polyposis and alleviate respiratory symptoms not only in NERD, but also in NIBR, even though urine LTE4 levels remained elevated. However, since the reactions in some NIBR patients could lead to serious adverse events, aspirin desensitization in NIBR subjects should be performed only when it is strongly indicated in selected patients with no previous severe reactions to NSAIDs. In NIBR subjects who experienced previous severe reactions in multiple organ systems, the procedure of aspirin desensitization, if necessary, should be carefully monitored and the administration of biological agents such as dupilumab, if available, should be considered a safer therapeutic option in these cases.
Interestingly, uLTE4 levels were increased after aspirin desensitization and remained elevated throughout the follow-up period. It should be emphasized that urticarial rash and stomach-ache in NIBR patients also disappeared while patients were taking daily aspirin. These data suggest that the pathogenesis of nasal polyposis cannot be explained by cysLT overproduction alone and that aspirin desensitization could be useful to alleviate both respiratory and non-respiratory symptoms in NIBR subjects.
Interestingly, a recent study also found that the clinical benefit of high-dose aspirin desensitization in NERD was independent of a reduction of mast cell activation and cysLT production. They reported paradoxically increased uLTE4 levels 8 weeks after aspirin desensitization compared to the baseline levels and concluded that high-dose aspirin therapy did not restore the impaired eicosanoid pathway.38 According to their study findings and ours, the therapeutic effect of aspirin desensitization was not directly correlated with a change of arachidonic acid metabolism.
There are some limitations to this study. Aspirin desensitization was performed in only 6 patients in our cohort; therefore, the comparative success rates and potential adverse reactions of aspirin desensitization between NERD and NIBR patients could not be analyzed. Further studies with a larger sample size are needed to compare the long-term prognosis between NERD and NIBR, to understand the mechanism of aspirin desensitization for the improvement of respiratory and extra-respiratory symptoms and to evaluate its risk-benefit ratio of aspirin desensitization in NIBR subjects.
In conclusion, NIBR is not uncommon among patients diagnosed with NSAID hypersensitivity in Thailand. Increased uLTE4 levels upon aspirin provocation suggested a diagnosis of NSAID cross-reactivity, while baseline uLTE4 levels were not distinguishable between NSAID-tolerant and NSAID-sensitive subjects. Our study indicates that aspirin desensitization is effective not only in NERD but also in NIBR. The persistently high levels of uLTE4 in spite of clinical improvement in NSAID-sensitive patients after successful aspirin desensitization suggest that elevated leukotrienes alone cannot explain the pathogenesis of NSAID hypersensitivity reactions.
ACKNOWLEDGMENTS
This study was supported by the Ratchadaphiseksomphot fund, Faculty of Medicine, Chulalongkorn University, grant No. RA55/19 and the Skin and Allergy Research Unit, Chulalongkorn University, Bangkok, Thailand. Study data were collected and managed using Research Electronic Data Capture (REDCap) hosted at HIV Netherlands Australia Thailand Research Collaboration. The authors thank Thitima Kantachatvanich, MD for providing patient information.
Disclosure: There are no financial or other issues that might lead to conflict of interest.
SUPPLEMENTARY MATERIALS
Supplementary Table S1
Clinical characteristics of patients with confirmed NSAID-induced immediate reactions
Supplementary Fig. S1
Representative photos of skin rash demonstrated during aspirin desensitization in NIBR patients. | IBUPROFEN, INDOMETHACIN, MEFENAMIC ACID | DrugsGivenReaction | CC BY-NC | 33474858 | 18,863,279 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Bronchospasm'. | Clinical Characteristics, Urinary Leukotriene E4 Levels, and Aspirin Desensitization Results in Patients With NSAID-Induced Blended Reactions.
OBJECTIVE
Data on non-steroidal anti-inflammatory drug (NSAID) hypersensitivity in Southeast Asia are scarce. Increased urinary leukotriene E4 (uLTE4) levels have been suggested as a biomarker of NSAID-exacerbated respiratory disease (NERD). This study investigated clinical patterns of NSAID sensitivity in Thailand and the diagnostic roles of uLTE4 measurement in various phenotypes.
METHODS
The clinical phenotypes in 92 Thai adults with cross-reactive NSAID hypersensitivity were characterized based on the clinical history and drug provocation. The uLTE4 levels were measured at baseline, after aspirin provocation and after desensitization.
RESULTS
More than half of the patients (56.5%) presented with cutaneous symptoms (NSAID-exacerbated cutaneous disease), while one-third (33.7%) developed symptoms in at least 2 systems (NSAID-induced blended reactions; NIBR). Fifty-two patients underwent drug provocation and 59.6% of them yielded positive results. After drug provocation, a significant number of patients with confirmed NSAID cross-reactivity experienced clinical symptoms in more than one organ system. The uLTE4 levels at baseline were comparable between the NSAID-tolerant and NSAID-sensitive groups, but were substantially increased after aspirin provocation predominantly in NERD (983.4 pg/mg creatinine) and NIBR (501.0 pg/mg creatinine) compared to NSAID-tolerant subjects (122.1 pg/mg creatinine, P < 0.01 and 0.05, respectively). The uLTE4 levels were elevated after aspirin desensitization, although nasal polyposis and asthma were under control in 3 NERD and 3 NIBR subjects.
CONCLUSIONS
NIBR is not uncommon among NSAID-sensitive patients in Thailand. The diagnostic value of basal uLTE4 levels was limited, but increased uLTE4 levels upon aspirin provocation suggest NSAID cross-reactivity with respiratory components. This study indicates that aspirin desensitization, if necessary, might be effective in both NERD and NIBR.
BACKGROUND
ClinicalTrials.gov Identifier: NCT03849625.
INTRODUCTION
Hypersensitivity reactions to aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most common drug allergic reactions in clinical practice. They are generally categorized into 5 major phenotypes: NSAID-exacerbated respiratory disease (NERD), NSAID-exacerbated cutaneous (urticaria/angioedema) disease (NECD) in patients with underlying chronic urticaria, NSAID-induced urticaria/angioedema (NIUA) in patients without underlying chronic urticaria, single NSAID-induced urticaria/angioedema or anaphylaxis, and single NSAID-induced delayed hypersensitivity reactions.1 The first 3 phenotypes are non-immunologically mediated, and patients can develop cross-reactive hypersensitivity to chemically unrelated NSAIDs, while the latter 2 are selective NSAID sensitivities associated with drug-specific immunoglobulin E (IgE) and T-cell response, respectively.
Genetic and epigenetic variations play significant roles in the development of NERD.2 The proposed underlying mechanism is that the disturbance in arachidonic acid synthesis pathways leads to overproduction of cysteinyl leukotrienes (cysLT) and persistent airway inflammation.3 Mast cells are believed to be the major source of cysLT, but platelet-adherent leukocytes may be responsible for cysLT overproduction in NERD as well.4 The consumption of drugs inhibiting the cyclooxygenase-1 (COX-1) enzyme, such as aspirin and conventional NSAIDs, aggravates respiratory symptoms by enhancing cysLT production in NSAID-sensitive subjects, while the administration of specific COX-2 inhibitors, such as celecoxib, is generally safe.56 Besides aspirin/NSAID avoidance, aspirin desensitization has also been proven to be helpful for long term management in NERD subjects. Beneficial effects of aspirin desensitization in preventing nasal polyp recurrence and control symptoms of chronic rhinosinusitis and asthma have been well documented.7 Rapid aspirin desensitization has shown to be effective for the treatment of coronary artery disease in patients with a history of aspirin/NSAID-induced urticaria/angioedema, but it is not indicated for the treatment of chronic urticaria.8
Worldwide epidemiological data on clinical characteristics of NSAID hypersensitivity are limited. Most studies on NERD were performed in the United States and northern European countries.9101112 However, the predominant manifestation in Latin Americans and southern Europeans is the cutaneous phenotype (NIUA, NECD, and NSAID-induced isolated periorbital angioedema).1314 Studies in Asian populations have suggested that the prevalence of the NERD phenotype is not common in this region of the world. A study performed in China indicated that the prevalence of NSAID hypersensitivity in Chinese patients with chronic rhinosinusitis is very low (0.57%) compared to their European counterparts.15 It was also noted that NSAID-induced blended reactions (NIBR) are common in young Asian, atopic children in Singapore.16 Reports from Singapore and Thailand indicated that aspirin/NSAID-induced angioedema/urticaria is probably the prominent phenotype in Southeast Asia, with acetaminophen hypersensitivity being frequent.1718
In clinical practice, the current classification of cross-reactive NSAID hypersensitivity into 3 distinct phenotypes has some limitations. Clinical characteristics in NSAID-sensitive patients may not be well defined, and a combination of respiratory and cutaneous or other symptoms, such as gastrointestinal symptoms (mixed or blended reactions), is frequently observed.19 A previous report stated that aspirin nasal provocation is potentially useful for diagnosing patients with the blended reaction as well.20 However, the role of aspirin desensitization in other phenotypes of NSAID hypersensitivity, besides NERD, for long-term management of inflammatory airway diseases has not yet been established. Whether aspirin desensitization would be effective in controlling asthma and the recurrence of nasal polyposis after sinus surgery in NIBR is currently unknown.
At present, cross-reactive types of NSAID hypersensitivity can only be diagnosed by careful history taking and controlled-provocation testing, since there is no reliable in vitro method to confirm the diagnosis.21 There is evidence that basal urinary levels of leukotriene E4 (uLTE4), a stable product of the cysLT synthesis pathway, are elevated in NERD patients and could be a potential biomarker for differentiating between NSAID-sensitive and NSAID-tolerant asthmatics. However, these data are still controversial.222324 There have also been preliminary studies showing that uLTE4 levels might be increased in NECD.2526 Whether the measurement of basal uLTE4 levels could be a diagnostic marker for any phenotype of NSAID hypersensitivity is yet to be explored.
The purpose of this study was to analyze the clinical characteristics of patients diagnosed with NSAID-induced immediate reactions in Thailand and to explore whether the measurement of uLTE4 levels would be helpful in identifying NSAID-sensitive subjects or in differentiating among different phenotypes of cross-reactive NSAID hypersensitivities.
MATERIALS AND METHODS
Patient recruitment
Adult patients (18 years of age and older) with a suggestive history of NSAID-induced hypersensitivity reaction visiting the allergy clinic at King Chulalongkorn University Hospital between June 2014 and July 2018 were recruited into this study. Those with a history compatible with drug-induced non-immediate reactions (maculopapular rash, fixed drug eruption, acute generalized exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms, Stevens-Johnson syndrome/toxic epidermal necrolysis) or NSAID-related side effects were excluded. The status of NSAID-induced immediate hypersensitivity was diagnosed in patients with a well-documented drug allergy history or in patients with a suggestive history of NSAID sensitivity who yielded a positive drug provocation test as follows.
Clinical diagnosis of NSAID hypersensitivity
The diagnosis of cross-reactive NSAID hypersensitivity was clinically made in patients with a well-documented history of multiple episodes of respiratory, cutaneous, and/or gastrointestinal reactions within 2 hours after exposure to at least 2 different NSAID classes.1212728 Patient demographic data were collected, including the underlying diseases, atopic family history, and details on drug allergy history as well as the presenting symptoms and types of the culprit NSAIDs.
Aspirin provocation test
Oral aspirin provocation was performed in patients with a suggestive medical history or in those who had a history of an immediate reaction to a single NSAID to confirm the diagnosis of cross-reactive NSAID hypersensitivity according to the EAACI/GA2LEN guidelines, with some modifications.293031 Four increasing doses of aspirin (40.5, 81, 150, and 300 mg) were administered at 90-minute intervals until a positive reaction occurred. Clinical symptoms, fractional exhaled nitric oxide (FeNO), and the forced expiratory volume in 1 second (FEV1) were monitored to evaluate the reaction. A positive provocation test was defined if any of the following reactions developed: lower respiratory/bronchial reaction (a 15% decrease in FEV1 plus naso-ocular reaction or a 20% decrease in FEV1 alone), upper respiratory/naso-ocular reaction (nasal congestion and rhinorrhea; conjunctival injection), cutaneous reactions (urticaria/angioedema, periorbital edema), and/or other reactions (gastrointestinal symptoms such as nausea/vomiting, stomach cramps, and diarrhea). The test was considered negative if a patient tolerated the final dose (300 mg of aspirin) without any significant symptoms mentioned above.
Oral provocation test (OPT) with other NSAIDs, acetaminophen, or celecoxib
Patients with a history of an immediate reaction to only aspirin were challenged with escalating doses of ibuprofen to confirm the diagnosis of cross-reactive NSAID sensitivity. Patients with a history of an immediate reaction to a single NSAID were provoked with the suspected drug to verify the status of single NSAID hypersensitivity after a negative aspirin provocation test. Escalating doses of ibuprofen, diclofenac, and acetaminophen were administered, if applicable, as follows: ibuprofen (50, 100, and 200 mg), diclofenac (6.25, 12.5, and 25 mg), and acetaminophen (125, 250, and 500 mg). Celecoxib was also provoked in 3 doses (50, 100, and 200 mg) in patients with confirmed hypersensitivity to multiple NSAIDs who were willing to identify a safe alternative drug. The provocation test for each drug was performed on separate days at least 7 days apart. Each dose of drug provocation was provided at 90-minute intervals until the final dose was reached.
Classification of NSAID hypersensitivity according to drug provocation test results
Patients with cross-reactive NSAID phenotypes were classified according to the results of the drug provocation test as 1) NECD/NIUA if they developed cutaneous symptoms alone; 2) NERD if they developed respiratory symptoms alone; and 3) NIBR if they developed a combination of symptoms involving more than one organ system (respiratory, cutaneous, and/or gastrointestinal symptoms). Single NSAID hypersensitivity was diagnosed in patients with a positive provocation test to the suspected NSAID, but a negative aspirin provocation test. Patients who had negative provocations to both aspirin and the suspected culprit drug were labeled as NSAID-tolerant subjects. NECD/NIUA were purposely categorized together in our study to compare the differences and similarities between patients diagnosed with NSAID-induced cutaneous reactions and -respiratory reactions. Moreover, NECD and NIUA share similar background characteristics from a clinical point of view and some patients diagnosed with NIUA eventually evolve to NECD over time.32
Skin prick tests with common aeroallergens in Thailand (mixed dust mites, mixed cockroaches, mixed mold, cat dander, dog hair, and southern grass mix; ALK-Abello, Hørsholm, Denmark) were also examined in tested patients to identify atopic status. Wheal size ≥ 3 mm was considered a positive test.
Measurement of FeNO and the FEV1 in patients who underwent drug provocation test
FeNO was measured in all participants at baseline and after drug provocation by using a portable electrochemical analyzer (NObreath®; Bedfont Scientific Ltd, Maidstone, UK) according to the ATS/ERS recommendations.33 Measurements of FEV1 were also performed using a Vitalograph spirometer (Vitalograph®, Buckingham, UK). The best of 3 repeated attempts was recorded.
The uLTE4 measurement
The uLTE4 levels were measured by a leukotriene E4 ELISA kit (Cayman Chemical, Ann Arbor, MI, USA) at baseline and 90 minutes after the final dose of drug provocation, as well as at the follow-up visits after aspirin desensitization and reported after adjustment to urine creatinine levels.
Aspirin desensitization
Outpatient aspirin desensitization was performed in NSAID-sensitive patients who were referred from otolaryngologists to prevent the recurrence of nasal polyposis. The procedure was carried out according to the intranasal ketorolac and modified aspirin challenge 2-day protocol.34 Aspirin desensitization was completed after patients were able to tolerate a 325-mg dose of aspirin by the end of day 2 and experience no symptoms, changes in nasal flow rates, or decrease in FEV1 values. The prescribed maintenance dose of aspirin was 325 mg twice a day.
Statistical analysis
Patient characteristics are reported as means ± standard deviation for quantitative analysis, and median and interquartile range (IQR) are used to describe non-parametric data. The Mann-Whitney U test and Kruskal-Wallis test with Dunn's multiple comparisons were used to analyze the differences between 2 groups and more than 2 groups, respectively. Statistical analyses were performed using GraphPad Prism 8.3 software (GraphPad Software Inc., San Diego, CA, USA). P values < 0.05 were considered statistically significant.
Ethical considerations
Patients enrolled in this study were those who recruited in the study entitled “Characteristics of Patients Diagnosed With NSAID Sensitivity in Thailand” registered at ClinicalTrials.gov (NCT03849625). The study was approved by the Ethics and Research Committee of the Faculty of Medicine, Chulalongkorn University, Approval Number: COA No. 659/2012 and informed consent was obtained from all participants.
RESULTS
A total of 158 adult patients with a suspected history of NSAID hypersensitivity between 2015 and 2018 at King Chulalongkorn Memorial Hospital were initially recruited into this study as shown in Fig. 1. Thirty-five patients with a history compatible with a non-immediate hypersensitivity reaction and 4 subjects with clinical symptoms compatible with NSAID-related side effects were later excluded.
Fig. 1 Schematic diagram of patient selection for this study.
A total of 158 patients with a suspected history of NSAID hypersensitivity were initially recruited into this study. Cross-reactive NSAID hypersensitivity was clinically diagnosed in 67 patients with a well-documented drug allergy history and verified by a positive drug provocation test in 25 patients with a suggestive history of NSAID reactions.
NSAID, non-steroidal anti-inflammatory drug.
Cross-reactive NSAID hypersensitivity was clinically diagnosed in 67 patients with a convincing drug allergy history as defined in the methods section. The remaining 52 patients with a suggestive history of NSAID hypersensitivity underwent an OPT to confirm NSAID cross-reactivity status. Fifteen out of 25 patients with confirmed NSAID cross-reactivity were subsequently provoked with celecoxib to find a safe alternative NSAID. Single NSAID/acetaminophen hypersensitivity was verified in 6 patients who tolerated aspirin provocation but developed an allergic reaction upon re-challenge with acetaminophen or diclofenac.
Demographic data of adult patients with cross-reactive NSAID hypersensitivity
The clinical characteristics of adult patients with cross-reactive NSAID hypersensitivity are shown in Table 1 (n = 92). Most patients were females (77.2%) with an average age of 45.7 ± 13.4 years. The average age of onset was 32.2 ± 13.3 years and about half of them had atopic family history. The majority of them (56.5%) reported only cutaneous symptoms such as facial angioedema and/or acute urticarial rash, after NSAID exposure, while 9.8% of them developed only respiratory symptoms. Interestingly, about 33.7% of the patients experienced a combination of symptoms in multiple organ systems as shown in Fig. 2. The groups of NSAIDs frequently responsible for hypersensitivity reactions were propionic acid derivatives and acetic acid derivatives. Although inflammatory airway diseases (chronic sinusitis, nasal polyposis, and asthma) were significantly more common in patients who experienced only respiratory reactions after exposure to an NSAID compared to the other phenotypes, a significant portion of the patients reporting blended reactions had underlying airway diseases and chronic urticaria as well. Acetaminophen intolerance was also reported in about one-third (35.9%) of NSAID-sensitive subjects.
Table 1 Clinical characteristics among different phenotypes of patients with cross-reactive NSAID hypersensitivity (n = 92)
Phenotypes NECD/NIUA (n = 52) NERD (n = 9) NIBR (n = 31) Total (n = 92)
Gender (female/male) 37/15 6/3 28/3 71/21
Age (yr) 43.6 ± 12.3 47.3 ± 11.9 48.7 ± 15.3 45.7 ± 13.4
Age of onset (yr) 31.3 ± 13.8 34.6 ± 11.0 33.1 ± 13.3 32.2 ± 13.3
Underlying disease (%)
Chronic urticaria 13.5 11.1 29.0 18.5
Chronic sinusitis* 13.5 55.6 32.3 23.9
Nasal polyposis* 7.7 66.7 16.1 16.3
Asthma* 17.3 88.9 35.5 30.4
Atopic family history (%) 42.3 55.6 61.3 50.0
Drug exposure time to symptom onset (min) 58.8 ± 31.9 48.3 ± 34.3 47.6 ± 29.9 54.0 ± 31.6
Presenting symptoms (%)*
Facial/periorbital angioedema 71.2 0.0 74.2 65.2
Acute urticaria 73.1 0.0 61.3 62.0
Naso-ocular reaction 0.0 33.3 61.3 23.9
Acute asthma 0.0 88.9 67.7 31.5
Gastrointestinal symptoms 0.0 0.0 16.1 5.4
Implicated NSAIDs (%)†
Salicylic acids 23.1 55.6 35.5 30.4
Propionic acids 44.2 22.2 54.8 45.7
Acetic acids 23.1 22.2 48.4 31.5
Enolic acids 7.7 0.0 6.5 6.5
Anthranilic/fenamic acids 28.8 11.1 29.0 27.2
Acetaminophen intolerance (%)§ 28.8 22.2 51.6 35.9
Values are presented as number (%) or mean ± standard deviation. Each patient could present with multiple symptoms and from more than one implicated drug.
NSAID, non-steroidal anti-inflammatory drug; NECD, non-steroidal anti-inflammatory drug-exacerbated cutaneous (urticaria/angioedema) disease in patients with underlying chronic urticaria; NIUA, non-steroidal anti-inflammatory drug-induced urticaria/angioedema in patients without underlying chronic urticaria; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
*P < 0.05 among different phenotypes. †Examples of commonly implicated drugs in this study based on NSAID classification: 1) Salicylic acids: acetylsalicylic acid (aspirin), salicylic acid, diflunisal, salsalate; 2) Propionic acids: ibuprofen, naproxen, ketoprofen, fenoprofen, flurbiprofen; 3) Acetic acids: indomethacin, ketorolac, diclofenac, sulindac; 4) Enolic acids: piroxicam, meloxicam, tenoxicam; 5) Anthranilic/fenamic acids: mefenamic acid, flufenamic acid. §Acetaminophen intolerance: cannot tolerate acetaminophen higher than 500 mg.
Fig. 2 Clinical presentations in patients with cross-reactive NSAID hypersensitivity.
A proportional Venn diagram shows that about half of patients with cross-reactive NSAID hypersensitivity in Thailand reported only cutaneous symptoms after NSAID exposure, while one-third of them experienced NSAID-induced blended reactions.
NSAID, non-steroidal anti-inflammatory drug.
Clinical respiratory parameters and uLTE4 levels in different phenotypes of patients with cross-reactive NSAID hypersensitivity confirmed by positive OPT
NSAID hypersensitivity was confirmed in 59.6% (31/52) of the tested patients with a history of NSAID-induced immediate reactions. The majority of patients with cross-reactive NSAID hypersensitivity (17/25) according to OPT results were atopic individuals. The common phenotypes of patients with confirmed cross-reactive NSAID sensitivity were NECD/NIUA, NIBR, and NERD, respectively, as shown in Supplementary Table S1.
The average FeNO, %predicted FEV1, and uLTE4 levels were measured at baseline and after provocation with aspirin/NSAID in 25 NSAID cross-reactive and 21 NSAID-tolerant subjects as shown in Table 2. At baseline, patients with confirmed NSAID cross-reactivity (NSAID-sensitive group) had higher FeNO (P < 0.01) and slightly less %predicted FEV1 compared to the NSAID-tolerant subjects, while basal uLTE4 levels between NSAID-sensitive and NSAID-tolerant groups were comparable. After provocation, %predicted FEV1 was substantially reduced in NSAID-sensitive subjects, whereas uLTE4 levels were significantly elevated compared to the NSAID-tolerant group (P < 0.01). Celecoxib provocation was well tolerated in all NSAID-sensitive subjects. No statistical differences in the average FeNO, %predicted FEV1, or uLTE4 levels in 15 NSAID-sensitive patients (7 NECD/NIUA, 4 NIBR, 4 NERD) after celecoxib provocation were observed compared to those in NSAID-tolerant subjects.
Table 2 Respiratory parameters and uLTE4 levels in NSAID-sensitive subjects upon provocation with aspirin or celecoxib compared to NSAID-tolerant subjects
Characteristics Baseline After aspirin (OPT) P value*
NSAID tolerant (n = 21)
FeNO (ppb) 13.0 (8.5–19.5) 10.2 (7.0–16.8) 0.03
%predicted FEV1 100.8 (82.8–115.9) 99.0 (75.2–118.2) 0.90
uLTE4 (pg/mg creatinine) 116.3 (66.5–305.4) 122.1 (63.5–173.8) 0.17
NSAID sensitive (n = 25)
FeNO (ppb) 27.0 (17.8–40.9)† 18.0 (10.5–31.0) <0.01
%predicted FEV1 86.7 (63.3–104.9) 74.6 (52.4–89.8)† <0.01
uLTE4 (pg/mg creatinine) 118.3 (93.2–407.2) 204.9 (90.6–817.8)† <0.01
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; OPT, oral provocation test; ppb, parts per billion; FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in 1 second.
*P values before vs. after provocation test, Wilcoxon signed-rank test; †P < 0.01 compared to the NSAID-tolerant subjects.
According to the subgroup analysis, 10 NECD/NIUA, 9 NIBR, and 6 NERD were categorized as shown in Fig. 3. At baseline, %predicted FEV1 was not significantly different among different types of cross-reactive NSAID hypersensitivity, although those in patients with confirmed NIBR were lowest (64.9%, IQR 56.9–97.3). The significant differences in basal FeNO levels (P < 0.01) among the 3 different phenotypes were observed. The basal FeNO levels were significantly higher in NIBR (36.9%, IQR 27.0–95.4) than in NSAID-tolerant subjects (P < 0.01). After aspirin OPT, the reduction of %FEV1 was considerably higher in patients with confirmed NERD (22.0%, IQR 16.0-28.8), followed by NIBR (13.3%, IQR 7.6–28.0), compared to those in NSAID-tolerant groups (P < 0.01). Basal uLTE4 levels were not significantly different among the 3 phenotypes. Interestingly, uLTE4 levels after aspirin provocation were significantly higher in NERD and NIBR patients than in the NECD/NIUA and NSAID-tolerant groups (P < 0.05 and < 0.01, respectively).
Fig. 3 Respiratory parameters and uLTE4 levels in different phenotypes of NSAID-sensitive subjects compared to NSAID-tolerant subjects.
Baseline FeNO in NIBR and NERD were higher than those in the NSAID-tolerant group. After aspirin provocation, % predicted FEV1 in NERD and NIBR were significantly reduced from the baseline while uLTE4 levels were much higher than those in NSAID-tolerant subjects.
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; FEV1, forced expiratory volume in 1 second.
*P values < 0.05, †P values < 0.01.
Effects of aspirin desensitization on uLTE4 levels in patients diagnosed with NERD and NIBR
Aspirin desensitization was performed in selected patients (3 NERD and 3 NIBR) who had pre-existing inflammatory airway diseases and a history of recurrent nasal polyposis after surgery as shown in Table 3. The maintenance dose of aspirin was 650 mg/day during the first 6 months and reduced to 325 mg/day afterward. Levels of uLTE4 were measured at baseline after aspirin desensitization and serially followed up for 2–3 years as demonstrated in Fig. 4. Other than respiratory symptoms, acute urticarial rash and gastrointestinal symptoms (abdominal cramp/nausea/diarrhea) were also aggravated in NIBR subjects during aspirin desensitization as shown in Supplementary Fig. S1, but gradually relieved with supportive treatment. No sinus surgery was required for nasal polyp recurrence, and asthma symptoms were under control after aspirin desensitization in all 6 cases. Up to 3 years after aspirin desensitization, however, uLTE4 levels were significantly increased and remained elevated throughout the follow-up period, although urticarial rash and gastrointestinal symptoms were no longer observed while taking aspirin.
Table 3 Details of patients with cross-reactive NSAID hypersensitivity undergoing aspirin desensitization in this study
Patients (sex/year) Underlying diseases History of adverse drug reactions Indication for aspirin desensitization Follow-up duration (months) Asthma control before/after aspirin desensitization Recurrent nasal polyposis after aspirin desensitization Skin symptoms after aspirin desensitization Gastrointestinal symptoms after aspirin desensitization
1. NERD (M/46) Chronic sinusitis, nasal polyposis, asthma Acute asthma 20 min after taking aspirin 2 recurrent nasal polyps 74 Partly controlled with high dose ICS-LABA and add-on LTRA/well controlled with low dose ICS None NA NA
2. NERD (M/54) Chronic rhinitis, nasal polyposis, asthma Acute asthma, blocked nose 1 hr after taking aspirin 3 recurrent nasal polyps 24 Uncontrolled with high dose ICS-LABA and add-on LTRA/well controlled with medium dose ICS-LABA None NA NA
3. NERD (M/56) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked nose 1 hr after taking ibuprofen 6 recurrent nasal polyps 32 Partly controlled asthma with high dose ICS-LABA and add-on LTRA/well controlled with medium dose ICS-LABA None NA NA
4. NIBR (M/48) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked nose, conjunctival injection, urticarial rash 2 hr after taking aspirin 3 recurrent nasal polyps 72 Partly controlled with medium dose ICS-LABA/well controlled with low dose ICS-LABA None No rash after taking aspirin NA
5. NIBR (F/65) Chronic sinusitis, nasal polyposis, chronic urticaria, asthma (history of cardiac arrest from severe asthma) Urticarial rash, periorbital angioedema, blocked nose, conjunctival injection, rhinorrhea, bronchospasm/wheezing, hoarseness of voice 1 hr after taking aspirin, ibuprofen, mefenamic acid, acetaminophen 2 recurrent nasal polyps 48 Uncontrolled with high dose ICS-LABA and add-on LTRA/well controlled with low dose ICS-LABA None No rash after taking aspirin, chronic urticaria resolved NA
6. NIBR (F/38) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked/running nose, stomach cramp, diarrhea, periorbital angioedema, urticaria 30 min after taking ibuprofen, indomethacin, mefenamic acid 2 recurrent nasal polyps 21 Partly controlled with medium dose ICS-LABA/well controlled, with medium dose ICS-LABA None No rash after taking aspirin No gastrointestinal symptoms after taking aspirin
NSAID, non-steroidal anti-inflammatory drug; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; ICS, inhaled corticosteroid; LABA, long-acting beta-agonist; LTRA, leukotriene receptor antagonist; NA, not applicable (no symptoms prior to aspirin desensitization); NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
Fig. 4 uLTE4 levels in NSAID-sensitive subjects after aspirin desensitization.
Our study demonstrated that uLTE4 levels (pg/mg creatinine) in 3 NERD and 3 NIBR patients were increased and remained elevated up to 3 years after aspirin desensitization even though recurrent nasal polyposis was successfully prevented in all cases.
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
DISCUSSION
Most studies on NSAID hypersensitivity have focused on NERD, although worldwide epidemiological data suggest that NECD/NIUA might be more common. Recent data have demonstrated that some patients cannot be categorized into the current classification of NSAID hypersensitivity, for example those with NSAID-induced periorbital angioedema and NIBR.1419 These patients may also have underlying chronic airway diseases; however, the role of aspirin desensitization in the prevention of recurrent nasal polyposis and control of airway inflammation in NSAID-sensitive subjects other than the NERD phenotype has never been reported.
The leading presentations in NSAID-sensitive subjects in this study were periorbital angioedema, acute urticaria, bronchial symptoms, and naso-ocular reactions, respectively. Even those confirmed with NSAID exposure, a significant number of patients in our cohort also showed clinical responses in more than 1 organ system, indicating that the prevalence of NIBR was higher than previously thought. Although patients with IgE-mediated anaphylaxis might also present with multiple organ involvement, the fact that most of the reactions took about 1–2 hours to occur and the ability to react to multiple NSAIDs with dissimilar chemical structures made them more compatible with the non-immunologic effect of the drugs.
Facial angioedema around the periorbital area was the most common presenting symptom in Thai patients. Upon NSAID provocation, however, the predominant periorbital angioedema often accompanied by blocked nose, running nose, and itchy/red eyes. After a thorough examination, small urticarial rash on the trunk and extremities, and expiratory wheezing were occasionally detected, although frequently asymptomatic. It is noteworthy that periorbital angioedema may persist for hours or days while urticarial rash and respiratory symptoms are quickly resolved after treatment. As a result, NIBR could be underdiagnosed if history taking is not thoroughly reviewed, since symptoms with lesser severity in other organ systems may be unnoticed. In addition, the COX-1 inhibitor properties of the exposed NSAIDs could affect the phenotype of NSAID sensitivity reported by patients as some patients experienced both asthmatic attack and periorbital angioedema/generalized urticaria after taking aspirin but reported only periorbital edema after taking acetaminophen.
It is practically difficult to clearly distinguish between NSAID-induced periorbital angioedema and NSAID-induced naso-ocular reactions (upper airway manifestations of NERD), since patients occasionally experienced periorbital swelling, red/swollen eyes with tearing, and nasal congestion at the same time. In our opinion, the majority of NSAID hypersensitivity in the Thai population would be described as “NSAID-induced blended reaction with predominant periorbital angioedema” and probably related to “NSAID-induced isolated periorbital angioedema” phenotype as proposed by the Spanish group. It is interesting to note that the prevalence of atopic disease was high in this patient group. We speculate that the increased leukotriene production after NSAID consumption could lead to the worsening of pre-existing mucosal inflammation around the nose and eyes in patients who already suffered from the late-phase reaction of persistent allergic rhinitis.
Our study did not find any difference in terms of basal uLTE4 levels between NSAID-sensitive and NSAID-tolerant subjects. However, uLTE4 levels were higher in NSAID-sensitive patients, particularly in NERD and NIBR subjects, after the NSAID challenge compared to those in the NSAID-tolerant group. Though basal uLTE4 levels may not be a suitable marker to screen NSAID sensitivity status, elevated uLTE4 levels after aspirin OPT could be the supporting evidence for the diagnosis of cross-reactive NSAID hypersensitivity in cases where the clinical response is equivocal. Our study demonstrated that the degree of defective leukotriene homeostasis after exposure to drugs affecting the cyclo-oxygenase pathway might be related to the severity of respiratory involvement upon NSAID exposure.35 The fact that uLTE4 levels were barely changed after celecoxib provocation in patients with NSAID cross-reactivity confirms that celecoxib is a safe alternative NSAID in these patient groups.
According to our study, the patterns of NSAID hypersensitivity in southeast Asians are similar to those in southern Europeans and Latin Americans, and somewhat different from those reported in patients of northern European descent. Previous data suggested that aspirin nasal provocation could potentially diagnose some NSAID-sensitive patients presenting with predominant cutaneous reactions.3637 Retrospectively, some of these patients might be re-classified as the NIBR phenotype, since a decreased nasal volume was also observed. In other words, patients diagnosed with an NSAID-induced cutaneous reaction who positively reacted to NSAID nasal provocation, especially those with a periorbital reaction, might be NIBR subjects with subclinical airway involvement.
The novelties of this study were the findings that NIBR accounted for about one-third of adult patients with cross-reactive NSAID hypersensitivity and that aspirin desensitization could successfully prevent the recurrence of nasal polyposis and alleviate respiratory symptoms not only in NERD, but also in NIBR, even though urine LTE4 levels remained elevated. However, since the reactions in some NIBR patients could lead to serious adverse events, aspirin desensitization in NIBR subjects should be performed only when it is strongly indicated in selected patients with no previous severe reactions to NSAIDs. In NIBR subjects who experienced previous severe reactions in multiple organ systems, the procedure of aspirin desensitization, if necessary, should be carefully monitored and the administration of biological agents such as dupilumab, if available, should be considered a safer therapeutic option in these cases.
Interestingly, uLTE4 levels were increased after aspirin desensitization and remained elevated throughout the follow-up period. It should be emphasized that urticarial rash and stomach-ache in NIBR patients also disappeared while patients were taking daily aspirin. These data suggest that the pathogenesis of nasal polyposis cannot be explained by cysLT overproduction alone and that aspirin desensitization could be useful to alleviate both respiratory and non-respiratory symptoms in NIBR subjects.
Interestingly, a recent study also found that the clinical benefit of high-dose aspirin desensitization in NERD was independent of a reduction of mast cell activation and cysLT production. They reported paradoxically increased uLTE4 levels 8 weeks after aspirin desensitization compared to the baseline levels and concluded that high-dose aspirin therapy did not restore the impaired eicosanoid pathway.38 According to their study findings and ours, the therapeutic effect of aspirin desensitization was not directly correlated with a change of arachidonic acid metabolism.
There are some limitations to this study. Aspirin desensitization was performed in only 6 patients in our cohort; therefore, the comparative success rates and potential adverse reactions of aspirin desensitization between NERD and NIBR patients could not be analyzed. Further studies with a larger sample size are needed to compare the long-term prognosis between NERD and NIBR, to understand the mechanism of aspirin desensitization for the improvement of respiratory and extra-respiratory symptoms and to evaluate its risk-benefit ratio of aspirin desensitization in NIBR subjects.
In conclusion, NIBR is not uncommon among patients diagnosed with NSAID hypersensitivity in Thailand. Increased uLTE4 levels upon aspirin provocation suggested a diagnosis of NSAID cross-reactivity, while baseline uLTE4 levels were not distinguishable between NSAID-tolerant and NSAID-sensitive subjects. Our study indicates that aspirin desensitization is effective not only in NERD but also in NIBR. The persistently high levels of uLTE4 in spite of clinical improvement in NSAID-sensitive patients after successful aspirin desensitization suggest that elevated leukotrienes alone cannot explain the pathogenesis of NSAID hypersensitivity reactions.
ACKNOWLEDGMENTS
This study was supported by the Ratchadaphiseksomphot fund, Faculty of Medicine, Chulalongkorn University, grant No. RA55/19 and the Skin and Allergy Research Unit, Chulalongkorn University, Bangkok, Thailand. Study data were collected and managed using Research Electronic Data Capture (REDCap) hosted at HIV Netherlands Australia Thailand Research Collaboration. The authors thank Thitima Kantachatvanich, MD for providing patient information.
Disclosure: There are no financial or other issues that might lead to conflict of interest.
SUPPLEMENTARY MATERIALS
Supplementary Table S1
Clinical characteristics of patients with confirmed NSAID-induced immediate reactions
Supplementary Fig. S1
Representative photos of skin rash demonstrated during aspirin desensitization in NIBR patients. | ACETAMINOPHEN\HYDROCODONE, ASPIRIN, IBUPROFEN, MEFENAMIC ACID | DrugsGivenReaction | CC BY-NC | 33474858 | 19,056,205 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Dermatitis allergic'. | Clinical Characteristics, Urinary Leukotriene E4 Levels, and Aspirin Desensitization Results in Patients With NSAID-Induced Blended Reactions.
OBJECTIVE
Data on non-steroidal anti-inflammatory drug (NSAID) hypersensitivity in Southeast Asia are scarce. Increased urinary leukotriene E4 (uLTE4) levels have been suggested as a biomarker of NSAID-exacerbated respiratory disease (NERD). This study investigated clinical patterns of NSAID sensitivity in Thailand and the diagnostic roles of uLTE4 measurement in various phenotypes.
METHODS
The clinical phenotypes in 92 Thai adults with cross-reactive NSAID hypersensitivity were characterized based on the clinical history and drug provocation. The uLTE4 levels were measured at baseline, after aspirin provocation and after desensitization.
RESULTS
More than half of the patients (56.5%) presented with cutaneous symptoms (NSAID-exacerbated cutaneous disease), while one-third (33.7%) developed symptoms in at least 2 systems (NSAID-induced blended reactions; NIBR). Fifty-two patients underwent drug provocation and 59.6% of them yielded positive results. After drug provocation, a significant number of patients with confirmed NSAID cross-reactivity experienced clinical symptoms in more than one organ system. The uLTE4 levels at baseline were comparable between the NSAID-tolerant and NSAID-sensitive groups, but were substantially increased after aspirin provocation predominantly in NERD (983.4 pg/mg creatinine) and NIBR (501.0 pg/mg creatinine) compared to NSAID-tolerant subjects (122.1 pg/mg creatinine, P < 0.01 and 0.05, respectively). The uLTE4 levels were elevated after aspirin desensitization, although nasal polyposis and asthma were under control in 3 NERD and 3 NIBR subjects.
CONCLUSIONS
NIBR is not uncommon among NSAID-sensitive patients in Thailand. The diagnostic value of basal uLTE4 levels was limited, but increased uLTE4 levels upon aspirin provocation suggest NSAID cross-reactivity with respiratory components. This study indicates that aspirin desensitization, if necessary, might be effective in both NERD and NIBR.
BACKGROUND
ClinicalTrials.gov Identifier: NCT03849625.
INTRODUCTION
Hypersensitivity reactions to aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most common drug allergic reactions in clinical practice. They are generally categorized into 5 major phenotypes: NSAID-exacerbated respiratory disease (NERD), NSAID-exacerbated cutaneous (urticaria/angioedema) disease (NECD) in patients with underlying chronic urticaria, NSAID-induced urticaria/angioedema (NIUA) in patients without underlying chronic urticaria, single NSAID-induced urticaria/angioedema or anaphylaxis, and single NSAID-induced delayed hypersensitivity reactions.1 The first 3 phenotypes are non-immunologically mediated, and patients can develop cross-reactive hypersensitivity to chemically unrelated NSAIDs, while the latter 2 are selective NSAID sensitivities associated with drug-specific immunoglobulin E (IgE) and T-cell response, respectively.
Genetic and epigenetic variations play significant roles in the development of NERD.2 The proposed underlying mechanism is that the disturbance in arachidonic acid synthesis pathways leads to overproduction of cysteinyl leukotrienes (cysLT) and persistent airway inflammation.3 Mast cells are believed to be the major source of cysLT, but platelet-adherent leukocytes may be responsible for cysLT overproduction in NERD as well.4 The consumption of drugs inhibiting the cyclooxygenase-1 (COX-1) enzyme, such as aspirin and conventional NSAIDs, aggravates respiratory symptoms by enhancing cysLT production in NSAID-sensitive subjects, while the administration of specific COX-2 inhibitors, such as celecoxib, is generally safe.56 Besides aspirin/NSAID avoidance, aspirin desensitization has also been proven to be helpful for long term management in NERD subjects. Beneficial effects of aspirin desensitization in preventing nasal polyp recurrence and control symptoms of chronic rhinosinusitis and asthma have been well documented.7 Rapid aspirin desensitization has shown to be effective for the treatment of coronary artery disease in patients with a history of aspirin/NSAID-induced urticaria/angioedema, but it is not indicated for the treatment of chronic urticaria.8
Worldwide epidemiological data on clinical characteristics of NSAID hypersensitivity are limited. Most studies on NERD were performed in the United States and northern European countries.9101112 However, the predominant manifestation in Latin Americans and southern Europeans is the cutaneous phenotype (NIUA, NECD, and NSAID-induced isolated periorbital angioedema).1314 Studies in Asian populations have suggested that the prevalence of the NERD phenotype is not common in this region of the world. A study performed in China indicated that the prevalence of NSAID hypersensitivity in Chinese patients with chronic rhinosinusitis is very low (0.57%) compared to their European counterparts.15 It was also noted that NSAID-induced blended reactions (NIBR) are common in young Asian, atopic children in Singapore.16 Reports from Singapore and Thailand indicated that aspirin/NSAID-induced angioedema/urticaria is probably the prominent phenotype in Southeast Asia, with acetaminophen hypersensitivity being frequent.1718
In clinical practice, the current classification of cross-reactive NSAID hypersensitivity into 3 distinct phenotypes has some limitations. Clinical characteristics in NSAID-sensitive patients may not be well defined, and a combination of respiratory and cutaneous or other symptoms, such as gastrointestinal symptoms (mixed or blended reactions), is frequently observed.19 A previous report stated that aspirin nasal provocation is potentially useful for diagnosing patients with the blended reaction as well.20 However, the role of aspirin desensitization in other phenotypes of NSAID hypersensitivity, besides NERD, for long-term management of inflammatory airway diseases has not yet been established. Whether aspirin desensitization would be effective in controlling asthma and the recurrence of nasal polyposis after sinus surgery in NIBR is currently unknown.
At present, cross-reactive types of NSAID hypersensitivity can only be diagnosed by careful history taking and controlled-provocation testing, since there is no reliable in vitro method to confirm the diagnosis.21 There is evidence that basal urinary levels of leukotriene E4 (uLTE4), a stable product of the cysLT synthesis pathway, are elevated in NERD patients and could be a potential biomarker for differentiating between NSAID-sensitive and NSAID-tolerant asthmatics. However, these data are still controversial.222324 There have also been preliminary studies showing that uLTE4 levels might be increased in NECD.2526 Whether the measurement of basal uLTE4 levels could be a diagnostic marker for any phenotype of NSAID hypersensitivity is yet to be explored.
The purpose of this study was to analyze the clinical characteristics of patients diagnosed with NSAID-induced immediate reactions in Thailand and to explore whether the measurement of uLTE4 levels would be helpful in identifying NSAID-sensitive subjects or in differentiating among different phenotypes of cross-reactive NSAID hypersensitivities.
MATERIALS AND METHODS
Patient recruitment
Adult patients (18 years of age and older) with a suggestive history of NSAID-induced hypersensitivity reaction visiting the allergy clinic at King Chulalongkorn University Hospital between June 2014 and July 2018 were recruited into this study. Those with a history compatible with drug-induced non-immediate reactions (maculopapular rash, fixed drug eruption, acute generalized exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms, Stevens-Johnson syndrome/toxic epidermal necrolysis) or NSAID-related side effects were excluded. The status of NSAID-induced immediate hypersensitivity was diagnosed in patients with a well-documented drug allergy history or in patients with a suggestive history of NSAID sensitivity who yielded a positive drug provocation test as follows.
Clinical diagnosis of NSAID hypersensitivity
The diagnosis of cross-reactive NSAID hypersensitivity was clinically made in patients with a well-documented history of multiple episodes of respiratory, cutaneous, and/or gastrointestinal reactions within 2 hours after exposure to at least 2 different NSAID classes.1212728 Patient demographic data were collected, including the underlying diseases, atopic family history, and details on drug allergy history as well as the presenting symptoms and types of the culprit NSAIDs.
Aspirin provocation test
Oral aspirin provocation was performed in patients with a suggestive medical history or in those who had a history of an immediate reaction to a single NSAID to confirm the diagnosis of cross-reactive NSAID hypersensitivity according to the EAACI/GA2LEN guidelines, with some modifications.293031 Four increasing doses of aspirin (40.5, 81, 150, and 300 mg) were administered at 90-minute intervals until a positive reaction occurred. Clinical symptoms, fractional exhaled nitric oxide (FeNO), and the forced expiratory volume in 1 second (FEV1) were monitored to evaluate the reaction. A positive provocation test was defined if any of the following reactions developed: lower respiratory/bronchial reaction (a 15% decrease in FEV1 plus naso-ocular reaction or a 20% decrease in FEV1 alone), upper respiratory/naso-ocular reaction (nasal congestion and rhinorrhea; conjunctival injection), cutaneous reactions (urticaria/angioedema, periorbital edema), and/or other reactions (gastrointestinal symptoms such as nausea/vomiting, stomach cramps, and diarrhea). The test was considered negative if a patient tolerated the final dose (300 mg of aspirin) without any significant symptoms mentioned above.
Oral provocation test (OPT) with other NSAIDs, acetaminophen, or celecoxib
Patients with a history of an immediate reaction to only aspirin were challenged with escalating doses of ibuprofen to confirm the diagnosis of cross-reactive NSAID sensitivity. Patients with a history of an immediate reaction to a single NSAID were provoked with the suspected drug to verify the status of single NSAID hypersensitivity after a negative aspirin provocation test. Escalating doses of ibuprofen, diclofenac, and acetaminophen were administered, if applicable, as follows: ibuprofen (50, 100, and 200 mg), diclofenac (6.25, 12.5, and 25 mg), and acetaminophen (125, 250, and 500 mg). Celecoxib was also provoked in 3 doses (50, 100, and 200 mg) in patients with confirmed hypersensitivity to multiple NSAIDs who were willing to identify a safe alternative drug. The provocation test for each drug was performed on separate days at least 7 days apart. Each dose of drug provocation was provided at 90-minute intervals until the final dose was reached.
Classification of NSAID hypersensitivity according to drug provocation test results
Patients with cross-reactive NSAID phenotypes were classified according to the results of the drug provocation test as 1) NECD/NIUA if they developed cutaneous symptoms alone; 2) NERD if they developed respiratory symptoms alone; and 3) NIBR if they developed a combination of symptoms involving more than one organ system (respiratory, cutaneous, and/or gastrointestinal symptoms). Single NSAID hypersensitivity was diagnosed in patients with a positive provocation test to the suspected NSAID, but a negative aspirin provocation test. Patients who had negative provocations to both aspirin and the suspected culprit drug were labeled as NSAID-tolerant subjects. NECD/NIUA were purposely categorized together in our study to compare the differences and similarities between patients diagnosed with NSAID-induced cutaneous reactions and -respiratory reactions. Moreover, NECD and NIUA share similar background characteristics from a clinical point of view and some patients diagnosed with NIUA eventually evolve to NECD over time.32
Skin prick tests with common aeroallergens in Thailand (mixed dust mites, mixed cockroaches, mixed mold, cat dander, dog hair, and southern grass mix; ALK-Abello, Hørsholm, Denmark) were also examined in tested patients to identify atopic status. Wheal size ≥ 3 mm was considered a positive test.
Measurement of FeNO and the FEV1 in patients who underwent drug provocation test
FeNO was measured in all participants at baseline and after drug provocation by using a portable electrochemical analyzer (NObreath®; Bedfont Scientific Ltd, Maidstone, UK) according to the ATS/ERS recommendations.33 Measurements of FEV1 were also performed using a Vitalograph spirometer (Vitalograph®, Buckingham, UK). The best of 3 repeated attempts was recorded.
The uLTE4 measurement
The uLTE4 levels were measured by a leukotriene E4 ELISA kit (Cayman Chemical, Ann Arbor, MI, USA) at baseline and 90 minutes after the final dose of drug provocation, as well as at the follow-up visits after aspirin desensitization and reported after adjustment to urine creatinine levels.
Aspirin desensitization
Outpatient aspirin desensitization was performed in NSAID-sensitive patients who were referred from otolaryngologists to prevent the recurrence of nasal polyposis. The procedure was carried out according to the intranasal ketorolac and modified aspirin challenge 2-day protocol.34 Aspirin desensitization was completed after patients were able to tolerate a 325-mg dose of aspirin by the end of day 2 and experience no symptoms, changes in nasal flow rates, or decrease in FEV1 values. The prescribed maintenance dose of aspirin was 325 mg twice a day.
Statistical analysis
Patient characteristics are reported as means ± standard deviation for quantitative analysis, and median and interquartile range (IQR) are used to describe non-parametric data. The Mann-Whitney U test and Kruskal-Wallis test with Dunn's multiple comparisons were used to analyze the differences between 2 groups and more than 2 groups, respectively. Statistical analyses were performed using GraphPad Prism 8.3 software (GraphPad Software Inc., San Diego, CA, USA). P values < 0.05 were considered statistically significant.
Ethical considerations
Patients enrolled in this study were those who recruited in the study entitled “Characteristics of Patients Diagnosed With NSAID Sensitivity in Thailand” registered at ClinicalTrials.gov (NCT03849625). The study was approved by the Ethics and Research Committee of the Faculty of Medicine, Chulalongkorn University, Approval Number: COA No. 659/2012 and informed consent was obtained from all participants.
RESULTS
A total of 158 adult patients with a suspected history of NSAID hypersensitivity between 2015 and 2018 at King Chulalongkorn Memorial Hospital were initially recruited into this study as shown in Fig. 1. Thirty-five patients with a history compatible with a non-immediate hypersensitivity reaction and 4 subjects with clinical symptoms compatible with NSAID-related side effects were later excluded.
Fig. 1 Schematic diagram of patient selection for this study.
A total of 158 patients with a suspected history of NSAID hypersensitivity were initially recruited into this study. Cross-reactive NSAID hypersensitivity was clinically diagnosed in 67 patients with a well-documented drug allergy history and verified by a positive drug provocation test in 25 patients with a suggestive history of NSAID reactions.
NSAID, non-steroidal anti-inflammatory drug.
Cross-reactive NSAID hypersensitivity was clinically diagnosed in 67 patients with a convincing drug allergy history as defined in the methods section. The remaining 52 patients with a suggestive history of NSAID hypersensitivity underwent an OPT to confirm NSAID cross-reactivity status. Fifteen out of 25 patients with confirmed NSAID cross-reactivity were subsequently provoked with celecoxib to find a safe alternative NSAID. Single NSAID/acetaminophen hypersensitivity was verified in 6 patients who tolerated aspirin provocation but developed an allergic reaction upon re-challenge with acetaminophen or diclofenac.
Demographic data of adult patients with cross-reactive NSAID hypersensitivity
The clinical characteristics of adult patients with cross-reactive NSAID hypersensitivity are shown in Table 1 (n = 92). Most patients were females (77.2%) with an average age of 45.7 ± 13.4 years. The average age of onset was 32.2 ± 13.3 years and about half of them had atopic family history. The majority of them (56.5%) reported only cutaneous symptoms such as facial angioedema and/or acute urticarial rash, after NSAID exposure, while 9.8% of them developed only respiratory symptoms. Interestingly, about 33.7% of the patients experienced a combination of symptoms in multiple organ systems as shown in Fig. 2. The groups of NSAIDs frequently responsible for hypersensitivity reactions were propionic acid derivatives and acetic acid derivatives. Although inflammatory airway diseases (chronic sinusitis, nasal polyposis, and asthma) were significantly more common in patients who experienced only respiratory reactions after exposure to an NSAID compared to the other phenotypes, a significant portion of the patients reporting blended reactions had underlying airway diseases and chronic urticaria as well. Acetaminophen intolerance was also reported in about one-third (35.9%) of NSAID-sensitive subjects.
Table 1 Clinical characteristics among different phenotypes of patients with cross-reactive NSAID hypersensitivity (n = 92)
Phenotypes NECD/NIUA (n = 52) NERD (n = 9) NIBR (n = 31) Total (n = 92)
Gender (female/male) 37/15 6/3 28/3 71/21
Age (yr) 43.6 ± 12.3 47.3 ± 11.9 48.7 ± 15.3 45.7 ± 13.4
Age of onset (yr) 31.3 ± 13.8 34.6 ± 11.0 33.1 ± 13.3 32.2 ± 13.3
Underlying disease (%)
Chronic urticaria 13.5 11.1 29.0 18.5
Chronic sinusitis* 13.5 55.6 32.3 23.9
Nasal polyposis* 7.7 66.7 16.1 16.3
Asthma* 17.3 88.9 35.5 30.4
Atopic family history (%) 42.3 55.6 61.3 50.0
Drug exposure time to symptom onset (min) 58.8 ± 31.9 48.3 ± 34.3 47.6 ± 29.9 54.0 ± 31.6
Presenting symptoms (%)*
Facial/periorbital angioedema 71.2 0.0 74.2 65.2
Acute urticaria 73.1 0.0 61.3 62.0
Naso-ocular reaction 0.0 33.3 61.3 23.9
Acute asthma 0.0 88.9 67.7 31.5
Gastrointestinal symptoms 0.0 0.0 16.1 5.4
Implicated NSAIDs (%)†
Salicylic acids 23.1 55.6 35.5 30.4
Propionic acids 44.2 22.2 54.8 45.7
Acetic acids 23.1 22.2 48.4 31.5
Enolic acids 7.7 0.0 6.5 6.5
Anthranilic/fenamic acids 28.8 11.1 29.0 27.2
Acetaminophen intolerance (%)§ 28.8 22.2 51.6 35.9
Values are presented as number (%) or mean ± standard deviation. Each patient could present with multiple symptoms and from more than one implicated drug.
NSAID, non-steroidal anti-inflammatory drug; NECD, non-steroidal anti-inflammatory drug-exacerbated cutaneous (urticaria/angioedema) disease in patients with underlying chronic urticaria; NIUA, non-steroidal anti-inflammatory drug-induced urticaria/angioedema in patients without underlying chronic urticaria; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
*P < 0.05 among different phenotypes. †Examples of commonly implicated drugs in this study based on NSAID classification: 1) Salicylic acids: acetylsalicylic acid (aspirin), salicylic acid, diflunisal, salsalate; 2) Propionic acids: ibuprofen, naproxen, ketoprofen, fenoprofen, flurbiprofen; 3) Acetic acids: indomethacin, ketorolac, diclofenac, sulindac; 4) Enolic acids: piroxicam, meloxicam, tenoxicam; 5) Anthranilic/fenamic acids: mefenamic acid, flufenamic acid. §Acetaminophen intolerance: cannot tolerate acetaminophen higher than 500 mg.
Fig. 2 Clinical presentations in patients with cross-reactive NSAID hypersensitivity.
A proportional Venn diagram shows that about half of patients with cross-reactive NSAID hypersensitivity in Thailand reported only cutaneous symptoms after NSAID exposure, while one-third of them experienced NSAID-induced blended reactions.
NSAID, non-steroidal anti-inflammatory drug.
Clinical respiratory parameters and uLTE4 levels in different phenotypes of patients with cross-reactive NSAID hypersensitivity confirmed by positive OPT
NSAID hypersensitivity was confirmed in 59.6% (31/52) of the tested patients with a history of NSAID-induced immediate reactions. The majority of patients with cross-reactive NSAID hypersensitivity (17/25) according to OPT results were atopic individuals. The common phenotypes of patients with confirmed cross-reactive NSAID sensitivity were NECD/NIUA, NIBR, and NERD, respectively, as shown in Supplementary Table S1.
The average FeNO, %predicted FEV1, and uLTE4 levels were measured at baseline and after provocation with aspirin/NSAID in 25 NSAID cross-reactive and 21 NSAID-tolerant subjects as shown in Table 2. At baseline, patients with confirmed NSAID cross-reactivity (NSAID-sensitive group) had higher FeNO (P < 0.01) and slightly less %predicted FEV1 compared to the NSAID-tolerant subjects, while basal uLTE4 levels between NSAID-sensitive and NSAID-tolerant groups were comparable. After provocation, %predicted FEV1 was substantially reduced in NSAID-sensitive subjects, whereas uLTE4 levels were significantly elevated compared to the NSAID-tolerant group (P < 0.01). Celecoxib provocation was well tolerated in all NSAID-sensitive subjects. No statistical differences in the average FeNO, %predicted FEV1, or uLTE4 levels in 15 NSAID-sensitive patients (7 NECD/NIUA, 4 NIBR, 4 NERD) after celecoxib provocation were observed compared to those in NSAID-tolerant subjects.
Table 2 Respiratory parameters and uLTE4 levels in NSAID-sensitive subjects upon provocation with aspirin or celecoxib compared to NSAID-tolerant subjects
Characteristics Baseline After aspirin (OPT) P value*
NSAID tolerant (n = 21)
FeNO (ppb) 13.0 (8.5–19.5) 10.2 (7.0–16.8) 0.03
%predicted FEV1 100.8 (82.8–115.9) 99.0 (75.2–118.2) 0.90
uLTE4 (pg/mg creatinine) 116.3 (66.5–305.4) 122.1 (63.5–173.8) 0.17
NSAID sensitive (n = 25)
FeNO (ppb) 27.0 (17.8–40.9)† 18.0 (10.5–31.0) <0.01
%predicted FEV1 86.7 (63.3–104.9) 74.6 (52.4–89.8)† <0.01
uLTE4 (pg/mg creatinine) 118.3 (93.2–407.2) 204.9 (90.6–817.8)† <0.01
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; OPT, oral provocation test; ppb, parts per billion; FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in 1 second.
*P values before vs. after provocation test, Wilcoxon signed-rank test; †P < 0.01 compared to the NSAID-tolerant subjects.
According to the subgroup analysis, 10 NECD/NIUA, 9 NIBR, and 6 NERD were categorized as shown in Fig. 3. At baseline, %predicted FEV1 was not significantly different among different types of cross-reactive NSAID hypersensitivity, although those in patients with confirmed NIBR were lowest (64.9%, IQR 56.9–97.3). The significant differences in basal FeNO levels (P < 0.01) among the 3 different phenotypes were observed. The basal FeNO levels were significantly higher in NIBR (36.9%, IQR 27.0–95.4) than in NSAID-tolerant subjects (P < 0.01). After aspirin OPT, the reduction of %FEV1 was considerably higher in patients with confirmed NERD (22.0%, IQR 16.0-28.8), followed by NIBR (13.3%, IQR 7.6–28.0), compared to those in NSAID-tolerant groups (P < 0.01). Basal uLTE4 levels were not significantly different among the 3 phenotypes. Interestingly, uLTE4 levels after aspirin provocation were significantly higher in NERD and NIBR patients than in the NECD/NIUA and NSAID-tolerant groups (P < 0.05 and < 0.01, respectively).
Fig. 3 Respiratory parameters and uLTE4 levels in different phenotypes of NSAID-sensitive subjects compared to NSAID-tolerant subjects.
Baseline FeNO in NIBR and NERD were higher than those in the NSAID-tolerant group. After aspirin provocation, % predicted FEV1 in NERD and NIBR were significantly reduced from the baseline while uLTE4 levels were much higher than those in NSAID-tolerant subjects.
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; FEV1, forced expiratory volume in 1 second.
*P values < 0.05, †P values < 0.01.
Effects of aspirin desensitization on uLTE4 levels in patients diagnosed with NERD and NIBR
Aspirin desensitization was performed in selected patients (3 NERD and 3 NIBR) who had pre-existing inflammatory airway diseases and a history of recurrent nasal polyposis after surgery as shown in Table 3. The maintenance dose of aspirin was 650 mg/day during the first 6 months and reduced to 325 mg/day afterward. Levels of uLTE4 were measured at baseline after aspirin desensitization and serially followed up for 2–3 years as demonstrated in Fig. 4. Other than respiratory symptoms, acute urticarial rash and gastrointestinal symptoms (abdominal cramp/nausea/diarrhea) were also aggravated in NIBR subjects during aspirin desensitization as shown in Supplementary Fig. S1, but gradually relieved with supportive treatment. No sinus surgery was required for nasal polyp recurrence, and asthma symptoms were under control after aspirin desensitization in all 6 cases. Up to 3 years after aspirin desensitization, however, uLTE4 levels were significantly increased and remained elevated throughout the follow-up period, although urticarial rash and gastrointestinal symptoms were no longer observed while taking aspirin.
Table 3 Details of patients with cross-reactive NSAID hypersensitivity undergoing aspirin desensitization in this study
Patients (sex/year) Underlying diseases History of adverse drug reactions Indication for aspirin desensitization Follow-up duration (months) Asthma control before/after aspirin desensitization Recurrent nasal polyposis after aspirin desensitization Skin symptoms after aspirin desensitization Gastrointestinal symptoms after aspirin desensitization
1. NERD (M/46) Chronic sinusitis, nasal polyposis, asthma Acute asthma 20 min after taking aspirin 2 recurrent nasal polyps 74 Partly controlled with high dose ICS-LABA and add-on LTRA/well controlled with low dose ICS None NA NA
2. NERD (M/54) Chronic rhinitis, nasal polyposis, asthma Acute asthma, blocked nose 1 hr after taking aspirin 3 recurrent nasal polyps 24 Uncontrolled with high dose ICS-LABA and add-on LTRA/well controlled with medium dose ICS-LABA None NA NA
3. NERD (M/56) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked nose 1 hr after taking ibuprofen 6 recurrent nasal polyps 32 Partly controlled asthma with high dose ICS-LABA and add-on LTRA/well controlled with medium dose ICS-LABA None NA NA
4. NIBR (M/48) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked nose, conjunctival injection, urticarial rash 2 hr after taking aspirin 3 recurrent nasal polyps 72 Partly controlled with medium dose ICS-LABA/well controlled with low dose ICS-LABA None No rash after taking aspirin NA
5. NIBR (F/65) Chronic sinusitis, nasal polyposis, chronic urticaria, asthma (history of cardiac arrest from severe asthma) Urticarial rash, periorbital angioedema, blocked nose, conjunctival injection, rhinorrhea, bronchospasm/wheezing, hoarseness of voice 1 hr after taking aspirin, ibuprofen, mefenamic acid, acetaminophen 2 recurrent nasal polyps 48 Uncontrolled with high dose ICS-LABA and add-on LTRA/well controlled with low dose ICS-LABA None No rash after taking aspirin, chronic urticaria resolved NA
6. NIBR (F/38) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked/running nose, stomach cramp, diarrhea, periorbital angioedema, urticaria 30 min after taking ibuprofen, indomethacin, mefenamic acid 2 recurrent nasal polyps 21 Partly controlled with medium dose ICS-LABA/well controlled, with medium dose ICS-LABA None No rash after taking aspirin No gastrointestinal symptoms after taking aspirin
NSAID, non-steroidal anti-inflammatory drug; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; ICS, inhaled corticosteroid; LABA, long-acting beta-agonist; LTRA, leukotriene receptor antagonist; NA, not applicable (no symptoms prior to aspirin desensitization); NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
Fig. 4 uLTE4 levels in NSAID-sensitive subjects after aspirin desensitization.
Our study demonstrated that uLTE4 levels (pg/mg creatinine) in 3 NERD and 3 NIBR patients were increased and remained elevated up to 3 years after aspirin desensitization even though recurrent nasal polyposis was successfully prevented in all cases.
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
DISCUSSION
Most studies on NSAID hypersensitivity have focused on NERD, although worldwide epidemiological data suggest that NECD/NIUA might be more common. Recent data have demonstrated that some patients cannot be categorized into the current classification of NSAID hypersensitivity, for example those with NSAID-induced periorbital angioedema and NIBR.1419 These patients may also have underlying chronic airway diseases; however, the role of aspirin desensitization in the prevention of recurrent nasal polyposis and control of airway inflammation in NSAID-sensitive subjects other than the NERD phenotype has never been reported.
The leading presentations in NSAID-sensitive subjects in this study were periorbital angioedema, acute urticaria, bronchial symptoms, and naso-ocular reactions, respectively. Even those confirmed with NSAID exposure, a significant number of patients in our cohort also showed clinical responses in more than 1 organ system, indicating that the prevalence of NIBR was higher than previously thought. Although patients with IgE-mediated anaphylaxis might also present with multiple organ involvement, the fact that most of the reactions took about 1–2 hours to occur and the ability to react to multiple NSAIDs with dissimilar chemical structures made them more compatible with the non-immunologic effect of the drugs.
Facial angioedema around the periorbital area was the most common presenting symptom in Thai patients. Upon NSAID provocation, however, the predominant periorbital angioedema often accompanied by blocked nose, running nose, and itchy/red eyes. After a thorough examination, small urticarial rash on the trunk and extremities, and expiratory wheezing were occasionally detected, although frequently asymptomatic. It is noteworthy that periorbital angioedema may persist for hours or days while urticarial rash and respiratory symptoms are quickly resolved after treatment. As a result, NIBR could be underdiagnosed if history taking is not thoroughly reviewed, since symptoms with lesser severity in other organ systems may be unnoticed. In addition, the COX-1 inhibitor properties of the exposed NSAIDs could affect the phenotype of NSAID sensitivity reported by patients as some patients experienced both asthmatic attack and periorbital angioedema/generalized urticaria after taking aspirin but reported only periorbital edema after taking acetaminophen.
It is practically difficult to clearly distinguish between NSAID-induced periorbital angioedema and NSAID-induced naso-ocular reactions (upper airway manifestations of NERD), since patients occasionally experienced periorbital swelling, red/swollen eyes with tearing, and nasal congestion at the same time. In our opinion, the majority of NSAID hypersensitivity in the Thai population would be described as “NSAID-induced blended reaction with predominant periorbital angioedema” and probably related to “NSAID-induced isolated periorbital angioedema” phenotype as proposed by the Spanish group. It is interesting to note that the prevalence of atopic disease was high in this patient group. We speculate that the increased leukotriene production after NSAID consumption could lead to the worsening of pre-existing mucosal inflammation around the nose and eyes in patients who already suffered from the late-phase reaction of persistent allergic rhinitis.
Our study did not find any difference in terms of basal uLTE4 levels between NSAID-sensitive and NSAID-tolerant subjects. However, uLTE4 levels were higher in NSAID-sensitive patients, particularly in NERD and NIBR subjects, after the NSAID challenge compared to those in the NSAID-tolerant group. Though basal uLTE4 levels may not be a suitable marker to screen NSAID sensitivity status, elevated uLTE4 levels after aspirin OPT could be the supporting evidence for the diagnosis of cross-reactive NSAID hypersensitivity in cases where the clinical response is equivocal. Our study demonstrated that the degree of defective leukotriene homeostasis after exposure to drugs affecting the cyclo-oxygenase pathway might be related to the severity of respiratory involvement upon NSAID exposure.35 The fact that uLTE4 levels were barely changed after celecoxib provocation in patients with NSAID cross-reactivity confirms that celecoxib is a safe alternative NSAID in these patient groups.
According to our study, the patterns of NSAID hypersensitivity in southeast Asians are similar to those in southern Europeans and Latin Americans, and somewhat different from those reported in patients of northern European descent. Previous data suggested that aspirin nasal provocation could potentially diagnose some NSAID-sensitive patients presenting with predominant cutaneous reactions.3637 Retrospectively, some of these patients might be re-classified as the NIBR phenotype, since a decreased nasal volume was also observed. In other words, patients diagnosed with an NSAID-induced cutaneous reaction who positively reacted to NSAID nasal provocation, especially those with a periorbital reaction, might be NIBR subjects with subclinical airway involvement.
The novelties of this study were the findings that NIBR accounted for about one-third of adult patients with cross-reactive NSAID hypersensitivity and that aspirin desensitization could successfully prevent the recurrence of nasal polyposis and alleviate respiratory symptoms not only in NERD, but also in NIBR, even though urine LTE4 levels remained elevated. However, since the reactions in some NIBR patients could lead to serious adverse events, aspirin desensitization in NIBR subjects should be performed only when it is strongly indicated in selected patients with no previous severe reactions to NSAIDs. In NIBR subjects who experienced previous severe reactions in multiple organ systems, the procedure of aspirin desensitization, if necessary, should be carefully monitored and the administration of biological agents such as dupilumab, if available, should be considered a safer therapeutic option in these cases.
Interestingly, uLTE4 levels were increased after aspirin desensitization and remained elevated throughout the follow-up period. It should be emphasized that urticarial rash and stomach-ache in NIBR patients also disappeared while patients were taking daily aspirin. These data suggest that the pathogenesis of nasal polyposis cannot be explained by cysLT overproduction alone and that aspirin desensitization could be useful to alleviate both respiratory and non-respiratory symptoms in NIBR subjects.
Interestingly, a recent study also found that the clinical benefit of high-dose aspirin desensitization in NERD was independent of a reduction of mast cell activation and cysLT production. They reported paradoxically increased uLTE4 levels 8 weeks after aspirin desensitization compared to the baseline levels and concluded that high-dose aspirin therapy did not restore the impaired eicosanoid pathway.38 According to their study findings and ours, the therapeutic effect of aspirin desensitization was not directly correlated with a change of arachidonic acid metabolism.
There are some limitations to this study. Aspirin desensitization was performed in only 6 patients in our cohort; therefore, the comparative success rates and potential adverse reactions of aspirin desensitization between NERD and NIBR patients could not be analyzed. Further studies with a larger sample size are needed to compare the long-term prognosis between NERD and NIBR, to understand the mechanism of aspirin desensitization for the improvement of respiratory and extra-respiratory symptoms and to evaluate its risk-benefit ratio of aspirin desensitization in NIBR subjects.
In conclusion, NIBR is not uncommon among patients diagnosed with NSAID hypersensitivity in Thailand. Increased uLTE4 levels upon aspirin provocation suggested a diagnosis of NSAID cross-reactivity, while baseline uLTE4 levels were not distinguishable between NSAID-tolerant and NSAID-sensitive subjects. Our study indicates that aspirin desensitization is effective not only in NERD but also in NIBR. The persistently high levels of uLTE4 in spite of clinical improvement in NSAID-sensitive patients after successful aspirin desensitization suggest that elevated leukotrienes alone cannot explain the pathogenesis of NSAID hypersensitivity reactions.
ACKNOWLEDGMENTS
This study was supported by the Ratchadaphiseksomphot fund, Faculty of Medicine, Chulalongkorn University, grant No. RA55/19 and the Skin and Allergy Research Unit, Chulalongkorn University, Bangkok, Thailand. Study data were collected and managed using Research Electronic Data Capture (REDCap) hosted at HIV Netherlands Australia Thailand Research Collaboration. The authors thank Thitima Kantachatvanich, MD for providing patient information.
Disclosure: There are no financial or other issues that might lead to conflict of interest.
SUPPLEMENTARY MATERIALS
Supplementary Table S1
Clinical characteristics of patients with confirmed NSAID-induced immediate reactions
Supplementary Fig. S1
Representative photos of skin rash demonstrated during aspirin desensitization in NIBR patients. | IBUPROFEN, INDOMETHACIN, MEFENAMIC ACID | DrugsGivenReaction | CC BY-NC | 33474858 | 18,863,279 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Diarrhoea'. | Clinical Characteristics, Urinary Leukotriene E4 Levels, and Aspirin Desensitization Results in Patients With NSAID-Induced Blended Reactions.
OBJECTIVE
Data on non-steroidal anti-inflammatory drug (NSAID) hypersensitivity in Southeast Asia are scarce. Increased urinary leukotriene E4 (uLTE4) levels have been suggested as a biomarker of NSAID-exacerbated respiratory disease (NERD). This study investigated clinical patterns of NSAID sensitivity in Thailand and the diagnostic roles of uLTE4 measurement in various phenotypes.
METHODS
The clinical phenotypes in 92 Thai adults with cross-reactive NSAID hypersensitivity were characterized based on the clinical history and drug provocation. The uLTE4 levels were measured at baseline, after aspirin provocation and after desensitization.
RESULTS
More than half of the patients (56.5%) presented with cutaneous symptoms (NSAID-exacerbated cutaneous disease), while one-third (33.7%) developed symptoms in at least 2 systems (NSAID-induced blended reactions; NIBR). Fifty-two patients underwent drug provocation and 59.6% of them yielded positive results. After drug provocation, a significant number of patients with confirmed NSAID cross-reactivity experienced clinical symptoms in more than one organ system. The uLTE4 levels at baseline were comparable between the NSAID-tolerant and NSAID-sensitive groups, but were substantially increased after aspirin provocation predominantly in NERD (983.4 pg/mg creatinine) and NIBR (501.0 pg/mg creatinine) compared to NSAID-tolerant subjects (122.1 pg/mg creatinine, P < 0.01 and 0.05, respectively). The uLTE4 levels were elevated after aspirin desensitization, although nasal polyposis and asthma were under control in 3 NERD and 3 NIBR subjects.
CONCLUSIONS
NIBR is not uncommon among NSAID-sensitive patients in Thailand. The diagnostic value of basal uLTE4 levels was limited, but increased uLTE4 levels upon aspirin provocation suggest NSAID cross-reactivity with respiratory components. This study indicates that aspirin desensitization, if necessary, might be effective in both NERD and NIBR.
BACKGROUND
ClinicalTrials.gov Identifier: NCT03849625.
INTRODUCTION
Hypersensitivity reactions to aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most common drug allergic reactions in clinical practice. They are generally categorized into 5 major phenotypes: NSAID-exacerbated respiratory disease (NERD), NSAID-exacerbated cutaneous (urticaria/angioedema) disease (NECD) in patients with underlying chronic urticaria, NSAID-induced urticaria/angioedema (NIUA) in patients without underlying chronic urticaria, single NSAID-induced urticaria/angioedema or anaphylaxis, and single NSAID-induced delayed hypersensitivity reactions.1 The first 3 phenotypes are non-immunologically mediated, and patients can develop cross-reactive hypersensitivity to chemically unrelated NSAIDs, while the latter 2 are selective NSAID sensitivities associated with drug-specific immunoglobulin E (IgE) and T-cell response, respectively.
Genetic and epigenetic variations play significant roles in the development of NERD.2 The proposed underlying mechanism is that the disturbance in arachidonic acid synthesis pathways leads to overproduction of cysteinyl leukotrienes (cysLT) and persistent airway inflammation.3 Mast cells are believed to be the major source of cysLT, but platelet-adherent leukocytes may be responsible for cysLT overproduction in NERD as well.4 The consumption of drugs inhibiting the cyclooxygenase-1 (COX-1) enzyme, such as aspirin and conventional NSAIDs, aggravates respiratory symptoms by enhancing cysLT production in NSAID-sensitive subjects, while the administration of specific COX-2 inhibitors, such as celecoxib, is generally safe.56 Besides aspirin/NSAID avoidance, aspirin desensitization has also been proven to be helpful for long term management in NERD subjects. Beneficial effects of aspirin desensitization in preventing nasal polyp recurrence and control symptoms of chronic rhinosinusitis and asthma have been well documented.7 Rapid aspirin desensitization has shown to be effective for the treatment of coronary artery disease in patients with a history of aspirin/NSAID-induced urticaria/angioedema, but it is not indicated for the treatment of chronic urticaria.8
Worldwide epidemiological data on clinical characteristics of NSAID hypersensitivity are limited. Most studies on NERD were performed in the United States and northern European countries.9101112 However, the predominant manifestation in Latin Americans and southern Europeans is the cutaneous phenotype (NIUA, NECD, and NSAID-induced isolated periorbital angioedema).1314 Studies in Asian populations have suggested that the prevalence of the NERD phenotype is not common in this region of the world. A study performed in China indicated that the prevalence of NSAID hypersensitivity in Chinese patients with chronic rhinosinusitis is very low (0.57%) compared to their European counterparts.15 It was also noted that NSAID-induced blended reactions (NIBR) are common in young Asian, atopic children in Singapore.16 Reports from Singapore and Thailand indicated that aspirin/NSAID-induced angioedema/urticaria is probably the prominent phenotype in Southeast Asia, with acetaminophen hypersensitivity being frequent.1718
In clinical practice, the current classification of cross-reactive NSAID hypersensitivity into 3 distinct phenotypes has some limitations. Clinical characteristics in NSAID-sensitive patients may not be well defined, and a combination of respiratory and cutaneous or other symptoms, such as gastrointestinal symptoms (mixed or blended reactions), is frequently observed.19 A previous report stated that aspirin nasal provocation is potentially useful for diagnosing patients with the blended reaction as well.20 However, the role of aspirin desensitization in other phenotypes of NSAID hypersensitivity, besides NERD, for long-term management of inflammatory airway diseases has not yet been established. Whether aspirin desensitization would be effective in controlling asthma and the recurrence of nasal polyposis after sinus surgery in NIBR is currently unknown.
At present, cross-reactive types of NSAID hypersensitivity can only be diagnosed by careful history taking and controlled-provocation testing, since there is no reliable in vitro method to confirm the diagnosis.21 There is evidence that basal urinary levels of leukotriene E4 (uLTE4), a stable product of the cysLT synthesis pathway, are elevated in NERD patients and could be a potential biomarker for differentiating between NSAID-sensitive and NSAID-tolerant asthmatics. However, these data are still controversial.222324 There have also been preliminary studies showing that uLTE4 levels might be increased in NECD.2526 Whether the measurement of basal uLTE4 levels could be a diagnostic marker for any phenotype of NSAID hypersensitivity is yet to be explored.
The purpose of this study was to analyze the clinical characteristics of patients diagnosed with NSAID-induced immediate reactions in Thailand and to explore whether the measurement of uLTE4 levels would be helpful in identifying NSAID-sensitive subjects or in differentiating among different phenotypes of cross-reactive NSAID hypersensitivities.
MATERIALS AND METHODS
Patient recruitment
Adult patients (18 years of age and older) with a suggestive history of NSAID-induced hypersensitivity reaction visiting the allergy clinic at King Chulalongkorn University Hospital between June 2014 and July 2018 were recruited into this study. Those with a history compatible with drug-induced non-immediate reactions (maculopapular rash, fixed drug eruption, acute generalized exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms, Stevens-Johnson syndrome/toxic epidermal necrolysis) or NSAID-related side effects were excluded. The status of NSAID-induced immediate hypersensitivity was diagnosed in patients with a well-documented drug allergy history or in patients with a suggestive history of NSAID sensitivity who yielded a positive drug provocation test as follows.
Clinical diagnosis of NSAID hypersensitivity
The diagnosis of cross-reactive NSAID hypersensitivity was clinically made in patients with a well-documented history of multiple episodes of respiratory, cutaneous, and/or gastrointestinal reactions within 2 hours after exposure to at least 2 different NSAID classes.1212728 Patient demographic data were collected, including the underlying diseases, atopic family history, and details on drug allergy history as well as the presenting symptoms and types of the culprit NSAIDs.
Aspirin provocation test
Oral aspirin provocation was performed in patients with a suggestive medical history or in those who had a history of an immediate reaction to a single NSAID to confirm the diagnosis of cross-reactive NSAID hypersensitivity according to the EAACI/GA2LEN guidelines, with some modifications.293031 Four increasing doses of aspirin (40.5, 81, 150, and 300 mg) were administered at 90-minute intervals until a positive reaction occurred. Clinical symptoms, fractional exhaled nitric oxide (FeNO), and the forced expiratory volume in 1 second (FEV1) were monitored to evaluate the reaction. A positive provocation test was defined if any of the following reactions developed: lower respiratory/bronchial reaction (a 15% decrease in FEV1 plus naso-ocular reaction or a 20% decrease in FEV1 alone), upper respiratory/naso-ocular reaction (nasal congestion and rhinorrhea; conjunctival injection), cutaneous reactions (urticaria/angioedema, periorbital edema), and/or other reactions (gastrointestinal symptoms such as nausea/vomiting, stomach cramps, and diarrhea). The test was considered negative if a patient tolerated the final dose (300 mg of aspirin) without any significant symptoms mentioned above.
Oral provocation test (OPT) with other NSAIDs, acetaminophen, or celecoxib
Patients with a history of an immediate reaction to only aspirin were challenged with escalating doses of ibuprofen to confirm the diagnosis of cross-reactive NSAID sensitivity. Patients with a history of an immediate reaction to a single NSAID were provoked with the suspected drug to verify the status of single NSAID hypersensitivity after a negative aspirin provocation test. Escalating doses of ibuprofen, diclofenac, and acetaminophen were administered, if applicable, as follows: ibuprofen (50, 100, and 200 mg), diclofenac (6.25, 12.5, and 25 mg), and acetaminophen (125, 250, and 500 mg). Celecoxib was also provoked in 3 doses (50, 100, and 200 mg) in patients with confirmed hypersensitivity to multiple NSAIDs who were willing to identify a safe alternative drug. The provocation test for each drug was performed on separate days at least 7 days apart. Each dose of drug provocation was provided at 90-minute intervals until the final dose was reached.
Classification of NSAID hypersensitivity according to drug provocation test results
Patients with cross-reactive NSAID phenotypes were classified according to the results of the drug provocation test as 1) NECD/NIUA if they developed cutaneous symptoms alone; 2) NERD if they developed respiratory symptoms alone; and 3) NIBR if they developed a combination of symptoms involving more than one organ system (respiratory, cutaneous, and/or gastrointestinal symptoms). Single NSAID hypersensitivity was diagnosed in patients with a positive provocation test to the suspected NSAID, but a negative aspirin provocation test. Patients who had negative provocations to both aspirin and the suspected culprit drug were labeled as NSAID-tolerant subjects. NECD/NIUA were purposely categorized together in our study to compare the differences and similarities between patients diagnosed with NSAID-induced cutaneous reactions and -respiratory reactions. Moreover, NECD and NIUA share similar background characteristics from a clinical point of view and some patients diagnosed with NIUA eventually evolve to NECD over time.32
Skin prick tests with common aeroallergens in Thailand (mixed dust mites, mixed cockroaches, mixed mold, cat dander, dog hair, and southern grass mix; ALK-Abello, Hørsholm, Denmark) were also examined in tested patients to identify atopic status. Wheal size ≥ 3 mm was considered a positive test.
Measurement of FeNO and the FEV1 in patients who underwent drug provocation test
FeNO was measured in all participants at baseline and after drug provocation by using a portable electrochemical analyzer (NObreath®; Bedfont Scientific Ltd, Maidstone, UK) according to the ATS/ERS recommendations.33 Measurements of FEV1 were also performed using a Vitalograph spirometer (Vitalograph®, Buckingham, UK). The best of 3 repeated attempts was recorded.
The uLTE4 measurement
The uLTE4 levels were measured by a leukotriene E4 ELISA kit (Cayman Chemical, Ann Arbor, MI, USA) at baseline and 90 minutes after the final dose of drug provocation, as well as at the follow-up visits after aspirin desensitization and reported after adjustment to urine creatinine levels.
Aspirin desensitization
Outpatient aspirin desensitization was performed in NSAID-sensitive patients who were referred from otolaryngologists to prevent the recurrence of nasal polyposis. The procedure was carried out according to the intranasal ketorolac and modified aspirin challenge 2-day protocol.34 Aspirin desensitization was completed after patients were able to tolerate a 325-mg dose of aspirin by the end of day 2 and experience no symptoms, changes in nasal flow rates, or decrease in FEV1 values. The prescribed maintenance dose of aspirin was 325 mg twice a day.
Statistical analysis
Patient characteristics are reported as means ± standard deviation for quantitative analysis, and median and interquartile range (IQR) are used to describe non-parametric data. The Mann-Whitney U test and Kruskal-Wallis test with Dunn's multiple comparisons were used to analyze the differences between 2 groups and more than 2 groups, respectively. Statistical analyses were performed using GraphPad Prism 8.3 software (GraphPad Software Inc., San Diego, CA, USA). P values < 0.05 were considered statistically significant.
Ethical considerations
Patients enrolled in this study were those who recruited in the study entitled “Characteristics of Patients Diagnosed With NSAID Sensitivity in Thailand” registered at ClinicalTrials.gov (NCT03849625). The study was approved by the Ethics and Research Committee of the Faculty of Medicine, Chulalongkorn University, Approval Number: COA No. 659/2012 and informed consent was obtained from all participants.
RESULTS
A total of 158 adult patients with a suspected history of NSAID hypersensitivity between 2015 and 2018 at King Chulalongkorn Memorial Hospital were initially recruited into this study as shown in Fig. 1. Thirty-five patients with a history compatible with a non-immediate hypersensitivity reaction and 4 subjects with clinical symptoms compatible with NSAID-related side effects were later excluded.
Fig. 1 Schematic diagram of patient selection for this study.
A total of 158 patients with a suspected history of NSAID hypersensitivity were initially recruited into this study. Cross-reactive NSAID hypersensitivity was clinically diagnosed in 67 patients with a well-documented drug allergy history and verified by a positive drug provocation test in 25 patients with a suggestive history of NSAID reactions.
NSAID, non-steroidal anti-inflammatory drug.
Cross-reactive NSAID hypersensitivity was clinically diagnosed in 67 patients with a convincing drug allergy history as defined in the methods section. The remaining 52 patients with a suggestive history of NSAID hypersensitivity underwent an OPT to confirm NSAID cross-reactivity status. Fifteen out of 25 patients with confirmed NSAID cross-reactivity were subsequently provoked with celecoxib to find a safe alternative NSAID. Single NSAID/acetaminophen hypersensitivity was verified in 6 patients who tolerated aspirin provocation but developed an allergic reaction upon re-challenge with acetaminophen or diclofenac.
Demographic data of adult patients with cross-reactive NSAID hypersensitivity
The clinical characteristics of adult patients with cross-reactive NSAID hypersensitivity are shown in Table 1 (n = 92). Most patients were females (77.2%) with an average age of 45.7 ± 13.4 years. The average age of onset was 32.2 ± 13.3 years and about half of them had atopic family history. The majority of them (56.5%) reported only cutaneous symptoms such as facial angioedema and/or acute urticarial rash, after NSAID exposure, while 9.8% of them developed only respiratory symptoms. Interestingly, about 33.7% of the patients experienced a combination of symptoms in multiple organ systems as shown in Fig. 2. The groups of NSAIDs frequently responsible for hypersensitivity reactions were propionic acid derivatives and acetic acid derivatives. Although inflammatory airway diseases (chronic sinusitis, nasal polyposis, and asthma) were significantly more common in patients who experienced only respiratory reactions after exposure to an NSAID compared to the other phenotypes, a significant portion of the patients reporting blended reactions had underlying airway diseases and chronic urticaria as well. Acetaminophen intolerance was also reported in about one-third (35.9%) of NSAID-sensitive subjects.
Table 1 Clinical characteristics among different phenotypes of patients with cross-reactive NSAID hypersensitivity (n = 92)
Phenotypes NECD/NIUA (n = 52) NERD (n = 9) NIBR (n = 31) Total (n = 92)
Gender (female/male) 37/15 6/3 28/3 71/21
Age (yr) 43.6 ± 12.3 47.3 ± 11.9 48.7 ± 15.3 45.7 ± 13.4
Age of onset (yr) 31.3 ± 13.8 34.6 ± 11.0 33.1 ± 13.3 32.2 ± 13.3
Underlying disease (%)
Chronic urticaria 13.5 11.1 29.0 18.5
Chronic sinusitis* 13.5 55.6 32.3 23.9
Nasal polyposis* 7.7 66.7 16.1 16.3
Asthma* 17.3 88.9 35.5 30.4
Atopic family history (%) 42.3 55.6 61.3 50.0
Drug exposure time to symptom onset (min) 58.8 ± 31.9 48.3 ± 34.3 47.6 ± 29.9 54.0 ± 31.6
Presenting symptoms (%)*
Facial/periorbital angioedema 71.2 0.0 74.2 65.2
Acute urticaria 73.1 0.0 61.3 62.0
Naso-ocular reaction 0.0 33.3 61.3 23.9
Acute asthma 0.0 88.9 67.7 31.5
Gastrointestinal symptoms 0.0 0.0 16.1 5.4
Implicated NSAIDs (%)†
Salicylic acids 23.1 55.6 35.5 30.4
Propionic acids 44.2 22.2 54.8 45.7
Acetic acids 23.1 22.2 48.4 31.5
Enolic acids 7.7 0.0 6.5 6.5
Anthranilic/fenamic acids 28.8 11.1 29.0 27.2
Acetaminophen intolerance (%)§ 28.8 22.2 51.6 35.9
Values are presented as number (%) or mean ± standard deviation. Each patient could present with multiple symptoms and from more than one implicated drug.
NSAID, non-steroidal anti-inflammatory drug; NECD, non-steroidal anti-inflammatory drug-exacerbated cutaneous (urticaria/angioedema) disease in patients with underlying chronic urticaria; NIUA, non-steroidal anti-inflammatory drug-induced urticaria/angioedema in patients without underlying chronic urticaria; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
*P < 0.05 among different phenotypes. †Examples of commonly implicated drugs in this study based on NSAID classification: 1) Salicylic acids: acetylsalicylic acid (aspirin), salicylic acid, diflunisal, salsalate; 2) Propionic acids: ibuprofen, naproxen, ketoprofen, fenoprofen, flurbiprofen; 3) Acetic acids: indomethacin, ketorolac, diclofenac, sulindac; 4) Enolic acids: piroxicam, meloxicam, tenoxicam; 5) Anthranilic/fenamic acids: mefenamic acid, flufenamic acid. §Acetaminophen intolerance: cannot tolerate acetaminophen higher than 500 mg.
Fig. 2 Clinical presentations in patients with cross-reactive NSAID hypersensitivity.
A proportional Venn diagram shows that about half of patients with cross-reactive NSAID hypersensitivity in Thailand reported only cutaneous symptoms after NSAID exposure, while one-third of them experienced NSAID-induced blended reactions.
NSAID, non-steroidal anti-inflammatory drug.
Clinical respiratory parameters and uLTE4 levels in different phenotypes of patients with cross-reactive NSAID hypersensitivity confirmed by positive OPT
NSAID hypersensitivity was confirmed in 59.6% (31/52) of the tested patients with a history of NSAID-induced immediate reactions. The majority of patients with cross-reactive NSAID hypersensitivity (17/25) according to OPT results were atopic individuals. The common phenotypes of patients with confirmed cross-reactive NSAID sensitivity were NECD/NIUA, NIBR, and NERD, respectively, as shown in Supplementary Table S1.
The average FeNO, %predicted FEV1, and uLTE4 levels were measured at baseline and after provocation with aspirin/NSAID in 25 NSAID cross-reactive and 21 NSAID-tolerant subjects as shown in Table 2. At baseline, patients with confirmed NSAID cross-reactivity (NSAID-sensitive group) had higher FeNO (P < 0.01) and slightly less %predicted FEV1 compared to the NSAID-tolerant subjects, while basal uLTE4 levels between NSAID-sensitive and NSAID-tolerant groups were comparable. After provocation, %predicted FEV1 was substantially reduced in NSAID-sensitive subjects, whereas uLTE4 levels were significantly elevated compared to the NSAID-tolerant group (P < 0.01). Celecoxib provocation was well tolerated in all NSAID-sensitive subjects. No statistical differences in the average FeNO, %predicted FEV1, or uLTE4 levels in 15 NSAID-sensitive patients (7 NECD/NIUA, 4 NIBR, 4 NERD) after celecoxib provocation were observed compared to those in NSAID-tolerant subjects.
Table 2 Respiratory parameters and uLTE4 levels in NSAID-sensitive subjects upon provocation with aspirin or celecoxib compared to NSAID-tolerant subjects
Characteristics Baseline After aspirin (OPT) P value*
NSAID tolerant (n = 21)
FeNO (ppb) 13.0 (8.5–19.5) 10.2 (7.0–16.8) 0.03
%predicted FEV1 100.8 (82.8–115.9) 99.0 (75.2–118.2) 0.90
uLTE4 (pg/mg creatinine) 116.3 (66.5–305.4) 122.1 (63.5–173.8) 0.17
NSAID sensitive (n = 25)
FeNO (ppb) 27.0 (17.8–40.9)† 18.0 (10.5–31.0) <0.01
%predicted FEV1 86.7 (63.3–104.9) 74.6 (52.4–89.8)† <0.01
uLTE4 (pg/mg creatinine) 118.3 (93.2–407.2) 204.9 (90.6–817.8)† <0.01
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; OPT, oral provocation test; ppb, parts per billion; FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in 1 second.
*P values before vs. after provocation test, Wilcoxon signed-rank test; †P < 0.01 compared to the NSAID-tolerant subjects.
According to the subgroup analysis, 10 NECD/NIUA, 9 NIBR, and 6 NERD were categorized as shown in Fig. 3. At baseline, %predicted FEV1 was not significantly different among different types of cross-reactive NSAID hypersensitivity, although those in patients with confirmed NIBR were lowest (64.9%, IQR 56.9–97.3). The significant differences in basal FeNO levels (P < 0.01) among the 3 different phenotypes were observed. The basal FeNO levels were significantly higher in NIBR (36.9%, IQR 27.0–95.4) than in NSAID-tolerant subjects (P < 0.01). After aspirin OPT, the reduction of %FEV1 was considerably higher in patients with confirmed NERD (22.0%, IQR 16.0-28.8), followed by NIBR (13.3%, IQR 7.6–28.0), compared to those in NSAID-tolerant groups (P < 0.01). Basal uLTE4 levels were not significantly different among the 3 phenotypes. Interestingly, uLTE4 levels after aspirin provocation were significantly higher in NERD and NIBR patients than in the NECD/NIUA and NSAID-tolerant groups (P < 0.05 and < 0.01, respectively).
Fig. 3 Respiratory parameters and uLTE4 levels in different phenotypes of NSAID-sensitive subjects compared to NSAID-tolerant subjects.
Baseline FeNO in NIBR and NERD were higher than those in the NSAID-tolerant group. After aspirin provocation, % predicted FEV1 in NERD and NIBR were significantly reduced from the baseline while uLTE4 levels were much higher than those in NSAID-tolerant subjects.
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; FEV1, forced expiratory volume in 1 second.
*P values < 0.05, †P values < 0.01.
Effects of aspirin desensitization on uLTE4 levels in patients diagnosed with NERD and NIBR
Aspirin desensitization was performed in selected patients (3 NERD and 3 NIBR) who had pre-existing inflammatory airway diseases and a history of recurrent nasal polyposis after surgery as shown in Table 3. The maintenance dose of aspirin was 650 mg/day during the first 6 months and reduced to 325 mg/day afterward. Levels of uLTE4 were measured at baseline after aspirin desensitization and serially followed up for 2–3 years as demonstrated in Fig. 4. Other than respiratory symptoms, acute urticarial rash and gastrointestinal symptoms (abdominal cramp/nausea/diarrhea) were also aggravated in NIBR subjects during aspirin desensitization as shown in Supplementary Fig. S1, but gradually relieved with supportive treatment. No sinus surgery was required for nasal polyp recurrence, and asthma symptoms were under control after aspirin desensitization in all 6 cases. Up to 3 years after aspirin desensitization, however, uLTE4 levels were significantly increased and remained elevated throughout the follow-up period, although urticarial rash and gastrointestinal symptoms were no longer observed while taking aspirin.
Table 3 Details of patients with cross-reactive NSAID hypersensitivity undergoing aspirin desensitization in this study
Patients (sex/year) Underlying diseases History of adverse drug reactions Indication for aspirin desensitization Follow-up duration (months) Asthma control before/after aspirin desensitization Recurrent nasal polyposis after aspirin desensitization Skin symptoms after aspirin desensitization Gastrointestinal symptoms after aspirin desensitization
1. NERD (M/46) Chronic sinusitis, nasal polyposis, asthma Acute asthma 20 min after taking aspirin 2 recurrent nasal polyps 74 Partly controlled with high dose ICS-LABA and add-on LTRA/well controlled with low dose ICS None NA NA
2. NERD (M/54) Chronic rhinitis, nasal polyposis, asthma Acute asthma, blocked nose 1 hr after taking aspirin 3 recurrent nasal polyps 24 Uncontrolled with high dose ICS-LABA and add-on LTRA/well controlled with medium dose ICS-LABA None NA NA
3. NERD (M/56) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked nose 1 hr after taking ibuprofen 6 recurrent nasal polyps 32 Partly controlled asthma with high dose ICS-LABA and add-on LTRA/well controlled with medium dose ICS-LABA None NA NA
4. NIBR (M/48) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked nose, conjunctival injection, urticarial rash 2 hr after taking aspirin 3 recurrent nasal polyps 72 Partly controlled with medium dose ICS-LABA/well controlled with low dose ICS-LABA None No rash after taking aspirin NA
5. NIBR (F/65) Chronic sinusitis, nasal polyposis, chronic urticaria, asthma (history of cardiac arrest from severe asthma) Urticarial rash, periorbital angioedema, blocked nose, conjunctival injection, rhinorrhea, bronchospasm/wheezing, hoarseness of voice 1 hr after taking aspirin, ibuprofen, mefenamic acid, acetaminophen 2 recurrent nasal polyps 48 Uncontrolled with high dose ICS-LABA and add-on LTRA/well controlled with low dose ICS-LABA None No rash after taking aspirin, chronic urticaria resolved NA
6. NIBR (F/38) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked/running nose, stomach cramp, diarrhea, periorbital angioedema, urticaria 30 min after taking ibuprofen, indomethacin, mefenamic acid 2 recurrent nasal polyps 21 Partly controlled with medium dose ICS-LABA/well controlled, with medium dose ICS-LABA None No rash after taking aspirin No gastrointestinal symptoms after taking aspirin
NSAID, non-steroidal anti-inflammatory drug; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; ICS, inhaled corticosteroid; LABA, long-acting beta-agonist; LTRA, leukotriene receptor antagonist; NA, not applicable (no symptoms prior to aspirin desensitization); NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
Fig. 4 uLTE4 levels in NSAID-sensitive subjects after aspirin desensitization.
Our study demonstrated that uLTE4 levels (pg/mg creatinine) in 3 NERD and 3 NIBR patients were increased and remained elevated up to 3 years after aspirin desensitization even though recurrent nasal polyposis was successfully prevented in all cases.
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
DISCUSSION
Most studies on NSAID hypersensitivity have focused on NERD, although worldwide epidemiological data suggest that NECD/NIUA might be more common. Recent data have demonstrated that some patients cannot be categorized into the current classification of NSAID hypersensitivity, for example those with NSAID-induced periorbital angioedema and NIBR.1419 These patients may also have underlying chronic airway diseases; however, the role of aspirin desensitization in the prevention of recurrent nasal polyposis and control of airway inflammation in NSAID-sensitive subjects other than the NERD phenotype has never been reported.
The leading presentations in NSAID-sensitive subjects in this study were periorbital angioedema, acute urticaria, bronchial symptoms, and naso-ocular reactions, respectively. Even those confirmed with NSAID exposure, a significant number of patients in our cohort also showed clinical responses in more than 1 organ system, indicating that the prevalence of NIBR was higher than previously thought. Although patients with IgE-mediated anaphylaxis might also present with multiple organ involvement, the fact that most of the reactions took about 1–2 hours to occur and the ability to react to multiple NSAIDs with dissimilar chemical structures made them more compatible with the non-immunologic effect of the drugs.
Facial angioedema around the periorbital area was the most common presenting symptom in Thai patients. Upon NSAID provocation, however, the predominant periorbital angioedema often accompanied by blocked nose, running nose, and itchy/red eyes. After a thorough examination, small urticarial rash on the trunk and extremities, and expiratory wheezing were occasionally detected, although frequently asymptomatic. It is noteworthy that periorbital angioedema may persist for hours or days while urticarial rash and respiratory symptoms are quickly resolved after treatment. As a result, NIBR could be underdiagnosed if history taking is not thoroughly reviewed, since symptoms with lesser severity in other organ systems may be unnoticed. In addition, the COX-1 inhibitor properties of the exposed NSAIDs could affect the phenotype of NSAID sensitivity reported by patients as some patients experienced both asthmatic attack and periorbital angioedema/generalized urticaria after taking aspirin but reported only periorbital edema after taking acetaminophen.
It is practically difficult to clearly distinguish between NSAID-induced periorbital angioedema and NSAID-induced naso-ocular reactions (upper airway manifestations of NERD), since patients occasionally experienced periorbital swelling, red/swollen eyes with tearing, and nasal congestion at the same time. In our opinion, the majority of NSAID hypersensitivity in the Thai population would be described as “NSAID-induced blended reaction with predominant periorbital angioedema” and probably related to “NSAID-induced isolated periorbital angioedema” phenotype as proposed by the Spanish group. It is interesting to note that the prevalence of atopic disease was high in this patient group. We speculate that the increased leukotriene production after NSAID consumption could lead to the worsening of pre-existing mucosal inflammation around the nose and eyes in patients who already suffered from the late-phase reaction of persistent allergic rhinitis.
Our study did not find any difference in terms of basal uLTE4 levels between NSAID-sensitive and NSAID-tolerant subjects. However, uLTE4 levels were higher in NSAID-sensitive patients, particularly in NERD and NIBR subjects, after the NSAID challenge compared to those in the NSAID-tolerant group. Though basal uLTE4 levels may not be a suitable marker to screen NSAID sensitivity status, elevated uLTE4 levels after aspirin OPT could be the supporting evidence for the diagnosis of cross-reactive NSAID hypersensitivity in cases where the clinical response is equivocal. Our study demonstrated that the degree of defective leukotriene homeostasis after exposure to drugs affecting the cyclo-oxygenase pathway might be related to the severity of respiratory involvement upon NSAID exposure.35 The fact that uLTE4 levels were barely changed after celecoxib provocation in patients with NSAID cross-reactivity confirms that celecoxib is a safe alternative NSAID in these patient groups.
According to our study, the patterns of NSAID hypersensitivity in southeast Asians are similar to those in southern Europeans and Latin Americans, and somewhat different from those reported in patients of northern European descent. Previous data suggested that aspirin nasal provocation could potentially diagnose some NSAID-sensitive patients presenting with predominant cutaneous reactions.3637 Retrospectively, some of these patients might be re-classified as the NIBR phenotype, since a decreased nasal volume was also observed. In other words, patients diagnosed with an NSAID-induced cutaneous reaction who positively reacted to NSAID nasal provocation, especially those with a periorbital reaction, might be NIBR subjects with subclinical airway involvement.
The novelties of this study were the findings that NIBR accounted for about one-third of adult patients with cross-reactive NSAID hypersensitivity and that aspirin desensitization could successfully prevent the recurrence of nasal polyposis and alleviate respiratory symptoms not only in NERD, but also in NIBR, even though urine LTE4 levels remained elevated. However, since the reactions in some NIBR patients could lead to serious adverse events, aspirin desensitization in NIBR subjects should be performed only when it is strongly indicated in selected patients with no previous severe reactions to NSAIDs. In NIBR subjects who experienced previous severe reactions in multiple organ systems, the procedure of aspirin desensitization, if necessary, should be carefully monitored and the administration of biological agents such as dupilumab, if available, should be considered a safer therapeutic option in these cases.
Interestingly, uLTE4 levels were increased after aspirin desensitization and remained elevated throughout the follow-up period. It should be emphasized that urticarial rash and stomach-ache in NIBR patients also disappeared while patients were taking daily aspirin. These data suggest that the pathogenesis of nasal polyposis cannot be explained by cysLT overproduction alone and that aspirin desensitization could be useful to alleviate both respiratory and non-respiratory symptoms in NIBR subjects.
Interestingly, a recent study also found that the clinical benefit of high-dose aspirin desensitization in NERD was independent of a reduction of mast cell activation and cysLT production. They reported paradoxically increased uLTE4 levels 8 weeks after aspirin desensitization compared to the baseline levels and concluded that high-dose aspirin therapy did not restore the impaired eicosanoid pathway.38 According to their study findings and ours, the therapeutic effect of aspirin desensitization was not directly correlated with a change of arachidonic acid metabolism.
There are some limitations to this study. Aspirin desensitization was performed in only 6 patients in our cohort; therefore, the comparative success rates and potential adverse reactions of aspirin desensitization between NERD and NIBR patients could not be analyzed. Further studies with a larger sample size are needed to compare the long-term prognosis between NERD and NIBR, to understand the mechanism of aspirin desensitization for the improvement of respiratory and extra-respiratory symptoms and to evaluate its risk-benefit ratio of aspirin desensitization in NIBR subjects.
In conclusion, NIBR is not uncommon among patients diagnosed with NSAID hypersensitivity in Thailand. Increased uLTE4 levels upon aspirin provocation suggested a diagnosis of NSAID cross-reactivity, while baseline uLTE4 levels were not distinguishable between NSAID-tolerant and NSAID-sensitive subjects. Our study indicates that aspirin desensitization is effective not only in NERD but also in NIBR. The persistently high levels of uLTE4 in spite of clinical improvement in NSAID-sensitive patients after successful aspirin desensitization suggest that elevated leukotrienes alone cannot explain the pathogenesis of NSAID hypersensitivity reactions.
ACKNOWLEDGMENTS
This study was supported by the Ratchadaphiseksomphot fund, Faculty of Medicine, Chulalongkorn University, grant No. RA55/19 and the Skin and Allergy Research Unit, Chulalongkorn University, Bangkok, Thailand. Study data were collected and managed using Research Electronic Data Capture (REDCap) hosted at HIV Netherlands Australia Thailand Research Collaboration. The authors thank Thitima Kantachatvanich, MD for providing patient information.
Disclosure: There are no financial or other issues that might lead to conflict of interest.
SUPPLEMENTARY MATERIALS
Supplementary Table S1
Clinical characteristics of patients with confirmed NSAID-induced immediate reactions
Supplementary Fig. S1
Representative photos of skin rash demonstrated during aspirin desensitization in NIBR patients. | IBUPROFEN, INDOMETHACIN, MEFENAMIC ACID | DrugsGivenReaction | CC BY-NC | 33474858 | 18,863,279 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nasal congestion'. | Clinical Characteristics, Urinary Leukotriene E4 Levels, and Aspirin Desensitization Results in Patients With NSAID-Induced Blended Reactions.
OBJECTIVE
Data on non-steroidal anti-inflammatory drug (NSAID) hypersensitivity in Southeast Asia are scarce. Increased urinary leukotriene E4 (uLTE4) levels have been suggested as a biomarker of NSAID-exacerbated respiratory disease (NERD). This study investigated clinical patterns of NSAID sensitivity in Thailand and the diagnostic roles of uLTE4 measurement in various phenotypes.
METHODS
The clinical phenotypes in 92 Thai adults with cross-reactive NSAID hypersensitivity were characterized based on the clinical history and drug provocation. The uLTE4 levels were measured at baseline, after aspirin provocation and after desensitization.
RESULTS
More than half of the patients (56.5%) presented with cutaneous symptoms (NSAID-exacerbated cutaneous disease), while one-third (33.7%) developed symptoms in at least 2 systems (NSAID-induced blended reactions; NIBR). Fifty-two patients underwent drug provocation and 59.6% of them yielded positive results. After drug provocation, a significant number of patients with confirmed NSAID cross-reactivity experienced clinical symptoms in more than one organ system. The uLTE4 levels at baseline were comparable between the NSAID-tolerant and NSAID-sensitive groups, but were substantially increased after aspirin provocation predominantly in NERD (983.4 pg/mg creatinine) and NIBR (501.0 pg/mg creatinine) compared to NSAID-tolerant subjects (122.1 pg/mg creatinine, P < 0.01 and 0.05, respectively). The uLTE4 levels were elevated after aspirin desensitization, although nasal polyposis and asthma were under control in 3 NERD and 3 NIBR subjects.
CONCLUSIONS
NIBR is not uncommon among NSAID-sensitive patients in Thailand. The diagnostic value of basal uLTE4 levels was limited, but increased uLTE4 levels upon aspirin provocation suggest NSAID cross-reactivity with respiratory components. This study indicates that aspirin desensitization, if necessary, might be effective in both NERD and NIBR.
BACKGROUND
ClinicalTrials.gov Identifier: NCT03849625.
INTRODUCTION
Hypersensitivity reactions to aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most common drug allergic reactions in clinical practice. They are generally categorized into 5 major phenotypes: NSAID-exacerbated respiratory disease (NERD), NSAID-exacerbated cutaneous (urticaria/angioedema) disease (NECD) in patients with underlying chronic urticaria, NSAID-induced urticaria/angioedema (NIUA) in patients without underlying chronic urticaria, single NSAID-induced urticaria/angioedema or anaphylaxis, and single NSAID-induced delayed hypersensitivity reactions.1 The first 3 phenotypes are non-immunologically mediated, and patients can develop cross-reactive hypersensitivity to chemically unrelated NSAIDs, while the latter 2 are selective NSAID sensitivities associated with drug-specific immunoglobulin E (IgE) and T-cell response, respectively.
Genetic and epigenetic variations play significant roles in the development of NERD.2 The proposed underlying mechanism is that the disturbance in arachidonic acid synthesis pathways leads to overproduction of cysteinyl leukotrienes (cysLT) and persistent airway inflammation.3 Mast cells are believed to be the major source of cysLT, but platelet-adherent leukocytes may be responsible for cysLT overproduction in NERD as well.4 The consumption of drugs inhibiting the cyclooxygenase-1 (COX-1) enzyme, such as aspirin and conventional NSAIDs, aggravates respiratory symptoms by enhancing cysLT production in NSAID-sensitive subjects, while the administration of specific COX-2 inhibitors, such as celecoxib, is generally safe.56 Besides aspirin/NSAID avoidance, aspirin desensitization has also been proven to be helpful for long term management in NERD subjects. Beneficial effects of aspirin desensitization in preventing nasal polyp recurrence and control symptoms of chronic rhinosinusitis and asthma have been well documented.7 Rapid aspirin desensitization has shown to be effective for the treatment of coronary artery disease in patients with a history of aspirin/NSAID-induced urticaria/angioedema, but it is not indicated for the treatment of chronic urticaria.8
Worldwide epidemiological data on clinical characteristics of NSAID hypersensitivity are limited. Most studies on NERD were performed in the United States and northern European countries.9101112 However, the predominant manifestation in Latin Americans and southern Europeans is the cutaneous phenotype (NIUA, NECD, and NSAID-induced isolated periorbital angioedema).1314 Studies in Asian populations have suggested that the prevalence of the NERD phenotype is not common in this region of the world. A study performed in China indicated that the prevalence of NSAID hypersensitivity in Chinese patients with chronic rhinosinusitis is very low (0.57%) compared to their European counterparts.15 It was also noted that NSAID-induced blended reactions (NIBR) are common in young Asian, atopic children in Singapore.16 Reports from Singapore and Thailand indicated that aspirin/NSAID-induced angioedema/urticaria is probably the prominent phenotype in Southeast Asia, with acetaminophen hypersensitivity being frequent.1718
In clinical practice, the current classification of cross-reactive NSAID hypersensitivity into 3 distinct phenotypes has some limitations. Clinical characteristics in NSAID-sensitive patients may not be well defined, and a combination of respiratory and cutaneous or other symptoms, such as gastrointestinal symptoms (mixed or blended reactions), is frequently observed.19 A previous report stated that aspirin nasal provocation is potentially useful for diagnosing patients with the blended reaction as well.20 However, the role of aspirin desensitization in other phenotypes of NSAID hypersensitivity, besides NERD, for long-term management of inflammatory airway diseases has not yet been established. Whether aspirin desensitization would be effective in controlling asthma and the recurrence of nasal polyposis after sinus surgery in NIBR is currently unknown.
At present, cross-reactive types of NSAID hypersensitivity can only be diagnosed by careful history taking and controlled-provocation testing, since there is no reliable in vitro method to confirm the diagnosis.21 There is evidence that basal urinary levels of leukotriene E4 (uLTE4), a stable product of the cysLT synthesis pathway, are elevated in NERD patients and could be a potential biomarker for differentiating between NSAID-sensitive and NSAID-tolerant asthmatics. However, these data are still controversial.222324 There have also been preliminary studies showing that uLTE4 levels might be increased in NECD.2526 Whether the measurement of basal uLTE4 levels could be a diagnostic marker for any phenotype of NSAID hypersensitivity is yet to be explored.
The purpose of this study was to analyze the clinical characteristics of patients diagnosed with NSAID-induced immediate reactions in Thailand and to explore whether the measurement of uLTE4 levels would be helpful in identifying NSAID-sensitive subjects or in differentiating among different phenotypes of cross-reactive NSAID hypersensitivities.
MATERIALS AND METHODS
Patient recruitment
Adult patients (18 years of age and older) with a suggestive history of NSAID-induced hypersensitivity reaction visiting the allergy clinic at King Chulalongkorn University Hospital between June 2014 and July 2018 were recruited into this study. Those with a history compatible with drug-induced non-immediate reactions (maculopapular rash, fixed drug eruption, acute generalized exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms, Stevens-Johnson syndrome/toxic epidermal necrolysis) or NSAID-related side effects were excluded. The status of NSAID-induced immediate hypersensitivity was diagnosed in patients with a well-documented drug allergy history or in patients with a suggestive history of NSAID sensitivity who yielded a positive drug provocation test as follows.
Clinical diagnosis of NSAID hypersensitivity
The diagnosis of cross-reactive NSAID hypersensitivity was clinically made in patients with a well-documented history of multiple episodes of respiratory, cutaneous, and/or gastrointestinal reactions within 2 hours after exposure to at least 2 different NSAID classes.1212728 Patient demographic data were collected, including the underlying diseases, atopic family history, and details on drug allergy history as well as the presenting symptoms and types of the culprit NSAIDs.
Aspirin provocation test
Oral aspirin provocation was performed in patients with a suggestive medical history or in those who had a history of an immediate reaction to a single NSAID to confirm the diagnosis of cross-reactive NSAID hypersensitivity according to the EAACI/GA2LEN guidelines, with some modifications.293031 Four increasing doses of aspirin (40.5, 81, 150, and 300 mg) were administered at 90-minute intervals until a positive reaction occurred. Clinical symptoms, fractional exhaled nitric oxide (FeNO), and the forced expiratory volume in 1 second (FEV1) were monitored to evaluate the reaction. A positive provocation test was defined if any of the following reactions developed: lower respiratory/bronchial reaction (a 15% decrease in FEV1 plus naso-ocular reaction or a 20% decrease in FEV1 alone), upper respiratory/naso-ocular reaction (nasal congestion and rhinorrhea; conjunctival injection), cutaneous reactions (urticaria/angioedema, periorbital edema), and/or other reactions (gastrointestinal symptoms such as nausea/vomiting, stomach cramps, and diarrhea). The test was considered negative if a patient tolerated the final dose (300 mg of aspirin) without any significant symptoms mentioned above.
Oral provocation test (OPT) with other NSAIDs, acetaminophen, or celecoxib
Patients with a history of an immediate reaction to only aspirin were challenged with escalating doses of ibuprofen to confirm the diagnosis of cross-reactive NSAID sensitivity. Patients with a history of an immediate reaction to a single NSAID were provoked with the suspected drug to verify the status of single NSAID hypersensitivity after a negative aspirin provocation test. Escalating doses of ibuprofen, diclofenac, and acetaminophen were administered, if applicable, as follows: ibuprofen (50, 100, and 200 mg), diclofenac (6.25, 12.5, and 25 mg), and acetaminophen (125, 250, and 500 mg). Celecoxib was also provoked in 3 doses (50, 100, and 200 mg) in patients with confirmed hypersensitivity to multiple NSAIDs who were willing to identify a safe alternative drug. The provocation test for each drug was performed on separate days at least 7 days apart. Each dose of drug provocation was provided at 90-minute intervals until the final dose was reached.
Classification of NSAID hypersensitivity according to drug provocation test results
Patients with cross-reactive NSAID phenotypes were classified according to the results of the drug provocation test as 1) NECD/NIUA if they developed cutaneous symptoms alone; 2) NERD if they developed respiratory symptoms alone; and 3) NIBR if they developed a combination of symptoms involving more than one organ system (respiratory, cutaneous, and/or gastrointestinal symptoms). Single NSAID hypersensitivity was diagnosed in patients with a positive provocation test to the suspected NSAID, but a negative aspirin provocation test. Patients who had negative provocations to both aspirin and the suspected culprit drug were labeled as NSAID-tolerant subjects. NECD/NIUA were purposely categorized together in our study to compare the differences and similarities between patients diagnosed with NSAID-induced cutaneous reactions and -respiratory reactions. Moreover, NECD and NIUA share similar background characteristics from a clinical point of view and some patients diagnosed with NIUA eventually evolve to NECD over time.32
Skin prick tests with common aeroallergens in Thailand (mixed dust mites, mixed cockroaches, mixed mold, cat dander, dog hair, and southern grass mix; ALK-Abello, Hørsholm, Denmark) were also examined in tested patients to identify atopic status. Wheal size ≥ 3 mm was considered a positive test.
Measurement of FeNO and the FEV1 in patients who underwent drug provocation test
FeNO was measured in all participants at baseline and after drug provocation by using a portable electrochemical analyzer (NObreath®; Bedfont Scientific Ltd, Maidstone, UK) according to the ATS/ERS recommendations.33 Measurements of FEV1 were also performed using a Vitalograph spirometer (Vitalograph®, Buckingham, UK). The best of 3 repeated attempts was recorded.
The uLTE4 measurement
The uLTE4 levels were measured by a leukotriene E4 ELISA kit (Cayman Chemical, Ann Arbor, MI, USA) at baseline and 90 minutes after the final dose of drug provocation, as well as at the follow-up visits after aspirin desensitization and reported after adjustment to urine creatinine levels.
Aspirin desensitization
Outpatient aspirin desensitization was performed in NSAID-sensitive patients who were referred from otolaryngologists to prevent the recurrence of nasal polyposis. The procedure was carried out according to the intranasal ketorolac and modified aspirin challenge 2-day protocol.34 Aspirin desensitization was completed after patients were able to tolerate a 325-mg dose of aspirin by the end of day 2 and experience no symptoms, changes in nasal flow rates, or decrease in FEV1 values. The prescribed maintenance dose of aspirin was 325 mg twice a day.
Statistical analysis
Patient characteristics are reported as means ± standard deviation for quantitative analysis, and median and interquartile range (IQR) are used to describe non-parametric data. The Mann-Whitney U test and Kruskal-Wallis test with Dunn's multiple comparisons were used to analyze the differences between 2 groups and more than 2 groups, respectively. Statistical analyses were performed using GraphPad Prism 8.3 software (GraphPad Software Inc., San Diego, CA, USA). P values < 0.05 were considered statistically significant.
Ethical considerations
Patients enrolled in this study were those who recruited in the study entitled “Characteristics of Patients Diagnosed With NSAID Sensitivity in Thailand” registered at ClinicalTrials.gov (NCT03849625). The study was approved by the Ethics and Research Committee of the Faculty of Medicine, Chulalongkorn University, Approval Number: COA No. 659/2012 and informed consent was obtained from all participants.
RESULTS
A total of 158 adult patients with a suspected history of NSAID hypersensitivity between 2015 and 2018 at King Chulalongkorn Memorial Hospital were initially recruited into this study as shown in Fig. 1. Thirty-five patients with a history compatible with a non-immediate hypersensitivity reaction and 4 subjects with clinical symptoms compatible with NSAID-related side effects were later excluded.
Fig. 1 Schematic diagram of patient selection for this study.
A total of 158 patients with a suspected history of NSAID hypersensitivity were initially recruited into this study. Cross-reactive NSAID hypersensitivity was clinically diagnosed in 67 patients with a well-documented drug allergy history and verified by a positive drug provocation test in 25 patients with a suggestive history of NSAID reactions.
NSAID, non-steroidal anti-inflammatory drug.
Cross-reactive NSAID hypersensitivity was clinically diagnosed in 67 patients with a convincing drug allergy history as defined in the methods section. The remaining 52 patients with a suggestive history of NSAID hypersensitivity underwent an OPT to confirm NSAID cross-reactivity status. Fifteen out of 25 patients with confirmed NSAID cross-reactivity were subsequently provoked with celecoxib to find a safe alternative NSAID. Single NSAID/acetaminophen hypersensitivity was verified in 6 patients who tolerated aspirin provocation but developed an allergic reaction upon re-challenge with acetaminophen or diclofenac.
Demographic data of adult patients with cross-reactive NSAID hypersensitivity
The clinical characteristics of adult patients with cross-reactive NSAID hypersensitivity are shown in Table 1 (n = 92). Most patients were females (77.2%) with an average age of 45.7 ± 13.4 years. The average age of onset was 32.2 ± 13.3 years and about half of them had atopic family history. The majority of them (56.5%) reported only cutaneous symptoms such as facial angioedema and/or acute urticarial rash, after NSAID exposure, while 9.8% of them developed only respiratory symptoms. Interestingly, about 33.7% of the patients experienced a combination of symptoms in multiple organ systems as shown in Fig. 2. The groups of NSAIDs frequently responsible for hypersensitivity reactions were propionic acid derivatives and acetic acid derivatives. Although inflammatory airway diseases (chronic sinusitis, nasal polyposis, and asthma) were significantly more common in patients who experienced only respiratory reactions after exposure to an NSAID compared to the other phenotypes, a significant portion of the patients reporting blended reactions had underlying airway diseases and chronic urticaria as well. Acetaminophen intolerance was also reported in about one-third (35.9%) of NSAID-sensitive subjects.
Table 1 Clinical characteristics among different phenotypes of patients with cross-reactive NSAID hypersensitivity (n = 92)
Phenotypes NECD/NIUA (n = 52) NERD (n = 9) NIBR (n = 31) Total (n = 92)
Gender (female/male) 37/15 6/3 28/3 71/21
Age (yr) 43.6 ± 12.3 47.3 ± 11.9 48.7 ± 15.3 45.7 ± 13.4
Age of onset (yr) 31.3 ± 13.8 34.6 ± 11.0 33.1 ± 13.3 32.2 ± 13.3
Underlying disease (%)
Chronic urticaria 13.5 11.1 29.0 18.5
Chronic sinusitis* 13.5 55.6 32.3 23.9
Nasal polyposis* 7.7 66.7 16.1 16.3
Asthma* 17.3 88.9 35.5 30.4
Atopic family history (%) 42.3 55.6 61.3 50.0
Drug exposure time to symptom onset (min) 58.8 ± 31.9 48.3 ± 34.3 47.6 ± 29.9 54.0 ± 31.6
Presenting symptoms (%)*
Facial/periorbital angioedema 71.2 0.0 74.2 65.2
Acute urticaria 73.1 0.0 61.3 62.0
Naso-ocular reaction 0.0 33.3 61.3 23.9
Acute asthma 0.0 88.9 67.7 31.5
Gastrointestinal symptoms 0.0 0.0 16.1 5.4
Implicated NSAIDs (%)†
Salicylic acids 23.1 55.6 35.5 30.4
Propionic acids 44.2 22.2 54.8 45.7
Acetic acids 23.1 22.2 48.4 31.5
Enolic acids 7.7 0.0 6.5 6.5
Anthranilic/fenamic acids 28.8 11.1 29.0 27.2
Acetaminophen intolerance (%)§ 28.8 22.2 51.6 35.9
Values are presented as number (%) or mean ± standard deviation. Each patient could present with multiple symptoms and from more than one implicated drug.
NSAID, non-steroidal anti-inflammatory drug; NECD, non-steroidal anti-inflammatory drug-exacerbated cutaneous (urticaria/angioedema) disease in patients with underlying chronic urticaria; NIUA, non-steroidal anti-inflammatory drug-induced urticaria/angioedema in patients without underlying chronic urticaria; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
*P < 0.05 among different phenotypes. †Examples of commonly implicated drugs in this study based on NSAID classification: 1) Salicylic acids: acetylsalicylic acid (aspirin), salicylic acid, diflunisal, salsalate; 2) Propionic acids: ibuprofen, naproxen, ketoprofen, fenoprofen, flurbiprofen; 3) Acetic acids: indomethacin, ketorolac, diclofenac, sulindac; 4) Enolic acids: piroxicam, meloxicam, tenoxicam; 5) Anthranilic/fenamic acids: mefenamic acid, flufenamic acid. §Acetaminophen intolerance: cannot tolerate acetaminophen higher than 500 mg.
Fig. 2 Clinical presentations in patients with cross-reactive NSAID hypersensitivity.
A proportional Venn diagram shows that about half of patients with cross-reactive NSAID hypersensitivity in Thailand reported only cutaneous symptoms after NSAID exposure, while one-third of them experienced NSAID-induced blended reactions.
NSAID, non-steroidal anti-inflammatory drug.
Clinical respiratory parameters and uLTE4 levels in different phenotypes of patients with cross-reactive NSAID hypersensitivity confirmed by positive OPT
NSAID hypersensitivity was confirmed in 59.6% (31/52) of the tested patients with a history of NSAID-induced immediate reactions. The majority of patients with cross-reactive NSAID hypersensitivity (17/25) according to OPT results were atopic individuals. The common phenotypes of patients with confirmed cross-reactive NSAID sensitivity were NECD/NIUA, NIBR, and NERD, respectively, as shown in Supplementary Table S1.
The average FeNO, %predicted FEV1, and uLTE4 levels were measured at baseline and after provocation with aspirin/NSAID in 25 NSAID cross-reactive and 21 NSAID-tolerant subjects as shown in Table 2. At baseline, patients with confirmed NSAID cross-reactivity (NSAID-sensitive group) had higher FeNO (P < 0.01) and slightly less %predicted FEV1 compared to the NSAID-tolerant subjects, while basal uLTE4 levels between NSAID-sensitive and NSAID-tolerant groups were comparable. After provocation, %predicted FEV1 was substantially reduced in NSAID-sensitive subjects, whereas uLTE4 levels were significantly elevated compared to the NSAID-tolerant group (P < 0.01). Celecoxib provocation was well tolerated in all NSAID-sensitive subjects. No statistical differences in the average FeNO, %predicted FEV1, or uLTE4 levels in 15 NSAID-sensitive patients (7 NECD/NIUA, 4 NIBR, 4 NERD) after celecoxib provocation were observed compared to those in NSAID-tolerant subjects.
Table 2 Respiratory parameters and uLTE4 levels in NSAID-sensitive subjects upon provocation with aspirin or celecoxib compared to NSAID-tolerant subjects
Characteristics Baseline After aspirin (OPT) P value*
NSAID tolerant (n = 21)
FeNO (ppb) 13.0 (8.5–19.5) 10.2 (7.0–16.8) 0.03
%predicted FEV1 100.8 (82.8–115.9) 99.0 (75.2–118.2) 0.90
uLTE4 (pg/mg creatinine) 116.3 (66.5–305.4) 122.1 (63.5–173.8) 0.17
NSAID sensitive (n = 25)
FeNO (ppb) 27.0 (17.8–40.9)† 18.0 (10.5–31.0) <0.01
%predicted FEV1 86.7 (63.3–104.9) 74.6 (52.4–89.8)† <0.01
uLTE4 (pg/mg creatinine) 118.3 (93.2–407.2) 204.9 (90.6–817.8)† <0.01
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; OPT, oral provocation test; ppb, parts per billion; FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in 1 second.
*P values before vs. after provocation test, Wilcoxon signed-rank test; †P < 0.01 compared to the NSAID-tolerant subjects.
According to the subgroup analysis, 10 NECD/NIUA, 9 NIBR, and 6 NERD were categorized as shown in Fig. 3. At baseline, %predicted FEV1 was not significantly different among different types of cross-reactive NSAID hypersensitivity, although those in patients with confirmed NIBR were lowest (64.9%, IQR 56.9–97.3). The significant differences in basal FeNO levels (P < 0.01) among the 3 different phenotypes were observed. The basal FeNO levels were significantly higher in NIBR (36.9%, IQR 27.0–95.4) than in NSAID-tolerant subjects (P < 0.01). After aspirin OPT, the reduction of %FEV1 was considerably higher in patients with confirmed NERD (22.0%, IQR 16.0-28.8), followed by NIBR (13.3%, IQR 7.6–28.0), compared to those in NSAID-tolerant groups (P < 0.01). Basal uLTE4 levels were not significantly different among the 3 phenotypes. Interestingly, uLTE4 levels after aspirin provocation were significantly higher in NERD and NIBR patients than in the NECD/NIUA and NSAID-tolerant groups (P < 0.05 and < 0.01, respectively).
Fig. 3 Respiratory parameters and uLTE4 levels in different phenotypes of NSAID-sensitive subjects compared to NSAID-tolerant subjects.
Baseline FeNO in NIBR and NERD were higher than those in the NSAID-tolerant group. After aspirin provocation, % predicted FEV1 in NERD and NIBR were significantly reduced from the baseline while uLTE4 levels were much higher than those in NSAID-tolerant subjects.
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; FEV1, forced expiratory volume in 1 second.
*P values < 0.05, †P values < 0.01.
Effects of aspirin desensitization on uLTE4 levels in patients diagnosed with NERD and NIBR
Aspirin desensitization was performed in selected patients (3 NERD and 3 NIBR) who had pre-existing inflammatory airway diseases and a history of recurrent nasal polyposis after surgery as shown in Table 3. The maintenance dose of aspirin was 650 mg/day during the first 6 months and reduced to 325 mg/day afterward. Levels of uLTE4 were measured at baseline after aspirin desensitization and serially followed up for 2–3 years as demonstrated in Fig. 4. Other than respiratory symptoms, acute urticarial rash and gastrointestinal symptoms (abdominal cramp/nausea/diarrhea) were also aggravated in NIBR subjects during aspirin desensitization as shown in Supplementary Fig. S1, but gradually relieved with supportive treatment. No sinus surgery was required for nasal polyp recurrence, and asthma symptoms were under control after aspirin desensitization in all 6 cases. Up to 3 years after aspirin desensitization, however, uLTE4 levels were significantly increased and remained elevated throughout the follow-up period, although urticarial rash and gastrointestinal symptoms were no longer observed while taking aspirin.
Table 3 Details of patients with cross-reactive NSAID hypersensitivity undergoing aspirin desensitization in this study
Patients (sex/year) Underlying diseases History of adverse drug reactions Indication for aspirin desensitization Follow-up duration (months) Asthma control before/after aspirin desensitization Recurrent nasal polyposis after aspirin desensitization Skin symptoms after aspirin desensitization Gastrointestinal symptoms after aspirin desensitization
1. NERD (M/46) Chronic sinusitis, nasal polyposis, asthma Acute asthma 20 min after taking aspirin 2 recurrent nasal polyps 74 Partly controlled with high dose ICS-LABA and add-on LTRA/well controlled with low dose ICS None NA NA
2. NERD (M/54) Chronic rhinitis, nasal polyposis, asthma Acute asthma, blocked nose 1 hr after taking aspirin 3 recurrent nasal polyps 24 Uncontrolled with high dose ICS-LABA and add-on LTRA/well controlled with medium dose ICS-LABA None NA NA
3. NERD (M/56) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked nose 1 hr after taking ibuprofen 6 recurrent nasal polyps 32 Partly controlled asthma with high dose ICS-LABA and add-on LTRA/well controlled with medium dose ICS-LABA None NA NA
4. NIBR (M/48) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked nose, conjunctival injection, urticarial rash 2 hr after taking aspirin 3 recurrent nasal polyps 72 Partly controlled with medium dose ICS-LABA/well controlled with low dose ICS-LABA None No rash after taking aspirin NA
5. NIBR (F/65) Chronic sinusitis, nasal polyposis, chronic urticaria, asthma (history of cardiac arrest from severe asthma) Urticarial rash, periorbital angioedema, blocked nose, conjunctival injection, rhinorrhea, bronchospasm/wheezing, hoarseness of voice 1 hr after taking aspirin, ibuprofen, mefenamic acid, acetaminophen 2 recurrent nasal polyps 48 Uncontrolled with high dose ICS-LABA and add-on LTRA/well controlled with low dose ICS-LABA None No rash after taking aspirin, chronic urticaria resolved NA
6. NIBR (F/38) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked/running nose, stomach cramp, diarrhea, periorbital angioedema, urticaria 30 min after taking ibuprofen, indomethacin, mefenamic acid 2 recurrent nasal polyps 21 Partly controlled with medium dose ICS-LABA/well controlled, with medium dose ICS-LABA None No rash after taking aspirin No gastrointestinal symptoms after taking aspirin
NSAID, non-steroidal anti-inflammatory drug; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; ICS, inhaled corticosteroid; LABA, long-acting beta-agonist; LTRA, leukotriene receptor antagonist; NA, not applicable (no symptoms prior to aspirin desensitization); NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
Fig. 4 uLTE4 levels in NSAID-sensitive subjects after aspirin desensitization.
Our study demonstrated that uLTE4 levels (pg/mg creatinine) in 3 NERD and 3 NIBR patients were increased and remained elevated up to 3 years after aspirin desensitization even though recurrent nasal polyposis was successfully prevented in all cases.
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
DISCUSSION
Most studies on NSAID hypersensitivity have focused on NERD, although worldwide epidemiological data suggest that NECD/NIUA might be more common. Recent data have demonstrated that some patients cannot be categorized into the current classification of NSAID hypersensitivity, for example those with NSAID-induced periorbital angioedema and NIBR.1419 These patients may also have underlying chronic airway diseases; however, the role of aspirin desensitization in the prevention of recurrent nasal polyposis and control of airway inflammation in NSAID-sensitive subjects other than the NERD phenotype has never been reported.
The leading presentations in NSAID-sensitive subjects in this study were periorbital angioedema, acute urticaria, bronchial symptoms, and naso-ocular reactions, respectively. Even those confirmed with NSAID exposure, a significant number of patients in our cohort also showed clinical responses in more than 1 organ system, indicating that the prevalence of NIBR was higher than previously thought. Although patients with IgE-mediated anaphylaxis might also present with multiple organ involvement, the fact that most of the reactions took about 1–2 hours to occur and the ability to react to multiple NSAIDs with dissimilar chemical structures made them more compatible with the non-immunologic effect of the drugs.
Facial angioedema around the periorbital area was the most common presenting symptom in Thai patients. Upon NSAID provocation, however, the predominant periorbital angioedema often accompanied by blocked nose, running nose, and itchy/red eyes. After a thorough examination, small urticarial rash on the trunk and extremities, and expiratory wheezing were occasionally detected, although frequently asymptomatic. It is noteworthy that periorbital angioedema may persist for hours or days while urticarial rash and respiratory symptoms are quickly resolved after treatment. As a result, NIBR could be underdiagnosed if history taking is not thoroughly reviewed, since symptoms with lesser severity in other organ systems may be unnoticed. In addition, the COX-1 inhibitor properties of the exposed NSAIDs could affect the phenotype of NSAID sensitivity reported by patients as some patients experienced both asthmatic attack and periorbital angioedema/generalized urticaria after taking aspirin but reported only periorbital edema after taking acetaminophen.
It is practically difficult to clearly distinguish between NSAID-induced periorbital angioedema and NSAID-induced naso-ocular reactions (upper airway manifestations of NERD), since patients occasionally experienced periorbital swelling, red/swollen eyes with tearing, and nasal congestion at the same time. In our opinion, the majority of NSAID hypersensitivity in the Thai population would be described as “NSAID-induced blended reaction with predominant periorbital angioedema” and probably related to “NSAID-induced isolated periorbital angioedema” phenotype as proposed by the Spanish group. It is interesting to note that the prevalence of atopic disease was high in this patient group. We speculate that the increased leukotriene production after NSAID consumption could lead to the worsening of pre-existing mucosal inflammation around the nose and eyes in patients who already suffered from the late-phase reaction of persistent allergic rhinitis.
Our study did not find any difference in terms of basal uLTE4 levels between NSAID-sensitive and NSAID-tolerant subjects. However, uLTE4 levels were higher in NSAID-sensitive patients, particularly in NERD and NIBR subjects, after the NSAID challenge compared to those in the NSAID-tolerant group. Though basal uLTE4 levels may not be a suitable marker to screen NSAID sensitivity status, elevated uLTE4 levels after aspirin OPT could be the supporting evidence for the diagnosis of cross-reactive NSAID hypersensitivity in cases where the clinical response is equivocal. Our study demonstrated that the degree of defective leukotriene homeostasis after exposure to drugs affecting the cyclo-oxygenase pathway might be related to the severity of respiratory involvement upon NSAID exposure.35 The fact that uLTE4 levels were barely changed after celecoxib provocation in patients with NSAID cross-reactivity confirms that celecoxib is a safe alternative NSAID in these patient groups.
According to our study, the patterns of NSAID hypersensitivity in southeast Asians are similar to those in southern Europeans and Latin Americans, and somewhat different from those reported in patients of northern European descent. Previous data suggested that aspirin nasal provocation could potentially diagnose some NSAID-sensitive patients presenting with predominant cutaneous reactions.3637 Retrospectively, some of these patients might be re-classified as the NIBR phenotype, since a decreased nasal volume was also observed. In other words, patients diagnosed with an NSAID-induced cutaneous reaction who positively reacted to NSAID nasal provocation, especially those with a periorbital reaction, might be NIBR subjects with subclinical airway involvement.
The novelties of this study were the findings that NIBR accounted for about one-third of adult patients with cross-reactive NSAID hypersensitivity and that aspirin desensitization could successfully prevent the recurrence of nasal polyposis and alleviate respiratory symptoms not only in NERD, but also in NIBR, even though urine LTE4 levels remained elevated. However, since the reactions in some NIBR patients could lead to serious adverse events, aspirin desensitization in NIBR subjects should be performed only when it is strongly indicated in selected patients with no previous severe reactions to NSAIDs. In NIBR subjects who experienced previous severe reactions in multiple organ systems, the procedure of aspirin desensitization, if necessary, should be carefully monitored and the administration of biological agents such as dupilumab, if available, should be considered a safer therapeutic option in these cases.
Interestingly, uLTE4 levels were increased after aspirin desensitization and remained elevated throughout the follow-up period. It should be emphasized that urticarial rash and stomach-ache in NIBR patients also disappeared while patients were taking daily aspirin. These data suggest that the pathogenesis of nasal polyposis cannot be explained by cysLT overproduction alone and that aspirin desensitization could be useful to alleviate both respiratory and non-respiratory symptoms in NIBR subjects.
Interestingly, a recent study also found that the clinical benefit of high-dose aspirin desensitization in NERD was independent of a reduction of mast cell activation and cysLT production. They reported paradoxically increased uLTE4 levels 8 weeks after aspirin desensitization compared to the baseline levels and concluded that high-dose aspirin therapy did not restore the impaired eicosanoid pathway.38 According to their study findings and ours, the therapeutic effect of aspirin desensitization was not directly correlated with a change of arachidonic acid metabolism.
There are some limitations to this study. Aspirin desensitization was performed in only 6 patients in our cohort; therefore, the comparative success rates and potential adverse reactions of aspirin desensitization between NERD and NIBR patients could not be analyzed. Further studies with a larger sample size are needed to compare the long-term prognosis between NERD and NIBR, to understand the mechanism of aspirin desensitization for the improvement of respiratory and extra-respiratory symptoms and to evaluate its risk-benefit ratio of aspirin desensitization in NIBR subjects.
In conclusion, NIBR is not uncommon among patients diagnosed with NSAID hypersensitivity in Thailand. Increased uLTE4 levels upon aspirin provocation suggested a diagnosis of NSAID cross-reactivity, while baseline uLTE4 levels were not distinguishable between NSAID-tolerant and NSAID-sensitive subjects. Our study indicates that aspirin desensitization is effective not only in NERD but also in NIBR. The persistently high levels of uLTE4 in spite of clinical improvement in NSAID-sensitive patients after successful aspirin desensitization suggest that elevated leukotrienes alone cannot explain the pathogenesis of NSAID hypersensitivity reactions.
ACKNOWLEDGMENTS
This study was supported by the Ratchadaphiseksomphot fund, Faculty of Medicine, Chulalongkorn University, grant No. RA55/19 and the Skin and Allergy Research Unit, Chulalongkorn University, Bangkok, Thailand. Study data were collected and managed using Research Electronic Data Capture (REDCap) hosted at HIV Netherlands Australia Thailand Research Collaboration. The authors thank Thitima Kantachatvanich, MD for providing patient information.
Disclosure: There are no financial or other issues that might lead to conflict of interest.
SUPPLEMENTARY MATERIALS
Supplementary Table S1
Clinical characteristics of patients with confirmed NSAID-induced immediate reactions
Supplementary Fig. S1
Representative photos of skin rash demonstrated during aspirin desensitization in NIBR patients. | ACETAMINOPHEN\HYDROCODONE, ASPIRIN, IBUPROFEN, MEFENAMIC ACID | DrugsGivenReaction | CC BY-NC | 33474858 | 19,056,205 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Periorbital swelling'. | Clinical Characteristics, Urinary Leukotriene E4 Levels, and Aspirin Desensitization Results in Patients With NSAID-Induced Blended Reactions.
OBJECTIVE
Data on non-steroidal anti-inflammatory drug (NSAID) hypersensitivity in Southeast Asia are scarce. Increased urinary leukotriene E4 (uLTE4) levels have been suggested as a biomarker of NSAID-exacerbated respiratory disease (NERD). This study investigated clinical patterns of NSAID sensitivity in Thailand and the diagnostic roles of uLTE4 measurement in various phenotypes.
METHODS
The clinical phenotypes in 92 Thai adults with cross-reactive NSAID hypersensitivity were characterized based on the clinical history and drug provocation. The uLTE4 levels were measured at baseline, after aspirin provocation and after desensitization.
RESULTS
More than half of the patients (56.5%) presented with cutaneous symptoms (NSAID-exacerbated cutaneous disease), while one-third (33.7%) developed symptoms in at least 2 systems (NSAID-induced blended reactions; NIBR). Fifty-two patients underwent drug provocation and 59.6% of them yielded positive results. After drug provocation, a significant number of patients with confirmed NSAID cross-reactivity experienced clinical symptoms in more than one organ system. The uLTE4 levels at baseline were comparable between the NSAID-tolerant and NSAID-sensitive groups, but were substantially increased after aspirin provocation predominantly in NERD (983.4 pg/mg creatinine) and NIBR (501.0 pg/mg creatinine) compared to NSAID-tolerant subjects (122.1 pg/mg creatinine, P < 0.01 and 0.05, respectively). The uLTE4 levels were elevated after aspirin desensitization, although nasal polyposis and asthma were under control in 3 NERD and 3 NIBR subjects.
CONCLUSIONS
NIBR is not uncommon among NSAID-sensitive patients in Thailand. The diagnostic value of basal uLTE4 levels was limited, but increased uLTE4 levels upon aspirin provocation suggest NSAID cross-reactivity with respiratory components. This study indicates that aspirin desensitization, if necessary, might be effective in both NERD and NIBR.
BACKGROUND
ClinicalTrials.gov Identifier: NCT03849625.
INTRODUCTION
Hypersensitivity reactions to aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most common drug allergic reactions in clinical practice. They are generally categorized into 5 major phenotypes: NSAID-exacerbated respiratory disease (NERD), NSAID-exacerbated cutaneous (urticaria/angioedema) disease (NECD) in patients with underlying chronic urticaria, NSAID-induced urticaria/angioedema (NIUA) in patients without underlying chronic urticaria, single NSAID-induced urticaria/angioedema or anaphylaxis, and single NSAID-induced delayed hypersensitivity reactions.1 The first 3 phenotypes are non-immunologically mediated, and patients can develop cross-reactive hypersensitivity to chemically unrelated NSAIDs, while the latter 2 are selective NSAID sensitivities associated with drug-specific immunoglobulin E (IgE) and T-cell response, respectively.
Genetic and epigenetic variations play significant roles in the development of NERD.2 The proposed underlying mechanism is that the disturbance in arachidonic acid synthesis pathways leads to overproduction of cysteinyl leukotrienes (cysLT) and persistent airway inflammation.3 Mast cells are believed to be the major source of cysLT, but platelet-adherent leukocytes may be responsible for cysLT overproduction in NERD as well.4 The consumption of drugs inhibiting the cyclooxygenase-1 (COX-1) enzyme, such as aspirin and conventional NSAIDs, aggravates respiratory symptoms by enhancing cysLT production in NSAID-sensitive subjects, while the administration of specific COX-2 inhibitors, such as celecoxib, is generally safe.56 Besides aspirin/NSAID avoidance, aspirin desensitization has also been proven to be helpful for long term management in NERD subjects. Beneficial effects of aspirin desensitization in preventing nasal polyp recurrence and control symptoms of chronic rhinosinusitis and asthma have been well documented.7 Rapid aspirin desensitization has shown to be effective for the treatment of coronary artery disease in patients with a history of aspirin/NSAID-induced urticaria/angioedema, but it is not indicated for the treatment of chronic urticaria.8
Worldwide epidemiological data on clinical characteristics of NSAID hypersensitivity are limited. Most studies on NERD were performed in the United States and northern European countries.9101112 However, the predominant manifestation in Latin Americans and southern Europeans is the cutaneous phenotype (NIUA, NECD, and NSAID-induced isolated periorbital angioedema).1314 Studies in Asian populations have suggested that the prevalence of the NERD phenotype is not common in this region of the world. A study performed in China indicated that the prevalence of NSAID hypersensitivity in Chinese patients with chronic rhinosinusitis is very low (0.57%) compared to their European counterparts.15 It was also noted that NSAID-induced blended reactions (NIBR) are common in young Asian, atopic children in Singapore.16 Reports from Singapore and Thailand indicated that aspirin/NSAID-induced angioedema/urticaria is probably the prominent phenotype in Southeast Asia, with acetaminophen hypersensitivity being frequent.1718
In clinical practice, the current classification of cross-reactive NSAID hypersensitivity into 3 distinct phenotypes has some limitations. Clinical characteristics in NSAID-sensitive patients may not be well defined, and a combination of respiratory and cutaneous or other symptoms, such as gastrointestinal symptoms (mixed or blended reactions), is frequently observed.19 A previous report stated that aspirin nasal provocation is potentially useful for diagnosing patients with the blended reaction as well.20 However, the role of aspirin desensitization in other phenotypes of NSAID hypersensitivity, besides NERD, for long-term management of inflammatory airway diseases has not yet been established. Whether aspirin desensitization would be effective in controlling asthma and the recurrence of nasal polyposis after sinus surgery in NIBR is currently unknown.
At present, cross-reactive types of NSAID hypersensitivity can only be diagnosed by careful history taking and controlled-provocation testing, since there is no reliable in vitro method to confirm the diagnosis.21 There is evidence that basal urinary levels of leukotriene E4 (uLTE4), a stable product of the cysLT synthesis pathway, are elevated in NERD patients and could be a potential biomarker for differentiating between NSAID-sensitive and NSAID-tolerant asthmatics. However, these data are still controversial.222324 There have also been preliminary studies showing that uLTE4 levels might be increased in NECD.2526 Whether the measurement of basal uLTE4 levels could be a diagnostic marker for any phenotype of NSAID hypersensitivity is yet to be explored.
The purpose of this study was to analyze the clinical characteristics of patients diagnosed with NSAID-induced immediate reactions in Thailand and to explore whether the measurement of uLTE4 levels would be helpful in identifying NSAID-sensitive subjects or in differentiating among different phenotypes of cross-reactive NSAID hypersensitivities.
MATERIALS AND METHODS
Patient recruitment
Adult patients (18 years of age and older) with a suggestive history of NSAID-induced hypersensitivity reaction visiting the allergy clinic at King Chulalongkorn University Hospital between June 2014 and July 2018 were recruited into this study. Those with a history compatible with drug-induced non-immediate reactions (maculopapular rash, fixed drug eruption, acute generalized exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms, Stevens-Johnson syndrome/toxic epidermal necrolysis) or NSAID-related side effects were excluded. The status of NSAID-induced immediate hypersensitivity was diagnosed in patients with a well-documented drug allergy history or in patients with a suggestive history of NSAID sensitivity who yielded a positive drug provocation test as follows.
Clinical diagnosis of NSAID hypersensitivity
The diagnosis of cross-reactive NSAID hypersensitivity was clinically made in patients with a well-documented history of multiple episodes of respiratory, cutaneous, and/or gastrointestinal reactions within 2 hours after exposure to at least 2 different NSAID classes.1212728 Patient demographic data were collected, including the underlying diseases, atopic family history, and details on drug allergy history as well as the presenting symptoms and types of the culprit NSAIDs.
Aspirin provocation test
Oral aspirin provocation was performed in patients with a suggestive medical history or in those who had a history of an immediate reaction to a single NSAID to confirm the diagnosis of cross-reactive NSAID hypersensitivity according to the EAACI/GA2LEN guidelines, with some modifications.293031 Four increasing doses of aspirin (40.5, 81, 150, and 300 mg) were administered at 90-minute intervals until a positive reaction occurred. Clinical symptoms, fractional exhaled nitric oxide (FeNO), and the forced expiratory volume in 1 second (FEV1) were monitored to evaluate the reaction. A positive provocation test was defined if any of the following reactions developed: lower respiratory/bronchial reaction (a 15% decrease in FEV1 plus naso-ocular reaction or a 20% decrease in FEV1 alone), upper respiratory/naso-ocular reaction (nasal congestion and rhinorrhea; conjunctival injection), cutaneous reactions (urticaria/angioedema, periorbital edema), and/or other reactions (gastrointestinal symptoms such as nausea/vomiting, stomach cramps, and diarrhea). The test was considered negative if a patient tolerated the final dose (300 mg of aspirin) without any significant symptoms mentioned above.
Oral provocation test (OPT) with other NSAIDs, acetaminophen, or celecoxib
Patients with a history of an immediate reaction to only aspirin were challenged with escalating doses of ibuprofen to confirm the diagnosis of cross-reactive NSAID sensitivity. Patients with a history of an immediate reaction to a single NSAID were provoked with the suspected drug to verify the status of single NSAID hypersensitivity after a negative aspirin provocation test. Escalating doses of ibuprofen, diclofenac, and acetaminophen were administered, if applicable, as follows: ibuprofen (50, 100, and 200 mg), diclofenac (6.25, 12.5, and 25 mg), and acetaminophen (125, 250, and 500 mg). Celecoxib was also provoked in 3 doses (50, 100, and 200 mg) in patients with confirmed hypersensitivity to multiple NSAIDs who were willing to identify a safe alternative drug. The provocation test for each drug was performed on separate days at least 7 days apart. Each dose of drug provocation was provided at 90-minute intervals until the final dose was reached.
Classification of NSAID hypersensitivity according to drug provocation test results
Patients with cross-reactive NSAID phenotypes were classified according to the results of the drug provocation test as 1) NECD/NIUA if they developed cutaneous symptoms alone; 2) NERD if they developed respiratory symptoms alone; and 3) NIBR if they developed a combination of symptoms involving more than one organ system (respiratory, cutaneous, and/or gastrointestinal symptoms). Single NSAID hypersensitivity was diagnosed in patients with a positive provocation test to the suspected NSAID, but a negative aspirin provocation test. Patients who had negative provocations to both aspirin and the suspected culprit drug were labeled as NSAID-tolerant subjects. NECD/NIUA were purposely categorized together in our study to compare the differences and similarities between patients diagnosed with NSAID-induced cutaneous reactions and -respiratory reactions. Moreover, NECD and NIUA share similar background characteristics from a clinical point of view and some patients diagnosed with NIUA eventually evolve to NECD over time.32
Skin prick tests with common aeroallergens in Thailand (mixed dust mites, mixed cockroaches, mixed mold, cat dander, dog hair, and southern grass mix; ALK-Abello, Hørsholm, Denmark) were also examined in tested patients to identify atopic status. Wheal size ≥ 3 mm was considered a positive test.
Measurement of FeNO and the FEV1 in patients who underwent drug provocation test
FeNO was measured in all participants at baseline and after drug provocation by using a portable electrochemical analyzer (NObreath®; Bedfont Scientific Ltd, Maidstone, UK) according to the ATS/ERS recommendations.33 Measurements of FEV1 were also performed using a Vitalograph spirometer (Vitalograph®, Buckingham, UK). The best of 3 repeated attempts was recorded.
The uLTE4 measurement
The uLTE4 levels were measured by a leukotriene E4 ELISA kit (Cayman Chemical, Ann Arbor, MI, USA) at baseline and 90 minutes after the final dose of drug provocation, as well as at the follow-up visits after aspirin desensitization and reported after adjustment to urine creatinine levels.
Aspirin desensitization
Outpatient aspirin desensitization was performed in NSAID-sensitive patients who were referred from otolaryngologists to prevent the recurrence of nasal polyposis. The procedure was carried out according to the intranasal ketorolac and modified aspirin challenge 2-day protocol.34 Aspirin desensitization was completed after patients were able to tolerate a 325-mg dose of aspirin by the end of day 2 and experience no symptoms, changes in nasal flow rates, or decrease in FEV1 values. The prescribed maintenance dose of aspirin was 325 mg twice a day.
Statistical analysis
Patient characteristics are reported as means ± standard deviation for quantitative analysis, and median and interquartile range (IQR) are used to describe non-parametric data. The Mann-Whitney U test and Kruskal-Wallis test with Dunn's multiple comparisons were used to analyze the differences between 2 groups and more than 2 groups, respectively. Statistical analyses were performed using GraphPad Prism 8.3 software (GraphPad Software Inc., San Diego, CA, USA). P values < 0.05 were considered statistically significant.
Ethical considerations
Patients enrolled in this study were those who recruited in the study entitled “Characteristics of Patients Diagnosed With NSAID Sensitivity in Thailand” registered at ClinicalTrials.gov (NCT03849625). The study was approved by the Ethics and Research Committee of the Faculty of Medicine, Chulalongkorn University, Approval Number: COA No. 659/2012 and informed consent was obtained from all participants.
RESULTS
A total of 158 adult patients with a suspected history of NSAID hypersensitivity between 2015 and 2018 at King Chulalongkorn Memorial Hospital were initially recruited into this study as shown in Fig. 1. Thirty-five patients with a history compatible with a non-immediate hypersensitivity reaction and 4 subjects with clinical symptoms compatible with NSAID-related side effects were later excluded.
Fig. 1 Schematic diagram of patient selection for this study.
A total of 158 patients with a suspected history of NSAID hypersensitivity were initially recruited into this study. Cross-reactive NSAID hypersensitivity was clinically diagnosed in 67 patients with a well-documented drug allergy history and verified by a positive drug provocation test in 25 patients with a suggestive history of NSAID reactions.
NSAID, non-steroidal anti-inflammatory drug.
Cross-reactive NSAID hypersensitivity was clinically diagnosed in 67 patients with a convincing drug allergy history as defined in the methods section. The remaining 52 patients with a suggestive history of NSAID hypersensitivity underwent an OPT to confirm NSAID cross-reactivity status. Fifteen out of 25 patients with confirmed NSAID cross-reactivity were subsequently provoked with celecoxib to find a safe alternative NSAID. Single NSAID/acetaminophen hypersensitivity was verified in 6 patients who tolerated aspirin provocation but developed an allergic reaction upon re-challenge with acetaminophen or diclofenac.
Demographic data of adult patients with cross-reactive NSAID hypersensitivity
The clinical characteristics of adult patients with cross-reactive NSAID hypersensitivity are shown in Table 1 (n = 92). Most patients were females (77.2%) with an average age of 45.7 ± 13.4 years. The average age of onset was 32.2 ± 13.3 years and about half of them had atopic family history. The majority of them (56.5%) reported only cutaneous symptoms such as facial angioedema and/or acute urticarial rash, after NSAID exposure, while 9.8% of them developed only respiratory symptoms. Interestingly, about 33.7% of the patients experienced a combination of symptoms in multiple organ systems as shown in Fig. 2. The groups of NSAIDs frequently responsible for hypersensitivity reactions were propionic acid derivatives and acetic acid derivatives. Although inflammatory airway diseases (chronic sinusitis, nasal polyposis, and asthma) were significantly more common in patients who experienced only respiratory reactions after exposure to an NSAID compared to the other phenotypes, a significant portion of the patients reporting blended reactions had underlying airway diseases and chronic urticaria as well. Acetaminophen intolerance was also reported in about one-third (35.9%) of NSAID-sensitive subjects.
Table 1 Clinical characteristics among different phenotypes of patients with cross-reactive NSAID hypersensitivity (n = 92)
Phenotypes NECD/NIUA (n = 52) NERD (n = 9) NIBR (n = 31) Total (n = 92)
Gender (female/male) 37/15 6/3 28/3 71/21
Age (yr) 43.6 ± 12.3 47.3 ± 11.9 48.7 ± 15.3 45.7 ± 13.4
Age of onset (yr) 31.3 ± 13.8 34.6 ± 11.0 33.1 ± 13.3 32.2 ± 13.3
Underlying disease (%)
Chronic urticaria 13.5 11.1 29.0 18.5
Chronic sinusitis* 13.5 55.6 32.3 23.9
Nasal polyposis* 7.7 66.7 16.1 16.3
Asthma* 17.3 88.9 35.5 30.4
Atopic family history (%) 42.3 55.6 61.3 50.0
Drug exposure time to symptom onset (min) 58.8 ± 31.9 48.3 ± 34.3 47.6 ± 29.9 54.0 ± 31.6
Presenting symptoms (%)*
Facial/periorbital angioedema 71.2 0.0 74.2 65.2
Acute urticaria 73.1 0.0 61.3 62.0
Naso-ocular reaction 0.0 33.3 61.3 23.9
Acute asthma 0.0 88.9 67.7 31.5
Gastrointestinal symptoms 0.0 0.0 16.1 5.4
Implicated NSAIDs (%)†
Salicylic acids 23.1 55.6 35.5 30.4
Propionic acids 44.2 22.2 54.8 45.7
Acetic acids 23.1 22.2 48.4 31.5
Enolic acids 7.7 0.0 6.5 6.5
Anthranilic/fenamic acids 28.8 11.1 29.0 27.2
Acetaminophen intolerance (%)§ 28.8 22.2 51.6 35.9
Values are presented as number (%) or mean ± standard deviation. Each patient could present with multiple symptoms and from more than one implicated drug.
NSAID, non-steroidal anti-inflammatory drug; NECD, non-steroidal anti-inflammatory drug-exacerbated cutaneous (urticaria/angioedema) disease in patients with underlying chronic urticaria; NIUA, non-steroidal anti-inflammatory drug-induced urticaria/angioedema in patients without underlying chronic urticaria; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
*P < 0.05 among different phenotypes. †Examples of commonly implicated drugs in this study based on NSAID classification: 1) Salicylic acids: acetylsalicylic acid (aspirin), salicylic acid, diflunisal, salsalate; 2) Propionic acids: ibuprofen, naproxen, ketoprofen, fenoprofen, flurbiprofen; 3) Acetic acids: indomethacin, ketorolac, diclofenac, sulindac; 4) Enolic acids: piroxicam, meloxicam, tenoxicam; 5) Anthranilic/fenamic acids: mefenamic acid, flufenamic acid. §Acetaminophen intolerance: cannot tolerate acetaminophen higher than 500 mg.
Fig. 2 Clinical presentations in patients with cross-reactive NSAID hypersensitivity.
A proportional Venn diagram shows that about half of patients with cross-reactive NSAID hypersensitivity in Thailand reported only cutaneous symptoms after NSAID exposure, while one-third of them experienced NSAID-induced blended reactions.
NSAID, non-steroidal anti-inflammatory drug.
Clinical respiratory parameters and uLTE4 levels in different phenotypes of patients with cross-reactive NSAID hypersensitivity confirmed by positive OPT
NSAID hypersensitivity was confirmed in 59.6% (31/52) of the tested patients with a history of NSAID-induced immediate reactions. The majority of patients with cross-reactive NSAID hypersensitivity (17/25) according to OPT results were atopic individuals. The common phenotypes of patients with confirmed cross-reactive NSAID sensitivity were NECD/NIUA, NIBR, and NERD, respectively, as shown in Supplementary Table S1.
The average FeNO, %predicted FEV1, and uLTE4 levels were measured at baseline and after provocation with aspirin/NSAID in 25 NSAID cross-reactive and 21 NSAID-tolerant subjects as shown in Table 2. At baseline, patients with confirmed NSAID cross-reactivity (NSAID-sensitive group) had higher FeNO (P < 0.01) and slightly less %predicted FEV1 compared to the NSAID-tolerant subjects, while basal uLTE4 levels between NSAID-sensitive and NSAID-tolerant groups were comparable. After provocation, %predicted FEV1 was substantially reduced in NSAID-sensitive subjects, whereas uLTE4 levels were significantly elevated compared to the NSAID-tolerant group (P < 0.01). Celecoxib provocation was well tolerated in all NSAID-sensitive subjects. No statistical differences in the average FeNO, %predicted FEV1, or uLTE4 levels in 15 NSAID-sensitive patients (7 NECD/NIUA, 4 NIBR, 4 NERD) after celecoxib provocation were observed compared to those in NSAID-tolerant subjects.
Table 2 Respiratory parameters and uLTE4 levels in NSAID-sensitive subjects upon provocation with aspirin or celecoxib compared to NSAID-tolerant subjects
Characteristics Baseline After aspirin (OPT) P value*
NSAID tolerant (n = 21)
FeNO (ppb) 13.0 (8.5–19.5) 10.2 (7.0–16.8) 0.03
%predicted FEV1 100.8 (82.8–115.9) 99.0 (75.2–118.2) 0.90
uLTE4 (pg/mg creatinine) 116.3 (66.5–305.4) 122.1 (63.5–173.8) 0.17
NSAID sensitive (n = 25)
FeNO (ppb) 27.0 (17.8–40.9)† 18.0 (10.5–31.0) <0.01
%predicted FEV1 86.7 (63.3–104.9) 74.6 (52.4–89.8)† <0.01
uLTE4 (pg/mg creatinine) 118.3 (93.2–407.2) 204.9 (90.6–817.8)† <0.01
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; OPT, oral provocation test; ppb, parts per billion; FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in 1 second.
*P values before vs. after provocation test, Wilcoxon signed-rank test; †P < 0.01 compared to the NSAID-tolerant subjects.
According to the subgroup analysis, 10 NECD/NIUA, 9 NIBR, and 6 NERD were categorized as shown in Fig. 3. At baseline, %predicted FEV1 was not significantly different among different types of cross-reactive NSAID hypersensitivity, although those in patients with confirmed NIBR were lowest (64.9%, IQR 56.9–97.3). The significant differences in basal FeNO levels (P < 0.01) among the 3 different phenotypes were observed. The basal FeNO levels were significantly higher in NIBR (36.9%, IQR 27.0–95.4) than in NSAID-tolerant subjects (P < 0.01). After aspirin OPT, the reduction of %FEV1 was considerably higher in patients with confirmed NERD (22.0%, IQR 16.0-28.8), followed by NIBR (13.3%, IQR 7.6–28.0), compared to those in NSAID-tolerant groups (P < 0.01). Basal uLTE4 levels were not significantly different among the 3 phenotypes. Interestingly, uLTE4 levels after aspirin provocation were significantly higher in NERD and NIBR patients than in the NECD/NIUA and NSAID-tolerant groups (P < 0.05 and < 0.01, respectively).
Fig. 3 Respiratory parameters and uLTE4 levels in different phenotypes of NSAID-sensitive subjects compared to NSAID-tolerant subjects.
Baseline FeNO in NIBR and NERD were higher than those in the NSAID-tolerant group. After aspirin provocation, % predicted FEV1 in NERD and NIBR were significantly reduced from the baseline while uLTE4 levels were much higher than those in NSAID-tolerant subjects.
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; FEV1, forced expiratory volume in 1 second.
*P values < 0.05, †P values < 0.01.
Effects of aspirin desensitization on uLTE4 levels in patients diagnosed with NERD and NIBR
Aspirin desensitization was performed in selected patients (3 NERD and 3 NIBR) who had pre-existing inflammatory airway diseases and a history of recurrent nasal polyposis after surgery as shown in Table 3. The maintenance dose of aspirin was 650 mg/day during the first 6 months and reduced to 325 mg/day afterward. Levels of uLTE4 were measured at baseline after aspirin desensitization and serially followed up for 2–3 years as demonstrated in Fig. 4. Other than respiratory symptoms, acute urticarial rash and gastrointestinal symptoms (abdominal cramp/nausea/diarrhea) were also aggravated in NIBR subjects during aspirin desensitization as shown in Supplementary Fig. S1, but gradually relieved with supportive treatment. No sinus surgery was required for nasal polyp recurrence, and asthma symptoms were under control after aspirin desensitization in all 6 cases. Up to 3 years after aspirin desensitization, however, uLTE4 levels were significantly increased and remained elevated throughout the follow-up period, although urticarial rash and gastrointestinal symptoms were no longer observed while taking aspirin.
Table 3 Details of patients with cross-reactive NSAID hypersensitivity undergoing aspirin desensitization in this study
Patients (sex/year) Underlying diseases History of adverse drug reactions Indication for aspirin desensitization Follow-up duration (months) Asthma control before/after aspirin desensitization Recurrent nasal polyposis after aspirin desensitization Skin symptoms after aspirin desensitization Gastrointestinal symptoms after aspirin desensitization
1. NERD (M/46) Chronic sinusitis, nasal polyposis, asthma Acute asthma 20 min after taking aspirin 2 recurrent nasal polyps 74 Partly controlled with high dose ICS-LABA and add-on LTRA/well controlled with low dose ICS None NA NA
2. NERD (M/54) Chronic rhinitis, nasal polyposis, asthma Acute asthma, blocked nose 1 hr after taking aspirin 3 recurrent nasal polyps 24 Uncontrolled with high dose ICS-LABA and add-on LTRA/well controlled with medium dose ICS-LABA None NA NA
3. NERD (M/56) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked nose 1 hr after taking ibuprofen 6 recurrent nasal polyps 32 Partly controlled asthma with high dose ICS-LABA and add-on LTRA/well controlled with medium dose ICS-LABA None NA NA
4. NIBR (M/48) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked nose, conjunctival injection, urticarial rash 2 hr after taking aspirin 3 recurrent nasal polyps 72 Partly controlled with medium dose ICS-LABA/well controlled with low dose ICS-LABA None No rash after taking aspirin NA
5. NIBR (F/65) Chronic sinusitis, nasal polyposis, chronic urticaria, asthma (history of cardiac arrest from severe asthma) Urticarial rash, periorbital angioedema, blocked nose, conjunctival injection, rhinorrhea, bronchospasm/wheezing, hoarseness of voice 1 hr after taking aspirin, ibuprofen, mefenamic acid, acetaminophen 2 recurrent nasal polyps 48 Uncontrolled with high dose ICS-LABA and add-on LTRA/well controlled with low dose ICS-LABA None No rash after taking aspirin, chronic urticaria resolved NA
6. NIBR (F/38) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked/running nose, stomach cramp, diarrhea, periorbital angioedema, urticaria 30 min after taking ibuprofen, indomethacin, mefenamic acid 2 recurrent nasal polyps 21 Partly controlled with medium dose ICS-LABA/well controlled, with medium dose ICS-LABA None No rash after taking aspirin No gastrointestinal symptoms after taking aspirin
NSAID, non-steroidal anti-inflammatory drug; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; ICS, inhaled corticosteroid; LABA, long-acting beta-agonist; LTRA, leukotriene receptor antagonist; NA, not applicable (no symptoms prior to aspirin desensitization); NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
Fig. 4 uLTE4 levels in NSAID-sensitive subjects after aspirin desensitization.
Our study demonstrated that uLTE4 levels (pg/mg creatinine) in 3 NERD and 3 NIBR patients were increased and remained elevated up to 3 years after aspirin desensitization even though recurrent nasal polyposis was successfully prevented in all cases.
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
DISCUSSION
Most studies on NSAID hypersensitivity have focused on NERD, although worldwide epidemiological data suggest that NECD/NIUA might be more common. Recent data have demonstrated that some patients cannot be categorized into the current classification of NSAID hypersensitivity, for example those with NSAID-induced periorbital angioedema and NIBR.1419 These patients may also have underlying chronic airway diseases; however, the role of aspirin desensitization in the prevention of recurrent nasal polyposis and control of airway inflammation in NSAID-sensitive subjects other than the NERD phenotype has never been reported.
The leading presentations in NSAID-sensitive subjects in this study were periorbital angioedema, acute urticaria, bronchial symptoms, and naso-ocular reactions, respectively. Even those confirmed with NSAID exposure, a significant number of patients in our cohort also showed clinical responses in more than 1 organ system, indicating that the prevalence of NIBR was higher than previously thought. Although patients with IgE-mediated anaphylaxis might also present with multiple organ involvement, the fact that most of the reactions took about 1–2 hours to occur and the ability to react to multiple NSAIDs with dissimilar chemical structures made them more compatible with the non-immunologic effect of the drugs.
Facial angioedema around the periorbital area was the most common presenting symptom in Thai patients. Upon NSAID provocation, however, the predominant periorbital angioedema often accompanied by blocked nose, running nose, and itchy/red eyes. After a thorough examination, small urticarial rash on the trunk and extremities, and expiratory wheezing were occasionally detected, although frequently asymptomatic. It is noteworthy that periorbital angioedema may persist for hours or days while urticarial rash and respiratory symptoms are quickly resolved after treatment. As a result, NIBR could be underdiagnosed if history taking is not thoroughly reviewed, since symptoms with lesser severity in other organ systems may be unnoticed. In addition, the COX-1 inhibitor properties of the exposed NSAIDs could affect the phenotype of NSAID sensitivity reported by patients as some patients experienced both asthmatic attack and periorbital angioedema/generalized urticaria after taking aspirin but reported only periorbital edema after taking acetaminophen.
It is practically difficult to clearly distinguish between NSAID-induced periorbital angioedema and NSAID-induced naso-ocular reactions (upper airway manifestations of NERD), since patients occasionally experienced periorbital swelling, red/swollen eyes with tearing, and nasal congestion at the same time. In our opinion, the majority of NSAID hypersensitivity in the Thai population would be described as “NSAID-induced blended reaction with predominant periorbital angioedema” and probably related to “NSAID-induced isolated periorbital angioedema” phenotype as proposed by the Spanish group. It is interesting to note that the prevalence of atopic disease was high in this patient group. We speculate that the increased leukotriene production after NSAID consumption could lead to the worsening of pre-existing mucosal inflammation around the nose and eyes in patients who already suffered from the late-phase reaction of persistent allergic rhinitis.
Our study did not find any difference in terms of basal uLTE4 levels between NSAID-sensitive and NSAID-tolerant subjects. However, uLTE4 levels were higher in NSAID-sensitive patients, particularly in NERD and NIBR subjects, after the NSAID challenge compared to those in the NSAID-tolerant group. Though basal uLTE4 levels may not be a suitable marker to screen NSAID sensitivity status, elevated uLTE4 levels after aspirin OPT could be the supporting evidence for the diagnosis of cross-reactive NSAID hypersensitivity in cases where the clinical response is equivocal. Our study demonstrated that the degree of defective leukotriene homeostasis after exposure to drugs affecting the cyclo-oxygenase pathway might be related to the severity of respiratory involvement upon NSAID exposure.35 The fact that uLTE4 levels were barely changed after celecoxib provocation in patients with NSAID cross-reactivity confirms that celecoxib is a safe alternative NSAID in these patient groups.
According to our study, the patterns of NSAID hypersensitivity in southeast Asians are similar to those in southern Europeans and Latin Americans, and somewhat different from those reported in patients of northern European descent. Previous data suggested that aspirin nasal provocation could potentially diagnose some NSAID-sensitive patients presenting with predominant cutaneous reactions.3637 Retrospectively, some of these patients might be re-classified as the NIBR phenotype, since a decreased nasal volume was also observed. In other words, patients diagnosed with an NSAID-induced cutaneous reaction who positively reacted to NSAID nasal provocation, especially those with a periorbital reaction, might be NIBR subjects with subclinical airway involvement.
The novelties of this study were the findings that NIBR accounted for about one-third of adult patients with cross-reactive NSAID hypersensitivity and that aspirin desensitization could successfully prevent the recurrence of nasal polyposis and alleviate respiratory symptoms not only in NERD, but also in NIBR, even though urine LTE4 levels remained elevated. However, since the reactions in some NIBR patients could lead to serious adverse events, aspirin desensitization in NIBR subjects should be performed only when it is strongly indicated in selected patients with no previous severe reactions to NSAIDs. In NIBR subjects who experienced previous severe reactions in multiple organ systems, the procedure of aspirin desensitization, if necessary, should be carefully monitored and the administration of biological agents such as dupilumab, if available, should be considered a safer therapeutic option in these cases.
Interestingly, uLTE4 levels were increased after aspirin desensitization and remained elevated throughout the follow-up period. It should be emphasized that urticarial rash and stomach-ache in NIBR patients also disappeared while patients were taking daily aspirin. These data suggest that the pathogenesis of nasal polyposis cannot be explained by cysLT overproduction alone and that aspirin desensitization could be useful to alleviate both respiratory and non-respiratory symptoms in NIBR subjects.
Interestingly, a recent study also found that the clinical benefit of high-dose aspirin desensitization in NERD was independent of a reduction of mast cell activation and cysLT production. They reported paradoxically increased uLTE4 levels 8 weeks after aspirin desensitization compared to the baseline levels and concluded that high-dose aspirin therapy did not restore the impaired eicosanoid pathway.38 According to their study findings and ours, the therapeutic effect of aspirin desensitization was not directly correlated with a change of arachidonic acid metabolism.
There are some limitations to this study. Aspirin desensitization was performed in only 6 patients in our cohort; therefore, the comparative success rates and potential adverse reactions of aspirin desensitization between NERD and NIBR patients could not be analyzed. Further studies with a larger sample size are needed to compare the long-term prognosis between NERD and NIBR, to understand the mechanism of aspirin desensitization for the improvement of respiratory and extra-respiratory symptoms and to evaluate its risk-benefit ratio of aspirin desensitization in NIBR subjects.
In conclusion, NIBR is not uncommon among patients diagnosed with NSAID hypersensitivity in Thailand. Increased uLTE4 levels upon aspirin provocation suggested a diagnosis of NSAID cross-reactivity, while baseline uLTE4 levels were not distinguishable between NSAID-tolerant and NSAID-sensitive subjects. Our study indicates that aspirin desensitization is effective not only in NERD but also in NIBR. The persistently high levels of uLTE4 in spite of clinical improvement in NSAID-sensitive patients after successful aspirin desensitization suggest that elevated leukotrienes alone cannot explain the pathogenesis of NSAID hypersensitivity reactions.
ACKNOWLEDGMENTS
This study was supported by the Ratchadaphiseksomphot fund, Faculty of Medicine, Chulalongkorn University, grant No. RA55/19 and the Skin and Allergy Research Unit, Chulalongkorn University, Bangkok, Thailand. Study data were collected and managed using Research Electronic Data Capture (REDCap) hosted at HIV Netherlands Australia Thailand Research Collaboration. The authors thank Thitima Kantachatvanich, MD for providing patient information.
Disclosure: There are no financial or other issues that might lead to conflict of interest.
SUPPLEMENTARY MATERIALS
Supplementary Table S1
Clinical characteristics of patients with confirmed NSAID-induced immediate reactions
Supplementary Fig. S1
Representative photos of skin rash demonstrated during aspirin desensitization in NIBR patients. | ACETAMINOPHEN\HYDROCODONE, ASPIRIN, IBUPROFEN, MEFENAMIC ACID | DrugsGivenReaction | CC BY-NC | 33474858 | 19,056,205 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Type I hypersensitivity'. | Clinical Characteristics, Urinary Leukotriene E4 Levels, and Aspirin Desensitization Results in Patients With NSAID-Induced Blended Reactions.
OBJECTIVE
Data on non-steroidal anti-inflammatory drug (NSAID) hypersensitivity in Southeast Asia are scarce. Increased urinary leukotriene E4 (uLTE4) levels have been suggested as a biomarker of NSAID-exacerbated respiratory disease (NERD). This study investigated clinical patterns of NSAID sensitivity in Thailand and the diagnostic roles of uLTE4 measurement in various phenotypes.
METHODS
The clinical phenotypes in 92 Thai adults with cross-reactive NSAID hypersensitivity were characterized based on the clinical history and drug provocation. The uLTE4 levels were measured at baseline, after aspirin provocation and after desensitization.
RESULTS
More than half of the patients (56.5%) presented with cutaneous symptoms (NSAID-exacerbated cutaneous disease), while one-third (33.7%) developed symptoms in at least 2 systems (NSAID-induced blended reactions; NIBR). Fifty-two patients underwent drug provocation and 59.6% of them yielded positive results. After drug provocation, a significant number of patients with confirmed NSAID cross-reactivity experienced clinical symptoms in more than one organ system. The uLTE4 levels at baseline were comparable between the NSAID-tolerant and NSAID-sensitive groups, but were substantially increased after aspirin provocation predominantly in NERD (983.4 pg/mg creatinine) and NIBR (501.0 pg/mg creatinine) compared to NSAID-tolerant subjects (122.1 pg/mg creatinine, P < 0.01 and 0.05, respectively). The uLTE4 levels were elevated after aspirin desensitization, although nasal polyposis and asthma were under control in 3 NERD and 3 NIBR subjects.
CONCLUSIONS
NIBR is not uncommon among NSAID-sensitive patients in Thailand. The diagnostic value of basal uLTE4 levels was limited, but increased uLTE4 levels upon aspirin provocation suggest NSAID cross-reactivity with respiratory components. This study indicates that aspirin desensitization, if necessary, might be effective in both NERD and NIBR.
BACKGROUND
ClinicalTrials.gov Identifier: NCT03849625.
INTRODUCTION
Hypersensitivity reactions to aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most common drug allergic reactions in clinical practice. They are generally categorized into 5 major phenotypes: NSAID-exacerbated respiratory disease (NERD), NSAID-exacerbated cutaneous (urticaria/angioedema) disease (NECD) in patients with underlying chronic urticaria, NSAID-induced urticaria/angioedema (NIUA) in patients without underlying chronic urticaria, single NSAID-induced urticaria/angioedema or anaphylaxis, and single NSAID-induced delayed hypersensitivity reactions.1 The first 3 phenotypes are non-immunologically mediated, and patients can develop cross-reactive hypersensitivity to chemically unrelated NSAIDs, while the latter 2 are selective NSAID sensitivities associated with drug-specific immunoglobulin E (IgE) and T-cell response, respectively.
Genetic and epigenetic variations play significant roles in the development of NERD.2 The proposed underlying mechanism is that the disturbance in arachidonic acid synthesis pathways leads to overproduction of cysteinyl leukotrienes (cysLT) and persistent airway inflammation.3 Mast cells are believed to be the major source of cysLT, but platelet-adherent leukocytes may be responsible for cysLT overproduction in NERD as well.4 The consumption of drugs inhibiting the cyclooxygenase-1 (COX-1) enzyme, such as aspirin and conventional NSAIDs, aggravates respiratory symptoms by enhancing cysLT production in NSAID-sensitive subjects, while the administration of specific COX-2 inhibitors, such as celecoxib, is generally safe.56 Besides aspirin/NSAID avoidance, aspirin desensitization has also been proven to be helpful for long term management in NERD subjects. Beneficial effects of aspirin desensitization in preventing nasal polyp recurrence and control symptoms of chronic rhinosinusitis and asthma have been well documented.7 Rapid aspirin desensitization has shown to be effective for the treatment of coronary artery disease in patients with a history of aspirin/NSAID-induced urticaria/angioedema, but it is not indicated for the treatment of chronic urticaria.8
Worldwide epidemiological data on clinical characteristics of NSAID hypersensitivity are limited. Most studies on NERD were performed in the United States and northern European countries.9101112 However, the predominant manifestation in Latin Americans and southern Europeans is the cutaneous phenotype (NIUA, NECD, and NSAID-induced isolated periorbital angioedema).1314 Studies in Asian populations have suggested that the prevalence of the NERD phenotype is not common in this region of the world. A study performed in China indicated that the prevalence of NSAID hypersensitivity in Chinese patients with chronic rhinosinusitis is very low (0.57%) compared to their European counterparts.15 It was also noted that NSAID-induced blended reactions (NIBR) are common in young Asian, atopic children in Singapore.16 Reports from Singapore and Thailand indicated that aspirin/NSAID-induced angioedema/urticaria is probably the prominent phenotype in Southeast Asia, with acetaminophen hypersensitivity being frequent.1718
In clinical practice, the current classification of cross-reactive NSAID hypersensitivity into 3 distinct phenotypes has some limitations. Clinical characteristics in NSAID-sensitive patients may not be well defined, and a combination of respiratory and cutaneous or other symptoms, such as gastrointestinal symptoms (mixed or blended reactions), is frequently observed.19 A previous report stated that aspirin nasal provocation is potentially useful for diagnosing patients with the blended reaction as well.20 However, the role of aspirin desensitization in other phenotypes of NSAID hypersensitivity, besides NERD, for long-term management of inflammatory airway diseases has not yet been established. Whether aspirin desensitization would be effective in controlling asthma and the recurrence of nasal polyposis after sinus surgery in NIBR is currently unknown.
At present, cross-reactive types of NSAID hypersensitivity can only be diagnosed by careful history taking and controlled-provocation testing, since there is no reliable in vitro method to confirm the diagnosis.21 There is evidence that basal urinary levels of leukotriene E4 (uLTE4), a stable product of the cysLT synthesis pathway, are elevated in NERD patients and could be a potential biomarker for differentiating between NSAID-sensitive and NSAID-tolerant asthmatics. However, these data are still controversial.222324 There have also been preliminary studies showing that uLTE4 levels might be increased in NECD.2526 Whether the measurement of basal uLTE4 levels could be a diagnostic marker for any phenotype of NSAID hypersensitivity is yet to be explored.
The purpose of this study was to analyze the clinical characteristics of patients diagnosed with NSAID-induced immediate reactions in Thailand and to explore whether the measurement of uLTE4 levels would be helpful in identifying NSAID-sensitive subjects or in differentiating among different phenotypes of cross-reactive NSAID hypersensitivities.
MATERIALS AND METHODS
Patient recruitment
Adult patients (18 years of age and older) with a suggestive history of NSAID-induced hypersensitivity reaction visiting the allergy clinic at King Chulalongkorn University Hospital between June 2014 and July 2018 were recruited into this study. Those with a history compatible with drug-induced non-immediate reactions (maculopapular rash, fixed drug eruption, acute generalized exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms, Stevens-Johnson syndrome/toxic epidermal necrolysis) or NSAID-related side effects were excluded. The status of NSAID-induced immediate hypersensitivity was diagnosed in patients with a well-documented drug allergy history or in patients with a suggestive history of NSAID sensitivity who yielded a positive drug provocation test as follows.
Clinical diagnosis of NSAID hypersensitivity
The diagnosis of cross-reactive NSAID hypersensitivity was clinically made in patients with a well-documented history of multiple episodes of respiratory, cutaneous, and/or gastrointestinal reactions within 2 hours after exposure to at least 2 different NSAID classes.1212728 Patient demographic data were collected, including the underlying diseases, atopic family history, and details on drug allergy history as well as the presenting symptoms and types of the culprit NSAIDs.
Aspirin provocation test
Oral aspirin provocation was performed in patients with a suggestive medical history or in those who had a history of an immediate reaction to a single NSAID to confirm the diagnosis of cross-reactive NSAID hypersensitivity according to the EAACI/GA2LEN guidelines, with some modifications.293031 Four increasing doses of aspirin (40.5, 81, 150, and 300 mg) were administered at 90-minute intervals until a positive reaction occurred. Clinical symptoms, fractional exhaled nitric oxide (FeNO), and the forced expiratory volume in 1 second (FEV1) were monitored to evaluate the reaction. A positive provocation test was defined if any of the following reactions developed: lower respiratory/bronchial reaction (a 15% decrease in FEV1 plus naso-ocular reaction or a 20% decrease in FEV1 alone), upper respiratory/naso-ocular reaction (nasal congestion and rhinorrhea; conjunctival injection), cutaneous reactions (urticaria/angioedema, periorbital edema), and/or other reactions (gastrointestinal symptoms such as nausea/vomiting, stomach cramps, and diarrhea). The test was considered negative if a patient tolerated the final dose (300 mg of aspirin) without any significant symptoms mentioned above.
Oral provocation test (OPT) with other NSAIDs, acetaminophen, or celecoxib
Patients with a history of an immediate reaction to only aspirin were challenged with escalating doses of ibuprofen to confirm the diagnosis of cross-reactive NSAID sensitivity. Patients with a history of an immediate reaction to a single NSAID were provoked with the suspected drug to verify the status of single NSAID hypersensitivity after a negative aspirin provocation test. Escalating doses of ibuprofen, diclofenac, and acetaminophen were administered, if applicable, as follows: ibuprofen (50, 100, and 200 mg), diclofenac (6.25, 12.5, and 25 mg), and acetaminophen (125, 250, and 500 mg). Celecoxib was also provoked in 3 doses (50, 100, and 200 mg) in patients with confirmed hypersensitivity to multiple NSAIDs who were willing to identify a safe alternative drug. The provocation test for each drug was performed on separate days at least 7 days apart. Each dose of drug provocation was provided at 90-minute intervals until the final dose was reached.
Classification of NSAID hypersensitivity according to drug provocation test results
Patients with cross-reactive NSAID phenotypes were classified according to the results of the drug provocation test as 1) NECD/NIUA if they developed cutaneous symptoms alone; 2) NERD if they developed respiratory symptoms alone; and 3) NIBR if they developed a combination of symptoms involving more than one organ system (respiratory, cutaneous, and/or gastrointestinal symptoms). Single NSAID hypersensitivity was diagnosed in patients with a positive provocation test to the suspected NSAID, but a negative aspirin provocation test. Patients who had negative provocations to both aspirin and the suspected culprit drug were labeled as NSAID-tolerant subjects. NECD/NIUA were purposely categorized together in our study to compare the differences and similarities between patients diagnosed with NSAID-induced cutaneous reactions and -respiratory reactions. Moreover, NECD and NIUA share similar background characteristics from a clinical point of view and some patients diagnosed with NIUA eventually evolve to NECD over time.32
Skin prick tests with common aeroallergens in Thailand (mixed dust mites, mixed cockroaches, mixed mold, cat dander, dog hair, and southern grass mix; ALK-Abello, Hørsholm, Denmark) were also examined in tested patients to identify atopic status. Wheal size ≥ 3 mm was considered a positive test.
Measurement of FeNO and the FEV1 in patients who underwent drug provocation test
FeNO was measured in all participants at baseline and after drug provocation by using a portable electrochemical analyzer (NObreath®; Bedfont Scientific Ltd, Maidstone, UK) according to the ATS/ERS recommendations.33 Measurements of FEV1 were also performed using a Vitalograph spirometer (Vitalograph®, Buckingham, UK). The best of 3 repeated attempts was recorded.
The uLTE4 measurement
The uLTE4 levels were measured by a leukotriene E4 ELISA kit (Cayman Chemical, Ann Arbor, MI, USA) at baseline and 90 minutes after the final dose of drug provocation, as well as at the follow-up visits after aspirin desensitization and reported after adjustment to urine creatinine levels.
Aspirin desensitization
Outpatient aspirin desensitization was performed in NSAID-sensitive patients who were referred from otolaryngologists to prevent the recurrence of nasal polyposis. The procedure was carried out according to the intranasal ketorolac and modified aspirin challenge 2-day protocol.34 Aspirin desensitization was completed after patients were able to tolerate a 325-mg dose of aspirin by the end of day 2 and experience no symptoms, changes in nasal flow rates, or decrease in FEV1 values. The prescribed maintenance dose of aspirin was 325 mg twice a day.
Statistical analysis
Patient characteristics are reported as means ± standard deviation for quantitative analysis, and median and interquartile range (IQR) are used to describe non-parametric data. The Mann-Whitney U test and Kruskal-Wallis test with Dunn's multiple comparisons were used to analyze the differences between 2 groups and more than 2 groups, respectively. Statistical analyses were performed using GraphPad Prism 8.3 software (GraphPad Software Inc., San Diego, CA, USA). P values < 0.05 were considered statistically significant.
Ethical considerations
Patients enrolled in this study were those who recruited in the study entitled “Characteristics of Patients Diagnosed With NSAID Sensitivity in Thailand” registered at ClinicalTrials.gov (NCT03849625). The study was approved by the Ethics and Research Committee of the Faculty of Medicine, Chulalongkorn University, Approval Number: COA No. 659/2012 and informed consent was obtained from all participants.
RESULTS
A total of 158 adult patients with a suspected history of NSAID hypersensitivity between 2015 and 2018 at King Chulalongkorn Memorial Hospital were initially recruited into this study as shown in Fig. 1. Thirty-five patients with a history compatible with a non-immediate hypersensitivity reaction and 4 subjects with clinical symptoms compatible with NSAID-related side effects were later excluded.
Fig. 1 Schematic diagram of patient selection for this study.
A total of 158 patients with a suspected history of NSAID hypersensitivity were initially recruited into this study. Cross-reactive NSAID hypersensitivity was clinically diagnosed in 67 patients with a well-documented drug allergy history and verified by a positive drug provocation test in 25 patients with a suggestive history of NSAID reactions.
NSAID, non-steroidal anti-inflammatory drug.
Cross-reactive NSAID hypersensitivity was clinically diagnosed in 67 patients with a convincing drug allergy history as defined in the methods section. The remaining 52 patients with a suggestive history of NSAID hypersensitivity underwent an OPT to confirm NSAID cross-reactivity status. Fifteen out of 25 patients with confirmed NSAID cross-reactivity were subsequently provoked with celecoxib to find a safe alternative NSAID. Single NSAID/acetaminophen hypersensitivity was verified in 6 patients who tolerated aspirin provocation but developed an allergic reaction upon re-challenge with acetaminophen or diclofenac.
Demographic data of adult patients with cross-reactive NSAID hypersensitivity
The clinical characteristics of adult patients with cross-reactive NSAID hypersensitivity are shown in Table 1 (n = 92). Most patients were females (77.2%) with an average age of 45.7 ± 13.4 years. The average age of onset was 32.2 ± 13.3 years and about half of them had atopic family history. The majority of them (56.5%) reported only cutaneous symptoms such as facial angioedema and/or acute urticarial rash, after NSAID exposure, while 9.8% of them developed only respiratory symptoms. Interestingly, about 33.7% of the patients experienced a combination of symptoms in multiple organ systems as shown in Fig. 2. The groups of NSAIDs frequently responsible for hypersensitivity reactions were propionic acid derivatives and acetic acid derivatives. Although inflammatory airway diseases (chronic sinusitis, nasal polyposis, and asthma) were significantly more common in patients who experienced only respiratory reactions after exposure to an NSAID compared to the other phenotypes, a significant portion of the patients reporting blended reactions had underlying airway diseases and chronic urticaria as well. Acetaminophen intolerance was also reported in about one-third (35.9%) of NSAID-sensitive subjects.
Table 1 Clinical characteristics among different phenotypes of patients with cross-reactive NSAID hypersensitivity (n = 92)
Phenotypes NECD/NIUA (n = 52) NERD (n = 9) NIBR (n = 31) Total (n = 92)
Gender (female/male) 37/15 6/3 28/3 71/21
Age (yr) 43.6 ± 12.3 47.3 ± 11.9 48.7 ± 15.3 45.7 ± 13.4
Age of onset (yr) 31.3 ± 13.8 34.6 ± 11.0 33.1 ± 13.3 32.2 ± 13.3
Underlying disease (%)
Chronic urticaria 13.5 11.1 29.0 18.5
Chronic sinusitis* 13.5 55.6 32.3 23.9
Nasal polyposis* 7.7 66.7 16.1 16.3
Asthma* 17.3 88.9 35.5 30.4
Atopic family history (%) 42.3 55.6 61.3 50.0
Drug exposure time to symptom onset (min) 58.8 ± 31.9 48.3 ± 34.3 47.6 ± 29.9 54.0 ± 31.6
Presenting symptoms (%)*
Facial/periorbital angioedema 71.2 0.0 74.2 65.2
Acute urticaria 73.1 0.0 61.3 62.0
Naso-ocular reaction 0.0 33.3 61.3 23.9
Acute asthma 0.0 88.9 67.7 31.5
Gastrointestinal symptoms 0.0 0.0 16.1 5.4
Implicated NSAIDs (%)†
Salicylic acids 23.1 55.6 35.5 30.4
Propionic acids 44.2 22.2 54.8 45.7
Acetic acids 23.1 22.2 48.4 31.5
Enolic acids 7.7 0.0 6.5 6.5
Anthranilic/fenamic acids 28.8 11.1 29.0 27.2
Acetaminophen intolerance (%)§ 28.8 22.2 51.6 35.9
Values are presented as number (%) or mean ± standard deviation. Each patient could present with multiple symptoms and from more than one implicated drug.
NSAID, non-steroidal anti-inflammatory drug; NECD, non-steroidal anti-inflammatory drug-exacerbated cutaneous (urticaria/angioedema) disease in patients with underlying chronic urticaria; NIUA, non-steroidal anti-inflammatory drug-induced urticaria/angioedema in patients without underlying chronic urticaria; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
*P < 0.05 among different phenotypes. †Examples of commonly implicated drugs in this study based on NSAID classification: 1) Salicylic acids: acetylsalicylic acid (aspirin), salicylic acid, diflunisal, salsalate; 2) Propionic acids: ibuprofen, naproxen, ketoprofen, fenoprofen, flurbiprofen; 3) Acetic acids: indomethacin, ketorolac, diclofenac, sulindac; 4) Enolic acids: piroxicam, meloxicam, tenoxicam; 5) Anthranilic/fenamic acids: mefenamic acid, flufenamic acid. §Acetaminophen intolerance: cannot tolerate acetaminophen higher than 500 mg.
Fig. 2 Clinical presentations in patients with cross-reactive NSAID hypersensitivity.
A proportional Venn diagram shows that about half of patients with cross-reactive NSAID hypersensitivity in Thailand reported only cutaneous symptoms after NSAID exposure, while one-third of them experienced NSAID-induced blended reactions.
NSAID, non-steroidal anti-inflammatory drug.
Clinical respiratory parameters and uLTE4 levels in different phenotypes of patients with cross-reactive NSAID hypersensitivity confirmed by positive OPT
NSAID hypersensitivity was confirmed in 59.6% (31/52) of the tested patients with a history of NSAID-induced immediate reactions. The majority of patients with cross-reactive NSAID hypersensitivity (17/25) according to OPT results were atopic individuals. The common phenotypes of patients with confirmed cross-reactive NSAID sensitivity were NECD/NIUA, NIBR, and NERD, respectively, as shown in Supplementary Table S1.
The average FeNO, %predicted FEV1, and uLTE4 levels were measured at baseline and after provocation with aspirin/NSAID in 25 NSAID cross-reactive and 21 NSAID-tolerant subjects as shown in Table 2. At baseline, patients with confirmed NSAID cross-reactivity (NSAID-sensitive group) had higher FeNO (P < 0.01) and slightly less %predicted FEV1 compared to the NSAID-tolerant subjects, while basal uLTE4 levels between NSAID-sensitive and NSAID-tolerant groups were comparable. After provocation, %predicted FEV1 was substantially reduced in NSAID-sensitive subjects, whereas uLTE4 levels were significantly elevated compared to the NSAID-tolerant group (P < 0.01). Celecoxib provocation was well tolerated in all NSAID-sensitive subjects. No statistical differences in the average FeNO, %predicted FEV1, or uLTE4 levels in 15 NSAID-sensitive patients (7 NECD/NIUA, 4 NIBR, 4 NERD) after celecoxib provocation were observed compared to those in NSAID-tolerant subjects.
Table 2 Respiratory parameters and uLTE4 levels in NSAID-sensitive subjects upon provocation with aspirin or celecoxib compared to NSAID-tolerant subjects
Characteristics Baseline After aspirin (OPT) P value*
NSAID tolerant (n = 21)
FeNO (ppb) 13.0 (8.5–19.5) 10.2 (7.0–16.8) 0.03
%predicted FEV1 100.8 (82.8–115.9) 99.0 (75.2–118.2) 0.90
uLTE4 (pg/mg creatinine) 116.3 (66.5–305.4) 122.1 (63.5–173.8) 0.17
NSAID sensitive (n = 25)
FeNO (ppb) 27.0 (17.8–40.9)† 18.0 (10.5–31.0) <0.01
%predicted FEV1 86.7 (63.3–104.9) 74.6 (52.4–89.8)† <0.01
uLTE4 (pg/mg creatinine) 118.3 (93.2–407.2) 204.9 (90.6–817.8)† <0.01
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; OPT, oral provocation test; ppb, parts per billion; FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in 1 second.
*P values before vs. after provocation test, Wilcoxon signed-rank test; †P < 0.01 compared to the NSAID-tolerant subjects.
According to the subgroup analysis, 10 NECD/NIUA, 9 NIBR, and 6 NERD were categorized as shown in Fig. 3. At baseline, %predicted FEV1 was not significantly different among different types of cross-reactive NSAID hypersensitivity, although those in patients with confirmed NIBR were lowest (64.9%, IQR 56.9–97.3). The significant differences in basal FeNO levels (P < 0.01) among the 3 different phenotypes were observed. The basal FeNO levels were significantly higher in NIBR (36.9%, IQR 27.0–95.4) than in NSAID-tolerant subjects (P < 0.01). After aspirin OPT, the reduction of %FEV1 was considerably higher in patients with confirmed NERD (22.0%, IQR 16.0-28.8), followed by NIBR (13.3%, IQR 7.6–28.0), compared to those in NSAID-tolerant groups (P < 0.01). Basal uLTE4 levels were not significantly different among the 3 phenotypes. Interestingly, uLTE4 levels after aspirin provocation were significantly higher in NERD and NIBR patients than in the NECD/NIUA and NSAID-tolerant groups (P < 0.05 and < 0.01, respectively).
Fig. 3 Respiratory parameters and uLTE4 levels in different phenotypes of NSAID-sensitive subjects compared to NSAID-tolerant subjects.
Baseline FeNO in NIBR and NERD were higher than those in the NSAID-tolerant group. After aspirin provocation, % predicted FEV1 in NERD and NIBR were significantly reduced from the baseline while uLTE4 levels were much higher than those in NSAID-tolerant subjects.
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; FEV1, forced expiratory volume in 1 second.
*P values < 0.05, †P values < 0.01.
Effects of aspirin desensitization on uLTE4 levels in patients diagnosed with NERD and NIBR
Aspirin desensitization was performed in selected patients (3 NERD and 3 NIBR) who had pre-existing inflammatory airway diseases and a history of recurrent nasal polyposis after surgery as shown in Table 3. The maintenance dose of aspirin was 650 mg/day during the first 6 months and reduced to 325 mg/day afterward. Levels of uLTE4 were measured at baseline after aspirin desensitization and serially followed up for 2–3 years as demonstrated in Fig. 4. Other than respiratory symptoms, acute urticarial rash and gastrointestinal symptoms (abdominal cramp/nausea/diarrhea) were also aggravated in NIBR subjects during aspirin desensitization as shown in Supplementary Fig. S1, but gradually relieved with supportive treatment. No sinus surgery was required for nasal polyp recurrence, and asthma symptoms were under control after aspirin desensitization in all 6 cases. Up to 3 years after aspirin desensitization, however, uLTE4 levels were significantly increased and remained elevated throughout the follow-up period, although urticarial rash and gastrointestinal symptoms were no longer observed while taking aspirin.
Table 3 Details of patients with cross-reactive NSAID hypersensitivity undergoing aspirin desensitization in this study
Patients (sex/year) Underlying diseases History of adverse drug reactions Indication for aspirin desensitization Follow-up duration (months) Asthma control before/after aspirin desensitization Recurrent nasal polyposis after aspirin desensitization Skin symptoms after aspirin desensitization Gastrointestinal symptoms after aspirin desensitization
1. NERD (M/46) Chronic sinusitis, nasal polyposis, asthma Acute asthma 20 min after taking aspirin 2 recurrent nasal polyps 74 Partly controlled with high dose ICS-LABA and add-on LTRA/well controlled with low dose ICS None NA NA
2. NERD (M/54) Chronic rhinitis, nasal polyposis, asthma Acute asthma, blocked nose 1 hr after taking aspirin 3 recurrent nasal polyps 24 Uncontrolled with high dose ICS-LABA and add-on LTRA/well controlled with medium dose ICS-LABA None NA NA
3. NERD (M/56) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked nose 1 hr after taking ibuprofen 6 recurrent nasal polyps 32 Partly controlled asthma with high dose ICS-LABA and add-on LTRA/well controlled with medium dose ICS-LABA None NA NA
4. NIBR (M/48) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked nose, conjunctival injection, urticarial rash 2 hr after taking aspirin 3 recurrent nasal polyps 72 Partly controlled with medium dose ICS-LABA/well controlled with low dose ICS-LABA None No rash after taking aspirin NA
5. NIBR (F/65) Chronic sinusitis, nasal polyposis, chronic urticaria, asthma (history of cardiac arrest from severe asthma) Urticarial rash, periorbital angioedema, blocked nose, conjunctival injection, rhinorrhea, bronchospasm/wheezing, hoarseness of voice 1 hr after taking aspirin, ibuprofen, mefenamic acid, acetaminophen 2 recurrent nasal polyps 48 Uncontrolled with high dose ICS-LABA and add-on LTRA/well controlled with low dose ICS-LABA None No rash after taking aspirin, chronic urticaria resolved NA
6. NIBR (F/38) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked/running nose, stomach cramp, diarrhea, periorbital angioedema, urticaria 30 min after taking ibuprofen, indomethacin, mefenamic acid 2 recurrent nasal polyps 21 Partly controlled with medium dose ICS-LABA/well controlled, with medium dose ICS-LABA None No rash after taking aspirin No gastrointestinal symptoms after taking aspirin
NSAID, non-steroidal anti-inflammatory drug; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; ICS, inhaled corticosteroid; LABA, long-acting beta-agonist; LTRA, leukotriene receptor antagonist; NA, not applicable (no symptoms prior to aspirin desensitization); NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
Fig. 4 uLTE4 levels in NSAID-sensitive subjects after aspirin desensitization.
Our study demonstrated that uLTE4 levels (pg/mg creatinine) in 3 NERD and 3 NIBR patients were increased and remained elevated up to 3 years after aspirin desensitization even though recurrent nasal polyposis was successfully prevented in all cases.
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
DISCUSSION
Most studies on NSAID hypersensitivity have focused on NERD, although worldwide epidemiological data suggest that NECD/NIUA might be more common. Recent data have demonstrated that some patients cannot be categorized into the current classification of NSAID hypersensitivity, for example those with NSAID-induced periorbital angioedema and NIBR.1419 These patients may also have underlying chronic airway diseases; however, the role of aspirin desensitization in the prevention of recurrent nasal polyposis and control of airway inflammation in NSAID-sensitive subjects other than the NERD phenotype has never been reported.
The leading presentations in NSAID-sensitive subjects in this study were periorbital angioedema, acute urticaria, bronchial symptoms, and naso-ocular reactions, respectively. Even those confirmed with NSAID exposure, a significant number of patients in our cohort also showed clinical responses in more than 1 organ system, indicating that the prevalence of NIBR was higher than previously thought. Although patients with IgE-mediated anaphylaxis might also present with multiple organ involvement, the fact that most of the reactions took about 1–2 hours to occur and the ability to react to multiple NSAIDs with dissimilar chemical structures made them more compatible with the non-immunologic effect of the drugs.
Facial angioedema around the periorbital area was the most common presenting symptom in Thai patients. Upon NSAID provocation, however, the predominant periorbital angioedema often accompanied by blocked nose, running nose, and itchy/red eyes. After a thorough examination, small urticarial rash on the trunk and extremities, and expiratory wheezing were occasionally detected, although frequently asymptomatic. It is noteworthy that periorbital angioedema may persist for hours or days while urticarial rash and respiratory symptoms are quickly resolved after treatment. As a result, NIBR could be underdiagnosed if history taking is not thoroughly reviewed, since symptoms with lesser severity in other organ systems may be unnoticed. In addition, the COX-1 inhibitor properties of the exposed NSAIDs could affect the phenotype of NSAID sensitivity reported by patients as some patients experienced both asthmatic attack and periorbital angioedema/generalized urticaria after taking aspirin but reported only periorbital edema after taking acetaminophen.
It is practically difficult to clearly distinguish between NSAID-induced periorbital angioedema and NSAID-induced naso-ocular reactions (upper airway manifestations of NERD), since patients occasionally experienced periorbital swelling, red/swollen eyes with tearing, and nasal congestion at the same time. In our opinion, the majority of NSAID hypersensitivity in the Thai population would be described as “NSAID-induced blended reaction with predominant periorbital angioedema” and probably related to “NSAID-induced isolated periorbital angioedema” phenotype as proposed by the Spanish group. It is interesting to note that the prevalence of atopic disease was high in this patient group. We speculate that the increased leukotriene production after NSAID consumption could lead to the worsening of pre-existing mucosal inflammation around the nose and eyes in patients who already suffered from the late-phase reaction of persistent allergic rhinitis.
Our study did not find any difference in terms of basal uLTE4 levels between NSAID-sensitive and NSAID-tolerant subjects. However, uLTE4 levels were higher in NSAID-sensitive patients, particularly in NERD and NIBR subjects, after the NSAID challenge compared to those in the NSAID-tolerant group. Though basal uLTE4 levels may not be a suitable marker to screen NSAID sensitivity status, elevated uLTE4 levels after aspirin OPT could be the supporting evidence for the diagnosis of cross-reactive NSAID hypersensitivity in cases where the clinical response is equivocal. Our study demonstrated that the degree of defective leukotriene homeostasis after exposure to drugs affecting the cyclo-oxygenase pathway might be related to the severity of respiratory involvement upon NSAID exposure.35 The fact that uLTE4 levels were barely changed after celecoxib provocation in patients with NSAID cross-reactivity confirms that celecoxib is a safe alternative NSAID in these patient groups.
According to our study, the patterns of NSAID hypersensitivity in southeast Asians are similar to those in southern Europeans and Latin Americans, and somewhat different from those reported in patients of northern European descent. Previous data suggested that aspirin nasal provocation could potentially diagnose some NSAID-sensitive patients presenting with predominant cutaneous reactions.3637 Retrospectively, some of these patients might be re-classified as the NIBR phenotype, since a decreased nasal volume was also observed. In other words, patients diagnosed with an NSAID-induced cutaneous reaction who positively reacted to NSAID nasal provocation, especially those with a periorbital reaction, might be NIBR subjects with subclinical airway involvement.
The novelties of this study were the findings that NIBR accounted for about one-third of adult patients with cross-reactive NSAID hypersensitivity and that aspirin desensitization could successfully prevent the recurrence of nasal polyposis and alleviate respiratory symptoms not only in NERD, but also in NIBR, even though urine LTE4 levels remained elevated. However, since the reactions in some NIBR patients could lead to serious adverse events, aspirin desensitization in NIBR subjects should be performed only when it is strongly indicated in selected patients with no previous severe reactions to NSAIDs. In NIBR subjects who experienced previous severe reactions in multiple organ systems, the procedure of aspirin desensitization, if necessary, should be carefully monitored and the administration of biological agents such as dupilumab, if available, should be considered a safer therapeutic option in these cases.
Interestingly, uLTE4 levels were increased after aspirin desensitization and remained elevated throughout the follow-up period. It should be emphasized that urticarial rash and stomach-ache in NIBR patients also disappeared while patients were taking daily aspirin. These data suggest that the pathogenesis of nasal polyposis cannot be explained by cysLT overproduction alone and that aspirin desensitization could be useful to alleviate both respiratory and non-respiratory symptoms in NIBR subjects.
Interestingly, a recent study also found that the clinical benefit of high-dose aspirin desensitization in NERD was independent of a reduction of mast cell activation and cysLT production. They reported paradoxically increased uLTE4 levels 8 weeks after aspirin desensitization compared to the baseline levels and concluded that high-dose aspirin therapy did not restore the impaired eicosanoid pathway.38 According to their study findings and ours, the therapeutic effect of aspirin desensitization was not directly correlated with a change of arachidonic acid metabolism.
There are some limitations to this study. Aspirin desensitization was performed in only 6 patients in our cohort; therefore, the comparative success rates and potential adverse reactions of aspirin desensitization between NERD and NIBR patients could not be analyzed. Further studies with a larger sample size are needed to compare the long-term prognosis between NERD and NIBR, to understand the mechanism of aspirin desensitization for the improvement of respiratory and extra-respiratory symptoms and to evaluate its risk-benefit ratio of aspirin desensitization in NIBR subjects.
In conclusion, NIBR is not uncommon among patients diagnosed with NSAID hypersensitivity in Thailand. Increased uLTE4 levels upon aspirin provocation suggested a diagnosis of NSAID cross-reactivity, while baseline uLTE4 levels were not distinguishable between NSAID-tolerant and NSAID-sensitive subjects. Our study indicates that aspirin desensitization is effective not only in NERD but also in NIBR. The persistently high levels of uLTE4 in spite of clinical improvement in NSAID-sensitive patients after successful aspirin desensitization suggest that elevated leukotrienes alone cannot explain the pathogenesis of NSAID hypersensitivity reactions.
ACKNOWLEDGMENTS
This study was supported by the Ratchadaphiseksomphot fund, Faculty of Medicine, Chulalongkorn University, grant No. RA55/19 and the Skin and Allergy Research Unit, Chulalongkorn University, Bangkok, Thailand. Study data were collected and managed using Research Electronic Data Capture (REDCap) hosted at HIV Netherlands Australia Thailand Research Collaboration. The authors thank Thitima Kantachatvanich, MD for providing patient information.
Disclosure: There are no financial or other issues that might lead to conflict of interest.
SUPPLEMENTARY MATERIALS
Supplementary Table S1
Clinical characteristics of patients with confirmed NSAID-induced immediate reactions
Supplementary Fig. S1
Representative photos of skin rash demonstrated during aspirin desensitization in NIBR patients. | IBUPROFEN, INDOMETHACIN, MEFENAMIC ACID | DrugsGivenReaction | CC BY-NC | 33474858 | 18,863,279 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Wheezing'. | Clinical Characteristics, Urinary Leukotriene E4 Levels, and Aspirin Desensitization Results in Patients With NSAID-Induced Blended Reactions.
OBJECTIVE
Data on non-steroidal anti-inflammatory drug (NSAID) hypersensitivity in Southeast Asia are scarce. Increased urinary leukotriene E4 (uLTE4) levels have been suggested as a biomarker of NSAID-exacerbated respiratory disease (NERD). This study investigated clinical patterns of NSAID sensitivity in Thailand and the diagnostic roles of uLTE4 measurement in various phenotypes.
METHODS
The clinical phenotypes in 92 Thai adults with cross-reactive NSAID hypersensitivity were characterized based on the clinical history and drug provocation. The uLTE4 levels were measured at baseline, after aspirin provocation and after desensitization.
RESULTS
More than half of the patients (56.5%) presented with cutaneous symptoms (NSAID-exacerbated cutaneous disease), while one-third (33.7%) developed symptoms in at least 2 systems (NSAID-induced blended reactions; NIBR). Fifty-two patients underwent drug provocation and 59.6% of them yielded positive results. After drug provocation, a significant number of patients with confirmed NSAID cross-reactivity experienced clinical symptoms in more than one organ system. The uLTE4 levels at baseline were comparable between the NSAID-tolerant and NSAID-sensitive groups, but were substantially increased after aspirin provocation predominantly in NERD (983.4 pg/mg creatinine) and NIBR (501.0 pg/mg creatinine) compared to NSAID-tolerant subjects (122.1 pg/mg creatinine, P < 0.01 and 0.05, respectively). The uLTE4 levels were elevated after aspirin desensitization, although nasal polyposis and asthma were under control in 3 NERD and 3 NIBR subjects.
CONCLUSIONS
NIBR is not uncommon among NSAID-sensitive patients in Thailand. The diagnostic value of basal uLTE4 levels was limited, but increased uLTE4 levels upon aspirin provocation suggest NSAID cross-reactivity with respiratory components. This study indicates that aspirin desensitization, if necessary, might be effective in both NERD and NIBR.
BACKGROUND
ClinicalTrials.gov Identifier: NCT03849625.
INTRODUCTION
Hypersensitivity reactions to aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most common drug allergic reactions in clinical practice. They are generally categorized into 5 major phenotypes: NSAID-exacerbated respiratory disease (NERD), NSAID-exacerbated cutaneous (urticaria/angioedema) disease (NECD) in patients with underlying chronic urticaria, NSAID-induced urticaria/angioedema (NIUA) in patients without underlying chronic urticaria, single NSAID-induced urticaria/angioedema or anaphylaxis, and single NSAID-induced delayed hypersensitivity reactions.1 The first 3 phenotypes are non-immunologically mediated, and patients can develop cross-reactive hypersensitivity to chemically unrelated NSAIDs, while the latter 2 are selective NSAID sensitivities associated with drug-specific immunoglobulin E (IgE) and T-cell response, respectively.
Genetic and epigenetic variations play significant roles in the development of NERD.2 The proposed underlying mechanism is that the disturbance in arachidonic acid synthesis pathways leads to overproduction of cysteinyl leukotrienes (cysLT) and persistent airway inflammation.3 Mast cells are believed to be the major source of cysLT, but platelet-adherent leukocytes may be responsible for cysLT overproduction in NERD as well.4 The consumption of drugs inhibiting the cyclooxygenase-1 (COX-1) enzyme, such as aspirin and conventional NSAIDs, aggravates respiratory symptoms by enhancing cysLT production in NSAID-sensitive subjects, while the administration of specific COX-2 inhibitors, such as celecoxib, is generally safe.56 Besides aspirin/NSAID avoidance, aspirin desensitization has also been proven to be helpful for long term management in NERD subjects. Beneficial effects of aspirin desensitization in preventing nasal polyp recurrence and control symptoms of chronic rhinosinusitis and asthma have been well documented.7 Rapid aspirin desensitization has shown to be effective for the treatment of coronary artery disease in patients with a history of aspirin/NSAID-induced urticaria/angioedema, but it is not indicated for the treatment of chronic urticaria.8
Worldwide epidemiological data on clinical characteristics of NSAID hypersensitivity are limited. Most studies on NERD were performed in the United States and northern European countries.9101112 However, the predominant manifestation in Latin Americans and southern Europeans is the cutaneous phenotype (NIUA, NECD, and NSAID-induced isolated periorbital angioedema).1314 Studies in Asian populations have suggested that the prevalence of the NERD phenotype is not common in this region of the world. A study performed in China indicated that the prevalence of NSAID hypersensitivity in Chinese patients with chronic rhinosinusitis is very low (0.57%) compared to their European counterparts.15 It was also noted that NSAID-induced blended reactions (NIBR) are common in young Asian, atopic children in Singapore.16 Reports from Singapore and Thailand indicated that aspirin/NSAID-induced angioedema/urticaria is probably the prominent phenotype in Southeast Asia, with acetaminophen hypersensitivity being frequent.1718
In clinical practice, the current classification of cross-reactive NSAID hypersensitivity into 3 distinct phenotypes has some limitations. Clinical characteristics in NSAID-sensitive patients may not be well defined, and a combination of respiratory and cutaneous or other symptoms, such as gastrointestinal symptoms (mixed or blended reactions), is frequently observed.19 A previous report stated that aspirin nasal provocation is potentially useful for diagnosing patients with the blended reaction as well.20 However, the role of aspirin desensitization in other phenotypes of NSAID hypersensitivity, besides NERD, for long-term management of inflammatory airway diseases has not yet been established. Whether aspirin desensitization would be effective in controlling asthma and the recurrence of nasal polyposis after sinus surgery in NIBR is currently unknown.
At present, cross-reactive types of NSAID hypersensitivity can only be diagnosed by careful history taking and controlled-provocation testing, since there is no reliable in vitro method to confirm the diagnosis.21 There is evidence that basal urinary levels of leukotriene E4 (uLTE4), a stable product of the cysLT synthesis pathway, are elevated in NERD patients and could be a potential biomarker for differentiating between NSAID-sensitive and NSAID-tolerant asthmatics. However, these data are still controversial.222324 There have also been preliminary studies showing that uLTE4 levels might be increased in NECD.2526 Whether the measurement of basal uLTE4 levels could be a diagnostic marker for any phenotype of NSAID hypersensitivity is yet to be explored.
The purpose of this study was to analyze the clinical characteristics of patients diagnosed with NSAID-induced immediate reactions in Thailand and to explore whether the measurement of uLTE4 levels would be helpful in identifying NSAID-sensitive subjects or in differentiating among different phenotypes of cross-reactive NSAID hypersensitivities.
MATERIALS AND METHODS
Patient recruitment
Adult patients (18 years of age and older) with a suggestive history of NSAID-induced hypersensitivity reaction visiting the allergy clinic at King Chulalongkorn University Hospital between June 2014 and July 2018 were recruited into this study. Those with a history compatible with drug-induced non-immediate reactions (maculopapular rash, fixed drug eruption, acute generalized exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms, Stevens-Johnson syndrome/toxic epidermal necrolysis) or NSAID-related side effects were excluded. The status of NSAID-induced immediate hypersensitivity was diagnosed in patients with a well-documented drug allergy history or in patients with a suggestive history of NSAID sensitivity who yielded a positive drug provocation test as follows.
Clinical diagnosis of NSAID hypersensitivity
The diagnosis of cross-reactive NSAID hypersensitivity was clinically made in patients with a well-documented history of multiple episodes of respiratory, cutaneous, and/or gastrointestinal reactions within 2 hours after exposure to at least 2 different NSAID classes.1212728 Patient demographic data were collected, including the underlying diseases, atopic family history, and details on drug allergy history as well as the presenting symptoms and types of the culprit NSAIDs.
Aspirin provocation test
Oral aspirin provocation was performed in patients with a suggestive medical history or in those who had a history of an immediate reaction to a single NSAID to confirm the diagnosis of cross-reactive NSAID hypersensitivity according to the EAACI/GA2LEN guidelines, with some modifications.293031 Four increasing doses of aspirin (40.5, 81, 150, and 300 mg) were administered at 90-minute intervals until a positive reaction occurred. Clinical symptoms, fractional exhaled nitric oxide (FeNO), and the forced expiratory volume in 1 second (FEV1) were monitored to evaluate the reaction. A positive provocation test was defined if any of the following reactions developed: lower respiratory/bronchial reaction (a 15% decrease in FEV1 plus naso-ocular reaction or a 20% decrease in FEV1 alone), upper respiratory/naso-ocular reaction (nasal congestion and rhinorrhea; conjunctival injection), cutaneous reactions (urticaria/angioedema, periorbital edema), and/or other reactions (gastrointestinal symptoms such as nausea/vomiting, stomach cramps, and diarrhea). The test was considered negative if a patient tolerated the final dose (300 mg of aspirin) without any significant symptoms mentioned above.
Oral provocation test (OPT) with other NSAIDs, acetaminophen, or celecoxib
Patients with a history of an immediate reaction to only aspirin were challenged with escalating doses of ibuprofen to confirm the diagnosis of cross-reactive NSAID sensitivity. Patients with a history of an immediate reaction to a single NSAID were provoked with the suspected drug to verify the status of single NSAID hypersensitivity after a negative aspirin provocation test. Escalating doses of ibuprofen, diclofenac, and acetaminophen were administered, if applicable, as follows: ibuprofen (50, 100, and 200 mg), diclofenac (6.25, 12.5, and 25 mg), and acetaminophen (125, 250, and 500 mg). Celecoxib was also provoked in 3 doses (50, 100, and 200 mg) in patients with confirmed hypersensitivity to multiple NSAIDs who were willing to identify a safe alternative drug. The provocation test for each drug was performed on separate days at least 7 days apart. Each dose of drug provocation was provided at 90-minute intervals until the final dose was reached.
Classification of NSAID hypersensitivity according to drug provocation test results
Patients with cross-reactive NSAID phenotypes were classified according to the results of the drug provocation test as 1) NECD/NIUA if they developed cutaneous symptoms alone; 2) NERD if they developed respiratory symptoms alone; and 3) NIBR if they developed a combination of symptoms involving more than one organ system (respiratory, cutaneous, and/or gastrointestinal symptoms). Single NSAID hypersensitivity was diagnosed in patients with a positive provocation test to the suspected NSAID, but a negative aspirin provocation test. Patients who had negative provocations to both aspirin and the suspected culprit drug were labeled as NSAID-tolerant subjects. NECD/NIUA were purposely categorized together in our study to compare the differences and similarities between patients diagnosed with NSAID-induced cutaneous reactions and -respiratory reactions. Moreover, NECD and NIUA share similar background characteristics from a clinical point of view and some patients diagnosed with NIUA eventually evolve to NECD over time.32
Skin prick tests with common aeroallergens in Thailand (mixed dust mites, mixed cockroaches, mixed mold, cat dander, dog hair, and southern grass mix; ALK-Abello, Hørsholm, Denmark) were also examined in tested patients to identify atopic status. Wheal size ≥ 3 mm was considered a positive test.
Measurement of FeNO and the FEV1 in patients who underwent drug provocation test
FeNO was measured in all participants at baseline and after drug provocation by using a portable electrochemical analyzer (NObreath®; Bedfont Scientific Ltd, Maidstone, UK) according to the ATS/ERS recommendations.33 Measurements of FEV1 were also performed using a Vitalograph spirometer (Vitalograph®, Buckingham, UK). The best of 3 repeated attempts was recorded.
The uLTE4 measurement
The uLTE4 levels were measured by a leukotriene E4 ELISA kit (Cayman Chemical, Ann Arbor, MI, USA) at baseline and 90 minutes after the final dose of drug provocation, as well as at the follow-up visits after aspirin desensitization and reported after adjustment to urine creatinine levels.
Aspirin desensitization
Outpatient aspirin desensitization was performed in NSAID-sensitive patients who were referred from otolaryngologists to prevent the recurrence of nasal polyposis. The procedure was carried out according to the intranasal ketorolac and modified aspirin challenge 2-day protocol.34 Aspirin desensitization was completed after patients were able to tolerate a 325-mg dose of aspirin by the end of day 2 and experience no symptoms, changes in nasal flow rates, or decrease in FEV1 values. The prescribed maintenance dose of aspirin was 325 mg twice a day.
Statistical analysis
Patient characteristics are reported as means ± standard deviation for quantitative analysis, and median and interquartile range (IQR) are used to describe non-parametric data. The Mann-Whitney U test and Kruskal-Wallis test with Dunn's multiple comparisons were used to analyze the differences between 2 groups and more than 2 groups, respectively. Statistical analyses were performed using GraphPad Prism 8.3 software (GraphPad Software Inc., San Diego, CA, USA). P values < 0.05 were considered statistically significant.
Ethical considerations
Patients enrolled in this study were those who recruited in the study entitled “Characteristics of Patients Diagnosed With NSAID Sensitivity in Thailand” registered at ClinicalTrials.gov (NCT03849625). The study was approved by the Ethics and Research Committee of the Faculty of Medicine, Chulalongkorn University, Approval Number: COA No. 659/2012 and informed consent was obtained from all participants.
RESULTS
A total of 158 adult patients with a suspected history of NSAID hypersensitivity between 2015 and 2018 at King Chulalongkorn Memorial Hospital were initially recruited into this study as shown in Fig. 1. Thirty-five patients with a history compatible with a non-immediate hypersensitivity reaction and 4 subjects with clinical symptoms compatible with NSAID-related side effects were later excluded.
Fig. 1 Schematic diagram of patient selection for this study.
A total of 158 patients with a suspected history of NSAID hypersensitivity were initially recruited into this study. Cross-reactive NSAID hypersensitivity was clinically diagnosed in 67 patients with a well-documented drug allergy history and verified by a positive drug provocation test in 25 patients with a suggestive history of NSAID reactions.
NSAID, non-steroidal anti-inflammatory drug.
Cross-reactive NSAID hypersensitivity was clinically diagnosed in 67 patients with a convincing drug allergy history as defined in the methods section. The remaining 52 patients with a suggestive history of NSAID hypersensitivity underwent an OPT to confirm NSAID cross-reactivity status. Fifteen out of 25 patients with confirmed NSAID cross-reactivity were subsequently provoked with celecoxib to find a safe alternative NSAID. Single NSAID/acetaminophen hypersensitivity was verified in 6 patients who tolerated aspirin provocation but developed an allergic reaction upon re-challenge with acetaminophen or diclofenac.
Demographic data of adult patients with cross-reactive NSAID hypersensitivity
The clinical characteristics of adult patients with cross-reactive NSAID hypersensitivity are shown in Table 1 (n = 92). Most patients were females (77.2%) with an average age of 45.7 ± 13.4 years. The average age of onset was 32.2 ± 13.3 years and about half of them had atopic family history. The majority of them (56.5%) reported only cutaneous symptoms such as facial angioedema and/or acute urticarial rash, after NSAID exposure, while 9.8% of them developed only respiratory symptoms. Interestingly, about 33.7% of the patients experienced a combination of symptoms in multiple organ systems as shown in Fig. 2. The groups of NSAIDs frequently responsible for hypersensitivity reactions were propionic acid derivatives and acetic acid derivatives. Although inflammatory airway diseases (chronic sinusitis, nasal polyposis, and asthma) were significantly more common in patients who experienced only respiratory reactions after exposure to an NSAID compared to the other phenotypes, a significant portion of the patients reporting blended reactions had underlying airway diseases and chronic urticaria as well. Acetaminophen intolerance was also reported in about one-third (35.9%) of NSAID-sensitive subjects.
Table 1 Clinical characteristics among different phenotypes of patients with cross-reactive NSAID hypersensitivity (n = 92)
Phenotypes NECD/NIUA (n = 52) NERD (n = 9) NIBR (n = 31) Total (n = 92)
Gender (female/male) 37/15 6/3 28/3 71/21
Age (yr) 43.6 ± 12.3 47.3 ± 11.9 48.7 ± 15.3 45.7 ± 13.4
Age of onset (yr) 31.3 ± 13.8 34.6 ± 11.0 33.1 ± 13.3 32.2 ± 13.3
Underlying disease (%)
Chronic urticaria 13.5 11.1 29.0 18.5
Chronic sinusitis* 13.5 55.6 32.3 23.9
Nasal polyposis* 7.7 66.7 16.1 16.3
Asthma* 17.3 88.9 35.5 30.4
Atopic family history (%) 42.3 55.6 61.3 50.0
Drug exposure time to symptom onset (min) 58.8 ± 31.9 48.3 ± 34.3 47.6 ± 29.9 54.0 ± 31.6
Presenting symptoms (%)*
Facial/periorbital angioedema 71.2 0.0 74.2 65.2
Acute urticaria 73.1 0.0 61.3 62.0
Naso-ocular reaction 0.0 33.3 61.3 23.9
Acute asthma 0.0 88.9 67.7 31.5
Gastrointestinal symptoms 0.0 0.0 16.1 5.4
Implicated NSAIDs (%)†
Salicylic acids 23.1 55.6 35.5 30.4
Propionic acids 44.2 22.2 54.8 45.7
Acetic acids 23.1 22.2 48.4 31.5
Enolic acids 7.7 0.0 6.5 6.5
Anthranilic/fenamic acids 28.8 11.1 29.0 27.2
Acetaminophen intolerance (%)§ 28.8 22.2 51.6 35.9
Values are presented as number (%) or mean ± standard deviation. Each patient could present with multiple symptoms and from more than one implicated drug.
NSAID, non-steroidal anti-inflammatory drug; NECD, non-steroidal anti-inflammatory drug-exacerbated cutaneous (urticaria/angioedema) disease in patients with underlying chronic urticaria; NIUA, non-steroidal anti-inflammatory drug-induced urticaria/angioedema in patients without underlying chronic urticaria; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
*P < 0.05 among different phenotypes. †Examples of commonly implicated drugs in this study based on NSAID classification: 1) Salicylic acids: acetylsalicylic acid (aspirin), salicylic acid, diflunisal, salsalate; 2) Propionic acids: ibuprofen, naproxen, ketoprofen, fenoprofen, flurbiprofen; 3) Acetic acids: indomethacin, ketorolac, diclofenac, sulindac; 4) Enolic acids: piroxicam, meloxicam, tenoxicam; 5) Anthranilic/fenamic acids: mefenamic acid, flufenamic acid. §Acetaminophen intolerance: cannot tolerate acetaminophen higher than 500 mg.
Fig. 2 Clinical presentations in patients with cross-reactive NSAID hypersensitivity.
A proportional Venn diagram shows that about half of patients with cross-reactive NSAID hypersensitivity in Thailand reported only cutaneous symptoms after NSAID exposure, while one-third of them experienced NSAID-induced blended reactions.
NSAID, non-steroidal anti-inflammatory drug.
Clinical respiratory parameters and uLTE4 levels in different phenotypes of patients with cross-reactive NSAID hypersensitivity confirmed by positive OPT
NSAID hypersensitivity was confirmed in 59.6% (31/52) of the tested patients with a history of NSAID-induced immediate reactions. The majority of patients with cross-reactive NSAID hypersensitivity (17/25) according to OPT results were atopic individuals. The common phenotypes of patients with confirmed cross-reactive NSAID sensitivity were NECD/NIUA, NIBR, and NERD, respectively, as shown in Supplementary Table S1.
The average FeNO, %predicted FEV1, and uLTE4 levels were measured at baseline and after provocation with aspirin/NSAID in 25 NSAID cross-reactive and 21 NSAID-tolerant subjects as shown in Table 2. At baseline, patients with confirmed NSAID cross-reactivity (NSAID-sensitive group) had higher FeNO (P < 0.01) and slightly less %predicted FEV1 compared to the NSAID-tolerant subjects, while basal uLTE4 levels between NSAID-sensitive and NSAID-tolerant groups were comparable. After provocation, %predicted FEV1 was substantially reduced in NSAID-sensitive subjects, whereas uLTE4 levels were significantly elevated compared to the NSAID-tolerant group (P < 0.01). Celecoxib provocation was well tolerated in all NSAID-sensitive subjects. No statistical differences in the average FeNO, %predicted FEV1, or uLTE4 levels in 15 NSAID-sensitive patients (7 NECD/NIUA, 4 NIBR, 4 NERD) after celecoxib provocation were observed compared to those in NSAID-tolerant subjects.
Table 2 Respiratory parameters and uLTE4 levels in NSAID-sensitive subjects upon provocation with aspirin or celecoxib compared to NSAID-tolerant subjects
Characteristics Baseline After aspirin (OPT) P value*
NSAID tolerant (n = 21)
FeNO (ppb) 13.0 (8.5–19.5) 10.2 (7.0–16.8) 0.03
%predicted FEV1 100.8 (82.8–115.9) 99.0 (75.2–118.2) 0.90
uLTE4 (pg/mg creatinine) 116.3 (66.5–305.4) 122.1 (63.5–173.8) 0.17
NSAID sensitive (n = 25)
FeNO (ppb) 27.0 (17.8–40.9)† 18.0 (10.5–31.0) <0.01
%predicted FEV1 86.7 (63.3–104.9) 74.6 (52.4–89.8)† <0.01
uLTE4 (pg/mg creatinine) 118.3 (93.2–407.2) 204.9 (90.6–817.8)† <0.01
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; OPT, oral provocation test; ppb, parts per billion; FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in 1 second.
*P values before vs. after provocation test, Wilcoxon signed-rank test; †P < 0.01 compared to the NSAID-tolerant subjects.
According to the subgroup analysis, 10 NECD/NIUA, 9 NIBR, and 6 NERD were categorized as shown in Fig. 3. At baseline, %predicted FEV1 was not significantly different among different types of cross-reactive NSAID hypersensitivity, although those in patients with confirmed NIBR were lowest (64.9%, IQR 56.9–97.3). The significant differences in basal FeNO levels (P < 0.01) among the 3 different phenotypes were observed. The basal FeNO levels were significantly higher in NIBR (36.9%, IQR 27.0–95.4) than in NSAID-tolerant subjects (P < 0.01). After aspirin OPT, the reduction of %FEV1 was considerably higher in patients with confirmed NERD (22.0%, IQR 16.0-28.8), followed by NIBR (13.3%, IQR 7.6–28.0), compared to those in NSAID-tolerant groups (P < 0.01). Basal uLTE4 levels were not significantly different among the 3 phenotypes. Interestingly, uLTE4 levels after aspirin provocation were significantly higher in NERD and NIBR patients than in the NECD/NIUA and NSAID-tolerant groups (P < 0.05 and < 0.01, respectively).
Fig. 3 Respiratory parameters and uLTE4 levels in different phenotypes of NSAID-sensitive subjects compared to NSAID-tolerant subjects.
Baseline FeNO in NIBR and NERD were higher than those in the NSAID-tolerant group. After aspirin provocation, % predicted FEV1 in NERD and NIBR were significantly reduced from the baseline while uLTE4 levels were much higher than those in NSAID-tolerant subjects.
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; FEV1, forced expiratory volume in 1 second.
*P values < 0.05, †P values < 0.01.
Effects of aspirin desensitization on uLTE4 levels in patients diagnosed with NERD and NIBR
Aspirin desensitization was performed in selected patients (3 NERD and 3 NIBR) who had pre-existing inflammatory airway diseases and a history of recurrent nasal polyposis after surgery as shown in Table 3. The maintenance dose of aspirin was 650 mg/day during the first 6 months and reduced to 325 mg/day afterward. Levels of uLTE4 were measured at baseline after aspirin desensitization and serially followed up for 2–3 years as demonstrated in Fig. 4. Other than respiratory symptoms, acute urticarial rash and gastrointestinal symptoms (abdominal cramp/nausea/diarrhea) were also aggravated in NIBR subjects during aspirin desensitization as shown in Supplementary Fig. S1, but gradually relieved with supportive treatment. No sinus surgery was required for nasal polyp recurrence, and asthma symptoms were under control after aspirin desensitization in all 6 cases. Up to 3 years after aspirin desensitization, however, uLTE4 levels were significantly increased and remained elevated throughout the follow-up period, although urticarial rash and gastrointestinal symptoms were no longer observed while taking aspirin.
Table 3 Details of patients with cross-reactive NSAID hypersensitivity undergoing aspirin desensitization in this study
Patients (sex/year) Underlying diseases History of adverse drug reactions Indication for aspirin desensitization Follow-up duration (months) Asthma control before/after aspirin desensitization Recurrent nasal polyposis after aspirin desensitization Skin symptoms after aspirin desensitization Gastrointestinal symptoms after aspirin desensitization
1. NERD (M/46) Chronic sinusitis, nasal polyposis, asthma Acute asthma 20 min after taking aspirin 2 recurrent nasal polyps 74 Partly controlled with high dose ICS-LABA and add-on LTRA/well controlled with low dose ICS None NA NA
2. NERD (M/54) Chronic rhinitis, nasal polyposis, asthma Acute asthma, blocked nose 1 hr after taking aspirin 3 recurrent nasal polyps 24 Uncontrolled with high dose ICS-LABA and add-on LTRA/well controlled with medium dose ICS-LABA None NA NA
3. NERD (M/56) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked nose 1 hr after taking ibuprofen 6 recurrent nasal polyps 32 Partly controlled asthma with high dose ICS-LABA and add-on LTRA/well controlled with medium dose ICS-LABA None NA NA
4. NIBR (M/48) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked nose, conjunctival injection, urticarial rash 2 hr after taking aspirin 3 recurrent nasal polyps 72 Partly controlled with medium dose ICS-LABA/well controlled with low dose ICS-LABA None No rash after taking aspirin NA
5. NIBR (F/65) Chronic sinusitis, nasal polyposis, chronic urticaria, asthma (history of cardiac arrest from severe asthma) Urticarial rash, periorbital angioedema, blocked nose, conjunctival injection, rhinorrhea, bronchospasm/wheezing, hoarseness of voice 1 hr after taking aspirin, ibuprofen, mefenamic acid, acetaminophen 2 recurrent nasal polyps 48 Uncontrolled with high dose ICS-LABA and add-on LTRA/well controlled with low dose ICS-LABA None No rash after taking aspirin, chronic urticaria resolved NA
6. NIBR (F/38) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked/running nose, stomach cramp, diarrhea, periorbital angioedema, urticaria 30 min after taking ibuprofen, indomethacin, mefenamic acid 2 recurrent nasal polyps 21 Partly controlled with medium dose ICS-LABA/well controlled, with medium dose ICS-LABA None No rash after taking aspirin No gastrointestinal symptoms after taking aspirin
NSAID, non-steroidal anti-inflammatory drug; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; ICS, inhaled corticosteroid; LABA, long-acting beta-agonist; LTRA, leukotriene receptor antagonist; NA, not applicable (no symptoms prior to aspirin desensitization); NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
Fig. 4 uLTE4 levels in NSAID-sensitive subjects after aspirin desensitization.
Our study demonstrated that uLTE4 levels (pg/mg creatinine) in 3 NERD and 3 NIBR patients were increased and remained elevated up to 3 years after aspirin desensitization even though recurrent nasal polyposis was successfully prevented in all cases.
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
DISCUSSION
Most studies on NSAID hypersensitivity have focused on NERD, although worldwide epidemiological data suggest that NECD/NIUA might be more common. Recent data have demonstrated that some patients cannot be categorized into the current classification of NSAID hypersensitivity, for example those with NSAID-induced periorbital angioedema and NIBR.1419 These patients may also have underlying chronic airway diseases; however, the role of aspirin desensitization in the prevention of recurrent nasal polyposis and control of airway inflammation in NSAID-sensitive subjects other than the NERD phenotype has never been reported.
The leading presentations in NSAID-sensitive subjects in this study were periorbital angioedema, acute urticaria, bronchial symptoms, and naso-ocular reactions, respectively. Even those confirmed with NSAID exposure, a significant number of patients in our cohort also showed clinical responses in more than 1 organ system, indicating that the prevalence of NIBR was higher than previously thought. Although patients with IgE-mediated anaphylaxis might also present with multiple organ involvement, the fact that most of the reactions took about 1–2 hours to occur and the ability to react to multiple NSAIDs with dissimilar chemical structures made them more compatible with the non-immunologic effect of the drugs.
Facial angioedema around the periorbital area was the most common presenting symptom in Thai patients. Upon NSAID provocation, however, the predominant periorbital angioedema often accompanied by blocked nose, running nose, and itchy/red eyes. After a thorough examination, small urticarial rash on the trunk and extremities, and expiratory wheezing were occasionally detected, although frequently asymptomatic. It is noteworthy that periorbital angioedema may persist for hours or days while urticarial rash and respiratory symptoms are quickly resolved after treatment. As a result, NIBR could be underdiagnosed if history taking is not thoroughly reviewed, since symptoms with lesser severity in other organ systems may be unnoticed. In addition, the COX-1 inhibitor properties of the exposed NSAIDs could affect the phenotype of NSAID sensitivity reported by patients as some patients experienced both asthmatic attack and periorbital angioedema/generalized urticaria after taking aspirin but reported only periorbital edema after taking acetaminophen.
It is practically difficult to clearly distinguish between NSAID-induced periorbital angioedema and NSAID-induced naso-ocular reactions (upper airway manifestations of NERD), since patients occasionally experienced periorbital swelling, red/swollen eyes with tearing, and nasal congestion at the same time. In our opinion, the majority of NSAID hypersensitivity in the Thai population would be described as “NSAID-induced blended reaction with predominant periorbital angioedema” and probably related to “NSAID-induced isolated periorbital angioedema” phenotype as proposed by the Spanish group. It is interesting to note that the prevalence of atopic disease was high in this patient group. We speculate that the increased leukotriene production after NSAID consumption could lead to the worsening of pre-existing mucosal inflammation around the nose and eyes in patients who already suffered from the late-phase reaction of persistent allergic rhinitis.
Our study did not find any difference in terms of basal uLTE4 levels between NSAID-sensitive and NSAID-tolerant subjects. However, uLTE4 levels were higher in NSAID-sensitive patients, particularly in NERD and NIBR subjects, after the NSAID challenge compared to those in the NSAID-tolerant group. Though basal uLTE4 levels may not be a suitable marker to screen NSAID sensitivity status, elevated uLTE4 levels after aspirin OPT could be the supporting evidence for the diagnosis of cross-reactive NSAID hypersensitivity in cases where the clinical response is equivocal. Our study demonstrated that the degree of defective leukotriene homeostasis after exposure to drugs affecting the cyclo-oxygenase pathway might be related to the severity of respiratory involvement upon NSAID exposure.35 The fact that uLTE4 levels were barely changed after celecoxib provocation in patients with NSAID cross-reactivity confirms that celecoxib is a safe alternative NSAID in these patient groups.
According to our study, the patterns of NSAID hypersensitivity in southeast Asians are similar to those in southern Europeans and Latin Americans, and somewhat different from those reported in patients of northern European descent. Previous data suggested that aspirin nasal provocation could potentially diagnose some NSAID-sensitive patients presenting with predominant cutaneous reactions.3637 Retrospectively, some of these patients might be re-classified as the NIBR phenotype, since a decreased nasal volume was also observed. In other words, patients diagnosed with an NSAID-induced cutaneous reaction who positively reacted to NSAID nasal provocation, especially those with a periorbital reaction, might be NIBR subjects with subclinical airway involvement.
The novelties of this study were the findings that NIBR accounted for about one-third of adult patients with cross-reactive NSAID hypersensitivity and that aspirin desensitization could successfully prevent the recurrence of nasal polyposis and alleviate respiratory symptoms not only in NERD, but also in NIBR, even though urine LTE4 levels remained elevated. However, since the reactions in some NIBR patients could lead to serious adverse events, aspirin desensitization in NIBR subjects should be performed only when it is strongly indicated in selected patients with no previous severe reactions to NSAIDs. In NIBR subjects who experienced previous severe reactions in multiple organ systems, the procedure of aspirin desensitization, if necessary, should be carefully monitored and the administration of biological agents such as dupilumab, if available, should be considered a safer therapeutic option in these cases.
Interestingly, uLTE4 levels were increased after aspirin desensitization and remained elevated throughout the follow-up period. It should be emphasized that urticarial rash and stomach-ache in NIBR patients also disappeared while patients were taking daily aspirin. These data suggest that the pathogenesis of nasal polyposis cannot be explained by cysLT overproduction alone and that aspirin desensitization could be useful to alleviate both respiratory and non-respiratory symptoms in NIBR subjects.
Interestingly, a recent study also found that the clinical benefit of high-dose aspirin desensitization in NERD was independent of a reduction of mast cell activation and cysLT production. They reported paradoxically increased uLTE4 levels 8 weeks after aspirin desensitization compared to the baseline levels and concluded that high-dose aspirin therapy did not restore the impaired eicosanoid pathway.38 According to their study findings and ours, the therapeutic effect of aspirin desensitization was not directly correlated with a change of arachidonic acid metabolism.
There are some limitations to this study. Aspirin desensitization was performed in only 6 patients in our cohort; therefore, the comparative success rates and potential adverse reactions of aspirin desensitization between NERD and NIBR patients could not be analyzed. Further studies with a larger sample size are needed to compare the long-term prognosis between NERD and NIBR, to understand the mechanism of aspirin desensitization for the improvement of respiratory and extra-respiratory symptoms and to evaluate its risk-benefit ratio of aspirin desensitization in NIBR subjects.
In conclusion, NIBR is not uncommon among patients diagnosed with NSAID hypersensitivity in Thailand. Increased uLTE4 levels upon aspirin provocation suggested a diagnosis of NSAID cross-reactivity, while baseline uLTE4 levels were not distinguishable between NSAID-tolerant and NSAID-sensitive subjects. Our study indicates that aspirin desensitization is effective not only in NERD but also in NIBR. The persistently high levels of uLTE4 in spite of clinical improvement in NSAID-sensitive patients after successful aspirin desensitization suggest that elevated leukotrienes alone cannot explain the pathogenesis of NSAID hypersensitivity reactions.
ACKNOWLEDGMENTS
This study was supported by the Ratchadaphiseksomphot fund, Faculty of Medicine, Chulalongkorn University, grant No. RA55/19 and the Skin and Allergy Research Unit, Chulalongkorn University, Bangkok, Thailand. Study data were collected and managed using Research Electronic Data Capture (REDCap) hosted at HIV Netherlands Australia Thailand Research Collaboration. The authors thank Thitima Kantachatvanich, MD for providing patient information.
Disclosure: There are no financial or other issues that might lead to conflict of interest.
SUPPLEMENTARY MATERIALS
Supplementary Table S1
Clinical characteristics of patients with confirmed NSAID-induced immediate reactions
Supplementary Fig. S1
Representative photos of skin rash demonstrated during aspirin desensitization in NIBR patients. | ACETAMINOPHEN\HYDROCODONE, ASPIRIN, IBUPROFEN, MEFENAMIC ACID | DrugsGivenReaction | CC BY-NC | 33474858 | 19,056,205 | 2021-03 |
What was the dosage of drug 'ACETAMINOPHEN\HYDROCODONE'? | Clinical Characteristics, Urinary Leukotriene E4 Levels, and Aspirin Desensitization Results in Patients With NSAID-Induced Blended Reactions.
OBJECTIVE
Data on non-steroidal anti-inflammatory drug (NSAID) hypersensitivity in Southeast Asia are scarce. Increased urinary leukotriene E4 (uLTE4) levels have been suggested as a biomarker of NSAID-exacerbated respiratory disease (NERD). This study investigated clinical patterns of NSAID sensitivity in Thailand and the diagnostic roles of uLTE4 measurement in various phenotypes.
METHODS
The clinical phenotypes in 92 Thai adults with cross-reactive NSAID hypersensitivity were characterized based on the clinical history and drug provocation. The uLTE4 levels were measured at baseline, after aspirin provocation and after desensitization.
RESULTS
More than half of the patients (56.5%) presented with cutaneous symptoms (NSAID-exacerbated cutaneous disease), while one-third (33.7%) developed symptoms in at least 2 systems (NSAID-induced blended reactions; NIBR). Fifty-two patients underwent drug provocation and 59.6% of them yielded positive results. After drug provocation, a significant number of patients with confirmed NSAID cross-reactivity experienced clinical symptoms in more than one organ system. The uLTE4 levels at baseline were comparable between the NSAID-tolerant and NSAID-sensitive groups, but were substantially increased after aspirin provocation predominantly in NERD (983.4 pg/mg creatinine) and NIBR (501.0 pg/mg creatinine) compared to NSAID-tolerant subjects (122.1 pg/mg creatinine, P < 0.01 and 0.05, respectively). The uLTE4 levels were elevated after aspirin desensitization, although nasal polyposis and asthma were under control in 3 NERD and 3 NIBR subjects.
CONCLUSIONS
NIBR is not uncommon among NSAID-sensitive patients in Thailand. The diagnostic value of basal uLTE4 levels was limited, but increased uLTE4 levels upon aspirin provocation suggest NSAID cross-reactivity with respiratory components. This study indicates that aspirin desensitization, if necessary, might be effective in both NERD and NIBR.
BACKGROUND
ClinicalTrials.gov Identifier: NCT03849625.
INTRODUCTION
Hypersensitivity reactions to aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most common drug allergic reactions in clinical practice. They are generally categorized into 5 major phenotypes: NSAID-exacerbated respiratory disease (NERD), NSAID-exacerbated cutaneous (urticaria/angioedema) disease (NECD) in patients with underlying chronic urticaria, NSAID-induced urticaria/angioedema (NIUA) in patients without underlying chronic urticaria, single NSAID-induced urticaria/angioedema or anaphylaxis, and single NSAID-induced delayed hypersensitivity reactions.1 The first 3 phenotypes are non-immunologically mediated, and patients can develop cross-reactive hypersensitivity to chemically unrelated NSAIDs, while the latter 2 are selective NSAID sensitivities associated with drug-specific immunoglobulin E (IgE) and T-cell response, respectively.
Genetic and epigenetic variations play significant roles in the development of NERD.2 The proposed underlying mechanism is that the disturbance in arachidonic acid synthesis pathways leads to overproduction of cysteinyl leukotrienes (cysLT) and persistent airway inflammation.3 Mast cells are believed to be the major source of cysLT, but platelet-adherent leukocytes may be responsible for cysLT overproduction in NERD as well.4 The consumption of drugs inhibiting the cyclooxygenase-1 (COX-1) enzyme, such as aspirin and conventional NSAIDs, aggravates respiratory symptoms by enhancing cysLT production in NSAID-sensitive subjects, while the administration of specific COX-2 inhibitors, such as celecoxib, is generally safe.56 Besides aspirin/NSAID avoidance, aspirin desensitization has also been proven to be helpful for long term management in NERD subjects. Beneficial effects of aspirin desensitization in preventing nasal polyp recurrence and control symptoms of chronic rhinosinusitis and asthma have been well documented.7 Rapid aspirin desensitization has shown to be effective for the treatment of coronary artery disease in patients with a history of aspirin/NSAID-induced urticaria/angioedema, but it is not indicated for the treatment of chronic urticaria.8
Worldwide epidemiological data on clinical characteristics of NSAID hypersensitivity are limited. Most studies on NERD were performed in the United States and northern European countries.9101112 However, the predominant manifestation in Latin Americans and southern Europeans is the cutaneous phenotype (NIUA, NECD, and NSAID-induced isolated periorbital angioedema).1314 Studies in Asian populations have suggested that the prevalence of the NERD phenotype is not common in this region of the world. A study performed in China indicated that the prevalence of NSAID hypersensitivity in Chinese patients with chronic rhinosinusitis is very low (0.57%) compared to their European counterparts.15 It was also noted that NSAID-induced blended reactions (NIBR) are common in young Asian, atopic children in Singapore.16 Reports from Singapore and Thailand indicated that aspirin/NSAID-induced angioedema/urticaria is probably the prominent phenotype in Southeast Asia, with acetaminophen hypersensitivity being frequent.1718
In clinical practice, the current classification of cross-reactive NSAID hypersensitivity into 3 distinct phenotypes has some limitations. Clinical characteristics in NSAID-sensitive patients may not be well defined, and a combination of respiratory and cutaneous or other symptoms, such as gastrointestinal symptoms (mixed or blended reactions), is frequently observed.19 A previous report stated that aspirin nasal provocation is potentially useful for diagnosing patients with the blended reaction as well.20 However, the role of aspirin desensitization in other phenotypes of NSAID hypersensitivity, besides NERD, for long-term management of inflammatory airway diseases has not yet been established. Whether aspirin desensitization would be effective in controlling asthma and the recurrence of nasal polyposis after sinus surgery in NIBR is currently unknown.
At present, cross-reactive types of NSAID hypersensitivity can only be diagnosed by careful history taking and controlled-provocation testing, since there is no reliable in vitro method to confirm the diagnosis.21 There is evidence that basal urinary levels of leukotriene E4 (uLTE4), a stable product of the cysLT synthesis pathway, are elevated in NERD patients and could be a potential biomarker for differentiating between NSAID-sensitive and NSAID-tolerant asthmatics. However, these data are still controversial.222324 There have also been preliminary studies showing that uLTE4 levels might be increased in NECD.2526 Whether the measurement of basal uLTE4 levels could be a diagnostic marker for any phenotype of NSAID hypersensitivity is yet to be explored.
The purpose of this study was to analyze the clinical characteristics of patients diagnosed with NSAID-induced immediate reactions in Thailand and to explore whether the measurement of uLTE4 levels would be helpful in identifying NSAID-sensitive subjects or in differentiating among different phenotypes of cross-reactive NSAID hypersensitivities.
MATERIALS AND METHODS
Patient recruitment
Adult patients (18 years of age and older) with a suggestive history of NSAID-induced hypersensitivity reaction visiting the allergy clinic at King Chulalongkorn University Hospital between June 2014 and July 2018 were recruited into this study. Those with a history compatible with drug-induced non-immediate reactions (maculopapular rash, fixed drug eruption, acute generalized exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms, Stevens-Johnson syndrome/toxic epidermal necrolysis) or NSAID-related side effects were excluded. The status of NSAID-induced immediate hypersensitivity was diagnosed in patients with a well-documented drug allergy history or in patients with a suggestive history of NSAID sensitivity who yielded a positive drug provocation test as follows.
Clinical diagnosis of NSAID hypersensitivity
The diagnosis of cross-reactive NSAID hypersensitivity was clinically made in patients with a well-documented history of multiple episodes of respiratory, cutaneous, and/or gastrointestinal reactions within 2 hours after exposure to at least 2 different NSAID classes.1212728 Patient demographic data were collected, including the underlying diseases, atopic family history, and details on drug allergy history as well as the presenting symptoms and types of the culprit NSAIDs.
Aspirin provocation test
Oral aspirin provocation was performed in patients with a suggestive medical history or in those who had a history of an immediate reaction to a single NSAID to confirm the diagnosis of cross-reactive NSAID hypersensitivity according to the EAACI/GA2LEN guidelines, with some modifications.293031 Four increasing doses of aspirin (40.5, 81, 150, and 300 mg) were administered at 90-minute intervals until a positive reaction occurred. Clinical symptoms, fractional exhaled nitric oxide (FeNO), and the forced expiratory volume in 1 second (FEV1) were monitored to evaluate the reaction. A positive provocation test was defined if any of the following reactions developed: lower respiratory/bronchial reaction (a 15% decrease in FEV1 plus naso-ocular reaction or a 20% decrease in FEV1 alone), upper respiratory/naso-ocular reaction (nasal congestion and rhinorrhea; conjunctival injection), cutaneous reactions (urticaria/angioedema, periorbital edema), and/or other reactions (gastrointestinal symptoms such as nausea/vomiting, stomach cramps, and diarrhea). The test was considered negative if a patient tolerated the final dose (300 mg of aspirin) without any significant symptoms mentioned above.
Oral provocation test (OPT) with other NSAIDs, acetaminophen, or celecoxib
Patients with a history of an immediate reaction to only aspirin were challenged with escalating doses of ibuprofen to confirm the diagnosis of cross-reactive NSAID sensitivity. Patients with a history of an immediate reaction to a single NSAID were provoked with the suspected drug to verify the status of single NSAID hypersensitivity after a negative aspirin provocation test. Escalating doses of ibuprofen, diclofenac, and acetaminophen were administered, if applicable, as follows: ibuprofen (50, 100, and 200 mg), diclofenac (6.25, 12.5, and 25 mg), and acetaminophen (125, 250, and 500 mg). Celecoxib was also provoked in 3 doses (50, 100, and 200 mg) in patients with confirmed hypersensitivity to multiple NSAIDs who were willing to identify a safe alternative drug. The provocation test for each drug was performed on separate days at least 7 days apart. Each dose of drug provocation was provided at 90-minute intervals until the final dose was reached.
Classification of NSAID hypersensitivity according to drug provocation test results
Patients with cross-reactive NSAID phenotypes were classified according to the results of the drug provocation test as 1) NECD/NIUA if they developed cutaneous symptoms alone; 2) NERD if they developed respiratory symptoms alone; and 3) NIBR if they developed a combination of symptoms involving more than one organ system (respiratory, cutaneous, and/or gastrointestinal symptoms). Single NSAID hypersensitivity was diagnosed in patients with a positive provocation test to the suspected NSAID, but a negative aspirin provocation test. Patients who had negative provocations to both aspirin and the suspected culprit drug were labeled as NSAID-tolerant subjects. NECD/NIUA were purposely categorized together in our study to compare the differences and similarities between patients diagnosed with NSAID-induced cutaneous reactions and -respiratory reactions. Moreover, NECD and NIUA share similar background characteristics from a clinical point of view and some patients diagnosed with NIUA eventually evolve to NECD over time.32
Skin prick tests with common aeroallergens in Thailand (mixed dust mites, mixed cockroaches, mixed mold, cat dander, dog hair, and southern grass mix; ALK-Abello, Hørsholm, Denmark) were also examined in tested patients to identify atopic status. Wheal size ≥ 3 mm was considered a positive test.
Measurement of FeNO and the FEV1 in patients who underwent drug provocation test
FeNO was measured in all participants at baseline and after drug provocation by using a portable electrochemical analyzer (NObreath®; Bedfont Scientific Ltd, Maidstone, UK) according to the ATS/ERS recommendations.33 Measurements of FEV1 were also performed using a Vitalograph spirometer (Vitalograph®, Buckingham, UK). The best of 3 repeated attempts was recorded.
The uLTE4 measurement
The uLTE4 levels were measured by a leukotriene E4 ELISA kit (Cayman Chemical, Ann Arbor, MI, USA) at baseline and 90 minutes after the final dose of drug provocation, as well as at the follow-up visits after aspirin desensitization and reported after adjustment to urine creatinine levels.
Aspirin desensitization
Outpatient aspirin desensitization was performed in NSAID-sensitive patients who were referred from otolaryngologists to prevent the recurrence of nasal polyposis. The procedure was carried out according to the intranasal ketorolac and modified aspirin challenge 2-day protocol.34 Aspirin desensitization was completed after patients were able to tolerate a 325-mg dose of aspirin by the end of day 2 and experience no symptoms, changes in nasal flow rates, or decrease in FEV1 values. The prescribed maintenance dose of aspirin was 325 mg twice a day.
Statistical analysis
Patient characteristics are reported as means ± standard deviation for quantitative analysis, and median and interquartile range (IQR) are used to describe non-parametric data. The Mann-Whitney U test and Kruskal-Wallis test with Dunn's multiple comparisons were used to analyze the differences between 2 groups and more than 2 groups, respectively. Statistical analyses were performed using GraphPad Prism 8.3 software (GraphPad Software Inc., San Diego, CA, USA). P values < 0.05 were considered statistically significant.
Ethical considerations
Patients enrolled in this study were those who recruited in the study entitled “Characteristics of Patients Diagnosed With NSAID Sensitivity in Thailand” registered at ClinicalTrials.gov (NCT03849625). The study was approved by the Ethics and Research Committee of the Faculty of Medicine, Chulalongkorn University, Approval Number: COA No. 659/2012 and informed consent was obtained from all participants.
RESULTS
A total of 158 adult patients with a suspected history of NSAID hypersensitivity between 2015 and 2018 at King Chulalongkorn Memorial Hospital were initially recruited into this study as shown in Fig. 1. Thirty-five patients with a history compatible with a non-immediate hypersensitivity reaction and 4 subjects with clinical symptoms compatible with NSAID-related side effects were later excluded.
Fig. 1 Schematic diagram of patient selection for this study.
A total of 158 patients with a suspected history of NSAID hypersensitivity were initially recruited into this study. Cross-reactive NSAID hypersensitivity was clinically diagnosed in 67 patients with a well-documented drug allergy history and verified by a positive drug provocation test in 25 patients with a suggestive history of NSAID reactions.
NSAID, non-steroidal anti-inflammatory drug.
Cross-reactive NSAID hypersensitivity was clinically diagnosed in 67 patients with a convincing drug allergy history as defined in the methods section. The remaining 52 patients with a suggestive history of NSAID hypersensitivity underwent an OPT to confirm NSAID cross-reactivity status. Fifteen out of 25 patients with confirmed NSAID cross-reactivity were subsequently provoked with celecoxib to find a safe alternative NSAID. Single NSAID/acetaminophen hypersensitivity was verified in 6 patients who tolerated aspirin provocation but developed an allergic reaction upon re-challenge with acetaminophen or diclofenac.
Demographic data of adult patients with cross-reactive NSAID hypersensitivity
The clinical characteristics of adult patients with cross-reactive NSAID hypersensitivity are shown in Table 1 (n = 92). Most patients were females (77.2%) with an average age of 45.7 ± 13.4 years. The average age of onset was 32.2 ± 13.3 years and about half of them had atopic family history. The majority of them (56.5%) reported only cutaneous symptoms such as facial angioedema and/or acute urticarial rash, after NSAID exposure, while 9.8% of them developed only respiratory symptoms. Interestingly, about 33.7% of the patients experienced a combination of symptoms in multiple organ systems as shown in Fig. 2. The groups of NSAIDs frequently responsible for hypersensitivity reactions were propionic acid derivatives and acetic acid derivatives. Although inflammatory airway diseases (chronic sinusitis, nasal polyposis, and asthma) were significantly more common in patients who experienced only respiratory reactions after exposure to an NSAID compared to the other phenotypes, a significant portion of the patients reporting blended reactions had underlying airway diseases and chronic urticaria as well. Acetaminophen intolerance was also reported in about one-third (35.9%) of NSAID-sensitive subjects.
Table 1 Clinical characteristics among different phenotypes of patients with cross-reactive NSAID hypersensitivity (n = 92)
Phenotypes NECD/NIUA (n = 52) NERD (n = 9) NIBR (n = 31) Total (n = 92)
Gender (female/male) 37/15 6/3 28/3 71/21
Age (yr) 43.6 ± 12.3 47.3 ± 11.9 48.7 ± 15.3 45.7 ± 13.4
Age of onset (yr) 31.3 ± 13.8 34.6 ± 11.0 33.1 ± 13.3 32.2 ± 13.3
Underlying disease (%)
Chronic urticaria 13.5 11.1 29.0 18.5
Chronic sinusitis* 13.5 55.6 32.3 23.9
Nasal polyposis* 7.7 66.7 16.1 16.3
Asthma* 17.3 88.9 35.5 30.4
Atopic family history (%) 42.3 55.6 61.3 50.0
Drug exposure time to symptom onset (min) 58.8 ± 31.9 48.3 ± 34.3 47.6 ± 29.9 54.0 ± 31.6
Presenting symptoms (%)*
Facial/periorbital angioedema 71.2 0.0 74.2 65.2
Acute urticaria 73.1 0.0 61.3 62.0
Naso-ocular reaction 0.0 33.3 61.3 23.9
Acute asthma 0.0 88.9 67.7 31.5
Gastrointestinal symptoms 0.0 0.0 16.1 5.4
Implicated NSAIDs (%)†
Salicylic acids 23.1 55.6 35.5 30.4
Propionic acids 44.2 22.2 54.8 45.7
Acetic acids 23.1 22.2 48.4 31.5
Enolic acids 7.7 0.0 6.5 6.5
Anthranilic/fenamic acids 28.8 11.1 29.0 27.2
Acetaminophen intolerance (%)§ 28.8 22.2 51.6 35.9
Values are presented as number (%) or mean ± standard deviation. Each patient could present with multiple symptoms and from more than one implicated drug.
NSAID, non-steroidal anti-inflammatory drug; NECD, non-steroidal anti-inflammatory drug-exacerbated cutaneous (urticaria/angioedema) disease in patients with underlying chronic urticaria; NIUA, non-steroidal anti-inflammatory drug-induced urticaria/angioedema in patients without underlying chronic urticaria; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
*P < 0.05 among different phenotypes. †Examples of commonly implicated drugs in this study based on NSAID classification: 1) Salicylic acids: acetylsalicylic acid (aspirin), salicylic acid, diflunisal, salsalate; 2) Propionic acids: ibuprofen, naproxen, ketoprofen, fenoprofen, flurbiprofen; 3) Acetic acids: indomethacin, ketorolac, diclofenac, sulindac; 4) Enolic acids: piroxicam, meloxicam, tenoxicam; 5) Anthranilic/fenamic acids: mefenamic acid, flufenamic acid. §Acetaminophen intolerance: cannot tolerate acetaminophen higher than 500 mg.
Fig. 2 Clinical presentations in patients with cross-reactive NSAID hypersensitivity.
A proportional Venn diagram shows that about half of patients with cross-reactive NSAID hypersensitivity in Thailand reported only cutaneous symptoms after NSAID exposure, while one-third of them experienced NSAID-induced blended reactions.
NSAID, non-steroidal anti-inflammatory drug.
Clinical respiratory parameters and uLTE4 levels in different phenotypes of patients with cross-reactive NSAID hypersensitivity confirmed by positive OPT
NSAID hypersensitivity was confirmed in 59.6% (31/52) of the tested patients with a history of NSAID-induced immediate reactions. The majority of patients with cross-reactive NSAID hypersensitivity (17/25) according to OPT results were atopic individuals. The common phenotypes of patients with confirmed cross-reactive NSAID sensitivity were NECD/NIUA, NIBR, and NERD, respectively, as shown in Supplementary Table S1.
The average FeNO, %predicted FEV1, and uLTE4 levels were measured at baseline and after provocation with aspirin/NSAID in 25 NSAID cross-reactive and 21 NSAID-tolerant subjects as shown in Table 2. At baseline, patients with confirmed NSAID cross-reactivity (NSAID-sensitive group) had higher FeNO (P < 0.01) and slightly less %predicted FEV1 compared to the NSAID-tolerant subjects, while basal uLTE4 levels between NSAID-sensitive and NSAID-tolerant groups were comparable. After provocation, %predicted FEV1 was substantially reduced in NSAID-sensitive subjects, whereas uLTE4 levels were significantly elevated compared to the NSAID-tolerant group (P < 0.01). Celecoxib provocation was well tolerated in all NSAID-sensitive subjects. No statistical differences in the average FeNO, %predicted FEV1, or uLTE4 levels in 15 NSAID-sensitive patients (7 NECD/NIUA, 4 NIBR, 4 NERD) after celecoxib provocation were observed compared to those in NSAID-tolerant subjects.
Table 2 Respiratory parameters and uLTE4 levels in NSAID-sensitive subjects upon provocation with aspirin or celecoxib compared to NSAID-tolerant subjects
Characteristics Baseline After aspirin (OPT) P value*
NSAID tolerant (n = 21)
FeNO (ppb) 13.0 (8.5–19.5) 10.2 (7.0–16.8) 0.03
%predicted FEV1 100.8 (82.8–115.9) 99.0 (75.2–118.2) 0.90
uLTE4 (pg/mg creatinine) 116.3 (66.5–305.4) 122.1 (63.5–173.8) 0.17
NSAID sensitive (n = 25)
FeNO (ppb) 27.0 (17.8–40.9)† 18.0 (10.5–31.0) <0.01
%predicted FEV1 86.7 (63.3–104.9) 74.6 (52.4–89.8)† <0.01
uLTE4 (pg/mg creatinine) 118.3 (93.2–407.2) 204.9 (90.6–817.8)† <0.01
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; OPT, oral provocation test; ppb, parts per billion; FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in 1 second.
*P values before vs. after provocation test, Wilcoxon signed-rank test; †P < 0.01 compared to the NSAID-tolerant subjects.
According to the subgroup analysis, 10 NECD/NIUA, 9 NIBR, and 6 NERD were categorized as shown in Fig. 3. At baseline, %predicted FEV1 was not significantly different among different types of cross-reactive NSAID hypersensitivity, although those in patients with confirmed NIBR were lowest (64.9%, IQR 56.9–97.3). The significant differences in basal FeNO levels (P < 0.01) among the 3 different phenotypes were observed. The basal FeNO levels were significantly higher in NIBR (36.9%, IQR 27.0–95.4) than in NSAID-tolerant subjects (P < 0.01). After aspirin OPT, the reduction of %FEV1 was considerably higher in patients with confirmed NERD (22.0%, IQR 16.0-28.8), followed by NIBR (13.3%, IQR 7.6–28.0), compared to those in NSAID-tolerant groups (P < 0.01). Basal uLTE4 levels were not significantly different among the 3 phenotypes. Interestingly, uLTE4 levels after aspirin provocation were significantly higher in NERD and NIBR patients than in the NECD/NIUA and NSAID-tolerant groups (P < 0.05 and < 0.01, respectively).
Fig. 3 Respiratory parameters and uLTE4 levels in different phenotypes of NSAID-sensitive subjects compared to NSAID-tolerant subjects.
Baseline FeNO in NIBR and NERD were higher than those in the NSAID-tolerant group. After aspirin provocation, % predicted FEV1 in NERD and NIBR were significantly reduced from the baseline while uLTE4 levels were much higher than those in NSAID-tolerant subjects.
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; FEV1, forced expiratory volume in 1 second.
*P values < 0.05, †P values < 0.01.
Effects of aspirin desensitization on uLTE4 levels in patients diagnosed with NERD and NIBR
Aspirin desensitization was performed in selected patients (3 NERD and 3 NIBR) who had pre-existing inflammatory airway diseases and a history of recurrent nasal polyposis after surgery as shown in Table 3. The maintenance dose of aspirin was 650 mg/day during the first 6 months and reduced to 325 mg/day afterward. Levels of uLTE4 were measured at baseline after aspirin desensitization and serially followed up for 2–3 years as demonstrated in Fig. 4. Other than respiratory symptoms, acute urticarial rash and gastrointestinal symptoms (abdominal cramp/nausea/diarrhea) were also aggravated in NIBR subjects during aspirin desensitization as shown in Supplementary Fig. S1, but gradually relieved with supportive treatment. No sinus surgery was required for nasal polyp recurrence, and asthma symptoms were under control after aspirin desensitization in all 6 cases. Up to 3 years after aspirin desensitization, however, uLTE4 levels were significantly increased and remained elevated throughout the follow-up period, although urticarial rash and gastrointestinal symptoms were no longer observed while taking aspirin.
Table 3 Details of patients with cross-reactive NSAID hypersensitivity undergoing aspirin desensitization in this study
Patients (sex/year) Underlying diseases History of adverse drug reactions Indication for aspirin desensitization Follow-up duration (months) Asthma control before/after aspirin desensitization Recurrent nasal polyposis after aspirin desensitization Skin symptoms after aspirin desensitization Gastrointestinal symptoms after aspirin desensitization
1. NERD (M/46) Chronic sinusitis, nasal polyposis, asthma Acute asthma 20 min after taking aspirin 2 recurrent nasal polyps 74 Partly controlled with high dose ICS-LABA and add-on LTRA/well controlled with low dose ICS None NA NA
2. NERD (M/54) Chronic rhinitis, nasal polyposis, asthma Acute asthma, blocked nose 1 hr after taking aspirin 3 recurrent nasal polyps 24 Uncontrolled with high dose ICS-LABA and add-on LTRA/well controlled with medium dose ICS-LABA None NA NA
3. NERD (M/56) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked nose 1 hr after taking ibuprofen 6 recurrent nasal polyps 32 Partly controlled asthma with high dose ICS-LABA and add-on LTRA/well controlled with medium dose ICS-LABA None NA NA
4. NIBR (M/48) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked nose, conjunctival injection, urticarial rash 2 hr after taking aspirin 3 recurrent nasal polyps 72 Partly controlled with medium dose ICS-LABA/well controlled with low dose ICS-LABA None No rash after taking aspirin NA
5. NIBR (F/65) Chronic sinusitis, nasal polyposis, chronic urticaria, asthma (history of cardiac arrest from severe asthma) Urticarial rash, periorbital angioedema, blocked nose, conjunctival injection, rhinorrhea, bronchospasm/wheezing, hoarseness of voice 1 hr after taking aspirin, ibuprofen, mefenamic acid, acetaminophen 2 recurrent nasal polyps 48 Uncontrolled with high dose ICS-LABA and add-on LTRA/well controlled with low dose ICS-LABA None No rash after taking aspirin, chronic urticaria resolved NA
6. NIBR (F/38) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked/running nose, stomach cramp, diarrhea, periorbital angioedema, urticaria 30 min after taking ibuprofen, indomethacin, mefenamic acid 2 recurrent nasal polyps 21 Partly controlled with medium dose ICS-LABA/well controlled, with medium dose ICS-LABA None No rash after taking aspirin No gastrointestinal symptoms after taking aspirin
NSAID, non-steroidal anti-inflammatory drug; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; ICS, inhaled corticosteroid; LABA, long-acting beta-agonist; LTRA, leukotriene receptor antagonist; NA, not applicable (no symptoms prior to aspirin desensitization); NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
Fig. 4 uLTE4 levels in NSAID-sensitive subjects after aspirin desensitization.
Our study demonstrated that uLTE4 levels (pg/mg creatinine) in 3 NERD and 3 NIBR patients were increased and remained elevated up to 3 years after aspirin desensitization even though recurrent nasal polyposis was successfully prevented in all cases.
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
DISCUSSION
Most studies on NSAID hypersensitivity have focused on NERD, although worldwide epidemiological data suggest that NECD/NIUA might be more common. Recent data have demonstrated that some patients cannot be categorized into the current classification of NSAID hypersensitivity, for example those with NSAID-induced periorbital angioedema and NIBR.1419 These patients may also have underlying chronic airway diseases; however, the role of aspirin desensitization in the prevention of recurrent nasal polyposis and control of airway inflammation in NSAID-sensitive subjects other than the NERD phenotype has never been reported.
The leading presentations in NSAID-sensitive subjects in this study were periorbital angioedema, acute urticaria, bronchial symptoms, and naso-ocular reactions, respectively. Even those confirmed with NSAID exposure, a significant number of patients in our cohort also showed clinical responses in more than 1 organ system, indicating that the prevalence of NIBR was higher than previously thought. Although patients with IgE-mediated anaphylaxis might also present with multiple organ involvement, the fact that most of the reactions took about 1–2 hours to occur and the ability to react to multiple NSAIDs with dissimilar chemical structures made them more compatible with the non-immunologic effect of the drugs.
Facial angioedema around the periorbital area was the most common presenting symptom in Thai patients. Upon NSAID provocation, however, the predominant periorbital angioedema often accompanied by blocked nose, running nose, and itchy/red eyes. After a thorough examination, small urticarial rash on the trunk and extremities, and expiratory wheezing were occasionally detected, although frequently asymptomatic. It is noteworthy that periorbital angioedema may persist for hours or days while urticarial rash and respiratory symptoms are quickly resolved after treatment. As a result, NIBR could be underdiagnosed if history taking is not thoroughly reviewed, since symptoms with lesser severity in other organ systems may be unnoticed. In addition, the COX-1 inhibitor properties of the exposed NSAIDs could affect the phenotype of NSAID sensitivity reported by patients as some patients experienced both asthmatic attack and periorbital angioedema/generalized urticaria after taking aspirin but reported only periorbital edema after taking acetaminophen.
It is practically difficult to clearly distinguish between NSAID-induced periorbital angioedema and NSAID-induced naso-ocular reactions (upper airway manifestations of NERD), since patients occasionally experienced periorbital swelling, red/swollen eyes with tearing, and nasal congestion at the same time. In our opinion, the majority of NSAID hypersensitivity in the Thai population would be described as “NSAID-induced blended reaction with predominant periorbital angioedema” and probably related to “NSAID-induced isolated periorbital angioedema” phenotype as proposed by the Spanish group. It is interesting to note that the prevalence of atopic disease was high in this patient group. We speculate that the increased leukotriene production after NSAID consumption could lead to the worsening of pre-existing mucosal inflammation around the nose and eyes in patients who already suffered from the late-phase reaction of persistent allergic rhinitis.
Our study did not find any difference in terms of basal uLTE4 levels between NSAID-sensitive and NSAID-tolerant subjects. However, uLTE4 levels were higher in NSAID-sensitive patients, particularly in NERD and NIBR subjects, after the NSAID challenge compared to those in the NSAID-tolerant group. Though basal uLTE4 levels may not be a suitable marker to screen NSAID sensitivity status, elevated uLTE4 levels after aspirin OPT could be the supporting evidence for the diagnosis of cross-reactive NSAID hypersensitivity in cases where the clinical response is equivocal. Our study demonstrated that the degree of defective leukotriene homeostasis after exposure to drugs affecting the cyclo-oxygenase pathway might be related to the severity of respiratory involvement upon NSAID exposure.35 The fact that uLTE4 levels were barely changed after celecoxib provocation in patients with NSAID cross-reactivity confirms that celecoxib is a safe alternative NSAID in these patient groups.
According to our study, the patterns of NSAID hypersensitivity in southeast Asians are similar to those in southern Europeans and Latin Americans, and somewhat different from those reported in patients of northern European descent. Previous data suggested that aspirin nasal provocation could potentially diagnose some NSAID-sensitive patients presenting with predominant cutaneous reactions.3637 Retrospectively, some of these patients might be re-classified as the NIBR phenotype, since a decreased nasal volume was also observed. In other words, patients diagnosed with an NSAID-induced cutaneous reaction who positively reacted to NSAID nasal provocation, especially those with a periorbital reaction, might be NIBR subjects with subclinical airway involvement.
The novelties of this study were the findings that NIBR accounted for about one-third of adult patients with cross-reactive NSAID hypersensitivity and that aspirin desensitization could successfully prevent the recurrence of nasal polyposis and alleviate respiratory symptoms not only in NERD, but also in NIBR, even though urine LTE4 levels remained elevated. However, since the reactions in some NIBR patients could lead to serious adverse events, aspirin desensitization in NIBR subjects should be performed only when it is strongly indicated in selected patients with no previous severe reactions to NSAIDs. In NIBR subjects who experienced previous severe reactions in multiple organ systems, the procedure of aspirin desensitization, if necessary, should be carefully monitored and the administration of biological agents such as dupilumab, if available, should be considered a safer therapeutic option in these cases.
Interestingly, uLTE4 levels were increased after aspirin desensitization and remained elevated throughout the follow-up period. It should be emphasized that urticarial rash and stomach-ache in NIBR patients also disappeared while patients were taking daily aspirin. These data suggest that the pathogenesis of nasal polyposis cannot be explained by cysLT overproduction alone and that aspirin desensitization could be useful to alleviate both respiratory and non-respiratory symptoms in NIBR subjects.
Interestingly, a recent study also found that the clinical benefit of high-dose aspirin desensitization in NERD was independent of a reduction of mast cell activation and cysLT production. They reported paradoxically increased uLTE4 levels 8 weeks after aspirin desensitization compared to the baseline levels and concluded that high-dose aspirin therapy did not restore the impaired eicosanoid pathway.38 According to their study findings and ours, the therapeutic effect of aspirin desensitization was not directly correlated with a change of arachidonic acid metabolism.
There are some limitations to this study. Aspirin desensitization was performed in only 6 patients in our cohort; therefore, the comparative success rates and potential adverse reactions of aspirin desensitization between NERD and NIBR patients could not be analyzed. Further studies with a larger sample size are needed to compare the long-term prognosis between NERD and NIBR, to understand the mechanism of aspirin desensitization for the improvement of respiratory and extra-respiratory symptoms and to evaluate its risk-benefit ratio of aspirin desensitization in NIBR subjects.
In conclusion, NIBR is not uncommon among patients diagnosed with NSAID hypersensitivity in Thailand. Increased uLTE4 levels upon aspirin provocation suggested a diagnosis of NSAID cross-reactivity, while baseline uLTE4 levels were not distinguishable between NSAID-tolerant and NSAID-sensitive subjects. Our study indicates that aspirin desensitization is effective not only in NERD but also in NIBR. The persistently high levels of uLTE4 in spite of clinical improvement in NSAID-sensitive patients after successful aspirin desensitization suggest that elevated leukotrienes alone cannot explain the pathogenesis of NSAID hypersensitivity reactions.
ACKNOWLEDGMENTS
This study was supported by the Ratchadaphiseksomphot fund, Faculty of Medicine, Chulalongkorn University, grant No. RA55/19 and the Skin and Allergy Research Unit, Chulalongkorn University, Bangkok, Thailand. Study data were collected and managed using Research Electronic Data Capture (REDCap) hosted at HIV Netherlands Australia Thailand Research Collaboration. The authors thank Thitima Kantachatvanich, MD for providing patient information.
Disclosure: There are no financial or other issues that might lead to conflict of interest.
SUPPLEMENTARY MATERIALS
Supplementary Table S1
Clinical characteristics of patients with confirmed NSAID-induced immediate reactions
Supplementary Fig. S1
Representative photos of skin rash demonstrated during aspirin desensitization in NIBR patients. | UNKNOWN | DrugDosageText | CC BY-NC | 33474858 | 19,056,205 | 2021-03 |
What was the dosage of drug 'ASPIRIN'? | Clinical Characteristics, Urinary Leukotriene E4 Levels, and Aspirin Desensitization Results in Patients With NSAID-Induced Blended Reactions.
OBJECTIVE
Data on non-steroidal anti-inflammatory drug (NSAID) hypersensitivity in Southeast Asia are scarce. Increased urinary leukotriene E4 (uLTE4) levels have been suggested as a biomarker of NSAID-exacerbated respiratory disease (NERD). This study investigated clinical patterns of NSAID sensitivity in Thailand and the diagnostic roles of uLTE4 measurement in various phenotypes.
METHODS
The clinical phenotypes in 92 Thai adults with cross-reactive NSAID hypersensitivity were characterized based on the clinical history and drug provocation. The uLTE4 levels were measured at baseline, after aspirin provocation and after desensitization.
RESULTS
More than half of the patients (56.5%) presented with cutaneous symptoms (NSAID-exacerbated cutaneous disease), while one-third (33.7%) developed symptoms in at least 2 systems (NSAID-induced blended reactions; NIBR). Fifty-two patients underwent drug provocation and 59.6% of them yielded positive results. After drug provocation, a significant number of patients with confirmed NSAID cross-reactivity experienced clinical symptoms in more than one organ system. The uLTE4 levels at baseline were comparable between the NSAID-tolerant and NSAID-sensitive groups, but were substantially increased after aspirin provocation predominantly in NERD (983.4 pg/mg creatinine) and NIBR (501.0 pg/mg creatinine) compared to NSAID-tolerant subjects (122.1 pg/mg creatinine, P < 0.01 and 0.05, respectively). The uLTE4 levels were elevated after aspirin desensitization, although nasal polyposis and asthma were under control in 3 NERD and 3 NIBR subjects.
CONCLUSIONS
NIBR is not uncommon among NSAID-sensitive patients in Thailand. The diagnostic value of basal uLTE4 levels was limited, but increased uLTE4 levels upon aspirin provocation suggest NSAID cross-reactivity with respiratory components. This study indicates that aspirin desensitization, if necessary, might be effective in both NERD and NIBR.
BACKGROUND
ClinicalTrials.gov Identifier: NCT03849625.
INTRODUCTION
Hypersensitivity reactions to aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most common drug allergic reactions in clinical practice. They are generally categorized into 5 major phenotypes: NSAID-exacerbated respiratory disease (NERD), NSAID-exacerbated cutaneous (urticaria/angioedema) disease (NECD) in patients with underlying chronic urticaria, NSAID-induced urticaria/angioedema (NIUA) in patients without underlying chronic urticaria, single NSAID-induced urticaria/angioedema or anaphylaxis, and single NSAID-induced delayed hypersensitivity reactions.1 The first 3 phenotypes are non-immunologically mediated, and patients can develop cross-reactive hypersensitivity to chemically unrelated NSAIDs, while the latter 2 are selective NSAID sensitivities associated with drug-specific immunoglobulin E (IgE) and T-cell response, respectively.
Genetic and epigenetic variations play significant roles in the development of NERD.2 The proposed underlying mechanism is that the disturbance in arachidonic acid synthesis pathways leads to overproduction of cysteinyl leukotrienes (cysLT) and persistent airway inflammation.3 Mast cells are believed to be the major source of cysLT, but platelet-adherent leukocytes may be responsible for cysLT overproduction in NERD as well.4 The consumption of drugs inhibiting the cyclooxygenase-1 (COX-1) enzyme, such as aspirin and conventional NSAIDs, aggravates respiratory symptoms by enhancing cysLT production in NSAID-sensitive subjects, while the administration of specific COX-2 inhibitors, such as celecoxib, is generally safe.56 Besides aspirin/NSAID avoidance, aspirin desensitization has also been proven to be helpful for long term management in NERD subjects. Beneficial effects of aspirin desensitization in preventing nasal polyp recurrence and control symptoms of chronic rhinosinusitis and asthma have been well documented.7 Rapid aspirin desensitization has shown to be effective for the treatment of coronary artery disease in patients with a history of aspirin/NSAID-induced urticaria/angioedema, but it is not indicated for the treatment of chronic urticaria.8
Worldwide epidemiological data on clinical characteristics of NSAID hypersensitivity are limited. Most studies on NERD were performed in the United States and northern European countries.9101112 However, the predominant manifestation in Latin Americans and southern Europeans is the cutaneous phenotype (NIUA, NECD, and NSAID-induced isolated periorbital angioedema).1314 Studies in Asian populations have suggested that the prevalence of the NERD phenotype is not common in this region of the world. A study performed in China indicated that the prevalence of NSAID hypersensitivity in Chinese patients with chronic rhinosinusitis is very low (0.57%) compared to their European counterparts.15 It was also noted that NSAID-induced blended reactions (NIBR) are common in young Asian, atopic children in Singapore.16 Reports from Singapore and Thailand indicated that aspirin/NSAID-induced angioedema/urticaria is probably the prominent phenotype in Southeast Asia, with acetaminophen hypersensitivity being frequent.1718
In clinical practice, the current classification of cross-reactive NSAID hypersensitivity into 3 distinct phenotypes has some limitations. Clinical characteristics in NSAID-sensitive patients may not be well defined, and a combination of respiratory and cutaneous or other symptoms, such as gastrointestinal symptoms (mixed or blended reactions), is frequently observed.19 A previous report stated that aspirin nasal provocation is potentially useful for diagnosing patients with the blended reaction as well.20 However, the role of aspirin desensitization in other phenotypes of NSAID hypersensitivity, besides NERD, for long-term management of inflammatory airway diseases has not yet been established. Whether aspirin desensitization would be effective in controlling asthma and the recurrence of nasal polyposis after sinus surgery in NIBR is currently unknown.
At present, cross-reactive types of NSAID hypersensitivity can only be diagnosed by careful history taking and controlled-provocation testing, since there is no reliable in vitro method to confirm the diagnosis.21 There is evidence that basal urinary levels of leukotriene E4 (uLTE4), a stable product of the cysLT synthesis pathway, are elevated in NERD patients and could be a potential biomarker for differentiating between NSAID-sensitive and NSAID-tolerant asthmatics. However, these data are still controversial.222324 There have also been preliminary studies showing that uLTE4 levels might be increased in NECD.2526 Whether the measurement of basal uLTE4 levels could be a diagnostic marker for any phenotype of NSAID hypersensitivity is yet to be explored.
The purpose of this study was to analyze the clinical characteristics of patients diagnosed with NSAID-induced immediate reactions in Thailand and to explore whether the measurement of uLTE4 levels would be helpful in identifying NSAID-sensitive subjects or in differentiating among different phenotypes of cross-reactive NSAID hypersensitivities.
MATERIALS AND METHODS
Patient recruitment
Adult patients (18 years of age and older) with a suggestive history of NSAID-induced hypersensitivity reaction visiting the allergy clinic at King Chulalongkorn University Hospital between June 2014 and July 2018 were recruited into this study. Those with a history compatible with drug-induced non-immediate reactions (maculopapular rash, fixed drug eruption, acute generalized exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms, Stevens-Johnson syndrome/toxic epidermal necrolysis) or NSAID-related side effects were excluded. The status of NSAID-induced immediate hypersensitivity was diagnosed in patients with a well-documented drug allergy history or in patients with a suggestive history of NSAID sensitivity who yielded a positive drug provocation test as follows.
Clinical diagnosis of NSAID hypersensitivity
The diagnosis of cross-reactive NSAID hypersensitivity was clinically made in patients with a well-documented history of multiple episodes of respiratory, cutaneous, and/or gastrointestinal reactions within 2 hours after exposure to at least 2 different NSAID classes.1212728 Patient demographic data were collected, including the underlying diseases, atopic family history, and details on drug allergy history as well as the presenting symptoms and types of the culprit NSAIDs.
Aspirin provocation test
Oral aspirin provocation was performed in patients with a suggestive medical history or in those who had a history of an immediate reaction to a single NSAID to confirm the diagnosis of cross-reactive NSAID hypersensitivity according to the EAACI/GA2LEN guidelines, with some modifications.293031 Four increasing doses of aspirin (40.5, 81, 150, and 300 mg) were administered at 90-minute intervals until a positive reaction occurred. Clinical symptoms, fractional exhaled nitric oxide (FeNO), and the forced expiratory volume in 1 second (FEV1) were monitored to evaluate the reaction. A positive provocation test was defined if any of the following reactions developed: lower respiratory/bronchial reaction (a 15% decrease in FEV1 plus naso-ocular reaction or a 20% decrease in FEV1 alone), upper respiratory/naso-ocular reaction (nasal congestion and rhinorrhea; conjunctival injection), cutaneous reactions (urticaria/angioedema, periorbital edema), and/or other reactions (gastrointestinal symptoms such as nausea/vomiting, stomach cramps, and diarrhea). The test was considered negative if a patient tolerated the final dose (300 mg of aspirin) without any significant symptoms mentioned above.
Oral provocation test (OPT) with other NSAIDs, acetaminophen, or celecoxib
Patients with a history of an immediate reaction to only aspirin were challenged with escalating doses of ibuprofen to confirm the diagnosis of cross-reactive NSAID sensitivity. Patients with a history of an immediate reaction to a single NSAID were provoked with the suspected drug to verify the status of single NSAID hypersensitivity after a negative aspirin provocation test. Escalating doses of ibuprofen, diclofenac, and acetaminophen were administered, if applicable, as follows: ibuprofen (50, 100, and 200 mg), diclofenac (6.25, 12.5, and 25 mg), and acetaminophen (125, 250, and 500 mg). Celecoxib was also provoked in 3 doses (50, 100, and 200 mg) in patients with confirmed hypersensitivity to multiple NSAIDs who were willing to identify a safe alternative drug. The provocation test for each drug was performed on separate days at least 7 days apart. Each dose of drug provocation was provided at 90-minute intervals until the final dose was reached.
Classification of NSAID hypersensitivity according to drug provocation test results
Patients with cross-reactive NSAID phenotypes were classified according to the results of the drug provocation test as 1) NECD/NIUA if they developed cutaneous symptoms alone; 2) NERD if they developed respiratory symptoms alone; and 3) NIBR if they developed a combination of symptoms involving more than one organ system (respiratory, cutaneous, and/or gastrointestinal symptoms). Single NSAID hypersensitivity was diagnosed in patients with a positive provocation test to the suspected NSAID, but a negative aspirin provocation test. Patients who had negative provocations to both aspirin and the suspected culprit drug were labeled as NSAID-tolerant subjects. NECD/NIUA were purposely categorized together in our study to compare the differences and similarities between patients diagnosed with NSAID-induced cutaneous reactions and -respiratory reactions. Moreover, NECD and NIUA share similar background characteristics from a clinical point of view and some patients diagnosed with NIUA eventually evolve to NECD over time.32
Skin prick tests with common aeroallergens in Thailand (mixed dust mites, mixed cockroaches, mixed mold, cat dander, dog hair, and southern grass mix; ALK-Abello, Hørsholm, Denmark) were also examined in tested patients to identify atopic status. Wheal size ≥ 3 mm was considered a positive test.
Measurement of FeNO and the FEV1 in patients who underwent drug provocation test
FeNO was measured in all participants at baseline and after drug provocation by using a portable electrochemical analyzer (NObreath®; Bedfont Scientific Ltd, Maidstone, UK) according to the ATS/ERS recommendations.33 Measurements of FEV1 were also performed using a Vitalograph spirometer (Vitalograph®, Buckingham, UK). The best of 3 repeated attempts was recorded.
The uLTE4 measurement
The uLTE4 levels were measured by a leukotriene E4 ELISA kit (Cayman Chemical, Ann Arbor, MI, USA) at baseline and 90 minutes after the final dose of drug provocation, as well as at the follow-up visits after aspirin desensitization and reported after adjustment to urine creatinine levels.
Aspirin desensitization
Outpatient aspirin desensitization was performed in NSAID-sensitive patients who were referred from otolaryngologists to prevent the recurrence of nasal polyposis. The procedure was carried out according to the intranasal ketorolac and modified aspirin challenge 2-day protocol.34 Aspirin desensitization was completed after patients were able to tolerate a 325-mg dose of aspirin by the end of day 2 and experience no symptoms, changes in nasal flow rates, or decrease in FEV1 values. The prescribed maintenance dose of aspirin was 325 mg twice a day.
Statistical analysis
Patient characteristics are reported as means ± standard deviation for quantitative analysis, and median and interquartile range (IQR) are used to describe non-parametric data. The Mann-Whitney U test and Kruskal-Wallis test with Dunn's multiple comparisons were used to analyze the differences between 2 groups and more than 2 groups, respectively. Statistical analyses were performed using GraphPad Prism 8.3 software (GraphPad Software Inc., San Diego, CA, USA). P values < 0.05 were considered statistically significant.
Ethical considerations
Patients enrolled in this study were those who recruited in the study entitled “Characteristics of Patients Diagnosed With NSAID Sensitivity in Thailand” registered at ClinicalTrials.gov (NCT03849625). The study was approved by the Ethics and Research Committee of the Faculty of Medicine, Chulalongkorn University, Approval Number: COA No. 659/2012 and informed consent was obtained from all participants.
RESULTS
A total of 158 adult patients with a suspected history of NSAID hypersensitivity between 2015 and 2018 at King Chulalongkorn Memorial Hospital were initially recruited into this study as shown in Fig. 1. Thirty-five patients with a history compatible with a non-immediate hypersensitivity reaction and 4 subjects with clinical symptoms compatible with NSAID-related side effects were later excluded.
Fig. 1 Schematic diagram of patient selection for this study.
A total of 158 patients with a suspected history of NSAID hypersensitivity were initially recruited into this study. Cross-reactive NSAID hypersensitivity was clinically diagnosed in 67 patients with a well-documented drug allergy history and verified by a positive drug provocation test in 25 patients with a suggestive history of NSAID reactions.
NSAID, non-steroidal anti-inflammatory drug.
Cross-reactive NSAID hypersensitivity was clinically diagnosed in 67 patients with a convincing drug allergy history as defined in the methods section. The remaining 52 patients with a suggestive history of NSAID hypersensitivity underwent an OPT to confirm NSAID cross-reactivity status. Fifteen out of 25 patients with confirmed NSAID cross-reactivity were subsequently provoked with celecoxib to find a safe alternative NSAID. Single NSAID/acetaminophen hypersensitivity was verified in 6 patients who tolerated aspirin provocation but developed an allergic reaction upon re-challenge with acetaminophen or diclofenac.
Demographic data of adult patients with cross-reactive NSAID hypersensitivity
The clinical characteristics of adult patients with cross-reactive NSAID hypersensitivity are shown in Table 1 (n = 92). Most patients were females (77.2%) with an average age of 45.7 ± 13.4 years. The average age of onset was 32.2 ± 13.3 years and about half of them had atopic family history. The majority of them (56.5%) reported only cutaneous symptoms such as facial angioedema and/or acute urticarial rash, after NSAID exposure, while 9.8% of them developed only respiratory symptoms. Interestingly, about 33.7% of the patients experienced a combination of symptoms in multiple organ systems as shown in Fig. 2. The groups of NSAIDs frequently responsible for hypersensitivity reactions were propionic acid derivatives and acetic acid derivatives. Although inflammatory airway diseases (chronic sinusitis, nasal polyposis, and asthma) were significantly more common in patients who experienced only respiratory reactions after exposure to an NSAID compared to the other phenotypes, a significant portion of the patients reporting blended reactions had underlying airway diseases and chronic urticaria as well. Acetaminophen intolerance was also reported in about one-third (35.9%) of NSAID-sensitive subjects.
Table 1 Clinical characteristics among different phenotypes of patients with cross-reactive NSAID hypersensitivity (n = 92)
Phenotypes NECD/NIUA (n = 52) NERD (n = 9) NIBR (n = 31) Total (n = 92)
Gender (female/male) 37/15 6/3 28/3 71/21
Age (yr) 43.6 ± 12.3 47.3 ± 11.9 48.7 ± 15.3 45.7 ± 13.4
Age of onset (yr) 31.3 ± 13.8 34.6 ± 11.0 33.1 ± 13.3 32.2 ± 13.3
Underlying disease (%)
Chronic urticaria 13.5 11.1 29.0 18.5
Chronic sinusitis* 13.5 55.6 32.3 23.9
Nasal polyposis* 7.7 66.7 16.1 16.3
Asthma* 17.3 88.9 35.5 30.4
Atopic family history (%) 42.3 55.6 61.3 50.0
Drug exposure time to symptom onset (min) 58.8 ± 31.9 48.3 ± 34.3 47.6 ± 29.9 54.0 ± 31.6
Presenting symptoms (%)*
Facial/periorbital angioedema 71.2 0.0 74.2 65.2
Acute urticaria 73.1 0.0 61.3 62.0
Naso-ocular reaction 0.0 33.3 61.3 23.9
Acute asthma 0.0 88.9 67.7 31.5
Gastrointestinal symptoms 0.0 0.0 16.1 5.4
Implicated NSAIDs (%)†
Salicylic acids 23.1 55.6 35.5 30.4
Propionic acids 44.2 22.2 54.8 45.7
Acetic acids 23.1 22.2 48.4 31.5
Enolic acids 7.7 0.0 6.5 6.5
Anthranilic/fenamic acids 28.8 11.1 29.0 27.2
Acetaminophen intolerance (%)§ 28.8 22.2 51.6 35.9
Values are presented as number (%) or mean ± standard deviation. Each patient could present with multiple symptoms and from more than one implicated drug.
NSAID, non-steroidal anti-inflammatory drug; NECD, non-steroidal anti-inflammatory drug-exacerbated cutaneous (urticaria/angioedema) disease in patients with underlying chronic urticaria; NIUA, non-steroidal anti-inflammatory drug-induced urticaria/angioedema in patients without underlying chronic urticaria; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
*P < 0.05 among different phenotypes. †Examples of commonly implicated drugs in this study based on NSAID classification: 1) Salicylic acids: acetylsalicylic acid (aspirin), salicylic acid, diflunisal, salsalate; 2) Propionic acids: ibuprofen, naproxen, ketoprofen, fenoprofen, flurbiprofen; 3) Acetic acids: indomethacin, ketorolac, diclofenac, sulindac; 4) Enolic acids: piroxicam, meloxicam, tenoxicam; 5) Anthranilic/fenamic acids: mefenamic acid, flufenamic acid. §Acetaminophen intolerance: cannot tolerate acetaminophen higher than 500 mg.
Fig. 2 Clinical presentations in patients with cross-reactive NSAID hypersensitivity.
A proportional Venn diagram shows that about half of patients with cross-reactive NSAID hypersensitivity in Thailand reported only cutaneous symptoms after NSAID exposure, while one-third of them experienced NSAID-induced blended reactions.
NSAID, non-steroidal anti-inflammatory drug.
Clinical respiratory parameters and uLTE4 levels in different phenotypes of patients with cross-reactive NSAID hypersensitivity confirmed by positive OPT
NSAID hypersensitivity was confirmed in 59.6% (31/52) of the tested patients with a history of NSAID-induced immediate reactions. The majority of patients with cross-reactive NSAID hypersensitivity (17/25) according to OPT results were atopic individuals. The common phenotypes of patients with confirmed cross-reactive NSAID sensitivity were NECD/NIUA, NIBR, and NERD, respectively, as shown in Supplementary Table S1.
The average FeNO, %predicted FEV1, and uLTE4 levels were measured at baseline and after provocation with aspirin/NSAID in 25 NSAID cross-reactive and 21 NSAID-tolerant subjects as shown in Table 2. At baseline, patients with confirmed NSAID cross-reactivity (NSAID-sensitive group) had higher FeNO (P < 0.01) and slightly less %predicted FEV1 compared to the NSAID-tolerant subjects, while basal uLTE4 levels between NSAID-sensitive and NSAID-tolerant groups were comparable. After provocation, %predicted FEV1 was substantially reduced in NSAID-sensitive subjects, whereas uLTE4 levels were significantly elevated compared to the NSAID-tolerant group (P < 0.01). Celecoxib provocation was well tolerated in all NSAID-sensitive subjects. No statistical differences in the average FeNO, %predicted FEV1, or uLTE4 levels in 15 NSAID-sensitive patients (7 NECD/NIUA, 4 NIBR, 4 NERD) after celecoxib provocation were observed compared to those in NSAID-tolerant subjects.
Table 2 Respiratory parameters and uLTE4 levels in NSAID-sensitive subjects upon provocation with aspirin or celecoxib compared to NSAID-tolerant subjects
Characteristics Baseline After aspirin (OPT) P value*
NSAID tolerant (n = 21)
FeNO (ppb) 13.0 (8.5–19.5) 10.2 (7.0–16.8) 0.03
%predicted FEV1 100.8 (82.8–115.9) 99.0 (75.2–118.2) 0.90
uLTE4 (pg/mg creatinine) 116.3 (66.5–305.4) 122.1 (63.5–173.8) 0.17
NSAID sensitive (n = 25)
FeNO (ppb) 27.0 (17.8–40.9)† 18.0 (10.5–31.0) <0.01
%predicted FEV1 86.7 (63.3–104.9) 74.6 (52.4–89.8)† <0.01
uLTE4 (pg/mg creatinine) 118.3 (93.2–407.2) 204.9 (90.6–817.8)† <0.01
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; OPT, oral provocation test; ppb, parts per billion; FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in 1 second.
*P values before vs. after provocation test, Wilcoxon signed-rank test; †P < 0.01 compared to the NSAID-tolerant subjects.
According to the subgroup analysis, 10 NECD/NIUA, 9 NIBR, and 6 NERD were categorized as shown in Fig. 3. At baseline, %predicted FEV1 was not significantly different among different types of cross-reactive NSAID hypersensitivity, although those in patients with confirmed NIBR were lowest (64.9%, IQR 56.9–97.3). The significant differences in basal FeNO levels (P < 0.01) among the 3 different phenotypes were observed. The basal FeNO levels were significantly higher in NIBR (36.9%, IQR 27.0–95.4) than in NSAID-tolerant subjects (P < 0.01). After aspirin OPT, the reduction of %FEV1 was considerably higher in patients with confirmed NERD (22.0%, IQR 16.0-28.8), followed by NIBR (13.3%, IQR 7.6–28.0), compared to those in NSAID-tolerant groups (P < 0.01). Basal uLTE4 levels were not significantly different among the 3 phenotypes. Interestingly, uLTE4 levels after aspirin provocation were significantly higher in NERD and NIBR patients than in the NECD/NIUA and NSAID-tolerant groups (P < 0.05 and < 0.01, respectively).
Fig. 3 Respiratory parameters and uLTE4 levels in different phenotypes of NSAID-sensitive subjects compared to NSAID-tolerant subjects.
Baseline FeNO in NIBR and NERD were higher than those in the NSAID-tolerant group. After aspirin provocation, % predicted FEV1 in NERD and NIBR were significantly reduced from the baseline while uLTE4 levels were much higher than those in NSAID-tolerant subjects.
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; FEV1, forced expiratory volume in 1 second.
*P values < 0.05, †P values < 0.01.
Effects of aspirin desensitization on uLTE4 levels in patients diagnosed with NERD and NIBR
Aspirin desensitization was performed in selected patients (3 NERD and 3 NIBR) who had pre-existing inflammatory airway diseases and a history of recurrent nasal polyposis after surgery as shown in Table 3. The maintenance dose of aspirin was 650 mg/day during the first 6 months and reduced to 325 mg/day afterward. Levels of uLTE4 were measured at baseline after aspirin desensitization and serially followed up for 2–3 years as demonstrated in Fig. 4. Other than respiratory symptoms, acute urticarial rash and gastrointestinal symptoms (abdominal cramp/nausea/diarrhea) were also aggravated in NIBR subjects during aspirin desensitization as shown in Supplementary Fig. S1, but gradually relieved with supportive treatment. No sinus surgery was required for nasal polyp recurrence, and asthma symptoms were under control after aspirin desensitization in all 6 cases. Up to 3 years after aspirin desensitization, however, uLTE4 levels were significantly increased and remained elevated throughout the follow-up period, although urticarial rash and gastrointestinal symptoms were no longer observed while taking aspirin.
Table 3 Details of patients with cross-reactive NSAID hypersensitivity undergoing aspirin desensitization in this study
Patients (sex/year) Underlying diseases History of adverse drug reactions Indication for aspirin desensitization Follow-up duration (months) Asthma control before/after aspirin desensitization Recurrent nasal polyposis after aspirin desensitization Skin symptoms after aspirin desensitization Gastrointestinal symptoms after aspirin desensitization
1. NERD (M/46) Chronic sinusitis, nasal polyposis, asthma Acute asthma 20 min after taking aspirin 2 recurrent nasal polyps 74 Partly controlled with high dose ICS-LABA and add-on LTRA/well controlled with low dose ICS None NA NA
2. NERD (M/54) Chronic rhinitis, nasal polyposis, asthma Acute asthma, blocked nose 1 hr after taking aspirin 3 recurrent nasal polyps 24 Uncontrolled with high dose ICS-LABA and add-on LTRA/well controlled with medium dose ICS-LABA None NA NA
3. NERD (M/56) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked nose 1 hr after taking ibuprofen 6 recurrent nasal polyps 32 Partly controlled asthma with high dose ICS-LABA and add-on LTRA/well controlled with medium dose ICS-LABA None NA NA
4. NIBR (M/48) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked nose, conjunctival injection, urticarial rash 2 hr after taking aspirin 3 recurrent nasal polyps 72 Partly controlled with medium dose ICS-LABA/well controlled with low dose ICS-LABA None No rash after taking aspirin NA
5. NIBR (F/65) Chronic sinusitis, nasal polyposis, chronic urticaria, asthma (history of cardiac arrest from severe asthma) Urticarial rash, periorbital angioedema, blocked nose, conjunctival injection, rhinorrhea, bronchospasm/wheezing, hoarseness of voice 1 hr after taking aspirin, ibuprofen, mefenamic acid, acetaminophen 2 recurrent nasal polyps 48 Uncontrolled with high dose ICS-LABA and add-on LTRA/well controlled with low dose ICS-LABA None No rash after taking aspirin, chronic urticaria resolved NA
6. NIBR (F/38) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked/running nose, stomach cramp, diarrhea, periorbital angioedema, urticaria 30 min after taking ibuprofen, indomethacin, mefenamic acid 2 recurrent nasal polyps 21 Partly controlled with medium dose ICS-LABA/well controlled, with medium dose ICS-LABA None No rash after taking aspirin No gastrointestinal symptoms after taking aspirin
NSAID, non-steroidal anti-inflammatory drug; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; ICS, inhaled corticosteroid; LABA, long-acting beta-agonist; LTRA, leukotriene receptor antagonist; NA, not applicable (no symptoms prior to aspirin desensitization); NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
Fig. 4 uLTE4 levels in NSAID-sensitive subjects after aspirin desensitization.
Our study demonstrated that uLTE4 levels (pg/mg creatinine) in 3 NERD and 3 NIBR patients were increased and remained elevated up to 3 years after aspirin desensitization even though recurrent nasal polyposis was successfully prevented in all cases.
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
DISCUSSION
Most studies on NSAID hypersensitivity have focused on NERD, although worldwide epidemiological data suggest that NECD/NIUA might be more common. Recent data have demonstrated that some patients cannot be categorized into the current classification of NSAID hypersensitivity, for example those with NSAID-induced periorbital angioedema and NIBR.1419 These patients may also have underlying chronic airway diseases; however, the role of aspirin desensitization in the prevention of recurrent nasal polyposis and control of airway inflammation in NSAID-sensitive subjects other than the NERD phenotype has never been reported.
The leading presentations in NSAID-sensitive subjects in this study were periorbital angioedema, acute urticaria, bronchial symptoms, and naso-ocular reactions, respectively. Even those confirmed with NSAID exposure, a significant number of patients in our cohort also showed clinical responses in more than 1 organ system, indicating that the prevalence of NIBR was higher than previously thought. Although patients with IgE-mediated anaphylaxis might also present with multiple organ involvement, the fact that most of the reactions took about 1–2 hours to occur and the ability to react to multiple NSAIDs with dissimilar chemical structures made them more compatible with the non-immunologic effect of the drugs.
Facial angioedema around the periorbital area was the most common presenting symptom in Thai patients. Upon NSAID provocation, however, the predominant periorbital angioedema often accompanied by blocked nose, running nose, and itchy/red eyes. After a thorough examination, small urticarial rash on the trunk and extremities, and expiratory wheezing were occasionally detected, although frequently asymptomatic. It is noteworthy that periorbital angioedema may persist for hours or days while urticarial rash and respiratory symptoms are quickly resolved after treatment. As a result, NIBR could be underdiagnosed if history taking is not thoroughly reviewed, since symptoms with lesser severity in other organ systems may be unnoticed. In addition, the COX-1 inhibitor properties of the exposed NSAIDs could affect the phenotype of NSAID sensitivity reported by patients as some patients experienced both asthmatic attack and periorbital angioedema/generalized urticaria after taking aspirin but reported only periorbital edema after taking acetaminophen.
It is practically difficult to clearly distinguish between NSAID-induced periorbital angioedema and NSAID-induced naso-ocular reactions (upper airway manifestations of NERD), since patients occasionally experienced periorbital swelling, red/swollen eyes with tearing, and nasal congestion at the same time. In our opinion, the majority of NSAID hypersensitivity in the Thai population would be described as “NSAID-induced blended reaction with predominant periorbital angioedema” and probably related to “NSAID-induced isolated periorbital angioedema” phenotype as proposed by the Spanish group. It is interesting to note that the prevalence of atopic disease was high in this patient group. We speculate that the increased leukotriene production after NSAID consumption could lead to the worsening of pre-existing mucosal inflammation around the nose and eyes in patients who already suffered from the late-phase reaction of persistent allergic rhinitis.
Our study did not find any difference in terms of basal uLTE4 levels between NSAID-sensitive and NSAID-tolerant subjects. However, uLTE4 levels were higher in NSAID-sensitive patients, particularly in NERD and NIBR subjects, after the NSAID challenge compared to those in the NSAID-tolerant group. Though basal uLTE4 levels may not be a suitable marker to screen NSAID sensitivity status, elevated uLTE4 levels after aspirin OPT could be the supporting evidence for the diagnosis of cross-reactive NSAID hypersensitivity in cases where the clinical response is equivocal. Our study demonstrated that the degree of defective leukotriene homeostasis after exposure to drugs affecting the cyclo-oxygenase pathway might be related to the severity of respiratory involvement upon NSAID exposure.35 The fact that uLTE4 levels were barely changed after celecoxib provocation in patients with NSAID cross-reactivity confirms that celecoxib is a safe alternative NSAID in these patient groups.
According to our study, the patterns of NSAID hypersensitivity in southeast Asians are similar to those in southern Europeans and Latin Americans, and somewhat different from those reported in patients of northern European descent. Previous data suggested that aspirin nasal provocation could potentially diagnose some NSAID-sensitive patients presenting with predominant cutaneous reactions.3637 Retrospectively, some of these patients might be re-classified as the NIBR phenotype, since a decreased nasal volume was also observed. In other words, patients diagnosed with an NSAID-induced cutaneous reaction who positively reacted to NSAID nasal provocation, especially those with a periorbital reaction, might be NIBR subjects with subclinical airway involvement.
The novelties of this study were the findings that NIBR accounted for about one-third of adult patients with cross-reactive NSAID hypersensitivity and that aspirin desensitization could successfully prevent the recurrence of nasal polyposis and alleviate respiratory symptoms not only in NERD, but also in NIBR, even though urine LTE4 levels remained elevated. However, since the reactions in some NIBR patients could lead to serious adverse events, aspirin desensitization in NIBR subjects should be performed only when it is strongly indicated in selected patients with no previous severe reactions to NSAIDs. In NIBR subjects who experienced previous severe reactions in multiple organ systems, the procedure of aspirin desensitization, if necessary, should be carefully monitored and the administration of biological agents such as dupilumab, if available, should be considered a safer therapeutic option in these cases.
Interestingly, uLTE4 levels were increased after aspirin desensitization and remained elevated throughout the follow-up period. It should be emphasized that urticarial rash and stomach-ache in NIBR patients also disappeared while patients were taking daily aspirin. These data suggest that the pathogenesis of nasal polyposis cannot be explained by cysLT overproduction alone and that aspirin desensitization could be useful to alleviate both respiratory and non-respiratory symptoms in NIBR subjects.
Interestingly, a recent study also found that the clinical benefit of high-dose aspirin desensitization in NERD was independent of a reduction of mast cell activation and cysLT production. They reported paradoxically increased uLTE4 levels 8 weeks after aspirin desensitization compared to the baseline levels and concluded that high-dose aspirin therapy did not restore the impaired eicosanoid pathway.38 According to their study findings and ours, the therapeutic effect of aspirin desensitization was not directly correlated with a change of arachidonic acid metabolism.
There are some limitations to this study. Aspirin desensitization was performed in only 6 patients in our cohort; therefore, the comparative success rates and potential adverse reactions of aspirin desensitization between NERD and NIBR patients could not be analyzed. Further studies with a larger sample size are needed to compare the long-term prognosis between NERD and NIBR, to understand the mechanism of aspirin desensitization for the improvement of respiratory and extra-respiratory symptoms and to evaluate its risk-benefit ratio of aspirin desensitization in NIBR subjects.
In conclusion, NIBR is not uncommon among patients diagnosed with NSAID hypersensitivity in Thailand. Increased uLTE4 levels upon aspirin provocation suggested a diagnosis of NSAID cross-reactivity, while baseline uLTE4 levels were not distinguishable between NSAID-tolerant and NSAID-sensitive subjects. Our study indicates that aspirin desensitization is effective not only in NERD but also in NIBR. The persistently high levels of uLTE4 in spite of clinical improvement in NSAID-sensitive patients after successful aspirin desensitization suggest that elevated leukotrienes alone cannot explain the pathogenesis of NSAID hypersensitivity reactions.
ACKNOWLEDGMENTS
This study was supported by the Ratchadaphiseksomphot fund, Faculty of Medicine, Chulalongkorn University, grant No. RA55/19 and the Skin and Allergy Research Unit, Chulalongkorn University, Bangkok, Thailand. Study data were collected and managed using Research Electronic Data Capture (REDCap) hosted at HIV Netherlands Australia Thailand Research Collaboration. The authors thank Thitima Kantachatvanich, MD for providing patient information.
Disclosure: There are no financial or other issues that might lead to conflict of interest.
SUPPLEMENTARY MATERIALS
Supplementary Table S1
Clinical characteristics of patients with confirmed NSAID-induced immediate reactions
Supplementary Fig. S1
Representative photos of skin rash demonstrated during aspirin desensitization in NIBR patients. | UNKNOWN | DrugDosageText | CC BY-NC | 33474858 | 19,056,205 | 2021-03 |
What was the dosage of drug 'IBUPROFEN'? | Clinical Characteristics, Urinary Leukotriene E4 Levels, and Aspirin Desensitization Results in Patients With NSAID-Induced Blended Reactions.
OBJECTIVE
Data on non-steroidal anti-inflammatory drug (NSAID) hypersensitivity in Southeast Asia are scarce. Increased urinary leukotriene E4 (uLTE4) levels have been suggested as a biomarker of NSAID-exacerbated respiratory disease (NERD). This study investigated clinical patterns of NSAID sensitivity in Thailand and the diagnostic roles of uLTE4 measurement in various phenotypes.
METHODS
The clinical phenotypes in 92 Thai adults with cross-reactive NSAID hypersensitivity were characterized based on the clinical history and drug provocation. The uLTE4 levels were measured at baseline, after aspirin provocation and after desensitization.
RESULTS
More than half of the patients (56.5%) presented with cutaneous symptoms (NSAID-exacerbated cutaneous disease), while one-third (33.7%) developed symptoms in at least 2 systems (NSAID-induced blended reactions; NIBR). Fifty-two patients underwent drug provocation and 59.6% of them yielded positive results. After drug provocation, a significant number of patients with confirmed NSAID cross-reactivity experienced clinical symptoms in more than one organ system. The uLTE4 levels at baseline were comparable between the NSAID-tolerant and NSAID-sensitive groups, but were substantially increased after aspirin provocation predominantly in NERD (983.4 pg/mg creatinine) and NIBR (501.0 pg/mg creatinine) compared to NSAID-tolerant subjects (122.1 pg/mg creatinine, P < 0.01 and 0.05, respectively). The uLTE4 levels were elevated after aspirin desensitization, although nasal polyposis and asthma were under control in 3 NERD and 3 NIBR subjects.
CONCLUSIONS
NIBR is not uncommon among NSAID-sensitive patients in Thailand. The diagnostic value of basal uLTE4 levels was limited, but increased uLTE4 levels upon aspirin provocation suggest NSAID cross-reactivity with respiratory components. This study indicates that aspirin desensitization, if necessary, might be effective in both NERD and NIBR.
BACKGROUND
ClinicalTrials.gov Identifier: NCT03849625.
INTRODUCTION
Hypersensitivity reactions to aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most common drug allergic reactions in clinical practice. They are generally categorized into 5 major phenotypes: NSAID-exacerbated respiratory disease (NERD), NSAID-exacerbated cutaneous (urticaria/angioedema) disease (NECD) in patients with underlying chronic urticaria, NSAID-induced urticaria/angioedema (NIUA) in patients without underlying chronic urticaria, single NSAID-induced urticaria/angioedema or anaphylaxis, and single NSAID-induced delayed hypersensitivity reactions.1 The first 3 phenotypes are non-immunologically mediated, and patients can develop cross-reactive hypersensitivity to chemically unrelated NSAIDs, while the latter 2 are selective NSAID sensitivities associated with drug-specific immunoglobulin E (IgE) and T-cell response, respectively.
Genetic and epigenetic variations play significant roles in the development of NERD.2 The proposed underlying mechanism is that the disturbance in arachidonic acid synthesis pathways leads to overproduction of cysteinyl leukotrienes (cysLT) and persistent airway inflammation.3 Mast cells are believed to be the major source of cysLT, but platelet-adherent leukocytes may be responsible for cysLT overproduction in NERD as well.4 The consumption of drugs inhibiting the cyclooxygenase-1 (COX-1) enzyme, such as aspirin and conventional NSAIDs, aggravates respiratory symptoms by enhancing cysLT production in NSAID-sensitive subjects, while the administration of specific COX-2 inhibitors, such as celecoxib, is generally safe.56 Besides aspirin/NSAID avoidance, aspirin desensitization has also been proven to be helpful for long term management in NERD subjects. Beneficial effects of aspirin desensitization in preventing nasal polyp recurrence and control symptoms of chronic rhinosinusitis and asthma have been well documented.7 Rapid aspirin desensitization has shown to be effective for the treatment of coronary artery disease in patients with a history of aspirin/NSAID-induced urticaria/angioedema, but it is not indicated for the treatment of chronic urticaria.8
Worldwide epidemiological data on clinical characteristics of NSAID hypersensitivity are limited. Most studies on NERD were performed in the United States and northern European countries.9101112 However, the predominant manifestation in Latin Americans and southern Europeans is the cutaneous phenotype (NIUA, NECD, and NSAID-induced isolated periorbital angioedema).1314 Studies in Asian populations have suggested that the prevalence of the NERD phenotype is not common in this region of the world. A study performed in China indicated that the prevalence of NSAID hypersensitivity in Chinese patients with chronic rhinosinusitis is very low (0.57%) compared to their European counterparts.15 It was also noted that NSAID-induced blended reactions (NIBR) are common in young Asian, atopic children in Singapore.16 Reports from Singapore and Thailand indicated that aspirin/NSAID-induced angioedema/urticaria is probably the prominent phenotype in Southeast Asia, with acetaminophen hypersensitivity being frequent.1718
In clinical practice, the current classification of cross-reactive NSAID hypersensitivity into 3 distinct phenotypes has some limitations. Clinical characteristics in NSAID-sensitive patients may not be well defined, and a combination of respiratory and cutaneous or other symptoms, such as gastrointestinal symptoms (mixed or blended reactions), is frequently observed.19 A previous report stated that aspirin nasal provocation is potentially useful for diagnosing patients with the blended reaction as well.20 However, the role of aspirin desensitization in other phenotypes of NSAID hypersensitivity, besides NERD, for long-term management of inflammatory airway diseases has not yet been established. Whether aspirin desensitization would be effective in controlling asthma and the recurrence of nasal polyposis after sinus surgery in NIBR is currently unknown.
At present, cross-reactive types of NSAID hypersensitivity can only be diagnosed by careful history taking and controlled-provocation testing, since there is no reliable in vitro method to confirm the diagnosis.21 There is evidence that basal urinary levels of leukotriene E4 (uLTE4), a stable product of the cysLT synthesis pathway, are elevated in NERD patients and could be a potential biomarker for differentiating between NSAID-sensitive and NSAID-tolerant asthmatics. However, these data are still controversial.222324 There have also been preliminary studies showing that uLTE4 levels might be increased in NECD.2526 Whether the measurement of basal uLTE4 levels could be a diagnostic marker for any phenotype of NSAID hypersensitivity is yet to be explored.
The purpose of this study was to analyze the clinical characteristics of patients diagnosed with NSAID-induced immediate reactions in Thailand and to explore whether the measurement of uLTE4 levels would be helpful in identifying NSAID-sensitive subjects or in differentiating among different phenotypes of cross-reactive NSAID hypersensitivities.
MATERIALS AND METHODS
Patient recruitment
Adult patients (18 years of age and older) with a suggestive history of NSAID-induced hypersensitivity reaction visiting the allergy clinic at King Chulalongkorn University Hospital between June 2014 and July 2018 were recruited into this study. Those with a history compatible with drug-induced non-immediate reactions (maculopapular rash, fixed drug eruption, acute generalized exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms, Stevens-Johnson syndrome/toxic epidermal necrolysis) or NSAID-related side effects were excluded. The status of NSAID-induced immediate hypersensitivity was diagnosed in patients with a well-documented drug allergy history or in patients with a suggestive history of NSAID sensitivity who yielded a positive drug provocation test as follows.
Clinical diagnosis of NSAID hypersensitivity
The diagnosis of cross-reactive NSAID hypersensitivity was clinically made in patients with a well-documented history of multiple episodes of respiratory, cutaneous, and/or gastrointestinal reactions within 2 hours after exposure to at least 2 different NSAID classes.1212728 Patient demographic data were collected, including the underlying diseases, atopic family history, and details on drug allergy history as well as the presenting symptoms and types of the culprit NSAIDs.
Aspirin provocation test
Oral aspirin provocation was performed in patients with a suggestive medical history or in those who had a history of an immediate reaction to a single NSAID to confirm the diagnosis of cross-reactive NSAID hypersensitivity according to the EAACI/GA2LEN guidelines, with some modifications.293031 Four increasing doses of aspirin (40.5, 81, 150, and 300 mg) were administered at 90-minute intervals until a positive reaction occurred. Clinical symptoms, fractional exhaled nitric oxide (FeNO), and the forced expiratory volume in 1 second (FEV1) were monitored to evaluate the reaction. A positive provocation test was defined if any of the following reactions developed: lower respiratory/bronchial reaction (a 15% decrease in FEV1 plus naso-ocular reaction or a 20% decrease in FEV1 alone), upper respiratory/naso-ocular reaction (nasal congestion and rhinorrhea; conjunctival injection), cutaneous reactions (urticaria/angioedema, periorbital edema), and/or other reactions (gastrointestinal symptoms such as nausea/vomiting, stomach cramps, and diarrhea). The test was considered negative if a patient tolerated the final dose (300 mg of aspirin) without any significant symptoms mentioned above.
Oral provocation test (OPT) with other NSAIDs, acetaminophen, or celecoxib
Patients with a history of an immediate reaction to only aspirin were challenged with escalating doses of ibuprofen to confirm the diagnosis of cross-reactive NSAID sensitivity. Patients with a history of an immediate reaction to a single NSAID were provoked with the suspected drug to verify the status of single NSAID hypersensitivity after a negative aspirin provocation test. Escalating doses of ibuprofen, diclofenac, and acetaminophen were administered, if applicable, as follows: ibuprofen (50, 100, and 200 mg), diclofenac (6.25, 12.5, and 25 mg), and acetaminophen (125, 250, and 500 mg). Celecoxib was also provoked in 3 doses (50, 100, and 200 mg) in patients with confirmed hypersensitivity to multiple NSAIDs who were willing to identify a safe alternative drug. The provocation test for each drug was performed on separate days at least 7 days apart. Each dose of drug provocation was provided at 90-minute intervals until the final dose was reached.
Classification of NSAID hypersensitivity according to drug provocation test results
Patients with cross-reactive NSAID phenotypes were classified according to the results of the drug provocation test as 1) NECD/NIUA if they developed cutaneous symptoms alone; 2) NERD if they developed respiratory symptoms alone; and 3) NIBR if they developed a combination of symptoms involving more than one organ system (respiratory, cutaneous, and/or gastrointestinal symptoms). Single NSAID hypersensitivity was diagnosed in patients with a positive provocation test to the suspected NSAID, but a negative aspirin provocation test. Patients who had negative provocations to both aspirin and the suspected culprit drug were labeled as NSAID-tolerant subjects. NECD/NIUA were purposely categorized together in our study to compare the differences and similarities between patients diagnosed with NSAID-induced cutaneous reactions and -respiratory reactions. Moreover, NECD and NIUA share similar background characteristics from a clinical point of view and some patients diagnosed with NIUA eventually evolve to NECD over time.32
Skin prick tests with common aeroallergens in Thailand (mixed dust mites, mixed cockroaches, mixed mold, cat dander, dog hair, and southern grass mix; ALK-Abello, Hørsholm, Denmark) were also examined in tested patients to identify atopic status. Wheal size ≥ 3 mm was considered a positive test.
Measurement of FeNO and the FEV1 in patients who underwent drug provocation test
FeNO was measured in all participants at baseline and after drug provocation by using a portable electrochemical analyzer (NObreath®; Bedfont Scientific Ltd, Maidstone, UK) according to the ATS/ERS recommendations.33 Measurements of FEV1 were also performed using a Vitalograph spirometer (Vitalograph®, Buckingham, UK). The best of 3 repeated attempts was recorded.
The uLTE4 measurement
The uLTE4 levels were measured by a leukotriene E4 ELISA kit (Cayman Chemical, Ann Arbor, MI, USA) at baseline and 90 minutes after the final dose of drug provocation, as well as at the follow-up visits after aspirin desensitization and reported after adjustment to urine creatinine levels.
Aspirin desensitization
Outpatient aspirin desensitization was performed in NSAID-sensitive patients who were referred from otolaryngologists to prevent the recurrence of nasal polyposis. The procedure was carried out according to the intranasal ketorolac and modified aspirin challenge 2-day protocol.34 Aspirin desensitization was completed after patients were able to tolerate a 325-mg dose of aspirin by the end of day 2 and experience no symptoms, changes in nasal flow rates, or decrease in FEV1 values. The prescribed maintenance dose of aspirin was 325 mg twice a day.
Statistical analysis
Patient characteristics are reported as means ± standard deviation for quantitative analysis, and median and interquartile range (IQR) are used to describe non-parametric data. The Mann-Whitney U test and Kruskal-Wallis test with Dunn's multiple comparisons were used to analyze the differences between 2 groups and more than 2 groups, respectively. Statistical analyses were performed using GraphPad Prism 8.3 software (GraphPad Software Inc., San Diego, CA, USA). P values < 0.05 were considered statistically significant.
Ethical considerations
Patients enrolled in this study were those who recruited in the study entitled “Characteristics of Patients Diagnosed With NSAID Sensitivity in Thailand” registered at ClinicalTrials.gov (NCT03849625). The study was approved by the Ethics and Research Committee of the Faculty of Medicine, Chulalongkorn University, Approval Number: COA No. 659/2012 and informed consent was obtained from all participants.
RESULTS
A total of 158 adult patients with a suspected history of NSAID hypersensitivity between 2015 and 2018 at King Chulalongkorn Memorial Hospital were initially recruited into this study as shown in Fig. 1. Thirty-five patients with a history compatible with a non-immediate hypersensitivity reaction and 4 subjects with clinical symptoms compatible with NSAID-related side effects were later excluded.
Fig. 1 Schematic diagram of patient selection for this study.
A total of 158 patients with a suspected history of NSAID hypersensitivity were initially recruited into this study. Cross-reactive NSAID hypersensitivity was clinically diagnosed in 67 patients with a well-documented drug allergy history and verified by a positive drug provocation test in 25 patients with a suggestive history of NSAID reactions.
NSAID, non-steroidal anti-inflammatory drug.
Cross-reactive NSAID hypersensitivity was clinically diagnosed in 67 patients with a convincing drug allergy history as defined in the methods section. The remaining 52 patients with a suggestive history of NSAID hypersensitivity underwent an OPT to confirm NSAID cross-reactivity status. Fifteen out of 25 patients with confirmed NSAID cross-reactivity were subsequently provoked with celecoxib to find a safe alternative NSAID. Single NSAID/acetaminophen hypersensitivity was verified in 6 patients who tolerated aspirin provocation but developed an allergic reaction upon re-challenge with acetaminophen or diclofenac.
Demographic data of adult patients with cross-reactive NSAID hypersensitivity
The clinical characteristics of adult patients with cross-reactive NSAID hypersensitivity are shown in Table 1 (n = 92). Most patients were females (77.2%) with an average age of 45.7 ± 13.4 years. The average age of onset was 32.2 ± 13.3 years and about half of them had atopic family history. The majority of them (56.5%) reported only cutaneous symptoms such as facial angioedema and/or acute urticarial rash, after NSAID exposure, while 9.8% of them developed only respiratory symptoms. Interestingly, about 33.7% of the patients experienced a combination of symptoms in multiple organ systems as shown in Fig. 2. The groups of NSAIDs frequently responsible for hypersensitivity reactions were propionic acid derivatives and acetic acid derivatives. Although inflammatory airway diseases (chronic sinusitis, nasal polyposis, and asthma) were significantly more common in patients who experienced only respiratory reactions after exposure to an NSAID compared to the other phenotypes, a significant portion of the patients reporting blended reactions had underlying airway diseases and chronic urticaria as well. Acetaminophen intolerance was also reported in about one-third (35.9%) of NSAID-sensitive subjects.
Table 1 Clinical characteristics among different phenotypes of patients with cross-reactive NSAID hypersensitivity (n = 92)
Phenotypes NECD/NIUA (n = 52) NERD (n = 9) NIBR (n = 31) Total (n = 92)
Gender (female/male) 37/15 6/3 28/3 71/21
Age (yr) 43.6 ± 12.3 47.3 ± 11.9 48.7 ± 15.3 45.7 ± 13.4
Age of onset (yr) 31.3 ± 13.8 34.6 ± 11.0 33.1 ± 13.3 32.2 ± 13.3
Underlying disease (%)
Chronic urticaria 13.5 11.1 29.0 18.5
Chronic sinusitis* 13.5 55.6 32.3 23.9
Nasal polyposis* 7.7 66.7 16.1 16.3
Asthma* 17.3 88.9 35.5 30.4
Atopic family history (%) 42.3 55.6 61.3 50.0
Drug exposure time to symptom onset (min) 58.8 ± 31.9 48.3 ± 34.3 47.6 ± 29.9 54.0 ± 31.6
Presenting symptoms (%)*
Facial/periorbital angioedema 71.2 0.0 74.2 65.2
Acute urticaria 73.1 0.0 61.3 62.0
Naso-ocular reaction 0.0 33.3 61.3 23.9
Acute asthma 0.0 88.9 67.7 31.5
Gastrointestinal symptoms 0.0 0.0 16.1 5.4
Implicated NSAIDs (%)†
Salicylic acids 23.1 55.6 35.5 30.4
Propionic acids 44.2 22.2 54.8 45.7
Acetic acids 23.1 22.2 48.4 31.5
Enolic acids 7.7 0.0 6.5 6.5
Anthranilic/fenamic acids 28.8 11.1 29.0 27.2
Acetaminophen intolerance (%)§ 28.8 22.2 51.6 35.9
Values are presented as number (%) or mean ± standard deviation. Each patient could present with multiple symptoms and from more than one implicated drug.
NSAID, non-steroidal anti-inflammatory drug; NECD, non-steroidal anti-inflammatory drug-exacerbated cutaneous (urticaria/angioedema) disease in patients with underlying chronic urticaria; NIUA, non-steroidal anti-inflammatory drug-induced urticaria/angioedema in patients without underlying chronic urticaria; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
*P < 0.05 among different phenotypes. †Examples of commonly implicated drugs in this study based on NSAID classification: 1) Salicylic acids: acetylsalicylic acid (aspirin), salicylic acid, diflunisal, salsalate; 2) Propionic acids: ibuprofen, naproxen, ketoprofen, fenoprofen, flurbiprofen; 3) Acetic acids: indomethacin, ketorolac, diclofenac, sulindac; 4) Enolic acids: piroxicam, meloxicam, tenoxicam; 5) Anthranilic/fenamic acids: mefenamic acid, flufenamic acid. §Acetaminophen intolerance: cannot tolerate acetaminophen higher than 500 mg.
Fig. 2 Clinical presentations in patients with cross-reactive NSAID hypersensitivity.
A proportional Venn diagram shows that about half of patients with cross-reactive NSAID hypersensitivity in Thailand reported only cutaneous symptoms after NSAID exposure, while one-third of them experienced NSAID-induced blended reactions.
NSAID, non-steroidal anti-inflammatory drug.
Clinical respiratory parameters and uLTE4 levels in different phenotypes of patients with cross-reactive NSAID hypersensitivity confirmed by positive OPT
NSAID hypersensitivity was confirmed in 59.6% (31/52) of the tested patients with a history of NSAID-induced immediate reactions. The majority of patients with cross-reactive NSAID hypersensitivity (17/25) according to OPT results were atopic individuals. The common phenotypes of patients with confirmed cross-reactive NSAID sensitivity were NECD/NIUA, NIBR, and NERD, respectively, as shown in Supplementary Table S1.
The average FeNO, %predicted FEV1, and uLTE4 levels were measured at baseline and after provocation with aspirin/NSAID in 25 NSAID cross-reactive and 21 NSAID-tolerant subjects as shown in Table 2. At baseline, patients with confirmed NSAID cross-reactivity (NSAID-sensitive group) had higher FeNO (P < 0.01) and slightly less %predicted FEV1 compared to the NSAID-tolerant subjects, while basal uLTE4 levels between NSAID-sensitive and NSAID-tolerant groups were comparable. After provocation, %predicted FEV1 was substantially reduced in NSAID-sensitive subjects, whereas uLTE4 levels were significantly elevated compared to the NSAID-tolerant group (P < 0.01). Celecoxib provocation was well tolerated in all NSAID-sensitive subjects. No statistical differences in the average FeNO, %predicted FEV1, or uLTE4 levels in 15 NSAID-sensitive patients (7 NECD/NIUA, 4 NIBR, 4 NERD) after celecoxib provocation were observed compared to those in NSAID-tolerant subjects.
Table 2 Respiratory parameters and uLTE4 levels in NSAID-sensitive subjects upon provocation with aspirin or celecoxib compared to NSAID-tolerant subjects
Characteristics Baseline After aspirin (OPT) P value*
NSAID tolerant (n = 21)
FeNO (ppb) 13.0 (8.5–19.5) 10.2 (7.0–16.8) 0.03
%predicted FEV1 100.8 (82.8–115.9) 99.0 (75.2–118.2) 0.90
uLTE4 (pg/mg creatinine) 116.3 (66.5–305.4) 122.1 (63.5–173.8) 0.17
NSAID sensitive (n = 25)
FeNO (ppb) 27.0 (17.8–40.9)† 18.0 (10.5–31.0) <0.01
%predicted FEV1 86.7 (63.3–104.9) 74.6 (52.4–89.8)† <0.01
uLTE4 (pg/mg creatinine) 118.3 (93.2–407.2) 204.9 (90.6–817.8)† <0.01
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; OPT, oral provocation test; ppb, parts per billion; FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in 1 second.
*P values before vs. after provocation test, Wilcoxon signed-rank test; †P < 0.01 compared to the NSAID-tolerant subjects.
According to the subgroup analysis, 10 NECD/NIUA, 9 NIBR, and 6 NERD were categorized as shown in Fig. 3. At baseline, %predicted FEV1 was not significantly different among different types of cross-reactive NSAID hypersensitivity, although those in patients with confirmed NIBR were lowest (64.9%, IQR 56.9–97.3). The significant differences in basal FeNO levels (P < 0.01) among the 3 different phenotypes were observed. The basal FeNO levels were significantly higher in NIBR (36.9%, IQR 27.0–95.4) than in NSAID-tolerant subjects (P < 0.01). After aspirin OPT, the reduction of %FEV1 was considerably higher in patients with confirmed NERD (22.0%, IQR 16.0-28.8), followed by NIBR (13.3%, IQR 7.6–28.0), compared to those in NSAID-tolerant groups (P < 0.01). Basal uLTE4 levels were not significantly different among the 3 phenotypes. Interestingly, uLTE4 levels after aspirin provocation were significantly higher in NERD and NIBR patients than in the NECD/NIUA and NSAID-tolerant groups (P < 0.05 and < 0.01, respectively).
Fig. 3 Respiratory parameters and uLTE4 levels in different phenotypes of NSAID-sensitive subjects compared to NSAID-tolerant subjects.
Baseline FeNO in NIBR and NERD were higher than those in the NSAID-tolerant group. After aspirin provocation, % predicted FEV1 in NERD and NIBR were significantly reduced from the baseline while uLTE4 levels were much higher than those in NSAID-tolerant subjects.
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; FEV1, forced expiratory volume in 1 second.
*P values < 0.05, †P values < 0.01.
Effects of aspirin desensitization on uLTE4 levels in patients diagnosed with NERD and NIBR
Aspirin desensitization was performed in selected patients (3 NERD and 3 NIBR) who had pre-existing inflammatory airway diseases and a history of recurrent nasal polyposis after surgery as shown in Table 3. The maintenance dose of aspirin was 650 mg/day during the first 6 months and reduced to 325 mg/day afterward. Levels of uLTE4 were measured at baseline after aspirin desensitization and serially followed up for 2–3 years as demonstrated in Fig. 4. Other than respiratory symptoms, acute urticarial rash and gastrointestinal symptoms (abdominal cramp/nausea/diarrhea) were also aggravated in NIBR subjects during aspirin desensitization as shown in Supplementary Fig. S1, but gradually relieved with supportive treatment. No sinus surgery was required for nasal polyp recurrence, and asthma symptoms were under control after aspirin desensitization in all 6 cases. Up to 3 years after aspirin desensitization, however, uLTE4 levels were significantly increased and remained elevated throughout the follow-up period, although urticarial rash and gastrointestinal symptoms were no longer observed while taking aspirin.
Table 3 Details of patients with cross-reactive NSAID hypersensitivity undergoing aspirin desensitization in this study
Patients (sex/year) Underlying diseases History of adverse drug reactions Indication for aspirin desensitization Follow-up duration (months) Asthma control before/after aspirin desensitization Recurrent nasal polyposis after aspirin desensitization Skin symptoms after aspirin desensitization Gastrointestinal symptoms after aspirin desensitization
1. NERD (M/46) Chronic sinusitis, nasal polyposis, asthma Acute asthma 20 min after taking aspirin 2 recurrent nasal polyps 74 Partly controlled with high dose ICS-LABA and add-on LTRA/well controlled with low dose ICS None NA NA
2. NERD (M/54) Chronic rhinitis, nasal polyposis, asthma Acute asthma, blocked nose 1 hr after taking aspirin 3 recurrent nasal polyps 24 Uncontrolled with high dose ICS-LABA and add-on LTRA/well controlled with medium dose ICS-LABA None NA NA
3. NERD (M/56) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked nose 1 hr after taking ibuprofen 6 recurrent nasal polyps 32 Partly controlled asthma with high dose ICS-LABA and add-on LTRA/well controlled with medium dose ICS-LABA None NA NA
4. NIBR (M/48) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked nose, conjunctival injection, urticarial rash 2 hr after taking aspirin 3 recurrent nasal polyps 72 Partly controlled with medium dose ICS-LABA/well controlled with low dose ICS-LABA None No rash after taking aspirin NA
5. NIBR (F/65) Chronic sinusitis, nasal polyposis, chronic urticaria, asthma (history of cardiac arrest from severe asthma) Urticarial rash, periorbital angioedema, blocked nose, conjunctival injection, rhinorrhea, bronchospasm/wheezing, hoarseness of voice 1 hr after taking aspirin, ibuprofen, mefenamic acid, acetaminophen 2 recurrent nasal polyps 48 Uncontrolled with high dose ICS-LABA and add-on LTRA/well controlled with low dose ICS-LABA None No rash after taking aspirin, chronic urticaria resolved NA
6. NIBR (F/38) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked/running nose, stomach cramp, diarrhea, periorbital angioedema, urticaria 30 min after taking ibuprofen, indomethacin, mefenamic acid 2 recurrent nasal polyps 21 Partly controlled with medium dose ICS-LABA/well controlled, with medium dose ICS-LABA None No rash after taking aspirin No gastrointestinal symptoms after taking aspirin
NSAID, non-steroidal anti-inflammatory drug; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; ICS, inhaled corticosteroid; LABA, long-acting beta-agonist; LTRA, leukotriene receptor antagonist; NA, not applicable (no symptoms prior to aspirin desensitization); NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
Fig. 4 uLTE4 levels in NSAID-sensitive subjects after aspirin desensitization.
Our study demonstrated that uLTE4 levels (pg/mg creatinine) in 3 NERD and 3 NIBR patients were increased and remained elevated up to 3 years after aspirin desensitization even though recurrent nasal polyposis was successfully prevented in all cases.
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
DISCUSSION
Most studies on NSAID hypersensitivity have focused on NERD, although worldwide epidemiological data suggest that NECD/NIUA might be more common. Recent data have demonstrated that some patients cannot be categorized into the current classification of NSAID hypersensitivity, for example those with NSAID-induced periorbital angioedema and NIBR.1419 These patients may also have underlying chronic airway diseases; however, the role of aspirin desensitization in the prevention of recurrent nasal polyposis and control of airway inflammation in NSAID-sensitive subjects other than the NERD phenotype has never been reported.
The leading presentations in NSAID-sensitive subjects in this study were periorbital angioedema, acute urticaria, bronchial symptoms, and naso-ocular reactions, respectively. Even those confirmed with NSAID exposure, a significant number of patients in our cohort also showed clinical responses in more than 1 organ system, indicating that the prevalence of NIBR was higher than previously thought. Although patients with IgE-mediated anaphylaxis might also present with multiple organ involvement, the fact that most of the reactions took about 1–2 hours to occur and the ability to react to multiple NSAIDs with dissimilar chemical structures made them more compatible with the non-immunologic effect of the drugs.
Facial angioedema around the periorbital area was the most common presenting symptom in Thai patients. Upon NSAID provocation, however, the predominant periorbital angioedema often accompanied by blocked nose, running nose, and itchy/red eyes. After a thorough examination, small urticarial rash on the trunk and extremities, and expiratory wheezing were occasionally detected, although frequently asymptomatic. It is noteworthy that periorbital angioedema may persist for hours or days while urticarial rash and respiratory symptoms are quickly resolved after treatment. As a result, NIBR could be underdiagnosed if history taking is not thoroughly reviewed, since symptoms with lesser severity in other organ systems may be unnoticed. In addition, the COX-1 inhibitor properties of the exposed NSAIDs could affect the phenotype of NSAID sensitivity reported by patients as some patients experienced both asthmatic attack and periorbital angioedema/generalized urticaria after taking aspirin but reported only periorbital edema after taking acetaminophen.
It is practically difficult to clearly distinguish between NSAID-induced periorbital angioedema and NSAID-induced naso-ocular reactions (upper airway manifestations of NERD), since patients occasionally experienced periorbital swelling, red/swollen eyes with tearing, and nasal congestion at the same time. In our opinion, the majority of NSAID hypersensitivity in the Thai population would be described as “NSAID-induced blended reaction with predominant periorbital angioedema” and probably related to “NSAID-induced isolated periorbital angioedema” phenotype as proposed by the Spanish group. It is interesting to note that the prevalence of atopic disease was high in this patient group. We speculate that the increased leukotriene production after NSAID consumption could lead to the worsening of pre-existing mucosal inflammation around the nose and eyes in patients who already suffered from the late-phase reaction of persistent allergic rhinitis.
Our study did not find any difference in terms of basal uLTE4 levels between NSAID-sensitive and NSAID-tolerant subjects. However, uLTE4 levels were higher in NSAID-sensitive patients, particularly in NERD and NIBR subjects, after the NSAID challenge compared to those in the NSAID-tolerant group. Though basal uLTE4 levels may not be a suitable marker to screen NSAID sensitivity status, elevated uLTE4 levels after aspirin OPT could be the supporting evidence for the diagnosis of cross-reactive NSAID hypersensitivity in cases where the clinical response is equivocal. Our study demonstrated that the degree of defective leukotriene homeostasis after exposure to drugs affecting the cyclo-oxygenase pathway might be related to the severity of respiratory involvement upon NSAID exposure.35 The fact that uLTE4 levels were barely changed after celecoxib provocation in patients with NSAID cross-reactivity confirms that celecoxib is a safe alternative NSAID in these patient groups.
According to our study, the patterns of NSAID hypersensitivity in southeast Asians are similar to those in southern Europeans and Latin Americans, and somewhat different from those reported in patients of northern European descent. Previous data suggested that aspirin nasal provocation could potentially diagnose some NSAID-sensitive patients presenting with predominant cutaneous reactions.3637 Retrospectively, some of these patients might be re-classified as the NIBR phenotype, since a decreased nasal volume was also observed. In other words, patients diagnosed with an NSAID-induced cutaneous reaction who positively reacted to NSAID nasal provocation, especially those with a periorbital reaction, might be NIBR subjects with subclinical airway involvement.
The novelties of this study were the findings that NIBR accounted for about one-third of adult patients with cross-reactive NSAID hypersensitivity and that aspirin desensitization could successfully prevent the recurrence of nasal polyposis and alleviate respiratory symptoms not only in NERD, but also in NIBR, even though urine LTE4 levels remained elevated. However, since the reactions in some NIBR patients could lead to serious adverse events, aspirin desensitization in NIBR subjects should be performed only when it is strongly indicated in selected patients with no previous severe reactions to NSAIDs. In NIBR subjects who experienced previous severe reactions in multiple organ systems, the procedure of aspirin desensitization, if necessary, should be carefully monitored and the administration of biological agents such as dupilumab, if available, should be considered a safer therapeutic option in these cases.
Interestingly, uLTE4 levels were increased after aspirin desensitization and remained elevated throughout the follow-up period. It should be emphasized that urticarial rash and stomach-ache in NIBR patients also disappeared while patients were taking daily aspirin. These data suggest that the pathogenesis of nasal polyposis cannot be explained by cysLT overproduction alone and that aspirin desensitization could be useful to alleviate both respiratory and non-respiratory symptoms in NIBR subjects.
Interestingly, a recent study also found that the clinical benefit of high-dose aspirin desensitization in NERD was independent of a reduction of mast cell activation and cysLT production. They reported paradoxically increased uLTE4 levels 8 weeks after aspirin desensitization compared to the baseline levels and concluded that high-dose aspirin therapy did not restore the impaired eicosanoid pathway.38 According to their study findings and ours, the therapeutic effect of aspirin desensitization was not directly correlated with a change of arachidonic acid metabolism.
There are some limitations to this study. Aspirin desensitization was performed in only 6 patients in our cohort; therefore, the comparative success rates and potential adverse reactions of aspirin desensitization between NERD and NIBR patients could not be analyzed. Further studies with a larger sample size are needed to compare the long-term prognosis between NERD and NIBR, to understand the mechanism of aspirin desensitization for the improvement of respiratory and extra-respiratory symptoms and to evaluate its risk-benefit ratio of aspirin desensitization in NIBR subjects.
In conclusion, NIBR is not uncommon among patients diagnosed with NSAID hypersensitivity in Thailand. Increased uLTE4 levels upon aspirin provocation suggested a diagnosis of NSAID cross-reactivity, while baseline uLTE4 levels were not distinguishable between NSAID-tolerant and NSAID-sensitive subjects. Our study indicates that aspirin desensitization is effective not only in NERD but also in NIBR. The persistently high levels of uLTE4 in spite of clinical improvement in NSAID-sensitive patients after successful aspirin desensitization suggest that elevated leukotrienes alone cannot explain the pathogenesis of NSAID hypersensitivity reactions.
ACKNOWLEDGMENTS
This study was supported by the Ratchadaphiseksomphot fund, Faculty of Medicine, Chulalongkorn University, grant No. RA55/19 and the Skin and Allergy Research Unit, Chulalongkorn University, Bangkok, Thailand. Study data were collected and managed using Research Electronic Data Capture (REDCap) hosted at HIV Netherlands Australia Thailand Research Collaboration. The authors thank Thitima Kantachatvanich, MD for providing patient information.
Disclosure: There are no financial or other issues that might lead to conflict of interest.
SUPPLEMENTARY MATERIALS
Supplementary Table S1
Clinical characteristics of patients with confirmed NSAID-induced immediate reactions
Supplementary Fig. S1
Representative photos of skin rash demonstrated during aspirin desensitization in NIBR patients. | UNKNOWN | DrugDosageText | CC BY-NC | 33474858 | 19,056,205 | 2021-03 |
What was the dosage of drug 'MEFENAMIC ACID'? | Clinical Characteristics, Urinary Leukotriene E4 Levels, and Aspirin Desensitization Results in Patients With NSAID-Induced Blended Reactions.
OBJECTIVE
Data on non-steroidal anti-inflammatory drug (NSAID) hypersensitivity in Southeast Asia are scarce. Increased urinary leukotriene E4 (uLTE4) levels have been suggested as a biomarker of NSAID-exacerbated respiratory disease (NERD). This study investigated clinical patterns of NSAID sensitivity in Thailand and the diagnostic roles of uLTE4 measurement in various phenotypes.
METHODS
The clinical phenotypes in 92 Thai adults with cross-reactive NSAID hypersensitivity were characterized based on the clinical history and drug provocation. The uLTE4 levels were measured at baseline, after aspirin provocation and after desensitization.
RESULTS
More than half of the patients (56.5%) presented with cutaneous symptoms (NSAID-exacerbated cutaneous disease), while one-third (33.7%) developed symptoms in at least 2 systems (NSAID-induced blended reactions; NIBR). Fifty-two patients underwent drug provocation and 59.6% of them yielded positive results. After drug provocation, a significant number of patients with confirmed NSAID cross-reactivity experienced clinical symptoms in more than one organ system. The uLTE4 levels at baseline were comparable between the NSAID-tolerant and NSAID-sensitive groups, but were substantially increased after aspirin provocation predominantly in NERD (983.4 pg/mg creatinine) and NIBR (501.0 pg/mg creatinine) compared to NSAID-tolerant subjects (122.1 pg/mg creatinine, P < 0.01 and 0.05, respectively). The uLTE4 levels were elevated after aspirin desensitization, although nasal polyposis and asthma were under control in 3 NERD and 3 NIBR subjects.
CONCLUSIONS
NIBR is not uncommon among NSAID-sensitive patients in Thailand. The diagnostic value of basal uLTE4 levels was limited, but increased uLTE4 levels upon aspirin provocation suggest NSAID cross-reactivity with respiratory components. This study indicates that aspirin desensitization, if necessary, might be effective in both NERD and NIBR.
BACKGROUND
ClinicalTrials.gov Identifier: NCT03849625.
INTRODUCTION
Hypersensitivity reactions to aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most common drug allergic reactions in clinical practice. They are generally categorized into 5 major phenotypes: NSAID-exacerbated respiratory disease (NERD), NSAID-exacerbated cutaneous (urticaria/angioedema) disease (NECD) in patients with underlying chronic urticaria, NSAID-induced urticaria/angioedema (NIUA) in patients without underlying chronic urticaria, single NSAID-induced urticaria/angioedema or anaphylaxis, and single NSAID-induced delayed hypersensitivity reactions.1 The first 3 phenotypes are non-immunologically mediated, and patients can develop cross-reactive hypersensitivity to chemically unrelated NSAIDs, while the latter 2 are selective NSAID sensitivities associated with drug-specific immunoglobulin E (IgE) and T-cell response, respectively.
Genetic and epigenetic variations play significant roles in the development of NERD.2 The proposed underlying mechanism is that the disturbance in arachidonic acid synthesis pathways leads to overproduction of cysteinyl leukotrienes (cysLT) and persistent airway inflammation.3 Mast cells are believed to be the major source of cysLT, but platelet-adherent leukocytes may be responsible for cysLT overproduction in NERD as well.4 The consumption of drugs inhibiting the cyclooxygenase-1 (COX-1) enzyme, such as aspirin and conventional NSAIDs, aggravates respiratory symptoms by enhancing cysLT production in NSAID-sensitive subjects, while the administration of specific COX-2 inhibitors, such as celecoxib, is generally safe.56 Besides aspirin/NSAID avoidance, aspirin desensitization has also been proven to be helpful for long term management in NERD subjects. Beneficial effects of aspirin desensitization in preventing nasal polyp recurrence and control symptoms of chronic rhinosinusitis and asthma have been well documented.7 Rapid aspirin desensitization has shown to be effective for the treatment of coronary artery disease in patients with a history of aspirin/NSAID-induced urticaria/angioedema, but it is not indicated for the treatment of chronic urticaria.8
Worldwide epidemiological data on clinical characteristics of NSAID hypersensitivity are limited. Most studies on NERD were performed in the United States and northern European countries.9101112 However, the predominant manifestation in Latin Americans and southern Europeans is the cutaneous phenotype (NIUA, NECD, and NSAID-induced isolated periorbital angioedema).1314 Studies in Asian populations have suggested that the prevalence of the NERD phenotype is not common in this region of the world. A study performed in China indicated that the prevalence of NSAID hypersensitivity in Chinese patients with chronic rhinosinusitis is very low (0.57%) compared to their European counterparts.15 It was also noted that NSAID-induced blended reactions (NIBR) are common in young Asian, atopic children in Singapore.16 Reports from Singapore and Thailand indicated that aspirin/NSAID-induced angioedema/urticaria is probably the prominent phenotype in Southeast Asia, with acetaminophen hypersensitivity being frequent.1718
In clinical practice, the current classification of cross-reactive NSAID hypersensitivity into 3 distinct phenotypes has some limitations. Clinical characteristics in NSAID-sensitive patients may not be well defined, and a combination of respiratory and cutaneous or other symptoms, such as gastrointestinal symptoms (mixed or blended reactions), is frequently observed.19 A previous report stated that aspirin nasal provocation is potentially useful for diagnosing patients with the blended reaction as well.20 However, the role of aspirin desensitization in other phenotypes of NSAID hypersensitivity, besides NERD, for long-term management of inflammatory airway diseases has not yet been established. Whether aspirin desensitization would be effective in controlling asthma and the recurrence of nasal polyposis after sinus surgery in NIBR is currently unknown.
At present, cross-reactive types of NSAID hypersensitivity can only be diagnosed by careful history taking and controlled-provocation testing, since there is no reliable in vitro method to confirm the diagnosis.21 There is evidence that basal urinary levels of leukotriene E4 (uLTE4), a stable product of the cysLT synthesis pathway, are elevated in NERD patients and could be a potential biomarker for differentiating between NSAID-sensitive and NSAID-tolerant asthmatics. However, these data are still controversial.222324 There have also been preliminary studies showing that uLTE4 levels might be increased in NECD.2526 Whether the measurement of basal uLTE4 levels could be a diagnostic marker for any phenotype of NSAID hypersensitivity is yet to be explored.
The purpose of this study was to analyze the clinical characteristics of patients diagnosed with NSAID-induced immediate reactions in Thailand and to explore whether the measurement of uLTE4 levels would be helpful in identifying NSAID-sensitive subjects or in differentiating among different phenotypes of cross-reactive NSAID hypersensitivities.
MATERIALS AND METHODS
Patient recruitment
Adult patients (18 years of age and older) with a suggestive history of NSAID-induced hypersensitivity reaction visiting the allergy clinic at King Chulalongkorn University Hospital between June 2014 and July 2018 were recruited into this study. Those with a history compatible with drug-induced non-immediate reactions (maculopapular rash, fixed drug eruption, acute generalized exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms, Stevens-Johnson syndrome/toxic epidermal necrolysis) or NSAID-related side effects were excluded. The status of NSAID-induced immediate hypersensitivity was diagnosed in patients with a well-documented drug allergy history or in patients with a suggestive history of NSAID sensitivity who yielded a positive drug provocation test as follows.
Clinical diagnosis of NSAID hypersensitivity
The diagnosis of cross-reactive NSAID hypersensitivity was clinically made in patients with a well-documented history of multiple episodes of respiratory, cutaneous, and/or gastrointestinal reactions within 2 hours after exposure to at least 2 different NSAID classes.1212728 Patient demographic data were collected, including the underlying diseases, atopic family history, and details on drug allergy history as well as the presenting symptoms and types of the culprit NSAIDs.
Aspirin provocation test
Oral aspirin provocation was performed in patients with a suggestive medical history or in those who had a history of an immediate reaction to a single NSAID to confirm the diagnosis of cross-reactive NSAID hypersensitivity according to the EAACI/GA2LEN guidelines, with some modifications.293031 Four increasing doses of aspirin (40.5, 81, 150, and 300 mg) were administered at 90-minute intervals until a positive reaction occurred. Clinical symptoms, fractional exhaled nitric oxide (FeNO), and the forced expiratory volume in 1 second (FEV1) were monitored to evaluate the reaction. A positive provocation test was defined if any of the following reactions developed: lower respiratory/bronchial reaction (a 15% decrease in FEV1 plus naso-ocular reaction or a 20% decrease in FEV1 alone), upper respiratory/naso-ocular reaction (nasal congestion and rhinorrhea; conjunctival injection), cutaneous reactions (urticaria/angioedema, periorbital edema), and/or other reactions (gastrointestinal symptoms such as nausea/vomiting, stomach cramps, and diarrhea). The test was considered negative if a patient tolerated the final dose (300 mg of aspirin) without any significant symptoms mentioned above.
Oral provocation test (OPT) with other NSAIDs, acetaminophen, or celecoxib
Patients with a history of an immediate reaction to only aspirin were challenged with escalating doses of ibuprofen to confirm the diagnosis of cross-reactive NSAID sensitivity. Patients with a history of an immediate reaction to a single NSAID were provoked with the suspected drug to verify the status of single NSAID hypersensitivity after a negative aspirin provocation test. Escalating doses of ibuprofen, diclofenac, and acetaminophen were administered, if applicable, as follows: ibuprofen (50, 100, and 200 mg), diclofenac (6.25, 12.5, and 25 mg), and acetaminophen (125, 250, and 500 mg). Celecoxib was also provoked in 3 doses (50, 100, and 200 mg) in patients with confirmed hypersensitivity to multiple NSAIDs who were willing to identify a safe alternative drug. The provocation test for each drug was performed on separate days at least 7 days apart. Each dose of drug provocation was provided at 90-minute intervals until the final dose was reached.
Classification of NSAID hypersensitivity according to drug provocation test results
Patients with cross-reactive NSAID phenotypes were classified according to the results of the drug provocation test as 1) NECD/NIUA if they developed cutaneous symptoms alone; 2) NERD if they developed respiratory symptoms alone; and 3) NIBR if they developed a combination of symptoms involving more than one organ system (respiratory, cutaneous, and/or gastrointestinal symptoms). Single NSAID hypersensitivity was diagnosed in patients with a positive provocation test to the suspected NSAID, but a negative aspirin provocation test. Patients who had negative provocations to both aspirin and the suspected culprit drug were labeled as NSAID-tolerant subjects. NECD/NIUA were purposely categorized together in our study to compare the differences and similarities between patients diagnosed with NSAID-induced cutaneous reactions and -respiratory reactions. Moreover, NECD and NIUA share similar background characteristics from a clinical point of view and some patients diagnosed with NIUA eventually evolve to NECD over time.32
Skin prick tests with common aeroallergens in Thailand (mixed dust mites, mixed cockroaches, mixed mold, cat dander, dog hair, and southern grass mix; ALK-Abello, Hørsholm, Denmark) were also examined in tested patients to identify atopic status. Wheal size ≥ 3 mm was considered a positive test.
Measurement of FeNO and the FEV1 in patients who underwent drug provocation test
FeNO was measured in all participants at baseline and after drug provocation by using a portable electrochemical analyzer (NObreath®; Bedfont Scientific Ltd, Maidstone, UK) according to the ATS/ERS recommendations.33 Measurements of FEV1 were also performed using a Vitalograph spirometer (Vitalograph®, Buckingham, UK). The best of 3 repeated attempts was recorded.
The uLTE4 measurement
The uLTE4 levels were measured by a leukotriene E4 ELISA kit (Cayman Chemical, Ann Arbor, MI, USA) at baseline and 90 minutes after the final dose of drug provocation, as well as at the follow-up visits after aspirin desensitization and reported after adjustment to urine creatinine levels.
Aspirin desensitization
Outpatient aspirin desensitization was performed in NSAID-sensitive patients who were referred from otolaryngologists to prevent the recurrence of nasal polyposis. The procedure was carried out according to the intranasal ketorolac and modified aspirin challenge 2-day protocol.34 Aspirin desensitization was completed after patients were able to tolerate a 325-mg dose of aspirin by the end of day 2 and experience no symptoms, changes in nasal flow rates, or decrease in FEV1 values. The prescribed maintenance dose of aspirin was 325 mg twice a day.
Statistical analysis
Patient characteristics are reported as means ± standard deviation for quantitative analysis, and median and interquartile range (IQR) are used to describe non-parametric data. The Mann-Whitney U test and Kruskal-Wallis test with Dunn's multiple comparisons were used to analyze the differences between 2 groups and more than 2 groups, respectively. Statistical analyses were performed using GraphPad Prism 8.3 software (GraphPad Software Inc., San Diego, CA, USA). P values < 0.05 were considered statistically significant.
Ethical considerations
Patients enrolled in this study were those who recruited in the study entitled “Characteristics of Patients Diagnosed With NSAID Sensitivity in Thailand” registered at ClinicalTrials.gov (NCT03849625). The study was approved by the Ethics and Research Committee of the Faculty of Medicine, Chulalongkorn University, Approval Number: COA No. 659/2012 and informed consent was obtained from all participants.
RESULTS
A total of 158 adult patients with a suspected history of NSAID hypersensitivity between 2015 and 2018 at King Chulalongkorn Memorial Hospital were initially recruited into this study as shown in Fig. 1. Thirty-five patients with a history compatible with a non-immediate hypersensitivity reaction and 4 subjects with clinical symptoms compatible with NSAID-related side effects were later excluded.
Fig. 1 Schematic diagram of patient selection for this study.
A total of 158 patients with a suspected history of NSAID hypersensitivity were initially recruited into this study. Cross-reactive NSAID hypersensitivity was clinically diagnosed in 67 patients with a well-documented drug allergy history and verified by a positive drug provocation test in 25 patients with a suggestive history of NSAID reactions.
NSAID, non-steroidal anti-inflammatory drug.
Cross-reactive NSAID hypersensitivity was clinically diagnosed in 67 patients with a convincing drug allergy history as defined in the methods section. The remaining 52 patients with a suggestive history of NSAID hypersensitivity underwent an OPT to confirm NSAID cross-reactivity status. Fifteen out of 25 patients with confirmed NSAID cross-reactivity were subsequently provoked with celecoxib to find a safe alternative NSAID. Single NSAID/acetaminophen hypersensitivity was verified in 6 patients who tolerated aspirin provocation but developed an allergic reaction upon re-challenge with acetaminophen or diclofenac.
Demographic data of adult patients with cross-reactive NSAID hypersensitivity
The clinical characteristics of adult patients with cross-reactive NSAID hypersensitivity are shown in Table 1 (n = 92). Most patients were females (77.2%) with an average age of 45.7 ± 13.4 years. The average age of onset was 32.2 ± 13.3 years and about half of them had atopic family history. The majority of them (56.5%) reported only cutaneous symptoms such as facial angioedema and/or acute urticarial rash, after NSAID exposure, while 9.8% of them developed only respiratory symptoms. Interestingly, about 33.7% of the patients experienced a combination of symptoms in multiple organ systems as shown in Fig. 2. The groups of NSAIDs frequently responsible for hypersensitivity reactions were propionic acid derivatives and acetic acid derivatives. Although inflammatory airway diseases (chronic sinusitis, nasal polyposis, and asthma) were significantly more common in patients who experienced only respiratory reactions after exposure to an NSAID compared to the other phenotypes, a significant portion of the patients reporting blended reactions had underlying airway diseases and chronic urticaria as well. Acetaminophen intolerance was also reported in about one-third (35.9%) of NSAID-sensitive subjects.
Table 1 Clinical characteristics among different phenotypes of patients with cross-reactive NSAID hypersensitivity (n = 92)
Phenotypes NECD/NIUA (n = 52) NERD (n = 9) NIBR (n = 31) Total (n = 92)
Gender (female/male) 37/15 6/3 28/3 71/21
Age (yr) 43.6 ± 12.3 47.3 ± 11.9 48.7 ± 15.3 45.7 ± 13.4
Age of onset (yr) 31.3 ± 13.8 34.6 ± 11.0 33.1 ± 13.3 32.2 ± 13.3
Underlying disease (%)
Chronic urticaria 13.5 11.1 29.0 18.5
Chronic sinusitis* 13.5 55.6 32.3 23.9
Nasal polyposis* 7.7 66.7 16.1 16.3
Asthma* 17.3 88.9 35.5 30.4
Atopic family history (%) 42.3 55.6 61.3 50.0
Drug exposure time to symptom onset (min) 58.8 ± 31.9 48.3 ± 34.3 47.6 ± 29.9 54.0 ± 31.6
Presenting symptoms (%)*
Facial/periorbital angioedema 71.2 0.0 74.2 65.2
Acute urticaria 73.1 0.0 61.3 62.0
Naso-ocular reaction 0.0 33.3 61.3 23.9
Acute asthma 0.0 88.9 67.7 31.5
Gastrointestinal symptoms 0.0 0.0 16.1 5.4
Implicated NSAIDs (%)†
Salicylic acids 23.1 55.6 35.5 30.4
Propionic acids 44.2 22.2 54.8 45.7
Acetic acids 23.1 22.2 48.4 31.5
Enolic acids 7.7 0.0 6.5 6.5
Anthranilic/fenamic acids 28.8 11.1 29.0 27.2
Acetaminophen intolerance (%)§ 28.8 22.2 51.6 35.9
Values are presented as number (%) or mean ± standard deviation. Each patient could present with multiple symptoms and from more than one implicated drug.
NSAID, non-steroidal anti-inflammatory drug; NECD, non-steroidal anti-inflammatory drug-exacerbated cutaneous (urticaria/angioedema) disease in patients with underlying chronic urticaria; NIUA, non-steroidal anti-inflammatory drug-induced urticaria/angioedema in patients without underlying chronic urticaria; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
*P < 0.05 among different phenotypes. †Examples of commonly implicated drugs in this study based on NSAID classification: 1) Salicylic acids: acetylsalicylic acid (aspirin), salicylic acid, diflunisal, salsalate; 2) Propionic acids: ibuprofen, naproxen, ketoprofen, fenoprofen, flurbiprofen; 3) Acetic acids: indomethacin, ketorolac, diclofenac, sulindac; 4) Enolic acids: piroxicam, meloxicam, tenoxicam; 5) Anthranilic/fenamic acids: mefenamic acid, flufenamic acid. §Acetaminophen intolerance: cannot tolerate acetaminophen higher than 500 mg.
Fig. 2 Clinical presentations in patients with cross-reactive NSAID hypersensitivity.
A proportional Venn diagram shows that about half of patients with cross-reactive NSAID hypersensitivity in Thailand reported only cutaneous symptoms after NSAID exposure, while one-third of them experienced NSAID-induced blended reactions.
NSAID, non-steroidal anti-inflammatory drug.
Clinical respiratory parameters and uLTE4 levels in different phenotypes of patients with cross-reactive NSAID hypersensitivity confirmed by positive OPT
NSAID hypersensitivity was confirmed in 59.6% (31/52) of the tested patients with a history of NSAID-induced immediate reactions. The majority of patients with cross-reactive NSAID hypersensitivity (17/25) according to OPT results were atopic individuals. The common phenotypes of patients with confirmed cross-reactive NSAID sensitivity were NECD/NIUA, NIBR, and NERD, respectively, as shown in Supplementary Table S1.
The average FeNO, %predicted FEV1, and uLTE4 levels were measured at baseline and after provocation with aspirin/NSAID in 25 NSAID cross-reactive and 21 NSAID-tolerant subjects as shown in Table 2. At baseline, patients with confirmed NSAID cross-reactivity (NSAID-sensitive group) had higher FeNO (P < 0.01) and slightly less %predicted FEV1 compared to the NSAID-tolerant subjects, while basal uLTE4 levels between NSAID-sensitive and NSAID-tolerant groups were comparable. After provocation, %predicted FEV1 was substantially reduced in NSAID-sensitive subjects, whereas uLTE4 levels were significantly elevated compared to the NSAID-tolerant group (P < 0.01). Celecoxib provocation was well tolerated in all NSAID-sensitive subjects. No statistical differences in the average FeNO, %predicted FEV1, or uLTE4 levels in 15 NSAID-sensitive patients (7 NECD/NIUA, 4 NIBR, 4 NERD) after celecoxib provocation were observed compared to those in NSAID-tolerant subjects.
Table 2 Respiratory parameters and uLTE4 levels in NSAID-sensitive subjects upon provocation with aspirin or celecoxib compared to NSAID-tolerant subjects
Characteristics Baseline After aspirin (OPT) P value*
NSAID tolerant (n = 21)
FeNO (ppb) 13.0 (8.5–19.5) 10.2 (7.0–16.8) 0.03
%predicted FEV1 100.8 (82.8–115.9) 99.0 (75.2–118.2) 0.90
uLTE4 (pg/mg creatinine) 116.3 (66.5–305.4) 122.1 (63.5–173.8) 0.17
NSAID sensitive (n = 25)
FeNO (ppb) 27.0 (17.8–40.9)† 18.0 (10.5–31.0) <0.01
%predicted FEV1 86.7 (63.3–104.9) 74.6 (52.4–89.8)† <0.01
uLTE4 (pg/mg creatinine) 118.3 (93.2–407.2) 204.9 (90.6–817.8)† <0.01
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; OPT, oral provocation test; ppb, parts per billion; FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in 1 second.
*P values before vs. after provocation test, Wilcoxon signed-rank test; †P < 0.01 compared to the NSAID-tolerant subjects.
According to the subgroup analysis, 10 NECD/NIUA, 9 NIBR, and 6 NERD were categorized as shown in Fig. 3. At baseline, %predicted FEV1 was not significantly different among different types of cross-reactive NSAID hypersensitivity, although those in patients with confirmed NIBR were lowest (64.9%, IQR 56.9–97.3). The significant differences in basal FeNO levels (P < 0.01) among the 3 different phenotypes were observed. The basal FeNO levels were significantly higher in NIBR (36.9%, IQR 27.0–95.4) than in NSAID-tolerant subjects (P < 0.01). After aspirin OPT, the reduction of %FEV1 was considerably higher in patients with confirmed NERD (22.0%, IQR 16.0-28.8), followed by NIBR (13.3%, IQR 7.6–28.0), compared to those in NSAID-tolerant groups (P < 0.01). Basal uLTE4 levels were not significantly different among the 3 phenotypes. Interestingly, uLTE4 levels after aspirin provocation were significantly higher in NERD and NIBR patients than in the NECD/NIUA and NSAID-tolerant groups (P < 0.05 and < 0.01, respectively).
Fig. 3 Respiratory parameters and uLTE4 levels in different phenotypes of NSAID-sensitive subjects compared to NSAID-tolerant subjects.
Baseline FeNO in NIBR and NERD were higher than those in the NSAID-tolerant group. After aspirin provocation, % predicted FEV1 in NERD and NIBR were significantly reduced from the baseline while uLTE4 levels were much higher than those in NSAID-tolerant subjects.
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; FEV1, forced expiratory volume in 1 second.
*P values < 0.05, †P values < 0.01.
Effects of aspirin desensitization on uLTE4 levels in patients diagnosed with NERD and NIBR
Aspirin desensitization was performed in selected patients (3 NERD and 3 NIBR) who had pre-existing inflammatory airway diseases and a history of recurrent nasal polyposis after surgery as shown in Table 3. The maintenance dose of aspirin was 650 mg/day during the first 6 months and reduced to 325 mg/day afterward. Levels of uLTE4 were measured at baseline after aspirin desensitization and serially followed up for 2–3 years as demonstrated in Fig. 4. Other than respiratory symptoms, acute urticarial rash and gastrointestinal symptoms (abdominal cramp/nausea/diarrhea) were also aggravated in NIBR subjects during aspirin desensitization as shown in Supplementary Fig. S1, but gradually relieved with supportive treatment. No sinus surgery was required for nasal polyp recurrence, and asthma symptoms were under control after aspirin desensitization in all 6 cases. Up to 3 years after aspirin desensitization, however, uLTE4 levels were significantly increased and remained elevated throughout the follow-up period, although urticarial rash and gastrointestinal symptoms were no longer observed while taking aspirin.
Table 3 Details of patients with cross-reactive NSAID hypersensitivity undergoing aspirin desensitization in this study
Patients (sex/year) Underlying diseases History of adverse drug reactions Indication for aspirin desensitization Follow-up duration (months) Asthma control before/after aspirin desensitization Recurrent nasal polyposis after aspirin desensitization Skin symptoms after aspirin desensitization Gastrointestinal symptoms after aspirin desensitization
1. NERD (M/46) Chronic sinusitis, nasal polyposis, asthma Acute asthma 20 min after taking aspirin 2 recurrent nasal polyps 74 Partly controlled with high dose ICS-LABA and add-on LTRA/well controlled with low dose ICS None NA NA
2. NERD (M/54) Chronic rhinitis, nasal polyposis, asthma Acute asthma, blocked nose 1 hr after taking aspirin 3 recurrent nasal polyps 24 Uncontrolled with high dose ICS-LABA and add-on LTRA/well controlled with medium dose ICS-LABA None NA NA
3. NERD (M/56) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked nose 1 hr after taking ibuprofen 6 recurrent nasal polyps 32 Partly controlled asthma with high dose ICS-LABA and add-on LTRA/well controlled with medium dose ICS-LABA None NA NA
4. NIBR (M/48) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked nose, conjunctival injection, urticarial rash 2 hr after taking aspirin 3 recurrent nasal polyps 72 Partly controlled with medium dose ICS-LABA/well controlled with low dose ICS-LABA None No rash after taking aspirin NA
5. NIBR (F/65) Chronic sinusitis, nasal polyposis, chronic urticaria, asthma (history of cardiac arrest from severe asthma) Urticarial rash, periorbital angioedema, blocked nose, conjunctival injection, rhinorrhea, bronchospasm/wheezing, hoarseness of voice 1 hr after taking aspirin, ibuprofen, mefenamic acid, acetaminophen 2 recurrent nasal polyps 48 Uncontrolled with high dose ICS-LABA and add-on LTRA/well controlled with low dose ICS-LABA None No rash after taking aspirin, chronic urticaria resolved NA
6. NIBR (F/38) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked/running nose, stomach cramp, diarrhea, periorbital angioedema, urticaria 30 min after taking ibuprofen, indomethacin, mefenamic acid 2 recurrent nasal polyps 21 Partly controlled with medium dose ICS-LABA/well controlled, with medium dose ICS-LABA None No rash after taking aspirin No gastrointestinal symptoms after taking aspirin
NSAID, non-steroidal anti-inflammatory drug; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; ICS, inhaled corticosteroid; LABA, long-acting beta-agonist; LTRA, leukotriene receptor antagonist; NA, not applicable (no symptoms prior to aspirin desensitization); NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
Fig. 4 uLTE4 levels in NSAID-sensitive subjects after aspirin desensitization.
Our study demonstrated that uLTE4 levels (pg/mg creatinine) in 3 NERD and 3 NIBR patients were increased and remained elevated up to 3 years after aspirin desensitization even though recurrent nasal polyposis was successfully prevented in all cases.
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
DISCUSSION
Most studies on NSAID hypersensitivity have focused on NERD, although worldwide epidemiological data suggest that NECD/NIUA might be more common. Recent data have demonstrated that some patients cannot be categorized into the current classification of NSAID hypersensitivity, for example those with NSAID-induced periorbital angioedema and NIBR.1419 These patients may also have underlying chronic airway diseases; however, the role of aspirin desensitization in the prevention of recurrent nasal polyposis and control of airway inflammation in NSAID-sensitive subjects other than the NERD phenotype has never been reported.
The leading presentations in NSAID-sensitive subjects in this study were periorbital angioedema, acute urticaria, bronchial symptoms, and naso-ocular reactions, respectively. Even those confirmed with NSAID exposure, a significant number of patients in our cohort also showed clinical responses in more than 1 organ system, indicating that the prevalence of NIBR was higher than previously thought. Although patients with IgE-mediated anaphylaxis might also present with multiple organ involvement, the fact that most of the reactions took about 1–2 hours to occur and the ability to react to multiple NSAIDs with dissimilar chemical structures made them more compatible with the non-immunologic effect of the drugs.
Facial angioedema around the periorbital area was the most common presenting symptom in Thai patients. Upon NSAID provocation, however, the predominant periorbital angioedema often accompanied by blocked nose, running nose, and itchy/red eyes. After a thorough examination, small urticarial rash on the trunk and extremities, and expiratory wheezing were occasionally detected, although frequently asymptomatic. It is noteworthy that periorbital angioedema may persist for hours or days while urticarial rash and respiratory symptoms are quickly resolved after treatment. As a result, NIBR could be underdiagnosed if history taking is not thoroughly reviewed, since symptoms with lesser severity in other organ systems may be unnoticed. In addition, the COX-1 inhibitor properties of the exposed NSAIDs could affect the phenotype of NSAID sensitivity reported by patients as some patients experienced both asthmatic attack and periorbital angioedema/generalized urticaria after taking aspirin but reported only periorbital edema after taking acetaminophen.
It is practically difficult to clearly distinguish between NSAID-induced periorbital angioedema and NSAID-induced naso-ocular reactions (upper airway manifestations of NERD), since patients occasionally experienced periorbital swelling, red/swollen eyes with tearing, and nasal congestion at the same time. In our opinion, the majority of NSAID hypersensitivity in the Thai population would be described as “NSAID-induced blended reaction with predominant periorbital angioedema” and probably related to “NSAID-induced isolated periorbital angioedema” phenotype as proposed by the Spanish group. It is interesting to note that the prevalence of atopic disease was high in this patient group. We speculate that the increased leukotriene production after NSAID consumption could lead to the worsening of pre-existing mucosal inflammation around the nose and eyes in patients who already suffered from the late-phase reaction of persistent allergic rhinitis.
Our study did not find any difference in terms of basal uLTE4 levels between NSAID-sensitive and NSAID-tolerant subjects. However, uLTE4 levels were higher in NSAID-sensitive patients, particularly in NERD and NIBR subjects, after the NSAID challenge compared to those in the NSAID-tolerant group. Though basal uLTE4 levels may not be a suitable marker to screen NSAID sensitivity status, elevated uLTE4 levels after aspirin OPT could be the supporting evidence for the diagnosis of cross-reactive NSAID hypersensitivity in cases where the clinical response is equivocal. Our study demonstrated that the degree of defective leukotriene homeostasis after exposure to drugs affecting the cyclo-oxygenase pathway might be related to the severity of respiratory involvement upon NSAID exposure.35 The fact that uLTE4 levels were barely changed after celecoxib provocation in patients with NSAID cross-reactivity confirms that celecoxib is a safe alternative NSAID in these patient groups.
According to our study, the patterns of NSAID hypersensitivity in southeast Asians are similar to those in southern Europeans and Latin Americans, and somewhat different from those reported in patients of northern European descent. Previous data suggested that aspirin nasal provocation could potentially diagnose some NSAID-sensitive patients presenting with predominant cutaneous reactions.3637 Retrospectively, some of these patients might be re-classified as the NIBR phenotype, since a decreased nasal volume was also observed. In other words, patients diagnosed with an NSAID-induced cutaneous reaction who positively reacted to NSAID nasal provocation, especially those with a periorbital reaction, might be NIBR subjects with subclinical airway involvement.
The novelties of this study were the findings that NIBR accounted for about one-third of adult patients with cross-reactive NSAID hypersensitivity and that aspirin desensitization could successfully prevent the recurrence of nasal polyposis and alleviate respiratory symptoms not only in NERD, but also in NIBR, even though urine LTE4 levels remained elevated. However, since the reactions in some NIBR patients could lead to serious adverse events, aspirin desensitization in NIBR subjects should be performed only when it is strongly indicated in selected patients with no previous severe reactions to NSAIDs. In NIBR subjects who experienced previous severe reactions in multiple organ systems, the procedure of aspirin desensitization, if necessary, should be carefully monitored and the administration of biological agents such as dupilumab, if available, should be considered a safer therapeutic option in these cases.
Interestingly, uLTE4 levels were increased after aspirin desensitization and remained elevated throughout the follow-up period. It should be emphasized that urticarial rash and stomach-ache in NIBR patients also disappeared while patients were taking daily aspirin. These data suggest that the pathogenesis of nasal polyposis cannot be explained by cysLT overproduction alone and that aspirin desensitization could be useful to alleviate both respiratory and non-respiratory symptoms in NIBR subjects.
Interestingly, a recent study also found that the clinical benefit of high-dose aspirin desensitization in NERD was independent of a reduction of mast cell activation and cysLT production. They reported paradoxically increased uLTE4 levels 8 weeks after aspirin desensitization compared to the baseline levels and concluded that high-dose aspirin therapy did not restore the impaired eicosanoid pathway.38 According to their study findings and ours, the therapeutic effect of aspirin desensitization was not directly correlated with a change of arachidonic acid metabolism.
There are some limitations to this study. Aspirin desensitization was performed in only 6 patients in our cohort; therefore, the comparative success rates and potential adverse reactions of aspirin desensitization between NERD and NIBR patients could not be analyzed. Further studies with a larger sample size are needed to compare the long-term prognosis between NERD and NIBR, to understand the mechanism of aspirin desensitization for the improvement of respiratory and extra-respiratory symptoms and to evaluate its risk-benefit ratio of aspirin desensitization in NIBR subjects.
In conclusion, NIBR is not uncommon among patients diagnosed with NSAID hypersensitivity in Thailand. Increased uLTE4 levels upon aspirin provocation suggested a diagnosis of NSAID cross-reactivity, while baseline uLTE4 levels were not distinguishable between NSAID-tolerant and NSAID-sensitive subjects. Our study indicates that aspirin desensitization is effective not only in NERD but also in NIBR. The persistently high levels of uLTE4 in spite of clinical improvement in NSAID-sensitive patients after successful aspirin desensitization suggest that elevated leukotrienes alone cannot explain the pathogenesis of NSAID hypersensitivity reactions.
ACKNOWLEDGMENTS
This study was supported by the Ratchadaphiseksomphot fund, Faculty of Medicine, Chulalongkorn University, grant No. RA55/19 and the Skin and Allergy Research Unit, Chulalongkorn University, Bangkok, Thailand. Study data were collected and managed using Research Electronic Data Capture (REDCap) hosted at HIV Netherlands Australia Thailand Research Collaboration. The authors thank Thitima Kantachatvanich, MD for providing patient information.
Disclosure: There are no financial or other issues that might lead to conflict of interest.
SUPPLEMENTARY MATERIALS
Supplementary Table S1
Clinical characteristics of patients with confirmed NSAID-induced immediate reactions
Supplementary Fig. S1
Representative photos of skin rash demonstrated during aspirin desensitization in NIBR patients. | UNKNOWN | DrugDosageText | CC BY-NC | 33474858 | 19,056,205 | 2021-03 |
What was the outcome of reaction 'Urticaria'? | Clinical Characteristics, Urinary Leukotriene E4 Levels, and Aspirin Desensitization Results in Patients With NSAID-Induced Blended Reactions.
OBJECTIVE
Data on non-steroidal anti-inflammatory drug (NSAID) hypersensitivity in Southeast Asia are scarce. Increased urinary leukotriene E4 (uLTE4) levels have been suggested as a biomarker of NSAID-exacerbated respiratory disease (NERD). This study investigated clinical patterns of NSAID sensitivity in Thailand and the diagnostic roles of uLTE4 measurement in various phenotypes.
METHODS
The clinical phenotypes in 92 Thai adults with cross-reactive NSAID hypersensitivity were characterized based on the clinical history and drug provocation. The uLTE4 levels were measured at baseline, after aspirin provocation and after desensitization.
RESULTS
More than half of the patients (56.5%) presented with cutaneous symptoms (NSAID-exacerbated cutaneous disease), while one-third (33.7%) developed symptoms in at least 2 systems (NSAID-induced blended reactions; NIBR). Fifty-two patients underwent drug provocation and 59.6% of them yielded positive results. After drug provocation, a significant number of patients with confirmed NSAID cross-reactivity experienced clinical symptoms in more than one organ system. The uLTE4 levels at baseline were comparable between the NSAID-tolerant and NSAID-sensitive groups, but were substantially increased after aspirin provocation predominantly in NERD (983.4 pg/mg creatinine) and NIBR (501.0 pg/mg creatinine) compared to NSAID-tolerant subjects (122.1 pg/mg creatinine, P < 0.01 and 0.05, respectively). The uLTE4 levels were elevated after aspirin desensitization, although nasal polyposis and asthma were under control in 3 NERD and 3 NIBR subjects.
CONCLUSIONS
NIBR is not uncommon among NSAID-sensitive patients in Thailand. The diagnostic value of basal uLTE4 levels was limited, but increased uLTE4 levels upon aspirin provocation suggest NSAID cross-reactivity with respiratory components. This study indicates that aspirin desensitization, if necessary, might be effective in both NERD and NIBR.
BACKGROUND
ClinicalTrials.gov Identifier: NCT03849625.
INTRODUCTION
Hypersensitivity reactions to aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most common drug allergic reactions in clinical practice. They are generally categorized into 5 major phenotypes: NSAID-exacerbated respiratory disease (NERD), NSAID-exacerbated cutaneous (urticaria/angioedema) disease (NECD) in patients with underlying chronic urticaria, NSAID-induced urticaria/angioedema (NIUA) in patients without underlying chronic urticaria, single NSAID-induced urticaria/angioedema or anaphylaxis, and single NSAID-induced delayed hypersensitivity reactions.1 The first 3 phenotypes are non-immunologically mediated, and patients can develop cross-reactive hypersensitivity to chemically unrelated NSAIDs, while the latter 2 are selective NSAID sensitivities associated with drug-specific immunoglobulin E (IgE) and T-cell response, respectively.
Genetic and epigenetic variations play significant roles in the development of NERD.2 The proposed underlying mechanism is that the disturbance in arachidonic acid synthesis pathways leads to overproduction of cysteinyl leukotrienes (cysLT) and persistent airway inflammation.3 Mast cells are believed to be the major source of cysLT, but platelet-adherent leukocytes may be responsible for cysLT overproduction in NERD as well.4 The consumption of drugs inhibiting the cyclooxygenase-1 (COX-1) enzyme, such as aspirin and conventional NSAIDs, aggravates respiratory symptoms by enhancing cysLT production in NSAID-sensitive subjects, while the administration of specific COX-2 inhibitors, such as celecoxib, is generally safe.56 Besides aspirin/NSAID avoidance, aspirin desensitization has also been proven to be helpful for long term management in NERD subjects. Beneficial effects of aspirin desensitization in preventing nasal polyp recurrence and control symptoms of chronic rhinosinusitis and asthma have been well documented.7 Rapid aspirin desensitization has shown to be effective for the treatment of coronary artery disease in patients with a history of aspirin/NSAID-induced urticaria/angioedema, but it is not indicated for the treatment of chronic urticaria.8
Worldwide epidemiological data on clinical characteristics of NSAID hypersensitivity are limited. Most studies on NERD were performed in the United States and northern European countries.9101112 However, the predominant manifestation in Latin Americans and southern Europeans is the cutaneous phenotype (NIUA, NECD, and NSAID-induced isolated periorbital angioedema).1314 Studies in Asian populations have suggested that the prevalence of the NERD phenotype is not common in this region of the world. A study performed in China indicated that the prevalence of NSAID hypersensitivity in Chinese patients with chronic rhinosinusitis is very low (0.57%) compared to their European counterparts.15 It was also noted that NSAID-induced blended reactions (NIBR) are common in young Asian, atopic children in Singapore.16 Reports from Singapore and Thailand indicated that aspirin/NSAID-induced angioedema/urticaria is probably the prominent phenotype in Southeast Asia, with acetaminophen hypersensitivity being frequent.1718
In clinical practice, the current classification of cross-reactive NSAID hypersensitivity into 3 distinct phenotypes has some limitations. Clinical characteristics in NSAID-sensitive patients may not be well defined, and a combination of respiratory and cutaneous or other symptoms, such as gastrointestinal symptoms (mixed or blended reactions), is frequently observed.19 A previous report stated that aspirin nasal provocation is potentially useful for diagnosing patients with the blended reaction as well.20 However, the role of aspirin desensitization in other phenotypes of NSAID hypersensitivity, besides NERD, for long-term management of inflammatory airway diseases has not yet been established. Whether aspirin desensitization would be effective in controlling asthma and the recurrence of nasal polyposis after sinus surgery in NIBR is currently unknown.
At present, cross-reactive types of NSAID hypersensitivity can only be diagnosed by careful history taking and controlled-provocation testing, since there is no reliable in vitro method to confirm the diagnosis.21 There is evidence that basal urinary levels of leukotriene E4 (uLTE4), a stable product of the cysLT synthesis pathway, are elevated in NERD patients and could be a potential biomarker for differentiating between NSAID-sensitive and NSAID-tolerant asthmatics. However, these data are still controversial.222324 There have also been preliminary studies showing that uLTE4 levels might be increased in NECD.2526 Whether the measurement of basal uLTE4 levels could be a diagnostic marker for any phenotype of NSAID hypersensitivity is yet to be explored.
The purpose of this study was to analyze the clinical characteristics of patients diagnosed with NSAID-induced immediate reactions in Thailand and to explore whether the measurement of uLTE4 levels would be helpful in identifying NSAID-sensitive subjects or in differentiating among different phenotypes of cross-reactive NSAID hypersensitivities.
MATERIALS AND METHODS
Patient recruitment
Adult patients (18 years of age and older) with a suggestive history of NSAID-induced hypersensitivity reaction visiting the allergy clinic at King Chulalongkorn University Hospital between June 2014 and July 2018 were recruited into this study. Those with a history compatible with drug-induced non-immediate reactions (maculopapular rash, fixed drug eruption, acute generalized exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms, Stevens-Johnson syndrome/toxic epidermal necrolysis) or NSAID-related side effects were excluded. The status of NSAID-induced immediate hypersensitivity was diagnosed in patients with a well-documented drug allergy history or in patients with a suggestive history of NSAID sensitivity who yielded a positive drug provocation test as follows.
Clinical diagnosis of NSAID hypersensitivity
The diagnosis of cross-reactive NSAID hypersensitivity was clinically made in patients with a well-documented history of multiple episodes of respiratory, cutaneous, and/or gastrointestinal reactions within 2 hours after exposure to at least 2 different NSAID classes.1212728 Patient demographic data were collected, including the underlying diseases, atopic family history, and details on drug allergy history as well as the presenting symptoms and types of the culprit NSAIDs.
Aspirin provocation test
Oral aspirin provocation was performed in patients with a suggestive medical history or in those who had a history of an immediate reaction to a single NSAID to confirm the diagnosis of cross-reactive NSAID hypersensitivity according to the EAACI/GA2LEN guidelines, with some modifications.293031 Four increasing doses of aspirin (40.5, 81, 150, and 300 mg) were administered at 90-minute intervals until a positive reaction occurred. Clinical symptoms, fractional exhaled nitric oxide (FeNO), and the forced expiratory volume in 1 second (FEV1) were monitored to evaluate the reaction. A positive provocation test was defined if any of the following reactions developed: lower respiratory/bronchial reaction (a 15% decrease in FEV1 plus naso-ocular reaction or a 20% decrease in FEV1 alone), upper respiratory/naso-ocular reaction (nasal congestion and rhinorrhea; conjunctival injection), cutaneous reactions (urticaria/angioedema, periorbital edema), and/or other reactions (gastrointestinal symptoms such as nausea/vomiting, stomach cramps, and diarrhea). The test was considered negative if a patient tolerated the final dose (300 mg of aspirin) without any significant symptoms mentioned above.
Oral provocation test (OPT) with other NSAIDs, acetaminophen, or celecoxib
Patients with a history of an immediate reaction to only aspirin were challenged with escalating doses of ibuprofen to confirm the diagnosis of cross-reactive NSAID sensitivity. Patients with a history of an immediate reaction to a single NSAID were provoked with the suspected drug to verify the status of single NSAID hypersensitivity after a negative aspirin provocation test. Escalating doses of ibuprofen, diclofenac, and acetaminophen were administered, if applicable, as follows: ibuprofen (50, 100, and 200 mg), diclofenac (6.25, 12.5, and 25 mg), and acetaminophen (125, 250, and 500 mg). Celecoxib was also provoked in 3 doses (50, 100, and 200 mg) in patients with confirmed hypersensitivity to multiple NSAIDs who were willing to identify a safe alternative drug. The provocation test for each drug was performed on separate days at least 7 days apart. Each dose of drug provocation was provided at 90-minute intervals until the final dose was reached.
Classification of NSAID hypersensitivity according to drug provocation test results
Patients with cross-reactive NSAID phenotypes were classified according to the results of the drug provocation test as 1) NECD/NIUA if they developed cutaneous symptoms alone; 2) NERD if they developed respiratory symptoms alone; and 3) NIBR if they developed a combination of symptoms involving more than one organ system (respiratory, cutaneous, and/or gastrointestinal symptoms). Single NSAID hypersensitivity was diagnosed in patients with a positive provocation test to the suspected NSAID, but a negative aspirin provocation test. Patients who had negative provocations to both aspirin and the suspected culprit drug were labeled as NSAID-tolerant subjects. NECD/NIUA were purposely categorized together in our study to compare the differences and similarities between patients diagnosed with NSAID-induced cutaneous reactions and -respiratory reactions. Moreover, NECD and NIUA share similar background characteristics from a clinical point of view and some patients diagnosed with NIUA eventually evolve to NECD over time.32
Skin prick tests with common aeroallergens in Thailand (mixed dust mites, mixed cockroaches, mixed mold, cat dander, dog hair, and southern grass mix; ALK-Abello, Hørsholm, Denmark) were also examined in tested patients to identify atopic status. Wheal size ≥ 3 mm was considered a positive test.
Measurement of FeNO and the FEV1 in patients who underwent drug provocation test
FeNO was measured in all participants at baseline and after drug provocation by using a portable electrochemical analyzer (NObreath®; Bedfont Scientific Ltd, Maidstone, UK) according to the ATS/ERS recommendations.33 Measurements of FEV1 were also performed using a Vitalograph spirometer (Vitalograph®, Buckingham, UK). The best of 3 repeated attempts was recorded.
The uLTE4 measurement
The uLTE4 levels were measured by a leukotriene E4 ELISA kit (Cayman Chemical, Ann Arbor, MI, USA) at baseline and 90 minutes after the final dose of drug provocation, as well as at the follow-up visits after aspirin desensitization and reported after adjustment to urine creatinine levels.
Aspirin desensitization
Outpatient aspirin desensitization was performed in NSAID-sensitive patients who were referred from otolaryngologists to prevent the recurrence of nasal polyposis. The procedure was carried out according to the intranasal ketorolac and modified aspirin challenge 2-day protocol.34 Aspirin desensitization was completed after patients were able to tolerate a 325-mg dose of aspirin by the end of day 2 and experience no symptoms, changes in nasal flow rates, or decrease in FEV1 values. The prescribed maintenance dose of aspirin was 325 mg twice a day.
Statistical analysis
Patient characteristics are reported as means ± standard deviation for quantitative analysis, and median and interquartile range (IQR) are used to describe non-parametric data. The Mann-Whitney U test and Kruskal-Wallis test with Dunn's multiple comparisons were used to analyze the differences between 2 groups and more than 2 groups, respectively. Statistical analyses were performed using GraphPad Prism 8.3 software (GraphPad Software Inc., San Diego, CA, USA). P values < 0.05 were considered statistically significant.
Ethical considerations
Patients enrolled in this study were those who recruited in the study entitled “Characteristics of Patients Diagnosed With NSAID Sensitivity in Thailand” registered at ClinicalTrials.gov (NCT03849625). The study was approved by the Ethics and Research Committee of the Faculty of Medicine, Chulalongkorn University, Approval Number: COA No. 659/2012 and informed consent was obtained from all participants.
RESULTS
A total of 158 adult patients with a suspected history of NSAID hypersensitivity between 2015 and 2018 at King Chulalongkorn Memorial Hospital were initially recruited into this study as shown in Fig. 1. Thirty-five patients with a history compatible with a non-immediate hypersensitivity reaction and 4 subjects with clinical symptoms compatible with NSAID-related side effects were later excluded.
Fig. 1 Schematic diagram of patient selection for this study.
A total of 158 patients with a suspected history of NSAID hypersensitivity were initially recruited into this study. Cross-reactive NSAID hypersensitivity was clinically diagnosed in 67 patients with a well-documented drug allergy history and verified by a positive drug provocation test in 25 patients with a suggestive history of NSAID reactions.
NSAID, non-steroidal anti-inflammatory drug.
Cross-reactive NSAID hypersensitivity was clinically diagnosed in 67 patients with a convincing drug allergy history as defined in the methods section. The remaining 52 patients with a suggestive history of NSAID hypersensitivity underwent an OPT to confirm NSAID cross-reactivity status. Fifteen out of 25 patients with confirmed NSAID cross-reactivity were subsequently provoked with celecoxib to find a safe alternative NSAID. Single NSAID/acetaminophen hypersensitivity was verified in 6 patients who tolerated aspirin provocation but developed an allergic reaction upon re-challenge with acetaminophen or diclofenac.
Demographic data of adult patients with cross-reactive NSAID hypersensitivity
The clinical characteristics of adult patients with cross-reactive NSAID hypersensitivity are shown in Table 1 (n = 92). Most patients were females (77.2%) with an average age of 45.7 ± 13.4 years. The average age of onset was 32.2 ± 13.3 years and about half of them had atopic family history. The majority of them (56.5%) reported only cutaneous symptoms such as facial angioedema and/or acute urticarial rash, after NSAID exposure, while 9.8% of them developed only respiratory symptoms. Interestingly, about 33.7% of the patients experienced a combination of symptoms in multiple organ systems as shown in Fig. 2. The groups of NSAIDs frequently responsible for hypersensitivity reactions were propionic acid derivatives and acetic acid derivatives. Although inflammatory airway diseases (chronic sinusitis, nasal polyposis, and asthma) were significantly more common in patients who experienced only respiratory reactions after exposure to an NSAID compared to the other phenotypes, a significant portion of the patients reporting blended reactions had underlying airway diseases and chronic urticaria as well. Acetaminophen intolerance was also reported in about one-third (35.9%) of NSAID-sensitive subjects.
Table 1 Clinical characteristics among different phenotypes of patients with cross-reactive NSAID hypersensitivity (n = 92)
Phenotypes NECD/NIUA (n = 52) NERD (n = 9) NIBR (n = 31) Total (n = 92)
Gender (female/male) 37/15 6/3 28/3 71/21
Age (yr) 43.6 ± 12.3 47.3 ± 11.9 48.7 ± 15.3 45.7 ± 13.4
Age of onset (yr) 31.3 ± 13.8 34.6 ± 11.0 33.1 ± 13.3 32.2 ± 13.3
Underlying disease (%)
Chronic urticaria 13.5 11.1 29.0 18.5
Chronic sinusitis* 13.5 55.6 32.3 23.9
Nasal polyposis* 7.7 66.7 16.1 16.3
Asthma* 17.3 88.9 35.5 30.4
Atopic family history (%) 42.3 55.6 61.3 50.0
Drug exposure time to symptom onset (min) 58.8 ± 31.9 48.3 ± 34.3 47.6 ± 29.9 54.0 ± 31.6
Presenting symptoms (%)*
Facial/periorbital angioedema 71.2 0.0 74.2 65.2
Acute urticaria 73.1 0.0 61.3 62.0
Naso-ocular reaction 0.0 33.3 61.3 23.9
Acute asthma 0.0 88.9 67.7 31.5
Gastrointestinal symptoms 0.0 0.0 16.1 5.4
Implicated NSAIDs (%)†
Salicylic acids 23.1 55.6 35.5 30.4
Propionic acids 44.2 22.2 54.8 45.7
Acetic acids 23.1 22.2 48.4 31.5
Enolic acids 7.7 0.0 6.5 6.5
Anthranilic/fenamic acids 28.8 11.1 29.0 27.2
Acetaminophen intolerance (%)§ 28.8 22.2 51.6 35.9
Values are presented as number (%) or mean ± standard deviation. Each patient could present with multiple symptoms and from more than one implicated drug.
NSAID, non-steroidal anti-inflammatory drug; NECD, non-steroidal anti-inflammatory drug-exacerbated cutaneous (urticaria/angioedema) disease in patients with underlying chronic urticaria; NIUA, non-steroidal anti-inflammatory drug-induced urticaria/angioedema in patients without underlying chronic urticaria; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
*P < 0.05 among different phenotypes. †Examples of commonly implicated drugs in this study based on NSAID classification: 1) Salicylic acids: acetylsalicylic acid (aspirin), salicylic acid, diflunisal, salsalate; 2) Propionic acids: ibuprofen, naproxen, ketoprofen, fenoprofen, flurbiprofen; 3) Acetic acids: indomethacin, ketorolac, diclofenac, sulindac; 4) Enolic acids: piroxicam, meloxicam, tenoxicam; 5) Anthranilic/fenamic acids: mefenamic acid, flufenamic acid. §Acetaminophen intolerance: cannot tolerate acetaminophen higher than 500 mg.
Fig. 2 Clinical presentations in patients with cross-reactive NSAID hypersensitivity.
A proportional Venn diagram shows that about half of patients with cross-reactive NSAID hypersensitivity in Thailand reported only cutaneous symptoms after NSAID exposure, while one-third of them experienced NSAID-induced blended reactions.
NSAID, non-steroidal anti-inflammatory drug.
Clinical respiratory parameters and uLTE4 levels in different phenotypes of patients with cross-reactive NSAID hypersensitivity confirmed by positive OPT
NSAID hypersensitivity was confirmed in 59.6% (31/52) of the tested patients with a history of NSAID-induced immediate reactions. The majority of patients with cross-reactive NSAID hypersensitivity (17/25) according to OPT results were atopic individuals. The common phenotypes of patients with confirmed cross-reactive NSAID sensitivity were NECD/NIUA, NIBR, and NERD, respectively, as shown in Supplementary Table S1.
The average FeNO, %predicted FEV1, and uLTE4 levels were measured at baseline and after provocation with aspirin/NSAID in 25 NSAID cross-reactive and 21 NSAID-tolerant subjects as shown in Table 2. At baseline, patients with confirmed NSAID cross-reactivity (NSAID-sensitive group) had higher FeNO (P < 0.01) and slightly less %predicted FEV1 compared to the NSAID-tolerant subjects, while basal uLTE4 levels between NSAID-sensitive and NSAID-tolerant groups were comparable. After provocation, %predicted FEV1 was substantially reduced in NSAID-sensitive subjects, whereas uLTE4 levels were significantly elevated compared to the NSAID-tolerant group (P < 0.01). Celecoxib provocation was well tolerated in all NSAID-sensitive subjects. No statistical differences in the average FeNO, %predicted FEV1, or uLTE4 levels in 15 NSAID-sensitive patients (7 NECD/NIUA, 4 NIBR, 4 NERD) after celecoxib provocation were observed compared to those in NSAID-tolerant subjects.
Table 2 Respiratory parameters and uLTE4 levels in NSAID-sensitive subjects upon provocation with aspirin or celecoxib compared to NSAID-tolerant subjects
Characteristics Baseline After aspirin (OPT) P value*
NSAID tolerant (n = 21)
FeNO (ppb) 13.0 (8.5–19.5) 10.2 (7.0–16.8) 0.03
%predicted FEV1 100.8 (82.8–115.9) 99.0 (75.2–118.2) 0.90
uLTE4 (pg/mg creatinine) 116.3 (66.5–305.4) 122.1 (63.5–173.8) 0.17
NSAID sensitive (n = 25)
FeNO (ppb) 27.0 (17.8–40.9)† 18.0 (10.5–31.0) <0.01
%predicted FEV1 86.7 (63.3–104.9) 74.6 (52.4–89.8)† <0.01
uLTE4 (pg/mg creatinine) 118.3 (93.2–407.2) 204.9 (90.6–817.8)† <0.01
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; OPT, oral provocation test; ppb, parts per billion; FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in 1 second.
*P values before vs. after provocation test, Wilcoxon signed-rank test; †P < 0.01 compared to the NSAID-tolerant subjects.
According to the subgroup analysis, 10 NECD/NIUA, 9 NIBR, and 6 NERD were categorized as shown in Fig. 3. At baseline, %predicted FEV1 was not significantly different among different types of cross-reactive NSAID hypersensitivity, although those in patients with confirmed NIBR were lowest (64.9%, IQR 56.9–97.3). The significant differences in basal FeNO levels (P < 0.01) among the 3 different phenotypes were observed. The basal FeNO levels were significantly higher in NIBR (36.9%, IQR 27.0–95.4) than in NSAID-tolerant subjects (P < 0.01). After aspirin OPT, the reduction of %FEV1 was considerably higher in patients with confirmed NERD (22.0%, IQR 16.0-28.8), followed by NIBR (13.3%, IQR 7.6–28.0), compared to those in NSAID-tolerant groups (P < 0.01). Basal uLTE4 levels were not significantly different among the 3 phenotypes. Interestingly, uLTE4 levels after aspirin provocation were significantly higher in NERD and NIBR patients than in the NECD/NIUA and NSAID-tolerant groups (P < 0.05 and < 0.01, respectively).
Fig. 3 Respiratory parameters and uLTE4 levels in different phenotypes of NSAID-sensitive subjects compared to NSAID-tolerant subjects.
Baseline FeNO in NIBR and NERD were higher than those in the NSAID-tolerant group. After aspirin provocation, % predicted FEV1 in NERD and NIBR were significantly reduced from the baseline while uLTE4 levels were much higher than those in NSAID-tolerant subjects.
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; FEV1, forced expiratory volume in 1 second.
*P values < 0.05, †P values < 0.01.
Effects of aspirin desensitization on uLTE4 levels in patients diagnosed with NERD and NIBR
Aspirin desensitization was performed in selected patients (3 NERD and 3 NIBR) who had pre-existing inflammatory airway diseases and a history of recurrent nasal polyposis after surgery as shown in Table 3. The maintenance dose of aspirin was 650 mg/day during the first 6 months and reduced to 325 mg/day afterward. Levels of uLTE4 were measured at baseline after aspirin desensitization and serially followed up for 2–3 years as demonstrated in Fig. 4. Other than respiratory symptoms, acute urticarial rash and gastrointestinal symptoms (abdominal cramp/nausea/diarrhea) were also aggravated in NIBR subjects during aspirin desensitization as shown in Supplementary Fig. S1, but gradually relieved with supportive treatment. No sinus surgery was required for nasal polyp recurrence, and asthma symptoms were under control after aspirin desensitization in all 6 cases. Up to 3 years after aspirin desensitization, however, uLTE4 levels were significantly increased and remained elevated throughout the follow-up period, although urticarial rash and gastrointestinal symptoms were no longer observed while taking aspirin.
Table 3 Details of patients with cross-reactive NSAID hypersensitivity undergoing aspirin desensitization in this study
Patients (sex/year) Underlying diseases History of adverse drug reactions Indication for aspirin desensitization Follow-up duration (months) Asthma control before/after aspirin desensitization Recurrent nasal polyposis after aspirin desensitization Skin symptoms after aspirin desensitization Gastrointestinal symptoms after aspirin desensitization
1. NERD (M/46) Chronic sinusitis, nasal polyposis, asthma Acute asthma 20 min after taking aspirin 2 recurrent nasal polyps 74 Partly controlled with high dose ICS-LABA and add-on LTRA/well controlled with low dose ICS None NA NA
2. NERD (M/54) Chronic rhinitis, nasal polyposis, asthma Acute asthma, blocked nose 1 hr after taking aspirin 3 recurrent nasal polyps 24 Uncontrolled with high dose ICS-LABA and add-on LTRA/well controlled with medium dose ICS-LABA None NA NA
3. NERD (M/56) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked nose 1 hr after taking ibuprofen 6 recurrent nasal polyps 32 Partly controlled asthma with high dose ICS-LABA and add-on LTRA/well controlled with medium dose ICS-LABA None NA NA
4. NIBR (M/48) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked nose, conjunctival injection, urticarial rash 2 hr after taking aspirin 3 recurrent nasal polyps 72 Partly controlled with medium dose ICS-LABA/well controlled with low dose ICS-LABA None No rash after taking aspirin NA
5. NIBR (F/65) Chronic sinusitis, nasal polyposis, chronic urticaria, asthma (history of cardiac arrest from severe asthma) Urticarial rash, periorbital angioedema, blocked nose, conjunctival injection, rhinorrhea, bronchospasm/wheezing, hoarseness of voice 1 hr after taking aspirin, ibuprofen, mefenamic acid, acetaminophen 2 recurrent nasal polyps 48 Uncontrolled with high dose ICS-LABA and add-on LTRA/well controlled with low dose ICS-LABA None No rash after taking aspirin, chronic urticaria resolved NA
6. NIBR (F/38) Chronic sinusitis, nasal polyposis, asthma Acute asthma, blocked/running nose, stomach cramp, diarrhea, periorbital angioedema, urticaria 30 min after taking ibuprofen, indomethacin, mefenamic acid 2 recurrent nasal polyps 21 Partly controlled with medium dose ICS-LABA/well controlled, with medium dose ICS-LABA None No rash after taking aspirin No gastrointestinal symptoms after taking aspirin
NSAID, non-steroidal anti-inflammatory drug; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; ICS, inhaled corticosteroid; LABA, long-acting beta-agonist; LTRA, leukotriene receptor antagonist; NA, not applicable (no symptoms prior to aspirin desensitization); NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
Fig. 4 uLTE4 levels in NSAID-sensitive subjects after aspirin desensitization.
Our study demonstrated that uLTE4 levels (pg/mg creatinine) in 3 NERD and 3 NIBR patients were increased and remained elevated up to 3 years after aspirin desensitization even though recurrent nasal polyposis was successfully prevented in all cases.
uLTE4, urinary leukotriene E4; NSAID, non-steroidal anti-inflammatory drug; NERD, non-steroidal anti-inflammatory drug-exacerbated respiratory disease; NIBR, non-steroidal anti-inflammatory drug-induced blended reactions.
DISCUSSION
Most studies on NSAID hypersensitivity have focused on NERD, although worldwide epidemiological data suggest that NECD/NIUA might be more common. Recent data have demonstrated that some patients cannot be categorized into the current classification of NSAID hypersensitivity, for example those with NSAID-induced periorbital angioedema and NIBR.1419 These patients may also have underlying chronic airway diseases; however, the role of aspirin desensitization in the prevention of recurrent nasal polyposis and control of airway inflammation in NSAID-sensitive subjects other than the NERD phenotype has never been reported.
The leading presentations in NSAID-sensitive subjects in this study were periorbital angioedema, acute urticaria, bronchial symptoms, and naso-ocular reactions, respectively. Even those confirmed with NSAID exposure, a significant number of patients in our cohort also showed clinical responses in more than 1 organ system, indicating that the prevalence of NIBR was higher than previously thought. Although patients with IgE-mediated anaphylaxis might also present with multiple organ involvement, the fact that most of the reactions took about 1–2 hours to occur and the ability to react to multiple NSAIDs with dissimilar chemical structures made them more compatible with the non-immunologic effect of the drugs.
Facial angioedema around the periorbital area was the most common presenting symptom in Thai patients. Upon NSAID provocation, however, the predominant periorbital angioedema often accompanied by blocked nose, running nose, and itchy/red eyes. After a thorough examination, small urticarial rash on the trunk and extremities, and expiratory wheezing were occasionally detected, although frequently asymptomatic. It is noteworthy that periorbital angioedema may persist for hours or days while urticarial rash and respiratory symptoms are quickly resolved after treatment. As a result, NIBR could be underdiagnosed if history taking is not thoroughly reviewed, since symptoms with lesser severity in other organ systems may be unnoticed. In addition, the COX-1 inhibitor properties of the exposed NSAIDs could affect the phenotype of NSAID sensitivity reported by patients as some patients experienced both asthmatic attack and periorbital angioedema/generalized urticaria after taking aspirin but reported only periorbital edema after taking acetaminophen.
It is practically difficult to clearly distinguish between NSAID-induced periorbital angioedema and NSAID-induced naso-ocular reactions (upper airway manifestations of NERD), since patients occasionally experienced periorbital swelling, red/swollen eyes with tearing, and nasal congestion at the same time. In our opinion, the majority of NSAID hypersensitivity in the Thai population would be described as “NSAID-induced blended reaction with predominant periorbital angioedema” and probably related to “NSAID-induced isolated periorbital angioedema” phenotype as proposed by the Spanish group. It is interesting to note that the prevalence of atopic disease was high in this patient group. We speculate that the increased leukotriene production after NSAID consumption could lead to the worsening of pre-existing mucosal inflammation around the nose and eyes in patients who already suffered from the late-phase reaction of persistent allergic rhinitis.
Our study did not find any difference in terms of basal uLTE4 levels between NSAID-sensitive and NSAID-tolerant subjects. However, uLTE4 levels were higher in NSAID-sensitive patients, particularly in NERD and NIBR subjects, after the NSAID challenge compared to those in the NSAID-tolerant group. Though basal uLTE4 levels may not be a suitable marker to screen NSAID sensitivity status, elevated uLTE4 levels after aspirin OPT could be the supporting evidence for the diagnosis of cross-reactive NSAID hypersensitivity in cases where the clinical response is equivocal. Our study demonstrated that the degree of defective leukotriene homeostasis after exposure to drugs affecting the cyclo-oxygenase pathway might be related to the severity of respiratory involvement upon NSAID exposure.35 The fact that uLTE4 levels were barely changed after celecoxib provocation in patients with NSAID cross-reactivity confirms that celecoxib is a safe alternative NSAID in these patient groups.
According to our study, the patterns of NSAID hypersensitivity in southeast Asians are similar to those in southern Europeans and Latin Americans, and somewhat different from those reported in patients of northern European descent. Previous data suggested that aspirin nasal provocation could potentially diagnose some NSAID-sensitive patients presenting with predominant cutaneous reactions.3637 Retrospectively, some of these patients might be re-classified as the NIBR phenotype, since a decreased nasal volume was also observed. In other words, patients diagnosed with an NSAID-induced cutaneous reaction who positively reacted to NSAID nasal provocation, especially those with a periorbital reaction, might be NIBR subjects with subclinical airway involvement.
The novelties of this study were the findings that NIBR accounted for about one-third of adult patients with cross-reactive NSAID hypersensitivity and that aspirin desensitization could successfully prevent the recurrence of nasal polyposis and alleviate respiratory symptoms not only in NERD, but also in NIBR, even though urine LTE4 levels remained elevated. However, since the reactions in some NIBR patients could lead to serious adverse events, aspirin desensitization in NIBR subjects should be performed only when it is strongly indicated in selected patients with no previous severe reactions to NSAIDs. In NIBR subjects who experienced previous severe reactions in multiple organ systems, the procedure of aspirin desensitization, if necessary, should be carefully monitored and the administration of biological agents such as dupilumab, if available, should be considered a safer therapeutic option in these cases.
Interestingly, uLTE4 levels were increased after aspirin desensitization and remained elevated throughout the follow-up period. It should be emphasized that urticarial rash and stomach-ache in NIBR patients also disappeared while patients were taking daily aspirin. These data suggest that the pathogenesis of nasal polyposis cannot be explained by cysLT overproduction alone and that aspirin desensitization could be useful to alleviate both respiratory and non-respiratory symptoms in NIBR subjects.
Interestingly, a recent study also found that the clinical benefit of high-dose aspirin desensitization in NERD was independent of a reduction of mast cell activation and cysLT production. They reported paradoxically increased uLTE4 levels 8 weeks after aspirin desensitization compared to the baseline levels and concluded that high-dose aspirin therapy did not restore the impaired eicosanoid pathway.38 According to their study findings and ours, the therapeutic effect of aspirin desensitization was not directly correlated with a change of arachidonic acid metabolism.
There are some limitations to this study. Aspirin desensitization was performed in only 6 patients in our cohort; therefore, the comparative success rates and potential adverse reactions of aspirin desensitization between NERD and NIBR patients could not be analyzed. Further studies with a larger sample size are needed to compare the long-term prognosis between NERD and NIBR, to understand the mechanism of aspirin desensitization for the improvement of respiratory and extra-respiratory symptoms and to evaluate its risk-benefit ratio of aspirin desensitization in NIBR subjects.
In conclusion, NIBR is not uncommon among patients diagnosed with NSAID hypersensitivity in Thailand. Increased uLTE4 levels upon aspirin provocation suggested a diagnosis of NSAID cross-reactivity, while baseline uLTE4 levels were not distinguishable between NSAID-tolerant and NSAID-sensitive subjects. Our study indicates that aspirin desensitization is effective not only in NERD but also in NIBR. The persistently high levels of uLTE4 in spite of clinical improvement in NSAID-sensitive patients after successful aspirin desensitization suggest that elevated leukotrienes alone cannot explain the pathogenesis of NSAID hypersensitivity reactions.
ACKNOWLEDGMENTS
This study was supported by the Ratchadaphiseksomphot fund, Faculty of Medicine, Chulalongkorn University, grant No. RA55/19 and the Skin and Allergy Research Unit, Chulalongkorn University, Bangkok, Thailand. Study data were collected and managed using Research Electronic Data Capture (REDCap) hosted at HIV Netherlands Australia Thailand Research Collaboration. The authors thank Thitima Kantachatvanich, MD for providing patient information.
Disclosure: There are no financial or other issues that might lead to conflict of interest.
SUPPLEMENTARY MATERIALS
Supplementary Table S1
Clinical characteristics of patients with confirmed NSAID-induced immediate reactions
Supplementary Fig. S1
Representative photos of skin rash demonstrated during aspirin desensitization in NIBR patients. | Recovered | ReactionOutcome | CC BY-NC | 33474858 | 19,056,205 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Bradycardia'. | Severe Hypotension, Bradycardia and Asystole after Sugammadex Administration in an Elderly Patient.
Background and Objectives: Sugammadex is a modified γ-cyclodextrin largely used to prevent postoperative residual neuromuscular blockade induced by neuromuscular aminosteroid blocking agents. Although Sugammadex is considered more efficacious and safer than other drugs, such as Neostigmine, significant and serious complications after its administration, such as hypersensitivity, anaphylaxis and, more recently, severe cardiac events, are reported. Case presentation: In this report, we describe the case of an 80-year-old male with no medical history of cardiovascular disease who was scheduled for percutaneous nephrolithotripsy under general anesthesia. The intraoperative course was uneventful; however, the patient developed a rapid and severe hypotension, asystole and cardiac arrest after Sugammadex administration. Spontaneous cardiac activity and hemodynamic stability was restored with pharmacological therapy and chest compression. The patient was stabilized and discharged uneventfully on postoperative day 10. Conclusions: The potential causes of cardiac arrest after Sugammadex administration have been carefully considered, yet all indications point to Sugammadex as the direct causative agent. On the basis of laboratory and clinical tests, we can exclude among the cause of bradycardia, Kounis syndrome, acute myocardial infarction, coronary spasm and other arrhythmias, but not anaphylaxis. Although Sugammadex is considered an increasingly important option in the prevention of postoperative residual neuromuscular blockade, anesthesiologists should consider it a causative agent of cardiac arrest during surgery. This case highlights the necessity of increased pharmacovigilance and further studies to examine Sugammadex safety and mechanism through which it may cause severe bradycardia, hypotension and cardiac arrest.
1. Introduction
The modified γ-cyclodextrin Sugammadex is widely used to antagonize the post-operative residual neuromuscular blockade induced by neuromuscular aminosteroid blocking agents (NMBAs), such as Rocuronium bromide or Vecuronium bromide, used in adult anesthesia to ease endotracheal intubation, mechanical ventilation and surgical access. In detail, Sugammadex binds NMBA clearing nicotinic receptors, quickly reversing residual neuromuscular blockade and reducing the risk of postoperative respiratory complications.
Sugammadex has been reported to be more efficacious and safer than other drugs, such as Neostigmine, with lower incidence of common adverse drug reactions (ADRs) such as postoperative nausea and vomiting, dry mouth, tachycardia and dizziness [1,2,3]. However, the incidence of significant ADRs is almost similar between Sugammadex and Neostigmine: hypersensitivity, anaphylaxis [4,5] and, more recently, severe cardiac events such as coronary vasospasm and acute coronary syndrome [6,7,8], AV block [9], hypotension [10] and bradycardia with or without cardiac arrest [11,12,13,14] are described.
2. Case Presentation
In this report, we describe the case of bradycardia and cardiac arrest after Sugammadex administration in an elderly patient undergoing percutaneous nephrolithotripsy under general anesthesia for renal pelvis and calyceal lithiasis. The patient is an 80-year-old male (158 cm, 55 kg) in polytherapy for hypothyroidism, hyperuricemia, diabetes and chronic obstructive pulmonary disease with 50 mg Levothyroxine, 300 mg Allopurinol, 500 mg Metformin and 322 µg Aclidinium Bromide inhalation, respectively. However, he had no specific past medical history about coronary heart disease or any other cardiovascular disease. The results of preoperative electrocardiogram (ECG), chest X-ray and laboratory tests were normal. The patient went into surgery after premedication with 2 mg Midazolam intravenously (i.v.). Antibiotic prophylaxis was performed with 1 g Cefotaxime i.v.; ECG, noninvasive blood pressure (NIBP), end-tidal carbon dioxide (EtCO2) and oxygen saturation (SpO2) were monitored throughout the surgery.
The patient’s initial vital signs were: NIBP 120/70 mmHg, SpO2 98% and heart rate 75 beats/min. General mask ventilation was applied with 10% oxygen, and tracheal intubation was done without accident 2 min after Rocuronium administration. General anesthesia was induced with 140 mg Propofol and a total of 30 mg Rocuronium and, after tracheal intubation, was maintained with 2% (v/v) Sevoflurane and 0.3 mg Fentanyl. The second part of the surgery was done in a prone position. The patient’s intraoperative vital signs were maintained within the following ranges: systolic blood pressure: 120–130 mmHg; diastolic blood pressure: 70–80 mmHg, heart rate: 80–110 bpm, SpO2: 100%, EtCO2: 37%. An additional 10 mg Rocuronium was administered during the surgery to maintain muscle relaxation, so the total dose of Rocuronium was 40 mg. The total fluid input was 2500 mL (crystalloids). The intraoperative course was uneventful.
At the surgery end, the Sevoflurane administration was stopped and, after 5 min, 200 mg Sugammadex was administered to the patient: one minute later he developed severe bradycardia with heart rate below 35 beats/min and systolic blood pressure decreased to below 50 mmHg, and was promptly treated with a total of 10 mg Ephedrine and 1 mg Atropine i.v. to restore normal heart rate and systolic blood pressure. However, the patient’s clinical condition rapidly worsened with the onset of severe hypotension, asystole and cardiac arrest. Concomitant cardiopulmonary resuscitation with chest compression was performed for 1 min, restoring spontaneous cardiac activity and hemodynamic stability; the patient was transferred to the intensive care unit (ICU). Arterial blood gas after resuscitation showed: pH 7.32, PaO2: 126 mmHg, PaCO2: 25 mmHg, base excess: −8.4 mmol/L, HCO3: 19 mmol/L, lactate: 8 mmol/L, Na+: 136 mEq/L, Mg2+: 1.58 mg/dl, K+: 3.1 mEq/L, Ca2+: 7 mEq/L, glucose: 150 mg/dl and hemoglobin: 10.6 g/dl. Cardiac enzymes and troponins were normal, and postoperative cardiac workup including ECG and transthoracic echocardiography did not show any pathological sign. The patient was stabilized with optimal oxygen saturation level and spontaneous respiration during the following 3 days in ICU, transferred to the urology ward on postoperative day 3 and discharged uneventfully on postoperative day 10.
3. Discussion
The main clues point to Sugammadex as the cause of bradycardia, hypotension and cardiac arrest, both for the temporal proximity of administration and for the occurrence of similar, albeit rare, reports in the literature [15,16] as well as for the drug therapy used to resuscitate the patient based uniquely to Ephedrine and Atropine. Using the Naranjo nomogram, a 7 point-score (probable) was set to this report (Table 1).
The Sugammadex data sheet clearly states that “Cases of marked bradycardia, some of which have resulted in cardiac arrest, have been observed within minutes after the administration of [Sugammadex]”. The incidence of marked bradycardia at three different Sugammadex doses (2, 4 and 16 mg/kg) in pooled phase 1–3 patients was respectively 1, 1 and 5%. Although, our patient received a dose closer to 4 mg/kg, according to the Sugammadex prescribing information, this dose should not have conferred higher risk for the ADR observed, considering that low-dose Sugammadex (2 mg/kg) does not seem to protect against the chance that life-threatening bradycardia can occur [15]. Moreover, from 2009 to 2020, 292 cases of major cardiac events were reported after Sugammadex/Sugammadex sodium administration in the FAERS database [16], including bradycardia (n = 159), cardiac arrest (n = 115) and cardio-respiratory arrest (n = 18). In the same timeframe, Neostigmine/Neostigmine bromide or methylsulfate has been associated with 75 events, including bradycardia (n = 39), cardiac arrest (n = 28) and cardio-respiratory arrest (n = 8). The analysis, in the same period, of the frequency of total cardiovascular ADRs in respect to allergic or immune-based events shows very close values (567 vs. 574 ADRs, respectively).
Although Sugammadex-induced anaphylaxis is commonly associated with generalized skin rash, wheezing, bronchospasm and tachycardia [4,5] and our patient did not show these clinical signs, allergic-reaction symptoms during anesthesia could be nonspecific, and anaphylaxis-induced cardiovascular collapse has been reported. No other symptoms commonly linked to generalized anaphylaxis (e.g., increased peak inspiratory pressures seen with mechanical ventilation, initial drop in EtCO2 and facial or soft palate edema) were observed in the patient. Considering the absence of information about tryptase level or subsequent allergy testing with Sugammadex, we formally cannot exclude anaphylaxis as the primary cause of cardiac arrest [18]. Nonetheless, the fact that our patient responded to a single dose of Ephedrine and Atropine without a relapse of hemodynamic instability and without having to recourse instead to Epinephrine boluses or drip would suggest a greater likelihood of a direct cardiovascular effect rather than secondary to anaphylaxis. Moreover, in the Summary of Product Information released by EMA [19] it is stated that bradycardia induced by Sugammadex should be treated by an anticholinergic agent such as Atropine.
Conversely, no evidence of Kounis syndrome, as recently reported associated with Sugammadex administration, or acute myocardial infarction accompanied by coronary spasm or other arrhythmias were observed [6,7,8], considering the rapid recovery without a relapse of hemodynamic instability, the unnecessity of vasodilators administration and clinical and laboratory normal results during the hours following the cardiac arrest. Moreover, the patient, despite his advanced age, had no medical history of cardiovascular disease or of allergic reactions before this event, unlike patients described in similar reports that are characterized, at least, by hypertension [12,13,14]. Currently, there is no information in the literature about possible drug–drug interaction between Sugammadex and the patient’s polytherapy.
4. Conclusions
In conclusion, although Sugammadex provides an important option for anesthesiologists in the prevention of postoperative residual neuromuscular blockade, it should be considered as a causative agent of cardiac arrest during surgery, directly or following anaphylaxis, even at the lowest recommended doses. For this reason, Sugammadex should be administered slowly, always with full ECG and hemodynamic changes monitoring after its administration [18], and anesthesiologists should be more rigorous in their ADRs reporting to pharmacovigilance agencies. Furthermore, it would be desirable to investigate the genetic and molecular mechanisms that induce the cardiovascular effects of Sugammadex in a specific subpopulation of patients.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author Contributions
C.F., A.M., D.M. and C.R. collected all patient data and drafted the manuscript. C.P., S.C. and E.F. collaborated on manuscript writing. C.F., G.M. and R.F. participated in the care of the patient. All authors gave their comments on the article and approved the final version. All authors have read and agreed to the published version of the manuscript.
Funding
This research was funded by AIFA (Agenzia Italiana del Farmaco): Progetti regionali di Farmacovigilanza (CUP D39E19000990001).
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Informed consent of the patient was obtained.
Data Availability Statement
Data and material are available on reasonable request.
Conflicts of Interest
The authors declare no conflict of interest.
medicina-57-00079-t001_Table 1Table 1 Naranjo nomogram for the assessment of adverse drug reaction (ADR). This questionnaire designed by Naranjo et al. [17] establishes whether an ADR was caused or not by a drug. The ADR is assigned to a probability category from the total score as follows: “definite” if the overall score is 9 or higher, “probable” for a score of 5–8, “possible” for a score of 1–4 and “doubtful” if the score is 0 or less. Bolded numbers apply to the patient’s case.
Assessment Questions Yes No Don’t Know
1. Are there previous conclusive reports on the ADR?
+1
0 0
2. Did ADR appear after the suspected drug was given?
+2
−1 0
3. Did the ADR improve when the drug was discontinued, or a specific antagonist was given?
+1
0 0
4. Did the ADR appear when the drug was re-administered? +2 −1
0
5. Are there alternative causes that could have caused the ADR? −1
+2
0
6. Did the reaction reappear when a placebo was given? −1 +1
0
7. Was the drug detected in any body fluid in toxic concentrations? +1 0
0
8. Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? +1 0
0
9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? +1
0
0
10. Was the ADR confirmed by any objective evidence?
+1
0 0
Total Score
7 = Probable | ACLIDINIUM BROMIDE, ALLOPURINOL, CEFOTAXIME SODIUM, FENTANYL, LEVOTHYROXINE SODIUM, METFORMIN HYDROCHLORIDE, MIDAZOLAM, OXYGEN, PROPOFOL, ROCURONIUM BROMIDE, SEVOFLURANE, SUGAMMADEX SODIUM | DrugsGivenReaction | CC BY | 33477765 | 20,168,163 | 2021-01-19 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardiac arrest'. | Severe Hypotension, Bradycardia and Asystole after Sugammadex Administration in an Elderly Patient.
Background and Objectives: Sugammadex is a modified γ-cyclodextrin largely used to prevent postoperative residual neuromuscular blockade induced by neuromuscular aminosteroid blocking agents. Although Sugammadex is considered more efficacious and safer than other drugs, such as Neostigmine, significant and serious complications after its administration, such as hypersensitivity, anaphylaxis and, more recently, severe cardiac events, are reported. Case presentation: In this report, we describe the case of an 80-year-old male with no medical history of cardiovascular disease who was scheduled for percutaneous nephrolithotripsy under general anesthesia. The intraoperative course was uneventful; however, the patient developed a rapid and severe hypotension, asystole and cardiac arrest after Sugammadex administration. Spontaneous cardiac activity and hemodynamic stability was restored with pharmacological therapy and chest compression. The patient was stabilized and discharged uneventfully on postoperative day 10. Conclusions: The potential causes of cardiac arrest after Sugammadex administration have been carefully considered, yet all indications point to Sugammadex as the direct causative agent. On the basis of laboratory and clinical tests, we can exclude among the cause of bradycardia, Kounis syndrome, acute myocardial infarction, coronary spasm and other arrhythmias, but not anaphylaxis. Although Sugammadex is considered an increasingly important option in the prevention of postoperative residual neuromuscular blockade, anesthesiologists should consider it a causative agent of cardiac arrest during surgery. This case highlights the necessity of increased pharmacovigilance and further studies to examine Sugammadex safety and mechanism through which it may cause severe bradycardia, hypotension and cardiac arrest.
1. Introduction
The modified γ-cyclodextrin Sugammadex is widely used to antagonize the post-operative residual neuromuscular blockade induced by neuromuscular aminosteroid blocking agents (NMBAs), such as Rocuronium bromide or Vecuronium bromide, used in adult anesthesia to ease endotracheal intubation, mechanical ventilation and surgical access. In detail, Sugammadex binds NMBA clearing nicotinic receptors, quickly reversing residual neuromuscular blockade and reducing the risk of postoperative respiratory complications.
Sugammadex has been reported to be more efficacious and safer than other drugs, such as Neostigmine, with lower incidence of common adverse drug reactions (ADRs) such as postoperative nausea and vomiting, dry mouth, tachycardia and dizziness [1,2,3]. However, the incidence of significant ADRs is almost similar between Sugammadex and Neostigmine: hypersensitivity, anaphylaxis [4,5] and, more recently, severe cardiac events such as coronary vasospasm and acute coronary syndrome [6,7,8], AV block [9], hypotension [10] and bradycardia with or without cardiac arrest [11,12,13,14] are described.
2. Case Presentation
In this report, we describe the case of bradycardia and cardiac arrest after Sugammadex administration in an elderly patient undergoing percutaneous nephrolithotripsy under general anesthesia for renal pelvis and calyceal lithiasis. The patient is an 80-year-old male (158 cm, 55 kg) in polytherapy for hypothyroidism, hyperuricemia, diabetes and chronic obstructive pulmonary disease with 50 mg Levothyroxine, 300 mg Allopurinol, 500 mg Metformin and 322 µg Aclidinium Bromide inhalation, respectively. However, he had no specific past medical history about coronary heart disease or any other cardiovascular disease. The results of preoperative electrocardiogram (ECG), chest X-ray and laboratory tests were normal. The patient went into surgery after premedication with 2 mg Midazolam intravenously (i.v.). Antibiotic prophylaxis was performed with 1 g Cefotaxime i.v.; ECG, noninvasive blood pressure (NIBP), end-tidal carbon dioxide (EtCO2) and oxygen saturation (SpO2) were monitored throughout the surgery.
The patient’s initial vital signs were: NIBP 120/70 mmHg, SpO2 98% and heart rate 75 beats/min. General mask ventilation was applied with 10% oxygen, and tracheal intubation was done without accident 2 min after Rocuronium administration. General anesthesia was induced with 140 mg Propofol and a total of 30 mg Rocuronium and, after tracheal intubation, was maintained with 2% (v/v) Sevoflurane and 0.3 mg Fentanyl. The second part of the surgery was done in a prone position. The patient’s intraoperative vital signs were maintained within the following ranges: systolic blood pressure: 120–130 mmHg; diastolic blood pressure: 70–80 mmHg, heart rate: 80–110 bpm, SpO2: 100%, EtCO2: 37%. An additional 10 mg Rocuronium was administered during the surgery to maintain muscle relaxation, so the total dose of Rocuronium was 40 mg. The total fluid input was 2500 mL (crystalloids). The intraoperative course was uneventful.
At the surgery end, the Sevoflurane administration was stopped and, after 5 min, 200 mg Sugammadex was administered to the patient: one minute later he developed severe bradycardia with heart rate below 35 beats/min and systolic blood pressure decreased to below 50 mmHg, and was promptly treated with a total of 10 mg Ephedrine and 1 mg Atropine i.v. to restore normal heart rate and systolic blood pressure. However, the patient’s clinical condition rapidly worsened with the onset of severe hypotension, asystole and cardiac arrest. Concomitant cardiopulmonary resuscitation with chest compression was performed for 1 min, restoring spontaneous cardiac activity and hemodynamic stability; the patient was transferred to the intensive care unit (ICU). Arterial blood gas after resuscitation showed: pH 7.32, PaO2: 126 mmHg, PaCO2: 25 mmHg, base excess: −8.4 mmol/L, HCO3: 19 mmol/L, lactate: 8 mmol/L, Na+: 136 mEq/L, Mg2+: 1.58 mg/dl, K+: 3.1 mEq/L, Ca2+: 7 mEq/L, glucose: 150 mg/dl and hemoglobin: 10.6 g/dl. Cardiac enzymes and troponins were normal, and postoperative cardiac workup including ECG and transthoracic echocardiography did not show any pathological sign. The patient was stabilized with optimal oxygen saturation level and spontaneous respiration during the following 3 days in ICU, transferred to the urology ward on postoperative day 3 and discharged uneventfully on postoperative day 10.
3. Discussion
The main clues point to Sugammadex as the cause of bradycardia, hypotension and cardiac arrest, both for the temporal proximity of administration and for the occurrence of similar, albeit rare, reports in the literature [15,16] as well as for the drug therapy used to resuscitate the patient based uniquely to Ephedrine and Atropine. Using the Naranjo nomogram, a 7 point-score (probable) was set to this report (Table 1).
The Sugammadex data sheet clearly states that “Cases of marked bradycardia, some of which have resulted in cardiac arrest, have been observed within minutes after the administration of [Sugammadex]”. The incidence of marked bradycardia at three different Sugammadex doses (2, 4 and 16 mg/kg) in pooled phase 1–3 patients was respectively 1, 1 and 5%. Although, our patient received a dose closer to 4 mg/kg, according to the Sugammadex prescribing information, this dose should not have conferred higher risk for the ADR observed, considering that low-dose Sugammadex (2 mg/kg) does not seem to protect against the chance that life-threatening bradycardia can occur [15]. Moreover, from 2009 to 2020, 292 cases of major cardiac events were reported after Sugammadex/Sugammadex sodium administration in the FAERS database [16], including bradycardia (n = 159), cardiac arrest (n = 115) and cardio-respiratory arrest (n = 18). In the same timeframe, Neostigmine/Neostigmine bromide or methylsulfate has been associated with 75 events, including bradycardia (n = 39), cardiac arrest (n = 28) and cardio-respiratory arrest (n = 8). The analysis, in the same period, of the frequency of total cardiovascular ADRs in respect to allergic or immune-based events shows very close values (567 vs. 574 ADRs, respectively).
Although Sugammadex-induced anaphylaxis is commonly associated with generalized skin rash, wheezing, bronchospasm and tachycardia [4,5] and our patient did not show these clinical signs, allergic-reaction symptoms during anesthesia could be nonspecific, and anaphylaxis-induced cardiovascular collapse has been reported. No other symptoms commonly linked to generalized anaphylaxis (e.g., increased peak inspiratory pressures seen with mechanical ventilation, initial drop in EtCO2 and facial or soft palate edema) were observed in the patient. Considering the absence of information about tryptase level or subsequent allergy testing with Sugammadex, we formally cannot exclude anaphylaxis as the primary cause of cardiac arrest [18]. Nonetheless, the fact that our patient responded to a single dose of Ephedrine and Atropine without a relapse of hemodynamic instability and without having to recourse instead to Epinephrine boluses or drip would suggest a greater likelihood of a direct cardiovascular effect rather than secondary to anaphylaxis. Moreover, in the Summary of Product Information released by EMA [19] it is stated that bradycardia induced by Sugammadex should be treated by an anticholinergic agent such as Atropine.
Conversely, no evidence of Kounis syndrome, as recently reported associated with Sugammadex administration, or acute myocardial infarction accompanied by coronary spasm or other arrhythmias were observed [6,7,8], considering the rapid recovery without a relapse of hemodynamic instability, the unnecessity of vasodilators administration and clinical and laboratory normal results during the hours following the cardiac arrest. Moreover, the patient, despite his advanced age, had no medical history of cardiovascular disease or of allergic reactions before this event, unlike patients described in similar reports that are characterized, at least, by hypertension [12,13,14]. Currently, there is no information in the literature about possible drug–drug interaction between Sugammadex and the patient’s polytherapy.
4. Conclusions
In conclusion, although Sugammadex provides an important option for anesthesiologists in the prevention of postoperative residual neuromuscular blockade, it should be considered as a causative agent of cardiac arrest during surgery, directly or following anaphylaxis, even at the lowest recommended doses. For this reason, Sugammadex should be administered slowly, always with full ECG and hemodynamic changes monitoring after its administration [18], and anesthesiologists should be more rigorous in their ADRs reporting to pharmacovigilance agencies. Furthermore, it would be desirable to investigate the genetic and molecular mechanisms that induce the cardiovascular effects of Sugammadex in a specific subpopulation of patients.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author Contributions
C.F., A.M., D.M. and C.R. collected all patient data and drafted the manuscript. C.P., S.C. and E.F. collaborated on manuscript writing. C.F., G.M. and R.F. participated in the care of the patient. All authors gave their comments on the article and approved the final version. All authors have read and agreed to the published version of the manuscript.
Funding
This research was funded by AIFA (Agenzia Italiana del Farmaco): Progetti regionali di Farmacovigilanza (CUP D39E19000990001).
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Informed consent of the patient was obtained.
Data Availability Statement
Data and material are available on reasonable request.
Conflicts of Interest
The authors declare no conflict of interest.
medicina-57-00079-t001_Table 1Table 1 Naranjo nomogram for the assessment of adverse drug reaction (ADR). This questionnaire designed by Naranjo et al. [17] establishes whether an ADR was caused or not by a drug. The ADR is assigned to a probability category from the total score as follows: “definite” if the overall score is 9 or higher, “probable” for a score of 5–8, “possible” for a score of 1–4 and “doubtful” if the score is 0 or less. Bolded numbers apply to the patient’s case.
Assessment Questions Yes No Don’t Know
1. Are there previous conclusive reports on the ADR?
+1
0 0
2. Did ADR appear after the suspected drug was given?
+2
−1 0
3. Did the ADR improve when the drug was discontinued, or a specific antagonist was given?
+1
0 0
4. Did the ADR appear when the drug was re-administered? +2 −1
0
5. Are there alternative causes that could have caused the ADR? −1
+2
0
6. Did the reaction reappear when a placebo was given? −1 +1
0
7. Was the drug detected in any body fluid in toxic concentrations? +1 0
0
8. Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? +1 0
0
9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? +1
0
0
10. Was the ADR confirmed by any objective evidence?
+1
0 0
Total Score
7 = Probable | ACLIDINIUM BROMIDE, ALLOPURINOL, CEFOTAXIME SODIUM, FENTANYL, LEVOTHYROXINE SODIUM, METFORMIN HYDROCHLORIDE, MIDAZOLAM, OXYGEN, PROPOFOL, ROCURONIUM BROMIDE, SEVOFLURANE, SUGAMMADEX SODIUM | DrugsGivenReaction | CC BY | 33477765 | 20,168,163 | 2021-01-19 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypotension'. | Severe Hypotension, Bradycardia and Asystole after Sugammadex Administration in an Elderly Patient.
Background and Objectives: Sugammadex is a modified γ-cyclodextrin largely used to prevent postoperative residual neuromuscular blockade induced by neuromuscular aminosteroid blocking agents. Although Sugammadex is considered more efficacious and safer than other drugs, such as Neostigmine, significant and serious complications after its administration, such as hypersensitivity, anaphylaxis and, more recently, severe cardiac events, are reported. Case presentation: In this report, we describe the case of an 80-year-old male with no medical history of cardiovascular disease who was scheduled for percutaneous nephrolithotripsy under general anesthesia. The intraoperative course was uneventful; however, the patient developed a rapid and severe hypotension, asystole and cardiac arrest after Sugammadex administration. Spontaneous cardiac activity and hemodynamic stability was restored with pharmacological therapy and chest compression. The patient was stabilized and discharged uneventfully on postoperative day 10. Conclusions: The potential causes of cardiac arrest after Sugammadex administration have been carefully considered, yet all indications point to Sugammadex as the direct causative agent. On the basis of laboratory and clinical tests, we can exclude among the cause of bradycardia, Kounis syndrome, acute myocardial infarction, coronary spasm and other arrhythmias, but not anaphylaxis. Although Sugammadex is considered an increasingly important option in the prevention of postoperative residual neuromuscular blockade, anesthesiologists should consider it a causative agent of cardiac arrest during surgery. This case highlights the necessity of increased pharmacovigilance and further studies to examine Sugammadex safety and mechanism through which it may cause severe bradycardia, hypotension and cardiac arrest.
1. Introduction
The modified γ-cyclodextrin Sugammadex is widely used to antagonize the post-operative residual neuromuscular blockade induced by neuromuscular aminosteroid blocking agents (NMBAs), such as Rocuronium bromide or Vecuronium bromide, used in adult anesthesia to ease endotracheal intubation, mechanical ventilation and surgical access. In detail, Sugammadex binds NMBA clearing nicotinic receptors, quickly reversing residual neuromuscular blockade and reducing the risk of postoperative respiratory complications.
Sugammadex has been reported to be more efficacious and safer than other drugs, such as Neostigmine, with lower incidence of common adverse drug reactions (ADRs) such as postoperative nausea and vomiting, dry mouth, tachycardia and dizziness [1,2,3]. However, the incidence of significant ADRs is almost similar between Sugammadex and Neostigmine: hypersensitivity, anaphylaxis [4,5] and, more recently, severe cardiac events such as coronary vasospasm and acute coronary syndrome [6,7,8], AV block [9], hypotension [10] and bradycardia with or without cardiac arrest [11,12,13,14] are described.
2. Case Presentation
In this report, we describe the case of bradycardia and cardiac arrest after Sugammadex administration in an elderly patient undergoing percutaneous nephrolithotripsy under general anesthesia for renal pelvis and calyceal lithiasis. The patient is an 80-year-old male (158 cm, 55 kg) in polytherapy for hypothyroidism, hyperuricemia, diabetes and chronic obstructive pulmonary disease with 50 mg Levothyroxine, 300 mg Allopurinol, 500 mg Metformin and 322 µg Aclidinium Bromide inhalation, respectively. However, he had no specific past medical history about coronary heart disease or any other cardiovascular disease. The results of preoperative electrocardiogram (ECG), chest X-ray and laboratory tests were normal. The patient went into surgery after premedication with 2 mg Midazolam intravenously (i.v.). Antibiotic prophylaxis was performed with 1 g Cefotaxime i.v.; ECG, noninvasive blood pressure (NIBP), end-tidal carbon dioxide (EtCO2) and oxygen saturation (SpO2) were monitored throughout the surgery.
The patient’s initial vital signs were: NIBP 120/70 mmHg, SpO2 98% and heart rate 75 beats/min. General mask ventilation was applied with 10% oxygen, and tracheal intubation was done without accident 2 min after Rocuronium administration. General anesthesia was induced with 140 mg Propofol and a total of 30 mg Rocuronium and, after tracheal intubation, was maintained with 2% (v/v) Sevoflurane and 0.3 mg Fentanyl. The second part of the surgery was done in a prone position. The patient’s intraoperative vital signs were maintained within the following ranges: systolic blood pressure: 120–130 mmHg; diastolic blood pressure: 70–80 mmHg, heart rate: 80–110 bpm, SpO2: 100%, EtCO2: 37%. An additional 10 mg Rocuronium was administered during the surgery to maintain muscle relaxation, so the total dose of Rocuronium was 40 mg. The total fluid input was 2500 mL (crystalloids). The intraoperative course was uneventful.
At the surgery end, the Sevoflurane administration was stopped and, after 5 min, 200 mg Sugammadex was administered to the patient: one minute later he developed severe bradycardia with heart rate below 35 beats/min and systolic blood pressure decreased to below 50 mmHg, and was promptly treated with a total of 10 mg Ephedrine and 1 mg Atropine i.v. to restore normal heart rate and systolic blood pressure. However, the patient’s clinical condition rapidly worsened with the onset of severe hypotension, asystole and cardiac arrest. Concomitant cardiopulmonary resuscitation with chest compression was performed for 1 min, restoring spontaneous cardiac activity and hemodynamic stability; the patient was transferred to the intensive care unit (ICU). Arterial blood gas after resuscitation showed: pH 7.32, PaO2: 126 mmHg, PaCO2: 25 mmHg, base excess: −8.4 mmol/L, HCO3: 19 mmol/L, lactate: 8 mmol/L, Na+: 136 mEq/L, Mg2+: 1.58 mg/dl, K+: 3.1 mEq/L, Ca2+: 7 mEq/L, glucose: 150 mg/dl and hemoglobin: 10.6 g/dl. Cardiac enzymes and troponins were normal, and postoperative cardiac workup including ECG and transthoracic echocardiography did not show any pathological sign. The patient was stabilized with optimal oxygen saturation level and spontaneous respiration during the following 3 days in ICU, transferred to the urology ward on postoperative day 3 and discharged uneventfully on postoperative day 10.
3. Discussion
The main clues point to Sugammadex as the cause of bradycardia, hypotension and cardiac arrest, both for the temporal proximity of administration and for the occurrence of similar, albeit rare, reports in the literature [15,16] as well as for the drug therapy used to resuscitate the patient based uniquely to Ephedrine and Atropine. Using the Naranjo nomogram, a 7 point-score (probable) was set to this report (Table 1).
The Sugammadex data sheet clearly states that “Cases of marked bradycardia, some of which have resulted in cardiac arrest, have been observed within minutes after the administration of [Sugammadex]”. The incidence of marked bradycardia at three different Sugammadex doses (2, 4 and 16 mg/kg) in pooled phase 1–3 patients was respectively 1, 1 and 5%. Although, our patient received a dose closer to 4 mg/kg, according to the Sugammadex prescribing information, this dose should not have conferred higher risk for the ADR observed, considering that low-dose Sugammadex (2 mg/kg) does not seem to protect against the chance that life-threatening bradycardia can occur [15]. Moreover, from 2009 to 2020, 292 cases of major cardiac events were reported after Sugammadex/Sugammadex sodium administration in the FAERS database [16], including bradycardia (n = 159), cardiac arrest (n = 115) and cardio-respiratory arrest (n = 18). In the same timeframe, Neostigmine/Neostigmine bromide or methylsulfate has been associated with 75 events, including bradycardia (n = 39), cardiac arrest (n = 28) and cardio-respiratory arrest (n = 8). The analysis, in the same period, of the frequency of total cardiovascular ADRs in respect to allergic or immune-based events shows very close values (567 vs. 574 ADRs, respectively).
Although Sugammadex-induced anaphylaxis is commonly associated with generalized skin rash, wheezing, bronchospasm and tachycardia [4,5] and our patient did not show these clinical signs, allergic-reaction symptoms during anesthesia could be nonspecific, and anaphylaxis-induced cardiovascular collapse has been reported. No other symptoms commonly linked to generalized anaphylaxis (e.g., increased peak inspiratory pressures seen with mechanical ventilation, initial drop in EtCO2 and facial or soft palate edema) were observed in the patient. Considering the absence of information about tryptase level or subsequent allergy testing with Sugammadex, we formally cannot exclude anaphylaxis as the primary cause of cardiac arrest [18]. Nonetheless, the fact that our patient responded to a single dose of Ephedrine and Atropine without a relapse of hemodynamic instability and without having to recourse instead to Epinephrine boluses or drip would suggest a greater likelihood of a direct cardiovascular effect rather than secondary to anaphylaxis. Moreover, in the Summary of Product Information released by EMA [19] it is stated that bradycardia induced by Sugammadex should be treated by an anticholinergic agent such as Atropine.
Conversely, no evidence of Kounis syndrome, as recently reported associated with Sugammadex administration, or acute myocardial infarction accompanied by coronary spasm or other arrhythmias were observed [6,7,8], considering the rapid recovery without a relapse of hemodynamic instability, the unnecessity of vasodilators administration and clinical and laboratory normal results during the hours following the cardiac arrest. Moreover, the patient, despite his advanced age, had no medical history of cardiovascular disease or of allergic reactions before this event, unlike patients described in similar reports that are characterized, at least, by hypertension [12,13,14]. Currently, there is no information in the literature about possible drug–drug interaction between Sugammadex and the patient’s polytherapy.
4. Conclusions
In conclusion, although Sugammadex provides an important option for anesthesiologists in the prevention of postoperative residual neuromuscular blockade, it should be considered as a causative agent of cardiac arrest during surgery, directly or following anaphylaxis, even at the lowest recommended doses. For this reason, Sugammadex should be administered slowly, always with full ECG and hemodynamic changes monitoring after its administration [18], and anesthesiologists should be more rigorous in their ADRs reporting to pharmacovigilance agencies. Furthermore, it would be desirable to investigate the genetic and molecular mechanisms that induce the cardiovascular effects of Sugammadex in a specific subpopulation of patients.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author Contributions
C.F., A.M., D.M. and C.R. collected all patient data and drafted the manuscript. C.P., S.C. and E.F. collaborated on manuscript writing. C.F., G.M. and R.F. participated in the care of the patient. All authors gave their comments on the article and approved the final version. All authors have read and agreed to the published version of the manuscript.
Funding
This research was funded by AIFA (Agenzia Italiana del Farmaco): Progetti regionali di Farmacovigilanza (CUP D39E19000990001).
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Informed consent of the patient was obtained.
Data Availability Statement
Data and material are available on reasonable request.
Conflicts of Interest
The authors declare no conflict of interest.
medicina-57-00079-t001_Table 1Table 1 Naranjo nomogram for the assessment of adverse drug reaction (ADR). This questionnaire designed by Naranjo et al. [17] establishes whether an ADR was caused or not by a drug. The ADR is assigned to a probability category from the total score as follows: “definite” if the overall score is 9 or higher, “probable” for a score of 5–8, “possible” for a score of 1–4 and “doubtful” if the score is 0 or less. Bolded numbers apply to the patient’s case.
Assessment Questions Yes No Don’t Know
1. Are there previous conclusive reports on the ADR?
+1
0 0
2. Did ADR appear after the suspected drug was given?
+2
−1 0
3. Did the ADR improve when the drug was discontinued, or a specific antagonist was given?
+1
0 0
4. Did the ADR appear when the drug was re-administered? +2 −1
0
5. Are there alternative causes that could have caused the ADR? −1
+2
0
6. Did the reaction reappear when a placebo was given? −1 +1
0
7. Was the drug detected in any body fluid in toxic concentrations? +1 0
0
8. Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? +1 0
0
9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? +1
0
0
10. Was the ADR confirmed by any objective evidence?
+1
0 0
Total Score
7 = Probable | ACLIDINIUM BROMIDE, ALLOPURINOL, CEFOTAXIME SODIUM, FENTANYL, LEVOTHYROXINE SODIUM, METFORMIN HYDROCHLORIDE, MIDAZOLAM, OXYGEN, PROPOFOL, ROCURONIUM BROMIDE, SEVOFLURANE, SUGAMMADEX SODIUM | DrugsGivenReaction | CC BY | 33477765 | 20,168,163 | 2021-01-19 |
What is the weight of the patient? | Severe Hypotension, Bradycardia and Asystole after Sugammadex Administration in an Elderly Patient.
Background and Objectives: Sugammadex is a modified γ-cyclodextrin largely used to prevent postoperative residual neuromuscular blockade induced by neuromuscular aminosteroid blocking agents. Although Sugammadex is considered more efficacious and safer than other drugs, such as Neostigmine, significant and serious complications after its administration, such as hypersensitivity, anaphylaxis and, more recently, severe cardiac events, are reported. Case presentation: In this report, we describe the case of an 80-year-old male with no medical history of cardiovascular disease who was scheduled for percutaneous nephrolithotripsy under general anesthesia. The intraoperative course was uneventful; however, the patient developed a rapid and severe hypotension, asystole and cardiac arrest after Sugammadex administration. Spontaneous cardiac activity and hemodynamic stability was restored with pharmacological therapy and chest compression. The patient was stabilized and discharged uneventfully on postoperative day 10. Conclusions: The potential causes of cardiac arrest after Sugammadex administration have been carefully considered, yet all indications point to Sugammadex as the direct causative agent. On the basis of laboratory and clinical tests, we can exclude among the cause of bradycardia, Kounis syndrome, acute myocardial infarction, coronary spasm and other arrhythmias, but not anaphylaxis. Although Sugammadex is considered an increasingly important option in the prevention of postoperative residual neuromuscular blockade, anesthesiologists should consider it a causative agent of cardiac arrest during surgery. This case highlights the necessity of increased pharmacovigilance and further studies to examine Sugammadex safety and mechanism through which it may cause severe bradycardia, hypotension and cardiac arrest.
1. Introduction
The modified γ-cyclodextrin Sugammadex is widely used to antagonize the post-operative residual neuromuscular blockade induced by neuromuscular aminosteroid blocking agents (NMBAs), such as Rocuronium bromide or Vecuronium bromide, used in adult anesthesia to ease endotracheal intubation, mechanical ventilation and surgical access. In detail, Sugammadex binds NMBA clearing nicotinic receptors, quickly reversing residual neuromuscular blockade and reducing the risk of postoperative respiratory complications.
Sugammadex has been reported to be more efficacious and safer than other drugs, such as Neostigmine, with lower incidence of common adverse drug reactions (ADRs) such as postoperative nausea and vomiting, dry mouth, tachycardia and dizziness [1,2,3]. However, the incidence of significant ADRs is almost similar between Sugammadex and Neostigmine: hypersensitivity, anaphylaxis [4,5] and, more recently, severe cardiac events such as coronary vasospasm and acute coronary syndrome [6,7,8], AV block [9], hypotension [10] and bradycardia with or without cardiac arrest [11,12,13,14] are described.
2. Case Presentation
In this report, we describe the case of bradycardia and cardiac arrest after Sugammadex administration in an elderly patient undergoing percutaneous nephrolithotripsy under general anesthesia for renal pelvis and calyceal lithiasis. The patient is an 80-year-old male (158 cm, 55 kg) in polytherapy for hypothyroidism, hyperuricemia, diabetes and chronic obstructive pulmonary disease with 50 mg Levothyroxine, 300 mg Allopurinol, 500 mg Metformin and 322 µg Aclidinium Bromide inhalation, respectively. However, he had no specific past medical history about coronary heart disease or any other cardiovascular disease. The results of preoperative electrocardiogram (ECG), chest X-ray and laboratory tests were normal. The patient went into surgery after premedication with 2 mg Midazolam intravenously (i.v.). Antibiotic prophylaxis was performed with 1 g Cefotaxime i.v.; ECG, noninvasive blood pressure (NIBP), end-tidal carbon dioxide (EtCO2) and oxygen saturation (SpO2) were monitored throughout the surgery.
The patient’s initial vital signs were: NIBP 120/70 mmHg, SpO2 98% and heart rate 75 beats/min. General mask ventilation was applied with 10% oxygen, and tracheal intubation was done without accident 2 min after Rocuronium administration. General anesthesia was induced with 140 mg Propofol and a total of 30 mg Rocuronium and, after tracheal intubation, was maintained with 2% (v/v) Sevoflurane and 0.3 mg Fentanyl. The second part of the surgery was done in a prone position. The patient’s intraoperative vital signs were maintained within the following ranges: systolic blood pressure: 120–130 mmHg; diastolic blood pressure: 70–80 mmHg, heart rate: 80–110 bpm, SpO2: 100%, EtCO2: 37%. An additional 10 mg Rocuronium was administered during the surgery to maintain muscle relaxation, so the total dose of Rocuronium was 40 mg. The total fluid input was 2500 mL (crystalloids). The intraoperative course was uneventful.
At the surgery end, the Sevoflurane administration was stopped and, after 5 min, 200 mg Sugammadex was administered to the patient: one minute later he developed severe bradycardia with heart rate below 35 beats/min and systolic blood pressure decreased to below 50 mmHg, and was promptly treated with a total of 10 mg Ephedrine and 1 mg Atropine i.v. to restore normal heart rate and systolic blood pressure. However, the patient’s clinical condition rapidly worsened with the onset of severe hypotension, asystole and cardiac arrest. Concomitant cardiopulmonary resuscitation with chest compression was performed for 1 min, restoring spontaneous cardiac activity and hemodynamic stability; the patient was transferred to the intensive care unit (ICU). Arterial blood gas after resuscitation showed: pH 7.32, PaO2: 126 mmHg, PaCO2: 25 mmHg, base excess: −8.4 mmol/L, HCO3: 19 mmol/L, lactate: 8 mmol/L, Na+: 136 mEq/L, Mg2+: 1.58 mg/dl, K+: 3.1 mEq/L, Ca2+: 7 mEq/L, glucose: 150 mg/dl and hemoglobin: 10.6 g/dl. Cardiac enzymes and troponins were normal, and postoperative cardiac workup including ECG and transthoracic echocardiography did not show any pathological sign. The patient was stabilized with optimal oxygen saturation level and spontaneous respiration during the following 3 days in ICU, transferred to the urology ward on postoperative day 3 and discharged uneventfully on postoperative day 10.
3. Discussion
The main clues point to Sugammadex as the cause of bradycardia, hypotension and cardiac arrest, both for the temporal proximity of administration and for the occurrence of similar, albeit rare, reports in the literature [15,16] as well as for the drug therapy used to resuscitate the patient based uniquely to Ephedrine and Atropine. Using the Naranjo nomogram, a 7 point-score (probable) was set to this report (Table 1).
The Sugammadex data sheet clearly states that “Cases of marked bradycardia, some of which have resulted in cardiac arrest, have been observed within minutes after the administration of [Sugammadex]”. The incidence of marked bradycardia at three different Sugammadex doses (2, 4 and 16 mg/kg) in pooled phase 1–3 patients was respectively 1, 1 and 5%. Although, our patient received a dose closer to 4 mg/kg, according to the Sugammadex prescribing information, this dose should not have conferred higher risk for the ADR observed, considering that low-dose Sugammadex (2 mg/kg) does not seem to protect against the chance that life-threatening bradycardia can occur [15]. Moreover, from 2009 to 2020, 292 cases of major cardiac events were reported after Sugammadex/Sugammadex sodium administration in the FAERS database [16], including bradycardia (n = 159), cardiac arrest (n = 115) and cardio-respiratory arrest (n = 18). In the same timeframe, Neostigmine/Neostigmine bromide or methylsulfate has been associated with 75 events, including bradycardia (n = 39), cardiac arrest (n = 28) and cardio-respiratory arrest (n = 8). The analysis, in the same period, of the frequency of total cardiovascular ADRs in respect to allergic or immune-based events shows very close values (567 vs. 574 ADRs, respectively).
Although Sugammadex-induced anaphylaxis is commonly associated with generalized skin rash, wheezing, bronchospasm and tachycardia [4,5] and our patient did not show these clinical signs, allergic-reaction symptoms during anesthesia could be nonspecific, and anaphylaxis-induced cardiovascular collapse has been reported. No other symptoms commonly linked to generalized anaphylaxis (e.g., increased peak inspiratory pressures seen with mechanical ventilation, initial drop in EtCO2 and facial or soft palate edema) were observed in the patient. Considering the absence of information about tryptase level or subsequent allergy testing with Sugammadex, we formally cannot exclude anaphylaxis as the primary cause of cardiac arrest [18]. Nonetheless, the fact that our patient responded to a single dose of Ephedrine and Atropine without a relapse of hemodynamic instability and without having to recourse instead to Epinephrine boluses or drip would suggest a greater likelihood of a direct cardiovascular effect rather than secondary to anaphylaxis. Moreover, in the Summary of Product Information released by EMA [19] it is stated that bradycardia induced by Sugammadex should be treated by an anticholinergic agent such as Atropine.
Conversely, no evidence of Kounis syndrome, as recently reported associated with Sugammadex administration, or acute myocardial infarction accompanied by coronary spasm or other arrhythmias were observed [6,7,8], considering the rapid recovery without a relapse of hemodynamic instability, the unnecessity of vasodilators administration and clinical and laboratory normal results during the hours following the cardiac arrest. Moreover, the patient, despite his advanced age, had no medical history of cardiovascular disease or of allergic reactions before this event, unlike patients described in similar reports that are characterized, at least, by hypertension [12,13,14]. Currently, there is no information in the literature about possible drug–drug interaction between Sugammadex and the patient’s polytherapy.
4. Conclusions
In conclusion, although Sugammadex provides an important option for anesthesiologists in the prevention of postoperative residual neuromuscular blockade, it should be considered as a causative agent of cardiac arrest during surgery, directly or following anaphylaxis, even at the lowest recommended doses. For this reason, Sugammadex should be administered slowly, always with full ECG and hemodynamic changes monitoring after its administration [18], and anesthesiologists should be more rigorous in their ADRs reporting to pharmacovigilance agencies. Furthermore, it would be desirable to investigate the genetic and molecular mechanisms that induce the cardiovascular effects of Sugammadex in a specific subpopulation of patients.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author Contributions
C.F., A.M., D.M. and C.R. collected all patient data and drafted the manuscript. C.P., S.C. and E.F. collaborated on manuscript writing. C.F., G.M. and R.F. participated in the care of the patient. All authors gave their comments on the article and approved the final version. All authors have read and agreed to the published version of the manuscript.
Funding
This research was funded by AIFA (Agenzia Italiana del Farmaco): Progetti regionali di Farmacovigilanza (CUP D39E19000990001).
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Informed consent of the patient was obtained.
Data Availability Statement
Data and material are available on reasonable request.
Conflicts of Interest
The authors declare no conflict of interest.
medicina-57-00079-t001_Table 1Table 1 Naranjo nomogram for the assessment of adverse drug reaction (ADR). This questionnaire designed by Naranjo et al. [17] establishes whether an ADR was caused or not by a drug. The ADR is assigned to a probability category from the total score as follows: “definite” if the overall score is 9 or higher, “probable” for a score of 5–8, “possible” for a score of 1–4 and “doubtful” if the score is 0 or less. Bolded numbers apply to the patient’s case.
Assessment Questions Yes No Don’t Know
1. Are there previous conclusive reports on the ADR?
+1
0 0
2. Did ADR appear after the suspected drug was given?
+2
−1 0
3. Did the ADR improve when the drug was discontinued, or a specific antagonist was given?
+1
0 0
4. Did the ADR appear when the drug was re-administered? +2 −1
0
5. Are there alternative causes that could have caused the ADR? −1
+2
0
6. Did the reaction reappear when a placebo was given? −1 +1
0
7. Was the drug detected in any body fluid in toxic concentrations? +1 0
0
8. Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? +1 0
0
9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? +1
0
0
10. Was the ADR confirmed by any objective evidence?
+1
0 0
Total Score
7 = Probable | 55 kg. | Weight | CC BY | 33477765 | 20,168,163 | 2021-01-19 |
What was the administration route of drug 'CEFOTAXIME SODIUM'? | Severe Hypotension, Bradycardia and Asystole after Sugammadex Administration in an Elderly Patient.
Background and Objectives: Sugammadex is a modified γ-cyclodextrin largely used to prevent postoperative residual neuromuscular blockade induced by neuromuscular aminosteroid blocking agents. Although Sugammadex is considered more efficacious and safer than other drugs, such as Neostigmine, significant and serious complications after its administration, such as hypersensitivity, anaphylaxis and, more recently, severe cardiac events, are reported. Case presentation: In this report, we describe the case of an 80-year-old male with no medical history of cardiovascular disease who was scheduled for percutaneous nephrolithotripsy under general anesthesia. The intraoperative course was uneventful; however, the patient developed a rapid and severe hypotension, asystole and cardiac arrest after Sugammadex administration. Spontaneous cardiac activity and hemodynamic stability was restored with pharmacological therapy and chest compression. The patient was stabilized and discharged uneventfully on postoperative day 10. Conclusions: The potential causes of cardiac arrest after Sugammadex administration have been carefully considered, yet all indications point to Sugammadex as the direct causative agent. On the basis of laboratory and clinical tests, we can exclude among the cause of bradycardia, Kounis syndrome, acute myocardial infarction, coronary spasm and other arrhythmias, but not anaphylaxis. Although Sugammadex is considered an increasingly important option in the prevention of postoperative residual neuromuscular blockade, anesthesiologists should consider it a causative agent of cardiac arrest during surgery. This case highlights the necessity of increased pharmacovigilance and further studies to examine Sugammadex safety and mechanism through which it may cause severe bradycardia, hypotension and cardiac arrest.
1. Introduction
The modified γ-cyclodextrin Sugammadex is widely used to antagonize the post-operative residual neuromuscular blockade induced by neuromuscular aminosteroid blocking agents (NMBAs), such as Rocuronium bromide or Vecuronium bromide, used in adult anesthesia to ease endotracheal intubation, mechanical ventilation and surgical access. In detail, Sugammadex binds NMBA clearing nicotinic receptors, quickly reversing residual neuromuscular blockade and reducing the risk of postoperative respiratory complications.
Sugammadex has been reported to be more efficacious and safer than other drugs, such as Neostigmine, with lower incidence of common adverse drug reactions (ADRs) such as postoperative nausea and vomiting, dry mouth, tachycardia and dizziness [1,2,3]. However, the incidence of significant ADRs is almost similar between Sugammadex and Neostigmine: hypersensitivity, anaphylaxis [4,5] and, more recently, severe cardiac events such as coronary vasospasm and acute coronary syndrome [6,7,8], AV block [9], hypotension [10] and bradycardia with or without cardiac arrest [11,12,13,14] are described.
2. Case Presentation
In this report, we describe the case of bradycardia and cardiac arrest after Sugammadex administration in an elderly patient undergoing percutaneous nephrolithotripsy under general anesthesia for renal pelvis and calyceal lithiasis. The patient is an 80-year-old male (158 cm, 55 kg) in polytherapy for hypothyroidism, hyperuricemia, diabetes and chronic obstructive pulmonary disease with 50 mg Levothyroxine, 300 mg Allopurinol, 500 mg Metformin and 322 µg Aclidinium Bromide inhalation, respectively. However, he had no specific past medical history about coronary heart disease or any other cardiovascular disease. The results of preoperative electrocardiogram (ECG), chest X-ray and laboratory tests were normal. The patient went into surgery after premedication with 2 mg Midazolam intravenously (i.v.). Antibiotic prophylaxis was performed with 1 g Cefotaxime i.v.; ECG, noninvasive blood pressure (NIBP), end-tidal carbon dioxide (EtCO2) and oxygen saturation (SpO2) were monitored throughout the surgery.
The patient’s initial vital signs were: NIBP 120/70 mmHg, SpO2 98% and heart rate 75 beats/min. General mask ventilation was applied with 10% oxygen, and tracheal intubation was done without accident 2 min after Rocuronium administration. General anesthesia was induced with 140 mg Propofol and a total of 30 mg Rocuronium and, after tracheal intubation, was maintained with 2% (v/v) Sevoflurane and 0.3 mg Fentanyl. The second part of the surgery was done in a prone position. The patient’s intraoperative vital signs were maintained within the following ranges: systolic blood pressure: 120–130 mmHg; diastolic blood pressure: 70–80 mmHg, heart rate: 80–110 bpm, SpO2: 100%, EtCO2: 37%. An additional 10 mg Rocuronium was administered during the surgery to maintain muscle relaxation, so the total dose of Rocuronium was 40 mg. The total fluid input was 2500 mL (crystalloids). The intraoperative course was uneventful.
At the surgery end, the Sevoflurane administration was stopped and, after 5 min, 200 mg Sugammadex was administered to the patient: one minute later he developed severe bradycardia with heart rate below 35 beats/min and systolic blood pressure decreased to below 50 mmHg, and was promptly treated with a total of 10 mg Ephedrine and 1 mg Atropine i.v. to restore normal heart rate and systolic blood pressure. However, the patient’s clinical condition rapidly worsened with the onset of severe hypotension, asystole and cardiac arrest. Concomitant cardiopulmonary resuscitation with chest compression was performed for 1 min, restoring spontaneous cardiac activity and hemodynamic stability; the patient was transferred to the intensive care unit (ICU). Arterial blood gas after resuscitation showed: pH 7.32, PaO2: 126 mmHg, PaCO2: 25 mmHg, base excess: −8.4 mmol/L, HCO3: 19 mmol/L, lactate: 8 mmol/L, Na+: 136 mEq/L, Mg2+: 1.58 mg/dl, K+: 3.1 mEq/L, Ca2+: 7 mEq/L, glucose: 150 mg/dl and hemoglobin: 10.6 g/dl. Cardiac enzymes and troponins were normal, and postoperative cardiac workup including ECG and transthoracic echocardiography did not show any pathological sign. The patient was stabilized with optimal oxygen saturation level and spontaneous respiration during the following 3 days in ICU, transferred to the urology ward on postoperative day 3 and discharged uneventfully on postoperative day 10.
3. Discussion
The main clues point to Sugammadex as the cause of bradycardia, hypotension and cardiac arrest, both for the temporal proximity of administration and for the occurrence of similar, albeit rare, reports in the literature [15,16] as well as for the drug therapy used to resuscitate the patient based uniquely to Ephedrine and Atropine. Using the Naranjo nomogram, a 7 point-score (probable) was set to this report (Table 1).
The Sugammadex data sheet clearly states that “Cases of marked bradycardia, some of which have resulted in cardiac arrest, have been observed within minutes after the administration of [Sugammadex]”. The incidence of marked bradycardia at three different Sugammadex doses (2, 4 and 16 mg/kg) in pooled phase 1–3 patients was respectively 1, 1 and 5%. Although, our patient received a dose closer to 4 mg/kg, according to the Sugammadex prescribing information, this dose should not have conferred higher risk for the ADR observed, considering that low-dose Sugammadex (2 mg/kg) does not seem to protect against the chance that life-threatening bradycardia can occur [15]. Moreover, from 2009 to 2020, 292 cases of major cardiac events were reported after Sugammadex/Sugammadex sodium administration in the FAERS database [16], including bradycardia (n = 159), cardiac arrest (n = 115) and cardio-respiratory arrest (n = 18). In the same timeframe, Neostigmine/Neostigmine bromide or methylsulfate has been associated with 75 events, including bradycardia (n = 39), cardiac arrest (n = 28) and cardio-respiratory arrest (n = 8). The analysis, in the same period, of the frequency of total cardiovascular ADRs in respect to allergic or immune-based events shows very close values (567 vs. 574 ADRs, respectively).
Although Sugammadex-induced anaphylaxis is commonly associated with generalized skin rash, wheezing, bronchospasm and tachycardia [4,5] and our patient did not show these clinical signs, allergic-reaction symptoms during anesthesia could be nonspecific, and anaphylaxis-induced cardiovascular collapse has been reported. No other symptoms commonly linked to generalized anaphylaxis (e.g., increased peak inspiratory pressures seen with mechanical ventilation, initial drop in EtCO2 and facial or soft palate edema) were observed in the patient. Considering the absence of information about tryptase level or subsequent allergy testing with Sugammadex, we formally cannot exclude anaphylaxis as the primary cause of cardiac arrest [18]. Nonetheless, the fact that our patient responded to a single dose of Ephedrine and Atropine without a relapse of hemodynamic instability and without having to recourse instead to Epinephrine boluses or drip would suggest a greater likelihood of a direct cardiovascular effect rather than secondary to anaphylaxis. Moreover, in the Summary of Product Information released by EMA [19] it is stated that bradycardia induced by Sugammadex should be treated by an anticholinergic agent such as Atropine.
Conversely, no evidence of Kounis syndrome, as recently reported associated with Sugammadex administration, or acute myocardial infarction accompanied by coronary spasm or other arrhythmias were observed [6,7,8], considering the rapid recovery without a relapse of hemodynamic instability, the unnecessity of vasodilators administration and clinical and laboratory normal results during the hours following the cardiac arrest. Moreover, the patient, despite his advanced age, had no medical history of cardiovascular disease or of allergic reactions before this event, unlike patients described in similar reports that are characterized, at least, by hypertension [12,13,14]. Currently, there is no information in the literature about possible drug–drug interaction between Sugammadex and the patient’s polytherapy.
4. Conclusions
In conclusion, although Sugammadex provides an important option for anesthesiologists in the prevention of postoperative residual neuromuscular blockade, it should be considered as a causative agent of cardiac arrest during surgery, directly or following anaphylaxis, even at the lowest recommended doses. For this reason, Sugammadex should be administered slowly, always with full ECG and hemodynamic changes monitoring after its administration [18], and anesthesiologists should be more rigorous in their ADRs reporting to pharmacovigilance agencies. Furthermore, it would be desirable to investigate the genetic and molecular mechanisms that induce the cardiovascular effects of Sugammadex in a specific subpopulation of patients.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author Contributions
C.F., A.M., D.M. and C.R. collected all patient data and drafted the manuscript. C.P., S.C. and E.F. collaborated on manuscript writing. C.F., G.M. and R.F. participated in the care of the patient. All authors gave their comments on the article and approved the final version. All authors have read and agreed to the published version of the manuscript.
Funding
This research was funded by AIFA (Agenzia Italiana del Farmaco): Progetti regionali di Farmacovigilanza (CUP D39E19000990001).
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Informed consent of the patient was obtained.
Data Availability Statement
Data and material are available on reasonable request.
Conflicts of Interest
The authors declare no conflict of interest.
medicina-57-00079-t001_Table 1Table 1 Naranjo nomogram for the assessment of adverse drug reaction (ADR). This questionnaire designed by Naranjo et al. [17] establishes whether an ADR was caused or not by a drug. The ADR is assigned to a probability category from the total score as follows: “definite” if the overall score is 9 or higher, “probable” for a score of 5–8, “possible” for a score of 1–4 and “doubtful” if the score is 0 or less. Bolded numbers apply to the patient’s case.
Assessment Questions Yes No Don’t Know
1. Are there previous conclusive reports on the ADR?
+1
0 0
2. Did ADR appear after the suspected drug was given?
+2
−1 0
3. Did the ADR improve when the drug was discontinued, or a specific antagonist was given?
+1
0 0
4. Did the ADR appear when the drug was re-administered? +2 −1
0
5. Are there alternative causes that could have caused the ADR? −1
+2
0
6. Did the reaction reappear when a placebo was given? −1 +1
0
7. Was the drug detected in any body fluid in toxic concentrations? +1 0
0
8. Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? +1 0
0
9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? +1
0
0
10. Was the ADR confirmed by any objective evidence?
+1
0 0
Total Score
7 = Probable | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33477765 | 20,168,163 | 2021-01-19 |
What was the administration route of drug 'MIDAZOLAM'? | Severe Hypotension, Bradycardia and Asystole after Sugammadex Administration in an Elderly Patient.
Background and Objectives: Sugammadex is a modified γ-cyclodextrin largely used to prevent postoperative residual neuromuscular blockade induced by neuromuscular aminosteroid blocking agents. Although Sugammadex is considered more efficacious and safer than other drugs, such as Neostigmine, significant and serious complications after its administration, such as hypersensitivity, anaphylaxis and, more recently, severe cardiac events, are reported. Case presentation: In this report, we describe the case of an 80-year-old male with no medical history of cardiovascular disease who was scheduled for percutaneous nephrolithotripsy under general anesthesia. The intraoperative course was uneventful; however, the patient developed a rapid and severe hypotension, asystole and cardiac arrest after Sugammadex administration. Spontaneous cardiac activity and hemodynamic stability was restored with pharmacological therapy and chest compression. The patient was stabilized and discharged uneventfully on postoperative day 10. Conclusions: The potential causes of cardiac arrest after Sugammadex administration have been carefully considered, yet all indications point to Sugammadex as the direct causative agent. On the basis of laboratory and clinical tests, we can exclude among the cause of bradycardia, Kounis syndrome, acute myocardial infarction, coronary spasm and other arrhythmias, but not anaphylaxis. Although Sugammadex is considered an increasingly important option in the prevention of postoperative residual neuromuscular blockade, anesthesiologists should consider it a causative agent of cardiac arrest during surgery. This case highlights the necessity of increased pharmacovigilance and further studies to examine Sugammadex safety and mechanism through which it may cause severe bradycardia, hypotension and cardiac arrest.
1. Introduction
The modified γ-cyclodextrin Sugammadex is widely used to antagonize the post-operative residual neuromuscular blockade induced by neuromuscular aminosteroid blocking agents (NMBAs), such as Rocuronium bromide or Vecuronium bromide, used in adult anesthesia to ease endotracheal intubation, mechanical ventilation and surgical access. In detail, Sugammadex binds NMBA clearing nicotinic receptors, quickly reversing residual neuromuscular blockade and reducing the risk of postoperative respiratory complications.
Sugammadex has been reported to be more efficacious and safer than other drugs, such as Neostigmine, with lower incidence of common adverse drug reactions (ADRs) such as postoperative nausea and vomiting, dry mouth, tachycardia and dizziness [1,2,3]. However, the incidence of significant ADRs is almost similar between Sugammadex and Neostigmine: hypersensitivity, anaphylaxis [4,5] and, more recently, severe cardiac events such as coronary vasospasm and acute coronary syndrome [6,7,8], AV block [9], hypotension [10] and bradycardia with or without cardiac arrest [11,12,13,14] are described.
2. Case Presentation
In this report, we describe the case of bradycardia and cardiac arrest after Sugammadex administration in an elderly patient undergoing percutaneous nephrolithotripsy under general anesthesia for renal pelvis and calyceal lithiasis. The patient is an 80-year-old male (158 cm, 55 kg) in polytherapy for hypothyroidism, hyperuricemia, diabetes and chronic obstructive pulmonary disease with 50 mg Levothyroxine, 300 mg Allopurinol, 500 mg Metformin and 322 µg Aclidinium Bromide inhalation, respectively. However, he had no specific past medical history about coronary heart disease or any other cardiovascular disease. The results of preoperative electrocardiogram (ECG), chest X-ray and laboratory tests were normal. The patient went into surgery after premedication with 2 mg Midazolam intravenously (i.v.). Antibiotic prophylaxis was performed with 1 g Cefotaxime i.v.; ECG, noninvasive blood pressure (NIBP), end-tidal carbon dioxide (EtCO2) and oxygen saturation (SpO2) were monitored throughout the surgery.
The patient’s initial vital signs were: NIBP 120/70 mmHg, SpO2 98% and heart rate 75 beats/min. General mask ventilation was applied with 10% oxygen, and tracheal intubation was done without accident 2 min after Rocuronium administration. General anesthesia was induced with 140 mg Propofol and a total of 30 mg Rocuronium and, after tracheal intubation, was maintained with 2% (v/v) Sevoflurane and 0.3 mg Fentanyl. The second part of the surgery was done in a prone position. The patient’s intraoperative vital signs were maintained within the following ranges: systolic blood pressure: 120–130 mmHg; diastolic blood pressure: 70–80 mmHg, heart rate: 80–110 bpm, SpO2: 100%, EtCO2: 37%. An additional 10 mg Rocuronium was administered during the surgery to maintain muscle relaxation, so the total dose of Rocuronium was 40 mg. The total fluid input was 2500 mL (crystalloids). The intraoperative course was uneventful.
At the surgery end, the Sevoflurane administration was stopped and, after 5 min, 200 mg Sugammadex was administered to the patient: one minute later he developed severe bradycardia with heart rate below 35 beats/min and systolic blood pressure decreased to below 50 mmHg, and was promptly treated with a total of 10 mg Ephedrine and 1 mg Atropine i.v. to restore normal heart rate and systolic blood pressure. However, the patient’s clinical condition rapidly worsened with the onset of severe hypotension, asystole and cardiac arrest. Concomitant cardiopulmonary resuscitation with chest compression was performed for 1 min, restoring spontaneous cardiac activity and hemodynamic stability; the patient was transferred to the intensive care unit (ICU). Arterial blood gas after resuscitation showed: pH 7.32, PaO2: 126 mmHg, PaCO2: 25 mmHg, base excess: −8.4 mmol/L, HCO3: 19 mmol/L, lactate: 8 mmol/L, Na+: 136 mEq/L, Mg2+: 1.58 mg/dl, K+: 3.1 mEq/L, Ca2+: 7 mEq/L, glucose: 150 mg/dl and hemoglobin: 10.6 g/dl. Cardiac enzymes and troponins were normal, and postoperative cardiac workup including ECG and transthoracic echocardiography did not show any pathological sign. The patient was stabilized with optimal oxygen saturation level and spontaneous respiration during the following 3 days in ICU, transferred to the urology ward on postoperative day 3 and discharged uneventfully on postoperative day 10.
3. Discussion
The main clues point to Sugammadex as the cause of bradycardia, hypotension and cardiac arrest, both for the temporal proximity of administration and for the occurrence of similar, albeit rare, reports in the literature [15,16] as well as for the drug therapy used to resuscitate the patient based uniquely to Ephedrine and Atropine. Using the Naranjo nomogram, a 7 point-score (probable) was set to this report (Table 1).
The Sugammadex data sheet clearly states that “Cases of marked bradycardia, some of which have resulted in cardiac arrest, have been observed within minutes after the administration of [Sugammadex]”. The incidence of marked bradycardia at three different Sugammadex doses (2, 4 and 16 mg/kg) in pooled phase 1–3 patients was respectively 1, 1 and 5%. Although, our patient received a dose closer to 4 mg/kg, according to the Sugammadex prescribing information, this dose should not have conferred higher risk for the ADR observed, considering that low-dose Sugammadex (2 mg/kg) does not seem to protect against the chance that life-threatening bradycardia can occur [15]. Moreover, from 2009 to 2020, 292 cases of major cardiac events were reported after Sugammadex/Sugammadex sodium administration in the FAERS database [16], including bradycardia (n = 159), cardiac arrest (n = 115) and cardio-respiratory arrest (n = 18). In the same timeframe, Neostigmine/Neostigmine bromide or methylsulfate has been associated with 75 events, including bradycardia (n = 39), cardiac arrest (n = 28) and cardio-respiratory arrest (n = 8). The analysis, in the same period, of the frequency of total cardiovascular ADRs in respect to allergic or immune-based events shows very close values (567 vs. 574 ADRs, respectively).
Although Sugammadex-induced anaphylaxis is commonly associated with generalized skin rash, wheezing, bronchospasm and tachycardia [4,5] and our patient did not show these clinical signs, allergic-reaction symptoms during anesthesia could be nonspecific, and anaphylaxis-induced cardiovascular collapse has been reported. No other symptoms commonly linked to generalized anaphylaxis (e.g., increased peak inspiratory pressures seen with mechanical ventilation, initial drop in EtCO2 and facial or soft palate edema) were observed in the patient. Considering the absence of information about tryptase level or subsequent allergy testing with Sugammadex, we formally cannot exclude anaphylaxis as the primary cause of cardiac arrest [18]. Nonetheless, the fact that our patient responded to a single dose of Ephedrine and Atropine without a relapse of hemodynamic instability and without having to recourse instead to Epinephrine boluses or drip would suggest a greater likelihood of a direct cardiovascular effect rather than secondary to anaphylaxis. Moreover, in the Summary of Product Information released by EMA [19] it is stated that bradycardia induced by Sugammadex should be treated by an anticholinergic agent such as Atropine.
Conversely, no evidence of Kounis syndrome, as recently reported associated with Sugammadex administration, or acute myocardial infarction accompanied by coronary spasm or other arrhythmias were observed [6,7,8], considering the rapid recovery without a relapse of hemodynamic instability, the unnecessity of vasodilators administration and clinical and laboratory normal results during the hours following the cardiac arrest. Moreover, the patient, despite his advanced age, had no medical history of cardiovascular disease or of allergic reactions before this event, unlike patients described in similar reports that are characterized, at least, by hypertension [12,13,14]. Currently, there is no information in the literature about possible drug–drug interaction between Sugammadex and the patient’s polytherapy.
4. Conclusions
In conclusion, although Sugammadex provides an important option for anesthesiologists in the prevention of postoperative residual neuromuscular blockade, it should be considered as a causative agent of cardiac arrest during surgery, directly or following anaphylaxis, even at the lowest recommended doses. For this reason, Sugammadex should be administered slowly, always with full ECG and hemodynamic changes monitoring after its administration [18], and anesthesiologists should be more rigorous in their ADRs reporting to pharmacovigilance agencies. Furthermore, it would be desirable to investigate the genetic and molecular mechanisms that induce the cardiovascular effects of Sugammadex in a specific subpopulation of patients.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author Contributions
C.F., A.M., D.M. and C.R. collected all patient data and drafted the manuscript. C.P., S.C. and E.F. collaborated on manuscript writing. C.F., G.M. and R.F. participated in the care of the patient. All authors gave their comments on the article and approved the final version. All authors have read and agreed to the published version of the manuscript.
Funding
This research was funded by AIFA (Agenzia Italiana del Farmaco): Progetti regionali di Farmacovigilanza (CUP D39E19000990001).
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Informed consent of the patient was obtained.
Data Availability Statement
Data and material are available on reasonable request.
Conflicts of Interest
The authors declare no conflict of interest.
medicina-57-00079-t001_Table 1Table 1 Naranjo nomogram for the assessment of adverse drug reaction (ADR). This questionnaire designed by Naranjo et al. [17] establishes whether an ADR was caused or not by a drug. The ADR is assigned to a probability category from the total score as follows: “definite” if the overall score is 9 or higher, “probable” for a score of 5–8, “possible” for a score of 1–4 and “doubtful” if the score is 0 or less. Bolded numbers apply to the patient’s case.
Assessment Questions Yes No Don’t Know
1. Are there previous conclusive reports on the ADR?
+1
0 0
2. Did ADR appear after the suspected drug was given?
+2
−1 0
3. Did the ADR improve when the drug was discontinued, or a specific antagonist was given?
+1
0 0
4. Did the ADR appear when the drug was re-administered? +2 −1
0
5. Are there alternative causes that could have caused the ADR? −1
+2
0
6. Did the reaction reappear when a placebo was given? −1 +1
0
7. Was the drug detected in any body fluid in toxic concentrations? +1 0
0
8. Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? +1 0
0
9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? +1
0
0
10. Was the ADR confirmed by any objective evidence?
+1
0 0
Total Score
7 = Probable | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33477765 | 20,168,163 | 2021-01-19 |
What was the outcome of reaction 'Bradycardia'? | Severe Hypotension, Bradycardia and Asystole after Sugammadex Administration in an Elderly Patient.
Background and Objectives: Sugammadex is a modified γ-cyclodextrin largely used to prevent postoperative residual neuromuscular blockade induced by neuromuscular aminosteroid blocking agents. Although Sugammadex is considered more efficacious and safer than other drugs, such as Neostigmine, significant and serious complications after its administration, such as hypersensitivity, anaphylaxis and, more recently, severe cardiac events, are reported. Case presentation: In this report, we describe the case of an 80-year-old male with no medical history of cardiovascular disease who was scheduled for percutaneous nephrolithotripsy under general anesthesia. The intraoperative course was uneventful; however, the patient developed a rapid and severe hypotension, asystole and cardiac arrest after Sugammadex administration. Spontaneous cardiac activity and hemodynamic stability was restored with pharmacological therapy and chest compression. The patient was stabilized and discharged uneventfully on postoperative day 10. Conclusions: The potential causes of cardiac arrest after Sugammadex administration have been carefully considered, yet all indications point to Sugammadex as the direct causative agent. On the basis of laboratory and clinical tests, we can exclude among the cause of bradycardia, Kounis syndrome, acute myocardial infarction, coronary spasm and other arrhythmias, but not anaphylaxis. Although Sugammadex is considered an increasingly important option in the prevention of postoperative residual neuromuscular blockade, anesthesiologists should consider it a causative agent of cardiac arrest during surgery. This case highlights the necessity of increased pharmacovigilance and further studies to examine Sugammadex safety and mechanism through which it may cause severe bradycardia, hypotension and cardiac arrest.
1. Introduction
The modified γ-cyclodextrin Sugammadex is widely used to antagonize the post-operative residual neuromuscular blockade induced by neuromuscular aminosteroid blocking agents (NMBAs), such as Rocuronium bromide or Vecuronium bromide, used in adult anesthesia to ease endotracheal intubation, mechanical ventilation and surgical access. In detail, Sugammadex binds NMBA clearing nicotinic receptors, quickly reversing residual neuromuscular blockade and reducing the risk of postoperative respiratory complications.
Sugammadex has been reported to be more efficacious and safer than other drugs, such as Neostigmine, with lower incidence of common adverse drug reactions (ADRs) such as postoperative nausea and vomiting, dry mouth, tachycardia and dizziness [1,2,3]. However, the incidence of significant ADRs is almost similar between Sugammadex and Neostigmine: hypersensitivity, anaphylaxis [4,5] and, more recently, severe cardiac events such as coronary vasospasm and acute coronary syndrome [6,7,8], AV block [9], hypotension [10] and bradycardia with or without cardiac arrest [11,12,13,14] are described.
2. Case Presentation
In this report, we describe the case of bradycardia and cardiac arrest after Sugammadex administration in an elderly patient undergoing percutaneous nephrolithotripsy under general anesthesia for renal pelvis and calyceal lithiasis. The patient is an 80-year-old male (158 cm, 55 kg) in polytherapy for hypothyroidism, hyperuricemia, diabetes and chronic obstructive pulmonary disease with 50 mg Levothyroxine, 300 mg Allopurinol, 500 mg Metformin and 322 µg Aclidinium Bromide inhalation, respectively. However, he had no specific past medical history about coronary heart disease or any other cardiovascular disease. The results of preoperative electrocardiogram (ECG), chest X-ray and laboratory tests were normal. The patient went into surgery after premedication with 2 mg Midazolam intravenously (i.v.). Antibiotic prophylaxis was performed with 1 g Cefotaxime i.v.; ECG, noninvasive blood pressure (NIBP), end-tidal carbon dioxide (EtCO2) and oxygen saturation (SpO2) were monitored throughout the surgery.
The patient’s initial vital signs were: NIBP 120/70 mmHg, SpO2 98% and heart rate 75 beats/min. General mask ventilation was applied with 10% oxygen, and tracheal intubation was done without accident 2 min after Rocuronium administration. General anesthesia was induced with 140 mg Propofol and a total of 30 mg Rocuronium and, after tracheal intubation, was maintained with 2% (v/v) Sevoflurane and 0.3 mg Fentanyl. The second part of the surgery was done in a prone position. The patient’s intraoperative vital signs were maintained within the following ranges: systolic blood pressure: 120–130 mmHg; diastolic blood pressure: 70–80 mmHg, heart rate: 80–110 bpm, SpO2: 100%, EtCO2: 37%. An additional 10 mg Rocuronium was administered during the surgery to maintain muscle relaxation, so the total dose of Rocuronium was 40 mg. The total fluid input was 2500 mL (crystalloids). The intraoperative course was uneventful.
At the surgery end, the Sevoflurane administration was stopped and, after 5 min, 200 mg Sugammadex was administered to the patient: one minute later he developed severe bradycardia with heart rate below 35 beats/min and systolic blood pressure decreased to below 50 mmHg, and was promptly treated with a total of 10 mg Ephedrine and 1 mg Atropine i.v. to restore normal heart rate and systolic blood pressure. However, the patient’s clinical condition rapidly worsened with the onset of severe hypotension, asystole and cardiac arrest. Concomitant cardiopulmonary resuscitation with chest compression was performed for 1 min, restoring spontaneous cardiac activity and hemodynamic stability; the patient was transferred to the intensive care unit (ICU). Arterial blood gas after resuscitation showed: pH 7.32, PaO2: 126 mmHg, PaCO2: 25 mmHg, base excess: −8.4 mmol/L, HCO3: 19 mmol/L, lactate: 8 mmol/L, Na+: 136 mEq/L, Mg2+: 1.58 mg/dl, K+: 3.1 mEq/L, Ca2+: 7 mEq/L, glucose: 150 mg/dl and hemoglobin: 10.6 g/dl. Cardiac enzymes and troponins were normal, and postoperative cardiac workup including ECG and transthoracic echocardiography did not show any pathological sign. The patient was stabilized with optimal oxygen saturation level and spontaneous respiration during the following 3 days in ICU, transferred to the urology ward on postoperative day 3 and discharged uneventfully on postoperative day 10.
3. Discussion
The main clues point to Sugammadex as the cause of bradycardia, hypotension and cardiac arrest, both for the temporal proximity of administration and for the occurrence of similar, albeit rare, reports in the literature [15,16] as well as for the drug therapy used to resuscitate the patient based uniquely to Ephedrine and Atropine. Using the Naranjo nomogram, a 7 point-score (probable) was set to this report (Table 1).
The Sugammadex data sheet clearly states that “Cases of marked bradycardia, some of which have resulted in cardiac arrest, have been observed within minutes after the administration of [Sugammadex]”. The incidence of marked bradycardia at three different Sugammadex doses (2, 4 and 16 mg/kg) in pooled phase 1–3 patients was respectively 1, 1 and 5%. Although, our patient received a dose closer to 4 mg/kg, according to the Sugammadex prescribing information, this dose should not have conferred higher risk for the ADR observed, considering that low-dose Sugammadex (2 mg/kg) does not seem to protect against the chance that life-threatening bradycardia can occur [15]. Moreover, from 2009 to 2020, 292 cases of major cardiac events were reported after Sugammadex/Sugammadex sodium administration in the FAERS database [16], including bradycardia (n = 159), cardiac arrest (n = 115) and cardio-respiratory arrest (n = 18). In the same timeframe, Neostigmine/Neostigmine bromide or methylsulfate has been associated with 75 events, including bradycardia (n = 39), cardiac arrest (n = 28) and cardio-respiratory arrest (n = 8). The analysis, in the same period, of the frequency of total cardiovascular ADRs in respect to allergic or immune-based events shows very close values (567 vs. 574 ADRs, respectively).
Although Sugammadex-induced anaphylaxis is commonly associated with generalized skin rash, wheezing, bronchospasm and tachycardia [4,5] and our patient did not show these clinical signs, allergic-reaction symptoms during anesthesia could be nonspecific, and anaphylaxis-induced cardiovascular collapse has been reported. No other symptoms commonly linked to generalized anaphylaxis (e.g., increased peak inspiratory pressures seen with mechanical ventilation, initial drop in EtCO2 and facial or soft palate edema) were observed in the patient. Considering the absence of information about tryptase level or subsequent allergy testing with Sugammadex, we formally cannot exclude anaphylaxis as the primary cause of cardiac arrest [18]. Nonetheless, the fact that our patient responded to a single dose of Ephedrine and Atropine without a relapse of hemodynamic instability and without having to recourse instead to Epinephrine boluses or drip would suggest a greater likelihood of a direct cardiovascular effect rather than secondary to anaphylaxis. Moreover, in the Summary of Product Information released by EMA [19] it is stated that bradycardia induced by Sugammadex should be treated by an anticholinergic agent such as Atropine.
Conversely, no evidence of Kounis syndrome, as recently reported associated with Sugammadex administration, or acute myocardial infarction accompanied by coronary spasm or other arrhythmias were observed [6,7,8], considering the rapid recovery without a relapse of hemodynamic instability, the unnecessity of vasodilators administration and clinical and laboratory normal results during the hours following the cardiac arrest. Moreover, the patient, despite his advanced age, had no medical history of cardiovascular disease or of allergic reactions before this event, unlike patients described in similar reports that are characterized, at least, by hypertension [12,13,14]. Currently, there is no information in the literature about possible drug–drug interaction between Sugammadex and the patient’s polytherapy.
4. Conclusions
In conclusion, although Sugammadex provides an important option for anesthesiologists in the prevention of postoperative residual neuromuscular blockade, it should be considered as a causative agent of cardiac arrest during surgery, directly or following anaphylaxis, even at the lowest recommended doses. For this reason, Sugammadex should be administered slowly, always with full ECG and hemodynamic changes monitoring after its administration [18], and anesthesiologists should be more rigorous in their ADRs reporting to pharmacovigilance agencies. Furthermore, it would be desirable to investigate the genetic and molecular mechanisms that induce the cardiovascular effects of Sugammadex in a specific subpopulation of patients.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author Contributions
C.F., A.M., D.M. and C.R. collected all patient data and drafted the manuscript. C.P., S.C. and E.F. collaborated on manuscript writing. C.F., G.M. and R.F. participated in the care of the patient. All authors gave their comments on the article and approved the final version. All authors have read and agreed to the published version of the manuscript.
Funding
This research was funded by AIFA (Agenzia Italiana del Farmaco): Progetti regionali di Farmacovigilanza (CUP D39E19000990001).
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Informed consent of the patient was obtained.
Data Availability Statement
Data and material are available on reasonable request.
Conflicts of Interest
The authors declare no conflict of interest.
medicina-57-00079-t001_Table 1Table 1 Naranjo nomogram for the assessment of adverse drug reaction (ADR). This questionnaire designed by Naranjo et al. [17] establishes whether an ADR was caused or not by a drug. The ADR is assigned to a probability category from the total score as follows: “definite” if the overall score is 9 or higher, “probable” for a score of 5–8, “possible” for a score of 1–4 and “doubtful” if the score is 0 or less. Bolded numbers apply to the patient’s case.
Assessment Questions Yes No Don’t Know
1. Are there previous conclusive reports on the ADR?
+1
0 0
2. Did ADR appear after the suspected drug was given?
+2
−1 0
3. Did the ADR improve when the drug was discontinued, or a specific antagonist was given?
+1
0 0
4. Did the ADR appear when the drug was re-administered? +2 −1
0
5. Are there alternative causes that could have caused the ADR? −1
+2
0
6. Did the reaction reappear when a placebo was given? −1 +1
0
7. Was the drug detected in any body fluid in toxic concentrations? +1 0
0
8. Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? +1 0
0
9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? +1
0
0
10. Was the ADR confirmed by any objective evidence?
+1
0 0
Total Score
7 = Probable | Recovered | ReactionOutcome | CC BY | 33477765 | 20,168,163 | 2021-01-19 |
What was the outcome of reaction 'Cardiac arrest'? | Severe Hypotension, Bradycardia and Asystole after Sugammadex Administration in an Elderly Patient.
Background and Objectives: Sugammadex is a modified γ-cyclodextrin largely used to prevent postoperative residual neuromuscular blockade induced by neuromuscular aminosteroid blocking agents. Although Sugammadex is considered more efficacious and safer than other drugs, such as Neostigmine, significant and serious complications after its administration, such as hypersensitivity, anaphylaxis and, more recently, severe cardiac events, are reported. Case presentation: In this report, we describe the case of an 80-year-old male with no medical history of cardiovascular disease who was scheduled for percutaneous nephrolithotripsy under general anesthesia. The intraoperative course was uneventful; however, the patient developed a rapid and severe hypotension, asystole and cardiac arrest after Sugammadex administration. Spontaneous cardiac activity and hemodynamic stability was restored with pharmacological therapy and chest compression. The patient was stabilized and discharged uneventfully on postoperative day 10. Conclusions: The potential causes of cardiac arrest after Sugammadex administration have been carefully considered, yet all indications point to Sugammadex as the direct causative agent. On the basis of laboratory and clinical tests, we can exclude among the cause of bradycardia, Kounis syndrome, acute myocardial infarction, coronary spasm and other arrhythmias, but not anaphylaxis. Although Sugammadex is considered an increasingly important option in the prevention of postoperative residual neuromuscular blockade, anesthesiologists should consider it a causative agent of cardiac arrest during surgery. This case highlights the necessity of increased pharmacovigilance and further studies to examine Sugammadex safety and mechanism through which it may cause severe bradycardia, hypotension and cardiac arrest.
1. Introduction
The modified γ-cyclodextrin Sugammadex is widely used to antagonize the post-operative residual neuromuscular blockade induced by neuromuscular aminosteroid blocking agents (NMBAs), such as Rocuronium bromide or Vecuronium bromide, used in adult anesthesia to ease endotracheal intubation, mechanical ventilation and surgical access. In detail, Sugammadex binds NMBA clearing nicotinic receptors, quickly reversing residual neuromuscular blockade and reducing the risk of postoperative respiratory complications.
Sugammadex has been reported to be more efficacious and safer than other drugs, such as Neostigmine, with lower incidence of common adverse drug reactions (ADRs) such as postoperative nausea and vomiting, dry mouth, tachycardia and dizziness [1,2,3]. However, the incidence of significant ADRs is almost similar between Sugammadex and Neostigmine: hypersensitivity, anaphylaxis [4,5] and, more recently, severe cardiac events such as coronary vasospasm and acute coronary syndrome [6,7,8], AV block [9], hypotension [10] and bradycardia with or without cardiac arrest [11,12,13,14] are described.
2. Case Presentation
In this report, we describe the case of bradycardia and cardiac arrest after Sugammadex administration in an elderly patient undergoing percutaneous nephrolithotripsy under general anesthesia for renal pelvis and calyceal lithiasis. The patient is an 80-year-old male (158 cm, 55 kg) in polytherapy for hypothyroidism, hyperuricemia, diabetes and chronic obstructive pulmonary disease with 50 mg Levothyroxine, 300 mg Allopurinol, 500 mg Metformin and 322 µg Aclidinium Bromide inhalation, respectively. However, he had no specific past medical history about coronary heart disease or any other cardiovascular disease. The results of preoperative electrocardiogram (ECG), chest X-ray and laboratory tests were normal. The patient went into surgery after premedication with 2 mg Midazolam intravenously (i.v.). Antibiotic prophylaxis was performed with 1 g Cefotaxime i.v.; ECG, noninvasive blood pressure (NIBP), end-tidal carbon dioxide (EtCO2) and oxygen saturation (SpO2) were monitored throughout the surgery.
The patient’s initial vital signs were: NIBP 120/70 mmHg, SpO2 98% and heart rate 75 beats/min. General mask ventilation was applied with 10% oxygen, and tracheal intubation was done without accident 2 min after Rocuronium administration. General anesthesia was induced with 140 mg Propofol and a total of 30 mg Rocuronium and, after tracheal intubation, was maintained with 2% (v/v) Sevoflurane and 0.3 mg Fentanyl. The second part of the surgery was done in a prone position. The patient’s intraoperative vital signs were maintained within the following ranges: systolic blood pressure: 120–130 mmHg; diastolic blood pressure: 70–80 mmHg, heart rate: 80–110 bpm, SpO2: 100%, EtCO2: 37%. An additional 10 mg Rocuronium was administered during the surgery to maintain muscle relaxation, so the total dose of Rocuronium was 40 mg. The total fluid input was 2500 mL (crystalloids). The intraoperative course was uneventful.
At the surgery end, the Sevoflurane administration was stopped and, after 5 min, 200 mg Sugammadex was administered to the patient: one minute later he developed severe bradycardia with heart rate below 35 beats/min and systolic blood pressure decreased to below 50 mmHg, and was promptly treated with a total of 10 mg Ephedrine and 1 mg Atropine i.v. to restore normal heart rate and systolic blood pressure. However, the patient’s clinical condition rapidly worsened with the onset of severe hypotension, asystole and cardiac arrest. Concomitant cardiopulmonary resuscitation with chest compression was performed for 1 min, restoring spontaneous cardiac activity and hemodynamic stability; the patient was transferred to the intensive care unit (ICU). Arterial blood gas after resuscitation showed: pH 7.32, PaO2: 126 mmHg, PaCO2: 25 mmHg, base excess: −8.4 mmol/L, HCO3: 19 mmol/L, lactate: 8 mmol/L, Na+: 136 mEq/L, Mg2+: 1.58 mg/dl, K+: 3.1 mEq/L, Ca2+: 7 mEq/L, glucose: 150 mg/dl and hemoglobin: 10.6 g/dl. Cardiac enzymes and troponins were normal, and postoperative cardiac workup including ECG and transthoracic echocardiography did not show any pathological sign. The patient was stabilized with optimal oxygen saturation level and spontaneous respiration during the following 3 days in ICU, transferred to the urology ward on postoperative day 3 and discharged uneventfully on postoperative day 10.
3. Discussion
The main clues point to Sugammadex as the cause of bradycardia, hypotension and cardiac arrest, both for the temporal proximity of administration and for the occurrence of similar, albeit rare, reports in the literature [15,16] as well as for the drug therapy used to resuscitate the patient based uniquely to Ephedrine and Atropine. Using the Naranjo nomogram, a 7 point-score (probable) was set to this report (Table 1).
The Sugammadex data sheet clearly states that “Cases of marked bradycardia, some of which have resulted in cardiac arrest, have been observed within minutes after the administration of [Sugammadex]”. The incidence of marked bradycardia at three different Sugammadex doses (2, 4 and 16 mg/kg) in pooled phase 1–3 patients was respectively 1, 1 and 5%. Although, our patient received a dose closer to 4 mg/kg, according to the Sugammadex prescribing information, this dose should not have conferred higher risk for the ADR observed, considering that low-dose Sugammadex (2 mg/kg) does not seem to protect against the chance that life-threatening bradycardia can occur [15]. Moreover, from 2009 to 2020, 292 cases of major cardiac events were reported after Sugammadex/Sugammadex sodium administration in the FAERS database [16], including bradycardia (n = 159), cardiac arrest (n = 115) and cardio-respiratory arrest (n = 18). In the same timeframe, Neostigmine/Neostigmine bromide or methylsulfate has been associated with 75 events, including bradycardia (n = 39), cardiac arrest (n = 28) and cardio-respiratory arrest (n = 8). The analysis, in the same period, of the frequency of total cardiovascular ADRs in respect to allergic or immune-based events shows very close values (567 vs. 574 ADRs, respectively).
Although Sugammadex-induced anaphylaxis is commonly associated with generalized skin rash, wheezing, bronchospasm and tachycardia [4,5] and our patient did not show these clinical signs, allergic-reaction symptoms during anesthesia could be nonspecific, and anaphylaxis-induced cardiovascular collapse has been reported. No other symptoms commonly linked to generalized anaphylaxis (e.g., increased peak inspiratory pressures seen with mechanical ventilation, initial drop in EtCO2 and facial or soft palate edema) were observed in the patient. Considering the absence of information about tryptase level or subsequent allergy testing with Sugammadex, we formally cannot exclude anaphylaxis as the primary cause of cardiac arrest [18]. Nonetheless, the fact that our patient responded to a single dose of Ephedrine and Atropine without a relapse of hemodynamic instability and without having to recourse instead to Epinephrine boluses or drip would suggest a greater likelihood of a direct cardiovascular effect rather than secondary to anaphylaxis. Moreover, in the Summary of Product Information released by EMA [19] it is stated that bradycardia induced by Sugammadex should be treated by an anticholinergic agent such as Atropine.
Conversely, no evidence of Kounis syndrome, as recently reported associated with Sugammadex administration, or acute myocardial infarction accompanied by coronary spasm or other arrhythmias were observed [6,7,8], considering the rapid recovery without a relapse of hemodynamic instability, the unnecessity of vasodilators administration and clinical and laboratory normal results during the hours following the cardiac arrest. Moreover, the patient, despite his advanced age, had no medical history of cardiovascular disease or of allergic reactions before this event, unlike patients described in similar reports that are characterized, at least, by hypertension [12,13,14]. Currently, there is no information in the literature about possible drug–drug interaction between Sugammadex and the patient’s polytherapy.
4. Conclusions
In conclusion, although Sugammadex provides an important option for anesthesiologists in the prevention of postoperative residual neuromuscular blockade, it should be considered as a causative agent of cardiac arrest during surgery, directly or following anaphylaxis, even at the lowest recommended doses. For this reason, Sugammadex should be administered slowly, always with full ECG and hemodynamic changes monitoring after its administration [18], and anesthesiologists should be more rigorous in their ADRs reporting to pharmacovigilance agencies. Furthermore, it would be desirable to investigate the genetic and molecular mechanisms that induce the cardiovascular effects of Sugammadex in a specific subpopulation of patients.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author Contributions
C.F., A.M., D.M. and C.R. collected all patient data and drafted the manuscript. C.P., S.C. and E.F. collaborated on manuscript writing. C.F., G.M. and R.F. participated in the care of the patient. All authors gave their comments on the article and approved the final version. All authors have read and agreed to the published version of the manuscript.
Funding
This research was funded by AIFA (Agenzia Italiana del Farmaco): Progetti regionali di Farmacovigilanza (CUP D39E19000990001).
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Informed consent of the patient was obtained.
Data Availability Statement
Data and material are available on reasonable request.
Conflicts of Interest
The authors declare no conflict of interest.
medicina-57-00079-t001_Table 1Table 1 Naranjo nomogram for the assessment of adverse drug reaction (ADR). This questionnaire designed by Naranjo et al. [17] establishes whether an ADR was caused or not by a drug. The ADR is assigned to a probability category from the total score as follows: “definite” if the overall score is 9 or higher, “probable” for a score of 5–8, “possible” for a score of 1–4 and “doubtful” if the score is 0 or less. Bolded numbers apply to the patient’s case.
Assessment Questions Yes No Don’t Know
1. Are there previous conclusive reports on the ADR?
+1
0 0
2. Did ADR appear after the suspected drug was given?
+2
−1 0
3. Did the ADR improve when the drug was discontinued, or a specific antagonist was given?
+1
0 0
4. Did the ADR appear when the drug was re-administered? +2 −1
0
5. Are there alternative causes that could have caused the ADR? −1
+2
0
6. Did the reaction reappear when a placebo was given? −1 +1
0
7. Was the drug detected in any body fluid in toxic concentrations? +1 0
0
8. Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? +1 0
0
9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? +1
0
0
10. Was the ADR confirmed by any objective evidence?
+1
0 0
Total Score
7 = Probable | Recovered | ReactionOutcome | CC BY | 33477765 | 20,168,163 | 2021-01-19 |
What was the outcome of reaction 'Hypotension'? | Severe Hypotension, Bradycardia and Asystole after Sugammadex Administration in an Elderly Patient.
Background and Objectives: Sugammadex is a modified γ-cyclodextrin largely used to prevent postoperative residual neuromuscular blockade induced by neuromuscular aminosteroid blocking agents. Although Sugammadex is considered more efficacious and safer than other drugs, such as Neostigmine, significant and serious complications after its administration, such as hypersensitivity, anaphylaxis and, more recently, severe cardiac events, are reported. Case presentation: In this report, we describe the case of an 80-year-old male with no medical history of cardiovascular disease who was scheduled for percutaneous nephrolithotripsy under general anesthesia. The intraoperative course was uneventful; however, the patient developed a rapid and severe hypotension, asystole and cardiac arrest after Sugammadex administration. Spontaneous cardiac activity and hemodynamic stability was restored with pharmacological therapy and chest compression. The patient was stabilized and discharged uneventfully on postoperative day 10. Conclusions: The potential causes of cardiac arrest after Sugammadex administration have been carefully considered, yet all indications point to Sugammadex as the direct causative agent. On the basis of laboratory and clinical tests, we can exclude among the cause of bradycardia, Kounis syndrome, acute myocardial infarction, coronary spasm and other arrhythmias, but not anaphylaxis. Although Sugammadex is considered an increasingly important option in the prevention of postoperative residual neuromuscular blockade, anesthesiologists should consider it a causative agent of cardiac arrest during surgery. This case highlights the necessity of increased pharmacovigilance and further studies to examine Sugammadex safety and mechanism through which it may cause severe bradycardia, hypotension and cardiac arrest.
1. Introduction
The modified γ-cyclodextrin Sugammadex is widely used to antagonize the post-operative residual neuromuscular blockade induced by neuromuscular aminosteroid blocking agents (NMBAs), such as Rocuronium bromide or Vecuronium bromide, used in adult anesthesia to ease endotracheal intubation, mechanical ventilation and surgical access. In detail, Sugammadex binds NMBA clearing nicotinic receptors, quickly reversing residual neuromuscular blockade and reducing the risk of postoperative respiratory complications.
Sugammadex has been reported to be more efficacious and safer than other drugs, such as Neostigmine, with lower incidence of common adverse drug reactions (ADRs) such as postoperative nausea and vomiting, dry mouth, tachycardia and dizziness [1,2,3]. However, the incidence of significant ADRs is almost similar between Sugammadex and Neostigmine: hypersensitivity, anaphylaxis [4,5] and, more recently, severe cardiac events such as coronary vasospasm and acute coronary syndrome [6,7,8], AV block [9], hypotension [10] and bradycardia with or without cardiac arrest [11,12,13,14] are described.
2. Case Presentation
In this report, we describe the case of bradycardia and cardiac arrest after Sugammadex administration in an elderly patient undergoing percutaneous nephrolithotripsy under general anesthesia for renal pelvis and calyceal lithiasis. The patient is an 80-year-old male (158 cm, 55 kg) in polytherapy for hypothyroidism, hyperuricemia, diabetes and chronic obstructive pulmonary disease with 50 mg Levothyroxine, 300 mg Allopurinol, 500 mg Metformin and 322 µg Aclidinium Bromide inhalation, respectively. However, he had no specific past medical history about coronary heart disease or any other cardiovascular disease. The results of preoperative electrocardiogram (ECG), chest X-ray and laboratory tests were normal. The patient went into surgery after premedication with 2 mg Midazolam intravenously (i.v.). Antibiotic prophylaxis was performed with 1 g Cefotaxime i.v.; ECG, noninvasive blood pressure (NIBP), end-tidal carbon dioxide (EtCO2) and oxygen saturation (SpO2) were monitored throughout the surgery.
The patient’s initial vital signs were: NIBP 120/70 mmHg, SpO2 98% and heart rate 75 beats/min. General mask ventilation was applied with 10% oxygen, and tracheal intubation was done without accident 2 min after Rocuronium administration. General anesthesia was induced with 140 mg Propofol and a total of 30 mg Rocuronium and, after tracheal intubation, was maintained with 2% (v/v) Sevoflurane and 0.3 mg Fentanyl. The second part of the surgery was done in a prone position. The patient’s intraoperative vital signs were maintained within the following ranges: systolic blood pressure: 120–130 mmHg; diastolic blood pressure: 70–80 mmHg, heart rate: 80–110 bpm, SpO2: 100%, EtCO2: 37%. An additional 10 mg Rocuronium was administered during the surgery to maintain muscle relaxation, so the total dose of Rocuronium was 40 mg. The total fluid input was 2500 mL (crystalloids). The intraoperative course was uneventful.
At the surgery end, the Sevoflurane administration was stopped and, after 5 min, 200 mg Sugammadex was administered to the patient: one minute later he developed severe bradycardia with heart rate below 35 beats/min and systolic blood pressure decreased to below 50 mmHg, and was promptly treated with a total of 10 mg Ephedrine and 1 mg Atropine i.v. to restore normal heart rate and systolic blood pressure. However, the patient’s clinical condition rapidly worsened with the onset of severe hypotension, asystole and cardiac arrest. Concomitant cardiopulmonary resuscitation with chest compression was performed for 1 min, restoring spontaneous cardiac activity and hemodynamic stability; the patient was transferred to the intensive care unit (ICU). Arterial blood gas after resuscitation showed: pH 7.32, PaO2: 126 mmHg, PaCO2: 25 mmHg, base excess: −8.4 mmol/L, HCO3: 19 mmol/L, lactate: 8 mmol/L, Na+: 136 mEq/L, Mg2+: 1.58 mg/dl, K+: 3.1 mEq/L, Ca2+: 7 mEq/L, glucose: 150 mg/dl and hemoglobin: 10.6 g/dl. Cardiac enzymes and troponins were normal, and postoperative cardiac workup including ECG and transthoracic echocardiography did not show any pathological sign. The patient was stabilized with optimal oxygen saturation level and spontaneous respiration during the following 3 days in ICU, transferred to the urology ward on postoperative day 3 and discharged uneventfully on postoperative day 10.
3. Discussion
The main clues point to Sugammadex as the cause of bradycardia, hypotension and cardiac arrest, both for the temporal proximity of administration and for the occurrence of similar, albeit rare, reports in the literature [15,16] as well as for the drug therapy used to resuscitate the patient based uniquely to Ephedrine and Atropine. Using the Naranjo nomogram, a 7 point-score (probable) was set to this report (Table 1).
The Sugammadex data sheet clearly states that “Cases of marked bradycardia, some of which have resulted in cardiac arrest, have been observed within minutes after the administration of [Sugammadex]”. The incidence of marked bradycardia at three different Sugammadex doses (2, 4 and 16 mg/kg) in pooled phase 1–3 patients was respectively 1, 1 and 5%. Although, our patient received a dose closer to 4 mg/kg, according to the Sugammadex prescribing information, this dose should not have conferred higher risk for the ADR observed, considering that low-dose Sugammadex (2 mg/kg) does not seem to protect against the chance that life-threatening bradycardia can occur [15]. Moreover, from 2009 to 2020, 292 cases of major cardiac events were reported after Sugammadex/Sugammadex sodium administration in the FAERS database [16], including bradycardia (n = 159), cardiac arrest (n = 115) and cardio-respiratory arrest (n = 18). In the same timeframe, Neostigmine/Neostigmine bromide or methylsulfate has been associated with 75 events, including bradycardia (n = 39), cardiac arrest (n = 28) and cardio-respiratory arrest (n = 8). The analysis, in the same period, of the frequency of total cardiovascular ADRs in respect to allergic or immune-based events shows very close values (567 vs. 574 ADRs, respectively).
Although Sugammadex-induced anaphylaxis is commonly associated with generalized skin rash, wheezing, bronchospasm and tachycardia [4,5] and our patient did not show these clinical signs, allergic-reaction symptoms during anesthesia could be nonspecific, and anaphylaxis-induced cardiovascular collapse has been reported. No other symptoms commonly linked to generalized anaphylaxis (e.g., increased peak inspiratory pressures seen with mechanical ventilation, initial drop in EtCO2 and facial or soft palate edema) were observed in the patient. Considering the absence of information about tryptase level or subsequent allergy testing with Sugammadex, we formally cannot exclude anaphylaxis as the primary cause of cardiac arrest [18]. Nonetheless, the fact that our patient responded to a single dose of Ephedrine and Atropine without a relapse of hemodynamic instability and without having to recourse instead to Epinephrine boluses or drip would suggest a greater likelihood of a direct cardiovascular effect rather than secondary to anaphylaxis. Moreover, in the Summary of Product Information released by EMA [19] it is stated that bradycardia induced by Sugammadex should be treated by an anticholinergic agent such as Atropine.
Conversely, no evidence of Kounis syndrome, as recently reported associated with Sugammadex administration, or acute myocardial infarction accompanied by coronary spasm or other arrhythmias were observed [6,7,8], considering the rapid recovery without a relapse of hemodynamic instability, the unnecessity of vasodilators administration and clinical and laboratory normal results during the hours following the cardiac arrest. Moreover, the patient, despite his advanced age, had no medical history of cardiovascular disease or of allergic reactions before this event, unlike patients described in similar reports that are characterized, at least, by hypertension [12,13,14]. Currently, there is no information in the literature about possible drug–drug interaction between Sugammadex and the patient’s polytherapy.
4. Conclusions
In conclusion, although Sugammadex provides an important option for anesthesiologists in the prevention of postoperative residual neuromuscular blockade, it should be considered as a causative agent of cardiac arrest during surgery, directly or following anaphylaxis, even at the lowest recommended doses. For this reason, Sugammadex should be administered slowly, always with full ECG and hemodynamic changes monitoring after its administration [18], and anesthesiologists should be more rigorous in their ADRs reporting to pharmacovigilance agencies. Furthermore, it would be desirable to investigate the genetic and molecular mechanisms that induce the cardiovascular effects of Sugammadex in a specific subpopulation of patients.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author Contributions
C.F., A.M., D.M. and C.R. collected all patient data and drafted the manuscript. C.P., S.C. and E.F. collaborated on manuscript writing. C.F., G.M. and R.F. participated in the care of the patient. All authors gave their comments on the article and approved the final version. All authors have read and agreed to the published version of the manuscript.
Funding
This research was funded by AIFA (Agenzia Italiana del Farmaco): Progetti regionali di Farmacovigilanza (CUP D39E19000990001).
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Informed consent of the patient was obtained.
Data Availability Statement
Data and material are available on reasonable request.
Conflicts of Interest
The authors declare no conflict of interest.
medicina-57-00079-t001_Table 1Table 1 Naranjo nomogram for the assessment of adverse drug reaction (ADR). This questionnaire designed by Naranjo et al. [17] establishes whether an ADR was caused or not by a drug. The ADR is assigned to a probability category from the total score as follows: “definite” if the overall score is 9 or higher, “probable” for a score of 5–8, “possible” for a score of 1–4 and “doubtful” if the score is 0 or less. Bolded numbers apply to the patient’s case.
Assessment Questions Yes No Don’t Know
1. Are there previous conclusive reports on the ADR?
+1
0 0
2. Did ADR appear after the suspected drug was given?
+2
−1 0
3. Did the ADR improve when the drug was discontinued, or a specific antagonist was given?
+1
0 0
4. Did the ADR appear when the drug was re-administered? +2 −1
0
5. Are there alternative causes that could have caused the ADR? −1
+2
0
6. Did the reaction reappear when a placebo was given? −1 +1
0
7. Was the drug detected in any body fluid in toxic concentrations? +1 0
0
8. Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? +1 0
0
9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? +1
0
0
10. Was the ADR confirmed by any objective evidence?
+1
0 0
Total Score
7 = Probable | Recovered | ReactionOutcome | CC BY | 33477765 | 20,168,163 | 2021-01-19 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Squamous cell carcinoma'. | Safe Administration of Cemiplimab to a Kidney Transplant Patient with Locally Advanced Squamous Cell Carcinoma of the Scalp.
Immunotherapies directed at T-cell activation through antibodies targeting checkpoint proteins, such as programmed cell death 1 (PD1), are rapidly becoming the new standard of care in the treatment of several malignancies. Cemiplimab is a monoclonal antibody targeting PD1 that has recently emerged as a highly active treatment for locally advanced and metastatic cutaneous squamous cell carcinoma (CSCC). Patients who have received an organ transplant (OTRs) have been traditionally excluded from clinical trials with checkpoint inhibitors (CIs), given concerns for organ rejection. Renal transplant recipients (RTRs) are more likely to develop cancers than the general population, and skin cancers are among the most frequent malignancies. We report the case of a 72-year-old man with a history of a kidney transplant who presented with a rapidly growing, locally advanced squamous cell carcinoma (SCC) of the scalp that recurred within four weeks from surgical resection. The patient was able to safely receive ten cycles of cemiplimab so far with significant clinical benefit, and no issues with his kidney function, while continuing immunosuppression with low dose prednisone alone. An ongoing clinical trial (NCT04339062) is further exploring the safety of CIs in patients with metastatic CSCC who have previously received allogeneic hematopoietic stem cell transplant or a kidney transplant.
1. Introduction
The introduction of T-cell-targeted immunomodulators that block the immune checkpoints CTLA-4, PD1, or PDL1 represents one of the most significant advances in oncology in the last decade. Since ipilimumab was approved by the Federal Drug Administration (FDA) in 2011 for the treatment of melanoma, six additional checkpoint inhibitors have entered the therapeutic armamentarium of several solid and hematologic malignancies [1].
Cemiplimab is a recombinant IgG4 monoclonal antibody that inhibits PD1, approved by the FDA in 2018 for the treatment of patients with metastatic or locally advanced cutaneous squamous cell carcinoma (CSCC) who are not candidates for curative surgery or curative radiation. This approval was based on clinically meaningful and durable objective response rates in patients with CSCC in two clinical trials [2].
Solid organ transplant recipients have increased rates of cancer with higher incidence of CSCC [3]. In renal transplant recipients (RTRs), CSSC affects over 50% of patients, occurring earlier and behaving more aggressively than in non-transplant patients [4]. RTRs have been traditionally excluded from clinical trials with checkpoint inhibitors (Cis) due to concerns for T-cell activation and transplant rejection.
Here, we present the case of a kidney transplant patient with a rapidly-progressing, recurrent CSS of the scalp, who received the anti-PD1 antibody cemiplimab without any significant complications. To our knowledge, this is the first case of safe administration of this CI to a transplant patient on low dose prednisone alone for immunosuppression.
2. Case Presentation
A 72-year-old man with a history of allogeneic kidney transplantation from a living related donor ten years prior developed a highly-aggressive recurrent squamous cell carcinoma (SCC) of the scalp after undergoing multiple prior resections. The patient had several comorbidities, including hypertension, hyperlipidemia, diabetes mellitus Type 2, heart failure with left ventricular ejection fraction around 30%, severe peripheral artery disease, for which he previously underwent bypass surgery, and endarterectomy. Overall, his Eastern Cooperative Oncology Group (ECOG) performance status was 2. After kidney transplant, the patient had been on different immunosuppressive drugs including tacrolimus, mycophenolate mofetil and prednisone.
The patient had extensive local SCC involving the majority of his scalp, with no evidence on examination or imaging for either regional or metastatic disease. MRI of the brain and neck was done and showed irregularly enhancing scalp lesions without evidence of adjacent osseous or intracranial extension (largest lesion was 4.7 cm by 3.4 cm (Figure 1A)). PET/CT was significant for fluorodeoxyglucose (FDG) avid soft tissue masses in the left scalp, consistent with the patient’s known malignancy (standardized uptake value, SUV up to 4.7 (Figure 1B)). After tumor board discussion, decision was made for surgical resection; he underwent radical resection including full thickness resection of his scalp, and removal of the underlying external cortex of his calvarium, with placement of a collagen/glycosaminoglycan allograft to encourage granulation in preparation to receive a split thickness skin graft. Pathology showed a moderately differentiated SCC with negative margins (the closest, deep margin was 2 mm); size was 8.3 cm, depth of invasion was 1.1 cm; perineural invasion was identified. Within four weeks since resection, the patient developed extensive dermal metastasis surrounding the resection bed, which on biopsy were confirmed to be poorly differentiated CSCC.
Mycophenolate mofetil was stopped, and the patient continued immunosuppression with only low dose prednisone (5 mg daily). At that point, the patient was willing to consider systemic treatment, including a CI, despite the lack of safety data in transplant patients and the theoretical risks of kidney rejection.
After further multidisciplinary discussion with the surgical and transplant teams, given the fact he was not a candidate for any aggressive regimen due to his performance status, decision was made for immunotherapy with cemiplimab 350 mg IV every 3 weeks. The patient’s baseline creatinine and glomerular filtration rate (GFR) before starting cemiplimab were 1.5 and 46, respectively.
After the first administration of cemiplimab, the patient started noticing decrease in size of several scalp lesions, with additional benefit noticed after further treatment (Figure 2A,B); creatinine and GFR were 1.08 and 67, respectively, after a total of six cycles. At that point, cemiplimab was stopped because the patient had to undergo vascular surgeries of the lower extremities and split thickness graft to the scalp. Surgeries were complicated by wound infection from polymicrobial flora that required protracted antibiotic therapy. Cemiplimab was on hold for about five months with some progression of disease in the scalp, but it was ultimately resumed, with ongoing clinical benefit after a total of 10 cycles (Figure 2C). Overall, the patient has tolerated this drug very well so far without any significant issues. Creatinine and GFR before cycle 10 were 0.85 and 87, respectively (Table 1). Spearman’s rank correlation (Graphpad Prism software, San Diego, CA, USA. www.graphpad.com) and t-testing with equal variance were used to analyze the changes in creatinine/GFR through the patient’s 10 cycles of therapy. Over time, creatinine level decreased and GFR improved during treatment with a strong positive correlation between cycle of treatment and kidney function (0.837, p = 0.003); creatinine/GFR levels between the first three cycles of treatment compared to the last three cycles were significantly improved (p = 0.02).
3. Discussion
Patients who undergo a renal transplant are approximately three times more likely to develop different type of cancers than the general population [5]. Risk factors specific to the transplant population include the type, extent, and duration of immunosuppression. CSCC is the most common skin cancer in renal transplant patients. In comparison with SCC in immunocompetent patients, SCC in organ transplant recipients is more likely to manifest as aggressive disease [6,7,8]. While the modulation of immunotherapy plays an important role in the management of these patients, additional cancer-directed treatments are often necessary to achieve appropriate tumor control. Systemic therapies based on platinum agents, capecitabine, or cetuximab can help achieving tumor responses, but such responses are generally short-lived; additionally, these drugs can be problematic in patients with a suboptimal performance status due to multiple comorbidities.
PD1 is a receptor of the immunoglobulin superfamily expressed on T cells, B cells, and NK cells; it negatively regulates the T-cell antigen receptor signaling by interacting with specific ligands expressed in multiple tumor types, including tumor cells. While the expression of the ligand PD-L1 can serve as a potent mechanism for potentially immunogenic tumors to escape from host immune responses, blockade of the PD1–PD–L1 interaction through specific monoclonal antibodies has shown to provide effective and durable antitumor effects in several malignancies [9,10,11].
In non-transplant patients with locally advanced or metastatic SCC that is not amenable to treatment with surgery or radiation therapy, the anti-PD1 monoclonal antibodies cemiplimab and pembrolizumab have recently shown to be potentially more active and relatively less toxic than traditional chemotherapy. Unfortunately, the efficacy and safety of these agents in OTRs is unknown at this time, given the exclusion of such patients from clinical trials. Furthermore, case reports and small retrospective series have described transplant rejection in at least 40% of subjects who received CIs after undergoing a kidney transplant [12,13,14,15,16,17].
In particular, De Bruyn et al. [13] reported 48 cases of RTRs and liver recipients who had received CIs; of the 29 RTRs, 13 (45%) experienced rejection. From a cancer standpoint, 7 out of 13 patients who had a rejection (53%) had a favorable outcome.
In another review of 39 OTRs treated with CIs, rejections rates were highest in the 23 RTR (48%), compared to liver (36%) and cardiac (20%) transplant patients [14].
Manohar et al. [15] recently conducted a literature search and reviewed 27 studies that reported outcomes of 44 RTRs who had received treatment with CIs; 11% of these patients presented with metastatic CSCC, 68% had melanoma, while the remaining patients had either lung, Merkel cell, urothelial, or duodenal carcinomas. Most patients received a CI as a single agent: nivolumab in 34% cases, pembrolizumab in 25%, ipilimumab in 20%, and avelumab in one patient; the remaining cases received two different CIs sequentially. Overall, 18 patients (41%) were reported to have acute rejection of the renal allograft with a median time of 24 days; eventually, 15 out of these 18 patients had allograft failure (83%), and 8 patients died. Reported types of acute allograft rejection were cellular rejection (33%), mixed cellular and antibody-mediated rejection (17%), and unspecified type (50%). Baseline immunosuppressive regimen data were available for 31 patients: 48% of them were on a triple regimen with a calcineurin inhibitor, such as tacrolimus or cyclosporine, mycophenolate mofetil, and low-dose steroids.
In another large systematic review, 83 OTRs were treated with CIs (about two-thirds received anti-PD1/PDL1 therapy, 16% anti-CTLA-4, 11% combination therapy) [16]. This study included 53 RTRs; allograft rejection occurred in 40% of patients, leading to end-stage organ failure in 71% of cases. Outcomes were similar across organs and immunotherapy regimens. Patients on no other immunosuppressive treatment besides corticosteroids at initiation of CIs had a higher risk of rejection. RTR was the only group where there was similar mortality in patients with and without rejection, suggesting that CIs may be a better option in these patients where hemodialysis is a life-saving alternative in case of rejection [16,17].
Ali et al. [18] recently reported successful administration of cemiplimab to an 81-year-old patient with advanced CSCC on sirolimus and prednisone for immunosuppression after renal transplantation. Sirolimus is a known inhibitor of the mechanistic target of rapamycin (mTOR). Interestingly, mTOR inhibitors have been shown to reduce the growth and proliferation of tumor cells in vitro and in vivo mouse models [19]. In a mixed-organ cohort of OTRs, patients taking sirolimus after developing post-transplant cancer showed lower risk of developing skin cancer [20]. The immunosuppression provided by sirolimus to the patient above may have mitigated the rejection effect from cemiplimab, while boosting the anti-cancer response.
The improvement in kidney function observed in our patient over time is difficult to interpret; it may be related to closer patient’s monitoring with frequent assessments of his hydration status in the context of multiple office and hospital visits.
4. Summary
To our knowledge, this is the first report of safe administration of the anti-PD1 monoclonal antibody cemiplimab in a kidney transplant patient with recurrent, locally advanced SCC of the scalp treated with prednisone alone for immunosuppression. The ongoing phase 1/2 CONTACT clinical trial is exploring the safety and effectiveness of cemiplimab in subjects with advanced SCC who have previously received an allogeneic hematopoietic stem cell transplant or kidney transplant (NCT04339062); all patients on this trial are required to be on immunosuppression with prednisone and either sirolimus or everolimus.
Acknowledgments
Our sincere thanks to the patient for his courage and consent to share his story in the hope other transplant patients may benefit from his experience.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author Contributions
Conceptualization, L.P.; methodology, L.P. and T.J.O.; formal analysis: L.P. and T.J.O.; investigation: L.P. and T.J.O., resources: L.P. and T.J.O.; data curation: L.P. and T.J.O., writing-original draft preparation: L.P.; writing-review and editing: L.P. and T.J.O.; visualization: L.P. and T.J.O.; supervision, L.P.; project administration: L.P. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Representative pre-treatment, post-contrast, T1-weighted, sagittal MRI images (A) and fused PET-CT images (B) show disease extension predominantly from the vertex scalp to the left lateral temple region.
Figure 2 (A) Multiple nodules consistent with cutaneous squamous cell carcinoma on the left temporal area before starting cemiplimab; (B) tumor regression after three cycles of cemiplimab; (C) response after a total of 10 cycles of cemiplimab.
curroncol-28-00057-t001_Table 1Table 1 Changes in creatinine and glomerular filtration rate (GFR) during treatment with cemiplimab (before each cycle).
Cemiplimab Creatinine
(Ref Range < l.5 mg/dL) GFR
(Ref Range > 60 mL/min/BSA)
C#1 1.2 60
C#2 1.1 66
C#3 1.0 74
C#4 1.2 60
C#5 1.2 60
C#6 1.0 74
C#7 0.97 78
C#8 0.88 86
C#9 0.91 84
C#10 0.85 87
Ref = reference; C = cycle. | MYCOPHENOLATE MOFETIL, PREDNISONE, TACROLIMUS | DrugsGivenReaction | CC BY | 33477979 | 19,099,795 | 2021-01-19 |
What was the dosage of drug 'MYCOPHENOLATE MOFETIL'? | Safe Administration of Cemiplimab to a Kidney Transplant Patient with Locally Advanced Squamous Cell Carcinoma of the Scalp.
Immunotherapies directed at T-cell activation through antibodies targeting checkpoint proteins, such as programmed cell death 1 (PD1), are rapidly becoming the new standard of care in the treatment of several malignancies. Cemiplimab is a monoclonal antibody targeting PD1 that has recently emerged as a highly active treatment for locally advanced and metastatic cutaneous squamous cell carcinoma (CSCC). Patients who have received an organ transplant (OTRs) have been traditionally excluded from clinical trials with checkpoint inhibitors (CIs), given concerns for organ rejection. Renal transplant recipients (RTRs) are more likely to develop cancers than the general population, and skin cancers are among the most frequent malignancies. We report the case of a 72-year-old man with a history of a kidney transplant who presented with a rapidly growing, locally advanced squamous cell carcinoma (SCC) of the scalp that recurred within four weeks from surgical resection. The patient was able to safely receive ten cycles of cemiplimab so far with significant clinical benefit, and no issues with his kidney function, while continuing immunosuppression with low dose prednisone alone. An ongoing clinical trial (NCT04339062) is further exploring the safety of CIs in patients with metastatic CSCC who have previously received allogeneic hematopoietic stem cell transplant or a kidney transplant.
1. Introduction
The introduction of T-cell-targeted immunomodulators that block the immune checkpoints CTLA-4, PD1, or PDL1 represents one of the most significant advances in oncology in the last decade. Since ipilimumab was approved by the Federal Drug Administration (FDA) in 2011 for the treatment of melanoma, six additional checkpoint inhibitors have entered the therapeutic armamentarium of several solid and hematologic malignancies [1].
Cemiplimab is a recombinant IgG4 monoclonal antibody that inhibits PD1, approved by the FDA in 2018 for the treatment of patients with metastatic or locally advanced cutaneous squamous cell carcinoma (CSCC) who are not candidates for curative surgery or curative radiation. This approval was based on clinically meaningful and durable objective response rates in patients with CSCC in two clinical trials [2].
Solid organ transplant recipients have increased rates of cancer with higher incidence of CSCC [3]. In renal transplant recipients (RTRs), CSSC affects over 50% of patients, occurring earlier and behaving more aggressively than in non-transplant patients [4]. RTRs have been traditionally excluded from clinical trials with checkpoint inhibitors (Cis) due to concerns for T-cell activation and transplant rejection.
Here, we present the case of a kidney transplant patient with a rapidly-progressing, recurrent CSS of the scalp, who received the anti-PD1 antibody cemiplimab without any significant complications. To our knowledge, this is the first case of safe administration of this CI to a transplant patient on low dose prednisone alone for immunosuppression.
2. Case Presentation
A 72-year-old man with a history of allogeneic kidney transplantation from a living related donor ten years prior developed a highly-aggressive recurrent squamous cell carcinoma (SCC) of the scalp after undergoing multiple prior resections. The patient had several comorbidities, including hypertension, hyperlipidemia, diabetes mellitus Type 2, heart failure with left ventricular ejection fraction around 30%, severe peripheral artery disease, for which he previously underwent bypass surgery, and endarterectomy. Overall, his Eastern Cooperative Oncology Group (ECOG) performance status was 2. After kidney transplant, the patient had been on different immunosuppressive drugs including tacrolimus, mycophenolate mofetil and prednisone.
The patient had extensive local SCC involving the majority of his scalp, with no evidence on examination or imaging for either regional or metastatic disease. MRI of the brain and neck was done and showed irregularly enhancing scalp lesions without evidence of adjacent osseous or intracranial extension (largest lesion was 4.7 cm by 3.4 cm (Figure 1A)). PET/CT was significant for fluorodeoxyglucose (FDG) avid soft tissue masses in the left scalp, consistent with the patient’s known malignancy (standardized uptake value, SUV up to 4.7 (Figure 1B)). After tumor board discussion, decision was made for surgical resection; he underwent radical resection including full thickness resection of his scalp, and removal of the underlying external cortex of his calvarium, with placement of a collagen/glycosaminoglycan allograft to encourage granulation in preparation to receive a split thickness skin graft. Pathology showed a moderately differentiated SCC with negative margins (the closest, deep margin was 2 mm); size was 8.3 cm, depth of invasion was 1.1 cm; perineural invasion was identified. Within four weeks since resection, the patient developed extensive dermal metastasis surrounding the resection bed, which on biopsy were confirmed to be poorly differentiated CSCC.
Mycophenolate mofetil was stopped, and the patient continued immunosuppression with only low dose prednisone (5 mg daily). At that point, the patient was willing to consider systemic treatment, including a CI, despite the lack of safety data in transplant patients and the theoretical risks of kidney rejection.
After further multidisciplinary discussion with the surgical and transplant teams, given the fact he was not a candidate for any aggressive regimen due to his performance status, decision was made for immunotherapy with cemiplimab 350 mg IV every 3 weeks. The patient’s baseline creatinine and glomerular filtration rate (GFR) before starting cemiplimab were 1.5 and 46, respectively.
After the first administration of cemiplimab, the patient started noticing decrease in size of several scalp lesions, with additional benefit noticed after further treatment (Figure 2A,B); creatinine and GFR were 1.08 and 67, respectively, after a total of six cycles. At that point, cemiplimab was stopped because the patient had to undergo vascular surgeries of the lower extremities and split thickness graft to the scalp. Surgeries were complicated by wound infection from polymicrobial flora that required protracted antibiotic therapy. Cemiplimab was on hold for about five months with some progression of disease in the scalp, but it was ultimately resumed, with ongoing clinical benefit after a total of 10 cycles (Figure 2C). Overall, the patient has tolerated this drug very well so far without any significant issues. Creatinine and GFR before cycle 10 were 0.85 and 87, respectively (Table 1). Spearman’s rank correlation (Graphpad Prism software, San Diego, CA, USA. www.graphpad.com) and t-testing with equal variance were used to analyze the changes in creatinine/GFR through the patient’s 10 cycles of therapy. Over time, creatinine level decreased and GFR improved during treatment with a strong positive correlation between cycle of treatment and kidney function (0.837, p = 0.003); creatinine/GFR levels between the first three cycles of treatment compared to the last three cycles were significantly improved (p = 0.02).
3. Discussion
Patients who undergo a renal transplant are approximately three times more likely to develop different type of cancers than the general population [5]. Risk factors specific to the transplant population include the type, extent, and duration of immunosuppression. CSCC is the most common skin cancer in renal transplant patients. In comparison with SCC in immunocompetent patients, SCC in organ transplant recipients is more likely to manifest as aggressive disease [6,7,8]. While the modulation of immunotherapy plays an important role in the management of these patients, additional cancer-directed treatments are often necessary to achieve appropriate tumor control. Systemic therapies based on platinum agents, capecitabine, or cetuximab can help achieving tumor responses, but such responses are generally short-lived; additionally, these drugs can be problematic in patients with a suboptimal performance status due to multiple comorbidities.
PD1 is a receptor of the immunoglobulin superfamily expressed on T cells, B cells, and NK cells; it negatively regulates the T-cell antigen receptor signaling by interacting with specific ligands expressed in multiple tumor types, including tumor cells. While the expression of the ligand PD-L1 can serve as a potent mechanism for potentially immunogenic tumors to escape from host immune responses, blockade of the PD1–PD–L1 interaction through specific monoclonal antibodies has shown to provide effective and durable antitumor effects in several malignancies [9,10,11].
In non-transplant patients with locally advanced or metastatic SCC that is not amenable to treatment with surgery or radiation therapy, the anti-PD1 monoclonal antibodies cemiplimab and pembrolizumab have recently shown to be potentially more active and relatively less toxic than traditional chemotherapy. Unfortunately, the efficacy and safety of these agents in OTRs is unknown at this time, given the exclusion of such patients from clinical trials. Furthermore, case reports and small retrospective series have described transplant rejection in at least 40% of subjects who received CIs after undergoing a kidney transplant [12,13,14,15,16,17].
In particular, De Bruyn et al. [13] reported 48 cases of RTRs and liver recipients who had received CIs; of the 29 RTRs, 13 (45%) experienced rejection. From a cancer standpoint, 7 out of 13 patients who had a rejection (53%) had a favorable outcome.
In another review of 39 OTRs treated with CIs, rejections rates were highest in the 23 RTR (48%), compared to liver (36%) and cardiac (20%) transplant patients [14].
Manohar et al. [15] recently conducted a literature search and reviewed 27 studies that reported outcomes of 44 RTRs who had received treatment with CIs; 11% of these patients presented with metastatic CSCC, 68% had melanoma, while the remaining patients had either lung, Merkel cell, urothelial, or duodenal carcinomas. Most patients received a CI as a single agent: nivolumab in 34% cases, pembrolizumab in 25%, ipilimumab in 20%, and avelumab in one patient; the remaining cases received two different CIs sequentially. Overall, 18 patients (41%) were reported to have acute rejection of the renal allograft with a median time of 24 days; eventually, 15 out of these 18 patients had allograft failure (83%), and 8 patients died. Reported types of acute allograft rejection were cellular rejection (33%), mixed cellular and antibody-mediated rejection (17%), and unspecified type (50%). Baseline immunosuppressive regimen data were available for 31 patients: 48% of them were on a triple regimen with a calcineurin inhibitor, such as tacrolimus or cyclosporine, mycophenolate mofetil, and low-dose steroids.
In another large systematic review, 83 OTRs were treated with CIs (about two-thirds received anti-PD1/PDL1 therapy, 16% anti-CTLA-4, 11% combination therapy) [16]. This study included 53 RTRs; allograft rejection occurred in 40% of patients, leading to end-stage organ failure in 71% of cases. Outcomes were similar across organs and immunotherapy regimens. Patients on no other immunosuppressive treatment besides corticosteroids at initiation of CIs had a higher risk of rejection. RTR was the only group where there was similar mortality in patients with and without rejection, suggesting that CIs may be a better option in these patients where hemodialysis is a life-saving alternative in case of rejection [16,17].
Ali et al. [18] recently reported successful administration of cemiplimab to an 81-year-old patient with advanced CSCC on sirolimus and prednisone for immunosuppression after renal transplantation. Sirolimus is a known inhibitor of the mechanistic target of rapamycin (mTOR). Interestingly, mTOR inhibitors have been shown to reduce the growth and proliferation of tumor cells in vitro and in vivo mouse models [19]. In a mixed-organ cohort of OTRs, patients taking sirolimus after developing post-transplant cancer showed lower risk of developing skin cancer [20]. The immunosuppression provided by sirolimus to the patient above may have mitigated the rejection effect from cemiplimab, while boosting the anti-cancer response.
The improvement in kidney function observed in our patient over time is difficult to interpret; it may be related to closer patient’s monitoring with frequent assessments of his hydration status in the context of multiple office and hospital visits.
4. Summary
To our knowledge, this is the first report of safe administration of the anti-PD1 monoclonal antibody cemiplimab in a kidney transplant patient with recurrent, locally advanced SCC of the scalp treated with prednisone alone for immunosuppression. The ongoing phase 1/2 CONTACT clinical trial is exploring the safety and effectiveness of cemiplimab in subjects with advanced SCC who have previously received an allogeneic hematopoietic stem cell transplant or kidney transplant (NCT04339062); all patients on this trial are required to be on immunosuppression with prednisone and either sirolimus or everolimus.
Acknowledgments
Our sincere thanks to the patient for his courage and consent to share his story in the hope other transplant patients may benefit from his experience.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author Contributions
Conceptualization, L.P.; methodology, L.P. and T.J.O.; formal analysis: L.P. and T.J.O.; investigation: L.P. and T.J.O., resources: L.P. and T.J.O.; data curation: L.P. and T.J.O., writing-original draft preparation: L.P.; writing-review and editing: L.P. and T.J.O.; visualization: L.P. and T.J.O.; supervision, L.P.; project administration: L.P. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Representative pre-treatment, post-contrast, T1-weighted, sagittal MRI images (A) and fused PET-CT images (B) show disease extension predominantly from the vertex scalp to the left lateral temple region.
Figure 2 (A) Multiple nodules consistent with cutaneous squamous cell carcinoma on the left temporal area before starting cemiplimab; (B) tumor regression after three cycles of cemiplimab; (C) response after a total of 10 cycles of cemiplimab.
curroncol-28-00057-t001_Table 1Table 1 Changes in creatinine and glomerular filtration rate (GFR) during treatment with cemiplimab (before each cycle).
Cemiplimab Creatinine
(Ref Range < l.5 mg/dL) GFR
(Ref Range > 60 mL/min/BSA)
C#1 1.2 60
C#2 1.1 66
C#3 1.0 74
C#4 1.2 60
C#5 1.2 60
C#6 1.0 74
C#7 0.97 78
C#8 0.88 86
C#9 0.91 84
C#10 0.85 87
Ref = reference; C = cycle. | UNKNOWN | DrugDosageText | CC BY | 33477979 | 19,099,795 | 2021-01-19 |
What was the dosage of drug 'TACROLIMUS'? | Safe Administration of Cemiplimab to a Kidney Transplant Patient with Locally Advanced Squamous Cell Carcinoma of the Scalp.
Immunotherapies directed at T-cell activation through antibodies targeting checkpoint proteins, such as programmed cell death 1 (PD1), are rapidly becoming the new standard of care in the treatment of several malignancies. Cemiplimab is a monoclonal antibody targeting PD1 that has recently emerged as a highly active treatment for locally advanced and metastatic cutaneous squamous cell carcinoma (CSCC). Patients who have received an organ transplant (OTRs) have been traditionally excluded from clinical trials with checkpoint inhibitors (CIs), given concerns for organ rejection. Renal transplant recipients (RTRs) are more likely to develop cancers than the general population, and skin cancers are among the most frequent malignancies. We report the case of a 72-year-old man with a history of a kidney transplant who presented with a rapidly growing, locally advanced squamous cell carcinoma (SCC) of the scalp that recurred within four weeks from surgical resection. The patient was able to safely receive ten cycles of cemiplimab so far with significant clinical benefit, and no issues with his kidney function, while continuing immunosuppression with low dose prednisone alone. An ongoing clinical trial (NCT04339062) is further exploring the safety of CIs in patients with metastatic CSCC who have previously received allogeneic hematopoietic stem cell transplant or a kidney transplant.
1. Introduction
The introduction of T-cell-targeted immunomodulators that block the immune checkpoints CTLA-4, PD1, or PDL1 represents one of the most significant advances in oncology in the last decade. Since ipilimumab was approved by the Federal Drug Administration (FDA) in 2011 for the treatment of melanoma, six additional checkpoint inhibitors have entered the therapeutic armamentarium of several solid and hematologic malignancies [1].
Cemiplimab is a recombinant IgG4 monoclonal antibody that inhibits PD1, approved by the FDA in 2018 for the treatment of patients with metastatic or locally advanced cutaneous squamous cell carcinoma (CSCC) who are not candidates for curative surgery or curative radiation. This approval was based on clinically meaningful and durable objective response rates in patients with CSCC in two clinical trials [2].
Solid organ transplant recipients have increased rates of cancer with higher incidence of CSCC [3]. In renal transplant recipients (RTRs), CSSC affects over 50% of patients, occurring earlier and behaving more aggressively than in non-transplant patients [4]. RTRs have been traditionally excluded from clinical trials with checkpoint inhibitors (Cis) due to concerns for T-cell activation and transplant rejection.
Here, we present the case of a kidney transplant patient with a rapidly-progressing, recurrent CSS of the scalp, who received the anti-PD1 antibody cemiplimab without any significant complications. To our knowledge, this is the first case of safe administration of this CI to a transplant patient on low dose prednisone alone for immunosuppression.
2. Case Presentation
A 72-year-old man with a history of allogeneic kidney transplantation from a living related donor ten years prior developed a highly-aggressive recurrent squamous cell carcinoma (SCC) of the scalp after undergoing multiple prior resections. The patient had several comorbidities, including hypertension, hyperlipidemia, diabetes mellitus Type 2, heart failure with left ventricular ejection fraction around 30%, severe peripheral artery disease, for which he previously underwent bypass surgery, and endarterectomy. Overall, his Eastern Cooperative Oncology Group (ECOG) performance status was 2. After kidney transplant, the patient had been on different immunosuppressive drugs including tacrolimus, mycophenolate mofetil and prednisone.
The patient had extensive local SCC involving the majority of his scalp, with no evidence on examination or imaging for either regional or metastatic disease. MRI of the brain and neck was done and showed irregularly enhancing scalp lesions without evidence of adjacent osseous or intracranial extension (largest lesion was 4.7 cm by 3.4 cm (Figure 1A)). PET/CT was significant for fluorodeoxyglucose (FDG) avid soft tissue masses in the left scalp, consistent with the patient’s known malignancy (standardized uptake value, SUV up to 4.7 (Figure 1B)). After tumor board discussion, decision was made for surgical resection; he underwent radical resection including full thickness resection of his scalp, and removal of the underlying external cortex of his calvarium, with placement of a collagen/glycosaminoglycan allograft to encourage granulation in preparation to receive a split thickness skin graft. Pathology showed a moderately differentiated SCC with negative margins (the closest, deep margin was 2 mm); size was 8.3 cm, depth of invasion was 1.1 cm; perineural invasion was identified. Within four weeks since resection, the patient developed extensive dermal metastasis surrounding the resection bed, which on biopsy were confirmed to be poorly differentiated CSCC.
Mycophenolate mofetil was stopped, and the patient continued immunosuppression with only low dose prednisone (5 mg daily). At that point, the patient was willing to consider systemic treatment, including a CI, despite the lack of safety data in transplant patients and the theoretical risks of kidney rejection.
After further multidisciplinary discussion with the surgical and transplant teams, given the fact he was not a candidate for any aggressive regimen due to his performance status, decision was made for immunotherapy with cemiplimab 350 mg IV every 3 weeks. The patient’s baseline creatinine and glomerular filtration rate (GFR) before starting cemiplimab were 1.5 and 46, respectively.
After the first administration of cemiplimab, the patient started noticing decrease in size of several scalp lesions, with additional benefit noticed after further treatment (Figure 2A,B); creatinine and GFR were 1.08 and 67, respectively, after a total of six cycles. At that point, cemiplimab was stopped because the patient had to undergo vascular surgeries of the lower extremities and split thickness graft to the scalp. Surgeries were complicated by wound infection from polymicrobial flora that required protracted antibiotic therapy. Cemiplimab was on hold for about five months with some progression of disease in the scalp, but it was ultimately resumed, with ongoing clinical benefit after a total of 10 cycles (Figure 2C). Overall, the patient has tolerated this drug very well so far without any significant issues. Creatinine and GFR before cycle 10 were 0.85 and 87, respectively (Table 1). Spearman’s rank correlation (Graphpad Prism software, San Diego, CA, USA. www.graphpad.com) and t-testing with equal variance were used to analyze the changes in creatinine/GFR through the patient’s 10 cycles of therapy. Over time, creatinine level decreased and GFR improved during treatment with a strong positive correlation between cycle of treatment and kidney function (0.837, p = 0.003); creatinine/GFR levels between the first three cycles of treatment compared to the last three cycles were significantly improved (p = 0.02).
3. Discussion
Patients who undergo a renal transplant are approximately three times more likely to develop different type of cancers than the general population [5]. Risk factors specific to the transplant population include the type, extent, and duration of immunosuppression. CSCC is the most common skin cancer in renal transplant patients. In comparison with SCC in immunocompetent patients, SCC in organ transplant recipients is more likely to manifest as aggressive disease [6,7,8]. While the modulation of immunotherapy plays an important role in the management of these patients, additional cancer-directed treatments are often necessary to achieve appropriate tumor control. Systemic therapies based on platinum agents, capecitabine, or cetuximab can help achieving tumor responses, but such responses are generally short-lived; additionally, these drugs can be problematic in patients with a suboptimal performance status due to multiple comorbidities.
PD1 is a receptor of the immunoglobulin superfamily expressed on T cells, B cells, and NK cells; it negatively regulates the T-cell antigen receptor signaling by interacting with specific ligands expressed in multiple tumor types, including tumor cells. While the expression of the ligand PD-L1 can serve as a potent mechanism for potentially immunogenic tumors to escape from host immune responses, blockade of the PD1–PD–L1 interaction through specific monoclonal antibodies has shown to provide effective and durable antitumor effects in several malignancies [9,10,11].
In non-transplant patients with locally advanced or metastatic SCC that is not amenable to treatment with surgery or radiation therapy, the anti-PD1 monoclonal antibodies cemiplimab and pembrolizumab have recently shown to be potentially more active and relatively less toxic than traditional chemotherapy. Unfortunately, the efficacy and safety of these agents in OTRs is unknown at this time, given the exclusion of such patients from clinical trials. Furthermore, case reports and small retrospective series have described transplant rejection in at least 40% of subjects who received CIs after undergoing a kidney transplant [12,13,14,15,16,17].
In particular, De Bruyn et al. [13] reported 48 cases of RTRs and liver recipients who had received CIs; of the 29 RTRs, 13 (45%) experienced rejection. From a cancer standpoint, 7 out of 13 patients who had a rejection (53%) had a favorable outcome.
In another review of 39 OTRs treated with CIs, rejections rates were highest in the 23 RTR (48%), compared to liver (36%) and cardiac (20%) transplant patients [14].
Manohar et al. [15] recently conducted a literature search and reviewed 27 studies that reported outcomes of 44 RTRs who had received treatment with CIs; 11% of these patients presented with metastatic CSCC, 68% had melanoma, while the remaining patients had either lung, Merkel cell, urothelial, or duodenal carcinomas. Most patients received a CI as a single agent: nivolumab in 34% cases, pembrolizumab in 25%, ipilimumab in 20%, and avelumab in one patient; the remaining cases received two different CIs sequentially. Overall, 18 patients (41%) were reported to have acute rejection of the renal allograft with a median time of 24 days; eventually, 15 out of these 18 patients had allograft failure (83%), and 8 patients died. Reported types of acute allograft rejection were cellular rejection (33%), mixed cellular and antibody-mediated rejection (17%), and unspecified type (50%). Baseline immunosuppressive regimen data were available for 31 patients: 48% of them were on a triple regimen with a calcineurin inhibitor, such as tacrolimus or cyclosporine, mycophenolate mofetil, and low-dose steroids.
In another large systematic review, 83 OTRs were treated with CIs (about two-thirds received anti-PD1/PDL1 therapy, 16% anti-CTLA-4, 11% combination therapy) [16]. This study included 53 RTRs; allograft rejection occurred in 40% of patients, leading to end-stage organ failure in 71% of cases. Outcomes were similar across organs and immunotherapy regimens. Patients on no other immunosuppressive treatment besides corticosteroids at initiation of CIs had a higher risk of rejection. RTR was the only group where there was similar mortality in patients with and without rejection, suggesting that CIs may be a better option in these patients where hemodialysis is a life-saving alternative in case of rejection [16,17].
Ali et al. [18] recently reported successful administration of cemiplimab to an 81-year-old patient with advanced CSCC on sirolimus and prednisone for immunosuppression after renal transplantation. Sirolimus is a known inhibitor of the mechanistic target of rapamycin (mTOR). Interestingly, mTOR inhibitors have been shown to reduce the growth and proliferation of tumor cells in vitro and in vivo mouse models [19]. In a mixed-organ cohort of OTRs, patients taking sirolimus after developing post-transplant cancer showed lower risk of developing skin cancer [20]. The immunosuppression provided by sirolimus to the patient above may have mitigated the rejection effect from cemiplimab, while boosting the anti-cancer response.
The improvement in kidney function observed in our patient over time is difficult to interpret; it may be related to closer patient’s monitoring with frequent assessments of his hydration status in the context of multiple office and hospital visits.
4. Summary
To our knowledge, this is the first report of safe administration of the anti-PD1 monoclonal antibody cemiplimab in a kidney transplant patient with recurrent, locally advanced SCC of the scalp treated with prednisone alone for immunosuppression. The ongoing phase 1/2 CONTACT clinical trial is exploring the safety and effectiveness of cemiplimab in subjects with advanced SCC who have previously received an allogeneic hematopoietic stem cell transplant or kidney transplant (NCT04339062); all patients on this trial are required to be on immunosuppression with prednisone and either sirolimus or everolimus.
Acknowledgments
Our sincere thanks to the patient for his courage and consent to share his story in the hope other transplant patients may benefit from his experience.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author Contributions
Conceptualization, L.P.; methodology, L.P. and T.J.O.; formal analysis: L.P. and T.J.O.; investigation: L.P. and T.J.O., resources: L.P. and T.J.O.; data curation: L.P. and T.J.O., writing-original draft preparation: L.P.; writing-review and editing: L.P. and T.J.O.; visualization: L.P. and T.J.O.; supervision, L.P.; project administration: L.P. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Representative pre-treatment, post-contrast, T1-weighted, sagittal MRI images (A) and fused PET-CT images (B) show disease extension predominantly from the vertex scalp to the left lateral temple region.
Figure 2 (A) Multiple nodules consistent with cutaneous squamous cell carcinoma on the left temporal area before starting cemiplimab; (B) tumor regression after three cycles of cemiplimab; (C) response after a total of 10 cycles of cemiplimab.
curroncol-28-00057-t001_Table 1Table 1 Changes in creatinine and glomerular filtration rate (GFR) during treatment with cemiplimab (before each cycle).
Cemiplimab Creatinine
(Ref Range < l.5 mg/dL) GFR
(Ref Range > 60 mL/min/BSA)
C#1 1.2 60
C#2 1.1 66
C#3 1.0 74
C#4 1.2 60
C#5 1.2 60
C#6 1.0 74
C#7 0.97 78
C#8 0.88 86
C#9 0.91 84
C#10 0.85 87
Ref = reference; C = cycle. | UNKNOWN | DrugDosageText | CC BY | 33477979 | 19,099,795 | 2021-01-19 |
What was the outcome of reaction 'Squamous cell carcinoma'? | Safe Administration of Cemiplimab to a Kidney Transplant Patient with Locally Advanced Squamous Cell Carcinoma of the Scalp.
Immunotherapies directed at T-cell activation through antibodies targeting checkpoint proteins, such as programmed cell death 1 (PD1), are rapidly becoming the new standard of care in the treatment of several malignancies. Cemiplimab is a monoclonal antibody targeting PD1 that has recently emerged as a highly active treatment for locally advanced and metastatic cutaneous squamous cell carcinoma (CSCC). Patients who have received an organ transplant (OTRs) have been traditionally excluded from clinical trials with checkpoint inhibitors (CIs), given concerns for organ rejection. Renal transplant recipients (RTRs) are more likely to develop cancers than the general population, and skin cancers are among the most frequent malignancies. We report the case of a 72-year-old man with a history of a kidney transplant who presented with a rapidly growing, locally advanced squamous cell carcinoma (SCC) of the scalp that recurred within four weeks from surgical resection. The patient was able to safely receive ten cycles of cemiplimab so far with significant clinical benefit, and no issues with his kidney function, while continuing immunosuppression with low dose prednisone alone. An ongoing clinical trial (NCT04339062) is further exploring the safety of CIs in patients with metastatic CSCC who have previously received allogeneic hematopoietic stem cell transplant or a kidney transplant.
1. Introduction
The introduction of T-cell-targeted immunomodulators that block the immune checkpoints CTLA-4, PD1, or PDL1 represents one of the most significant advances in oncology in the last decade. Since ipilimumab was approved by the Federal Drug Administration (FDA) in 2011 for the treatment of melanoma, six additional checkpoint inhibitors have entered the therapeutic armamentarium of several solid and hematologic malignancies [1].
Cemiplimab is a recombinant IgG4 monoclonal antibody that inhibits PD1, approved by the FDA in 2018 for the treatment of patients with metastatic or locally advanced cutaneous squamous cell carcinoma (CSCC) who are not candidates for curative surgery or curative radiation. This approval was based on clinically meaningful and durable objective response rates in patients with CSCC in two clinical trials [2].
Solid organ transplant recipients have increased rates of cancer with higher incidence of CSCC [3]. In renal transplant recipients (RTRs), CSSC affects over 50% of patients, occurring earlier and behaving more aggressively than in non-transplant patients [4]. RTRs have been traditionally excluded from clinical trials with checkpoint inhibitors (Cis) due to concerns for T-cell activation and transplant rejection.
Here, we present the case of a kidney transplant patient with a rapidly-progressing, recurrent CSS of the scalp, who received the anti-PD1 antibody cemiplimab without any significant complications. To our knowledge, this is the first case of safe administration of this CI to a transplant patient on low dose prednisone alone for immunosuppression.
2. Case Presentation
A 72-year-old man with a history of allogeneic kidney transplantation from a living related donor ten years prior developed a highly-aggressive recurrent squamous cell carcinoma (SCC) of the scalp after undergoing multiple prior resections. The patient had several comorbidities, including hypertension, hyperlipidemia, diabetes mellitus Type 2, heart failure with left ventricular ejection fraction around 30%, severe peripheral artery disease, for which he previously underwent bypass surgery, and endarterectomy. Overall, his Eastern Cooperative Oncology Group (ECOG) performance status was 2. After kidney transplant, the patient had been on different immunosuppressive drugs including tacrolimus, mycophenolate mofetil and prednisone.
The patient had extensive local SCC involving the majority of his scalp, with no evidence on examination or imaging for either regional or metastatic disease. MRI of the brain and neck was done and showed irregularly enhancing scalp lesions without evidence of adjacent osseous or intracranial extension (largest lesion was 4.7 cm by 3.4 cm (Figure 1A)). PET/CT was significant for fluorodeoxyglucose (FDG) avid soft tissue masses in the left scalp, consistent with the patient’s known malignancy (standardized uptake value, SUV up to 4.7 (Figure 1B)). After tumor board discussion, decision was made for surgical resection; he underwent radical resection including full thickness resection of his scalp, and removal of the underlying external cortex of his calvarium, with placement of a collagen/glycosaminoglycan allograft to encourage granulation in preparation to receive a split thickness skin graft. Pathology showed a moderately differentiated SCC with negative margins (the closest, deep margin was 2 mm); size was 8.3 cm, depth of invasion was 1.1 cm; perineural invasion was identified. Within four weeks since resection, the patient developed extensive dermal metastasis surrounding the resection bed, which on biopsy were confirmed to be poorly differentiated CSCC.
Mycophenolate mofetil was stopped, and the patient continued immunosuppression with only low dose prednisone (5 mg daily). At that point, the patient was willing to consider systemic treatment, including a CI, despite the lack of safety data in transplant patients and the theoretical risks of kidney rejection.
After further multidisciplinary discussion with the surgical and transplant teams, given the fact he was not a candidate for any aggressive regimen due to his performance status, decision was made for immunotherapy with cemiplimab 350 mg IV every 3 weeks. The patient’s baseline creatinine and glomerular filtration rate (GFR) before starting cemiplimab were 1.5 and 46, respectively.
After the first administration of cemiplimab, the patient started noticing decrease in size of several scalp lesions, with additional benefit noticed after further treatment (Figure 2A,B); creatinine and GFR were 1.08 and 67, respectively, after a total of six cycles. At that point, cemiplimab was stopped because the patient had to undergo vascular surgeries of the lower extremities and split thickness graft to the scalp. Surgeries were complicated by wound infection from polymicrobial flora that required protracted antibiotic therapy. Cemiplimab was on hold for about five months with some progression of disease in the scalp, but it was ultimately resumed, with ongoing clinical benefit after a total of 10 cycles (Figure 2C). Overall, the patient has tolerated this drug very well so far without any significant issues. Creatinine and GFR before cycle 10 were 0.85 and 87, respectively (Table 1). Spearman’s rank correlation (Graphpad Prism software, San Diego, CA, USA. www.graphpad.com) and t-testing with equal variance were used to analyze the changes in creatinine/GFR through the patient’s 10 cycles of therapy. Over time, creatinine level decreased and GFR improved during treatment with a strong positive correlation between cycle of treatment and kidney function (0.837, p = 0.003); creatinine/GFR levels between the first three cycles of treatment compared to the last three cycles were significantly improved (p = 0.02).
3. Discussion
Patients who undergo a renal transplant are approximately three times more likely to develop different type of cancers than the general population [5]. Risk factors specific to the transplant population include the type, extent, and duration of immunosuppression. CSCC is the most common skin cancer in renal transplant patients. In comparison with SCC in immunocompetent patients, SCC in organ transplant recipients is more likely to manifest as aggressive disease [6,7,8]. While the modulation of immunotherapy plays an important role in the management of these patients, additional cancer-directed treatments are often necessary to achieve appropriate tumor control. Systemic therapies based on platinum agents, capecitabine, or cetuximab can help achieving tumor responses, but such responses are generally short-lived; additionally, these drugs can be problematic in patients with a suboptimal performance status due to multiple comorbidities.
PD1 is a receptor of the immunoglobulin superfamily expressed on T cells, B cells, and NK cells; it negatively regulates the T-cell antigen receptor signaling by interacting with specific ligands expressed in multiple tumor types, including tumor cells. While the expression of the ligand PD-L1 can serve as a potent mechanism for potentially immunogenic tumors to escape from host immune responses, blockade of the PD1–PD–L1 interaction through specific monoclonal antibodies has shown to provide effective and durable antitumor effects in several malignancies [9,10,11].
In non-transplant patients with locally advanced or metastatic SCC that is not amenable to treatment with surgery or radiation therapy, the anti-PD1 monoclonal antibodies cemiplimab and pembrolizumab have recently shown to be potentially more active and relatively less toxic than traditional chemotherapy. Unfortunately, the efficacy and safety of these agents in OTRs is unknown at this time, given the exclusion of such patients from clinical trials. Furthermore, case reports and small retrospective series have described transplant rejection in at least 40% of subjects who received CIs after undergoing a kidney transplant [12,13,14,15,16,17].
In particular, De Bruyn et al. [13] reported 48 cases of RTRs and liver recipients who had received CIs; of the 29 RTRs, 13 (45%) experienced rejection. From a cancer standpoint, 7 out of 13 patients who had a rejection (53%) had a favorable outcome.
In another review of 39 OTRs treated with CIs, rejections rates were highest in the 23 RTR (48%), compared to liver (36%) and cardiac (20%) transplant patients [14].
Manohar et al. [15] recently conducted a literature search and reviewed 27 studies that reported outcomes of 44 RTRs who had received treatment with CIs; 11% of these patients presented with metastatic CSCC, 68% had melanoma, while the remaining patients had either lung, Merkel cell, urothelial, or duodenal carcinomas. Most patients received a CI as a single agent: nivolumab in 34% cases, pembrolizumab in 25%, ipilimumab in 20%, and avelumab in one patient; the remaining cases received two different CIs sequentially. Overall, 18 patients (41%) were reported to have acute rejection of the renal allograft with a median time of 24 days; eventually, 15 out of these 18 patients had allograft failure (83%), and 8 patients died. Reported types of acute allograft rejection were cellular rejection (33%), mixed cellular and antibody-mediated rejection (17%), and unspecified type (50%). Baseline immunosuppressive regimen data were available for 31 patients: 48% of them were on a triple regimen with a calcineurin inhibitor, such as tacrolimus or cyclosporine, mycophenolate mofetil, and low-dose steroids.
In another large systematic review, 83 OTRs were treated with CIs (about two-thirds received anti-PD1/PDL1 therapy, 16% anti-CTLA-4, 11% combination therapy) [16]. This study included 53 RTRs; allograft rejection occurred in 40% of patients, leading to end-stage organ failure in 71% of cases. Outcomes were similar across organs and immunotherapy regimens. Patients on no other immunosuppressive treatment besides corticosteroids at initiation of CIs had a higher risk of rejection. RTR was the only group where there was similar mortality in patients with and without rejection, suggesting that CIs may be a better option in these patients where hemodialysis is a life-saving alternative in case of rejection [16,17].
Ali et al. [18] recently reported successful administration of cemiplimab to an 81-year-old patient with advanced CSCC on sirolimus and prednisone for immunosuppression after renal transplantation. Sirolimus is a known inhibitor of the mechanistic target of rapamycin (mTOR). Interestingly, mTOR inhibitors have been shown to reduce the growth and proliferation of tumor cells in vitro and in vivo mouse models [19]. In a mixed-organ cohort of OTRs, patients taking sirolimus after developing post-transplant cancer showed lower risk of developing skin cancer [20]. The immunosuppression provided by sirolimus to the patient above may have mitigated the rejection effect from cemiplimab, while boosting the anti-cancer response.
The improvement in kidney function observed in our patient over time is difficult to interpret; it may be related to closer patient’s monitoring with frequent assessments of his hydration status in the context of multiple office and hospital visits.
4. Summary
To our knowledge, this is the first report of safe administration of the anti-PD1 monoclonal antibody cemiplimab in a kidney transplant patient with recurrent, locally advanced SCC of the scalp treated with prednisone alone for immunosuppression. The ongoing phase 1/2 CONTACT clinical trial is exploring the safety and effectiveness of cemiplimab in subjects with advanced SCC who have previously received an allogeneic hematopoietic stem cell transplant or kidney transplant (NCT04339062); all patients on this trial are required to be on immunosuppression with prednisone and either sirolimus or everolimus.
Acknowledgments
Our sincere thanks to the patient for his courage and consent to share his story in the hope other transplant patients may benefit from his experience.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author Contributions
Conceptualization, L.P.; methodology, L.P. and T.J.O.; formal analysis: L.P. and T.J.O.; investigation: L.P. and T.J.O., resources: L.P. and T.J.O.; data curation: L.P. and T.J.O., writing-original draft preparation: L.P.; writing-review and editing: L.P. and T.J.O.; visualization: L.P. and T.J.O.; supervision, L.P.; project administration: L.P. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Conflicts of Interest
The authors declare no conflict of interest.
Figure 1 Representative pre-treatment, post-contrast, T1-weighted, sagittal MRI images (A) and fused PET-CT images (B) show disease extension predominantly from the vertex scalp to the left lateral temple region.
Figure 2 (A) Multiple nodules consistent with cutaneous squamous cell carcinoma on the left temporal area before starting cemiplimab; (B) tumor regression after three cycles of cemiplimab; (C) response after a total of 10 cycles of cemiplimab.
curroncol-28-00057-t001_Table 1Table 1 Changes in creatinine and glomerular filtration rate (GFR) during treatment with cemiplimab (before each cycle).
Cemiplimab Creatinine
(Ref Range < l.5 mg/dL) GFR
(Ref Range > 60 mL/min/BSA)
C#1 1.2 60
C#2 1.1 66
C#3 1.0 74
C#4 1.2 60
C#5 1.2 60
C#6 1.0 74
C#7 0.97 78
C#8 0.88 86
C#9 0.91 84
C#10 0.85 87
Ref = reference; C = cycle. | Recovering | ReactionOutcome | CC BY | 33477979 | 19,099,795 | 2021-01-19 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Embedded device'. | May chronic cough in chronic obstructive pulmonary disease be a contraindication of Percutaneous Endoscopic Gastrostomy placement: a case report.
BACKGROUND
Percutaneous Endoscopic Gastrostomy (PEG) can involve some complications, despite the good safety of its track record. The Buried Bumper Syndrome (BBS) is a rare, late and dangerous complication that consists in the erosion of the internal bumper through the gastric wall. Case presentation We report the development of BBS in a man with chronic obstructive pulmonary disease (COPD) who had a persistent chronic cough which was prevalently but not solely in the morning and required placement of a PEG tube for continuous infusion of Levodopa/carbidopa intestinal gel for advanced Parkinson's disease.
CONCLUSIONS
We believe that COPD with chronic cough while not representing an absolute contraindication to PEG placement, may potentially cause BBS and therefore an appropriate regimen of tube care by expert personnel is mandatory in this setting.
Background
Percutaneous endoscopic gastrostomy (PEG) is considered a safe procedure to provide long term enteral nutrition and enteral access [1]. In addition, the PEG tube can be used to intubate the proximal jejunum with an extension tube (J-PEG) to allow the pharmacological treatment of Advanced Parkinson’s Disease through a continuous delivery of levodopa (L-Dopa)/carbidopa intestinal gel (LCIG). It represents a new approach in patients with Advanced Parkinson’s Disease who respond to oral administration of L-Dopa therapy but with dyskinesias and motor fluctuations which are poorly managed by optimized oral therapy alone [2].
Although it has been generally considered safe, PEG tube placement can be associated with many potential complications that can be classified as minor or major. Major complications include aspiration pneumonia, hemorrhage, buried bumper syndrome (BBS), colon perforation during the PEG insertion, necrotizing fasciitis [1, 3–5]. An unusual and late complication could be the BBS that occurs when the internal bumper erodes from the lumen of the stomach into the gastric wall or subcutaneous tissue. BBS is due to excessive tension between the internal and external bumpers that causes ischemic necrosis of the gastric wall. It usually manifests with the signs and symptoms of infection due to leakage of gastric content from around the PEG tube insertion site in the peristomal site. We may observe fixity of the PEG tube, abdominal pain and resistance to water or nutritional solution infusion. Inability to insert PEG tube, loss of patency and leakage around the PEG tube are considered to be a typical symptomatic triad [6]. However, if the tube is not removed as soon as possible, severe complications might happen such as perforation of the stomach, peritonitis and death [7–9].
Case presentation
A 57 years old man affected by Advanced Parkinson’s Disease was selected for J-PEG placement to allow the continuous administration of LCIG in duodenum (AbbVie PEG polyurethane Tube 20 F). We obtained informed consent. He had a smoking history of 30/40 cigarettes per day for the past 30 years reporting a chronic cough, prevalently but not solely in the morning. On examination he appeared overweight (BMI = 29) with an abdominal fat distribution. Lung clinical examination revealed a barrel chest decreased brief sounds, with moderate inspiratory and expiratory wheezing, he used accessory muscles of respiration. There were signs and symptoms of chronic obstructive pulmonary disease (COPD); spirometry showed a ratio of forced expiratory volume in 1s (FEV1) and forced vital capacity (FVC) slightly lower than normal (65%); and low maximum expiratory flow (MEF was 80% at 25% and 50%). There were no absolute contraindication to place PEG tube. A pull-technique was used and a routine post insertion endoscopic confirmation of satisfactory PEG placement (AbbVie PEG polyurethane Tube 20 F) was performed at the end of the procedure. The PEG appeared successfully placed. Thirteen days later the tube was unable to infuse solution, there was a peritubal leak and the patient had abdominal pain with signs of edema and erythema of the tube insertion area. On the clinical examination we observed that during cough attack abdomen of our patient become prominent. Endoscopic evaluation showed that gastric mucosa covering internal gastrostomy site resulted in a complete closure of the orifice with visualization of only the J-tube extension. The internal bumper was not visible on the gastric wall but mucosa was ulcerated at the presumed site (Fig. 1). The patient underwent computed tomography (CT) (Fig. 2) of the abdomen, BBS was recognized and the device was removed by using a needle-knife assisted endoscopic dissection technique. After one week, following a thorough multidisciplinary evaluation due to the patient’s considerable anesthesiological risk, we positioned a new PEG-tube endoscopically in an area at a distance from the one used previously. Unfortunately, however, one month later the BBS presented again..Because the internal bumper was not visible endoscopically due to its dislocation into the abdominal wall, a microinvasive endoscopic needle knife-assisted approach was not feasible, and, therefore, we removed it surgically.Fig. 1 Endoscopic image of BBS, the internal bumper is not visible on the gastric wall
Fig. 2 Computed Tomography (CT) image demonstrating a BBS type 3
Discussion and conclusion
BBS is usually a late and rare complication of PEG occurring in 0.3–2.4% of the patients [1]. BBS usually appears no earlier than 4 months after PEG placement. Nevertheless it has been described a case of BBS after three weeks from tube placement [9]. In our patient, BBS occurred thirteen days after PEG insertion and then again after one month. The case of our patient suggests that COPD and chronic cough may represent a potential cause of BBS, even though the association between COPD with chronic cough and BBS as in our case does not necessarily imply a cause-effect relationship. Our case report underlines the important role of the traction performed by the respiratory movements in a patient with COPD with little airway obstruction, as evaluated by spirometry. The persistent cough produced a traction of the PEG tube and a bumper compression which in turn lead to gastric wall erosion. We cannot completely rule out the possibility that too much tension was placed on the bumper during PEG tube insertion or that there had been a lack of appropriate management of the tube. The first time, after thirteen days from the first positioning, there was a displacement corresponding to a type 3 BBS because the internal bumper appeared total visible at mobilization. The second time, after one month from the second PEG placement, a deep type 4 BBS occurred. This is according to Richter-Schraq HJ et al. who described 4 types of BBS: in type 1 the internal bumper is outside the body or in the subcutaneous tissue; in type 2 the internal bumper is partially visible in gastric lumen; in type 3 the internal bumper is not visible in the gastric lumen and is in the most superficial layers of the gastric wall; in type 4 the internal bumper is not visible in the gastric cavity and is in the deeper layers of the gastric wall [7]. BBS is a dangerous major complication of the PEG placement because it may cause infection, necrotizing fasciitis [3, 10], peritonitis and consequently septic shock with a fatal outcome [8]. Absolute contraindication to PEG placement are pharyngeal and esophageal occlusion for pull technique, active serious coagulopathy, hemodynamic instability, sepsis, severe ascites, peritonitis, peritoneal carcinomatosis, portal hypertension with gastric varices, total gastrectomy [1, 11]. Our patient had none of these absolute contraindications. Moreover some studies associated COPD at a higher risk of fatal outcome due to an increased susceptibility of COPD patients to develop gastroesophageal reflux disease that is strictly associated to a higher aspiration pneumonia risk, rather than a higher risk of BBS rising [12]. We believe that COPD with chronic cough may cause the displacement of the internal bumper thus causing BBS. Therefore, in case of a complication such as BBS it is important to have a radiologic evaluation in order to better assess the problem and possibly solving it through a surgical approach.
PEG is a safe for enteral nutrition and J-PEG has a fundamental role in the pharmacological treatment of Advanced Parkinson’s Disease as well as to ability to feed directly into the jejunum. PEG tube placement may have complications and BBS is one of these ones. PEG-related complications are mostly prevented by an appropriate tube care.. It is essential for all patients, but particularly in those who have a chronic cough, that during the daily tube cleaning the PEG is not only rotated, but advanced further into the stomach and then pulled back until set to the correct length and tension. In these patients, the tube needs to have some slack to accommodate the excursion of the abdominal wall during forced expiration while coughing. In order to avoid BBS, some PEG tubes with externally removable internal bumpers were found useful in the treatment of BBS allowing the bumper removal by external traction without any endoscopic or surgical methods [13].
COPD with chronic cough does not represent a contraindication to placement of PEG tube but in our opinion, by facilitating movements of internal bumper, it may favor erosion of internal bumper from gastric lumen into the gastric wall or subcutaneous tissue thus causing BBS. Therefore, based on this case report, not only much attention should be paid to PEG placement but also an accurate post-procedure tube care should be strongly advised in this particular setting.
Abbreviations
PEGPercutaneous endoscopic gastrostomy
BBSBuried bumper syndrome
COPDChronic obstructive pulmonary disease
J-PEGPEG with jejunal extension tube
L-DopaLevodopa
LCIGLevodopa/carbidopa intestinal gel
BMIBody max index
FEV1Forced expiratory volume in 1s
FVCForced vital capacity
MEFMaximum expiratory flow
CTComputed tomography
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
A. G. Gravina and A. Tessitore have contributed equally to this work.
Acknowledgements
Research activity of Dr. Antonietta G. Gravina was supported by the Valere Program.
Authors’ contributions
AGG and FF: draft of the manuscript; AT: neurologist who proposed the placement of PEG-J for Parkinson's therapy in this patient; AGG, MRA and VMO: performed upper gastrointestinal endoscopy and PEG placement; FF and FN: anesthesia evaluation and deep sedation during PEG placement; MD: references serch; MR: references serch and revision; AGG, AT, FF, CL, MR, AF: critical review of the manuscript. All authors were involved in writing the paper and had final approval of the submitted and published versions.
Funding
No funding to declare.
Availability of data and materials
All the data supporting our findings can be found in the patient hospital medical report. Unlikely, we don't have an electronic repository at out Institution. All the personal patients' data, including biochemical, endoscopic and radiological exams, are stored on paper at our hospital. Therefore we can't share our data.
Ethics approval and consent to participate
Not applicable.
Consent for publication
The patient provided written consent for the publication of identifying information and/or images.
Competing interests
The authors declare that they have no competing interests. | CARBIDOPA\LEVODOPA | DrugsGivenReaction | CC BY | 33478385 | 18,959,148 | 2021-01-21 |
What was the administration route of drug 'CARBIDOPA\LEVODOPA'? | May chronic cough in chronic obstructive pulmonary disease be a contraindication of Percutaneous Endoscopic Gastrostomy placement: a case report.
BACKGROUND
Percutaneous Endoscopic Gastrostomy (PEG) can involve some complications, despite the good safety of its track record. The Buried Bumper Syndrome (BBS) is a rare, late and dangerous complication that consists in the erosion of the internal bumper through the gastric wall. Case presentation We report the development of BBS in a man with chronic obstructive pulmonary disease (COPD) who had a persistent chronic cough which was prevalently but not solely in the morning and required placement of a PEG tube for continuous infusion of Levodopa/carbidopa intestinal gel for advanced Parkinson's disease.
CONCLUSIONS
We believe that COPD with chronic cough while not representing an absolute contraindication to PEG placement, may potentially cause BBS and therefore an appropriate regimen of tube care by expert personnel is mandatory in this setting.
Background
Percutaneous endoscopic gastrostomy (PEG) is considered a safe procedure to provide long term enteral nutrition and enteral access [1]. In addition, the PEG tube can be used to intubate the proximal jejunum with an extension tube (J-PEG) to allow the pharmacological treatment of Advanced Parkinson’s Disease through a continuous delivery of levodopa (L-Dopa)/carbidopa intestinal gel (LCIG). It represents a new approach in patients with Advanced Parkinson’s Disease who respond to oral administration of L-Dopa therapy but with dyskinesias and motor fluctuations which are poorly managed by optimized oral therapy alone [2].
Although it has been generally considered safe, PEG tube placement can be associated with many potential complications that can be classified as minor or major. Major complications include aspiration pneumonia, hemorrhage, buried bumper syndrome (BBS), colon perforation during the PEG insertion, necrotizing fasciitis [1, 3–5]. An unusual and late complication could be the BBS that occurs when the internal bumper erodes from the lumen of the stomach into the gastric wall or subcutaneous tissue. BBS is due to excessive tension between the internal and external bumpers that causes ischemic necrosis of the gastric wall. It usually manifests with the signs and symptoms of infection due to leakage of gastric content from around the PEG tube insertion site in the peristomal site. We may observe fixity of the PEG tube, abdominal pain and resistance to water or nutritional solution infusion. Inability to insert PEG tube, loss of patency and leakage around the PEG tube are considered to be a typical symptomatic triad [6]. However, if the tube is not removed as soon as possible, severe complications might happen such as perforation of the stomach, peritonitis and death [7–9].
Case presentation
A 57 years old man affected by Advanced Parkinson’s Disease was selected for J-PEG placement to allow the continuous administration of LCIG in duodenum (AbbVie PEG polyurethane Tube 20 F). We obtained informed consent. He had a smoking history of 30/40 cigarettes per day for the past 30 years reporting a chronic cough, prevalently but not solely in the morning. On examination he appeared overweight (BMI = 29) with an abdominal fat distribution. Lung clinical examination revealed a barrel chest decreased brief sounds, with moderate inspiratory and expiratory wheezing, he used accessory muscles of respiration. There were signs and symptoms of chronic obstructive pulmonary disease (COPD); spirometry showed a ratio of forced expiratory volume in 1s (FEV1) and forced vital capacity (FVC) slightly lower than normal (65%); and low maximum expiratory flow (MEF was 80% at 25% and 50%). There were no absolute contraindication to place PEG tube. A pull-technique was used and a routine post insertion endoscopic confirmation of satisfactory PEG placement (AbbVie PEG polyurethane Tube 20 F) was performed at the end of the procedure. The PEG appeared successfully placed. Thirteen days later the tube was unable to infuse solution, there was a peritubal leak and the patient had abdominal pain with signs of edema and erythema of the tube insertion area. On the clinical examination we observed that during cough attack abdomen of our patient become prominent. Endoscopic evaluation showed that gastric mucosa covering internal gastrostomy site resulted in a complete closure of the orifice with visualization of only the J-tube extension. The internal bumper was not visible on the gastric wall but mucosa was ulcerated at the presumed site (Fig. 1). The patient underwent computed tomography (CT) (Fig. 2) of the abdomen, BBS was recognized and the device was removed by using a needle-knife assisted endoscopic dissection technique. After one week, following a thorough multidisciplinary evaluation due to the patient’s considerable anesthesiological risk, we positioned a new PEG-tube endoscopically in an area at a distance from the one used previously. Unfortunately, however, one month later the BBS presented again..Because the internal bumper was not visible endoscopically due to its dislocation into the abdominal wall, a microinvasive endoscopic needle knife-assisted approach was not feasible, and, therefore, we removed it surgically.Fig. 1 Endoscopic image of BBS, the internal bumper is not visible on the gastric wall
Fig. 2 Computed Tomography (CT) image demonstrating a BBS type 3
Discussion and conclusion
BBS is usually a late and rare complication of PEG occurring in 0.3–2.4% of the patients [1]. BBS usually appears no earlier than 4 months after PEG placement. Nevertheless it has been described a case of BBS after three weeks from tube placement [9]. In our patient, BBS occurred thirteen days after PEG insertion and then again after one month. The case of our patient suggests that COPD and chronic cough may represent a potential cause of BBS, even though the association between COPD with chronic cough and BBS as in our case does not necessarily imply a cause-effect relationship. Our case report underlines the important role of the traction performed by the respiratory movements in a patient with COPD with little airway obstruction, as evaluated by spirometry. The persistent cough produced a traction of the PEG tube and a bumper compression which in turn lead to gastric wall erosion. We cannot completely rule out the possibility that too much tension was placed on the bumper during PEG tube insertion or that there had been a lack of appropriate management of the tube. The first time, after thirteen days from the first positioning, there was a displacement corresponding to a type 3 BBS because the internal bumper appeared total visible at mobilization. The second time, after one month from the second PEG placement, a deep type 4 BBS occurred. This is according to Richter-Schraq HJ et al. who described 4 types of BBS: in type 1 the internal bumper is outside the body or in the subcutaneous tissue; in type 2 the internal bumper is partially visible in gastric lumen; in type 3 the internal bumper is not visible in the gastric lumen and is in the most superficial layers of the gastric wall; in type 4 the internal bumper is not visible in the gastric cavity and is in the deeper layers of the gastric wall [7]. BBS is a dangerous major complication of the PEG placement because it may cause infection, necrotizing fasciitis [3, 10], peritonitis and consequently septic shock with a fatal outcome [8]. Absolute contraindication to PEG placement are pharyngeal and esophageal occlusion for pull technique, active serious coagulopathy, hemodynamic instability, sepsis, severe ascites, peritonitis, peritoneal carcinomatosis, portal hypertension with gastric varices, total gastrectomy [1, 11]. Our patient had none of these absolute contraindications. Moreover some studies associated COPD at a higher risk of fatal outcome due to an increased susceptibility of COPD patients to develop gastroesophageal reflux disease that is strictly associated to a higher aspiration pneumonia risk, rather than a higher risk of BBS rising [12]. We believe that COPD with chronic cough may cause the displacement of the internal bumper thus causing BBS. Therefore, in case of a complication such as BBS it is important to have a radiologic evaluation in order to better assess the problem and possibly solving it through a surgical approach.
PEG is a safe for enteral nutrition and J-PEG has a fundamental role in the pharmacological treatment of Advanced Parkinson’s Disease as well as to ability to feed directly into the jejunum. PEG tube placement may have complications and BBS is one of these ones. PEG-related complications are mostly prevented by an appropriate tube care.. It is essential for all patients, but particularly in those who have a chronic cough, that during the daily tube cleaning the PEG is not only rotated, but advanced further into the stomach and then pulled back until set to the correct length and tension. In these patients, the tube needs to have some slack to accommodate the excursion of the abdominal wall during forced expiration while coughing. In order to avoid BBS, some PEG tubes with externally removable internal bumpers were found useful in the treatment of BBS allowing the bumper removal by external traction without any endoscopic or surgical methods [13].
COPD with chronic cough does not represent a contraindication to placement of PEG tube but in our opinion, by facilitating movements of internal bumper, it may favor erosion of internal bumper from gastric lumen into the gastric wall or subcutaneous tissue thus causing BBS. Therefore, based on this case report, not only much attention should be paid to PEG placement but also an accurate post-procedure tube care should be strongly advised in this particular setting.
Abbreviations
PEGPercutaneous endoscopic gastrostomy
BBSBuried bumper syndrome
COPDChronic obstructive pulmonary disease
J-PEGPEG with jejunal extension tube
L-DopaLevodopa
LCIGLevodopa/carbidopa intestinal gel
BMIBody max index
FEV1Forced expiratory volume in 1s
FVCForced vital capacity
MEFMaximum expiratory flow
CTComputed tomography
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
A. G. Gravina and A. Tessitore have contributed equally to this work.
Acknowledgements
Research activity of Dr. Antonietta G. Gravina was supported by the Valere Program.
Authors’ contributions
AGG and FF: draft of the manuscript; AT: neurologist who proposed the placement of PEG-J for Parkinson's therapy in this patient; AGG, MRA and VMO: performed upper gastrointestinal endoscopy and PEG placement; FF and FN: anesthesia evaluation and deep sedation during PEG placement; MD: references serch; MR: references serch and revision; AGG, AT, FF, CL, MR, AF: critical review of the manuscript. All authors were involved in writing the paper and had final approval of the submitted and published versions.
Funding
No funding to declare.
Availability of data and materials
All the data supporting our findings can be found in the patient hospital medical report. Unlikely, we don't have an electronic repository at out Institution. All the personal patients' data, including biochemical, endoscopic and radiological exams, are stored on paper at our hospital. Therefore we can't share our data.
Ethics approval and consent to participate
Not applicable.
Consent for publication
The patient provided written consent for the publication of identifying information and/or images.
Competing interests
The authors declare that they have no competing interests. | Other | DrugAdministrationRoute | CC BY | 33478385 | 18,959,148 | 2021-01-21 |
What was the outcome of reaction 'Embedded device'? | May chronic cough in chronic obstructive pulmonary disease be a contraindication of Percutaneous Endoscopic Gastrostomy placement: a case report.
BACKGROUND
Percutaneous Endoscopic Gastrostomy (PEG) can involve some complications, despite the good safety of its track record. The Buried Bumper Syndrome (BBS) is a rare, late and dangerous complication that consists in the erosion of the internal bumper through the gastric wall. Case presentation We report the development of BBS in a man with chronic obstructive pulmonary disease (COPD) who had a persistent chronic cough which was prevalently but not solely in the morning and required placement of a PEG tube for continuous infusion of Levodopa/carbidopa intestinal gel for advanced Parkinson's disease.
CONCLUSIONS
We believe that COPD with chronic cough while not representing an absolute contraindication to PEG placement, may potentially cause BBS and therefore an appropriate regimen of tube care by expert personnel is mandatory in this setting.
Background
Percutaneous endoscopic gastrostomy (PEG) is considered a safe procedure to provide long term enteral nutrition and enteral access [1]. In addition, the PEG tube can be used to intubate the proximal jejunum with an extension tube (J-PEG) to allow the pharmacological treatment of Advanced Parkinson’s Disease through a continuous delivery of levodopa (L-Dopa)/carbidopa intestinal gel (LCIG). It represents a new approach in patients with Advanced Parkinson’s Disease who respond to oral administration of L-Dopa therapy but with dyskinesias and motor fluctuations which are poorly managed by optimized oral therapy alone [2].
Although it has been generally considered safe, PEG tube placement can be associated with many potential complications that can be classified as minor or major. Major complications include aspiration pneumonia, hemorrhage, buried bumper syndrome (BBS), colon perforation during the PEG insertion, necrotizing fasciitis [1, 3–5]. An unusual and late complication could be the BBS that occurs when the internal bumper erodes from the lumen of the stomach into the gastric wall or subcutaneous tissue. BBS is due to excessive tension between the internal and external bumpers that causes ischemic necrosis of the gastric wall. It usually manifests with the signs and symptoms of infection due to leakage of gastric content from around the PEG tube insertion site in the peristomal site. We may observe fixity of the PEG tube, abdominal pain and resistance to water or nutritional solution infusion. Inability to insert PEG tube, loss of patency and leakage around the PEG tube are considered to be a typical symptomatic triad [6]. However, if the tube is not removed as soon as possible, severe complications might happen such as perforation of the stomach, peritonitis and death [7–9].
Case presentation
A 57 years old man affected by Advanced Parkinson’s Disease was selected for J-PEG placement to allow the continuous administration of LCIG in duodenum (AbbVie PEG polyurethane Tube 20 F). We obtained informed consent. He had a smoking history of 30/40 cigarettes per day for the past 30 years reporting a chronic cough, prevalently but not solely in the morning. On examination he appeared overweight (BMI = 29) with an abdominal fat distribution. Lung clinical examination revealed a barrel chest decreased brief sounds, with moderate inspiratory and expiratory wheezing, he used accessory muscles of respiration. There were signs and symptoms of chronic obstructive pulmonary disease (COPD); spirometry showed a ratio of forced expiratory volume in 1s (FEV1) and forced vital capacity (FVC) slightly lower than normal (65%); and low maximum expiratory flow (MEF was 80% at 25% and 50%). There were no absolute contraindication to place PEG tube. A pull-technique was used and a routine post insertion endoscopic confirmation of satisfactory PEG placement (AbbVie PEG polyurethane Tube 20 F) was performed at the end of the procedure. The PEG appeared successfully placed. Thirteen days later the tube was unable to infuse solution, there was a peritubal leak and the patient had abdominal pain with signs of edema and erythema of the tube insertion area. On the clinical examination we observed that during cough attack abdomen of our patient become prominent. Endoscopic evaluation showed that gastric mucosa covering internal gastrostomy site resulted in a complete closure of the orifice with visualization of only the J-tube extension. The internal bumper was not visible on the gastric wall but mucosa was ulcerated at the presumed site (Fig. 1). The patient underwent computed tomography (CT) (Fig. 2) of the abdomen, BBS was recognized and the device was removed by using a needle-knife assisted endoscopic dissection technique. After one week, following a thorough multidisciplinary evaluation due to the patient’s considerable anesthesiological risk, we positioned a new PEG-tube endoscopically in an area at a distance from the one used previously. Unfortunately, however, one month later the BBS presented again..Because the internal bumper was not visible endoscopically due to its dislocation into the abdominal wall, a microinvasive endoscopic needle knife-assisted approach was not feasible, and, therefore, we removed it surgically.Fig. 1 Endoscopic image of BBS, the internal bumper is not visible on the gastric wall
Fig. 2 Computed Tomography (CT) image demonstrating a BBS type 3
Discussion and conclusion
BBS is usually a late and rare complication of PEG occurring in 0.3–2.4% of the patients [1]. BBS usually appears no earlier than 4 months after PEG placement. Nevertheless it has been described a case of BBS after three weeks from tube placement [9]. In our patient, BBS occurred thirteen days after PEG insertion and then again after one month. The case of our patient suggests that COPD and chronic cough may represent a potential cause of BBS, even though the association between COPD with chronic cough and BBS as in our case does not necessarily imply a cause-effect relationship. Our case report underlines the important role of the traction performed by the respiratory movements in a patient with COPD with little airway obstruction, as evaluated by spirometry. The persistent cough produced a traction of the PEG tube and a bumper compression which in turn lead to gastric wall erosion. We cannot completely rule out the possibility that too much tension was placed on the bumper during PEG tube insertion or that there had been a lack of appropriate management of the tube. The first time, after thirteen days from the first positioning, there was a displacement corresponding to a type 3 BBS because the internal bumper appeared total visible at mobilization. The second time, after one month from the second PEG placement, a deep type 4 BBS occurred. This is according to Richter-Schraq HJ et al. who described 4 types of BBS: in type 1 the internal bumper is outside the body or in the subcutaneous tissue; in type 2 the internal bumper is partially visible in gastric lumen; in type 3 the internal bumper is not visible in the gastric lumen and is in the most superficial layers of the gastric wall; in type 4 the internal bumper is not visible in the gastric cavity and is in the deeper layers of the gastric wall [7]. BBS is a dangerous major complication of the PEG placement because it may cause infection, necrotizing fasciitis [3, 10], peritonitis and consequently septic shock with a fatal outcome [8]. Absolute contraindication to PEG placement are pharyngeal and esophageal occlusion for pull technique, active serious coagulopathy, hemodynamic instability, sepsis, severe ascites, peritonitis, peritoneal carcinomatosis, portal hypertension with gastric varices, total gastrectomy [1, 11]. Our patient had none of these absolute contraindications. Moreover some studies associated COPD at a higher risk of fatal outcome due to an increased susceptibility of COPD patients to develop gastroesophageal reflux disease that is strictly associated to a higher aspiration pneumonia risk, rather than a higher risk of BBS rising [12]. We believe that COPD with chronic cough may cause the displacement of the internal bumper thus causing BBS. Therefore, in case of a complication such as BBS it is important to have a radiologic evaluation in order to better assess the problem and possibly solving it through a surgical approach.
PEG is a safe for enteral nutrition and J-PEG has a fundamental role in the pharmacological treatment of Advanced Parkinson’s Disease as well as to ability to feed directly into the jejunum. PEG tube placement may have complications and BBS is one of these ones. PEG-related complications are mostly prevented by an appropriate tube care.. It is essential for all patients, but particularly in those who have a chronic cough, that during the daily tube cleaning the PEG is not only rotated, but advanced further into the stomach and then pulled back until set to the correct length and tension. In these patients, the tube needs to have some slack to accommodate the excursion of the abdominal wall during forced expiration while coughing. In order to avoid BBS, some PEG tubes with externally removable internal bumpers were found useful in the treatment of BBS allowing the bumper removal by external traction without any endoscopic or surgical methods [13].
COPD with chronic cough does not represent a contraindication to placement of PEG tube but in our opinion, by facilitating movements of internal bumper, it may favor erosion of internal bumper from gastric lumen into the gastric wall or subcutaneous tissue thus causing BBS. Therefore, based on this case report, not only much attention should be paid to PEG placement but also an accurate post-procedure tube care should be strongly advised in this particular setting.
Abbreviations
PEGPercutaneous endoscopic gastrostomy
BBSBuried bumper syndrome
COPDChronic obstructive pulmonary disease
J-PEGPEG with jejunal extension tube
L-DopaLevodopa
LCIGLevodopa/carbidopa intestinal gel
BMIBody max index
FEV1Forced expiratory volume in 1s
FVCForced vital capacity
MEFMaximum expiratory flow
CTComputed tomography
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
A. G. Gravina and A. Tessitore have contributed equally to this work.
Acknowledgements
Research activity of Dr. Antonietta G. Gravina was supported by the Valere Program.
Authors’ contributions
AGG and FF: draft of the manuscript; AT: neurologist who proposed the placement of PEG-J for Parkinson's therapy in this patient; AGG, MRA and VMO: performed upper gastrointestinal endoscopy and PEG placement; FF and FN: anesthesia evaluation and deep sedation during PEG placement; MD: references serch; MR: references serch and revision; AGG, AT, FF, CL, MR, AF: critical review of the manuscript. All authors were involved in writing the paper and had final approval of the submitted and published versions.
Funding
No funding to declare.
Availability of data and materials
All the data supporting our findings can be found in the patient hospital medical report. Unlikely, we don't have an electronic repository at out Institution. All the personal patients' data, including biochemical, endoscopic and radiological exams, are stored on paper at our hospital. Therefore we can't share our data.
Ethics approval and consent to participate
Not applicable.
Consent for publication
The patient provided written consent for the publication of identifying information and/or images.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33478385 | 18,959,148 | 2021-01-21 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Diffuse large B-cell lymphoma originating from the rectum and diagnosed after rectal perforation during the treatment of ulcerative colitis: a case report.
BACKGROUND
Gastrointestinal lymphomas like diffuse large B-cell lymphoma (DLBCL) are rare complications of ulcerative colitis (UC), and only a few studies have reported intestinal ulcers caused by DLBCL, which got perforated during the treatment of UC.
METHODS
A 43-year-old man with severe lower abdominal pain and an 8-year history of UC was admitted in our hospital. He was diagnosed UC since 8 years and received a maintenance oral dose of 5-aminosalicylic acid, and no other immunosuppressive drugs. A deep rectal ulcer was endoscopically diagnosed 10 months before admission, no malignancy or cytomegalovirus infection was detected on biopsy. After 7 months a further endoscopy with biopsies confirmed the finding and the absence of malignancy. Three months later the patient developed sudden abdominal pain and was admitted in our hospital. Rectal perforation was suspected on X-ray and computed tomography imaging, and an emergency surgery was performed. Surgical exploration revealed a perforation on the anterior wall of the rectum. A subtotal colectomy with temporary ileostomy was performed. Pathology examinations showed lymphocyte infiltration of all of the layers of the perforated site and an immunohistochemical evaluation revealed DLBCL. Clinical staging was stage IV, and the patient received a 6-months regimen of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy. Positron emission tomography restaging revealed disappearance of distant uptake and a slight uptake in the residual rectum, and completion proctectomy with ileal pouch-anal anastomosis was performed. No residual tumor in the specimen was found, and the patient was disease-free at 2 years follow-up.
CONCLUSIONS
DLBCL may increase the frequency of perforation and is a poor prognostic risk factor for patients with UC. This case study emphasizes the importance of careful medical surveillance and repeated endoscopic biopsies during the treatment of UC.
Background
Intestinal perforations are rare in patients with ulcerative colitis (UC) since the inflammation is usually limited to the submucosal layer. The incidence of perforation in UC is reported to be approximately 3% [1]. On the other hand, the incidence rate of perforations in gastrointestinal lymphoma is relatively high [2–4]. Therefore, gastrointestinal lymphomas can increase the risk of perforation in patients with UC.
Colon cancer is a common complication of UC, but inflammatory bowel disease (IBD), on its own, is not recognized as a risk factor for gastrointestinal lymphoma [5–8]. Previous studies have shown that long-term immunosuppressive drugs and tumor necrosis factor (TNF) inhibitor therapy in patients with UC induce gastrointestinal lymphoma [9, 10]. It has been suggested that long-term therapy with immunosuppressive drugs and TNF inhibitor cause immunosuppression and increase the incidence of Epstein-Barr virus (EBV)—positive lymphomas (i.e., diffuse large B-cell lymphoma (DLBCL)) [11]. However, other studies have reported cases of DLBCL in UC patients not treated with immunosuppressive drugs and TNF inhibitors [12, 13].
Here, we report a case of rectal DLBCL that got perforated while the patient was being treated with 5-aminosalicylic acid (5-ASA) and prednisolone for UC.
Case presentation
A 43-year-old man with severe lower abdominal pain was admitted to our hospital our hospital for medical treatment. He had an 8-year history of ulcerative proctitis, a form of UC. When the diagnosis of UC was made, he was administered a maintenance oral dose of 5-ASA, and no other immunosuppressive drugs (i.e., azathioprine and TNF inhibitors) were prescribed. Ten months before the onset of the sudden abdominal pain, a deep rectal ulcer was detected on endoscopy. An endoscopic examination revealed a grade 3 ulcer according to the Mayo endoscopic subscore (Fig. 1). Inflammation of the mucosa near the ulcer was slight and diagnosed as grade 1. On biopsy performed at the same time, there was no malignancy or cytomegalovirus (CMV) infection. The posology of 5-ASA was increased; he began taking a daily suppository of 5-ASA and Budesonide. Three months before the onset of the sudden abdominal pain, another endoscopic biopsy from the ulcer and pathological analysis were performed. Similar to the last time, the ulcer was diagnosed as grade 3, and there was no malignancy. Five days prior to the onset of the sudden abdominal pain, a daily dose of 40 mg of oral prednisolone was prescribed for the ulcer, as we clinically diagnosed that it did not respond to 5-ASA and Budesonide. Laboratory investigations revealed a slightly elevated C-reactive protein level, an elevated white blood cell count, no increase in tumor markers (carcinoembryonic antigen = 0.4 ng/mL, carbohydrate antigen 19–9 = 8.1 U/mL, carbohydrate antigen 125 = 14.4 U/mL), and CMV C 7-antigen. Preoperative investigation of soluble interleukin-2 receptor was not done. On the day of admission, the patient complained of severe lower abdominal pain. He had rebound tenderness with muscular defense. There was no fever, and laboratory tests showed non-elevated values for C-reactive protein (0.16 mg/L) and white blood cell count (7700/μL). Abdominal X-ray showed colon distension. Computed tomography (CT) of the abdomen and pelvis revealed intraperitoneal free air and an abnormal colon distension (Fig. 2a). The pelvic CT scan also suggested a perforation of the rectum but did not clearly reveal the presence of the lymphoma (Fig. 2b). These results indicated that the patient had a perforation rectal ulcer secondary to active UC. A subtotal colectomy with end ileostomy was performed. During the surgery, a fistula was discovered at the rectosigmoid region (Fig. 3). Pathological examination of the resected rectum revealed atypical lymphocyte infiltration in all of the layers of the rectal wall. Inflammation of the rectal mucosa in the non-perforated part was mild and evaluated as grades 1–2 according to Matt’s histological classification. There was no inflammation of the colonic mucosa (Fig. 4). Immunohistochemical staining was positive for the following: cluster of differentiation 20 (CD 20) markers, cluster of differentiation 10 (CD 10) markers, B-cell lymphoma 6 (BCL-6) proteins and multiple myeloma oncogene 1 (MUM-1)-stained atypical lymphocytes (Fig. 5). From these results, the pathological findings revealed that rectal perforation was related to DLBCL with UC. The stained specimen on immunohistochemistry was also positive for EBV (Fig. 6).Fig. 1 Endoscopy examination. The deep ulcer was detected and diagnosed grade 3 according to the Mayo endoscopic subscore
Fig. 2 Preoperative CT findings. Abdominal CT scan showing intraperitoneal free air and colon distension, suspicious of gastrointestinal perforation (a). Pelvic CT scan showing the perforation site in the rectum but does not clearly reveal the presence of the lymphoma (b)
Fig. 3 Resected rectosigmoid colon specimen. The perforation site is visible on the resected rectosigmoid colon. The mucosa is mostly normal except for the perforation site
Fig. 4 H&E stained slide from the perforation site. Pathological examination of the resected specimen showing atypical lymphocytes infiltration in all the layers of the rectal wall (× 40)
Fig. 5 Immunohistochemical examinations from the perforation site. Atypical lymphocytes are CD 20 positive (a), CD 10 positive (b), BCL-6 positive (c), and MUM-1 positive (d), (× 200)
Fig. 6 Tumor cells are positive for EBV on in situ hybridization, suggesting that tumor cells are infected with EBV (× 200)
A postoperative fluorodeoxyglucose-positron emission tomography revealed an abnormal uptake in the postero-inferior area of the liver surface (S 7) and in the residual rectum margin. The standardized uptake value max (SUV max) of the liver region was 7.2, and the SUV max of the residual rectum was 11.1. Consequently, the patient was evaluated as having stage IV lymphoma according to the Lugano classification [14] and was treated with R-CHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) 2 months after the surgery. Six courses of chemotherapy were effective in correcting the abnormal uptake in the liver region without any complications. However, the abnormal uptake in the residual rectal wall slightly persisted after the six courses (SUV max = 3.6). Ileal pouch-anal anastomosis was performed 9 months after the primary surgery, and a histopathological examination of the residual rectum was done. There was no evidence of residual tumor, especially in the remnant rectal margin. The diverted ileostomy was closed, and he was disease-free. No recurrence was noted upon re-evaluation two years after his first surgery.
Discussion and conclusions
The incidence of perforation in UC patients is rare because the inflammation in UC is usually limited to the submucosa. Patients usually take high doses of steroids or immunosuppressive drugs for the treatment in the active phase UC. CMV infection counteracts the use of immunosuppressive drugs and favors the development of toxic megacolon, which is a major cause of perforation in UC. The incidence rate of perforation in UC is reported to be around 3% [1].
However, the incidence rate of perforations in gastrointestinal lymphoma is approximately 9–22% and is higher than that in high-grade lymphoma (i.e., DLBCL) [2–4]. Primary gastrointestinal lymphoma may decrease the mechanical strength of the gastrointestinal wall and cause intestinal perforation [3, 15]. Some studies have found that perforation is a poor prognostic factor in patients with high-grade lymphomas like DLBCL [2–4, 16]. Vaidya reported that nearly half of the perforation events in gastrointestinal lymphoma occur at the time of diagnosis of gastrointestinal lymphoma suggesting that these perforations could not be avoided by prior interventions [3].Thus, it may be important to diagnose gastrointestinal lymphoma before it gets perforated, especially in UC patients.
The risk of gastrointestinal lymphoma is not higher in UC patients than in the general population [7]. Several previous studies have found that UC patients receiving thiopurines exhibit markedly increased relative risk of gastrointestinal lymphoma [9, 10]. Kandiel et al. reported an approximate fourfold increased risk of lymphoma in IBD patients treated with azathioprine [9]. Moreover, more than 90% of UC patients with gastrointestinal lymphoma receiving thiopurines complained of EBV infections [11]. Immunosuppressive therapy induces EBV infection and EBV-positive lymphomas (i.e., DLBCL). However, some studies have reported cases where DLBCL occurred in UC patients who were not administered immunosuppressive drugs [12, 13]. These cases suggest that DLBCL may occur regardless of whether immunosuppressive drugs are used or not.
In this case study, abnormal colon distension due to progression of the UC led to perforation of the DLBCL-induced ulcer. Immunosuppressive drugs were not administered, while steroids were administered only 5 days prior to the perforation. The incidence rate of perforation in patients with UC is low. However, whether the prevalence of gastrointestinal lymphoma in UC patients is high or not is still unclear, but the incidence rate of perforations in gastrointestinal lymphoma is relatively high. DLBCL may increase the frequency of perforation and is a poor prognostic risk factor for patients with UC. In this case, we performed two preoperative endoscopic biopsies of the ulcer, but we neither obtained a DLBCL-positive nor a CMV-infected specimen. DLBCL often causes ulcerations. Therefore, it is important to distinguish between a DLBCL ulcer and a UC ulcer by performing an endoscopic biopsy for choosing appropriate treatment for the ulcer. Hence, when a therapy-resistant colonic ulcer is detected in UC, biopsies from multiple points of the ulcer should be performed to confirm the presence of DLBCL to prevent perforation. In conclusion, gastrointestinal lymphomas such as DLBCL are rare in patients with UC, and bowel perforations induced by DLBCL ulcers in such patients are extremely rare. This case report emphasizes the importance of careful medical surveillance and repeated endoscopic biopsies in patients with UC.
Abbreviations
5-ASA5-Aminosalicylic acid
CMVCytomegalovirus
DLBLCLDiffuse large B-cell lymphoma
EBVEpstein–Barr virus
IBDInflammatory bowel disease
MUMMultiple myeloma oncogene
TNFTumor necrosis factor
UCUlcerative colitis
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to thank Editage (www.editage.com) for English language editing.
Authors’ contributions
ST conceptualized and wrote the original draft. SY, TM, FM, and YK treated the subject and revised the manuscript critically. IK and NR wrote, reviewed, and edited the work. All the authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
Not applicable.
Ethical approval and consent to participate
The Institutional Review Board of Coloproctology Center Takano Hospital Ethics Committee approved to the present case report.
Consent for publication
Written informed consent for publication has been obtained from the patient. The consent can be provided on request.
Competing interests
The authors have no conflicts of interest to declare. | BUDESONIDE, MESALAMINE | DrugsGivenReaction | CC BY | 33478454 | 18,941,161 | 2021-01-21 |
What was the administration route of drug 'BUDESONIDE'? | Diffuse large B-cell lymphoma originating from the rectum and diagnosed after rectal perforation during the treatment of ulcerative colitis: a case report.
BACKGROUND
Gastrointestinal lymphomas like diffuse large B-cell lymphoma (DLBCL) are rare complications of ulcerative colitis (UC), and only a few studies have reported intestinal ulcers caused by DLBCL, which got perforated during the treatment of UC.
METHODS
A 43-year-old man with severe lower abdominal pain and an 8-year history of UC was admitted in our hospital. He was diagnosed UC since 8 years and received a maintenance oral dose of 5-aminosalicylic acid, and no other immunosuppressive drugs. A deep rectal ulcer was endoscopically diagnosed 10 months before admission, no malignancy or cytomegalovirus infection was detected on biopsy. After 7 months a further endoscopy with biopsies confirmed the finding and the absence of malignancy. Three months later the patient developed sudden abdominal pain and was admitted in our hospital. Rectal perforation was suspected on X-ray and computed tomography imaging, and an emergency surgery was performed. Surgical exploration revealed a perforation on the anterior wall of the rectum. A subtotal colectomy with temporary ileostomy was performed. Pathology examinations showed lymphocyte infiltration of all of the layers of the perforated site and an immunohistochemical evaluation revealed DLBCL. Clinical staging was stage IV, and the patient received a 6-months regimen of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy. Positron emission tomography restaging revealed disappearance of distant uptake and a slight uptake in the residual rectum, and completion proctectomy with ileal pouch-anal anastomosis was performed. No residual tumor in the specimen was found, and the patient was disease-free at 2 years follow-up.
CONCLUSIONS
DLBCL may increase the frequency of perforation and is a poor prognostic risk factor for patients with UC. This case study emphasizes the importance of careful medical surveillance and repeated endoscopic biopsies during the treatment of UC.
Background
Intestinal perforations are rare in patients with ulcerative colitis (UC) since the inflammation is usually limited to the submucosal layer. The incidence of perforation in UC is reported to be approximately 3% [1]. On the other hand, the incidence rate of perforations in gastrointestinal lymphoma is relatively high [2–4]. Therefore, gastrointestinal lymphomas can increase the risk of perforation in patients with UC.
Colon cancer is a common complication of UC, but inflammatory bowel disease (IBD), on its own, is not recognized as a risk factor for gastrointestinal lymphoma [5–8]. Previous studies have shown that long-term immunosuppressive drugs and tumor necrosis factor (TNF) inhibitor therapy in patients with UC induce gastrointestinal lymphoma [9, 10]. It has been suggested that long-term therapy with immunosuppressive drugs and TNF inhibitor cause immunosuppression and increase the incidence of Epstein-Barr virus (EBV)—positive lymphomas (i.e., diffuse large B-cell lymphoma (DLBCL)) [11]. However, other studies have reported cases of DLBCL in UC patients not treated with immunosuppressive drugs and TNF inhibitors [12, 13].
Here, we report a case of rectal DLBCL that got perforated while the patient was being treated with 5-aminosalicylic acid (5-ASA) and prednisolone for UC.
Case presentation
A 43-year-old man with severe lower abdominal pain was admitted to our hospital our hospital for medical treatment. He had an 8-year history of ulcerative proctitis, a form of UC. When the diagnosis of UC was made, he was administered a maintenance oral dose of 5-ASA, and no other immunosuppressive drugs (i.e., azathioprine and TNF inhibitors) were prescribed. Ten months before the onset of the sudden abdominal pain, a deep rectal ulcer was detected on endoscopy. An endoscopic examination revealed a grade 3 ulcer according to the Mayo endoscopic subscore (Fig. 1). Inflammation of the mucosa near the ulcer was slight and diagnosed as grade 1. On biopsy performed at the same time, there was no malignancy or cytomegalovirus (CMV) infection. The posology of 5-ASA was increased; he began taking a daily suppository of 5-ASA and Budesonide. Three months before the onset of the sudden abdominal pain, another endoscopic biopsy from the ulcer and pathological analysis were performed. Similar to the last time, the ulcer was diagnosed as grade 3, and there was no malignancy. Five days prior to the onset of the sudden abdominal pain, a daily dose of 40 mg of oral prednisolone was prescribed for the ulcer, as we clinically diagnosed that it did not respond to 5-ASA and Budesonide. Laboratory investigations revealed a slightly elevated C-reactive protein level, an elevated white blood cell count, no increase in tumor markers (carcinoembryonic antigen = 0.4 ng/mL, carbohydrate antigen 19–9 = 8.1 U/mL, carbohydrate antigen 125 = 14.4 U/mL), and CMV C 7-antigen. Preoperative investigation of soluble interleukin-2 receptor was not done. On the day of admission, the patient complained of severe lower abdominal pain. He had rebound tenderness with muscular defense. There was no fever, and laboratory tests showed non-elevated values for C-reactive protein (0.16 mg/L) and white blood cell count (7700/μL). Abdominal X-ray showed colon distension. Computed tomography (CT) of the abdomen and pelvis revealed intraperitoneal free air and an abnormal colon distension (Fig. 2a). The pelvic CT scan also suggested a perforation of the rectum but did not clearly reveal the presence of the lymphoma (Fig. 2b). These results indicated that the patient had a perforation rectal ulcer secondary to active UC. A subtotal colectomy with end ileostomy was performed. During the surgery, a fistula was discovered at the rectosigmoid region (Fig. 3). Pathological examination of the resected rectum revealed atypical lymphocyte infiltration in all of the layers of the rectal wall. Inflammation of the rectal mucosa in the non-perforated part was mild and evaluated as grades 1–2 according to Matt’s histological classification. There was no inflammation of the colonic mucosa (Fig. 4). Immunohistochemical staining was positive for the following: cluster of differentiation 20 (CD 20) markers, cluster of differentiation 10 (CD 10) markers, B-cell lymphoma 6 (BCL-6) proteins and multiple myeloma oncogene 1 (MUM-1)-stained atypical lymphocytes (Fig. 5). From these results, the pathological findings revealed that rectal perforation was related to DLBCL with UC. The stained specimen on immunohistochemistry was also positive for EBV (Fig. 6).Fig. 1 Endoscopy examination. The deep ulcer was detected and diagnosed grade 3 according to the Mayo endoscopic subscore
Fig. 2 Preoperative CT findings. Abdominal CT scan showing intraperitoneal free air and colon distension, suspicious of gastrointestinal perforation (a). Pelvic CT scan showing the perforation site in the rectum but does not clearly reveal the presence of the lymphoma (b)
Fig. 3 Resected rectosigmoid colon specimen. The perforation site is visible on the resected rectosigmoid colon. The mucosa is mostly normal except for the perforation site
Fig. 4 H&E stained slide from the perforation site. Pathological examination of the resected specimen showing atypical lymphocytes infiltration in all the layers of the rectal wall (× 40)
Fig. 5 Immunohistochemical examinations from the perforation site. Atypical lymphocytes are CD 20 positive (a), CD 10 positive (b), BCL-6 positive (c), and MUM-1 positive (d), (× 200)
Fig. 6 Tumor cells are positive for EBV on in situ hybridization, suggesting that tumor cells are infected with EBV (× 200)
A postoperative fluorodeoxyglucose-positron emission tomography revealed an abnormal uptake in the postero-inferior area of the liver surface (S 7) and in the residual rectum margin. The standardized uptake value max (SUV max) of the liver region was 7.2, and the SUV max of the residual rectum was 11.1. Consequently, the patient was evaluated as having stage IV lymphoma according to the Lugano classification [14] and was treated with R-CHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) 2 months after the surgery. Six courses of chemotherapy were effective in correcting the abnormal uptake in the liver region without any complications. However, the abnormal uptake in the residual rectal wall slightly persisted after the six courses (SUV max = 3.6). Ileal pouch-anal anastomosis was performed 9 months after the primary surgery, and a histopathological examination of the residual rectum was done. There was no evidence of residual tumor, especially in the remnant rectal margin. The diverted ileostomy was closed, and he was disease-free. No recurrence was noted upon re-evaluation two years after his first surgery.
Discussion and conclusions
The incidence of perforation in UC patients is rare because the inflammation in UC is usually limited to the submucosa. Patients usually take high doses of steroids or immunosuppressive drugs for the treatment in the active phase UC. CMV infection counteracts the use of immunosuppressive drugs and favors the development of toxic megacolon, which is a major cause of perforation in UC. The incidence rate of perforation in UC is reported to be around 3% [1].
However, the incidence rate of perforations in gastrointestinal lymphoma is approximately 9–22% and is higher than that in high-grade lymphoma (i.e., DLBCL) [2–4]. Primary gastrointestinal lymphoma may decrease the mechanical strength of the gastrointestinal wall and cause intestinal perforation [3, 15]. Some studies have found that perforation is a poor prognostic factor in patients with high-grade lymphomas like DLBCL [2–4, 16]. Vaidya reported that nearly half of the perforation events in gastrointestinal lymphoma occur at the time of diagnosis of gastrointestinal lymphoma suggesting that these perforations could not be avoided by prior interventions [3].Thus, it may be important to diagnose gastrointestinal lymphoma before it gets perforated, especially in UC patients.
The risk of gastrointestinal lymphoma is not higher in UC patients than in the general population [7]. Several previous studies have found that UC patients receiving thiopurines exhibit markedly increased relative risk of gastrointestinal lymphoma [9, 10]. Kandiel et al. reported an approximate fourfold increased risk of lymphoma in IBD patients treated with azathioprine [9]. Moreover, more than 90% of UC patients with gastrointestinal lymphoma receiving thiopurines complained of EBV infections [11]. Immunosuppressive therapy induces EBV infection and EBV-positive lymphomas (i.e., DLBCL). However, some studies have reported cases where DLBCL occurred in UC patients who were not administered immunosuppressive drugs [12, 13]. These cases suggest that DLBCL may occur regardless of whether immunosuppressive drugs are used or not.
In this case study, abnormal colon distension due to progression of the UC led to perforation of the DLBCL-induced ulcer. Immunosuppressive drugs were not administered, while steroids were administered only 5 days prior to the perforation. The incidence rate of perforation in patients with UC is low. However, whether the prevalence of gastrointestinal lymphoma in UC patients is high or not is still unclear, but the incidence rate of perforations in gastrointestinal lymphoma is relatively high. DLBCL may increase the frequency of perforation and is a poor prognostic risk factor for patients with UC. In this case, we performed two preoperative endoscopic biopsies of the ulcer, but we neither obtained a DLBCL-positive nor a CMV-infected specimen. DLBCL often causes ulcerations. Therefore, it is important to distinguish between a DLBCL ulcer and a UC ulcer by performing an endoscopic biopsy for choosing appropriate treatment for the ulcer. Hence, when a therapy-resistant colonic ulcer is detected in UC, biopsies from multiple points of the ulcer should be performed to confirm the presence of DLBCL to prevent perforation. In conclusion, gastrointestinal lymphomas such as DLBCL are rare in patients with UC, and bowel perforations induced by DLBCL ulcers in such patients are extremely rare. This case report emphasizes the importance of careful medical surveillance and repeated endoscopic biopsies in patients with UC.
Abbreviations
5-ASA5-Aminosalicylic acid
CMVCytomegalovirus
DLBLCLDiffuse large B-cell lymphoma
EBVEpstein–Barr virus
IBDInflammatory bowel disease
MUMMultiple myeloma oncogene
TNFTumor necrosis factor
UCUlcerative colitis
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We would like to thank Editage (www.editage.com) for English language editing.
Authors’ contributions
ST conceptualized and wrote the original draft. SY, TM, FM, and YK treated the subject and revised the manuscript critically. IK and NR wrote, reviewed, and edited the work. All the authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
Not applicable.
Ethical approval and consent to participate
The Institutional Review Board of Coloproctology Center Takano Hospital Ethics Committee approved to the present case report.
Consent for publication
Written informed consent for publication has been obtained from the patient. The consent can be provided on request.
Competing interests
The authors have no conflicts of interest to declare. | Rectal | DrugAdministrationRoute | CC BY | 33478454 | 18,941,161 | 2021-01-21 |
What was the dosage of drug 'MESALAMINE'? | Diffuse large B-cell lymphoma originating from the rectum and diagnosed after rectal perforation during the treatment of ulcerative colitis: a case report.
BACKGROUND
Gastrointestinal lymphomas like diffuse large B-cell lymphoma (DLBCL) are rare complications of ulcerative colitis (UC), and only a few studies have reported intestinal ulcers caused by DLBCL, which got perforated during the treatment of UC.
METHODS
A 43-year-old man with severe lower abdominal pain and an 8-year history of UC was admitted in our hospital. He was diagnosed UC since 8 years and received a maintenance oral dose of 5-aminosalicylic acid, and no other immunosuppressive drugs. A deep rectal ulcer was endoscopically diagnosed 10 months before admission, no malignancy or cytomegalovirus infection was detected on biopsy. After 7 months a further endoscopy with biopsies confirmed the finding and the absence of malignancy. Three months later the patient developed sudden abdominal pain and was admitted in our hospital. Rectal perforation was suspected on X-ray and computed tomography imaging, and an emergency surgery was performed. Surgical exploration revealed a perforation on the anterior wall of the rectum. A subtotal colectomy with temporary ileostomy was performed. Pathology examinations showed lymphocyte infiltration of all of the layers of the perforated site and an immunohistochemical evaluation revealed DLBCL. Clinical staging was stage IV, and the patient received a 6-months regimen of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy. Positron emission tomography restaging revealed disappearance of distant uptake and a slight uptake in the residual rectum, and completion proctectomy with ileal pouch-anal anastomosis was performed. No residual tumor in the specimen was found, and the patient was disease-free at 2 years follow-up.
CONCLUSIONS
DLBCL may increase the frequency of perforation and is a poor prognostic risk factor for patients with UC. This case study emphasizes the importance of careful medical surveillance and repeated endoscopic biopsies during the treatment of UC.
Background
Intestinal perforations are rare in patients with ulcerative colitis (UC) since the inflammation is usually limited to the submucosal layer. The incidence of perforation in UC is reported to be approximately 3% [1]. On the other hand, the incidence rate of perforations in gastrointestinal lymphoma is relatively high [2–4]. Therefore, gastrointestinal lymphomas can increase the risk of perforation in patients with UC.
Colon cancer is a common complication of UC, but inflammatory bowel disease (IBD), on its own, is not recognized as a risk factor for gastrointestinal lymphoma [5–8]. Previous studies have shown that long-term immunosuppressive drugs and tumor necrosis factor (TNF) inhibitor therapy in patients with UC induce gastrointestinal lymphoma [9, 10]. It has been suggested that long-term therapy with immunosuppressive drugs and TNF inhibitor cause immunosuppression and increase the incidence of Epstein-Barr virus (EBV)—positive lymphomas (i.e., diffuse large B-cell lymphoma (DLBCL)) [11]. However, other studies have reported cases of DLBCL in UC patients not treated with immunosuppressive drugs and TNF inhibitors [12, 13].
Here, we report a case of rectal DLBCL that got perforated while the patient was being treated with 5-aminosalicylic acid (5-ASA) and prednisolone for UC.
Case presentation
A 43-year-old man with severe lower abdominal pain was admitted to our hospital our hospital for medical treatment. He had an 8-year history of ulcerative proctitis, a form of UC. When the diagnosis of UC was made, he was administered a maintenance oral dose of 5-ASA, and no other immunosuppressive drugs (i.e., azathioprine and TNF inhibitors) were prescribed. Ten months before the onset of the sudden abdominal pain, a deep rectal ulcer was detected on endoscopy. An endoscopic examination revealed a grade 3 ulcer according to the Mayo endoscopic subscore (Fig. 1). Inflammation of the mucosa near the ulcer was slight and diagnosed as grade 1. On biopsy performed at the same time, there was no malignancy or cytomegalovirus (CMV) infection. The posology of 5-ASA was increased; he began taking a daily suppository of 5-ASA and Budesonide. Three months before the onset of the sudden abdominal pain, another endoscopic biopsy from the ulcer and pathological analysis were performed. Similar to the last time, the ulcer was diagnosed as grade 3, and there was no malignancy. Five days prior to the onset of the sudden abdominal pain, a daily dose of 40 mg of oral prednisolone was prescribed for the ulcer, as we clinically diagnosed that it did not respond to 5-ASA and Budesonide. Laboratory investigations revealed a slightly elevated C-reactive protein level, an elevated white blood cell count, no increase in tumor markers (carcinoembryonic antigen = 0.4 ng/mL, carbohydrate antigen 19–9 = 8.1 U/mL, carbohydrate antigen 125 = 14.4 U/mL), and CMV C 7-antigen. Preoperative investigation of soluble interleukin-2 receptor was not done. On the day of admission, the patient complained of severe lower abdominal pain. He had rebound tenderness with muscular defense. There was no fever, and laboratory tests showed non-elevated values for C-reactive protein (0.16 mg/L) and white blood cell count (7700/μL). Abdominal X-ray showed colon distension. Computed tomography (CT) of the abdomen and pelvis revealed intraperitoneal free air and an abnormal colon distension (Fig. 2a). The pelvic CT scan also suggested a perforation of the rectum but did not clearly reveal the presence of the lymphoma (Fig. 2b). These results indicated that the patient had a perforation rectal ulcer secondary to active UC. A subtotal colectomy with end ileostomy was performed. During the surgery, a fistula was discovered at the rectosigmoid region (Fig. 3). Pathological examination of the resected rectum revealed atypical lymphocyte infiltration in all of the layers of the rectal wall. Inflammation of the rectal mucosa in the non-perforated part was mild and evaluated as grades 1–2 according to Matt’s histological classification. There was no inflammation of the colonic mucosa (Fig. 4). Immunohistochemical staining was positive for the following: cluster of differentiation 20 (CD 20) markers, cluster of differentiation 10 (CD 10) markers, B-cell lymphoma 6 (BCL-6) proteins and multiple myeloma oncogene 1 (MUM-1)-stained atypical lymphocytes (Fig. 5). From these results, the pathological findings revealed that rectal perforation was related to DLBCL with UC. The stained specimen on immunohistochemistry was also positive for EBV (Fig. 6).Fig. 1 Endoscopy examination. The deep ulcer was detected and diagnosed grade 3 according to the Mayo endoscopic subscore
Fig. 2 Preoperative CT findings. Abdominal CT scan showing intraperitoneal free air and colon distension, suspicious of gastrointestinal perforation (a). Pelvic CT scan showing the perforation site in the rectum but does not clearly reveal the presence of the lymphoma (b)
Fig. 3 Resected rectosigmoid colon specimen. The perforation site is visible on the resected rectosigmoid colon. The mucosa is mostly normal except for the perforation site
Fig. 4 H&E stained slide from the perforation site. Pathological examination of the resected specimen showing atypical lymphocytes infiltration in all the layers of the rectal wall (× 40)
Fig. 5 Immunohistochemical examinations from the perforation site. Atypical lymphocytes are CD 20 positive (a), CD 10 positive (b), BCL-6 positive (c), and MUM-1 positive (d), (× 200)
Fig. 6 Tumor cells are positive for EBV on in situ hybridization, suggesting that tumor cells are infected with EBV (× 200)
A postoperative fluorodeoxyglucose-positron emission tomography revealed an abnormal uptake in the postero-inferior area of the liver surface (S 7) and in the residual rectum margin. The standardized uptake value max (SUV max) of the liver region was 7.2, and the SUV max of the residual rectum was 11.1. Consequently, the patient was evaluated as having stage IV lymphoma according to the Lugano classification [14] and was treated with R-CHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) 2 months after the surgery. Six courses of chemotherapy were effective in correcting the abnormal uptake in the liver region without any complications. However, the abnormal uptake in the residual rectal wall slightly persisted after the six courses (SUV max = 3.6). Ileal pouch-anal anastomosis was performed 9 months after the primary surgery, and a histopathological examination of the residual rectum was done. There was no evidence of residual tumor, especially in the remnant rectal margin. The diverted ileostomy was closed, and he was disease-free. No recurrence was noted upon re-evaluation two years after his first surgery.
Discussion and conclusions
The incidence of perforation in UC patients is rare because the inflammation in UC is usually limited to the submucosa. Patients usually take high doses of steroids or immunosuppressive drugs for the treatment in the active phase UC. CMV infection counteracts the use of immunosuppressive drugs and favors the development of toxic megacolon, which is a major cause of perforation in UC. The incidence rate of perforation in UC is reported to be around 3% [1].
However, the incidence rate of perforations in gastrointestinal lymphoma is approximately 9–22% and is higher than that in high-grade lymphoma (i.e., DLBCL) [2–4]. Primary gastrointestinal lymphoma may decrease the mechanical strength of the gastrointestinal wall and cause intestinal perforation [3, 15]. Some studies have found that perforation is a poor prognostic factor in patients with high-grade lymphomas like DLBCL [2–4, 16]. Vaidya reported that nearly half of the perforation events in gastrointestinal lymphoma occur at the time of diagnosis of gastrointestinal lymphoma suggesting that these perforations could not be avoided by prior interventions [3].Thus, it may be important to diagnose gastrointestinal lymphoma before it gets perforated, especially in UC patients.
The risk of gastrointestinal lymphoma is not higher in UC patients than in the general population [7]. Several previous studies have found that UC patients receiving thiopurines exhibit markedly increased relative risk of gastrointestinal lymphoma [9, 10]. Kandiel et al. reported an approximate fourfold increased risk of lymphoma in IBD patients treated with azathioprine [9]. Moreover, more than 90% of UC patients with gastrointestinal lymphoma receiving thiopurines complained of EBV infections [11]. Immunosuppressive therapy induces EBV infection and EBV-positive lymphomas (i.e., DLBCL). However, some studies have reported cases where DLBCL occurred in UC patients who were not administered immunosuppressive drugs [12, 13]. These cases suggest that DLBCL may occur regardless of whether immunosuppressive drugs are used or not.
In this case study, abnormal colon distension due to progression of the UC led to perforation of the DLBCL-induced ulcer. Immunosuppressive drugs were not administered, while steroids were administered only 5 days prior to the perforation. The incidence rate of perforation in patients with UC is low. However, whether the prevalence of gastrointestinal lymphoma in UC patients is high or not is still unclear, but the incidence rate of perforations in gastrointestinal lymphoma is relatively high. DLBCL may increase the frequency of perforation and is a poor prognostic risk factor for patients with UC. In this case, we performed two preoperative endoscopic biopsies of the ulcer, but we neither obtained a DLBCL-positive nor a CMV-infected specimen. DLBCL often causes ulcerations. Therefore, it is important to distinguish between a DLBCL ulcer and a UC ulcer by performing an endoscopic biopsy for choosing appropriate treatment for the ulcer. Hence, when a therapy-resistant colonic ulcer is detected in UC, biopsies from multiple points of the ulcer should be performed to confirm the presence of DLBCL to prevent perforation. In conclusion, gastrointestinal lymphomas such as DLBCL are rare in patients with UC, and bowel perforations induced by DLBCL ulcers in such patients are extremely rare. This case report emphasizes the importance of careful medical surveillance and repeated endoscopic biopsies in patients with UC.
Abbreviations
5-ASA5-Aminosalicylic acid
CMVCytomegalovirus
DLBLCLDiffuse large B-cell lymphoma
EBVEpstein–Barr virus
IBDInflammatory bowel disease
MUMMultiple myeloma oncogene
TNFTumor necrosis factor
UCUlcerative colitis
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Acknowledgements
We would like to thank Editage (www.editage.com) for English language editing.
Authors’ contributions
ST conceptualized and wrote the original draft. SY, TM, FM, and YK treated the subject and revised the manuscript critically. IK and NR wrote, reviewed, and edited the work. All the authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
Not applicable.
Ethical approval and consent to participate
The Institutional Review Board of Coloproctology Center Takano Hospital Ethics Committee approved to the present case report.
Consent for publication
Written informed consent for publication has been obtained from the patient. The consent can be provided on request.
Competing interests
The authors have no conflicts of interest to declare. | MAINTENANCE THERAPY | DrugDosageText | CC BY | 33478454 | 18,941,161 | 2021-01-21 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug hypersensitivity'. | A 64-Year-Old Man with Low Back Pain Due to Clostridium perfringens Lumbar Discitis.
BACKGROUND Lumbar discitis caused by Clostridium perfringens is extremely rare. There have only been 7 published cases of confirmed discitis caused by Clostridium perfringens. We write this report to underscore this unusual relationship by discussing an additional case and providing a review of the previously published cases so clinicians can adequately evaluate and treat patients presenting with discitis. CASE REPORT A 64-year-old morbidly obese man presented with an acute onset of worsening back pain and generalized weakness after incurring physical trauma related to falling. Additionally, he also developed fever and chills before the presentation. Based on the clinical presentation and elevated serum levels of inflammatory markers, magnetic resonance imaging was ordered, which showed L5-S1 discitis with extension of infection into the epidural space. Fluoroscopy-guided aspiration of the L5-S1 epidural space facilitated the detection of Clostridium perfringens as the involved pathogen. Based on the antibiotic susceptibility report, the patient was treated with intravenous ampicillin for 8 weeks, after which his symptoms resolved. CONCLUSIONS Diagnosis of discitis can be very challenging due to its ambiguous clinical presentation, especially in the elderly population due to the presence of underlying degenerative changes. Even though Clostridium perfringens remains a rare cause of lumbar discitis, it should be considered as a pathogen capable of causing infection of the vertebrae and intervertebral discs, thus allowing clinicians to make necessary diagnostic evaluations to provide appropriate targeted treatment to patients presenting with discitis.
Background
Clostridium perfringens is a spore-forming, anaerobic, gram-positive bacillus that is part of the normal intestinal flora. It can cause gas gangrene, cellulitis, and gastroenteritis. Anaerobic causes of discitis involving Clostridium perfringens bacteria are rarely seen. There are only 7 confirmed cases of discitis caused by C. perfringens published to date [1–7]. We report an unusual case of a 67-year-old man who presented with an acute onset of fever and worsening back pain and was discovered to have infectious L5–S1 discitis caused by C. perfringens. Along with our case report, we also provide a literature review with a comparison of the published cases of discitis caused by C. perfringens for a better understanding of this rare presentation.
Case Report
A 67-year-old man presented to the Emergency Department (ED) with complaints of generalized weakness for 4 days. He had repeatedly fallen at home 3 days prior to the arrival in the ED and he had a dull lower-back pain since then. The pain was controlled for a couple of days, but prior to his presentation to the ED, he noted that his pain was worsening. In addition, he noted generalized weakness without any lower-extremity weakness. He developed fever and chills at home but did not take his temperature. He did not report any productive cough, dysuria, hematuria, bowel/bladder incontinence, nausea, vomiting, diarrhea, headache, abdominal pain, or leg swelling. Hiss past medical history was significant for hypothyroidism, diabetes mellitus type 2, morbid obesity (weight 140 kg), and gout. His medication list included levothyroxine, metformin, and allopurinol. His surgical history included bilateral rotator cuff surgeries, right hammertoes, bilateral cataracts status after extraction, and colonoscopy. Family history was significant for hypertension in his father. He had never smoked cigarettes and denied alcohol use or use of illicit substances. He was allergic to ciprofloxacin (reaction unknown).
On examination, the patient had mild tachypnea and was mildly febrile. His vital signs examination revealed blood pressure of 126/76 mmHg, heart rate of 104 beats per minute, temperature of 39°C (102.3°F), respiratory rate of 18 breaths per minute, and oxygen saturation of 94% on nasal cannula at 2 liters. His mucus membranes were slightly dry. There were no crackles or rhonchi on respiratory examination. He did not have any hepatosplenomegaly or abdominal tenderness on examination. An examination of his back revealed mild tenderness on palpation of the lumbosacral spine. He did not have tenderness on palpation of cervical or thoracic spines. He had no palpable paraspinal muscle spasm. Neurologically, sensation was intact to light touch in all lower extremities, but subjectively decreased in the feet. He had 5/5 strength in his bilateral extensor hallucis longus, peroneals, gastroc soleus complex, hamstrings, quadriceps, and iliopsoas. He had no pain with range of motion of the hips. He had negative straight leg raise bilaterally. He had bilateral down-going toes with Babinski testing. He had a slow, steady gait. He was alert, awake, and oriented to time, place, and person. A skin exam showed no lesions or rash. Results of the systemic examination were within normal limits otherwise.
Laboratory studies on presentation showed leukocytosis (17.2 k/uL) with bands (17%), mild thrombocytopenia (158 k/uL), hyperglycemia (235 mg/dL), lactic acidosis (3.5 mmol/L), elevated D-dimer (635 ng/ml), elevated ESR (erythrocyte sedimentation rate – 50 mm/h), elevated CRP (C-reactive protein – 194 mg/L), and normal renal function (Table 1). Urine analysis did not suggest urinary tract infection. A chest X-ray did not show any abnormal findings. A computed tomography (CT) angiogram of the chest was done to rule out pulmonary embolism and it did not show any signs of pulmonary embolism or pneumonia, but showed bibasilar atelectasis. A lumbar spine X-ray showed lumbar spondylosis but no evidence of fracture.
Due to back pain and elevated inflammatory markers, a magnetic resonance imaging (MRI) of the lumbosacral spine with and without contrast was obtained. It showed abnormal thin enhancement within the L5–S1 disc contiguous with infiltrative enhancement in the epidural space of the lumbosacral junction, concerning for discitis with extension of infection into the epidural space. No large focal fluid collection was identified to suggest a drainable abscess formation. Degenerative disc disease was present (Figure 1). Blood cultures were obtained as well. He was started on IV ceftriaxone 2 g and IV vancomycin empirically based on the MRI findings.
The patient also underwent fluoroscopy-guided L5–S1 aspiration of the epidural space, and 2 mL of brown blood-tinged fluid was removed and sent for culture. The procedure was performed after starting the empiric antibiotics. An initial gram stain was negative. Meanwhile, the patient was continued on antibiotic and other supportive care. His back pain improved, and his fever also resolved. White cell counts gradually improved. Inflammatory markers also improved (Table 1). He slowly started working with physical therapy.
After 4 days, his spinal fluid cultures grew light growth of slow-growing anaerobic Clostridium perfringens (identified by a Microscan rapid anerobic panel using biochemical properties). Based on the sensitivity report (Table 2), antibiotics were switched to IV ampicillin. His blood cultures showed no growth. Due to the identification of C. perfringens, we did a CT scan of the abdomen and pelvis with contrast to look for gastrointestinal causes, and it showed mild sigmoid diverticulosis but no masses, bowel thickening, or inflammation. On day 7, he underwent colonoscopy and had 3 sessile polyps of 3–5 mm removed from the transverse colon and the descending colon (Figure 2). A biopsy of these polyps identified them to be tubular adenomas. On recommendation of the infectious disease specialist and back surgeon, on the 8th day of the hospitalization, the patient was discharged to a skilled nursing facility for IV ampicillin therapy for 8 weeks, which resulted in clinical improvement.
Discussion
Clostridium perfringens is a spore-forming, anaerobic, gram-positive bacillus that is part of the normal intestinal flora of humans and animals [1]. According to the Centers for Disease Control and Prevention (CDC), C. perfringens is a leading cause of food-borne illness in the United States, causing nearly 1 million cases every year [8]. Ingesting a significant amount of this bacteria can generate sufficient toxin to cause illness, leading to an imbalance in the normal intestinal flora, which is a common pathological mechanism behind its foodborne illness presentation. However, endogenous organisms can also lead to endogenous infections in general when normal bacterial flora disseminate to a sterile part of the human body. This can occur when there is a break in the natural barrier between sterile and nonsterile environments of the body. C. perfringens is no exception to this method of pathogenesis. Gas gangrene, cellulitis, and gastroenteritis are common manifestations of its endogenous infections. However, C. perfringens causing discitis is a very rare phenomenon.
Only 7 confirmed cases of C. perfringens discitis have been published [1–7]. We present an additional case in this report, underscoring its potential to cause infection of the vertebrae and inter-vertebral discs. The main features of 6 of these published cases are outlined in Table 3. One commonality present among all the published cases is patient presentation with low back pain, whether acute or chronic, accompanied with elevated ESR and CRP levels.
Among the 7 reported cases, 2 had diverticular disease as a potential risk factor, and hematogenous dissemination of C. perfringens from gastrointestinal tract to the lumbar spine was postulated as the probable cause of their discitis [2,4]. Yang et al. carried out a retrospective cohort study showing that the intraabdominal (52.7%) and lower respiratory tract (19.4%) were the leading sources of C. perfringens bacteremia [9]. The present case was an elderly patient without any significant immunocompromise and no concomitant infections. Diverticulosis was also discovered in this patient, with diagnostic workup completed after identification of C. perfringens on L5–S1 aspiration. Additionally, the 3 polyps removed were identified to be tubular adenomas, for which the patient was recommended to follow up with a gastroenterologist after discharge.
We postulate that our patient’s discitis likely originated from the gastrointestinal tract after infiltrating the vascular submucosal tissue, which led to its dissemination to the lumbar intervertebral disc area.
Our patient was on empiric IV ceftriaxone and IV vancomycin for 4 days until identification of C. perfringens, and the antibiotic regimen was then switched to targeted IV ampicillin. It is important to note, however, that antibiotic treatment was empirically started prior to the use of fine-needle biopsy to identify the involved pathogen. Additionally, there exists a small possibility of site contamination resulting from the process of needle biopsy itself, but this is very unlikely due to the sterile technique and substantial measures taken during the procedure to minimize the chances of contamination. It is possible that the initial broad empiric antibiotic treatment the patient received could have lowered the presence of C. perfringens at the site of infection, but IV ampicillin alone should be used in patients presenting with discitis due to C. perfringens [10]. A randomized controlled trial carried out by Bernard et al. provides evidence for continuing antibiotic treatment for 6 weeks for treating intervertebral osteomyelitis. This trial suggested that reduction of antibiotic treatment duration from 12 weeks to 6 weeks is not substandard when compared to 12 weeks [10]. Nonetheless, our patient continued to receive outpatient IV ampicillin therapy for 8 weeks, which resulted in resolution of the symptoms.
Additionally, while the presented case shares some similarities with the previously reported cases, it does contain several differences. For example, the time between onset of symptoms and adequate diagnosis was several weeks to months in the previous cases. Our case resulted in an adequate diagnosis in only 4 days. This shows the need for prompt diagnosis allowing for the use of targeted antibiotic therapy early in the course of the disease to improve morbidity. Not all previously reported cases identified gas in the lesions. Beguiristain’s and Yong’s case reports did not report lesions with gas. We believe that in our case the time between the onset and diagnosis was the key, and the diagnosis was made rather quickly before gas could form within the lesions.
Conclusions
Although C. perfringens is a rare cause of discitis, it should be considered as a pathogen capable of causing infection of the vertebrae and intervertebral discs. Only 7 confirmed cases have been previously published. Patients often present with complaints of back pain and may or may not have associated fever. Diagnosis of discitis can be very challenging because of vague clinical presentation, especially in the elderly due to pre-existing back pain related to degenerative changes of the spine. Laboratory workup can be significant for elevated ESR and CRP levels. MRI of the spine is the best imaging method, followed by the image-guided aspiration and culture. CT of the abdomen/pelvis along with colonoscopy should also be performed to identify any risk factors and/or potential portals of entry. Treatment with IV ampicillin for 6 weeks appears to be the appropriate treatment. Through comparison of our case with previously published cases, we highlight the importance of thorough evaluation and prompt initiation of diagnostic measures in patients with back pain and discitis in order to start the necessary antibiotic therapy and limit the morbidity and mortality.
Conflict of interests
None.
Abbreviations
C. perfringensClostridium perfringens
EREmergency Room;
ESRerythrocyte sedimentationrate;
CDCCenters for Disease Control and Prevention;
CTcomputed tomography;
IVintravenous;
MRImagnetic resonance imaging
Figure 1. MRI of lower lumbar spine demonstrating abnormal enhancement within the L5–S1 disc, consistent with discitis (blue arrow).
Figure 2. CT of abdomen and pelvis shows air-filled diverticula (yellow arrow) of the sigmoid colon.
Table 1. Laboratory data.
Laboratory test Reference range Day 1 Day 8 (discharge day)
White blood cell count 3.9–10.5 k/uL 17.2 k/uL 6.3 k/uL
Red blood cell count 4.33–5.73 M/uL 4.9 M/uL 4.5 M/uL
Hemoglobin 13.6–17.0 gm/dl 14.3 gm/dl 13.8 gm/dl
Hematocrit 40.0–54.0% 43.6% 40.6%
Platelet count 150–450 k/uL 158 k/uL 185 k/uL
Prothrombin 10.68–13.72 seconds 13.1 seconds 13.2 seconds
INR 1.1 1.1
D-dimer 0–253.5 ng/ml 635 ng/ml –
Sodium 135–145 mmol/L 135 mmol/L 137 mmol/L
Potassium 3.4–5.1 mmol/L 4.5 mmol/L 4.3 mmol/L
Chloride 98–107 mmol/L 103 mmol/L 102 mmol/L
Carbon dioxide 22–30 mmol/L 21 mmol/L 26 mmol/L
Blood urea nitrogen 7–17 mg/dL 10 mg/dL 12 mg/dL
Creatinine 0.7–1.2 mg/dL 0.7 mg/dL 0.8 mg/dL
Glucose 60–110 mg/dL 235 mg/dL 120 mg/dL
Lactic acid 0.7–1.9 mmol/L 3.5 mmol/L –
C-reactive protein 0.0–9.9 mg/L 194 mg/L 62 mg/L
ESR 0–25 mm/hr 50 mm/hr 19 mm/hr
Table 2. Antimicrobial susceptibilities of C. perfringens.
Antibiotic MIC (μg/ml) Interpretation
Amoxicillin/Clavulanate ≤0.5 S
Ampicillin ≤0.5 S
Ampicillin/Sulbactam ≤0.5 S
Cefotetan ≤4 S
Cefoxitin ≤1 S
Chloramphenicol 4 S
Clindamycin 1 S
Meropenem ≤0.5 S
Metronidazole 16 I
Penicillin ≤0.06 S
Tetracycline 1 S
Piperacillin/Tazobactam 0.5 S
S – sensitive; I – intermediate; R – resistant; MIC – minimum inhibitory concentration; Drug susceptibility testing as per Clinical and Laboratory Standards. Institute guidelines (CLSI M11).
Table 3. Main features of published Clostridium perfringens discitis cases.
Authors Sex Age (years) Disc level Risk factors Presentation Blood culture Needle biopsy
Lotte et al. [1] F 83 L4/L5 Nil gastrointestinal pathology on CT Chronic lumbar back pain over 6 months Negative Positive
Caudron et al. [2] F 79 L4/L5 Colonic diverticulosis Low back pain over 2 months Negative Positive
Bednar [3] M 68 L4/L5 Laminotomy, discotomy Acute back pain over 6 weeks Positive Positive
Pate and Katz [4] F 62 L3/L4 Diverticular disease Low back pain over 6 weeks Positive Negative after 3 days of antibiotics
Beguiristain et al. [5] M 33 L1/L2 No obvious risk factors Low back pain over 7 days Not completed Positive
Seller et al. [6] M 64 L5 No obvious risk factors Low back pain, urinary retention, and an inability to walk Positive Unknown
Yong and Lam [7] M 80 T10/T11 C. perfringens bacteremia Back pain over 5 weeks Positive Negative | ALLOPURINOL, CIPROFLOXACIN, LEVOTHYROXINE, METFORMIN HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33479190 | 18,868,938 | 2021-01-22 |
What is the weight of the patient? | A 64-Year-Old Man with Low Back Pain Due to Clostridium perfringens Lumbar Discitis.
BACKGROUND Lumbar discitis caused by Clostridium perfringens is extremely rare. There have only been 7 published cases of confirmed discitis caused by Clostridium perfringens. We write this report to underscore this unusual relationship by discussing an additional case and providing a review of the previously published cases so clinicians can adequately evaluate and treat patients presenting with discitis. CASE REPORT A 64-year-old morbidly obese man presented with an acute onset of worsening back pain and generalized weakness after incurring physical trauma related to falling. Additionally, he also developed fever and chills before the presentation. Based on the clinical presentation and elevated serum levels of inflammatory markers, magnetic resonance imaging was ordered, which showed L5-S1 discitis with extension of infection into the epidural space. Fluoroscopy-guided aspiration of the L5-S1 epidural space facilitated the detection of Clostridium perfringens as the involved pathogen. Based on the antibiotic susceptibility report, the patient was treated with intravenous ampicillin for 8 weeks, after which his symptoms resolved. CONCLUSIONS Diagnosis of discitis can be very challenging due to its ambiguous clinical presentation, especially in the elderly population due to the presence of underlying degenerative changes. Even though Clostridium perfringens remains a rare cause of lumbar discitis, it should be considered as a pathogen capable of causing infection of the vertebrae and intervertebral discs, thus allowing clinicians to make necessary diagnostic evaluations to provide appropriate targeted treatment to patients presenting with discitis.
Background
Clostridium perfringens is a spore-forming, anaerobic, gram-positive bacillus that is part of the normal intestinal flora. It can cause gas gangrene, cellulitis, and gastroenteritis. Anaerobic causes of discitis involving Clostridium perfringens bacteria are rarely seen. There are only 7 confirmed cases of discitis caused by C. perfringens published to date [1–7]. We report an unusual case of a 67-year-old man who presented with an acute onset of fever and worsening back pain and was discovered to have infectious L5–S1 discitis caused by C. perfringens. Along with our case report, we also provide a literature review with a comparison of the published cases of discitis caused by C. perfringens for a better understanding of this rare presentation.
Case Report
A 67-year-old man presented to the Emergency Department (ED) with complaints of generalized weakness for 4 days. He had repeatedly fallen at home 3 days prior to the arrival in the ED and he had a dull lower-back pain since then. The pain was controlled for a couple of days, but prior to his presentation to the ED, he noted that his pain was worsening. In addition, he noted generalized weakness without any lower-extremity weakness. He developed fever and chills at home but did not take his temperature. He did not report any productive cough, dysuria, hematuria, bowel/bladder incontinence, nausea, vomiting, diarrhea, headache, abdominal pain, or leg swelling. Hiss past medical history was significant for hypothyroidism, diabetes mellitus type 2, morbid obesity (weight 140 kg), and gout. His medication list included levothyroxine, metformin, and allopurinol. His surgical history included bilateral rotator cuff surgeries, right hammertoes, bilateral cataracts status after extraction, and colonoscopy. Family history was significant for hypertension in his father. He had never smoked cigarettes and denied alcohol use or use of illicit substances. He was allergic to ciprofloxacin (reaction unknown).
On examination, the patient had mild tachypnea and was mildly febrile. His vital signs examination revealed blood pressure of 126/76 mmHg, heart rate of 104 beats per minute, temperature of 39°C (102.3°F), respiratory rate of 18 breaths per minute, and oxygen saturation of 94% on nasal cannula at 2 liters. His mucus membranes were slightly dry. There were no crackles or rhonchi on respiratory examination. He did not have any hepatosplenomegaly or abdominal tenderness on examination. An examination of his back revealed mild tenderness on palpation of the lumbosacral spine. He did not have tenderness on palpation of cervical or thoracic spines. He had no palpable paraspinal muscle spasm. Neurologically, sensation was intact to light touch in all lower extremities, but subjectively decreased in the feet. He had 5/5 strength in his bilateral extensor hallucis longus, peroneals, gastroc soleus complex, hamstrings, quadriceps, and iliopsoas. He had no pain with range of motion of the hips. He had negative straight leg raise bilaterally. He had bilateral down-going toes with Babinski testing. He had a slow, steady gait. He was alert, awake, and oriented to time, place, and person. A skin exam showed no lesions or rash. Results of the systemic examination were within normal limits otherwise.
Laboratory studies on presentation showed leukocytosis (17.2 k/uL) with bands (17%), mild thrombocytopenia (158 k/uL), hyperglycemia (235 mg/dL), lactic acidosis (3.5 mmol/L), elevated D-dimer (635 ng/ml), elevated ESR (erythrocyte sedimentation rate – 50 mm/h), elevated CRP (C-reactive protein – 194 mg/L), and normal renal function (Table 1). Urine analysis did not suggest urinary tract infection. A chest X-ray did not show any abnormal findings. A computed tomography (CT) angiogram of the chest was done to rule out pulmonary embolism and it did not show any signs of pulmonary embolism or pneumonia, but showed bibasilar atelectasis. A lumbar spine X-ray showed lumbar spondylosis but no evidence of fracture.
Due to back pain and elevated inflammatory markers, a magnetic resonance imaging (MRI) of the lumbosacral spine with and without contrast was obtained. It showed abnormal thin enhancement within the L5–S1 disc contiguous with infiltrative enhancement in the epidural space of the lumbosacral junction, concerning for discitis with extension of infection into the epidural space. No large focal fluid collection was identified to suggest a drainable abscess formation. Degenerative disc disease was present (Figure 1). Blood cultures were obtained as well. He was started on IV ceftriaxone 2 g and IV vancomycin empirically based on the MRI findings.
The patient also underwent fluoroscopy-guided L5–S1 aspiration of the epidural space, and 2 mL of brown blood-tinged fluid was removed and sent for culture. The procedure was performed after starting the empiric antibiotics. An initial gram stain was negative. Meanwhile, the patient was continued on antibiotic and other supportive care. His back pain improved, and his fever also resolved. White cell counts gradually improved. Inflammatory markers also improved (Table 1). He slowly started working with physical therapy.
After 4 days, his spinal fluid cultures grew light growth of slow-growing anaerobic Clostridium perfringens (identified by a Microscan rapid anerobic panel using biochemical properties). Based on the sensitivity report (Table 2), antibiotics were switched to IV ampicillin. His blood cultures showed no growth. Due to the identification of C. perfringens, we did a CT scan of the abdomen and pelvis with contrast to look for gastrointestinal causes, and it showed mild sigmoid diverticulosis but no masses, bowel thickening, or inflammation. On day 7, he underwent colonoscopy and had 3 sessile polyps of 3–5 mm removed from the transverse colon and the descending colon (Figure 2). A biopsy of these polyps identified them to be tubular adenomas. On recommendation of the infectious disease specialist and back surgeon, on the 8th day of the hospitalization, the patient was discharged to a skilled nursing facility for IV ampicillin therapy for 8 weeks, which resulted in clinical improvement.
Discussion
Clostridium perfringens is a spore-forming, anaerobic, gram-positive bacillus that is part of the normal intestinal flora of humans and animals [1]. According to the Centers for Disease Control and Prevention (CDC), C. perfringens is a leading cause of food-borne illness in the United States, causing nearly 1 million cases every year [8]. Ingesting a significant amount of this bacteria can generate sufficient toxin to cause illness, leading to an imbalance in the normal intestinal flora, which is a common pathological mechanism behind its foodborne illness presentation. However, endogenous organisms can also lead to endogenous infections in general when normal bacterial flora disseminate to a sterile part of the human body. This can occur when there is a break in the natural barrier between sterile and nonsterile environments of the body. C. perfringens is no exception to this method of pathogenesis. Gas gangrene, cellulitis, and gastroenteritis are common manifestations of its endogenous infections. However, C. perfringens causing discitis is a very rare phenomenon.
Only 7 confirmed cases of C. perfringens discitis have been published [1–7]. We present an additional case in this report, underscoring its potential to cause infection of the vertebrae and inter-vertebral discs. The main features of 6 of these published cases are outlined in Table 3. One commonality present among all the published cases is patient presentation with low back pain, whether acute or chronic, accompanied with elevated ESR and CRP levels.
Among the 7 reported cases, 2 had diverticular disease as a potential risk factor, and hematogenous dissemination of C. perfringens from gastrointestinal tract to the lumbar spine was postulated as the probable cause of their discitis [2,4]. Yang et al. carried out a retrospective cohort study showing that the intraabdominal (52.7%) and lower respiratory tract (19.4%) were the leading sources of C. perfringens bacteremia [9]. The present case was an elderly patient without any significant immunocompromise and no concomitant infections. Diverticulosis was also discovered in this patient, with diagnostic workup completed after identification of C. perfringens on L5–S1 aspiration. Additionally, the 3 polyps removed were identified to be tubular adenomas, for which the patient was recommended to follow up with a gastroenterologist after discharge.
We postulate that our patient’s discitis likely originated from the gastrointestinal tract after infiltrating the vascular submucosal tissue, which led to its dissemination to the lumbar intervertebral disc area.
Our patient was on empiric IV ceftriaxone and IV vancomycin for 4 days until identification of C. perfringens, and the antibiotic regimen was then switched to targeted IV ampicillin. It is important to note, however, that antibiotic treatment was empirically started prior to the use of fine-needle biopsy to identify the involved pathogen. Additionally, there exists a small possibility of site contamination resulting from the process of needle biopsy itself, but this is very unlikely due to the sterile technique and substantial measures taken during the procedure to minimize the chances of contamination. It is possible that the initial broad empiric antibiotic treatment the patient received could have lowered the presence of C. perfringens at the site of infection, but IV ampicillin alone should be used in patients presenting with discitis due to C. perfringens [10]. A randomized controlled trial carried out by Bernard et al. provides evidence for continuing antibiotic treatment for 6 weeks for treating intervertebral osteomyelitis. This trial suggested that reduction of antibiotic treatment duration from 12 weeks to 6 weeks is not substandard when compared to 12 weeks [10]. Nonetheless, our patient continued to receive outpatient IV ampicillin therapy for 8 weeks, which resulted in resolution of the symptoms.
Additionally, while the presented case shares some similarities with the previously reported cases, it does contain several differences. For example, the time between onset of symptoms and adequate diagnosis was several weeks to months in the previous cases. Our case resulted in an adequate diagnosis in only 4 days. This shows the need for prompt diagnosis allowing for the use of targeted antibiotic therapy early in the course of the disease to improve morbidity. Not all previously reported cases identified gas in the lesions. Beguiristain’s and Yong’s case reports did not report lesions with gas. We believe that in our case the time between the onset and diagnosis was the key, and the diagnosis was made rather quickly before gas could form within the lesions.
Conclusions
Although C. perfringens is a rare cause of discitis, it should be considered as a pathogen capable of causing infection of the vertebrae and intervertebral discs. Only 7 confirmed cases have been previously published. Patients often present with complaints of back pain and may or may not have associated fever. Diagnosis of discitis can be very challenging because of vague clinical presentation, especially in the elderly due to pre-existing back pain related to degenerative changes of the spine. Laboratory workup can be significant for elevated ESR and CRP levels. MRI of the spine is the best imaging method, followed by the image-guided aspiration and culture. CT of the abdomen/pelvis along with colonoscopy should also be performed to identify any risk factors and/or potential portals of entry. Treatment with IV ampicillin for 6 weeks appears to be the appropriate treatment. Through comparison of our case with previously published cases, we highlight the importance of thorough evaluation and prompt initiation of diagnostic measures in patients with back pain and discitis in order to start the necessary antibiotic therapy and limit the morbidity and mortality.
Conflict of interests
None.
Abbreviations
C. perfringensClostridium perfringens
EREmergency Room;
ESRerythrocyte sedimentationrate;
CDCCenters for Disease Control and Prevention;
CTcomputed tomography;
IVintravenous;
MRImagnetic resonance imaging
Figure 1. MRI of lower lumbar spine demonstrating abnormal enhancement within the L5–S1 disc, consistent with discitis (blue arrow).
Figure 2. CT of abdomen and pelvis shows air-filled diverticula (yellow arrow) of the sigmoid colon.
Table 1. Laboratory data.
Laboratory test Reference range Day 1 Day 8 (discharge day)
White blood cell count 3.9–10.5 k/uL 17.2 k/uL 6.3 k/uL
Red blood cell count 4.33–5.73 M/uL 4.9 M/uL 4.5 M/uL
Hemoglobin 13.6–17.0 gm/dl 14.3 gm/dl 13.8 gm/dl
Hematocrit 40.0–54.0% 43.6% 40.6%
Platelet count 150–450 k/uL 158 k/uL 185 k/uL
Prothrombin 10.68–13.72 seconds 13.1 seconds 13.2 seconds
INR 1.1 1.1
D-dimer 0–253.5 ng/ml 635 ng/ml –
Sodium 135–145 mmol/L 135 mmol/L 137 mmol/L
Potassium 3.4–5.1 mmol/L 4.5 mmol/L 4.3 mmol/L
Chloride 98–107 mmol/L 103 mmol/L 102 mmol/L
Carbon dioxide 22–30 mmol/L 21 mmol/L 26 mmol/L
Blood urea nitrogen 7–17 mg/dL 10 mg/dL 12 mg/dL
Creatinine 0.7–1.2 mg/dL 0.7 mg/dL 0.8 mg/dL
Glucose 60–110 mg/dL 235 mg/dL 120 mg/dL
Lactic acid 0.7–1.9 mmol/L 3.5 mmol/L –
C-reactive protein 0.0–9.9 mg/L 194 mg/L 62 mg/L
ESR 0–25 mm/hr 50 mm/hr 19 mm/hr
Table 2. Antimicrobial susceptibilities of C. perfringens.
Antibiotic MIC (μg/ml) Interpretation
Amoxicillin/Clavulanate ≤0.5 S
Ampicillin ≤0.5 S
Ampicillin/Sulbactam ≤0.5 S
Cefotetan ≤4 S
Cefoxitin ≤1 S
Chloramphenicol 4 S
Clindamycin 1 S
Meropenem ≤0.5 S
Metronidazole 16 I
Penicillin ≤0.06 S
Tetracycline 1 S
Piperacillin/Tazobactam 0.5 S
S – sensitive; I – intermediate; R – resistant; MIC – minimum inhibitory concentration; Drug susceptibility testing as per Clinical and Laboratory Standards. Institute guidelines (CLSI M11).
Table 3. Main features of published Clostridium perfringens discitis cases.
Authors Sex Age (years) Disc level Risk factors Presentation Blood culture Needle biopsy
Lotte et al. [1] F 83 L4/L5 Nil gastrointestinal pathology on CT Chronic lumbar back pain over 6 months Negative Positive
Caudron et al. [2] F 79 L4/L5 Colonic diverticulosis Low back pain over 2 months Negative Positive
Bednar [3] M 68 L4/L5 Laminotomy, discotomy Acute back pain over 6 weeks Positive Positive
Pate and Katz [4] F 62 L3/L4 Diverticular disease Low back pain over 6 weeks Positive Negative after 3 days of antibiotics
Beguiristain et al. [5] M 33 L1/L2 No obvious risk factors Low back pain over 7 days Not completed Positive
Seller et al. [6] M 64 L5 No obvious risk factors Low back pain, urinary retention, and an inability to walk Positive Unknown
Yong and Lam [7] M 80 T10/T11 C. perfringens bacteremia Back pain over 5 weeks Positive Negative | 140 kg. | Weight | CC BY-NC-ND | 33479190 | 18,868,938 | 2021-01-22 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'COVID-19'. | Disease-Modifying Therapies and Coronavirus Disease 2019 Severity in Multiple Sclerosis.
This study was undertaken to assess the impact of immunosuppressive and immunomodulatory therapies on the severity of coronavirus disease 2019 (COVID-19) in people with multiple sclerosis (PwMS).
We retrospectively collected data of PwMS with suspected or confirmed COVID-19. All the patients had complete follow-up to death or recovery. Severe COVID-19 was defined by a 3-level variable: mild disease not requiring hospitalization versus pneumonia or hospitalization versus intensive care unit (ICU) admission or death. We evaluated baseline characteristics and MS therapies associated with severe COVID-19 by multivariate and propensity score (PS)-weighted ordinal logistic models. Sensitivity analyses were run to confirm the results.
Of 844 PwMS with suspected (n = 565) or confirmed (n = 279) COVID-19, 13 (1.54%) died; 11 of them were in a progressive MS phase, and 8 were without any therapy. Thirty-eight (4.5%) were admitted to an ICU; 99 (11.7%) had radiologically documented pneumonia; 96 (11.4%) were hospitalized. After adjusting for region, age, sex, progressive MS course, Expanded Disability Status Scale, disease duration, body mass index, comorbidities, and recent methylprednisolone use, therapy with an anti-CD20 agent (ocrelizumab or rituximab) was significantly associated (odds ratio [OR] = 2.37, 95% confidence interval [CI] = 1.18-4.74, p = 0.015) with increased risk of severe COVID-19. Recent use (<1 month) of methylprednisolone was also associated with a worse outcome (OR = 5.24, 95% CI = 2.20-12.53, p = 0.001). Results were confirmed by the PS-weighted analysis and by all the sensitivity analyses.
This study showed an acceptable level of safety of therapies with a broad array of mechanisms of action. However, some specific elements of risk emerged. These will need to be considered while the COVID-19 pandemic persists. ANN NEUROL 2021;89:780-789.
The COVID‐19 pandemic and the many questions about the postpandemic period complicate the management of patients who need therapies that impact on the immune system. Data available so far are overall reassuring, excluding major safety issues. 1 , 2 , 3 , 4 However, the robustness of results is not optimal due to the relatively small samples, collected in a situation of urgency. Furthermore, for most of the autoimmune diseases, many possible therapies are available, thus increasing the heterogeneity of the datasets. It is therefore necessary to rely on larger and better characterized case series to improve data quality and relevance. The results will inform clinical decisions that will have a long‐term impact, given the chronicity of the diseases, the duration of therapies, and the long‐lasting effects of some treatments.
Multiple sclerosis (MS) is the major cause of neurological disability in young adults, with approximately 2.3 million people affected worldwide. 5 Up to 70% of people with MS (PwMS) are treated with disease‐modifying therapies (DMTs) that impact on the immune response and may carry an increased probability of infection. 6 This risk must be balanced against the consequences of poorly controlled MS. Hence, reliably assessing the risk of coronavirus disease 2019 (COVID‐19) in these patients is an important public health issue, and more data are needed to guide clinical practice, as pointed out in recent reviews. 7 So far, the largest study based on data is the paper on the French cohort, 3 but the sample size did not allow drawing conclusions about the association of DMTs and COVID‐19 severity.
We present the results of an observational study on PwMS with a confirmed or suspected COVID‐19 infection, based on clinician‐reported data. The study was conducted in Italy, a high‐prevalence area for MS 8 that was the first European country to suffer the effects of the pandemic. The results are presented after the preplanned sample size needed to reach conclusions on the effect of DMTs on COVID‐19 severity was reached.
Patients and Methods
Data Sources
We obtained clinician‐reported demographic and clinical data on PwMS with a confirmed or suspected COVID‐19 infection from 85 Italian MS centers (Supplementary Table S2). We used a common web‐based electronic case report form (eCRF) to collect the data and a unified protocol to analyze them. Data were obtained after data‐sharing agreements between the Italian MS Society, the Italian Neurological Society, the University of Genoa, and all the MS centers involved. Demographic, MS history, COVID‐19 infection, and follow‐up data were collected. The study was approved by the regional ethics committee of Liguria (University of Genoa; n 130/2020–DB id 10433) and at a national level by the Italian Medicines Agency.
Study Population
We included adult MS patients who had been in contact with their neurologist because of a confirmed or suspected infection by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) during the observation period (January 15 to September 10, 2020). The confirmed cases were those with a positive test (reverse transcriptase polymerase chain reaction on nasal and pharyngeal swabs) for SARS‐CoV‐2 or a positive serological test obtained at any point during the observation period; the suspected cases were those who had radiological findings or symptoms highly suggestive of SARS‐CoV‐2 infection, according to medical judgment (cough, fever, shortness of breath, sudden onset of anosmia, ageusia, dysgeusia), and/or had close contact with a confirmed COVID‐19 case in the 14 days prior to the onset of symptoms. Data were collected retrospectively from the first contact until an outcome (death or recovery), taking as baseline the day of symptoms appearance. The first contact was a hospital visit, a phone call, or a web‐based visit, upon patients' or clinicians' request. Clinicians collected data by reviewing patients' clinical charts.
Variables Assessed
Collected data are detailed in the eCRF. We collected demographic data, including age, sex, body mass index (BMI), patient‐reported race and ethnic group, work status, number of cohabitants and number of cohabitants positive for SARS‐CoV‐2 infection, patient‐reported smoking and drinking status, and comorbidities; MS history data, including type of MS (relapsing–remitting MS [RRMS], primary progressive, or secondary progressive), disease onset date, Expanded Disability Status Scale (EDSS), DMTs at the date of symptoms start, and date of last treatment dose; and COVID‐19 infection data, including suspected geographic area of infection, symptoms, laboratory and radiological data, hospitalization, pneumonia and severity of pneumonia according to radiological examinations and ventilation support, therapies for COVID‐19, intensive care unit (ICU) admission, and recovery or death.
Each week a query for follow up update was sent to all centers, until they filled the outcome report (death or recovery).
End Points
We run 2 main analyses on the following primary endpoints: (1) observed number of deaths over the whole follow‐up; and (2) severe COVID‐19 characterized by a 3‐level variable; the highest severity level was death or ICU admission, the intermediate severity level was diagnosis of pneumonia or hospitalization, and the lowest severity level was a milder disease with no need for hospitalization or documented diagnosis of pneumonia.
Statistical Analysis
The web‐based data collection started on March 1, 2020 and closed for the analysis on September 10, 2020. The first date of symptom appearance retrospectively reported was January 15, 2020. All the patients had complete follow‐up to death or recovery.
For the sample size calculations, we determined that 800 patients were needed, assuming a rate of severe outcomes (death, ICU admission, pneumonia, or hospitalization) of 20% in the reference group and a comparison group made of 15% of the full cohort, to have a power of 90% to detect an increased risk of severe outcome in the comparison group quantified by an odds ratio (OR) = 2.0 at a confidence level of 0.05.
To make efficient use of the available data, we used multiple imputation of missing values for missing baseline data. Imputation was performed using chained equations, 9 where each incomplete variable is imputed by a separate model and implemented trough the "mice" R package. Continuous variables (age, height, weight, BMI, and disease duration) were parameterized as numeric data and imputed with the predictive mean matching method, whereas polytomous logistic regression was used for the unordered categorical variables (such as MS phenotype). EDSS and disease duration were used to impute the MS phenotype; age and MS phenotype were used to impute disease duration; age, height, or weight was used to impute BMI.
To assess risk factors at symptoms onset for a severe disease course, we ran a multivariate ordinal logistic regression assuming proportional ORs with severe outcome (defined as a 3‐level factor) as the dependent variable, after assessing that the assumptions of proportional odds were satisfied. The ORs reflect the multiplicative change in the odds of being at a higher level of the dependent variable for every one‐unit increase of the independent variable. The multivariate model included age, sex, BMI, EDSS, disease duration, MS disease phase (RRMS vs progressive), presence of comorbidities, methylprednisolone use within 1 month since COVID‐19 symptoms onset, and DMT class as independent variables, stratified by macroregion (defined as Lombardy; Northern Italy, including Piedmont, Veneto, Emilia‐Romagna, and Liguria; and the rest of Italy). DMT class was coded as an 8‐level variable as no therapy, interferon, glatiramer‐acetate, teriflunomide, dimethyl fumarate, natalizumab, anti‐CD20 (rituximab or ocrelizumab), or other. Alemtuzumab and cladribine were grouped in the “other” group, because the number of patients in these two therapeutic arms was too low to draw meaningful conclusions. “No therapy” was used as the reference category. We also ran the same ordinal logistic analysis after a multinomial propensity score (PS) weighting, as an alternative method to balance the differences of baseline characteristics among patients treated with different DMTs. The weights were calculated using an iterative robust approach based on the Generalized Boosted Model (GBM). 10 The balance among treatment groups was defined by the standardized mean difference, and the optimal GBM iteration was found by minimizing this quantity.
Results were also presented taking dimethyl fumarate, which is the most frequently used therapy in Italy, as the reference therapy group (Supplementary Appendix). Additional analyses were focused on the anti‐CD20 therapies using the same multivariate ordinal logistic model adjusted for all the baseline variables; we investigated the effect of being on anti‐CD20 versus not being on anti‐CD20, the effect of the distance from last infusion (0–3 months, >3 months), and the effect of the time since therapy start (<6 months, 6–12 months, >12 months).
Sensitivity analyses were run by repeating all the analyses on the subgroup of confirmed cases only, in the subgroup of patients with a RRMS course, in a model including only patients with complete baseline data with no imputation and using a leave one out procedure rerunning the analysis excluding one of the 3 major centers (Brescia, Bergamo, Milan) at a time (Supplementary Appendix).
Role of the Funding Source
Roche donated the web‐based platform for data collection. Roche did not have any role in study design; in analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.
Results
Patients Characteristics
On September 10, 844 PwMS with complete follow‐up from first contact to the outcome (recovery or death) from 85 centers were included in the dataset (Supplementary Appendix). Thirty‐four percent (286/844) of patients were from 3 centers in Lombardy (ASST Spedali Civili, Brescia‐Montichiari; Papa Giovanni XXIII Hospital, Bergamo; and San Raffaele Hospital, Milan); the distribution of patients by region is shown in Supplementary Table S3.
Table 1 reports the baseline demographic and clinical characteristics of the cohort. The mean age was 45 years (range = 18–82), the percentage of females was 70.3%, the median EDSS was 2 (interquartile range [IQR] = 1.50–4), and the proportion of progressive patients was 16%. Six hundred ninety‐three (82%) patients were treated with a DMT at the time of COVID‐19 presumed symptoms onset.
TABLE 1 Baseline Demographic and Clinical Characteristics of Included Patients
Characteristic Overall, N = 844 Suspected, n = 565 Confirmed, n = 279
Age, n (%)
<40 yr 279 (33.1) 203 (35.9) 76 (27.2)
40–59 yr 471 (55.8) 312 (55.2) 159 (57.0)
60–79 yr 92 (10.9) 50 (8.8) 42 (15.1)
≥80 yr 2 (0.2) 0 (0.0) 2 (0.7)
Female sex, n (%) 593 (70.3) 410 (72.6) 183 (65.6)
BMI, mean (SD) 23.82 (4.37) 23.61 (4.37) 24.28 (4.37)
Comorbidities, n (%) 188 (22.3) 115 (20.4) 73 (26.2)
MS phenotype, n (%)
Primary progressive 44 (5.2) 24 (4.2) 20 (7.2)
Relapsing–remitting 676 (80.1) 469 (83.0) 207 (74.2)
Secondary progressive 91 (10.8) 46 (8.1) 45 (16.1)
Missing data 33 (3.9) 26 (4.6) 7 (2.5)
MS disease duration, median (IQR) 10.2 (4.7–17.1) 9.6 (4.3–16.2) 11.8 (5.4–18.5)
EDSS, median (IQR) 2 (1.50–4) 2 (1.50–3.50) 2 (1.50–4)
MS treatment, n (%)
Dimethyl fumarate 174 (20.6) 131 (23.2) 43 (15.4)
Fingolimod 94 (11.1) 59 (10.4) 35 (12.5)
Ocrelizumab 89 (10.5) 58 (10.3) 31 (11.1)
Natalizumab 85 (10.1) 51 (9.0) 34 (12.2)
Interferon 73 (8.6) 52 (9.2) 21 (7.5)
Copaxone 70 (8.3) 52 (9.2) 18 (6.5)
Teriflunomide 64 (7.6) 37 (6.5) 27 (9.7)
Alemtuzumab 14 (1.7) 11 (1.9) 3 (1.1)
Cladribine 11 (1.3) 7 (1.2) 4 (1.4)
Azathioprine 10 (1.2) 4 (0.7) 6 (2.2)
Rituximab 5 (0.6) 4 (0.7) 1 (0.4)
Methotrexate 1 (0.1) 1 (0.2) 0 (0.0)
Mitoxantrone 1 (0.1) 1 (0.2) 0 (0.0)
Other 2 (0.2) 2 (0.4) 0 (0.0)
None 151 (17.9) 95 (16.8) 56 (20.1)
Previous methylprednisolone, n (%) 26 (3.1) 16 (2.8) 10 (3.6)
BMI = body mass index; EDSS = Expanded Disability Status Scale; IQR = interquartile range; MS = multiple sclerosis; SD = standard deviation.
Three hundred eighty‐four patients (45.5%) had at least one laboratory test executed for the COVID‐19 diagnosis; 307 (36.4%) patients were tested in the active phase with a swab and 127 (15.0%) had a serological test after recovery. Overall, 279 (33.1%) were classified as confirmed cases. Because the test during the pandemic peak was done only in the most severe patients, confirmed cases are expected to be more severe than suspected cases. In the confirmed cases subgroup, there was a higher proportion of older subjects than in the suspected cases subgroup (>60 years = 16% vs 9%) and more patients in the progressive MS phase (23% vs 12%).
The baseline characteristics of the cohort according to DMT received are reported in Table 2; patients with no therapy were older (mean age = 53.4 years), with a higher EDSS (mean EDSS = 5.5) and with a higher proportion of progressive patients (45.7%) than patients treated with DMTs. Among treated patients, those treated with interferon, glatiramer‐acetate, or teriflunomide were older than those in other DMT groups, and patients treated with anti‐CD20 had a higher EDSS (mean EDSS = 3) and a larger portion of progressive patients (25.6%) than those treated with other DMTs, but not larger than the untreated group.
TABLE 2 Baseline Demographic and Clinical Characteristics of Included Patients according to Disease‐Modifying Therapy Received
Characteristic No Therapy, n = 151 IFN, n = 73 GA, n = 70 Teri, n = 64 DMF, n = 174 FTY, n = 94 Nat, n = 85 Anti‐CD20, n = 94 a Other, n = 39
Age, mean (SD) 53.4 (13.4) 47.5 (10.5) 45.7 (11.3) 49.1 (9.4) 41.4 (10.9) 44.2 (9.5) 37.9 (9.8) 42.0 (10.0) 42.2 (13.8)
Female sex, n (%) 104 (68.9) 53 (72.6) 48 (68.6) 44 (68.8) 114 (65.5) 74 (78.7) 64 (75.3) 64 (68.1) 28 (71.8)
BMI, mean (SD) 24.6 (4.6) 24.3 (2.7) 25.2 (5.0) 24.7 (4.5) 23.3 (4.1) 23.9 (5.2) 22.7 (4.1) 22.6 (3.7) 23.2 (3.8)
MS phenotype, n (%)
Primary progressive 22 (14.6) 0 (0.0) 1 (1.4) 0 (0.0) 0 (0.0) 2 (2.1) 1 (1.2) 16 (17.0) 2 (5.1)
Relapsing–remitting 65 (43.0) 65 (89.0) 64 (91.4) 59 (92.2) 165 (94.8) 81 (86.2) 83 (97.6) 67 (71.3) 27 (69.2)
Secondary progressive 47 (31.1) 6 (8.2) 2 (2.9) 3 (4.7) 5 (2.9) 9 (9.6) 0 (0.0) 9 (9.6) 10 (25.6)
Missing data 17 (11.3) 2 (2.7) 3 (4.3) 2 (3.1) 4 (2.3) 2 (2.1) 1 (1.2) 2 (2.1) 0 (0.0)
MS disease duration, median yr (IQR) 16.2 (8–23) 12.0 (6–19) 10.1 (5–17) 11.4 (6–15) 5.5 (3–13) 11.8 (7–18) 9.1 (5–15) 8.2 (4–13) 12.9 (5–18)
EDSS, median (IQR) 5.5 (2–7) 1.5 (1–2.5) 1.5 (1–2) 2.0 (1.5–3) 1.5 (1–2) 2.0 (1.5–3) 2.0 (1.5–3) 3.0 (1.5–4.5) 3.0 (1.5–6)
Methylprednisolone, b n (%) 9 (6.0) 2 (2.7) 1 (1.4) 2 (3.1) 4 (2.3) 4 (4.3) 1 (1.2) 1 (1.1) 2 (5.1)
a Ocrelizumab or rituximab.
b One month before symptoms onset.
BMI = body mass index; DMF = dimethyl fumarate; EDSS = Expanded Disability Status Scale; FTY = fingolimod; GA = glatiramer‐acetate; IFN = interferon; IQR = interquartile range; MS = multiple sclerosis; Nat = natalizumab; SD = standard deviation; Teri = teriflunomide.
Thirteen (1.54%) patients died, and their characteristics are described in Table 3; 8 of them were PwMS with no therapy, all in a progressive disease phase (1 primary progressive MS, 7 secondary progressive MS). Five of them were treated (rituximab, ocrelizumab, natalizumab, glatiramer‐acetate, dimethyl fumarate), and only 2 of them were in a RRMS phase (glatiramer‐acetate and natalizumab). The mean time from symptoms to death was 18 days (range = 5–54 days).
TABLE 3 Characteristics of Deceased Patients
Sex, Age, yr Disease Duration Disease Phase EDSS Therapy Comorbidities
M, 63 33 SPMS 7 No therapy Diabetes
M, 67 2 PPMS 7.5 No therapy CHD, hypertension, HBV
M, 68 21 SPMS 6 Dimethyl fumarate Cerebrovascular disease, hypertension, depression, TBC
F, 57 20 SPMS 9 No therapy No
M, 76 17 SPMS 6.5 No therapy CHD, hypertension, depression, dyslipidemia
F, 52 1 RRMS 5 Natalizumab No
F, 50 27 SPMS 6 Ocrelizumab No
M, 59 33 SPMS 9 No therapy No
F, 68 19 SPMS 5.5 No therapy No
F, 54 20 SPMS 7 Rituximab No
M, 64 10 RRMS 2 Glatiramer‐acetate No
M, 63 33 SPMS 6.5 No therapy Diabetes, bipolar disorder
M, 60 30 SPMS 9 No therapy Hypertension, cerebrovascular disease, CHD
CHD = coronary heart disease; F = female; HBV = hepatitis B virus; M = male; PPMS = primary progressive multiple sclerosis; RRMS = relapsing–remitting multiple sclerosis; SPMS = secondary progressive multiple sclerosis; TBC = tuberculosis.
Risk Factors for a Severe COVID‐19 Outcome
Thirty‐eight (4.5%) patients were admitted to an ICU (7 of them died); 99 cases (11.7%) of radiologically documented pneumonia were reported; 96 patients (11.4%) were hospitalized. Forty‐four patients (5.2%) were in the highest severity class (death or ICU admission), and 92 patients (10.9%) were in the intermediate severity class (pneumonia or hospitalization). Twenty‐six patients (3.1%) received methylprednisolone in the month preceding the first symptoms of COVID‐19.
Risk factors for severe COVID‐19 in univariate, multivariate, and PS‐weighted analysis are reported in Table 4. The assumptions of proportional odds were satisfied. Older age, male sex, higher EDSS, longer MS duration, presence of comorbidities, and progressive MS course were all risk factors for a more severe disease in univariate analysis. Methylprednisolone use within 1 month before COVID‐19 symptoms onset was associated with increased risk (OR = 3.38, 95% confidence interval [CI] = 1.49–7.67, p = 0.004). Taking no therapy as the reference category indicated a reduced risk for all the DMTs, with OR ranging from 0.34 to 0.50, except for the anti‐CD20 therapies (ocrelizumab/rituximab, OR = 0.94). When adjusting the OR in the multivariate model, the risk factors with a significant impact on COVID‐19 severity were age, sex, EDSS, recent use of methylprednisolone, and anti‐CD20 therapy. Age and EDSS fully explained the apparent risk associated with no therapy as compared to the other DMTs, and the only treatment associated with a higher risk of a severe COVID‐19 disease was anti‐CD20 therapy (OR = 2.37, 95% CI = 1.18–4.74, p = 0.015). Also, the increased risk associated with the use of recent methylprednisolone was confirmed (OR = 5.24, 95% CI = 2.20–12.53, p = 0.001). The PS‐weighted characteristics of patients according to the different DMTs received are reported in Supplementary Table S11. The DMT effects on COVID‐19 severity are replicated by the PS‐weighted analysis. The OR for anti‐CD20 therapy was 3.91 (95% CI = 1.71–8.91, p = 0.001).
TABLE 4 Univariate, Multivariate, and PS‐Weighted Ordinal Logistic Regression Models Evaluating Risk Factors for Severe Coronavirus Disease 2019 a
Univariate Analysis, n = 844 b Multivariate Analysis, n = 844 b PS Analysis, n = 844 b
Variable OR (95% CI) p OR (95% CI) p OR (95% CI) p
Age, yr 1.06 (1.04–1.08) <0.001 1.06 (1.03–1.08) <0.001 1.06 (1.03–1.10) 0.001
Sex, F vs M 0.64 (0.40–1.03) 0.068 0.69 (0.45–1.04) 0.076 0.83 (0.50–1.39) 0.49
Progressive vs RRMS 4.14 (2.70–6.35) <0.001 1.59 (0.81–3.01) 0.18 1.76 (0.70–4.40) 0.23
EDSS 1.33 (1.22–1.45) <0.001 1.07 (0.93–1.22) 0.40 1.08 (0.86–1.35) 0.50
Disease duration, yr 1.04 (1.02–1.06) <0.011 1.00 (0.98–1.03) 0.99 0.99 (0.96–1.02) 0.57
BMI 1.01 (0.97–1.05) 0.53 0.98 (0.94–1.02) 0.44 0.99 (0.93–1.02) 0.74
Comorbidities, yes 1.70 (1.13–2.56) 0.012 0.93 (0.58–1.47) 0.74 0.82 (0.48–1.42) 0.48
Methylprednisolone c 3.38 (1.49–7.67) 0.004 5.24 (2.20–12.53) 0.001 2.51 (0.99–6.44) 0.05
DMT
No therapy d 1 (ref) 1 (ref) 1 (ref)
Interferon 0.35 (0.15–0.79) 0.012 0.67 (0.28–1.65) 0.39 0.71 (0.29–1.78) 0.48
Glatiramer‐acetate 0.34 (0.14–0.81) 0.015 0.77 (0.29–2.00) 0.59 1.19 (0.30–4.87) 0.80
Teriflunomide 0.48 (0.21–1.07) 0.07 0.86 (0.36–2.08) 0.74 1.17 (0.41–3.63) 0.76
Dimethyl fumarate 0.38 (0.20–0.70) 0.002 1.12 (0.55–2.30) 0.75 1.29 (0.58–2.87) 0.62
Natalizumab 0.35 (0.16–0.76) 0.009 1.30 (0.53–3.22) 0.57 1.77 (0.61–5.07) 0.29
Fingolimod 0.50 (0.26–0.98) 0.04 1.19 (0.57–2.52) 0.64 1.48 (0.66–3.34) 0.34
Anti‐CD20 e 0.94 (0.52–1.08) 0.85 2.37 (1.18–4.74) 0.015 3.91 (1.71–8.91) 0.001
Other 0.38 (0.14–1.04) 0.06 0.71 (0.28–2.65) 0.39 1.50 (0.40–5.71) 0.55
a Intensive care unit or death vs hospitalization or pneumonia vs milder symptoms not requiring hospitalization and no documented pneumonia.
b All the analyses are adjusted for macroregion (Lombardy; Northern Italy, including Veneto, Emilia‐Romagna, Piedmont, and Liguria; and the rest of Italy).
c One month before symptoms onset.
d No therapy was chosen as the reference class.
e Ocrelizumab or rituximab.
BMI = body mass index; CI = confidence interval; DMT = disease‐modifying therapy; EDSS = Expanded Disability Status Scale; F = female; M = male; OR = odds ratio; PS = propensity score; RRMS = relapsing–remitting multiple sclerosis.
The results taking dimethyl fumarate as the reference category are reported in the Supplementary Appendix and are in line with the above results. All the sensitivity analyses confirmed these findings; the anti‐CD20–treated patients had an OR = 2.62 (p = 0.05) in the subgroup of confirmed cases, an OR = 2.87 (p = 0.03) in the subgroup of RRMS patients, and an OR = 2.69 (p = 0.026) using only complete baseline data with no imputation (Supplementary Appendix).
A further result that deserves attention is the risk reduction observed in patients treated with interferon (OR = 0.67); however, this does not reach a statistical significance. Among the 73 patients on interferon, no ICU admissions or deaths were recorded.
To give an idea of the absolute risk of severe COVID‐19 according to DMT, Figure 1 reports the percentage of patients with severe events (pneumonia, hospitalization, ICU, or death) in the group treated with anti‐CD20, in the untreated group, and in the group treated with other DMTs. To adjust these values for the confounding factors, the figure was restricted to patients <65 years old and with EDSS < 6.5 (n = 733), and presented separately for the RRMS (n = 675) and progressive MS (n = 58) groups. The percentage of subjects with severe events was higher in the group of patients treated with anti‐CD20 both in the RRMS and in the progressive MS patients; in the RRMS group, the proportion of patients deceased or admitted to ICU in the anti‐CD20 group was 6.1%, versus 4.2% in the untreated and 2.2% in the other DMTs group. In the progressive MS group, it was 12.5% in the anti‐CD20 group, 10.5% in the untreated group, and 4.3% in the other DMTs group. The percentage of patients with an intermediate severity (pneumonia or hospitalization) had the same trend of increase in the anti‐CD20 group.
FIGURE 1 Percentage of patients with pneumonia/hospitalization and intensive care unit (ICU)/death in the subgroup of subjects with age < 65 years and Expanded Disability Status Scale < 6.5, according to multiple sclerosis (MS) phenotype (relapsing–remitting vs progressive MS), in the anti‐CD20, no therapy, and other therapies groups. DMT = disease‐modifying therapy.
The increase of risk associated with anti‐CD20 was maintained on hard end points (death or ICU admission), even if the small number of events did not allow this to reach statistical significance (Supplementary Appendix).
The adjusted OR for anti‐CD20 therapy versus all the other therapies was 2.37 (95% CI = 1.36–4.12, p = 0.002). Exploratory analyses revealed no association between COVID‐19 severity and the time passed since the last anti‐CD20 infusion (OR = 2.77, 95% CI = 1.31–5.89, p = 0.012 for last infusion within 3 months and OR = 2.05, 95% CI = 0.97–4.28, p = 0.023 for last infusion before 3 months), whereas there was a trend with therapy duration; as compared to PwMS treated with other therapies, patients on anti‐CD20 therapy for <6 months had an OR = 1.65 (95% CI = 0.56–4.90, p = 0.36), patients on anti‐CD20 therapy for 6–12 months had an OR = 2.24 (95% CI = 0.91–5.55, p = 0.08), and patients on anti‐CD20 therapy for >12 months had an OR = 2.98 (95% CI = 1.37–6.46, p = 0.006; Supplementary Appendix).
No severe outcomes (no pneumonia, hospitalization, ICU, or death) were observed in the 11 patients treated with cladribine or in the 14 patients treated with alemtuzumab.
Discussion
This study shows an acceptable level of safety of immunomodulatory and immunosuppressive therapies in MS during the COVID‐19 pandemic. However, two results deserve attention.
First, 11 of 13 deaths occurred in persons with advanced disease and disability (median EDSS = 7). The median age of people who died was 63 years versus a median age of 45 years for those who recovered. Higher EDSS was associated in multivariate analysis with COVID‐19 severity also in the French MS population. 3 These findings strengthen the need to enforce prevention strategies for people with advanced disability and older age during the pandemic. 11
Second, we observed an increased frequency of a severe COVID‐19 in people treated with anti‐CD20 therapies compared to other DMTs. Smaller case series suggested an increased susceptibility to COVID‐19 in PwMS taking B‐cell–depleting monoclonal antibodies, 12 , 13 , 14 without major effects on the severity of COVID‐19. 13 , 14 , 15 In the largest study published so far (the French study), DMT exposure was not included in the multivariate model. The results of the univariate analysis are very similar to those presented here. 3 It will be informative to evaluate the OR for the impact of DMTs on severity in the French cohort in the multivariate model, to check the size of effect, irrespective of the statistical significance. Data are available about the general risk of infections during DMTs for MS; a nationwide Swedish cohort examined the infection risks in PwMS treated with DMTs. 16 In that study, rituximab was associated with the highest rate of serious infections. However, the use of herpes antivirals was lower with rituximab compared to fingolimod and natalizumab; ocrelizumab clinical trials reported an increased risk of respiratory tract infections, 17 , 18 and safety issues emerged in diseases other than MS. 19 With respect to the association with treatment duration, it has been shown that long‐term anti‐CD20 treatment is associated with the risk of hypogammaglobulinemia in neuromyelitis optica‐spectrum disorder. 20 A protracted treatment may impact on the protective, anti–SARS‐CoV‐2 humoral response 21 and on a pre‐existing humoral and cellular immune repertoire, recently described in unexposed individuals. 22 , 23
We did not observe a link between time to last infusion of ocrelizumab and COVID‐19 risk. This preliminary result needs to be confirmed, but it is consistent with the idea that the immunological effects of ocrelizumab may last longer than 6 months. Reducing the frequency of dosing, or adjusting it according to the monitoring of B‐cell repopulation kinetics in individual patients, 20 may maintain efficacy while limiting the risk of infection. 24 A similar strategy deserves attention also in view of future vaccinations. 25 However, it may not be without risks linked to the re‐expansion of autoreactive B cells. 26
The role of interferon treatment and the severity of COVID‐19 is of high interest. Our data indicated a decrease of risk associated with interferon, even if it did not reach statistical significance. The majority of laboratory studies are in line with this preliminary observation, suggesting that supplementing type I interferons may circumvent a defective response that, in people with severe COVID‐19, may depend on various mechanisms including the presence of anti‐interferon autoantibodies, 27 a genetically defective type I interferon response, 28 , 29 or the ability of SARS‐CoV‐2 to neutralize the antiviral effects of type I interferons. 30 A recent clinical trial of interferon beta‐1b and lopinavir–ritonavir in Middle East respiratory syndrome 31 supports this hypothesis, but a negative trial of interferon beta‐1b, alone or in combination with lopinavir, does not. 32 It is possible that timing in the administration of type I interferons is crucial, as early therapy is associated with favorable clinical responses. 33 This is in accord with our observation in patients who are already under interferon beta therapy when they develop COVID‐19.
Importantly, methylprednisolone in the month preceding the first symptoms of COVID‐19 was significantly associated with a worse outcome. This aspect was not considered in previous reports, is in agreement with data in other autoimmune diseases, 34 and is relevant in assessing the risk of DMTs (ie, COVID‐19 risk vs steroid‐sparing potential).
This study has limitations that must be considered when evaluating the results. First, we included in the study not only confirmed but also suspected cases. For this reason, we cannot exclude that the suspected cases suffered from infections other than COVID‐19. We took the decision of including suspected cases because, during the pandemic peak in Italy, only the most severe cases (often after hospitalization) were tested. Hence, including only confirmed cases would have limited the representativeness of our sample. The inclusion of patients suffering from non–COVID‐19 infections might have diluted the effect of the detected association, resulting in a conservative approach. Furthermore, we reran all the main analyses on the subgroup of confirmed cases, obtaining similar and even stronger results, despite the smaller sample size. A second relevant bias might derive from differences in awareness and expectations of risks in patients receiving therapies with stronger immunosuppressive effect. This might have favored more frequent contacts with treating neurologists, resulting in increased attention to ocrelizumab or rituximab patients. However, the same should have been true also for other intravenous therapies. Finally, although the multivariate analysis adjusts the effect of DMTs on COVID‐19 severity for the main confounding factors, we cannot exclude that some residual confounding can partly explain the observed associations.
Overall, this study shows an acceptable safety profile of DMTs in MS during the COVID‐19 pandemic. The differences that emerged among the various DMTs are in agreement with previous knowledge about infections in PwMS. The results are also plausible based on current biological knowledge, although the exact mechanisms that affect the risk of COVID‐19 remain uncertain. It will be important to look at other ongoing studies 35 to verify whether they confirm our findings and to compare the new clinical insight in other autoimmune diseases. This may stimulate new laboratory research and shed new light on the biology of SARS‐CoV‐2 infection and on the pathophysiology of the different autoimmune diseases.
Author Contributions
All authors contributed to the conception and design of the study; the Musc‐19 Study Group contributed to the acquisition and analysis of data; M.P.S., I.S., L.C., and M.S. contributed to drafting the text and preparing the figures.
Potential Conflicts of Interest
M.P.S. reports a grant from Roche to cover data management of this study; Roche makes ocrelizumab, which is one of the DMTs assessed in this study. The remaining authors have nothing to report.
Supporting information
APPENDIX S1. Supporting Information
Click here for additional data file.
Acknowledgments
The Musc‐19 Study Group thanks Roche for donating the web‐based platform for data collection and the Department of Informatics, Bioengineering, Robotics, and Systems Engineering, University of Genoa, for its help in installing the platform. | GLATIRAMER ACETATE | DrugsGivenReaction | CC BY-NC | 33480077 | 19,299,189 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Coronavirus infection'. | Disease-Modifying Therapies and Coronavirus Disease 2019 Severity in Multiple Sclerosis.
This study was undertaken to assess the impact of immunosuppressive and immunomodulatory therapies on the severity of coronavirus disease 2019 (COVID-19) in people with multiple sclerosis (PwMS).
We retrospectively collected data of PwMS with suspected or confirmed COVID-19. All the patients had complete follow-up to death or recovery. Severe COVID-19 was defined by a 3-level variable: mild disease not requiring hospitalization versus pneumonia or hospitalization versus intensive care unit (ICU) admission or death. We evaluated baseline characteristics and MS therapies associated with severe COVID-19 by multivariate and propensity score (PS)-weighted ordinal logistic models. Sensitivity analyses were run to confirm the results.
Of 844 PwMS with suspected (n = 565) or confirmed (n = 279) COVID-19, 13 (1.54%) died; 11 of them were in a progressive MS phase, and 8 were without any therapy. Thirty-eight (4.5%) were admitted to an ICU; 99 (11.7%) had radiologically documented pneumonia; 96 (11.4%) were hospitalized. After adjusting for region, age, sex, progressive MS course, Expanded Disability Status Scale, disease duration, body mass index, comorbidities, and recent methylprednisolone use, therapy with an anti-CD20 agent (ocrelizumab or rituximab) was significantly associated (odds ratio [OR] = 2.37, 95% confidence interval [CI] = 1.18-4.74, p = 0.015) with increased risk of severe COVID-19. Recent use (<1 month) of methylprednisolone was also associated with a worse outcome (OR = 5.24, 95% CI = 2.20-12.53, p = 0.001). Results were confirmed by the PS-weighted analysis and by all the sensitivity analyses.
This study showed an acceptable level of safety of therapies with a broad array of mechanisms of action. However, some specific elements of risk emerged. These will need to be considered while the COVID-19 pandemic persists. ANN NEUROL 2021;89:780-789.
The COVID‐19 pandemic and the many questions about the postpandemic period complicate the management of patients who need therapies that impact on the immune system. Data available so far are overall reassuring, excluding major safety issues. 1 , 2 , 3 , 4 However, the robustness of results is not optimal due to the relatively small samples, collected in a situation of urgency. Furthermore, for most of the autoimmune diseases, many possible therapies are available, thus increasing the heterogeneity of the datasets. It is therefore necessary to rely on larger and better characterized case series to improve data quality and relevance. The results will inform clinical decisions that will have a long‐term impact, given the chronicity of the diseases, the duration of therapies, and the long‐lasting effects of some treatments.
Multiple sclerosis (MS) is the major cause of neurological disability in young adults, with approximately 2.3 million people affected worldwide. 5 Up to 70% of people with MS (PwMS) are treated with disease‐modifying therapies (DMTs) that impact on the immune response and may carry an increased probability of infection. 6 This risk must be balanced against the consequences of poorly controlled MS. Hence, reliably assessing the risk of coronavirus disease 2019 (COVID‐19) in these patients is an important public health issue, and more data are needed to guide clinical practice, as pointed out in recent reviews. 7 So far, the largest study based on data is the paper on the French cohort, 3 but the sample size did not allow drawing conclusions about the association of DMTs and COVID‐19 severity.
We present the results of an observational study on PwMS with a confirmed or suspected COVID‐19 infection, based on clinician‐reported data. The study was conducted in Italy, a high‐prevalence area for MS 8 that was the first European country to suffer the effects of the pandemic. The results are presented after the preplanned sample size needed to reach conclusions on the effect of DMTs on COVID‐19 severity was reached.
Patients and Methods
Data Sources
We obtained clinician‐reported demographic and clinical data on PwMS with a confirmed or suspected COVID‐19 infection from 85 Italian MS centers (Supplementary Table S2). We used a common web‐based electronic case report form (eCRF) to collect the data and a unified protocol to analyze them. Data were obtained after data‐sharing agreements between the Italian MS Society, the Italian Neurological Society, the University of Genoa, and all the MS centers involved. Demographic, MS history, COVID‐19 infection, and follow‐up data were collected. The study was approved by the regional ethics committee of Liguria (University of Genoa; n 130/2020–DB id 10433) and at a national level by the Italian Medicines Agency.
Study Population
We included adult MS patients who had been in contact with their neurologist because of a confirmed or suspected infection by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) during the observation period (January 15 to September 10, 2020). The confirmed cases were those with a positive test (reverse transcriptase polymerase chain reaction on nasal and pharyngeal swabs) for SARS‐CoV‐2 or a positive serological test obtained at any point during the observation period; the suspected cases were those who had radiological findings or symptoms highly suggestive of SARS‐CoV‐2 infection, according to medical judgment (cough, fever, shortness of breath, sudden onset of anosmia, ageusia, dysgeusia), and/or had close contact with a confirmed COVID‐19 case in the 14 days prior to the onset of symptoms. Data were collected retrospectively from the first contact until an outcome (death or recovery), taking as baseline the day of symptoms appearance. The first contact was a hospital visit, a phone call, or a web‐based visit, upon patients' or clinicians' request. Clinicians collected data by reviewing patients' clinical charts.
Variables Assessed
Collected data are detailed in the eCRF. We collected demographic data, including age, sex, body mass index (BMI), patient‐reported race and ethnic group, work status, number of cohabitants and number of cohabitants positive for SARS‐CoV‐2 infection, patient‐reported smoking and drinking status, and comorbidities; MS history data, including type of MS (relapsing–remitting MS [RRMS], primary progressive, or secondary progressive), disease onset date, Expanded Disability Status Scale (EDSS), DMTs at the date of symptoms start, and date of last treatment dose; and COVID‐19 infection data, including suspected geographic area of infection, symptoms, laboratory and radiological data, hospitalization, pneumonia and severity of pneumonia according to radiological examinations and ventilation support, therapies for COVID‐19, intensive care unit (ICU) admission, and recovery or death.
Each week a query for follow up update was sent to all centers, until they filled the outcome report (death or recovery).
End Points
We run 2 main analyses on the following primary endpoints: (1) observed number of deaths over the whole follow‐up; and (2) severe COVID‐19 characterized by a 3‐level variable; the highest severity level was death or ICU admission, the intermediate severity level was diagnosis of pneumonia or hospitalization, and the lowest severity level was a milder disease with no need for hospitalization or documented diagnosis of pneumonia.
Statistical Analysis
The web‐based data collection started on March 1, 2020 and closed for the analysis on September 10, 2020. The first date of symptom appearance retrospectively reported was January 15, 2020. All the patients had complete follow‐up to death or recovery.
For the sample size calculations, we determined that 800 patients were needed, assuming a rate of severe outcomes (death, ICU admission, pneumonia, or hospitalization) of 20% in the reference group and a comparison group made of 15% of the full cohort, to have a power of 90% to detect an increased risk of severe outcome in the comparison group quantified by an odds ratio (OR) = 2.0 at a confidence level of 0.05.
To make efficient use of the available data, we used multiple imputation of missing values for missing baseline data. Imputation was performed using chained equations, 9 where each incomplete variable is imputed by a separate model and implemented trough the "mice" R package. Continuous variables (age, height, weight, BMI, and disease duration) were parameterized as numeric data and imputed with the predictive mean matching method, whereas polytomous logistic regression was used for the unordered categorical variables (such as MS phenotype). EDSS and disease duration were used to impute the MS phenotype; age and MS phenotype were used to impute disease duration; age, height, or weight was used to impute BMI.
To assess risk factors at symptoms onset for a severe disease course, we ran a multivariate ordinal logistic regression assuming proportional ORs with severe outcome (defined as a 3‐level factor) as the dependent variable, after assessing that the assumptions of proportional odds were satisfied. The ORs reflect the multiplicative change in the odds of being at a higher level of the dependent variable for every one‐unit increase of the independent variable. The multivariate model included age, sex, BMI, EDSS, disease duration, MS disease phase (RRMS vs progressive), presence of comorbidities, methylprednisolone use within 1 month since COVID‐19 symptoms onset, and DMT class as independent variables, stratified by macroregion (defined as Lombardy; Northern Italy, including Piedmont, Veneto, Emilia‐Romagna, and Liguria; and the rest of Italy). DMT class was coded as an 8‐level variable as no therapy, interferon, glatiramer‐acetate, teriflunomide, dimethyl fumarate, natalizumab, anti‐CD20 (rituximab or ocrelizumab), or other. Alemtuzumab and cladribine were grouped in the “other” group, because the number of patients in these two therapeutic arms was too low to draw meaningful conclusions. “No therapy” was used as the reference category. We also ran the same ordinal logistic analysis after a multinomial propensity score (PS) weighting, as an alternative method to balance the differences of baseline characteristics among patients treated with different DMTs. The weights were calculated using an iterative robust approach based on the Generalized Boosted Model (GBM). 10 The balance among treatment groups was defined by the standardized mean difference, and the optimal GBM iteration was found by minimizing this quantity.
Results were also presented taking dimethyl fumarate, which is the most frequently used therapy in Italy, as the reference therapy group (Supplementary Appendix). Additional analyses were focused on the anti‐CD20 therapies using the same multivariate ordinal logistic model adjusted for all the baseline variables; we investigated the effect of being on anti‐CD20 versus not being on anti‐CD20, the effect of the distance from last infusion (0–3 months, >3 months), and the effect of the time since therapy start (<6 months, 6–12 months, >12 months).
Sensitivity analyses were run by repeating all the analyses on the subgroup of confirmed cases only, in the subgroup of patients with a RRMS course, in a model including only patients with complete baseline data with no imputation and using a leave one out procedure rerunning the analysis excluding one of the 3 major centers (Brescia, Bergamo, Milan) at a time (Supplementary Appendix).
Role of the Funding Source
Roche donated the web‐based platform for data collection. Roche did not have any role in study design; in analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.
Results
Patients Characteristics
On September 10, 844 PwMS with complete follow‐up from first contact to the outcome (recovery or death) from 85 centers were included in the dataset (Supplementary Appendix). Thirty‐four percent (286/844) of patients were from 3 centers in Lombardy (ASST Spedali Civili, Brescia‐Montichiari; Papa Giovanni XXIII Hospital, Bergamo; and San Raffaele Hospital, Milan); the distribution of patients by region is shown in Supplementary Table S3.
Table 1 reports the baseline demographic and clinical characteristics of the cohort. The mean age was 45 years (range = 18–82), the percentage of females was 70.3%, the median EDSS was 2 (interquartile range [IQR] = 1.50–4), and the proportion of progressive patients was 16%. Six hundred ninety‐three (82%) patients were treated with a DMT at the time of COVID‐19 presumed symptoms onset.
TABLE 1 Baseline Demographic and Clinical Characteristics of Included Patients
Characteristic Overall, N = 844 Suspected, n = 565 Confirmed, n = 279
Age, n (%)
<40 yr 279 (33.1) 203 (35.9) 76 (27.2)
40–59 yr 471 (55.8) 312 (55.2) 159 (57.0)
60–79 yr 92 (10.9) 50 (8.8) 42 (15.1)
≥80 yr 2 (0.2) 0 (0.0) 2 (0.7)
Female sex, n (%) 593 (70.3) 410 (72.6) 183 (65.6)
BMI, mean (SD) 23.82 (4.37) 23.61 (4.37) 24.28 (4.37)
Comorbidities, n (%) 188 (22.3) 115 (20.4) 73 (26.2)
MS phenotype, n (%)
Primary progressive 44 (5.2) 24 (4.2) 20 (7.2)
Relapsing–remitting 676 (80.1) 469 (83.0) 207 (74.2)
Secondary progressive 91 (10.8) 46 (8.1) 45 (16.1)
Missing data 33 (3.9) 26 (4.6) 7 (2.5)
MS disease duration, median (IQR) 10.2 (4.7–17.1) 9.6 (4.3–16.2) 11.8 (5.4–18.5)
EDSS, median (IQR) 2 (1.50–4) 2 (1.50–3.50) 2 (1.50–4)
MS treatment, n (%)
Dimethyl fumarate 174 (20.6) 131 (23.2) 43 (15.4)
Fingolimod 94 (11.1) 59 (10.4) 35 (12.5)
Ocrelizumab 89 (10.5) 58 (10.3) 31 (11.1)
Natalizumab 85 (10.1) 51 (9.0) 34 (12.2)
Interferon 73 (8.6) 52 (9.2) 21 (7.5)
Copaxone 70 (8.3) 52 (9.2) 18 (6.5)
Teriflunomide 64 (7.6) 37 (6.5) 27 (9.7)
Alemtuzumab 14 (1.7) 11 (1.9) 3 (1.1)
Cladribine 11 (1.3) 7 (1.2) 4 (1.4)
Azathioprine 10 (1.2) 4 (0.7) 6 (2.2)
Rituximab 5 (0.6) 4 (0.7) 1 (0.4)
Methotrexate 1 (0.1) 1 (0.2) 0 (0.0)
Mitoxantrone 1 (0.1) 1 (0.2) 0 (0.0)
Other 2 (0.2) 2 (0.4) 0 (0.0)
None 151 (17.9) 95 (16.8) 56 (20.1)
Previous methylprednisolone, n (%) 26 (3.1) 16 (2.8) 10 (3.6)
BMI = body mass index; EDSS = Expanded Disability Status Scale; IQR = interquartile range; MS = multiple sclerosis; SD = standard deviation.
Three hundred eighty‐four patients (45.5%) had at least one laboratory test executed for the COVID‐19 diagnosis; 307 (36.4%) patients were tested in the active phase with a swab and 127 (15.0%) had a serological test after recovery. Overall, 279 (33.1%) were classified as confirmed cases. Because the test during the pandemic peak was done only in the most severe patients, confirmed cases are expected to be more severe than suspected cases. In the confirmed cases subgroup, there was a higher proportion of older subjects than in the suspected cases subgroup (>60 years = 16% vs 9%) and more patients in the progressive MS phase (23% vs 12%).
The baseline characteristics of the cohort according to DMT received are reported in Table 2; patients with no therapy were older (mean age = 53.4 years), with a higher EDSS (mean EDSS = 5.5) and with a higher proportion of progressive patients (45.7%) than patients treated with DMTs. Among treated patients, those treated with interferon, glatiramer‐acetate, or teriflunomide were older than those in other DMT groups, and patients treated with anti‐CD20 had a higher EDSS (mean EDSS = 3) and a larger portion of progressive patients (25.6%) than those treated with other DMTs, but not larger than the untreated group.
TABLE 2 Baseline Demographic and Clinical Characteristics of Included Patients according to Disease‐Modifying Therapy Received
Characteristic No Therapy, n = 151 IFN, n = 73 GA, n = 70 Teri, n = 64 DMF, n = 174 FTY, n = 94 Nat, n = 85 Anti‐CD20, n = 94 a Other, n = 39
Age, mean (SD) 53.4 (13.4) 47.5 (10.5) 45.7 (11.3) 49.1 (9.4) 41.4 (10.9) 44.2 (9.5) 37.9 (9.8) 42.0 (10.0) 42.2 (13.8)
Female sex, n (%) 104 (68.9) 53 (72.6) 48 (68.6) 44 (68.8) 114 (65.5) 74 (78.7) 64 (75.3) 64 (68.1) 28 (71.8)
BMI, mean (SD) 24.6 (4.6) 24.3 (2.7) 25.2 (5.0) 24.7 (4.5) 23.3 (4.1) 23.9 (5.2) 22.7 (4.1) 22.6 (3.7) 23.2 (3.8)
MS phenotype, n (%)
Primary progressive 22 (14.6) 0 (0.0) 1 (1.4) 0 (0.0) 0 (0.0) 2 (2.1) 1 (1.2) 16 (17.0) 2 (5.1)
Relapsing–remitting 65 (43.0) 65 (89.0) 64 (91.4) 59 (92.2) 165 (94.8) 81 (86.2) 83 (97.6) 67 (71.3) 27 (69.2)
Secondary progressive 47 (31.1) 6 (8.2) 2 (2.9) 3 (4.7) 5 (2.9) 9 (9.6) 0 (0.0) 9 (9.6) 10 (25.6)
Missing data 17 (11.3) 2 (2.7) 3 (4.3) 2 (3.1) 4 (2.3) 2 (2.1) 1 (1.2) 2 (2.1) 0 (0.0)
MS disease duration, median yr (IQR) 16.2 (8–23) 12.0 (6–19) 10.1 (5–17) 11.4 (6–15) 5.5 (3–13) 11.8 (7–18) 9.1 (5–15) 8.2 (4–13) 12.9 (5–18)
EDSS, median (IQR) 5.5 (2–7) 1.5 (1–2.5) 1.5 (1–2) 2.0 (1.5–3) 1.5 (1–2) 2.0 (1.5–3) 2.0 (1.5–3) 3.0 (1.5–4.5) 3.0 (1.5–6)
Methylprednisolone, b n (%) 9 (6.0) 2 (2.7) 1 (1.4) 2 (3.1) 4 (2.3) 4 (4.3) 1 (1.2) 1 (1.1) 2 (5.1)
a Ocrelizumab or rituximab.
b One month before symptoms onset.
BMI = body mass index; DMF = dimethyl fumarate; EDSS = Expanded Disability Status Scale; FTY = fingolimod; GA = glatiramer‐acetate; IFN = interferon; IQR = interquartile range; MS = multiple sclerosis; Nat = natalizumab; SD = standard deviation; Teri = teriflunomide.
Thirteen (1.54%) patients died, and their characteristics are described in Table 3; 8 of them were PwMS with no therapy, all in a progressive disease phase (1 primary progressive MS, 7 secondary progressive MS). Five of them were treated (rituximab, ocrelizumab, natalizumab, glatiramer‐acetate, dimethyl fumarate), and only 2 of them were in a RRMS phase (glatiramer‐acetate and natalizumab). The mean time from symptoms to death was 18 days (range = 5–54 days).
TABLE 3 Characteristics of Deceased Patients
Sex, Age, yr Disease Duration Disease Phase EDSS Therapy Comorbidities
M, 63 33 SPMS 7 No therapy Diabetes
M, 67 2 PPMS 7.5 No therapy CHD, hypertension, HBV
M, 68 21 SPMS 6 Dimethyl fumarate Cerebrovascular disease, hypertension, depression, TBC
F, 57 20 SPMS 9 No therapy No
M, 76 17 SPMS 6.5 No therapy CHD, hypertension, depression, dyslipidemia
F, 52 1 RRMS 5 Natalizumab No
F, 50 27 SPMS 6 Ocrelizumab No
M, 59 33 SPMS 9 No therapy No
F, 68 19 SPMS 5.5 No therapy No
F, 54 20 SPMS 7 Rituximab No
M, 64 10 RRMS 2 Glatiramer‐acetate No
M, 63 33 SPMS 6.5 No therapy Diabetes, bipolar disorder
M, 60 30 SPMS 9 No therapy Hypertension, cerebrovascular disease, CHD
CHD = coronary heart disease; F = female; HBV = hepatitis B virus; M = male; PPMS = primary progressive multiple sclerosis; RRMS = relapsing–remitting multiple sclerosis; SPMS = secondary progressive multiple sclerosis; TBC = tuberculosis.
Risk Factors for a Severe COVID‐19 Outcome
Thirty‐eight (4.5%) patients were admitted to an ICU (7 of them died); 99 cases (11.7%) of radiologically documented pneumonia were reported; 96 patients (11.4%) were hospitalized. Forty‐four patients (5.2%) were in the highest severity class (death or ICU admission), and 92 patients (10.9%) were in the intermediate severity class (pneumonia or hospitalization). Twenty‐six patients (3.1%) received methylprednisolone in the month preceding the first symptoms of COVID‐19.
Risk factors for severe COVID‐19 in univariate, multivariate, and PS‐weighted analysis are reported in Table 4. The assumptions of proportional odds were satisfied. Older age, male sex, higher EDSS, longer MS duration, presence of comorbidities, and progressive MS course were all risk factors for a more severe disease in univariate analysis. Methylprednisolone use within 1 month before COVID‐19 symptoms onset was associated with increased risk (OR = 3.38, 95% confidence interval [CI] = 1.49–7.67, p = 0.004). Taking no therapy as the reference category indicated a reduced risk for all the DMTs, with OR ranging from 0.34 to 0.50, except for the anti‐CD20 therapies (ocrelizumab/rituximab, OR = 0.94). When adjusting the OR in the multivariate model, the risk factors with a significant impact on COVID‐19 severity were age, sex, EDSS, recent use of methylprednisolone, and anti‐CD20 therapy. Age and EDSS fully explained the apparent risk associated with no therapy as compared to the other DMTs, and the only treatment associated with a higher risk of a severe COVID‐19 disease was anti‐CD20 therapy (OR = 2.37, 95% CI = 1.18–4.74, p = 0.015). Also, the increased risk associated with the use of recent methylprednisolone was confirmed (OR = 5.24, 95% CI = 2.20–12.53, p = 0.001). The PS‐weighted characteristics of patients according to the different DMTs received are reported in Supplementary Table S11. The DMT effects on COVID‐19 severity are replicated by the PS‐weighted analysis. The OR for anti‐CD20 therapy was 3.91 (95% CI = 1.71–8.91, p = 0.001).
TABLE 4 Univariate, Multivariate, and PS‐Weighted Ordinal Logistic Regression Models Evaluating Risk Factors for Severe Coronavirus Disease 2019 a
Univariate Analysis, n = 844 b Multivariate Analysis, n = 844 b PS Analysis, n = 844 b
Variable OR (95% CI) p OR (95% CI) p OR (95% CI) p
Age, yr 1.06 (1.04–1.08) <0.001 1.06 (1.03–1.08) <0.001 1.06 (1.03–1.10) 0.001
Sex, F vs M 0.64 (0.40–1.03) 0.068 0.69 (0.45–1.04) 0.076 0.83 (0.50–1.39) 0.49
Progressive vs RRMS 4.14 (2.70–6.35) <0.001 1.59 (0.81–3.01) 0.18 1.76 (0.70–4.40) 0.23
EDSS 1.33 (1.22–1.45) <0.001 1.07 (0.93–1.22) 0.40 1.08 (0.86–1.35) 0.50
Disease duration, yr 1.04 (1.02–1.06) <0.011 1.00 (0.98–1.03) 0.99 0.99 (0.96–1.02) 0.57
BMI 1.01 (0.97–1.05) 0.53 0.98 (0.94–1.02) 0.44 0.99 (0.93–1.02) 0.74
Comorbidities, yes 1.70 (1.13–2.56) 0.012 0.93 (0.58–1.47) 0.74 0.82 (0.48–1.42) 0.48
Methylprednisolone c 3.38 (1.49–7.67) 0.004 5.24 (2.20–12.53) 0.001 2.51 (0.99–6.44) 0.05
DMT
No therapy d 1 (ref) 1 (ref) 1 (ref)
Interferon 0.35 (0.15–0.79) 0.012 0.67 (0.28–1.65) 0.39 0.71 (0.29–1.78) 0.48
Glatiramer‐acetate 0.34 (0.14–0.81) 0.015 0.77 (0.29–2.00) 0.59 1.19 (0.30–4.87) 0.80
Teriflunomide 0.48 (0.21–1.07) 0.07 0.86 (0.36–2.08) 0.74 1.17 (0.41–3.63) 0.76
Dimethyl fumarate 0.38 (0.20–0.70) 0.002 1.12 (0.55–2.30) 0.75 1.29 (0.58–2.87) 0.62
Natalizumab 0.35 (0.16–0.76) 0.009 1.30 (0.53–3.22) 0.57 1.77 (0.61–5.07) 0.29
Fingolimod 0.50 (0.26–0.98) 0.04 1.19 (0.57–2.52) 0.64 1.48 (0.66–3.34) 0.34
Anti‐CD20 e 0.94 (0.52–1.08) 0.85 2.37 (1.18–4.74) 0.015 3.91 (1.71–8.91) 0.001
Other 0.38 (0.14–1.04) 0.06 0.71 (0.28–2.65) 0.39 1.50 (0.40–5.71) 0.55
a Intensive care unit or death vs hospitalization or pneumonia vs milder symptoms not requiring hospitalization and no documented pneumonia.
b All the analyses are adjusted for macroregion (Lombardy; Northern Italy, including Veneto, Emilia‐Romagna, Piedmont, and Liguria; and the rest of Italy).
c One month before symptoms onset.
d No therapy was chosen as the reference class.
e Ocrelizumab or rituximab.
BMI = body mass index; CI = confidence interval; DMT = disease‐modifying therapy; EDSS = Expanded Disability Status Scale; F = female; M = male; OR = odds ratio; PS = propensity score; RRMS = relapsing–remitting multiple sclerosis.
The results taking dimethyl fumarate as the reference category are reported in the Supplementary Appendix and are in line with the above results. All the sensitivity analyses confirmed these findings; the anti‐CD20–treated patients had an OR = 2.62 (p = 0.05) in the subgroup of confirmed cases, an OR = 2.87 (p = 0.03) in the subgroup of RRMS patients, and an OR = 2.69 (p = 0.026) using only complete baseline data with no imputation (Supplementary Appendix).
A further result that deserves attention is the risk reduction observed in patients treated with interferon (OR = 0.67); however, this does not reach a statistical significance. Among the 73 patients on interferon, no ICU admissions or deaths were recorded.
To give an idea of the absolute risk of severe COVID‐19 according to DMT, Figure 1 reports the percentage of patients with severe events (pneumonia, hospitalization, ICU, or death) in the group treated with anti‐CD20, in the untreated group, and in the group treated with other DMTs. To adjust these values for the confounding factors, the figure was restricted to patients <65 years old and with EDSS < 6.5 (n = 733), and presented separately for the RRMS (n = 675) and progressive MS (n = 58) groups. The percentage of subjects with severe events was higher in the group of patients treated with anti‐CD20 both in the RRMS and in the progressive MS patients; in the RRMS group, the proportion of patients deceased or admitted to ICU in the anti‐CD20 group was 6.1%, versus 4.2% in the untreated and 2.2% in the other DMTs group. In the progressive MS group, it was 12.5% in the anti‐CD20 group, 10.5% in the untreated group, and 4.3% in the other DMTs group. The percentage of patients with an intermediate severity (pneumonia or hospitalization) had the same trend of increase in the anti‐CD20 group.
FIGURE 1 Percentage of patients with pneumonia/hospitalization and intensive care unit (ICU)/death in the subgroup of subjects with age < 65 years and Expanded Disability Status Scale < 6.5, according to multiple sclerosis (MS) phenotype (relapsing–remitting vs progressive MS), in the anti‐CD20, no therapy, and other therapies groups. DMT = disease‐modifying therapy.
The increase of risk associated with anti‐CD20 was maintained on hard end points (death or ICU admission), even if the small number of events did not allow this to reach statistical significance (Supplementary Appendix).
The adjusted OR for anti‐CD20 therapy versus all the other therapies was 2.37 (95% CI = 1.36–4.12, p = 0.002). Exploratory analyses revealed no association between COVID‐19 severity and the time passed since the last anti‐CD20 infusion (OR = 2.77, 95% CI = 1.31–5.89, p = 0.012 for last infusion within 3 months and OR = 2.05, 95% CI = 0.97–4.28, p = 0.023 for last infusion before 3 months), whereas there was a trend with therapy duration; as compared to PwMS treated with other therapies, patients on anti‐CD20 therapy for <6 months had an OR = 1.65 (95% CI = 0.56–4.90, p = 0.36), patients on anti‐CD20 therapy for 6–12 months had an OR = 2.24 (95% CI = 0.91–5.55, p = 0.08), and patients on anti‐CD20 therapy for >12 months had an OR = 2.98 (95% CI = 1.37–6.46, p = 0.006; Supplementary Appendix).
No severe outcomes (no pneumonia, hospitalization, ICU, or death) were observed in the 11 patients treated with cladribine or in the 14 patients treated with alemtuzumab.
Discussion
This study shows an acceptable level of safety of immunomodulatory and immunosuppressive therapies in MS during the COVID‐19 pandemic. However, two results deserve attention.
First, 11 of 13 deaths occurred in persons with advanced disease and disability (median EDSS = 7). The median age of people who died was 63 years versus a median age of 45 years for those who recovered. Higher EDSS was associated in multivariate analysis with COVID‐19 severity also in the French MS population. 3 These findings strengthen the need to enforce prevention strategies for people with advanced disability and older age during the pandemic. 11
Second, we observed an increased frequency of a severe COVID‐19 in people treated with anti‐CD20 therapies compared to other DMTs. Smaller case series suggested an increased susceptibility to COVID‐19 in PwMS taking B‐cell–depleting monoclonal antibodies, 12 , 13 , 14 without major effects on the severity of COVID‐19. 13 , 14 , 15 In the largest study published so far (the French study), DMT exposure was not included in the multivariate model. The results of the univariate analysis are very similar to those presented here. 3 It will be informative to evaluate the OR for the impact of DMTs on severity in the French cohort in the multivariate model, to check the size of effect, irrespective of the statistical significance. Data are available about the general risk of infections during DMTs for MS; a nationwide Swedish cohort examined the infection risks in PwMS treated with DMTs. 16 In that study, rituximab was associated with the highest rate of serious infections. However, the use of herpes antivirals was lower with rituximab compared to fingolimod and natalizumab; ocrelizumab clinical trials reported an increased risk of respiratory tract infections, 17 , 18 and safety issues emerged in diseases other than MS. 19 With respect to the association with treatment duration, it has been shown that long‐term anti‐CD20 treatment is associated with the risk of hypogammaglobulinemia in neuromyelitis optica‐spectrum disorder. 20 A protracted treatment may impact on the protective, anti–SARS‐CoV‐2 humoral response 21 and on a pre‐existing humoral and cellular immune repertoire, recently described in unexposed individuals. 22 , 23
We did not observe a link between time to last infusion of ocrelizumab and COVID‐19 risk. This preliminary result needs to be confirmed, but it is consistent with the idea that the immunological effects of ocrelizumab may last longer than 6 months. Reducing the frequency of dosing, or adjusting it according to the monitoring of B‐cell repopulation kinetics in individual patients, 20 may maintain efficacy while limiting the risk of infection. 24 A similar strategy deserves attention also in view of future vaccinations. 25 However, it may not be without risks linked to the re‐expansion of autoreactive B cells. 26
The role of interferon treatment and the severity of COVID‐19 is of high interest. Our data indicated a decrease of risk associated with interferon, even if it did not reach statistical significance. The majority of laboratory studies are in line with this preliminary observation, suggesting that supplementing type I interferons may circumvent a defective response that, in people with severe COVID‐19, may depend on various mechanisms including the presence of anti‐interferon autoantibodies, 27 a genetically defective type I interferon response, 28 , 29 or the ability of SARS‐CoV‐2 to neutralize the antiviral effects of type I interferons. 30 A recent clinical trial of interferon beta‐1b and lopinavir–ritonavir in Middle East respiratory syndrome 31 supports this hypothesis, but a negative trial of interferon beta‐1b, alone or in combination with lopinavir, does not. 32 It is possible that timing in the administration of type I interferons is crucial, as early therapy is associated with favorable clinical responses. 33 This is in accord with our observation in patients who are already under interferon beta therapy when they develop COVID‐19.
Importantly, methylprednisolone in the month preceding the first symptoms of COVID‐19 was significantly associated with a worse outcome. This aspect was not considered in previous reports, is in agreement with data in other autoimmune diseases, 34 and is relevant in assessing the risk of DMTs (ie, COVID‐19 risk vs steroid‐sparing potential).
This study has limitations that must be considered when evaluating the results. First, we included in the study not only confirmed but also suspected cases. For this reason, we cannot exclude that the suspected cases suffered from infections other than COVID‐19. We took the decision of including suspected cases because, during the pandemic peak in Italy, only the most severe cases (often after hospitalization) were tested. Hence, including only confirmed cases would have limited the representativeness of our sample. The inclusion of patients suffering from non–COVID‐19 infections might have diluted the effect of the detected association, resulting in a conservative approach. Furthermore, we reran all the main analyses on the subgroup of confirmed cases, obtaining similar and even stronger results, despite the smaller sample size. A second relevant bias might derive from differences in awareness and expectations of risks in patients receiving therapies with stronger immunosuppressive effect. This might have favored more frequent contacts with treating neurologists, resulting in increased attention to ocrelizumab or rituximab patients. However, the same should have been true also for other intravenous therapies. Finally, although the multivariate analysis adjusts the effect of DMTs on COVID‐19 severity for the main confounding factors, we cannot exclude that some residual confounding can partly explain the observed associations.
Overall, this study shows an acceptable safety profile of DMTs in MS during the COVID‐19 pandemic. The differences that emerged among the various DMTs are in agreement with previous knowledge about infections in PwMS. The results are also plausible based on current biological knowledge, although the exact mechanisms that affect the risk of COVID‐19 remain uncertain. It will be important to look at other ongoing studies 35 to verify whether they confirm our findings and to compare the new clinical insight in other autoimmune diseases. This may stimulate new laboratory research and shed new light on the biology of SARS‐CoV‐2 infection and on the pathophysiology of the different autoimmune diseases.
Author Contributions
All authors contributed to the conception and design of the study; the Musc‐19 Study Group contributed to the acquisition and analysis of data; M.P.S., I.S., L.C., and M.S. contributed to drafting the text and preparing the figures.
Potential Conflicts of Interest
M.P.S. reports a grant from Roche to cover data management of this study; Roche makes ocrelizumab, which is one of the DMTs assessed in this study. The remaining authors have nothing to report.
Supporting information
APPENDIX S1. Supporting Information
Click here for additional data file.
Acknowledgments
The Musc‐19 Study Group thanks Roche for donating the web‐based platform for data collection and the Department of Informatics, Bioengineering, Robotics, and Systems Engineering, University of Genoa, for its help in installing the platform. | RITUXIMAB | DrugsGivenReaction | CC BY-NC | 33480077 | 17,774,031 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Disease-Modifying Therapies and Coronavirus Disease 2019 Severity in Multiple Sclerosis.
This study was undertaken to assess the impact of immunosuppressive and immunomodulatory therapies on the severity of coronavirus disease 2019 (COVID-19) in people with multiple sclerosis (PwMS).
We retrospectively collected data of PwMS with suspected or confirmed COVID-19. All the patients had complete follow-up to death or recovery. Severe COVID-19 was defined by a 3-level variable: mild disease not requiring hospitalization versus pneumonia or hospitalization versus intensive care unit (ICU) admission or death. We evaluated baseline characteristics and MS therapies associated with severe COVID-19 by multivariate and propensity score (PS)-weighted ordinal logistic models. Sensitivity analyses were run to confirm the results.
Of 844 PwMS with suspected (n = 565) or confirmed (n = 279) COVID-19, 13 (1.54%) died; 11 of them were in a progressive MS phase, and 8 were without any therapy. Thirty-eight (4.5%) were admitted to an ICU; 99 (11.7%) had radiologically documented pneumonia; 96 (11.4%) were hospitalized. After adjusting for region, age, sex, progressive MS course, Expanded Disability Status Scale, disease duration, body mass index, comorbidities, and recent methylprednisolone use, therapy with an anti-CD20 agent (ocrelizumab or rituximab) was significantly associated (odds ratio [OR] = 2.37, 95% confidence interval [CI] = 1.18-4.74, p = 0.015) with increased risk of severe COVID-19. Recent use (<1 month) of methylprednisolone was also associated with a worse outcome (OR = 5.24, 95% CI = 2.20-12.53, p = 0.001). Results were confirmed by the PS-weighted analysis and by all the sensitivity analyses.
This study showed an acceptable level of safety of therapies with a broad array of mechanisms of action. However, some specific elements of risk emerged. These will need to be considered while the COVID-19 pandemic persists. ANN NEUROL 2021;89:780-789.
The COVID‐19 pandemic and the many questions about the postpandemic period complicate the management of patients who need therapies that impact on the immune system. Data available so far are overall reassuring, excluding major safety issues. 1 , 2 , 3 , 4 However, the robustness of results is not optimal due to the relatively small samples, collected in a situation of urgency. Furthermore, for most of the autoimmune diseases, many possible therapies are available, thus increasing the heterogeneity of the datasets. It is therefore necessary to rely on larger and better characterized case series to improve data quality and relevance. The results will inform clinical decisions that will have a long‐term impact, given the chronicity of the diseases, the duration of therapies, and the long‐lasting effects of some treatments.
Multiple sclerosis (MS) is the major cause of neurological disability in young adults, with approximately 2.3 million people affected worldwide. 5 Up to 70% of people with MS (PwMS) are treated with disease‐modifying therapies (DMTs) that impact on the immune response and may carry an increased probability of infection. 6 This risk must be balanced against the consequences of poorly controlled MS. Hence, reliably assessing the risk of coronavirus disease 2019 (COVID‐19) in these patients is an important public health issue, and more data are needed to guide clinical practice, as pointed out in recent reviews. 7 So far, the largest study based on data is the paper on the French cohort, 3 but the sample size did not allow drawing conclusions about the association of DMTs and COVID‐19 severity.
We present the results of an observational study on PwMS with a confirmed or suspected COVID‐19 infection, based on clinician‐reported data. The study was conducted in Italy, a high‐prevalence area for MS 8 that was the first European country to suffer the effects of the pandemic. The results are presented after the preplanned sample size needed to reach conclusions on the effect of DMTs on COVID‐19 severity was reached.
Patients and Methods
Data Sources
We obtained clinician‐reported demographic and clinical data on PwMS with a confirmed or suspected COVID‐19 infection from 85 Italian MS centers (Supplementary Table S2). We used a common web‐based electronic case report form (eCRF) to collect the data and a unified protocol to analyze them. Data were obtained after data‐sharing agreements between the Italian MS Society, the Italian Neurological Society, the University of Genoa, and all the MS centers involved. Demographic, MS history, COVID‐19 infection, and follow‐up data were collected. The study was approved by the regional ethics committee of Liguria (University of Genoa; n 130/2020–DB id 10433) and at a national level by the Italian Medicines Agency.
Study Population
We included adult MS patients who had been in contact with their neurologist because of a confirmed or suspected infection by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) during the observation period (January 15 to September 10, 2020). The confirmed cases were those with a positive test (reverse transcriptase polymerase chain reaction on nasal and pharyngeal swabs) for SARS‐CoV‐2 or a positive serological test obtained at any point during the observation period; the suspected cases were those who had radiological findings or symptoms highly suggestive of SARS‐CoV‐2 infection, according to medical judgment (cough, fever, shortness of breath, sudden onset of anosmia, ageusia, dysgeusia), and/or had close contact with a confirmed COVID‐19 case in the 14 days prior to the onset of symptoms. Data were collected retrospectively from the first contact until an outcome (death or recovery), taking as baseline the day of symptoms appearance. The first contact was a hospital visit, a phone call, or a web‐based visit, upon patients' or clinicians' request. Clinicians collected data by reviewing patients' clinical charts.
Variables Assessed
Collected data are detailed in the eCRF. We collected demographic data, including age, sex, body mass index (BMI), patient‐reported race and ethnic group, work status, number of cohabitants and number of cohabitants positive for SARS‐CoV‐2 infection, patient‐reported smoking and drinking status, and comorbidities; MS history data, including type of MS (relapsing–remitting MS [RRMS], primary progressive, or secondary progressive), disease onset date, Expanded Disability Status Scale (EDSS), DMTs at the date of symptoms start, and date of last treatment dose; and COVID‐19 infection data, including suspected geographic area of infection, symptoms, laboratory and radiological data, hospitalization, pneumonia and severity of pneumonia according to radiological examinations and ventilation support, therapies for COVID‐19, intensive care unit (ICU) admission, and recovery or death.
Each week a query for follow up update was sent to all centers, until they filled the outcome report (death or recovery).
End Points
We run 2 main analyses on the following primary endpoints: (1) observed number of deaths over the whole follow‐up; and (2) severe COVID‐19 characterized by a 3‐level variable; the highest severity level was death or ICU admission, the intermediate severity level was diagnosis of pneumonia or hospitalization, and the lowest severity level was a milder disease with no need for hospitalization or documented diagnosis of pneumonia.
Statistical Analysis
The web‐based data collection started on March 1, 2020 and closed for the analysis on September 10, 2020. The first date of symptom appearance retrospectively reported was January 15, 2020. All the patients had complete follow‐up to death or recovery.
For the sample size calculations, we determined that 800 patients were needed, assuming a rate of severe outcomes (death, ICU admission, pneumonia, or hospitalization) of 20% in the reference group and a comparison group made of 15% of the full cohort, to have a power of 90% to detect an increased risk of severe outcome in the comparison group quantified by an odds ratio (OR) = 2.0 at a confidence level of 0.05.
To make efficient use of the available data, we used multiple imputation of missing values for missing baseline data. Imputation was performed using chained equations, 9 where each incomplete variable is imputed by a separate model and implemented trough the "mice" R package. Continuous variables (age, height, weight, BMI, and disease duration) were parameterized as numeric data and imputed with the predictive mean matching method, whereas polytomous logistic regression was used for the unordered categorical variables (such as MS phenotype). EDSS and disease duration were used to impute the MS phenotype; age and MS phenotype were used to impute disease duration; age, height, or weight was used to impute BMI.
To assess risk factors at symptoms onset for a severe disease course, we ran a multivariate ordinal logistic regression assuming proportional ORs with severe outcome (defined as a 3‐level factor) as the dependent variable, after assessing that the assumptions of proportional odds were satisfied. The ORs reflect the multiplicative change in the odds of being at a higher level of the dependent variable for every one‐unit increase of the independent variable. The multivariate model included age, sex, BMI, EDSS, disease duration, MS disease phase (RRMS vs progressive), presence of comorbidities, methylprednisolone use within 1 month since COVID‐19 symptoms onset, and DMT class as independent variables, stratified by macroregion (defined as Lombardy; Northern Italy, including Piedmont, Veneto, Emilia‐Romagna, and Liguria; and the rest of Italy). DMT class was coded as an 8‐level variable as no therapy, interferon, glatiramer‐acetate, teriflunomide, dimethyl fumarate, natalizumab, anti‐CD20 (rituximab or ocrelizumab), or other. Alemtuzumab and cladribine were grouped in the “other” group, because the number of patients in these two therapeutic arms was too low to draw meaningful conclusions. “No therapy” was used as the reference category. We also ran the same ordinal logistic analysis after a multinomial propensity score (PS) weighting, as an alternative method to balance the differences of baseline characteristics among patients treated with different DMTs. The weights were calculated using an iterative robust approach based on the Generalized Boosted Model (GBM). 10 The balance among treatment groups was defined by the standardized mean difference, and the optimal GBM iteration was found by minimizing this quantity.
Results were also presented taking dimethyl fumarate, which is the most frequently used therapy in Italy, as the reference therapy group (Supplementary Appendix). Additional analyses were focused on the anti‐CD20 therapies using the same multivariate ordinal logistic model adjusted for all the baseline variables; we investigated the effect of being on anti‐CD20 versus not being on anti‐CD20, the effect of the distance from last infusion (0–3 months, >3 months), and the effect of the time since therapy start (<6 months, 6–12 months, >12 months).
Sensitivity analyses were run by repeating all the analyses on the subgroup of confirmed cases only, in the subgroup of patients with a RRMS course, in a model including only patients with complete baseline data with no imputation and using a leave one out procedure rerunning the analysis excluding one of the 3 major centers (Brescia, Bergamo, Milan) at a time (Supplementary Appendix).
Role of the Funding Source
Roche donated the web‐based platform for data collection. Roche did not have any role in study design; in analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.
Results
Patients Characteristics
On September 10, 844 PwMS with complete follow‐up from first contact to the outcome (recovery or death) from 85 centers were included in the dataset (Supplementary Appendix). Thirty‐four percent (286/844) of patients were from 3 centers in Lombardy (ASST Spedali Civili, Brescia‐Montichiari; Papa Giovanni XXIII Hospital, Bergamo; and San Raffaele Hospital, Milan); the distribution of patients by region is shown in Supplementary Table S3.
Table 1 reports the baseline demographic and clinical characteristics of the cohort. The mean age was 45 years (range = 18–82), the percentage of females was 70.3%, the median EDSS was 2 (interquartile range [IQR] = 1.50–4), and the proportion of progressive patients was 16%. Six hundred ninety‐three (82%) patients were treated with a DMT at the time of COVID‐19 presumed symptoms onset.
TABLE 1 Baseline Demographic and Clinical Characteristics of Included Patients
Characteristic Overall, N = 844 Suspected, n = 565 Confirmed, n = 279
Age, n (%)
<40 yr 279 (33.1) 203 (35.9) 76 (27.2)
40–59 yr 471 (55.8) 312 (55.2) 159 (57.0)
60–79 yr 92 (10.9) 50 (8.8) 42 (15.1)
≥80 yr 2 (0.2) 0 (0.0) 2 (0.7)
Female sex, n (%) 593 (70.3) 410 (72.6) 183 (65.6)
BMI, mean (SD) 23.82 (4.37) 23.61 (4.37) 24.28 (4.37)
Comorbidities, n (%) 188 (22.3) 115 (20.4) 73 (26.2)
MS phenotype, n (%)
Primary progressive 44 (5.2) 24 (4.2) 20 (7.2)
Relapsing–remitting 676 (80.1) 469 (83.0) 207 (74.2)
Secondary progressive 91 (10.8) 46 (8.1) 45 (16.1)
Missing data 33 (3.9) 26 (4.6) 7 (2.5)
MS disease duration, median (IQR) 10.2 (4.7–17.1) 9.6 (4.3–16.2) 11.8 (5.4–18.5)
EDSS, median (IQR) 2 (1.50–4) 2 (1.50–3.50) 2 (1.50–4)
MS treatment, n (%)
Dimethyl fumarate 174 (20.6) 131 (23.2) 43 (15.4)
Fingolimod 94 (11.1) 59 (10.4) 35 (12.5)
Ocrelizumab 89 (10.5) 58 (10.3) 31 (11.1)
Natalizumab 85 (10.1) 51 (9.0) 34 (12.2)
Interferon 73 (8.6) 52 (9.2) 21 (7.5)
Copaxone 70 (8.3) 52 (9.2) 18 (6.5)
Teriflunomide 64 (7.6) 37 (6.5) 27 (9.7)
Alemtuzumab 14 (1.7) 11 (1.9) 3 (1.1)
Cladribine 11 (1.3) 7 (1.2) 4 (1.4)
Azathioprine 10 (1.2) 4 (0.7) 6 (2.2)
Rituximab 5 (0.6) 4 (0.7) 1 (0.4)
Methotrexate 1 (0.1) 1 (0.2) 0 (0.0)
Mitoxantrone 1 (0.1) 1 (0.2) 0 (0.0)
Other 2 (0.2) 2 (0.4) 0 (0.0)
None 151 (17.9) 95 (16.8) 56 (20.1)
Previous methylprednisolone, n (%) 26 (3.1) 16 (2.8) 10 (3.6)
BMI = body mass index; EDSS = Expanded Disability Status Scale; IQR = interquartile range; MS = multiple sclerosis; SD = standard deviation.
Three hundred eighty‐four patients (45.5%) had at least one laboratory test executed for the COVID‐19 diagnosis; 307 (36.4%) patients were tested in the active phase with a swab and 127 (15.0%) had a serological test after recovery. Overall, 279 (33.1%) were classified as confirmed cases. Because the test during the pandemic peak was done only in the most severe patients, confirmed cases are expected to be more severe than suspected cases. In the confirmed cases subgroup, there was a higher proportion of older subjects than in the suspected cases subgroup (>60 years = 16% vs 9%) and more patients in the progressive MS phase (23% vs 12%).
The baseline characteristics of the cohort according to DMT received are reported in Table 2; patients with no therapy were older (mean age = 53.4 years), with a higher EDSS (mean EDSS = 5.5) and with a higher proportion of progressive patients (45.7%) than patients treated with DMTs. Among treated patients, those treated with interferon, glatiramer‐acetate, or teriflunomide were older than those in other DMT groups, and patients treated with anti‐CD20 had a higher EDSS (mean EDSS = 3) and a larger portion of progressive patients (25.6%) than those treated with other DMTs, but not larger than the untreated group.
TABLE 2 Baseline Demographic and Clinical Characteristics of Included Patients according to Disease‐Modifying Therapy Received
Characteristic No Therapy, n = 151 IFN, n = 73 GA, n = 70 Teri, n = 64 DMF, n = 174 FTY, n = 94 Nat, n = 85 Anti‐CD20, n = 94 a Other, n = 39
Age, mean (SD) 53.4 (13.4) 47.5 (10.5) 45.7 (11.3) 49.1 (9.4) 41.4 (10.9) 44.2 (9.5) 37.9 (9.8) 42.0 (10.0) 42.2 (13.8)
Female sex, n (%) 104 (68.9) 53 (72.6) 48 (68.6) 44 (68.8) 114 (65.5) 74 (78.7) 64 (75.3) 64 (68.1) 28 (71.8)
BMI, mean (SD) 24.6 (4.6) 24.3 (2.7) 25.2 (5.0) 24.7 (4.5) 23.3 (4.1) 23.9 (5.2) 22.7 (4.1) 22.6 (3.7) 23.2 (3.8)
MS phenotype, n (%)
Primary progressive 22 (14.6) 0 (0.0) 1 (1.4) 0 (0.0) 0 (0.0) 2 (2.1) 1 (1.2) 16 (17.0) 2 (5.1)
Relapsing–remitting 65 (43.0) 65 (89.0) 64 (91.4) 59 (92.2) 165 (94.8) 81 (86.2) 83 (97.6) 67 (71.3) 27 (69.2)
Secondary progressive 47 (31.1) 6 (8.2) 2 (2.9) 3 (4.7) 5 (2.9) 9 (9.6) 0 (0.0) 9 (9.6) 10 (25.6)
Missing data 17 (11.3) 2 (2.7) 3 (4.3) 2 (3.1) 4 (2.3) 2 (2.1) 1 (1.2) 2 (2.1) 0 (0.0)
MS disease duration, median yr (IQR) 16.2 (8–23) 12.0 (6–19) 10.1 (5–17) 11.4 (6–15) 5.5 (3–13) 11.8 (7–18) 9.1 (5–15) 8.2 (4–13) 12.9 (5–18)
EDSS, median (IQR) 5.5 (2–7) 1.5 (1–2.5) 1.5 (1–2) 2.0 (1.5–3) 1.5 (1–2) 2.0 (1.5–3) 2.0 (1.5–3) 3.0 (1.5–4.5) 3.0 (1.5–6)
Methylprednisolone, b n (%) 9 (6.0) 2 (2.7) 1 (1.4) 2 (3.1) 4 (2.3) 4 (4.3) 1 (1.2) 1 (1.1) 2 (5.1)
a Ocrelizumab or rituximab.
b One month before symptoms onset.
BMI = body mass index; DMF = dimethyl fumarate; EDSS = Expanded Disability Status Scale; FTY = fingolimod; GA = glatiramer‐acetate; IFN = interferon; IQR = interquartile range; MS = multiple sclerosis; Nat = natalizumab; SD = standard deviation; Teri = teriflunomide.
Thirteen (1.54%) patients died, and their characteristics are described in Table 3; 8 of them were PwMS with no therapy, all in a progressive disease phase (1 primary progressive MS, 7 secondary progressive MS). Five of them were treated (rituximab, ocrelizumab, natalizumab, glatiramer‐acetate, dimethyl fumarate), and only 2 of them were in a RRMS phase (glatiramer‐acetate and natalizumab). The mean time from symptoms to death was 18 days (range = 5–54 days).
TABLE 3 Characteristics of Deceased Patients
Sex, Age, yr Disease Duration Disease Phase EDSS Therapy Comorbidities
M, 63 33 SPMS 7 No therapy Diabetes
M, 67 2 PPMS 7.5 No therapy CHD, hypertension, HBV
M, 68 21 SPMS 6 Dimethyl fumarate Cerebrovascular disease, hypertension, depression, TBC
F, 57 20 SPMS 9 No therapy No
M, 76 17 SPMS 6.5 No therapy CHD, hypertension, depression, dyslipidemia
F, 52 1 RRMS 5 Natalizumab No
F, 50 27 SPMS 6 Ocrelizumab No
M, 59 33 SPMS 9 No therapy No
F, 68 19 SPMS 5.5 No therapy No
F, 54 20 SPMS 7 Rituximab No
M, 64 10 RRMS 2 Glatiramer‐acetate No
M, 63 33 SPMS 6.5 No therapy Diabetes, bipolar disorder
M, 60 30 SPMS 9 No therapy Hypertension, cerebrovascular disease, CHD
CHD = coronary heart disease; F = female; HBV = hepatitis B virus; M = male; PPMS = primary progressive multiple sclerosis; RRMS = relapsing–remitting multiple sclerosis; SPMS = secondary progressive multiple sclerosis; TBC = tuberculosis.
Risk Factors for a Severe COVID‐19 Outcome
Thirty‐eight (4.5%) patients were admitted to an ICU (7 of them died); 99 cases (11.7%) of radiologically documented pneumonia were reported; 96 patients (11.4%) were hospitalized. Forty‐four patients (5.2%) were in the highest severity class (death or ICU admission), and 92 patients (10.9%) were in the intermediate severity class (pneumonia or hospitalization). Twenty‐six patients (3.1%) received methylprednisolone in the month preceding the first symptoms of COVID‐19.
Risk factors for severe COVID‐19 in univariate, multivariate, and PS‐weighted analysis are reported in Table 4. The assumptions of proportional odds were satisfied. Older age, male sex, higher EDSS, longer MS duration, presence of comorbidities, and progressive MS course were all risk factors for a more severe disease in univariate analysis. Methylprednisolone use within 1 month before COVID‐19 symptoms onset was associated with increased risk (OR = 3.38, 95% confidence interval [CI] = 1.49–7.67, p = 0.004). Taking no therapy as the reference category indicated a reduced risk for all the DMTs, with OR ranging from 0.34 to 0.50, except for the anti‐CD20 therapies (ocrelizumab/rituximab, OR = 0.94). When adjusting the OR in the multivariate model, the risk factors with a significant impact on COVID‐19 severity were age, sex, EDSS, recent use of methylprednisolone, and anti‐CD20 therapy. Age and EDSS fully explained the apparent risk associated with no therapy as compared to the other DMTs, and the only treatment associated with a higher risk of a severe COVID‐19 disease was anti‐CD20 therapy (OR = 2.37, 95% CI = 1.18–4.74, p = 0.015). Also, the increased risk associated with the use of recent methylprednisolone was confirmed (OR = 5.24, 95% CI = 2.20–12.53, p = 0.001). The PS‐weighted characteristics of patients according to the different DMTs received are reported in Supplementary Table S11. The DMT effects on COVID‐19 severity are replicated by the PS‐weighted analysis. The OR for anti‐CD20 therapy was 3.91 (95% CI = 1.71–8.91, p = 0.001).
TABLE 4 Univariate, Multivariate, and PS‐Weighted Ordinal Logistic Regression Models Evaluating Risk Factors for Severe Coronavirus Disease 2019 a
Univariate Analysis, n = 844 b Multivariate Analysis, n = 844 b PS Analysis, n = 844 b
Variable OR (95% CI) p OR (95% CI) p OR (95% CI) p
Age, yr 1.06 (1.04–1.08) <0.001 1.06 (1.03–1.08) <0.001 1.06 (1.03–1.10) 0.001
Sex, F vs M 0.64 (0.40–1.03) 0.068 0.69 (0.45–1.04) 0.076 0.83 (0.50–1.39) 0.49
Progressive vs RRMS 4.14 (2.70–6.35) <0.001 1.59 (0.81–3.01) 0.18 1.76 (0.70–4.40) 0.23
EDSS 1.33 (1.22–1.45) <0.001 1.07 (0.93–1.22) 0.40 1.08 (0.86–1.35) 0.50
Disease duration, yr 1.04 (1.02–1.06) <0.011 1.00 (0.98–1.03) 0.99 0.99 (0.96–1.02) 0.57
BMI 1.01 (0.97–1.05) 0.53 0.98 (0.94–1.02) 0.44 0.99 (0.93–1.02) 0.74
Comorbidities, yes 1.70 (1.13–2.56) 0.012 0.93 (0.58–1.47) 0.74 0.82 (0.48–1.42) 0.48
Methylprednisolone c 3.38 (1.49–7.67) 0.004 5.24 (2.20–12.53) 0.001 2.51 (0.99–6.44) 0.05
DMT
No therapy d 1 (ref) 1 (ref) 1 (ref)
Interferon 0.35 (0.15–0.79) 0.012 0.67 (0.28–1.65) 0.39 0.71 (0.29–1.78) 0.48
Glatiramer‐acetate 0.34 (0.14–0.81) 0.015 0.77 (0.29–2.00) 0.59 1.19 (0.30–4.87) 0.80
Teriflunomide 0.48 (0.21–1.07) 0.07 0.86 (0.36–2.08) 0.74 1.17 (0.41–3.63) 0.76
Dimethyl fumarate 0.38 (0.20–0.70) 0.002 1.12 (0.55–2.30) 0.75 1.29 (0.58–2.87) 0.62
Natalizumab 0.35 (0.16–0.76) 0.009 1.30 (0.53–3.22) 0.57 1.77 (0.61–5.07) 0.29
Fingolimod 0.50 (0.26–0.98) 0.04 1.19 (0.57–2.52) 0.64 1.48 (0.66–3.34) 0.34
Anti‐CD20 e 0.94 (0.52–1.08) 0.85 2.37 (1.18–4.74) 0.015 3.91 (1.71–8.91) 0.001
Other 0.38 (0.14–1.04) 0.06 0.71 (0.28–2.65) 0.39 1.50 (0.40–5.71) 0.55
a Intensive care unit or death vs hospitalization or pneumonia vs milder symptoms not requiring hospitalization and no documented pneumonia.
b All the analyses are adjusted for macroregion (Lombardy; Northern Italy, including Veneto, Emilia‐Romagna, Piedmont, and Liguria; and the rest of Italy).
c One month before symptoms onset.
d No therapy was chosen as the reference class.
e Ocrelizumab or rituximab.
BMI = body mass index; CI = confidence interval; DMT = disease‐modifying therapy; EDSS = Expanded Disability Status Scale; F = female; M = male; OR = odds ratio; PS = propensity score; RRMS = relapsing–remitting multiple sclerosis.
The results taking dimethyl fumarate as the reference category are reported in the Supplementary Appendix and are in line with the above results. All the sensitivity analyses confirmed these findings; the anti‐CD20–treated patients had an OR = 2.62 (p = 0.05) in the subgroup of confirmed cases, an OR = 2.87 (p = 0.03) in the subgroup of RRMS patients, and an OR = 2.69 (p = 0.026) using only complete baseline data with no imputation (Supplementary Appendix).
A further result that deserves attention is the risk reduction observed in patients treated with interferon (OR = 0.67); however, this does not reach a statistical significance. Among the 73 patients on interferon, no ICU admissions or deaths were recorded.
To give an idea of the absolute risk of severe COVID‐19 according to DMT, Figure 1 reports the percentage of patients with severe events (pneumonia, hospitalization, ICU, or death) in the group treated with anti‐CD20, in the untreated group, and in the group treated with other DMTs. To adjust these values for the confounding factors, the figure was restricted to patients <65 years old and with EDSS < 6.5 (n = 733), and presented separately for the RRMS (n = 675) and progressive MS (n = 58) groups. The percentage of subjects with severe events was higher in the group of patients treated with anti‐CD20 both in the RRMS and in the progressive MS patients; in the RRMS group, the proportion of patients deceased or admitted to ICU in the anti‐CD20 group was 6.1%, versus 4.2% in the untreated and 2.2% in the other DMTs group. In the progressive MS group, it was 12.5% in the anti‐CD20 group, 10.5% in the untreated group, and 4.3% in the other DMTs group. The percentage of patients with an intermediate severity (pneumonia or hospitalization) had the same trend of increase in the anti‐CD20 group.
FIGURE 1 Percentage of patients with pneumonia/hospitalization and intensive care unit (ICU)/death in the subgroup of subjects with age < 65 years and Expanded Disability Status Scale < 6.5, according to multiple sclerosis (MS) phenotype (relapsing–remitting vs progressive MS), in the anti‐CD20, no therapy, and other therapies groups. DMT = disease‐modifying therapy.
The increase of risk associated with anti‐CD20 was maintained on hard end points (death or ICU admission), even if the small number of events did not allow this to reach statistical significance (Supplementary Appendix).
The adjusted OR for anti‐CD20 therapy versus all the other therapies was 2.37 (95% CI = 1.36–4.12, p = 0.002). Exploratory analyses revealed no association between COVID‐19 severity and the time passed since the last anti‐CD20 infusion (OR = 2.77, 95% CI = 1.31–5.89, p = 0.012 for last infusion within 3 months and OR = 2.05, 95% CI = 0.97–4.28, p = 0.023 for last infusion before 3 months), whereas there was a trend with therapy duration; as compared to PwMS treated with other therapies, patients on anti‐CD20 therapy for <6 months had an OR = 1.65 (95% CI = 0.56–4.90, p = 0.36), patients on anti‐CD20 therapy for 6–12 months had an OR = 2.24 (95% CI = 0.91–5.55, p = 0.08), and patients on anti‐CD20 therapy for >12 months had an OR = 2.98 (95% CI = 1.37–6.46, p = 0.006; Supplementary Appendix).
No severe outcomes (no pneumonia, hospitalization, ICU, or death) were observed in the 11 patients treated with cladribine or in the 14 patients treated with alemtuzumab.
Discussion
This study shows an acceptable level of safety of immunomodulatory and immunosuppressive therapies in MS during the COVID‐19 pandemic. However, two results deserve attention.
First, 11 of 13 deaths occurred in persons with advanced disease and disability (median EDSS = 7). The median age of people who died was 63 years versus a median age of 45 years for those who recovered. Higher EDSS was associated in multivariate analysis with COVID‐19 severity also in the French MS population. 3 These findings strengthen the need to enforce prevention strategies for people with advanced disability and older age during the pandemic. 11
Second, we observed an increased frequency of a severe COVID‐19 in people treated with anti‐CD20 therapies compared to other DMTs. Smaller case series suggested an increased susceptibility to COVID‐19 in PwMS taking B‐cell–depleting monoclonal antibodies, 12 , 13 , 14 without major effects on the severity of COVID‐19. 13 , 14 , 15 In the largest study published so far (the French study), DMT exposure was not included in the multivariate model. The results of the univariate analysis are very similar to those presented here. 3 It will be informative to evaluate the OR for the impact of DMTs on severity in the French cohort in the multivariate model, to check the size of effect, irrespective of the statistical significance. Data are available about the general risk of infections during DMTs for MS; a nationwide Swedish cohort examined the infection risks in PwMS treated with DMTs. 16 In that study, rituximab was associated with the highest rate of serious infections. However, the use of herpes antivirals was lower with rituximab compared to fingolimod and natalizumab; ocrelizumab clinical trials reported an increased risk of respiratory tract infections, 17 , 18 and safety issues emerged in diseases other than MS. 19 With respect to the association with treatment duration, it has been shown that long‐term anti‐CD20 treatment is associated with the risk of hypogammaglobulinemia in neuromyelitis optica‐spectrum disorder. 20 A protracted treatment may impact on the protective, anti–SARS‐CoV‐2 humoral response 21 and on a pre‐existing humoral and cellular immune repertoire, recently described in unexposed individuals. 22 , 23
We did not observe a link between time to last infusion of ocrelizumab and COVID‐19 risk. This preliminary result needs to be confirmed, but it is consistent with the idea that the immunological effects of ocrelizumab may last longer than 6 months. Reducing the frequency of dosing, or adjusting it according to the monitoring of B‐cell repopulation kinetics in individual patients, 20 may maintain efficacy while limiting the risk of infection. 24 A similar strategy deserves attention also in view of future vaccinations. 25 However, it may not be without risks linked to the re‐expansion of autoreactive B cells. 26
The role of interferon treatment and the severity of COVID‐19 is of high interest. Our data indicated a decrease of risk associated with interferon, even if it did not reach statistical significance. The majority of laboratory studies are in line with this preliminary observation, suggesting that supplementing type I interferons may circumvent a defective response that, in people with severe COVID‐19, may depend on various mechanisms including the presence of anti‐interferon autoantibodies, 27 a genetically defective type I interferon response, 28 , 29 or the ability of SARS‐CoV‐2 to neutralize the antiviral effects of type I interferons. 30 A recent clinical trial of interferon beta‐1b and lopinavir–ritonavir in Middle East respiratory syndrome 31 supports this hypothesis, but a negative trial of interferon beta‐1b, alone or in combination with lopinavir, does not. 32 It is possible that timing in the administration of type I interferons is crucial, as early therapy is associated with favorable clinical responses. 33 This is in accord with our observation in patients who are already under interferon beta therapy when they develop COVID‐19.
Importantly, methylprednisolone in the month preceding the first symptoms of COVID‐19 was significantly associated with a worse outcome. This aspect was not considered in previous reports, is in agreement with data in other autoimmune diseases, 34 and is relevant in assessing the risk of DMTs (ie, COVID‐19 risk vs steroid‐sparing potential).
This study has limitations that must be considered when evaluating the results. First, we included in the study not only confirmed but also suspected cases. For this reason, we cannot exclude that the suspected cases suffered from infections other than COVID‐19. We took the decision of including suspected cases because, during the pandemic peak in Italy, only the most severe cases (often after hospitalization) were tested. Hence, including only confirmed cases would have limited the representativeness of our sample. The inclusion of patients suffering from non–COVID‐19 infections might have diluted the effect of the detected association, resulting in a conservative approach. Furthermore, we reran all the main analyses on the subgroup of confirmed cases, obtaining similar and even stronger results, despite the smaller sample size. A second relevant bias might derive from differences in awareness and expectations of risks in patients receiving therapies with stronger immunosuppressive effect. This might have favored more frequent contacts with treating neurologists, resulting in increased attention to ocrelizumab or rituximab patients. However, the same should have been true also for other intravenous therapies. Finally, although the multivariate analysis adjusts the effect of DMTs on COVID‐19 severity for the main confounding factors, we cannot exclude that some residual confounding can partly explain the observed associations.
Overall, this study shows an acceptable safety profile of DMTs in MS during the COVID‐19 pandemic. The differences that emerged among the various DMTs are in agreement with previous knowledge about infections in PwMS. The results are also plausible based on current biological knowledge, although the exact mechanisms that affect the risk of COVID‐19 remain uncertain. It will be important to look at other ongoing studies 35 to verify whether they confirm our findings and to compare the new clinical insight in other autoimmune diseases. This may stimulate new laboratory research and shed new light on the biology of SARS‐CoV‐2 infection and on the pathophysiology of the different autoimmune diseases.
Author Contributions
All authors contributed to the conception and design of the study; the Musc‐19 Study Group contributed to the acquisition and analysis of data; M.P.S., I.S., L.C., and M.S. contributed to drafting the text and preparing the figures.
Potential Conflicts of Interest
M.P.S. reports a grant from Roche to cover data management of this study; Roche makes ocrelizumab, which is one of the DMTs assessed in this study. The remaining authors have nothing to report.
Supporting information
APPENDIX S1. Supporting Information
Click here for additional data file.
Acknowledgments
The Musc‐19 Study Group thanks Roche for donating the web‐based platform for data collection and the Department of Informatics, Bioengineering, Robotics, and Systems Engineering, University of Genoa, for its help in installing the platform. | RITUXIMAB | DrugsGivenReaction | CC BY-NC | 33480077 | 17,774,031 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Progressive multifocal leukoencephalopathy'. | Disease-Modifying Therapies and Coronavirus Disease 2019 Severity in Multiple Sclerosis.
This study was undertaken to assess the impact of immunosuppressive and immunomodulatory therapies on the severity of coronavirus disease 2019 (COVID-19) in people with multiple sclerosis (PwMS).
We retrospectively collected data of PwMS with suspected or confirmed COVID-19. All the patients had complete follow-up to death or recovery. Severe COVID-19 was defined by a 3-level variable: mild disease not requiring hospitalization versus pneumonia or hospitalization versus intensive care unit (ICU) admission or death. We evaluated baseline characteristics and MS therapies associated with severe COVID-19 by multivariate and propensity score (PS)-weighted ordinal logistic models. Sensitivity analyses were run to confirm the results.
Of 844 PwMS with suspected (n = 565) or confirmed (n = 279) COVID-19, 13 (1.54%) died; 11 of them were in a progressive MS phase, and 8 were without any therapy. Thirty-eight (4.5%) were admitted to an ICU; 99 (11.7%) had radiologically documented pneumonia; 96 (11.4%) were hospitalized. After adjusting for region, age, sex, progressive MS course, Expanded Disability Status Scale, disease duration, body mass index, comorbidities, and recent methylprednisolone use, therapy with an anti-CD20 agent (ocrelizumab or rituximab) was significantly associated (odds ratio [OR] = 2.37, 95% confidence interval [CI] = 1.18-4.74, p = 0.015) with increased risk of severe COVID-19. Recent use (<1 month) of methylprednisolone was also associated with a worse outcome (OR = 5.24, 95% CI = 2.20-12.53, p = 0.001). Results were confirmed by the PS-weighted analysis and by all the sensitivity analyses.
This study showed an acceptable level of safety of therapies with a broad array of mechanisms of action. However, some specific elements of risk emerged. These will need to be considered while the COVID-19 pandemic persists. ANN NEUROL 2021;89:780-789.
The COVID‐19 pandemic and the many questions about the postpandemic period complicate the management of patients who need therapies that impact on the immune system. Data available so far are overall reassuring, excluding major safety issues. 1 , 2 , 3 , 4 However, the robustness of results is not optimal due to the relatively small samples, collected in a situation of urgency. Furthermore, for most of the autoimmune diseases, many possible therapies are available, thus increasing the heterogeneity of the datasets. It is therefore necessary to rely on larger and better characterized case series to improve data quality and relevance. The results will inform clinical decisions that will have a long‐term impact, given the chronicity of the diseases, the duration of therapies, and the long‐lasting effects of some treatments.
Multiple sclerosis (MS) is the major cause of neurological disability in young adults, with approximately 2.3 million people affected worldwide. 5 Up to 70% of people with MS (PwMS) are treated with disease‐modifying therapies (DMTs) that impact on the immune response and may carry an increased probability of infection. 6 This risk must be balanced against the consequences of poorly controlled MS. Hence, reliably assessing the risk of coronavirus disease 2019 (COVID‐19) in these patients is an important public health issue, and more data are needed to guide clinical practice, as pointed out in recent reviews. 7 So far, the largest study based on data is the paper on the French cohort, 3 but the sample size did not allow drawing conclusions about the association of DMTs and COVID‐19 severity.
We present the results of an observational study on PwMS with a confirmed or suspected COVID‐19 infection, based on clinician‐reported data. The study was conducted in Italy, a high‐prevalence area for MS 8 that was the first European country to suffer the effects of the pandemic. The results are presented after the preplanned sample size needed to reach conclusions on the effect of DMTs on COVID‐19 severity was reached.
Patients and Methods
Data Sources
We obtained clinician‐reported demographic and clinical data on PwMS with a confirmed or suspected COVID‐19 infection from 85 Italian MS centers (Supplementary Table S2). We used a common web‐based electronic case report form (eCRF) to collect the data and a unified protocol to analyze them. Data were obtained after data‐sharing agreements between the Italian MS Society, the Italian Neurological Society, the University of Genoa, and all the MS centers involved. Demographic, MS history, COVID‐19 infection, and follow‐up data were collected. The study was approved by the regional ethics committee of Liguria (University of Genoa; n 130/2020–DB id 10433) and at a national level by the Italian Medicines Agency.
Study Population
We included adult MS patients who had been in contact with their neurologist because of a confirmed or suspected infection by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) during the observation period (January 15 to September 10, 2020). The confirmed cases were those with a positive test (reverse transcriptase polymerase chain reaction on nasal and pharyngeal swabs) for SARS‐CoV‐2 or a positive serological test obtained at any point during the observation period; the suspected cases were those who had radiological findings or symptoms highly suggestive of SARS‐CoV‐2 infection, according to medical judgment (cough, fever, shortness of breath, sudden onset of anosmia, ageusia, dysgeusia), and/or had close contact with a confirmed COVID‐19 case in the 14 days prior to the onset of symptoms. Data were collected retrospectively from the first contact until an outcome (death or recovery), taking as baseline the day of symptoms appearance. The first contact was a hospital visit, a phone call, or a web‐based visit, upon patients' or clinicians' request. Clinicians collected data by reviewing patients' clinical charts.
Variables Assessed
Collected data are detailed in the eCRF. We collected demographic data, including age, sex, body mass index (BMI), patient‐reported race and ethnic group, work status, number of cohabitants and number of cohabitants positive for SARS‐CoV‐2 infection, patient‐reported smoking and drinking status, and comorbidities; MS history data, including type of MS (relapsing–remitting MS [RRMS], primary progressive, or secondary progressive), disease onset date, Expanded Disability Status Scale (EDSS), DMTs at the date of symptoms start, and date of last treatment dose; and COVID‐19 infection data, including suspected geographic area of infection, symptoms, laboratory and radiological data, hospitalization, pneumonia and severity of pneumonia according to radiological examinations and ventilation support, therapies for COVID‐19, intensive care unit (ICU) admission, and recovery or death.
Each week a query for follow up update was sent to all centers, until they filled the outcome report (death or recovery).
End Points
We run 2 main analyses on the following primary endpoints: (1) observed number of deaths over the whole follow‐up; and (2) severe COVID‐19 characterized by a 3‐level variable; the highest severity level was death or ICU admission, the intermediate severity level was diagnosis of pneumonia or hospitalization, and the lowest severity level was a milder disease with no need for hospitalization or documented diagnosis of pneumonia.
Statistical Analysis
The web‐based data collection started on March 1, 2020 and closed for the analysis on September 10, 2020. The first date of symptom appearance retrospectively reported was January 15, 2020. All the patients had complete follow‐up to death or recovery.
For the sample size calculations, we determined that 800 patients were needed, assuming a rate of severe outcomes (death, ICU admission, pneumonia, or hospitalization) of 20% in the reference group and a comparison group made of 15% of the full cohort, to have a power of 90% to detect an increased risk of severe outcome in the comparison group quantified by an odds ratio (OR) = 2.0 at a confidence level of 0.05.
To make efficient use of the available data, we used multiple imputation of missing values for missing baseline data. Imputation was performed using chained equations, 9 where each incomplete variable is imputed by a separate model and implemented trough the "mice" R package. Continuous variables (age, height, weight, BMI, and disease duration) were parameterized as numeric data and imputed with the predictive mean matching method, whereas polytomous logistic regression was used for the unordered categorical variables (such as MS phenotype). EDSS and disease duration were used to impute the MS phenotype; age and MS phenotype were used to impute disease duration; age, height, or weight was used to impute BMI.
To assess risk factors at symptoms onset for a severe disease course, we ran a multivariate ordinal logistic regression assuming proportional ORs with severe outcome (defined as a 3‐level factor) as the dependent variable, after assessing that the assumptions of proportional odds were satisfied. The ORs reflect the multiplicative change in the odds of being at a higher level of the dependent variable for every one‐unit increase of the independent variable. The multivariate model included age, sex, BMI, EDSS, disease duration, MS disease phase (RRMS vs progressive), presence of comorbidities, methylprednisolone use within 1 month since COVID‐19 symptoms onset, and DMT class as independent variables, stratified by macroregion (defined as Lombardy; Northern Italy, including Piedmont, Veneto, Emilia‐Romagna, and Liguria; and the rest of Italy). DMT class was coded as an 8‐level variable as no therapy, interferon, glatiramer‐acetate, teriflunomide, dimethyl fumarate, natalizumab, anti‐CD20 (rituximab or ocrelizumab), or other. Alemtuzumab and cladribine were grouped in the “other” group, because the number of patients in these two therapeutic arms was too low to draw meaningful conclusions. “No therapy” was used as the reference category. We also ran the same ordinal logistic analysis after a multinomial propensity score (PS) weighting, as an alternative method to balance the differences of baseline characteristics among patients treated with different DMTs. The weights were calculated using an iterative robust approach based on the Generalized Boosted Model (GBM). 10 The balance among treatment groups was defined by the standardized mean difference, and the optimal GBM iteration was found by minimizing this quantity.
Results were also presented taking dimethyl fumarate, which is the most frequently used therapy in Italy, as the reference therapy group (Supplementary Appendix). Additional analyses were focused on the anti‐CD20 therapies using the same multivariate ordinal logistic model adjusted for all the baseline variables; we investigated the effect of being on anti‐CD20 versus not being on anti‐CD20, the effect of the distance from last infusion (0–3 months, >3 months), and the effect of the time since therapy start (<6 months, 6–12 months, >12 months).
Sensitivity analyses were run by repeating all the analyses on the subgroup of confirmed cases only, in the subgroup of patients with a RRMS course, in a model including only patients with complete baseline data with no imputation and using a leave one out procedure rerunning the analysis excluding one of the 3 major centers (Brescia, Bergamo, Milan) at a time (Supplementary Appendix).
Role of the Funding Source
Roche donated the web‐based platform for data collection. Roche did not have any role in study design; in analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.
Results
Patients Characteristics
On September 10, 844 PwMS with complete follow‐up from first contact to the outcome (recovery or death) from 85 centers were included in the dataset (Supplementary Appendix). Thirty‐four percent (286/844) of patients were from 3 centers in Lombardy (ASST Spedali Civili, Brescia‐Montichiari; Papa Giovanni XXIII Hospital, Bergamo; and San Raffaele Hospital, Milan); the distribution of patients by region is shown in Supplementary Table S3.
Table 1 reports the baseline demographic and clinical characteristics of the cohort. The mean age was 45 years (range = 18–82), the percentage of females was 70.3%, the median EDSS was 2 (interquartile range [IQR] = 1.50–4), and the proportion of progressive patients was 16%. Six hundred ninety‐three (82%) patients were treated with a DMT at the time of COVID‐19 presumed symptoms onset.
TABLE 1 Baseline Demographic and Clinical Characteristics of Included Patients
Characteristic Overall, N = 844 Suspected, n = 565 Confirmed, n = 279
Age, n (%)
<40 yr 279 (33.1) 203 (35.9) 76 (27.2)
40–59 yr 471 (55.8) 312 (55.2) 159 (57.0)
60–79 yr 92 (10.9) 50 (8.8) 42 (15.1)
≥80 yr 2 (0.2) 0 (0.0) 2 (0.7)
Female sex, n (%) 593 (70.3) 410 (72.6) 183 (65.6)
BMI, mean (SD) 23.82 (4.37) 23.61 (4.37) 24.28 (4.37)
Comorbidities, n (%) 188 (22.3) 115 (20.4) 73 (26.2)
MS phenotype, n (%)
Primary progressive 44 (5.2) 24 (4.2) 20 (7.2)
Relapsing–remitting 676 (80.1) 469 (83.0) 207 (74.2)
Secondary progressive 91 (10.8) 46 (8.1) 45 (16.1)
Missing data 33 (3.9) 26 (4.6) 7 (2.5)
MS disease duration, median (IQR) 10.2 (4.7–17.1) 9.6 (4.3–16.2) 11.8 (5.4–18.5)
EDSS, median (IQR) 2 (1.50–4) 2 (1.50–3.50) 2 (1.50–4)
MS treatment, n (%)
Dimethyl fumarate 174 (20.6) 131 (23.2) 43 (15.4)
Fingolimod 94 (11.1) 59 (10.4) 35 (12.5)
Ocrelizumab 89 (10.5) 58 (10.3) 31 (11.1)
Natalizumab 85 (10.1) 51 (9.0) 34 (12.2)
Interferon 73 (8.6) 52 (9.2) 21 (7.5)
Copaxone 70 (8.3) 52 (9.2) 18 (6.5)
Teriflunomide 64 (7.6) 37 (6.5) 27 (9.7)
Alemtuzumab 14 (1.7) 11 (1.9) 3 (1.1)
Cladribine 11 (1.3) 7 (1.2) 4 (1.4)
Azathioprine 10 (1.2) 4 (0.7) 6 (2.2)
Rituximab 5 (0.6) 4 (0.7) 1 (0.4)
Methotrexate 1 (0.1) 1 (0.2) 0 (0.0)
Mitoxantrone 1 (0.1) 1 (0.2) 0 (0.0)
Other 2 (0.2) 2 (0.4) 0 (0.0)
None 151 (17.9) 95 (16.8) 56 (20.1)
Previous methylprednisolone, n (%) 26 (3.1) 16 (2.8) 10 (3.6)
BMI = body mass index; EDSS = Expanded Disability Status Scale; IQR = interquartile range; MS = multiple sclerosis; SD = standard deviation.
Three hundred eighty‐four patients (45.5%) had at least one laboratory test executed for the COVID‐19 diagnosis; 307 (36.4%) patients were tested in the active phase with a swab and 127 (15.0%) had a serological test after recovery. Overall, 279 (33.1%) were classified as confirmed cases. Because the test during the pandemic peak was done only in the most severe patients, confirmed cases are expected to be more severe than suspected cases. In the confirmed cases subgroup, there was a higher proportion of older subjects than in the suspected cases subgroup (>60 years = 16% vs 9%) and more patients in the progressive MS phase (23% vs 12%).
The baseline characteristics of the cohort according to DMT received are reported in Table 2; patients with no therapy were older (mean age = 53.4 years), with a higher EDSS (mean EDSS = 5.5) and with a higher proportion of progressive patients (45.7%) than patients treated with DMTs. Among treated patients, those treated with interferon, glatiramer‐acetate, or teriflunomide were older than those in other DMT groups, and patients treated with anti‐CD20 had a higher EDSS (mean EDSS = 3) and a larger portion of progressive patients (25.6%) than those treated with other DMTs, but not larger than the untreated group.
TABLE 2 Baseline Demographic and Clinical Characteristics of Included Patients according to Disease‐Modifying Therapy Received
Characteristic No Therapy, n = 151 IFN, n = 73 GA, n = 70 Teri, n = 64 DMF, n = 174 FTY, n = 94 Nat, n = 85 Anti‐CD20, n = 94 a Other, n = 39
Age, mean (SD) 53.4 (13.4) 47.5 (10.5) 45.7 (11.3) 49.1 (9.4) 41.4 (10.9) 44.2 (9.5) 37.9 (9.8) 42.0 (10.0) 42.2 (13.8)
Female sex, n (%) 104 (68.9) 53 (72.6) 48 (68.6) 44 (68.8) 114 (65.5) 74 (78.7) 64 (75.3) 64 (68.1) 28 (71.8)
BMI, mean (SD) 24.6 (4.6) 24.3 (2.7) 25.2 (5.0) 24.7 (4.5) 23.3 (4.1) 23.9 (5.2) 22.7 (4.1) 22.6 (3.7) 23.2 (3.8)
MS phenotype, n (%)
Primary progressive 22 (14.6) 0 (0.0) 1 (1.4) 0 (0.0) 0 (0.0) 2 (2.1) 1 (1.2) 16 (17.0) 2 (5.1)
Relapsing–remitting 65 (43.0) 65 (89.0) 64 (91.4) 59 (92.2) 165 (94.8) 81 (86.2) 83 (97.6) 67 (71.3) 27 (69.2)
Secondary progressive 47 (31.1) 6 (8.2) 2 (2.9) 3 (4.7) 5 (2.9) 9 (9.6) 0 (0.0) 9 (9.6) 10 (25.6)
Missing data 17 (11.3) 2 (2.7) 3 (4.3) 2 (3.1) 4 (2.3) 2 (2.1) 1 (1.2) 2 (2.1) 0 (0.0)
MS disease duration, median yr (IQR) 16.2 (8–23) 12.0 (6–19) 10.1 (5–17) 11.4 (6–15) 5.5 (3–13) 11.8 (7–18) 9.1 (5–15) 8.2 (4–13) 12.9 (5–18)
EDSS, median (IQR) 5.5 (2–7) 1.5 (1–2.5) 1.5 (1–2) 2.0 (1.5–3) 1.5 (1–2) 2.0 (1.5–3) 2.0 (1.5–3) 3.0 (1.5–4.5) 3.0 (1.5–6)
Methylprednisolone, b n (%) 9 (6.0) 2 (2.7) 1 (1.4) 2 (3.1) 4 (2.3) 4 (4.3) 1 (1.2) 1 (1.1) 2 (5.1)
a Ocrelizumab or rituximab.
b One month before symptoms onset.
BMI = body mass index; DMF = dimethyl fumarate; EDSS = Expanded Disability Status Scale; FTY = fingolimod; GA = glatiramer‐acetate; IFN = interferon; IQR = interquartile range; MS = multiple sclerosis; Nat = natalizumab; SD = standard deviation; Teri = teriflunomide.
Thirteen (1.54%) patients died, and their characteristics are described in Table 3; 8 of them were PwMS with no therapy, all in a progressive disease phase (1 primary progressive MS, 7 secondary progressive MS). Five of them were treated (rituximab, ocrelizumab, natalizumab, glatiramer‐acetate, dimethyl fumarate), and only 2 of them were in a RRMS phase (glatiramer‐acetate and natalizumab). The mean time from symptoms to death was 18 days (range = 5–54 days).
TABLE 3 Characteristics of Deceased Patients
Sex, Age, yr Disease Duration Disease Phase EDSS Therapy Comorbidities
M, 63 33 SPMS 7 No therapy Diabetes
M, 67 2 PPMS 7.5 No therapy CHD, hypertension, HBV
M, 68 21 SPMS 6 Dimethyl fumarate Cerebrovascular disease, hypertension, depression, TBC
F, 57 20 SPMS 9 No therapy No
M, 76 17 SPMS 6.5 No therapy CHD, hypertension, depression, dyslipidemia
F, 52 1 RRMS 5 Natalizumab No
F, 50 27 SPMS 6 Ocrelizumab No
M, 59 33 SPMS 9 No therapy No
F, 68 19 SPMS 5.5 No therapy No
F, 54 20 SPMS 7 Rituximab No
M, 64 10 RRMS 2 Glatiramer‐acetate No
M, 63 33 SPMS 6.5 No therapy Diabetes, bipolar disorder
M, 60 30 SPMS 9 No therapy Hypertension, cerebrovascular disease, CHD
CHD = coronary heart disease; F = female; HBV = hepatitis B virus; M = male; PPMS = primary progressive multiple sclerosis; RRMS = relapsing–remitting multiple sclerosis; SPMS = secondary progressive multiple sclerosis; TBC = tuberculosis.
Risk Factors for a Severe COVID‐19 Outcome
Thirty‐eight (4.5%) patients were admitted to an ICU (7 of them died); 99 cases (11.7%) of radiologically documented pneumonia were reported; 96 patients (11.4%) were hospitalized. Forty‐four patients (5.2%) were in the highest severity class (death or ICU admission), and 92 patients (10.9%) were in the intermediate severity class (pneumonia or hospitalization). Twenty‐six patients (3.1%) received methylprednisolone in the month preceding the first symptoms of COVID‐19.
Risk factors for severe COVID‐19 in univariate, multivariate, and PS‐weighted analysis are reported in Table 4. The assumptions of proportional odds were satisfied. Older age, male sex, higher EDSS, longer MS duration, presence of comorbidities, and progressive MS course were all risk factors for a more severe disease in univariate analysis. Methylprednisolone use within 1 month before COVID‐19 symptoms onset was associated with increased risk (OR = 3.38, 95% confidence interval [CI] = 1.49–7.67, p = 0.004). Taking no therapy as the reference category indicated a reduced risk for all the DMTs, with OR ranging from 0.34 to 0.50, except for the anti‐CD20 therapies (ocrelizumab/rituximab, OR = 0.94). When adjusting the OR in the multivariate model, the risk factors with a significant impact on COVID‐19 severity were age, sex, EDSS, recent use of methylprednisolone, and anti‐CD20 therapy. Age and EDSS fully explained the apparent risk associated with no therapy as compared to the other DMTs, and the only treatment associated with a higher risk of a severe COVID‐19 disease was anti‐CD20 therapy (OR = 2.37, 95% CI = 1.18–4.74, p = 0.015). Also, the increased risk associated with the use of recent methylprednisolone was confirmed (OR = 5.24, 95% CI = 2.20–12.53, p = 0.001). The PS‐weighted characteristics of patients according to the different DMTs received are reported in Supplementary Table S11. The DMT effects on COVID‐19 severity are replicated by the PS‐weighted analysis. The OR for anti‐CD20 therapy was 3.91 (95% CI = 1.71–8.91, p = 0.001).
TABLE 4 Univariate, Multivariate, and PS‐Weighted Ordinal Logistic Regression Models Evaluating Risk Factors for Severe Coronavirus Disease 2019 a
Univariate Analysis, n = 844 b Multivariate Analysis, n = 844 b PS Analysis, n = 844 b
Variable OR (95% CI) p OR (95% CI) p OR (95% CI) p
Age, yr 1.06 (1.04–1.08) <0.001 1.06 (1.03–1.08) <0.001 1.06 (1.03–1.10) 0.001
Sex, F vs M 0.64 (0.40–1.03) 0.068 0.69 (0.45–1.04) 0.076 0.83 (0.50–1.39) 0.49
Progressive vs RRMS 4.14 (2.70–6.35) <0.001 1.59 (0.81–3.01) 0.18 1.76 (0.70–4.40) 0.23
EDSS 1.33 (1.22–1.45) <0.001 1.07 (0.93–1.22) 0.40 1.08 (0.86–1.35) 0.50
Disease duration, yr 1.04 (1.02–1.06) <0.011 1.00 (0.98–1.03) 0.99 0.99 (0.96–1.02) 0.57
BMI 1.01 (0.97–1.05) 0.53 0.98 (0.94–1.02) 0.44 0.99 (0.93–1.02) 0.74
Comorbidities, yes 1.70 (1.13–2.56) 0.012 0.93 (0.58–1.47) 0.74 0.82 (0.48–1.42) 0.48
Methylprednisolone c 3.38 (1.49–7.67) 0.004 5.24 (2.20–12.53) 0.001 2.51 (0.99–6.44) 0.05
DMT
No therapy d 1 (ref) 1 (ref) 1 (ref)
Interferon 0.35 (0.15–0.79) 0.012 0.67 (0.28–1.65) 0.39 0.71 (0.29–1.78) 0.48
Glatiramer‐acetate 0.34 (0.14–0.81) 0.015 0.77 (0.29–2.00) 0.59 1.19 (0.30–4.87) 0.80
Teriflunomide 0.48 (0.21–1.07) 0.07 0.86 (0.36–2.08) 0.74 1.17 (0.41–3.63) 0.76
Dimethyl fumarate 0.38 (0.20–0.70) 0.002 1.12 (0.55–2.30) 0.75 1.29 (0.58–2.87) 0.62
Natalizumab 0.35 (0.16–0.76) 0.009 1.30 (0.53–3.22) 0.57 1.77 (0.61–5.07) 0.29
Fingolimod 0.50 (0.26–0.98) 0.04 1.19 (0.57–2.52) 0.64 1.48 (0.66–3.34) 0.34
Anti‐CD20 e 0.94 (0.52–1.08) 0.85 2.37 (1.18–4.74) 0.015 3.91 (1.71–8.91) 0.001
Other 0.38 (0.14–1.04) 0.06 0.71 (0.28–2.65) 0.39 1.50 (0.40–5.71) 0.55
a Intensive care unit or death vs hospitalization or pneumonia vs milder symptoms not requiring hospitalization and no documented pneumonia.
b All the analyses are adjusted for macroregion (Lombardy; Northern Italy, including Veneto, Emilia‐Romagna, Piedmont, and Liguria; and the rest of Italy).
c One month before symptoms onset.
d No therapy was chosen as the reference class.
e Ocrelizumab or rituximab.
BMI = body mass index; CI = confidence interval; DMT = disease‐modifying therapy; EDSS = Expanded Disability Status Scale; F = female; M = male; OR = odds ratio; PS = propensity score; RRMS = relapsing–remitting multiple sclerosis.
The results taking dimethyl fumarate as the reference category are reported in the Supplementary Appendix and are in line with the above results. All the sensitivity analyses confirmed these findings; the anti‐CD20–treated patients had an OR = 2.62 (p = 0.05) in the subgroup of confirmed cases, an OR = 2.87 (p = 0.03) in the subgroup of RRMS patients, and an OR = 2.69 (p = 0.026) using only complete baseline data with no imputation (Supplementary Appendix).
A further result that deserves attention is the risk reduction observed in patients treated with interferon (OR = 0.67); however, this does not reach a statistical significance. Among the 73 patients on interferon, no ICU admissions or deaths were recorded.
To give an idea of the absolute risk of severe COVID‐19 according to DMT, Figure 1 reports the percentage of patients with severe events (pneumonia, hospitalization, ICU, or death) in the group treated with anti‐CD20, in the untreated group, and in the group treated with other DMTs. To adjust these values for the confounding factors, the figure was restricted to patients <65 years old and with EDSS < 6.5 (n = 733), and presented separately for the RRMS (n = 675) and progressive MS (n = 58) groups. The percentage of subjects with severe events was higher in the group of patients treated with anti‐CD20 both in the RRMS and in the progressive MS patients; in the RRMS group, the proportion of patients deceased or admitted to ICU in the anti‐CD20 group was 6.1%, versus 4.2% in the untreated and 2.2% in the other DMTs group. In the progressive MS group, it was 12.5% in the anti‐CD20 group, 10.5% in the untreated group, and 4.3% in the other DMTs group. The percentage of patients with an intermediate severity (pneumonia or hospitalization) had the same trend of increase in the anti‐CD20 group.
FIGURE 1 Percentage of patients with pneumonia/hospitalization and intensive care unit (ICU)/death in the subgroup of subjects with age < 65 years and Expanded Disability Status Scale < 6.5, according to multiple sclerosis (MS) phenotype (relapsing–remitting vs progressive MS), in the anti‐CD20, no therapy, and other therapies groups. DMT = disease‐modifying therapy.
The increase of risk associated with anti‐CD20 was maintained on hard end points (death or ICU admission), even if the small number of events did not allow this to reach statistical significance (Supplementary Appendix).
The adjusted OR for anti‐CD20 therapy versus all the other therapies was 2.37 (95% CI = 1.36–4.12, p = 0.002). Exploratory analyses revealed no association between COVID‐19 severity and the time passed since the last anti‐CD20 infusion (OR = 2.77, 95% CI = 1.31–5.89, p = 0.012 for last infusion within 3 months and OR = 2.05, 95% CI = 0.97–4.28, p = 0.023 for last infusion before 3 months), whereas there was a trend with therapy duration; as compared to PwMS treated with other therapies, patients on anti‐CD20 therapy for <6 months had an OR = 1.65 (95% CI = 0.56–4.90, p = 0.36), patients on anti‐CD20 therapy for 6–12 months had an OR = 2.24 (95% CI = 0.91–5.55, p = 0.08), and patients on anti‐CD20 therapy for >12 months had an OR = 2.98 (95% CI = 1.37–6.46, p = 0.006; Supplementary Appendix).
No severe outcomes (no pneumonia, hospitalization, ICU, or death) were observed in the 11 patients treated with cladribine or in the 14 patients treated with alemtuzumab.
Discussion
This study shows an acceptable level of safety of immunomodulatory and immunosuppressive therapies in MS during the COVID‐19 pandemic. However, two results deserve attention.
First, 11 of 13 deaths occurred in persons with advanced disease and disability (median EDSS = 7). The median age of people who died was 63 years versus a median age of 45 years for those who recovered. Higher EDSS was associated in multivariate analysis with COVID‐19 severity also in the French MS population. 3 These findings strengthen the need to enforce prevention strategies for people with advanced disability and older age during the pandemic. 11
Second, we observed an increased frequency of a severe COVID‐19 in people treated with anti‐CD20 therapies compared to other DMTs. Smaller case series suggested an increased susceptibility to COVID‐19 in PwMS taking B‐cell–depleting monoclonal antibodies, 12 , 13 , 14 without major effects on the severity of COVID‐19. 13 , 14 , 15 In the largest study published so far (the French study), DMT exposure was not included in the multivariate model. The results of the univariate analysis are very similar to those presented here. 3 It will be informative to evaluate the OR for the impact of DMTs on severity in the French cohort in the multivariate model, to check the size of effect, irrespective of the statistical significance. Data are available about the general risk of infections during DMTs for MS; a nationwide Swedish cohort examined the infection risks in PwMS treated with DMTs. 16 In that study, rituximab was associated with the highest rate of serious infections. However, the use of herpes antivirals was lower with rituximab compared to fingolimod and natalizumab; ocrelizumab clinical trials reported an increased risk of respiratory tract infections, 17 , 18 and safety issues emerged in diseases other than MS. 19 With respect to the association with treatment duration, it has been shown that long‐term anti‐CD20 treatment is associated with the risk of hypogammaglobulinemia in neuromyelitis optica‐spectrum disorder. 20 A protracted treatment may impact on the protective, anti–SARS‐CoV‐2 humoral response 21 and on a pre‐existing humoral and cellular immune repertoire, recently described in unexposed individuals. 22 , 23
We did not observe a link between time to last infusion of ocrelizumab and COVID‐19 risk. This preliminary result needs to be confirmed, but it is consistent with the idea that the immunological effects of ocrelizumab may last longer than 6 months. Reducing the frequency of dosing, or adjusting it according to the monitoring of B‐cell repopulation kinetics in individual patients, 20 may maintain efficacy while limiting the risk of infection. 24 A similar strategy deserves attention also in view of future vaccinations. 25 However, it may not be without risks linked to the re‐expansion of autoreactive B cells. 26
The role of interferon treatment and the severity of COVID‐19 is of high interest. Our data indicated a decrease of risk associated with interferon, even if it did not reach statistical significance. The majority of laboratory studies are in line with this preliminary observation, suggesting that supplementing type I interferons may circumvent a defective response that, in people with severe COVID‐19, may depend on various mechanisms including the presence of anti‐interferon autoantibodies, 27 a genetically defective type I interferon response, 28 , 29 or the ability of SARS‐CoV‐2 to neutralize the antiviral effects of type I interferons. 30 A recent clinical trial of interferon beta‐1b and lopinavir–ritonavir in Middle East respiratory syndrome 31 supports this hypothesis, but a negative trial of interferon beta‐1b, alone or in combination with lopinavir, does not. 32 It is possible that timing in the administration of type I interferons is crucial, as early therapy is associated with favorable clinical responses. 33 This is in accord with our observation in patients who are already under interferon beta therapy when they develop COVID‐19.
Importantly, methylprednisolone in the month preceding the first symptoms of COVID‐19 was significantly associated with a worse outcome. This aspect was not considered in previous reports, is in agreement with data in other autoimmune diseases, 34 and is relevant in assessing the risk of DMTs (ie, COVID‐19 risk vs steroid‐sparing potential).
This study has limitations that must be considered when evaluating the results. First, we included in the study not only confirmed but also suspected cases. For this reason, we cannot exclude that the suspected cases suffered from infections other than COVID‐19. We took the decision of including suspected cases because, during the pandemic peak in Italy, only the most severe cases (often after hospitalization) were tested. Hence, including only confirmed cases would have limited the representativeness of our sample. The inclusion of patients suffering from non–COVID‐19 infections might have diluted the effect of the detected association, resulting in a conservative approach. Furthermore, we reran all the main analyses on the subgroup of confirmed cases, obtaining similar and even stronger results, despite the smaller sample size. A second relevant bias might derive from differences in awareness and expectations of risks in patients receiving therapies with stronger immunosuppressive effect. This might have favored more frequent contacts with treating neurologists, resulting in increased attention to ocrelizumab or rituximab patients. However, the same should have been true also for other intravenous therapies. Finally, although the multivariate analysis adjusts the effect of DMTs on COVID‐19 severity for the main confounding factors, we cannot exclude that some residual confounding can partly explain the observed associations.
Overall, this study shows an acceptable safety profile of DMTs in MS during the COVID‐19 pandemic. The differences that emerged among the various DMTs are in agreement with previous knowledge about infections in PwMS. The results are also plausible based on current biological knowledge, although the exact mechanisms that affect the risk of COVID‐19 remain uncertain. It will be important to look at other ongoing studies 35 to verify whether they confirm our findings and to compare the new clinical insight in other autoimmune diseases. This may stimulate new laboratory research and shed new light on the biology of SARS‐CoV‐2 infection and on the pathophysiology of the different autoimmune diseases.
Author Contributions
All authors contributed to the conception and design of the study; the Musc‐19 Study Group contributed to the acquisition and analysis of data; M.P.S., I.S., L.C., and M.S. contributed to drafting the text and preparing the figures.
Potential Conflicts of Interest
M.P.S. reports a grant from Roche to cover data management of this study; Roche makes ocrelizumab, which is one of the DMTs assessed in this study. The remaining authors have nothing to report.
Supporting information
APPENDIX S1. Supporting Information
Click here for additional data file.
Acknowledgments
The Musc‐19 Study Group thanks Roche for donating the web‐based platform for data collection and the Department of Informatics, Bioengineering, Robotics, and Systems Engineering, University of Genoa, for its help in installing the platform. | FINGOLIMOD | DrugsGivenReaction | CC BY-NC | 33480077 | 19,620,789 | 2021-04 |
What was the outcome of reaction 'COVID-19'? | Disease-Modifying Therapies and Coronavirus Disease 2019 Severity in Multiple Sclerosis.
This study was undertaken to assess the impact of immunosuppressive and immunomodulatory therapies on the severity of coronavirus disease 2019 (COVID-19) in people with multiple sclerosis (PwMS).
We retrospectively collected data of PwMS with suspected or confirmed COVID-19. All the patients had complete follow-up to death or recovery. Severe COVID-19 was defined by a 3-level variable: mild disease not requiring hospitalization versus pneumonia or hospitalization versus intensive care unit (ICU) admission or death. We evaluated baseline characteristics and MS therapies associated with severe COVID-19 by multivariate and propensity score (PS)-weighted ordinal logistic models. Sensitivity analyses were run to confirm the results.
Of 844 PwMS with suspected (n = 565) or confirmed (n = 279) COVID-19, 13 (1.54%) died; 11 of them were in a progressive MS phase, and 8 were without any therapy. Thirty-eight (4.5%) were admitted to an ICU; 99 (11.7%) had radiologically documented pneumonia; 96 (11.4%) were hospitalized. After adjusting for region, age, sex, progressive MS course, Expanded Disability Status Scale, disease duration, body mass index, comorbidities, and recent methylprednisolone use, therapy with an anti-CD20 agent (ocrelizumab or rituximab) was significantly associated (odds ratio [OR] = 2.37, 95% confidence interval [CI] = 1.18-4.74, p = 0.015) with increased risk of severe COVID-19. Recent use (<1 month) of methylprednisolone was also associated with a worse outcome (OR = 5.24, 95% CI = 2.20-12.53, p = 0.001). Results were confirmed by the PS-weighted analysis and by all the sensitivity analyses.
This study showed an acceptable level of safety of therapies with a broad array of mechanisms of action. However, some specific elements of risk emerged. These will need to be considered while the COVID-19 pandemic persists. ANN NEUROL 2021;89:780-789.
The COVID‐19 pandemic and the many questions about the postpandemic period complicate the management of patients who need therapies that impact on the immune system. Data available so far are overall reassuring, excluding major safety issues. 1 , 2 , 3 , 4 However, the robustness of results is not optimal due to the relatively small samples, collected in a situation of urgency. Furthermore, for most of the autoimmune diseases, many possible therapies are available, thus increasing the heterogeneity of the datasets. It is therefore necessary to rely on larger and better characterized case series to improve data quality and relevance. The results will inform clinical decisions that will have a long‐term impact, given the chronicity of the diseases, the duration of therapies, and the long‐lasting effects of some treatments.
Multiple sclerosis (MS) is the major cause of neurological disability in young adults, with approximately 2.3 million people affected worldwide. 5 Up to 70% of people with MS (PwMS) are treated with disease‐modifying therapies (DMTs) that impact on the immune response and may carry an increased probability of infection. 6 This risk must be balanced against the consequences of poorly controlled MS. Hence, reliably assessing the risk of coronavirus disease 2019 (COVID‐19) in these patients is an important public health issue, and more data are needed to guide clinical practice, as pointed out in recent reviews. 7 So far, the largest study based on data is the paper on the French cohort, 3 but the sample size did not allow drawing conclusions about the association of DMTs and COVID‐19 severity.
We present the results of an observational study on PwMS with a confirmed or suspected COVID‐19 infection, based on clinician‐reported data. The study was conducted in Italy, a high‐prevalence area for MS 8 that was the first European country to suffer the effects of the pandemic. The results are presented after the preplanned sample size needed to reach conclusions on the effect of DMTs on COVID‐19 severity was reached.
Patients and Methods
Data Sources
We obtained clinician‐reported demographic and clinical data on PwMS with a confirmed or suspected COVID‐19 infection from 85 Italian MS centers (Supplementary Table S2). We used a common web‐based electronic case report form (eCRF) to collect the data and a unified protocol to analyze them. Data were obtained after data‐sharing agreements between the Italian MS Society, the Italian Neurological Society, the University of Genoa, and all the MS centers involved. Demographic, MS history, COVID‐19 infection, and follow‐up data were collected. The study was approved by the regional ethics committee of Liguria (University of Genoa; n 130/2020–DB id 10433) and at a national level by the Italian Medicines Agency.
Study Population
We included adult MS patients who had been in contact with their neurologist because of a confirmed or suspected infection by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) during the observation period (January 15 to September 10, 2020). The confirmed cases were those with a positive test (reverse transcriptase polymerase chain reaction on nasal and pharyngeal swabs) for SARS‐CoV‐2 or a positive serological test obtained at any point during the observation period; the suspected cases were those who had radiological findings or symptoms highly suggestive of SARS‐CoV‐2 infection, according to medical judgment (cough, fever, shortness of breath, sudden onset of anosmia, ageusia, dysgeusia), and/or had close contact with a confirmed COVID‐19 case in the 14 days prior to the onset of symptoms. Data were collected retrospectively from the first contact until an outcome (death or recovery), taking as baseline the day of symptoms appearance. The first contact was a hospital visit, a phone call, or a web‐based visit, upon patients' or clinicians' request. Clinicians collected data by reviewing patients' clinical charts.
Variables Assessed
Collected data are detailed in the eCRF. We collected demographic data, including age, sex, body mass index (BMI), patient‐reported race and ethnic group, work status, number of cohabitants and number of cohabitants positive for SARS‐CoV‐2 infection, patient‐reported smoking and drinking status, and comorbidities; MS history data, including type of MS (relapsing–remitting MS [RRMS], primary progressive, or secondary progressive), disease onset date, Expanded Disability Status Scale (EDSS), DMTs at the date of symptoms start, and date of last treatment dose; and COVID‐19 infection data, including suspected geographic area of infection, symptoms, laboratory and radiological data, hospitalization, pneumonia and severity of pneumonia according to radiological examinations and ventilation support, therapies for COVID‐19, intensive care unit (ICU) admission, and recovery or death.
Each week a query for follow up update was sent to all centers, until they filled the outcome report (death or recovery).
End Points
We run 2 main analyses on the following primary endpoints: (1) observed number of deaths over the whole follow‐up; and (2) severe COVID‐19 characterized by a 3‐level variable; the highest severity level was death or ICU admission, the intermediate severity level was diagnosis of pneumonia or hospitalization, and the lowest severity level was a milder disease with no need for hospitalization or documented diagnosis of pneumonia.
Statistical Analysis
The web‐based data collection started on March 1, 2020 and closed for the analysis on September 10, 2020. The first date of symptom appearance retrospectively reported was January 15, 2020. All the patients had complete follow‐up to death or recovery.
For the sample size calculations, we determined that 800 patients were needed, assuming a rate of severe outcomes (death, ICU admission, pneumonia, or hospitalization) of 20% in the reference group and a comparison group made of 15% of the full cohort, to have a power of 90% to detect an increased risk of severe outcome in the comparison group quantified by an odds ratio (OR) = 2.0 at a confidence level of 0.05.
To make efficient use of the available data, we used multiple imputation of missing values for missing baseline data. Imputation was performed using chained equations, 9 where each incomplete variable is imputed by a separate model and implemented trough the "mice" R package. Continuous variables (age, height, weight, BMI, and disease duration) were parameterized as numeric data and imputed with the predictive mean matching method, whereas polytomous logistic regression was used for the unordered categorical variables (such as MS phenotype). EDSS and disease duration were used to impute the MS phenotype; age and MS phenotype were used to impute disease duration; age, height, or weight was used to impute BMI.
To assess risk factors at symptoms onset for a severe disease course, we ran a multivariate ordinal logistic regression assuming proportional ORs with severe outcome (defined as a 3‐level factor) as the dependent variable, after assessing that the assumptions of proportional odds were satisfied. The ORs reflect the multiplicative change in the odds of being at a higher level of the dependent variable for every one‐unit increase of the independent variable. The multivariate model included age, sex, BMI, EDSS, disease duration, MS disease phase (RRMS vs progressive), presence of comorbidities, methylprednisolone use within 1 month since COVID‐19 symptoms onset, and DMT class as independent variables, stratified by macroregion (defined as Lombardy; Northern Italy, including Piedmont, Veneto, Emilia‐Romagna, and Liguria; and the rest of Italy). DMT class was coded as an 8‐level variable as no therapy, interferon, glatiramer‐acetate, teriflunomide, dimethyl fumarate, natalizumab, anti‐CD20 (rituximab or ocrelizumab), or other. Alemtuzumab and cladribine were grouped in the “other” group, because the number of patients in these two therapeutic arms was too low to draw meaningful conclusions. “No therapy” was used as the reference category. We also ran the same ordinal logistic analysis after a multinomial propensity score (PS) weighting, as an alternative method to balance the differences of baseline characteristics among patients treated with different DMTs. The weights were calculated using an iterative robust approach based on the Generalized Boosted Model (GBM). 10 The balance among treatment groups was defined by the standardized mean difference, and the optimal GBM iteration was found by minimizing this quantity.
Results were also presented taking dimethyl fumarate, which is the most frequently used therapy in Italy, as the reference therapy group (Supplementary Appendix). Additional analyses were focused on the anti‐CD20 therapies using the same multivariate ordinal logistic model adjusted for all the baseline variables; we investigated the effect of being on anti‐CD20 versus not being on anti‐CD20, the effect of the distance from last infusion (0–3 months, >3 months), and the effect of the time since therapy start (<6 months, 6–12 months, >12 months).
Sensitivity analyses were run by repeating all the analyses on the subgroup of confirmed cases only, in the subgroup of patients with a RRMS course, in a model including only patients with complete baseline data with no imputation and using a leave one out procedure rerunning the analysis excluding one of the 3 major centers (Brescia, Bergamo, Milan) at a time (Supplementary Appendix).
Role of the Funding Source
Roche donated the web‐based platform for data collection. Roche did not have any role in study design; in analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.
Results
Patients Characteristics
On September 10, 844 PwMS with complete follow‐up from first contact to the outcome (recovery or death) from 85 centers were included in the dataset (Supplementary Appendix). Thirty‐four percent (286/844) of patients were from 3 centers in Lombardy (ASST Spedali Civili, Brescia‐Montichiari; Papa Giovanni XXIII Hospital, Bergamo; and San Raffaele Hospital, Milan); the distribution of patients by region is shown in Supplementary Table S3.
Table 1 reports the baseline demographic and clinical characteristics of the cohort. The mean age was 45 years (range = 18–82), the percentage of females was 70.3%, the median EDSS was 2 (interquartile range [IQR] = 1.50–4), and the proportion of progressive patients was 16%. Six hundred ninety‐three (82%) patients were treated with a DMT at the time of COVID‐19 presumed symptoms onset.
TABLE 1 Baseline Demographic and Clinical Characteristics of Included Patients
Characteristic Overall, N = 844 Suspected, n = 565 Confirmed, n = 279
Age, n (%)
<40 yr 279 (33.1) 203 (35.9) 76 (27.2)
40–59 yr 471 (55.8) 312 (55.2) 159 (57.0)
60–79 yr 92 (10.9) 50 (8.8) 42 (15.1)
≥80 yr 2 (0.2) 0 (0.0) 2 (0.7)
Female sex, n (%) 593 (70.3) 410 (72.6) 183 (65.6)
BMI, mean (SD) 23.82 (4.37) 23.61 (4.37) 24.28 (4.37)
Comorbidities, n (%) 188 (22.3) 115 (20.4) 73 (26.2)
MS phenotype, n (%)
Primary progressive 44 (5.2) 24 (4.2) 20 (7.2)
Relapsing–remitting 676 (80.1) 469 (83.0) 207 (74.2)
Secondary progressive 91 (10.8) 46 (8.1) 45 (16.1)
Missing data 33 (3.9) 26 (4.6) 7 (2.5)
MS disease duration, median (IQR) 10.2 (4.7–17.1) 9.6 (4.3–16.2) 11.8 (5.4–18.5)
EDSS, median (IQR) 2 (1.50–4) 2 (1.50–3.50) 2 (1.50–4)
MS treatment, n (%)
Dimethyl fumarate 174 (20.6) 131 (23.2) 43 (15.4)
Fingolimod 94 (11.1) 59 (10.4) 35 (12.5)
Ocrelizumab 89 (10.5) 58 (10.3) 31 (11.1)
Natalizumab 85 (10.1) 51 (9.0) 34 (12.2)
Interferon 73 (8.6) 52 (9.2) 21 (7.5)
Copaxone 70 (8.3) 52 (9.2) 18 (6.5)
Teriflunomide 64 (7.6) 37 (6.5) 27 (9.7)
Alemtuzumab 14 (1.7) 11 (1.9) 3 (1.1)
Cladribine 11 (1.3) 7 (1.2) 4 (1.4)
Azathioprine 10 (1.2) 4 (0.7) 6 (2.2)
Rituximab 5 (0.6) 4 (0.7) 1 (0.4)
Methotrexate 1 (0.1) 1 (0.2) 0 (0.0)
Mitoxantrone 1 (0.1) 1 (0.2) 0 (0.0)
Other 2 (0.2) 2 (0.4) 0 (0.0)
None 151 (17.9) 95 (16.8) 56 (20.1)
Previous methylprednisolone, n (%) 26 (3.1) 16 (2.8) 10 (3.6)
BMI = body mass index; EDSS = Expanded Disability Status Scale; IQR = interquartile range; MS = multiple sclerosis; SD = standard deviation.
Three hundred eighty‐four patients (45.5%) had at least one laboratory test executed for the COVID‐19 diagnosis; 307 (36.4%) patients were tested in the active phase with a swab and 127 (15.0%) had a serological test after recovery. Overall, 279 (33.1%) were classified as confirmed cases. Because the test during the pandemic peak was done only in the most severe patients, confirmed cases are expected to be more severe than suspected cases. In the confirmed cases subgroup, there was a higher proportion of older subjects than in the suspected cases subgroup (>60 years = 16% vs 9%) and more patients in the progressive MS phase (23% vs 12%).
The baseline characteristics of the cohort according to DMT received are reported in Table 2; patients with no therapy were older (mean age = 53.4 years), with a higher EDSS (mean EDSS = 5.5) and with a higher proportion of progressive patients (45.7%) than patients treated with DMTs. Among treated patients, those treated with interferon, glatiramer‐acetate, or teriflunomide were older than those in other DMT groups, and patients treated with anti‐CD20 had a higher EDSS (mean EDSS = 3) and a larger portion of progressive patients (25.6%) than those treated with other DMTs, but not larger than the untreated group.
TABLE 2 Baseline Demographic and Clinical Characteristics of Included Patients according to Disease‐Modifying Therapy Received
Characteristic No Therapy, n = 151 IFN, n = 73 GA, n = 70 Teri, n = 64 DMF, n = 174 FTY, n = 94 Nat, n = 85 Anti‐CD20, n = 94 a Other, n = 39
Age, mean (SD) 53.4 (13.4) 47.5 (10.5) 45.7 (11.3) 49.1 (9.4) 41.4 (10.9) 44.2 (9.5) 37.9 (9.8) 42.0 (10.0) 42.2 (13.8)
Female sex, n (%) 104 (68.9) 53 (72.6) 48 (68.6) 44 (68.8) 114 (65.5) 74 (78.7) 64 (75.3) 64 (68.1) 28 (71.8)
BMI, mean (SD) 24.6 (4.6) 24.3 (2.7) 25.2 (5.0) 24.7 (4.5) 23.3 (4.1) 23.9 (5.2) 22.7 (4.1) 22.6 (3.7) 23.2 (3.8)
MS phenotype, n (%)
Primary progressive 22 (14.6) 0 (0.0) 1 (1.4) 0 (0.0) 0 (0.0) 2 (2.1) 1 (1.2) 16 (17.0) 2 (5.1)
Relapsing–remitting 65 (43.0) 65 (89.0) 64 (91.4) 59 (92.2) 165 (94.8) 81 (86.2) 83 (97.6) 67 (71.3) 27 (69.2)
Secondary progressive 47 (31.1) 6 (8.2) 2 (2.9) 3 (4.7) 5 (2.9) 9 (9.6) 0 (0.0) 9 (9.6) 10 (25.6)
Missing data 17 (11.3) 2 (2.7) 3 (4.3) 2 (3.1) 4 (2.3) 2 (2.1) 1 (1.2) 2 (2.1) 0 (0.0)
MS disease duration, median yr (IQR) 16.2 (8–23) 12.0 (6–19) 10.1 (5–17) 11.4 (6–15) 5.5 (3–13) 11.8 (7–18) 9.1 (5–15) 8.2 (4–13) 12.9 (5–18)
EDSS, median (IQR) 5.5 (2–7) 1.5 (1–2.5) 1.5 (1–2) 2.0 (1.5–3) 1.5 (1–2) 2.0 (1.5–3) 2.0 (1.5–3) 3.0 (1.5–4.5) 3.0 (1.5–6)
Methylprednisolone, b n (%) 9 (6.0) 2 (2.7) 1 (1.4) 2 (3.1) 4 (2.3) 4 (4.3) 1 (1.2) 1 (1.1) 2 (5.1)
a Ocrelizumab or rituximab.
b One month before symptoms onset.
BMI = body mass index; DMF = dimethyl fumarate; EDSS = Expanded Disability Status Scale; FTY = fingolimod; GA = glatiramer‐acetate; IFN = interferon; IQR = interquartile range; MS = multiple sclerosis; Nat = natalizumab; SD = standard deviation; Teri = teriflunomide.
Thirteen (1.54%) patients died, and their characteristics are described in Table 3; 8 of them were PwMS with no therapy, all in a progressive disease phase (1 primary progressive MS, 7 secondary progressive MS). Five of them were treated (rituximab, ocrelizumab, natalizumab, glatiramer‐acetate, dimethyl fumarate), and only 2 of them were in a RRMS phase (glatiramer‐acetate and natalizumab). The mean time from symptoms to death was 18 days (range = 5–54 days).
TABLE 3 Characteristics of Deceased Patients
Sex, Age, yr Disease Duration Disease Phase EDSS Therapy Comorbidities
M, 63 33 SPMS 7 No therapy Diabetes
M, 67 2 PPMS 7.5 No therapy CHD, hypertension, HBV
M, 68 21 SPMS 6 Dimethyl fumarate Cerebrovascular disease, hypertension, depression, TBC
F, 57 20 SPMS 9 No therapy No
M, 76 17 SPMS 6.5 No therapy CHD, hypertension, depression, dyslipidemia
F, 52 1 RRMS 5 Natalizumab No
F, 50 27 SPMS 6 Ocrelizumab No
M, 59 33 SPMS 9 No therapy No
F, 68 19 SPMS 5.5 No therapy No
F, 54 20 SPMS 7 Rituximab No
M, 64 10 RRMS 2 Glatiramer‐acetate No
M, 63 33 SPMS 6.5 No therapy Diabetes, bipolar disorder
M, 60 30 SPMS 9 No therapy Hypertension, cerebrovascular disease, CHD
CHD = coronary heart disease; F = female; HBV = hepatitis B virus; M = male; PPMS = primary progressive multiple sclerosis; RRMS = relapsing–remitting multiple sclerosis; SPMS = secondary progressive multiple sclerosis; TBC = tuberculosis.
Risk Factors for a Severe COVID‐19 Outcome
Thirty‐eight (4.5%) patients were admitted to an ICU (7 of them died); 99 cases (11.7%) of radiologically documented pneumonia were reported; 96 patients (11.4%) were hospitalized. Forty‐four patients (5.2%) were in the highest severity class (death or ICU admission), and 92 patients (10.9%) were in the intermediate severity class (pneumonia or hospitalization). Twenty‐six patients (3.1%) received methylprednisolone in the month preceding the first symptoms of COVID‐19.
Risk factors for severe COVID‐19 in univariate, multivariate, and PS‐weighted analysis are reported in Table 4. The assumptions of proportional odds were satisfied. Older age, male sex, higher EDSS, longer MS duration, presence of comorbidities, and progressive MS course were all risk factors for a more severe disease in univariate analysis. Methylprednisolone use within 1 month before COVID‐19 symptoms onset was associated with increased risk (OR = 3.38, 95% confidence interval [CI] = 1.49–7.67, p = 0.004). Taking no therapy as the reference category indicated a reduced risk for all the DMTs, with OR ranging from 0.34 to 0.50, except for the anti‐CD20 therapies (ocrelizumab/rituximab, OR = 0.94). When adjusting the OR in the multivariate model, the risk factors with a significant impact on COVID‐19 severity were age, sex, EDSS, recent use of methylprednisolone, and anti‐CD20 therapy. Age and EDSS fully explained the apparent risk associated with no therapy as compared to the other DMTs, and the only treatment associated with a higher risk of a severe COVID‐19 disease was anti‐CD20 therapy (OR = 2.37, 95% CI = 1.18–4.74, p = 0.015). Also, the increased risk associated with the use of recent methylprednisolone was confirmed (OR = 5.24, 95% CI = 2.20–12.53, p = 0.001). The PS‐weighted characteristics of patients according to the different DMTs received are reported in Supplementary Table S11. The DMT effects on COVID‐19 severity are replicated by the PS‐weighted analysis. The OR for anti‐CD20 therapy was 3.91 (95% CI = 1.71–8.91, p = 0.001).
TABLE 4 Univariate, Multivariate, and PS‐Weighted Ordinal Logistic Regression Models Evaluating Risk Factors for Severe Coronavirus Disease 2019 a
Univariate Analysis, n = 844 b Multivariate Analysis, n = 844 b PS Analysis, n = 844 b
Variable OR (95% CI) p OR (95% CI) p OR (95% CI) p
Age, yr 1.06 (1.04–1.08) <0.001 1.06 (1.03–1.08) <0.001 1.06 (1.03–1.10) 0.001
Sex, F vs M 0.64 (0.40–1.03) 0.068 0.69 (0.45–1.04) 0.076 0.83 (0.50–1.39) 0.49
Progressive vs RRMS 4.14 (2.70–6.35) <0.001 1.59 (0.81–3.01) 0.18 1.76 (0.70–4.40) 0.23
EDSS 1.33 (1.22–1.45) <0.001 1.07 (0.93–1.22) 0.40 1.08 (0.86–1.35) 0.50
Disease duration, yr 1.04 (1.02–1.06) <0.011 1.00 (0.98–1.03) 0.99 0.99 (0.96–1.02) 0.57
BMI 1.01 (0.97–1.05) 0.53 0.98 (0.94–1.02) 0.44 0.99 (0.93–1.02) 0.74
Comorbidities, yes 1.70 (1.13–2.56) 0.012 0.93 (0.58–1.47) 0.74 0.82 (0.48–1.42) 0.48
Methylprednisolone c 3.38 (1.49–7.67) 0.004 5.24 (2.20–12.53) 0.001 2.51 (0.99–6.44) 0.05
DMT
No therapy d 1 (ref) 1 (ref) 1 (ref)
Interferon 0.35 (0.15–0.79) 0.012 0.67 (0.28–1.65) 0.39 0.71 (0.29–1.78) 0.48
Glatiramer‐acetate 0.34 (0.14–0.81) 0.015 0.77 (0.29–2.00) 0.59 1.19 (0.30–4.87) 0.80
Teriflunomide 0.48 (0.21–1.07) 0.07 0.86 (0.36–2.08) 0.74 1.17 (0.41–3.63) 0.76
Dimethyl fumarate 0.38 (0.20–0.70) 0.002 1.12 (0.55–2.30) 0.75 1.29 (0.58–2.87) 0.62
Natalizumab 0.35 (0.16–0.76) 0.009 1.30 (0.53–3.22) 0.57 1.77 (0.61–5.07) 0.29
Fingolimod 0.50 (0.26–0.98) 0.04 1.19 (0.57–2.52) 0.64 1.48 (0.66–3.34) 0.34
Anti‐CD20 e 0.94 (0.52–1.08) 0.85 2.37 (1.18–4.74) 0.015 3.91 (1.71–8.91) 0.001
Other 0.38 (0.14–1.04) 0.06 0.71 (0.28–2.65) 0.39 1.50 (0.40–5.71) 0.55
a Intensive care unit or death vs hospitalization or pneumonia vs milder symptoms not requiring hospitalization and no documented pneumonia.
b All the analyses are adjusted for macroregion (Lombardy; Northern Italy, including Veneto, Emilia‐Romagna, Piedmont, and Liguria; and the rest of Italy).
c One month before symptoms onset.
d No therapy was chosen as the reference class.
e Ocrelizumab or rituximab.
BMI = body mass index; CI = confidence interval; DMT = disease‐modifying therapy; EDSS = Expanded Disability Status Scale; F = female; M = male; OR = odds ratio; PS = propensity score; RRMS = relapsing–remitting multiple sclerosis.
The results taking dimethyl fumarate as the reference category are reported in the Supplementary Appendix and are in line with the above results. All the sensitivity analyses confirmed these findings; the anti‐CD20–treated patients had an OR = 2.62 (p = 0.05) in the subgroup of confirmed cases, an OR = 2.87 (p = 0.03) in the subgroup of RRMS patients, and an OR = 2.69 (p = 0.026) using only complete baseline data with no imputation (Supplementary Appendix).
A further result that deserves attention is the risk reduction observed in patients treated with interferon (OR = 0.67); however, this does not reach a statistical significance. Among the 73 patients on interferon, no ICU admissions or deaths were recorded.
To give an idea of the absolute risk of severe COVID‐19 according to DMT, Figure 1 reports the percentage of patients with severe events (pneumonia, hospitalization, ICU, or death) in the group treated with anti‐CD20, in the untreated group, and in the group treated with other DMTs. To adjust these values for the confounding factors, the figure was restricted to patients <65 years old and with EDSS < 6.5 (n = 733), and presented separately for the RRMS (n = 675) and progressive MS (n = 58) groups. The percentage of subjects with severe events was higher in the group of patients treated with anti‐CD20 both in the RRMS and in the progressive MS patients; in the RRMS group, the proportion of patients deceased or admitted to ICU in the anti‐CD20 group was 6.1%, versus 4.2% in the untreated and 2.2% in the other DMTs group. In the progressive MS group, it was 12.5% in the anti‐CD20 group, 10.5% in the untreated group, and 4.3% in the other DMTs group. The percentage of patients with an intermediate severity (pneumonia or hospitalization) had the same trend of increase in the anti‐CD20 group.
FIGURE 1 Percentage of patients with pneumonia/hospitalization and intensive care unit (ICU)/death in the subgroup of subjects with age < 65 years and Expanded Disability Status Scale < 6.5, according to multiple sclerosis (MS) phenotype (relapsing–remitting vs progressive MS), in the anti‐CD20, no therapy, and other therapies groups. DMT = disease‐modifying therapy.
The increase of risk associated with anti‐CD20 was maintained on hard end points (death or ICU admission), even if the small number of events did not allow this to reach statistical significance (Supplementary Appendix).
The adjusted OR for anti‐CD20 therapy versus all the other therapies was 2.37 (95% CI = 1.36–4.12, p = 0.002). Exploratory analyses revealed no association between COVID‐19 severity and the time passed since the last anti‐CD20 infusion (OR = 2.77, 95% CI = 1.31–5.89, p = 0.012 for last infusion within 3 months and OR = 2.05, 95% CI = 0.97–4.28, p = 0.023 for last infusion before 3 months), whereas there was a trend with therapy duration; as compared to PwMS treated with other therapies, patients on anti‐CD20 therapy for <6 months had an OR = 1.65 (95% CI = 0.56–4.90, p = 0.36), patients on anti‐CD20 therapy for 6–12 months had an OR = 2.24 (95% CI = 0.91–5.55, p = 0.08), and patients on anti‐CD20 therapy for >12 months had an OR = 2.98 (95% CI = 1.37–6.46, p = 0.006; Supplementary Appendix).
No severe outcomes (no pneumonia, hospitalization, ICU, or death) were observed in the 11 patients treated with cladribine or in the 14 patients treated with alemtuzumab.
Discussion
This study shows an acceptable level of safety of immunomodulatory and immunosuppressive therapies in MS during the COVID‐19 pandemic. However, two results deserve attention.
First, 11 of 13 deaths occurred in persons with advanced disease and disability (median EDSS = 7). The median age of people who died was 63 years versus a median age of 45 years for those who recovered. Higher EDSS was associated in multivariate analysis with COVID‐19 severity also in the French MS population. 3 These findings strengthen the need to enforce prevention strategies for people with advanced disability and older age during the pandemic. 11
Second, we observed an increased frequency of a severe COVID‐19 in people treated with anti‐CD20 therapies compared to other DMTs. Smaller case series suggested an increased susceptibility to COVID‐19 in PwMS taking B‐cell–depleting monoclonal antibodies, 12 , 13 , 14 without major effects on the severity of COVID‐19. 13 , 14 , 15 In the largest study published so far (the French study), DMT exposure was not included in the multivariate model. The results of the univariate analysis are very similar to those presented here. 3 It will be informative to evaluate the OR for the impact of DMTs on severity in the French cohort in the multivariate model, to check the size of effect, irrespective of the statistical significance. Data are available about the general risk of infections during DMTs for MS; a nationwide Swedish cohort examined the infection risks in PwMS treated with DMTs. 16 In that study, rituximab was associated with the highest rate of serious infections. However, the use of herpes antivirals was lower with rituximab compared to fingolimod and natalizumab; ocrelizumab clinical trials reported an increased risk of respiratory tract infections, 17 , 18 and safety issues emerged in diseases other than MS. 19 With respect to the association with treatment duration, it has been shown that long‐term anti‐CD20 treatment is associated with the risk of hypogammaglobulinemia in neuromyelitis optica‐spectrum disorder. 20 A protracted treatment may impact on the protective, anti–SARS‐CoV‐2 humoral response 21 and on a pre‐existing humoral and cellular immune repertoire, recently described in unexposed individuals. 22 , 23
We did not observe a link between time to last infusion of ocrelizumab and COVID‐19 risk. This preliminary result needs to be confirmed, but it is consistent with the idea that the immunological effects of ocrelizumab may last longer than 6 months. Reducing the frequency of dosing, or adjusting it according to the monitoring of B‐cell repopulation kinetics in individual patients, 20 may maintain efficacy while limiting the risk of infection. 24 A similar strategy deserves attention also in view of future vaccinations. 25 However, it may not be without risks linked to the re‐expansion of autoreactive B cells. 26
The role of interferon treatment and the severity of COVID‐19 is of high interest. Our data indicated a decrease of risk associated with interferon, even if it did not reach statistical significance. The majority of laboratory studies are in line with this preliminary observation, suggesting that supplementing type I interferons may circumvent a defective response that, in people with severe COVID‐19, may depend on various mechanisms including the presence of anti‐interferon autoantibodies, 27 a genetically defective type I interferon response, 28 , 29 or the ability of SARS‐CoV‐2 to neutralize the antiviral effects of type I interferons. 30 A recent clinical trial of interferon beta‐1b and lopinavir–ritonavir in Middle East respiratory syndrome 31 supports this hypothesis, but a negative trial of interferon beta‐1b, alone or in combination with lopinavir, does not. 32 It is possible that timing in the administration of type I interferons is crucial, as early therapy is associated with favorable clinical responses. 33 This is in accord with our observation in patients who are already under interferon beta therapy when they develop COVID‐19.
Importantly, methylprednisolone in the month preceding the first symptoms of COVID‐19 was significantly associated with a worse outcome. This aspect was not considered in previous reports, is in agreement with data in other autoimmune diseases, 34 and is relevant in assessing the risk of DMTs (ie, COVID‐19 risk vs steroid‐sparing potential).
This study has limitations that must be considered when evaluating the results. First, we included in the study not only confirmed but also suspected cases. For this reason, we cannot exclude that the suspected cases suffered from infections other than COVID‐19. We took the decision of including suspected cases because, during the pandemic peak in Italy, only the most severe cases (often after hospitalization) were tested. Hence, including only confirmed cases would have limited the representativeness of our sample. The inclusion of patients suffering from non–COVID‐19 infections might have diluted the effect of the detected association, resulting in a conservative approach. Furthermore, we reran all the main analyses on the subgroup of confirmed cases, obtaining similar and even stronger results, despite the smaller sample size. A second relevant bias might derive from differences in awareness and expectations of risks in patients receiving therapies with stronger immunosuppressive effect. This might have favored more frequent contacts with treating neurologists, resulting in increased attention to ocrelizumab or rituximab patients. However, the same should have been true also for other intravenous therapies. Finally, although the multivariate analysis adjusts the effect of DMTs on COVID‐19 severity for the main confounding factors, we cannot exclude that some residual confounding can partly explain the observed associations.
Overall, this study shows an acceptable safety profile of DMTs in MS during the COVID‐19 pandemic. The differences that emerged among the various DMTs are in agreement with previous knowledge about infections in PwMS. The results are also plausible based on current biological knowledge, although the exact mechanisms that affect the risk of COVID‐19 remain uncertain. It will be important to look at other ongoing studies 35 to verify whether they confirm our findings and to compare the new clinical insight in other autoimmune diseases. This may stimulate new laboratory research and shed new light on the biology of SARS‐CoV‐2 infection and on the pathophysiology of the different autoimmune diseases.
Author Contributions
All authors contributed to the conception and design of the study; the Musc‐19 Study Group contributed to the acquisition and analysis of data; M.P.S., I.S., L.C., and M.S. contributed to drafting the text and preparing the figures.
Potential Conflicts of Interest
M.P.S. reports a grant from Roche to cover data management of this study; Roche makes ocrelizumab, which is one of the DMTs assessed in this study. The remaining authors have nothing to report.
Supporting information
APPENDIX S1. Supporting Information
Click here for additional data file.
Acknowledgments
The Musc‐19 Study Group thanks Roche for donating the web‐based platform for data collection and the Department of Informatics, Bioengineering, Robotics, and Systems Engineering, University of Genoa, for its help in installing the platform. | Fatal | ReactionOutcome | CC BY-NC | 33480077 | 19,299,189 | 2021-04 |
What was the outcome of reaction 'Coronavirus infection'? | Disease-Modifying Therapies and Coronavirus Disease 2019 Severity in Multiple Sclerosis.
This study was undertaken to assess the impact of immunosuppressive and immunomodulatory therapies on the severity of coronavirus disease 2019 (COVID-19) in people with multiple sclerosis (PwMS).
We retrospectively collected data of PwMS with suspected or confirmed COVID-19. All the patients had complete follow-up to death or recovery. Severe COVID-19 was defined by a 3-level variable: mild disease not requiring hospitalization versus pneumonia or hospitalization versus intensive care unit (ICU) admission or death. We evaluated baseline characteristics and MS therapies associated with severe COVID-19 by multivariate and propensity score (PS)-weighted ordinal logistic models. Sensitivity analyses were run to confirm the results.
Of 844 PwMS with suspected (n = 565) or confirmed (n = 279) COVID-19, 13 (1.54%) died; 11 of them were in a progressive MS phase, and 8 were without any therapy. Thirty-eight (4.5%) were admitted to an ICU; 99 (11.7%) had radiologically documented pneumonia; 96 (11.4%) were hospitalized. After adjusting for region, age, sex, progressive MS course, Expanded Disability Status Scale, disease duration, body mass index, comorbidities, and recent methylprednisolone use, therapy with an anti-CD20 agent (ocrelizumab or rituximab) was significantly associated (odds ratio [OR] = 2.37, 95% confidence interval [CI] = 1.18-4.74, p = 0.015) with increased risk of severe COVID-19. Recent use (<1 month) of methylprednisolone was also associated with a worse outcome (OR = 5.24, 95% CI = 2.20-12.53, p = 0.001). Results were confirmed by the PS-weighted analysis and by all the sensitivity analyses.
This study showed an acceptable level of safety of therapies with a broad array of mechanisms of action. However, some specific elements of risk emerged. These will need to be considered while the COVID-19 pandemic persists. ANN NEUROL 2021;89:780-789.
The COVID‐19 pandemic and the many questions about the postpandemic period complicate the management of patients who need therapies that impact on the immune system. Data available so far are overall reassuring, excluding major safety issues. 1 , 2 , 3 , 4 However, the robustness of results is not optimal due to the relatively small samples, collected in a situation of urgency. Furthermore, for most of the autoimmune diseases, many possible therapies are available, thus increasing the heterogeneity of the datasets. It is therefore necessary to rely on larger and better characterized case series to improve data quality and relevance. The results will inform clinical decisions that will have a long‐term impact, given the chronicity of the diseases, the duration of therapies, and the long‐lasting effects of some treatments.
Multiple sclerosis (MS) is the major cause of neurological disability in young adults, with approximately 2.3 million people affected worldwide. 5 Up to 70% of people with MS (PwMS) are treated with disease‐modifying therapies (DMTs) that impact on the immune response and may carry an increased probability of infection. 6 This risk must be balanced against the consequences of poorly controlled MS. Hence, reliably assessing the risk of coronavirus disease 2019 (COVID‐19) in these patients is an important public health issue, and more data are needed to guide clinical practice, as pointed out in recent reviews. 7 So far, the largest study based on data is the paper on the French cohort, 3 but the sample size did not allow drawing conclusions about the association of DMTs and COVID‐19 severity.
We present the results of an observational study on PwMS with a confirmed or suspected COVID‐19 infection, based on clinician‐reported data. The study was conducted in Italy, a high‐prevalence area for MS 8 that was the first European country to suffer the effects of the pandemic. The results are presented after the preplanned sample size needed to reach conclusions on the effect of DMTs on COVID‐19 severity was reached.
Patients and Methods
Data Sources
We obtained clinician‐reported demographic and clinical data on PwMS with a confirmed or suspected COVID‐19 infection from 85 Italian MS centers (Supplementary Table S2). We used a common web‐based electronic case report form (eCRF) to collect the data and a unified protocol to analyze them. Data were obtained after data‐sharing agreements between the Italian MS Society, the Italian Neurological Society, the University of Genoa, and all the MS centers involved. Demographic, MS history, COVID‐19 infection, and follow‐up data were collected. The study was approved by the regional ethics committee of Liguria (University of Genoa; n 130/2020–DB id 10433) and at a national level by the Italian Medicines Agency.
Study Population
We included adult MS patients who had been in contact with their neurologist because of a confirmed or suspected infection by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) during the observation period (January 15 to September 10, 2020). The confirmed cases were those with a positive test (reverse transcriptase polymerase chain reaction on nasal and pharyngeal swabs) for SARS‐CoV‐2 or a positive serological test obtained at any point during the observation period; the suspected cases were those who had radiological findings or symptoms highly suggestive of SARS‐CoV‐2 infection, according to medical judgment (cough, fever, shortness of breath, sudden onset of anosmia, ageusia, dysgeusia), and/or had close contact with a confirmed COVID‐19 case in the 14 days prior to the onset of symptoms. Data were collected retrospectively from the first contact until an outcome (death or recovery), taking as baseline the day of symptoms appearance. The first contact was a hospital visit, a phone call, or a web‐based visit, upon patients' or clinicians' request. Clinicians collected data by reviewing patients' clinical charts.
Variables Assessed
Collected data are detailed in the eCRF. We collected demographic data, including age, sex, body mass index (BMI), patient‐reported race and ethnic group, work status, number of cohabitants and number of cohabitants positive for SARS‐CoV‐2 infection, patient‐reported smoking and drinking status, and comorbidities; MS history data, including type of MS (relapsing–remitting MS [RRMS], primary progressive, or secondary progressive), disease onset date, Expanded Disability Status Scale (EDSS), DMTs at the date of symptoms start, and date of last treatment dose; and COVID‐19 infection data, including suspected geographic area of infection, symptoms, laboratory and radiological data, hospitalization, pneumonia and severity of pneumonia according to radiological examinations and ventilation support, therapies for COVID‐19, intensive care unit (ICU) admission, and recovery or death.
Each week a query for follow up update was sent to all centers, until they filled the outcome report (death or recovery).
End Points
We run 2 main analyses on the following primary endpoints: (1) observed number of deaths over the whole follow‐up; and (2) severe COVID‐19 characterized by a 3‐level variable; the highest severity level was death or ICU admission, the intermediate severity level was diagnosis of pneumonia or hospitalization, and the lowest severity level was a milder disease with no need for hospitalization or documented diagnosis of pneumonia.
Statistical Analysis
The web‐based data collection started on March 1, 2020 and closed for the analysis on September 10, 2020. The first date of symptom appearance retrospectively reported was January 15, 2020. All the patients had complete follow‐up to death or recovery.
For the sample size calculations, we determined that 800 patients were needed, assuming a rate of severe outcomes (death, ICU admission, pneumonia, or hospitalization) of 20% in the reference group and a comparison group made of 15% of the full cohort, to have a power of 90% to detect an increased risk of severe outcome in the comparison group quantified by an odds ratio (OR) = 2.0 at a confidence level of 0.05.
To make efficient use of the available data, we used multiple imputation of missing values for missing baseline data. Imputation was performed using chained equations, 9 where each incomplete variable is imputed by a separate model and implemented trough the "mice" R package. Continuous variables (age, height, weight, BMI, and disease duration) were parameterized as numeric data and imputed with the predictive mean matching method, whereas polytomous logistic regression was used for the unordered categorical variables (such as MS phenotype). EDSS and disease duration were used to impute the MS phenotype; age and MS phenotype were used to impute disease duration; age, height, or weight was used to impute BMI.
To assess risk factors at symptoms onset for a severe disease course, we ran a multivariate ordinal logistic regression assuming proportional ORs with severe outcome (defined as a 3‐level factor) as the dependent variable, after assessing that the assumptions of proportional odds were satisfied. The ORs reflect the multiplicative change in the odds of being at a higher level of the dependent variable for every one‐unit increase of the independent variable. The multivariate model included age, sex, BMI, EDSS, disease duration, MS disease phase (RRMS vs progressive), presence of comorbidities, methylprednisolone use within 1 month since COVID‐19 symptoms onset, and DMT class as independent variables, stratified by macroregion (defined as Lombardy; Northern Italy, including Piedmont, Veneto, Emilia‐Romagna, and Liguria; and the rest of Italy). DMT class was coded as an 8‐level variable as no therapy, interferon, glatiramer‐acetate, teriflunomide, dimethyl fumarate, natalizumab, anti‐CD20 (rituximab or ocrelizumab), or other. Alemtuzumab and cladribine were grouped in the “other” group, because the number of patients in these two therapeutic arms was too low to draw meaningful conclusions. “No therapy” was used as the reference category. We also ran the same ordinal logistic analysis after a multinomial propensity score (PS) weighting, as an alternative method to balance the differences of baseline characteristics among patients treated with different DMTs. The weights were calculated using an iterative robust approach based on the Generalized Boosted Model (GBM). 10 The balance among treatment groups was defined by the standardized mean difference, and the optimal GBM iteration was found by minimizing this quantity.
Results were also presented taking dimethyl fumarate, which is the most frequently used therapy in Italy, as the reference therapy group (Supplementary Appendix). Additional analyses were focused on the anti‐CD20 therapies using the same multivariate ordinal logistic model adjusted for all the baseline variables; we investigated the effect of being on anti‐CD20 versus not being on anti‐CD20, the effect of the distance from last infusion (0–3 months, >3 months), and the effect of the time since therapy start (<6 months, 6–12 months, >12 months).
Sensitivity analyses were run by repeating all the analyses on the subgroup of confirmed cases only, in the subgroup of patients with a RRMS course, in a model including only patients with complete baseline data with no imputation and using a leave one out procedure rerunning the analysis excluding one of the 3 major centers (Brescia, Bergamo, Milan) at a time (Supplementary Appendix).
Role of the Funding Source
Roche donated the web‐based platform for data collection. Roche did not have any role in study design; in analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.
Results
Patients Characteristics
On September 10, 844 PwMS with complete follow‐up from first contact to the outcome (recovery or death) from 85 centers were included in the dataset (Supplementary Appendix). Thirty‐four percent (286/844) of patients were from 3 centers in Lombardy (ASST Spedali Civili, Brescia‐Montichiari; Papa Giovanni XXIII Hospital, Bergamo; and San Raffaele Hospital, Milan); the distribution of patients by region is shown in Supplementary Table S3.
Table 1 reports the baseline demographic and clinical characteristics of the cohort. The mean age was 45 years (range = 18–82), the percentage of females was 70.3%, the median EDSS was 2 (interquartile range [IQR] = 1.50–4), and the proportion of progressive patients was 16%. Six hundred ninety‐three (82%) patients were treated with a DMT at the time of COVID‐19 presumed symptoms onset.
TABLE 1 Baseline Demographic and Clinical Characteristics of Included Patients
Characteristic Overall, N = 844 Suspected, n = 565 Confirmed, n = 279
Age, n (%)
<40 yr 279 (33.1) 203 (35.9) 76 (27.2)
40–59 yr 471 (55.8) 312 (55.2) 159 (57.0)
60–79 yr 92 (10.9) 50 (8.8) 42 (15.1)
≥80 yr 2 (0.2) 0 (0.0) 2 (0.7)
Female sex, n (%) 593 (70.3) 410 (72.6) 183 (65.6)
BMI, mean (SD) 23.82 (4.37) 23.61 (4.37) 24.28 (4.37)
Comorbidities, n (%) 188 (22.3) 115 (20.4) 73 (26.2)
MS phenotype, n (%)
Primary progressive 44 (5.2) 24 (4.2) 20 (7.2)
Relapsing–remitting 676 (80.1) 469 (83.0) 207 (74.2)
Secondary progressive 91 (10.8) 46 (8.1) 45 (16.1)
Missing data 33 (3.9) 26 (4.6) 7 (2.5)
MS disease duration, median (IQR) 10.2 (4.7–17.1) 9.6 (4.3–16.2) 11.8 (5.4–18.5)
EDSS, median (IQR) 2 (1.50–4) 2 (1.50–3.50) 2 (1.50–4)
MS treatment, n (%)
Dimethyl fumarate 174 (20.6) 131 (23.2) 43 (15.4)
Fingolimod 94 (11.1) 59 (10.4) 35 (12.5)
Ocrelizumab 89 (10.5) 58 (10.3) 31 (11.1)
Natalizumab 85 (10.1) 51 (9.0) 34 (12.2)
Interferon 73 (8.6) 52 (9.2) 21 (7.5)
Copaxone 70 (8.3) 52 (9.2) 18 (6.5)
Teriflunomide 64 (7.6) 37 (6.5) 27 (9.7)
Alemtuzumab 14 (1.7) 11 (1.9) 3 (1.1)
Cladribine 11 (1.3) 7 (1.2) 4 (1.4)
Azathioprine 10 (1.2) 4 (0.7) 6 (2.2)
Rituximab 5 (0.6) 4 (0.7) 1 (0.4)
Methotrexate 1 (0.1) 1 (0.2) 0 (0.0)
Mitoxantrone 1 (0.1) 1 (0.2) 0 (0.0)
Other 2 (0.2) 2 (0.4) 0 (0.0)
None 151 (17.9) 95 (16.8) 56 (20.1)
Previous methylprednisolone, n (%) 26 (3.1) 16 (2.8) 10 (3.6)
BMI = body mass index; EDSS = Expanded Disability Status Scale; IQR = interquartile range; MS = multiple sclerosis; SD = standard deviation.
Three hundred eighty‐four patients (45.5%) had at least one laboratory test executed for the COVID‐19 diagnosis; 307 (36.4%) patients were tested in the active phase with a swab and 127 (15.0%) had a serological test after recovery. Overall, 279 (33.1%) were classified as confirmed cases. Because the test during the pandemic peak was done only in the most severe patients, confirmed cases are expected to be more severe than suspected cases. In the confirmed cases subgroup, there was a higher proportion of older subjects than in the suspected cases subgroup (>60 years = 16% vs 9%) and more patients in the progressive MS phase (23% vs 12%).
The baseline characteristics of the cohort according to DMT received are reported in Table 2; patients with no therapy were older (mean age = 53.4 years), with a higher EDSS (mean EDSS = 5.5) and with a higher proportion of progressive patients (45.7%) than patients treated with DMTs. Among treated patients, those treated with interferon, glatiramer‐acetate, or teriflunomide were older than those in other DMT groups, and patients treated with anti‐CD20 had a higher EDSS (mean EDSS = 3) and a larger portion of progressive patients (25.6%) than those treated with other DMTs, but not larger than the untreated group.
TABLE 2 Baseline Demographic and Clinical Characteristics of Included Patients according to Disease‐Modifying Therapy Received
Characteristic No Therapy, n = 151 IFN, n = 73 GA, n = 70 Teri, n = 64 DMF, n = 174 FTY, n = 94 Nat, n = 85 Anti‐CD20, n = 94 a Other, n = 39
Age, mean (SD) 53.4 (13.4) 47.5 (10.5) 45.7 (11.3) 49.1 (9.4) 41.4 (10.9) 44.2 (9.5) 37.9 (9.8) 42.0 (10.0) 42.2 (13.8)
Female sex, n (%) 104 (68.9) 53 (72.6) 48 (68.6) 44 (68.8) 114 (65.5) 74 (78.7) 64 (75.3) 64 (68.1) 28 (71.8)
BMI, mean (SD) 24.6 (4.6) 24.3 (2.7) 25.2 (5.0) 24.7 (4.5) 23.3 (4.1) 23.9 (5.2) 22.7 (4.1) 22.6 (3.7) 23.2 (3.8)
MS phenotype, n (%)
Primary progressive 22 (14.6) 0 (0.0) 1 (1.4) 0 (0.0) 0 (0.0) 2 (2.1) 1 (1.2) 16 (17.0) 2 (5.1)
Relapsing–remitting 65 (43.0) 65 (89.0) 64 (91.4) 59 (92.2) 165 (94.8) 81 (86.2) 83 (97.6) 67 (71.3) 27 (69.2)
Secondary progressive 47 (31.1) 6 (8.2) 2 (2.9) 3 (4.7) 5 (2.9) 9 (9.6) 0 (0.0) 9 (9.6) 10 (25.6)
Missing data 17 (11.3) 2 (2.7) 3 (4.3) 2 (3.1) 4 (2.3) 2 (2.1) 1 (1.2) 2 (2.1) 0 (0.0)
MS disease duration, median yr (IQR) 16.2 (8–23) 12.0 (6–19) 10.1 (5–17) 11.4 (6–15) 5.5 (3–13) 11.8 (7–18) 9.1 (5–15) 8.2 (4–13) 12.9 (5–18)
EDSS, median (IQR) 5.5 (2–7) 1.5 (1–2.5) 1.5 (1–2) 2.0 (1.5–3) 1.5 (1–2) 2.0 (1.5–3) 2.0 (1.5–3) 3.0 (1.5–4.5) 3.0 (1.5–6)
Methylprednisolone, b n (%) 9 (6.0) 2 (2.7) 1 (1.4) 2 (3.1) 4 (2.3) 4 (4.3) 1 (1.2) 1 (1.1) 2 (5.1)
a Ocrelizumab or rituximab.
b One month before symptoms onset.
BMI = body mass index; DMF = dimethyl fumarate; EDSS = Expanded Disability Status Scale; FTY = fingolimod; GA = glatiramer‐acetate; IFN = interferon; IQR = interquartile range; MS = multiple sclerosis; Nat = natalizumab; SD = standard deviation; Teri = teriflunomide.
Thirteen (1.54%) patients died, and their characteristics are described in Table 3; 8 of them were PwMS with no therapy, all in a progressive disease phase (1 primary progressive MS, 7 secondary progressive MS). Five of them were treated (rituximab, ocrelizumab, natalizumab, glatiramer‐acetate, dimethyl fumarate), and only 2 of them were in a RRMS phase (glatiramer‐acetate and natalizumab). The mean time from symptoms to death was 18 days (range = 5–54 days).
TABLE 3 Characteristics of Deceased Patients
Sex, Age, yr Disease Duration Disease Phase EDSS Therapy Comorbidities
M, 63 33 SPMS 7 No therapy Diabetes
M, 67 2 PPMS 7.5 No therapy CHD, hypertension, HBV
M, 68 21 SPMS 6 Dimethyl fumarate Cerebrovascular disease, hypertension, depression, TBC
F, 57 20 SPMS 9 No therapy No
M, 76 17 SPMS 6.5 No therapy CHD, hypertension, depression, dyslipidemia
F, 52 1 RRMS 5 Natalizumab No
F, 50 27 SPMS 6 Ocrelizumab No
M, 59 33 SPMS 9 No therapy No
F, 68 19 SPMS 5.5 No therapy No
F, 54 20 SPMS 7 Rituximab No
M, 64 10 RRMS 2 Glatiramer‐acetate No
M, 63 33 SPMS 6.5 No therapy Diabetes, bipolar disorder
M, 60 30 SPMS 9 No therapy Hypertension, cerebrovascular disease, CHD
CHD = coronary heart disease; F = female; HBV = hepatitis B virus; M = male; PPMS = primary progressive multiple sclerosis; RRMS = relapsing–remitting multiple sclerosis; SPMS = secondary progressive multiple sclerosis; TBC = tuberculosis.
Risk Factors for a Severe COVID‐19 Outcome
Thirty‐eight (4.5%) patients were admitted to an ICU (7 of them died); 99 cases (11.7%) of radiologically documented pneumonia were reported; 96 patients (11.4%) were hospitalized. Forty‐four patients (5.2%) were in the highest severity class (death or ICU admission), and 92 patients (10.9%) were in the intermediate severity class (pneumonia or hospitalization). Twenty‐six patients (3.1%) received methylprednisolone in the month preceding the first symptoms of COVID‐19.
Risk factors for severe COVID‐19 in univariate, multivariate, and PS‐weighted analysis are reported in Table 4. The assumptions of proportional odds were satisfied. Older age, male sex, higher EDSS, longer MS duration, presence of comorbidities, and progressive MS course were all risk factors for a more severe disease in univariate analysis. Methylprednisolone use within 1 month before COVID‐19 symptoms onset was associated with increased risk (OR = 3.38, 95% confidence interval [CI] = 1.49–7.67, p = 0.004). Taking no therapy as the reference category indicated a reduced risk for all the DMTs, with OR ranging from 0.34 to 0.50, except for the anti‐CD20 therapies (ocrelizumab/rituximab, OR = 0.94). When adjusting the OR in the multivariate model, the risk factors with a significant impact on COVID‐19 severity were age, sex, EDSS, recent use of methylprednisolone, and anti‐CD20 therapy. Age and EDSS fully explained the apparent risk associated with no therapy as compared to the other DMTs, and the only treatment associated with a higher risk of a severe COVID‐19 disease was anti‐CD20 therapy (OR = 2.37, 95% CI = 1.18–4.74, p = 0.015). Also, the increased risk associated with the use of recent methylprednisolone was confirmed (OR = 5.24, 95% CI = 2.20–12.53, p = 0.001). The PS‐weighted characteristics of patients according to the different DMTs received are reported in Supplementary Table S11. The DMT effects on COVID‐19 severity are replicated by the PS‐weighted analysis. The OR for anti‐CD20 therapy was 3.91 (95% CI = 1.71–8.91, p = 0.001).
TABLE 4 Univariate, Multivariate, and PS‐Weighted Ordinal Logistic Regression Models Evaluating Risk Factors for Severe Coronavirus Disease 2019 a
Univariate Analysis, n = 844 b Multivariate Analysis, n = 844 b PS Analysis, n = 844 b
Variable OR (95% CI) p OR (95% CI) p OR (95% CI) p
Age, yr 1.06 (1.04–1.08) <0.001 1.06 (1.03–1.08) <0.001 1.06 (1.03–1.10) 0.001
Sex, F vs M 0.64 (0.40–1.03) 0.068 0.69 (0.45–1.04) 0.076 0.83 (0.50–1.39) 0.49
Progressive vs RRMS 4.14 (2.70–6.35) <0.001 1.59 (0.81–3.01) 0.18 1.76 (0.70–4.40) 0.23
EDSS 1.33 (1.22–1.45) <0.001 1.07 (0.93–1.22) 0.40 1.08 (0.86–1.35) 0.50
Disease duration, yr 1.04 (1.02–1.06) <0.011 1.00 (0.98–1.03) 0.99 0.99 (0.96–1.02) 0.57
BMI 1.01 (0.97–1.05) 0.53 0.98 (0.94–1.02) 0.44 0.99 (0.93–1.02) 0.74
Comorbidities, yes 1.70 (1.13–2.56) 0.012 0.93 (0.58–1.47) 0.74 0.82 (0.48–1.42) 0.48
Methylprednisolone c 3.38 (1.49–7.67) 0.004 5.24 (2.20–12.53) 0.001 2.51 (0.99–6.44) 0.05
DMT
No therapy d 1 (ref) 1 (ref) 1 (ref)
Interferon 0.35 (0.15–0.79) 0.012 0.67 (0.28–1.65) 0.39 0.71 (0.29–1.78) 0.48
Glatiramer‐acetate 0.34 (0.14–0.81) 0.015 0.77 (0.29–2.00) 0.59 1.19 (0.30–4.87) 0.80
Teriflunomide 0.48 (0.21–1.07) 0.07 0.86 (0.36–2.08) 0.74 1.17 (0.41–3.63) 0.76
Dimethyl fumarate 0.38 (0.20–0.70) 0.002 1.12 (0.55–2.30) 0.75 1.29 (0.58–2.87) 0.62
Natalizumab 0.35 (0.16–0.76) 0.009 1.30 (0.53–3.22) 0.57 1.77 (0.61–5.07) 0.29
Fingolimod 0.50 (0.26–0.98) 0.04 1.19 (0.57–2.52) 0.64 1.48 (0.66–3.34) 0.34
Anti‐CD20 e 0.94 (0.52–1.08) 0.85 2.37 (1.18–4.74) 0.015 3.91 (1.71–8.91) 0.001
Other 0.38 (0.14–1.04) 0.06 0.71 (0.28–2.65) 0.39 1.50 (0.40–5.71) 0.55
a Intensive care unit or death vs hospitalization or pneumonia vs milder symptoms not requiring hospitalization and no documented pneumonia.
b All the analyses are adjusted for macroregion (Lombardy; Northern Italy, including Veneto, Emilia‐Romagna, Piedmont, and Liguria; and the rest of Italy).
c One month before symptoms onset.
d No therapy was chosen as the reference class.
e Ocrelizumab or rituximab.
BMI = body mass index; CI = confidence interval; DMT = disease‐modifying therapy; EDSS = Expanded Disability Status Scale; F = female; M = male; OR = odds ratio; PS = propensity score; RRMS = relapsing–remitting multiple sclerosis.
The results taking dimethyl fumarate as the reference category are reported in the Supplementary Appendix and are in line with the above results. All the sensitivity analyses confirmed these findings; the anti‐CD20–treated patients had an OR = 2.62 (p = 0.05) in the subgroup of confirmed cases, an OR = 2.87 (p = 0.03) in the subgroup of RRMS patients, and an OR = 2.69 (p = 0.026) using only complete baseline data with no imputation (Supplementary Appendix).
A further result that deserves attention is the risk reduction observed in patients treated with interferon (OR = 0.67); however, this does not reach a statistical significance. Among the 73 patients on interferon, no ICU admissions or deaths were recorded.
To give an idea of the absolute risk of severe COVID‐19 according to DMT, Figure 1 reports the percentage of patients with severe events (pneumonia, hospitalization, ICU, or death) in the group treated with anti‐CD20, in the untreated group, and in the group treated with other DMTs. To adjust these values for the confounding factors, the figure was restricted to patients <65 years old and with EDSS < 6.5 (n = 733), and presented separately for the RRMS (n = 675) and progressive MS (n = 58) groups. The percentage of subjects with severe events was higher in the group of patients treated with anti‐CD20 both in the RRMS and in the progressive MS patients; in the RRMS group, the proportion of patients deceased or admitted to ICU in the anti‐CD20 group was 6.1%, versus 4.2% in the untreated and 2.2% in the other DMTs group. In the progressive MS group, it was 12.5% in the anti‐CD20 group, 10.5% in the untreated group, and 4.3% in the other DMTs group. The percentage of patients with an intermediate severity (pneumonia or hospitalization) had the same trend of increase in the anti‐CD20 group.
FIGURE 1 Percentage of patients with pneumonia/hospitalization and intensive care unit (ICU)/death in the subgroup of subjects with age < 65 years and Expanded Disability Status Scale < 6.5, according to multiple sclerosis (MS) phenotype (relapsing–remitting vs progressive MS), in the anti‐CD20, no therapy, and other therapies groups. DMT = disease‐modifying therapy.
The increase of risk associated with anti‐CD20 was maintained on hard end points (death or ICU admission), even if the small number of events did not allow this to reach statistical significance (Supplementary Appendix).
The adjusted OR for anti‐CD20 therapy versus all the other therapies was 2.37 (95% CI = 1.36–4.12, p = 0.002). Exploratory analyses revealed no association between COVID‐19 severity and the time passed since the last anti‐CD20 infusion (OR = 2.77, 95% CI = 1.31–5.89, p = 0.012 for last infusion within 3 months and OR = 2.05, 95% CI = 0.97–4.28, p = 0.023 for last infusion before 3 months), whereas there was a trend with therapy duration; as compared to PwMS treated with other therapies, patients on anti‐CD20 therapy for <6 months had an OR = 1.65 (95% CI = 0.56–4.90, p = 0.36), patients on anti‐CD20 therapy for 6–12 months had an OR = 2.24 (95% CI = 0.91–5.55, p = 0.08), and patients on anti‐CD20 therapy for >12 months had an OR = 2.98 (95% CI = 1.37–6.46, p = 0.006; Supplementary Appendix).
No severe outcomes (no pneumonia, hospitalization, ICU, or death) were observed in the 11 patients treated with cladribine or in the 14 patients treated with alemtuzumab.
Discussion
This study shows an acceptable level of safety of immunomodulatory and immunosuppressive therapies in MS during the COVID‐19 pandemic. However, two results deserve attention.
First, 11 of 13 deaths occurred in persons with advanced disease and disability (median EDSS = 7). The median age of people who died was 63 years versus a median age of 45 years for those who recovered. Higher EDSS was associated in multivariate analysis with COVID‐19 severity also in the French MS population. 3 These findings strengthen the need to enforce prevention strategies for people with advanced disability and older age during the pandemic. 11
Second, we observed an increased frequency of a severe COVID‐19 in people treated with anti‐CD20 therapies compared to other DMTs. Smaller case series suggested an increased susceptibility to COVID‐19 in PwMS taking B‐cell–depleting monoclonal antibodies, 12 , 13 , 14 without major effects on the severity of COVID‐19. 13 , 14 , 15 In the largest study published so far (the French study), DMT exposure was not included in the multivariate model. The results of the univariate analysis are very similar to those presented here. 3 It will be informative to evaluate the OR for the impact of DMTs on severity in the French cohort in the multivariate model, to check the size of effect, irrespective of the statistical significance. Data are available about the general risk of infections during DMTs for MS; a nationwide Swedish cohort examined the infection risks in PwMS treated with DMTs. 16 In that study, rituximab was associated with the highest rate of serious infections. However, the use of herpes antivirals was lower with rituximab compared to fingolimod and natalizumab; ocrelizumab clinical trials reported an increased risk of respiratory tract infections, 17 , 18 and safety issues emerged in diseases other than MS. 19 With respect to the association with treatment duration, it has been shown that long‐term anti‐CD20 treatment is associated with the risk of hypogammaglobulinemia in neuromyelitis optica‐spectrum disorder. 20 A protracted treatment may impact on the protective, anti–SARS‐CoV‐2 humoral response 21 and on a pre‐existing humoral and cellular immune repertoire, recently described in unexposed individuals. 22 , 23
We did not observe a link between time to last infusion of ocrelizumab and COVID‐19 risk. This preliminary result needs to be confirmed, but it is consistent with the idea that the immunological effects of ocrelizumab may last longer than 6 months. Reducing the frequency of dosing, or adjusting it according to the monitoring of B‐cell repopulation kinetics in individual patients, 20 may maintain efficacy while limiting the risk of infection. 24 A similar strategy deserves attention also in view of future vaccinations. 25 However, it may not be without risks linked to the re‐expansion of autoreactive B cells. 26
The role of interferon treatment and the severity of COVID‐19 is of high interest. Our data indicated a decrease of risk associated with interferon, even if it did not reach statistical significance. The majority of laboratory studies are in line with this preliminary observation, suggesting that supplementing type I interferons may circumvent a defective response that, in people with severe COVID‐19, may depend on various mechanisms including the presence of anti‐interferon autoantibodies, 27 a genetically defective type I interferon response, 28 , 29 or the ability of SARS‐CoV‐2 to neutralize the antiviral effects of type I interferons. 30 A recent clinical trial of interferon beta‐1b and lopinavir–ritonavir in Middle East respiratory syndrome 31 supports this hypothesis, but a negative trial of interferon beta‐1b, alone or in combination with lopinavir, does not. 32 It is possible that timing in the administration of type I interferons is crucial, as early therapy is associated with favorable clinical responses. 33 This is in accord with our observation in patients who are already under interferon beta therapy when they develop COVID‐19.
Importantly, methylprednisolone in the month preceding the first symptoms of COVID‐19 was significantly associated with a worse outcome. This aspect was not considered in previous reports, is in agreement with data in other autoimmune diseases, 34 and is relevant in assessing the risk of DMTs (ie, COVID‐19 risk vs steroid‐sparing potential).
This study has limitations that must be considered when evaluating the results. First, we included in the study not only confirmed but also suspected cases. For this reason, we cannot exclude that the suspected cases suffered from infections other than COVID‐19. We took the decision of including suspected cases because, during the pandemic peak in Italy, only the most severe cases (often after hospitalization) were tested. Hence, including only confirmed cases would have limited the representativeness of our sample. The inclusion of patients suffering from non–COVID‐19 infections might have diluted the effect of the detected association, resulting in a conservative approach. Furthermore, we reran all the main analyses on the subgroup of confirmed cases, obtaining similar and even stronger results, despite the smaller sample size. A second relevant bias might derive from differences in awareness and expectations of risks in patients receiving therapies with stronger immunosuppressive effect. This might have favored more frequent contacts with treating neurologists, resulting in increased attention to ocrelizumab or rituximab patients. However, the same should have been true also for other intravenous therapies. Finally, although the multivariate analysis adjusts the effect of DMTs on COVID‐19 severity for the main confounding factors, we cannot exclude that some residual confounding can partly explain the observed associations.
Overall, this study shows an acceptable safety profile of DMTs in MS during the COVID‐19 pandemic. The differences that emerged among the various DMTs are in agreement with previous knowledge about infections in PwMS. The results are also plausible based on current biological knowledge, although the exact mechanisms that affect the risk of COVID‐19 remain uncertain. It will be important to look at other ongoing studies 35 to verify whether they confirm our findings and to compare the new clinical insight in other autoimmune diseases. This may stimulate new laboratory research and shed new light on the biology of SARS‐CoV‐2 infection and on the pathophysiology of the different autoimmune diseases.
Author Contributions
All authors contributed to the conception and design of the study; the Musc‐19 Study Group contributed to the acquisition and analysis of data; M.P.S., I.S., L.C., and M.S. contributed to drafting the text and preparing the figures.
Potential Conflicts of Interest
M.P.S. reports a grant from Roche to cover data management of this study; Roche makes ocrelizumab, which is one of the DMTs assessed in this study. The remaining authors have nothing to report.
Supporting information
APPENDIX S1. Supporting Information
Click here for additional data file.
Acknowledgments
The Musc‐19 Study Group thanks Roche for donating the web‐based platform for data collection and the Department of Informatics, Bioengineering, Robotics, and Systems Engineering, University of Genoa, for its help in installing the platform. | Fatal | ReactionOutcome | CC BY-NC | 33480077 | 17,774,031 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Breast cancer recurrent'. | Favorable survival with combined treatment in a metastatic breast cancer patient undergoing hemodialysis: A case report.
BACKGROUND
Management of breast cancer patients undergoing hemodialysis (HD) is difficult because of a lack of evidence about drug selection, dose adjustment, and surgical procedures. We herein present a case of metastatic breast cancer in a patient undergoing HD.
METHODS
A 58-year-old Japanese woman with breast cancer undergoing HD underwent total mastectomy of the left breast and left axillary dissection. Histopathological examination revealed invasive ductal carcinoma, and the diagnosis was pT2N3cM0 Stage ⅢC. Immunostaining of the resected specimen indicated that the tumor was estrogen receptor-positive, progesterone receptor-negative, human epithelial growth factor receptor 2-positive, and the Ki-67 labeling index was 70%. A postoperative positron emission tomography/computed tomography (PET/CT) scan indicated fluorodeoxyglucose uptake in the supraclavicular nodes. She received adjuvant therapy of epirubicin and cyclophosphamide followed by docetaxel, trastuzumab (T-mab) and radiation therapy. However, she developed multiple liver metastases during adjuvant T-mab and hormone therapy. Therefore, her regimen was changed to trastuzumab emtansine (T-DM1) as first-line therapy, T-mab, pertuzumab (P-mab), and eribulin as second-line therapy, and T-mab, P-mab, and weekly paclitaxel as third-line therapy. Eventually, she was administered fourth-line treatment of T-mab, P-mab, and vinorelbine because of adverse events. She has survived more than 25 months after the initial detection of recurrence of breast cancer and maintained quality of life.
CONCLUSIONS
We report a case of breast cancer in a patient undergoing HD. It is very difficult to identify the appropriate drugs and dosages in patients undergoing HD to improve survival and quality of life.
1 Introduction
The risk of cancer, including breast cancer, is increased among patients undergoing hemodialysis (HD) [1,2]. In the United States, women undergoing HD are 42% more likely to develop breast cancer than the general population [1]. Unlike age, family history of breast cancer, early menarche, late menopause, late pregnancy, long-term hormone replacement therapy, radiation exposure, and benign breast diseases, chronic kidney disease (CKD) is not a major risk factor for breast cancer [3,4].
There are few studies on anticancer drugs and other drugs used in cancer therapy in patients undergoing HD, even though CKD, HD, and peritoneal dialysis do not limit the possibility of surgical treatment and radiotherapy. We herein present a case of HD with relatively long-term survival after diagnosis of multiple liver metastases detected during adjuvant therapy after surgery for locally advanced breast cancer.
2 Presentation of case
A 58-year-old Japanese woman undergoing HD developed a nodule in the left breast that was observed on chest computed tomography (CT). A dual-source CT scan showed an enhanced breast nodule 2.3 cm in diameter in the left breast (Fig. 1a), and enhanced CT indicated a swollen axillary lymph node (Fig. 1b). Needle biopsy was performed, and the pathological findings of the specimen indicated invasive ductal carcinoma that was estrogen receptor-positive, progesterone receptor-negative, and human epidermal growth factor receptor 2-positive by immunohistochemistry. Fine-needle aspiration cytology of the left axillary lymph node showed malignancy. The patient was diagnosed with primary breast cancer (cT2N1MX Stage ⅡB according to the Union for International Cancer Control classification).Fig. 1 (a) Dual-source computed tomography (CT) revealed breast cancer, and (b) plane CT revealed metastatic axillary lymph nodes.
Fig. 1
She underwent total mastectomy of the left breast and left axillary dissection. The pathological evaluation confirmed invasive ductal carcinoma (2.4 cm) and 10 metastatic axillary lymph nodes. A postoperative positron emission tomography/computed tomography (PET/CT) scan showed uptake in the supraclavicular lymph nodes (Fig. 2) but not in distant organs (pT2N3cM0 Stage IIIC).Fig. 2 Positron emission tomography (PET)/computed tomography showed a hot spot in a metastatic supraclavicular lymph node (arrow).
Fig. 2
We administered the combined systemic therapy regimen for patients with pT2N3cM0 Stage IIIC breast cancer, which included epirubicin and cyclophosphamide (EC) (100 mg/m2 and 600 mg/m2, respectively) four times every 3 weeks, followed by docetaxel (DTX) (75 mg/m2) and trastuzumab (T-mab) (8 mg/kg loading dose and 6 mg/kg thereafter) four times every 3 weeks for adjuvant therapy. She received 70% of the full-dose of EC, 80% of the full-dose of DTX, and the full-dose of T-mab.
We used the vascular access (VA) for HD on the patient’s right forearm for the administration of anticancer drugs, which was on the opposite side of the surgical site. However, thrombosis developed in the VA after two rounds of EC. The patient also developed febrile neutropenia (FN), hemorrhagic cystitis, and anemia, which required thrombolytic therapy, antibiotics, granulocyte colony-stimulating factor, and blood transfusions. EC therapy was discontinued, and a central venous access port (CV port) was created at the right internal jugular vein. After that, the patient received four cycles of DTX and T-mab, followed by PMRT of 50 Gy in 25 fractions and 10 Gy in 5 fractions to the supraclavicular and internal mammary nodes. The patient then received full-dose T-mab monotherapy every 3 weeks, which was scheduled for 14 cycles and full-dose letrozole, which was scheduled for 10 years, as additional adjuvant therapy. However, one year after surgery, PET/CT indicated multiple metastases (Fig. 3), and blood tests revealed an increase in serum CA15-3.Fig. 3 Positron emission tomography (PET)/computed tomography indicated multiple hot spots in the liver (arrows).
Fig. 3
Trastuzumab emtansine (T-DM1) was administered as the first-line treatment for the recurrence. She received a full-dose of T-DM1 (3.6 mg/kg every 3 weeks) for a total of 10 cycles among 32 weeks. However, the liver metastases did not respond, so she was administered for nine cycles of full-dose T-mab, pertuzumab (P-mab) (840 mg loading dose and 420 mg thereafter), and 70% of the full-dose of eribulin (1.4 mg/m2 on days 1 and 8 every 3 weeks) among 33 weeks. However, the liver metastases continued to grow, and we administered third-line treatment of full-dose T-mab, P-mab, and weekly paclitaxel (PTX) at 70% of the full dose (90 mg/m2) among 29 weeks. The third-line treatment was administered for nine cycles, and a partial response was observed in the liver metastases. However, the patient refused to continue the therapy because of grade 2 systemic edema and numbness in the fingers. Currently, full-dose T-mab, P-mab, and 60% of the full dose of vinorelbine (VNR; 25 mg/m2 on days 1 and 8 every 3 weeks) are being administered as the fourth-line treatment. She has survived more than 25 months after the initial detection of recurrence of breast cancer and maintained quality of life.
3 Discussion
In this report, we describe a patient with metastatic breast cancer who was undergoing HD. She had favorable survival and acceptable quality of life using a reduced dosage and several types of drugs, despite the difficulty of dose control. Drug dosages may need to be adjusted in some patients, but the lack of appropriate drug dosage can reduce overall survival [5]. A previous study reported that patients receiving a higher relative dose intensity (RDI) of anticancer drugs had better clinical outcomes than those receiving a lower RDI among patients with metastatic solid tumors, including breast cancer [6], but there are currently no data in patients undergoing HD.
The survival of patients with breast cancer who are receiving dialysis is still unknown. CKD is not a significant factor in overall survival or disease-free survival in patients with breast cancer [7]. In fact, the patient in the present report had a favorable survival even after breast cancer recurrence. However, the number of cases in the literature is limited, and there is no other report describing the survival of patients with breast cancer who are receiving HD.
Regarding the treatment of breast cancer patients who are receiving HD, the most important clinical issue is drug selection and dosage adjustment. The recommendations for dosage adjustment for oncological therapy among patients receiving HD are shown in Table 1 [8,9]. Most drugs are safe to administer in patients receiving HD, and methotrexate is the only drug that should be avoided. It is recommended that capecitabine, cyclophosphamide, DTX, doxorubicin, epirubicin, and VNR be administered at reduced doses. There are insufficient data on HD patients receiving tamoxifen, anastrozole, letrozole, and newer targeted agents, such as cyclin-dependent kinase 4/6 inhibitors, lapatinib, T-mab, P-mab, T-DM1, and atezolizumab. However, even drugs that do not require dose reduction should be reduced if they cause myelotoxicity or cardiotoxicity. However, these recommendations are general; therefore, for patients without CKD, dose reduction depends on the patient’s adverse events (AEs). In this case, we reduced the dose of EC to 70%, that of DTX to 80%, that of eribulin to 70%, that of PTX to 70%, and that of VNR to 60%. Even drugs that are generally administered at the full dose had to be reduced due to AEs, including thrombosis, FN, hemorrhagic cystitis, and anemia. Although there is no recommended dosage reduction in the literature for T-DM1, T-mab, P-mab, and letrozole [8], we were able to administer these drugs at the full dose without any major AEs.Table 1 Summary of pharmacokinetics and safety of oncological therapies for breast cancer in hemodialysis patients.
Table 1Drug Elimination Dose reduction in HD Bednarek A8) Recommended dose in HD Janus N9) safety
capecitabine Urinary Recommended dose reduction by 50% No data Safe (limited data)
cyclophosphamide Urinary Recommended dose reduction by 20% Reduction of 25% Hemorrhagic cystitis
docetaxel Faeces Not specified 65 mg/m2 Safe
paclitaxel Faeces Not specified Standard dose Safe
doxorubicin Faeces Recommended dose reduction by 20% Standard dose Inceased risk of cardiotoxicity
epirubicin Faeces Recommended dose reduction Standard dose Inceased risk of cardiotoxicity
vinorelbine Faeces Probably necessary (up to 50%) Reduction of 20%–33% Inceased myelotoxicity (limited data)
tamoxifen Faeces Not indicated − Safe
anastrozole Faeces Not indicated − Safe
letrozole Urinary Not specified − No data
palbociclib Faeces Not specified − No data
lapatinib Faeces Not indicated − Safe (limited data)
trastuzumab No data Not indicated − Inceased risk of cardiotoxicity
pertuzumab No data Not indicated − No data
trastuzumab emtansine Faeces Not indicated − Inceased risk of cardiotoxicity
atezolizumab No data Not indicated − Safe (very limited data)
Another issue is among patients undergoing HD is the VA, particularly for patients who undergo axillary dissection. If the dissection range includes the VA site, it may be preferable to place a VA on the opposite side of the surgical site prior to operation to reduce the risk of VA issues. Another alternative is to use a temporary VA for the short term. However, no previous report was found. It might be useful to confirm the effect of the operation on the original VA. In our case, the patient’s VA was on the opposite side of the surgical site, so it was unaffected by the surgery.
Intravenous administered of anticancer drugs should be considered. In our case, the venous pressure in the internal jugular vein was increased by the VA on the non-affected side. It is usually recommended to create a CV port to prevent vasculitis caused by anticancer drugs, but we need to consider the risks of venous pressure increase. We initially decided to administer anticancer drugs from the VA for HD, but the patient developed thrombosis, and we created a CV port via the internal jugular vein on the VA side without any complications. This case is reported in line with the SCARE Guideline [10].
4 Conclusion
We report a case of breast cancer diagnosed during HD with multiple liver metastases that developed during postoperative adjuvant therapy. It is very difficult to manage patients undergoing HD with the appropriate drugs and dosage to improve survival and quality of life.
Declaration of Competing Interest
None.
Funding
None.
Ethical approval
None.
Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
Author contribution
Megumi Matsumoto conceptualized the study. Hiroshi Yano, Ryota Otsubo, and Aya Tanaka collaborated in the patient’s care. Takeshi Nagayasu provided input on the manuscript.
Registration of research studies
Researchregistry 6411.
Guarantor
Megumi Matsumoto.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Acknowledgements
We would like to thank Editage (www.editage.com) for English language editing. | ADO-TRASTUZUMAB EMTANSINE, CYCLOPHOSPHAMIDE, DOCETAXEL, ERIBULIN, LETROZOLE, PACLITAXEL, PERTUZUMAB, TRASTUZUMAB, VINORELBINE TARTRATE | DrugsGivenReaction | CC BY | 33482449 | 18,846,201 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Carbohydrate antigen 15-3 increased'. | Favorable survival with combined treatment in a metastatic breast cancer patient undergoing hemodialysis: A case report.
BACKGROUND
Management of breast cancer patients undergoing hemodialysis (HD) is difficult because of a lack of evidence about drug selection, dose adjustment, and surgical procedures. We herein present a case of metastatic breast cancer in a patient undergoing HD.
METHODS
A 58-year-old Japanese woman with breast cancer undergoing HD underwent total mastectomy of the left breast and left axillary dissection. Histopathological examination revealed invasive ductal carcinoma, and the diagnosis was pT2N3cM0 Stage ⅢC. Immunostaining of the resected specimen indicated that the tumor was estrogen receptor-positive, progesterone receptor-negative, human epithelial growth factor receptor 2-positive, and the Ki-67 labeling index was 70%. A postoperative positron emission tomography/computed tomography (PET/CT) scan indicated fluorodeoxyglucose uptake in the supraclavicular nodes. She received adjuvant therapy of epirubicin and cyclophosphamide followed by docetaxel, trastuzumab (T-mab) and radiation therapy. However, she developed multiple liver metastases during adjuvant T-mab and hormone therapy. Therefore, her regimen was changed to trastuzumab emtansine (T-DM1) as first-line therapy, T-mab, pertuzumab (P-mab), and eribulin as second-line therapy, and T-mab, P-mab, and weekly paclitaxel as third-line therapy. Eventually, she was administered fourth-line treatment of T-mab, P-mab, and vinorelbine because of adverse events. She has survived more than 25 months after the initial detection of recurrence of breast cancer and maintained quality of life.
CONCLUSIONS
We report a case of breast cancer in a patient undergoing HD. It is very difficult to identify the appropriate drugs and dosages in patients undergoing HD to improve survival and quality of life.
1 Introduction
The risk of cancer, including breast cancer, is increased among patients undergoing hemodialysis (HD) [1,2]. In the United States, women undergoing HD are 42% more likely to develop breast cancer than the general population [1]. Unlike age, family history of breast cancer, early menarche, late menopause, late pregnancy, long-term hormone replacement therapy, radiation exposure, and benign breast diseases, chronic kidney disease (CKD) is not a major risk factor for breast cancer [3,4].
There are few studies on anticancer drugs and other drugs used in cancer therapy in patients undergoing HD, even though CKD, HD, and peritoneal dialysis do not limit the possibility of surgical treatment and radiotherapy. We herein present a case of HD with relatively long-term survival after diagnosis of multiple liver metastases detected during adjuvant therapy after surgery for locally advanced breast cancer.
2 Presentation of case
A 58-year-old Japanese woman undergoing HD developed a nodule in the left breast that was observed on chest computed tomography (CT). A dual-source CT scan showed an enhanced breast nodule 2.3 cm in diameter in the left breast (Fig. 1a), and enhanced CT indicated a swollen axillary lymph node (Fig. 1b). Needle biopsy was performed, and the pathological findings of the specimen indicated invasive ductal carcinoma that was estrogen receptor-positive, progesterone receptor-negative, and human epidermal growth factor receptor 2-positive by immunohistochemistry. Fine-needle aspiration cytology of the left axillary lymph node showed malignancy. The patient was diagnosed with primary breast cancer (cT2N1MX Stage ⅡB according to the Union for International Cancer Control classification).Fig. 1 (a) Dual-source computed tomography (CT) revealed breast cancer, and (b) plane CT revealed metastatic axillary lymph nodes.
Fig. 1
She underwent total mastectomy of the left breast and left axillary dissection. The pathological evaluation confirmed invasive ductal carcinoma (2.4 cm) and 10 metastatic axillary lymph nodes. A postoperative positron emission tomography/computed tomography (PET/CT) scan showed uptake in the supraclavicular lymph nodes (Fig. 2) but not in distant organs (pT2N3cM0 Stage IIIC).Fig. 2 Positron emission tomography (PET)/computed tomography showed a hot spot in a metastatic supraclavicular lymph node (arrow).
Fig. 2
We administered the combined systemic therapy regimen for patients with pT2N3cM0 Stage IIIC breast cancer, which included epirubicin and cyclophosphamide (EC) (100 mg/m2 and 600 mg/m2, respectively) four times every 3 weeks, followed by docetaxel (DTX) (75 mg/m2) and trastuzumab (T-mab) (8 mg/kg loading dose and 6 mg/kg thereafter) four times every 3 weeks for adjuvant therapy. She received 70% of the full-dose of EC, 80% of the full-dose of DTX, and the full-dose of T-mab.
We used the vascular access (VA) for HD on the patient’s right forearm for the administration of anticancer drugs, which was on the opposite side of the surgical site. However, thrombosis developed in the VA after two rounds of EC. The patient also developed febrile neutropenia (FN), hemorrhagic cystitis, and anemia, which required thrombolytic therapy, antibiotics, granulocyte colony-stimulating factor, and blood transfusions. EC therapy was discontinued, and a central venous access port (CV port) was created at the right internal jugular vein. After that, the patient received four cycles of DTX and T-mab, followed by PMRT of 50 Gy in 25 fractions and 10 Gy in 5 fractions to the supraclavicular and internal mammary nodes. The patient then received full-dose T-mab monotherapy every 3 weeks, which was scheduled for 14 cycles and full-dose letrozole, which was scheduled for 10 years, as additional adjuvant therapy. However, one year after surgery, PET/CT indicated multiple metastases (Fig. 3), and blood tests revealed an increase in serum CA15-3.Fig. 3 Positron emission tomography (PET)/computed tomography indicated multiple hot spots in the liver (arrows).
Fig. 3
Trastuzumab emtansine (T-DM1) was administered as the first-line treatment for the recurrence. She received a full-dose of T-DM1 (3.6 mg/kg every 3 weeks) for a total of 10 cycles among 32 weeks. However, the liver metastases did not respond, so she was administered for nine cycles of full-dose T-mab, pertuzumab (P-mab) (840 mg loading dose and 420 mg thereafter), and 70% of the full-dose of eribulin (1.4 mg/m2 on days 1 and 8 every 3 weeks) among 33 weeks. However, the liver metastases continued to grow, and we administered third-line treatment of full-dose T-mab, P-mab, and weekly paclitaxel (PTX) at 70% of the full dose (90 mg/m2) among 29 weeks. The third-line treatment was administered for nine cycles, and a partial response was observed in the liver metastases. However, the patient refused to continue the therapy because of grade 2 systemic edema and numbness in the fingers. Currently, full-dose T-mab, P-mab, and 60% of the full dose of vinorelbine (VNR; 25 mg/m2 on days 1 and 8 every 3 weeks) are being administered as the fourth-line treatment. She has survived more than 25 months after the initial detection of recurrence of breast cancer and maintained quality of life.
3 Discussion
In this report, we describe a patient with metastatic breast cancer who was undergoing HD. She had favorable survival and acceptable quality of life using a reduced dosage and several types of drugs, despite the difficulty of dose control. Drug dosages may need to be adjusted in some patients, but the lack of appropriate drug dosage can reduce overall survival [5]. A previous study reported that patients receiving a higher relative dose intensity (RDI) of anticancer drugs had better clinical outcomes than those receiving a lower RDI among patients with metastatic solid tumors, including breast cancer [6], but there are currently no data in patients undergoing HD.
The survival of patients with breast cancer who are receiving dialysis is still unknown. CKD is not a significant factor in overall survival or disease-free survival in patients with breast cancer [7]. In fact, the patient in the present report had a favorable survival even after breast cancer recurrence. However, the number of cases in the literature is limited, and there is no other report describing the survival of patients with breast cancer who are receiving HD.
Regarding the treatment of breast cancer patients who are receiving HD, the most important clinical issue is drug selection and dosage adjustment. The recommendations for dosage adjustment for oncological therapy among patients receiving HD are shown in Table 1 [8,9]. Most drugs are safe to administer in patients receiving HD, and methotrexate is the only drug that should be avoided. It is recommended that capecitabine, cyclophosphamide, DTX, doxorubicin, epirubicin, and VNR be administered at reduced doses. There are insufficient data on HD patients receiving tamoxifen, anastrozole, letrozole, and newer targeted agents, such as cyclin-dependent kinase 4/6 inhibitors, lapatinib, T-mab, P-mab, T-DM1, and atezolizumab. However, even drugs that do not require dose reduction should be reduced if they cause myelotoxicity or cardiotoxicity. However, these recommendations are general; therefore, for patients without CKD, dose reduction depends on the patient’s adverse events (AEs). In this case, we reduced the dose of EC to 70%, that of DTX to 80%, that of eribulin to 70%, that of PTX to 70%, and that of VNR to 60%. Even drugs that are generally administered at the full dose had to be reduced due to AEs, including thrombosis, FN, hemorrhagic cystitis, and anemia. Although there is no recommended dosage reduction in the literature for T-DM1, T-mab, P-mab, and letrozole [8], we were able to administer these drugs at the full dose without any major AEs.Table 1 Summary of pharmacokinetics and safety of oncological therapies for breast cancer in hemodialysis patients.
Table 1Drug Elimination Dose reduction in HD Bednarek A8) Recommended dose in HD Janus N9) safety
capecitabine Urinary Recommended dose reduction by 50% No data Safe (limited data)
cyclophosphamide Urinary Recommended dose reduction by 20% Reduction of 25% Hemorrhagic cystitis
docetaxel Faeces Not specified 65 mg/m2 Safe
paclitaxel Faeces Not specified Standard dose Safe
doxorubicin Faeces Recommended dose reduction by 20% Standard dose Inceased risk of cardiotoxicity
epirubicin Faeces Recommended dose reduction Standard dose Inceased risk of cardiotoxicity
vinorelbine Faeces Probably necessary (up to 50%) Reduction of 20%–33% Inceased myelotoxicity (limited data)
tamoxifen Faeces Not indicated − Safe
anastrozole Faeces Not indicated − Safe
letrozole Urinary Not specified − No data
palbociclib Faeces Not specified − No data
lapatinib Faeces Not indicated − Safe (limited data)
trastuzumab No data Not indicated − Inceased risk of cardiotoxicity
pertuzumab No data Not indicated − No data
trastuzumab emtansine Faeces Not indicated − Inceased risk of cardiotoxicity
atezolizumab No data Not indicated − Safe (very limited data)
Another issue is among patients undergoing HD is the VA, particularly for patients who undergo axillary dissection. If the dissection range includes the VA site, it may be preferable to place a VA on the opposite side of the surgical site prior to operation to reduce the risk of VA issues. Another alternative is to use a temporary VA for the short term. However, no previous report was found. It might be useful to confirm the effect of the operation on the original VA. In our case, the patient’s VA was on the opposite side of the surgical site, so it was unaffected by the surgery.
Intravenous administered of anticancer drugs should be considered. In our case, the venous pressure in the internal jugular vein was increased by the VA on the non-affected side. It is usually recommended to create a CV port to prevent vasculitis caused by anticancer drugs, but we need to consider the risks of venous pressure increase. We initially decided to administer anticancer drugs from the VA for HD, but the patient developed thrombosis, and we created a CV port via the internal jugular vein on the VA side without any complications. This case is reported in line with the SCARE Guideline [10].
4 Conclusion
We report a case of breast cancer diagnosed during HD with multiple liver metastases that developed during postoperative adjuvant therapy. It is very difficult to manage patients undergoing HD with the appropriate drugs and dosage to improve survival and quality of life.
Declaration of Competing Interest
None.
Funding
None.
Ethical approval
None.
Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
Author contribution
Megumi Matsumoto conceptualized the study. Hiroshi Yano, Ryota Otsubo, and Aya Tanaka collaborated in the patient’s care. Takeshi Nagayasu provided input on the manuscript.
Registration of research studies
Researchregistry 6411.
Guarantor
Megumi Matsumoto.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Acknowledgements
We would like to thank Editage (www.editage.com) for English language editing. | ADO-TRASTUZUMAB EMTANSINE, CYCLOPHOSPHAMIDE, DOCETAXEL, ERIBULIN, LETROZOLE, PACLITAXEL, PERTUZUMAB, TRASTUZUMAB, VINORELBINE TARTRATE | DrugsGivenReaction | CC BY | 33482449 | 18,846,201 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Metastases to liver'. | Favorable survival with combined treatment in a metastatic breast cancer patient undergoing hemodialysis: A case report.
BACKGROUND
Management of breast cancer patients undergoing hemodialysis (HD) is difficult because of a lack of evidence about drug selection, dose adjustment, and surgical procedures. We herein present a case of metastatic breast cancer in a patient undergoing HD.
METHODS
A 58-year-old Japanese woman with breast cancer undergoing HD underwent total mastectomy of the left breast and left axillary dissection. Histopathological examination revealed invasive ductal carcinoma, and the diagnosis was pT2N3cM0 Stage ⅢC. Immunostaining of the resected specimen indicated that the tumor was estrogen receptor-positive, progesterone receptor-negative, human epithelial growth factor receptor 2-positive, and the Ki-67 labeling index was 70%. A postoperative positron emission tomography/computed tomography (PET/CT) scan indicated fluorodeoxyglucose uptake in the supraclavicular nodes. She received adjuvant therapy of epirubicin and cyclophosphamide followed by docetaxel, trastuzumab (T-mab) and radiation therapy. However, she developed multiple liver metastases during adjuvant T-mab and hormone therapy. Therefore, her regimen was changed to trastuzumab emtansine (T-DM1) as first-line therapy, T-mab, pertuzumab (P-mab), and eribulin as second-line therapy, and T-mab, P-mab, and weekly paclitaxel as third-line therapy. Eventually, she was administered fourth-line treatment of T-mab, P-mab, and vinorelbine because of adverse events. She has survived more than 25 months after the initial detection of recurrence of breast cancer and maintained quality of life.
CONCLUSIONS
We report a case of breast cancer in a patient undergoing HD. It is very difficult to identify the appropriate drugs and dosages in patients undergoing HD to improve survival and quality of life.
1 Introduction
The risk of cancer, including breast cancer, is increased among patients undergoing hemodialysis (HD) [1,2]. In the United States, women undergoing HD are 42% more likely to develop breast cancer than the general population [1]. Unlike age, family history of breast cancer, early menarche, late menopause, late pregnancy, long-term hormone replacement therapy, radiation exposure, and benign breast diseases, chronic kidney disease (CKD) is not a major risk factor for breast cancer [3,4].
There are few studies on anticancer drugs and other drugs used in cancer therapy in patients undergoing HD, even though CKD, HD, and peritoneal dialysis do not limit the possibility of surgical treatment and radiotherapy. We herein present a case of HD with relatively long-term survival after diagnosis of multiple liver metastases detected during adjuvant therapy after surgery for locally advanced breast cancer.
2 Presentation of case
A 58-year-old Japanese woman undergoing HD developed a nodule in the left breast that was observed on chest computed tomography (CT). A dual-source CT scan showed an enhanced breast nodule 2.3 cm in diameter in the left breast (Fig. 1a), and enhanced CT indicated a swollen axillary lymph node (Fig. 1b). Needle biopsy was performed, and the pathological findings of the specimen indicated invasive ductal carcinoma that was estrogen receptor-positive, progesterone receptor-negative, and human epidermal growth factor receptor 2-positive by immunohistochemistry. Fine-needle aspiration cytology of the left axillary lymph node showed malignancy. The patient was diagnosed with primary breast cancer (cT2N1MX Stage ⅡB according to the Union for International Cancer Control classification).Fig. 1 (a) Dual-source computed tomography (CT) revealed breast cancer, and (b) plane CT revealed metastatic axillary lymph nodes.
Fig. 1
She underwent total mastectomy of the left breast and left axillary dissection. The pathological evaluation confirmed invasive ductal carcinoma (2.4 cm) and 10 metastatic axillary lymph nodes. A postoperative positron emission tomography/computed tomography (PET/CT) scan showed uptake in the supraclavicular lymph nodes (Fig. 2) but not in distant organs (pT2N3cM0 Stage IIIC).Fig. 2 Positron emission tomography (PET)/computed tomography showed a hot spot in a metastatic supraclavicular lymph node (arrow).
Fig. 2
We administered the combined systemic therapy regimen for patients with pT2N3cM0 Stage IIIC breast cancer, which included epirubicin and cyclophosphamide (EC) (100 mg/m2 and 600 mg/m2, respectively) four times every 3 weeks, followed by docetaxel (DTX) (75 mg/m2) and trastuzumab (T-mab) (8 mg/kg loading dose and 6 mg/kg thereafter) four times every 3 weeks for adjuvant therapy. She received 70% of the full-dose of EC, 80% of the full-dose of DTX, and the full-dose of T-mab.
We used the vascular access (VA) for HD on the patient’s right forearm for the administration of anticancer drugs, which was on the opposite side of the surgical site. However, thrombosis developed in the VA after two rounds of EC. The patient also developed febrile neutropenia (FN), hemorrhagic cystitis, and anemia, which required thrombolytic therapy, antibiotics, granulocyte colony-stimulating factor, and blood transfusions. EC therapy was discontinued, and a central venous access port (CV port) was created at the right internal jugular vein. After that, the patient received four cycles of DTX and T-mab, followed by PMRT of 50 Gy in 25 fractions and 10 Gy in 5 fractions to the supraclavicular and internal mammary nodes. The patient then received full-dose T-mab monotherapy every 3 weeks, which was scheduled for 14 cycles and full-dose letrozole, which was scheduled for 10 years, as additional adjuvant therapy. However, one year after surgery, PET/CT indicated multiple metastases (Fig. 3), and blood tests revealed an increase in serum CA15-3.Fig. 3 Positron emission tomography (PET)/computed tomography indicated multiple hot spots in the liver (arrows).
Fig. 3
Trastuzumab emtansine (T-DM1) was administered as the first-line treatment for the recurrence. She received a full-dose of T-DM1 (3.6 mg/kg every 3 weeks) for a total of 10 cycles among 32 weeks. However, the liver metastases did not respond, so she was administered for nine cycles of full-dose T-mab, pertuzumab (P-mab) (840 mg loading dose and 420 mg thereafter), and 70% of the full-dose of eribulin (1.4 mg/m2 on days 1 and 8 every 3 weeks) among 33 weeks. However, the liver metastases continued to grow, and we administered third-line treatment of full-dose T-mab, P-mab, and weekly paclitaxel (PTX) at 70% of the full dose (90 mg/m2) among 29 weeks. The third-line treatment was administered for nine cycles, and a partial response was observed in the liver metastases. However, the patient refused to continue the therapy because of grade 2 systemic edema and numbness in the fingers. Currently, full-dose T-mab, P-mab, and 60% of the full dose of vinorelbine (VNR; 25 mg/m2 on days 1 and 8 every 3 weeks) are being administered as the fourth-line treatment. She has survived more than 25 months after the initial detection of recurrence of breast cancer and maintained quality of life.
3 Discussion
In this report, we describe a patient with metastatic breast cancer who was undergoing HD. She had favorable survival and acceptable quality of life using a reduced dosage and several types of drugs, despite the difficulty of dose control. Drug dosages may need to be adjusted in some patients, but the lack of appropriate drug dosage can reduce overall survival [5]. A previous study reported that patients receiving a higher relative dose intensity (RDI) of anticancer drugs had better clinical outcomes than those receiving a lower RDI among patients with metastatic solid tumors, including breast cancer [6], but there are currently no data in patients undergoing HD.
The survival of patients with breast cancer who are receiving dialysis is still unknown. CKD is not a significant factor in overall survival or disease-free survival in patients with breast cancer [7]. In fact, the patient in the present report had a favorable survival even after breast cancer recurrence. However, the number of cases in the literature is limited, and there is no other report describing the survival of patients with breast cancer who are receiving HD.
Regarding the treatment of breast cancer patients who are receiving HD, the most important clinical issue is drug selection and dosage adjustment. The recommendations for dosage adjustment for oncological therapy among patients receiving HD are shown in Table 1 [8,9]. Most drugs are safe to administer in patients receiving HD, and methotrexate is the only drug that should be avoided. It is recommended that capecitabine, cyclophosphamide, DTX, doxorubicin, epirubicin, and VNR be administered at reduced doses. There are insufficient data on HD patients receiving tamoxifen, anastrozole, letrozole, and newer targeted agents, such as cyclin-dependent kinase 4/6 inhibitors, lapatinib, T-mab, P-mab, T-DM1, and atezolizumab. However, even drugs that do not require dose reduction should be reduced if they cause myelotoxicity or cardiotoxicity. However, these recommendations are general; therefore, for patients without CKD, dose reduction depends on the patient’s adverse events (AEs). In this case, we reduced the dose of EC to 70%, that of DTX to 80%, that of eribulin to 70%, that of PTX to 70%, and that of VNR to 60%. Even drugs that are generally administered at the full dose had to be reduced due to AEs, including thrombosis, FN, hemorrhagic cystitis, and anemia. Although there is no recommended dosage reduction in the literature for T-DM1, T-mab, P-mab, and letrozole [8], we were able to administer these drugs at the full dose without any major AEs.Table 1 Summary of pharmacokinetics and safety of oncological therapies for breast cancer in hemodialysis patients.
Table 1Drug Elimination Dose reduction in HD Bednarek A8) Recommended dose in HD Janus N9) safety
capecitabine Urinary Recommended dose reduction by 50% No data Safe (limited data)
cyclophosphamide Urinary Recommended dose reduction by 20% Reduction of 25% Hemorrhagic cystitis
docetaxel Faeces Not specified 65 mg/m2 Safe
paclitaxel Faeces Not specified Standard dose Safe
doxorubicin Faeces Recommended dose reduction by 20% Standard dose Inceased risk of cardiotoxicity
epirubicin Faeces Recommended dose reduction Standard dose Inceased risk of cardiotoxicity
vinorelbine Faeces Probably necessary (up to 50%) Reduction of 20%–33% Inceased myelotoxicity (limited data)
tamoxifen Faeces Not indicated − Safe
anastrozole Faeces Not indicated − Safe
letrozole Urinary Not specified − No data
palbociclib Faeces Not specified − No data
lapatinib Faeces Not indicated − Safe (limited data)
trastuzumab No data Not indicated − Inceased risk of cardiotoxicity
pertuzumab No data Not indicated − No data
trastuzumab emtansine Faeces Not indicated − Inceased risk of cardiotoxicity
atezolizumab No data Not indicated − Safe (very limited data)
Another issue is among patients undergoing HD is the VA, particularly for patients who undergo axillary dissection. If the dissection range includes the VA site, it may be preferable to place a VA on the opposite side of the surgical site prior to operation to reduce the risk of VA issues. Another alternative is to use a temporary VA for the short term. However, no previous report was found. It might be useful to confirm the effect of the operation on the original VA. In our case, the patient’s VA was on the opposite side of the surgical site, so it was unaffected by the surgery.
Intravenous administered of anticancer drugs should be considered. In our case, the venous pressure in the internal jugular vein was increased by the VA on the non-affected side. It is usually recommended to create a CV port to prevent vasculitis caused by anticancer drugs, but we need to consider the risks of venous pressure increase. We initially decided to administer anticancer drugs from the VA for HD, but the patient developed thrombosis, and we created a CV port via the internal jugular vein on the VA side without any complications. This case is reported in line with the SCARE Guideline [10].
4 Conclusion
We report a case of breast cancer diagnosed during HD with multiple liver metastases that developed during postoperative adjuvant therapy. It is very difficult to manage patients undergoing HD with the appropriate drugs and dosage to improve survival and quality of life.
Declaration of Competing Interest
None.
Funding
None.
Ethical approval
None.
Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
Author contribution
Megumi Matsumoto conceptualized the study. Hiroshi Yano, Ryota Otsubo, and Aya Tanaka collaborated in the patient’s care. Takeshi Nagayasu provided input on the manuscript.
Registration of research studies
Researchregistry 6411.
Guarantor
Megumi Matsumoto.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Acknowledgements
We would like to thank Editage (www.editage.com) for English language editing. | ADO-TRASTUZUMAB EMTANSINE, CYCLOPHOSPHAMIDE, DOCETAXEL, ERIBULIN, LETROZOLE, PACLITAXEL, PERTUZUMAB, TRASTUZUMAB, VINORELBINE TARTRATE | DrugsGivenReaction | CC BY | 33482449 | 18,846,201 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Favorable survival with combined treatment in a metastatic breast cancer patient undergoing hemodialysis: A case report.
BACKGROUND
Management of breast cancer patients undergoing hemodialysis (HD) is difficult because of a lack of evidence about drug selection, dose adjustment, and surgical procedures. We herein present a case of metastatic breast cancer in a patient undergoing HD.
METHODS
A 58-year-old Japanese woman with breast cancer undergoing HD underwent total mastectomy of the left breast and left axillary dissection. Histopathological examination revealed invasive ductal carcinoma, and the diagnosis was pT2N3cM0 Stage ⅢC. Immunostaining of the resected specimen indicated that the tumor was estrogen receptor-positive, progesterone receptor-negative, human epithelial growth factor receptor 2-positive, and the Ki-67 labeling index was 70%. A postoperative positron emission tomography/computed tomography (PET/CT) scan indicated fluorodeoxyglucose uptake in the supraclavicular nodes. She received adjuvant therapy of epirubicin and cyclophosphamide followed by docetaxel, trastuzumab (T-mab) and radiation therapy. However, she developed multiple liver metastases during adjuvant T-mab and hormone therapy. Therefore, her regimen was changed to trastuzumab emtansine (T-DM1) as first-line therapy, T-mab, pertuzumab (P-mab), and eribulin as second-line therapy, and T-mab, P-mab, and weekly paclitaxel as third-line therapy. Eventually, she was administered fourth-line treatment of T-mab, P-mab, and vinorelbine because of adverse events. She has survived more than 25 months after the initial detection of recurrence of breast cancer and maintained quality of life.
CONCLUSIONS
We report a case of breast cancer in a patient undergoing HD. It is very difficult to identify the appropriate drugs and dosages in patients undergoing HD to improve survival and quality of life.
1 Introduction
The risk of cancer, including breast cancer, is increased among patients undergoing hemodialysis (HD) [1,2]. In the United States, women undergoing HD are 42% more likely to develop breast cancer than the general population [1]. Unlike age, family history of breast cancer, early menarche, late menopause, late pregnancy, long-term hormone replacement therapy, radiation exposure, and benign breast diseases, chronic kidney disease (CKD) is not a major risk factor for breast cancer [3,4].
There are few studies on anticancer drugs and other drugs used in cancer therapy in patients undergoing HD, even though CKD, HD, and peritoneal dialysis do not limit the possibility of surgical treatment and radiotherapy. We herein present a case of HD with relatively long-term survival after diagnosis of multiple liver metastases detected during adjuvant therapy after surgery for locally advanced breast cancer.
2 Presentation of case
A 58-year-old Japanese woman undergoing HD developed a nodule in the left breast that was observed on chest computed tomography (CT). A dual-source CT scan showed an enhanced breast nodule 2.3 cm in diameter in the left breast (Fig. 1a), and enhanced CT indicated a swollen axillary lymph node (Fig. 1b). Needle biopsy was performed, and the pathological findings of the specimen indicated invasive ductal carcinoma that was estrogen receptor-positive, progesterone receptor-negative, and human epidermal growth factor receptor 2-positive by immunohistochemistry. Fine-needle aspiration cytology of the left axillary lymph node showed malignancy. The patient was diagnosed with primary breast cancer (cT2N1MX Stage ⅡB according to the Union for International Cancer Control classification).Fig. 1 (a) Dual-source computed tomography (CT) revealed breast cancer, and (b) plane CT revealed metastatic axillary lymph nodes.
Fig. 1
She underwent total mastectomy of the left breast and left axillary dissection. The pathological evaluation confirmed invasive ductal carcinoma (2.4 cm) and 10 metastatic axillary lymph nodes. A postoperative positron emission tomography/computed tomography (PET/CT) scan showed uptake in the supraclavicular lymph nodes (Fig. 2) but not in distant organs (pT2N3cM0 Stage IIIC).Fig. 2 Positron emission tomography (PET)/computed tomography showed a hot spot in a metastatic supraclavicular lymph node (arrow).
Fig. 2
We administered the combined systemic therapy regimen for patients with pT2N3cM0 Stage IIIC breast cancer, which included epirubicin and cyclophosphamide (EC) (100 mg/m2 and 600 mg/m2, respectively) four times every 3 weeks, followed by docetaxel (DTX) (75 mg/m2) and trastuzumab (T-mab) (8 mg/kg loading dose and 6 mg/kg thereafter) four times every 3 weeks for adjuvant therapy. She received 70% of the full-dose of EC, 80% of the full-dose of DTX, and the full-dose of T-mab.
We used the vascular access (VA) for HD on the patient’s right forearm for the administration of anticancer drugs, which was on the opposite side of the surgical site. However, thrombosis developed in the VA after two rounds of EC. The patient also developed febrile neutropenia (FN), hemorrhagic cystitis, and anemia, which required thrombolytic therapy, antibiotics, granulocyte colony-stimulating factor, and blood transfusions. EC therapy was discontinued, and a central venous access port (CV port) was created at the right internal jugular vein. After that, the patient received four cycles of DTX and T-mab, followed by PMRT of 50 Gy in 25 fractions and 10 Gy in 5 fractions to the supraclavicular and internal mammary nodes. The patient then received full-dose T-mab monotherapy every 3 weeks, which was scheduled for 14 cycles and full-dose letrozole, which was scheduled for 10 years, as additional adjuvant therapy. However, one year after surgery, PET/CT indicated multiple metastases (Fig. 3), and blood tests revealed an increase in serum CA15-3.Fig. 3 Positron emission tomography (PET)/computed tomography indicated multiple hot spots in the liver (arrows).
Fig. 3
Trastuzumab emtansine (T-DM1) was administered as the first-line treatment for the recurrence. She received a full-dose of T-DM1 (3.6 mg/kg every 3 weeks) for a total of 10 cycles among 32 weeks. However, the liver metastases did not respond, so she was administered for nine cycles of full-dose T-mab, pertuzumab (P-mab) (840 mg loading dose and 420 mg thereafter), and 70% of the full-dose of eribulin (1.4 mg/m2 on days 1 and 8 every 3 weeks) among 33 weeks. However, the liver metastases continued to grow, and we administered third-line treatment of full-dose T-mab, P-mab, and weekly paclitaxel (PTX) at 70% of the full dose (90 mg/m2) among 29 weeks. The third-line treatment was administered for nine cycles, and a partial response was observed in the liver metastases. However, the patient refused to continue the therapy because of grade 2 systemic edema and numbness in the fingers. Currently, full-dose T-mab, P-mab, and 60% of the full dose of vinorelbine (VNR; 25 mg/m2 on days 1 and 8 every 3 weeks) are being administered as the fourth-line treatment. She has survived more than 25 months after the initial detection of recurrence of breast cancer and maintained quality of life.
3 Discussion
In this report, we describe a patient with metastatic breast cancer who was undergoing HD. She had favorable survival and acceptable quality of life using a reduced dosage and several types of drugs, despite the difficulty of dose control. Drug dosages may need to be adjusted in some patients, but the lack of appropriate drug dosage can reduce overall survival [5]. A previous study reported that patients receiving a higher relative dose intensity (RDI) of anticancer drugs had better clinical outcomes than those receiving a lower RDI among patients with metastatic solid tumors, including breast cancer [6], but there are currently no data in patients undergoing HD.
The survival of patients with breast cancer who are receiving dialysis is still unknown. CKD is not a significant factor in overall survival or disease-free survival in patients with breast cancer [7]. In fact, the patient in the present report had a favorable survival even after breast cancer recurrence. However, the number of cases in the literature is limited, and there is no other report describing the survival of patients with breast cancer who are receiving HD.
Regarding the treatment of breast cancer patients who are receiving HD, the most important clinical issue is drug selection and dosage adjustment. The recommendations for dosage adjustment for oncological therapy among patients receiving HD are shown in Table 1 [8,9]. Most drugs are safe to administer in patients receiving HD, and methotrexate is the only drug that should be avoided. It is recommended that capecitabine, cyclophosphamide, DTX, doxorubicin, epirubicin, and VNR be administered at reduced doses. There are insufficient data on HD patients receiving tamoxifen, anastrozole, letrozole, and newer targeted agents, such as cyclin-dependent kinase 4/6 inhibitors, lapatinib, T-mab, P-mab, T-DM1, and atezolizumab. However, even drugs that do not require dose reduction should be reduced if they cause myelotoxicity or cardiotoxicity. However, these recommendations are general; therefore, for patients without CKD, dose reduction depends on the patient’s adverse events (AEs). In this case, we reduced the dose of EC to 70%, that of DTX to 80%, that of eribulin to 70%, that of PTX to 70%, and that of VNR to 60%. Even drugs that are generally administered at the full dose had to be reduced due to AEs, including thrombosis, FN, hemorrhagic cystitis, and anemia. Although there is no recommended dosage reduction in the literature for T-DM1, T-mab, P-mab, and letrozole [8], we were able to administer these drugs at the full dose without any major AEs.Table 1 Summary of pharmacokinetics and safety of oncological therapies for breast cancer in hemodialysis patients.
Table 1Drug Elimination Dose reduction in HD Bednarek A8) Recommended dose in HD Janus N9) safety
capecitabine Urinary Recommended dose reduction by 50% No data Safe (limited data)
cyclophosphamide Urinary Recommended dose reduction by 20% Reduction of 25% Hemorrhagic cystitis
docetaxel Faeces Not specified 65 mg/m2 Safe
paclitaxel Faeces Not specified Standard dose Safe
doxorubicin Faeces Recommended dose reduction by 20% Standard dose Inceased risk of cardiotoxicity
epirubicin Faeces Recommended dose reduction Standard dose Inceased risk of cardiotoxicity
vinorelbine Faeces Probably necessary (up to 50%) Reduction of 20%–33% Inceased myelotoxicity (limited data)
tamoxifen Faeces Not indicated − Safe
anastrozole Faeces Not indicated − Safe
letrozole Urinary Not specified − No data
palbociclib Faeces Not specified − No data
lapatinib Faeces Not indicated − Safe (limited data)
trastuzumab No data Not indicated − Inceased risk of cardiotoxicity
pertuzumab No data Not indicated − No data
trastuzumab emtansine Faeces Not indicated − Inceased risk of cardiotoxicity
atezolizumab No data Not indicated − Safe (very limited data)
Another issue is among patients undergoing HD is the VA, particularly for patients who undergo axillary dissection. If the dissection range includes the VA site, it may be preferable to place a VA on the opposite side of the surgical site prior to operation to reduce the risk of VA issues. Another alternative is to use a temporary VA for the short term. However, no previous report was found. It might be useful to confirm the effect of the operation on the original VA. In our case, the patient’s VA was on the opposite side of the surgical site, so it was unaffected by the surgery.
Intravenous administered of anticancer drugs should be considered. In our case, the venous pressure in the internal jugular vein was increased by the VA on the non-affected side. It is usually recommended to create a CV port to prevent vasculitis caused by anticancer drugs, but we need to consider the risks of venous pressure increase. We initially decided to administer anticancer drugs from the VA for HD, but the patient developed thrombosis, and we created a CV port via the internal jugular vein on the VA side without any complications. This case is reported in line with the SCARE Guideline [10].
4 Conclusion
We report a case of breast cancer diagnosed during HD with multiple liver metastases that developed during postoperative adjuvant therapy. It is very difficult to manage patients undergoing HD with the appropriate drugs and dosage to improve survival and quality of life.
Declaration of Competing Interest
None.
Funding
None.
Ethical approval
None.
Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
Author contribution
Megumi Matsumoto conceptualized the study. Hiroshi Yano, Ryota Otsubo, and Aya Tanaka collaborated in the patient’s care. Takeshi Nagayasu provided input on the manuscript.
Registration of research studies
Researchregistry 6411.
Guarantor
Megumi Matsumoto.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Acknowledgements
We would like to thank Editage (www.editage.com) for English language editing. | ADO-TRASTUZUMAB EMTANSINE, CYCLOPHOSPHAMIDE, DOCETAXEL, ERIBULIN, LETROZOLE, PACLITAXEL, PERTUZUMAB, TRASTUZUMAB, VINORELBINE TARTRATE | DrugsGivenReaction | CC BY | 33482449 | 18,846,201 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapy non-responder'. | Favorable survival with combined treatment in a metastatic breast cancer patient undergoing hemodialysis: A case report.
BACKGROUND
Management of breast cancer patients undergoing hemodialysis (HD) is difficult because of a lack of evidence about drug selection, dose adjustment, and surgical procedures. We herein present a case of metastatic breast cancer in a patient undergoing HD.
METHODS
A 58-year-old Japanese woman with breast cancer undergoing HD underwent total mastectomy of the left breast and left axillary dissection. Histopathological examination revealed invasive ductal carcinoma, and the diagnosis was pT2N3cM0 Stage ⅢC. Immunostaining of the resected specimen indicated that the tumor was estrogen receptor-positive, progesterone receptor-negative, human epithelial growth factor receptor 2-positive, and the Ki-67 labeling index was 70%. A postoperative positron emission tomography/computed tomography (PET/CT) scan indicated fluorodeoxyglucose uptake in the supraclavicular nodes. She received adjuvant therapy of epirubicin and cyclophosphamide followed by docetaxel, trastuzumab (T-mab) and radiation therapy. However, she developed multiple liver metastases during adjuvant T-mab and hormone therapy. Therefore, her regimen was changed to trastuzumab emtansine (T-DM1) as first-line therapy, T-mab, pertuzumab (P-mab), and eribulin as second-line therapy, and T-mab, P-mab, and weekly paclitaxel as third-line therapy. Eventually, she was administered fourth-line treatment of T-mab, P-mab, and vinorelbine because of adverse events. She has survived more than 25 months after the initial detection of recurrence of breast cancer and maintained quality of life.
CONCLUSIONS
We report a case of breast cancer in a patient undergoing HD. It is very difficult to identify the appropriate drugs and dosages in patients undergoing HD to improve survival and quality of life.
1 Introduction
The risk of cancer, including breast cancer, is increased among patients undergoing hemodialysis (HD) [1,2]. In the United States, women undergoing HD are 42% more likely to develop breast cancer than the general population [1]. Unlike age, family history of breast cancer, early menarche, late menopause, late pregnancy, long-term hormone replacement therapy, radiation exposure, and benign breast diseases, chronic kidney disease (CKD) is not a major risk factor for breast cancer [3,4].
There are few studies on anticancer drugs and other drugs used in cancer therapy in patients undergoing HD, even though CKD, HD, and peritoneal dialysis do not limit the possibility of surgical treatment and radiotherapy. We herein present a case of HD with relatively long-term survival after diagnosis of multiple liver metastases detected during adjuvant therapy after surgery for locally advanced breast cancer.
2 Presentation of case
A 58-year-old Japanese woman undergoing HD developed a nodule in the left breast that was observed on chest computed tomography (CT). A dual-source CT scan showed an enhanced breast nodule 2.3 cm in diameter in the left breast (Fig. 1a), and enhanced CT indicated a swollen axillary lymph node (Fig. 1b). Needle biopsy was performed, and the pathological findings of the specimen indicated invasive ductal carcinoma that was estrogen receptor-positive, progesterone receptor-negative, and human epidermal growth factor receptor 2-positive by immunohistochemistry. Fine-needle aspiration cytology of the left axillary lymph node showed malignancy. The patient was diagnosed with primary breast cancer (cT2N1MX Stage ⅡB according to the Union for International Cancer Control classification).Fig. 1 (a) Dual-source computed tomography (CT) revealed breast cancer, and (b) plane CT revealed metastatic axillary lymph nodes.
Fig. 1
She underwent total mastectomy of the left breast and left axillary dissection. The pathological evaluation confirmed invasive ductal carcinoma (2.4 cm) and 10 metastatic axillary lymph nodes. A postoperative positron emission tomography/computed tomography (PET/CT) scan showed uptake in the supraclavicular lymph nodes (Fig. 2) but not in distant organs (pT2N3cM0 Stage IIIC).Fig. 2 Positron emission tomography (PET)/computed tomography showed a hot spot in a metastatic supraclavicular lymph node (arrow).
Fig. 2
We administered the combined systemic therapy regimen for patients with pT2N3cM0 Stage IIIC breast cancer, which included epirubicin and cyclophosphamide (EC) (100 mg/m2 and 600 mg/m2, respectively) four times every 3 weeks, followed by docetaxel (DTX) (75 mg/m2) and trastuzumab (T-mab) (8 mg/kg loading dose and 6 mg/kg thereafter) four times every 3 weeks for adjuvant therapy. She received 70% of the full-dose of EC, 80% of the full-dose of DTX, and the full-dose of T-mab.
We used the vascular access (VA) for HD on the patient’s right forearm for the administration of anticancer drugs, which was on the opposite side of the surgical site. However, thrombosis developed in the VA after two rounds of EC. The patient also developed febrile neutropenia (FN), hemorrhagic cystitis, and anemia, which required thrombolytic therapy, antibiotics, granulocyte colony-stimulating factor, and blood transfusions. EC therapy was discontinued, and a central venous access port (CV port) was created at the right internal jugular vein. After that, the patient received four cycles of DTX and T-mab, followed by PMRT of 50 Gy in 25 fractions and 10 Gy in 5 fractions to the supraclavicular and internal mammary nodes. The patient then received full-dose T-mab monotherapy every 3 weeks, which was scheduled for 14 cycles and full-dose letrozole, which was scheduled for 10 years, as additional adjuvant therapy. However, one year after surgery, PET/CT indicated multiple metastases (Fig. 3), and blood tests revealed an increase in serum CA15-3.Fig. 3 Positron emission tomography (PET)/computed tomography indicated multiple hot spots in the liver (arrows).
Fig. 3
Trastuzumab emtansine (T-DM1) was administered as the first-line treatment for the recurrence. She received a full-dose of T-DM1 (3.6 mg/kg every 3 weeks) for a total of 10 cycles among 32 weeks. However, the liver metastases did not respond, so she was administered for nine cycles of full-dose T-mab, pertuzumab (P-mab) (840 mg loading dose and 420 mg thereafter), and 70% of the full-dose of eribulin (1.4 mg/m2 on days 1 and 8 every 3 weeks) among 33 weeks. However, the liver metastases continued to grow, and we administered third-line treatment of full-dose T-mab, P-mab, and weekly paclitaxel (PTX) at 70% of the full dose (90 mg/m2) among 29 weeks. The third-line treatment was administered for nine cycles, and a partial response was observed in the liver metastases. However, the patient refused to continue the therapy because of grade 2 systemic edema and numbness in the fingers. Currently, full-dose T-mab, P-mab, and 60% of the full dose of vinorelbine (VNR; 25 mg/m2 on days 1 and 8 every 3 weeks) are being administered as the fourth-line treatment. She has survived more than 25 months after the initial detection of recurrence of breast cancer and maintained quality of life.
3 Discussion
In this report, we describe a patient with metastatic breast cancer who was undergoing HD. She had favorable survival and acceptable quality of life using a reduced dosage and several types of drugs, despite the difficulty of dose control. Drug dosages may need to be adjusted in some patients, but the lack of appropriate drug dosage can reduce overall survival [5]. A previous study reported that patients receiving a higher relative dose intensity (RDI) of anticancer drugs had better clinical outcomes than those receiving a lower RDI among patients with metastatic solid tumors, including breast cancer [6], but there are currently no data in patients undergoing HD.
The survival of patients with breast cancer who are receiving dialysis is still unknown. CKD is not a significant factor in overall survival or disease-free survival in patients with breast cancer [7]. In fact, the patient in the present report had a favorable survival even after breast cancer recurrence. However, the number of cases in the literature is limited, and there is no other report describing the survival of patients with breast cancer who are receiving HD.
Regarding the treatment of breast cancer patients who are receiving HD, the most important clinical issue is drug selection and dosage adjustment. The recommendations for dosage adjustment for oncological therapy among patients receiving HD are shown in Table 1 [8,9]. Most drugs are safe to administer in patients receiving HD, and methotrexate is the only drug that should be avoided. It is recommended that capecitabine, cyclophosphamide, DTX, doxorubicin, epirubicin, and VNR be administered at reduced doses. There are insufficient data on HD patients receiving tamoxifen, anastrozole, letrozole, and newer targeted agents, such as cyclin-dependent kinase 4/6 inhibitors, lapatinib, T-mab, P-mab, T-DM1, and atezolizumab. However, even drugs that do not require dose reduction should be reduced if they cause myelotoxicity or cardiotoxicity. However, these recommendations are general; therefore, for patients without CKD, dose reduction depends on the patient’s adverse events (AEs). In this case, we reduced the dose of EC to 70%, that of DTX to 80%, that of eribulin to 70%, that of PTX to 70%, and that of VNR to 60%. Even drugs that are generally administered at the full dose had to be reduced due to AEs, including thrombosis, FN, hemorrhagic cystitis, and anemia. Although there is no recommended dosage reduction in the literature for T-DM1, T-mab, P-mab, and letrozole [8], we were able to administer these drugs at the full dose without any major AEs.Table 1 Summary of pharmacokinetics and safety of oncological therapies for breast cancer in hemodialysis patients.
Table 1Drug Elimination Dose reduction in HD Bednarek A8) Recommended dose in HD Janus N9) safety
capecitabine Urinary Recommended dose reduction by 50% No data Safe (limited data)
cyclophosphamide Urinary Recommended dose reduction by 20% Reduction of 25% Hemorrhagic cystitis
docetaxel Faeces Not specified 65 mg/m2 Safe
paclitaxel Faeces Not specified Standard dose Safe
doxorubicin Faeces Recommended dose reduction by 20% Standard dose Inceased risk of cardiotoxicity
epirubicin Faeces Recommended dose reduction Standard dose Inceased risk of cardiotoxicity
vinorelbine Faeces Probably necessary (up to 50%) Reduction of 20%–33% Inceased myelotoxicity (limited data)
tamoxifen Faeces Not indicated − Safe
anastrozole Faeces Not indicated − Safe
letrozole Urinary Not specified − No data
palbociclib Faeces Not specified − No data
lapatinib Faeces Not indicated − Safe (limited data)
trastuzumab No data Not indicated − Inceased risk of cardiotoxicity
pertuzumab No data Not indicated − No data
trastuzumab emtansine Faeces Not indicated − Inceased risk of cardiotoxicity
atezolizumab No data Not indicated − Safe (very limited data)
Another issue is among patients undergoing HD is the VA, particularly for patients who undergo axillary dissection. If the dissection range includes the VA site, it may be preferable to place a VA on the opposite side of the surgical site prior to operation to reduce the risk of VA issues. Another alternative is to use a temporary VA for the short term. However, no previous report was found. It might be useful to confirm the effect of the operation on the original VA. In our case, the patient’s VA was on the opposite side of the surgical site, so it was unaffected by the surgery.
Intravenous administered of anticancer drugs should be considered. In our case, the venous pressure in the internal jugular vein was increased by the VA on the non-affected side. It is usually recommended to create a CV port to prevent vasculitis caused by anticancer drugs, but we need to consider the risks of venous pressure increase. We initially decided to administer anticancer drugs from the VA for HD, but the patient developed thrombosis, and we created a CV port via the internal jugular vein on the VA side without any complications. This case is reported in line with the SCARE Guideline [10].
4 Conclusion
We report a case of breast cancer diagnosed during HD with multiple liver metastases that developed during postoperative adjuvant therapy. It is very difficult to manage patients undergoing HD with the appropriate drugs and dosage to improve survival and quality of life.
Declaration of Competing Interest
None.
Funding
None.
Ethical approval
None.
Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
Author contribution
Megumi Matsumoto conceptualized the study. Hiroshi Yano, Ryota Otsubo, and Aya Tanaka collaborated in the patient’s care. Takeshi Nagayasu provided input on the manuscript.
Registration of research studies
Researchregistry 6411.
Guarantor
Megumi Matsumoto.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Acknowledgements
We would like to thank Editage (www.editage.com) for English language editing. | ADO-TRASTUZUMAB EMTANSINE, CYCLOPHOSPHAMIDE, DOCETAXEL, EPIRUBICIN, TRASTUZUMAB | DrugsGivenReaction | CC BY | 33482449 | 19,030,585 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapy partial responder'. | Favorable survival with combined treatment in a metastatic breast cancer patient undergoing hemodialysis: A case report.
BACKGROUND
Management of breast cancer patients undergoing hemodialysis (HD) is difficult because of a lack of evidence about drug selection, dose adjustment, and surgical procedures. We herein present a case of metastatic breast cancer in a patient undergoing HD.
METHODS
A 58-year-old Japanese woman with breast cancer undergoing HD underwent total mastectomy of the left breast and left axillary dissection. Histopathological examination revealed invasive ductal carcinoma, and the diagnosis was pT2N3cM0 Stage ⅢC. Immunostaining of the resected specimen indicated that the tumor was estrogen receptor-positive, progesterone receptor-negative, human epithelial growth factor receptor 2-positive, and the Ki-67 labeling index was 70%. A postoperative positron emission tomography/computed tomography (PET/CT) scan indicated fluorodeoxyglucose uptake in the supraclavicular nodes. She received adjuvant therapy of epirubicin and cyclophosphamide followed by docetaxel, trastuzumab (T-mab) and radiation therapy. However, she developed multiple liver metastases during adjuvant T-mab and hormone therapy. Therefore, her regimen was changed to trastuzumab emtansine (T-DM1) as first-line therapy, T-mab, pertuzumab (P-mab), and eribulin as second-line therapy, and T-mab, P-mab, and weekly paclitaxel as third-line therapy. Eventually, she was administered fourth-line treatment of T-mab, P-mab, and vinorelbine because of adverse events. She has survived more than 25 months after the initial detection of recurrence of breast cancer and maintained quality of life.
CONCLUSIONS
We report a case of breast cancer in a patient undergoing HD. It is very difficult to identify the appropriate drugs and dosages in patients undergoing HD to improve survival and quality of life.
1 Introduction
The risk of cancer, including breast cancer, is increased among patients undergoing hemodialysis (HD) [1,2]. In the United States, women undergoing HD are 42% more likely to develop breast cancer than the general population [1]. Unlike age, family history of breast cancer, early menarche, late menopause, late pregnancy, long-term hormone replacement therapy, radiation exposure, and benign breast diseases, chronic kidney disease (CKD) is not a major risk factor for breast cancer [3,4].
There are few studies on anticancer drugs and other drugs used in cancer therapy in patients undergoing HD, even though CKD, HD, and peritoneal dialysis do not limit the possibility of surgical treatment and radiotherapy. We herein present a case of HD with relatively long-term survival after diagnosis of multiple liver metastases detected during adjuvant therapy after surgery for locally advanced breast cancer.
2 Presentation of case
A 58-year-old Japanese woman undergoing HD developed a nodule in the left breast that was observed on chest computed tomography (CT). A dual-source CT scan showed an enhanced breast nodule 2.3 cm in diameter in the left breast (Fig. 1a), and enhanced CT indicated a swollen axillary lymph node (Fig. 1b). Needle biopsy was performed, and the pathological findings of the specimen indicated invasive ductal carcinoma that was estrogen receptor-positive, progesterone receptor-negative, and human epidermal growth factor receptor 2-positive by immunohistochemistry. Fine-needle aspiration cytology of the left axillary lymph node showed malignancy. The patient was diagnosed with primary breast cancer (cT2N1MX Stage ⅡB according to the Union for International Cancer Control classification).Fig. 1 (a) Dual-source computed tomography (CT) revealed breast cancer, and (b) plane CT revealed metastatic axillary lymph nodes.
Fig. 1
She underwent total mastectomy of the left breast and left axillary dissection. The pathological evaluation confirmed invasive ductal carcinoma (2.4 cm) and 10 metastatic axillary lymph nodes. A postoperative positron emission tomography/computed tomography (PET/CT) scan showed uptake in the supraclavicular lymph nodes (Fig. 2) but not in distant organs (pT2N3cM0 Stage IIIC).Fig. 2 Positron emission tomography (PET)/computed tomography showed a hot spot in a metastatic supraclavicular lymph node (arrow).
Fig. 2
We administered the combined systemic therapy regimen for patients with pT2N3cM0 Stage IIIC breast cancer, which included epirubicin and cyclophosphamide (EC) (100 mg/m2 and 600 mg/m2, respectively) four times every 3 weeks, followed by docetaxel (DTX) (75 mg/m2) and trastuzumab (T-mab) (8 mg/kg loading dose and 6 mg/kg thereafter) four times every 3 weeks for adjuvant therapy. She received 70% of the full-dose of EC, 80% of the full-dose of DTX, and the full-dose of T-mab.
We used the vascular access (VA) for HD on the patient’s right forearm for the administration of anticancer drugs, which was on the opposite side of the surgical site. However, thrombosis developed in the VA after two rounds of EC. The patient also developed febrile neutropenia (FN), hemorrhagic cystitis, and anemia, which required thrombolytic therapy, antibiotics, granulocyte colony-stimulating factor, and blood transfusions. EC therapy was discontinued, and a central venous access port (CV port) was created at the right internal jugular vein. After that, the patient received four cycles of DTX and T-mab, followed by PMRT of 50 Gy in 25 fractions and 10 Gy in 5 fractions to the supraclavicular and internal mammary nodes. The patient then received full-dose T-mab monotherapy every 3 weeks, which was scheduled for 14 cycles and full-dose letrozole, which was scheduled for 10 years, as additional adjuvant therapy. However, one year after surgery, PET/CT indicated multiple metastases (Fig. 3), and blood tests revealed an increase in serum CA15-3.Fig. 3 Positron emission tomography (PET)/computed tomography indicated multiple hot spots in the liver (arrows).
Fig. 3
Trastuzumab emtansine (T-DM1) was administered as the first-line treatment for the recurrence. She received a full-dose of T-DM1 (3.6 mg/kg every 3 weeks) for a total of 10 cycles among 32 weeks. However, the liver metastases did not respond, so she was administered for nine cycles of full-dose T-mab, pertuzumab (P-mab) (840 mg loading dose and 420 mg thereafter), and 70% of the full-dose of eribulin (1.4 mg/m2 on days 1 and 8 every 3 weeks) among 33 weeks. However, the liver metastases continued to grow, and we administered third-line treatment of full-dose T-mab, P-mab, and weekly paclitaxel (PTX) at 70% of the full dose (90 mg/m2) among 29 weeks. The third-line treatment was administered for nine cycles, and a partial response was observed in the liver metastases. However, the patient refused to continue the therapy because of grade 2 systemic edema and numbness in the fingers. Currently, full-dose T-mab, P-mab, and 60% of the full dose of vinorelbine (VNR; 25 mg/m2 on days 1 and 8 every 3 weeks) are being administered as the fourth-line treatment. She has survived more than 25 months after the initial detection of recurrence of breast cancer and maintained quality of life.
3 Discussion
In this report, we describe a patient with metastatic breast cancer who was undergoing HD. She had favorable survival and acceptable quality of life using a reduced dosage and several types of drugs, despite the difficulty of dose control. Drug dosages may need to be adjusted in some patients, but the lack of appropriate drug dosage can reduce overall survival [5]. A previous study reported that patients receiving a higher relative dose intensity (RDI) of anticancer drugs had better clinical outcomes than those receiving a lower RDI among patients with metastatic solid tumors, including breast cancer [6], but there are currently no data in patients undergoing HD.
The survival of patients with breast cancer who are receiving dialysis is still unknown. CKD is not a significant factor in overall survival or disease-free survival in patients with breast cancer [7]. In fact, the patient in the present report had a favorable survival even after breast cancer recurrence. However, the number of cases in the literature is limited, and there is no other report describing the survival of patients with breast cancer who are receiving HD.
Regarding the treatment of breast cancer patients who are receiving HD, the most important clinical issue is drug selection and dosage adjustment. The recommendations for dosage adjustment for oncological therapy among patients receiving HD are shown in Table 1 [8,9]. Most drugs are safe to administer in patients receiving HD, and methotrexate is the only drug that should be avoided. It is recommended that capecitabine, cyclophosphamide, DTX, doxorubicin, epirubicin, and VNR be administered at reduced doses. There are insufficient data on HD patients receiving tamoxifen, anastrozole, letrozole, and newer targeted agents, such as cyclin-dependent kinase 4/6 inhibitors, lapatinib, T-mab, P-mab, T-DM1, and atezolizumab. However, even drugs that do not require dose reduction should be reduced if they cause myelotoxicity or cardiotoxicity. However, these recommendations are general; therefore, for patients without CKD, dose reduction depends on the patient’s adverse events (AEs). In this case, we reduced the dose of EC to 70%, that of DTX to 80%, that of eribulin to 70%, that of PTX to 70%, and that of VNR to 60%. Even drugs that are generally administered at the full dose had to be reduced due to AEs, including thrombosis, FN, hemorrhagic cystitis, and anemia. Although there is no recommended dosage reduction in the literature for T-DM1, T-mab, P-mab, and letrozole [8], we were able to administer these drugs at the full dose without any major AEs.Table 1 Summary of pharmacokinetics and safety of oncological therapies for breast cancer in hemodialysis patients.
Table 1Drug Elimination Dose reduction in HD Bednarek A8) Recommended dose in HD Janus N9) safety
capecitabine Urinary Recommended dose reduction by 50% No data Safe (limited data)
cyclophosphamide Urinary Recommended dose reduction by 20% Reduction of 25% Hemorrhagic cystitis
docetaxel Faeces Not specified 65 mg/m2 Safe
paclitaxel Faeces Not specified Standard dose Safe
doxorubicin Faeces Recommended dose reduction by 20% Standard dose Inceased risk of cardiotoxicity
epirubicin Faeces Recommended dose reduction Standard dose Inceased risk of cardiotoxicity
vinorelbine Faeces Probably necessary (up to 50%) Reduction of 20%–33% Inceased myelotoxicity (limited data)
tamoxifen Faeces Not indicated − Safe
anastrozole Faeces Not indicated − Safe
letrozole Urinary Not specified − No data
palbociclib Faeces Not specified − No data
lapatinib Faeces Not indicated − Safe (limited data)
trastuzumab No data Not indicated − Inceased risk of cardiotoxicity
pertuzumab No data Not indicated − No data
trastuzumab emtansine Faeces Not indicated − Inceased risk of cardiotoxicity
atezolizumab No data Not indicated − Safe (very limited data)
Another issue is among patients undergoing HD is the VA, particularly for patients who undergo axillary dissection. If the dissection range includes the VA site, it may be preferable to place a VA on the opposite side of the surgical site prior to operation to reduce the risk of VA issues. Another alternative is to use a temporary VA for the short term. However, no previous report was found. It might be useful to confirm the effect of the operation on the original VA. In our case, the patient’s VA was on the opposite side of the surgical site, so it was unaffected by the surgery.
Intravenous administered of anticancer drugs should be considered. In our case, the venous pressure in the internal jugular vein was increased by the VA on the non-affected side. It is usually recommended to create a CV port to prevent vasculitis caused by anticancer drugs, but we need to consider the risks of venous pressure increase. We initially decided to administer anticancer drugs from the VA for HD, but the patient developed thrombosis, and we created a CV port via the internal jugular vein on the VA side without any complications. This case is reported in line with the SCARE Guideline [10].
4 Conclusion
We report a case of breast cancer diagnosed during HD with multiple liver metastases that developed during postoperative adjuvant therapy. It is very difficult to manage patients undergoing HD with the appropriate drugs and dosage to improve survival and quality of life.
Declaration of Competing Interest
None.
Funding
None.
Ethical approval
None.
Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
Author contribution
Megumi Matsumoto conceptualized the study. Hiroshi Yano, Ryota Otsubo, and Aya Tanaka collaborated in the patient’s care. Takeshi Nagayasu provided input on the manuscript.
Registration of research studies
Researchregistry 6411.
Guarantor
Megumi Matsumoto.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Acknowledgements
We would like to thank Editage (www.editage.com) for English language editing. | ADO-TRASTUZUMAB EMTANSINE, CYCLOPHOSPHAMIDE, DOCETAXEL, EPIRUBICIN, ERIBULIN, LETROZOLE, PACLITAXEL, PERTUZUMAB, TRASTUZUMAB | DrugsGivenReaction | CC BY | 33482449 | 19,033,862 | 2021-02 |
What was the administration route of drug 'CYCLOPHOSPHAMIDE'? | Favorable survival with combined treatment in a metastatic breast cancer patient undergoing hemodialysis: A case report.
BACKGROUND
Management of breast cancer patients undergoing hemodialysis (HD) is difficult because of a lack of evidence about drug selection, dose adjustment, and surgical procedures. We herein present a case of metastatic breast cancer in a patient undergoing HD.
METHODS
A 58-year-old Japanese woman with breast cancer undergoing HD underwent total mastectomy of the left breast and left axillary dissection. Histopathological examination revealed invasive ductal carcinoma, and the diagnosis was pT2N3cM0 Stage ⅢC. Immunostaining of the resected specimen indicated that the tumor was estrogen receptor-positive, progesterone receptor-negative, human epithelial growth factor receptor 2-positive, and the Ki-67 labeling index was 70%. A postoperative positron emission tomography/computed tomography (PET/CT) scan indicated fluorodeoxyglucose uptake in the supraclavicular nodes. She received adjuvant therapy of epirubicin and cyclophosphamide followed by docetaxel, trastuzumab (T-mab) and radiation therapy. However, she developed multiple liver metastases during adjuvant T-mab and hormone therapy. Therefore, her regimen was changed to trastuzumab emtansine (T-DM1) as first-line therapy, T-mab, pertuzumab (P-mab), and eribulin as second-line therapy, and T-mab, P-mab, and weekly paclitaxel as third-line therapy. Eventually, she was administered fourth-line treatment of T-mab, P-mab, and vinorelbine because of adverse events. She has survived more than 25 months after the initial detection of recurrence of breast cancer and maintained quality of life.
CONCLUSIONS
We report a case of breast cancer in a patient undergoing HD. It is very difficult to identify the appropriate drugs and dosages in patients undergoing HD to improve survival and quality of life.
1 Introduction
The risk of cancer, including breast cancer, is increased among patients undergoing hemodialysis (HD) [1,2]. In the United States, women undergoing HD are 42% more likely to develop breast cancer than the general population [1]. Unlike age, family history of breast cancer, early menarche, late menopause, late pregnancy, long-term hormone replacement therapy, radiation exposure, and benign breast diseases, chronic kidney disease (CKD) is not a major risk factor for breast cancer [3,4].
There are few studies on anticancer drugs and other drugs used in cancer therapy in patients undergoing HD, even though CKD, HD, and peritoneal dialysis do not limit the possibility of surgical treatment and radiotherapy. We herein present a case of HD with relatively long-term survival after diagnosis of multiple liver metastases detected during adjuvant therapy after surgery for locally advanced breast cancer.
2 Presentation of case
A 58-year-old Japanese woman undergoing HD developed a nodule in the left breast that was observed on chest computed tomography (CT). A dual-source CT scan showed an enhanced breast nodule 2.3 cm in diameter in the left breast (Fig. 1a), and enhanced CT indicated a swollen axillary lymph node (Fig. 1b). Needle biopsy was performed, and the pathological findings of the specimen indicated invasive ductal carcinoma that was estrogen receptor-positive, progesterone receptor-negative, and human epidermal growth factor receptor 2-positive by immunohistochemistry. Fine-needle aspiration cytology of the left axillary lymph node showed malignancy. The patient was diagnosed with primary breast cancer (cT2N1MX Stage ⅡB according to the Union for International Cancer Control classification).Fig. 1 (a) Dual-source computed tomography (CT) revealed breast cancer, and (b) plane CT revealed metastatic axillary lymph nodes.
Fig. 1
She underwent total mastectomy of the left breast and left axillary dissection. The pathological evaluation confirmed invasive ductal carcinoma (2.4 cm) and 10 metastatic axillary lymph nodes. A postoperative positron emission tomography/computed tomography (PET/CT) scan showed uptake in the supraclavicular lymph nodes (Fig. 2) but not in distant organs (pT2N3cM0 Stage IIIC).Fig. 2 Positron emission tomography (PET)/computed tomography showed a hot spot in a metastatic supraclavicular lymph node (arrow).
Fig. 2
We administered the combined systemic therapy regimen for patients with pT2N3cM0 Stage IIIC breast cancer, which included epirubicin and cyclophosphamide (EC) (100 mg/m2 and 600 mg/m2, respectively) four times every 3 weeks, followed by docetaxel (DTX) (75 mg/m2) and trastuzumab (T-mab) (8 mg/kg loading dose and 6 mg/kg thereafter) four times every 3 weeks for adjuvant therapy. She received 70% of the full-dose of EC, 80% of the full-dose of DTX, and the full-dose of T-mab.
We used the vascular access (VA) for HD on the patient’s right forearm for the administration of anticancer drugs, which was on the opposite side of the surgical site. However, thrombosis developed in the VA after two rounds of EC. The patient also developed febrile neutropenia (FN), hemorrhagic cystitis, and anemia, which required thrombolytic therapy, antibiotics, granulocyte colony-stimulating factor, and blood transfusions. EC therapy was discontinued, and a central venous access port (CV port) was created at the right internal jugular vein. After that, the patient received four cycles of DTX and T-mab, followed by PMRT of 50 Gy in 25 fractions and 10 Gy in 5 fractions to the supraclavicular and internal mammary nodes. The patient then received full-dose T-mab monotherapy every 3 weeks, which was scheduled for 14 cycles and full-dose letrozole, which was scheduled for 10 years, as additional adjuvant therapy. However, one year after surgery, PET/CT indicated multiple metastases (Fig. 3), and blood tests revealed an increase in serum CA15-3.Fig. 3 Positron emission tomography (PET)/computed tomography indicated multiple hot spots in the liver (arrows).
Fig. 3
Trastuzumab emtansine (T-DM1) was administered as the first-line treatment for the recurrence. She received a full-dose of T-DM1 (3.6 mg/kg every 3 weeks) for a total of 10 cycles among 32 weeks. However, the liver metastases did not respond, so she was administered for nine cycles of full-dose T-mab, pertuzumab (P-mab) (840 mg loading dose and 420 mg thereafter), and 70% of the full-dose of eribulin (1.4 mg/m2 on days 1 and 8 every 3 weeks) among 33 weeks. However, the liver metastases continued to grow, and we administered third-line treatment of full-dose T-mab, P-mab, and weekly paclitaxel (PTX) at 70% of the full dose (90 mg/m2) among 29 weeks. The third-line treatment was administered for nine cycles, and a partial response was observed in the liver metastases. However, the patient refused to continue the therapy because of grade 2 systemic edema and numbness in the fingers. Currently, full-dose T-mab, P-mab, and 60% of the full dose of vinorelbine (VNR; 25 mg/m2 on days 1 and 8 every 3 weeks) are being administered as the fourth-line treatment. She has survived more than 25 months after the initial detection of recurrence of breast cancer and maintained quality of life.
3 Discussion
In this report, we describe a patient with metastatic breast cancer who was undergoing HD. She had favorable survival and acceptable quality of life using a reduced dosage and several types of drugs, despite the difficulty of dose control. Drug dosages may need to be adjusted in some patients, but the lack of appropriate drug dosage can reduce overall survival [5]. A previous study reported that patients receiving a higher relative dose intensity (RDI) of anticancer drugs had better clinical outcomes than those receiving a lower RDI among patients with metastatic solid tumors, including breast cancer [6], but there are currently no data in patients undergoing HD.
The survival of patients with breast cancer who are receiving dialysis is still unknown. CKD is not a significant factor in overall survival or disease-free survival in patients with breast cancer [7]. In fact, the patient in the present report had a favorable survival even after breast cancer recurrence. However, the number of cases in the literature is limited, and there is no other report describing the survival of patients with breast cancer who are receiving HD.
Regarding the treatment of breast cancer patients who are receiving HD, the most important clinical issue is drug selection and dosage adjustment. The recommendations for dosage adjustment for oncological therapy among patients receiving HD are shown in Table 1 [8,9]. Most drugs are safe to administer in patients receiving HD, and methotrexate is the only drug that should be avoided. It is recommended that capecitabine, cyclophosphamide, DTX, doxorubicin, epirubicin, and VNR be administered at reduced doses. There are insufficient data on HD patients receiving tamoxifen, anastrozole, letrozole, and newer targeted agents, such as cyclin-dependent kinase 4/6 inhibitors, lapatinib, T-mab, P-mab, T-DM1, and atezolizumab. However, even drugs that do not require dose reduction should be reduced if they cause myelotoxicity or cardiotoxicity. However, these recommendations are general; therefore, for patients without CKD, dose reduction depends on the patient’s adverse events (AEs). In this case, we reduced the dose of EC to 70%, that of DTX to 80%, that of eribulin to 70%, that of PTX to 70%, and that of VNR to 60%. Even drugs that are generally administered at the full dose had to be reduced due to AEs, including thrombosis, FN, hemorrhagic cystitis, and anemia. Although there is no recommended dosage reduction in the literature for T-DM1, T-mab, P-mab, and letrozole [8], we were able to administer these drugs at the full dose without any major AEs.Table 1 Summary of pharmacokinetics and safety of oncological therapies for breast cancer in hemodialysis patients.
Table 1Drug Elimination Dose reduction in HD Bednarek A8) Recommended dose in HD Janus N9) safety
capecitabine Urinary Recommended dose reduction by 50% No data Safe (limited data)
cyclophosphamide Urinary Recommended dose reduction by 20% Reduction of 25% Hemorrhagic cystitis
docetaxel Faeces Not specified 65 mg/m2 Safe
paclitaxel Faeces Not specified Standard dose Safe
doxorubicin Faeces Recommended dose reduction by 20% Standard dose Inceased risk of cardiotoxicity
epirubicin Faeces Recommended dose reduction Standard dose Inceased risk of cardiotoxicity
vinorelbine Faeces Probably necessary (up to 50%) Reduction of 20%–33% Inceased myelotoxicity (limited data)
tamoxifen Faeces Not indicated − Safe
anastrozole Faeces Not indicated − Safe
letrozole Urinary Not specified − No data
palbociclib Faeces Not specified − No data
lapatinib Faeces Not indicated − Safe (limited data)
trastuzumab No data Not indicated − Inceased risk of cardiotoxicity
pertuzumab No data Not indicated − No data
trastuzumab emtansine Faeces Not indicated − Inceased risk of cardiotoxicity
atezolizumab No data Not indicated − Safe (very limited data)
Another issue is among patients undergoing HD is the VA, particularly for patients who undergo axillary dissection. If the dissection range includes the VA site, it may be preferable to place a VA on the opposite side of the surgical site prior to operation to reduce the risk of VA issues. Another alternative is to use a temporary VA for the short term. However, no previous report was found. It might be useful to confirm the effect of the operation on the original VA. In our case, the patient’s VA was on the opposite side of the surgical site, so it was unaffected by the surgery.
Intravenous administered of anticancer drugs should be considered. In our case, the venous pressure in the internal jugular vein was increased by the VA on the non-affected side. It is usually recommended to create a CV port to prevent vasculitis caused by anticancer drugs, but we need to consider the risks of venous pressure increase. We initially decided to administer anticancer drugs from the VA for HD, but the patient developed thrombosis, and we created a CV port via the internal jugular vein on the VA side without any complications. This case is reported in line with the SCARE Guideline [10].
4 Conclusion
We report a case of breast cancer diagnosed during HD with multiple liver metastases that developed during postoperative adjuvant therapy. It is very difficult to manage patients undergoing HD with the appropriate drugs and dosage to improve survival and quality of life.
Declaration of Competing Interest
None.
Funding
None.
Ethical approval
None.
Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
Author contribution
Megumi Matsumoto conceptualized the study. Hiroshi Yano, Ryota Otsubo, and Aya Tanaka collaborated in the patient’s care. Takeshi Nagayasu provided input on the manuscript.
Registration of research studies
Researchregistry 6411.
Guarantor
Megumi Matsumoto.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Acknowledgements
We would like to thank Editage (www.editage.com) for English language editing. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33482449 | 19,030,585 | 2021-02 |
What was the administration route of drug 'DOCETAXEL'? | Favorable survival with combined treatment in a metastatic breast cancer patient undergoing hemodialysis: A case report.
BACKGROUND
Management of breast cancer patients undergoing hemodialysis (HD) is difficult because of a lack of evidence about drug selection, dose adjustment, and surgical procedures. We herein present a case of metastatic breast cancer in a patient undergoing HD.
METHODS
A 58-year-old Japanese woman with breast cancer undergoing HD underwent total mastectomy of the left breast and left axillary dissection. Histopathological examination revealed invasive ductal carcinoma, and the diagnosis was pT2N3cM0 Stage ⅢC. Immunostaining of the resected specimen indicated that the tumor was estrogen receptor-positive, progesterone receptor-negative, human epithelial growth factor receptor 2-positive, and the Ki-67 labeling index was 70%. A postoperative positron emission tomography/computed tomography (PET/CT) scan indicated fluorodeoxyglucose uptake in the supraclavicular nodes. She received adjuvant therapy of epirubicin and cyclophosphamide followed by docetaxel, trastuzumab (T-mab) and radiation therapy. However, she developed multiple liver metastases during adjuvant T-mab and hormone therapy. Therefore, her regimen was changed to trastuzumab emtansine (T-DM1) as first-line therapy, T-mab, pertuzumab (P-mab), and eribulin as second-line therapy, and T-mab, P-mab, and weekly paclitaxel as third-line therapy. Eventually, she was administered fourth-line treatment of T-mab, P-mab, and vinorelbine because of adverse events. She has survived more than 25 months after the initial detection of recurrence of breast cancer and maintained quality of life.
CONCLUSIONS
We report a case of breast cancer in a patient undergoing HD. It is very difficult to identify the appropriate drugs and dosages in patients undergoing HD to improve survival and quality of life.
1 Introduction
The risk of cancer, including breast cancer, is increased among patients undergoing hemodialysis (HD) [1,2]. In the United States, women undergoing HD are 42% more likely to develop breast cancer than the general population [1]. Unlike age, family history of breast cancer, early menarche, late menopause, late pregnancy, long-term hormone replacement therapy, radiation exposure, and benign breast diseases, chronic kidney disease (CKD) is not a major risk factor for breast cancer [3,4].
There are few studies on anticancer drugs and other drugs used in cancer therapy in patients undergoing HD, even though CKD, HD, and peritoneal dialysis do not limit the possibility of surgical treatment and radiotherapy. We herein present a case of HD with relatively long-term survival after diagnosis of multiple liver metastases detected during adjuvant therapy after surgery for locally advanced breast cancer.
2 Presentation of case
A 58-year-old Japanese woman undergoing HD developed a nodule in the left breast that was observed on chest computed tomography (CT). A dual-source CT scan showed an enhanced breast nodule 2.3 cm in diameter in the left breast (Fig. 1a), and enhanced CT indicated a swollen axillary lymph node (Fig. 1b). Needle biopsy was performed, and the pathological findings of the specimen indicated invasive ductal carcinoma that was estrogen receptor-positive, progesterone receptor-negative, and human epidermal growth factor receptor 2-positive by immunohistochemistry. Fine-needle aspiration cytology of the left axillary lymph node showed malignancy. The patient was diagnosed with primary breast cancer (cT2N1MX Stage ⅡB according to the Union for International Cancer Control classification).Fig. 1 (a) Dual-source computed tomography (CT) revealed breast cancer, and (b) plane CT revealed metastatic axillary lymph nodes.
Fig. 1
She underwent total mastectomy of the left breast and left axillary dissection. The pathological evaluation confirmed invasive ductal carcinoma (2.4 cm) and 10 metastatic axillary lymph nodes. A postoperative positron emission tomography/computed tomography (PET/CT) scan showed uptake in the supraclavicular lymph nodes (Fig. 2) but not in distant organs (pT2N3cM0 Stage IIIC).Fig. 2 Positron emission tomography (PET)/computed tomography showed a hot spot in a metastatic supraclavicular lymph node (arrow).
Fig. 2
We administered the combined systemic therapy regimen for patients with pT2N3cM0 Stage IIIC breast cancer, which included epirubicin and cyclophosphamide (EC) (100 mg/m2 and 600 mg/m2, respectively) four times every 3 weeks, followed by docetaxel (DTX) (75 mg/m2) and trastuzumab (T-mab) (8 mg/kg loading dose and 6 mg/kg thereafter) four times every 3 weeks for adjuvant therapy. She received 70% of the full-dose of EC, 80% of the full-dose of DTX, and the full-dose of T-mab.
We used the vascular access (VA) for HD on the patient’s right forearm for the administration of anticancer drugs, which was on the opposite side of the surgical site. However, thrombosis developed in the VA after two rounds of EC. The patient also developed febrile neutropenia (FN), hemorrhagic cystitis, and anemia, which required thrombolytic therapy, antibiotics, granulocyte colony-stimulating factor, and blood transfusions. EC therapy was discontinued, and a central venous access port (CV port) was created at the right internal jugular vein. After that, the patient received four cycles of DTX and T-mab, followed by PMRT of 50 Gy in 25 fractions and 10 Gy in 5 fractions to the supraclavicular and internal mammary nodes. The patient then received full-dose T-mab monotherapy every 3 weeks, which was scheduled for 14 cycles and full-dose letrozole, which was scheduled for 10 years, as additional adjuvant therapy. However, one year after surgery, PET/CT indicated multiple metastases (Fig. 3), and blood tests revealed an increase in serum CA15-3.Fig. 3 Positron emission tomography (PET)/computed tomography indicated multiple hot spots in the liver (arrows).
Fig. 3
Trastuzumab emtansine (T-DM1) was administered as the first-line treatment for the recurrence. She received a full-dose of T-DM1 (3.6 mg/kg every 3 weeks) for a total of 10 cycles among 32 weeks. However, the liver metastases did not respond, so she was administered for nine cycles of full-dose T-mab, pertuzumab (P-mab) (840 mg loading dose and 420 mg thereafter), and 70% of the full-dose of eribulin (1.4 mg/m2 on days 1 and 8 every 3 weeks) among 33 weeks. However, the liver metastases continued to grow, and we administered third-line treatment of full-dose T-mab, P-mab, and weekly paclitaxel (PTX) at 70% of the full dose (90 mg/m2) among 29 weeks. The third-line treatment was administered for nine cycles, and a partial response was observed in the liver metastases. However, the patient refused to continue the therapy because of grade 2 systemic edema and numbness in the fingers. Currently, full-dose T-mab, P-mab, and 60% of the full dose of vinorelbine (VNR; 25 mg/m2 on days 1 and 8 every 3 weeks) are being administered as the fourth-line treatment. She has survived more than 25 months after the initial detection of recurrence of breast cancer and maintained quality of life.
3 Discussion
In this report, we describe a patient with metastatic breast cancer who was undergoing HD. She had favorable survival and acceptable quality of life using a reduced dosage and several types of drugs, despite the difficulty of dose control. Drug dosages may need to be adjusted in some patients, but the lack of appropriate drug dosage can reduce overall survival [5]. A previous study reported that patients receiving a higher relative dose intensity (RDI) of anticancer drugs had better clinical outcomes than those receiving a lower RDI among patients with metastatic solid tumors, including breast cancer [6], but there are currently no data in patients undergoing HD.
The survival of patients with breast cancer who are receiving dialysis is still unknown. CKD is not a significant factor in overall survival or disease-free survival in patients with breast cancer [7]. In fact, the patient in the present report had a favorable survival even after breast cancer recurrence. However, the number of cases in the literature is limited, and there is no other report describing the survival of patients with breast cancer who are receiving HD.
Regarding the treatment of breast cancer patients who are receiving HD, the most important clinical issue is drug selection and dosage adjustment. The recommendations for dosage adjustment for oncological therapy among patients receiving HD are shown in Table 1 [8,9]. Most drugs are safe to administer in patients receiving HD, and methotrexate is the only drug that should be avoided. It is recommended that capecitabine, cyclophosphamide, DTX, doxorubicin, epirubicin, and VNR be administered at reduced doses. There are insufficient data on HD patients receiving tamoxifen, anastrozole, letrozole, and newer targeted agents, such as cyclin-dependent kinase 4/6 inhibitors, lapatinib, T-mab, P-mab, T-DM1, and atezolizumab. However, even drugs that do not require dose reduction should be reduced if they cause myelotoxicity or cardiotoxicity. However, these recommendations are general; therefore, for patients without CKD, dose reduction depends on the patient’s adverse events (AEs). In this case, we reduced the dose of EC to 70%, that of DTX to 80%, that of eribulin to 70%, that of PTX to 70%, and that of VNR to 60%. Even drugs that are generally administered at the full dose had to be reduced due to AEs, including thrombosis, FN, hemorrhagic cystitis, and anemia. Although there is no recommended dosage reduction in the literature for T-DM1, T-mab, P-mab, and letrozole [8], we were able to administer these drugs at the full dose without any major AEs.Table 1 Summary of pharmacokinetics and safety of oncological therapies for breast cancer in hemodialysis patients.
Table 1Drug Elimination Dose reduction in HD Bednarek A8) Recommended dose in HD Janus N9) safety
capecitabine Urinary Recommended dose reduction by 50% No data Safe (limited data)
cyclophosphamide Urinary Recommended dose reduction by 20% Reduction of 25% Hemorrhagic cystitis
docetaxel Faeces Not specified 65 mg/m2 Safe
paclitaxel Faeces Not specified Standard dose Safe
doxorubicin Faeces Recommended dose reduction by 20% Standard dose Inceased risk of cardiotoxicity
epirubicin Faeces Recommended dose reduction Standard dose Inceased risk of cardiotoxicity
vinorelbine Faeces Probably necessary (up to 50%) Reduction of 20%–33% Inceased myelotoxicity (limited data)
tamoxifen Faeces Not indicated − Safe
anastrozole Faeces Not indicated − Safe
letrozole Urinary Not specified − No data
palbociclib Faeces Not specified − No data
lapatinib Faeces Not indicated − Safe (limited data)
trastuzumab No data Not indicated − Inceased risk of cardiotoxicity
pertuzumab No data Not indicated − No data
trastuzumab emtansine Faeces Not indicated − Inceased risk of cardiotoxicity
atezolizumab No data Not indicated − Safe (very limited data)
Another issue is among patients undergoing HD is the VA, particularly for patients who undergo axillary dissection. If the dissection range includes the VA site, it may be preferable to place a VA on the opposite side of the surgical site prior to operation to reduce the risk of VA issues. Another alternative is to use a temporary VA for the short term. However, no previous report was found. It might be useful to confirm the effect of the operation on the original VA. In our case, the patient’s VA was on the opposite side of the surgical site, so it was unaffected by the surgery.
Intravenous administered of anticancer drugs should be considered. In our case, the venous pressure in the internal jugular vein was increased by the VA on the non-affected side. It is usually recommended to create a CV port to prevent vasculitis caused by anticancer drugs, but we need to consider the risks of venous pressure increase. We initially decided to administer anticancer drugs from the VA for HD, but the patient developed thrombosis, and we created a CV port via the internal jugular vein on the VA side without any complications. This case is reported in line with the SCARE Guideline [10].
4 Conclusion
We report a case of breast cancer diagnosed during HD with multiple liver metastases that developed during postoperative adjuvant therapy. It is very difficult to manage patients undergoing HD with the appropriate drugs and dosage to improve survival and quality of life.
Declaration of Competing Interest
None.
Funding
None.
Ethical approval
None.
Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
Author contribution
Megumi Matsumoto conceptualized the study. Hiroshi Yano, Ryota Otsubo, and Aya Tanaka collaborated in the patient’s care. Takeshi Nagayasu provided input on the manuscript.
Registration of research studies
Researchregistry 6411.
Guarantor
Megumi Matsumoto.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Acknowledgements
We would like to thank Editage (www.editage.com) for English language editing. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33482449 | 19,030,585 | 2021-02 |
What was the administration route of drug 'EPIRUBICIN'? | Favorable survival with combined treatment in a metastatic breast cancer patient undergoing hemodialysis: A case report.
BACKGROUND
Management of breast cancer patients undergoing hemodialysis (HD) is difficult because of a lack of evidence about drug selection, dose adjustment, and surgical procedures. We herein present a case of metastatic breast cancer in a patient undergoing HD.
METHODS
A 58-year-old Japanese woman with breast cancer undergoing HD underwent total mastectomy of the left breast and left axillary dissection. Histopathological examination revealed invasive ductal carcinoma, and the diagnosis was pT2N3cM0 Stage ⅢC. Immunostaining of the resected specimen indicated that the tumor was estrogen receptor-positive, progesterone receptor-negative, human epithelial growth factor receptor 2-positive, and the Ki-67 labeling index was 70%. A postoperative positron emission tomography/computed tomography (PET/CT) scan indicated fluorodeoxyglucose uptake in the supraclavicular nodes. She received adjuvant therapy of epirubicin and cyclophosphamide followed by docetaxel, trastuzumab (T-mab) and radiation therapy. However, she developed multiple liver metastases during adjuvant T-mab and hormone therapy. Therefore, her regimen was changed to trastuzumab emtansine (T-DM1) as first-line therapy, T-mab, pertuzumab (P-mab), and eribulin as second-line therapy, and T-mab, P-mab, and weekly paclitaxel as third-line therapy. Eventually, she was administered fourth-line treatment of T-mab, P-mab, and vinorelbine because of adverse events. She has survived more than 25 months after the initial detection of recurrence of breast cancer and maintained quality of life.
CONCLUSIONS
We report a case of breast cancer in a patient undergoing HD. It is very difficult to identify the appropriate drugs and dosages in patients undergoing HD to improve survival and quality of life.
1 Introduction
The risk of cancer, including breast cancer, is increased among patients undergoing hemodialysis (HD) [1,2]. In the United States, women undergoing HD are 42% more likely to develop breast cancer than the general population [1]. Unlike age, family history of breast cancer, early menarche, late menopause, late pregnancy, long-term hormone replacement therapy, radiation exposure, and benign breast diseases, chronic kidney disease (CKD) is not a major risk factor for breast cancer [3,4].
There are few studies on anticancer drugs and other drugs used in cancer therapy in patients undergoing HD, even though CKD, HD, and peritoneal dialysis do not limit the possibility of surgical treatment and radiotherapy. We herein present a case of HD with relatively long-term survival after diagnosis of multiple liver metastases detected during adjuvant therapy after surgery for locally advanced breast cancer.
2 Presentation of case
A 58-year-old Japanese woman undergoing HD developed a nodule in the left breast that was observed on chest computed tomography (CT). A dual-source CT scan showed an enhanced breast nodule 2.3 cm in diameter in the left breast (Fig. 1a), and enhanced CT indicated a swollen axillary lymph node (Fig. 1b). Needle biopsy was performed, and the pathological findings of the specimen indicated invasive ductal carcinoma that was estrogen receptor-positive, progesterone receptor-negative, and human epidermal growth factor receptor 2-positive by immunohistochemistry. Fine-needle aspiration cytology of the left axillary lymph node showed malignancy. The patient was diagnosed with primary breast cancer (cT2N1MX Stage ⅡB according to the Union for International Cancer Control classification).Fig. 1 (a) Dual-source computed tomography (CT) revealed breast cancer, and (b) plane CT revealed metastatic axillary lymph nodes.
Fig. 1
She underwent total mastectomy of the left breast and left axillary dissection. The pathological evaluation confirmed invasive ductal carcinoma (2.4 cm) and 10 metastatic axillary lymph nodes. A postoperative positron emission tomography/computed tomography (PET/CT) scan showed uptake in the supraclavicular lymph nodes (Fig. 2) but not in distant organs (pT2N3cM0 Stage IIIC).Fig. 2 Positron emission tomography (PET)/computed tomography showed a hot spot in a metastatic supraclavicular lymph node (arrow).
Fig. 2
We administered the combined systemic therapy regimen for patients with pT2N3cM0 Stage IIIC breast cancer, which included epirubicin and cyclophosphamide (EC) (100 mg/m2 and 600 mg/m2, respectively) four times every 3 weeks, followed by docetaxel (DTX) (75 mg/m2) and trastuzumab (T-mab) (8 mg/kg loading dose and 6 mg/kg thereafter) four times every 3 weeks for adjuvant therapy. She received 70% of the full-dose of EC, 80% of the full-dose of DTX, and the full-dose of T-mab.
We used the vascular access (VA) for HD on the patient’s right forearm for the administration of anticancer drugs, which was on the opposite side of the surgical site. However, thrombosis developed in the VA after two rounds of EC. The patient also developed febrile neutropenia (FN), hemorrhagic cystitis, and anemia, which required thrombolytic therapy, antibiotics, granulocyte colony-stimulating factor, and blood transfusions. EC therapy was discontinued, and a central venous access port (CV port) was created at the right internal jugular vein. After that, the patient received four cycles of DTX and T-mab, followed by PMRT of 50 Gy in 25 fractions and 10 Gy in 5 fractions to the supraclavicular and internal mammary nodes. The patient then received full-dose T-mab monotherapy every 3 weeks, which was scheduled for 14 cycles and full-dose letrozole, which was scheduled for 10 years, as additional adjuvant therapy. However, one year after surgery, PET/CT indicated multiple metastases (Fig. 3), and blood tests revealed an increase in serum CA15-3.Fig. 3 Positron emission tomography (PET)/computed tomography indicated multiple hot spots in the liver (arrows).
Fig. 3
Trastuzumab emtansine (T-DM1) was administered as the first-line treatment for the recurrence. She received a full-dose of T-DM1 (3.6 mg/kg every 3 weeks) for a total of 10 cycles among 32 weeks. However, the liver metastases did not respond, so she was administered for nine cycles of full-dose T-mab, pertuzumab (P-mab) (840 mg loading dose and 420 mg thereafter), and 70% of the full-dose of eribulin (1.4 mg/m2 on days 1 and 8 every 3 weeks) among 33 weeks. However, the liver metastases continued to grow, and we administered third-line treatment of full-dose T-mab, P-mab, and weekly paclitaxel (PTX) at 70% of the full dose (90 mg/m2) among 29 weeks. The third-line treatment was administered for nine cycles, and a partial response was observed in the liver metastases. However, the patient refused to continue the therapy because of grade 2 systemic edema and numbness in the fingers. Currently, full-dose T-mab, P-mab, and 60% of the full dose of vinorelbine (VNR; 25 mg/m2 on days 1 and 8 every 3 weeks) are being administered as the fourth-line treatment. She has survived more than 25 months after the initial detection of recurrence of breast cancer and maintained quality of life.
3 Discussion
In this report, we describe a patient with metastatic breast cancer who was undergoing HD. She had favorable survival and acceptable quality of life using a reduced dosage and several types of drugs, despite the difficulty of dose control. Drug dosages may need to be adjusted in some patients, but the lack of appropriate drug dosage can reduce overall survival [5]. A previous study reported that patients receiving a higher relative dose intensity (RDI) of anticancer drugs had better clinical outcomes than those receiving a lower RDI among patients with metastatic solid tumors, including breast cancer [6], but there are currently no data in patients undergoing HD.
The survival of patients with breast cancer who are receiving dialysis is still unknown. CKD is not a significant factor in overall survival or disease-free survival in patients with breast cancer [7]. In fact, the patient in the present report had a favorable survival even after breast cancer recurrence. However, the number of cases in the literature is limited, and there is no other report describing the survival of patients with breast cancer who are receiving HD.
Regarding the treatment of breast cancer patients who are receiving HD, the most important clinical issue is drug selection and dosage adjustment. The recommendations for dosage adjustment for oncological therapy among patients receiving HD are shown in Table 1 [8,9]. Most drugs are safe to administer in patients receiving HD, and methotrexate is the only drug that should be avoided. It is recommended that capecitabine, cyclophosphamide, DTX, doxorubicin, epirubicin, and VNR be administered at reduced doses. There are insufficient data on HD patients receiving tamoxifen, anastrozole, letrozole, and newer targeted agents, such as cyclin-dependent kinase 4/6 inhibitors, lapatinib, T-mab, P-mab, T-DM1, and atezolizumab. However, even drugs that do not require dose reduction should be reduced if they cause myelotoxicity or cardiotoxicity. However, these recommendations are general; therefore, for patients without CKD, dose reduction depends on the patient’s adverse events (AEs). In this case, we reduced the dose of EC to 70%, that of DTX to 80%, that of eribulin to 70%, that of PTX to 70%, and that of VNR to 60%. Even drugs that are generally administered at the full dose had to be reduced due to AEs, including thrombosis, FN, hemorrhagic cystitis, and anemia. Although there is no recommended dosage reduction in the literature for T-DM1, T-mab, P-mab, and letrozole [8], we were able to administer these drugs at the full dose without any major AEs.Table 1 Summary of pharmacokinetics and safety of oncological therapies for breast cancer in hemodialysis patients.
Table 1Drug Elimination Dose reduction in HD Bednarek A8) Recommended dose in HD Janus N9) safety
capecitabine Urinary Recommended dose reduction by 50% No data Safe (limited data)
cyclophosphamide Urinary Recommended dose reduction by 20% Reduction of 25% Hemorrhagic cystitis
docetaxel Faeces Not specified 65 mg/m2 Safe
paclitaxel Faeces Not specified Standard dose Safe
doxorubicin Faeces Recommended dose reduction by 20% Standard dose Inceased risk of cardiotoxicity
epirubicin Faeces Recommended dose reduction Standard dose Inceased risk of cardiotoxicity
vinorelbine Faeces Probably necessary (up to 50%) Reduction of 20%–33% Inceased myelotoxicity (limited data)
tamoxifen Faeces Not indicated − Safe
anastrozole Faeces Not indicated − Safe
letrozole Urinary Not specified − No data
palbociclib Faeces Not specified − No data
lapatinib Faeces Not indicated − Safe (limited data)
trastuzumab No data Not indicated − Inceased risk of cardiotoxicity
pertuzumab No data Not indicated − No data
trastuzumab emtansine Faeces Not indicated − Inceased risk of cardiotoxicity
atezolizumab No data Not indicated − Safe (very limited data)
Another issue is among patients undergoing HD is the VA, particularly for patients who undergo axillary dissection. If the dissection range includes the VA site, it may be preferable to place a VA on the opposite side of the surgical site prior to operation to reduce the risk of VA issues. Another alternative is to use a temporary VA for the short term. However, no previous report was found. It might be useful to confirm the effect of the operation on the original VA. In our case, the patient’s VA was on the opposite side of the surgical site, so it was unaffected by the surgery.
Intravenous administered of anticancer drugs should be considered. In our case, the venous pressure in the internal jugular vein was increased by the VA on the non-affected side. It is usually recommended to create a CV port to prevent vasculitis caused by anticancer drugs, but we need to consider the risks of venous pressure increase. We initially decided to administer anticancer drugs from the VA for HD, but the patient developed thrombosis, and we created a CV port via the internal jugular vein on the VA side without any complications. This case is reported in line with the SCARE Guideline [10].
4 Conclusion
We report a case of breast cancer diagnosed during HD with multiple liver metastases that developed during postoperative adjuvant therapy. It is very difficult to manage patients undergoing HD with the appropriate drugs and dosage to improve survival and quality of life.
Declaration of Competing Interest
None.
Funding
None.
Ethical approval
None.
Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
Author contribution
Megumi Matsumoto conceptualized the study. Hiroshi Yano, Ryota Otsubo, and Aya Tanaka collaborated in the patient’s care. Takeshi Nagayasu provided input on the manuscript.
Registration of research studies
Researchregistry 6411.
Guarantor
Megumi Matsumoto.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Acknowledgements
We would like to thank Editage (www.editage.com) for English language editing. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33482449 | 19,030,585 | 2021-02 |
What was the administration route of drug 'PERTUZUMAB'? | Favorable survival with combined treatment in a metastatic breast cancer patient undergoing hemodialysis: A case report.
BACKGROUND
Management of breast cancer patients undergoing hemodialysis (HD) is difficult because of a lack of evidence about drug selection, dose adjustment, and surgical procedures. We herein present a case of metastatic breast cancer in a patient undergoing HD.
METHODS
A 58-year-old Japanese woman with breast cancer undergoing HD underwent total mastectomy of the left breast and left axillary dissection. Histopathological examination revealed invasive ductal carcinoma, and the diagnosis was pT2N3cM0 Stage ⅢC. Immunostaining of the resected specimen indicated that the tumor was estrogen receptor-positive, progesterone receptor-negative, human epithelial growth factor receptor 2-positive, and the Ki-67 labeling index was 70%. A postoperative positron emission tomography/computed tomography (PET/CT) scan indicated fluorodeoxyglucose uptake in the supraclavicular nodes. She received adjuvant therapy of epirubicin and cyclophosphamide followed by docetaxel, trastuzumab (T-mab) and radiation therapy. However, she developed multiple liver metastases during adjuvant T-mab and hormone therapy. Therefore, her regimen was changed to trastuzumab emtansine (T-DM1) as first-line therapy, T-mab, pertuzumab (P-mab), and eribulin as second-line therapy, and T-mab, P-mab, and weekly paclitaxel as third-line therapy. Eventually, she was administered fourth-line treatment of T-mab, P-mab, and vinorelbine because of adverse events. She has survived more than 25 months after the initial detection of recurrence of breast cancer and maintained quality of life.
CONCLUSIONS
We report a case of breast cancer in a patient undergoing HD. It is very difficult to identify the appropriate drugs and dosages in patients undergoing HD to improve survival and quality of life.
1 Introduction
The risk of cancer, including breast cancer, is increased among patients undergoing hemodialysis (HD) [1,2]. In the United States, women undergoing HD are 42% more likely to develop breast cancer than the general population [1]. Unlike age, family history of breast cancer, early menarche, late menopause, late pregnancy, long-term hormone replacement therapy, radiation exposure, and benign breast diseases, chronic kidney disease (CKD) is not a major risk factor for breast cancer [3,4].
There are few studies on anticancer drugs and other drugs used in cancer therapy in patients undergoing HD, even though CKD, HD, and peritoneal dialysis do not limit the possibility of surgical treatment and radiotherapy. We herein present a case of HD with relatively long-term survival after diagnosis of multiple liver metastases detected during adjuvant therapy after surgery for locally advanced breast cancer.
2 Presentation of case
A 58-year-old Japanese woman undergoing HD developed a nodule in the left breast that was observed on chest computed tomography (CT). A dual-source CT scan showed an enhanced breast nodule 2.3 cm in diameter in the left breast (Fig. 1a), and enhanced CT indicated a swollen axillary lymph node (Fig. 1b). Needle biopsy was performed, and the pathological findings of the specimen indicated invasive ductal carcinoma that was estrogen receptor-positive, progesterone receptor-negative, and human epidermal growth factor receptor 2-positive by immunohistochemistry. Fine-needle aspiration cytology of the left axillary lymph node showed malignancy. The patient was diagnosed with primary breast cancer (cT2N1MX Stage ⅡB according to the Union for International Cancer Control classification).Fig. 1 (a) Dual-source computed tomography (CT) revealed breast cancer, and (b) plane CT revealed metastatic axillary lymph nodes.
Fig. 1
She underwent total mastectomy of the left breast and left axillary dissection. The pathological evaluation confirmed invasive ductal carcinoma (2.4 cm) and 10 metastatic axillary lymph nodes. A postoperative positron emission tomography/computed tomography (PET/CT) scan showed uptake in the supraclavicular lymph nodes (Fig. 2) but not in distant organs (pT2N3cM0 Stage IIIC).Fig. 2 Positron emission tomography (PET)/computed tomography showed a hot spot in a metastatic supraclavicular lymph node (arrow).
Fig. 2
We administered the combined systemic therapy regimen for patients with pT2N3cM0 Stage IIIC breast cancer, which included epirubicin and cyclophosphamide (EC) (100 mg/m2 and 600 mg/m2, respectively) four times every 3 weeks, followed by docetaxel (DTX) (75 mg/m2) and trastuzumab (T-mab) (8 mg/kg loading dose and 6 mg/kg thereafter) four times every 3 weeks for adjuvant therapy. She received 70% of the full-dose of EC, 80% of the full-dose of DTX, and the full-dose of T-mab.
We used the vascular access (VA) for HD on the patient’s right forearm for the administration of anticancer drugs, which was on the opposite side of the surgical site. However, thrombosis developed in the VA after two rounds of EC. The patient also developed febrile neutropenia (FN), hemorrhagic cystitis, and anemia, which required thrombolytic therapy, antibiotics, granulocyte colony-stimulating factor, and blood transfusions. EC therapy was discontinued, and a central venous access port (CV port) was created at the right internal jugular vein. After that, the patient received four cycles of DTX and T-mab, followed by PMRT of 50 Gy in 25 fractions and 10 Gy in 5 fractions to the supraclavicular and internal mammary nodes. The patient then received full-dose T-mab monotherapy every 3 weeks, which was scheduled for 14 cycles and full-dose letrozole, which was scheduled for 10 years, as additional adjuvant therapy. However, one year after surgery, PET/CT indicated multiple metastases (Fig. 3), and blood tests revealed an increase in serum CA15-3.Fig. 3 Positron emission tomography (PET)/computed tomography indicated multiple hot spots in the liver (arrows).
Fig. 3
Trastuzumab emtansine (T-DM1) was administered as the first-line treatment for the recurrence. She received a full-dose of T-DM1 (3.6 mg/kg every 3 weeks) for a total of 10 cycles among 32 weeks. However, the liver metastases did not respond, so she was administered for nine cycles of full-dose T-mab, pertuzumab (P-mab) (840 mg loading dose and 420 mg thereafter), and 70% of the full-dose of eribulin (1.4 mg/m2 on days 1 and 8 every 3 weeks) among 33 weeks. However, the liver metastases continued to grow, and we administered third-line treatment of full-dose T-mab, P-mab, and weekly paclitaxel (PTX) at 70% of the full dose (90 mg/m2) among 29 weeks. The third-line treatment was administered for nine cycles, and a partial response was observed in the liver metastases. However, the patient refused to continue the therapy because of grade 2 systemic edema and numbness in the fingers. Currently, full-dose T-mab, P-mab, and 60% of the full dose of vinorelbine (VNR; 25 mg/m2 on days 1 and 8 every 3 weeks) are being administered as the fourth-line treatment. She has survived more than 25 months after the initial detection of recurrence of breast cancer and maintained quality of life.
3 Discussion
In this report, we describe a patient with metastatic breast cancer who was undergoing HD. She had favorable survival and acceptable quality of life using a reduced dosage and several types of drugs, despite the difficulty of dose control. Drug dosages may need to be adjusted in some patients, but the lack of appropriate drug dosage can reduce overall survival [5]. A previous study reported that patients receiving a higher relative dose intensity (RDI) of anticancer drugs had better clinical outcomes than those receiving a lower RDI among patients with metastatic solid tumors, including breast cancer [6], but there are currently no data in patients undergoing HD.
The survival of patients with breast cancer who are receiving dialysis is still unknown. CKD is not a significant factor in overall survival or disease-free survival in patients with breast cancer [7]. In fact, the patient in the present report had a favorable survival even after breast cancer recurrence. However, the number of cases in the literature is limited, and there is no other report describing the survival of patients with breast cancer who are receiving HD.
Regarding the treatment of breast cancer patients who are receiving HD, the most important clinical issue is drug selection and dosage adjustment. The recommendations for dosage adjustment for oncological therapy among patients receiving HD are shown in Table 1 [8,9]. Most drugs are safe to administer in patients receiving HD, and methotrexate is the only drug that should be avoided. It is recommended that capecitabine, cyclophosphamide, DTX, doxorubicin, epirubicin, and VNR be administered at reduced doses. There are insufficient data on HD patients receiving tamoxifen, anastrozole, letrozole, and newer targeted agents, such as cyclin-dependent kinase 4/6 inhibitors, lapatinib, T-mab, P-mab, T-DM1, and atezolizumab. However, even drugs that do not require dose reduction should be reduced if they cause myelotoxicity or cardiotoxicity. However, these recommendations are general; therefore, for patients without CKD, dose reduction depends on the patient’s adverse events (AEs). In this case, we reduced the dose of EC to 70%, that of DTX to 80%, that of eribulin to 70%, that of PTX to 70%, and that of VNR to 60%. Even drugs that are generally administered at the full dose had to be reduced due to AEs, including thrombosis, FN, hemorrhagic cystitis, and anemia. Although there is no recommended dosage reduction in the literature for T-DM1, T-mab, P-mab, and letrozole [8], we were able to administer these drugs at the full dose without any major AEs.Table 1 Summary of pharmacokinetics and safety of oncological therapies for breast cancer in hemodialysis patients.
Table 1Drug Elimination Dose reduction in HD Bednarek A8) Recommended dose in HD Janus N9) safety
capecitabine Urinary Recommended dose reduction by 50% No data Safe (limited data)
cyclophosphamide Urinary Recommended dose reduction by 20% Reduction of 25% Hemorrhagic cystitis
docetaxel Faeces Not specified 65 mg/m2 Safe
paclitaxel Faeces Not specified Standard dose Safe
doxorubicin Faeces Recommended dose reduction by 20% Standard dose Inceased risk of cardiotoxicity
epirubicin Faeces Recommended dose reduction Standard dose Inceased risk of cardiotoxicity
vinorelbine Faeces Probably necessary (up to 50%) Reduction of 20%–33% Inceased myelotoxicity (limited data)
tamoxifen Faeces Not indicated − Safe
anastrozole Faeces Not indicated − Safe
letrozole Urinary Not specified − No data
palbociclib Faeces Not specified − No data
lapatinib Faeces Not indicated − Safe (limited data)
trastuzumab No data Not indicated − Inceased risk of cardiotoxicity
pertuzumab No data Not indicated − No data
trastuzumab emtansine Faeces Not indicated − Inceased risk of cardiotoxicity
atezolizumab No data Not indicated − Safe (very limited data)
Another issue is among patients undergoing HD is the VA, particularly for patients who undergo axillary dissection. If the dissection range includes the VA site, it may be preferable to place a VA on the opposite side of the surgical site prior to operation to reduce the risk of VA issues. Another alternative is to use a temporary VA for the short term. However, no previous report was found. It might be useful to confirm the effect of the operation on the original VA. In our case, the patient’s VA was on the opposite side of the surgical site, so it was unaffected by the surgery.
Intravenous administered of anticancer drugs should be considered. In our case, the venous pressure in the internal jugular vein was increased by the VA on the non-affected side. It is usually recommended to create a CV port to prevent vasculitis caused by anticancer drugs, but we need to consider the risks of venous pressure increase. We initially decided to administer anticancer drugs from the VA for HD, but the patient developed thrombosis, and we created a CV port via the internal jugular vein on the VA side without any complications. This case is reported in line with the SCARE Guideline [10].
4 Conclusion
We report a case of breast cancer diagnosed during HD with multiple liver metastases that developed during postoperative adjuvant therapy. It is very difficult to manage patients undergoing HD with the appropriate drugs and dosage to improve survival and quality of life.
Declaration of Competing Interest
None.
Funding
None.
Ethical approval
None.
Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
Author contribution
Megumi Matsumoto conceptualized the study. Hiroshi Yano, Ryota Otsubo, and Aya Tanaka collaborated in the patient’s care. Takeshi Nagayasu provided input on the manuscript.
Registration of research studies
Researchregistry 6411.
Guarantor
Megumi Matsumoto.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Acknowledgements
We would like to thank Editage (www.editage.com) for English language editing. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33482449 | 18,846,201 | 2021-02 |
What was the administration route of drug 'TRASTUZUMAB'? | Favorable survival with combined treatment in a metastatic breast cancer patient undergoing hemodialysis: A case report.
BACKGROUND
Management of breast cancer patients undergoing hemodialysis (HD) is difficult because of a lack of evidence about drug selection, dose adjustment, and surgical procedures. We herein present a case of metastatic breast cancer in a patient undergoing HD.
METHODS
A 58-year-old Japanese woman with breast cancer undergoing HD underwent total mastectomy of the left breast and left axillary dissection. Histopathological examination revealed invasive ductal carcinoma, and the diagnosis was pT2N3cM0 Stage ⅢC. Immunostaining of the resected specimen indicated that the tumor was estrogen receptor-positive, progesterone receptor-negative, human epithelial growth factor receptor 2-positive, and the Ki-67 labeling index was 70%. A postoperative positron emission tomography/computed tomography (PET/CT) scan indicated fluorodeoxyglucose uptake in the supraclavicular nodes. She received adjuvant therapy of epirubicin and cyclophosphamide followed by docetaxel, trastuzumab (T-mab) and radiation therapy. However, she developed multiple liver metastases during adjuvant T-mab and hormone therapy. Therefore, her regimen was changed to trastuzumab emtansine (T-DM1) as first-line therapy, T-mab, pertuzumab (P-mab), and eribulin as second-line therapy, and T-mab, P-mab, and weekly paclitaxel as third-line therapy. Eventually, she was administered fourth-line treatment of T-mab, P-mab, and vinorelbine because of adverse events. She has survived more than 25 months after the initial detection of recurrence of breast cancer and maintained quality of life.
CONCLUSIONS
We report a case of breast cancer in a patient undergoing HD. It is very difficult to identify the appropriate drugs and dosages in patients undergoing HD to improve survival and quality of life.
1 Introduction
The risk of cancer, including breast cancer, is increased among patients undergoing hemodialysis (HD) [1,2]. In the United States, women undergoing HD are 42% more likely to develop breast cancer than the general population [1]. Unlike age, family history of breast cancer, early menarche, late menopause, late pregnancy, long-term hormone replacement therapy, radiation exposure, and benign breast diseases, chronic kidney disease (CKD) is not a major risk factor for breast cancer [3,4].
There are few studies on anticancer drugs and other drugs used in cancer therapy in patients undergoing HD, even though CKD, HD, and peritoneal dialysis do not limit the possibility of surgical treatment and radiotherapy. We herein present a case of HD with relatively long-term survival after diagnosis of multiple liver metastases detected during adjuvant therapy after surgery for locally advanced breast cancer.
2 Presentation of case
A 58-year-old Japanese woman undergoing HD developed a nodule in the left breast that was observed on chest computed tomography (CT). A dual-source CT scan showed an enhanced breast nodule 2.3 cm in diameter in the left breast (Fig. 1a), and enhanced CT indicated a swollen axillary lymph node (Fig. 1b). Needle biopsy was performed, and the pathological findings of the specimen indicated invasive ductal carcinoma that was estrogen receptor-positive, progesterone receptor-negative, and human epidermal growth factor receptor 2-positive by immunohistochemistry. Fine-needle aspiration cytology of the left axillary lymph node showed malignancy. The patient was diagnosed with primary breast cancer (cT2N1MX Stage ⅡB according to the Union for International Cancer Control classification).Fig. 1 (a) Dual-source computed tomography (CT) revealed breast cancer, and (b) plane CT revealed metastatic axillary lymph nodes.
Fig. 1
She underwent total mastectomy of the left breast and left axillary dissection. The pathological evaluation confirmed invasive ductal carcinoma (2.4 cm) and 10 metastatic axillary lymph nodes. A postoperative positron emission tomography/computed tomography (PET/CT) scan showed uptake in the supraclavicular lymph nodes (Fig. 2) but not in distant organs (pT2N3cM0 Stage IIIC).Fig. 2 Positron emission tomography (PET)/computed tomography showed a hot spot in a metastatic supraclavicular lymph node (arrow).
Fig. 2
We administered the combined systemic therapy regimen for patients with pT2N3cM0 Stage IIIC breast cancer, which included epirubicin and cyclophosphamide (EC) (100 mg/m2 and 600 mg/m2, respectively) four times every 3 weeks, followed by docetaxel (DTX) (75 mg/m2) and trastuzumab (T-mab) (8 mg/kg loading dose and 6 mg/kg thereafter) four times every 3 weeks for adjuvant therapy. She received 70% of the full-dose of EC, 80% of the full-dose of DTX, and the full-dose of T-mab.
We used the vascular access (VA) for HD on the patient’s right forearm for the administration of anticancer drugs, which was on the opposite side of the surgical site. However, thrombosis developed in the VA after two rounds of EC. The patient also developed febrile neutropenia (FN), hemorrhagic cystitis, and anemia, which required thrombolytic therapy, antibiotics, granulocyte colony-stimulating factor, and blood transfusions. EC therapy was discontinued, and a central venous access port (CV port) was created at the right internal jugular vein. After that, the patient received four cycles of DTX and T-mab, followed by PMRT of 50 Gy in 25 fractions and 10 Gy in 5 fractions to the supraclavicular and internal mammary nodes. The patient then received full-dose T-mab monotherapy every 3 weeks, which was scheduled for 14 cycles and full-dose letrozole, which was scheduled for 10 years, as additional adjuvant therapy. However, one year after surgery, PET/CT indicated multiple metastases (Fig. 3), and blood tests revealed an increase in serum CA15-3.Fig. 3 Positron emission tomography (PET)/computed tomography indicated multiple hot spots in the liver (arrows).
Fig. 3
Trastuzumab emtansine (T-DM1) was administered as the first-line treatment for the recurrence. She received a full-dose of T-DM1 (3.6 mg/kg every 3 weeks) for a total of 10 cycles among 32 weeks. However, the liver metastases did not respond, so she was administered for nine cycles of full-dose T-mab, pertuzumab (P-mab) (840 mg loading dose and 420 mg thereafter), and 70% of the full-dose of eribulin (1.4 mg/m2 on days 1 and 8 every 3 weeks) among 33 weeks. However, the liver metastases continued to grow, and we administered third-line treatment of full-dose T-mab, P-mab, and weekly paclitaxel (PTX) at 70% of the full dose (90 mg/m2) among 29 weeks. The third-line treatment was administered for nine cycles, and a partial response was observed in the liver metastases. However, the patient refused to continue the therapy because of grade 2 systemic edema and numbness in the fingers. Currently, full-dose T-mab, P-mab, and 60% of the full dose of vinorelbine (VNR; 25 mg/m2 on days 1 and 8 every 3 weeks) are being administered as the fourth-line treatment. She has survived more than 25 months after the initial detection of recurrence of breast cancer and maintained quality of life.
3 Discussion
In this report, we describe a patient with metastatic breast cancer who was undergoing HD. She had favorable survival and acceptable quality of life using a reduced dosage and several types of drugs, despite the difficulty of dose control. Drug dosages may need to be adjusted in some patients, but the lack of appropriate drug dosage can reduce overall survival [5]. A previous study reported that patients receiving a higher relative dose intensity (RDI) of anticancer drugs had better clinical outcomes than those receiving a lower RDI among patients with metastatic solid tumors, including breast cancer [6], but there are currently no data in patients undergoing HD.
The survival of patients with breast cancer who are receiving dialysis is still unknown. CKD is not a significant factor in overall survival or disease-free survival in patients with breast cancer [7]. In fact, the patient in the present report had a favorable survival even after breast cancer recurrence. However, the number of cases in the literature is limited, and there is no other report describing the survival of patients with breast cancer who are receiving HD.
Regarding the treatment of breast cancer patients who are receiving HD, the most important clinical issue is drug selection and dosage adjustment. The recommendations for dosage adjustment for oncological therapy among patients receiving HD are shown in Table 1 [8,9]. Most drugs are safe to administer in patients receiving HD, and methotrexate is the only drug that should be avoided. It is recommended that capecitabine, cyclophosphamide, DTX, doxorubicin, epirubicin, and VNR be administered at reduced doses. There are insufficient data on HD patients receiving tamoxifen, anastrozole, letrozole, and newer targeted agents, such as cyclin-dependent kinase 4/6 inhibitors, lapatinib, T-mab, P-mab, T-DM1, and atezolizumab. However, even drugs that do not require dose reduction should be reduced if they cause myelotoxicity or cardiotoxicity. However, these recommendations are general; therefore, for patients without CKD, dose reduction depends on the patient’s adverse events (AEs). In this case, we reduced the dose of EC to 70%, that of DTX to 80%, that of eribulin to 70%, that of PTX to 70%, and that of VNR to 60%. Even drugs that are generally administered at the full dose had to be reduced due to AEs, including thrombosis, FN, hemorrhagic cystitis, and anemia. Although there is no recommended dosage reduction in the literature for T-DM1, T-mab, P-mab, and letrozole [8], we were able to administer these drugs at the full dose without any major AEs.Table 1 Summary of pharmacokinetics and safety of oncological therapies for breast cancer in hemodialysis patients.
Table 1Drug Elimination Dose reduction in HD Bednarek A8) Recommended dose in HD Janus N9) safety
capecitabine Urinary Recommended dose reduction by 50% No data Safe (limited data)
cyclophosphamide Urinary Recommended dose reduction by 20% Reduction of 25% Hemorrhagic cystitis
docetaxel Faeces Not specified 65 mg/m2 Safe
paclitaxel Faeces Not specified Standard dose Safe
doxorubicin Faeces Recommended dose reduction by 20% Standard dose Inceased risk of cardiotoxicity
epirubicin Faeces Recommended dose reduction Standard dose Inceased risk of cardiotoxicity
vinorelbine Faeces Probably necessary (up to 50%) Reduction of 20%–33% Inceased myelotoxicity (limited data)
tamoxifen Faeces Not indicated − Safe
anastrozole Faeces Not indicated − Safe
letrozole Urinary Not specified − No data
palbociclib Faeces Not specified − No data
lapatinib Faeces Not indicated − Safe (limited data)
trastuzumab No data Not indicated − Inceased risk of cardiotoxicity
pertuzumab No data Not indicated − No data
trastuzumab emtansine Faeces Not indicated − Inceased risk of cardiotoxicity
atezolizumab No data Not indicated − Safe (very limited data)
Another issue is among patients undergoing HD is the VA, particularly for patients who undergo axillary dissection. If the dissection range includes the VA site, it may be preferable to place a VA on the opposite side of the surgical site prior to operation to reduce the risk of VA issues. Another alternative is to use a temporary VA for the short term. However, no previous report was found. It might be useful to confirm the effect of the operation on the original VA. In our case, the patient’s VA was on the opposite side of the surgical site, so it was unaffected by the surgery.
Intravenous administered of anticancer drugs should be considered. In our case, the venous pressure in the internal jugular vein was increased by the VA on the non-affected side. It is usually recommended to create a CV port to prevent vasculitis caused by anticancer drugs, but we need to consider the risks of venous pressure increase. We initially decided to administer anticancer drugs from the VA for HD, but the patient developed thrombosis, and we created a CV port via the internal jugular vein on the VA side without any complications. This case is reported in line with the SCARE Guideline [10].
4 Conclusion
We report a case of breast cancer diagnosed during HD with multiple liver metastases that developed during postoperative adjuvant therapy. It is very difficult to manage patients undergoing HD with the appropriate drugs and dosage to improve survival and quality of life.
Declaration of Competing Interest
None.
Funding
None.
Ethical approval
None.
Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
Author contribution
Megumi Matsumoto conceptualized the study. Hiroshi Yano, Ryota Otsubo, and Aya Tanaka collaborated in the patient’s care. Takeshi Nagayasu provided input on the manuscript.
Registration of research studies
Researchregistry 6411.
Guarantor
Megumi Matsumoto.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Acknowledgements
We would like to thank Editage (www.editage.com) for English language editing. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33482449 | 19,030,585 | 2021-02 |
What was the dosage of drug 'EPIRUBICIN HYDROCHLORIDE'? | Favorable survival with combined treatment in a metastatic breast cancer patient undergoing hemodialysis: A case report.
BACKGROUND
Management of breast cancer patients undergoing hemodialysis (HD) is difficult because of a lack of evidence about drug selection, dose adjustment, and surgical procedures. We herein present a case of metastatic breast cancer in a patient undergoing HD.
METHODS
A 58-year-old Japanese woman with breast cancer undergoing HD underwent total mastectomy of the left breast and left axillary dissection. Histopathological examination revealed invasive ductal carcinoma, and the diagnosis was pT2N3cM0 Stage ⅢC. Immunostaining of the resected specimen indicated that the tumor was estrogen receptor-positive, progesterone receptor-negative, human epithelial growth factor receptor 2-positive, and the Ki-67 labeling index was 70%. A postoperative positron emission tomography/computed tomography (PET/CT) scan indicated fluorodeoxyglucose uptake in the supraclavicular nodes. She received adjuvant therapy of epirubicin and cyclophosphamide followed by docetaxel, trastuzumab (T-mab) and radiation therapy. However, she developed multiple liver metastases during adjuvant T-mab and hormone therapy. Therefore, her regimen was changed to trastuzumab emtansine (T-DM1) as first-line therapy, T-mab, pertuzumab (P-mab), and eribulin as second-line therapy, and T-mab, P-mab, and weekly paclitaxel as third-line therapy. Eventually, she was administered fourth-line treatment of T-mab, P-mab, and vinorelbine because of adverse events. She has survived more than 25 months after the initial detection of recurrence of breast cancer and maintained quality of life.
CONCLUSIONS
We report a case of breast cancer in a patient undergoing HD. It is very difficult to identify the appropriate drugs and dosages in patients undergoing HD to improve survival and quality of life.
1 Introduction
The risk of cancer, including breast cancer, is increased among patients undergoing hemodialysis (HD) [1,2]. In the United States, women undergoing HD are 42% more likely to develop breast cancer than the general population [1]. Unlike age, family history of breast cancer, early menarche, late menopause, late pregnancy, long-term hormone replacement therapy, radiation exposure, and benign breast diseases, chronic kidney disease (CKD) is not a major risk factor for breast cancer [3,4].
There are few studies on anticancer drugs and other drugs used in cancer therapy in patients undergoing HD, even though CKD, HD, and peritoneal dialysis do not limit the possibility of surgical treatment and radiotherapy. We herein present a case of HD with relatively long-term survival after diagnosis of multiple liver metastases detected during adjuvant therapy after surgery for locally advanced breast cancer.
2 Presentation of case
A 58-year-old Japanese woman undergoing HD developed a nodule in the left breast that was observed on chest computed tomography (CT). A dual-source CT scan showed an enhanced breast nodule 2.3 cm in diameter in the left breast (Fig. 1a), and enhanced CT indicated a swollen axillary lymph node (Fig. 1b). Needle biopsy was performed, and the pathological findings of the specimen indicated invasive ductal carcinoma that was estrogen receptor-positive, progesterone receptor-negative, and human epidermal growth factor receptor 2-positive by immunohistochemistry. Fine-needle aspiration cytology of the left axillary lymph node showed malignancy. The patient was diagnosed with primary breast cancer (cT2N1MX Stage ⅡB according to the Union for International Cancer Control classification).Fig. 1 (a) Dual-source computed tomography (CT) revealed breast cancer, and (b) plane CT revealed metastatic axillary lymph nodes.
Fig. 1
She underwent total mastectomy of the left breast and left axillary dissection. The pathological evaluation confirmed invasive ductal carcinoma (2.4 cm) and 10 metastatic axillary lymph nodes. A postoperative positron emission tomography/computed tomography (PET/CT) scan showed uptake in the supraclavicular lymph nodes (Fig. 2) but not in distant organs (pT2N3cM0 Stage IIIC).Fig. 2 Positron emission tomography (PET)/computed tomography showed a hot spot in a metastatic supraclavicular lymph node (arrow).
Fig. 2
We administered the combined systemic therapy regimen for patients with pT2N3cM0 Stage IIIC breast cancer, which included epirubicin and cyclophosphamide (EC) (100 mg/m2 and 600 mg/m2, respectively) four times every 3 weeks, followed by docetaxel (DTX) (75 mg/m2) and trastuzumab (T-mab) (8 mg/kg loading dose and 6 mg/kg thereafter) four times every 3 weeks for adjuvant therapy. She received 70% of the full-dose of EC, 80% of the full-dose of DTX, and the full-dose of T-mab.
We used the vascular access (VA) for HD on the patient’s right forearm for the administration of anticancer drugs, which was on the opposite side of the surgical site. However, thrombosis developed in the VA after two rounds of EC. The patient also developed febrile neutropenia (FN), hemorrhagic cystitis, and anemia, which required thrombolytic therapy, antibiotics, granulocyte colony-stimulating factor, and blood transfusions. EC therapy was discontinued, and a central venous access port (CV port) was created at the right internal jugular vein. After that, the patient received four cycles of DTX and T-mab, followed by PMRT of 50 Gy in 25 fractions and 10 Gy in 5 fractions to the supraclavicular and internal mammary nodes. The patient then received full-dose T-mab monotherapy every 3 weeks, which was scheduled for 14 cycles and full-dose letrozole, which was scheduled for 10 years, as additional adjuvant therapy. However, one year after surgery, PET/CT indicated multiple metastases (Fig. 3), and blood tests revealed an increase in serum CA15-3.Fig. 3 Positron emission tomography (PET)/computed tomography indicated multiple hot spots in the liver (arrows).
Fig. 3
Trastuzumab emtansine (T-DM1) was administered as the first-line treatment for the recurrence. She received a full-dose of T-DM1 (3.6 mg/kg every 3 weeks) for a total of 10 cycles among 32 weeks. However, the liver metastases did not respond, so she was administered for nine cycles of full-dose T-mab, pertuzumab (P-mab) (840 mg loading dose and 420 mg thereafter), and 70% of the full-dose of eribulin (1.4 mg/m2 on days 1 and 8 every 3 weeks) among 33 weeks. However, the liver metastases continued to grow, and we administered third-line treatment of full-dose T-mab, P-mab, and weekly paclitaxel (PTX) at 70% of the full dose (90 mg/m2) among 29 weeks. The third-line treatment was administered for nine cycles, and a partial response was observed in the liver metastases. However, the patient refused to continue the therapy because of grade 2 systemic edema and numbness in the fingers. Currently, full-dose T-mab, P-mab, and 60% of the full dose of vinorelbine (VNR; 25 mg/m2 on days 1 and 8 every 3 weeks) are being administered as the fourth-line treatment. She has survived more than 25 months after the initial detection of recurrence of breast cancer and maintained quality of life.
3 Discussion
In this report, we describe a patient with metastatic breast cancer who was undergoing HD. She had favorable survival and acceptable quality of life using a reduced dosage and several types of drugs, despite the difficulty of dose control. Drug dosages may need to be adjusted in some patients, but the lack of appropriate drug dosage can reduce overall survival [5]. A previous study reported that patients receiving a higher relative dose intensity (RDI) of anticancer drugs had better clinical outcomes than those receiving a lower RDI among patients with metastatic solid tumors, including breast cancer [6], but there are currently no data in patients undergoing HD.
The survival of patients with breast cancer who are receiving dialysis is still unknown. CKD is not a significant factor in overall survival or disease-free survival in patients with breast cancer [7]. In fact, the patient in the present report had a favorable survival even after breast cancer recurrence. However, the number of cases in the literature is limited, and there is no other report describing the survival of patients with breast cancer who are receiving HD.
Regarding the treatment of breast cancer patients who are receiving HD, the most important clinical issue is drug selection and dosage adjustment. The recommendations for dosage adjustment for oncological therapy among patients receiving HD are shown in Table 1 [8,9]. Most drugs are safe to administer in patients receiving HD, and methotrexate is the only drug that should be avoided. It is recommended that capecitabine, cyclophosphamide, DTX, doxorubicin, epirubicin, and VNR be administered at reduced doses. There are insufficient data on HD patients receiving tamoxifen, anastrozole, letrozole, and newer targeted agents, such as cyclin-dependent kinase 4/6 inhibitors, lapatinib, T-mab, P-mab, T-DM1, and atezolizumab. However, even drugs that do not require dose reduction should be reduced if they cause myelotoxicity or cardiotoxicity. However, these recommendations are general; therefore, for patients without CKD, dose reduction depends on the patient’s adverse events (AEs). In this case, we reduced the dose of EC to 70%, that of DTX to 80%, that of eribulin to 70%, that of PTX to 70%, and that of VNR to 60%. Even drugs that are generally administered at the full dose had to be reduced due to AEs, including thrombosis, FN, hemorrhagic cystitis, and anemia. Although there is no recommended dosage reduction in the literature for T-DM1, T-mab, P-mab, and letrozole [8], we were able to administer these drugs at the full dose without any major AEs.Table 1 Summary of pharmacokinetics and safety of oncological therapies for breast cancer in hemodialysis patients.
Table 1Drug Elimination Dose reduction in HD Bednarek A8) Recommended dose in HD Janus N9) safety
capecitabine Urinary Recommended dose reduction by 50% No data Safe (limited data)
cyclophosphamide Urinary Recommended dose reduction by 20% Reduction of 25% Hemorrhagic cystitis
docetaxel Faeces Not specified 65 mg/m2 Safe
paclitaxel Faeces Not specified Standard dose Safe
doxorubicin Faeces Recommended dose reduction by 20% Standard dose Inceased risk of cardiotoxicity
epirubicin Faeces Recommended dose reduction Standard dose Inceased risk of cardiotoxicity
vinorelbine Faeces Probably necessary (up to 50%) Reduction of 20%–33% Inceased myelotoxicity (limited data)
tamoxifen Faeces Not indicated − Safe
anastrozole Faeces Not indicated − Safe
letrozole Urinary Not specified − No data
palbociclib Faeces Not specified − No data
lapatinib Faeces Not indicated − Safe (limited data)
trastuzumab No data Not indicated − Inceased risk of cardiotoxicity
pertuzumab No data Not indicated − No data
trastuzumab emtansine Faeces Not indicated − Inceased risk of cardiotoxicity
atezolizumab No data Not indicated − Safe (very limited data)
Another issue is among patients undergoing HD is the VA, particularly for patients who undergo axillary dissection. If the dissection range includes the VA site, it may be preferable to place a VA on the opposite side of the surgical site prior to operation to reduce the risk of VA issues. Another alternative is to use a temporary VA for the short term. However, no previous report was found. It might be useful to confirm the effect of the operation on the original VA. In our case, the patient’s VA was on the opposite side of the surgical site, so it was unaffected by the surgery.
Intravenous administered of anticancer drugs should be considered. In our case, the venous pressure in the internal jugular vein was increased by the VA on the non-affected side. It is usually recommended to create a CV port to prevent vasculitis caused by anticancer drugs, but we need to consider the risks of venous pressure increase. We initially decided to administer anticancer drugs from the VA for HD, but the patient developed thrombosis, and we created a CV port via the internal jugular vein on the VA side without any complications. This case is reported in line with the SCARE Guideline [10].
4 Conclusion
We report a case of breast cancer diagnosed during HD with multiple liver metastases that developed during postoperative adjuvant therapy. It is very difficult to manage patients undergoing HD with the appropriate drugs and dosage to improve survival and quality of life.
Declaration of Competing Interest
None.
Funding
None.
Ethical approval
None.
Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
Author contribution
Megumi Matsumoto conceptualized the study. Hiroshi Yano, Ryota Otsubo, and Aya Tanaka collaborated in the patient’s care. Takeshi Nagayasu provided input on the manuscript.
Registration of research studies
Researchregistry 6411.
Guarantor
Megumi Matsumoto.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Acknowledgements
We would like to thank Editage (www.editage.com) for English language editing. | 100 MG/M2, CYCLIC (FOUR TIMES EVERY 3 WEEKS) | DrugDosageText | CC BY | 33482449 | 18,991,560 | 2021-02 |
What was the dosage of drug 'VINORELBINE TARTRATE'? | Favorable survival with combined treatment in a metastatic breast cancer patient undergoing hemodialysis: A case report.
BACKGROUND
Management of breast cancer patients undergoing hemodialysis (HD) is difficult because of a lack of evidence about drug selection, dose adjustment, and surgical procedures. We herein present a case of metastatic breast cancer in a patient undergoing HD.
METHODS
A 58-year-old Japanese woman with breast cancer undergoing HD underwent total mastectomy of the left breast and left axillary dissection. Histopathological examination revealed invasive ductal carcinoma, and the diagnosis was pT2N3cM0 Stage ⅢC. Immunostaining of the resected specimen indicated that the tumor was estrogen receptor-positive, progesterone receptor-negative, human epithelial growth factor receptor 2-positive, and the Ki-67 labeling index was 70%. A postoperative positron emission tomography/computed tomography (PET/CT) scan indicated fluorodeoxyglucose uptake in the supraclavicular nodes. She received adjuvant therapy of epirubicin and cyclophosphamide followed by docetaxel, trastuzumab (T-mab) and radiation therapy. However, she developed multiple liver metastases during adjuvant T-mab and hormone therapy. Therefore, her regimen was changed to trastuzumab emtansine (T-DM1) as first-line therapy, T-mab, pertuzumab (P-mab), and eribulin as second-line therapy, and T-mab, P-mab, and weekly paclitaxel as third-line therapy. Eventually, she was administered fourth-line treatment of T-mab, P-mab, and vinorelbine because of adverse events. She has survived more than 25 months after the initial detection of recurrence of breast cancer and maintained quality of life.
CONCLUSIONS
We report a case of breast cancer in a patient undergoing HD. It is very difficult to identify the appropriate drugs and dosages in patients undergoing HD to improve survival and quality of life.
1 Introduction
The risk of cancer, including breast cancer, is increased among patients undergoing hemodialysis (HD) [1,2]. In the United States, women undergoing HD are 42% more likely to develop breast cancer than the general population [1]. Unlike age, family history of breast cancer, early menarche, late menopause, late pregnancy, long-term hormone replacement therapy, radiation exposure, and benign breast diseases, chronic kidney disease (CKD) is not a major risk factor for breast cancer [3,4].
There are few studies on anticancer drugs and other drugs used in cancer therapy in patients undergoing HD, even though CKD, HD, and peritoneal dialysis do not limit the possibility of surgical treatment and radiotherapy. We herein present a case of HD with relatively long-term survival after diagnosis of multiple liver metastases detected during adjuvant therapy after surgery for locally advanced breast cancer.
2 Presentation of case
A 58-year-old Japanese woman undergoing HD developed a nodule in the left breast that was observed on chest computed tomography (CT). A dual-source CT scan showed an enhanced breast nodule 2.3 cm in diameter in the left breast (Fig. 1a), and enhanced CT indicated a swollen axillary lymph node (Fig. 1b). Needle biopsy was performed, and the pathological findings of the specimen indicated invasive ductal carcinoma that was estrogen receptor-positive, progesterone receptor-negative, and human epidermal growth factor receptor 2-positive by immunohistochemistry. Fine-needle aspiration cytology of the left axillary lymph node showed malignancy. The patient was diagnosed with primary breast cancer (cT2N1MX Stage ⅡB according to the Union for International Cancer Control classification).Fig. 1 (a) Dual-source computed tomography (CT) revealed breast cancer, and (b) plane CT revealed metastatic axillary lymph nodes.
Fig. 1
She underwent total mastectomy of the left breast and left axillary dissection. The pathological evaluation confirmed invasive ductal carcinoma (2.4 cm) and 10 metastatic axillary lymph nodes. A postoperative positron emission tomography/computed tomography (PET/CT) scan showed uptake in the supraclavicular lymph nodes (Fig. 2) but not in distant organs (pT2N3cM0 Stage IIIC).Fig. 2 Positron emission tomography (PET)/computed tomography showed a hot spot in a metastatic supraclavicular lymph node (arrow).
Fig. 2
We administered the combined systemic therapy regimen for patients with pT2N3cM0 Stage IIIC breast cancer, which included epirubicin and cyclophosphamide (EC) (100 mg/m2 and 600 mg/m2, respectively) four times every 3 weeks, followed by docetaxel (DTX) (75 mg/m2) and trastuzumab (T-mab) (8 mg/kg loading dose and 6 mg/kg thereafter) four times every 3 weeks for adjuvant therapy. She received 70% of the full-dose of EC, 80% of the full-dose of DTX, and the full-dose of T-mab.
We used the vascular access (VA) for HD on the patient’s right forearm for the administration of anticancer drugs, which was on the opposite side of the surgical site. However, thrombosis developed in the VA after two rounds of EC. The patient also developed febrile neutropenia (FN), hemorrhagic cystitis, and anemia, which required thrombolytic therapy, antibiotics, granulocyte colony-stimulating factor, and blood transfusions. EC therapy was discontinued, and a central venous access port (CV port) was created at the right internal jugular vein. After that, the patient received four cycles of DTX and T-mab, followed by PMRT of 50 Gy in 25 fractions and 10 Gy in 5 fractions to the supraclavicular and internal mammary nodes. The patient then received full-dose T-mab monotherapy every 3 weeks, which was scheduled for 14 cycles and full-dose letrozole, which was scheduled for 10 years, as additional adjuvant therapy. However, one year after surgery, PET/CT indicated multiple metastases (Fig. 3), and blood tests revealed an increase in serum CA15-3.Fig. 3 Positron emission tomography (PET)/computed tomography indicated multiple hot spots in the liver (arrows).
Fig. 3
Trastuzumab emtansine (T-DM1) was administered as the first-line treatment for the recurrence. She received a full-dose of T-DM1 (3.6 mg/kg every 3 weeks) for a total of 10 cycles among 32 weeks. However, the liver metastases did not respond, so she was administered for nine cycles of full-dose T-mab, pertuzumab (P-mab) (840 mg loading dose and 420 mg thereafter), and 70% of the full-dose of eribulin (1.4 mg/m2 on days 1 and 8 every 3 weeks) among 33 weeks. However, the liver metastases continued to grow, and we administered third-line treatment of full-dose T-mab, P-mab, and weekly paclitaxel (PTX) at 70% of the full dose (90 mg/m2) among 29 weeks. The third-line treatment was administered for nine cycles, and a partial response was observed in the liver metastases. However, the patient refused to continue the therapy because of grade 2 systemic edema and numbness in the fingers. Currently, full-dose T-mab, P-mab, and 60% of the full dose of vinorelbine (VNR; 25 mg/m2 on days 1 and 8 every 3 weeks) are being administered as the fourth-line treatment. She has survived more than 25 months after the initial detection of recurrence of breast cancer and maintained quality of life.
3 Discussion
In this report, we describe a patient with metastatic breast cancer who was undergoing HD. She had favorable survival and acceptable quality of life using a reduced dosage and several types of drugs, despite the difficulty of dose control. Drug dosages may need to be adjusted in some patients, but the lack of appropriate drug dosage can reduce overall survival [5]. A previous study reported that patients receiving a higher relative dose intensity (RDI) of anticancer drugs had better clinical outcomes than those receiving a lower RDI among patients with metastatic solid tumors, including breast cancer [6], but there are currently no data in patients undergoing HD.
The survival of patients with breast cancer who are receiving dialysis is still unknown. CKD is not a significant factor in overall survival or disease-free survival in patients with breast cancer [7]. In fact, the patient in the present report had a favorable survival even after breast cancer recurrence. However, the number of cases in the literature is limited, and there is no other report describing the survival of patients with breast cancer who are receiving HD.
Regarding the treatment of breast cancer patients who are receiving HD, the most important clinical issue is drug selection and dosage adjustment. The recommendations for dosage adjustment for oncological therapy among patients receiving HD are shown in Table 1 [8,9]. Most drugs are safe to administer in patients receiving HD, and methotrexate is the only drug that should be avoided. It is recommended that capecitabine, cyclophosphamide, DTX, doxorubicin, epirubicin, and VNR be administered at reduced doses. There are insufficient data on HD patients receiving tamoxifen, anastrozole, letrozole, and newer targeted agents, such as cyclin-dependent kinase 4/6 inhibitors, lapatinib, T-mab, P-mab, T-DM1, and atezolizumab. However, even drugs that do not require dose reduction should be reduced if they cause myelotoxicity or cardiotoxicity. However, these recommendations are general; therefore, for patients without CKD, dose reduction depends on the patient’s adverse events (AEs). In this case, we reduced the dose of EC to 70%, that of DTX to 80%, that of eribulin to 70%, that of PTX to 70%, and that of VNR to 60%. Even drugs that are generally administered at the full dose had to be reduced due to AEs, including thrombosis, FN, hemorrhagic cystitis, and anemia. Although there is no recommended dosage reduction in the literature for T-DM1, T-mab, P-mab, and letrozole [8], we were able to administer these drugs at the full dose without any major AEs.Table 1 Summary of pharmacokinetics and safety of oncological therapies for breast cancer in hemodialysis patients.
Table 1Drug Elimination Dose reduction in HD Bednarek A8) Recommended dose in HD Janus N9) safety
capecitabine Urinary Recommended dose reduction by 50% No data Safe (limited data)
cyclophosphamide Urinary Recommended dose reduction by 20% Reduction of 25% Hemorrhagic cystitis
docetaxel Faeces Not specified 65 mg/m2 Safe
paclitaxel Faeces Not specified Standard dose Safe
doxorubicin Faeces Recommended dose reduction by 20% Standard dose Inceased risk of cardiotoxicity
epirubicin Faeces Recommended dose reduction Standard dose Inceased risk of cardiotoxicity
vinorelbine Faeces Probably necessary (up to 50%) Reduction of 20%–33% Inceased myelotoxicity (limited data)
tamoxifen Faeces Not indicated − Safe
anastrozole Faeces Not indicated − Safe
letrozole Urinary Not specified − No data
palbociclib Faeces Not specified − No data
lapatinib Faeces Not indicated − Safe (limited data)
trastuzumab No data Not indicated − Inceased risk of cardiotoxicity
pertuzumab No data Not indicated − No data
trastuzumab emtansine Faeces Not indicated − Inceased risk of cardiotoxicity
atezolizumab No data Not indicated − Safe (very limited data)
Another issue is among patients undergoing HD is the VA, particularly for patients who undergo axillary dissection. If the dissection range includes the VA site, it may be preferable to place a VA on the opposite side of the surgical site prior to operation to reduce the risk of VA issues. Another alternative is to use a temporary VA for the short term. However, no previous report was found. It might be useful to confirm the effect of the operation on the original VA. In our case, the patient’s VA was on the opposite side of the surgical site, so it was unaffected by the surgery.
Intravenous administered of anticancer drugs should be considered. In our case, the venous pressure in the internal jugular vein was increased by the VA on the non-affected side. It is usually recommended to create a CV port to prevent vasculitis caused by anticancer drugs, but we need to consider the risks of venous pressure increase. We initially decided to administer anticancer drugs from the VA for HD, but the patient developed thrombosis, and we created a CV port via the internal jugular vein on the VA side without any complications. This case is reported in line with the SCARE Guideline [10].
4 Conclusion
We report a case of breast cancer diagnosed during HD with multiple liver metastases that developed during postoperative adjuvant therapy. It is very difficult to manage patients undergoing HD with the appropriate drugs and dosage to improve survival and quality of life.
Declaration of Competing Interest
None.
Funding
None.
Ethical approval
None.
Consent
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
Author contribution
Megumi Matsumoto conceptualized the study. Hiroshi Yano, Ryota Otsubo, and Aya Tanaka collaborated in the patient’s care. Takeshi Nagayasu provided input on the manuscript.
Registration of research studies
Researchregistry 6411.
Guarantor
Megumi Matsumoto.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Acknowledgements
We would like to thank Editage (www.editage.com) for English language editing. | FOURTH?LINE TREATMENT, (VNR; 25 MG/M2 ON DAYS 1 AND 8 EVERY 3 WEEKS) | DrugDosageText | CC BY | 33482449 | 18,846,201 | 2021-02 |
What was the dosage of drug 'CYCLOSPORINE'? | Reconstruction using a frozen autograft for a skull and humeral lesion of synchronous multicentric osteosarcoma after undergoing successful neoadjuvant chemotherapy: a case report and review of the literature.
BACKGROUND
Synchronous multicentric osteosarcoma (SMOS) is a rare disease characterized by simultaneous multicentricity of intraosseous osteosarcoma without visceral involvement. SMOS, including a skull lesion, which occurs relatively rarely, and reconstruction using a frozen autograft after the excision of a lesion of SMOS has been infrequently reported previously.
METHODS
We report an 18-year-old girl with SMOS, with lesions located in the left distal femur, right proximal humerus, and left occipital bone. Her major complaint was pain and swelling around the left knee joint. Asymptomatic lesions of the humerus and skull bone were detected on a systemic bone scan. No visceral organ metastasis was observed. A biopsy of the distal femoral lesion revealed osteosarcoma. Based on the histological findings, multiple bone lesions, and absence of visceral lesion, the clinical diagnosis of SMOS was made. After five courses of neoadjuvant chemotherapy with a regimen of doxorubicin and cisplatin, reconstruction using a tumor prosthesis following wide excision of the left distal femur was performed, and total necrosis was histologically observed in the retracted specimen. Following three cycles of adjuvant chemotherapy, tumor excision and reconstruction with a frozen autograft treated with liquid nitrogen was conducted for both lesions of the humerus and skull, rather than tumor prosthesis or synthetics, in order to retain a normal shoulder function, and to obtain a good cosmetic and functional outcome after treatment of the skull lesion. Further adjuvant chemotherapy could not be administered after the completion of the surgical treatment for all lesions because the adverse events due to chemotherapy were observed. At over 5 years after the diagnosis, she remains clinically disease-free.
CONCLUSIONS
An early correct diagnosis, the proper management of chemotherapy, and surgical treatment for all lesions are essential for achieving a good clinical outcome, even in SMOS including a skull lesion. By performing reconstruction using a frozen autograft for a proximal humeral lesion and a skull lesion after confirming the good histological efficacy of neoadjuvant chemotherapy for the primary lesion, the excellent function of the shoulder joint and a good cosmetic outcome at the site of the skull lesion was acquired without complications or recurrence.
Synchronous multicentric osteosarcoma (SMOS) is characterized by simultaneous multicentricity of intraosseous lesion without visceral involvement, such as lung metastasis [1]. SMOS is a rare disease that accounts for approximately 1% of osteosarcomas, and had been reported to have a poor survival because of the difficulty of treating all lesions [2–7]. Domenico et al. reported that the 2-year overall survival of SMOS was approximately 30%, and the 5-year overall survival was < 10% [2]. There have been a few reports regarding the long-term survival of SMOS patients [2, 5, 6, 8]. No standard treatment algorithm has been previously reported because of its rarity, and most cases were treated according to the general guidelines for the management of osteosarcoma.
Osteosarcoma at the skull region is also rare, and acounting for only 6 to 8% of osteosarcomas [3, 9]. The mortality was reported to be about 50% at 5 years [9, 10]. The poor outcome was reported to be due to the difficulty of surgical treatment with a wide excision due to the complicated anatomy of the skull [10–12]. In most cases, synthetics or no reconstruction was selected after the excision of skull lesion. However, complications such as failure of synthetics, or infection, and local relapse of skull osteosarcoma often leads to severe functional disorders due to brain damage, such as extremity paralysis and meningitis, although metastases to the lung and brain are less frequent than extremity osteosarcoma [7, 13, 14].
Chemotherapy is very important for supporting the surgical outcome of tumor patients. In a few previous reports, long survivors of SMOS also had necessarily received chemotherapy, and more than 90% necrosis of the tumor cells in the specimen excised from the patients had been observed histologically [5, 7, 8]. Aggressive surgery with a clear margin for all lesions of SMOS is also essential for a good oncological outcome [5, 7, 8].Thus, planning of an appropriate strategy for the treatment of SMOS, which combines chemotherapy and surgery, is essential for obtaining a good clinical outcome (Fig. 1).Fig. 1 Our treatment strategy for synchronous multicentric osteosarcoma (SMOS)
We herein report an 18-year-old girl with multicentric synchronous osteosarcoma, including a skull lesion, and describe the clinical findings and treatment outcome for chemotherapy, two-stage tumor excision for all lesions. Our study was approved by the ethics committee of Kanazawa University Hospital (Institutional Review Board (IRB) number 2019–61(3094)) in compliance with the guidelines of the 1975 Declaration of Helsinki. Written informed consent was provided by the patient to obtain her case details and any accompanying images published.
Case presentation
An 18-year-old woman was referred to our department with a major complaint of a pain and swelling around the left distal femur. The symptom had been increasing for the past 6 months. She consulted a local doctor because her symptoms had not improved over time. Neither trauma nor injury was reported. Her previous history was also unremarkable, and no family history was found. A physical examination revealed swelling around her left distal femur and tenderness upon palpation. Neither ballottement of the left knee joint nor an evident soft tissue mass were observed. Laboratory tests revealed a threefold higher alkali-phosphatase level than the upper limit, but no other abnormal data, including the lactate dehydrogenase level and inflammation reaction, was found. A bone sclerotic lesion with periosteal reaction on the distal femur was found on X-ray (Fig. 2a, b). Computed tomogram (CT) of the left distal femur revealed a sclerotic and lytic lesion causing partial cortical destruction with soft tissue extension to the medial part of the surrounding muscles. No distant metastasis, including to the lung and regional lymph nodes, were observed on chest or abdominal CT. Magnetic resonance imaging (MRI) showed an intraosseous lesion combined with an unclear circumscribed extraosseous mass, which was hypointense on T1-weighted (Fig. 2c) and hyperintense on T2-weighted images. Unevenly contrasted lesion was observed on enhanced MRI (Fig. 2d). An open biopsy for the left distal femoral lesion was performed. Proliferation of pleomorphic spindle cells with nuclear atypia and brisk mitosis, producing a large amount of lace-like osteoid, were observed (Fig. 2e). A systemic Technetium-99 m scintigraphy (bone scan) (Fig. 3a) revealed other bone lesions of the left occipital bone (Fig. 3b) and right proximal humerus (Fig. 3c), in addition to the left distal femoral lesion (Fig. 3d), although no evident physical findings on either the right proximal humerus or left occipital bone were observed. However, a relatively strong uptake was observed at all three lesions. Thallium scintigram also revealed the strong accumulation of tracers only on the three bone lesions. A close examination by MRI revealed the enhancement of right proximal humeral bone lesion and left occipital bone lesion (Fig. 3e, f), the same as the left distal femoral lesion (Fig. 3g). Based on the histological findings, multiple bone lesions, and absence of visceral lesion, the clinical diagnosis of synchronous multicentric osteosarcoma (SMOS) was made. There is much debate in the previous studies as to whether it represents multiple primary tumors or metastatic disease. However, the case for multiple primary tumors was favored, because there was no obvious route for spread if the lungs were tumor-free, which was thought to rule out hematogenous metastasis. The prognosis of SMOS is generally considered to be poor according to the findings of previous studies [2–7].Fig. 2 Radiological and pathological findings of a bone lesion at the left distal femur. a, b Preoperative roentgenogram on the anteroposterior view (a), and the lateral view (b). c Intraosseous lesion combined with extraosseous lesion on MRI was observed, which was hypointense signal on T1 weighted images, and hyperintense signal on T2 weighted images. d Enhanced MRI revealed unevenly contrasted lesion on axial images. e Proliferation of pleomorphic spindle cells with nuclear atypia and brisk mitosis, producing a large amount of lace-like osteoid, were observed. White scale bar shows 100 µm
Fig. 3 Systemic bone scan and MRI findings before neoadjuvant chemotherapy. a–c Bone scan revealed uptake for the following three location (a); left occipital bone (b), right proximal humerus (c), and left distal femur (d). e The left occipital lesion on axial enhanced MRI, and a white arrow shows the intracortical lesion. f The right proximal humeral lesion on coronal enhanced MRI. g The left distal femoral lesion on coronal enhanced MRI
She underwent five courses of neoadjuvant chemotherapy with a regimen of doxorubicin and cisplatin, which was the same as the standard regimen for the treatment of osteosarcoma. The dose of doxorubicin was 60 mg/m2, and that of cisplatin was 120 mg/m2. The chemotherapy was performed every three weeks. After the completion of neoadjuvant chemotherapy, the uptake of all lesions on the bone scan diminished (Fig. 4a–d), and the enhancement of all lesions on MRI decreased (Fig. 4e–g). The accumulation of tracers on thallium scintigram also decreased. The chemotherapy was observed to be highly effective based on the radiological findings. The alkali-phosphatase level dramatically decreased and become normal in laboratory tests.Fig. 4 Systemic bone scan and MRI findings after five courses of neoadjuvant chemotherapy. a The uptake of all lesions on the bone scan was diminished. b Occipital bone lesion. c Right proximal humeral lesion. d Left distal femoral lesion. e The left occipital lesion had slightly shrunk in size on axial enhanced MRI (a white arrow shows the intracortical lesion.). f The enhancement was drastically decreased on coronal MRI of the right proximal humeral lesion. g The size and enhancement was decreased on coronal MRI of the distal femur
Surgical treatment of wide excision for the primary lesion of the left distal femur and reconstruction with megaprosthesis was planned at 4 months after the diagnosis. The distal femoral lesion was widely excised with extraosseous lesion and biopsy tract, preserving popliteal artery, veins and sciatic nerve (Fig. 5a). The bone was cut at 3 cm proximal from the edge of the bone lesion. A portion of the vastus medialis and intermedius were excised along with the tumor. The iodine-coated tumor prosthesis [15–17] was used for reconstruction (Fig. 5b, c). The pathological findings for the excised specimen revealed total necrosis of the lesion (Fig. 5d), and free surgical margins for both the bone and soft tissue lesions of the left distal femur.Fig. 5 Intraoperative photos, the postoperative roentgenogram, and the histological findings of the retracted specimen. a Wide excision of the left distal femoral lesion was performed. b Reconstruction using iodine-coated tumor prosthesis was performed. c Postoperative roentgenogram. d. Histological findings revealed the total necrosis of tumor cells of the retracted specimen tissue of the distal femur. White scale bar shows 100 µm
Since physical recovery from the primary surgery and wound healing were observed, adjuvant chemotherapy was resumed at seventeen days postoperatively for the residual lesions of the humerus and occipital bone. The regimen for an adjuvant chemotherapy was the same as a neoadjuvant chemotherapy. A mildly decreased cardiac function was observed on echocardiogram after the completion of the first course of adjuvant chemotherapy, and chemotherapy with another regimen of high-dose methotrexate (10 g/m2) and vincristine (2 mg/body) was performed for the second course of adjuvant chemotherapy. The improvement of cardiac function was confirmed, and the doxorubicin (60 mg/m2) and cisplatin (96 mg/m2, 80% dose of standard regimen) were given again for the third course of adjuvant chemotherapy. A total of eight courses of chemotherapy were completed, including three courses of adjuvant chemotherapy. The total dose of doxorubicin and cisplatin was 420 mg/m2 and 816 mg/m2, respectively. The humeral lesion had almost completely disappeared radiologically, and the occipital lesion was only slightly visible on images. Both the alkali-phosphatase level and the lactate dehydrogenase level remained normal in laboratory tests.
Tumor excision of both the humeral lesion and the occipital lesion, and reconstruction using a frozen autograft, rather than a tumor prosthesis or synthetics, was planned at 6 months after the diagnosis, because a histological analysis demonstrated that chemotherapy showed good efficacy in the treatment of the primary lesion. For the humeral lesion, the tumor location was identified using a fluoroscopy, based on preoperative MRI findings. For the skull lesion, the tumor location was identified with the assistance of a navigation system. At first, tumor excision for the occipital lesion was performed with a margin of at least 2 cm (Fig. 6a), and the excised bone was treated with liquid nitrogen for 20 min (Fig. 6b). The frozen autograft was dissolved at room temperature for 15 min, and washed by 0.3% iodine saline and distilled water (Fig. 6c). The autograft was returned to the original position with plate fixation (Fig. 6d). Then, hemicortical excision for the right proximal humeral lesion was performed with a margin of at least 2 cm, preserving axillary nerve, and then the excised bone was treated with liquid nitrogen for 20 min (Fig. 7a). The frozen autograft was dissolved at room temperature for 15 min, and washed by 0.3% iodine saline and distilled water (Fig. 7b). The autograft was returned to the original position with screw fixation (Fig. 7c, d).Fig. 6 Surgical treatment for a skull lesion and the postoperative roentgenogram. a Skull lesion was excised with wide margin. b, c The excised bone was treated with liquid nitrogen for twenty minutes (b), and dissolved at room temperature for 15 min, and then was washed with 0.3% iodine saline and distilled water (c). d The frozen bone was returned to the original position and plate fixation was performed. Postoperative roentgenogram was shown
Fig. 7 Surgical treatment for a proximal humeral lesion and the postoperative roentgenogram. a, b The retracted hemicortical bone of the proximal humeral lesion was treated with liquid nitrogen (a) and was dissolved at room temperature, and washed by 0.3% iodine saline and distilled water (b). c The frozen autograft was returned to the original position with screw fixation, preserving axillary nerve. d Postoperative roentgenogram was shown
Further chemotherapy was not administered after the second surgery because the adverse events due to chemotherapy, such as a myelosuppression and a mildly-decreased cardiac function, were observed. She was discharged from the hospital after the recovery from the surgery was confirmed. She was prudently observed under active surveillance, and underwent close follow-up examinations in an outpatient clinic every 3 or 4 months after discharge.
At 68 months’ follow-up after the detection of SMOS, a disease-free condition with neither local recurrence nor metastasis was obtained, and bone union for the humerus and skull lesion had also been achieved on images (Fig. 8a–c). The patient’s cardiac function was normal on an echocardiogram, and no other adverse events was observed at the last follow-up. Both the alkali-phosphatase level and the lactate dehydrogenase level remained normal in laboratory tests. An excellent function for both the upper extremity (30/30 points) and lower extremity (30/30 points) according to the International Society of Limb Salvage (ISOLS) score had been acquired. No neurological deficit was observed.Fig. 8 The postoperative roentgenogram at the latest follow-up. a Bone union at the osteotomy site for proximal humeral lesion, was completely achieved. b Bone union at the osteotomy site for skull lesion, was achieved. c Postoperative complications were not observed after tumor prosthesis reconstruction of the left distal femur
Discussion and conclusions
Multicentric osteosarcoma accounts for only approximately 1% of all osteosarcomas, and is divided into two types: synchronous and metachronous type [2, 3]. Domenico et al. reported that the median survival in patients with metachronous multicentric osteosarcoma (n = 34) was 43 months, while the median survival in those with SMOS (n = 22) was 14 months [2]. A particular poor prognosis was reported for SMOS patients, and there have been few previous report concerning long-term survivors of SMOS [2, 5, 6, 8]. To our knowledge, the survival of SMOS, including cases with skull lesions, tends to be extremely short (4–18 months) [7, 13, 14]. There were three main reasons for the successful outcome of the present case. First, the early correct identification of tumors at all locations could be made using a bone scan. Second, multiple chemotherapeutic agents, including doxorubicin and cisplatin, would contribute to the good response of the tumors, as histological examinations revealed complete necrosis in the excised specimen of the distal femur in our case. Third, surgical treatment for the other lesions could be performed with the reference to the results of neoadjuvant chemotherapy, which showed histological efficacy.
Our treatment strategy for SMOS is basically the same as that for osteosarcoma (Fig. 1). To identify precisely all of the locations of SMOS lesions before treatment is important for observing the treatment course. The good efficacy of chemotherapy is essential for obtaining good outcome. After the completion of neoadjuvant chemotherapy, a radiological assessment is performed to determine the efficacy of chemotherapy. If the course is assumed to have poor efficacy based on radiological assessment, the chemotherapy regimen should be changed. When good efficacy is radiologically confirmed after five or six courses of neoadjuvant chemotherapy, subsequent surgical excision of the primary lesion, with a wide margin, is planned and performed. Then, based on the pathological assessment of the efficacy of neoadjuvant chemotherapy in the excised specimen, an adjuvant chemotherapy regimen is selected. If the neoadjuvant chemotherapy shows good histological efficacy, three or four courses of adjuvant chemotherapy with the same regimen are performed, and an appropriate surgical treatment for the residual lesions is planned, including biological reconstruction, which can retain a normal function and achieve a good cosmetic outcome. If the histological efficacy of neoadjuvant chemotherapy is poor, the regimen should be changed for adjuvant chemotherapy, and surgical treatment with as wide an excision as possible and reconstruction using tumor prosthesis or synthetics, should be planned after several courses of chemotherapy.
When the surgical margins for all lesions are histologically clear, the primary treatment is considered to be over, or additional adjuvant chemotherapy may be considered if the patients can afford to undergo these treatments, with careful observation for adverse events. After completion of the primary treatment, the postoperative state will be prudently observed at follow-up in an outpatient clinic, with examinations every three or four months until at least five years at least after surgery.
Osteosarcoma commonly presents with lung metastases, and a standard examination includes chest CT. Additional examinations are not regularly performed except for when a patient presents symptoms, such as pain or swelling. Patients with skull osteosarcoma often present with headache, motor impairment, or cranial nerve palsies, depending on the tumor site [9–12]. However, in our case, no symptoms at the left occipital region or the right proximal humerus were observed, and it was not until a bone scan was performed that multicentric bone lesions were noted. A bone scan can assess the accumulation of tracers, thereby reflecting remodeling of the affected bone, and a systemic bone scan is useful as a regular examination for the early detection of other bone lesions [18], even if no symptoms are observed. Metachronous type multicentric osteosarcoma, or bone metastases of SMOS during the treatment course, might be due to tiny lesions with symptoms mild enough to be overlooked at the first visit. Therefore, the early correct identification of tumors at all locations is important when considering the strategy for SMOS.
Chemotherapy is very important for supporting the surgical outcome of tumor patients. In a few previous reports, long survivors of SMOS had necessarily received chemotherapy, and more than 90% necrosis of the tumor cells in the specimen excised from the patients had been observed histologically due to the efficacy of chemotherapy, which was assessed according to the Rosen and Huvos classification [5, 7, 8]. One patient received chemotherapy with a regimen of doxorubicin, cisplatin, ifosfamide, and methotrexate, and another received chemotherapy with a regimen of doxorubicin, cisplatin, and methotrexate [5, 7], while yet another patient received chemotherapy with a regimen of methotrexate, ifosfamide, bleomycin, doxorubicin, and cisplatin [8]. The present patient received chemotherapy with a regimen of doxorubicin, cisplatin, methotrexate, and etoposide. The two drugs, namely doxorubicin and cisplatin, have been commonly used for long survivors in previous SMOS patients including our case. Multiple chemotherapeutic agents including the above-mentioned two drugs might contribute to the good outcome observed in SMOS patients, although no definitive conclusions could be made due to the small sample population.
The histological confirmation of the efficacy of neoadjuvant chemotherapy in the whole section of the distal femoral lesion, especially the bone lesion, was necessary for determining whether the same regimen chemotherapy for the other two lesions should be continued or not. When a frozen autograft is used for reconstruction after wide excision, the efficacy of chemotherapy on excised soft tissue lesion can be evaluated histologically; however, the efficacy is not evaluated in bone lesion. Frozen autograft is available for almost all bone tumors and has been reported to be associated with many advantages, including preservation of the bone stock, retention of the joint function in cases in which the epiphysis is preserved, and the fact that the graft can be a perfect fit for the excised bone defect. However, the indications need to be well considered in each case. In cases involving multiple bone lesions, such as the present case, the selection of an appropriate treatment strategy is essential, and we referred to the results of a histological assessment of the effects of neoadjuvant chemotherapy on the primary bone lesion when considering treatment for residual lesions. In addition, the epiphysis could not be preserved in the present case because the lesion extended to the epiphysis. Thus, a tumor prosthesis was selected for reconstruction after wide excision of the distal femoral primary lesion.
Hemicortical excision with a clear margin and reconstruction using a frozen autograft treated with liquid nitrogen is reportedly a reliable technique for retaining a good joint function through minimally resection of the tumor and preservation of as much of the normal tissue around the resected tumor as possible [19–25]. This procedure was applied in our case because the neoadjuvant chemotherapy showed good histological efficacy for the primary lesion. In our case, an excellent right shoulder joint function was restored, and a bone union was achieved, and no recurrence or postoperative complications were observed (Fig. 8a).
Complete excision with a wide margin was associated with an improved survival, and local recurrence after surgery of the skull tumor is the major cause of treatment failure and decreases the survival rate. However, the anatomy of the head is complicated, and complete resection of the skull lesion is often difficult to achieve [10–12]. Synthetic or plate reconstruction after tumor excision is generally performed to protect the brain and fill bone defects, but there are sometimes cosmetic issues, and the complications, such as infection, or motor impairment due to brain damage, cannot be denied. Tumor excision of skull lesions and reconstruction using a frozen autograft treated with liquid nitrogen have been rarely reported [26–28]. However, this cryotherapy treatment and orthotopic transplantation method not only eliminates the tumor cells, but it also provides for bone filling which perfectly matches the same size as the bone defect, while also reducing the incidence rates of complications [19, 20, 26–28]. The good histological efficacy of neoadjuvant chemotherapy for the primary lesion was observed in our case; thus, reconstruction using a frozen autograft treated with liquid nitrogen after tumor excision with a clear margin, was applied. After surgery, a bone union was achieved without postoperative complications or local recurrence (Fig. 8b).
In conclusion, SMOS including a skull lesion is rare; nevertheless, the early, correct diagnosis, and proper strategy of chemotherapy and surgery for all lesions, are essential for ensuring a good clinical outcome. Reconstruction using a frozen autograft treated with liquid nitrogen was found to be feasible for bone lesions, including a skull lesion, even in a case of multicentric osteosarcoma, when the histological efficacy of neoadjuvant chemotherapy for the primary lesion was good. Our patient achieved an excellent right shoulder function, and a good cosmetic and functional outcome without any complications by reconstruction by following reconstruction using a frozen autograft. In addition, clinically disease-free survival of over five years after the diagnosis can be obtained, although further follow-up with regular close examinations will be required, as the survival associated with this disease is commonly poor.
Abbreviations
SMOSSynchronous multicentric osteosarcoma
CTComputed tomogram
MRIMagnetic resonance imaging
ISOLSInternational society of limb salvage
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Acknowledgements
We thank the past and the present other members of our department for their work.
Authors’ contributions
T.H., Y.N., H.K., and A.Yos. conceived and designed the study. N.T. performed histological examination of all the specimen. A.Yos. carried out data acquisition. H.T., A.K.,T.Y., Y.H., M.Se., and A.Yoh. provided assistance for data acquisition. T.H., Y.N., H.K., T.A., M.Sh. and I.K. managed the patients for the appropriate treatment and observed them at the follow-up outpatient clinic after treatment completion. T.H., Y.N., H.K., and A.Yos. contributed to the analysis and interpretation of laboratory data and critical appraisal. A.Yos. analyzed all the patient's data and wrote the manuscript. All authors read and approved the final manuscript.
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Availability of data and materials
All data generated or analyzed during the present study are included in this published article.
Ethics approval and consent to participate
The study was approved by the Ethical Institutional Review Board of the Kanazawa University Hospital (2019-061 (3094)), and written informed consent was obtained from all study participants.
Consent for publication
The written consent for publication of the manuscript, including personal and clinical details, and any identifying images, from the patient and her parents was obtained by the Kanazawa University Hospital.
Competing interests
The authors declare no conflicts of interest in association with the present study. | EVERY THREE WEEKS | DrugDosageText | CC BY | 33482784 | 19,052,054 | 2021-01-22 |
What was the dosage of drug 'DOXORUBICIN'? | Reconstruction using a frozen autograft for a skull and humeral lesion of synchronous multicentric osteosarcoma after undergoing successful neoadjuvant chemotherapy: a case report and review of the literature.
BACKGROUND
Synchronous multicentric osteosarcoma (SMOS) is a rare disease characterized by simultaneous multicentricity of intraosseous osteosarcoma without visceral involvement. SMOS, including a skull lesion, which occurs relatively rarely, and reconstruction using a frozen autograft after the excision of a lesion of SMOS has been infrequently reported previously.
METHODS
We report an 18-year-old girl with SMOS, with lesions located in the left distal femur, right proximal humerus, and left occipital bone. Her major complaint was pain and swelling around the left knee joint. Asymptomatic lesions of the humerus and skull bone were detected on a systemic bone scan. No visceral organ metastasis was observed. A biopsy of the distal femoral lesion revealed osteosarcoma. Based on the histological findings, multiple bone lesions, and absence of visceral lesion, the clinical diagnosis of SMOS was made. After five courses of neoadjuvant chemotherapy with a regimen of doxorubicin and cisplatin, reconstruction using a tumor prosthesis following wide excision of the left distal femur was performed, and total necrosis was histologically observed in the retracted specimen. Following three cycles of adjuvant chemotherapy, tumor excision and reconstruction with a frozen autograft treated with liquid nitrogen was conducted for both lesions of the humerus and skull, rather than tumor prosthesis or synthetics, in order to retain a normal shoulder function, and to obtain a good cosmetic and functional outcome after treatment of the skull lesion. Further adjuvant chemotherapy could not be administered after the completion of the surgical treatment for all lesions because the adverse events due to chemotherapy were observed. At over 5 years after the diagnosis, she remains clinically disease-free.
CONCLUSIONS
An early correct diagnosis, the proper management of chemotherapy, and surgical treatment for all lesions are essential for achieving a good clinical outcome, even in SMOS including a skull lesion. By performing reconstruction using a frozen autograft for a proximal humeral lesion and a skull lesion after confirming the good histological efficacy of neoadjuvant chemotherapy for the primary lesion, the excellent function of the shoulder joint and a good cosmetic outcome at the site of the skull lesion was acquired without complications or recurrence.
Synchronous multicentric osteosarcoma (SMOS) is characterized by simultaneous multicentricity of intraosseous lesion without visceral involvement, such as lung metastasis [1]. SMOS is a rare disease that accounts for approximately 1% of osteosarcomas, and had been reported to have a poor survival because of the difficulty of treating all lesions [2–7]. Domenico et al. reported that the 2-year overall survival of SMOS was approximately 30%, and the 5-year overall survival was < 10% [2]. There have been a few reports regarding the long-term survival of SMOS patients [2, 5, 6, 8]. No standard treatment algorithm has been previously reported because of its rarity, and most cases were treated according to the general guidelines for the management of osteosarcoma.
Osteosarcoma at the skull region is also rare, and acounting for only 6 to 8% of osteosarcomas [3, 9]. The mortality was reported to be about 50% at 5 years [9, 10]. The poor outcome was reported to be due to the difficulty of surgical treatment with a wide excision due to the complicated anatomy of the skull [10–12]. In most cases, synthetics or no reconstruction was selected after the excision of skull lesion. However, complications such as failure of synthetics, or infection, and local relapse of skull osteosarcoma often leads to severe functional disorders due to brain damage, such as extremity paralysis and meningitis, although metastases to the lung and brain are less frequent than extremity osteosarcoma [7, 13, 14].
Chemotherapy is very important for supporting the surgical outcome of tumor patients. In a few previous reports, long survivors of SMOS also had necessarily received chemotherapy, and more than 90% necrosis of the tumor cells in the specimen excised from the patients had been observed histologically [5, 7, 8]. Aggressive surgery with a clear margin for all lesions of SMOS is also essential for a good oncological outcome [5, 7, 8].Thus, planning of an appropriate strategy for the treatment of SMOS, which combines chemotherapy and surgery, is essential for obtaining a good clinical outcome (Fig. 1).Fig. 1 Our treatment strategy for synchronous multicentric osteosarcoma (SMOS)
We herein report an 18-year-old girl with multicentric synchronous osteosarcoma, including a skull lesion, and describe the clinical findings and treatment outcome for chemotherapy, two-stage tumor excision for all lesions. Our study was approved by the ethics committee of Kanazawa University Hospital (Institutional Review Board (IRB) number 2019–61(3094)) in compliance with the guidelines of the 1975 Declaration of Helsinki. Written informed consent was provided by the patient to obtain her case details and any accompanying images published.
Case presentation
An 18-year-old woman was referred to our department with a major complaint of a pain and swelling around the left distal femur. The symptom had been increasing for the past 6 months. She consulted a local doctor because her symptoms had not improved over time. Neither trauma nor injury was reported. Her previous history was also unremarkable, and no family history was found. A physical examination revealed swelling around her left distal femur and tenderness upon palpation. Neither ballottement of the left knee joint nor an evident soft tissue mass were observed. Laboratory tests revealed a threefold higher alkali-phosphatase level than the upper limit, but no other abnormal data, including the lactate dehydrogenase level and inflammation reaction, was found. A bone sclerotic lesion with periosteal reaction on the distal femur was found on X-ray (Fig. 2a, b). Computed tomogram (CT) of the left distal femur revealed a sclerotic and lytic lesion causing partial cortical destruction with soft tissue extension to the medial part of the surrounding muscles. No distant metastasis, including to the lung and regional lymph nodes, were observed on chest or abdominal CT. Magnetic resonance imaging (MRI) showed an intraosseous lesion combined with an unclear circumscribed extraosseous mass, which was hypointense on T1-weighted (Fig. 2c) and hyperintense on T2-weighted images. Unevenly contrasted lesion was observed on enhanced MRI (Fig. 2d). An open biopsy for the left distal femoral lesion was performed. Proliferation of pleomorphic spindle cells with nuclear atypia and brisk mitosis, producing a large amount of lace-like osteoid, were observed (Fig. 2e). A systemic Technetium-99 m scintigraphy (bone scan) (Fig. 3a) revealed other bone lesions of the left occipital bone (Fig. 3b) and right proximal humerus (Fig. 3c), in addition to the left distal femoral lesion (Fig. 3d), although no evident physical findings on either the right proximal humerus or left occipital bone were observed. However, a relatively strong uptake was observed at all three lesions. Thallium scintigram also revealed the strong accumulation of tracers only on the three bone lesions. A close examination by MRI revealed the enhancement of right proximal humeral bone lesion and left occipital bone lesion (Fig. 3e, f), the same as the left distal femoral lesion (Fig. 3g). Based on the histological findings, multiple bone lesions, and absence of visceral lesion, the clinical diagnosis of synchronous multicentric osteosarcoma (SMOS) was made. There is much debate in the previous studies as to whether it represents multiple primary tumors or metastatic disease. However, the case for multiple primary tumors was favored, because there was no obvious route for spread if the lungs were tumor-free, which was thought to rule out hematogenous metastasis. The prognosis of SMOS is generally considered to be poor according to the findings of previous studies [2–7].Fig. 2 Radiological and pathological findings of a bone lesion at the left distal femur. a, b Preoperative roentgenogram on the anteroposterior view (a), and the lateral view (b). c Intraosseous lesion combined with extraosseous lesion on MRI was observed, which was hypointense signal on T1 weighted images, and hyperintense signal on T2 weighted images. d Enhanced MRI revealed unevenly contrasted lesion on axial images. e Proliferation of pleomorphic spindle cells with nuclear atypia and brisk mitosis, producing a large amount of lace-like osteoid, were observed. White scale bar shows 100 µm
Fig. 3 Systemic bone scan and MRI findings before neoadjuvant chemotherapy. a–c Bone scan revealed uptake for the following three location (a); left occipital bone (b), right proximal humerus (c), and left distal femur (d). e The left occipital lesion on axial enhanced MRI, and a white arrow shows the intracortical lesion. f The right proximal humeral lesion on coronal enhanced MRI. g The left distal femoral lesion on coronal enhanced MRI
She underwent five courses of neoadjuvant chemotherapy with a regimen of doxorubicin and cisplatin, which was the same as the standard regimen for the treatment of osteosarcoma. The dose of doxorubicin was 60 mg/m2, and that of cisplatin was 120 mg/m2. The chemotherapy was performed every three weeks. After the completion of neoadjuvant chemotherapy, the uptake of all lesions on the bone scan diminished (Fig. 4a–d), and the enhancement of all lesions on MRI decreased (Fig. 4e–g). The accumulation of tracers on thallium scintigram also decreased. The chemotherapy was observed to be highly effective based on the radiological findings. The alkali-phosphatase level dramatically decreased and become normal in laboratory tests.Fig. 4 Systemic bone scan and MRI findings after five courses of neoadjuvant chemotherapy. a The uptake of all lesions on the bone scan was diminished. b Occipital bone lesion. c Right proximal humeral lesion. d Left distal femoral lesion. e The left occipital lesion had slightly shrunk in size on axial enhanced MRI (a white arrow shows the intracortical lesion.). f The enhancement was drastically decreased on coronal MRI of the right proximal humeral lesion. g The size and enhancement was decreased on coronal MRI of the distal femur
Surgical treatment of wide excision for the primary lesion of the left distal femur and reconstruction with megaprosthesis was planned at 4 months after the diagnosis. The distal femoral lesion was widely excised with extraosseous lesion and biopsy tract, preserving popliteal artery, veins and sciatic nerve (Fig. 5a). The bone was cut at 3 cm proximal from the edge of the bone lesion. A portion of the vastus medialis and intermedius were excised along with the tumor. The iodine-coated tumor prosthesis [15–17] was used for reconstruction (Fig. 5b, c). The pathological findings for the excised specimen revealed total necrosis of the lesion (Fig. 5d), and free surgical margins for both the bone and soft tissue lesions of the left distal femur.Fig. 5 Intraoperative photos, the postoperative roentgenogram, and the histological findings of the retracted specimen. a Wide excision of the left distal femoral lesion was performed. b Reconstruction using iodine-coated tumor prosthesis was performed. c Postoperative roentgenogram. d. Histological findings revealed the total necrosis of tumor cells of the retracted specimen tissue of the distal femur. White scale bar shows 100 µm
Since physical recovery from the primary surgery and wound healing were observed, adjuvant chemotherapy was resumed at seventeen days postoperatively for the residual lesions of the humerus and occipital bone. The regimen for an adjuvant chemotherapy was the same as a neoadjuvant chemotherapy. A mildly decreased cardiac function was observed on echocardiogram after the completion of the first course of adjuvant chemotherapy, and chemotherapy with another regimen of high-dose methotrexate (10 g/m2) and vincristine (2 mg/body) was performed for the second course of adjuvant chemotherapy. The improvement of cardiac function was confirmed, and the doxorubicin (60 mg/m2) and cisplatin (96 mg/m2, 80% dose of standard regimen) were given again for the third course of adjuvant chemotherapy. A total of eight courses of chemotherapy were completed, including three courses of adjuvant chemotherapy. The total dose of doxorubicin and cisplatin was 420 mg/m2 and 816 mg/m2, respectively. The humeral lesion had almost completely disappeared radiologically, and the occipital lesion was only slightly visible on images. Both the alkali-phosphatase level and the lactate dehydrogenase level remained normal in laboratory tests.
Tumor excision of both the humeral lesion and the occipital lesion, and reconstruction using a frozen autograft, rather than a tumor prosthesis or synthetics, was planned at 6 months after the diagnosis, because a histological analysis demonstrated that chemotherapy showed good efficacy in the treatment of the primary lesion. For the humeral lesion, the tumor location was identified using a fluoroscopy, based on preoperative MRI findings. For the skull lesion, the tumor location was identified with the assistance of a navigation system. At first, tumor excision for the occipital lesion was performed with a margin of at least 2 cm (Fig. 6a), and the excised bone was treated with liquid nitrogen for 20 min (Fig. 6b). The frozen autograft was dissolved at room temperature for 15 min, and washed by 0.3% iodine saline and distilled water (Fig. 6c). The autograft was returned to the original position with plate fixation (Fig. 6d). Then, hemicortical excision for the right proximal humeral lesion was performed with a margin of at least 2 cm, preserving axillary nerve, and then the excised bone was treated with liquid nitrogen for 20 min (Fig. 7a). The frozen autograft was dissolved at room temperature for 15 min, and washed by 0.3% iodine saline and distilled water (Fig. 7b). The autograft was returned to the original position with screw fixation (Fig. 7c, d).Fig. 6 Surgical treatment for a skull lesion and the postoperative roentgenogram. a Skull lesion was excised with wide margin. b, c The excised bone was treated with liquid nitrogen for twenty minutes (b), and dissolved at room temperature for 15 min, and then was washed with 0.3% iodine saline and distilled water (c). d The frozen bone was returned to the original position and plate fixation was performed. Postoperative roentgenogram was shown
Fig. 7 Surgical treatment for a proximal humeral lesion and the postoperative roentgenogram. a, b The retracted hemicortical bone of the proximal humeral lesion was treated with liquid nitrogen (a) and was dissolved at room temperature, and washed by 0.3% iodine saline and distilled water (b). c The frozen autograft was returned to the original position with screw fixation, preserving axillary nerve. d Postoperative roentgenogram was shown
Further chemotherapy was not administered after the second surgery because the adverse events due to chemotherapy, such as a myelosuppression and a mildly-decreased cardiac function, were observed. She was discharged from the hospital after the recovery from the surgery was confirmed. She was prudently observed under active surveillance, and underwent close follow-up examinations in an outpatient clinic every 3 or 4 months after discharge.
At 68 months’ follow-up after the detection of SMOS, a disease-free condition with neither local recurrence nor metastasis was obtained, and bone union for the humerus and skull lesion had also been achieved on images (Fig. 8a–c). The patient’s cardiac function was normal on an echocardiogram, and no other adverse events was observed at the last follow-up. Both the alkali-phosphatase level and the lactate dehydrogenase level remained normal in laboratory tests. An excellent function for both the upper extremity (30/30 points) and lower extremity (30/30 points) according to the International Society of Limb Salvage (ISOLS) score had been acquired. No neurological deficit was observed.Fig. 8 The postoperative roentgenogram at the latest follow-up. a Bone union at the osteotomy site for proximal humeral lesion, was completely achieved. b Bone union at the osteotomy site for skull lesion, was achieved. c Postoperative complications were not observed after tumor prosthesis reconstruction of the left distal femur
Discussion and conclusions
Multicentric osteosarcoma accounts for only approximately 1% of all osteosarcomas, and is divided into two types: synchronous and metachronous type [2, 3]. Domenico et al. reported that the median survival in patients with metachronous multicentric osteosarcoma (n = 34) was 43 months, while the median survival in those with SMOS (n = 22) was 14 months [2]. A particular poor prognosis was reported for SMOS patients, and there have been few previous report concerning long-term survivors of SMOS [2, 5, 6, 8]. To our knowledge, the survival of SMOS, including cases with skull lesions, tends to be extremely short (4–18 months) [7, 13, 14]. There were three main reasons for the successful outcome of the present case. First, the early correct identification of tumors at all locations could be made using a bone scan. Second, multiple chemotherapeutic agents, including doxorubicin and cisplatin, would contribute to the good response of the tumors, as histological examinations revealed complete necrosis in the excised specimen of the distal femur in our case. Third, surgical treatment for the other lesions could be performed with the reference to the results of neoadjuvant chemotherapy, which showed histological efficacy.
Our treatment strategy for SMOS is basically the same as that for osteosarcoma (Fig. 1). To identify precisely all of the locations of SMOS lesions before treatment is important for observing the treatment course. The good efficacy of chemotherapy is essential for obtaining good outcome. After the completion of neoadjuvant chemotherapy, a radiological assessment is performed to determine the efficacy of chemotherapy. If the course is assumed to have poor efficacy based on radiological assessment, the chemotherapy regimen should be changed. When good efficacy is radiologically confirmed after five or six courses of neoadjuvant chemotherapy, subsequent surgical excision of the primary lesion, with a wide margin, is planned and performed. Then, based on the pathological assessment of the efficacy of neoadjuvant chemotherapy in the excised specimen, an adjuvant chemotherapy regimen is selected. If the neoadjuvant chemotherapy shows good histological efficacy, three or four courses of adjuvant chemotherapy with the same regimen are performed, and an appropriate surgical treatment for the residual lesions is planned, including biological reconstruction, which can retain a normal function and achieve a good cosmetic outcome. If the histological efficacy of neoadjuvant chemotherapy is poor, the regimen should be changed for adjuvant chemotherapy, and surgical treatment with as wide an excision as possible and reconstruction using tumor prosthesis or synthetics, should be planned after several courses of chemotherapy.
When the surgical margins for all lesions are histologically clear, the primary treatment is considered to be over, or additional adjuvant chemotherapy may be considered if the patients can afford to undergo these treatments, with careful observation for adverse events. After completion of the primary treatment, the postoperative state will be prudently observed at follow-up in an outpatient clinic, with examinations every three or four months until at least five years at least after surgery.
Osteosarcoma commonly presents with lung metastases, and a standard examination includes chest CT. Additional examinations are not regularly performed except for when a patient presents symptoms, such as pain or swelling. Patients with skull osteosarcoma often present with headache, motor impairment, or cranial nerve palsies, depending on the tumor site [9–12]. However, in our case, no symptoms at the left occipital region or the right proximal humerus were observed, and it was not until a bone scan was performed that multicentric bone lesions were noted. A bone scan can assess the accumulation of tracers, thereby reflecting remodeling of the affected bone, and a systemic bone scan is useful as a regular examination for the early detection of other bone lesions [18], even if no symptoms are observed. Metachronous type multicentric osteosarcoma, or bone metastases of SMOS during the treatment course, might be due to tiny lesions with symptoms mild enough to be overlooked at the first visit. Therefore, the early correct identification of tumors at all locations is important when considering the strategy for SMOS.
Chemotherapy is very important for supporting the surgical outcome of tumor patients. In a few previous reports, long survivors of SMOS had necessarily received chemotherapy, and more than 90% necrosis of the tumor cells in the specimen excised from the patients had been observed histologically due to the efficacy of chemotherapy, which was assessed according to the Rosen and Huvos classification [5, 7, 8]. One patient received chemotherapy with a regimen of doxorubicin, cisplatin, ifosfamide, and methotrexate, and another received chemotherapy with a regimen of doxorubicin, cisplatin, and methotrexate [5, 7], while yet another patient received chemotherapy with a regimen of methotrexate, ifosfamide, bleomycin, doxorubicin, and cisplatin [8]. The present patient received chemotherapy with a regimen of doxorubicin, cisplatin, methotrexate, and etoposide. The two drugs, namely doxorubicin and cisplatin, have been commonly used for long survivors in previous SMOS patients including our case. Multiple chemotherapeutic agents including the above-mentioned two drugs might contribute to the good outcome observed in SMOS patients, although no definitive conclusions could be made due to the small sample population.
The histological confirmation of the efficacy of neoadjuvant chemotherapy in the whole section of the distal femoral lesion, especially the bone lesion, was necessary for determining whether the same regimen chemotherapy for the other two lesions should be continued or not. When a frozen autograft is used for reconstruction after wide excision, the efficacy of chemotherapy on excised soft tissue lesion can be evaluated histologically; however, the efficacy is not evaluated in bone lesion. Frozen autograft is available for almost all bone tumors and has been reported to be associated with many advantages, including preservation of the bone stock, retention of the joint function in cases in which the epiphysis is preserved, and the fact that the graft can be a perfect fit for the excised bone defect. However, the indications need to be well considered in each case. In cases involving multiple bone lesions, such as the present case, the selection of an appropriate treatment strategy is essential, and we referred to the results of a histological assessment of the effects of neoadjuvant chemotherapy on the primary bone lesion when considering treatment for residual lesions. In addition, the epiphysis could not be preserved in the present case because the lesion extended to the epiphysis. Thus, a tumor prosthesis was selected for reconstruction after wide excision of the distal femoral primary lesion.
Hemicortical excision with a clear margin and reconstruction using a frozen autograft treated with liquid nitrogen is reportedly a reliable technique for retaining a good joint function through minimally resection of the tumor and preservation of as much of the normal tissue around the resected tumor as possible [19–25]. This procedure was applied in our case because the neoadjuvant chemotherapy showed good histological efficacy for the primary lesion. In our case, an excellent right shoulder joint function was restored, and a bone union was achieved, and no recurrence or postoperative complications were observed (Fig. 8a).
Complete excision with a wide margin was associated with an improved survival, and local recurrence after surgery of the skull tumor is the major cause of treatment failure and decreases the survival rate. However, the anatomy of the head is complicated, and complete resection of the skull lesion is often difficult to achieve [10–12]. Synthetic or plate reconstruction after tumor excision is generally performed to protect the brain and fill bone defects, but there are sometimes cosmetic issues, and the complications, such as infection, or motor impairment due to brain damage, cannot be denied. Tumor excision of skull lesions and reconstruction using a frozen autograft treated with liquid nitrogen have been rarely reported [26–28]. However, this cryotherapy treatment and orthotopic transplantation method not only eliminates the tumor cells, but it also provides for bone filling which perfectly matches the same size as the bone defect, while also reducing the incidence rates of complications [19, 20, 26–28]. The good histological efficacy of neoadjuvant chemotherapy for the primary lesion was observed in our case; thus, reconstruction using a frozen autograft treated with liquid nitrogen after tumor excision with a clear margin, was applied. After surgery, a bone union was achieved without postoperative complications or local recurrence (Fig. 8b).
In conclusion, SMOS including a skull lesion is rare; nevertheless, the early, correct diagnosis, and proper strategy of chemotherapy and surgery for all lesions, are essential for ensuring a good clinical outcome. Reconstruction using a frozen autograft treated with liquid nitrogen was found to be feasible for bone lesions, including a skull lesion, even in a case of multicentric osteosarcoma, when the histological efficacy of neoadjuvant chemotherapy for the primary lesion was good. Our patient achieved an excellent right shoulder function, and a good cosmetic and functional outcome without any complications by reconstruction by following reconstruction using a frozen autograft. In addition, clinically disease-free survival of over five years after the diagnosis can be obtained, although further follow-up with regular close examinations will be required, as the survival associated with this disease is commonly poor.
Abbreviations
SMOSSynchronous multicentric osteosarcoma
CTComputed tomogram
MRIMagnetic resonance imaging
ISOLSInternational society of limb salvage
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Acknowledgements
We thank the past and the present other members of our department for their work.
Authors’ contributions
T.H., Y.N., H.K., and A.Yos. conceived and designed the study. N.T. performed histological examination of all the specimen. A.Yos. carried out data acquisition. H.T., A.K.,T.Y., Y.H., M.Se., and A.Yoh. provided assistance for data acquisition. T.H., Y.N., H.K., T.A., M.Sh. and I.K. managed the patients for the appropriate treatment and observed them at the follow-up outpatient clinic after treatment completion. T.H., Y.N., H.K., and A.Yos. contributed to the analysis and interpretation of laboratory data and critical appraisal. A.Yos. analyzed all the patient's data and wrote the manuscript. All authors read and approved the final manuscript.
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Availability of data and materials
All data generated or analyzed during the present study are included in this published article.
Ethics approval and consent to participate
The study was approved by the Ethical Institutional Review Board of the Kanazawa University Hospital (2019-061 (3094)), and written informed consent was obtained from all study participants.
Consent for publication
The written consent for publication of the manuscript, including personal and clinical details, and any identifying images, from the patient and her parents was obtained by the Kanazawa University Hospital.
Competing interests
The authors declare no conflicts of interest in association with the present study. | EVERY THREE WEEKS | DrugDosageText | CC BY | 33482784 | 19,052,054 | 2021-01-22 |
What was the dosage of drug 'ETOPOSIDE'? | Reconstruction using a frozen autograft for a skull and humeral lesion of synchronous multicentric osteosarcoma after undergoing successful neoadjuvant chemotherapy: a case report and review of the literature.
BACKGROUND
Synchronous multicentric osteosarcoma (SMOS) is a rare disease characterized by simultaneous multicentricity of intraosseous osteosarcoma without visceral involvement. SMOS, including a skull lesion, which occurs relatively rarely, and reconstruction using a frozen autograft after the excision of a lesion of SMOS has been infrequently reported previously.
METHODS
We report an 18-year-old girl with SMOS, with lesions located in the left distal femur, right proximal humerus, and left occipital bone. Her major complaint was pain and swelling around the left knee joint. Asymptomatic lesions of the humerus and skull bone were detected on a systemic bone scan. No visceral organ metastasis was observed. A biopsy of the distal femoral lesion revealed osteosarcoma. Based on the histological findings, multiple bone lesions, and absence of visceral lesion, the clinical diagnosis of SMOS was made. After five courses of neoadjuvant chemotherapy with a regimen of doxorubicin and cisplatin, reconstruction using a tumor prosthesis following wide excision of the left distal femur was performed, and total necrosis was histologically observed in the retracted specimen. Following three cycles of adjuvant chemotherapy, tumor excision and reconstruction with a frozen autograft treated with liquid nitrogen was conducted for both lesions of the humerus and skull, rather than tumor prosthesis or synthetics, in order to retain a normal shoulder function, and to obtain a good cosmetic and functional outcome after treatment of the skull lesion. Further adjuvant chemotherapy could not be administered after the completion of the surgical treatment for all lesions because the adverse events due to chemotherapy were observed. At over 5 years after the diagnosis, she remains clinically disease-free.
CONCLUSIONS
An early correct diagnosis, the proper management of chemotherapy, and surgical treatment for all lesions are essential for achieving a good clinical outcome, even in SMOS including a skull lesion. By performing reconstruction using a frozen autograft for a proximal humeral lesion and a skull lesion after confirming the good histological efficacy of neoadjuvant chemotherapy for the primary lesion, the excellent function of the shoulder joint and a good cosmetic outcome at the site of the skull lesion was acquired without complications or recurrence.
Synchronous multicentric osteosarcoma (SMOS) is characterized by simultaneous multicentricity of intraosseous lesion without visceral involvement, such as lung metastasis [1]. SMOS is a rare disease that accounts for approximately 1% of osteosarcomas, and had been reported to have a poor survival because of the difficulty of treating all lesions [2–7]. Domenico et al. reported that the 2-year overall survival of SMOS was approximately 30%, and the 5-year overall survival was < 10% [2]. There have been a few reports regarding the long-term survival of SMOS patients [2, 5, 6, 8]. No standard treatment algorithm has been previously reported because of its rarity, and most cases were treated according to the general guidelines for the management of osteosarcoma.
Osteosarcoma at the skull region is also rare, and acounting for only 6 to 8% of osteosarcomas [3, 9]. The mortality was reported to be about 50% at 5 years [9, 10]. The poor outcome was reported to be due to the difficulty of surgical treatment with a wide excision due to the complicated anatomy of the skull [10–12]. In most cases, synthetics or no reconstruction was selected after the excision of skull lesion. However, complications such as failure of synthetics, or infection, and local relapse of skull osteosarcoma often leads to severe functional disorders due to brain damage, such as extremity paralysis and meningitis, although metastases to the lung and brain are less frequent than extremity osteosarcoma [7, 13, 14].
Chemotherapy is very important for supporting the surgical outcome of tumor patients. In a few previous reports, long survivors of SMOS also had necessarily received chemotherapy, and more than 90% necrosis of the tumor cells in the specimen excised from the patients had been observed histologically [5, 7, 8]. Aggressive surgery with a clear margin for all lesions of SMOS is also essential for a good oncological outcome [5, 7, 8].Thus, planning of an appropriate strategy for the treatment of SMOS, which combines chemotherapy and surgery, is essential for obtaining a good clinical outcome (Fig. 1).Fig. 1 Our treatment strategy for synchronous multicentric osteosarcoma (SMOS)
We herein report an 18-year-old girl with multicentric synchronous osteosarcoma, including a skull lesion, and describe the clinical findings and treatment outcome for chemotherapy, two-stage tumor excision for all lesions. Our study was approved by the ethics committee of Kanazawa University Hospital (Institutional Review Board (IRB) number 2019–61(3094)) in compliance with the guidelines of the 1975 Declaration of Helsinki. Written informed consent was provided by the patient to obtain her case details and any accompanying images published.
Case presentation
An 18-year-old woman was referred to our department with a major complaint of a pain and swelling around the left distal femur. The symptom had been increasing for the past 6 months. She consulted a local doctor because her symptoms had not improved over time. Neither trauma nor injury was reported. Her previous history was also unremarkable, and no family history was found. A physical examination revealed swelling around her left distal femur and tenderness upon palpation. Neither ballottement of the left knee joint nor an evident soft tissue mass were observed. Laboratory tests revealed a threefold higher alkali-phosphatase level than the upper limit, but no other abnormal data, including the lactate dehydrogenase level and inflammation reaction, was found. A bone sclerotic lesion with periosteal reaction on the distal femur was found on X-ray (Fig. 2a, b). Computed tomogram (CT) of the left distal femur revealed a sclerotic and lytic lesion causing partial cortical destruction with soft tissue extension to the medial part of the surrounding muscles. No distant metastasis, including to the lung and regional lymph nodes, were observed on chest or abdominal CT. Magnetic resonance imaging (MRI) showed an intraosseous lesion combined with an unclear circumscribed extraosseous mass, which was hypointense on T1-weighted (Fig. 2c) and hyperintense on T2-weighted images. Unevenly contrasted lesion was observed on enhanced MRI (Fig. 2d). An open biopsy for the left distal femoral lesion was performed. Proliferation of pleomorphic spindle cells with nuclear atypia and brisk mitosis, producing a large amount of lace-like osteoid, were observed (Fig. 2e). A systemic Technetium-99 m scintigraphy (bone scan) (Fig. 3a) revealed other bone lesions of the left occipital bone (Fig. 3b) and right proximal humerus (Fig. 3c), in addition to the left distal femoral lesion (Fig. 3d), although no evident physical findings on either the right proximal humerus or left occipital bone were observed. However, a relatively strong uptake was observed at all three lesions. Thallium scintigram also revealed the strong accumulation of tracers only on the three bone lesions. A close examination by MRI revealed the enhancement of right proximal humeral bone lesion and left occipital bone lesion (Fig. 3e, f), the same as the left distal femoral lesion (Fig. 3g). Based on the histological findings, multiple bone lesions, and absence of visceral lesion, the clinical diagnosis of synchronous multicentric osteosarcoma (SMOS) was made. There is much debate in the previous studies as to whether it represents multiple primary tumors or metastatic disease. However, the case for multiple primary tumors was favored, because there was no obvious route for spread if the lungs were tumor-free, which was thought to rule out hematogenous metastasis. The prognosis of SMOS is generally considered to be poor according to the findings of previous studies [2–7].Fig. 2 Radiological and pathological findings of a bone lesion at the left distal femur. a, b Preoperative roentgenogram on the anteroposterior view (a), and the lateral view (b). c Intraosseous lesion combined with extraosseous lesion on MRI was observed, which was hypointense signal on T1 weighted images, and hyperintense signal on T2 weighted images. d Enhanced MRI revealed unevenly contrasted lesion on axial images. e Proliferation of pleomorphic spindle cells with nuclear atypia and brisk mitosis, producing a large amount of lace-like osteoid, were observed. White scale bar shows 100 µm
Fig. 3 Systemic bone scan and MRI findings before neoadjuvant chemotherapy. a–c Bone scan revealed uptake for the following three location (a); left occipital bone (b), right proximal humerus (c), and left distal femur (d). e The left occipital lesion on axial enhanced MRI, and a white arrow shows the intracortical lesion. f The right proximal humeral lesion on coronal enhanced MRI. g The left distal femoral lesion on coronal enhanced MRI
She underwent five courses of neoadjuvant chemotherapy with a regimen of doxorubicin and cisplatin, which was the same as the standard regimen for the treatment of osteosarcoma. The dose of doxorubicin was 60 mg/m2, and that of cisplatin was 120 mg/m2. The chemotherapy was performed every three weeks. After the completion of neoadjuvant chemotherapy, the uptake of all lesions on the bone scan diminished (Fig. 4a–d), and the enhancement of all lesions on MRI decreased (Fig. 4e–g). The accumulation of tracers on thallium scintigram also decreased. The chemotherapy was observed to be highly effective based on the radiological findings. The alkali-phosphatase level dramatically decreased and become normal in laboratory tests.Fig. 4 Systemic bone scan and MRI findings after five courses of neoadjuvant chemotherapy. a The uptake of all lesions on the bone scan was diminished. b Occipital bone lesion. c Right proximal humeral lesion. d Left distal femoral lesion. e The left occipital lesion had slightly shrunk in size on axial enhanced MRI (a white arrow shows the intracortical lesion.). f The enhancement was drastically decreased on coronal MRI of the right proximal humeral lesion. g The size and enhancement was decreased on coronal MRI of the distal femur
Surgical treatment of wide excision for the primary lesion of the left distal femur and reconstruction with megaprosthesis was planned at 4 months after the diagnosis. The distal femoral lesion was widely excised with extraosseous lesion and biopsy tract, preserving popliteal artery, veins and sciatic nerve (Fig. 5a). The bone was cut at 3 cm proximal from the edge of the bone lesion. A portion of the vastus medialis and intermedius were excised along with the tumor. The iodine-coated tumor prosthesis [15–17] was used for reconstruction (Fig. 5b, c). The pathological findings for the excised specimen revealed total necrosis of the lesion (Fig. 5d), and free surgical margins for both the bone and soft tissue lesions of the left distal femur.Fig. 5 Intraoperative photos, the postoperative roentgenogram, and the histological findings of the retracted specimen. a Wide excision of the left distal femoral lesion was performed. b Reconstruction using iodine-coated tumor prosthesis was performed. c Postoperative roentgenogram. d. Histological findings revealed the total necrosis of tumor cells of the retracted specimen tissue of the distal femur. White scale bar shows 100 µm
Since physical recovery from the primary surgery and wound healing were observed, adjuvant chemotherapy was resumed at seventeen days postoperatively for the residual lesions of the humerus and occipital bone. The regimen for an adjuvant chemotherapy was the same as a neoadjuvant chemotherapy. A mildly decreased cardiac function was observed on echocardiogram after the completion of the first course of adjuvant chemotherapy, and chemotherapy with another regimen of high-dose methotrexate (10 g/m2) and vincristine (2 mg/body) was performed for the second course of adjuvant chemotherapy. The improvement of cardiac function was confirmed, and the doxorubicin (60 mg/m2) and cisplatin (96 mg/m2, 80% dose of standard regimen) were given again for the third course of adjuvant chemotherapy. A total of eight courses of chemotherapy were completed, including three courses of adjuvant chemotherapy. The total dose of doxorubicin and cisplatin was 420 mg/m2 and 816 mg/m2, respectively. The humeral lesion had almost completely disappeared radiologically, and the occipital lesion was only slightly visible on images. Both the alkali-phosphatase level and the lactate dehydrogenase level remained normal in laboratory tests.
Tumor excision of both the humeral lesion and the occipital lesion, and reconstruction using a frozen autograft, rather than a tumor prosthesis or synthetics, was planned at 6 months after the diagnosis, because a histological analysis demonstrated that chemotherapy showed good efficacy in the treatment of the primary lesion. For the humeral lesion, the tumor location was identified using a fluoroscopy, based on preoperative MRI findings. For the skull lesion, the tumor location was identified with the assistance of a navigation system. At first, tumor excision for the occipital lesion was performed with a margin of at least 2 cm (Fig. 6a), and the excised bone was treated with liquid nitrogen for 20 min (Fig. 6b). The frozen autograft was dissolved at room temperature for 15 min, and washed by 0.3% iodine saline and distilled water (Fig. 6c). The autograft was returned to the original position with plate fixation (Fig. 6d). Then, hemicortical excision for the right proximal humeral lesion was performed with a margin of at least 2 cm, preserving axillary nerve, and then the excised bone was treated with liquid nitrogen for 20 min (Fig. 7a). The frozen autograft was dissolved at room temperature for 15 min, and washed by 0.3% iodine saline and distilled water (Fig. 7b). The autograft was returned to the original position with screw fixation (Fig. 7c, d).Fig. 6 Surgical treatment for a skull lesion and the postoperative roentgenogram. a Skull lesion was excised with wide margin. b, c The excised bone was treated with liquid nitrogen for twenty minutes (b), and dissolved at room temperature for 15 min, and then was washed with 0.3% iodine saline and distilled water (c). d The frozen bone was returned to the original position and plate fixation was performed. Postoperative roentgenogram was shown
Fig. 7 Surgical treatment for a proximal humeral lesion and the postoperative roentgenogram. a, b The retracted hemicortical bone of the proximal humeral lesion was treated with liquid nitrogen (a) and was dissolved at room temperature, and washed by 0.3% iodine saline and distilled water (b). c The frozen autograft was returned to the original position with screw fixation, preserving axillary nerve. d Postoperative roentgenogram was shown
Further chemotherapy was not administered after the second surgery because the adverse events due to chemotherapy, such as a myelosuppression and a mildly-decreased cardiac function, were observed. She was discharged from the hospital after the recovery from the surgery was confirmed. She was prudently observed under active surveillance, and underwent close follow-up examinations in an outpatient clinic every 3 or 4 months after discharge.
At 68 months’ follow-up after the detection of SMOS, a disease-free condition with neither local recurrence nor metastasis was obtained, and bone union for the humerus and skull lesion had also been achieved on images (Fig. 8a–c). The patient’s cardiac function was normal on an echocardiogram, and no other adverse events was observed at the last follow-up. Both the alkali-phosphatase level and the lactate dehydrogenase level remained normal in laboratory tests. An excellent function for both the upper extremity (30/30 points) and lower extremity (30/30 points) according to the International Society of Limb Salvage (ISOLS) score had been acquired. No neurological deficit was observed.Fig. 8 The postoperative roentgenogram at the latest follow-up. a Bone union at the osteotomy site for proximal humeral lesion, was completely achieved. b Bone union at the osteotomy site for skull lesion, was achieved. c Postoperative complications were not observed after tumor prosthesis reconstruction of the left distal femur
Discussion and conclusions
Multicentric osteosarcoma accounts for only approximately 1% of all osteosarcomas, and is divided into two types: synchronous and metachronous type [2, 3]. Domenico et al. reported that the median survival in patients with metachronous multicentric osteosarcoma (n = 34) was 43 months, while the median survival in those with SMOS (n = 22) was 14 months [2]. A particular poor prognosis was reported for SMOS patients, and there have been few previous report concerning long-term survivors of SMOS [2, 5, 6, 8]. To our knowledge, the survival of SMOS, including cases with skull lesions, tends to be extremely short (4–18 months) [7, 13, 14]. There were three main reasons for the successful outcome of the present case. First, the early correct identification of tumors at all locations could be made using a bone scan. Second, multiple chemotherapeutic agents, including doxorubicin and cisplatin, would contribute to the good response of the tumors, as histological examinations revealed complete necrosis in the excised specimen of the distal femur in our case. Third, surgical treatment for the other lesions could be performed with the reference to the results of neoadjuvant chemotherapy, which showed histological efficacy.
Our treatment strategy for SMOS is basically the same as that for osteosarcoma (Fig. 1). To identify precisely all of the locations of SMOS lesions before treatment is important for observing the treatment course. The good efficacy of chemotherapy is essential for obtaining good outcome. After the completion of neoadjuvant chemotherapy, a radiological assessment is performed to determine the efficacy of chemotherapy. If the course is assumed to have poor efficacy based on radiological assessment, the chemotherapy regimen should be changed. When good efficacy is radiologically confirmed after five or six courses of neoadjuvant chemotherapy, subsequent surgical excision of the primary lesion, with a wide margin, is planned and performed. Then, based on the pathological assessment of the efficacy of neoadjuvant chemotherapy in the excised specimen, an adjuvant chemotherapy regimen is selected. If the neoadjuvant chemotherapy shows good histological efficacy, three or four courses of adjuvant chemotherapy with the same regimen are performed, and an appropriate surgical treatment for the residual lesions is planned, including biological reconstruction, which can retain a normal function and achieve a good cosmetic outcome. If the histological efficacy of neoadjuvant chemotherapy is poor, the regimen should be changed for adjuvant chemotherapy, and surgical treatment with as wide an excision as possible and reconstruction using tumor prosthesis or synthetics, should be planned after several courses of chemotherapy.
When the surgical margins for all lesions are histologically clear, the primary treatment is considered to be over, or additional adjuvant chemotherapy may be considered if the patients can afford to undergo these treatments, with careful observation for adverse events. After completion of the primary treatment, the postoperative state will be prudently observed at follow-up in an outpatient clinic, with examinations every three or four months until at least five years at least after surgery.
Osteosarcoma commonly presents with lung metastases, and a standard examination includes chest CT. Additional examinations are not regularly performed except for when a patient presents symptoms, such as pain or swelling. Patients with skull osteosarcoma often present with headache, motor impairment, or cranial nerve palsies, depending on the tumor site [9–12]. However, in our case, no symptoms at the left occipital region or the right proximal humerus were observed, and it was not until a bone scan was performed that multicentric bone lesions were noted. A bone scan can assess the accumulation of tracers, thereby reflecting remodeling of the affected bone, and a systemic bone scan is useful as a regular examination for the early detection of other bone lesions [18], even if no symptoms are observed. Metachronous type multicentric osteosarcoma, or bone metastases of SMOS during the treatment course, might be due to tiny lesions with symptoms mild enough to be overlooked at the first visit. Therefore, the early correct identification of tumors at all locations is important when considering the strategy for SMOS.
Chemotherapy is very important for supporting the surgical outcome of tumor patients. In a few previous reports, long survivors of SMOS had necessarily received chemotherapy, and more than 90% necrosis of the tumor cells in the specimen excised from the patients had been observed histologically due to the efficacy of chemotherapy, which was assessed according to the Rosen and Huvos classification [5, 7, 8]. One patient received chemotherapy with a regimen of doxorubicin, cisplatin, ifosfamide, and methotrexate, and another received chemotherapy with a regimen of doxorubicin, cisplatin, and methotrexate [5, 7], while yet another patient received chemotherapy with a regimen of methotrexate, ifosfamide, bleomycin, doxorubicin, and cisplatin [8]. The present patient received chemotherapy with a regimen of doxorubicin, cisplatin, methotrexate, and etoposide. The two drugs, namely doxorubicin and cisplatin, have been commonly used for long survivors in previous SMOS patients including our case. Multiple chemotherapeutic agents including the above-mentioned two drugs might contribute to the good outcome observed in SMOS patients, although no definitive conclusions could be made due to the small sample population.
The histological confirmation of the efficacy of neoadjuvant chemotherapy in the whole section of the distal femoral lesion, especially the bone lesion, was necessary for determining whether the same regimen chemotherapy for the other two lesions should be continued or not. When a frozen autograft is used for reconstruction after wide excision, the efficacy of chemotherapy on excised soft tissue lesion can be evaluated histologically; however, the efficacy is not evaluated in bone lesion. Frozen autograft is available for almost all bone tumors and has been reported to be associated with many advantages, including preservation of the bone stock, retention of the joint function in cases in which the epiphysis is preserved, and the fact that the graft can be a perfect fit for the excised bone defect. However, the indications need to be well considered in each case. In cases involving multiple bone lesions, such as the present case, the selection of an appropriate treatment strategy is essential, and we referred to the results of a histological assessment of the effects of neoadjuvant chemotherapy on the primary bone lesion when considering treatment for residual lesions. In addition, the epiphysis could not be preserved in the present case because the lesion extended to the epiphysis. Thus, a tumor prosthesis was selected for reconstruction after wide excision of the distal femoral primary lesion.
Hemicortical excision with a clear margin and reconstruction using a frozen autograft treated with liquid nitrogen is reportedly a reliable technique for retaining a good joint function through minimally resection of the tumor and preservation of as much of the normal tissue around the resected tumor as possible [19–25]. This procedure was applied in our case because the neoadjuvant chemotherapy showed good histological efficacy for the primary lesion. In our case, an excellent right shoulder joint function was restored, and a bone union was achieved, and no recurrence or postoperative complications were observed (Fig. 8a).
Complete excision with a wide margin was associated with an improved survival, and local recurrence after surgery of the skull tumor is the major cause of treatment failure and decreases the survival rate. However, the anatomy of the head is complicated, and complete resection of the skull lesion is often difficult to achieve [10–12]. Synthetic or plate reconstruction after tumor excision is generally performed to protect the brain and fill bone defects, but there are sometimes cosmetic issues, and the complications, such as infection, or motor impairment due to brain damage, cannot be denied. Tumor excision of skull lesions and reconstruction using a frozen autograft treated with liquid nitrogen have been rarely reported [26–28]. However, this cryotherapy treatment and orthotopic transplantation method not only eliminates the tumor cells, but it also provides for bone filling which perfectly matches the same size as the bone defect, while also reducing the incidence rates of complications [19, 20, 26–28]. The good histological efficacy of neoadjuvant chemotherapy for the primary lesion was observed in our case; thus, reconstruction using a frozen autograft treated with liquid nitrogen after tumor excision with a clear margin, was applied. After surgery, a bone union was achieved without postoperative complications or local recurrence (Fig. 8b).
In conclusion, SMOS including a skull lesion is rare; nevertheless, the early, correct diagnosis, and proper strategy of chemotherapy and surgery for all lesions, are essential for ensuring a good clinical outcome. Reconstruction using a frozen autograft treated with liquid nitrogen was found to be feasible for bone lesions, including a skull lesion, even in a case of multicentric osteosarcoma, when the histological efficacy of neoadjuvant chemotherapy for the primary lesion was good. Our patient achieved an excellent right shoulder function, and a good cosmetic and functional outcome without any complications by reconstruction by following reconstruction using a frozen autograft. In addition, clinically disease-free survival of over five years after the diagnosis can be obtained, although further follow-up with regular close examinations will be required, as the survival associated with this disease is commonly poor.
Abbreviations
SMOSSynchronous multicentric osteosarcoma
CTComputed tomogram
MRIMagnetic resonance imaging
ISOLSInternational society of limb salvage
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank the past and the present other members of our department for their work.
Authors’ contributions
T.H., Y.N., H.K., and A.Yos. conceived and designed the study. N.T. performed histological examination of all the specimen. A.Yos. carried out data acquisition. H.T., A.K.,T.Y., Y.H., M.Se., and A.Yoh. provided assistance for data acquisition. T.H., Y.N., H.K., T.A., M.Sh. and I.K. managed the patients for the appropriate treatment and observed them at the follow-up outpatient clinic after treatment completion. T.H., Y.N., H.K., and A.Yos. contributed to the analysis and interpretation of laboratory data and critical appraisal. A.Yos. analyzed all the patient's data and wrote the manuscript. All authors read and approved the final manuscript.
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Availability of data and materials
All data generated or analyzed during the present study are included in this published article.
Ethics approval and consent to participate
The study was approved by the Ethical Institutional Review Board of the Kanazawa University Hospital (2019-061 (3094)), and written informed consent was obtained from all study participants.
Consent for publication
The written consent for publication of the manuscript, including personal and clinical details, and any identifying images, from the patient and her parents was obtained by the Kanazawa University Hospital.
Competing interests
The authors declare no conflicts of interest in association with the present study. | EVERY THREE WEEKS | DrugDosageText | CC BY | 33482784 | 19,052,054 | 2021-01-22 |
What was the dosage of drug 'VINCRISTINE SULFATE'? | Reconstruction using a frozen autograft for a skull and humeral lesion of synchronous multicentric osteosarcoma after undergoing successful neoadjuvant chemotherapy: a case report and review of the literature.
BACKGROUND
Synchronous multicentric osteosarcoma (SMOS) is a rare disease characterized by simultaneous multicentricity of intraosseous osteosarcoma without visceral involvement. SMOS, including a skull lesion, which occurs relatively rarely, and reconstruction using a frozen autograft after the excision of a lesion of SMOS has been infrequently reported previously.
METHODS
We report an 18-year-old girl with SMOS, with lesions located in the left distal femur, right proximal humerus, and left occipital bone. Her major complaint was pain and swelling around the left knee joint. Asymptomatic lesions of the humerus and skull bone were detected on a systemic bone scan. No visceral organ metastasis was observed. A biopsy of the distal femoral lesion revealed osteosarcoma. Based on the histological findings, multiple bone lesions, and absence of visceral lesion, the clinical diagnosis of SMOS was made. After five courses of neoadjuvant chemotherapy with a regimen of doxorubicin and cisplatin, reconstruction using a tumor prosthesis following wide excision of the left distal femur was performed, and total necrosis was histologically observed in the retracted specimen. Following three cycles of adjuvant chemotherapy, tumor excision and reconstruction with a frozen autograft treated with liquid nitrogen was conducted for both lesions of the humerus and skull, rather than tumor prosthesis or synthetics, in order to retain a normal shoulder function, and to obtain a good cosmetic and functional outcome after treatment of the skull lesion. Further adjuvant chemotherapy could not be administered after the completion of the surgical treatment for all lesions because the adverse events due to chemotherapy were observed. At over 5 years after the diagnosis, she remains clinically disease-free.
CONCLUSIONS
An early correct diagnosis, the proper management of chemotherapy, and surgical treatment for all lesions are essential for achieving a good clinical outcome, even in SMOS including a skull lesion. By performing reconstruction using a frozen autograft for a proximal humeral lesion and a skull lesion after confirming the good histological efficacy of neoadjuvant chemotherapy for the primary lesion, the excellent function of the shoulder joint and a good cosmetic outcome at the site of the skull lesion was acquired without complications or recurrence.
Synchronous multicentric osteosarcoma (SMOS) is characterized by simultaneous multicentricity of intraosseous lesion without visceral involvement, such as lung metastasis [1]. SMOS is a rare disease that accounts for approximately 1% of osteosarcomas, and had been reported to have a poor survival because of the difficulty of treating all lesions [2–7]. Domenico et al. reported that the 2-year overall survival of SMOS was approximately 30%, and the 5-year overall survival was < 10% [2]. There have been a few reports regarding the long-term survival of SMOS patients [2, 5, 6, 8]. No standard treatment algorithm has been previously reported because of its rarity, and most cases were treated according to the general guidelines for the management of osteosarcoma.
Osteosarcoma at the skull region is also rare, and acounting for only 6 to 8% of osteosarcomas [3, 9]. The mortality was reported to be about 50% at 5 years [9, 10]. The poor outcome was reported to be due to the difficulty of surgical treatment with a wide excision due to the complicated anatomy of the skull [10–12]. In most cases, synthetics or no reconstruction was selected after the excision of skull lesion. However, complications such as failure of synthetics, or infection, and local relapse of skull osteosarcoma often leads to severe functional disorders due to brain damage, such as extremity paralysis and meningitis, although metastases to the lung and brain are less frequent than extremity osteosarcoma [7, 13, 14].
Chemotherapy is very important for supporting the surgical outcome of tumor patients. In a few previous reports, long survivors of SMOS also had necessarily received chemotherapy, and more than 90% necrosis of the tumor cells in the specimen excised from the patients had been observed histologically [5, 7, 8]. Aggressive surgery with a clear margin for all lesions of SMOS is also essential for a good oncological outcome [5, 7, 8].Thus, planning of an appropriate strategy for the treatment of SMOS, which combines chemotherapy and surgery, is essential for obtaining a good clinical outcome (Fig. 1).Fig. 1 Our treatment strategy for synchronous multicentric osteosarcoma (SMOS)
We herein report an 18-year-old girl with multicentric synchronous osteosarcoma, including a skull lesion, and describe the clinical findings and treatment outcome for chemotherapy, two-stage tumor excision for all lesions. Our study was approved by the ethics committee of Kanazawa University Hospital (Institutional Review Board (IRB) number 2019–61(3094)) in compliance with the guidelines of the 1975 Declaration of Helsinki. Written informed consent was provided by the patient to obtain her case details and any accompanying images published.
Case presentation
An 18-year-old woman was referred to our department with a major complaint of a pain and swelling around the left distal femur. The symptom had been increasing for the past 6 months. She consulted a local doctor because her symptoms had not improved over time. Neither trauma nor injury was reported. Her previous history was also unremarkable, and no family history was found. A physical examination revealed swelling around her left distal femur and tenderness upon palpation. Neither ballottement of the left knee joint nor an evident soft tissue mass were observed. Laboratory tests revealed a threefold higher alkali-phosphatase level than the upper limit, but no other abnormal data, including the lactate dehydrogenase level and inflammation reaction, was found. A bone sclerotic lesion with periosteal reaction on the distal femur was found on X-ray (Fig. 2a, b). Computed tomogram (CT) of the left distal femur revealed a sclerotic and lytic lesion causing partial cortical destruction with soft tissue extension to the medial part of the surrounding muscles. No distant metastasis, including to the lung and regional lymph nodes, were observed on chest or abdominal CT. Magnetic resonance imaging (MRI) showed an intraosseous lesion combined with an unclear circumscribed extraosseous mass, which was hypointense on T1-weighted (Fig. 2c) and hyperintense on T2-weighted images. Unevenly contrasted lesion was observed on enhanced MRI (Fig. 2d). An open biopsy for the left distal femoral lesion was performed. Proliferation of pleomorphic spindle cells with nuclear atypia and brisk mitosis, producing a large amount of lace-like osteoid, were observed (Fig. 2e). A systemic Technetium-99 m scintigraphy (bone scan) (Fig. 3a) revealed other bone lesions of the left occipital bone (Fig. 3b) and right proximal humerus (Fig. 3c), in addition to the left distal femoral lesion (Fig. 3d), although no evident physical findings on either the right proximal humerus or left occipital bone were observed. However, a relatively strong uptake was observed at all three lesions. Thallium scintigram also revealed the strong accumulation of tracers only on the three bone lesions. A close examination by MRI revealed the enhancement of right proximal humeral bone lesion and left occipital bone lesion (Fig. 3e, f), the same as the left distal femoral lesion (Fig. 3g). Based on the histological findings, multiple bone lesions, and absence of visceral lesion, the clinical diagnosis of synchronous multicentric osteosarcoma (SMOS) was made. There is much debate in the previous studies as to whether it represents multiple primary tumors or metastatic disease. However, the case for multiple primary tumors was favored, because there was no obvious route for spread if the lungs were tumor-free, which was thought to rule out hematogenous metastasis. The prognosis of SMOS is generally considered to be poor according to the findings of previous studies [2–7].Fig. 2 Radiological and pathological findings of a bone lesion at the left distal femur. a, b Preoperative roentgenogram on the anteroposterior view (a), and the lateral view (b). c Intraosseous lesion combined with extraosseous lesion on MRI was observed, which was hypointense signal on T1 weighted images, and hyperintense signal on T2 weighted images. d Enhanced MRI revealed unevenly contrasted lesion on axial images. e Proliferation of pleomorphic spindle cells with nuclear atypia and brisk mitosis, producing a large amount of lace-like osteoid, were observed. White scale bar shows 100 µm
Fig. 3 Systemic bone scan and MRI findings before neoadjuvant chemotherapy. a–c Bone scan revealed uptake for the following three location (a); left occipital bone (b), right proximal humerus (c), and left distal femur (d). e The left occipital lesion on axial enhanced MRI, and a white arrow shows the intracortical lesion. f The right proximal humeral lesion on coronal enhanced MRI. g The left distal femoral lesion on coronal enhanced MRI
She underwent five courses of neoadjuvant chemotherapy with a regimen of doxorubicin and cisplatin, which was the same as the standard regimen for the treatment of osteosarcoma. The dose of doxorubicin was 60 mg/m2, and that of cisplatin was 120 mg/m2. The chemotherapy was performed every three weeks. After the completion of neoadjuvant chemotherapy, the uptake of all lesions on the bone scan diminished (Fig. 4a–d), and the enhancement of all lesions on MRI decreased (Fig. 4e–g). The accumulation of tracers on thallium scintigram also decreased. The chemotherapy was observed to be highly effective based on the radiological findings. The alkali-phosphatase level dramatically decreased and become normal in laboratory tests.Fig. 4 Systemic bone scan and MRI findings after five courses of neoadjuvant chemotherapy. a The uptake of all lesions on the bone scan was diminished. b Occipital bone lesion. c Right proximal humeral lesion. d Left distal femoral lesion. e The left occipital lesion had slightly shrunk in size on axial enhanced MRI (a white arrow shows the intracortical lesion.). f The enhancement was drastically decreased on coronal MRI of the right proximal humeral lesion. g The size and enhancement was decreased on coronal MRI of the distal femur
Surgical treatment of wide excision for the primary lesion of the left distal femur and reconstruction with megaprosthesis was planned at 4 months after the diagnosis. The distal femoral lesion was widely excised with extraosseous lesion and biopsy tract, preserving popliteal artery, veins and sciatic nerve (Fig. 5a). The bone was cut at 3 cm proximal from the edge of the bone lesion. A portion of the vastus medialis and intermedius were excised along with the tumor. The iodine-coated tumor prosthesis [15–17] was used for reconstruction (Fig. 5b, c). The pathological findings for the excised specimen revealed total necrosis of the lesion (Fig. 5d), and free surgical margins for both the bone and soft tissue lesions of the left distal femur.Fig. 5 Intraoperative photos, the postoperative roentgenogram, and the histological findings of the retracted specimen. a Wide excision of the left distal femoral lesion was performed. b Reconstruction using iodine-coated tumor prosthesis was performed. c Postoperative roentgenogram. d. Histological findings revealed the total necrosis of tumor cells of the retracted specimen tissue of the distal femur. White scale bar shows 100 µm
Since physical recovery from the primary surgery and wound healing were observed, adjuvant chemotherapy was resumed at seventeen days postoperatively for the residual lesions of the humerus and occipital bone. The regimen for an adjuvant chemotherapy was the same as a neoadjuvant chemotherapy. A mildly decreased cardiac function was observed on echocardiogram after the completion of the first course of adjuvant chemotherapy, and chemotherapy with another regimen of high-dose methotrexate (10 g/m2) and vincristine (2 mg/body) was performed for the second course of adjuvant chemotherapy. The improvement of cardiac function was confirmed, and the doxorubicin (60 mg/m2) and cisplatin (96 mg/m2, 80% dose of standard regimen) were given again for the third course of adjuvant chemotherapy. A total of eight courses of chemotherapy were completed, including three courses of adjuvant chemotherapy. The total dose of doxorubicin and cisplatin was 420 mg/m2 and 816 mg/m2, respectively. The humeral lesion had almost completely disappeared radiologically, and the occipital lesion was only slightly visible on images. Both the alkali-phosphatase level and the lactate dehydrogenase level remained normal in laboratory tests.
Tumor excision of both the humeral lesion and the occipital lesion, and reconstruction using a frozen autograft, rather than a tumor prosthesis or synthetics, was planned at 6 months after the diagnosis, because a histological analysis demonstrated that chemotherapy showed good efficacy in the treatment of the primary lesion. For the humeral lesion, the tumor location was identified using a fluoroscopy, based on preoperative MRI findings. For the skull lesion, the tumor location was identified with the assistance of a navigation system. At first, tumor excision for the occipital lesion was performed with a margin of at least 2 cm (Fig. 6a), and the excised bone was treated with liquid nitrogen for 20 min (Fig. 6b). The frozen autograft was dissolved at room temperature for 15 min, and washed by 0.3% iodine saline and distilled water (Fig. 6c). The autograft was returned to the original position with plate fixation (Fig. 6d). Then, hemicortical excision for the right proximal humeral lesion was performed with a margin of at least 2 cm, preserving axillary nerve, and then the excised bone was treated with liquid nitrogen for 20 min (Fig. 7a). The frozen autograft was dissolved at room temperature for 15 min, and washed by 0.3% iodine saline and distilled water (Fig. 7b). The autograft was returned to the original position with screw fixation (Fig. 7c, d).Fig. 6 Surgical treatment for a skull lesion and the postoperative roentgenogram. a Skull lesion was excised with wide margin. b, c The excised bone was treated with liquid nitrogen for twenty minutes (b), and dissolved at room temperature for 15 min, and then was washed with 0.3% iodine saline and distilled water (c). d The frozen bone was returned to the original position and plate fixation was performed. Postoperative roentgenogram was shown
Fig. 7 Surgical treatment for a proximal humeral lesion and the postoperative roentgenogram. a, b The retracted hemicortical bone of the proximal humeral lesion was treated with liquid nitrogen (a) and was dissolved at room temperature, and washed by 0.3% iodine saline and distilled water (b). c The frozen autograft was returned to the original position with screw fixation, preserving axillary nerve. d Postoperative roentgenogram was shown
Further chemotherapy was not administered after the second surgery because the adverse events due to chemotherapy, such as a myelosuppression and a mildly-decreased cardiac function, were observed. She was discharged from the hospital after the recovery from the surgery was confirmed. She was prudently observed under active surveillance, and underwent close follow-up examinations in an outpatient clinic every 3 or 4 months after discharge.
At 68 months’ follow-up after the detection of SMOS, a disease-free condition with neither local recurrence nor metastasis was obtained, and bone union for the humerus and skull lesion had also been achieved on images (Fig. 8a–c). The patient’s cardiac function was normal on an echocardiogram, and no other adverse events was observed at the last follow-up. Both the alkali-phosphatase level and the lactate dehydrogenase level remained normal in laboratory tests. An excellent function for both the upper extremity (30/30 points) and lower extremity (30/30 points) according to the International Society of Limb Salvage (ISOLS) score had been acquired. No neurological deficit was observed.Fig. 8 The postoperative roentgenogram at the latest follow-up. a Bone union at the osteotomy site for proximal humeral lesion, was completely achieved. b Bone union at the osteotomy site for skull lesion, was achieved. c Postoperative complications were not observed after tumor prosthesis reconstruction of the left distal femur
Discussion and conclusions
Multicentric osteosarcoma accounts for only approximately 1% of all osteosarcomas, and is divided into two types: synchronous and metachronous type [2, 3]. Domenico et al. reported that the median survival in patients with metachronous multicentric osteosarcoma (n = 34) was 43 months, while the median survival in those with SMOS (n = 22) was 14 months [2]. A particular poor prognosis was reported for SMOS patients, and there have been few previous report concerning long-term survivors of SMOS [2, 5, 6, 8]. To our knowledge, the survival of SMOS, including cases with skull lesions, tends to be extremely short (4–18 months) [7, 13, 14]. There were three main reasons for the successful outcome of the present case. First, the early correct identification of tumors at all locations could be made using a bone scan. Second, multiple chemotherapeutic agents, including doxorubicin and cisplatin, would contribute to the good response of the tumors, as histological examinations revealed complete necrosis in the excised specimen of the distal femur in our case. Third, surgical treatment for the other lesions could be performed with the reference to the results of neoadjuvant chemotherapy, which showed histological efficacy.
Our treatment strategy for SMOS is basically the same as that for osteosarcoma (Fig. 1). To identify precisely all of the locations of SMOS lesions before treatment is important for observing the treatment course. The good efficacy of chemotherapy is essential for obtaining good outcome. After the completion of neoadjuvant chemotherapy, a radiological assessment is performed to determine the efficacy of chemotherapy. If the course is assumed to have poor efficacy based on radiological assessment, the chemotherapy regimen should be changed. When good efficacy is radiologically confirmed after five or six courses of neoadjuvant chemotherapy, subsequent surgical excision of the primary lesion, with a wide margin, is planned and performed. Then, based on the pathological assessment of the efficacy of neoadjuvant chemotherapy in the excised specimen, an adjuvant chemotherapy regimen is selected. If the neoadjuvant chemotherapy shows good histological efficacy, three or four courses of adjuvant chemotherapy with the same regimen are performed, and an appropriate surgical treatment for the residual lesions is planned, including biological reconstruction, which can retain a normal function and achieve a good cosmetic outcome. If the histological efficacy of neoadjuvant chemotherapy is poor, the regimen should be changed for adjuvant chemotherapy, and surgical treatment with as wide an excision as possible and reconstruction using tumor prosthesis or synthetics, should be planned after several courses of chemotherapy.
When the surgical margins for all lesions are histologically clear, the primary treatment is considered to be over, or additional adjuvant chemotherapy may be considered if the patients can afford to undergo these treatments, with careful observation for adverse events. After completion of the primary treatment, the postoperative state will be prudently observed at follow-up in an outpatient clinic, with examinations every three or four months until at least five years at least after surgery.
Osteosarcoma commonly presents with lung metastases, and a standard examination includes chest CT. Additional examinations are not regularly performed except for when a patient presents symptoms, such as pain or swelling. Patients with skull osteosarcoma often present with headache, motor impairment, or cranial nerve palsies, depending on the tumor site [9–12]. However, in our case, no symptoms at the left occipital region or the right proximal humerus were observed, and it was not until a bone scan was performed that multicentric bone lesions were noted. A bone scan can assess the accumulation of tracers, thereby reflecting remodeling of the affected bone, and a systemic bone scan is useful as a regular examination for the early detection of other bone lesions [18], even if no symptoms are observed. Metachronous type multicentric osteosarcoma, or bone metastases of SMOS during the treatment course, might be due to tiny lesions with symptoms mild enough to be overlooked at the first visit. Therefore, the early correct identification of tumors at all locations is important when considering the strategy for SMOS.
Chemotherapy is very important for supporting the surgical outcome of tumor patients. In a few previous reports, long survivors of SMOS had necessarily received chemotherapy, and more than 90% necrosis of the tumor cells in the specimen excised from the patients had been observed histologically due to the efficacy of chemotherapy, which was assessed according to the Rosen and Huvos classification [5, 7, 8]. One patient received chemotherapy with a regimen of doxorubicin, cisplatin, ifosfamide, and methotrexate, and another received chemotherapy with a regimen of doxorubicin, cisplatin, and methotrexate [5, 7], while yet another patient received chemotherapy with a regimen of methotrexate, ifosfamide, bleomycin, doxorubicin, and cisplatin [8]. The present patient received chemotherapy with a regimen of doxorubicin, cisplatin, methotrexate, and etoposide. The two drugs, namely doxorubicin and cisplatin, have been commonly used for long survivors in previous SMOS patients including our case. Multiple chemotherapeutic agents including the above-mentioned two drugs might contribute to the good outcome observed in SMOS patients, although no definitive conclusions could be made due to the small sample population.
The histological confirmation of the efficacy of neoadjuvant chemotherapy in the whole section of the distal femoral lesion, especially the bone lesion, was necessary for determining whether the same regimen chemotherapy for the other two lesions should be continued or not. When a frozen autograft is used for reconstruction after wide excision, the efficacy of chemotherapy on excised soft tissue lesion can be evaluated histologically; however, the efficacy is not evaluated in bone lesion. Frozen autograft is available for almost all bone tumors and has been reported to be associated with many advantages, including preservation of the bone stock, retention of the joint function in cases in which the epiphysis is preserved, and the fact that the graft can be a perfect fit for the excised bone defect. However, the indications need to be well considered in each case. In cases involving multiple bone lesions, such as the present case, the selection of an appropriate treatment strategy is essential, and we referred to the results of a histological assessment of the effects of neoadjuvant chemotherapy on the primary bone lesion when considering treatment for residual lesions. In addition, the epiphysis could not be preserved in the present case because the lesion extended to the epiphysis. Thus, a tumor prosthesis was selected for reconstruction after wide excision of the distal femoral primary lesion.
Hemicortical excision with a clear margin and reconstruction using a frozen autograft treated with liquid nitrogen is reportedly a reliable technique for retaining a good joint function through minimally resection of the tumor and preservation of as much of the normal tissue around the resected tumor as possible [19–25]. This procedure was applied in our case because the neoadjuvant chemotherapy showed good histological efficacy for the primary lesion. In our case, an excellent right shoulder joint function was restored, and a bone union was achieved, and no recurrence or postoperative complications were observed (Fig. 8a).
Complete excision with a wide margin was associated with an improved survival, and local recurrence after surgery of the skull tumor is the major cause of treatment failure and decreases the survival rate. However, the anatomy of the head is complicated, and complete resection of the skull lesion is often difficult to achieve [10–12]. Synthetic or plate reconstruction after tumor excision is generally performed to protect the brain and fill bone defects, but there are sometimes cosmetic issues, and the complications, such as infection, or motor impairment due to brain damage, cannot be denied. Tumor excision of skull lesions and reconstruction using a frozen autograft treated with liquid nitrogen have been rarely reported [26–28]. However, this cryotherapy treatment and orthotopic transplantation method not only eliminates the tumor cells, but it also provides for bone filling which perfectly matches the same size as the bone defect, while also reducing the incidence rates of complications [19, 20, 26–28]. The good histological efficacy of neoadjuvant chemotherapy for the primary lesion was observed in our case; thus, reconstruction using a frozen autograft treated with liquid nitrogen after tumor excision with a clear margin, was applied. After surgery, a bone union was achieved without postoperative complications or local recurrence (Fig. 8b).
In conclusion, SMOS including a skull lesion is rare; nevertheless, the early, correct diagnosis, and proper strategy of chemotherapy and surgery for all lesions, are essential for ensuring a good clinical outcome. Reconstruction using a frozen autograft treated with liquid nitrogen was found to be feasible for bone lesions, including a skull lesion, even in a case of multicentric osteosarcoma, when the histological efficacy of neoadjuvant chemotherapy for the primary lesion was good. Our patient achieved an excellent right shoulder function, and a good cosmetic and functional outcome without any complications by reconstruction by following reconstruction using a frozen autograft. In addition, clinically disease-free survival of over five years after the diagnosis can be obtained, although further follow-up with regular close examinations will be required, as the survival associated with this disease is commonly poor.
Abbreviations
SMOSSynchronous multicentric osteosarcoma
CTComputed tomogram
MRIMagnetic resonance imaging
ISOLSInternational society of limb salvage
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank the past and the present other members of our department for their work.
Authors’ contributions
T.H., Y.N., H.K., and A.Yos. conceived and designed the study. N.T. performed histological examination of all the specimen. A.Yos. carried out data acquisition. H.T., A.K.,T.Y., Y.H., M.Se., and A.Yoh. provided assistance for data acquisition. T.H., Y.N., H.K., T.A., M.Sh. and I.K. managed the patients for the appropriate treatment and observed them at the follow-up outpatient clinic after treatment completion. T.H., Y.N., H.K., and A.Yos. contributed to the analysis and interpretation of laboratory data and critical appraisal. A.Yos. analyzed all the patient's data and wrote the manuscript. All authors read and approved the final manuscript.
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Availability of data and materials
All data generated or analyzed during the present study are included in this published article.
Ethics approval and consent to participate
The study was approved by the Ethical Institutional Review Board of the Kanazawa University Hospital (2019-061 (3094)), and written informed consent was obtained from all study participants.
Consent for publication
The written consent for publication of the manuscript, including personal and clinical details, and any identifying images, from the patient and her parents was obtained by the Kanazawa University Hospital.
Competing interests
The authors declare no conflicts of interest in association with the present study. | UNK (2 MG/BODY) | DrugDosageText | CC BY | 33482784 | 18,923,001 | 2021-01-22 |
What was the dosage of drug 'VINCRISTINE'? | Reconstruction using a frozen autograft for a skull and humeral lesion of synchronous multicentric osteosarcoma after undergoing successful neoadjuvant chemotherapy: a case report and review of the literature.
BACKGROUND
Synchronous multicentric osteosarcoma (SMOS) is a rare disease characterized by simultaneous multicentricity of intraosseous osteosarcoma without visceral involvement. SMOS, including a skull lesion, which occurs relatively rarely, and reconstruction using a frozen autograft after the excision of a lesion of SMOS has been infrequently reported previously.
METHODS
We report an 18-year-old girl with SMOS, with lesions located in the left distal femur, right proximal humerus, and left occipital bone. Her major complaint was pain and swelling around the left knee joint. Asymptomatic lesions of the humerus and skull bone were detected on a systemic bone scan. No visceral organ metastasis was observed. A biopsy of the distal femoral lesion revealed osteosarcoma. Based on the histological findings, multiple bone lesions, and absence of visceral lesion, the clinical diagnosis of SMOS was made. After five courses of neoadjuvant chemotherapy with a regimen of doxorubicin and cisplatin, reconstruction using a tumor prosthesis following wide excision of the left distal femur was performed, and total necrosis was histologically observed in the retracted specimen. Following three cycles of adjuvant chemotherapy, tumor excision and reconstruction with a frozen autograft treated with liquid nitrogen was conducted for both lesions of the humerus and skull, rather than tumor prosthesis or synthetics, in order to retain a normal shoulder function, and to obtain a good cosmetic and functional outcome after treatment of the skull lesion. Further adjuvant chemotherapy could not be administered after the completion of the surgical treatment for all lesions because the adverse events due to chemotherapy were observed. At over 5 years after the diagnosis, she remains clinically disease-free.
CONCLUSIONS
An early correct diagnosis, the proper management of chemotherapy, and surgical treatment for all lesions are essential for achieving a good clinical outcome, even in SMOS including a skull lesion. By performing reconstruction using a frozen autograft for a proximal humeral lesion and a skull lesion after confirming the good histological efficacy of neoadjuvant chemotherapy for the primary lesion, the excellent function of the shoulder joint and a good cosmetic outcome at the site of the skull lesion was acquired without complications or recurrence.
Synchronous multicentric osteosarcoma (SMOS) is characterized by simultaneous multicentricity of intraosseous lesion without visceral involvement, such as lung metastasis [1]. SMOS is a rare disease that accounts for approximately 1% of osteosarcomas, and had been reported to have a poor survival because of the difficulty of treating all lesions [2–7]. Domenico et al. reported that the 2-year overall survival of SMOS was approximately 30%, and the 5-year overall survival was < 10% [2]. There have been a few reports regarding the long-term survival of SMOS patients [2, 5, 6, 8]. No standard treatment algorithm has been previously reported because of its rarity, and most cases were treated according to the general guidelines for the management of osteosarcoma.
Osteosarcoma at the skull region is also rare, and acounting for only 6 to 8% of osteosarcomas [3, 9]. The mortality was reported to be about 50% at 5 years [9, 10]. The poor outcome was reported to be due to the difficulty of surgical treatment with a wide excision due to the complicated anatomy of the skull [10–12]. In most cases, synthetics or no reconstruction was selected after the excision of skull lesion. However, complications such as failure of synthetics, or infection, and local relapse of skull osteosarcoma often leads to severe functional disorders due to brain damage, such as extremity paralysis and meningitis, although metastases to the lung and brain are less frequent than extremity osteosarcoma [7, 13, 14].
Chemotherapy is very important for supporting the surgical outcome of tumor patients. In a few previous reports, long survivors of SMOS also had necessarily received chemotherapy, and more than 90% necrosis of the tumor cells in the specimen excised from the patients had been observed histologically [5, 7, 8]. Aggressive surgery with a clear margin for all lesions of SMOS is also essential for a good oncological outcome [5, 7, 8].Thus, planning of an appropriate strategy for the treatment of SMOS, which combines chemotherapy and surgery, is essential for obtaining a good clinical outcome (Fig. 1).Fig. 1 Our treatment strategy for synchronous multicentric osteosarcoma (SMOS)
We herein report an 18-year-old girl with multicentric synchronous osteosarcoma, including a skull lesion, and describe the clinical findings and treatment outcome for chemotherapy, two-stage tumor excision for all lesions. Our study was approved by the ethics committee of Kanazawa University Hospital (Institutional Review Board (IRB) number 2019–61(3094)) in compliance with the guidelines of the 1975 Declaration of Helsinki. Written informed consent was provided by the patient to obtain her case details and any accompanying images published.
Case presentation
An 18-year-old woman was referred to our department with a major complaint of a pain and swelling around the left distal femur. The symptom had been increasing for the past 6 months. She consulted a local doctor because her symptoms had not improved over time. Neither trauma nor injury was reported. Her previous history was also unremarkable, and no family history was found. A physical examination revealed swelling around her left distal femur and tenderness upon palpation. Neither ballottement of the left knee joint nor an evident soft tissue mass were observed. Laboratory tests revealed a threefold higher alkali-phosphatase level than the upper limit, but no other abnormal data, including the lactate dehydrogenase level and inflammation reaction, was found. A bone sclerotic lesion with periosteal reaction on the distal femur was found on X-ray (Fig. 2a, b). Computed tomogram (CT) of the left distal femur revealed a sclerotic and lytic lesion causing partial cortical destruction with soft tissue extension to the medial part of the surrounding muscles. No distant metastasis, including to the lung and regional lymph nodes, were observed on chest or abdominal CT. Magnetic resonance imaging (MRI) showed an intraosseous lesion combined with an unclear circumscribed extraosseous mass, which was hypointense on T1-weighted (Fig. 2c) and hyperintense on T2-weighted images. Unevenly contrasted lesion was observed on enhanced MRI (Fig. 2d). An open biopsy for the left distal femoral lesion was performed. Proliferation of pleomorphic spindle cells with nuclear atypia and brisk mitosis, producing a large amount of lace-like osteoid, were observed (Fig. 2e). A systemic Technetium-99 m scintigraphy (bone scan) (Fig. 3a) revealed other bone lesions of the left occipital bone (Fig. 3b) and right proximal humerus (Fig. 3c), in addition to the left distal femoral lesion (Fig. 3d), although no evident physical findings on either the right proximal humerus or left occipital bone were observed. However, a relatively strong uptake was observed at all three lesions. Thallium scintigram also revealed the strong accumulation of tracers only on the three bone lesions. A close examination by MRI revealed the enhancement of right proximal humeral bone lesion and left occipital bone lesion (Fig. 3e, f), the same as the left distal femoral lesion (Fig. 3g). Based on the histological findings, multiple bone lesions, and absence of visceral lesion, the clinical diagnosis of synchronous multicentric osteosarcoma (SMOS) was made. There is much debate in the previous studies as to whether it represents multiple primary tumors or metastatic disease. However, the case for multiple primary tumors was favored, because there was no obvious route for spread if the lungs were tumor-free, which was thought to rule out hematogenous metastasis. The prognosis of SMOS is generally considered to be poor according to the findings of previous studies [2–7].Fig. 2 Radiological and pathological findings of a bone lesion at the left distal femur. a, b Preoperative roentgenogram on the anteroposterior view (a), and the lateral view (b). c Intraosseous lesion combined with extraosseous lesion on MRI was observed, which was hypointense signal on T1 weighted images, and hyperintense signal on T2 weighted images. d Enhanced MRI revealed unevenly contrasted lesion on axial images. e Proliferation of pleomorphic spindle cells with nuclear atypia and brisk mitosis, producing a large amount of lace-like osteoid, were observed. White scale bar shows 100 µm
Fig. 3 Systemic bone scan and MRI findings before neoadjuvant chemotherapy. a–c Bone scan revealed uptake for the following three location (a); left occipital bone (b), right proximal humerus (c), and left distal femur (d). e The left occipital lesion on axial enhanced MRI, and a white arrow shows the intracortical lesion. f The right proximal humeral lesion on coronal enhanced MRI. g The left distal femoral lesion on coronal enhanced MRI
She underwent five courses of neoadjuvant chemotherapy with a regimen of doxorubicin and cisplatin, which was the same as the standard regimen for the treatment of osteosarcoma. The dose of doxorubicin was 60 mg/m2, and that of cisplatin was 120 mg/m2. The chemotherapy was performed every three weeks. After the completion of neoadjuvant chemotherapy, the uptake of all lesions on the bone scan diminished (Fig. 4a–d), and the enhancement of all lesions on MRI decreased (Fig. 4e–g). The accumulation of tracers on thallium scintigram also decreased. The chemotherapy was observed to be highly effective based on the radiological findings. The alkali-phosphatase level dramatically decreased and become normal in laboratory tests.Fig. 4 Systemic bone scan and MRI findings after five courses of neoadjuvant chemotherapy. a The uptake of all lesions on the bone scan was diminished. b Occipital bone lesion. c Right proximal humeral lesion. d Left distal femoral lesion. e The left occipital lesion had slightly shrunk in size on axial enhanced MRI (a white arrow shows the intracortical lesion.). f The enhancement was drastically decreased on coronal MRI of the right proximal humeral lesion. g The size and enhancement was decreased on coronal MRI of the distal femur
Surgical treatment of wide excision for the primary lesion of the left distal femur and reconstruction with megaprosthesis was planned at 4 months after the diagnosis. The distal femoral lesion was widely excised with extraosseous lesion and biopsy tract, preserving popliteal artery, veins and sciatic nerve (Fig. 5a). The bone was cut at 3 cm proximal from the edge of the bone lesion. A portion of the vastus medialis and intermedius were excised along with the tumor. The iodine-coated tumor prosthesis [15–17] was used for reconstruction (Fig. 5b, c). The pathological findings for the excised specimen revealed total necrosis of the lesion (Fig. 5d), and free surgical margins for both the bone and soft tissue lesions of the left distal femur.Fig. 5 Intraoperative photos, the postoperative roentgenogram, and the histological findings of the retracted specimen. a Wide excision of the left distal femoral lesion was performed. b Reconstruction using iodine-coated tumor prosthesis was performed. c Postoperative roentgenogram. d. Histological findings revealed the total necrosis of tumor cells of the retracted specimen tissue of the distal femur. White scale bar shows 100 µm
Since physical recovery from the primary surgery and wound healing were observed, adjuvant chemotherapy was resumed at seventeen days postoperatively for the residual lesions of the humerus and occipital bone. The regimen for an adjuvant chemotherapy was the same as a neoadjuvant chemotherapy. A mildly decreased cardiac function was observed on echocardiogram after the completion of the first course of adjuvant chemotherapy, and chemotherapy with another regimen of high-dose methotrexate (10 g/m2) and vincristine (2 mg/body) was performed for the second course of adjuvant chemotherapy. The improvement of cardiac function was confirmed, and the doxorubicin (60 mg/m2) and cisplatin (96 mg/m2, 80% dose of standard regimen) were given again for the third course of adjuvant chemotherapy. A total of eight courses of chemotherapy were completed, including three courses of adjuvant chemotherapy. The total dose of doxorubicin and cisplatin was 420 mg/m2 and 816 mg/m2, respectively. The humeral lesion had almost completely disappeared radiologically, and the occipital lesion was only slightly visible on images. Both the alkali-phosphatase level and the lactate dehydrogenase level remained normal in laboratory tests.
Tumor excision of both the humeral lesion and the occipital lesion, and reconstruction using a frozen autograft, rather than a tumor prosthesis or synthetics, was planned at 6 months after the diagnosis, because a histological analysis demonstrated that chemotherapy showed good efficacy in the treatment of the primary lesion. For the humeral lesion, the tumor location was identified using a fluoroscopy, based on preoperative MRI findings. For the skull lesion, the tumor location was identified with the assistance of a navigation system. At first, tumor excision for the occipital lesion was performed with a margin of at least 2 cm (Fig. 6a), and the excised bone was treated with liquid nitrogen for 20 min (Fig. 6b). The frozen autograft was dissolved at room temperature for 15 min, and washed by 0.3% iodine saline and distilled water (Fig. 6c). The autograft was returned to the original position with plate fixation (Fig. 6d). Then, hemicortical excision for the right proximal humeral lesion was performed with a margin of at least 2 cm, preserving axillary nerve, and then the excised bone was treated with liquid nitrogen for 20 min (Fig. 7a). The frozen autograft was dissolved at room temperature for 15 min, and washed by 0.3% iodine saline and distilled water (Fig. 7b). The autograft was returned to the original position with screw fixation (Fig. 7c, d).Fig. 6 Surgical treatment for a skull lesion and the postoperative roentgenogram. a Skull lesion was excised with wide margin. b, c The excised bone was treated with liquid nitrogen for twenty minutes (b), and dissolved at room temperature for 15 min, and then was washed with 0.3% iodine saline and distilled water (c). d The frozen bone was returned to the original position and plate fixation was performed. Postoperative roentgenogram was shown
Fig. 7 Surgical treatment for a proximal humeral lesion and the postoperative roentgenogram. a, b The retracted hemicortical bone of the proximal humeral lesion was treated with liquid nitrogen (a) and was dissolved at room temperature, and washed by 0.3% iodine saline and distilled water (b). c The frozen autograft was returned to the original position with screw fixation, preserving axillary nerve. d Postoperative roentgenogram was shown
Further chemotherapy was not administered after the second surgery because the adverse events due to chemotherapy, such as a myelosuppression and a mildly-decreased cardiac function, were observed. She was discharged from the hospital after the recovery from the surgery was confirmed. She was prudently observed under active surveillance, and underwent close follow-up examinations in an outpatient clinic every 3 or 4 months after discharge.
At 68 months’ follow-up after the detection of SMOS, a disease-free condition with neither local recurrence nor metastasis was obtained, and bone union for the humerus and skull lesion had also been achieved on images (Fig. 8a–c). The patient’s cardiac function was normal on an echocardiogram, and no other adverse events was observed at the last follow-up. Both the alkali-phosphatase level and the lactate dehydrogenase level remained normal in laboratory tests. An excellent function for both the upper extremity (30/30 points) and lower extremity (30/30 points) according to the International Society of Limb Salvage (ISOLS) score had been acquired. No neurological deficit was observed.Fig. 8 The postoperative roentgenogram at the latest follow-up. a Bone union at the osteotomy site for proximal humeral lesion, was completely achieved. b Bone union at the osteotomy site for skull lesion, was achieved. c Postoperative complications were not observed after tumor prosthesis reconstruction of the left distal femur
Discussion and conclusions
Multicentric osteosarcoma accounts for only approximately 1% of all osteosarcomas, and is divided into two types: synchronous and metachronous type [2, 3]. Domenico et al. reported that the median survival in patients with metachronous multicentric osteosarcoma (n = 34) was 43 months, while the median survival in those with SMOS (n = 22) was 14 months [2]. A particular poor prognosis was reported for SMOS patients, and there have been few previous report concerning long-term survivors of SMOS [2, 5, 6, 8]. To our knowledge, the survival of SMOS, including cases with skull lesions, tends to be extremely short (4–18 months) [7, 13, 14]. There were three main reasons for the successful outcome of the present case. First, the early correct identification of tumors at all locations could be made using a bone scan. Second, multiple chemotherapeutic agents, including doxorubicin and cisplatin, would contribute to the good response of the tumors, as histological examinations revealed complete necrosis in the excised specimen of the distal femur in our case. Third, surgical treatment for the other lesions could be performed with the reference to the results of neoadjuvant chemotherapy, which showed histological efficacy.
Our treatment strategy for SMOS is basically the same as that for osteosarcoma (Fig. 1). To identify precisely all of the locations of SMOS lesions before treatment is important for observing the treatment course. The good efficacy of chemotherapy is essential for obtaining good outcome. After the completion of neoadjuvant chemotherapy, a radiological assessment is performed to determine the efficacy of chemotherapy. If the course is assumed to have poor efficacy based on radiological assessment, the chemotherapy regimen should be changed. When good efficacy is radiologically confirmed after five or six courses of neoadjuvant chemotherapy, subsequent surgical excision of the primary lesion, with a wide margin, is planned and performed. Then, based on the pathological assessment of the efficacy of neoadjuvant chemotherapy in the excised specimen, an adjuvant chemotherapy regimen is selected. If the neoadjuvant chemotherapy shows good histological efficacy, three or four courses of adjuvant chemotherapy with the same regimen are performed, and an appropriate surgical treatment for the residual lesions is planned, including biological reconstruction, which can retain a normal function and achieve a good cosmetic outcome. If the histological efficacy of neoadjuvant chemotherapy is poor, the regimen should be changed for adjuvant chemotherapy, and surgical treatment with as wide an excision as possible and reconstruction using tumor prosthesis or synthetics, should be planned after several courses of chemotherapy.
When the surgical margins for all lesions are histologically clear, the primary treatment is considered to be over, or additional adjuvant chemotherapy may be considered if the patients can afford to undergo these treatments, with careful observation for adverse events. After completion of the primary treatment, the postoperative state will be prudently observed at follow-up in an outpatient clinic, with examinations every three or four months until at least five years at least after surgery.
Osteosarcoma commonly presents with lung metastases, and a standard examination includes chest CT. Additional examinations are not regularly performed except for when a patient presents symptoms, such as pain or swelling. Patients with skull osteosarcoma often present with headache, motor impairment, or cranial nerve palsies, depending on the tumor site [9–12]. However, in our case, no symptoms at the left occipital region or the right proximal humerus were observed, and it was not until a bone scan was performed that multicentric bone lesions were noted. A bone scan can assess the accumulation of tracers, thereby reflecting remodeling of the affected bone, and a systemic bone scan is useful as a regular examination for the early detection of other bone lesions [18], even if no symptoms are observed. Metachronous type multicentric osteosarcoma, or bone metastases of SMOS during the treatment course, might be due to tiny lesions with symptoms mild enough to be overlooked at the first visit. Therefore, the early correct identification of tumors at all locations is important when considering the strategy for SMOS.
Chemotherapy is very important for supporting the surgical outcome of tumor patients. In a few previous reports, long survivors of SMOS had necessarily received chemotherapy, and more than 90% necrosis of the tumor cells in the specimen excised from the patients had been observed histologically due to the efficacy of chemotherapy, which was assessed according to the Rosen and Huvos classification [5, 7, 8]. One patient received chemotherapy with a regimen of doxorubicin, cisplatin, ifosfamide, and methotrexate, and another received chemotherapy with a regimen of doxorubicin, cisplatin, and methotrexate [5, 7], while yet another patient received chemotherapy with a regimen of methotrexate, ifosfamide, bleomycin, doxorubicin, and cisplatin [8]. The present patient received chemotherapy with a regimen of doxorubicin, cisplatin, methotrexate, and etoposide. The two drugs, namely doxorubicin and cisplatin, have been commonly used for long survivors in previous SMOS patients including our case. Multiple chemotherapeutic agents including the above-mentioned two drugs might contribute to the good outcome observed in SMOS patients, although no definitive conclusions could be made due to the small sample population.
The histological confirmation of the efficacy of neoadjuvant chemotherapy in the whole section of the distal femoral lesion, especially the bone lesion, was necessary for determining whether the same regimen chemotherapy for the other two lesions should be continued or not. When a frozen autograft is used for reconstruction after wide excision, the efficacy of chemotherapy on excised soft tissue lesion can be evaluated histologically; however, the efficacy is not evaluated in bone lesion. Frozen autograft is available for almost all bone tumors and has been reported to be associated with many advantages, including preservation of the bone stock, retention of the joint function in cases in which the epiphysis is preserved, and the fact that the graft can be a perfect fit for the excised bone defect. However, the indications need to be well considered in each case. In cases involving multiple bone lesions, such as the present case, the selection of an appropriate treatment strategy is essential, and we referred to the results of a histological assessment of the effects of neoadjuvant chemotherapy on the primary bone lesion when considering treatment for residual lesions. In addition, the epiphysis could not be preserved in the present case because the lesion extended to the epiphysis. Thus, a tumor prosthesis was selected for reconstruction after wide excision of the distal femoral primary lesion.
Hemicortical excision with a clear margin and reconstruction using a frozen autograft treated with liquid nitrogen is reportedly a reliable technique for retaining a good joint function through minimally resection of the tumor and preservation of as much of the normal tissue around the resected tumor as possible [19–25]. This procedure was applied in our case because the neoadjuvant chemotherapy showed good histological efficacy for the primary lesion. In our case, an excellent right shoulder joint function was restored, and a bone union was achieved, and no recurrence or postoperative complications were observed (Fig. 8a).
Complete excision with a wide margin was associated with an improved survival, and local recurrence after surgery of the skull tumor is the major cause of treatment failure and decreases the survival rate. However, the anatomy of the head is complicated, and complete resection of the skull lesion is often difficult to achieve [10–12]. Synthetic or plate reconstruction after tumor excision is generally performed to protect the brain and fill bone defects, but there are sometimes cosmetic issues, and the complications, such as infection, or motor impairment due to brain damage, cannot be denied. Tumor excision of skull lesions and reconstruction using a frozen autograft treated with liquid nitrogen have been rarely reported [26–28]. However, this cryotherapy treatment and orthotopic transplantation method not only eliminates the tumor cells, but it also provides for bone filling which perfectly matches the same size as the bone defect, while also reducing the incidence rates of complications [19, 20, 26–28]. The good histological efficacy of neoadjuvant chemotherapy for the primary lesion was observed in our case; thus, reconstruction using a frozen autograft treated with liquid nitrogen after tumor excision with a clear margin, was applied. After surgery, a bone union was achieved without postoperative complications or local recurrence (Fig. 8b).
In conclusion, SMOS including a skull lesion is rare; nevertheless, the early, correct diagnosis, and proper strategy of chemotherapy and surgery for all lesions, are essential for ensuring a good clinical outcome. Reconstruction using a frozen autograft treated with liquid nitrogen was found to be feasible for bone lesions, including a skull lesion, even in a case of multicentric osteosarcoma, when the histological efficacy of neoadjuvant chemotherapy for the primary lesion was good. Our patient achieved an excellent right shoulder function, and a good cosmetic and functional outcome without any complications by reconstruction by following reconstruction using a frozen autograft. In addition, clinically disease-free survival of over five years after the diagnosis can be obtained, although further follow-up with regular close examinations will be required, as the survival associated with this disease is commonly poor.
Abbreviations
SMOSSynchronous multicentric osteosarcoma
CTComputed tomogram
MRIMagnetic resonance imaging
ISOLSInternational society of limb salvage
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Acknowledgements
We thank the past and the present other members of our department for their work.
Authors’ contributions
T.H., Y.N., H.K., and A.Yos. conceived and designed the study. N.T. performed histological examination of all the specimen. A.Yos. carried out data acquisition. H.T., A.K.,T.Y., Y.H., M.Se., and A.Yoh. provided assistance for data acquisition. T.H., Y.N., H.K., T.A., M.Sh. and I.K. managed the patients for the appropriate treatment and observed them at the follow-up outpatient clinic after treatment completion. T.H., Y.N., H.K., and A.Yos. contributed to the analysis and interpretation of laboratory data and critical appraisal. A.Yos. analyzed all the patient's data and wrote the manuscript. All authors read and approved the final manuscript.
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Availability of data and materials
All data generated or analyzed during the present study are included in this published article.
Ethics approval and consent to participate
The study was approved by the Ethical Institutional Review Board of the Kanazawa University Hospital (2019-061 (3094)), and written informed consent was obtained from all study participants.
Consent for publication
The written consent for publication of the manuscript, including personal and clinical details, and any identifying images, from the patient and her parents was obtained by the Kanazawa University Hospital.
Competing interests
The authors declare no conflicts of interest in association with the present study. | EVERY THREE WEEKS | DrugDosageText | CC BY | 33482784 | 19,052,054 | 2021-01-22 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Adrenal insufficiency'. | A Case of Adrenal Insufficiency Diagnosed Using Optimal Dosing of Cosyntropin During Stimulation Testing.
BACKGROUND This case report illustrates the difficulties that arise during diagnosis of adrenal insufficiency, especially in the general medicine setting. Symptoms can often be nonspecific, and when a serum cortisol level is checked, further difficulty exists as to how to interpret the results. The 250-μg cosyntropin dose or 1-μg dose are available for use in the diagnosis of adrenal insufficiency, but each test has its own indications, which will be discussed. CASE REPORT A 45-year-old woman presented with nausea, emesis, chills, and diaphoresis, symptoms that concerning for adrenal insufficiency. Her random serum cortisol levels were relatively low. Her ACTH levels were within normal range. She received additional testing with the ACTH stimulation test using both the 1-μg and the 250-μg dose. The 1-μg test was performed in the evening and showed an inadequate adrenal response. The 250-μg dose test, which is the criterion standard, was performed the following morning and excluded adrenal insufficiency. CONCLUSIONS With the use of the high-dose ACTH stimulation test performed in the early morning, this patient was able to avoid lifelong steroid replacement therapy that could potentially suppress the hypothalamic-pituitary-adrenal (HPA) axis, which of itself can lead to adrenal insufficiency. Careful consideration is needed in choosing the right modalities for diagnosis of adrenal insufficiency.
Background
Symptoms of adrenal insufficiency can often be nonspecific, and the diagnosis may sometimes elude physicians until adrenal crisis occurs. However, when serum cortisol level is checked, further difficulty exists regarding how to interpret the results. The adrenocorticotropic hormone (ACTH) test, also referred to as the cosyntropin stimulation test, is then used to further categorize the patient as adrenally “sufficient” or “insufficient.” Careful selection of the ACTH dose is required to yield an appropriate adrenal response. The use of the 250-μg cosyntropin dose test, also referred to as the high-dose ACTH test, is the criterion standard test for diagnosis of primary adrenal insufficiency. The 1-μg dose test, also referred to as the low-dose test, is mostly reserved for diagnosis of secondary adrenal insufficiency. Both tests should be performed in the early morning. Careful consideration of the results produced during the diagnostic process is imperative to avoid mislabeling of patients with a disease that requires lifelong treatment.
Case Report
We report the case of a 45-year-old woman with a history of asthma and psoriasis who presented with emesis. Home medications included monthly TNF-alpha inhibitor injections for psoriasis, triamcinolone acetonide topical spray, and budesonideformoterol inhaler. The use of inhaled steroids was inconsistent and infrequent, as was the use of the steroid spray. She started the TNF-alpha inhibitor injections a few months before presentation. The patient reported increased urinary frequency with no dysuria and excessive water intake for 2 days prior to presentation. On the day of admission, she started having nausea, chills, and diaphoresis while at work, followed by 2 episodes of nonbloody nonbilious emesis. She also had associated palpitations, lightheadedness, leg cramps, and shortness of breath. She had no chest pain. When she arrived at the emergency room, she had blood pressure of 107/59 mmHg, heart rate of 89 beats/min, respiratory rate of 16 breaths/min, temperature of 36.5°C and oxygen saturation of 98% on room air. Her physical exam revealed cold, clammy distal extremities but was otherwise unremarkable. A work-up was negative for human chorionic gonadotropin (hCG), high-sensitivity troponin, d-dimer, urine drug toxicology, lipase, blood alcohol level, and acetaminophen level. A complete blood count (CBC) was unremarkable. Results of a comprehensive metabolic panel were concerning for anion gap metabolic acidosis, hyponatremia, and hypokalemia (Table 1). Magnesium and TSH were within normal range. She was treated with intravenous potassium and albuterol nebulizer. Her laboratory results returned normal the following day, except for a random serum cortisol of 6.4 mcg/dL. ACTH was 7 pg/dL (reference range 6–58 pg/mL). Due to concern for adrenal insufficiency, a 1-μg cosyntropin test was performed in the evening, which showed a peak cortisol concentration of less than 18 mcg/dL. As the response was assessed as suboptimal, Endocrinology was consulted to offer a treatment plan for steroids. However, it was discovered then that the use of 1-μg cosyntropin was unintentional and the timing of performance was inappropriate, as this should have been performed in the early morning. Once this was recognized, the test was repeated the following morning using the criterion standard 250-μg cosyntropin dose. The patient then showed an adequate response and she was not started on steroids.
Discussion
Thomas Addison was the first to describe adrenal insufficiency (AI) in 1855. It can either be of primary etiology when adrenal glands fail to produce hormones, or of central etiology when the pituitary gland or hypothalamus fail to produce releasing hormones that activate adrenal hormone production. Commonly described symptoms include fatigue, weakness, anorexia, abdominal pain, weight loss, orthostatic hypotension, and salt craving. Characteristic hyperpigmentation of the skin is seen with primary adrenal failure [1]. Since symptoms are nonspecific, it is generally difficult for physicians to diagnose AI; most patients present to providers with symptoms of adrenal insufficiency 3 of 4 times before a correct diagnosis is made. The timing of serum cortisol sampling can also affect diagnosis, since secretion depends on the circadian rhythm and on the state of health. Generally, a random serum cortisol of over 14.5 mcg/dL (or 400 nmol/L) at any time of the day makes adrenal insufficiency highly unlikely, while a morning serum cortisol of less than 3.6 mcg/dL (or 100 nmol/L) strongly suggests adrenal failure [2]. Our patient’s cortisol level was 6.4 mcg/dL, and adrenal insufficiency could not be excluded with this test result alone.
The ACTH stimulation test is used when serum cortisol levels cannot provide a certain diagnosis. In this test, 250 μg of intravenous synthetic ACTH is given to the patient and serum cortisol is measured 30 and 60 min later. Cortisol values exceeding 18 to 20 mcg/dL either at the 30- or 60-min mark usually represent a normal response [3]. This test should be performed when cortisol levels are 3–15 mcg/dL, as was the case with our patient. It cannot be used to diagnose secondary adrenal insufficiency of recent onset (within 4–6 weeks), as the adrenal glands are not completely atrophic yet and are still producing cortisol, as in pituitary apoplexy or recent pituitary surgery [4]. If testing occurs when the patient is acutely ill, the test should be repeated at a later date [2]. In our case, the patient exhibited low random cortisol levels, likely in the setting of acute illness (hypokalemia, asthma exacerbation), which prompted more investigation with an ACTH stimulation test (see comparison in Table 2). Instead of the criterion standard 250-μg ACTH stimulation test, a 1-μg test was ordered. Some suggest that the 1-mcg test can be used for diagnosis of primary AI and this is often done in clinical practice, but the 250-mcg test is the criterion standard for diagnosis according to the Endocrine Society guidelines [5]. There is concern that the 250-mcg test may lead to supraphysiologic stimulation of the HPA axis and false-positive results [6]. However, others argue that the 1-mcg test carries the risk of mislabeling healthy individuals as adrenally insufficient [7]. According to the Endocrine Society guidelines, the 1-mcg test should be used only when cosyntropin is in short supply, as this test has not been validated yet and more studies are needed to compare it to the 250-mcg test [5,6].
There are instances when the 1 mcg ACTH stim test can be used to screen for disturbances of the hypothalamo-pituitary-adrenocortical axis. The 1-μg ACTH stimulation test has been shown to be more sensitive than the 250-μg test in diagnosing secondary adrenal insufficiency [8]. Our patient, however, had a normal ACTH level (7 pg/dL, with a reference range of 6–58 pg/mL); therefore, the use of a 250-μg test was most appropriate according to current guidelines [5]. The 1-μg test has also been shown to be superior in diagnosing adrenal insufficiency in critically ill ICU patients, although more studies are needed to validate this [3].
Chronic use of glucocorticoids can lead to adverse effects such as cardiovascular disease, hyperglycemia, infections, osteoporosis, neuropsychiatric events, and growth failure in children [9].
Gastrointestinal, ophthalmologic, and dermatologic disturbances are common as well [10]. Steroids exert negative feedback control on the HPA axis by suppressing the hypothalamus which produces corticotropin-releasing hormone (CRH) and the pituitary gland which produces ACTH. Since the adrenal glands are not stimulated anymore by the released hormones to produce cortisol, the result of chronic suppression is adrenal atrophy, especially when using high-dose steroids [9]. In our case, the long-term administration of steroid therapy to the patient was avoided with careful review of the diagnostic process and patient history, which prevented the development of all the above-mentioned adverse effects to an otherwise healthy individual.
It is important to note that steroid doses equivalent to 7.5 mg of prednisolone taken for 3 weeks or longer can lead to adrenal suppression. However, it has been found that people taking medications that reduce steroid metabolism (e.g., potent CYP3A4 inhibitors) can develop HPA axis suppression with co-administration of even small doses of exogenous steroid (typically, inhaled fluticasone) [2]. Our patient was not on any CYP3A4 inhibitors and her sporadic use of topical and inhaled steroid was very unlikely to have caused secondary AI due to withdrawal of medications.
Conclusions
This case demonstrates how the 250-μg ACTH (high-dose) stimulation test should be used for diagnosis of primary adrenal insufficiency (AI), as it is still the criterion standard. The 1-μg ACTH (low-dose) stimulation test can be used for diagnosis of primary AI, but only when the high-dose test is not available. On the other hand, the 1-μg ACTH stimulation test has been shown to be more sensitive than the 250-μg test in diagnosing secondary adrenal insufficiency. Both tests should be performed in the early morning. The clinician can offer the patient the best treatment strategies only after correctly using the most appropriate test. Our patient was an adrenally “sufficient” individual who did not require chronic replacement therapy. The steroids in this case could have harmed the patient, as long-term administration of this unnecessary medicine would have carried a multitude of adverse effects, including the risk of adrenal gland suppression. If further diagnostic difficulty exists, testing can always be repeated at a later date.
We thank Dr. Faisal Qureshi, who provided us with this case and who has provided superior mentoring in the field of Endocrinology for the residents of Saint Francis Hospital in Evanston, IL.
Table 1. Comprehensive metabolic panel (CMP) on day of admission.
Reference range
Glucose 170 mg/dL 70–99 mg/dL
BUN 10 mg/dL 7–25 mg/dL
Creatinine 0.71 mg/dL 0.6–1.2 mg/dL
Sodium 131 mmol/L 133–144 mmol/L
Potassium 2.9 mmol/L 3.5–5.1 mmol/L
Chloride 96 mmol/L 98–107 mmol/L
Table 2. Comparison between the 2 ACTH stimulation tests.
1 μg cosyntropin 250 μg cosyntropin
Cortisol#1 (base) 1.3 mcg/dL N/A
Cortisol 30 min 16.10 mcg/dL 19.9 mcg/dL
Cortisol 60 min 10.00 mcg/dL 24.5 mcg/dL
ACTH – adrenocorticotropic hormone. | BUDESONIDE\FORMOTEROL, TRIAMCINOLONE ACETONIDE | DrugsGivenReaction | CC BY-NC-ND | 33483462 | 18,927,415 | 2021-01-23 |
What was the dosage of drug 'BUDESONIDE\FORMOTEROL'? | A Case of Adrenal Insufficiency Diagnosed Using Optimal Dosing of Cosyntropin During Stimulation Testing.
BACKGROUND This case report illustrates the difficulties that arise during diagnosis of adrenal insufficiency, especially in the general medicine setting. Symptoms can often be nonspecific, and when a serum cortisol level is checked, further difficulty exists as to how to interpret the results. The 250-μg cosyntropin dose or 1-μg dose are available for use in the diagnosis of adrenal insufficiency, but each test has its own indications, which will be discussed. CASE REPORT A 45-year-old woman presented with nausea, emesis, chills, and diaphoresis, symptoms that concerning for adrenal insufficiency. Her random serum cortisol levels were relatively low. Her ACTH levels were within normal range. She received additional testing with the ACTH stimulation test using both the 1-μg and the 250-μg dose. The 1-μg test was performed in the evening and showed an inadequate adrenal response. The 250-μg dose test, which is the criterion standard, was performed the following morning and excluded adrenal insufficiency. CONCLUSIONS With the use of the high-dose ACTH stimulation test performed in the early morning, this patient was able to avoid lifelong steroid replacement therapy that could potentially suppress the hypothalamic-pituitary-adrenal (HPA) axis, which of itself can lead to adrenal insufficiency. Careful consideration is needed in choosing the right modalities for diagnosis of adrenal insufficiency.
Background
Symptoms of adrenal insufficiency can often be nonspecific, and the diagnosis may sometimes elude physicians until adrenal crisis occurs. However, when serum cortisol level is checked, further difficulty exists regarding how to interpret the results. The adrenocorticotropic hormone (ACTH) test, also referred to as the cosyntropin stimulation test, is then used to further categorize the patient as adrenally “sufficient” or “insufficient.” Careful selection of the ACTH dose is required to yield an appropriate adrenal response. The use of the 250-μg cosyntropin dose test, also referred to as the high-dose ACTH test, is the criterion standard test for diagnosis of primary adrenal insufficiency. The 1-μg dose test, also referred to as the low-dose test, is mostly reserved for diagnosis of secondary adrenal insufficiency. Both tests should be performed in the early morning. Careful consideration of the results produced during the diagnostic process is imperative to avoid mislabeling of patients with a disease that requires lifelong treatment.
Case Report
We report the case of a 45-year-old woman with a history of asthma and psoriasis who presented with emesis. Home medications included monthly TNF-alpha inhibitor injections for psoriasis, triamcinolone acetonide topical spray, and budesonideformoterol inhaler. The use of inhaled steroids was inconsistent and infrequent, as was the use of the steroid spray. She started the TNF-alpha inhibitor injections a few months before presentation. The patient reported increased urinary frequency with no dysuria and excessive water intake for 2 days prior to presentation. On the day of admission, she started having nausea, chills, and diaphoresis while at work, followed by 2 episodes of nonbloody nonbilious emesis. She also had associated palpitations, lightheadedness, leg cramps, and shortness of breath. She had no chest pain. When she arrived at the emergency room, she had blood pressure of 107/59 mmHg, heart rate of 89 beats/min, respiratory rate of 16 breaths/min, temperature of 36.5°C and oxygen saturation of 98% on room air. Her physical exam revealed cold, clammy distal extremities but was otherwise unremarkable. A work-up was negative for human chorionic gonadotropin (hCG), high-sensitivity troponin, d-dimer, urine drug toxicology, lipase, blood alcohol level, and acetaminophen level. A complete blood count (CBC) was unremarkable. Results of a comprehensive metabolic panel were concerning for anion gap metabolic acidosis, hyponatremia, and hypokalemia (Table 1). Magnesium and TSH were within normal range. She was treated with intravenous potassium and albuterol nebulizer. Her laboratory results returned normal the following day, except for a random serum cortisol of 6.4 mcg/dL. ACTH was 7 pg/dL (reference range 6–58 pg/mL). Due to concern for adrenal insufficiency, a 1-μg cosyntropin test was performed in the evening, which showed a peak cortisol concentration of less than 18 mcg/dL. As the response was assessed as suboptimal, Endocrinology was consulted to offer a treatment plan for steroids. However, it was discovered then that the use of 1-μg cosyntropin was unintentional and the timing of performance was inappropriate, as this should have been performed in the early morning. Once this was recognized, the test was repeated the following morning using the criterion standard 250-μg cosyntropin dose. The patient then showed an adequate response and she was not started on steroids.
Discussion
Thomas Addison was the first to describe adrenal insufficiency (AI) in 1855. It can either be of primary etiology when adrenal glands fail to produce hormones, or of central etiology when the pituitary gland or hypothalamus fail to produce releasing hormones that activate adrenal hormone production. Commonly described symptoms include fatigue, weakness, anorexia, abdominal pain, weight loss, orthostatic hypotension, and salt craving. Characteristic hyperpigmentation of the skin is seen with primary adrenal failure [1]. Since symptoms are nonspecific, it is generally difficult for physicians to diagnose AI; most patients present to providers with symptoms of adrenal insufficiency 3 of 4 times before a correct diagnosis is made. The timing of serum cortisol sampling can also affect diagnosis, since secretion depends on the circadian rhythm and on the state of health. Generally, a random serum cortisol of over 14.5 mcg/dL (or 400 nmol/L) at any time of the day makes adrenal insufficiency highly unlikely, while a morning serum cortisol of less than 3.6 mcg/dL (or 100 nmol/L) strongly suggests adrenal failure [2]. Our patient’s cortisol level was 6.4 mcg/dL, and adrenal insufficiency could not be excluded with this test result alone.
The ACTH stimulation test is used when serum cortisol levels cannot provide a certain diagnosis. In this test, 250 μg of intravenous synthetic ACTH is given to the patient and serum cortisol is measured 30 and 60 min later. Cortisol values exceeding 18 to 20 mcg/dL either at the 30- or 60-min mark usually represent a normal response [3]. This test should be performed when cortisol levels are 3–15 mcg/dL, as was the case with our patient. It cannot be used to diagnose secondary adrenal insufficiency of recent onset (within 4–6 weeks), as the adrenal glands are not completely atrophic yet and are still producing cortisol, as in pituitary apoplexy or recent pituitary surgery [4]. If testing occurs when the patient is acutely ill, the test should be repeated at a later date [2]. In our case, the patient exhibited low random cortisol levels, likely in the setting of acute illness (hypokalemia, asthma exacerbation), which prompted more investigation with an ACTH stimulation test (see comparison in Table 2). Instead of the criterion standard 250-μg ACTH stimulation test, a 1-μg test was ordered. Some suggest that the 1-mcg test can be used for diagnosis of primary AI and this is often done in clinical practice, but the 250-mcg test is the criterion standard for diagnosis according to the Endocrine Society guidelines [5]. There is concern that the 250-mcg test may lead to supraphysiologic stimulation of the HPA axis and false-positive results [6]. However, others argue that the 1-mcg test carries the risk of mislabeling healthy individuals as adrenally insufficient [7]. According to the Endocrine Society guidelines, the 1-mcg test should be used only when cosyntropin is in short supply, as this test has not been validated yet and more studies are needed to compare it to the 250-mcg test [5,6].
There are instances when the 1 mcg ACTH stim test can be used to screen for disturbances of the hypothalamo-pituitary-adrenocortical axis. The 1-μg ACTH stimulation test has been shown to be more sensitive than the 250-μg test in diagnosing secondary adrenal insufficiency [8]. Our patient, however, had a normal ACTH level (7 pg/dL, with a reference range of 6–58 pg/mL); therefore, the use of a 250-μg test was most appropriate according to current guidelines [5]. The 1-μg test has also been shown to be superior in diagnosing adrenal insufficiency in critically ill ICU patients, although more studies are needed to validate this [3].
Chronic use of glucocorticoids can lead to adverse effects such as cardiovascular disease, hyperglycemia, infections, osteoporosis, neuropsychiatric events, and growth failure in children [9].
Gastrointestinal, ophthalmologic, and dermatologic disturbances are common as well [10]. Steroids exert negative feedback control on the HPA axis by suppressing the hypothalamus which produces corticotropin-releasing hormone (CRH) and the pituitary gland which produces ACTH. Since the adrenal glands are not stimulated anymore by the released hormones to produce cortisol, the result of chronic suppression is adrenal atrophy, especially when using high-dose steroids [9]. In our case, the long-term administration of steroid therapy to the patient was avoided with careful review of the diagnostic process and patient history, which prevented the development of all the above-mentioned adverse effects to an otherwise healthy individual.
It is important to note that steroid doses equivalent to 7.5 mg of prednisolone taken for 3 weeks or longer can lead to adrenal suppression. However, it has been found that people taking medications that reduce steroid metabolism (e.g., potent CYP3A4 inhibitors) can develop HPA axis suppression with co-administration of even small doses of exogenous steroid (typically, inhaled fluticasone) [2]. Our patient was not on any CYP3A4 inhibitors and her sporadic use of topical and inhaled steroid was very unlikely to have caused secondary AI due to withdrawal of medications.
Conclusions
This case demonstrates how the 250-μg ACTH (high-dose) stimulation test should be used for diagnosis of primary adrenal insufficiency (AI), as it is still the criterion standard. The 1-μg ACTH (low-dose) stimulation test can be used for diagnosis of primary AI, but only when the high-dose test is not available. On the other hand, the 1-μg ACTH stimulation test has been shown to be more sensitive than the 250-μg test in diagnosing secondary adrenal insufficiency. Both tests should be performed in the early morning. The clinician can offer the patient the best treatment strategies only after correctly using the most appropriate test. Our patient was an adrenally “sufficient” individual who did not require chronic replacement therapy. The steroids in this case could have harmed the patient, as long-term administration of this unnecessary medicine would have carried a multitude of adverse effects, including the risk of adrenal gland suppression. If further diagnostic difficulty exists, testing can always be repeated at a later date.
We thank Dr. Faisal Qureshi, who provided us with this case and who has provided superior mentoring in the field of Endocrinology for the residents of Saint Francis Hospital in Evanston, IL.
Table 1. Comprehensive metabolic panel (CMP) on day of admission.
Reference range
Glucose 170 mg/dL 70–99 mg/dL
BUN 10 mg/dL 7–25 mg/dL
Creatinine 0.71 mg/dL 0.6–1.2 mg/dL
Sodium 131 mmol/L 133–144 mmol/L
Potassium 2.9 mmol/L 3.5–5.1 mmol/L
Chloride 96 mmol/L 98–107 mmol/L
Table 2. Comparison between the 2 ACTH stimulation tests.
1 μg cosyntropin 250 μg cosyntropin
Cortisol#1 (base) 1.3 mcg/dL N/A
Cortisol 30 min 16.10 mcg/dL 19.9 mcg/dL
Cortisol 60 min 10.00 mcg/dL 24.5 mcg/dL
ACTH – adrenocorticotropic hormone. | INHALER, UNK | DrugDosageText | CC BY-NC-ND | 33483462 | 18,927,415 | 2021-01-23 |
What was the dosage of drug 'TRIAMCINOLONE ACETONIDE'? | A Case of Adrenal Insufficiency Diagnosed Using Optimal Dosing of Cosyntropin During Stimulation Testing.
BACKGROUND This case report illustrates the difficulties that arise during diagnosis of adrenal insufficiency, especially in the general medicine setting. Symptoms can often be nonspecific, and when a serum cortisol level is checked, further difficulty exists as to how to interpret the results. The 250-μg cosyntropin dose or 1-μg dose are available for use in the diagnosis of adrenal insufficiency, but each test has its own indications, which will be discussed. CASE REPORT A 45-year-old woman presented with nausea, emesis, chills, and diaphoresis, symptoms that concerning for adrenal insufficiency. Her random serum cortisol levels were relatively low. Her ACTH levels were within normal range. She received additional testing with the ACTH stimulation test using both the 1-μg and the 250-μg dose. The 1-μg test was performed in the evening and showed an inadequate adrenal response. The 250-μg dose test, which is the criterion standard, was performed the following morning and excluded adrenal insufficiency. CONCLUSIONS With the use of the high-dose ACTH stimulation test performed in the early morning, this patient was able to avoid lifelong steroid replacement therapy that could potentially suppress the hypothalamic-pituitary-adrenal (HPA) axis, which of itself can lead to adrenal insufficiency. Careful consideration is needed in choosing the right modalities for diagnosis of adrenal insufficiency.
Background
Symptoms of adrenal insufficiency can often be nonspecific, and the diagnosis may sometimes elude physicians until adrenal crisis occurs. However, when serum cortisol level is checked, further difficulty exists regarding how to interpret the results. The adrenocorticotropic hormone (ACTH) test, also referred to as the cosyntropin stimulation test, is then used to further categorize the patient as adrenally “sufficient” or “insufficient.” Careful selection of the ACTH dose is required to yield an appropriate adrenal response. The use of the 250-μg cosyntropin dose test, also referred to as the high-dose ACTH test, is the criterion standard test for diagnosis of primary adrenal insufficiency. The 1-μg dose test, also referred to as the low-dose test, is mostly reserved for diagnosis of secondary adrenal insufficiency. Both tests should be performed in the early morning. Careful consideration of the results produced during the diagnostic process is imperative to avoid mislabeling of patients with a disease that requires lifelong treatment.
Case Report
We report the case of a 45-year-old woman with a history of asthma and psoriasis who presented with emesis. Home medications included monthly TNF-alpha inhibitor injections for psoriasis, triamcinolone acetonide topical spray, and budesonideformoterol inhaler. The use of inhaled steroids was inconsistent and infrequent, as was the use of the steroid spray. She started the TNF-alpha inhibitor injections a few months before presentation. The patient reported increased urinary frequency with no dysuria and excessive water intake for 2 days prior to presentation. On the day of admission, she started having nausea, chills, and diaphoresis while at work, followed by 2 episodes of nonbloody nonbilious emesis. She also had associated palpitations, lightheadedness, leg cramps, and shortness of breath. She had no chest pain. When she arrived at the emergency room, she had blood pressure of 107/59 mmHg, heart rate of 89 beats/min, respiratory rate of 16 breaths/min, temperature of 36.5°C and oxygen saturation of 98% on room air. Her physical exam revealed cold, clammy distal extremities but was otherwise unremarkable. A work-up was negative for human chorionic gonadotropin (hCG), high-sensitivity troponin, d-dimer, urine drug toxicology, lipase, blood alcohol level, and acetaminophen level. A complete blood count (CBC) was unremarkable. Results of a comprehensive metabolic panel were concerning for anion gap metabolic acidosis, hyponatremia, and hypokalemia (Table 1). Magnesium and TSH were within normal range. She was treated with intravenous potassium and albuterol nebulizer. Her laboratory results returned normal the following day, except for a random serum cortisol of 6.4 mcg/dL. ACTH was 7 pg/dL (reference range 6–58 pg/mL). Due to concern for adrenal insufficiency, a 1-μg cosyntropin test was performed in the evening, which showed a peak cortisol concentration of less than 18 mcg/dL. As the response was assessed as suboptimal, Endocrinology was consulted to offer a treatment plan for steroids. However, it was discovered then that the use of 1-μg cosyntropin was unintentional and the timing of performance was inappropriate, as this should have been performed in the early morning. Once this was recognized, the test was repeated the following morning using the criterion standard 250-μg cosyntropin dose. The patient then showed an adequate response and she was not started on steroids.
Discussion
Thomas Addison was the first to describe adrenal insufficiency (AI) in 1855. It can either be of primary etiology when adrenal glands fail to produce hormones, or of central etiology when the pituitary gland or hypothalamus fail to produce releasing hormones that activate adrenal hormone production. Commonly described symptoms include fatigue, weakness, anorexia, abdominal pain, weight loss, orthostatic hypotension, and salt craving. Characteristic hyperpigmentation of the skin is seen with primary adrenal failure [1]. Since symptoms are nonspecific, it is generally difficult for physicians to diagnose AI; most patients present to providers with symptoms of adrenal insufficiency 3 of 4 times before a correct diagnosis is made. The timing of serum cortisol sampling can also affect diagnosis, since secretion depends on the circadian rhythm and on the state of health. Generally, a random serum cortisol of over 14.5 mcg/dL (or 400 nmol/L) at any time of the day makes adrenal insufficiency highly unlikely, while a morning serum cortisol of less than 3.6 mcg/dL (or 100 nmol/L) strongly suggests adrenal failure [2]. Our patient’s cortisol level was 6.4 mcg/dL, and adrenal insufficiency could not be excluded with this test result alone.
The ACTH stimulation test is used when serum cortisol levels cannot provide a certain diagnosis. In this test, 250 μg of intravenous synthetic ACTH is given to the patient and serum cortisol is measured 30 and 60 min later. Cortisol values exceeding 18 to 20 mcg/dL either at the 30- or 60-min mark usually represent a normal response [3]. This test should be performed when cortisol levels are 3–15 mcg/dL, as was the case with our patient. It cannot be used to diagnose secondary adrenal insufficiency of recent onset (within 4–6 weeks), as the adrenal glands are not completely atrophic yet and are still producing cortisol, as in pituitary apoplexy or recent pituitary surgery [4]. If testing occurs when the patient is acutely ill, the test should be repeated at a later date [2]. In our case, the patient exhibited low random cortisol levels, likely in the setting of acute illness (hypokalemia, asthma exacerbation), which prompted more investigation with an ACTH stimulation test (see comparison in Table 2). Instead of the criterion standard 250-μg ACTH stimulation test, a 1-μg test was ordered. Some suggest that the 1-mcg test can be used for diagnosis of primary AI and this is often done in clinical practice, but the 250-mcg test is the criterion standard for diagnosis according to the Endocrine Society guidelines [5]. There is concern that the 250-mcg test may lead to supraphysiologic stimulation of the HPA axis and false-positive results [6]. However, others argue that the 1-mcg test carries the risk of mislabeling healthy individuals as adrenally insufficient [7]. According to the Endocrine Society guidelines, the 1-mcg test should be used only when cosyntropin is in short supply, as this test has not been validated yet and more studies are needed to compare it to the 250-mcg test [5,6].
There are instances when the 1 mcg ACTH stim test can be used to screen for disturbances of the hypothalamo-pituitary-adrenocortical axis. The 1-μg ACTH stimulation test has been shown to be more sensitive than the 250-μg test in diagnosing secondary adrenal insufficiency [8]. Our patient, however, had a normal ACTH level (7 pg/dL, with a reference range of 6–58 pg/mL); therefore, the use of a 250-μg test was most appropriate according to current guidelines [5]. The 1-μg test has also been shown to be superior in diagnosing adrenal insufficiency in critically ill ICU patients, although more studies are needed to validate this [3].
Chronic use of glucocorticoids can lead to adverse effects such as cardiovascular disease, hyperglycemia, infections, osteoporosis, neuropsychiatric events, and growth failure in children [9].
Gastrointestinal, ophthalmologic, and dermatologic disturbances are common as well [10]. Steroids exert negative feedback control on the HPA axis by suppressing the hypothalamus which produces corticotropin-releasing hormone (CRH) and the pituitary gland which produces ACTH. Since the adrenal glands are not stimulated anymore by the released hormones to produce cortisol, the result of chronic suppression is adrenal atrophy, especially when using high-dose steroids [9]. In our case, the long-term administration of steroid therapy to the patient was avoided with careful review of the diagnostic process and patient history, which prevented the development of all the above-mentioned adverse effects to an otherwise healthy individual.
It is important to note that steroid doses equivalent to 7.5 mg of prednisolone taken for 3 weeks or longer can lead to adrenal suppression. However, it has been found that people taking medications that reduce steroid metabolism (e.g., potent CYP3A4 inhibitors) can develop HPA axis suppression with co-administration of even small doses of exogenous steroid (typically, inhaled fluticasone) [2]. Our patient was not on any CYP3A4 inhibitors and her sporadic use of topical and inhaled steroid was very unlikely to have caused secondary AI due to withdrawal of medications.
Conclusions
This case demonstrates how the 250-μg ACTH (high-dose) stimulation test should be used for diagnosis of primary adrenal insufficiency (AI), as it is still the criterion standard. The 1-μg ACTH (low-dose) stimulation test can be used for diagnosis of primary AI, but only when the high-dose test is not available. On the other hand, the 1-μg ACTH stimulation test has been shown to be more sensitive than the 250-μg test in diagnosing secondary adrenal insufficiency. Both tests should be performed in the early morning. The clinician can offer the patient the best treatment strategies only after correctly using the most appropriate test. Our patient was an adrenally “sufficient” individual who did not require chronic replacement therapy. The steroids in this case could have harmed the patient, as long-term administration of this unnecessary medicine would have carried a multitude of adverse effects, including the risk of adrenal gland suppression. If further diagnostic difficulty exists, testing can always be repeated at a later date.
We thank Dr. Faisal Qureshi, who provided us with this case and who has provided superior mentoring in the field of Endocrinology for the residents of Saint Francis Hospital in Evanston, IL.
Table 1. Comprehensive metabolic panel (CMP) on day of admission.
Reference range
Glucose 170 mg/dL 70–99 mg/dL
BUN 10 mg/dL 7–25 mg/dL
Creatinine 0.71 mg/dL 0.6–1.2 mg/dL
Sodium 131 mmol/L 133–144 mmol/L
Potassium 2.9 mmol/L 3.5–5.1 mmol/L
Chloride 96 mmol/L 98–107 mmol/L
Table 2. Comparison between the 2 ACTH stimulation tests.
1 μg cosyntropin 250 μg cosyntropin
Cortisol#1 (base) 1.3 mcg/dL N/A
Cortisol 30 min 16.10 mcg/dL 19.9 mcg/dL
Cortisol 60 min 10.00 mcg/dL 24.5 mcg/dL
ACTH – adrenocorticotropic hormone. | UNK,TOPICAL SPRAY | DrugDosageText | CC BY-NC-ND | 33483462 | 18,927,415 | 2021-01-23 |
What was the outcome of reaction 'Adrenal insufficiency'? | A Case of Adrenal Insufficiency Diagnosed Using Optimal Dosing of Cosyntropin During Stimulation Testing.
BACKGROUND This case report illustrates the difficulties that arise during diagnosis of adrenal insufficiency, especially in the general medicine setting. Symptoms can often be nonspecific, and when a serum cortisol level is checked, further difficulty exists as to how to interpret the results. The 250-μg cosyntropin dose or 1-μg dose are available for use in the diagnosis of adrenal insufficiency, but each test has its own indications, which will be discussed. CASE REPORT A 45-year-old woman presented with nausea, emesis, chills, and diaphoresis, symptoms that concerning for adrenal insufficiency. Her random serum cortisol levels were relatively low. Her ACTH levels were within normal range. She received additional testing with the ACTH stimulation test using both the 1-μg and the 250-μg dose. The 1-μg test was performed in the evening and showed an inadequate adrenal response. The 250-μg dose test, which is the criterion standard, was performed the following morning and excluded adrenal insufficiency. CONCLUSIONS With the use of the high-dose ACTH stimulation test performed in the early morning, this patient was able to avoid lifelong steroid replacement therapy that could potentially suppress the hypothalamic-pituitary-adrenal (HPA) axis, which of itself can lead to adrenal insufficiency. Careful consideration is needed in choosing the right modalities for diagnosis of adrenal insufficiency.
Background
Symptoms of adrenal insufficiency can often be nonspecific, and the diagnosis may sometimes elude physicians until adrenal crisis occurs. However, when serum cortisol level is checked, further difficulty exists regarding how to interpret the results. The adrenocorticotropic hormone (ACTH) test, also referred to as the cosyntropin stimulation test, is then used to further categorize the patient as adrenally “sufficient” or “insufficient.” Careful selection of the ACTH dose is required to yield an appropriate adrenal response. The use of the 250-μg cosyntropin dose test, also referred to as the high-dose ACTH test, is the criterion standard test for diagnosis of primary adrenal insufficiency. The 1-μg dose test, also referred to as the low-dose test, is mostly reserved for diagnosis of secondary adrenal insufficiency. Both tests should be performed in the early morning. Careful consideration of the results produced during the diagnostic process is imperative to avoid mislabeling of patients with a disease that requires lifelong treatment.
Case Report
We report the case of a 45-year-old woman with a history of asthma and psoriasis who presented with emesis. Home medications included monthly TNF-alpha inhibitor injections for psoriasis, triamcinolone acetonide topical spray, and budesonideformoterol inhaler. The use of inhaled steroids was inconsistent and infrequent, as was the use of the steroid spray. She started the TNF-alpha inhibitor injections a few months before presentation. The patient reported increased urinary frequency with no dysuria and excessive water intake for 2 days prior to presentation. On the day of admission, she started having nausea, chills, and diaphoresis while at work, followed by 2 episodes of nonbloody nonbilious emesis. She also had associated palpitations, lightheadedness, leg cramps, and shortness of breath. She had no chest pain. When she arrived at the emergency room, she had blood pressure of 107/59 mmHg, heart rate of 89 beats/min, respiratory rate of 16 breaths/min, temperature of 36.5°C and oxygen saturation of 98% on room air. Her physical exam revealed cold, clammy distal extremities but was otherwise unremarkable. A work-up was negative for human chorionic gonadotropin (hCG), high-sensitivity troponin, d-dimer, urine drug toxicology, lipase, blood alcohol level, and acetaminophen level. A complete blood count (CBC) was unremarkable. Results of a comprehensive metabolic panel were concerning for anion gap metabolic acidosis, hyponatremia, and hypokalemia (Table 1). Magnesium and TSH were within normal range. She was treated with intravenous potassium and albuterol nebulizer. Her laboratory results returned normal the following day, except for a random serum cortisol of 6.4 mcg/dL. ACTH was 7 pg/dL (reference range 6–58 pg/mL). Due to concern for adrenal insufficiency, a 1-μg cosyntropin test was performed in the evening, which showed a peak cortisol concentration of less than 18 mcg/dL. As the response was assessed as suboptimal, Endocrinology was consulted to offer a treatment plan for steroids. However, it was discovered then that the use of 1-μg cosyntropin was unintentional and the timing of performance was inappropriate, as this should have been performed in the early morning. Once this was recognized, the test was repeated the following morning using the criterion standard 250-μg cosyntropin dose. The patient then showed an adequate response and she was not started on steroids.
Discussion
Thomas Addison was the first to describe adrenal insufficiency (AI) in 1855. It can either be of primary etiology when adrenal glands fail to produce hormones, or of central etiology when the pituitary gland or hypothalamus fail to produce releasing hormones that activate adrenal hormone production. Commonly described symptoms include fatigue, weakness, anorexia, abdominal pain, weight loss, orthostatic hypotension, and salt craving. Characteristic hyperpigmentation of the skin is seen with primary adrenal failure [1]. Since symptoms are nonspecific, it is generally difficult for physicians to diagnose AI; most patients present to providers with symptoms of adrenal insufficiency 3 of 4 times before a correct diagnosis is made. The timing of serum cortisol sampling can also affect diagnosis, since secretion depends on the circadian rhythm and on the state of health. Generally, a random serum cortisol of over 14.5 mcg/dL (or 400 nmol/L) at any time of the day makes adrenal insufficiency highly unlikely, while a morning serum cortisol of less than 3.6 mcg/dL (or 100 nmol/L) strongly suggests adrenal failure [2]. Our patient’s cortisol level was 6.4 mcg/dL, and adrenal insufficiency could not be excluded with this test result alone.
The ACTH stimulation test is used when serum cortisol levels cannot provide a certain diagnosis. In this test, 250 μg of intravenous synthetic ACTH is given to the patient and serum cortisol is measured 30 and 60 min later. Cortisol values exceeding 18 to 20 mcg/dL either at the 30- or 60-min mark usually represent a normal response [3]. This test should be performed when cortisol levels are 3–15 mcg/dL, as was the case with our patient. It cannot be used to diagnose secondary adrenal insufficiency of recent onset (within 4–6 weeks), as the adrenal glands are not completely atrophic yet and are still producing cortisol, as in pituitary apoplexy or recent pituitary surgery [4]. If testing occurs when the patient is acutely ill, the test should be repeated at a later date [2]. In our case, the patient exhibited low random cortisol levels, likely in the setting of acute illness (hypokalemia, asthma exacerbation), which prompted more investigation with an ACTH stimulation test (see comparison in Table 2). Instead of the criterion standard 250-μg ACTH stimulation test, a 1-μg test was ordered. Some suggest that the 1-mcg test can be used for diagnosis of primary AI and this is often done in clinical practice, but the 250-mcg test is the criterion standard for diagnosis according to the Endocrine Society guidelines [5]. There is concern that the 250-mcg test may lead to supraphysiologic stimulation of the HPA axis and false-positive results [6]. However, others argue that the 1-mcg test carries the risk of mislabeling healthy individuals as adrenally insufficient [7]. According to the Endocrine Society guidelines, the 1-mcg test should be used only when cosyntropin is in short supply, as this test has not been validated yet and more studies are needed to compare it to the 250-mcg test [5,6].
There are instances when the 1 mcg ACTH stim test can be used to screen for disturbances of the hypothalamo-pituitary-adrenocortical axis. The 1-μg ACTH stimulation test has been shown to be more sensitive than the 250-μg test in diagnosing secondary adrenal insufficiency [8]. Our patient, however, had a normal ACTH level (7 pg/dL, with a reference range of 6–58 pg/mL); therefore, the use of a 250-μg test was most appropriate according to current guidelines [5]. The 1-μg test has also been shown to be superior in diagnosing adrenal insufficiency in critically ill ICU patients, although more studies are needed to validate this [3].
Chronic use of glucocorticoids can lead to adverse effects such as cardiovascular disease, hyperglycemia, infections, osteoporosis, neuropsychiatric events, and growth failure in children [9].
Gastrointestinal, ophthalmologic, and dermatologic disturbances are common as well [10]. Steroids exert negative feedback control on the HPA axis by suppressing the hypothalamus which produces corticotropin-releasing hormone (CRH) and the pituitary gland which produces ACTH. Since the adrenal glands are not stimulated anymore by the released hormones to produce cortisol, the result of chronic suppression is adrenal atrophy, especially when using high-dose steroids [9]. In our case, the long-term administration of steroid therapy to the patient was avoided with careful review of the diagnostic process and patient history, which prevented the development of all the above-mentioned adverse effects to an otherwise healthy individual.
It is important to note that steroid doses equivalent to 7.5 mg of prednisolone taken for 3 weeks or longer can lead to adrenal suppression. However, it has been found that people taking medications that reduce steroid metabolism (e.g., potent CYP3A4 inhibitors) can develop HPA axis suppression with co-administration of even small doses of exogenous steroid (typically, inhaled fluticasone) [2]. Our patient was not on any CYP3A4 inhibitors and her sporadic use of topical and inhaled steroid was very unlikely to have caused secondary AI due to withdrawal of medications.
Conclusions
This case demonstrates how the 250-μg ACTH (high-dose) stimulation test should be used for diagnosis of primary adrenal insufficiency (AI), as it is still the criterion standard. The 1-μg ACTH (low-dose) stimulation test can be used for diagnosis of primary AI, but only when the high-dose test is not available. On the other hand, the 1-μg ACTH stimulation test has been shown to be more sensitive than the 250-μg test in diagnosing secondary adrenal insufficiency. Both tests should be performed in the early morning. The clinician can offer the patient the best treatment strategies only after correctly using the most appropriate test. Our patient was an adrenally “sufficient” individual who did not require chronic replacement therapy. The steroids in this case could have harmed the patient, as long-term administration of this unnecessary medicine would have carried a multitude of adverse effects, including the risk of adrenal gland suppression. If further diagnostic difficulty exists, testing can always be repeated at a later date.
We thank Dr. Faisal Qureshi, who provided us with this case and who has provided superior mentoring in the field of Endocrinology for the residents of Saint Francis Hospital in Evanston, IL.
Table 1. Comprehensive metabolic panel (CMP) on day of admission.
Reference range
Glucose 170 mg/dL 70–99 mg/dL
BUN 10 mg/dL 7–25 mg/dL
Creatinine 0.71 mg/dL 0.6–1.2 mg/dL
Sodium 131 mmol/L 133–144 mmol/L
Potassium 2.9 mmol/L 3.5–5.1 mmol/L
Chloride 96 mmol/L 98–107 mmol/L
Table 2. Comparison between the 2 ACTH stimulation tests.
1 μg cosyntropin 250 μg cosyntropin
Cortisol#1 (base) 1.3 mcg/dL N/A
Cortisol 30 min 16.10 mcg/dL 19.9 mcg/dL
Cortisol 60 min 10.00 mcg/dL 24.5 mcg/dL
ACTH – adrenocorticotropic hormone. | Recovering | ReactionOutcome | CC BY-NC-ND | 33483462 | 18,927,415 | 2021-01-23 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Adenocarcinoma'. | Development of an optimal protocol for molecular profiling of tumor cells in pleural effusions at single-cell level.
Liquid biopsy analyzes the current status of primary tumors and their metastatic regions. We aimed to develop an optimized protocol for single-cell sequencing of floating tumor cells (FTCs) in pleural effusion as a laboratory test. FTCs were enriched using a negative selection of white blood cells by a magnetic-activated cell sorting system, and CD45-negative and cytokeratin-positive selection using a microfluidic cell separation system with a dielectrophoretic array. The enriched tumor cells were subjected to whole-genome amplification (WGA) followed by genome sequencing. The FTC analysis detected an EGFR exon 19 deletion in Case 1 (12/19 cells, 63.2%), and EML4-ALK fusion (17/20 cells, 85%) with an alectinib-resistant mutation of ALK (p.G1202R) in Case 2. To eliminate WGA-associated errors and increase the uniformity of the WGA product, the protocol was revised to sequence multiple single FTCs individually. An analytical pipeline, accurate single-cell mutation detector (ASMD), was developed to identify somatic mutations of FTCs. The large numbers of WGA-associated errors were cleaned up, and the somatic mutations detected in FTCs by ASMD were concordant with those found in tissue specimens. This protocol is applicable to circulating tumor cells analysis of peripheral blood and expands the possibility of utilizing molecular profiling of cancers.
1 INTRODUCTION
A liquid biopsy refers to blood‐based cancer testing and involves detailed molecular analysis. Human blood samples contain several sources of cancer‐derived materials, such as circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and exosomes. 1 Analyses of these components enable clinicians to repeatedly and noninvasively evaluate the current status of primary tumors and their metastatic regions in cancer patients. 2
CTCs in lung cancer can be detected using CTC‐isolating technologies such as the CELLSEARCH system (Silicon Biosystems, Bologna, Italy) and filtration techniques. 3 , 4 , 5 The amount of CTCs in peripheral blood has been shown to be of prognostic value and to change depending on treatment response. 6 The DEPArray system (Silicon Biosystems) is a semiautomatic microfluidics apparatus that allows the isolation of rare cells, such as CTCs, 7 that may be subjected to further molecular profiling. 8
In addition to liquid biopsy of blood, other body fluids, such as pleural effusion, urine, and saliva, may contain genomic materials from tumors as well. 9 , 10 Malignant pleural effusion is a devastating complication of lung cancer, and sometimes the only source available for genetic profiling analysis. However, comprehensive molecular profiling of floating tumor cells (FTCs) in malignant pleural effusion has not been fully investigated. 11
Although the clinical utility of ctDNA analyses has been recently reported in lung cancer, 12 , 13 a clinical platform for DNA sequencing using CTCs has not yet been developed. In this study, we applied DEPArray technology to detect and sort tumor cells from malignant pleural effusion and established a protocol for molecular profiling.
2 MATERIALS AND METHODS
2.1 Patients and sample collection
As a pilot cohort study, we enrolled 2 patients with lung adenocarcinoma from the Department of Respiratory Medicine at Juntendo University Hospital in Tokyo. As an additional cohort, we enrolled 9 patients with either lung adenocarcinoma or another thoracic malignancy from the Department of Respiratory Medicine at Juntendo University Hospital in Tokyo or the Department of Thoracic Oncology at National Cancer Center Hospital in Tokyo. All study participants gave written informed consent. The study was approved by the Ethics Committee of National Cancer Center Research Institute (No. 2015‐202) and Juntendo University School of Medicine (No. 2014176). The malignant pleural effusion samples were collected by clinicians and stored on ice during sample processing. The enrichment process was initiated within 2 h after specimen collection.
2.2 Tumor cell enrichment with ferromagnetic beads
The collected samples were centrifuged at 400 × g for 10 min to separate blood cells, including FTCs, from the fluid. Following centrifugation, the supernatant was carefully removed, and the remaining cells were incubated with anti‐CD45 antibody ferromagnetic beads (Miltenyi Biotec, Bergisch Gladbach, Germany) for 15 min at 4°C. Afterward, CD45‐negative cells were selected by immunomagnetic separation using an autoMACS Pro Separator (Miltenyi Biotec) in accordance with the manufacturer's protocol. The negative fractions were collected and proceeded to cell lysis by incubation with RBC Lysis Buffer (Tonbo Biosciences, San Diego, CA) for 15 min at room temperature. The CD45‐negative cells were then incubated with anti‐CD235a (glycophorin A) antibody conjugated to phycoerythrin (PE) (BioLegend, San Diego, CA) followed by incubation with anti‐PE ferromagnetic beads (Miltenyi Biotec, Cologne, Germany) for 10 min at 4°C, respectively. Selection of CD235a‐negative cells was performed using magnetic‐activated cell sorting on an autoMACS. The number of enriched cells was counted using a Countess II FL Automated Cell Counter (Thermo Fisher Scientific, Waltham, MA).
2.3 Immunocytochemistry
The cells were fixed with 4% paraformaldehyde for 20 min at room temperature and stained with anti‐CD45 antibody conjugated to allophycocyanin (APC) (Miltenyi Biotec) for 30 min at room temperature. Then, the cells underwent permeabilization using an Inside Stain Kit (Miltenyi Biotec). Intracellular staining was carried out for 10 min at 4°C using anti‐pan cytokeratin (CK) antibody conjugated to PE (BioLegend). Nuclear staining was performed using Hoechst staining solution for 5 min at room temperature.
2.4 Single‐cell isolation using DEPArray
The immunolabeled cells were washed twice with SB115 buffer (Silicon Biosystems) and loaded onto a DEPArray cartridge (Silicon Biosystems). Chip scanning was performed using an automated fluorescence microscope to generate an image gallery on the DEPArray system. FTCs were selected in accordance with their morphology and staining pattern (Hoechst positive, CK positive, and CD45 negative) and automatically recovered into 200 µL tubes. All samples were washed in phosphate‐buffered saline (PBS) and then preserved at −80°C with 1 µL PBS.
2.5 Whole‐genome amplification
Single cells underwent whole‐genome amplification (WGA) using a SMARTer PicoPLEX WGA Kit (TaKaRa Bio Inc, Shiga, Japan) in accordance with the manufacturer's instructions, and the amplified products were purified with a MinElute polymerase chain reaction (PCR) Purification Kit (QIAGEN, Hilden, Germany). The DNA concentration was measured with a NanoDrop One UV‐Vis spectrophotometer (Thermo Fisher Scientific).
2.6 Library preparation for next‐generation sequencing
The DNA samples were prepared for analysis using 3 platforms: the AmpliSeq for Illumina Comprehensive Cancer Panel, the Todai OncoPanel (TOP), 14 and whole‐genome sequencing (WGS). AmpliSeq is an amplicon‐based cancer panel designed to detect somatic variants from whole exons of 409 genes associated with cancer. Library preparation was conducted following the manufacturer's instructions except for the number of PCR cycles, which was optimized for single‐cell sequencing. The TOP DNA panel is a hybridization capture‐based panel developed to detect single nucleotide variations (SNVs) and insertions/deletions of 464 genes. Library preparation of TOP was conducted as previously described. 14 WGS samples were prepared using a NEBNext Ultra DNA Library Prep Kit for Illumina (New England BioLabs, Ipswich, MA). Library concentration was measured using a Qubit 2.0 Fluorometer (Thermo Fisher Scientific). Library quality was considered to be sufficient if a single peak around 250‐350 bp was detected using the Agilent 2200 TapeStation system (Thermo Fisher Scientific). Sequencing analysis was performed on an Illumina HiSeq 2500 system (Illumina, San Diego, CA).
2.7 DNA extraction from leukocyte and formalin‐fixed paraffin‐embedded tissues
The CD45‐positive fractions isolated with autoMACS were analyzed as paired normal leukocytes. Genomic DNA was then extracted using a QIAamp DNA Mini Kit (QIAGEN). Genomic DNA of primary tumors was extracted from formalin‐fixed paraffin‐embedded (FFPE) tissues with a GeneRead DNA FFPE Kit (QIAGEN). Extracted DNA from the FFPE samples was analyzed using the TOP panel. FFPE specimen of Case 1 was a cell block of pleural effusion. FFPE specimen of Case 2 was collected from mediastinal lymph nodes. Both specimens were provided as treatment naïve cancer.
2.8 Sanger sequencing for EGFR exon 19 deletion
For capillary sequencing with a 3130xl Genetic Analyzer (Thermo Fisher Scientific), 10 ng of template DNA were used to amplify EGFR exon 19 with GoTaq G2 Hot Start Green Master Mix (Promega, Madison, WI) in accordance with the manufacturer's instructions. The primers used were 5′‐CATGTGGCACCATCTCACA‐3′ and 5′‐CCACACAGCAAAGCAGAAAC‐3′.
2.9 Identification of EML4‐ALK breakpoint
Next‐generation sequencing (NGS) reads spanning the EML4‐ALK fusion points were obtained by WGS, and to confirm the fusion point, 3 forward primers (f1, f2, and f3) at EML4 intron 6 and three reverse primers (r1, r2, and r3) at ALK intron 19 were designed. PCR analysis was performed in 2 FTC groups (each group consisted of whole‐genome amplified DNA from 10 single FTCs) with 5 primer sets: f1 and r1 (primer set 1), f1 and r2 (primer set 2), f1 and r3 (primer set 3), f2 and r3 (primer set 4), and f3 and r3 (primer set 5). The PCR products were analyzed by Sanger sequencing to identify the fusion sequence of EML4‐ALK. The primer sequences were: f1: 5′‐TAAATCCTGTGCCACGTCCC‐3′, f2: 5′‐GCTTTTTAAACTTTGGTGAAC‐3′, f3: 5′‐TAATATAGTGAGCACCTG‐3′, r1: 5′‐AGCTTCCGTTTTGGCTTGG‐3′, r2: 5′‐TGAGGTGCAGAATCAGGG‐3′, and r3: 5′‐TTCACCATCGTGATGGACAC‐3′.
2.10 Data analysis
The paired‐end reads were independently aligned to the human reference genome (hg38) using the Burrows‐Wheeler Alignment tool, 15 Bowtie 2 (http://bowtie‐bio.sourceforge.net/bowtie2/index.shtml), and NovoAlign (http://www.novocraft.com/products/novoalign/). Somatic mutations were called using MuTect (http://www.broadinstitute.org/cancer/cga/mutect), SomaticIndelDetector, and VarScan (http://varscan.sourceforge.net). Mutations were discarded if: (a) the read depth was <20 or the variant allele frequency (VAF) was <0.3, (b) they were present in paired leukocytes and whole‐genome amplified leukocyte DNA, or (c) they were present in normal human genomes in either the 1000 Genomes Project dataset (http://www.internationalgenome.org/) or our in‐house database. Gene mutations were annotated by SnpEff (http://snpeff.sourceforge.net).
2.11 Accurate single‐cell mutation detector (ASMD) pipeline
To accurately detect somatic mutations from FTCs by removing the WGA errors, we developed a four‐step analytical pipeline. First, the somatic mutations of single‐cell FTCs and leukocytes were identified and compared with those detected in bulk leukocytes from the same individual. Second, mutations were discarded if: (a) the read depth was <100, (b) the variant was not annotated as pathogenic by the ClinVar database and its VAF was <0.3, (c) the variant was annotated as pathogenic by the ClinVar database and its VAF was <.05, and (d) they were present in whole‐genome amplified DNA of non‐paired single‐cell leukocytes isolated with DEPArray. Third, mutations that were detected in only 1 of the FTCs from the same individual were excluded. Non‐pathogenic mutations detected in more than 1 case were also removed.
3 RESULTS
3.1 Patient profiles of the 2 pilot cases
The 2 lung adenocarcinoma patients enrolled in this study were admitted to the Department of Respiratory Medicine at Juntendo University Hospital in Tokyo. Case 1 was a 35‐y‐old woman diagnosed with lung adenocarcinoma with EGFR exon 19 deletion. Before commencing first‐line chemotherapy, 10 mL of pleural effusion was obtained. Case 2 was a 79‐y‐old male diagnosed with lung adenocarcinoma with EML4‐ALK fusion. Crizotinib, an anaplastic lymphoma kinase (ALK) and ROS1 kinase inhibitor, were administered for 7 mo. Then, due to disease progression, the drug was changed to alectinib, another ALK inhibitor. At 7 mo later, the patient relapsed with massive pleural effusion, 15 mL of which was obtained for this study (Figure 1A).
FIGURE 1 Patient profile and overview of FTC analysis. A, Patient general information, somatic mutation, and treatment history of the 2 pilot cases. B, Schematic of FTC isolation from malignant pleural effusion and sequencing. The pleural effusion specimen was collected, and cellular components were separated by centrifugation (Step 1). Using CD45 microbeads and CD235a microbeads, leukocytes and erythrocytes were removed using autoMACS. Then, the cells were fixed and stained with anti‐CD45 antibody‐APC, anti‐pan‐CK antibody‐PE, and Hoechst. FTC‐enriched samples were loaded onto a DEPArray cartridge, and chip scanning was performed. The immunolabeled cells were selected by their morphology and staining pattern and recovered into 200 µL tubes (Step 2). WGA was performed on single FTCs using PicoPLEX (Step 3). The amplified genome was analyzed by Sanger sequencing, AmpliSeq, the TOP, and WGS (Step 4). F, female; M, male
3.2 Isolation and sequencing of FTCs from malignant pleural effusion
Malignant pleural effusion was collected and centrifuged to separate the cellular components (Figure 1B, Step 1). Blood cell depletion was carried out using CD45‐microbeads and CD235a‐microbeads using autoMACS (Figure 1B, Step 2‐1). The CD45 antigen is expressed on all cells of hematopoietic origin except erythrocytes, platelets, and their precursor cells, and the CD235a antigen, a single‐pass transmembrane glycoprotein, is expressed on mature erythrocytes and erythroid precursor cells. Red blood cell lysis was performed using RBC Lysis Buffer. Then, the remaining cells were fixed and stained with anti‐CD45 antibody‐APC, anti‐pan‐CK antibody‐PE, and Hoechst stain solution (Figure 1B, Step 2‐2). Subsequently, the samples were loaded onto a DEPArray cartridge, and chip scanning was performed (Figure 1B, Step 2‐3). FTCs were sorted based on their morphology and staining pattern and recovered with 10 µL of elution buffer into 200 µL tubes (Figure 1B, Step 2‐4).
WGA was performed on single FTCs using PicoPLEX (Figure 1B, Step 3). The amplified DNA was subjected to Sanger sequencing, NGS analyses with Illumina Comprehensive Cancer Panel, TOP panel, and WGS (Figure 1B, Step 4).
3.3 Analysis of DEPArray and genotyping using Sanger sequencing
After FTC enrichment using autoMACS, 1812 and 7350 cells in Cases 1 and 2, respectively, were isolated with the dielectrophoretic cage. CD45‐negative and CK‐positive cells were further selected as FTCs; the FTC counts in Case 1 and 2 were 114 and 3787 cells, respectively (Figure 2). In total, 51 cells (the maximum capacity for the DEPArray system) from each case were collected into 200 µL tubes. Leukocytes from Case 1 (CD45‐positive, CK‐negative, and Hoechst‐positive cells) were also isolated as a negative control for the subsequent NGS analysis (Figure 2B).
FIGURE 2 Enumeration and image analysis of FTCs on DEPArray. A, The number of cells enriched using autoMACS and captured by dielectrophoretic cages was counted. CD45‐negative and CK‐positive cells were selected as FTCs and recovered (51 was the maximum capacity for the DEPArray system). Twenty single FTCs from each case underwent WGA, and genomic DNA of 19 and 20 cells from Cases 1 and 2, respectively, were successfully amplified. EGFR exon 19 of FTCs from Case 1 was analyzed by Sanger sequencing, which detected EGFR exon 19 deletion in 12 cells. FTCs from Case 2 were analyzed with EML4‐ALK fusion breakpoint sequencing, which detected EML4‐ALK fusion in 17 cells. B, Representative images of leukocytes (CD45 positive, CK negative, and Hoechst positive) are shown in the upper row, and images of FTCs (CD45 negative, CK positive, and Hoechst positive) are in the lower row. CK, cytokeratin; FTC, floating tumor cell
WGA of 20 single FTCs from each patient was performed using PicoPLEX. The genomes of 19 and 20 FTCs for Cases 1 and 2, respectively, were successfully amplified up to 2 µg. EGFR del L747_A750 was confirmed in 12/19 (63.2%) samples from Case 1 using Sanger sequencing (Figure 2A).
3.4 Whole‐genome sequencing
Because the 12 EGFR mutation‐positive samples from Case 1 were identified as tumor cells, they were subjected to further investigation using WGS. All 20 samples from Case 2 proceeded to WGS because no SNV information was available for Case 2. Library preparation for WGS was conducted for each single‐cell DNA sample individually.
Approximately 5‐20 million NGS reads were obtained from each single‐cell DNA sample (Figure S1A, B). However, because of uneven amplification of the genome, the mean coverage of each cell was extremely low (Figure S1B). The concentration of whole‐genome amplified single cells was approximately 100 ng/μL while that of the negative control (water) was less than 10 ng/μL, suggesting that the genome amplification was performed without contamination from environmental bacteria. The low mapped reads ratio was due to the low quality of base call as our analytical pipeline discarded the reads containing multiple masked bases.
Merging the NGS data of the single cells from the same case improved the coverage, suggesting that the amplified regions in the genome were random among the samples (Figure S1C, D). Amplification bias and coverage uniformity of merged data were assessed by Lorenz curves and Gini's coefficient. The Gini's coefficients were 0.21 (case 1) and 0.17 (case 2) (Figure S1E), which suggested that merging the data of multiple FTCs may be a reasonable approach to make the coverage uniform. Uneven WGA was also observed in a single‐cell analysis of H2228 lung cancer cells (Figure S2), suggesting that amplification bias is due to WGA and not acquired in the process of clinical sample preparation.
EGFR del L747_A750 was not detected using WGS in Case 1, because no reads were obtained around the EGFR exon 19 locus. In contrast, span reads of the EML4‐ALK fusion from merged NGS data of Case 2 were detected, despite the low number of mapped reads. To determine the genomic breakpoint of the fusion gene, we performed PCR using a primer set specific to the EML4‐ALK breakpoint (Figure 3A). The expected size of the PCR products was observed with primer sets 2 and 3 (Figure 3B), and the breakpoint sequence of EML4‐ALK was confirmed using Sanger sequencing (Figure 3C). EML4‐ALK fusion was further confirmed by PCR amplification in 17/20 (85%) isolated single cells from Case 2.
FIGURE 3 Identification of the EML4‐ALK breakpoint sequence in FTCs. A, WGS of Case 2 indicated a span read of EML4‐ALK fusion. To determine the breakpoint, 3 forward primers (f1, f2, and f3) and 3 reverse primers (r1, r2, and r3) were prepared. B, PCR was performed for each FTC group, which consisted of the amplified genome of 10 single FTCs. The results of electrophoresis of the PCR products are shown. The following 5 primer sets were used: primer set 1 (f1 and r1), primer set 2 (f1 and r2), primer set 3 (f1 and r3), primer set 4 (f2 and r3), and primer set 5 (f3 and r3). C, The breakpoint sequence of EML4 intron 6 to ALK intron 19 was identified using Sanger sequencing
3.5 Target sequencing by hybridization capture‐based and amplicon‐based methods
We merged 5 or 6 WGA samples to establish 2 or 3 sets of pooled DNAs (T1 and T2 for Case 1, and T1‐T3 for Case 2, respectively) for target sequencing. Target sequencing with a hybridization capture‐based method (TOP panel) and an amplicon‐based method (AmpliSeq) was performed on all pooled DNA sets (Table 1).
TABLE 1 Read summary and mutational analysis from each platforms
Case Case 1
Sample type FFPE FTC Leukocyte
Platform TOP WGS AmpliSeq TOP AmpliSeq TOP
Fixed/live Fixed Fixed Fixed Fixed Live Live
Sample set – – T1 T2 T1 T2 – – – –
Whole‐genome amplification N Y Y Y Y Y N Y N Y
Raw read number 5.3 × 107 2.0 × 108 9.7 × 107 8.8 × 107 4.6 × 107 3.4 × 107 1.1 × 108 9.1 × 107 9.4 × 107 8.4 × 106
Mapped read number 4.9 × 10⁷ 4.1 × 107 8.1 × 107 7.4 × 107 3.6 × 107 2.7 × 107 9.5 × 107 7.8 × 107 8.7 × 107 7.1 × 106
Mean coverage 123 0.85 5050 4561 293 229 5892 4783 740 87.9
Breadth of coverage % 1× / 20× (%) 99.8/99.2 23.9/0.2 90.6/82.9 90.1/82.7 90.4/67.6 89.0/64.6 96.3/95.5 91.0/82.6 99.9/99.7 83.9/50.0
Somatic mutation EGFR
del L747_A750
FGF4 E154L
ND EGFR del L747_A750
ERCC2 P475L
SYNE1 D397N
KMT2C D348N
EGFR del L747_A750
FGF4 E154L
– – – –
Case Case 2
Sample type FFPE FTC Leukocyte
Platform TOP WGS AmpliSeq TOP AmpliSeq TOP
Fixed/live Fixed Fixed Fixed Fixed Live Live
Sample set – – T1 T2 T3 T1 T2 T3 – –
Whole‐genome amplification N Y Y Y Y Y Y Y N N
Raw read number 2.9 × 107 2.0 × 108 9.1 × 107 1.0 × 108 9.4 × 107 3.6 × 107 3.1 × 107 4.8 × 107 9.6 × 107 7.6 × 107
Mapped read number 2.7 × 107 5.0 × 107 7.5 × 107 8.6 × 107 7.8 × 107 2.9 × 107 2.5 × 107 3.8 × 107 8.1 × 107 7.0 × 107
Mean coverage 10.6 1.14 4586 5280 4826 248 232 262 4919 947
Breadth of coverage % 1× / 20× (%) 99.3/5.3 27.9/0.3 91.6/84.8 92.8/86.6 93.1/87.9 91.1/68.1 92.7/71.0 92.7/71.0 96.2/95.6 99.8/99.5
Somatic mutation ND EML4‐ALK fusion EML4‐ALK fusion
ALK G1202R
EML4‐ALK fusion
ALK G1202R
– –
Note
Sequence read summary and detected mutations of FTCs, leukocytes, and tumor FFPE specimens.
Abbreviations: FFPE, formalin‐fixed paraffin‐embedded specimen; FTC, floating tumor cell; TOP, Todai OncoPanel; WGS, whole‐genome sequencing; n, not performed; y, performed; ND, not detected.
John Wiley & Sons, Ltd
The TOP panel analyses yielded a mean sequence coverage of 20× for 70% of the captured regions in the FTCs, while the same analyses in bulk white blood cells covered >99% of the target regions (Table 1 and Figure S3). The PCR cycles of AmpliSeq were optimized to increase the detection frequency of low amplification regions in WGA. We compared the sequencing coverage among samples prepared with 12, 16, 23, and 30 PCR cycles. The 20× coverage area was widest (>80%) after 23 cycles (Figure S4).
To eliminate WGA errors, sequence reads of bulk leukocytes and single leukocytes from the same individuals were compared. The mutations identified specifically in single leukocytes were regarded as WGA errors. The VAF of mutations only identified in single leukocytes was <0.3 (Figure S5). Therefore, mutations only found in single leukocytes were removed from mutation analyses for FTCs (Figure 4).
FIGURE 4 SNV distribution among each FTC set for Cases 1 and 2. A, Number of identified mutations in each FTC set of Case 1 analyzed by AmpliSeq and TOP. B, Number of identified mutations in each FTC set of Case 2 analyzed by AmpliSeq and TOP
EGFR exon 19 deletion was detected in T1 and T2 of Case 1 by both AmpliSeq and TOP (Figures 4A and S6A), whereas >200 sample‐specific or panel‐specific mutations were also identified. ALK p.G1202R, a known alectinib‐resistant mutation, was the only mutation identified throughout multiple samples from Case 2 by both panels (Figures 4B and S6B, and Table S1).
3.6 Development of the ASMD pipeline and validation in 9 cases
Considering the number of WGA‐associated errors and the low uniformity of the WGA product, it is preferable to sequence single CTCs individually. An analytical pipeline, ASMD was constructed to identify somatic mutations of CTCs, which were supported by multiple reads of different clones (Figure 5A). The FTC sequences of 9 additional cases were conducted to evaluate the utility of ASMD (Tables 2 and S2). For each case, except for Case 5, 5 FTCs were sequenced, which were performed using WGA and analyzed with TOP panels individually. The coverage was improved by merging the data of multiple FTCs (Figure 5B and Table S3). The large numbers of WGA‐associated errors were cleaned up, and the somatic mutations detected in FTCs by ASMD were concordant with those found in FFPE specimens, although some additional or depleted mutations were observed in FTCs, suggesting clonal evolution of the tumors during metastasis (Figure 5C and Table 3).
FIGURE 5 Precise analysis of somatic mutations in FTCs using the ASMD pipeline. A, The schema on the left shows the overview of the accurate single‐cell mutation detector (ASMD) pipeline. The ASMD identifies somatic mutations of FTCs, which are supported by multiple reads of different clones. The unique mutation identified in 1 sample and mutations with low VAF were discarded as WGA‐associated errors. The figure on the right shows that the sensitivity of the ASMD is dependent on the clonality of the variant (the ratio of the clone harboring the variant in the tumor) and the number (N) of FTC sequences. B, The average 20× cover ratio of single‐cell FTCs or the merged data of FTCs is shown. The coverage was improved by merging the data of multiple FTCs. C, The number of somatic mutations identified in tissue specimens or FTCs are indicated. The variants detected in both specimens are revealed in the Venn diagrams
TABLE 2 Patient profiles of 9 additional cases
Case no. Age Sex Cancer type Genomic aberration at diagnosis Analysis Treatment Current status
3 81 M LUAD EGFR ex19 del Cobas EGFR Mutation Test v2 Op PD
4 41 M LUAD EGFR ex19 del Cobas EGFR Mutation Test v2 Afatinib; CDDP + PEM; Clinical trial PD
5 36 M NUT midline carcinoma BRD4‐NUT IHC, FISH Pre‐treatment Pre‐treatment
6 68 M LUAD EGFR E709K/G719A Oncomine Afatinib PD
7 77 F LUAD EGFR L858R Cobas EGFR Mutation Test v2 Op; Osimertinib PD
8 50 F MPM ETV6 deletion, NF2 448‐1G > C, BAP1 D408fs*17, SF3B1 Y623C, PERM1 R921fs*87 FoundationOne CDx CDDP + PEM; Nivolumab; RT PD
9 60 M LUAD EGFR (−), ALK (−),ROS1 (−), PD‐L1 50% Cobas EGFR Mutation Test v2 Pembro; RT; CDDP + PEM PD
10 69 F LUAD ROS1 (+) Cobas EGFR Mutation Test v2, OncoGuide AmoyDx Pre‐treatment Pre‐treatment
11 67 F LUAD EGFR (−), ALK (−),ROS1 (−) NA CBDCA + PEM+Bev; Docetaxel; TS‐1; Atezolizumab PD
Note
Patient general information, genomic aberrations and analysis, treatment history, and current status of each case.
Abbreviations: Bev, bevacizumab; CDDP, cisplatin; F, female; FISH, fluorescence in situ hybridization; ICH, immunohistochemistry; LUAD, lung adenocarcinoma; M, male; MPM, malignant pleural mesothelioma; Op, operation; PD, progressive disease; PEM, pemetrexed; RT, radiation therapy.
John Wiley & Sons, Ltd
TABLE 3 Somatic mutations of 9 additional cases
Case no. Gene Variant VAF ClinVar COSMIC ASMD
Clone 1 Clone 2 Clone 3 Clone 4 Clone 5 Tissue
3 ACVR2A p.Met1fs 55.9 – 42.5 69.8 52.4 – – – Y
SMARCA4 p.Pro281Pro 30.8 – 30.1 – – – – – Y
TSC1 p.Ser526fs 63.2 71.7 24.5 49.7 72 – – – Y
EGFR p.Glu746_Ala750del – – 11.4 14.6 11.9 17.3 Drug_response 1163 Y
KMT2D p.Gly3822Gly 100 – – 100 99.6 15.1 – – Y
4 CHEK2 p.Arg117Gly – 5.9 9.1 11.1 – – Pathogenic/Likely_pathogenic 1 Y
PTEN c.802–2A > G – 7.4 5.7 5.9 – – Pathogenic/Likely_pathogenic 1 Y
FAT1 p.Val2071Ala – – – – 99.1 28.7 – – N
TP53 p.Met237Lys 100 99.6 100 99.8 100 24.8 Likely_pathogenic 18 Y
KMT2C p.Gly3322Asp 82.4 26.4 15.9 68.1 20 19.1 – 1 Y
EGFR p.Thr751Thr 41.7 – – 48 45.2 18.8 – – Y
EGFR p.Glu746_Ala750del 21.5 13.2 – 26 29.4 17.6 Drug_response 1163 Y
5 DICER1 p.Asp1810Gly 5.6 13.7 – NA NA – Pathogenic – Y
JAK1 p.Arg360Gln – – – NA NA 28.2 – – N
6 EGFR p.Glu709Lys 84 95.1 69.6 48.9 77.8 NA Drug_response 36 Y
EGFR p.Gly719Ala 83.8 97.6 70.6 48.2 78.5 NA Pathogenic 75 Y
IKZF1 p.His127Asn 56.8 21.8 93 32.5 35.7 NA – – Y
MST1 p.Arg461His 38.3 40.9 8.4 9.7 – NA – 2 Y
PMS1 c.583‐1G > A – – – 100 100 NA – 1 Y
TP53 p.Arg342* – – 100 99.6 100 NA Pathogenic 379 Y
7 TP53 p.Ala83fs 93.6 93.8 91.8 93.8 94.7 25.1 Pathogenic_HGVS.p – Y
8 ACTN2 p.Met361Val 44.6 88.8 36.2 36.6 75.8 – Uncertain_significance – Y
CDKN2A p.Arg80* 79.7 100 98.9 – 99.9 – Pathogenic 293 Y
TRAF3 p.Ile530Ile 36.2 33.3 – 40.9 37.1 50 – – Y
BRCA2 p.Leu709Leu 41.5 38.7 42.5 48.6 43.3 49.7 Benign – Y
SMO p.Lys575Met 98.7 66.8 – 46 – 49.1 – 4 Y
SDHAF2 p.Asn110Lys 67.5 – – 53.6 57.4 48.9 Uncertain_significance – Y
SOCS1 p.Phe113Phe – – – – – 48.1 – – N
RICTOR p.Ser1020Arg 23.9 – 68.6 38.7 5.7 47.6 – – Y
FGFR4 p.Gly528Ser – – – – – 47.5 – – N
ARID1B p.Arg1789Gln – – – – – 47.3 – – N
HAX1 p.Val172Ile 64 69.5 58.8 25.5 63.5 46.7 Benign/Likely_benign – Y
ERBB4 p.Val83Val – – – – – 46.4 _ – N
KLF5 p.Val357Val – – – – – 44.9 – – N
ZNF503 p.Ser16_Gly17dup – – – – – 42.2 – – N
MEF2A p.Gln421_Pro423dup – – 15 35.6 13.7 40.3 – – N
ATF7IP p.Thr175_Ala179del – – – – – 37.6 – – N
KLHL14 p.Asp83Gly – – – – – 35.8 – – N
MCC p.Ser25_Ser28dup – – – – – 26.2 – – N
SRP14 p.Pro117_Thr126del – – – – – 18.7 – – N
DNMT1 p.Thr161Ala – – – – – 11.3 – – N
9 BRCA1 p.Gln759* 6.8 – 6 – – – Pathogenic – Y
KARS p.Leu568Phe 51.6 99.4 – 58.6 – – – – Y
MELK p.Ile578Val 62.5 98.8 100 – 5 – – – Y
UGT1A5 p.Ala158Ala 77.6 9.3 5.8 98.7 82.4 – – 4 Y
INSR p.Arg7Arg – – – – – 81.9 – – N
MRE11A p.Met157Val – – – – – 80.2 Conflicting_interpretations 1 N
RECQL4 p.Asn406Lys – – – – 100 57.4 – – N
NOTCH1 p.Cys725Cys – – – – – 26 – – N
10 BRCA2 p.Glu425Glu 33.4 12.3 84.3 61.2 41 – Benign 1 Y
FAT1 p.Val476Met – – 46 38.9 – – – – Y
PTEN c.802‐2A > G – 8.3 – – 6.7 – Pathogenic/Likely_pathogenic 1 Y
TP63 p.Leu562Pro – 7.8 – 9 – – Likely_pathogenic – Y
TRAF7 p.Lys53Glu 39 6.3 7.5 75.2 38.5 68.8 – – Y
SPEN p.Thr819Ile – 53.4 – 66 44.7 61 – – Y
CEBPA p.Thr265Thr – – – – – 54.4 Benign 0 N
MPL p.Thr374Ala – 57.9 100 36.1 38.6 49.1 Benign/Likely_benign 1 Y
SH2B3 p.Ala36Ala – – – – – 47.8 – – N
FOXA1 p.Tyr394Cys – – – – – 45.4 – – N
MET p.Leu674Leu – – – – 49.6 45.1 – – N
KLF5 p.Glu419Gln – – – – – 39.2 – 5 N
FGFR4 p.Pro356Leu 99.9 – 18.3 28.9 – 38 – – N
ATXN1 p.Gln225del – – – 31.5 – 16.6 – – N
STAT3 p.Ile339Ile – – – – – 15.9 – – N
HAX1 p.Leu6Phe – – – – – 15.6 – – N
SETDB1 p.Ser983* – – – – – 14.7 – – N
SMARCA4 p.Ile1045Ile – – – – – 13.8 – – N
STAT3 p.Gln469* – – – – – 13.7 – – N
SMARCA4 p.Phe1234Leu – – – – – 13 – 3 N
NUP93 p.Glu14Lys – – – – – 10.4 – 37 N
11 FOXP1 p.Ala645Ala – – – 93.3 79 NA – – Y
IGF1R p.Ile601Val – 66.9 45.2 – – NA – – Y
NF2 p.Trp184* 9 – 14 – – NA Likely_pathogenic 3 Y
RAF1 p.Ser259Pro 16.5 – 30.7 – – NA Likely_pathogenic 5 Y
Note
The detected somatic mutations of FTCs (clone 1‐5) and tumor tissue specimens. The variant allele frequency (VAF) in each sample, the clinical significance of the variants annotated by ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/), and the variants’ count number reported in the COSMIC database v91 (https://cancer.sanger.ac.uk/cosmic) are indicated. The ASMD (accurate single‐cell mutation detector) column shows whether ASMD detected the variant as a somatic mutation in FTCs or not (Y/N).
Abbreviation: NA, not analyzed.
John Wiley & Sons, Ltd
4 DISCUSSION
This study is the first study to perform NGS of single cells in pleural effusions of multiple cases. The combination of autoMACS and DEPArray was applied to detect and enrich FTCs in pleural effusion. The enrichment method for only 10 mL of pleural effusion enables the diagnosis of carcinomatous pleuritis and the performance of comprehensive molecular profiling. In contrast with this method, the conventional techniques require a considerable amount of pleural effusion specimen for diagnosis. 11
The ALK p.G1202R mutation identified in Case 2 is located at the solvent front of the ALK domain and is recognized as an acquired mutation following ALK‐tyrosine kinase inhibitor (TKI) therapy. 16 , 17 Lorlatinib is known as effective against this mutation. 18 , 19 Therefore, if clinicians had chosen lorlatinib as the third‐line treatment, they might have controlled disease progression in Case 2. Unfortunately, the patient could not receive loratinib because his performance status was too poor due to the accumulation of pleural effusion.
Notably, in this study, targetable EGFR driver mutations were identified in 4 cases. Furthermore, potentially targetable variants, such as BRCA1 truncating mutation (case #9) and RAF1 oncogenic mutation (case #11) were identified. These may be acquired mutations that arose in response to treatment.
Genomic mutations in peripheral blood CTCs were first detected in non‐small‐cell lung cancer (NSCLC) patients in 2008 using the CTC‐Chip. 18 , 20 This study revealed EGFR TKI‐resistant mutations in some patients who experienced a faster progression compared with those without these mutations. Several other groups also detected EGFR mutations in CTCs. 21
NGS of single CTCs remains challenging because single cells do not contain a sufficient quantity of DNA for molecular analysis. Therefore, WGA is required for NGS analysis of CTCs, although the analyses of the first 2 cases indicated that the DNA amplification process is often error prone. Because the VAF of WGA error was <0.3, library construction was performed individually in single FTCs of the additional 9 cases to keep the VAF of somatic mutation in each cell high.
CTCs are highly heterogeneous, even within the same individuals. 22 Therefore, multiple single FTC sequencing should be performed to evaluate intratumor heterogeneity. Such data would provide insight into the origin of tumors and the molecular mechanism of disease progression and resistance acquisition. 23 It is estimated that ASMD analysis of 5 FTCs per case is capable of detecting mutations, which 68% of tumor cells harbor, at 90% sensitivity. Sequencing more clones can improve the sensitivity of the ASMD method, and the sample indexing technique before pooling for capture might be an efficient way to reduce the cost for capture probes.
Other issues to be overcome in the sequencing of WGA samples include a high allelic drop‐out rate, artifacts, and uneven genome amplification. Methods have been developed to minimize WGA amplification bias by reducing the limiting volume for multiple displacement amplification to avoid exponential preferential amplification 24 , 25 or looping of the amplicons to induce quasi‐linear amplification (MALBAC). 26 Despite these advances, WGA remains far from uniform.
There are several studies that compare the methods for WGA. 27 , 28 , 29 , 30 Optimization of library preparation using samples that have undergone WGA to ensure sufficient coverage of the target regions is required for the reliable molecular profiling of single cells. The ASMD pipeline improved the cover ratio by mutually compensating the regions that frequently dropped out. The concept of an ASMD pipeline is similar to ‘census‐based variant detection’ developed by Zhang et al. 31 There are 2 significant differences in ASMD from that method. First, ASMD uses sequence data from single‐cell and bulk leukocytes from the same individual to call somatic mutations. In particular, mutation identified non‐paired single‐cell leukocytes were used to exclude false‐positive mutations, which are errors that arise during WGA. Second, ASMD uses information on allele frequency combined with clinical annotation of variants to accurately call true‐positive mutations.
The CTC‐Chip was the first specific microfluidic device for CTC isolation. However, it captured many false‐positive results from the blood of healthy individuals. 32 Using a filtration technique and fluorescence in situ hybridization, Pailler et al detected ALK rearrangements in CTCs from NSCLC patients. 33 However, false‐positive results were also obtained due to contamination by normal endothelial cells and rare hematologic cells such as megakaryocytes. 34 Potential limitations of this study are as follows:
(1) The utility of single‐cell compared with bulk sequencing of pleural fluid is insufficiently well confirmed in this study. FTCs were concentrated at least 15 times in Case 1 through the sequential enrichment, considering that 114 candidate FTCs were sorted from 1812 captured cells on DEPArray after CD45 negative selection. In contrast, because the ratio of FTCs to blood cells in Case 2 was relatively high (approximately half of the captured cells were CK positive), the bulk analysis without enrichment might have also identified the ALK mutations. The actual utility of this enrichment technology depends on the FTC concentration in pleural effusion. The enrichment method must ensure that tumor cells can be efficiently recovered, even from a pleural effusion with a few tumor cells.
(2) The TOP panel basically cannot detect fusion genes as the panel does not include probes for fusion genes. Capture probes targeting the intronic region of fusions should be added to the TOP panel to cover fusion genes to strengthen the clinical utility of this method.
To capture tumor cells efficiently, further optimization with additional immunostaining may be necessary. Lustgarten et al reported that large numbers of epithelial cells were observed in benign effusions, and selection with an antibody to Claudin‐4 was required for epithelial cell adhesion molecule‐based CTC detection with the CELLSEARCH system. 35
An advantage of DNA sequencing for single tumor cells over ctDNA assay might be that it is not affected by patient‐related factors such as inflammatory conditions and autoimmune disorders that might contribute to the release of cell‐free DNA and could be confounding factors in ctDNA assays. 36 Furthermore, because ctDNA is often detected at very low VAF even in patients with advanced cancer, 37 , 38 , 39 , 40 sequencing of tumor cells in body fluids might be complementary to ctDNA assays.
It is notable that deep‐sequencing of EGFR using ctDNA from Case 1 could not detect the EGFR exon 19 deletion and that WGS with ctDNA from Case 2 could not identify the supporting reads for EML4‐ALK fusion (data not shown). A large‐scale study comparing the concordance among assays using tissues, ctDNA, FTCs, and CTCs is necessary to establish the clinical validity of molecular profiling for FTCs and CTCs.
Overall, we established an effective enrichment method of tumor cells from pleural effusion specimens using the autoMACS system and DEPArray. The optimized protocol is the first report of EML4‐ALK fusion detection from a single FTC. Furthermore, the novel ASMD pipeline dramatically improved the accuracy of the detection of mutations of FTCs and might also be applied to CTC analysis of peripheral blood.
We believe that this method expands the possibility of utilizing molecular profiling in primary and metastatic tumors, aids clinicians in their choice of appropriate drugs, and provides patients with more opportunities for personalized medicine.
CONFLICT OF INTEREST
The authors declare that they have no competing interests.
Supporting information
Fig S1‐S6
Click here for additional data file.
Table S1‐S3
Click here for additional data file.
ACKNOWLEDGMENTS
We thank A. Maruyama, S. Kaneko, and H. Tomita for technical assistance. This study was supported by the grants from the Program for Integrated Database of Clinical and Genomic Information under grant number JP19kk0205003, the Leading Advanced Projects for Medical Innovation (LEAP) under grant number JP18am0001001, the Project for Cancer Research And Therapeutic Evolution (P‐CREATE) under the Grant Number JP20cm0106502, and for the Practical Research for Innovative Cancer Control under Grant Number JP20ck0106536 from the Japan Agency for Medical Research and Development, AMED; a grant for Endowed Department (Department of Medical Genomics, Graduate School of Medicine, The University of Tokyo) from Eisai Co., Ltd. | ATEZOLIZUMAB, BEVACIZUMAB, CARBOPLATIN, DOCETAXEL, GIMERACIL\OTERACIL\TEGAFUR, PEMETREXED DISODIUM | DrugsGivenReaction | CC BY-NC | 33484069 | 19,280,573 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Oxygen saturation decreased'. | WALANT-Epinephrine injection may lead to short term, reversible episodes of critical oxygen saturation in the fingertips.
BACKGROUND
Although the WALANT technique's long-term safeness has been demonstrated in many studies, there are only few data investigating its short-term effects on tissue perfusion and oxygen levels. It was hypothesized that, temporarily, critical levels of tissue perfusion may occur.
METHODS
Seventeen patients, who were scheduled for different procedures in WALANT technique, were injected with 5-7 ml of 1% Articain containing 1:200,000 epinephrine at the finger base. Capillary-venous oxygen saturation, hemoglobin volume in the capillaries, and relative blood flow in the fingertips were recorded once per second by white light spectrometry and laser Doppler flowmetry before, during and after injection for an average of 32 min.
RESULTS
Clinically, no persistent tissue malperfusion was observed, and there were no postoperative complications. Capillary-venous oxygen saturation was reduced by ≥ 30% in seven patients. Critical levels of oxygen saturation were detected in four patients during 13 intervals, each lasting for 132.5 s on average. Oxygen saturation returned to noncritical values in all patients by the end of the observation period. Blood flow in the fingertips was reduced by more than 30% in nine patients, but no critical levels were observed, as with the hemoglobin. Three patients demonstrated a reactive increase in blood flow of more than 30% after injection.
CONCLUSIONS
Injection of tumescent local anesthesia containing epinephrine into finger base may temporarily cause a substantial reduction in blood flow and lead to critical levels of oxygen saturation in the fingertips. However, this was fully reversible within minutes and does not cause long-term complications.
Introduction
The injection of the tumescent local anesthetic lidocaine combined with epinephrine before finger surgery, known as the “Wide Awake Local Anesthesia No Tourniquet” (WALANT) technique, has been demonstrated to be safe from a long-term clinical perspective in many studies [1]. For quite some time, epinephrine was held responsible for finger necrosis, based on the case reports from before the 1950s [2, 3]. Meanwhile, authors have come to the agreement that the local anesthetic procaine was responsible for the described tissue necrosis and finger loss [2, 4]. In the early twenty-first century, the use of epinephrine as a chemical tourniquet in combination with local anesthetics began [5], and no cases of finger necrosis have been reported using lidocaine with epinephrine before 2000 [8]. Although its harmlessness has been clinically proven many times [6–9], textbooks and drug information continuously warn against its use in the acra [5, 10, 11], a dogma that has been passed on for generations [12]. Between 2014 and 2017, three case reports described total or partial finger necrosis after injection of lidocaine and epinephrine (1:100,000). Two resulted in the amputation of one or more finger end limbs, yet without having attempted reversal with phentolamine [13, 14]. In contrast, this proved effective in a third patient, whose postoperative finger ischemia could be reversed that way, saving the digit [15]. With regard to these case reports, one must consider, that in the time span they occurred, several thousand other operations in WALANT technique were performed successfully, without complications. Therefore, the overall risk of necrosis seems to be minimal while the benefits, such as a better intraoperative overview due to lower bleeding without tourniquet, the assessment of stability and gliding ability, predominately. Above all, cases that benefit in particular from WALANT technique are tendon surgery [1, 2, 4] and osteosynthesis [16, 17].
Nonetheless, there are only very few data about its short-term effects on tissue perfusion and oxygen supply after administering epinephrine [5, 18–20, 29]. Hence, this study’s aim was to investigate these by means of micro-lightguide spectrophotometry and laser Doppler flowmetry. Therein, this study focused on capillary-venous oxygen saturation (sO2), hemoglobin volume (rHb) in the capillaries, and relative blood flow in the fingertips. It was hypothesized that critical levels of tissue perfusion may occur after injection of Articain and epinephrine for WALANT.
Materials and methods
Ethical approval
This study was authorized by the ethics committee of our institution (137/18S). All patients had been scheduled for elective procedures regardless of participation in this study.
Patients and methods
In this prospective cohort study, the patients were recruited in our clinic from May through July 2019. Owing to technical difficulties, only 17 of initially 21 patients (9 women, 8 men) with a mean age of 55 years (range 23–79 years) could be included. They were scheduled for different procedures (15 patients: trigger finger release, 1 patient: mucoid cyst extirpation, 1 patient: removal of screw) using the WALANT technique, wherefore they were injected with 5–7 ml of 1% Articain containing 1:200,000 epinephrine subcutaneous at the palmar finger base, using a standardized technique as described by Harbison [21]. The patients were distracted by pressure outside the injection site and a 27G needle was introduced perpendicularly into the subcutaneous tissue. About 1 ml of solution was slowly injected and further infiltration was paused until the needle pain was gone. Then, the remaining solution was slowly injected without aiming for the digital nerves (Table 1). Patients with contraindications, such as allergic reactions, insufficient blood circulation (e.g., clinical signs, such as bluish discoloration, poor capillarization), Raynaud’s syndrome and glaucoma, were excluded. Tissue perfusion and blood flow were assessed using white light spectrometry and laser Doppler flowmetry (Oxygen to See, O2C, LEA, Germany, Fig. 1a).Table 1 Included patients’ demographic data: Age, operated fingers, affected side, injection volume, and complications
Patient
# Age
(years) Gender
(male/female) Operated finger
(D I–V) Affected side
(right/left) Injection volume
(ml) Complications
(yes/no)
1 62 Male III Right 6 No
2 58 Male II Right 5 No
3 57 Male Lll Left 6 No
4 81 Male V Right 5 No
5 55 Female IV Right 5 No
6 53 Female I Left 5 No
7 50 Female I Right 5 No
8 79 Female III Right 5 No
9 54 Female IV Right 5 No
10 60 Male V Right 7 No
11 25 Female III Left 5 No
12 73 Male III Left 5 No
13 48 Male IV Left 6 No
14 63 Female Lll Left 7 No
15 36 Male V Right 5 No
16 58 Female III Left 6 No
17 52 Female I Left 5 No
Fig. 1 Correct position of the detection probe
Measurement procedure
The Oxygen to See (O2C) method provides continuous measurement and precise data collection by combining white-light spectrometry and laser Doppler flowmetry. Tissue is irradiated with light from a broad band and laser light source, while a sensor measures the remission produced by the tissue. White light remission (wavelength range of 500–850 nm) determines oxygen saturation (sO2) and relative hemoglobin (rHb) by calculating the amount of light absorbed by the hemoglobin, depending on its oxygen levels. Laser Doppler flowmetry measures blood flow using the Doppler shift of laser light waves (wavelength: 830 nm) caused by the remission from moving erythrocytes in the capillaries. The measurements’ penetration depths depend on the selected probe, with the maximum depth being 8 mm [22–24].
Capillary-venous oxygen saturation (sO2 in %), hemoglobin volume in the capillaries (rHb in arbitrary units (AU)) and relative blood flow (in AU) in the fingertips were recorded once per second before, during and after injection of Articain and epinephrine, resulting in 43,956 data points. One patient’s (= patient 6 in Table 1) exemplary measurement curve for sO2 development after injection can be seen in Fig. 2.Fig. 2 Example of oxygen saturation at the fingertip (AU) over time after injection. Saturation levels drop by more than 30%, but critical levels are never reached. Minimum saturation occurs after 380 s
Critical levels, irreversible or long-term values that would lead to tissue damage, were defined as < 10% for oxygen saturation (sO2), < 5 arbitrary units (AU) for blood flow and < 15 AU/ > 90 AU for hemoglobin volume (rHb), as suggested in the literature [23, 25, 26]. In addition, patient records were assessed for postoperative complications (Table 1).
Evaluation of hemoglobin volume (rHb), oxygen saturation (sO2), and blood flow after injection
The phase from the start of the O2C measurement until injection of Articain and epinephrine was defined as “baseline”, which lasted for a mean time of 4 min (range 1–11 min, Fig. 3). The period after injection was called “observation”, lasting 32 min on average (range 29–79 min, Fig. 3). In addition, a third period was created, lasting from a midpoint (defined at 15 min after injection) until the end of the measurement (Fig. 3).Fig. 3 Sketch of the experimental set-up with mean times before (baseline) and after (observation values) injection and flow chart of the analysis procedure: a Baseline average and observation average were analyzed for changes in ≥ 30% (group A). b Baseline average and midpoint-end average were analyzed for changes in ≥ 30% (group B)
For data analysis, the single-point values of rHb, sO2 and blood flow, measured every second during the baseline and observation periods (see above), were averaged. In a second step, these average values were compared and analyzed for changes equal to or greater than 30% (Figs. 2, 3a) (= group A). The number of cases, in which such changes occurred, was determined.
Accordingly, the values measured for each of the parameters between the midpoint and the end of O2C were also averaged. These were then compared with the averaged values of the baseline period to evaluate whether the changes in this specific period were more pronounced than in the total observation phase. These results, too, were compared and analyzed for changes in equal to or greater than 30% (Fig. 3b) (= group B).
In a third step, the occurrence of critical levels of rHb (AU), sO2 (%) and blood flow (AU), as defined above, were examined for intervals of 60 s during the measurement by calculating rolling means. Their durations were recorded in seconds.
Statistics
Owing to the small number of patients and their heterogeneous nature, only descriptive statistics were performed, but no hypotheses were tested.
Results
Development of rHb, sO2, and blood flow after injection
Averages between baseline values and observation period (Group A) demonstrated a drop of 30% or more in three patients for rHb levels, in seven patients in sO2 levels and in nine patients in flow levels. When assessing averages between baseline and midpoint end (Group B), reductions in 30% or more were found in three patients for rHb levels, in seven patients for sO2 levels, and seven patients for blood flow levels.
Duration and proportion of critical oxygen saturation in the total observation time
The evaluation of the average values after injection showed a drop of the above-mentioned values, but without taking the previously defined critical values into account.
There were no critical values concerning rHb and blood flow throughout the entire investigation.
13 intervals of critical oxygen saturation with a mean duration of 132.5 s (range 4–482 s) were measured in four patients (Table 2). These intervals lasted a total of 1510 s and were most often found between 10 and 20 min after injection. At the end of the observation period, all patients demonstrated normal values.Table 2 Occurrence of critical values per patient and their duration
Time after injection (min) Duration (s)
Patient 1 3 220
16 91
19 4
19 7
23 71
26 177
Patient 3 2 138
9 482
21 64
Patient 8 5 345
Patient 13 1 44
2 76
15 15
17 121
Generally, there were no allergic or other unexpected long-term reactions. Apart from the temporary occurrence of critical oxygen saturation values, we could not detect any permanent arterial ischemia or venous congestion.
Discussion
The possibility to operate without a tourniquet is a major benefit for patients and surgeons [1, 4, 28]. The WALANT technique makes the surgeon independent of anesthesiologists and allows more flexibility in scheduling surgical treatments. WALANT represents an overall long-term, low-risk technique for every-day use. Apart from low general injection-related risks, such as infections and injuries to neurovascular structures, the contraindications to the injection of epinephrine, including allergic reactions, insufficient blood circulation, Raynaud’s syndrome and glaucoma must be considered. However, the combination of local anesthetic and epinephrine continues to be the topic of much discussion. Even though the application has been proven to be safe many times, textbooks and drug information warn against the use of local anesthetics with the addition of a vasoconstrictor in the acra, nose, ear, and penis.
In addition, there are recurring case reports of finger necrosis after injection for WALANT. For example, in 2014, eight hours after the excision of a skin tumor over a proximal interphalangeal (PIP) joint in WALANT anesthesia, a 16-year-old patient showed signs of ischemia, necessitating the amputation of the affected finger’s end limb. However, reversal of vasoconstriction with phentolamine had not been attempted and the authors could not rule out other causes of finger necrosis [14]. In 2017, an orthopedist in the United States injected lidocaine and 1:100,000 epinephrine for a trigger finger release and carpal tunnel decompression, leading to finger ischemia three hours postoperatively. This lasted for 14 h, until it could be reversed with phentolamine, saving the finger [15]. In the same year, in Canada, three fingers were injected for trigger finger release in WALANT technique. Phentolamine was not applied, leading to necrosis of two thirds of the index and middle finger end limbs and, subsequently, their amputation. The ring finger, whose tip also showed signs of necrosis, could be preserved [13].
Regarding the short-term effects of the WALANT technique on tissue perfusion and oxygen levels, there are very few data in scientific literature [5, 18–20, 29]. Therefore, it was examined tissue blood flow, capillary-venous oxygen saturation (sO2), and hemoglobin volume (rHb) in this study.
This study was able to perform complete and continuous monitoring of relevant post-capillary finger perfusion parameters after local injection for WALANT anesthesia. As the method of measurement used in this study is highly sensitive, however, not all critical values observed need to be considered clinically relevant. Even deep breathing can influence the parameters. Moreover, all values returned near baseline levels within the 30-min investigation period.
Many of our findings are in accordance with Altinyazar et al., who studied digital artery blood flow in 24 subjects, using color Doppler ultrasonography [5]. This was measured before digital blocking with lidocaine containing epinephrine, as well as 10, 60, and 90 min thereafter, resulting in a statistically significant decrease of blood flow rates. In addition, after 10 min of digital block, four patients showed no measurable blood flow, which, however, was restored within 60 or 90 min [5]. Although all values in all of our patients recovered within 30 min, the highest incidence of critical saturation was observed 10 to 20 min post-injection.
Concerning sO2, Sönmez et al. measured blood gas parameters before and 15 min after digital blocks, using lidocaine solutions with or without 1:80,000 epinephrine [18]. They reported that the sO2 first slightly increased, showing small reductions soon after. However, there were no significant differences whether the lidocaine was mixed with epinephrine or not [18]. In contrast, in this study, a continuous measurement is used and a more precise method of data collection, yielding similar results.
To determine changes in the blood flow, Sylaidis and Logan performed a quantitative study on 100 consecutive patients [19]. They measured the brachial and digital arterial systolic blood pressures before and after injection of 2% lidocaine and 1:80,000 epinephrine, finding that, although the digital blood pressures and the mean digital–brachial index decreased after the injections, this effect was completely reversible [19]. Schnabl et al. carried out a prospective, double-blinded, randomized study with 20 volunteers (80 fingers, without operation) [29]. The chronological course of changes in digit blood flow after injection of 0.75% ropivacaine and 1:1.000.000 epinephrine showed no significant changes with a following significant increase of skin perfusion (+ 66.6%) and prolonged pain reduction [29]. The blood flow measured at the fingertip was very variable in this study. On the one hand, this may be due to the sensitive measurement method; on the other hand, on the fingers’ extensor side, there remains sufficient regulation of the collateral vessels, so that blood flow in the fingertip remains relatively constant (unlike in the operating field).
Based on these data, however, no conclusions can be drawn as to how long one should wait after an injection, before starting the operation. McKee et al. found that after a subcutaneous infiltration of 5 ml lidocaine 1% with 1:100,000 epinephrine (0.01 mg/ml) into one arm, versus the same amount of lidocaine 1% without epinephrine into the other arm, the vasoconstrictive effect of lidocaine with epinephrine occurred after only 25 min (95% AI, 25.9 ± 5.1 min) [20]. In this study, a vasoconstrictive effect can be measured within a period of 10–20 min after injection, but normalizing within 30 min.
Despite the repeated demonstration of WALANT’s safety, phentolamine, an alpha-receptor blocker, may be used in the case of persistently low tissue perfusion. Injecting it as an antidote into the previously anesthetized area can remove the vasoconstrictive epinephrine effect (1 mg diluted in 1 ml saline) [2]. In our own practice, we have never had to use phentolamine over a course of more than 600 injections, as has D. Lalonde in the more than 2000 procedures he has performed using WALANT technique [27]. Nevertheless, like him, we always have the antidote available, to be prepared in the case of an emergency.
A limitation of this study is that the measurement is collected at the fingertip while the injection is done at the finger base. Presumably, the effect on the fingertip occurs after a delay, while the full effect on the finger base already exists, which leads to a time shift. Another limiting factor is the small number of cases and the variance of the injection volume and therefore the epinephrine related changes of the vasoconstrictive effect. Owing to the direct clinical preoperative application, the injection volume cannot always be completely standardized, since complete anesthesia must be ensured.
Conclusion
Injection of tumescent local anesthesia containing epinephrine may cause a substantial reduction of blood flow and may lead to critical levels of oxygen saturation in the fingertips. However, these ischemic events seem to be short term, fully reversible within minutes and do not cause long-term complications. The WALANT technique can be considered safe for most patients.
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Author contributions
All authors reviewed and edited the manuscript and approved the final version of the manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL. There is no funding source. This study received no specific financial support from a public, commercial or non-profit financing agency.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
This study was authorized by the ethics committee of our institution (137/18S). This article does not contain any studies with human participants or animals performed by any of the authors. | ARTICAINE, EPINEPHRINE | DrugsGivenReaction | CC BY | 33484301 | 19,715,987 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Peripheral ischaemia'. | WALANT-Epinephrine injection may lead to short term, reversible episodes of critical oxygen saturation in the fingertips.
BACKGROUND
Although the WALANT technique's long-term safeness has been demonstrated in many studies, there are only few data investigating its short-term effects on tissue perfusion and oxygen levels. It was hypothesized that, temporarily, critical levels of tissue perfusion may occur.
METHODS
Seventeen patients, who were scheduled for different procedures in WALANT technique, were injected with 5-7 ml of 1% Articain containing 1:200,000 epinephrine at the finger base. Capillary-venous oxygen saturation, hemoglobin volume in the capillaries, and relative blood flow in the fingertips were recorded once per second by white light spectrometry and laser Doppler flowmetry before, during and after injection for an average of 32 min.
RESULTS
Clinically, no persistent tissue malperfusion was observed, and there were no postoperative complications. Capillary-venous oxygen saturation was reduced by ≥ 30% in seven patients. Critical levels of oxygen saturation were detected in four patients during 13 intervals, each lasting for 132.5 s on average. Oxygen saturation returned to noncritical values in all patients by the end of the observation period. Blood flow in the fingertips was reduced by more than 30% in nine patients, but no critical levels were observed, as with the hemoglobin. Three patients demonstrated a reactive increase in blood flow of more than 30% after injection.
CONCLUSIONS
Injection of tumescent local anesthesia containing epinephrine into finger base may temporarily cause a substantial reduction in blood flow and lead to critical levels of oxygen saturation in the fingertips. However, this was fully reversible within minutes and does not cause long-term complications.
Introduction
The injection of the tumescent local anesthetic lidocaine combined with epinephrine before finger surgery, known as the “Wide Awake Local Anesthesia No Tourniquet” (WALANT) technique, has been demonstrated to be safe from a long-term clinical perspective in many studies [1]. For quite some time, epinephrine was held responsible for finger necrosis, based on the case reports from before the 1950s [2, 3]. Meanwhile, authors have come to the agreement that the local anesthetic procaine was responsible for the described tissue necrosis and finger loss [2, 4]. In the early twenty-first century, the use of epinephrine as a chemical tourniquet in combination with local anesthetics began [5], and no cases of finger necrosis have been reported using lidocaine with epinephrine before 2000 [8]. Although its harmlessness has been clinically proven many times [6–9], textbooks and drug information continuously warn against its use in the acra [5, 10, 11], a dogma that has been passed on for generations [12]. Between 2014 and 2017, three case reports described total or partial finger necrosis after injection of lidocaine and epinephrine (1:100,000). Two resulted in the amputation of one or more finger end limbs, yet without having attempted reversal with phentolamine [13, 14]. In contrast, this proved effective in a third patient, whose postoperative finger ischemia could be reversed that way, saving the digit [15]. With regard to these case reports, one must consider, that in the time span they occurred, several thousand other operations in WALANT technique were performed successfully, without complications. Therefore, the overall risk of necrosis seems to be minimal while the benefits, such as a better intraoperative overview due to lower bleeding without tourniquet, the assessment of stability and gliding ability, predominately. Above all, cases that benefit in particular from WALANT technique are tendon surgery [1, 2, 4] and osteosynthesis [16, 17].
Nonetheless, there are only very few data about its short-term effects on tissue perfusion and oxygen supply after administering epinephrine [5, 18–20, 29]. Hence, this study’s aim was to investigate these by means of micro-lightguide spectrophotometry and laser Doppler flowmetry. Therein, this study focused on capillary-venous oxygen saturation (sO2), hemoglobin volume (rHb) in the capillaries, and relative blood flow in the fingertips. It was hypothesized that critical levels of tissue perfusion may occur after injection of Articain and epinephrine for WALANT.
Materials and methods
Ethical approval
This study was authorized by the ethics committee of our institution (137/18S). All patients had been scheduled for elective procedures regardless of participation in this study.
Patients and methods
In this prospective cohort study, the patients were recruited in our clinic from May through July 2019. Owing to technical difficulties, only 17 of initially 21 patients (9 women, 8 men) with a mean age of 55 years (range 23–79 years) could be included. They were scheduled for different procedures (15 patients: trigger finger release, 1 patient: mucoid cyst extirpation, 1 patient: removal of screw) using the WALANT technique, wherefore they were injected with 5–7 ml of 1% Articain containing 1:200,000 epinephrine subcutaneous at the palmar finger base, using a standardized technique as described by Harbison [21]. The patients were distracted by pressure outside the injection site and a 27G needle was introduced perpendicularly into the subcutaneous tissue. About 1 ml of solution was slowly injected and further infiltration was paused until the needle pain was gone. Then, the remaining solution was slowly injected without aiming for the digital nerves (Table 1). Patients with contraindications, such as allergic reactions, insufficient blood circulation (e.g., clinical signs, such as bluish discoloration, poor capillarization), Raynaud’s syndrome and glaucoma, were excluded. Tissue perfusion and blood flow were assessed using white light spectrometry and laser Doppler flowmetry (Oxygen to See, O2C, LEA, Germany, Fig. 1a).Table 1 Included patients’ demographic data: Age, operated fingers, affected side, injection volume, and complications
Patient
# Age
(years) Gender
(male/female) Operated finger
(D I–V) Affected side
(right/left) Injection volume
(ml) Complications
(yes/no)
1 62 Male III Right 6 No
2 58 Male II Right 5 No
3 57 Male Lll Left 6 No
4 81 Male V Right 5 No
5 55 Female IV Right 5 No
6 53 Female I Left 5 No
7 50 Female I Right 5 No
8 79 Female III Right 5 No
9 54 Female IV Right 5 No
10 60 Male V Right 7 No
11 25 Female III Left 5 No
12 73 Male III Left 5 No
13 48 Male IV Left 6 No
14 63 Female Lll Left 7 No
15 36 Male V Right 5 No
16 58 Female III Left 6 No
17 52 Female I Left 5 No
Fig. 1 Correct position of the detection probe
Measurement procedure
The Oxygen to See (O2C) method provides continuous measurement and precise data collection by combining white-light spectrometry and laser Doppler flowmetry. Tissue is irradiated with light from a broad band and laser light source, while a sensor measures the remission produced by the tissue. White light remission (wavelength range of 500–850 nm) determines oxygen saturation (sO2) and relative hemoglobin (rHb) by calculating the amount of light absorbed by the hemoglobin, depending on its oxygen levels. Laser Doppler flowmetry measures blood flow using the Doppler shift of laser light waves (wavelength: 830 nm) caused by the remission from moving erythrocytes in the capillaries. The measurements’ penetration depths depend on the selected probe, with the maximum depth being 8 mm [22–24].
Capillary-venous oxygen saturation (sO2 in %), hemoglobin volume in the capillaries (rHb in arbitrary units (AU)) and relative blood flow (in AU) in the fingertips were recorded once per second before, during and after injection of Articain and epinephrine, resulting in 43,956 data points. One patient’s (= patient 6 in Table 1) exemplary measurement curve for sO2 development after injection can be seen in Fig. 2.Fig. 2 Example of oxygen saturation at the fingertip (AU) over time after injection. Saturation levels drop by more than 30%, but critical levels are never reached. Minimum saturation occurs after 380 s
Critical levels, irreversible or long-term values that would lead to tissue damage, were defined as < 10% for oxygen saturation (sO2), < 5 arbitrary units (AU) for blood flow and < 15 AU/ > 90 AU for hemoglobin volume (rHb), as suggested in the literature [23, 25, 26]. In addition, patient records were assessed for postoperative complications (Table 1).
Evaluation of hemoglobin volume (rHb), oxygen saturation (sO2), and blood flow after injection
The phase from the start of the O2C measurement until injection of Articain and epinephrine was defined as “baseline”, which lasted for a mean time of 4 min (range 1–11 min, Fig. 3). The period after injection was called “observation”, lasting 32 min on average (range 29–79 min, Fig. 3). In addition, a third period was created, lasting from a midpoint (defined at 15 min after injection) until the end of the measurement (Fig. 3).Fig. 3 Sketch of the experimental set-up with mean times before (baseline) and after (observation values) injection and flow chart of the analysis procedure: a Baseline average and observation average were analyzed for changes in ≥ 30% (group A). b Baseline average and midpoint-end average were analyzed for changes in ≥ 30% (group B)
For data analysis, the single-point values of rHb, sO2 and blood flow, measured every second during the baseline and observation periods (see above), were averaged. In a second step, these average values were compared and analyzed for changes equal to or greater than 30% (Figs. 2, 3a) (= group A). The number of cases, in which such changes occurred, was determined.
Accordingly, the values measured for each of the parameters between the midpoint and the end of O2C were also averaged. These were then compared with the averaged values of the baseline period to evaluate whether the changes in this specific period were more pronounced than in the total observation phase. These results, too, were compared and analyzed for changes in equal to or greater than 30% (Fig. 3b) (= group B).
In a third step, the occurrence of critical levels of rHb (AU), sO2 (%) and blood flow (AU), as defined above, were examined for intervals of 60 s during the measurement by calculating rolling means. Their durations were recorded in seconds.
Statistics
Owing to the small number of patients and their heterogeneous nature, only descriptive statistics were performed, but no hypotheses were tested.
Results
Development of rHb, sO2, and blood flow after injection
Averages between baseline values and observation period (Group A) demonstrated a drop of 30% or more in three patients for rHb levels, in seven patients in sO2 levels and in nine patients in flow levels. When assessing averages between baseline and midpoint end (Group B), reductions in 30% or more were found in three patients for rHb levels, in seven patients for sO2 levels, and seven patients for blood flow levels.
Duration and proportion of critical oxygen saturation in the total observation time
The evaluation of the average values after injection showed a drop of the above-mentioned values, but without taking the previously defined critical values into account.
There were no critical values concerning rHb and blood flow throughout the entire investigation.
13 intervals of critical oxygen saturation with a mean duration of 132.5 s (range 4–482 s) were measured in four patients (Table 2). These intervals lasted a total of 1510 s and were most often found between 10 and 20 min after injection. At the end of the observation period, all patients demonstrated normal values.Table 2 Occurrence of critical values per patient and their duration
Time after injection (min) Duration (s)
Patient 1 3 220
16 91
19 4
19 7
23 71
26 177
Patient 3 2 138
9 482
21 64
Patient 8 5 345
Patient 13 1 44
2 76
15 15
17 121
Generally, there were no allergic or other unexpected long-term reactions. Apart from the temporary occurrence of critical oxygen saturation values, we could not detect any permanent arterial ischemia or venous congestion.
Discussion
The possibility to operate without a tourniquet is a major benefit for patients and surgeons [1, 4, 28]. The WALANT technique makes the surgeon independent of anesthesiologists and allows more flexibility in scheduling surgical treatments. WALANT represents an overall long-term, low-risk technique for every-day use. Apart from low general injection-related risks, such as infections and injuries to neurovascular structures, the contraindications to the injection of epinephrine, including allergic reactions, insufficient blood circulation, Raynaud’s syndrome and glaucoma must be considered. However, the combination of local anesthetic and epinephrine continues to be the topic of much discussion. Even though the application has been proven to be safe many times, textbooks and drug information warn against the use of local anesthetics with the addition of a vasoconstrictor in the acra, nose, ear, and penis.
In addition, there are recurring case reports of finger necrosis after injection for WALANT. For example, in 2014, eight hours after the excision of a skin tumor over a proximal interphalangeal (PIP) joint in WALANT anesthesia, a 16-year-old patient showed signs of ischemia, necessitating the amputation of the affected finger’s end limb. However, reversal of vasoconstriction with phentolamine had not been attempted and the authors could not rule out other causes of finger necrosis [14]. In 2017, an orthopedist in the United States injected lidocaine and 1:100,000 epinephrine for a trigger finger release and carpal tunnel decompression, leading to finger ischemia three hours postoperatively. This lasted for 14 h, until it could be reversed with phentolamine, saving the finger [15]. In the same year, in Canada, three fingers were injected for trigger finger release in WALANT technique. Phentolamine was not applied, leading to necrosis of two thirds of the index and middle finger end limbs and, subsequently, their amputation. The ring finger, whose tip also showed signs of necrosis, could be preserved [13].
Regarding the short-term effects of the WALANT technique on tissue perfusion and oxygen levels, there are very few data in scientific literature [5, 18–20, 29]. Therefore, it was examined tissue blood flow, capillary-venous oxygen saturation (sO2), and hemoglobin volume (rHb) in this study.
This study was able to perform complete and continuous monitoring of relevant post-capillary finger perfusion parameters after local injection for WALANT anesthesia. As the method of measurement used in this study is highly sensitive, however, not all critical values observed need to be considered clinically relevant. Even deep breathing can influence the parameters. Moreover, all values returned near baseline levels within the 30-min investigation period.
Many of our findings are in accordance with Altinyazar et al., who studied digital artery blood flow in 24 subjects, using color Doppler ultrasonography [5]. This was measured before digital blocking with lidocaine containing epinephrine, as well as 10, 60, and 90 min thereafter, resulting in a statistically significant decrease of blood flow rates. In addition, after 10 min of digital block, four patients showed no measurable blood flow, which, however, was restored within 60 or 90 min [5]. Although all values in all of our patients recovered within 30 min, the highest incidence of critical saturation was observed 10 to 20 min post-injection.
Concerning sO2, Sönmez et al. measured blood gas parameters before and 15 min after digital blocks, using lidocaine solutions with or without 1:80,000 epinephrine [18]. They reported that the sO2 first slightly increased, showing small reductions soon after. However, there were no significant differences whether the lidocaine was mixed with epinephrine or not [18]. In contrast, in this study, a continuous measurement is used and a more precise method of data collection, yielding similar results.
To determine changes in the blood flow, Sylaidis and Logan performed a quantitative study on 100 consecutive patients [19]. They measured the brachial and digital arterial systolic blood pressures before and after injection of 2% lidocaine and 1:80,000 epinephrine, finding that, although the digital blood pressures and the mean digital–brachial index decreased after the injections, this effect was completely reversible [19]. Schnabl et al. carried out a prospective, double-blinded, randomized study with 20 volunteers (80 fingers, without operation) [29]. The chronological course of changes in digit blood flow after injection of 0.75% ropivacaine and 1:1.000.000 epinephrine showed no significant changes with a following significant increase of skin perfusion (+ 66.6%) and prolonged pain reduction [29]. The blood flow measured at the fingertip was very variable in this study. On the one hand, this may be due to the sensitive measurement method; on the other hand, on the fingers’ extensor side, there remains sufficient regulation of the collateral vessels, so that blood flow in the fingertip remains relatively constant (unlike in the operating field).
Based on these data, however, no conclusions can be drawn as to how long one should wait after an injection, before starting the operation. McKee et al. found that after a subcutaneous infiltration of 5 ml lidocaine 1% with 1:100,000 epinephrine (0.01 mg/ml) into one arm, versus the same amount of lidocaine 1% without epinephrine into the other arm, the vasoconstrictive effect of lidocaine with epinephrine occurred after only 25 min (95% AI, 25.9 ± 5.1 min) [20]. In this study, a vasoconstrictive effect can be measured within a period of 10–20 min after injection, but normalizing within 30 min.
Despite the repeated demonstration of WALANT’s safety, phentolamine, an alpha-receptor blocker, may be used in the case of persistently low tissue perfusion. Injecting it as an antidote into the previously anesthetized area can remove the vasoconstrictive epinephrine effect (1 mg diluted in 1 ml saline) [2]. In our own practice, we have never had to use phentolamine over a course of more than 600 injections, as has D. Lalonde in the more than 2000 procedures he has performed using WALANT technique [27]. Nevertheless, like him, we always have the antidote available, to be prepared in the case of an emergency.
A limitation of this study is that the measurement is collected at the fingertip while the injection is done at the finger base. Presumably, the effect on the fingertip occurs after a delay, while the full effect on the finger base already exists, which leads to a time shift. Another limiting factor is the small number of cases and the variance of the injection volume and therefore the epinephrine related changes of the vasoconstrictive effect. Owing to the direct clinical preoperative application, the injection volume cannot always be completely standardized, since complete anesthesia must be ensured.
Conclusion
Injection of tumescent local anesthesia containing epinephrine may cause a substantial reduction of blood flow and may lead to critical levels of oxygen saturation in the fingertips. However, these ischemic events seem to be short term, fully reversible within minutes and do not cause long-term complications. The WALANT technique can be considered safe for most patients.
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Author contributions
All authors reviewed and edited the manuscript and approved the final version of the manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL. There is no funding source. This study received no specific financial support from a public, commercial or non-profit financing agency.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
This study was authorized by the ethics committee of our institution (137/18S). This article does not contain any studies with human participants or animals performed by any of the authors. | ARTICAINE, EPINEPHRINE | DrugsGivenReaction | CC BY | 33484301 | 19,715,987 | 2021-03 |
What was the administration route of drug 'ARTICAINE'? | WALANT-Epinephrine injection may lead to short term, reversible episodes of critical oxygen saturation in the fingertips.
BACKGROUND
Although the WALANT technique's long-term safeness has been demonstrated in many studies, there are only few data investigating its short-term effects on tissue perfusion and oxygen levels. It was hypothesized that, temporarily, critical levels of tissue perfusion may occur.
METHODS
Seventeen patients, who were scheduled for different procedures in WALANT technique, were injected with 5-7 ml of 1% Articain containing 1:200,000 epinephrine at the finger base. Capillary-venous oxygen saturation, hemoglobin volume in the capillaries, and relative blood flow in the fingertips were recorded once per second by white light spectrometry and laser Doppler flowmetry before, during and after injection for an average of 32 min.
RESULTS
Clinically, no persistent tissue malperfusion was observed, and there were no postoperative complications. Capillary-venous oxygen saturation was reduced by ≥ 30% in seven patients. Critical levels of oxygen saturation were detected in four patients during 13 intervals, each lasting for 132.5 s on average. Oxygen saturation returned to noncritical values in all patients by the end of the observation period. Blood flow in the fingertips was reduced by more than 30% in nine patients, but no critical levels were observed, as with the hemoglobin. Three patients demonstrated a reactive increase in blood flow of more than 30% after injection.
CONCLUSIONS
Injection of tumescent local anesthesia containing epinephrine into finger base may temporarily cause a substantial reduction in blood flow and lead to critical levels of oxygen saturation in the fingertips. However, this was fully reversible within minutes and does not cause long-term complications.
Introduction
The injection of the tumescent local anesthetic lidocaine combined with epinephrine before finger surgery, known as the “Wide Awake Local Anesthesia No Tourniquet” (WALANT) technique, has been demonstrated to be safe from a long-term clinical perspective in many studies [1]. For quite some time, epinephrine was held responsible for finger necrosis, based on the case reports from before the 1950s [2, 3]. Meanwhile, authors have come to the agreement that the local anesthetic procaine was responsible for the described tissue necrosis and finger loss [2, 4]. In the early twenty-first century, the use of epinephrine as a chemical tourniquet in combination with local anesthetics began [5], and no cases of finger necrosis have been reported using lidocaine with epinephrine before 2000 [8]. Although its harmlessness has been clinically proven many times [6–9], textbooks and drug information continuously warn against its use in the acra [5, 10, 11], a dogma that has been passed on for generations [12]. Between 2014 and 2017, three case reports described total or partial finger necrosis after injection of lidocaine and epinephrine (1:100,000). Two resulted in the amputation of one or more finger end limbs, yet without having attempted reversal with phentolamine [13, 14]. In contrast, this proved effective in a third patient, whose postoperative finger ischemia could be reversed that way, saving the digit [15]. With regard to these case reports, one must consider, that in the time span they occurred, several thousand other operations in WALANT technique were performed successfully, without complications. Therefore, the overall risk of necrosis seems to be minimal while the benefits, such as a better intraoperative overview due to lower bleeding without tourniquet, the assessment of stability and gliding ability, predominately. Above all, cases that benefit in particular from WALANT technique are tendon surgery [1, 2, 4] and osteosynthesis [16, 17].
Nonetheless, there are only very few data about its short-term effects on tissue perfusion and oxygen supply after administering epinephrine [5, 18–20, 29]. Hence, this study’s aim was to investigate these by means of micro-lightguide spectrophotometry and laser Doppler flowmetry. Therein, this study focused on capillary-venous oxygen saturation (sO2), hemoglobin volume (rHb) in the capillaries, and relative blood flow in the fingertips. It was hypothesized that critical levels of tissue perfusion may occur after injection of Articain and epinephrine for WALANT.
Materials and methods
Ethical approval
This study was authorized by the ethics committee of our institution (137/18S). All patients had been scheduled for elective procedures regardless of participation in this study.
Patients and methods
In this prospective cohort study, the patients were recruited in our clinic from May through July 2019. Owing to technical difficulties, only 17 of initially 21 patients (9 women, 8 men) with a mean age of 55 years (range 23–79 years) could be included. They were scheduled for different procedures (15 patients: trigger finger release, 1 patient: mucoid cyst extirpation, 1 patient: removal of screw) using the WALANT technique, wherefore they were injected with 5–7 ml of 1% Articain containing 1:200,000 epinephrine subcutaneous at the palmar finger base, using a standardized technique as described by Harbison [21]. The patients were distracted by pressure outside the injection site and a 27G needle was introduced perpendicularly into the subcutaneous tissue. About 1 ml of solution was slowly injected and further infiltration was paused until the needle pain was gone. Then, the remaining solution was slowly injected without aiming for the digital nerves (Table 1). Patients with contraindications, such as allergic reactions, insufficient blood circulation (e.g., clinical signs, such as bluish discoloration, poor capillarization), Raynaud’s syndrome and glaucoma, were excluded. Tissue perfusion and blood flow were assessed using white light spectrometry and laser Doppler flowmetry (Oxygen to See, O2C, LEA, Germany, Fig. 1a).Table 1 Included patients’ demographic data: Age, operated fingers, affected side, injection volume, and complications
Patient
# Age
(years) Gender
(male/female) Operated finger
(D I–V) Affected side
(right/left) Injection volume
(ml) Complications
(yes/no)
1 62 Male III Right 6 No
2 58 Male II Right 5 No
3 57 Male Lll Left 6 No
4 81 Male V Right 5 No
5 55 Female IV Right 5 No
6 53 Female I Left 5 No
7 50 Female I Right 5 No
8 79 Female III Right 5 No
9 54 Female IV Right 5 No
10 60 Male V Right 7 No
11 25 Female III Left 5 No
12 73 Male III Left 5 No
13 48 Male IV Left 6 No
14 63 Female Lll Left 7 No
15 36 Male V Right 5 No
16 58 Female III Left 6 No
17 52 Female I Left 5 No
Fig. 1 Correct position of the detection probe
Measurement procedure
The Oxygen to See (O2C) method provides continuous measurement and precise data collection by combining white-light spectrometry and laser Doppler flowmetry. Tissue is irradiated with light from a broad band and laser light source, while a sensor measures the remission produced by the tissue. White light remission (wavelength range of 500–850 nm) determines oxygen saturation (sO2) and relative hemoglobin (rHb) by calculating the amount of light absorbed by the hemoglobin, depending on its oxygen levels. Laser Doppler flowmetry measures blood flow using the Doppler shift of laser light waves (wavelength: 830 nm) caused by the remission from moving erythrocytes in the capillaries. The measurements’ penetration depths depend on the selected probe, with the maximum depth being 8 mm [22–24].
Capillary-venous oxygen saturation (sO2 in %), hemoglobin volume in the capillaries (rHb in arbitrary units (AU)) and relative blood flow (in AU) in the fingertips were recorded once per second before, during and after injection of Articain and epinephrine, resulting in 43,956 data points. One patient’s (= patient 6 in Table 1) exemplary measurement curve for sO2 development after injection can be seen in Fig. 2.Fig. 2 Example of oxygen saturation at the fingertip (AU) over time after injection. Saturation levels drop by more than 30%, but critical levels are never reached. Minimum saturation occurs after 380 s
Critical levels, irreversible or long-term values that would lead to tissue damage, were defined as < 10% for oxygen saturation (sO2), < 5 arbitrary units (AU) for blood flow and < 15 AU/ > 90 AU for hemoglobin volume (rHb), as suggested in the literature [23, 25, 26]. In addition, patient records were assessed for postoperative complications (Table 1).
Evaluation of hemoglobin volume (rHb), oxygen saturation (sO2), and blood flow after injection
The phase from the start of the O2C measurement until injection of Articain and epinephrine was defined as “baseline”, which lasted for a mean time of 4 min (range 1–11 min, Fig. 3). The period after injection was called “observation”, lasting 32 min on average (range 29–79 min, Fig. 3). In addition, a third period was created, lasting from a midpoint (defined at 15 min after injection) until the end of the measurement (Fig. 3).Fig. 3 Sketch of the experimental set-up with mean times before (baseline) and after (observation values) injection and flow chart of the analysis procedure: a Baseline average and observation average were analyzed for changes in ≥ 30% (group A). b Baseline average and midpoint-end average were analyzed for changes in ≥ 30% (group B)
For data analysis, the single-point values of rHb, sO2 and blood flow, measured every second during the baseline and observation periods (see above), were averaged. In a second step, these average values were compared and analyzed for changes equal to or greater than 30% (Figs. 2, 3a) (= group A). The number of cases, in which such changes occurred, was determined.
Accordingly, the values measured for each of the parameters between the midpoint and the end of O2C were also averaged. These were then compared with the averaged values of the baseline period to evaluate whether the changes in this specific period were more pronounced than in the total observation phase. These results, too, were compared and analyzed for changes in equal to or greater than 30% (Fig. 3b) (= group B).
In a third step, the occurrence of critical levels of rHb (AU), sO2 (%) and blood flow (AU), as defined above, were examined for intervals of 60 s during the measurement by calculating rolling means. Their durations were recorded in seconds.
Statistics
Owing to the small number of patients and their heterogeneous nature, only descriptive statistics were performed, but no hypotheses were tested.
Results
Development of rHb, sO2, and blood flow after injection
Averages between baseline values and observation period (Group A) demonstrated a drop of 30% or more in three patients for rHb levels, in seven patients in sO2 levels and in nine patients in flow levels. When assessing averages between baseline and midpoint end (Group B), reductions in 30% or more were found in three patients for rHb levels, in seven patients for sO2 levels, and seven patients for blood flow levels.
Duration and proportion of critical oxygen saturation in the total observation time
The evaluation of the average values after injection showed a drop of the above-mentioned values, but without taking the previously defined critical values into account.
There were no critical values concerning rHb and blood flow throughout the entire investigation.
13 intervals of critical oxygen saturation with a mean duration of 132.5 s (range 4–482 s) were measured in four patients (Table 2). These intervals lasted a total of 1510 s and were most often found between 10 and 20 min after injection. At the end of the observation period, all patients demonstrated normal values.Table 2 Occurrence of critical values per patient and their duration
Time after injection (min) Duration (s)
Patient 1 3 220
16 91
19 4
19 7
23 71
26 177
Patient 3 2 138
9 482
21 64
Patient 8 5 345
Patient 13 1 44
2 76
15 15
17 121
Generally, there were no allergic or other unexpected long-term reactions. Apart from the temporary occurrence of critical oxygen saturation values, we could not detect any permanent arterial ischemia or venous congestion.
Discussion
The possibility to operate without a tourniquet is a major benefit for patients and surgeons [1, 4, 28]. The WALANT technique makes the surgeon independent of anesthesiologists and allows more flexibility in scheduling surgical treatments. WALANT represents an overall long-term, low-risk technique for every-day use. Apart from low general injection-related risks, such as infections and injuries to neurovascular structures, the contraindications to the injection of epinephrine, including allergic reactions, insufficient blood circulation, Raynaud’s syndrome and glaucoma must be considered. However, the combination of local anesthetic and epinephrine continues to be the topic of much discussion. Even though the application has been proven to be safe many times, textbooks and drug information warn against the use of local anesthetics with the addition of a vasoconstrictor in the acra, nose, ear, and penis.
In addition, there are recurring case reports of finger necrosis after injection for WALANT. For example, in 2014, eight hours after the excision of a skin tumor over a proximal interphalangeal (PIP) joint in WALANT anesthesia, a 16-year-old patient showed signs of ischemia, necessitating the amputation of the affected finger’s end limb. However, reversal of vasoconstriction with phentolamine had not been attempted and the authors could not rule out other causes of finger necrosis [14]. In 2017, an orthopedist in the United States injected lidocaine and 1:100,000 epinephrine for a trigger finger release and carpal tunnel decompression, leading to finger ischemia three hours postoperatively. This lasted for 14 h, until it could be reversed with phentolamine, saving the finger [15]. In the same year, in Canada, three fingers were injected for trigger finger release in WALANT technique. Phentolamine was not applied, leading to necrosis of two thirds of the index and middle finger end limbs and, subsequently, their amputation. The ring finger, whose tip also showed signs of necrosis, could be preserved [13].
Regarding the short-term effects of the WALANT technique on tissue perfusion and oxygen levels, there are very few data in scientific literature [5, 18–20, 29]. Therefore, it was examined tissue blood flow, capillary-venous oxygen saturation (sO2), and hemoglobin volume (rHb) in this study.
This study was able to perform complete and continuous monitoring of relevant post-capillary finger perfusion parameters after local injection for WALANT anesthesia. As the method of measurement used in this study is highly sensitive, however, not all critical values observed need to be considered clinically relevant. Even deep breathing can influence the parameters. Moreover, all values returned near baseline levels within the 30-min investigation period.
Many of our findings are in accordance with Altinyazar et al., who studied digital artery blood flow in 24 subjects, using color Doppler ultrasonography [5]. This was measured before digital blocking with lidocaine containing epinephrine, as well as 10, 60, and 90 min thereafter, resulting in a statistically significant decrease of blood flow rates. In addition, after 10 min of digital block, four patients showed no measurable blood flow, which, however, was restored within 60 or 90 min [5]. Although all values in all of our patients recovered within 30 min, the highest incidence of critical saturation was observed 10 to 20 min post-injection.
Concerning sO2, Sönmez et al. measured blood gas parameters before and 15 min after digital blocks, using lidocaine solutions with or without 1:80,000 epinephrine [18]. They reported that the sO2 first slightly increased, showing small reductions soon after. However, there were no significant differences whether the lidocaine was mixed with epinephrine or not [18]. In contrast, in this study, a continuous measurement is used and a more precise method of data collection, yielding similar results.
To determine changes in the blood flow, Sylaidis and Logan performed a quantitative study on 100 consecutive patients [19]. They measured the brachial and digital arterial systolic blood pressures before and after injection of 2% lidocaine and 1:80,000 epinephrine, finding that, although the digital blood pressures and the mean digital–brachial index decreased after the injections, this effect was completely reversible [19]. Schnabl et al. carried out a prospective, double-blinded, randomized study with 20 volunteers (80 fingers, without operation) [29]. The chronological course of changes in digit blood flow after injection of 0.75% ropivacaine and 1:1.000.000 epinephrine showed no significant changes with a following significant increase of skin perfusion (+ 66.6%) and prolonged pain reduction [29]. The blood flow measured at the fingertip was very variable in this study. On the one hand, this may be due to the sensitive measurement method; on the other hand, on the fingers’ extensor side, there remains sufficient regulation of the collateral vessels, so that blood flow in the fingertip remains relatively constant (unlike in the operating field).
Based on these data, however, no conclusions can be drawn as to how long one should wait after an injection, before starting the operation. McKee et al. found that after a subcutaneous infiltration of 5 ml lidocaine 1% with 1:100,000 epinephrine (0.01 mg/ml) into one arm, versus the same amount of lidocaine 1% without epinephrine into the other arm, the vasoconstrictive effect of lidocaine with epinephrine occurred after only 25 min (95% AI, 25.9 ± 5.1 min) [20]. In this study, a vasoconstrictive effect can be measured within a period of 10–20 min after injection, but normalizing within 30 min.
Despite the repeated demonstration of WALANT’s safety, phentolamine, an alpha-receptor blocker, may be used in the case of persistently low tissue perfusion. Injecting it as an antidote into the previously anesthetized area can remove the vasoconstrictive epinephrine effect (1 mg diluted in 1 ml saline) [2]. In our own practice, we have never had to use phentolamine over a course of more than 600 injections, as has D. Lalonde in the more than 2000 procedures he has performed using WALANT technique [27]. Nevertheless, like him, we always have the antidote available, to be prepared in the case of an emergency.
A limitation of this study is that the measurement is collected at the fingertip while the injection is done at the finger base. Presumably, the effect on the fingertip occurs after a delay, while the full effect on the finger base already exists, which leads to a time shift. Another limiting factor is the small number of cases and the variance of the injection volume and therefore the epinephrine related changes of the vasoconstrictive effect. Owing to the direct clinical preoperative application, the injection volume cannot always be completely standardized, since complete anesthesia must be ensured.
Conclusion
Injection of tumescent local anesthesia containing epinephrine may cause a substantial reduction of blood flow and may lead to critical levels of oxygen saturation in the fingertips. However, these ischemic events seem to be short term, fully reversible within minutes and do not cause long-term complications. The WALANT technique can be considered safe for most patients.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author contributions
All authors reviewed and edited the manuscript and approved the final version of the manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL. There is no funding source. This study received no specific financial support from a public, commercial or non-profit financing agency.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
This study was authorized by the ethics committee of our institution (137/18S). This article does not contain any studies with human participants or animals performed by any of the authors. | Subcutaneous | DrugAdministrationRoute | CC BY | 33484301 | 19,715,987 | 2021-03 |
What was the administration route of drug 'EPINEPHRINE'? | WALANT-Epinephrine injection may lead to short term, reversible episodes of critical oxygen saturation in the fingertips.
BACKGROUND
Although the WALANT technique's long-term safeness has been demonstrated in many studies, there are only few data investigating its short-term effects on tissue perfusion and oxygen levels. It was hypothesized that, temporarily, critical levels of tissue perfusion may occur.
METHODS
Seventeen patients, who were scheduled for different procedures in WALANT technique, were injected with 5-7 ml of 1% Articain containing 1:200,000 epinephrine at the finger base. Capillary-venous oxygen saturation, hemoglobin volume in the capillaries, and relative blood flow in the fingertips were recorded once per second by white light spectrometry and laser Doppler flowmetry before, during and after injection for an average of 32 min.
RESULTS
Clinically, no persistent tissue malperfusion was observed, and there were no postoperative complications. Capillary-venous oxygen saturation was reduced by ≥ 30% in seven patients. Critical levels of oxygen saturation were detected in four patients during 13 intervals, each lasting for 132.5 s on average. Oxygen saturation returned to noncritical values in all patients by the end of the observation period. Blood flow in the fingertips was reduced by more than 30% in nine patients, but no critical levels were observed, as with the hemoglobin. Three patients demonstrated a reactive increase in blood flow of more than 30% after injection.
CONCLUSIONS
Injection of tumescent local anesthesia containing epinephrine into finger base may temporarily cause a substantial reduction in blood flow and lead to critical levels of oxygen saturation in the fingertips. However, this was fully reversible within minutes and does not cause long-term complications.
Introduction
The injection of the tumescent local anesthetic lidocaine combined with epinephrine before finger surgery, known as the “Wide Awake Local Anesthesia No Tourniquet” (WALANT) technique, has been demonstrated to be safe from a long-term clinical perspective in many studies [1]. For quite some time, epinephrine was held responsible for finger necrosis, based on the case reports from before the 1950s [2, 3]. Meanwhile, authors have come to the agreement that the local anesthetic procaine was responsible for the described tissue necrosis and finger loss [2, 4]. In the early twenty-first century, the use of epinephrine as a chemical tourniquet in combination with local anesthetics began [5], and no cases of finger necrosis have been reported using lidocaine with epinephrine before 2000 [8]. Although its harmlessness has been clinically proven many times [6–9], textbooks and drug information continuously warn against its use in the acra [5, 10, 11], a dogma that has been passed on for generations [12]. Between 2014 and 2017, three case reports described total or partial finger necrosis after injection of lidocaine and epinephrine (1:100,000). Two resulted in the amputation of one or more finger end limbs, yet without having attempted reversal with phentolamine [13, 14]. In contrast, this proved effective in a third patient, whose postoperative finger ischemia could be reversed that way, saving the digit [15]. With regard to these case reports, one must consider, that in the time span they occurred, several thousand other operations in WALANT technique were performed successfully, without complications. Therefore, the overall risk of necrosis seems to be minimal while the benefits, such as a better intraoperative overview due to lower bleeding without tourniquet, the assessment of stability and gliding ability, predominately. Above all, cases that benefit in particular from WALANT technique are tendon surgery [1, 2, 4] and osteosynthesis [16, 17].
Nonetheless, there are only very few data about its short-term effects on tissue perfusion and oxygen supply after administering epinephrine [5, 18–20, 29]. Hence, this study’s aim was to investigate these by means of micro-lightguide spectrophotometry and laser Doppler flowmetry. Therein, this study focused on capillary-venous oxygen saturation (sO2), hemoglobin volume (rHb) in the capillaries, and relative blood flow in the fingertips. It was hypothesized that critical levels of tissue perfusion may occur after injection of Articain and epinephrine for WALANT.
Materials and methods
Ethical approval
This study was authorized by the ethics committee of our institution (137/18S). All patients had been scheduled for elective procedures regardless of participation in this study.
Patients and methods
In this prospective cohort study, the patients were recruited in our clinic from May through July 2019. Owing to technical difficulties, only 17 of initially 21 patients (9 women, 8 men) with a mean age of 55 years (range 23–79 years) could be included. They were scheduled for different procedures (15 patients: trigger finger release, 1 patient: mucoid cyst extirpation, 1 patient: removal of screw) using the WALANT technique, wherefore they were injected with 5–7 ml of 1% Articain containing 1:200,000 epinephrine subcutaneous at the palmar finger base, using a standardized technique as described by Harbison [21]. The patients were distracted by pressure outside the injection site and a 27G needle was introduced perpendicularly into the subcutaneous tissue. About 1 ml of solution was slowly injected and further infiltration was paused until the needle pain was gone. Then, the remaining solution was slowly injected without aiming for the digital nerves (Table 1). Patients with contraindications, such as allergic reactions, insufficient blood circulation (e.g., clinical signs, such as bluish discoloration, poor capillarization), Raynaud’s syndrome and glaucoma, were excluded. Tissue perfusion and blood flow were assessed using white light spectrometry and laser Doppler flowmetry (Oxygen to See, O2C, LEA, Germany, Fig. 1a).Table 1 Included patients’ demographic data: Age, operated fingers, affected side, injection volume, and complications
Patient
# Age
(years) Gender
(male/female) Operated finger
(D I–V) Affected side
(right/left) Injection volume
(ml) Complications
(yes/no)
1 62 Male III Right 6 No
2 58 Male II Right 5 No
3 57 Male Lll Left 6 No
4 81 Male V Right 5 No
5 55 Female IV Right 5 No
6 53 Female I Left 5 No
7 50 Female I Right 5 No
8 79 Female III Right 5 No
9 54 Female IV Right 5 No
10 60 Male V Right 7 No
11 25 Female III Left 5 No
12 73 Male III Left 5 No
13 48 Male IV Left 6 No
14 63 Female Lll Left 7 No
15 36 Male V Right 5 No
16 58 Female III Left 6 No
17 52 Female I Left 5 No
Fig. 1 Correct position of the detection probe
Measurement procedure
The Oxygen to See (O2C) method provides continuous measurement and precise data collection by combining white-light spectrometry and laser Doppler flowmetry. Tissue is irradiated with light from a broad band and laser light source, while a sensor measures the remission produced by the tissue. White light remission (wavelength range of 500–850 nm) determines oxygen saturation (sO2) and relative hemoglobin (rHb) by calculating the amount of light absorbed by the hemoglobin, depending on its oxygen levels. Laser Doppler flowmetry measures blood flow using the Doppler shift of laser light waves (wavelength: 830 nm) caused by the remission from moving erythrocytes in the capillaries. The measurements’ penetration depths depend on the selected probe, with the maximum depth being 8 mm [22–24].
Capillary-venous oxygen saturation (sO2 in %), hemoglobin volume in the capillaries (rHb in arbitrary units (AU)) and relative blood flow (in AU) in the fingertips were recorded once per second before, during and after injection of Articain and epinephrine, resulting in 43,956 data points. One patient’s (= patient 6 in Table 1) exemplary measurement curve for sO2 development after injection can be seen in Fig. 2.Fig. 2 Example of oxygen saturation at the fingertip (AU) over time after injection. Saturation levels drop by more than 30%, but critical levels are never reached. Minimum saturation occurs after 380 s
Critical levels, irreversible or long-term values that would lead to tissue damage, were defined as < 10% for oxygen saturation (sO2), < 5 arbitrary units (AU) for blood flow and < 15 AU/ > 90 AU for hemoglobin volume (rHb), as suggested in the literature [23, 25, 26]. In addition, patient records were assessed for postoperative complications (Table 1).
Evaluation of hemoglobin volume (rHb), oxygen saturation (sO2), and blood flow after injection
The phase from the start of the O2C measurement until injection of Articain and epinephrine was defined as “baseline”, which lasted for a mean time of 4 min (range 1–11 min, Fig. 3). The period after injection was called “observation”, lasting 32 min on average (range 29–79 min, Fig. 3). In addition, a third period was created, lasting from a midpoint (defined at 15 min after injection) until the end of the measurement (Fig. 3).Fig. 3 Sketch of the experimental set-up with mean times before (baseline) and after (observation values) injection and flow chart of the analysis procedure: a Baseline average and observation average were analyzed for changes in ≥ 30% (group A). b Baseline average and midpoint-end average were analyzed for changes in ≥ 30% (group B)
For data analysis, the single-point values of rHb, sO2 and blood flow, measured every second during the baseline and observation periods (see above), were averaged. In a second step, these average values were compared and analyzed for changes equal to or greater than 30% (Figs. 2, 3a) (= group A). The number of cases, in which such changes occurred, was determined.
Accordingly, the values measured for each of the parameters between the midpoint and the end of O2C were also averaged. These were then compared with the averaged values of the baseline period to evaluate whether the changes in this specific period were more pronounced than in the total observation phase. These results, too, were compared and analyzed for changes in equal to or greater than 30% (Fig. 3b) (= group B).
In a third step, the occurrence of critical levels of rHb (AU), sO2 (%) and blood flow (AU), as defined above, were examined for intervals of 60 s during the measurement by calculating rolling means. Their durations were recorded in seconds.
Statistics
Owing to the small number of patients and their heterogeneous nature, only descriptive statistics were performed, but no hypotheses were tested.
Results
Development of rHb, sO2, and blood flow after injection
Averages between baseline values and observation period (Group A) demonstrated a drop of 30% or more in three patients for rHb levels, in seven patients in sO2 levels and in nine patients in flow levels. When assessing averages between baseline and midpoint end (Group B), reductions in 30% or more were found in three patients for rHb levels, in seven patients for sO2 levels, and seven patients for blood flow levels.
Duration and proportion of critical oxygen saturation in the total observation time
The evaluation of the average values after injection showed a drop of the above-mentioned values, but without taking the previously defined critical values into account.
There were no critical values concerning rHb and blood flow throughout the entire investigation.
13 intervals of critical oxygen saturation with a mean duration of 132.5 s (range 4–482 s) were measured in four patients (Table 2). These intervals lasted a total of 1510 s and were most often found between 10 and 20 min after injection. At the end of the observation period, all patients demonstrated normal values.Table 2 Occurrence of critical values per patient and their duration
Time after injection (min) Duration (s)
Patient 1 3 220
16 91
19 4
19 7
23 71
26 177
Patient 3 2 138
9 482
21 64
Patient 8 5 345
Patient 13 1 44
2 76
15 15
17 121
Generally, there were no allergic or other unexpected long-term reactions. Apart from the temporary occurrence of critical oxygen saturation values, we could not detect any permanent arterial ischemia or venous congestion.
Discussion
The possibility to operate without a tourniquet is a major benefit for patients and surgeons [1, 4, 28]. The WALANT technique makes the surgeon independent of anesthesiologists and allows more flexibility in scheduling surgical treatments. WALANT represents an overall long-term, low-risk technique for every-day use. Apart from low general injection-related risks, such as infections and injuries to neurovascular structures, the contraindications to the injection of epinephrine, including allergic reactions, insufficient blood circulation, Raynaud’s syndrome and glaucoma must be considered. However, the combination of local anesthetic and epinephrine continues to be the topic of much discussion. Even though the application has been proven to be safe many times, textbooks and drug information warn against the use of local anesthetics with the addition of a vasoconstrictor in the acra, nose, ear, and penis.
In addition, there are recurring case reports of finger necrosis after injection for WALANT. For example, in 2014, eight hours after the excision of a skin tumor over a proximal interphalangeal (PIP) joint in WALANT anesthesia, a 16-year-old patient showed signs of ischemia, necessitating the amputation of the affected finger’s end limb. However, reversal of vasoconstriction with phentolamine had not been attempted and the authors could not rule out other causes of finger necrosis [14]. In 2017, an orthopedist in the United States injected lidocaine and 1:100,000 epinephrine for a trigger finger release and carpal tunnel decompression, leading to finger ischemia three hours postoperatively. This lasted for 14 h, until it could be reversed with phentolamine, saving the finger [15]. In the same year, in Canada, three fingers were injected for trigger finger release in WALANT technique. Phentolamine was not applied, leading to necrosis of two thirds of the index and middle finger end limbs and, subsequently, their amputation. The ring finger, whose tip also showed signs of necrosis, could be preserved [13].
Regarding the short-term effects of the WALANT technique on tissue perfusion and oxygen levels, there are very few data in scientific literature [5, 18–20, 29]. Therefore, it was examined tissue blood flow, capillary-venous oxygen saturation (sO2), and hemoglobin volume (rHb) in this study.
This study was able to perform complete and continuous monitoring of relevant post-capillary finger perfusion parameters after local injection for WALANT anesthesia. As the method of measurement used in this study is highly sensitive, however, not all critical values observed need to be considered clinically relevant. Even deep breathing can influence the parameters. Moreover, all values returned near baseline levels within the 30-min investigation period.
Many of our findings are in accordance with Altinyazar et al., who studied digital artery blood flow in 24 subjects, using color Doppler ultrasonography [5]. This was measured before digital blocking with lidocaine containing epinephrine, as well as 10, 60, and 90 min thereafter, resulting in a statistically significant decrease of blood flow rates. In addition, after 10 min of digital block, four patients showed no measurable blood flow, which, however, was restored within 60 or 90 min [5]. Although all values in all of our patients recovered within 30 min, the highest incidence of critical saturation was observed 10 to 20 min post-injection.
Concerning sO2, Sönmez et al. measured blood gas parameters before and 15 min after digital blocks, using lidocaine solutions with or without 1:80,000 epinephrine [18]. They reported that the sO2 first slightly increased, showing small reductions soon after. However, there were no significant differences whether the lidocaine was mixed with epinephrine or not [18]. In contrast, in this study, a continuous measurement is used and a more precise method of data collection, yielding similar results.
To determine changes in the blood flow, Sylaidis and Logan performed a quantitative study on 100 consecutive patients [19]. They measured the brachial and digital arterial systolic blood pressures before and after injection of 2% lidocaine and 1:80,000 epinephrine, finding that, although the digital blood pressures and the mean digital–brachial index decreased after the injections, this effect was completely reversible [19]. Schnabl et al. carried out a prospective, double-blinded, randomized study with 20 volunteers (80 fingers, without operation) [29]. The chronological course of changes in digit blood flow after injection of 0.75% ropivacaine and 1:1.000.000 epinephrine showed no significant changes with a following significant increase of skin perfusion (+ 66.6%) and prolonged pain reduction [29]. The blood flow measured at the fingertip was very variable in this study. On the one hand, this may be due to the sensitive measurement method; on the other hand, on the fingers’ extensor side, there remains sufficient regulation of the collateral vessels, so that blood flow in the fingertip remains relatively constant (unlike in the operating field).
Based on these data, however, no conclusions can be drawn as to how long one should wait after an injection, before starting the operation. McKee et al. found that after a subcutaneous infiltration of 5 ml lidocaine 1% with 1:100,000 epinephrine (0.01 mg/ml) into one arm, versus the same amount of lidocaine 1% without epinephrine into the other arm, the vasoconstrictive effect of lidocaine with epinephrine occurred after only 25 min (95% AI, 25.9 ± 5.1 min) [20]. In this study, a vasoconstrictive effect can be measured within a period of 10–20 min after injection, but normalizing within 30 min.
Despite the repeated demonstration of WALANT’s safety, phentolamine, an alpha-receptor blocker, may be used in the case of persistently low tissue perfusion. Injecting it as an antidote into the previously anesthetized area can remove the vasoconstrictive epinephrine effect (1 mg diluted in 1 ml saline) [2]. In our own practice, we have never had to use phentolamine over a course of more than 600 injections, as has D. Lalonde in the more than 2000 procedures he has performed using WALANT technique [27]. Nevertheless, like him, we always have the antidote available, to be prepared in the case of an emergency.
A limitation of this study is that the measurement is collected at the fingertip while the injection is done at the finger base. Presumably, the effect on the fingertip occurs after a delay, while the full effect on the finger base already exists, which leads to a time shift. Another limiting factor is the small number of cases and the variance of the injection volume and therefore the epinephrine related changes of the vasoconstrictive effect. Owing to the direct clinical preoperative application, the injection volume cannot always be completely standardized, since complete anesthesia must be ensured.
Conclusion
Injection of tumescent local anesthesia containing epinephrine may cause a substantial reduction of blood flow and may lead to critical levels of oxygen saturation in the fingertips. However, these ischemic events seem to be short term, fully reversible within minutes and do not cause long-term complications. The WALANT technique can be considered safe for most patients.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author contributions
All authors reviewed and edited the manuscript and approved the final version of the manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL. There is no funding source. This study received no specific financial support from a public, commercial or non-profit financing agency.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
This study was authorized by the ethics committee of our institution (137/18S). This article does not contain any studies with human participants or animals performed by any of the authors. | Subcutaneous | DrugAdministrationRoute | CC BY | 33484301 | 19,715,987 | 2021-03 |
What was the outcome of reaction 'Oxygen saturation decreased'? | WALANT-Epinephrine injection may lead to short term, reversible episodes of critical oxygen saturation in the fingertips.
BACKGROUND
Although the WALANT technique's long-term safeness has been demonstrated in many studies, there are only few data investigating its short-term effects on tissue perfusion and oxygen levels. It was hypothesized that, temporarily, critical levels of tissue perfusion may occur.
METHODS
Seventeen patients, who were scheduled for different procedures in WALANT technique, were injected with 5-7 ml of 1% Articain containing 1:200,000 epinephrine at the finger base. Capillary-venous oxygen saturation, hemoglobin volume in the capillaries, and relative blood flow in the fingertips were recorded once per second by white light spectrometry and laser Doppler flowmetry before, during and after injection for an average of 32 min.
RESULTS
Clinically, no persistent tissue malperfusion was observed, and there were no postoperative complications. Capillary-venous oxygen saturation was reduced by ≥ 30% in seven patients. Critical levels of oxygen saturation were detected in four patients during 13 intervals, each lasting for 132.5 s on average. Oxygen saturation returned to noncritical values in all patients by the end of the observation period. Blood flow in the fingertips was reduced by more than 30% in nine patients, but no critical levels were observed, as with the hemoglobin. Three patients demonstrated a reactive increase in blood flow of more than 30% after injection.
CONCLUSIONS
Injection of tumescent local anesthesia containing epinephrine into finger base may temporarily cause a substantial reduction in blood flow and lead to critical levels of oxygen saturation in the fingertips. However, this was fully reversible within minutes and does not cause long-term complications.
Introduction
The injection of the tumescent local anesthetic lidocaine combined with epinephrine before finger surgery, known as the “Wide Awake Local Anesthesia No Tourniquet” (WALANT) technique, has been demonstrated to be safe from a long-term clinical perspective in many studies [1]. For quite some time, epinephrine was held responsible for finger necrosis, based on the case reports from before the 1950s [2, 3]. Meanwhile, authors have come to the agreement that the local anesthetic procaine was responsible for the described tissue necrosis and finger loss [2, 4]. In the early twenty-first century, the use of epinephrine as a chemical tourniquet in combination with local anesthetics began [5], and no cases of finger necrosis have been reported using lidocaine with epinephrine before 2000 [8]. Although its harmlessness has been clinically proven many times [6–9], textbooks and drug information continuously warn against its use in the acra [5, 10, 11], a dogma that has been passed on for generations [12]. Between 2014 and 2017, three case reports described total or partial finger necrosis after injection of lidocaine and epinephrine (1:100,000). Two resulted in the amputation of one or more finger end limbs, yet without having attempted reversal with phentolamine [13, 14]. In contrast, this proved effective in a third patient, whose postoperative finger ischemia could be reversed that way, saving the digit [15]. With regard to these case reports, one must consider, that in the time span they occurred, several thousand other operations in WALANT technique were performed successfully, without complications. Therefore, the overall risk of necrosis seems to be minimal while the benefits, such as a better intraoperative overview due to lower bleeding without tourniquet, the assessment of stability and gliding ability, predominately. Above all, cases that benefit in particular from WALANT technique are tendon surgery [1, 2, 4] and osteosynthesis [16, 17].
Nonetheless, there are only very few data about its short-term effects on tissue perfusion and oxygen supply after administering epinephrine [5, 18–20, 29]. Hence, this study’s aim was to investigate these by means of micro-lightguide spectrophotometry and laser Doppler flowmetry. Therein, this study focused on capillary-venous oxygen saturation (sO2), hemoglobin volume (rHb) in the capillaries, and relative blood flow in the fingertips. It was hypothesized that critical levels of tissue perfusion may occur after injection of Articain and epinephrine for WALANT.
Materials and methods
Ethical approval
This study was authorized by the ethics committee of our institution (137/18S). All patients had been scheduled for elective procedures regardless of participation in this study.
Patients and methods
In this prospective cohort study, the patients were recruited in our clinic from May through July 2019. Owing to technical difficulties, only 17 of initially 21 patients (9 women, 8 men) with a mean age of 55 years (range 23–79 years) could be included. They were scheduled for different procedures (15 patients: trigger finger release, 1 patient: mucoid cyst extirpation, 1 patient: removal of screw) using the WALANT technique, wherefore they were injected with 5–7 ml of 1% Articain containing 1:200,000 epinephrine subcutaneous at the palmar finger base, using a standardized technique as described by Harbison [21]. The patients were distracted by pressure outside the injection site and a 27G needle was introduced perpendicularly into the subcutaneous tissue. About 1 ml of solution was slowly injected and further infiltration was paused until the needle pain was gone. Then, the remaining solution was slowly injected without aiming for the digital nerves (Table 1). Patients with contraindications, such as allergic reactions, insufficient blood circulation (e.g., clinical signs, such as bluish discoloration, poor capillarization), Raynaud’s syndrome and glaucoma, were excluded. Tissue perfusion and blood flow were assessed using white light spectrometry and laser Doppler flowmetry (Oxygen to See, O2C, LEA, Germany, Fig. 1a).Table 1 Included patients’ demographic data: Age, operated fingers, affected side, injection volume, and complications
Patient
# Age
(years) Gender
(male/female) Operated finger
(D I–V) Affected side
(right/left) Injection volume
(ml) Complications
(yes/no)
1 62 Male III Right 6 No
2 58 Male II Right 5 No
3 57 Male Lll Left 6 No
4 81 Male V Right 5 No
5 55 Female IV Right 5 No
6 53 Female I Left 5 No
7 50 Female I Right 5 No
8 79 Female III Right 5 No
9 54 Female IV Right 5 No
10 60 Male V Right 7 No
11 25 Female III Left 5 No
12 73 Male III Left 5 No
13 48 Male IV Left 6 No
14 63 Female Lll Left 7 No
15 36 Male V Right 5 No
16 58 Female III Left 6 No
17 52 Female I Left 5 No
Fig. 1 Correct position of the detection probe
Measurement procedure
The Oxygen to See (O2C) method provides continuous measurement and precise data collection by combining white-light spectrometry and laser Doppler flowmetry. Tissue is irradiated with light from a broad band and laser light source, while a sensor measures the remission produced by the tissue. White light remission (wavelength range of 500–850 nm) determines oxygen saturation (sO2) and relative hemoglobin (rHb) by calculating the amount of light absorbed by the hemoglobin, depending on its oxygen levels. Laser Doppler flowmetry measures blood flow using the Doppler shift of laser light waves (wavelength: 830 nm) caused by the remission from moving erythrocytes in the capillaries. The measurements’ penetration depths depend on the selected probe, with the maximum depth being 8 mm [22–24].
Capillary-venous oxygen saturation (sO2 in %), hemoglobin volume in the capillaries (rHb in arbitrary units (AU)) and relative blood flow (in AU) in the fingertips were recorded once per second before, during and after injection of Articain and epinephrine, resulting in 43,956 data points. One patient’s (= patient 6 in Table 1) exemplary measurement curve for sO2 development after injection can be seen in Fig. 2.Fig. 2 Example of oxygen saturation at the fingertip (AU) over time after injection. Saturation levels drop by more than 30%, but critical levels are never reached. Minimum saturation occurs after 380 s
Critical levels, irreversible or long-term values that would lead to tissue damage, were defined as < 10% for oxygen saturation (sO2), < 5 arbitrary units (AU) for blood flow and < 15 AU/ > 90 AU for hemoglobin volume (rHb), as suggested in the literature [23, 25, 26]. In addition, patient records were assessed for postoperative complications (Table 1).
Evaluation of hemoglobin volume (rHb), oxygen saturation (sO2), and blood flow after injection
The phase from the start of the O2C measurement until injection of Articain and epinephrine was defined as “baseline”, which lasted for a mean time of 4 min (range 1–11 min, Fig. 3). The period after injection was called “observation”, lasting 32 min on average (range 29–79 min, Fig. 3). In addition, a third period was created, lasting from a midpoint (defined at 15 min after injection) until the end of the measurement (Fig. 3).Fig. 3 Sketch of the experimental set-up with mean times before (baseline) and after (observation values) injection and flow chart of the analysis procedure: a Baseline average and observation average were analyzed for changes in ≥ 30% (group A). b Baseline average and midpoint-end average were analyzed for changes in ≥ 30% (group B)
For data analysis, the single-point values of rHb, sO2 and blood flow, measured every second during the baseline and observation periods (see above), were averaged. In a second step, these average values were compared and analyzed for changes equal to or greater than 30% (Figs. 2, 3a) (= group A). The number of cases, in which such changes occurred, was determined.
Accordingly, the values measured for each of the parameters between the midpoint and the end of O2C were also averaged. These were then compared with the averaged values of the baseline period to evaluate whether the changes in this specific period were more pronounced than in the total observation phase. These results, too, were compared and analyzed for changes in equal to or greater than 30% (Fig. 3b) (= group B).
In a third step, the occurrence of critical levels of rHb (AU), sO2 (%) and blood flow (AU), as defined above, were examined for intervals of 60 s during the measurement by calculating rolling means. Their durations were recorded in seconds.
Statistics
Owing to the small number of patients and their heterogeneous nature, only descriptive statistics were performed, but no hypotheses were tested.
Results
Development of rHb, sO2, and blood flow after injection
Averages between baseline values and observation period (Group A) demonstrated a drop of 30% or more in three patients for rHb levels, in seven patients in sO2 levels and in nine patients in flow levels. When assessing averages between baseline and midpoint end (Group B), reductions in 30% or more were found in three patients for rHb levels, in seven patients for sO2 levels, and seven patients for blood flow levels.
Duration and proportion of critical oxygen saturation in the total observation time
The evaluation of the average values after injection showed a drop of the above-mentioned values, but without taking the previously defined critical values into account.
There were no critical values concerning rHb and blood flow throughout the entire investigation.
13 intervals of critical oxygen saturation with a mean duration of 132.5 s (range 4–482 s) were measured in four patients (Table 2). These intervals lasted a total of 1510 s and were most often found between 10 and 20 min after injection. At the end of the observation period, all patients demonstrated normal values.Table 2 Occurrence of critical values per patient and their duration
Time after injection (min) Duration (s)
Patient 1 3 220
16 91
19 4
19 7
23 71
26 177
Patient 3 2 138
9 482
21 64
Patient 8 5 345
Patient 13 1 44
2 76
15 15
17 121
Generally, there were no allergic or other unexpected long-term reactions. Apart from the temporary occurrence of critical oxygen saturation values, we could not detect any permanent arterial ischemia or venous congestion.
Discussion
The possibility to operate without a tourniquet is a major benefit for patients and surgeons [1, 4, 28]. The WALANT technique makes the surgeon independent of anesthesiologists and allows more flexibility in scheduling surgical treatments. WALANT represents an overall long-term, low-risk technique for every-day use. Apart from low general injection-related risks, such as infections and injuries to neurovascular structures, the contraindications to the injection of epinephrine, including allergic reactions, insufficient blood circulation, Raynaud’s syndrome and glaucoma must be considered. However, the combination of local anesthetic and epinephrine continues to be the topic of much discussion. Even though the application has been proven to be safe many times, textbooks and drug information warn against the use of local anesthetics with the addition of a vasoconstrictor in the acra, nose, ear, and penis.
In addition, there are recurring case reports of finger necrosis after injection for WALANT. For example, in 2014, eight hours after the excision of a skin tumor over a proximal interphalangeal (PIP) joint in WALANT anesthesia, a 16-year-old patient showed signs of ischemia, necessitating the amputation of the affected finger’s end limb. However, reversal of vasoconstriction with phentolamine had not been attempted and the authors could not rule out other causes of finger necrosis [14]. In 2017, an orthopedist in the United States injected lidocaine and 1:100,000 epinephrine for a trigger finger release and carpal tunnel decompression, leading to finger ischemia three hours postoperatively. This lasted for 14 h, until it could be reversed with phentolamine, saving the finger [15]. In the same year, in Canada, three fingers were injected for trigger finger release in WALANT technique. Phentolamine was not applied, leading to necrosis of two thirds of the index and middle finger end limbs and, subsequently, their amputation. The ring finger, whose tip also showed signs of necrosis, could be preserved [13].
Regarding the short-term effects of the WALANT technique on tissue perfusion and oxygen levels, there are very few data in scientific literature [5, 18–20, 29]. Therefore, it was examined tissue blood flow, capillary-venous oxygen saturation (sO2), and hemoglobin volume (rHb) in this study.
This study was able to perform complete and continuous monitoring of relevant post-capillary finger perfusion parameters after local injection for WALANT anesthesia. As the method of measurement used in this study is highly sensitive, however, not all critical values observed need to be considered clinically relevant. Even deep breathing can influence the parameters. Moreover, all values returned near baseline levels within the 30-min investigation period.
Many of our findings are in accordance with Altinyazar et al., who studied digital artery blood flow in 24 subjects, using color Doppler ultrasonography [5]. This was measured before digital blocking with lidocaine containing epinephrine, as well as 10, 60, and 90 min thereafter, resulting in a statistically significant decrease of blood flow rates. In addition, after 10 min of digital block, four patients showed no measurable blood flow, which, however, was restored within 60 or 90 min [5]. Although all values in all of our patients recovered within 30 min, the highest incidence of critical saturation was observed 10 to 20 min post-injection.
Concerning sO2, Sönmez et al. measured blood gas parameters before and 15 min after digital blocks, using lidocaine solutions with or without 1:80,000 epinephrine [18]. They reported that the sO2 first slightly increased, showing small reductions soon after. However, there were no significant differences whether the lidocaine was mixed with epinephrine or not [18]. In contrast, in this study, a continuous measurement is used and a more precise method of data collection, yielding similar results.
To determine changes in the blood flow, Sylaidis and Logan performed a quantitative study on 100 consecutive patients [19]. They measured the brachial and digital arterial systolic blood pressures before and after injection of 2% lidocaine and 1:80,000 epinephrine, finding that, although the digital blood pressures and the mean digital–brachial index decreased after the injections, this effect was completely reversible [19]. Schnabl et al. carried out a prospective, double-blinded, randomized study with 20 volunteers (80 fingers, without operation) [29]. The chronological course of changes in digit blood flow after injection of 0.75% ropivacaine and 1:1.000.000 epinephrine showed no significant changes with a following significant increase of skin perfusion (+ 66.6%) and prolonged pain reduction [29]. The blood flow measured at the fingertip was very variable in this study. On the one hand, this may be due to the sensitive measurement method; on the other hand, on the fingers’ extensor side, there remains sufficient regulation of the collateral vessels, so that blood flow in the fingertip remains relatively constant (unlike in the operating field).
Based on these data, however, no conclusions can be drawn as to how long one should wait after an injection, before starting the operation. McKee et al. found that after a subcutaneous infiltration of 5 ml lidocaine 1% with 1:100,000 epinephrine (0.01 mg/ml) into one arm, versus the same amount of lidocaine 1% without epinephrine into the other arm, the vasoconstrictive effect of lidocaine with epinephrine occurred after only 25 min (95% AI, 25.9 ± 5.1 min) [20]. In this study, a vasoconstrictive effect can be measured within a period of 10–20 min after injection, but normalizing within 30 min.
Despite the repeated demonstration of WALANT’s safety, phentolamine, an alpha-receptor blocker, may be used in the case of persistently low tissue perfusion. Injecting it as an antidote into the previously anesthetized area can remove the vasoconstrictive epinephrine effect (1 mg diluted in 1 ml saline) [2]. In our own practice, we have never had to use phentolamine over a course of more than 600 injections, as has D. Lalonde in the more than 2000 procedures he has performed using WALANT technique [27]. Nevertheless, like him, we always have the antidote available, to be prepared in the case of an emergency.
A limitation of this study is that the measurement is collected at the fingertip while the injection is done at the finger base. Presumably, the effect on the fingertip occurs after a delay, while the full effect on the finger base already exists, which leads to a time shift. Another limiting factor is the small number of cases and the variance of the injection volume and therefore the epinephrine related changes of the vasoconstrictive effect. Owing to the direct clinical preoperative application, the injection volume cannot always be completely standardized, since complete anesthesia must be ensured.
Conclusion
Injection of tumescent local anesthesia containing epinephrine may cause a substantial reduction of blood flow and may lead to critical levels of oxygen saturation in the fingertips. However, these ischemic events seem to be short term, fully reversible within minutes and do not cause long-term complications. The WALANT technique can be considered safe for most patients.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author contributions
All authors reviewed and edited the manuscript and approved the final version of the manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL. There is no funding source. This study received no specific financial support from a public, commercial or non-profit financing agency.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
This study was authorized by the ethics committee of our institution (137/18S). This article does not contain any studies with human participants or animals performed by any of the authors. | Recovered | ReactionOutcome | CC BY | 33484301 | 19,715,987 | 2021-03 |
What was the outcome of reaction 'Peripheral ischaemia'? | WALANT-Epinephrine injection may lead to short term, reversible episodes of critical oxygen saturation in the fingertips.
BACKGROUND
Although the WALANT technique's long-term safeness has been demonstrated in many studies, there are only few data investigating its short-term effects on tissue perfusion and oxygen levels. It was hypothesized that, temporarily, critical levels of tissue perfusion may occur.
METHODS
Seventeen patients, who were scheduled for different procedures in WALANT technique, were injected with 5-7 ml of 1% Articain containing 1:200,000 epinephrine at the finger base. Capillary-venous oxygen saturation, hemoglobin volume in the capillaries, and relative blood flow in the fingertips were recorded once per second by white light spectrometry and laser Doppler flowmetry before, during and after injection for an average of 32 min.
RESULTS
Clinically, no persistent tissue malperfusion was observed, and there were no postoperative complications. Capillary-venous oxygen saturation was reduced by ≥ 30% in seven patients. Critical levels of oxygen saturation were detected in four patients during 13 intervals, each lasting for 132.5 s on average. Oxygen saturation returned to noncritical values in all patients by the end of the observation period. Blood flow in the fingertips was reduced by more than 30% in nine patients, but no critical levels were observed, as with the hemoglobin. Three patients demonstrated a reactive increase in blood flow of more than 30% after injection.
CONCLUSIONS
Injection of tumescent local anesthesia containing epinephrine into finger base may temporarily cause a substantial reduction in blood flow and lead to critical levels of oxygen saturation in the fingertips. However, this was fully reversible within minutes and does not cause long-term complications.
Introduction
The injection of the tumescent local anesthetic lidocaine combined with epinephrine before finger surgery, known as the “Wide Awake Local Anesthesia No Tourniquet” (WALANT) technique, has been demonstrated to be safe from a long-term clinical perspective in many studies [1]. For quite some time, epinephrine was held responsible for finger necrosis, based on the case reports from before the 1950s [2, 3]. Meanwhile, authors have come to the agreement that the local anesthetic procaine was responsible for the described tissue necrosis and finger loss [2, 4]. In the early twenty-first century, the use of epinephrine as a chemical tourniquet in combination with local anesthetics began [5], and no cases of finger necrosis have been reported using lidocaine with epinephrine before 2000 [8]. Although its harmlessness has been clinically proven many times [6–9], textbooks and drug information continuously warn against its use in the acra [5, 10, 11], a dogma that has been passed on for generations [12]. Between 2014 and 2017, three case reports described total or partial finger necrosis after injection of lidocaine and epinephrine (1:100,000). Two resulted in the amputation of one or more finger end limbs, yet without having attempted reversal with phentolamine [13, 14]. In contrast, this proved effective in a third patient, whose postoperative finger ischemia could be reversed that way, saving the digit [15]. With regard to these case reports, one must consider, that in the time span they occurred, several thousand other operations in WALANT technique were performed successfully, without complications. Therefore, the overall risk of necrosis seems to be minimal while the benefits, such as a better intraoperative overview due to lower bleeding without tourniquet, the assessment of stability and gliding ability, predominately. Above all, cases that benefit in particular from WALANT technique are tendon surgery [1, 2, 4] and osteosynthesis [16, 17].
Nonetheless, there are only very few data about its short-term effects on tissue perfusion and oxygen supply after administering epinephrine [5, 18–20, 29]. Hence, this study’s aim was to investigate these by means of micro-lightguide spectrophotometry and laser Doppler flowmetry. Therein, this study focused on capillary-venous oxygen saturation (sO2), hemoglobin volume (rHb) in the capillaries, and relative blood flow in the fingertips. It was hypothesized that critical levels of tissue perfusion may occur after injection of Articain and epinephrine for WALANT.
Materials and methods
Ethical approval
This study was authorized by the ethics committee of our institution (137/18S). All patients had been scheduled for elective procedures regardless of participation in this study.
Patients and methods
In this prospective cohort study, the patients were recruited in our clinic from May through July 2019. Owing to technical difficulties, only 17 of initially 21 patients (9 women, 8 men) with a mean age of 55 years (range 23–79 years) could be included. They were scheduled for different procedures (15 patients: trigger finger release, 1 patient: mucoid cyst extirpation, 1 patient: removal of screw) using the WALANT technique, wherefore they were injected with 5–7 ml of 1% Articain containing 1:200,000 epinephrine subcutaneous at the palmar finger base, using a standardized technique as described by Harbison [21]. The patients were distracted by pressure outside the injection site and a 27G needle was introduced perpendicularly into the subcutaneous tissue. About 1 ml of solution was slowly injected and further infiltration was paused until the needle pain was gone. Then, the remaining solution was slowly injected without aiming for the digital nerves (Table 1). Patients with contraindications, such as allergic reactions, insufficient blood circulation (e.g., clinical signs, such as bluish discoloration, poor capillarization), Raynaud’s syndrome and glaucoma, were excluded. Tissue perfusion and blood flow were assessed using white light spectrometry and laser Doppler flowmetry (Oxygen to See, O2C, LEA, Germany, Fig. 1a).Table 1 Included patients’ demographic data: Age, operated fingers, affected side, injection volume, and complications
Patient
# Age
(years) Gender
(male/female) Operated finger
(D I–V) Affected side
(right/left) Injection volume
(ml) Complications
(yes/no)
1 62 Male III Right 6 No
2 58 Male II Right 5 No
3 57 Male Lll Left 6 No
4 81 Male V Right 5 No
5 55 Female IV Right 5 No
6 53 Female I Left 5 No
7 50 Female I Right 5 No
8 79 Female III Right 5 No
9 54 Female IV Right 5 No
10 60 Male V Right 7 No
11 25 Female III Left 5 No
12 73 Male III Left 5 No
13 48 Male IV Left 6 No
14 63 Female Lll Left 7 No
15 36 Male V Right 5 No
16 58 Female III Left 6 No
17 52 Female I Left 5 No
Fig. 1 Correct position of the detection probe
Measurement procedure
The Oxygen to See (O2C) method provides continuous measurement and precise data collection by combining white-light spectrometry and laser Doppler flowmetry. Tissue is irradiated with light from a broad band and laser light source, while a sensor measures the remission produced by the tissue. White light remission (wavelength range of 500–850 nm) determines oxygen saturation (sO2) and relative hemoglobin (rHb) by calculating the amount of light absorbed by the hemoglobin, depending on its oxygen levels. Laser Doppler flowmetry measures blood flow using the Doppler shift of laser light waves (wavelength: 830 nm) caused by the remission from moving erythrocytes in the capillaries. The measurements’ penetration depths depend on the selected probe, with the maximum depth being 8 mm [22–24].
Capillary-venous oxygen saturation (sO2 in %), hemoglobin volume in the capillaries (rHb in arbitrary units (AU)) and relative blood flow (in AU) in the fingertips were recorded once per second before, during and after injection of Articain and epinephrine, resulting in 43,956 data points. One patient’s (= patient 6 in Table 1) exemplary measurement curve for sO2 development after injection can be seen in Fig. 2.Fig. 2 Example of oxygen saturation at the fingertip (AU) over time after injection. Saturation levels drop by more than 30%, but critical levels are never reached. Minimum saturation occurs after 380 s
Critical levels, irreversible or long-term values that would lead to tissue damage, were defined as < 10% for oxygen saturation (sO2), < 5 arbitrary units (AU) for blood flow and < 15 AU/ > 90 AU for hemoglobin volume (rHb), as suggested in the literature [23, 25, 26]. In addition, patient records were assessed for postoperative complications (Table 1).
Evaluation of hemoglobin volume (rHb), oxygen saturation (sO2), and blood flow after injection
The phase from the start of the O2C measurement until injection of Articain and epinephrine was defined as “baseline”, which lasted for a mean time of 4 min (range 1–11 min, Fig. 3). The period after injection was called “observation”, lasting 32 min on average (range 29–79 min, Fig. 3). In addition, a third period was created, lasting from a midpoint (defined at 15 min after injection) until the end of the measurement (Fig. 3).Fig. 3 Sketch of the experimental set-up with mean times before (baseline) and after (observation values) injection and flow chart of the analysis procedure: a Baseline average and observation average were analyzed for changes in ≥ 30% (group A). b Baseline average and midpoint-end average were analyzed for changes in ≥ 30% (group B)
For data analysis, the single-point values of rHb, sO2 and blood flow, measured every second during the baseline and observation periods (see above), were averaged. In a second step, these average values were compared and analyzed for changes equal to or greater than 30% (Figs. 2, 3a) (= group A). The number of cases, in which such changes occurred, was determined.
Accordingly, the values measured for each of the parameters between the midpoint and the end of O2C were also averaged. These were then compared with the averaged values of the baseline period to evaluate whether the changes in this specific period were more pronounced than in the total observation phase. These results, too, were compared and analyzed for changes in equal to or greater than 30% (Fig. 3b) (= group B).
In a third step, the occurrence of critical levels of rHb (AU), sO2 (%) and blood flow (AU), as defined above, were examined for intervals of 60 s during the measurement by calculating rolling means. Their durations were recorded in seconds.
Statistics
Owing to the small number of patients and their heterogeneous nature, only descriptive statistics were performed, but no hypotheses were tested.
Results
Development of rHb, sO2, and blood flow after injection
Averages between baseline values and observation period (Group A) demonstrated a drop of 30% or more in three patients for rHb levels, in seven patients in sO2 levels and in nine patients in flow levels. When assessing averages between baseline and midpoint end (Group B), reductions in 30% or more were found in three patients for rHb levels, in seven patients for sO2 levels, and seven patients for blood flow levels.
Duration and proportion of critical oxygen saturation in the total observation time
The evaluation of the average values after injection showed a drop of the above-mentioned values, but without taking the previously defined critical values into account.
There were no critical values concerning rHb and blood flow throughout the entire investigation.
13 intervals of critical oxygen saturation with a mean duration of 132.5 s (range 4–482 s) were measured in four patients (Table 2). These intervals lasted a total of 1510 s and were most often found between 10 and 20 min after injection. At the end of the observation period, all patients demonstrated normal values.Table 2 Occurrence of critical values per patient and their duration
Time after injection (min) Duration (s)
Patient 1 3 220
16 91
19 4
19 7
23 71
26 177
Patient 3 2 138
9 482
21 64
Patient 8 5 345
Patient 13 1 44
2 76
15 15
17 121
Generally, there were no allergic or other unexpected long-term reactions. Apart from the temporary occurrence of critical oxygen saturation values, we could not detect any permanent arterial ischemia or venous congestion.
Discussion
The possibility to operate without a tourniquet is a major benefit for patients and surgeons [1, 4, 28]. The WALANT technique makes the surgeon independent of anesthesiologists and allows more flexibility in scheduling surgical treatments. WALANT represents an overall long-term, low-risk technique for every-day use. Apart from low general injection-related risks, such as infections and injuries to neurovascular structures, the contraindications to the injection of epinephrine, including allergic reactions, insufficient blood circulation, Raynaud’s syndrome and glaucoma must be considered. However, the combination of local anesthetic and epinephrine continues to be the topic of much discussion. Even though the application has been proven to be safe many times, textbooks and drug information warn against the use of local anesthetics with the addition of a vasoconstrictor in the acra, nose, ear, and penis.
In addition, there are recurring case reports of finger necrosis after injection for WALANT. For example, in 2014, eight hours after the excision of a skin tumor over a proximal interphalangeal (PIP) joint in WALANT anesthesia, a 16-year-old patient showed signs of ischemia, necessitating the amputation of the affected finger’s end limb. However, reversal of vasoconstriction with phentolamine had not been attempted and the authors could not rule out other causes of finger necrosis [14]. In 2017, an orthopedist in the United States injected lidocaine and 1:100,000 epinephrine for a trigger finger release and carpal tunnel decompression, leading to finger ischemia three hours postoperatively. This lasted for 14 h, until it could be reversed with phentolamine, saving the finger [15]. In the same year, in Canada, three fingers were injected for trigger finger release in WALANT technique. Phentolamine was not applied, leading to necrosis of two thirds of the index and middle finger end limbs and, subsequently, their amputation. The ring finger, whose tip also showed signs of necrosis, could be preserved [13].
Regarding the short-term effects of the WALANT technique on tissue perfusion and oxygen levels, there are very few data in scientific literature [5, 18–20, 29]. Therefore, it was examined tissue blood flow, capillary-venous oxygen saturation (sO2), and hemoglobin volume (rHb) in this study.
This study was able to perform complete and continuous monitoring of relevant post-capillary finger perfusion parameters after local injection for WALANT anesthesia. As the method of measurement used in this study is highly sensitive, however, not all critical values observed need to be considered clinically relevant. Even deep breathing can influence the parameters. Moreover, all values returned near baseline levels within the 30-min investigation period.
Many of our findings are in accordance with Altinyazar et al., who studied digital artery blood flow in 24 subjects, using color Doppler ultrasonography [5]. This was measured before digital blocking with lidocaine containing epinephrine, as well as 10, 60, and 90 min thereafter, resulting in a statistically significant decrease of blood flow rates. In addition, after 10 min of digital block, four patients showed no measurable blood flow, which, however, was restored within 60 or 90 min [5]. Although all values in all of our patients recovered within 30 min, the highest incidence of critical saturation was observed 10 to 20 min post-injection.
Concerning sO2, Sönmez et al. measured blood gas parameters before and 15 min after digital blocks, using lidocaine solutions with or without 1:80,000 epinephrine [18]. They reported that the sO2 first slightly increased, showing small reductions soon after. However, there were no significant differences whether the lidocaine was mixed with epinephrine or not [18]. In contrast, in this study, a continuous measurement is used and a more precise method of data collection, yielding similar results.
To determine changes in the blood flow, Sylaidis and Logan performed a quantitative study on 100 consecutive patients [19]. They measured the brachial and digital arterial systolic blood pressures before and after injection of 2% lidocaine and 1:80,000 epinephrine, finding that, although the digital blood pressures and the mean digital–brachial index decreased after the injections, this effect was completely reversible [19]. Schnabl et al. carried out a prospective, double-blinded, randomized study with 20 volunteers (80 fingers, without operation) [29]. The chronological course of changes in digit blood flow after injection of 0.75% ropivacaine and 1:1.000.000 epinephrine showed no significant changes with a following significant increase of skin perfusion (+ 66.6%) and prolonged pain reduction [29]. The blood flow measured at the fingertip was very variable in this study. On the one hand, this may be due to the sensitive measurement method; on the other hand, on the fingers’ extensor side, there remains sufficient regulation of the collateral vessels, so that blood flow in the fingertip remains relatively constant (unlike in the operating field).
Based on these data, however, no conclusions can be drawn as to how long one should wait after an injection, before starting the operation. McKee et al. found that after a subcutaneous infiltration of 5 ml lidocaine 1% with 1:100,000 epinephrine (0.01 mg/ml) into one arm, versus the same amount of lidocaine 1% without epinephrine into the other arm, the vasoconstrictive effect of lidocaine with epinephrine occurred after only 25 min (95% AI, 25.9 ± 5.1 min) [20]. In this study, a vasoconstrictive effect can be measured within a period of 10–20 min after injection, but normalizing within 30 min.
Despite the repeated demonstration of WALANT’s safety, phentolamine, an alpha-receptor blocker, may be used in the case of persistently low tissue perfusion. Injecting it as an antidote into the previously anesthetized area can remove the vasoconstrictive epinephrine effect (1 mg diluted in 1 ml saline) [2]. In our own practice, we have never had to use phentolamine over a course of more than 600 injections, as has D. Lalonde in the more than 2000 procedures he has performed using WALANT technique [27]. Nevertheless, like him, we always have the antidote available, to be prepared in the case of an emergency.
A limitation of this study is that the measurement is collected at the fingertip while the injection is done at the finger base. Presumably, the effect on the fingertip occurs after a delay, while the full effect on the finger base already exists, which leads to a time shift. Another limiting factor is the small number of cases and the variance of the injection volume and therefore the epinephrine related changes of the vasoconstrictive effect. Owing to the direct clinical preoperative application, the injection volume cannot always be completely standardized, since complete anesthesia must be ensured.
Conclusion
Injection of tumescent local anesthesia containing epinephrine may cause a substantial reduction of blood flow and may lead to critical levels of oxygen saturation in the fingertips. However, these ischemic events seem to be short term, fully reversible within minutes and do not cause long-term complications. The WALANT technique can be considered safe for most patients.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Author contributions
All authors reviewed and edited the manuscript and approved the final version of the manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL. There is no funding source. This study received no specific financial support from a public, commercial or non-profit financing agency.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
This study was authorized by the ethics committee of our institution (137/18S). This article does not contain any studies with human participants or animals performed by any of the authors. | Recovered | ReactionOutcome | CC BY | 33484301 | 19,715,987 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypotonia neonatal'. | Successful treatment with Cinryze® replacement therapy of a pregnant patient with hereditary angioedema: a case report.
BACKGROUND
Hereditary angioedema (HAE) is a rare disease characterized with recurrent swelling of subcutaneous or mucosal tissue that resolves in approximately 3 days. It can be presented with peripheral edema, abdominal and life-threatening laryngeal angioedema. A variety of triggers are known to cause episodes of angioedema including estrogen exposure. There are different reports regarding the effect of pregnancy on HAE attacks, and in some patients, the pregnancy is a recognized triggering factor.
METHODS
We present a female Caucasian patient with pre-existing HAE and disease exacerbations during pregnancy, requiring prophylactic use of plasma-derived C1 inhibitor concentrate. She was treated with Cinryze® replacement therapy throughout the pregnancy 1000 IU i.v. 48 times. She gave birth to a healthy male infant, via C-section. After the delivery, the patient was symptom-free for 6 months and required no treatment for HAE.
CONCLUSIONS
In the case presented, the angioedema attacks worsened as the pregnancy progressed. The treatment with Cinryze® replacement therapy was effective and safe during pregnancy, with no adverse effects on the infant.
Introduction
Hereditary angioedema (HAE) is a rare disease characterized with recurrent swelling of subcutaneous or mucosal tissue, without pruritus or urticaria, that resolves in approximately 3 days. The disease can be presented with peripheral edema, abdominal, but also with life-threatening laryngeal angioedema [1].
Several types of HAE are described; the most explored one is due to C1 inhibitor deficiency, known as type I. It is caused by SERPING 1 mutation, on the long arm of chromosome 11, leading to C1 inhibitor deficiency which subsequently results in low C1 inhibitor and C4 protein levels in blood serum [2].
A variety of triggers, such as stress, surgical procedures, some medications (ACE inhibitors, estrogen-containing medication) are identified to cause episodes of angioedema [3, 4]. There are different reports regarding the effect of pregnancy on HAE attacks, and in some patients, the pregnancy is a known triggering factor.
We present a female patient with HAE and frequent disease exacerbations during pregnancy, that required prophylactic use of plasma-derived C1 inhibitor concentrate (pdC1) throughout the pregnancy.
Case presentation
We present a female Caucasian patient with HAE type I, diagnosed at the age of 26, with SERPING 1 mutation (confirmed by molecular testing), with very low C1inhibitor and C4 levels. Molecular testing was also positive for her father and brother. They also had low C1 inhibitor and C4 levels, but they never had any HAE symptoms.
Her symptoms of HAE first appeared when she was 15 years old, as swelling of her hand, without pain or urticaria. She was misdiagnosed with allergy-induced angioedema in the emergency department and was treated with glucocorticoids and antihistamines, without improvement. Edema subsided 3 days later. After that attack, peripheral angioedema appeared approximately once a year and lasted for a few days.
Since the age of 20 until the age of 26, she had several times very intense abdominal pain, with swelling, that required a visit to the emergency room (ER), where she would receive analgetic and proton -pump inhibitor (PPI) i.v., Gastroenterologist examined her, and after gastroscopy, the diagnosis of chronic erosive gastritis was established. Finally, at the age of 25, due to recurrent peripheral oedema, she was referred to clinical immunologist and allergist. After an extensive workup, at the age of 26, HAE type I was diagnosed.
Once HAE was diagnosed, she was treated with tranexamic acid (1000 mg daily orally) and icatibant 30 mg subcutaneously as on-demand therapy, which she had to use approximately once a year, due to abdominal angioedema.
In her medical history, at the age of 28, she had one spontaneous abortion at 8 weeks of pregnancy. Since the patient planned pregnancy, tranexamic acid was excluded, and recombinant C1 inhibitor, conestat alpha, was provided as on-demand therapy.
At the age of 29, in July 2018. patient came to the emergency room (ER) because of the swelling of her eyelids and lips, and she was treated with a total of 160 mg of methylprednisolone and chloropyramine 20 mg i.v. As she reported difficulty swallowing, an examination by ear, nose and throat (ENT) specialist was performed, and the edema of the epiglottis and sinus piriformis was established. Since there was no improvement after the anti-allergic therapy, recombinant C1 inhibitor was applied, (conestat alpha 2100 IU i.v.) and total regression of edema ensued a few hours later. She was admitted to the Department of Rheumatology, Clinical Immunology and Allergology for further observation.
Her social history revealed that she is a tradeswoman by profession, but is currently unemployed, married, living in a family house with her husband in a rural area, without any domestic animals in her household. The patient is a nonsmoker; she denied using alcohol, drugs or other medications. On admission, her temperature was 36.8°C, heart rate 76 beats/min, blood pressure 120/75 mmHg. There was no swelling of her face, neck or uvula. Her chest was clear to auscultation bilaterally, no wheezing. S1S2 were heard, no murmur, rubs or gallops. The abdomen was not distended; there was no tenderness on palpation and no organomegaly. There was no swelling or edema of her extremities. Neurological examination was unremarkable, with no nuchal rigidity, ophthalmic abnormalities, or cranial nerve signs.
During hospitalization, pregnancy was confirmed (8 weeks gestation). According to HAE guidelines, a pdC1 inhibitor is recommended in pregnancy, and Cinryze® was advised as only available pd1C1 inhibitor in our country at that time. In July 2018, she received the first application of Cinryze® 1000 IU i.v. and it was prescribed as on-demand therapy.
Two weeks later, she returned to the ER because of nausea and intense abdominal pain. Examination by obstetrics and gynaecology (OBGYN) specialist was performed, and complications related to pregnancy were excluded. The ultrasound of the abdomen displayed a small amount of fluid around the liver, spleen and intestines, and her blood workup was unremarkable.
After surgical and gastroenterologist (GE) examination she was referred to clinical immunologist and abdominal angioedema attack was diagnosed. She received Cinryze® 1000 iu i.v. and afterwards admitted to the Department for further evaluation. Blood workup revealed mild leukocytosis 14 ×109/L (ref. 3.4–9.7 × 109/L), normal C-reactive protein levels (5 mg/L; ref. <5) and elevated D-dimer levels >35000 Ug/L FEU (ref. 0–500) and low C4 0.04 g/L (ref. 0.1–0.4). Other blood workup was unremarkable: serum amylase 52U/L (ref. 30–110), lipase 9 U/L (0–160), LDH (s) 128 U/L (130–241), AST 24U/L (11–38), ALT 39 U/L (12–48), ALP 52 U/L (20–140), urea 1.6 mmol/L (2.8–8.3), creatinine (s) 49 umol/L (64–104), total bilirubin 11 umol/L (3-20), erythrocytes 4.31 × 1012/L (4.35–5.72), haemoglobin 131 g/L (138-175), thromocytes 189 × 109/L (158–424). Urine culture was sterile, EBV, CMV, Toxoplasma gondii serology revealed past contact.
Two hours after Cinryze® treatment, her symptoms resolved. On the next day, leukocyte levels were normal, and D-dimer values were significantly lower (4992 ug/L).
She was discharged from the hospital with Cinryze® i.v. as on-demand therapy and application of low weight molecular heparin s.c. (dalteparin 7500 IU s.c. once daily) was recommended through the entire pregnancy due to history of previous spontaneous abortion and elevated D-dimers.
After that episode, the attacks were more frequent, with abdominal angioedema attacks every 3 days, and peripheral edema with the swelling of hands almost every other day. At 17 weeks gestation, the patient was started on Cinryze® prophylactic therapy 1000 IU i.v., two times a week. As the pregnancy progressed, her attacks became more frequent despite prophylactic treatment, so during the final month of the pregnancy, she received Cinryze® every two to three days.
In January 2019, she gave birth to a male term infant (gestational age 38 weeks), via C-section. The newborn infant was eutrophic (birth weight 3370 g), and had an average head circumference (33 cm). Upon birth, the infant was mildly dyspneic, had regular heart rate (>120/min), pink skin colour, was mildly hypotonic and had normal reflexes. Apgar scores were 8 at 1ʹ and 8 at 5ʹ. Due to transitory tachypnea of the newborn, he required non-invasive respiratory support with heated and humidified high flow nasal cannula (HFNC) for six hours. The hospitalization was otherwise uneventful, and he was discharged after 8 days. Head ultrasound was normal; there were no signs of perinatal infection.
Before the C-section, the patient received Cinryze® 1000 IU iv. For the next two weeks after the delivery, prophylactic therapy was continued, and subsequently, icatibant as on-demand therapy was recommended. The patient chose not to breastfeed. After the delivery, the patient was symptom-free for 6 months and required no treatment for HAE. Her first abdominal attack after the symptom-free period was less intensive than during pregnancy. Overall, during the pregnancy, the patient in total received Cinryze® (1000 IU i.v.) 48 times.
Discussion
In the report we presented a female patient with HAE type I, with pregnancy as an exact trigger for HAE attacks, leading to the progression of the number of attacks as the pregnancy advanced, and the patient required prophylactic treatment. Interestingly, attacks started in the early pregnancy with a severe presentation of the disease that was not previously present, and resolved immediately after the delivery, leaving the patient symptom free for several months. There are only a few case reports and studies available, which give a detailed description of HAE worsening during the pregnancy, but to our knowledge, non showed such progression despite prophylactic therapy [5-9].
Hereditary angioedema is a rare disease that affects both male and female patients, but the attacks are more frequent in female patients [10]. The likely explanation is the possible effect of estrogen on the kallikrein-kinin system and subsequently on the disease course. [11]. Furthermore, it is known that HAE attacks can be precipitated by estrogen replacement therapy and contraceptive hormones [4, 10].
In our patient, the first symptom appeared during puberty onset. Although the SERPING 1 mutation and low levels of C1 inhibitor and C4 complement were found in her father and brother, she was the only member of the family with HAE symptoms.
The impact of pregnancy on HAE symptoms in patients is still unclear. Martinez-Saguer et al. showed that in 83% of pregnancies, attack rates increased during pregnancy with the highest rates in the second and third trimesters [12]. Czaller et al. in their study reported that attack frequency increases in 48% of pregnancies, most of them experienced worsening in the third trimester. Still, in 19% of the pregnancies, there was no influence on the course of HAE [9]. In contrast to these findings, Chinniah showed that women with HAE have significantly reduced or absent attacks in the last two trimesters of pregnancy [13].
In our patient, the first HAE symptom, when the pregnancy was revealed, was life-threatening laryngeal edema, whereas, before pregnancy, HAE symptoms were always presented as peripheral or abdominal edema. As the pregnancy progressed, her attacks became more frequent, especially in the last trimester, and were presented as abdominal and peripheral edema. Following the international WAO/EAACI guideline for the management of hereditary angioedema, the patient was treated with C1 inhibitor concentrate as prophylactic therapy during the pregnancy [1, 14].
Some authors suggest an increased number of attacks following frequent treatments with C1 concentrate [15]. This was not confirmed in our case, since our patient received 48 times pdC1 inhibitor concentrate and the attacks stopped after the delivery, and afterwards, she was a symptom-free for 6 months.
The patient was treated with pdC1 inhibitor concentrate Cinryze®, although there is no relevant epidemiological data regarding its safety during pregnancy. Until now, there are only a few case reports of its safety during pregnancy [16].
Conclusion
In the case presented, the angioedema attacks worsened as the pregnancy progressed. After delivery, the patient was symptom-free for six months. During the pregnancy, she was treated with pdC1 inhibitor concentrate Cinryze®, which showed to be a safe choice, although there is no relevant epidemiological data regarding its safety during pregnancy. Our report further confirms that Cinryze® therapy is effective and safe treatment during pregnancy, with no adverse effects on the infant.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
The authors acknowledge and thank the patient for her consent and insight, and also the staff and educators of the University Hospital Osijek, Croatia
Authors' contributions
ŽK and DK acquired, analyzed, and interpreted data and drafted the article and revised it critically for important intellectual content. VP and JMA revised the article critically for important intellectual content. All authors participated in writing the final manuscript. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
The study was approved by University Hospital Osijek Ethics committee No R2-1060/2020 and informed written consent was obtained.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
ŽK and VP has received speaker honorariums from Takeda Pharmaceuticals. DK owns stock in Takeda Pharmaceuticals. JMA declares that she has no conflict of interest. | HUMAN C1-ESTERASE INHIBITOR | DrugsGivenReaction | CC BY | 33485376 | 18,845,589 | 2021-01-24 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Maternal exposure during pregnancy'. | Successful treatment with Cinryze® replacement therapy of a pregnant patient with hereditary angioedema: a case report.
BACKGROUND
Hereditary angioedema (HAE) is a rare disease characterized with recurrent swelling of subcutaneous or mucosal tissue that resolves in approximately 3 days. It can be presented with peripheral edema, abdominal and life-threatening laryngeal angioedema. A variety of triggers are known to cause episodes of angioedema including estrogen exposure. There are different reports regarding the effect of pregnancy on HAE attacks, and in some patients, the pregnancy is a recognized triggering factor.
METHODS
We present a female Caucasian patient with pre-existing HAE and disease exacerbations during pregnancy, requiring prophylactic use of plasma-derived C1 inhibitor concentrate. She was treated with Cinryze® replacement therapy throughout the pregnancy 1000 IU i.v. 48 times. She gave birth to a healthy male infant, via C-section. After the delivery, the patient was symptom-free for 6 months and required no treatment for HAE.
CONCLUSIONS
In the case presented, the angioedema attacks worsened as the pregnancy progressed. The treatment with Cinryze® replacement therapy was effective and safe during pregnancy, with no adverse effects on the infant.
Introduction
Hereditary angioedema (HAE) is a rare disease characterized with recurrent swelling of subcutaneous or mucosal tissue, without pruritus or urticaria, that resolves in approximately 3 days. The disease can be presented with peripheral edema, abdominal, but also with life-threatening laryngeal angioedema [1].
Several types of HAE are described; the most explored one is due to C1 inhibitor deficiency, known as type I. It is caused by SERPING 1 mutation, on the long arm of chromosome 11, leading to C1 inhibitor deficiency which subsequently results in low C1 inhibitor and C4 protein levels in blood serum [2].
A variety of triggers, such as stress, surgical procedures, some medications (ACE inhibitors, estrogen-containing medication) are identified to cause episodes of angioedema [3, 4]. There are different reports regarding the effect of pregnancy on HAE attacks, and in some patients, the pregnancy is a known triggering factor.
We present a female patient with HAE and frequent disease exacerbations during pregnancy, that required prophylactic use of plasma-derived C1 inhibitor concentrate (pdC1) throughout the pregnancy.
Case presentation
We present a female Caucasian patient with HAE type I, diagnosed at the age of 26, with SERPING 1 mutation (confirmed by molecular testing), with very low C1inhibitor and C4 levels. Molecular testing was also positive for her father and brother. They also had low C1 inhibitor and C4 levels, but they never had any HAE symptoms.
Her symptoms of HAE first appeared when she was 15 years old, as swelling of her hand, without pain or urticaria. She was misdiagnosed with allergy-induced angioedema in the emergency department and was treated with glucocorticoids and antihistamines, without improvement. Edema subsided 3 days later. After that attack, peripheral angioedema appeared approximately once a year and lasted for a few days.
Since the age of 20 until the age of 26, she had several times very intense abdominal pain, with swelling, that required a visit to the emergency room (ER), where she would receive analgetic and proton -pump inhibitor (PPI) i.v., Gastroenterologist examined her, and after gastroscopy, the diagnosis of chronic erosive gastritis was established. Finally, at the age of 25, due to recurrent peripheral oedema, she was referred to clinical immunologist and allergist. After an extensive workup, at the age of 26, HAE type I was diagnosed.
Once HAE was diagnosed, she was treated with tranexamic acid (1000 mg daily orally) and icatibant 30 mg subcutaneously as on-demand therapy, which she had to use approximately once a year, due to abdominal angioedema.
In her medical history, at the age of 28, she had one spontaneous abortion at 8 weeks of pregnancy. Since the patient planned pregnancy, tranexamic acid was excluded, and recombinant C1 inhibitor, conestat alpha, was provided as on-demand therapy.
At the age of 29, in July 2018. patient came to the emergency room (ER) because of the swelling of her eyelids and lips, and she was treated with a total of 160 mg of methylprednisolone and chloropyramine 20 mg i.v. As she reported difficulty swallowing, an examination by ear, nose and throat (ENT) specialist was performed, and the edema of the epiglottis and sinus piriformis was established. Since there was no improvement after the anti-allergic therapy, recombinant C1 inhibitor was applied, (conestat alpha 2100 IU i.v.) and total regression of edema ensued a few hours later. She was admitted to the Department of Rheumatology, Clinical Immunology and Allergology for further observation.
Her social history revealed that she is a tradeswoman by profession, but is currently unemployed, married, living in a family house with her husband in a rural area, without any domestic animals in her household. The patient is a nonsmoker; she denied using alcohol, drugs or other medications. On admission, her temperature was 36.8°C, heart rate 76 beats/min, blood pressure 120/75 mmHg. There was no swelling of her face, neck or uvula. Her chest was clear to auscultation bilaterally, no wheezing. S1S2 were heard, no murmur, rubs or gallops. The abdomen was not distended; there was no tenderness on palpation and no organomegaly. There was no swelling or edema of her extremities. Neurological examination was unremarkable, with no nuchal rigidity, ophthalmic abnormalities, or cranial nerve signs.
During hospitalization, pregnancy was confirmed (8 weeks gestation). According to HAE guidelines, a pdC1 inhibitor is recommended in pregnancy, and Cinryze® was advised as only available pd1C1 inhibitor in our country at that time. In July 2018, she received the first application of Cinryze® 1000 IU i.v. and it was prescribed as on-demand therapy.
Two weeks later, she returned to the ER because of nausea and intense abdominal pain. Examination by obstetrics and gynaecology (OBGYN) specialist was performed, and complications related to pregnancy were excluded. The ultrasound of the abdomen displayed a small amount of fluid around the liver, spleen and intestines, and her blood workup was unremarkable.
After surgical and gastroenterologist (GE) examination she was referred to clinical immunologist and abdominal angioedema attack was diagnosed. She received Cinryze® 1000 iu i.v. and afterwards admitted to the Department for further evaluation. Blood workup revealed mild leukocytosis 14 ×109/L (ref. 3.4–9.7 × 109/L), normal C-reactive protein levels (5 mg/L; ref. <5) and elevated D-dimer levels >35000 Ug/L FEU (ref. 0–500) and low C4 0.04 g/L (ref. 0.1–0.4). Other blood workup was unremarkable: serum amylase 52U/L (ref. 30–110), lipase 9 U/L (0–160), LDH (s) 128 U/L (130–241), AST 24U/L (11–38), ALT 39 U/L (12–48), ALP 52 U/L (20–140), urea 1.6 mmol/L (2.8–8.3), creatinine (s) 49 umol/L (64–104), total bilirubin 11 umol/L (3-20), erythrocytes 4.31 × 1012/L (4.35–5.72), haemoglobin 131 g/L (138-175), thromocytes 189 × 109/L (158–424). Urine culture was sterile, EBV, CMV, Toxoplasma gondii serology revealed past contact.
Two hours after Cinryze® treatment, her symptoms resolved. On the next day, leukocyte levels were normal, and D-dimer values were significantly lower (4992 ug/L).
She was discharged from the hospital with Cinryze® i.v. as on-demand therapy and application of low weight molecular heparin s.c. (dalteparin 7500 IU s.c. once daily) was recommended through the entire pregnancy due to history of previous spontaneous abortion and elevated D-dimers.
After that episode, the attacks were more frequent, with abdominal angioedema attacks every 3 days, and peripheral edema with the swelling of hands almost every other day. At 17 weeks gestation, the patient was started on Cinryze® prophylactic therapy 1000 IU i.v., two times a week. As the pregnancy progressed, her attacks became more frequent despite prophylactic treatment, so during the final month of the pregnancy, she received Cinryze® every two to three days.
In January 2019, she gave birth to a male term infant (gestational age 38 weeks), via C-section. The newborn infant was eutrophic (birth weight 3370 g), and had an average head circumference (33 cm). Upon birth, the infant was mildly dyspneic, had regular heart rate (>120/min), pink skin colour, was mildly hypotonic and had normal reflexes. Apgar scores were 8 at 1ʹ and 8 at 5ʹ. Due to transitory tachypnea of the newborn, he required non-invasive respiratory support with heated and humidified high flow nasal cannula (HFNC) for six hours. The hospitalization was otherwise uneventful, and he was discharged after 8 days. Head ultrasound was normal; there were no signs of perinatal infection.
Before the C-section, the patient received Cinryze® 1000 IU iv. For the next two weeks after the delivery, prophylactic therapy was continued, and subsequently, icatibant as on-demand therapy was recommended. The patient chose not to breastfeed. After the delivery, the patient was symptom-free for 6 months and required no treatment for HAE. Her first abdominal attack after the symptom-free period was less intensive than during pregnancy. Overall, during the pregnancy, the patient in total received Cinryze® (1000 IU i.v.) 48 times.
Discussion
In the report we presented a female patient with HAE type I, with pregnancy as an exact trigger for HAE attacks, leading to the progression of the number of attacks as the pregnancy advanced, and the patient required prophylactic treatment. Interestingly, attacks started in the early pregnancy with a severe presentation of the disease that was not previously present, and resolved immediately after the delivery, leaving the patient symptom free for several months. There are only a few case reports and studies available, which give a detailed description of HAE worsening during the pregnancy, but to our knowledge, non showed such progression despite prophylactic therapy [5-9].
Hereditary angioedema is a rare disease that affects both male and female patients, but the attacks are more frequent in female patients [10]. The likely explanation is the possible effect of estrogen on the kallikrein-kinin system and subsequently on the disease course. [11]. Furthermore, it is known that HAE attacks can be precipitated by estrogen replacement therapy and contraceptive hormones [4, 10].
In our patient, the first symptom appeared during puberty onset. Although the SERPING 1 mutation and low levels of C1 inhibitor and C4 complement were found in her father and brother, she was the only member of the family with HAE symptoms.
The impact of pregnancy on HAE symptoms in patients is still unclear. Martinez-Saguer et al. showed that in 83% of pregnancies, attack rates increased during pregnancy with the highest rates in the second and third trimesters [12]. Czaller et al. in their study reported that attack frequency increases in 48% of pregnancies, most of them experienced worsening in the third trimester. Still, in 19% of the pregnancies, there was no influence on the course of HAE [9]. In contrast to these findings, Chinniah showed that women with HAE have significantly reduced or absent attacks in the last two trimesters of pregnancy [13].
In our patient, the first HAE symptom, when the pregnancy was revealed, was life-threatening laryngeal edema, whereas, before pregnancy, HAE symptoms were always presented as peripheral or abdominal edema. As the pregnancy progressed, her attacks became more frequent, especially in the last trimester, and were presented as abdominal and peripheral edema. Following the international WAO/EAACI guideline for the management of hereditary angioedema, the patient was treated with C1 inhibitor concentrate as prophylactic therapy during the pregnancy [1, 14].
Some authors suggest an increased number of attacks following frequent treatments with C1 concentrate [15]. This was not confirmed in our case, since our patient received 48 times pdC1 inhibitor concentrate and the attacks stopped after the delivery, and afterwards, she was a symptom-free for 6 months.
The patient was treated with pdC1 inhibitor concentrate Cinryze®, although there is no relevant epidemiological data regarding its safety during pregnancy. Until now, there are only a few case reports of its safety during pregnancy [16].
Conclusion
In the case presented, the angioedema attacks worsened as the pregnancy progressed. After delivery, the patient was symptom-free for six months. During the pregnancy, she was treated with pdC1 inhibitor concentrate Cinryze®, which showed to be a safe choice, although there is no relevant epidemiological data regarding its safety during pregnancy. Our report further confirms that Cinryze® therapy is effective and safe treatment during pregnancy, with no adverse effects on the infant.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
The authors acknowledge and thank the patient for her consent and insight, and also the staff and educators of the University Hospital Osijek, Croatia
Authors' contributions
ŽK and DK acquired, analyzed, and interpreted data and drafted the article and revised it critically for important intellectual content. VP and JMA revised the article critically for important intellectual content. All authors participated in writing the final manuscript. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
The study was approved by University Hospital Osijek Ethics committee No R2-1060/2020 and informed written consent was obtained.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
ŽK and VP has received speaker honorariums from Takeda Pharmaceuticals. DK owns stock in Takeda Pharmaceuticals. JMA declares that she has no conflict of interest. | CHLOROPYRAMINE, HUMAN C1-ESTERASE INHIBITOR, METHYLPREDNISOLONE | DrugsGivenReaction | CC BY | 33485376 | 18,845,587 | 2021-01-24 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Transient tachypnoea of the newborn'. | Successful treatment with Cinryze® replacement therapy of a pregnant patient with hereditary angioedema: a case report.
BACKGROUND
Hereditary angioedema (HAE) is a rare disease characterized with recurrent swelling of subcutaneous or mucosal tissue that resolves in approximately 3 days. It can be presented with peripheral edema, abdominal and life-threatening laryngeal angioedema. A variety of triggers are known to cause episodes of angioedema including estrogen exposure. There are different reports regarding the effect of pregnancy on HAE attacks, and in some patients, the pregnancy is a recognized triggering factor.
METHODS
We present a female Caucasian patient with pre-existing HAE and disease exacerbations during pregnancy, requiring prophylactic use of plasma-derived C1 inhibitor concentrate. She was treated with Cinryze® replacement therapy throughout the pregnancy 1000 IU i.v. 48 times. She gave birth to a healthy male infant, via C-section. After the delivery, the patient was symptom-free for 6 months and required no treatment for HAE.
CONCLUSIONS
In the case presented, the angioedema attacks worsened as the pregnancy progressed. The treatment with Cinryze® replacement therapy was effective and safe during pregnancy, with no adverse effects on the infant.
Introduction
Hereditary angioedema (HAE) is a rare disease characterized with recurrent swelling of subcutaneous or mucosal tissue, without pruritus or urticaria, that resolves in approximately 3 days. The disease can be presented with peripheral edema, abdominal, but also with life-threatening laryngeal angioedema [1].
Several types of HAE are described; the most explored one is due to C1 inhibitor deficiency, known as type I. It is caused by SERPING 1 mutation, on the long arm of chromosome 11, leading to C1 inhibitor deficiency which subsequently results in low C1 inhibitor and C4 protein levels in blood serum [2].
A variety of triggers, such as stress, surgical procedures, some medications (ACE inhibitors, estrogen-containing medication) are identified to cause episodes of angioedema [3, 4]. There are different reports regarding the effect of pregnancy on HAE attacks, and in some patients, the pregnancy is a known triggering factor.
We present a female patient with HAE and frequent disease exacerbations during pregnancy, that required prophylactic use of plasma-derived C1 inhibitor concentrate (pdC1) throughout the pregnancy.
Case presentation
We present a female Caucasian patient with HAE type I, diagnosed at the age of 26, with SERPING 1 mutation (confirmed by molecular testing), with very low C1inhibitor and C4 levels. Molecular testing was also positive for her father and brother. They also had low C1 inhibitor and C4 levels, but they never had any HAE symptoms.
Her symptoms of HAE first appeared when she was 15 years old, as swelling of her hand, without pain or urticaria. She was misdiagnosed with allergy-induced angioedema in the emergency department and was treated with glucocorticoids and antihistamines, without improvement. Edema subsided 3 days later. After that attack, peripheral angioedema appeared approximately once a year and lasted for a few days.
Since the age of 20 until the age of 26, she had several times very intense abdominal pain, with swelling, that required a visit to the emergency room (ER), where she would receive analgetic and proton -pump inhibitor (PPI) i.v., Gastroenterologist examined her, and after gastroscopy, the diagnosis of chronic erosive gastritis was established. Finally, at the age of 25, due to recurrent peripheral oedema, she was referred to clinical immunologist and allergist. After an extensive workup, at the age of 26, HAE type I was diagnosed.
Once HAE was diagnosed, she was treated with tranexamic acid (1000 mg daily orally) and icatibant 30 mg subcutaneously as on-demand therapy, which she had to use approximately once a year, due to abdominal angioedema.
In her medical history, at the age of 28, she had one spontaneous abortion at 8 weeks of pregnancy. Since the patient planned pregnancy, tranexamic acid was excluded, and recombinant C1 inhibitor, conestat alpha, was provided as on-demand therapy.
At the age of 29, in July 2018. patient came to the emergency room (ER) because of the swelling of her eyelids and lips, and she was treated with a total of 160 mg of methylprednisolone and chloropyramine 20 mg i.v. As she reported difficulty swallowing, an examination by ear, nose and throat (ENT) specialist was performed, and the edema of the epiglottis and sinus piriformis was established. Since there was no improvement after the anti-allergic therapy, recombinant C1 inhibitor was applied, (conestat alpha 2100 IU i.v.) and total regression of edema ensued a few hours later. She was admitted to the Department of Rheumatology, Clinical Immunology and Allergology for further observation.
Her social history revealed that she is a tradeswoman by profession, but is currently unemployed, married, living in a family house with her husband in a rural area, without any domestic animals in her household. The patient is a nonsmoker; she denied using alcohol, drugs or other medications. On admission, her temperature was 36.8°C, heart rate 76 beats/min, blood pressure 120/75 mmHg. There was no swelling of her face, neck or uvula. Her chest was clear to auscultation bilaterally, no wheezing. S1S2 were heard, no murmur, rubs or gallops. The abdomen was not distended; there was no tenderness on palpation and no organomegaly. There was no swelling or edema of her extremities. Neurological examination was unremarkable, with no nuchal rigidity, ophthalmic abnormalities, or cranial nerve signs.
During hospitalization, pregnancy was confirmed (8 weeks gestation). According to HAE guidelines, a pdC1 inhibitor is recommended in pregnancy, and Cinryze® was advised as only available pd1C1 inhibitor in our country at that time. In July 2018, she received the first application of Cinryze® 1000 IU i.v. and it was prescribed as on-demand therapy.
Two weeks later, she returned to the ER because of nausea and intense abdominal pain. Examination by obstetrics and gynaecology (OBGYN) specialist was performed, and complications related to pregnancy were excluded. The ultrasound of the abdomen displayed a small amount of fluid around the liver, spleen and intestines, and her blood workup was unremarkable.
After surgical and gastroenterologist (GE) examination she was referred to clinical immunologist and abdominal angioedema attack was diagnosed. She received Cinryze® 1000 iu i.v. and afterwards admitted to the Department for further evaluation. Blood workup revealed mild leukocytosis 14 ×109/L (ref. 3.4–9.7 × 109/L), normal C-reactive protein levels (5 mg/L; ref. <5) and elevated D-dimer levels >35000 Ug/L FEU (ref. 0–500) and low C4 0.04 g/L (ref. 0.1–0.4). Other blood workup was unremarkable: serum amylase 52U/L (ref. 30–110), lipase 9 U/L (0–160), LDH (s) 128 U/L (130–241), AST 24U/L (11–38), ALT 39 U/L (12–48), ALP 52 U/L (20–140), urea 1.6 mmol/L (2.8–8.3), creatinine (s) 49 umol/L (64–104), total bilirubin 11 umol/L (3-20), erythrocytes 4.31 × 1012/L (4.35–5.72), haemoglobin 131 g/L (138-175), thromocytes 189 × 109/L (158–424). Urine culture was sterile, EBV, CMV, Toxoplasma gondii serology revealed past contact.
Two hours after Cinryze® treatment, her symptoms resolved. On the next day, leukocyte levels were normal, and D-dimer values were significantly lower (4992 ug/L).
She was discharged from the hospital with Cinryze® i.v. as on-demand therapy and application of low weight molecular heparin s.c. (dalteparin 7500 IU s.c. once daily) was recommended through the entire pregnancy due to history of previous spontaneous abortion and elevated D-dimers.
After that episode, the attacks were more frequent, with abdominal angioedema attacks every 3 days, and peripheral edema with the swelling of hands almost every other day. At 17 weeks gestation, the patient was started on Cinryze® prophylactic therapy 1000 IU i.v., two times a week. As the pregnancy progressed, her attacks became more frequent despite prophylactic treatment, so during the final month of the pregnancy, she received Cinryze® every two to three days.
In January 2019, she gave birth to a male term infant (gestational age 38 weeks), via C-section. The newborn infant was eutrophic (birth weight 3370 g), and had an average head circumference (33 cm). Upon birth, the infant was mildly dyspneic, had regular heart rate (>120/min), pink skin colour, was mildly hypotonic and had normal reflexes. Apgar scores were 8 at 1ʹ and 8 at 5ʹ. Due to transitory tachypnea of the newborn, he required non-invasive respiratory support with heated and humidified high flow nasal cannula (HFNC) for six hours. The hospitalization was otherwise uneventful, and he was discharged after 8 days. Head ultrasound was normal; there were no signs of perinatal infection.
Before the C-section, the patient received Cinryze® 1000 IU iv. For the next two weeks after the delivery, prophylactic therapy was continued, and subsequently, icatibant as on-demand therapy was recommended. The patient chose not to breastfeed. After the delivery, the patient was symptom-free for 6 months and required no treatment for HAE. Her first abdominal attack after the symptom-free period was less intensive than during pregnancy. Overall, during the pregnancy, the patient in total received Cinryze® (1000 IU i.v.) 48 times.
Discussion
In the report we presented a female patient with HAE type I, with pregnancy as an exact trigger for HAE attacks, leading to the progression of the number of attacks as the pregnancy advanced, and the patient required prophylactic treatment. Interestingly, attacks started in the early pregnancy with a severe presentation of the disease that was not previously present, and resolved immediately after the delivery, leaving the patient symptom free for several months. There are only a few case reports and studies available, which give a detailed description of HAE worsening during the pregnancy, but to our knowledge, non showed such progression despite prophylactic therapy [5-9].
Hereditary angioedema is a rare disease that affects both male and female patients, but the attacks are more frequent in female patients [10]. The likely explanation is the possible effect of estrogen on the kallikrein-kinin system and subsequently on the disease course. [11]. Furthermore, it is known that HAE attacks can be precipitated by estrogen replacement therapy and contraceptive hormones [4, 10].
In our patient, the first symptom appeared during puberty onset. Although the SERPING 1 mutation and low levels of C1 inhibitor and C4 complement were found in her father and brother, she was the only member of the family with HAE symptoms.
The impact of pregnancy on HAE symptoms in patients is still unclear. Martinez-Saguer et al. showed that in 83% of pregnancies, attack rates increased during pregnancy with the highest rates in the second and third trimesters [12]. Czaller et al. in their study reported that attack frequency increases in 48% of pregnancies, most of them experienced worsening in the third trimester. Still, in 19% of the pregnancies, there was no influence on the course of HAE [9]. In contrast to these findings, Chinniah showed that women with HAE have significantly reduced or absent attacks in the last two trimesters of pregnancy [13].
In our patient, the first HAE symptom, when the pregnancy was revealed, was life-threatening laryngeal edema, whereas, before pregnancy, HAE symptoms were always presented as peripheral or abdominal edema. As the pregnancy progressed, her attacks became more frequent, especially in the last trimester, and were presented as abdominal and peripheral edema. Following the international WAO/EAACI guideline for the management of hereditary angioedema, the patient was treated with C1 inhibitor concentrate as prophylactic therapy during the pregnancy [1, 14].
Some authors suggest an increased number of attacks following frequent treatments with C1 concentrate [15]. This was not confirmed in our case, since our patient received 48 times pdC1 inhibitor concentrate and the attacks stopped after the delivery, and afterwards, she was a symptom-free for 6 months.
The patient was treated with pdC1 inhibitor concentrate Cinryze®, although there is no relevant epidemiological data regarding its safety during pregnancy. Until now, there are only a few case reports of its safety during pregnancy [16].
Conclusion
In the case presented, the angioedema attacks worsened as the pregnancy progressed. After delivery, the patient was symptom-free for six months. During the pregnancy, she was treated with pdC1 inhibitor concentrate Cinryze®, which showed to be a safe choice, although there is no relevant epidemiological data regarding its safety during pregnancy. Our report further confirms that Cinryze® therapy is effective and safe treatment during pregnancy, with no adverse effects on the infant.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
The authors acknowledge and thank the patient for her consent and insight, and also the staff and educators of the University Hospital Osijek, Croatia
Authors' contributions
ŽK and DK acquired, analyzed, and interpreted data and drafted the article and revised it critically for important intellectual content. VP and JMA revised the article critically for important intellectual content. All authors participated in writing the final manuscript. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
The study was approved by University Hospital Osijek Ethics committee No R2-1060/2020 and informed written consent was obtained.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
ŽK and VP has received speaker honorariums from Takeda Pharmaceuticals. DK owns stock in Takeda Pharmaceuticals. JMA declares that she has no conflict of interest. | HUMAN C1-ESTERASE INHIBITOR | DrugsGivenReaction | CC BY | 33485376 | 18,845,589 | 2021-01-24 |
What was the administration route of drug 'CHLOROPYRAMINE'? | Successful treatment with Cinryze® replacement therapy of a pregnant patient with hereditary angioedema: a case report.
BACKGROUND
Hereditary angioedema (HAE) is a rare disease characterized with recurrent swelling of subcutaneous or mucosal tissue that resolves in approximately 3 days. It can be presented with peripheral edema, abdominal and life-threatening laryngeal angioedema. A variety of triggers are known to cause episodes of angioedema including estrogen exposure. There are different reports regarding the effect of pregnancy on HAE attacks, and in some patients, the pregnancy is a recognized triggering factor.
METHODS
We present a female Caucasian patient with pre-existing HAE and disease exacerbations during pregnancy, requiring prophylactic use of plasma-derived C1 inhibitor concentrate. She was treated with Cinryze® replacement therapy throughout the pregnancy 1000 IU i.v. 48 times. She gave birth to a healthy male infant, via C-section. After the delivery, the patient was symptom-free for 6 months and required no treatment for HAE.
CONCLUSIONS
In the case presented, the angioedema attacks worsened as the pregnancy progressed. The treatment with Cinryze® replacement therapy was effective and safe during pregnancy, with no adverse effects on the infant.
Introduction
Hereditary angioedema (HAE) is a rare disease characterized with recurrent swelling of subcutaneous or mucosal tissue, without pruritus or urticaria, that resolves in approximately 3 days. The disease can be presented with peripheral edema, abdominal, but also with life-threatening laryngeal angioedema [1].
Several types of HAE are described; the most explored one is due to C1 inhibitor deficiency, known as type I. It is caused by SERPING 1 mutation, on the long arm of chromosome 11, leading to C1 inhibitor deficiency which subsequently results in low C1 inhibitor and C4 protein levels in blood serum [2].
A variety of triggers, such as stress, surgical procedures, some medications (ACE inhibitors, estrogen-containing medication) are identified to cause episodes of angioedema [3, 4]. There are different reports regarding the effect of pregnancy on HAE attacks, and in some patients, the pregnancy is a known triggering factor.
We present a female patient with HAE and frequent disease exacerbations during pregnancy, that required prophylactic use of plasma-derived C1 inhibitor concentrate (pdC1) throughout the pregnancy.
Case presentation
We present a female Caucasian patient with HAE type I, diagnosed at the age of 26, with SERPING 1 mutation (confirmed by molecular testing), with very low C1inhibitor and C4 levels. Molecular testing was also positive for her father and brother. They also had low C1 inhibitor and C4 levels, but they never had any HAE symptoms.
Her symptoms of HAE first appeared when she was 15 years old, as swelling of her hand, without pain or urticaria. She was misdiagnosed with allergy-induced angioedema in the emergency department and was treated with glucocorticoids and antihistamines, without improvement. Edema subsided 3 days later. After that attack, peripheral angioedema appeared approximately once a year and lasted for a few days.
Since the age of 20 until the age of 26, she had several times very intense abdominal pain, with swelling, that required a visit to the emergency room (ER), where she would receive analgetic and proton -pump inhibitor (PPI) i.v., Gastroenterologist examined her, and after gastroscopy, the diagnosis of chronic erosive gastritis was established. Finally, at the age of 25, due to recurrent peripheral oedema, she was referred to clinical immunologist and allergist. After an extensive workup, at the age of 26, HAE type I was diagnosed.
Once HAE was diagnosed, she was treated with tranexamic acid (1000 mg daily orally) and icatibant 30 mg subcutaneously as on-demand therapy, which she had to use approximately once a year, due to abdominal angioedema.
In her medical history, at the age of 28, she had one spontaneous abortion at 8 weeks of pregnancy. Since the patient planned pregnancy, tranexamic acid was excluded, and recombinant C1 inhibitor, conestat alpha, was provided as on-demand therapy.
At the age of 29, in July 2018. patient came to the emergency room (ER) because of the swelling of her eyelids and lips, and she was treated with a total of 160 mg of methylprednisolone and chloropyramine 20 mg i.v. As she reported difficulty swallowing, an examination by ear, nose and throat (ENT) specialist was performed, and the edema of the epiglottis and sinus piriformis was established. Since there was no improvement after the anti-allergic therapy, recombinant C1 inhibitor was applied, (conestat alpha 2100 IU i.v.) and total regression of edema ensued a few hours later. She was admitted to the Department of Rheumatology, Clinical Immunology and Allergology for further observation.
Her social history revealed that she is a tradeswoman by profession, but is currently unemployed, married, living in a family house with her husband in a rural area, without any domestic animals in her household. The patient is a nonsmoker; she denied using alcohol, drugs or other medications. On admission, her temperature was 36.8°C, heart rate 76 beats/min, blood pressure 120/75 mmHg. There was no swelling of her face, neck or uvula. Her chest was clear to auscultation bilaterally, no wheezing. S1S2 were heard, no murmur, rubs or gallops. The abdomen was not distended; there was no tenderness on palpation and no organomegaly. There was no swelling or edema of her extremities. Neurological examination was unremarkable, with no nuchal rigidity, ophthalmic abnormalities, or cranial nerve signs.
During hospitalization, pregnancy was confirmed (8 weeks gestation). According to HAE guidelines, a pdC1 inhibitor is recommended in pregnancy, and Cinryze® was advised as only available pd1C1 inhibitor in our country at that time. In July 2018, she received the first application of Cinryze® 1000 IU i.v. and it was prescribed as on-demand therapy.
Two weeks later, she returned to the ER because of nausea and intense abdominal pain. Examination by obstetrics and gynaecology (OBGYN) specialist was performed, and complications related to pregnancy were excluded. The ultrasound of the abdomen displayed a small amount of fluid around the liver, spleen and intestines, and her blood workup was unremarkable.
After surgical and gastroenterologist (GE) examination she was referred to clinical immunologist and abdominal angioedema attack was diagnosed. She received Cinryze® 1000 iu i.v. and afterwards admitted to the Department for further evaluation. Blood workup revealed mild leukocytosis 14 ×109/L (ref. 3.4–9.7 × 109/L), normal C-reactive protein levels (5 mg/L; ref. <5) and elevated D-dimer levels >35000 Ug/L FEU (ref. 0–500) and low C4 0.04 g/L (ref. 0.1–0.4). Other blood workup was unremarkable: serum amylase 52U/L (ref. 30–110), lipase 9 U/L (0–160), LDH (s) 128 U/L (130–241), AST 24U/L (11–38), ALT 39 U/L (12–48), ALP 52 U/L (20–140), urea 1.6 mmol/L (2.8–8.3), creatinine (s) 49 umol/L (64–104), total bilirubin 11 umol/L (3-20), erythrocytes 4.31 × 1012/L (4.35–5.72), haemoglobin 131 g/L (138-175), thromocytes 189 × 109/L (158–424). Urine culture was sterile, EBV, CMV, Toxoplasma gondii serology revealed past contact.
Two hours after Cinryze® treatment, her symptoms resolved. On the next day, leukocyte levels were normal, and D-dimer values were significantly lower (4992 ug/L).
She was discharged from the hospital with Cinryze® i.v. as on-demand therapy and application of low weight molecular heparin s.c. (dalteparin 7500 IU s.c. once daily) was recommended through the entire pregnancy due to history of previous spontaneous abortion and elevated D-dimers.
After that episode, the attacks were more frequent, with abdominal angioedema attacks every 3 days, and peripheral edema with the swelling of hands almost every other day. At 17 weeks gestation, the patient was started on Cinryze® prophylactic therapy 1000 IU i.v., two times a week. As the pregnancy progressed, her attacks became more frequent despite prophylactic treatment, so during the final month of the pregnancy, she received Cinryze® every two to three days.
In January 2019, she gave birth to a male term infant (gestational age 38 weeks), via C-section. The newborn infant was eutrophic (birth weight 3370 g), and had an average head circumference (33 cm). Upon birth, the infant was mildly dyspneic, had regular heart rate (>120/min), pink skin colour, was mildly hypotonic and had normal reflexes. Apgar scores were 8 at 1ʹ and 8 at 5ʹ. Due to transitory tachypnea of the newborn, he required non-invasive respiratory support with heated and humidified high flow nasal cannula (HFNC) for six hours. The hospitalization was otherwise uneventful, and he was discharged after 8 days. Head ultrasound was normal; there were no signs of perinatal infection.
Before the C-section, the patient received Cinryze® 1000 IU iv. For the next two weeks after the delivery, prophylactic therapy was continued, and subsequently, icatibant as on-demand therapy was recommended. The patient chose not to breastfeed. After the delivery, the patient was symptom-free for 6 months and required no treatment for HAE. Her first abdominal attack after the symptom-free period was less intensive than during pregnancy. Overall, during the pregnancy, the patient in total received Cinryze® (1000 IU i.v.) 48 times.
Discussion
In the report we presented a female patient with HAE type I, with pregnancy as an exact trigger for HAE attacks, leading to the progression of the number of attacks as the pregnancy advanced, and the patient required prophylactic treatment. Interestingly, attacks started in the early pregnancy with a severe presentation of the disease that was not previously present, and resolved immediately after the delivery, leaving the patient symptom free for several months. There are only a few case reports and studies available, which give a detailed description of HAE worsening during the pregnancy, but to our knowledge, non showed such progression despite prophylactic therapy [5-9].
Hereditary angioedema is a rare disease that affects both male and female patients, but the attacks are more frequent in female patients [10]. The likely explanation is the possible effect of estrogen on the kallikrein-kinin system and subsequently on the disease course. [11]. Furthermore, it is known that HAE attacks can be precipitated by estrogen replacement therapy and contraceptive hormones [4, 10].
In our patient, the first symptom appeared during puberty onset. Although the SERPING 1 mutation and low levels of C1 inhibitor and C4 complement were found in her father and brother, she was the only member of the family with HAE symptoms.
The impact of pregnancy on HAE symptoms in patients is still unclear. Martinez-Saguer et al. showed that in 83% of pregnancies, attack rates increased during pregnancy with the highest rates in the second and third trimesters [12]. Czaller et al. in their study reported that attack frequency increases in 48% of pregnancies, most of them experienced worsening in the third trimester. Still, in 19% of the pregnancies, there was no influence on the course of HAE [9]. In contrast to these findings, Chinniah showed that women with HAE have significantly reduced or absent attacks in the last two trimesters of pregnancy [13].
In our patient, the first HAE symptom, when the pregnancy was revealed, was life-threatening laryngeal edema, whereas, before pregnancy, HAE symptoms were always presented as peripheral or abdominal edema. As the pregnancy progressed, her attacks became more frequent, especially in the last trimester, and were presented as abdominal and peripheral edema. Following the international WAO/EAACI guideline for the management of hereditary angioedema, the patient was treated with C1 inhibitor concentrate as prophylactic therapy during the pregnancy [1, 14].
Some authors suggest an increased number of attacks following frequent treatments with C1 concentrate [15]. This was not confirmed in our case, since our patient received 48 times pdC1 inhibitor concentrate and the attacks stopped after the delivery, and afterwards, she was a symptom-free for 6 months.
The patient was treated with pdC1 inhibitor concentrate Cinryze®, although there is no relevant epidemiological data regarding its safety during pregnancy. Until now, there are only a few case reports of its safety during pregnancy [16].
Conclusion
In the case presented, the angioedema attacks worsened as the pregnancy progressed. After delivery, the patient was symptom-free for six months. During the pregnancy, she was treated with pdC1 inhibitor concentrate Cinryze®, which showed to be a safe choice, although there is no relevant epidemiological data regarding its safety during pregnancy. Our report further confirms that Cinryze® therapy is effective and safe treatment during pregnancy, with no adverse effects on the infant.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
The authors acknowledge and thank the patient for her consent and insight, and also the staff and educators of the University Hospital Osijek, Croatia
Authors' contributions
ŽK and DK acquired, analyzed, and interpreted data and drafted the article and revised it critically for important intellectual content. VP and JMA revised the article critically for important intellectual content. All authors participated in writing the final manuscript. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
The study was approved by University Hospital Osijek Ethics committee No R2-1060/2020 and informed written consent was obtained.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
ŽK and VP has received speaker honorariums from Takeda Pharmaceuticals. DK owns stock in Takeda Pharmaceuticals. JMA declares that she has no conflict of interest. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33485376 | 18,845,587 | 2021-01-24 |
What was the dosage of drug 'CHLOROPYRAMINE'? | Successful treatment with Cinryze® replacement therapy of a pregnant patient with hereditary angioedema: a case report.
BACKGROUND
Hereditary angioedema (HAE) is a rare disease characterized with recurrent swelling of subcutaneous or mucosal tissue that resolves in approximately 3 days. It can be presented with peripheral edema, abdominal and life-threatening laryngeal angioedema. A variety of triggers are known to cause episodes of angioedema including estrogen exposure. There are different reports regarding the effect of pregnancy on HAE attacks, and in some patients, the pregnancy is a recognized triggering factor.
METHODS
We present a female Caucasian patient with pre-existing HAE and disease exacerbations during pregnancy, requiring prophylactic use of plasma-derived C1 inhibitor concentrate. She was treated with Cinryze® replacement therapy throughout the pregnancy 1000 IU i.v. 48 times. She gave birth to a healthy male infant, via C-section. After the delivery, the patient was symptom-free for 6 months and required no treatment for HAE.
CONCLUSIONS
In the case presented, the angioedema attacks worsened as the pregnancy progressed. The treatment with Cinryze® replacement therapy was effective and safe during pregnancy, with no adverse effects on the infant.
Introduction
Hereditary angioedema (HAE) is a rare disease characterized with recurrent swelling of subcutaneous or mucosal tissue, without pruritus or urticaria, that resolves in approximately 3 days. The disease can be presented with peripheral edema, abdominal, but also with life-threatening laryngeal angioedema [1].
Several types of HAE are described; the most explored one is due to C1 inhibitor deficiency, known as type I. It is caused by SERPING 1 mutation, on the long arm of chromosome 11, leading to C1 inhibitor deficiency which subsequently results in low C1 inhibitor and C4 protein levels in blood serum [2].
A variety of triggers, such as stress, surgical procedures, some medications (ACE inhibitors, estrogen-containing medication) are identified to cause episodes of angioedema [3, 4]. There are different reports regarding the effect of pregnancy on HAE attacks, and in some patients, the pregnancy is a known triggering factor.
We present a female patient with HAE and frequent disease exacerbations during pregnancy, that required prophylactic use of plasma-derived C1 inhibitor concentrate (pdC1) throughout the pregnancy.
Case presentation
We present a female Caucasian patient with HAE type I, diagnosed at the age of 26, with SERPING 1 mutation (confirmed by molecular testing), with very low C1inhibitor and C4 levels. Molecular testing was also positive for her father and brother. They also had low C1 inhibitor and C4 levels, but they never had any HAE symptoms.
Her symptoms of HAE first appeared when she was 15 years old, as swelling of her hand, without pain or urticaria. She was misdiagnosed with allergy-induced angioedema in the emergency department and was treated with glucocorticoids and antihistamines, without improvement. Edema subsided 3 days later. After that attack, peripheral angioedema appeared approximately once a year and lasted for a few days.
Since the age of 20 until the age of 26, she had several times very intense abdominal pain, with swelling, that required a visit to the emergency room (ER), where she would receive analgetic and proton -pump inhibitor (PPI) i.v., Gastroenterologist examined her, and after gastroscopy, the diagnosis of chronic erosive gastritis was established. Finally, at the age of 25, due to recurrent peripheral oedema, she was referred to clinical immunologist and allergist. After an extensive workup, at the age of 26, HAE type I was diagnosed.
Once HAE was diagnosed, she was treated with tranexamic acid (1000 mg daily orally) and icatibant 30 mg subcutaneously as on-demand therapy, which she had to use approximately once a year, due to abdominal angioedema.
In her medical history, at the age of 28, she had one spontaneous abortion at 8 weeks of pregnancy. Since the patient planned pregnancy, tranexamic acid was excluded, and recombinant C1 inhibitor, conestat alpha, was provided as on-demand therapy.
At the age of 29, in July 2018. patient came to the emergency room (ER) because of the swelling of her eyelids and lips, and she was treated with a total of 160 mg of methylprednisolone and chloropyramine 20 mg i.v. As she reported difficulty swallowing, an examination by ear, nose and throat (ENT) specialist was performed, and the edema of the epiglottis and sinus piriformis was established. Since there was no improvement after the anti-allergic therapy, recombinant C1 inhibitor was applied, (conestat alpha 2100 IU i.v.) and total regression of edema ensued a few hours later. She was admitted to the Department of Rheumatology, Clinical Immunology and Allergology for further observation.
Her social history revealed that she is a tradeswoman by profession, but is currently unemployed, married, living in a family house with her husband in a rural area, without any domestic animals in her household. The patient is a nonsmoker; she denied using alcohol, drugs or other medications. On admission, her temperature was 36.8°C, heart rate 76 beats/min, blood pressure 120/75 mmHg. There was no swelling of her face, neck or uvula. Her chest was clear to auscultation bilaterally, no wheezing. S1S2 were heard, no murmur, rubs or gallops. The abdomen was not distended; there was no tenderness on palpation and no organomegaly. There was no swelling or edema of her extremities. Neurological examination was unremarkable, with no nuchal rigidity, ophthalmic abnormalities, or cranial nerve signs.
During hospitalization, pregnancy was confirmed (8 weeks gestation). According to HAE guidelines, a pdC1 inhibitor is recommended in pregnancy, and Cinryze® was advised as only available pd1C1 inhibitor in our country at that time. In July 2018, she received the first application of Cinryze® 1000 IU i.v. and it was prescribed as on-demand therapy.
Two weeks later, she returned to the ER because of nausea and intense abdominal pain. Examination by obstetrics and gynaecology (OBGYN) specialist was performed, and complications related to pregnancy were excluded. The ultrasound of the abdomen displayed a small amount of fluid around the liver, spleen and intestines, and her blood workup was unremarkable.
After surgical and gastroenterologist (GE) examination she was referred to clinical immunologist and abdominal angioedema attack was diagnosed. She received Cinryze® 1000 iu i.v. and afterwards admitted to the Department for further evaluation. Blood workup revealed mild leukocytosis 14 ×109/L (ref. 3.4–9.7 × 109/L), normal C-reactive protein levels (5 mg/L; ref. <5) and elevated D-dimer levels >35000 Ug/L FEU (ref. 0–500) and low C4 0.04 g/L (ref. 0.1–0.4). Other blood workup was unremarkable: serum amylase 52U/L (ref. 30–110), lipase 9 U/L (0–160), LDH (s) 128 U/L (130–241), AST 24U/L (11–38), ALT 39 U/L (12–48), ALP 52 U/L (20–140), urea 1.6 mmol/L (2.8–8.3), creatinine (s) 49 umol/L (64–104), total bilirubin 11 umol/L (3-20), erythrocytes 4.31 × 1012/L (4.35–5.72), haemoglobin 131 g/L (138-175), thromocytes 189 × 109/L (158–424). Urine culture was sterile, EBV, CMV, Toxoplasma gondii serology revealed past contact.
Two hours after Cinryze® treatment, her symptoms resolved. On the next day, leukocyte levels were normal, and D-dimer values were significantly lower (4992 ug/L).
She was discharged from the hospital with Cinryze® i.v. as on-demand therapy and application of low weight molecular heparin s.c. (dalteparin 7500 IU s.c. once daily) was recommended through the entire pregnancy due to history of previous spontaneous abortion and elevated D-dimers.
After that episode, the attacks were more frequent, with abdominal angioedema attacks every 3 days, and peripheral edema with the swelling of hands almost every other day. At 17 weeks gestation, the patient was started on Cinryze® prophylactic therapy 1000 IU i.v., two times a week. As the pregnancy progressed, her attacks became more frequent despite prophylactic treatment, so during the final month of the pregnancy, she received Cinryze® every two to three days.
In January 2019, she gave birth to a male term infant (gestational age 38 weeks), via C-section. The newborn infant was eutrophic (birth weight 3370 g), and had an average head circumference (33 cm). Upon birth, the infant was mildly dyspneic, had regular heart rate (>120/min), pink skin colour, was mildly hypotonic and had normal reflexes. Apgar scores were 8 at 1ʹ and 8 at 5ʹ. Due to transitory tachypnea of the newborn, he required non-invasive respiratory support with heated and humidified high flow nasal cannula (HFNC) for six hours. The hospitalization was otherwise uneventful, and he was discharged after 8 days. Head ultrasound was normal; there were no signs of perinatal infection.
Before the C-section, the patient received Cinryze® 1000 IU iv. For the next two weeks after the delivery, prophylactic therapy was continued, and subsequently, icatibant as on-demand therapy was recommended. The patient chose not to breastfeed. After the delivery, the patient was symptom-free for 6 months and required no treatment for HAE. Her first abdominal attack after the symptom-free period was less intensive than during pregnancy. Overall, during the pregnancy, the patient in total received Cinryze® (1000 IU i.v.) 48 times.
Discussion
In the report we presented a female patient with HAE type I, with pregnancy as an exact trigger for HAE attacks, leading to the progression of the number of attacks as the pregnancy advanced, and the patient required prophylactic treatment. Interestingly, attacks started in the early pregnancy with a severe presentation of the disease that was not previously present, and resolved immediately after the delivery, leaving the patient symptom free for several months. There are only a few case reports and studies available, which give a detailed description of HAE worsening during the pregnancy, but to our knowledge, non showed such progression despite prophylactic therapy [5-9].
Hereditary angioedema is a rare disease that affects both male and female patients, but the attacks are more frequent in female patients [10]. The likely explanation is the possible effect of estrogen on the kallikrein-kinin system and subsequently on the disease course. [11]. Furthermore, it is known that HAE attacks can be precipitated by estrogen replacement therapy and contraceptive hormones [4, 10].
In our patient, the first symptom appeared during puberty onset. Although the SERPING 1 mutation and low levels of C1 inhibitor and C4 complement were found in her father and brother, she was the only member of the family with HAE symptoms.
The impact of pregnancy on HAE symptoms in patients is still unclear. Martinez-Saguer et al. showed that in 83% of pregnancies, attack rates increased during pregnancy with the highest rates in the second and third trimesters [12]. Czaller et al. in their study reported that attack frequency increases in 48% of pregnancies, most of them experienced worsening in the third trimester. Still, in 19% of the pregnancies, there was no influence on the course of HAE [9]. In contrast to these findings, Chinniah showed that women with HAE have significantly reduced or absent attacks in the last two trimesters of pregnancy [13].
In our patient, the first HAE symptom, when the pregnancy was revealed, was life-threatening laryngeal edema, whereas, before pregnancy, HAE symptoms were always presented as peripheral or abdominal edema. As the pregnancy progressed, her attacks became more frequent, especially in the last trimester, and were presented as abdominal and peripheral edema. Following the international WAO/EAACI guideline for the management of hereditary angioedema, the patient was treated with C1 inhibitor concentrate as prophylactic therapy during the pregnancy [1, 14].
Some authors suggest an increased number of attacks following frequent treatments with C1 concentrate [15]. This was not confirmed in our case, since our patient received 48 times pdC1 inhibitor concentrate and the attacks stopped after the delivery, and afterwards, she was a symptom-free for 6 months.
The patient was treated with pdC1 inhibitor concentrate Cinryze®, although there is no relevant epidemiological data regarding its safety during pregnancy. Until now, there are only a few case reports of its safety during pregnancy [16].
Conclusion
In the case presented, the angioedema attacks worsened as the pregnancy progressed. After delivery, the patient was symptom-free for six months. During the pregnancy, she was treated with pdC1 inhibitor concentrate Cinryze®, which showed to be a safe choice, although there is no relevant epidemiological data regarding its safety during pregnancy. Our report further confirms that Cinryze® therapy is effective and safe treatment during pregnancy, with no adverse effects on the infant.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
The authors acknowledge and thank the patient for her consent and insight, and also the staff and educators of the University Hospital Osijek, Croatia
Authors' contributions
ŽK and DK acquired, analyzed, and interpreted data and drafted the article and revised it critically for important intellectual content. VP and JMA revised the article critically for important intellectual content. All authors participated in writing the final manuscript. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
The study was approved by University Hospital Osijek Ethics committee No R2-1060/2020 and informed written consent was obtained.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
ŽK and VP has received speaker honorariums from Takeda Pharmaceuticals. DK owns stock in Takeda Pharmaceuticals. JMA declares that she has no conflict of interest. | 20 MILLIGRAM | DrugDosageText | CC BY | 33485376 | 18,845,587 | 2021-01-24 |
What was the dosage of drug 'HUMAN C1-ESTERASE INHIBITOR'? | Successful treatment with Cinryze® replacement therapy of a pregnant patient with hereditary angioedema: a case report.
BACKGROUND
Hereditary angioedema (HAE) is a rare disease characterized with recurrent swelling of subcutaneous or mucosal tissue that resolves in approximately 3 days. It can be presented with peripheral edema, abdominal and life-threatening laryngeal angioedema. A variety of triggers are known to cause episodes of angioedema including estrogen exposure. There are different reports regarding the effect of pregnancy on HAE attacks, and in some patients, the pregnancy is a recognized triggering factor.
METHODS
We present a female Caucasian patient with pre-existing HAE and disease exacerbations during pregnancy, requiring prophylactic use of plasma-derived C1 inhibitor concentrate. She was treated with Cinryze® replacement therapy throughout the pregnancy 1000 IU i.v. 48 times. She gave birth to a healthy male infant, via C-section. After the delivery, the patient was symptom-free for 6 months and required no treatment for HAE.
CONCLUSIONS
In the case presented, the angioedema attacks worsened as the pregnancy progressed. The treatment with Cinryze® replacement therapy was effective and safe during pregnancy, with no adverse effects on the infant.
Introduction
Hereditary angioedema (HAE) is a rare disease characterized with recurrent swelling of subcutaneous or mucosal tissue, without pruritus or urticaria, that resolves in approximately 3 days. The disease can be presented with peripheral edema, abdominal, but also with life-threatening laryngeal angioedema [1].
Several types of HAE are described; the most explored one is due to C1 inhibitor deficiency, known as type I. It is caused by SERPING 1 mutation, on the long arm of chromosome 11, leading to C1 inhibitor deficiency which subsequently results in low C1 inhibitor and C4 protein levels in blood serum [2].
A variety of triggers, such as stress, surgical procedures, some medications (ACE inhibitors, estrogen-containing medication) are identified to cause episodes of angioedema [3, 4]. There are different reports regarding the effect of pregnancy on HAE attacks, and in some patients, the pregnancy is a known triggering factor.
We present a female patient with HAE and frequent disease exacerbations during pregnancy, that required prophylactic use of plasma-derived C1 inhibitor concentrate (pdC1) throughout the pregnancy.
Case presentation
We present a female Caucasian patient with HAE type I, diagnosed at the age of 26, with SERPING 1 mutation (confirmed by molecular testing), with very low C1inhibitor and C4 levels. Molecular testing was also positive for her father and brother. They also had low C1 inhibitor and C4 levels, but they never had any HAE symptoms.
Her symptoms of HAE first appeared when she was 15 years old, as swelling of her hand, without pain or urticaria. She was misdiagnosed with allergy-induced angioedema in the emergency department and was treated with glucocorticoids and antihistamines, without improvement. Edema subsided 3 days later. After that attack, peripheral angioedema appeared approximately once a year and lasted for a few days.
Since the age of 20 until the age of 26, she had several times very intense abdominal pain, with swelling, that required a visit to the emergency room (ER), where she would receive analgetic and proton -pump inhibitor (PPI) i.v., Gastroenterologist examined her, and after gastroscopy, the diagnosis of chronic erosive gastritis was established. Finally, at the age of 25, due to recurrent peripheral oedema, she was referred to clinical immunologist and allergist. After an extensive workup, at the age of 26, HAE type I was diagnosed.
Once HAE was diagnosed, she was treated with tranexamic acid (1000 mg daily orally) and icatibant 30 mg subcutaneously as on-demand therapy, which she had to use approximately once a year, due to abdominal angioedema.
In her medical history, at the age of 28, she had one spontaneous abortion at 8 weeks of pregnancy. Since the patient planned pregnancy, tranexamic acid was excluded, and recombinant C1 inhibitor, conestat alpha, was provided as on-demand therapy.
At the age of 29, in July 2018. patient came to the emergency room (ER) because of the swelling of her eyelids and lips, and she was treated with a total of 160 mg of methylprednisolone and chloropyramine 20 mg i.v. As she reported difficulty swallowing, an examination by ear, nose and throat (ENT) specialist was performed, and the edema of the epiglottis and sinus piriformis was established. Since there was no improvement after the anti-allergic therapy, recombinant C1 inhibitor was applied, (conestat alpha 2100 IU i.v.) and total regression of edema ensued a few hours later. She was admitted to the Department of Rheumatology, Clinical Immunology and Allergology for further observation.
Her social history revealed that she is a tradeswoman by profession, but is currently unemployed, married, living in a family house with her husband in a rural area, without any domestic animals in her household. The patient is a nonsmoker; she denied using alcohol, drugs or other medications. On admission, her temperature was 36.8°C, heart rate 76 beats/min, blood pressure 120/75 mmHg. There was no swelling of her face, neck or uvula. Her chest was clear to auscultation bilaterally, no wheezing. S1S2 were heard, no murmur, rubs or gallops. The abdomen was not distended; there was no tenderness on palpation and no organomegaly. There was no swelling or edema of her extremities. Neurological examination was unremarkable, with no nuchal rigidity, ophthalmic abnormalities, or cranial nerve signs.
During hospitalization, pregnancy was confirmed (8 weeks gestation). According to HAE guidelines, a pdC1 inhibitor is recommended in pregnancy, and Cinryze® was advised as only available pd1C1 inhibitor in our country at that time. In July 2018, she received the first application of Cinryze® 1000 IU i.v. and it was prescribed as on-demand therapy.
Two weeks later, she returned to the ER because of nausea and intense abdominal pain. Examination by obstetrics and gynaecology (OBGYN) specialist was performed, and complications related to pregnancy were excluded. The ultrasound of the abdomen displayed a small amount of fluid around the liver, spleen and intestines, and her blood workup was unremarkable.
After surgical and gastroenterologist (GE) examination she was referred to clinical immunologist and abdominal angioedema attack was diagnosed. She received Cinryze® 1000 iu i.v. and afterwards admitted to the Department for further evaluation. Blood workup revealed mild leukocytosis 14 ×109/L (ref. 3.4–9.7 × 109/L), normal C-reactive protein levels (5 mg/L; ref. <5) and elevated D-dimer levels >35000 Ug/L FEU (ref. 0–500) and low C4 0.04 g/L (ref. 0.1–0.4). Other blood workup was unremarkable: serum amylase 52U/L (ref. 30–110), lipase 9 U/L (0–160), LDH (s) 128 U/L (130–241), AST 24U/L (11–38), ALT 39 U/L (12–48), ALP 52 U/L (20–140), urea 1.6 mmol/L (2.8–8.3), creatinine (s) 49 umol/L (64–104), total bilirubin 11 umol/L (3-20), erythrocytes 4.31 × 1012/L (4.35–5.72), haemoglobin 131 g/L (138-175), thromocytes 189 × 109/L (158–424). Urine culture was sterile, EBV, CMV, Toxoplasma gondii serology revealed past contact.
Two hours after Cinryze® treatment, her symptoms resolved. On the next day, leukocyte levels were normal, and D-dimer values were significantly lower (4992 ug/L).
She was discharged from the hospital with Cinryze® i.v. as on-demand therapy and application of low weight molecular heparin s.c. (dalteparin 7500 IU s.c. once daily) was recommended through the entire pregnancy due to history of previous spontaneous abortion and elevated D-dimers.
After that episode, the attacks were more frequent, with abdominal angioedema attacks every 3 days, and peripheral edema with the swelling of hands almost every other day. At 17 weeks gestation, the patient was started on Cinryze® prophylactic therapy 1000 IU i.v., two times a week. As the pregnancy progressed, her attacks became more frequent despite prophylactic treatment, so during the final month of the pregnancy, she received Cinryze® every two to three days.
In January 2019, she gave birth to a male term infant (gestational age 38 weeks), via C-section. The newborn infant was eutrophic (birth weight 3370 g), and had an average head circumference (33 cm). Upon birth, the infant was mildly dyspneic, had regular heart rate (>120/min), pink skin colour, was mildly hypotonic and had normal reflexes. Apgar scores were 8 at 1ʹ and 8 at 5ʹ. Due to transitory tachypnea of the newborn, he required non-invasive respiratory support with heated and humidified high flow nasal cannula (HFNC) for six hours. The hospitalization was otherwise uneventful, and he was discharged after 8 days. Head ultrasound was normal; there were no signs of perinatal infection.
Before the C-section, the patient received Cinryze® 1000 IU iv. For the next two weeks after the delivery, prophylactic therapy was continued, and subsequently, icatibant as on-demand therapy was recommended. The patient chose not to breastfeed. After the delivery, the patient was symptom-free for 6 months and required no treatment for HAE. Her first abdominal attack after the symptom-free period was less intensive than during pregnancy. Overall, during the pregnancy, the patient in total received Cinryze® (1000 IU i.v.) 48 times.
Discussion
In the report we presented a female patient with HAE type I, with pregnancy as an exact trigger for HAE attacks, leading to the progression of the number of attacks as the pregnancy advanced, and the patient required prophylactic treatment. Interestingly, attacks started in the early pregnancy with a severe presentation of the disease that was not previously present, and resolved immediately after the delivery, leaving the patient symptom free for several months. There are only a few case reports and studies available, which give a detailed description of HAE worsening during the pregnancy, but to our knowledge, non showed such progression despite prophylactic therapy [5-9].
Hereditary angioedema is a rare disease that affects both male and female patients, but the attacks are more frequent in female patients [10]. The likely explanation is the possible effect of estrogen on the kallikrein-kinin system and subsequently on the disease course. [11]. Furthermore, it is known that HAE attacks can be precipitated by estrogen replacement therapy and contraceptive hormones [4, 10].
In our patient, the first symptom appeared during puberty onset. Although the SERPING 1 mutation and low levels of C1 inhibitor and C4 complement were found in her father and brother, she was the only member of the family with HAE symptoms.
The impact of pregnancy on HAE symptoms in patients is still unclear. Martinez-Saguer et al. showed that in 83% of pregnancies, attack rates increased during pregnancy with the highest rates in the second and third trimesters [12]. Czaller et al. in their study reported that attack frequency increases in 48% of pregnancies, most of them experienced worsening in the third trimester. Still, in 19% of the pregnancies, there was no influence on the course of HAE [9]. In contrast to these findings, Chinniah showed that women with HAE have significantly reduced or absent attacks in the last two trimesters of pregnancy [13].
In our patient, the first HAE symptom, when the pregnancy was revealed, was life-threatening laryngeal edema, whereas, before pregnancy, HAE symptoms were always presented as peripheral or abdominal edema. As the pregnancy progressed, her attacks became more frequent, especially in the last trimester, and were presented as abdominal and peripheral edema. Following the international WAO/EAACI guideline for the management of hereditary angioedema, the patient was treated with C1 inhibitor concentrate as prophylactic therapy during the pregnancy [1, 14].
Some authors suggest an increased number of attacks following frequent treatments with C1 concentrate [15]. This was not confirmed in our case, since our patient received 48 times pdC1 inhibitor concentrate and the attacks stopped after the delivery, and afterwards, she was a symptom-free for 6 months.
The patient was treated with pdC1 inhibitor concentrate Cinryze®, although there is no relevant epidemiological data regarding its safety during pregnancy. Until now, there are only a few case reports of its safety during pregnancy [16].
Conclusion
In the case presented, the angioedema attacks worsened as the pregnancy progressed. After delivery, the patient was symptom-free for six months. During the pregnancy, she was treated with pdC1 inhibitor concentrate Cinryze®, which showed to be a safe choice, although there is no relevant epidemiological data regarding its safety during pregnancy. Our report further confirms that Cinryze® therapy is effective and safe treatment during pregnancy, with no adverse effects on the infant.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
The authors acknowledge and thank the patient for her consent and insight, and also the staff and educators of the University Hospital Osijek, Croatia
Authors' contributions
ŽK and DK acquired, analyzed, and interpreted data and drafted the article and revised it critically for important intellectual content. VP and JMA revised the article critically for important intellectual content. All authors participated in writing the final manuscript. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
The study was approved by University Hospital Osijek Ethics committee No R2-1060/2020 and informed written consent was obtained.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
ŽK and VP has received speaker honorariums from Takeda Pharmaceuticals. DK owns stock in Takeda Pharmaceuticals. JMA declares that she has no conflict of interest. | 2100 IU | DrugDosageText | CC BY | 33485376 | 18,845,587 | 2021-01-24 |
What was the dosage of drug 'METHYLPREDNISOLONE'? | Successful treatment with Cinryze® replacement therapy of a pregnant patient with hereditary angioedema: a case report.
BACKGROUND
Hereditary angioedema (HAE) is a rare disease characterized with recurrent swelling of subcutaneous or mucosal tissue that resolves in approximately 3 days. It can be presented with peripheral edema, abdominal and life-threatening laryngeal angioedema. A variety of triggers are known to cause episodes of angioedema including estrogen exposure. There are different reports regarding the effect of pregnancy on HAE attacks, and in some patients, the pregnancy is a recognized triggering factor.
METHODS
We present a female Caucasian patient with pre-existing HAE and disease exacerbations during pregnancy, requiring prophylactic use of plasma-derived C1 inhibitor concentrate. She was treated with Cinryze® replacement therapy throughout the pregnancy 1000 IU i.v. 48 times. She gave birth to a healthy male infant, via C-section. After the delivery, the patient was symptom-free for 6 months and required no treatment for HAE.
CONCLUSIONS
In the case presented, the angioedema attacks worsened as the pregnancy progressed. The treatment with Cinryze® replacement therapy was effective and safe during pregnancy, with no adverse effects on the infant.
Introduction
Hereditary angioedema (HAE) is a rare disease characterized with recurrent swelling of subcutaneous or mucosal tissue, without pruritus or urticaria, that resolves in approximately 3 days. The disease can be presented with peripheral edema, abdominal, but also with life-threatening laryngeal angioedema [1].
Several types of HAE are described; the most explored one is due to C1 inhibitor deficiency, known as type I. It is caused by SERPING 1 mutation, on the long arm of chromosome 11, leading to C1 inhibitor deficiency which subsequently results in low C1 inhibitor and C4 protein levels in blood serum [2].
A variety of triggers, such as stress, surgical procedures, some medications (ACE inhibitors, estrogen-containing medication) are identified to cause episodes of angioedema [3, 4]. There are different reports regarding the effect of pregnancy on HAE attacks, and in some patients, the pregnancy is a known triggering factor.
We present a female patient with HAE and frequent disease exacerbations during pregnancy, that required prophylactic use of plasma-derived C1 inhibitor concentrate (pdC1) throughout the pregnancy.
Case presentation
We present a female Caucasian patient with HAE type I, diagnosed at the age of 26, with SERPING 1 mutation (confirmed by molecular testing), with very low C1inhibitor and C4 levels. Molecular testing was also positive for her father and brother. They also had low C1 inhibitor and C4 levels, but they never had any HAE symptoms.
Her symptoms of HAE first appeared when she was 15 years old, as swelling of her hand, without pain or urticaria. She was misdiagnosed with allergy-induced angioedema in the emergency department and was treated with glucocorticoids and antihistamines, without improvement. Edema subsided 3 days later. After that attack, peripheral angioedema appeared approximately once a year and lasted for a few days.
Since the age of 20 until the age of 26, she had several times very intense abdominal pain, with swelling, that required a visit to the emergency room (ER), where she would receive analgetic and proton -pump inhibitor (PPI) i.v., Gastroenterologist examined her, and after gastroscopy, the diagnosis of chronic erosive gastritis was established. Finally, at the age of 25, due to recurrent peripheral oedema, she was referred to clinical immunologist and allergist. After an extensive workup, at the age of 26, HAE type I was diagnosed.
Once HAE was diagnosed, she was treated with tranexamic acid (1000 mg daily orally) and icatibant 30 mg subcutaneously as on-demand therapy, which she had to use approximately once a year, due to abdominal angioedema.
In her medical history, at the age of 28, she had one spontaneous abortion at 8 weeks of pregnancy. Since the patient planned pregnancy, tranexamic acid was excluded, and recombinant C1 inhibitor, conestat alpha, was provided as on-demand therapy.
At the age of 29, in July 2018. patient came to the emergency room (ER) because of the swelling of her eyelids and lips, and she was treated with a total of 160 mg of methylprednisolone and chloropyramine 20 mg i.v. As she reported difficulty swallowing, an examination by ear, nose and throat (ENT) specialist was performed, and the edema of the epiglottis and sinus piriformis was established. Since there was no improvement after the anti-allergic therapy, recombinant C1 inhibitor was applied, (conestat alpha 2100 IU i.v.) and total regression of edema ensued a few hours later. She was admitted to the Department of Rheumatology, Clinical Immunology and Allergology for further observation.
Her social history revealed that she is a tradeswoman by profession, but is currently unemployed, married, living in a family house with her husband in a rural area, without any domestic animals in her household. The patient is a nonsmoker; she denied using alcohol, drugs or other medications. On admission, her temperature was 36.8°C, heart rate 76 beats/min, blood pressure 120/75 mmHg. There was no swelling of her face, neck or uvula. Her chest was clear to auscultation bilaterally, no wheezing. S1S2 were heard, no murmur, rubs or gallops. The abdomen was not distended; there was no tenderness on palpation and no organomegaly. There was no swelling or edema of her extremities. Neurological examination was unremarkable, with no nuchal rigidity, ophthalmic abnormalities, or cranial nerve signs.
During hospitalization, pregnancy was confirmed (8 weeks gestation). According to HAE guidelines, a pdC1 inhibitor is recommended in pregnancy, and Cinryze® was advised as only available pd1C1 inhibitor in our country at that time. In July 2018, she received the first application of Cinryze® 1000 IU i.v. and it was prescribed as on-demand therapy.
Two weeks later, she returned to the ER because of nausea and intense abdominal pain. Examination by obstetrics and gynaecology (OBGYN) specialist was performed, and complications related to pregnancy were excluded. The ultrasound of the abdomen displayed a small amount of fluid around the liver, spleen and intestines, and her blood workup was unremarkable.
After surgical and gastroenterologist (GE) examination she was referred to clinical immunologist and abdominal angioedema attack was diagnosed. She received Cinryze® 1000 iu i.v. and afterwards admitted to the Department for further evaluation. Blood workup revealed mild leukocytosis 14 ×109/L (ref. 3.4–9.7 × 109/L), normal C-reactive protein levels (5 mg/L; ref. <5) and elevated D-dimer levels >35000 Ug/L FEU (ref. 0–500) and low C4 0.04 g/L (ref. 0.1–0.4). Other blood workup was unremarkable: serum amylase 52U/L (ref. 30–110), lipase 9 U/L (0–160), LDH (s) 128 U/L (130–241), AST 24U/L (11–38), ALT 39 U/L (12–48), ALP 52 U/L (20–140), urea 1.6 mmol/L (2.8–8.3), creatinine (s) 49 umol/L (64–104), total bilirubin 11 umol/L (3-20), erythrocytes 4.31 × 1012/L (4.35–5.72), haemoglobin 131 g/L (138-175), thromocytes 189 × 109/L (158–424). Urine culture was sterile, EBV, CMV, Toxoplasma gondii serology revealed past contact.
Two hours after Cinryze® treatment, her symptoms resolved. On the next day, leukocyte levels were normal, and D-dimer values were significantly lower (4992 ug/L).
She was discharged from the hospital with Cinryze® i.v. as on-demand therapy and application of low weight molecular heparin s.c. (dalteparin 7500 IU s.c. once daily) was recommended through the entire pregnancy due to history of previous spontaneous abortion and elevated D-dimers.
After that episode, the attacks were more frequent, with abdominal angioedema attacks every 3 days, and peripheral edema with the swelling of hands almost every other day. At 17 weeks gestation, the patient was started on Cinryze® prophylactic therapy 1000 IU i.v., two times a week. As the pregnancy progressed, her attacks became more frequent despite prophylactic treatment, so during the final month of the pregnancy, she received Cinryze® every two to three days.
In January 2019, she gave birth to a male term infant (gestational age 38 weeks), via C-section. The newborn infant was eutrophic (birth weight 3370 g), and had an average head circumference (33 cm). Upon birth, the infant was mildly dyspneic, had regular heart rate (>120/min), pink skin colour, was mildly hypotonic and had normal reflexes. Apgar scores were 8 at 1ʹ and 8 at 5ʹ. Due to transitory tachypnea of the newborn, he required non-invasive respiratory support with heated and humidified high flow nasal cannula (HFNC) for six hours. The hospitalization was otherwise uneventful, and he was discharged after 8 days. Head ultrasound was normal; there were no signs of perinatal infection.
Before the C-section, the patient received Cinryze® 1000 IU iv. For the next two weeks after the delivery, prophylactic therapy was continued, and subsequently, icatibant as on-demand therapy was recommended. The patient chose not to breastfeed. After the delivery, the patient was symptom-free for 6 months and required no treatment for HAE. Her first abdominal attack after the symptom-free period was less intensive than during pregnancy. Overall, during the pregnancy, the patient in total received Cinryze® (1000 IU i.v.) 48 times.
Discussion
In the report we presented a female patient with HAE type I, with pregnancy as an exact trigger for HAE attacks, leading to the progression of the number of attacks as the pregnancy advanced, and the patient required prophylactic treatment. Interestingly, attacks started in the early pregnancy with a severe presentation of the disease that was not previously present, and resolved immediately after the delivery, leaving the patient symptom free for several months. There are only a few case reports and studies available, which give a detailed description of HAE worsening during the pregnancy, but to our knowledge, non showed such progression despite prophylactic therapy [5-9].
Hereditary angioedema is a rare disease that affects both male and female patients, but the attacks are more frequent in female patients [10]. The likely explanation is the possible effect of estrogen on the kallikrein-kinin system and subsequently on the disease course. [11]. Furthermore, it is known that HAE attacks can be precipitated by estrogen replacement therapy and contraceptive hormones [4, 10].
In our patient, the first symptom appeared during puberty onset. Although the SERPING 1 mutation and low levels of C1 inhibitor and C4 complement were found in her father and brother, she was the only member of the family with HAE symptoms.
The impact of pregnancy on HAE symptoms in patients is still unclear. Martinez-Saguer et al. showed that in 83% of pregnancies, attack rates increased during pregnancy with the highest rates in the second and third trimesters [12]. Czaller et al. in their study reported that attack frequency increases in 48% of pregnancies, most of them experienced worsening in the third trimester. Still, in 19% of the pregnancies, there was no influence on the course of HAE [9]. In contrast to these findings, Chinniah showed that women with HAE have significantly reduced or absent attacks in the last two trimesters of pregnancy [13].
In our patient, the first HAE symptom, when the pregnancy was revealed, was life-threatening laryngeal edema, whereas, before pregnancy, HAE symptoms were always presented as peripheral or abdominal edema. As the pregnancy progressed, her attacks became more frequent, especially in the last trimester, and were presented as abdominal and peripheral edema. Following the international WAO/EAACI guideline for the management of hereditary angioedema, the patient was treated with C1 inhibitor concentrate as prophylactic therapy during the pregnancy [1, 14].
Some authors suggest an increased number of attacks following frequent treatments with C1 concentrate [15]. This was not confirmed in our case, since our patient received 48 times pdC1 inhibitor concentrate and the attacks stopped after the delivery, and afterwards, she was a symptom-free for 6 months.
The patient was treated with pdC1 inhibitor concentrate Cinryze®, although there is no relevant epidemiological data regarding its safety during pregnancy. Until now, there are only a few case reports of its safety during pregnancy [16].
Conclusion
In the case presented, the angioedema attacks worsened as the pregnancy progressed. After delivery, the patient was symptom-free for six months. During the pregnancy, she was treated with pdC1 inhibitor concentrate Cinryze®, which showed to be a safe choice, although there is no relevant epidemiological data regarding its safety during pregnancy. Our report further confirms that Cinryze® therapy is effective and safe treatment during pregnancy, with no adverse effects on the infant.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
The authors acknowledge and thank the patient for her consent and insight, and also the staff and educators of the University Hospital Osijek, Croatia
Authors' contributions
ŽK and DK acquired, analyzed, and interpreted data and drafted the article and revised it critically for important intellectual content. VP and JMA revised the article critically for important intellectual content. All authors participated in writing the final manuscript. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
The study was approved by University Hospital Osijek Ethics committee No R2-1060/2020 and informed written consent was obtained.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
ŽK and VP has received speaker honorariums from Takeda Pharmaceuticals. DK owns stock in Takeda Pharmaceuticals. JMA declares that she has no conflict of interest. | 160 MILLIGRAM | DrugDosageText | CC BY | 33485376 | 18,845,587 | 2021-01-24 |
What was the outcome of reaction 'Hypotonia neonatal'? | Successful treatment with Cinryze® replacement therapy of a pregnant patient with hereditary angioedema: a case report.
BACKGROUND
Hereditary angioedema (HAE) is a rare disease characterized with recurrent swelling of subcutaneous or mucosal tissue that resolves in approximately 3 days. It can be presented with peripheral edema, abdominal and life-threatening laryngeal angioedema. A variety of triggers are known to cause episodes of angioedema including estrogen exposure. There are different reports regarding the effect of pregnancy on HAE attacks, and in some patients, the pregnancy is a recognized triggering factor.
METHODS
We present a female Caucasian patient with pre-existing HAE and disease exacerbations during pregnancy, requiring prophylactic use of plasma-derived C1 inhibitor concentrate. She was treated with Cinryze® replacement therapy throughout the pregnancy 1000 IU i.v. 48 times. She gave birth to a healthy male infant, via C-section. After the delivery, the patient was symptom-free for 6 months and required no treatment for HAE.
CONCLUSIONS
In the case presented, the angioedema attacks worsened as the pregnancy progressed. The treatment with Cinryze® replacement therapy was effective and safe during pregnancy, with no adverse effects on the infant.
Introduction
Hereditary angioedema (HAE) is a rare disease characterized with recurrent swelling of subcutaneous or mucosal tissue, without pruritus or urticaria, that resolves in approximately 3 days. The disease can be presented with peripheral edema, abdominal, but also with life-threatening laryngeal angioedema [1].
Several types of HAE are described; the most explored one is due to C1 inhibitor deficiency, known as type I. It is caused by SERPING 1 mutation, on the long arm of chromosome 11, leading to C1 inhibitor deficiency which subsequently results in low C1 inhibitor and C4 protein levels in blood serum [2].
A variety of triggers, such as stress, surgical procedures, some medications (ACE inhibitors, estrogen-containing medication) are identified to cause episodes of angioedema [3, 4]. There are different reports regarding the effect of pregnancy on HAE attacks, and in some patients, the pregnancy is a known triggering factor.
We present a female patient with HAE and frequent disease exacerbations during pregnancy, that required prophylactic use of plasma-derived C1 inhibitor concentrate (pdC1) throughout the pregnancy.
Case presentation
We present a female Caucasian patient with HAE type I, diagnosed at the age of 26, with SERPING 1 mutation (confirmed by molecular testing), with very low C1inhibitor and C4 levels. Molecular testing was also positive for her father and brother. They also had low C1 inhibitor and C4 levels, but they never had any HAE symptoms.
Her symptoms of HAE first appeared when she was 15 years old, as swelling of her hand, without pain or urticaria. She was misdiagnosed with allergy-induced angioedema in the emergency department and was treated with glucocorticoids and antihistamines, without improvement. Edema subsided 3 days later. After that attack, peripheral angioedema appeared approximately once a year and lasted for a few days.
Since the age of 20 until the age of 26, she had several times very intense abdominal pain, with swelling, that required a visit to the emergency room (ER), where she would receive analgetic and proton -pump inhibitor (PPI) i.v., Gastroenterologist examined her, and after gastroscopy, the diagnosis of chronic erosive gastritis was established. Finally, at the age of 25, due to recurrent peripheral oedema, she was referred to clinical immunologist and allergist. After an extensive workup, at the age of 26, HAE type I was diagnosed.
Once HAE was diagnosed, she was treated with tranexamic acid (1000 mg daily orally) and icatibant 30 mg subcutaneously as on-demand therapy, which she had to use approximately once a year, due to abdominal angioedema.
In her medical history, at the age of 28, she had one spontaneous abortion at 8 weeks of pregnancy. Since the patient planned pregnancy, tranexamic acid was excluded, and recombinant C1 inhibitor, conestat alpha, was provided as on-demand therapy.
At the age of 29, in July 2018. patient came to the emergency room (ER) because of the swelling of her eyelids and lips, and she was treated with a total of 160 mg of methylprednisolone and chloropyramine 20 mg i.v. As she reported difficulty swallowing, an examination by ear, nose and throat (ENT) specialist was performed, and the edema of the epiglottis and sinus piriformis was established. Since there was no improvement after the anti-allergic therapy, recombinant C1 inhibitor was applied, (conestat alpha 2100 IU i.v.) and total regression of edema ensued a few hours later. She was admitted to the Department of Rheumatology, Clinical Immunology and Allergology for further observation.
Her social history revealed that she is a tradeswoman by profession, but is currently unemployed, married, living in a family house with her husband in a rural area, without any domestic animals in her household. The patient is a nonsmoker; she denied using alcohol, drugs or other medications. On admission, her temperature was 36.8°C, heart rate 76 beats/min, blood pressure 120/75 mmHg. There was no swelling of her face, neck or uvula. Her chest was clear to auscultation bilaterally, no wheezing. S1S2 were heard, no murmur, rubs or gallops. The abdomen was not distended; there was no tenderness on palpation and no organomegaly. There was no swelling or edema of her extremities. Neurological examination was unremarkable, with no nuchal rigidity, ophthalmic abnormalities, or cranial nerve signs.
During hospitalization, pregnancy was confirmed (8 weeks gestation). According to HAE guidelines, a pdC1 inhibitor is recommended in pregnancy, and Cinryze® was advised as only available pd1C1 inhibitor in our country at that time. In July 2018, she received the first application of Cinryze® 1000 IU i.v. and it was prescribed as on-demand therapy.
Two weeks later, she returned to the ER because of nausea and intense abdominal pain. Examination by obstetrics and gynaecology (OBGYN) specialist was performed, and complications related to pregnancy were excluded. The ultrasound of the abdomen displayed a small amount of fluid around the liver, spleen and intestines, and her blood workup was unremarkable.
After surgical and gastroenterologist (GE) examination she was referred to clinical immunologist and abdominal angioedema attack was diagnosed. She received Cinryze® 1000 iu i.v. and afterwards admitted to the Department for further evaluation. Blood workup revealed mild leukocytosis 14 ×109/L (ref. 3.4–9.7 × 109/L), normal C-reactive protein levels (5 mg/L; ref. <5) and elevated D-dimer levels >35000 Ug/L FEU (ref. 0–500) and low C4 0.04 g/L (ref. 0.1–0.4). Other blood workup was unremarkable: serum amylase 52U/L (ref. 30–110), lipase 9 U/L (0–160), LDH (s) 128 U/L (130–241), AST 24U/L (11–38), ALT 39 U/L (12–48), ALP 52 U/L (20–140), urea 1.6 mmol/L (2.8–8.3), creatinine (s) 49 umol/L (64–104), total bilirubin 11 umol/L (3-20), erythrocytes 4.31 × 1012/L (4.35–5.72), haemoglobin 131 g/L (138-175), thromocytes 189 × 109/L (158–424). Urine culture was sterile, EBV, CMV, Toxoplasma gondii serology revealed past contact.
Two hours after Cinryze® treatment, her symptoms resolved. On the next day, leukocyte levels were normal, and D-dimer values were significantly lower (4992 ug/L).
She was discharged from the hospital with Cinryze® i.v. as on-demand therapy and application of low weight molecular heparin s.c. (dalteparin 7500 IU s.c. once daily) was recommended through the entire pregnancy due to history of previous spontaneous abortion and elevated D-dimers.
After that episode, the attacks were more frequent, with abdominal angioedema attacks every 3 days, and peripheral edema with the swelling of hands almost every other day. At 17 weeks gestation, the patient was started on Cinryze® prophylactic therapy 1000 IU i.v., two times a week. As the pregnancy progressed, her attacks became more frequent despite prophylactic treatment, so during the final month of the pregnancy, she received Cinryze® every two to three days.
In January 2019, she gave birth to a male term infant (gestational age 38 weeks), via C-section. The newborn infant was eutrophic (birth weight 3370 g), and had an average head circumference (33 cm). Upon birth, the infant was mildly dyspneic, had regular heart rate (>120/min), pink skin colour, was mildly hypotonic and had normal reflexes. Apgar scores were 8 at 1ʹ and 8 at 5ʹ. Due to transitory tachypnea of the newborn, he required non-invasive respiratory support with heated and humidified high flow nasal cannula (HFNC) for six hours. The hospitalization was otherwise uneventful, and he was discharged after 8 days. Head ultrasound was normal; there were no signs of perinatal infection.
Before the C-section, the patient received Cinryze® 1000 IU iv. For the next two weeks after the delivery, prophylactic therapy was continued, and subsequently, icatibant as on-demand therapy was recommended. The patient chose not to breastfeed. After the delivery, the patient was symptom-free for 6 months and required no treatment for HAE. Her first abdominal attack after the symptom-free period was less intensive than during pregnancy. Overall, during the pregnancy, the patient in total received Cinryze® (1000 IU i.v.) 48 times.
Discussion
In the report we presented a female patient with HAE type I, with pregnancy as an exact trigger for HAE attacks, leading to the progression of the number of attacks as the pregnancy advanced, and the patient required prophylactic treatment. Interestingly, attacks started in the early pregnancy with a severe presentation of the disease that was not previously present, and resolved immediately after the delivery, leaving the patient symptom free for several months. There are only a few case reports and studies available, which give a detailed description of HAE worsening during the pregnancy, but to our knowledge, non showed such progression despite prophylactic therapy [5-9].
Hereditary angioedema is a rare disease that affects both male and female patients, but the attacks are more frequent in female patients [10]. The likely explanation is the possible effect of estrogen on the kallikrein-kinin system and subsequently on the disease course. [11]. Furthermore, it is known that HAE attacks can be precipitated by estrogen replacement therapy and contraceptive hormones [4, 10].
In our patient, the first symptom appeared during puberty onset. Although the SERPING 1 mutation and low levels of C1 inhibitor and C4 complement were found in her father and brother, she was the only member of the family with HAE symptoms.
The impact of pregnancy on HAE symptoms in patients is still unclear. Martinez-Saguer et al. showed that in 83% of pregnancies, attack rates increased during pregnancy with the highest rates in the second and third trimesters [12]. Czaller et al. in their study reported that attack frequency increases in 48% of pregnancies, most of them experienced worsening in the third trimester. Still, in 19% of the pregnancies, there was no influence on the course of HAE [9]. In contrast to these findings, Chinniah showed that women with HAE have significantly reduced or absent attacks in the last two trimesters of pregnancy [13].
In our patient, the first HAE symptom, when the pregnancy was revealed, was life-threatening laryngeal edema, whereas, before pregnancy, HAE symptoms were always presented as peripheral or abdominal edema. As the pregnancy progressed, her attacks became more frequent, especially in the last trimester, and were presented as abdominal and peripheral edema. Following the international WAO/EAACI guideline for the management of hereditary angioedema, the patient was treated with C1 inhibitor concentrate as prophylactic therapy during the pregnancy [1, 14].
Some authors suggest an increased number of attacks following frequent treatments with C1 concentrate [15]. This was not confirmed in our case, since our patient received 48 times pdC1 inhibitor concentrate and the attacks stopped after the delivery, and afterwards, she was a symptom-free for 6 months.
The patient was treated with pdC1 inhibitor concentrate Cinryze®, although there is no relevant epidemiological data regarding its safety during pregnancy. Until now, there are only a few case reports of its safety during pregnancy [16].
Conclusion
In the case presented, the angioedema attacks worsened as the pregnancy progressed. After delivery, the patient was symptom-free for six months. During the pregnancy, she was treated with pdC1 inhibitor concentrate Cinryze®, which showed to be a safe choice, although there is no relevant epidemiological data regarding its safety during pregnancy. Our report further confirms that Cinryze® therapy is effective and safe treatment during pregnancy, with no adverse effects on the infant.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
The authors acknowledge and thank the patient for her consent and insight, and also the staff and educators of the University Hospital Osijek, Croatia
Authors' contributions
ŽK and DK acquired, analyzed, and interpreted data and drafted the article and revised it critically for important intellectual content. VP and JMA revised the article critically for important intellectual content. All authors participated in writing the final manuscript. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
The study was approved by University Hospital Osijek Ethics committee No R2-1060/2020 and informed written consent was obtained.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
ŽK and VP has received speaker honorariums from Takeda Pharmaceuticals. DK owns stock in Takeda Pharmaceuticals. JMA declares that she has no conflict of interest. | Recovered | ReactionOutcome | CC BY | 33485376 | 18,845,589 | 2021-01-24 |
What was the outcome of reaction 'Transient tachypnoea of the newborn'? | Successful treatment with Cinryze® replacement therapy of a pregnant patient with hereditary angioedema: a case report.
BACKGROUND
Hereditary angioedema (HAE) is a rare disease characterized with recurrent swelling of subcutaneous or mucosal tissue that resolves in approximately 3 days. It can be presented with peripheral edema, abdominal and life-threatening laryngeal angioedema. A variety of triggers are known to cause episodes of angioedema including estrogen exposure. There are different reports regarding the effect of pregnancy on HAE attacks, and in some patients, the pregnancy is a recognized triggering factor.
METHODS
We present a female Caucasian patient with pre-existing HAE and disease exacerbations during pregnancy, requiring prophylactic use of plasma-derived C1 inhibitor concentrate. She was treated with Cinryze® replacement therapy throughout the pregnancy 1000 IU i.v. 48 times. She gave birth to a healthy male infant, via C-section. After the delivery, the patient was symptom-free for 6 months and required no treatment for HAE.
CONCLUSIONS
In the case presented, the angioedema attacks worsened as the pregnancy progressed. The treatment with Cinryze® replacement therapy was effective and safe during pregnancy, with no adverse effects on the infant.
Introduction
Hereditary angioedema (HAE) is a rare disease characterized with recurrent swelling of subcutaneous or mucosal tissue, without pruritus or urticaria, that resolves in approximately 3 days. The disease can be presented with peripheral edema, abdominal, but also with life-threatening laryngeal angioedema [1].
Several types of HAE are described; the most explored one is due to C1 inhibitor deficiency, known as type I. It is caused by SERPING 1 mutation, on the long arm of chromosome 11, leading to C1 inhibitor deficiency which subsequently results in low C1 inhibitor and C4 protein levels in blood serum [2].
A variety of triggers, such as stress, surgical procedures, some medications (ACE inhibitors, estrogen-containing medication) are identified to cause episodes of angioedema [3, 4]. There are different reports regarding the effect of pregnancy on HAE attacks, and in some patients, the pregnancy is a known triggering factor.
We present a female patient with HAE and frequent disease exacerbations during pregnancy, that required prophylactic use of plasma-derived C1 inhibitor concentrate (pdC1) throughout the pregnancy.
Case presentation
We present a female Caucasian patient with HAE type I, diagnosed at the age of 26, with SERPING 1 mutation (confirmed by molecular testing), with very low C1inhibitor and C4 levels. Molecular testing was also positive for her father and brother. They also had low C1 inhibitor and C4 levels, but they never had any HAE symptoms.
Her symptoms of HAE first appeared when she was 15 years old, as swelling of her hand, without pain or urticaria. She was misdiagnosed with allergy-induced angioedema in the emergency department and was treated with glucocorticoids and antihistamines, without improvement. Edema subsided 3 days later. After that attack, peripheral angioedema appeared approximately once a year and lasted for a few days.
Since the age of 20 until the age of 26, she had several times very intense abdominal pain, with swelling, that required a visit to the emergency room (ER), where she would receive analgetic and proton -pump inhibitor (PPI) i.v., Gastroenterologist examined her, and after gastroscopy, the diagnosis of chronic erosive gastritis was established. Finally, at the age of 25, due to recurrent peripheral oedema, she was referred to clinical immunologist and allergist. After an extensive workup, at the age of 26, HAE type I was diagnosed.
Once HAE was diagnosed, she was treated with tranexamic acid (1000 mg daily orally) and icatibant 30 mg subcutaneously as on-demand therapy, which she had to use approximately once a year, due to abdominal angioedema.
In her medical history, at the age of 28, she had one spontaneous abortion at 8 weeks of pregnancy. Since the patient planned pregnancy, tranexamic acid was excluded, and recombinant C1 inhibitor, conestat alpha, was provided as on-demand therapy.
At the age of 29, in July 2018. patient came to the emergency room (ER) because of the swelling of her eyelids and lips, and she was treated with a total of 160 mg of methylprednisolone and chloropyramine 20 mg i.v. As she reported difficulty swallowing, an examination by ear, nose and throat (ENT) specialist was performed, and the edema of the epiglottis and sinus piriformis was established. Since there was no improvement after the anti-allergic therapy, recombinant C1 inhibitor was applied, (conestat alpha 2100 IU i.v.) and total regression of edema ensued a few hours later. She was admitted to the Department of Rheumatology, Clinical Immunology and Allergology for further observation.
Her social history revealed that she is a tradeswoman by profession, but is currently unemployed, married, living in a family house with her husband in a rural area, without any domestic animals in her household. The patient is a nonsmoker; she denied using alcohol, drugs or other medications. On admission, her temperature was 36.8°C, heart rate 76 beats/min, blood pressure 120/75 mmHg. There was no swelling of her face, neck or uvula. Her chest was clear to auscultation bilaterally, no wheezing. S1S2 were heard, no murmur, rubs or gallops. The abdomen was not distended; there was no tenderness on palpation and no organomegaly. There was no swelling or edema of her extremities. Neurological examination was unremarkable, with no nuchal rigidity, ophthalmic abnormalities, or cranial nerve signs.
During hospitalization, pregnancy was confirmed (8 weeks gestation). According to HAE guidelines, a pdC1 inhibitor is recommended in pregnancy, and Cinryze® was advised as only available pd1C1 inhibitor in our country at that time. In July 2018, she received the first application of Cinryze® 1000 IU i.v. and it was prescribed as on-demand therapy.
Two weeks later, she returned to the ER because of nausea and intense abdominal pain. Examination by obstetrics and gynaecology (OBGYN) specialist was performed, and complications related to pregnancy were excluded. The ultrasound of the abdomen displayed a small amount of fluid around the liver, spleen and intestines, and her blood workup was unremarkable.
After surgical and gastroenterologist (GE) examination she was referred to clinical immunologist and abdominal angioedema attack was diagnosed. She received Cinryze® 1000 iu i.v. and afterwards admitted to the Department for further evaluation. Blood workup revealed mild leukocytosis 14 ×109/L (ref. 3.4–9.7 × 109/L), normal C-reactive protein levels (5 mg/L; ref. <5) and elevated D-dimer levels >35000 Ug/L FEU (ref. 0–500) and low C4 0.04 g/L (ref. 0.1–0.4). Other blood workup was unremarkable: serum amylase 52U/L (ref. 30–110), lipase 9 U/L (0–160), LDH (s) 128 U/L (130–241), AST 24U/L (11–38), ALT 39 U/L (12–48), ALP 52 U/L (20–140), urea 1.6 mmol/L (2.8–8.3), creatinine (s) 49 umol/L (64–104), total bilirubin 11 umol/L (3-20), erythrocytes 4.31 × 1012/L (4.35–5.72), haemoglobin 131 g/L (138-175), thromocytes 189 × 109/L (158–424). Urine culture was sterile, EBV, CMV, Toxoplasma gondii serology revealed past contact.
Two hours after Cinryze® treatment, her symptoms resolved. On the next day, leukocyte levels were normal, and D-dimer values were significantly lower (4992 ug/L).
She was discharged from the hospital with Cinryze® i.v. as on-demand therapy and application of low weight molecular heparin s.c. (dalteparin 7500 IU s.c. once daily) was recommended through the entire pregnancy due to history of previous spontaneous abortion and elevated D-dimers.
After that episode, the attacks were more frequent, with abdominal angioedema attacks every 3 days, and peripheral edema with the swelling of hands almost every other day. At 17 weeks gestation, the patient was started on Cinryze® prophylactic therapy 1000 IU i.v., two times a week. As the pregnancy progressed, her attacks became more frequent despite prophylactic treatment, so during the final month of the pregnancy, she received Cinryze® every two to three days.
In January 2019, she gave birth to a male term infant (gestational age 38 weeks), via C-section. The newborn infant was eutrophic (birth weight 3370 g), and had an average head circumference (33 cm). Upon birth, the infant was mildly dyspneic, had regular heart rate (>120/min), pink skin colour, was mildly hypotonic and had normal reflexes. Apgar scores were 8 at 1ʹ and 8 at 5ʹ. Due to transitory tachypnea of the newborn, he required non-invasive respiratory support with heated and humidified high flow nasal cannula (HFNC) for six hours. The hospitalization was otherwise uneventful, and he was discharged after 8 days. Head ultrasound was normal; there were no signs of perinatal infection.
Before the C-section, the patient received Cinryze® 1000 IU iv. For the next two weeks after the delivery, prophylactic therapy was continued, and subsequently, icatibant as on-demand therapy was recommended. The patient chose not to breastfeed. After the delivery, the patient was symptom-free for 6 months and required no treatment for HAE. Her first abdominal attack after the symptom-free period was less intensive than during pregnancy. Overall, during the pregnancy, the patient in total received Cinryze® (1000 IU i.v.) 48 times.
Discussion
In the report we presented a female patient with HAE type I, with pregnancy as an exact trigger for HAE attacks, leading to the progression of the number of attacks as the pregnancy advanced, and the patient required prophylactic treatment. Interestingly, attacks started in the early pregnancy with a severe presentation of the disease that was not previously present, and resolved immediately after the delivery, leaving the patient symptom free for several months. There are only a few case reports and studies available, which give a detailed description of HAE worsening during the pregnancy, but to our knowledge, non showed such progression despite prophylactic therapy [5-9].
Hereditary angioedema is a rare disease that affects both male and female patients, but the attacks are more frequent in female patients [10]. The likely explanation is the possible effect of estrogen on the kallikrein-kinin system and subsequently on the disease course. [11]. Furthermore, it is known that HAE attacks can be precipitated by estrogen replacement therapy and contraceptive hormones [4, 10].
In our patient, the first symptom appeared during puberty onset. Although the SERPING 1 mutation and low levels of C1 inhibitor and C4 complement were found in her father and brother, she was the only member of the family with HAE symptoms.
The impact of pregnancy on HAE symptoms in patients is still unclear. Martinez-Saguer et al. showed that in 83% of pregnancies, attack rates increased during pregnancy with the highest rates in the second and third trimesters [12]. Czaller et al. in their study reported that attack frequency increases in 48% of pregnancies, most of them experienced worsening in the third trimester. Still, in 19% of the pregnancies, there was no influence on the course of HAE [9]. In contrast to these findings, Chinniah showed that women with HAE have significantly reduced or absent attacks in the last two trimesters of pregnancy [13].
In our patient, the first HAE symptom, when the pregnancy was revealed, was life-threatening laryngeal edema, whereas, before pregnancy, HAE symptoms were always presented as peripheral or abdominal edema. As the pregnancy progressed, her attacks became more frequent, especially in the last trimester, and were presented as abdominal and peripheral edema. Following the international WAO/EAACI guideline for the management of hereditary angioedema, the patient was treated with C1 inhibitor concentrate as prophylactic therapy during the pregnancy [1, 14].
Some authors suggest an increased number of attacks following frequent treatments with C1 concentrate [15]. This was not confirmed in our case, since our patient received 48 times pdC1 inhibitor concentrate and the attacks stopped after the delivery, and afterwards, she was a symptom-free for 6 months.
The patient was treated with pdC1 inhibitor concentrate Cinryze®, although there is no relevant epidemiological data regarding its safety during pregnancy. Until now, there are only a few case reports of its safety during pregnancy [16].
Conclusion
In the case presented, the angioedema attacks worsened as the pregnancy progressed. After delivery, the patient was symptom-free for six months. During the pregnancy, she was treated with pdC1 inhibitor concentrate Cinryze®, which showed to be a safe choice, although there is no relevant epidemiological data regarding its safety during pregnancy. Our report further confirms that Cinryze® therapy is effective and safe treatment during pregnancy, with no adverse effects on the infant.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
The authors acknowledge and thank the patient for her consent and insight, and also the staff and educators of the University Hospital Osijek, Croatia
Authors' contributions
ŽK and DK acquired, analyzed, and interpreted data and drafted the article and revised it critically for important intellectual content. VP and JMA revised the article critically for important intellectual content. All authors participated in writing the final manuscript. All authors read and approved the final manuscript.
Funding
None.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
The study was approved by University Hospital Osijek Ethics committee No R2-1060/2020 and informed written consent was obtained.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
ŽK and VP has received speaker honorariums from Takeda Pharmaceuticals. DK owns stock in Takeda Pharmaceuticals. JMA declares that she has no conflict of interest. | Recovered | ReactionOutcome | CC BY | 33485376 | 18,845,589 | 2021-01-24 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'BK virus infection'. | Unmasking viral sequences by metagenomic next-generation sequencing in adult human blood samples during steroid-refractory/dependent graft-versus-host disease.
Viral infections are common complications following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Allo-HSCT recipients with steroid-refractory/dependent graft-versus-host disease (GvHD) are highly immunosuppressed and are more vulnerable to infections with weakly pathogenic or commensal viruses. Here, twenty-five adult allo-HSCT recipients from 2016 to 2019 with acute or chronic steroid-refractory/dependent GvHD were enrolled in a prospective cohort at Geneva University Hospitals. We performed metagenomics next-generation sequencing (mNGS) analysis using a validated pipeline and de novo analysis on pooled routine plasma samples collected throughout the period of intensive steroid treatment or second-line GvHD therapy to identify weakly pathogenic, commensal, and unexpected viruses.
Median duration of intensive immunosuppression was 5.1 months (IQR 5.5). GvHD-related mortality rate was 36%. mNGS analysis detected viral nucleotide sequences in 24/25 patients. Sequences of ≥ 3 distinct viruses were detected in 16/25 patients; Anelloviridae (24/25) and human pegivirus-1 (9/25) were the most prevalent. In 7 patients with fatal outcomes, viral sequences not assessed by routine investigations were identified with mNGS and confirmed by RT-PCR. These cases included Usutu virus (1), rubella virus (1 vaccine strain and 1 wild-type), novel human astrovirus (HAstV) MLB2 (1), classic HAstV (1), human polyomavirus 6 and 7 (2), cutavirus (1), and bufavirus (1).
Clinically unrecognized viral infections were identified in 28% of highly immunocompromised allo-HSCT recipients with steroid-refractory/dependent GvHD in consecutive samples. These identified viruses have all been previously described in humans, but have poorly understood clinical significance. Rubella virus identification raises the possibility of re-emergence from past infections or vaccinations, or re-infection. Video abstract.
Background
Viral primary infections and reactivations are common complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and are associated with significant morbidity and mortality [1, 2]. Current routine clinical surveillance molecular assays detect specific nucleotide sequences targeting usual culprits including Epstein-Barr virus (EBV), cytomegalovirus (CMV), BK polyomavirus (BKPyV), and adenovirus [3]. Metagenomic next-generation sequencing’s (mNGS) unbiased approach broadens viral infection diagnosis, theoretically detecting “all” viral nucleotide sequences or viral infections present [4–7], and is increasingly used in clinical investigations [8]. Allo-HSCT recipients suffering from steroid-refractory/dependent acute or chronic graft-versus-host disease (GvHD) are highly immunosuppressed patients; GvHD immune dysregulation, mucosal barrier alteration [9–13], and multiple prolonged immunosuppressive treatments create a permissive environment for opportunistic viral infections [10, 11, 14]. These clinically unrecognized viral infections can present with limited symptoms/atypical manifestations and lead to intermittent or prolonged viremia [3]. Given the nonspecific clinical features of GvHD and some viral infections, viral infections may remain clinically unrecognized due to limitations of clinical molecular assays.
We hypothesized that some viral infections, which would normally remain undiagnosed with common clinical assays, occur during intense immunosuppressive therapy in steroid-refractory/dependent GvHD. This study aimed to identify viruses that are not routinely searched by RT-PCR routine assays in clinical practice, due to the lack of knowledge. Therefore, we used mNGS on pooled plasma samples of adult allo-HSCT patients with steroid-refractory/dependent acute or chronic GvHD to look for viruses that could be missed by biased technology.
Methods
Setting, study population, and design
This observational study was conducted at the Geneva University Hospitals (HUG), Switzerland. The study protocol was approved by the Geneva Cantonal Ethics Commission (project #2019-00511). Inclusion criteria were adult patients who received an allo-HSCT from 1 January 2016 to 31 December 2018 at the HUG, who were enrolled in the local monocentric infectious disease cohort of allo-HSCT patients, and who developed steroid-refractory/dependent acute or chronic GvHD. All included patients provided written consent before enrollment. The only exclusion criteria was the lack of informed written consent.
Plasma samples were prospectively collected during clinical management after allo-HSCT and stored in the Laboratory of Virology, HUG. We performed mNGS analysis on pooled plasma samples of each patient, collected throughout the period of intensive steroid treatment or second-line GvHD therapy.
Definitions
Steroid-refractory/dependent acute and chronic GvHD were defined according to the position statement of the GvHD experts in Schoemans et al. [15].
Microbiological methods
mNGS and sequence analysis
Each pool (corresponding to 4 to 10 plasma samples from each patient) was prepared to obtain a final volume of 220 μl. Pools were then centrifuged at 10,000×g for 10 min to remove cells. Two-hundred microliters of cell-free supernatant were treated with 20 μl of Turbo DNAse (2 U/μl) + 24 μl of 10x TURBO DNase Buffer (Ambion, Rotkreuz, Switzerland), according to the manufacturer’s instructions. Then, the whole volume was divided into two tubes of 120 μl each. One tube was then used for each of the two nucleic acid extraction procedures. Indeed, virus genome extractions were done using two previously published protocols in parallel [16], namely the RNA and DNA protocols optimized for the detection of RNA and DNA viral sequences, respectively.
For the RNA protocol, nucleic acids were extracted with TRIzol (Invitrogen, Carlsbad, CA, USA). Ribosomal RNA was removed (Ribo-Zero Gold depletion kit (Illumina, San Diego, USA) before libraries’ preparation (TruSeq total RNA preparation protocol (Illumina)). Libraries’ concentrations and sizes were analyzed using the Qubit (Life Technologies, Carlsbad, CA, USA) and the 2200 TapeStation instruments (Agilent, SantaClara, CA, USA), respectively. Each library was loaded individually in a single lane on the HiSeq 4000 platform (Illumina) using the 2 × 100-bp protocol with dual-indexing. The mean total number of read pairs obtained per pool was 328,936,594.84 (range 252,670,103 to 385,257,539).
For the DNA protocol, nucleic acids were extracted with the NucliSens easyMAG magnetic bead system (bioMérieux, Geneva, Switzerland). As previously published [16], double-stranded DNA synthesis was done with the DNA polymerase I, Large Fragment (Klenow) (New England BioLabs, Ipswich, MA, USA)). Libraries were prepared using the Nextera XT (Illumina) protocol. Libraries’ concentrations and sizes were analyzed using the Qubit (Life Technologies) and the 2200 TapeStation instruments (Agilent), respectively. Each library was loaded individually in a single lane on the HiSeq 4000 platform (Illumina) using the 2 × 100-bp protocol with dual-indexing. The mean total number of read pairs obtained per pool was 301,393,033.48 (range 122,939,325 to 377,758,795).
To check for potential contaminating viral sequences from environment or experimental reagents [17], four negative controls (i.e., Neg1-4) were submitted to the whole mNGS procedure. To assess the mNGS process efficiency, positive controls underwent the whole mNGS procedure (canine distemper virus (CDV)-spiked samples and a baculovirus (GenScript, Piscataway, NJ, USA) harboring 793 nucleotides of the CDV fusion gene were used as positive controls for the RNA and DNA protocols, respectively).
Paired reads were quality filtered using Trimmomatic [18]. Reads mapped against the human genome and transcriptome (hg38, gencode.V23) were removed using SNAP [19]. Remaining reads were analyzed using two methods in parallel as previously described [20]: (1) by a pipeline that used virusscan 1.0 (https://github.com/sib-swiss/virusscan) to map reads against the Virosaurus database (version V90v_2018_11) (https://viralzone.expasy.org/8676), which is designed to report vertebrate viruses, and (2) by de novo assembly. Only viruses with ≥ 300 nucleotides of coverage were reported. The raw sequence data were deposited in the NCBI Sequence Read Archive under BioProject accession number PRJNA641787.
Sequences were considered clinically recognized viruses if they corresponded to a virus known to reactivate in/be frequently found among allo-HSCT recipients [2, 4] or if the patient had a known chronic viral infection and clinically unrecognized viruses if not.
Confirmatory real-time (reverse transcription-)polymerase chain reaction (r(RT-)PCR) assays
Clinically unrecognized mNGS findings were confirmed on unpooled plasma by specific semi-quantitative or quantitative r(RT-)PCR assays as previously published; additional specimens (including plasma, cerebrospinal fluid, bronchoalveolar lavage (BAL) fluids, nasopharyngeal swabs, native urines, stools suspension, tissue biopsies or bone marrow) were tested when available and pertinent. Quantitative r(RT-)PCR assays were done for Mamastrovirus 1 (classical) using the updated human astrovirus (HAstV) combination [21], Mamastrovirus 6 (MLB2) using the MLB2 assay [22], Usutu virus [23], and bufavirus using the BuV (NS1) assay [24]. Semi-quantitative r(RT-)PCR assays were done for cutavirus using the CuV (VP2) assay [24], human polyomavirus (HPyV) 6 using the VP2 assay [25], HPyV-7 using the VP2 assay [25], and rubella virus [26].
Nucleic acids from plasma, cerebrospinal fluid, BAL fluids, nasopharyngeal swabs, urine, stools resuspended in PBS, and bone marrow were extracted individually from 190 μL of each specimen, spiked with 10 μL of standardized CDV as internal control [27], using the NucliSENS easyMAG (bioMérieux, Geneva, Switzerland) nucleic acid kit, according to the manufacturer’s instructions, and eluted in 25 μL. DNA and RNA were extracted from tissue biopsies using the QIAamp DNA FFPE Tissue Kit (Qiagen, Hombrechtikon, Switzerland) and High Pure FFPET RNA isolation kit (Roche Applied Sciences, Indianapolis, IN, USA), respectively, following the manufacturer’s instructions. For RNA viruses, the rRT-PCR assays were performed using the one-step QuantiTect Probe RT-PCR Kit (Qiagen, Hombrechtikon, Switzerland) in a StepOne Plus instrument (Applied Biosystems, Rotkreuz, Switzerland). For DNA viruses, the rPCR assays were performed using the TaqMan Universal PCR Master Mix (Applied Biosystems) in a StepOne Plus instrument (Applied Biosystems) for cutavirus and bufavirus or in a QuantStudio 5 instrument (Applied Biosystems) for HPyV6 and 7.
For quantitative r(RT)-PCR assays, standard curves and lower limit of quantifications (LOQ) were assessed using 10-fold serial dilutions of specific RNA oligonucleotides (Mamastrovirus 1 (classical) and 6 (MLB2): LOQ = 1.25E4 and 1.25E3 RNA copies/ml of plasma, respectively), RNA transcript (Usutu virus: LOQ = 1.32E2 RNA copies/ml of plasma), DNA oligonucleotides (bufavirus: LOQ = 1.32E3 DNA copies/ml of plasma), or plasmids (HPyV6 and 7: LOQ = 2.63E2 DNA copies/ml of plasma each) containing the target sequences.
Statistical analysis
Categorical variables were described by counts and percentages. Continuous variables were expressed as mean and standard deviation or median and interquartile range.
Results
Patient characteristics
We identified 25 adult allo-HSCT recipients with acute or chronic steroid-refractory/dependent GvHD. Table 1 shows the patient’s characteristics. The median duration of intensive immunosuppression was 5.1 months (IQR 5.5), and 22/25 patients received ruxolitinib. At the time of writing, fifteen patients have died, with 9 considered as GvHD-related.
Table 1 Patients’ characteristics (25 allo-HSCT patients)
Total
n = 25
Demographics
Sex (male), n (%) 16 (64.0)
Age, median (IQR) 58.0 (25.0)
Allo-HSCT considered in the analysis,
n
(%)
First 23 (92.0)
Second 2 (8.0)
Transplant source,
n
(%)
Bone marrow 5 (20)
Peripheral blood cells 20 (80)
Underlying disease,
n
(%)
Acute myeloid leukemia 10 (40.0)
Lymphoid malignancy 6 (24.0)
MDS/MDPS 3 (12.0)
Acute lymphoid leukemia 2 (8.0)
Othera 4 (16.0)
Risk score,
n
(%)
Low 0 (0)
Intermediate 18 (72.0)
High 7 (28.0)
Donor sex, M,
n
(%) 7 (28.0)
Donor age, median (IQR) 36 (16.5)
Donor match,
n
(%)
Donor-related 10 (40.0)
CMV donor/recipient constellation,
n
(%)
+/+ 12 (48.0)
−/+ 1 (4.0)
+/− 7 (28.0)
−/− 5 (20.0)
CMV prophylaxis, n (%) 1 (4.0)
Conditioning,
n
(%)
Myeloablative conditioning 5 (20.0)
GvHD prophylaxis,
n
(%)
Calcineurin inhibitor 24 (96.0)
Mycophenolate mofetil 17 (68.0)
Methotrexate 7 (28.0)
GvHD organ,
n
(%)
Digestive tract 17 (68.0)
Skin 15 (60.0)
Mouth 4 (16.0)
Liver 7 (28.0)
Lung 5 (20.0)
Eyes 2 (8.0)
Musculoskeletal 1 (4.0)
GvHD grade or severity,
n
(%)
Grade
2 9 (36.0)
3 3 (12.0)
4 6 (24.0)
Moderate 6 (24.0)
Severe 7 (28.0)
GvHD treatment,
n
(%)
Corticosteroids 24 (96.0)
Ruxolitinib 22 (88.0)
Calcineurin inhibitor 21 (84.0)
Mycophenolate mofetil 12 (48.0)
Photopheresis 12 (48.0)
Budenoside 5 (20.0)
Sirolimus 3 (12.0)
Tocilizumab 2 (8.0)
Otherb 6 (24.0)
Death,
n
(%) 15 (60.0)
Median delay from allo-HSCT, months (IQR) 11.2 (15.8)
One patient could have multiple GvHD prophylaxis and treatment, multiple organs with GvHD and multiple grades of severity. CMV prophylaxis: one patient (patient Ge24) received letermovir during the period of intensive steroid treatment or second-line GvHD therapy. GvHD grade refers to acute GvHD, GvHD severity refers to chronic GvHD. In two patients, there was no information on grade/severity. Only organs with grade GvHD ≥ 2 or severity ≥ moderate are reported
Abbreviations: IQR interquartile range, allo-HSCT allogeneic hematopoietic stem cell transplantation, MDS/MDPS myelodysplasic syndrome/myelodysplasic proliferative syndrome, ATG anti-thymocyte globulin
aOther includes: multiple myeloma (n = 2), chronic myeloid leukemia (n = 1) and mixed acute leukemia (n = 1)
bOther includes: azithromycine, montelukast, prolastin, vedolisumab, nilotinib, basilixumab, ibrutinib, and/or methotrexate
Viral sequences identified with mNGS and confirmatory analyses
The mNGS analysis revealed viral nucleotide sequences in all patients except Ge18 (24/25). In 16/25 patients, ≥ 3 distinct viral species were detected (Fig. 1). Figure 2 depicts the prevalence of each identified virus, and Table S1 provides detailed mNGS characteristics.
Fig. 1 Grid plot of viral sequences identified with mNGS in pooled plasma samples (25 allo-HSCT patients). Each line corresponds to viral sequences assigned to one virus; the bottom line corresponds to mNGS negative (Neg1-4) and positive (Pos1/2 DNA/RNA) control samples. Each column corresponds to one pool of plasma sample (one patient). Colors represent the approximate number of reads matching virus genome detected in each pool of plasma samples. *Since they were detected in one negative control, human papillomavirus sequences were considered as likely contaminant. # cross-contamination. Abbreviations: HAstV human astrovirus, TTV torque teno virus, TTMV torque teno minivirus, TTMDV torque teno midivirus, HSV-1 herpes simplex 1 virus, EBV Epstein-Barr virus, CMV cytomegalovirus, CTRL control
Fig. 2 Prevalence of viruses identified with mNGS in pooled plasma samples (25 allo-HSCT recipients). The vertical axis represents all identified viral sequences. The horizontal axis represents the number of patients in which sequences of each virus were identified. Abbreviations: TTV torque teno virus, TTMV torque teno minivirus, CMV cytomegalovirus, TTMDV torque teno midivirus, EBV Epstein-Barr virus, HSV-1 herpes simplex 1 virus, HAstV human astrovirus
Anelloviridae (torque teno virus (TTV), torque teno minivirus (TTMV) and torque teno midivirus (TTMDV)) and human pegivirus-1 (HPgV-1) were the most prevalent with sequences detected in 24/25 and 9/25 patients, respectively.
Other detected DNA viruses included BK polyomavirus (BKPyV) (7/25), CMV (5/25), and JC polyomavirus (JCPyV) (4/25), and also herpes simplex virus 1 (HSV-1), EBV, hepatitis B virus (HBV), bufavirus, cutavirus, and HPyV-6/7, each detected once (1/25). Except HPgV-1, the detected RNA viruses were less prevalent than DNA viruses and were HAstV (Mamastrovirus 1 and 6) and rubella virus, both detected twice (2/25), and also hepatitis E (HEV) and Usutu viruses, both detected once (1/25). The de novo analysis did not reveal other relevant sequences. Interestingly, sequences for TTV (11/24), CMV (3/5), EBV (1/1), and HBV (1/1) were detected in both DNA and RNA libraries, suggesting active viral replication (Figure S1).
Clinically recognized viral sequences
Although not routinely searched in clinical practice, Anelloviridae and HPgV-1 sequences were identified in 96% and 36% of patients and were classified among clinically recognized viral sequences as they are known to be highly prevalent among immunocompromised patients. In 14/25 patients, mNGS analysis identified sequences of latent DNA viruses known to reactivate in transplant recipients (EBV, CMV, HSV-1, BKPyV, JCPyV, HBV). At the RNA level, HEV was identified once.
The r(RT-)PCR assays performed during routine investigations confirmed the mNGS analysis (Table S2): patient Ge05 had a chronic HEV infection, and patient Ge14 had chronic HBV and cutaneous HSV-1 infections, and HSV-1 viremia. BKPyV and JCPyV were not systematically screened and were only revealed by mNGS analysis. However, BKPyV was screened in patient Ge06 and detected at low viral loads (VL) (1.41E2 and 1.44E3 copies/ml) in two plasma samples collected a few days apart from those included for mNGS analysis. In 12/25 patients, CMV and EBV were detected only by rPCR at low VL; no other expected virus was detected by routine molecular assays.
Clinically unrecognized viral sequences
We found clinically unrecognized sequences belonging to either rare and/or recently identified viruses (HAstV MLB2, Usutu virus, bufavirus, cutavirus, HPyV-6, and HPyV-7) or those not routinely assessed alongside GvHD (classic HAstV and rubella virus) in 7/25 patients, whose characteristics are detailed in Table 2.
Table 2 Clinical characteristics of 7 patients with clinically unrecognized viral sequences
Patient’s code Age, gender Underlying disease GvHD organ GvHD treatmentsa Outcome
Ge02 61, M Lymphoma Digestive, skin CSA, tacrolimus, corticosteroids, sirolimus, budenoside, photopheresis Death (GvHD-related)
Ge05 23, M Lymphoma Digestive, skin, lung CSA, MMF, tacrolimus, corticosteroids Death
Ge07 60, M ALL Digestive Tacrolimus, corticosteroids, photopheresis Death
Ge09 65, M AML Liver, digestiveb CSA, corticosteroids, tocilizumab Death
Ge12 44, M MM Digestive, liver CSA, corticosteroids, basiliximab, MMF Death
Ge14 31, M AML Digestive, liver Corticosteroids Death
Ge22 68, M MDPS Digestive, skin CSA, tacrolimus, corticosteroids, vedolisumab, prolastin Death
Age at the time of transplantation
Abbreviations: GvHD graft-versus-host disease, M male, ALL acute lymphoid leukemia, AML acute myeloid leukemia, MM multiple myeloma, MDPS myelodysplasic proliferative syndrome, CSA cyclosporine A, MMF mycophenolate mofetil
aAll patients had ruxolitinib as part of the GvHD treatment
bDigestive GvHD was not confirmed by biopsies
mNGS identifications of these clinically unrecognized viral sequences were confirmed by r(RT-)PCR in unpooled plasma samples. Whenever available during/after the period of sample selection, additional specimens and/or tissue biopsies were screened over a median period of 7.1 weeks (IQR 25.3). These findings are shown in Table 3.
Table 3 mNGS and r(RT-)PCR results of 7 patients with clinically unrecognized viral sequences
Viral species detected with mNGS Viral species confirmed with r(RT)-PCR assays
Patient’s code Virus Plasma, n (pos/total) Time period (days) Estimated viral load (mean log10 copies/ml plasma or CT values) Other positive biological specimen
Ge02 HPyV7 14/14 279 4.75 BM, BAL
Ge05 Usutu virus 2/5 7 4.66 –
Ge07 Cutavirus 6/10 98 37.9 Skin
Ge09 Bufavirus 6/12 81 3.73 Stools, duodenum
Ge12 Novel human astrovirus MLB2 2/6 14 3.24 Intestine, colon, BM
Ge14 Rubella virus 3/5 39 37.9 –
Classic human astrovirus 5/11 25 5.56 –
HPyV6 11/11 74 3.76 –
Ge22 Rubella virus 2/8 3 36.7 –
Pos/total corresponds to the number of positive samples on the total of screened samples. Time period corresponds to the time period during which samplings were found positive. CT values above 40 were considered negative. CT values are indicated in italics
Abbreviations: BM bone marrow, BAL bronchoalveolar lavage, CT cycle threshold
Brief clinical description of patients harboring clinically unrecognized viral sequences
Ge02: HPyV-7
A 61-year-old male, transplanted for lymphoma, developed digestive and skin GvHD; intensive immunosuppression for GvHD lasted from 12 to 16 months after transplantation (4-month sample period), when the patient died from a post-transplant EBV-related lymphoma disease. Beginning 9 months before death, we found HPyV-7 in all screened plasma samples. In addition, HPyV-7 was also found in a BAL and a bone marrow sample collected 8 months after transplantation (2.8 log10 DNA copies/ml and CT value 28, respectively).
Ge05: Usutu virus
A 23-year-old male, transplanted for lymphoma, developed digestive skin and lung GvHD; intensive immunosuppression for GvHD lasted from 1 to 24 months after transplantation (22-month sample period), when the patient died from a disseminated fungal infection and GvHD. We found Usutu virus in 2 plasma samples collected 7 days apart, a few days after a blood transfusion, and 1.5 months before death.
Ge07: cutavirus
A 60-year-old male, transplanted for acute lymphoblastic leukemia, developed digestive GvHD; intensive immunosuppression for GvHD lasted from 6 to 8 months after transplantation (2-month sample period), when the patient died from a disseminated fungal infection and GvHD. We found cutavirus in a skin biopsy performed 3 weeks before transplantation (CT of 35) and at low plasma VL for 3 months before death. Autopsy results confirmed digestive GvHD and a disseminated mold infection.
Ge09: bufavirus
A 65-year-old male, transplanted for acute myeloid leukemia (AML), developed liver GvHD; intensive immunosuppression for GvHD lasted from 5 to 7 months after transplantation (2 month sample period), when the patient died from GvHD. We detected bufavirus RNA in several plasma samples taken over 2 months before death. In addition, bufavirus was also found in stool samples collected the day of and 1.5 months after transplantation, at CT values of 38.2 and 34.7, respectively, and in a duodenal biopsy performed 5 months after transplantation (CT value 27.3), which revealed chronic duodenitis.
Ge12: HAstV MLB2
A 44-year-old male, transplanted for multiple myeloma, developed a digestive and liver GvHD; intensive immunosuppression for GvHD lasted from 15 days to 2 months after transplantation (2-month sample period), when the patient died from the GvHD. We detected HAstV MLB2 RNA in two plasma samples collected 14 days apart and shortly before death, in a colonic biopsy performed few days before death (CT value 27.9), and in several intestine, colonic, and bone marrow autopsy samples (mean CT values 25.8, 27.6, 28, respectively). Autopsy results confirmed liver and digestive GvHD and revealed chronic pulmonary GvHD.
Ge14: rubella virus, classic HAstV, HPyV-6
A 31-year-old male of Chinese origin, transplanted for AML, developed digestive and liver GvHD; intensive immunosuppression for GvHD lasted 9–11 months after transplantation (3-month sample period), when the patient died from an acute intestinal perforation in the context of recurrent digestive GvHD. In several plasma samples starting 1 month before death, we found classic HAstV RNA and low VLs of a wild-type Chinese rubella strain. HPyV-6 DNA was also persistently found in plasma samples starting 2 months before death. The patient was seropositive for rubella before transplantation.
Ge22: rubella virus
A 68-year-old Portuguese male, transplanted for myelodysplastic syndrome, developed digestive and skin GvHD; intensive immunosuppression for GvHD lasted from 4 to 6 months after transplantation (6-week sample period), when the patient died from GvHD. Two plasma samples were positive for rubella-vaccine RNA at low VLs. The patient was seropositive before transplantation.
Discussion
We analyzed viral sequences by mNGS in pooled plasma samples of 25 adult allo-HSCT patients with severe steroid-refractory/dependent GvHD. Viral nucleotide sequences were found in 96% of patients, and 64% of patients had ≥ 3 distinct viral species. Besides commensal (Anelloviridae and HPgV-1) and latent (EBV, CMV, HSV-1, BKPyV, JCPyV) viruses known to be highly prevalent/reactivate in allo-HSCT recipients, 28% of patients had clinically unrecognized viral sequences that are rarely/never reported in allo-HSCT patients, with unknown pathogenicity (bufavirus, cutavirus, HPyV-6/7, novel HAstV-MLB2, classic HAstV, rubella virus, and Usutu virus). Chronic HBV and HEV infections were also confirmed by mNGS in two patients.
Anelloviridae (TTV, TTMV, and TTMDV) were the most prevalent in this study, concordant with the high TTV viremia rate identified among allo-HSCT recipients [28–31]. The high TTV, TTMV, and TTMDV co-detection rate has been previously described [30]. Chronic anelloviruses infection/re-infection is common, but disease associations remain undetermined [32]. Among allo-HSCT recipients, two studies failed to demonstrate any association between TTV viremia and immune-related complication or other viral reactivations [28, 33], while a third reported higher TTV viremia in patients receiving corticosteroids for GvHD [29]. A recent study found higher TTV VL at 100 days post-transplantation predicts worse overall survival, and a higher risk of acute GvHD and infections [34]. Finally, a mNGS study revealed increased detection rates and number of Anelloviridae sequences in stool samples of allo-HSCT recipients several weeks after developing digestive GvHD [5], suggesting a consequence of GvHD-associated inflammation and/or immunosuppressive therapy. Altogether, these data suggest that TTV viremia could be a potential immunosuppression-marker, requiring further investigation.
HPgV-1 (a Flaviviridae [35]) viremia occurs in 1–4% of blood donors in developed countries [36] and up to 30% of allo-HSCT recipients but has not been associated with clinical consequences [3, 4]. Given the interaction of HPgV-1 with the immune system [37], the effect of persistent HPgV-1 viremia requires deeper investigation.
We found four species of HPyV (JCPyV, BKPyV, HPyV-6/7), with JCPyV viremia occurring in 16% of allo-HSCT recipients, agreeing with studies where concomitant use of multiple immunosuppressive treatments was associated with increased persistent viremia risk—although progressive multifocal leucoencephalopathy was rare [38]. In another study, JCPyV DNA detection rate in plasma decreased from 4/22 to 1/22 patients at 3 and 12–18 months after transplantation, respectively, while viremia was not linked to any clinical manifestation [39]. Our study’s BKPyV prevalence (28%) was lower than the 54% of another study [40]. Notably, our patients did not develop hemorrhagic cystitis.
Contamination or other bioinformatics errors were excluded for each of the clinically unrecognized viral sequences, by confirming the mNGS-identified viral sequences using r(RT-)PCR on blood and non-blood samples at different time-points. These assays found cutavirus (60%) and bufavirus (50%), two Protoparvoviruses, in plasma samples at low VL. Interestingly, available skin and digestive biopsy tissues, previously described as putative primary infection sites [24, 41, 42], were positive by PCR at or shortly before transplantation, indicating viral latency and reactivation under immunosuppressive conditions. Bufavirus was first discovered in stool samples of children in 2012, and the stool prevalence is about 0.3–4.1%, although high seroprevalence was identified in some countries [41, 42]. Bufavirus was recovered in stools of subjects with digestive symptoms, but not in asymptomatic controls [41]. Whether bufavirus influences syndromes attributed to digestive GvHD remains unknown. Cutavirus was discovered in 2016 in stools of diarrheic children in Brazil with a prevalence of about 1–1.6%, and curiously, some associations were made with cutaneous T cell lymphoma [24, 41]. To our knowledge, cutavirus and bufavirus viremia have not been described before.
Usutu virus (a Flaviviridae) is an arbovirus, endemic in Africa and several European countries, that frequently co-circulates with West Nile virus [43–45]. The virus enzootic cycle involves birds (main reservoir) and ornithophilic mosquitos (vectors); humans are incidental and dead-end hosts [43]. Less than 50 documented cases of acute Usutu virus infections have been reported in humans, most of them corresponding to the identification of Usutu virus genome in donated blood samples [45]. Human Usutu virus infection can be asymptomatic or associated with various clinical manifestations, including fever, rash, and neurological manifestations; the virus genome was detected in some cases in CSF or blood samples [43, 45, 46]. The virus can infect neurons, astrocytes, microglia cells, and induced pluripotent stem cell (IPSc)-derived human neuronal stem cells, with a reduction in cell proliferation, induction of antiviral response, and apoptosis [47]. In our study, Usutu virus was transiently identified shortly after a blood transfusion, but retrospective blood bag testing was impossible. Although blood transmission has not been described, screening over ≥ 130,000 blood donations revealed 38 positive donors [48, 49]. Although overt clinical consequences are absent in our patient, this flavivirus is known to cause occasional complications [45] and cannot be disregarded. If transmission occurred by transfusion, it is possible that only remnant RNA was transmitted, not infectious virus.
Astroviruses are well-recognized enteric viruses infecting mainly children, elderly, and immunocompromised patients [50]. HAstV MLB2 was identified a decade ago [51], and since then, it has been demonstrated that it is circulating in every continent [50]. In addition, it is associated with systemic and central nervous system infections [7, 52] and has been identified in stool samples of asymptomatic children [53]. In our mNGS study, classic HAstV was found in plasma samples of a patient with digestive GvHD shortly before death, and HAstV MLB2 was found at low VL in plasma samples of a patient with diarrhea due to digestive GvHD. In the latter, autopsy confirmed the presence of HAstV MLB2 RNA in several intestinal and colonic samples at significant VLs. The presence of astrovirus MLB2 in the digestive tract of the patient is thus evident, and HAstV viremia plausibly came from an intestinal spillover in the context of the GvHD and intestinal perforation.
HPyV-6 and 7 were discovered in 2010 [54] and have been identified in a wide range of clinical samples of healthy subjects, transplant recipients, and symptomatic immunocompetent patients [55–59]. They have been detected mostly in skin specimens of non-transplanted individuals and transplanted recipients with or without dermatological diseases, but the association with clinical manifestation is not established [55, 57, 59–61]. The reported seroprevalence rates of HPyV6 and HPyV7 in immunocompetent and immunocompromised adults varies from 69 to 84% and 35 to 72%, respectively [3]. The transmission route, tropism, pathogenic mechanisms, and potential association with human diseases are still not established. HPyV-6 DNA prevalence in healthy blood donors is 0.1% and 0.6% in kidney transplant recipients [3], while HPyV-7 has been detected in lung transplant recipients [3], yet no obvious clinical manifestations are associated with them. We report persistent HPyV-6/7 viremia in plasma samples of 2/25 allo-HSCT recipients over several months. Further investigations are needed to determine their pathogenicity.
Rubella virus was our most unexpected finding, yet the rubella reads for both patients mapped to different regions along the genome (rubella virus genome coverage of 3.69% and 5.47% for patients Ge14 and Ge22, respectively) and mNGS results were confirmed by specific rRT-PCR in several samples over a period of 39 and 3 days for patients Ge14 and Ge22, respectively.
Although rubella can persist in in vitro and animal models [62–64], it is not known to persist after vaccination or natural infection in humans, except in vaccinated immuno-deficient children [65–68]. Chronic rubella infection has also been hypothesized as causing Fuch’s heterochromic iridocyclitis, although the pathophysiology remains unknown [69, 70]. We found rubella sequences with low VLs in two patients, each with a distinct strain: a vaccine strain and a Chinese strain that was found in a patient who previously lived in China. Macrophages and keratinocytes are potential sites for rubella persistence [66], but retrospectively screened skin samples from one patient gave negative results. Both patients were seropositive before transplantation. Patients with GvHD frequently become seronegative for measles and rubella within 2 years after allo-HSCT [71]. Identification of the usual vaccine strain and a Chinese strain in a native Chinese, strongly argues for reactivation, in line with antibody loss after transplantation. Yet, we noted a decreased rubella IgG titer in one of both patients at the time of viremia, compared to the pre-transplant titers. Gonzalez et al. reported the case of a child who developed fulminant hepatitis after stem cell transplantation despite prior vaccination [72]. The hypothesis raised by the authors of a primary infection from a recently vaccinated contact implies that circulating vaccine strains in the population could be an issue for immunocompromised patients with waning antibodies. Whether rubella persistence could trigger GvHD after transplantation and where the viral reservoir would be are open questions.
A recent trial identified ruxolitinib as a second-line treatment for steroid-refractory GvHD, which has a poor prognosis and no approved clearly beneficial treatment [14, 73]: in the study, about 1/3 patients experienced a grade 3 infection, highlighting the importance of monitoring patients for infections. Our study reveals that some viral infections were overlooked by standard procedures, which may indicate that the 30% of infection risk associated with ruxolitinib could be underestimated, and raises the question of including mNGS analysis in the management of high-risk patients.
Among the 7 patients with clinically unrecognized viral sequences, most sequences were identified a few weeks before and, persisted until, patients’ deaths. Although neither the pathogenic nature of the viruses nor the clear associations with patient outcomes are proven, the identification of these viral sequences in patients’ blood during severe GvHD is relevant and reflects the altered immune response; monitoring these infections could help adjust immunosuppressive therapies. Among these patients, with nearly daily blood sample collection, such strategies could routinely be actionable by pooling plasma samples (overcoming transient viremia problems), with the aim of excluding disseminated infections before increasing immunosuppression, and unmasking a viral infection mimicking the GvHD syndrome.
The identification of HAstV and bufavirus in digestive tracts of patients with digestive GvHD may merely reflect the patient’s gut virome, but identification of enteric viruses in blood samples could indicate a disseminated infection that is triggered by GvHD inflammation or immunosuppressive treatment, which may require treatment adaptation.
These viral infections cannot be considered innocent bystanders. Most of the identified viruses can be shed asymptomatically, but certainly lead to organ disease under conditions where they become opportunistic pathogens, potentially causing unrecognized clinical features; they can also lead to a clinical exacerbation. The particular immunologic state of our population may influence this delicate balance between an indolent virus and its clinical impact.
A major limitation of this study is the small monocentric cohort. Additionally, including only allo-HSCT recipients with steroid-refractory/dependent GvHD precluded generalization of the results to all allo-HSCT recipients. Furthermore, we lacked control patients without GvHD. Despite the numerous viral infections revealed by mNGS, whether these are specific to patients with GvHD or to those treated with ruxolitinib, and if there is an association with clinical manifestations and/or an impact on the immune state of these patients, remains to be determined by appropriate studies. Notably, according to the comparison with routine diagnostic results and confirmatory r(RT-)PCR, our mNGS pipeline is accurate, although with a lower sensitivity compared to specific quantitative real-time PCR assays used in most routine laboratories.
Conclusions
Blood analysis of patients with steroid-refractory/dependent GvHD revealed clinically unrecognized viral sequences in 28% of patients, including rubella virus, novel protoparvoviruses, HPyV-6/7, Usutu virus, and HAstV-MLB2. These viruses have been described in humans, but rarely reported as causes of disease in allo-HSCT patients, or have unknown pathogenicity. Rubella virus identifications imply possible re-emergence from past infection or vaccination. Further investigations are needed to understand the clinical significance of these infections.
Supplementary Information
Additional file 1: Table S1. Detailed mNGS results per patient for the 25 adult allo-HSCT patients. Table S2. Comparison of mNGS results on the pooled plasma samples and of the routine r(RT-)PCR results on the corresponding plasma samples of the 25 patients. Figure S1. Boxplot of mapped reads of DNA viruses and corresponding mRNA detection with mNGS. The vertical axis represents the number of mapped reads. The horizontal axis represents all identified viral sequences of DNA viruses (left panel) and corresponding mRNA sequences (right panel). The numbers on the horizontal axis represent the number of patients in which sequences of each virus were identified. Abbreviations: HSV-1: herpes simplex 1 virus; CMV: cytomegalovirus; EBV: Epstein-Barr virus; TTMDV: torque teno midivirus; TTMV: torque teno minivirus; TTV: torque teno virus.
Publisher’s Note
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L. Kaiser and D. L. Vu contributed equally to this work.
Acknowledgements
The authors would like to thank Fiona Pigny for technical assistance and Erik Boehm for editorial assistance.
Authors’ contributions
MCZ, DLV, SC, and LK designed the research project. GV, MD, FL, and SC performed the mNGS and sequence analysis and r(RT-)PCR assays. VB, TAM, and JAL performed the biopsies histological examination. CVD, SML, and YC contributed to the interpretation of data regarding transplantation. MCZ, DLV, and SC collected and interpreted the data and wrote the first draft of the manuscript. All other authors revised and commented on the manuscript. The authors read and approved the final manuscript.
Funding
This work was supported by the “Projets Recherche et Développement (PRD)” of Geneva University Hospitals (grant number PRD 17-2019-I) and the Swiss National Science Foundation (grant number 320030_179507).
Availability of data and materials
The datasets generated and/or analyzed during the current study are available in the Dryad repository (10.5061/dryad.0k6djh9xp). The raw sequence data were deposited in the NCBI Sequence Read Archive under BioProject accession number PRJNA641787.
Ethics approval and consent to participate
The study protocol was approved by the Geneva Cantonal Ethics Commission (project #2019-00511).
Consent for publication
Not applicable
Competing interests
The authors declare that they have no competing interests. | CYCLOSPORINE, MYCOPHENOLATE MOFETIL, TACROLIMUS | DrugsGivenReaction | CC BY | 33487167 | 18,939,834 | 2021-01-24 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Chronic hepatitis'. | Unmasking viral sequences by metagenomic next-generation sequencing in adult human blood samples during steroid-refractory/dependent graft-versus-host disease.
Viral infections are common complications following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Allo-HSCT recipients with steroid-refractory/dependent graft-versus-host disease (GvHD) are highly immunosuppressed and are more vulnerable to infections with weakly pathogenic or commensal viruses. Here, twenty-five adult allo-HSCT recipients from 2016 to 2019 with acute or chronic steroid-refractory/dependent GvHD were enrolled in a prospective cohort at Geneva University Hospitals. We performed metagenomics next-generation sequencing (mNGS) analysis using a validated pipeline and de novo analysis on pooled routine plasma samples collected throughout the period of intensive steroid treatment or second-line GvHD therapy to identify weakly pathogenic, commensal, and unexpected viruses.
Median duration of intensive immunosuppression was 5.1 months (IQR 5.5). GvHD-related mortality rate was 36%. mNGS analysis detected viral nucleotide sequences in 24/25 patients. Sequences of ≥ 3 distinct viruses were detected in 16/25 patients; Anelloviridae (24/25) and human pegivirus-1 (9/25) were the most prevalent. In 7 patients with fatal outcomes, viral sequences not assessed by routine investigations were identified with mNGS and confirmed by RT-PCR. These cases included Usutu virus (1), rubella virus (1 vaccine strain and 1 wild-type), novel human astrovirus (HAstV) MLB2 (1), classic HAstV (1), human polyomavirus 6 and 7 (2), cutavirus (1), and bufavirus (1).
Clinically unrecognized viral infections were identified in 28% of highly immunocompromised allo-HSCT recipients with steroid-refractory/dependent GvHD in consecutive samples. These identified viruses have all been previously described in humans, but have poorly understood clinical significance. Rubella virus identification raises the possibility of re-emergence from past infections or vaccinations, or re-infection. Video abstract.
Background
Viral primary infections and reactivations are common complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and are associated with significant morbidity and mortality [1, 2]. Current routine clinical surveillance molecular assays detect specific nucleotide sequences targeting usual culprits including Epstein-Barr virus (EBV), cytomegalovirus (CMV), BK polyomavirus (BKPyV), and adenovirus [3]. Metagenomic next-generation sequencing’s (mNGS) unbiased approach broadens viral infection diagnosis, theoretically detecting “all” viral nucleotide sequences or viral infections present [4–7], and is increasingly used in clinical investigations [8]. Allo-HSCT recipients suffering from steroid-refractory/dependent acute or chronic graft-versus-host disease (GvHD) are highly immunosuppressed patients; GvHD immune dysregulation, mucosal barrier alteration [9–13], and multiple prolonged immunosuppressive treatments create a permissive environment for opportunistic viral infections [10, 11, 14]. These clinically unrecognized viral infections can present with limited symptoms/atypical manifestations and lead to intermittent or prolonged viremia [3]. Given the nonspecific clinical features of GvHD and some viral infections, viral infections may remain clinically unrecognized due to limitations of clinical molecular assays.
We hypothesized that some viral infections, which would normally remain undiagnosed with common clinical assays, occur during intense immunosuppressive therapy in steroid-refractory/dependent GvHD. This study aimed to identify viruses that are not routinely searched by RT-PCR routine assays in clinical practice, due to the lack of knowledge. Therefore, we used mNGS on pooled plasma samples of adult allo-HSCT patients with steroid-refractory/dependent acute or chronic GvHD to look for viruses that could be missed by biased technology.
Methods
Setting, study population, and design
This observational study was conducted at the Geneva University Hospitals (HUG), Switzerland. The study protocol was approved by the Geneva Cantonal Ethics Commission (project #2019-00511). Inclusion criteria were adult patients who received an allo-HSCT from 1 January 2016 to 31 December 2018 at the HUG, who were enrolled in the local monocentric infectious disease cohort of allo-HSCT patients, and who developed steroid-refractory/dependent acute or chronic GvHD. All included patients provided written consent before enrollment. The only exclusion criteria was the lack of informed written consent.
Plasma samples were prospectively collected during clinical management after allo-HSCT and stored in the Laboratory of Virology, HUG. We performed mNGS analysis on pooled plasma samples of each patient, collected throughout the period of intensive steroid treatment or second-line GvHD therapy.
Definitions
Steroid-refractory/dependent acute and chronic GvHD were defined according to the position statement of the GvHD experts in Schoemans et al. [15].
Microbiological methods
mNGS and sequence analysis
Each pool (corresponding to 4 to 10 plasma samples from each patient) was prepared to obtain a final volume of 220 μl. Pools were then centrifuged at 10,000×g for 10 min to remove cells. Two-hundred microliters of cell-free supernatant were treated with 20 μl of Turbo DNAse (2 U/μl) + 24 μl of 10x TURBO DNase Buffer (Ambion, Rotkreuz, Switzerland), according to the manufacturer’s instructions. Then, the whole volume was divided into two tubes of 120 μl each. One tube was then used for each of the two nucleic acid extraction procedures. Indeed, virus genome extractions were done using two previously published protocols in parallel [16], namely the RNA and DNA protocols optimized for the detection of RNA and DNA viral sequences, respectively.
For the RNA protocol, nucleic acids were extracted with TRIzol (Invitrogen, Carlsbad, CA, USA). Ribosomal RNA was removed (Ribo-Zero Gold depletion kit (Illumina, San Diego, USA) before libraries’ preparation (TruSeq total RNA preparation protocol (Illumina)). Libraries’ concentrations and sizes were analyzed using the Qubit (Life Technologies, Carlsbad, CA, USA) and the 2200 TapeStation instruments (Agilent, SantaClara, CA, USA), respectively. Each library was loaded individually in a single lane on the HiSeq 4000 platform (Illumina) using the 2 × 100-bp protocol with dual-indexing. The mean total number of read pairs obtained per pool was 328,936,594.84 (range 252,670,103 to 385,257,539).
For the DNA protocol, nucleic acids were extracted with the NucliSens easyMAG magnetic bead system (bioMérieux, Geneva, Switzerland). As previously published [16], double-stranded DNA synthesis was done with the DNA polymerase I, Large Fragment (Klenow) (New England BioLabs, Ipswich, MA, USA)). Libraries were prepared using the Nextera XT (Illumina) protocol. Libraries’ concentrations and sizes were analyzed using the Qubit (Life Technologies) and the 2200 TapeStation instruments (Agilent), respectively. Each library was loaded individually in a single lane on the HiSeq 4000 platform (Illumina) using the 2 × 100-bp protocol with dual-indexing. The mean total number of read pairs obtained per pool was 301,393,033.48 (range 122,939,325 to 377,758,795).
To check for potential contaminating viral sequences from environment or experimental reagents [17], four negative controls (i.e., Neg1-4) were submitted to the whole mNGS procedure. To assess the mNGS process efficiency, positive controls underwent the whole mNGS procedure (canine distemper virus (CDV)-spiked samples and a baculovirus (GenScript, Piscataway, NJ, USA) harboring 793 nucleotides of the CDV fusion gene were used as positive controls for the RNA and DNA protocols, respectively).
Paired reads were quality filtered using Trimmomatic [18]. Reads mapped against the human genome and transcriptome (hg38, gencode.V23) were removed using SNAP [19]. Remaining reads were analyzed using two methods in parallel as previously described [20]: (1) by a pipeline that used virusscan 1.0 (https://github.com/sib-swiss/virusscan) to map reads against the Virosaurus database (version V90v_2018_11) (https://viralzone.expasy.org/8676), which is designed to report vertebrate viruses, and (2) by de novo assembly. Only viruses with ≥ 300 nucleotides of coverage were reported. The raw sequence data were deposited in the NCBI Sequence Read Archive under BioProject accession number PRJNA641787.
Sequences were considered clinically recognized viruses if they corresponded to a virus known to reactivate in/be frequently found among allo-HSCT recipients [2, 4] or if the patient had a known chronic viral infection and clinically unrecognized viruses if not.
Confirmatory real-time (reverse transcription-)polymerase chain reaction (r(RT-)PCR) assays
Clinically unrecognized mNGS findings were confirmed on unpooled plasma by specific semi-quantitative or quantitative r(RT-)PCR assays as previously published; additional specimens (including plasma, cerebrospinal fluid, bronchoalveolar lavage (BAL) fluids, nasopharyngeal swabs, native urines, stools suspension, tissue biopsies or bone marrow) were tested when available and pertinent. Quantitative r(RT-)PCR assays were done for Mamastrovirus 1 (classical) using the updated human astrovirus (HAstV) combination [21], Mamastrovirus 6 (MLB2) using the MLB2 assay [22], Usutu virus [23], and bufavirus using the BuV (NS1) assay [24]. Semi-quantitative r(RT-)PCR assays were done for cutavirus using the CuV (VP2) assay [24], human polyomavirus (HPyV) 6 using the VP2 assay [25], HPyV-7 using the VP2 assay [25], and rubella virus [26].
Nucleic acids from plasma, cerebrospinal fluid, BAL fluids, nasopharyngeal swabs, urine, stools resuspended in PBS, and bone marrow were extracted individually from 190 μL of each specimen, spiked with 10 μL of standardized CDV as internal control [27], using the NucliSENS easyMAG (bioMérieux, Geneva, Switzerland) nucleic acid kit, according to the manufacturer’s instructions, and eluted in 25 μL. DNA and RNA were extracted from tissue biopsies using the QIAamp DNA FFPE Tissue Kit (Qiagen, Hombrechtikon, Switzerland) and High Pure FFPET RNA isolation kit (Roche Applied Sciences, Indianapolis, IN, USA), respectively, following the manufacturer’s instructions. For RNA viruses, the rRT-PCR assays were performed using the one-step QuantiTect Probe RT-PCR Kit (Qiagen, Hombrechtikon, Switzerland) in a StepOne Plus instrument (Applied Biosystems, Rotkreuz, Switzerland). For DNA viruses, the rPCR assays were performed using the TaqMan Universal PCR Master Mix (Applied Biosystems) in a StepOne Plus instrument (Applied Biosystems) for cutavirus and bufavirus or in a QuantStudio 5 instrument (Applied Biosystems) for HPyV6 and 7.
For quantitative r(RT)-PCR assays, standard curves and lower limit of quantifications (LOQ) were assessed using 10-fold serial dilutions of specific RNA oligonucleotides (Mamastrovirus 1 (classical) and 6 (MLB2): LOQ = 1.25E4 and 1.25E3 RNA copies/ml of plasma, respectively), RNA transcript (Usutu virus: LOQ = 1.32E2 RNA copies/ml of plasma), DNA oligonucleotides (bufavirus: LOQ = 1.32E3 DNA copies/ml of plasma), or plasmids (HPyV6 and 7: LOQ = 2.63E2 DNA copies/ml of plasma each) containing the target sequences.
Statistical analysis
Categorical variables were described by counts and percentages. Continuous variables were expressed as mean and standard deviation or median and interquartile range.
Results
Patient characteristics
We identified 25 adult allo-HSCT recipients with acute or chronic steroid-refractory/dependent GvHD. Table 1 shows the patient’s characteristics. The median duration of intensive immunosuppression was 5.1 months (IQR 5.5), and 22/25 patients received ruxolitinib. At the time of writing, fifteen patients have died, with 9 considered as GvHD-related.
Table 1 Patients’ characteristics (25 allo-HSCT patients)
Total
n = 25
Demographics
Sex (male), n (%) 16 (64.0)
Age, median (IQR) 58.0 (25.0)
Allo-HSCT considered in the analysis,
n
(%)
First 23 (92.0)
Second 2 (8.0)
Transplant source,
n
(%)
Bone marrow 5 (20)
Peripheral blood cells 20 (80)
Underlying disease,
n
(%)
Acute myeloid leukemia 10 (40.0)
Lymphoid malignancy 6 (24.0)
MDS/MDPS 3 (12.0)
Acute lymphoid leukemia 2 (8.0)
Othera 4 (16.0)
Risk score,
n
(%)
Low 0 (0)
Intermediate 18 (72.0)
High 7 (28.0)
Donor sex, M,
n
(%) 7 (28.0)
Donor age, median (IQR) 36 (16.5)
Donor match,
n
(%)
Donor-related 10 (40.0)
CMV donor/recipient constellation,
n
(%)
+/+ 12 (48.0)
−/+ 1 (4.0)
+/− 7 (28.0)
−/− 5 (20.0)
CMV prophylaxis, n (%) 1 (4.0)
Conditioning,
n
(%)
Myeloablative conditioning 5 (20.0)
GvHD prophylaxis,
n
(%)
Calcineurin inhibitor 24 (96.0)
Mycophenolate mofetil 17 (68.0)
Methotrexate 7 (28.0)
GvHD organ,
n
(%)
Digestive tract 17 (68.0)
Skin 15 (60.0)
Mouth 4 (16.0)
Liver 7 (28.0)
Lung 5 (20.0)
Eyes 2 (8.0)
Musculoskeletal 1 (4.0)
GvHD grade or severity,
n
(%)
Grade
2 9 (36.0)
3 3 (12.0)
4 6 (24.0)
Moderate 6 (24.0)
Severe 7 (28.0)
GvHD treatment,
n
(%)
Corticosteroids 24 (96.0)
Ruxolitinib 22 (88.0)
Calcineurin inhibitor 21 (84.0)
Mycophenolate mofetil 12 (48.0)
Photopheresis 12 (48.0)
Budenoside 5 (20.0)
Sirolimus 3 (12.0)
Tocilizumab 2 (8.0)
Otherb 6 (24.0)
Death,
n
(%) 15 (60.0)
Median delay from allo-HSCT, months (IQR) 11.2 (15.8)
One patient could have multiple GvHD prophylaxis and treatment, multiple organs with GvHD and multiple grades of severity. CMV prophylaxis: one patient (patient Ge24) received letermovir during the period of intensive steroid treatment or second-line GvHD therapy. GvHD grade refers to acute GvHD, GvHD severity refers to chronic GvHD. In two patients, there was no information on grade/severity. Only organs with grade GvHD ≥ 2 or severity ≥ moderate are reported
Abbreviations: IQR interquartile range, allo-HSCT allogeneic hematopoietic stem cell transplantation, MDS/MDPS myelodysplasic syndrome/myelodysplasic proliferative syndrome, ATG anti-thymocyte globulin
aOther includes: multiple myeloma (n = 2), chronic myeloid leukemia (n = 1) and mixed acute leukemia (n = 1)
bOther includes: azithromycine, montelukast, prolastin, vedolisumab, nilotinib, basilixumab, ibrutinib, and/or methotrexate
Viral sequences identified with mNGS and confirmatory analyses
The mNGS analysis revealed viral nucleotide sequences in all patients except Ge18 (24/25). In 16/25 patients, ≥ 3 distinct viral species were detected (Fig. 1). Figure 2 depicts the prevalence of each identified virus, and Table S1 provides detailed mNGS characteristics.
Fig. 1 Grid plot of viral sequences identified with mNGS in pooled plasma samples (25 allo-HSCT patients). Each line corresponds to viral sequences assigned to one virus; the bottom line corresponds to mNGS negative (Neg1-4) and positive (Pos1/2 DNA/RNA) control samples. Each column corresponds to one pool of plasma sample (one patient). Colors represent the approximate number of reads matching virus genome detected in each pool of plasma samples. *Since they were detected in one negative control, human papillomavirus sequences were considered as likely contaminant. # cross-contamination. Abbreviations: HAstV human astrovirus, TTV torque teno virus, TTMV torque teno minivirus, TTMDV torque teno midivirus, HSV-1 herpes simplex 1 virus, EBV Epstein-Barr virus, CMV cytomegalovirus, CTRL control
Fig. 2 Prevalence of viruses identified with mNGS in pooled plasma samples (25 allo-HSCT recipients). The vertical axis represents all identified viral sequences. The horizontal axis represents the number of patients in which sequences of each virus were identified. Abbreviations: TTV torque teno virus, TTMV torque teno minivirus, CMV cytomegalovirus, TTMDV torque teno midivirus, EBV Epstein-Barr virus, HSV-1 herpes simplex 1 virus, HAstV human astrovirus
Anelloviridae (torque teno virus (TTV), torque teno minivirus (TTMV) and torque teno midivirus (TTMDV)) and human pegivirus-1 (HPgV-1) were the most prevalent with sequences detected in 24/25 and 9/25 patients, respectively.
Other detected DNA viruses included BK polyomavirus (BKPyV) (7/25), CMV (5/25), and JC polyomavirus (JCPyV) (4/25), and also herpes simplex virus 1 (HSV-1), EBV, hepatitis B virus (HBV), bufavirus, cutavirus, and HPyV-6/7, each detected once (1/25). Except HPgV-1, the detected RNA viruses were less prevalent than DNA viruses and were HAstV (Mamastrovirus 1 and 6) and rubella virus, both detected twice (2/25), and also hepatitis E (HEV) and Usutu viruses, both detected once (1/25). The de novo analysis did not reveal other relevant sequences. Interestingly, sequences for TTV (11/24), CMV (3/5), EBV (1/1), and HBV (1/1) were detected in both DNA and RNA libraries, suggesting active viral replication (Figure S1).
Clinically recognized viral sequences
Although not routinely searched in clinical practice, Anelloviridae and HPgV-1 sequences were identified in 96% and 36% of patients and were classified among clinically recognized viral sequences as they are known to be highly prevalent among immunocompromised patients. In 14/25 patients, mNGS analysis identified sequences of latent DNA viruses known to reactivate in transplant recipients (EBV, CMV, HSV-1, BKPyV, JCPyV, HBV). At the RNA level, HEV was identified once.
The r(RT-)PCR assays performed during routine investigations confirmed the mNGS analysis (Table S2): patient Ge05 had a chronic HEV infection, and patient Ge14 had chronic HBV and cutaneous HSV-1 infections, and HSV-1 viremia. BKPyV and JCPyV were not systematically screened and were only revealed by mNGS analysis. However, BKPyV was screened in patient Ge06 and detected at low viral loads (VL) (1.41E2 and 1.44E3 copies/ml) in two plasma samples collected a few days apart from those included for mNGS analysis. In 12/25 patients, CMV and EBV were detected only by rPCR at low VL; no other expected virus was detected by routine molecular assays.
Clinically unrecognized viral sequences
We found clinically unrecognized sequences belonging to either rare and/or recently identified viruses (HAstV MLB2, Usutu virus, bufavirus, cutavirus, HPyV-6, and HPyV-7) or those not routinely assessed alongside GvHD (classic HAstV and rubella virus) in 7/25 patients, whose characteristics are detailed in Table 2.
Table 2 Clinical characteristics of 7 patients with clinically unrecognized viral sequences
Patient’s code Age, gender Underlying disease GvHD organ GvHD treatmentsa Outcome
Ge02 61, M Lymphoma Digestive, skin CSA, tacrolimus, corticosteroids, sirolimus, budenoside, photopheresis Death (GvHD-related)
Ge05 23, M Lymphoma Digestive, skin, lung CSA, MMF, tacrolimus, corticosteroids Death
Ge07 60, M ALL Digestive Tacrolimus, corticosteroids, photopheresis Death
Ge09 65, M AML Liver, digestiveb CSA, corticosteroids, tocilizumab Death
Ge12 44, M MM Digestive, liver CSA, corticosteroids, basiliximab, MMF Death
Ge14 31, M AML Digestive, liver Corticosteroids Death
Ge22 68, M MDPS Digestive, skin CSA, tacrolimus, corticosteroids, vedolisumab, prolastin Death
Age at the time of transplantation
Abbreviations: GvHD graft-versus-host disease, M male, ALL acute lymphoid leukemia, AML acute myeloid leukemia, MM multiple myeloma, MDPS myelodysplasic proliferative syndrome, CSA cyclosporine A, MMF mycophenolate mofetil
aAll patients had ruxolitinib as part of the GvHD treatment
bDigestive GvHD was not confirmed by biopsies
mNGS identifications of these clinically unrecognized viral sequences were confirmed by r(RT-)PCR in unpooled plasma samples. Whenever available during/after the period of sample selection, additional specimens and/or tissue biopsies were screened over a median period of 7.1 weeks (IQR 25.3). These findings are shown in Table 3.
Table 3 mNGS and r(RT-)PCR results of 7 patients with clinically unrecognized viral sequences
Viral species detected with mNGS Viral species confirmed with r(RT)-PCR assays
Patient’s code Virus Plasma, n (pos/total) Time period (days) Estimated viral load (mean log10 copies/ml plasma or CT values) Other positive biological specimen
Ge02 HPyV7 14/14 279 4.75 BM, BAL
Ge05 Usutu virus 2/5 7 4.66 –
Ge07 Cutavirus 6/10 98 37.9 Skin
Ge09 Bufavirus 6/12 81 3.73 Stools, duodenum
Ge12 Novel human astrovirus MLB2 2/6 14 3.24 Intestine, colon, BM
Ge14 Rubella virus 3/5 39 37.9 –
Classic human astrovirus 5/11 25 5.56 –
HPyV6 11/11 74 3.76 –
Ge22 Rubella virus 2/8 3 36.7 –
Pos/total corresponds to the number of positive samples on the total of screened samples. Time period corresponds to the time period during which samplings were found positive. CT values above 40 were considered negative. CT values are indicated in italics
Abbreviations: BM bone marrow, BAL bronchoalveolar lavage, CT cycle threshold
Brief clinical description of patients harboring clinically unrecognized viral sequences
Ge02: HPyV-7
A 61-year-old male, transplanted for lymphoma, developed digestive and skin GvHD; intensive immunosuppression for GvHD lasted from 12 to 16 months after transplantation (4-month sample period), when the patient died from a post-transplant EBV-related lymphoma disease. Beginning 9 months before death, we found HPyV-7 in all screened plasma samples. In addition, HPyV-7 was also found in a BAL and a bone marrow sample collected 8 months after transplantation (2.8 log10 DNA copies/ml and CT value 28, respectively).
Ge05: Usutu virus
A 23-year-old male, transplanted for lymphoma, developed digestive skin and lung GvHD; intensive immunosuppression for GvHD lasted from 1 to 24 months after transplantation (22-month sample period), when the patient died from a disseminated fungal infection and GvHD. We found Usutu virus in 2 plasma samples collected 7 days apart, a few days after a blood transfusion, and 1.5 months before death.
Ge07: cutavirus
A 60-year-old male, transplanted for acute lymphoblastic leukemia, developed digestive GvHD; intensive immunosuppression for GvHD lasted from 6 to 8 months after transplantation (2-month sample period), when the patient died from a disseminated fungal infection and GvHD. We found cutavirus in a skin biopsy performed 3 weeks before transplantation (CT of 35) and at low plasma VL for 3 months before death. Autopsy results confirmed digestive GvHD and a disseminated mold infection.
Ge09: bufavirus
A 65-year-old male, transplanted for acute myeloid leukemia (AML), developed liver GvHD; intensive immunosuppression for GvHD lasted from 5 to 7 months after transplantation (2 month sample period), when the patient died from GvHD. We detected bufavirus RNA in several plasma samples taken over 2 months before death. In addition, bufavirus was also found in stool samples collected the day of and 1.5 months after transplantation, at CT values of 38.2 and 34.7, respectively, and in a duodenal biopsy performed 5 months after transplantation (CT value 27.3), which revealed chronic duodenitis.
Ge12: HAstV MLB2
A 44-year-old male, transplanted for multiple myeloma, developed a digestive and liver GvHD; intensive immunosuppression for GvHD lasted from 15 days to 2 months after transplantation (2-month sample period), when the patient died from the GvHD. We detected HAstV MLB2 RNA in two plasma samples collected 14 days apart and shortly before death, in a colonic biopsy performed few days before death (CT value 27.9), and in several intestine, colonic, and bone marrow autopsy samples (mean CT values 25.8, 27.6, 28, respectively). Autopsy results confirmed liver and digestive GvHD and revealed chronic pulmonary GvHD.
Ge14: rubella virus, classic HAstV, HPyV-6
A 31-year-old male of Chinese origin, transplanted for AML, developed digestive and liver GvHD; intensive immunosuppression for GvHD lasted 9–11 months after transplantation (3-month sample period), when the patient died from an acute intestinal perforation in the context of recurrent digestive GvHD. In several plasma samples starting 1 month before death, we found classic HAstV RNA and low VLs of a wild-type Chinese rubella strain. HPyV-6 DNA was also persistently found in plasma samples starting 2 months before death. The patient was seropositive for rubella before transplantation.
Ge22: rubella virus
A 68-year-old Portuguese male, transplanted for myelodysplastic syndrome, developed digestive and skin GvHD; intensive immunosuppression for GvHD lasted from 4 to 6 months after transplantation (6-week sample period), when the patient died from GvHD. Two plasma samples were positive for rubella-vaccine RNA at low VLs. The patient was seropositive before transplantation.
Discussion
We analyzed viral sequences by mNGS in pooled plasma samples of 25 adult allo-HSCT patients with severe steroid-refractory/dependent GvHD. Viral nucleotide sequences were found in 96% of patients, and 64% of patients had ≥ 3 distinct viral species. Besides commensal (Anelloviridae and HPgV-1) and latent (EBV, CMV, HSV-1, BKPyV, JCPyV) viruses known to be highly prevalent/reactivate in allo-HSCT recipients, 28% of patients had clinically unrecognized viral sequences that are rarely/never reported in allo-HSCT patients, with unknown pathogenicity (bufavirus, cutavirus, HPyV-6/7, novel HAstV-MLB2, classic HAstV, rubella virus, and Usutu virus). Chronic HBV and HEV infections were also confirmed by mNGS in two patients.
Anelloviridae (TTV, TTMV, and TTMDV) were the most prevalent in this study, concordant with the high TTV viremia rate identified among allo-HSCT recipients [28–31]. The high TTV, TTMV, and TTMDV co-detection rate has been previously described [30]. Chronic anelloviruses infection/re-infection is common, but disease associations remain undetermined [32]. Among allo-HSCT recipients, two studies failed to demonstrate any association between TTV viremia and immune-related complication or other viral reactivations [28, 33], while a third reported higher TTV viremia in patients receiving corticosteroids for GvHD [29]. A recent study found higher TTV VL at 100 days post-transplantation predicts worse overall survival, and a higher risk of acute GvHD and infections [34]. Finally, a mNGS study revealed increased detection rates and number of Anelloviridae sequences in stool samples of allo-HSCT recipients several weeks after developing digestive GvHD [5], suggesting a consequence of GvHD-associated inflammation and/or immunosuppressive therapy. Altogether, these data suggest that TTV viremia could be a potential immunosuppression-marker, requiring further investigation.
HPgV-1 (a Flaviviridae [35]) viremia occurs in 1–4% of blood donors in developed countries [36] and up to 30% of allo-HSCT recipients but has not been associated with clinical consequences [3, 4]. Given the interaction of HPgV-1 with the immune system [37], the effect of persistent HPgV-1 viremia requires deeper investigation.
We found four species of HPyV (JCPyV, BKPyV, HPyV-6/7), with JCPyV viremia occurring in 16% of allo-HSCT recipients, agreeing with studies where concomitant use of multiple immunosuppressive treatments was associated with increased persistent viremia risk—although progressive multifocal leucoencephalopathy was rare [38]. In another study, JCPyV DNA detection rate in plasma decreased from 4/22 to 1/22 patients at 3 and 12–18 months after transplantation, respectively, while viremia was not linked to any clinical manifestation [39]. Our study’s BKPyV prevalence (28%) was lower than the 54% of another study [40]. Notably, our patients did not develop hemorrhagic cystitis.
Contamination or other bioinformatics errors were excluded for each of the clinically unrecognized viral sequences, by confirming the mNGS-identified viral sequences using r(RT-)PCR on blood and non-blood samples at different time-points. These assays found cutavirus (60%) and bufavirus (50%), two Protoparvoviruses, in plasma samples at low VL. Interestingly, available skin and digestive biopsy tissues, previously described as putative primary infection sites [24, 41, 42], were positive by PCR at or shortly before transplantation, indicating viral latency and reactivation under immunosuppressive conditions. Bufavirus was first discovered in stool samples of children in 2012, and the stool prevalence is about 0.3–4.1%, although high seroprevalence was identified in some countries [41, 42]. Bufavirus was recovered in stools of subjects with digestive symptoms, but not in asymptomatic controls [41]. Whether bufavirus influences syndromes attributed to digestive GvHD remains unknown. Cutavirus was discovered in 2016 in stools of diarrheic children in Brazil with a prevalence of about 1–1.6%, and curiously, some associations were made with cutaneous T cell lymphoma [24, 41]. To our knowledge, cutavirus and bufavirus viremia have not been described before.
Usutu virus (a Flaviviridae) is an arbovirus, endemic in Africa and several European countries, that frequently co-circulates with West Nile virus [43–45]. The virus enzootic cycle involves birds (main reservoir) and ornithophilic mosquitos (vectors); humans are incidental and dead-end hosts [43]. Less than 50 documented cases of acute Usutu virus infections have been reported in humans, most of them corresponding to the identification of Usutu virus genome in donated blood samples [45]. Human Usutu virus infection can be asymptomatic or associated with various clinical manifestations, including fever, rash, and neurological manifestations; the virus genome was detected in some cases in CSF or blood samples [43, 45, 46]. The virus can infect neurons, astrocytes, microglia cells, and induced pluripotent stem cell (IPSc)-derived human neuronal stem cells, with a reduction in cell proliferation, induction of antiviral response, and apoptosis [47]. In our study, Usutu virus was transiently identified shortly after a blood transfusion, but retrospective blood bag testing was impossible. Although blood transmission has not been described, screening over ≥ 130,000 blood donations revealed 38 positive donors [48, 49]. Although overt clinical consequences are absent in our patient, this flavivirus is known to cause occasional complications [45] and cannot be disregarded. If transmission occurred by transfusion, it is possible that only remnant RNA was transmitted, not infectious virus.
Astroviruses are well-recognized enteric viruses infecting mainly children, elderly, and immunocompromised patients [50]. HAstV MLB2 was identified a decade ago [51], and since then, it has been demonstrated that it is circulating in every continent [50]. In addition, it is associated with systemic and central nervous system infections [7, 52] and has been identified in stool samples of asymptomatic children [53]. In our mNGS study, classic HAstV was found in plasma samples of a patient with digestive GvHD shortly before death, and HAstV MLB2 was found at low VL in plasma samples of a patient with diarrhea due to digestive GvHD. In the latter, autopsy confirmed the presence of HAstV MLB2 RNA in several intestinal and colonic samples at significant VLs. The presence of astrovirus MLB2 in the digestive tract of the patient is thus evident, and HAstV viremia plausibly came from an intestinal spillover in the context of the GvHD and intestinal perforation.
HPyV-6 and 7 were discovered in 2010 [54] and have been identified in a wide range of clinical samples of healthy subjects, transplant recipients, and symptomatic immunocompetent patients [55–59]. They have been detected mostly in skin specimens of non-transplanted individuals and transplanted recipients with or without dermatological diseases, but the association with clinical manifestation is not established [55, 57, 59–61]. The reported seroprevalence rates of HPyV6 and HPyV7 in immunocompetent and immunocompromised adults varies from 69 to 84% and 35 to 72%, respectively [3]. The transmission route, tropism, pathogenic mechanisms, and potential association with human diseases are still not established. HPyV-6 DNA prevalence in healthy blood donors is 0.1% and 0.6% in kidney transplant recipients [3], while HPyV-7 has been detected in lung transplant recipients [3], yet no obvious clinical manifestations are associated with them. We report persistent HPyV-6/7 viremia in plasma samples of 2/25 allo-HSCT recipients over several months. Further investigations are needed to determine their pathogenicity.
Rubella virus was our most unexpected finding, yet the rubella reads for both patients mapped to different regions along the genome (rubella virus genome coverage of 3.69% and 5.47% for patients Ge14 and Ge22, respectively) and mNGS results were confirmed by specific rRT-PCR in several samples over a period of 39 and 3 days for patients Ge14 and Ge22, respectively.
Although rubella can persist in in vitro and animal models [62–64], it is not known to persist after vaccination or natural infection in humans, except in vaccinated immuno-deficient children [65–68]. Chronic rubella infection has also been hypothesized as causing Fuch’s heterochromic iridocyclitis, although the pathophysiology remains unknown [69, 70]. We found rubella sequences with low VLs in two patients, each with a distinct strain: a vaccine strain and a Chinese strain that was found in a patient who previously lived in China. Macrophages and keratinocytes are potential sites for rubella persistence [66], but retrospectively screened skin samples from one patient gave negative results. Both patients were seropositive before transplantation. Patients with GvHD frequently become seronegative for measles and rubella within 2 years after allo-HSCT [71]. Identification of the usual vaccine strain and a Chinese strain in a native Chinese, strongly argues for reactivation, in line with antibody loss after transplantation. Yet, we noted a decreased rubella IgG titer in one of both patients at the time of viremia, compared to the pre-transplant titers. Gonzalez et al. reported the case of a child who developed fulminant hepatitis after stem cell transplantation despite prior vaccination [72]. The hypothesis raised by the authors of a primary infection from a recently vaccinated contact implies that circulating vaccine strains in the population could be an issue for immunocompromised patients with waning antibodies. Whether rubella persistence could trigger GvHD after transplantation and where the viral reservoir would be are open questions.
A recent trial identified ruxolitinib as a second-line treatment for steroid-refractory GvHD, which has a poor prognosis and no approved clearly beneficial treatment [14, 73]: in the study, about 1/3 patients experienced a grade 3 infection, highlighting the importance of monitoring patients for infections. Our study reveals that some viral infections were overlooked by standard procedures, which may indicate that the 30% of infection risk associated with ruxolitinib could be underestimated, and raises the question of including mNGS analysis in the management of high-risk patients.
Among the 7 patients with clinically unrecognized viral sequences, most sequences were identified a few weeks before and, persisted until, patients’ deaths. Although neither the pathogenic nature of the viruses nor the clear associations with patient outcomes are proven, the identification of these viral sequences in patients’ blood during severe GvHD is relevant and reflects the altered immune response; monitoring these infections could help adjust immunosuppressive therapies. Among these patients, with nearly daily blood sample collection, such strategies could routinely be actionable by pooling plasma samples (overcoming transient viremia problems), with the aim of excluding disseminated infections before increasing immunosuppression, and unmasking a viral infection mimicking the GvHD syndrome.
The identification of HAstV and bufavirus in digestive tracts of patients with digestive GvHD may merely reflect the patient’s gut virome, but identification of enteric viruses in blood samples could indicate a disseminated infection that is triggered by GvHD inflammation or immunosuppressive treatment, which may require treatment adaptation.
These viral infections cannot be considered innocent bystanders. Most of the identified viruses can be shed asymptomatically, but certainly lead to organ disease under conditions where they become opportunistic pathogens, potentially causing unrecognized clinical features; they can also lead to a clinical exacerbation. The particular immunologic state of our population may influence this delicate balance between an indolent virus and its clinical impact.
A major limitation of this study is the small monocentric cohort. Additionally, including only allo-HSCT recipients with steroid-refractory/dependent GvHD precluded generalization of the results to all allo-HSCT recipients. Furthermore, we lacked control patients without GvHD. Despite the numerous viral infections revealed by mNGS, whether these are specific to patients with GvHD or to those treated with ruxolitinib, and if there is an association with clinical manifestations and/or an impact on the immune state of these patients, remains to be determined by appropriate studies. Notably, according to the comparison with routine diagnostic results and confirmatory r(RT-)PCR, our mNGS pipeline is accurate, although with a lower sensitivity compared to specific quantitative real-time PCR assays used in most routine laboratories.
Conclusions
Blood analysis of patients with steroid-refractory/dependent GvHD revealed clinically unrecognized viral sequences in 28% of patients, including rubella virus, novel protoparvoviruses, HPyV-6/7, Usutu virus, and HAstV-MLB2. These viruses have been described in humans, but rarely reported as causes of disease in allo-HSCT patients, or have unknown pathogenicity. Rubella virus identifications imply possible re-emergence from past infection or vaccination. Further investigations are needed to understand the clinical significance of these infections.
Supplementary Information
Additional file 1: Table S1. Detailed mNGS results per patient for the 25 adult allo-HSCT patients. Table S2. Comparison of mNGS results on the pooled plasma samples and of the routine r(RT-)PCR results on the corresponding plasma samples of the 25 patients. Figure S1. Boxplot of mapped reads of DNA viruses and corresponding mRNA detection with mNGS. The vertical axis represents the number of mapped reads. The horizontal axis represents all identified viral sequences of DNA viruses (left panel) and corresponding mRNA sequences (right panel). The numbers on the horizontal axis represent the number of patients in which sequences of each virus were identified. Abbreviations: HSV-1: herpes simplex 1 virus; CMV: cytomegalovirus; EBV: Epstein-Barr virus; TTMDV: torque teno midivirus; TTMV: torque teno minivirus; TTV: torque teno virus.
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L. Kaiser and D. L. Vu contributed equally to this work.
Acknowledgements
The authors would like to thank Fiona Pigny for technical assistance and Erik Boehm for editorial assistance.
Authors’ contributions
MCZ, DLV, SC, and LK designed the research project. GV, MD, FL, and SC performed the mNGS and sequence analysis and r(RT-)PCR assays. VB, TAM, and JAL performed the biopsies histological examination. CVD, SML, and YC contributed to the interpretation of data regarding transplantation. MCZ, DLV, and SC collected and interpreted the data and wrote the first draft of the manuscript. All other authors revised and commented on the manuscript. The authors read and approved the final manuscript.
Funding
This work was supported by the “Projets Recherche et Développement (PRD)” of Geneva University Hospitals (grant number PRD 17-2019-I) and the Swiss National Science Foundation (grant number 320030_179507).
Availability of data and materials
The datasets generated and/or analyzed during the current study are available in the Dryad repository (10.5061/dryad.0k6djh9xp). The raw sequence data were deposited in the NCBI Sequence Read Archive under BioProject accession number PRJNA641787.
Ethics approval and consent to participate
The study protocol was approved by the Geneva Cantonal Ethics Commission (project #2019-00511).
Consent for publication
Not applicable
Competing interests
The authors declare that they have no competing interests. | CYCLOSPORINE, MYCOPHENOLATE MOFETIL, TACROLIMUS | DrugsGivenReaction | CC BY | 33487167 | 18,939,834 | 2021-01-24 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hepatitis E'. | Unmasking viral sequences by metagenomic next-generation sequencing in adult human blood samples during steroid-refractory/dependent graft-versus-host disease.
Viral infections are common complications following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Allo-HSCT recipients with steroid-refractory/dependent graft-versus-host disease (GvHD) are highly immunosuppressed and are more vulnerable to infections with weakly pathogenic or commensal viruses. Here, twenty-five adult allo-HSCT recipients from 2016 to 2019 with acute or chronic steroid-refractory/dependent GvHD were enrolled in a prospective cohort at Geneva University Hospitals. We performed metagenomics next-generation sequencing (mNGS) analysis using a validated pipeline and de novo analysis on pooled routine plasma samples collected throughout the period of intensive steroid treatment or second-line GvHD therapy to identify weakly pathogenic, commensal, and unexpected viruses.
Median duration of intensive immunosuppression was 5.1 months (IQR 5.5). GvHD-related mortality rate was 36%. mNGS analysis detected viral nucleotide sequences in 24/25 patients. Sequences of ≥ 3 distinct viruses were detected in 16/25 patients; Anelloviridae (24/25) and human pegivirus-1 (9/25) were the most prevalent. In 7 patients with fatal outcomes, viral sequences not assessed by routine investigations were identified with mNGS and confirmed by RT-PCR. These cases included Usutu virus (1), rubella virus (1 vaccine strain and 1 wild-type), novel human astrovirus (HAstV) MLB2 (1), classic HAstV (1), human polyomavirus 6 and 7 (2), cutavirus (1), and bufavirus (1).
Clinically unrecognized viral infections were identified in 28% of highly immunocompromised allo-HSCT recipients with steroid-refractory/dependent GvHD in consecutive samples. These identified viruses have all been previously described in humans, but have poorly understood clinical significance. Rubella virus identification raises the possibility of re-emergence from past infections or vaccinations, or re-infection. Video abstract.
Background
Viral primary infections and reactivations are common complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and are associated with significant morbidity and mortality [1, 2]. Current routine clinical surveillance molecular assays detect specific nucleotide sequences targeting usual culprits including Epstein-Barr virus (EBV), cytomegalovirus (CMV), BK polyomavirus (BKPyV), and adenovirus [3]. Metagenomic next-generation sequencing’s (mNGS) unbiased approach broadens viral infection diagnosis, theoretically detecting “all” viral nucleotide sequences or viral infections present [4–7], and is increasingly used in clinical investigations [8]. Allo-HSCT recipients suffering from steroid-refractory/dependent acute or chronic graft-versus-host disease (GvHD) are highly immunosuppressed patients; GvHD immune dysregulation, mucosal barrier alteration [9–13], and multiple prolonged immunosuppressive treatments create a permissive environment for opportunistic viral infections [10, 11, 14]. These clinically unrecognized viral infections can present with limited symptoms/atypical manifestations and lead to intermittent or prolonged viremia [3]. Given the nonspecific clinical features of GvHD and some viral infections, viral infections may remain clinically unrecognized due to limitations of clinical molecular assays.
We hypothesized that some viral infections, which would normally remain undiagnosed with common clinical assays, occur during intense immunosuppressive therapy in steroid-refractory/dependent GvHD. This study aimed to identify viruses that are not routinely searched by RT-PCR routine assays in clinical practice, due to the lack of knowledge. Therefore, we used mNGS on pooled plasma samples of adult allo-HSCT patients with steroid-refractory/dependent acute or chronic GvHD to look for viruses that could be missed by biased technology.
Methods
Setting, study population, and design
This observational study was conducted at the Geneva University Hospitals (HUG), Switzerland. The study protocol was approved by the Geneva Cantonal Ethics Commission (project #2019-00511). Inclusion criteria were adult patients who received an allo-HSCT from 1 January 2016 to 31 December 2018 at the HUG, who were enrolled in the local monocentric infectious disease cohort of allo-HSCT patients, and who developed steroid-refractory/dependent acute or chronic GvHD. All included patients provided written consent before enrollment. The only exclusion criteria was the lack of informed written consent.
Plasma samples were prospectively collected during clinical management after allo-HSCT and stored in the Laboratory of Virology, HUG. We performed mNGS analysis on pooled plasma samples of each patient, collected throughout the period of intensive steroid treatment or second-line GvHD therapy.
Definitions
Steroid-refractory/dependent acute and chronic GvHD were defined according to the position statement of the GvHD experts in Schoemans et al. [15].
Microbiological methods
mNGS and sequence analysis
Each pool (corresponding to 4 to 10 plasma samples from each patient) was prepared to obtain a final volume of 220 μl. Pools were then centrifuged at 10,000×g for 10 min to remove cells. Two-hundred microliters of cell-free supernatant were treated with 20 μl of Turbo DNAse (2 U/μl) + 24 μl of 10x TURBO DNase Buffer (Ambion, Rotkreuz, Switzerland), according to the manufacturer’s instructions. Then, the whole volume was divided into two tubes of 120 μl each. One tube was then used for each of the two nucleic acid extraction procedures. Indeed, virus genome extractions were done using two previously published protocols in parallel [16], namely the RNA and DNA protocols optimized for the detection of RNA and DNA viral sequences, respectively.
For the RNA protocol, nucleic acids were extracted with TRIzol (Invitrogen, Carlsbad, CA, USA). Ribosomal RNA was removed (Ribo-Zero Gold depletion kit (Illumina, San Diego, USA) before libraries’ preparation (TruSeq total RNA preparation protocol (Illumina)). Libraries’ concentrations and sizes were analyzed using the Qubit (Life Technologies, Carlsbad, CA, USA) and the 2200 TapeStation instruments (Agilent, SantaClara, CA, USA), respectively. Each library was loaded individually in a single lane on the HiSeq 4000 platform (Illumina) using the 2 × 100-bp protocol with dual-indexing. The mean total number of read pairs obtained per pool was 328,936,594.84 (range 252,670,103 to 385,257,539).
For the DNA protocol, nucleic acids were extracted with the NucliSens easyMAG magnetic bead system (bioMérieux, Geneva, Switzerland). As previously published [16], double-stranded DNA synthesis was done with the DNA polymerase I, Large Fragment (Klenow) (New England BioLabs, Ipswich, MA, USA)). Libraries were prepared using the Nextera XT (Illumina) protocol. Libraries’ concentrations and sizes were analyzed using the Qubit (Life Technologies) and the 2200 TapeStation instruments (Agilent), respectively. Each library was loaded individually in a single lane on the HiSeq 4000 platform (Illumina) using the 2 × 100-bp protocol with dual-indexing. The mean total number of read pairs obtained per pool was 301,393,033.48 (range 122,939,325 to 377,758,795).
To check for potential contaminating viral sequences from environment or experimental reagents [17], four negative controls (i.e., Neg1-4) were submitted to the whole mNGS procedure. To assess the mNGS process efficiency, positive controls underwent the whole mNGS procedure (canine distemper virus (CDV)-spiked samples and a baculovirus (GenScript, Piscataway, NJ, USA) harboring 793 nucleotides of the CDV fusion gene were used as positive controls for the RNA and DNA protocols, respectively).
Paired reads were quality filtered using Trimmomatic [18]. Reads mapped against the human genome and transcriptome (hg38, gencode.V23) were removed using SNAP [19]. Remaining reads were analyzed using two methods in parallel as previously described [20]: (1) by a pipeline that used virusscan 1.0 (https://github.com/sib-swiss/virusscan) to map reads against the Virosaurus database (version V90v_2018_11) (https://viralzone.expasy.org/8676), which is designed to report vertebrate viruses, and (2) by de novo assembly. Only viruses with ≥ 300 nucleotides of coverage were reported. The raw sequence data were deposited in the NCBI Sequence Read Archive under BioProject accession number PRJNA641787.
Sequences were considered clinically recognized viruses if they corresponded to a virus known to reactivate in/be frequently found among allo-HSCT recipients [2, 4] or if the patient had a known chronic viral infection and clinically unrecognized viruses if not.
Confirmatory real-time (reverse transcription-)polymerase chain reaction (r(RT-)PCR) assays
Clinically unrecognized mNGS findings were confirmed on unpooled plasma by specific semi-quantitative or quantitative r(RT-)PCR assays as previously published; additional specimens (including plasma, cerebrospinal fluid, bronchoalveolar lavage (BAL) fluids, nasopharyngeal swabs, native urines, stools suspension, tissue biopsies or bone marrow) were tested when available and pertinent. Quantitative r(RT-)PCR assays were done for Mamastrovirus 1 (classical) using the updated human astrovirus (HAstV) combination [21], Mamastrovirus 6 (MLB2) using the MLB2 assay [22], Usutu virus [23], and bufavirus using the BuV (NS1) assay [24]. Semi-quantitative r(RT-)PCR assays were done for cutavirus using the CuV (VP2) assay [24], human polyomavirus (HPyV) 6 using the VP2 assay [25], HPyV-7 using the VP2 assay [25], and rubella virus [26].
Nucleic acids from plasma, cerebrospinal fluid, BAL fluids, nasopharyngeal swabs, urine, stools resuspended in PBS, and bone marrow were extracted individually from 190 μL of each specimen, spiked with 10 μL of standardized CDV as internal control [27], using the NucliSENS easyMAG (bioMérieux, Geneva, Switzerland) nucleic acid kit, according to the manufacturer’s instructions, and eluted in 25 μL. DNA and RNA were extracted from tissue biopsies using the QIAamp DNA FFPE Tissue Kit (Qiagen, Hombrechtikon, Switzerland) and High Pure FFPET RNA isolation kit (Roche Applied Sciences, Indianapolis, IN, USA), respectively, following the manufacturer’s instructions. For RNA viruses, the rRT-PCR assays were performed using the one-step QuantiTect Probe RT-PCR Kit (Qiagen, Hombrechtikon, Switzerland) in a StepOne Plus instrument (Applied Biosystems, Rotkreuz, Switzerland). For DNA viruses, the rPCR assays were performed using the TaqMan Universal PCR Master Mix (Applied Biosystems) in a StepOne Plus instrument (Applied Biosystems) for cutavirus and bufavirus or in a QuantStudio 5 instrument (Applied Biosystems) for HPyV6 and 7.
For quantitative r(RT)-PCR assays, standard curves and lower limit of quantifications (LOQ) were assessed using 10-fold serial dilutions of specific RNA oligonucleotides (Mamastrovirus 1 (classical) and 6 (MLB2): LOQ = 1.25E4 and 1.25E3 RNA copies/ml of plasma, respectively), RNA transcript (Usutu virus: LOQ = 1.32E2 RNA copies/ml of plasma), DNA oligonucleotides (bufavirus: LOQ = 1.32E3 DNA copies/ml of plasma), or plasmids (HPyV6 and 7: LOQ = 2.63E2 DNA copies/ml of plasma each) containing the target sequences.
Statistical analysis
Categorical variables were described by counts and percentages. Continuous variables were expressed as mean and standard deviation or median and interquartile range.
Results
Patient characteristics
We identified 25 adult allo-HSCT recipients with acute or chronic steroid-refractory/dependent GvHD. Table 1 shows the patient’s characteristics. The median duration of intensive immunosuppression was 5.1 months (IQR 5.5), and 22/25 patients received ruxolitinib. At the time of writing, fifteen patients have died, with 9 considered as GvHD-related.
Table 1 Patients’ characteristics (25 allo-HSCT patients)
Total
n = 25
Demographics
Sex (male), n (%) 16 (64.0)
Age, median (IQR) 58.0 (25.0)
Allo-HSCT considered in the analysis,
n
(%)
First 23 (92.0)
Second 2 (8.0)
Transplant source,
n
(%)
Bone marrow 5 (20)
Peripheral blood cells 20 (80)
Underlying disease,
n
(%)
Acute myeloid leukemia 10 (40.0)
Lymphoid malignancy 6 (24.0)
MDS/MDPS 3 (12.0)
Acute lymphoid leukemia 2 (8.0)
Othera 4 (16.0)
Risk score,
n
(%)
Low 0 (0)
Intermediate 18 (72.0)
High 7 (28.0)
Donor sex, M,
n
(%) 7 (28.0)
Donor age, median (IQR) 36 (16.5)
Donor match,
n
(%)
Donor-related 10 (40.0)
CMV donor/recipient constellation,
n
(%)
+/+ 12 (48.0)
−/+ 1 (4.0)
+/− 7 (28.0)
−/− 5 (20.0)
CMV prophylaxis, n (%) 1 (4.0)
Conditioning,
n
(%)
Myeloablative conditioning 5 (20.0)
GvHD prophylaxis,
n
(%)
Calcineurin inhibitor 24 (96.0)
Mycophenolate mofetil 17 (68.0)
Methotrexate 7 (28.0)
GvHD organ,
n
(%)
Digestive tract 17 (68.0)
Skin 15 (60.0)
Mouth 4 (16.0)
Liver 7 (28.0)
Lung 5 (20.0)
Eyes 2 (8.0)
Musculoskeletal 1 (4.0)
GvHD grade or severity,
n
(%)
Grade
2 9 (36.0)
3 3 (12.0)
4 6 (24.0)
Moderate 6 (24.0)
Severe 7 (28.0)
GvHD treatment,
n
(%)
Corticosteroids 24 (96.0)
Ruxolitinib 22 (88.0)
Calcineurin inhibitor 21 (84.0)
Mycophenolate mofetil 12 (48.0)
Photopheresis 12 (48.0)
Budenoside 5 (20.0)
Sirolimus 3 (12.0)
Tocilizumab 2 (8.0)
Otherb 6 (24.0)
Death,
n
(%) 15 (60.0)
Median delay from allo-HSCT, months (IQR) 11.2 (15.8)
One patient could have multiple GvHD prophylaxis and treatment, multiple organs with GvHD and multiple grades of severity. CMV prophylaxis: one patient (patient Ge24) received letermovir during the period of intensive steroid treatment or second-line GvHD therapy. GvHD grade refers to acute GvHD, GvHD severity refers to chronic GvHD. In two patients, there was no information on grade/severity. Only organs with grade GvHD ≥ 2 or severity ≥ moderate are reported
Abbreviations: IQR interquartile range, allo-HSCT allogeneic hematopoietic stem cell transplantation, MDS/MDPS myelodysplasic syndrome/myelodysplasic proliferative syndrome, ATG anti-thymocyte globulin
aOther includes: multiple myeloma (n = 2), chronic myeloid leukemia (n = 1) and mixed acute leukemia (n = 1)
bOther includes: azithromycine, montelukast, prolastin, vedolisumab, nilotinib, basilixumab, ibrutinib, and/or methotrexate
Viral sequences identified with mNGS and confirmatory analyses
The mNGS analysis revealed viral nucleotide sequences in all patients except Ge18 (24/25). In 16/25 patients, ≥ 3 distinct viral species were detected (Fig. 1). Figure 2 depicts the prevalence of each identified virus, and Table S1 provides detailed mNGS characteristics.
Fig. 1 Grid plot of viral sequences identified with mNGS in pooled plasma samples (25 allo-HSCT patients). Each line corresponds to viral sequences assigned to one virus; the bottom line corresponds to mNGS negative (Neg1-4) and positive (Pos1/2 DNA/RNA) control samples. Each column corresponds to one pool of plasma sample (one patient). Colors represent the approximate number of reads matching virus genome detected in each pool of plasma samples. *Since they were detected in one negative control, human papillomavirus sequences were considered as likely contaminant. # cross-contamination. Abbreviations: HAstV human astrovirus, TTV torque teno virus, TTMV torque teno minivirus, TTMDV torque teno midivirus, HSV-1 herpes simplex 1 virus, EBV Epstein-Barr virus, CMV cytomegalovirus, CTRL control
Fig. 2 Prevalence of viruses identified with mNGS in pooled plasma samples (25 allo-HSCT recipients). The vertical axis represents all identified viral sequences. The horizontal axis represents the number of patients in which sequences of each virus were identified. Abbreviations: TTV torque teno virus, TTMV torque teno minivirus, CMV cytomegalovirus, TTMDV torque teno midivirus, EBV Epstein-Barr virus, HSV-1 herpes simplex 1 virus, HAstV human astrovirus
Anelloviridae (torque teno virus (TTV), torque teno minivirus (TTMV) and torque teno midivirus (TTMDV)) and human pegivirus-1 (HPgV-1) were the most prevalent with sequences detected in 24/25 and 9/25 patients, respectively.
Other detected DNA viruses included BK polyomavirus (BKPyV) (7/25), CMV (5/25), and JC polyomavirus (JCPyV) (4/25), and also herpes simplex virus 1 (HSV-1), EBV, hepatitis B virus (HBV), bufavirus, cutavirus, and HPyV-6/7, each detected once (1/25). Except HPgV-1, the detected RNA viruses were less prevalent than DNA viruses and were HAstV (Mamastrovirus 1 and 6) and rubella virus, both detected twice (2/25), and also hepatitis E (HEV) and Usutu viruses, both detected once (1/25). The de novo analysis did not reveal other relevant sequences. Interestingly, sequences for TTV (11/24), CMV (3/5), EBV (1/1), and HBV (1/1) were detected in both DNA and RNA libraries, suggesting active viral replication (Figure S1).
Clinically recognized viral sequences
Although not routinely searched in clinical practice, Anelloviridae and HPgV-1 sequences were identified in 96% and 36% of patients and were classified among clinically recognized viral sequences as they are known to be highly prevalent among immunocompromised patients. In 14/25 patients, mNGS analysis identified sequences of latent DNA viruses known to reactivate in transplant recipients (EBV, CMV, HSV-1, BKPyV, JCPyV, HBV). At the RNA level, HEV was identified once.
The r(RT-)PCR assays performed during routine investigations confirmed the mNGS analysis (Table S2): patient Ge05 had a chronic HEV infection, and patient Ge14 had chronic HBV and cutaneous HSV-1 infections, and HSV-1 viremia. BKPyV and JCPyV were not systematically screened and were only revealed by mNGS analysis. However, BKPyV was screened in patient Ge06 and detected at low viral loads (VL) (1.41E2 and 1.44E3 copies/ml) in two plasma samples collected a few days apart from those included for mNGS analysis. In 12/25 patients, CMV and EBV were detected only by rPCR at low VL; no other expected virus was detected by routine molecular assays.
Clinically unrecognized viral sequences
We found clinically unrecognized sequences belonging to either rare and/or recently identified viruses (HAstV MLB2, Usutu virus, bufavirus, cutavirus, HPyV-6, and HPyV-7) or those not routinely assessed alongside GvHD (classic HAstV and rubella virus) in 7/25 patients, whose characteristics are detailed in Table 2.
Table 2 Clinical characteristics of 7 patients with clinically unrecognized viral sequences
Patient’s code Age, gender Underlying disease GvHD organ GvHD treatmentsa Outcome
Ge02 61, M Lymphoma Digestive, skin CSA, tacrolimus, corticosteroids, sirolimus, budenoside, photopheresis Death (GvHD-related)
Ge05 23, M Lymphoma Digestive, skin, lung CSA, MMF, tacrolimus, corticosteroids Death
Ge07 60, M ALL Digestive Tacrolimus, corticosteroids, photopheresis Death
Ge09 65, M AML Liver, digestiveb CSA, corticosteroids, tocilizumab Death
Ge12 44, M MM Digestive, liver CSA, corticosteroids, basiliximab, MMF Death
Ge14 31, M AML Digestive, liver Corticosteroids Death
Ge22 68, M MDPS Digestive, skin CSA, tacrolimus, corticosteroids, vedolisumab, prolastin Death
Age at the time of transplantation
Abbreviations: GvHD graft-versus-host disease, M male, ALL acute lymphoid leukemia, AML acute myeloid leukemia, MM multiple myeloma, MDPS myelodysplasic proliferative syndrome, CSA cyclosporine A, MMF mycophenolate mofetil
aAll patients had ruxolitinib as part of the GvHD treatment
bDigestive GvHD was not confirmed by biopsies
mNGS identifications of these clinically unrecognized viral sequences were confirmed by r(RT-)PCR in unpooled plasma samples. Whenever available during/after the period of sample selection, additional specimens and/or tissue biopsies were screened over a median period of 7.1 weeks (IQR 25.3). These findings are shown in Table 3.
Table 3 mNGS and r(RT-)PCR results of 7 patients with clinically unrecognized viral sequences
Viral species detected with mNGS Viral species confirmed with r(RT)-PCR assays
Patient’s code Virus Plasma, n (pos/total) Time period (days) Estimated viral load (mean log10 copies/ml plasma or CT values) Other positive biological specimen
Ge02 HPyV7 14/14 279 4.75 BM, BAL
Ge05 Usutu virus 2/5 7 4.66 –
Ge07 Cutavirus 6/10 98 37.9 Skin
Ge09 Bufavirus 6/12 81 3.73 Stools, duodenum
Ge12 Novel human astrovirus MLB2 2/6 14 3.24 Intestine, colon, BM
Ge14 Rubella virus 3/5 39 37.9 –
Classic human astrovirus 5/11 25 5.56 –
HPyV6 11/11 74 3.76 –
Ge22 Rubella virus 2/8 3 36.7 –
Pos/total corresponds to the number of positive samples on the total of screened samples. Time period corresponds to the time period during which samplings were found positive. CT values above 40 were considered negative. CT values are indicated in italics
Abbreviations: BM bone marrow, BAL bronchoalveolar lavage, CT cycle threshold
Brief clinical description of patients harboring clinically unrecognized viral sequences
Ge02: HPyV-7
A 61-year-old male, transplanted for lymphoma, developed digestive and skin GvHD; intensive immunosuppression for GvHD lasted from 12 to 16 months after transplantation (4-month sample period), when the patient died from a post-transplant EBV-related lymphoma disease. Beginning 9 months before death, we found HPyV-7 in all screened plasma samples. In addition, HPyV-7 was also found in a BAL and a bone marrow sample collected 8 months after transplantation (2.8 log10 DNA copies/ml and CT value 28, respectively).
Ge05: Usutu virus
A 23-year-old male, transplanted for lymphoma, developed digestive skin and lung GvHD; intensive immunosuppression for GvHD lasted from 1 to 24 months after transplantation (22-month sample period), when the patient died from a disseminated fungal infection and GvHD. We found Usutu virus in 2 plasma samples collected 7 days apart, a few days after a blood transfusion, and 1.5 months before death.
Ge07: cutavirus
A 60-year-old male, transplanted for acute lymphoblastic leukemia, developed digestive GvHD; intensive immunosuppression for GvHD lasted from 6 to 8 months after transplantation (2-month sample period), when the patient died from a disseminated fungal infection and GvHD. We found cutavirus in a skin biopsy performed 3 weeks before transplantation (CT of 35) and at low plasma VL for 3 months before death. Autopsy results confirmed digestive GvHD and a disseminated mold infection.
Ge09: bufavirus
A 65-year-old male, transplanted for acute myeloid leukemia (AML), developed liver GvHD; intensive immunosuppression for GvHD lasted from 5 to 7 months after transplantation (2 month sample period), when the patient died from GvHD. We detected bufavirus RNA in several plasma samples taken over 2 months before death. In addition, bufavirus was also found in stool samples collected the day of and 1.5 months after transplantation, at CT values of 38.2 and 34.7, respectively, and in a duodenal biopsy performed 5 months after transplantation (CT value 27.3), which revealed chronic duodenitis.
Ge12: HAstV MLB2
A 44-year-old male, transplanted for multiple myeloma, developed a digestive and liver GvHD; intensive immunosuppression for GvHD lasted from 15 days to 2 months after transplantation (2-month sample period), when the patient died from the GvHD. We detected HAstV MLB2 RNA in two plasma samples collected 14 days apart and shortly before death, in a colonic biopsy performed few days before death (CT value 27.9), and in several intestine, colonic, and bone marrow autopsy samples (mean CT values 25.8, 27.6, 28, respectively). Autopsy results confirmed liver and digestive GvHD and revealed chronic pulmonary GvHD.
Ge14: rubella virus, classic HAstV, HPyV-6
A 31-year-old male of Chinese origin, transplanted for AML, developed digestive and liver GvHD; intensive immunosuppression for GvHD lasted 9–11 months after transplantation (3-month sample period), when the patient died from an acute intestinal perforation in the context of recurrent digestive GvHD. In several plasma samples starting 1 month before death, we found classic HAstV RNA and low VLs of a wild-type Chinese rubella strain. HPyV-6 DNA was also persistently found in plasma samples starting 2 months before death. The patient was seropositive for rubella before transplantation.
Ge22: rubella virus
A 68-year-old Portuguese male, transplanted for myelodysplastic syndrome, developed digestive and skin GvHD; intensive immunosuppression for GvHD lasted from 4 to 6 months after transplantation (6-week sample period), when the patient died from GvHD. Two plasma samples were positive for rubella-vaccine RNA at low VLs. The patient was seropositive before transplantation.
Discussion
We analyzed viral sequences by mNGS in pooled plasma samples of 25 adult allo-HSCT patients with severe steroid-refractory/dependent GvHD. Viral nucleotide sequences were found in 96% of patients, and 64% of patients had ≥ 3 distinct viral species. Besides commensal (Anelloviridae and HPgV-1) and latent (EBV, CMV, HSV-1, BKPyV, JCPyV) viruses known to be highly prevalent/reactivate in allo-HSCT recipients, 28% of patients had clinically unrecognized viral sequences that are rarely/never reported in allo-HSCT patients, with unknown pathogenicity (bufavirus, cutavirus, HPyV-6/7, novel HAstV-MLB2, classic HAstV, rubella virus, and Usutu virus). Chronic HBV and HEV infections were also confirmed by mNGS in two patients.
Anelloviridae (TTV, TTMV, and TTMDV) were the most prevalent in this study, concordant with the high TTV viremia rate identified among allo-HSCT recipients [28–31]. The high TTV, TTMV, and TTMDV co-detection rate has been previously described [30]. Chronic anelloviruses infection/re-infection is common, but disease associations remain undetermined [32]. Among allo-HSCT recipients, two studies failed to demonstrate any association between TTV viremia and immune-related complication or other viral reactivations [28, 33], while a third reported higher TTV viremia in patients receiving corticosteroids for GvHD [29]. A recent study found higher TTV VL at 100 days post-transplantation predicts worse overall survival, and a higher risk of acute GvHD and infections [34]. Finally, a mNGS study revealed increased detection rates and number of Anelloviridae sequences in stool samples of allo-HSCT recipients several weeks after developing digestive GvHD [5], suggesting a consequence of GvHD-associated inflammation and/or immunosuppressive therapy. Altogether, these data suggest that TTV viremia could be a potential immunosuppression-marker, requiring further investigation.
HPgV-1 (a Flaviviridae [35]) viremia occurs in 1–4% of blood donors in developed countries [36] and up to 30% of allo-HSCT recipients but has not been associated with clinical consequences [3, 4]. Given the interaction of HPgV-1 with the immune system [37], the effect of persistent HPgV-1 viremia requires deeper investigation.
We found four species of HPyV (JCPyV, BKPyV, HPyV-6/7), with JCPyV viremia occurring in 16% of allo-HSCT recipients, agreeing with studies where concomitant use of multiple immunosuppressive treatments was associated with increased persistent viremia risk—although progressive multifocal leucoencephalopathy was rare [38]. In another study, JCPyV DNA detection rate in plasma decreased from 4/22 to 1/22 patients at 3 and 12–18 months after transplantation, respectively, while viremia was not linked to any clinical manifestation [39]. Our study’s BKPyV prevalence (28%) was lower than the 54% of another study [40]. Notably, our patients did not develop hemorrhagic cystitis.
Contamination or other bioinformatics errors were excluded for each of the clinically unrecognized viral sequences, by confirming the mNGS-identified viral sequences using r(RT-)PCR on blood and non-blood samples at different time-points. These assays found cutavirus (60%) and bufavirus (50%), two Protoparvoviruses, in plasma samples at low VL. Interestingly, available skin and digestive biopsy tissues, previously described as putative primary infection sites [24, 41, 42], were positive by PCR at or shortly before transplantation, indicating viral latency and reactivation under immunosuppressive conditions. Bufavirus was first discovered in stool samples of children in 2012, and the stool prevalence is about 0.3–4.1%, although high seroprevalence was identified in some countries [41, 42]. Bufavirus was recovered in stools of subjects with digestive symptoms, but not in asymptomatic controls [41]. Whether bufavirus influences syndromes attributed to digestive GvHD remains unknown. Cutavirus was discovered in 2016 in stools of diarrheic children in Brazil with a prevalence of about 1–1.6%, and curiously, some associations were made with cutaneous T cell lymphoma [24, 41]. To our knowledge, cutavirus and bufavirus viremia have not been described before.
Usutu virus (a Flaviviridae) is an arbovirus, endemic in Africa and several European countries, that frequently co-circulates with West Nile virus [43–45]. The virus enzootic cycle involves birds (main reservoir) and ornithophilic mosquitos (vectors); humans are incidental and dead-end hosts [43]. Less than 50 documented cases of acute Usutu virus infections have been reported in humans, most of them corresponding to the identification of Usutu virus genome in donated blood samples [45]. Human Usutu virus infection can be asymptomatic or associated with various clinical manifestations, including fever, rash, and neurological manifestations; the virus genome was detected in some cases in CSF or blood samples [43, 45, 46]. The virus can infect neurons, astrocytes, microglia cells, and induced pluripotent stem cell (IPSc)-derived human neuronal stem cells, with a reduction in cell proliferation, induction of antiviral response, and apoptosis [47]. In our study, Usutu virus was transiently identified shortly after a blood transfusion, but retrospective blood bag testing was impossible. Although blood transmission has not been described, screening over ≥ 130,000 blood donations revealed 38 positive donors [48, 49]. Although overt clinical consequences are absent in our patient, this flavivirus is known to cause occasional complications [45] and cannot be disregarded. If transmission occurred by transfusion, it is possible that only remnant RNA was transmitted, not infectious virus.
Astroviruses are well-recognized enteric viruses infecting mainly children, elderly, and immunocompromised patients [50]. HAstV MLB2 was identified a decade ago [51], and since then, it has been demonstrated that it is circulating in every continent [50]. In addition, it is associated with systemic and central nervous system infections [7, 52] and has been identified in stool samples of asymptomatic children [53]. In our mNGS study, classic HAstV was found in plasma samples of a patient with digestive GvHD shortly before death, and HAstV MLB2 was found at low VL in plasma samples of a patient with diarrhea due to digestive GvHD. In the latter, autopsy confirmed the presence of HAstV MLB2 RNA in several intestinal and colonic samples at significant VLs. The presence of astrovirus MLB2 in the digestive tract of the patient is thus evident, and HAstV viremia plausibly came from an intestinal spillover in the context of the GvHD and intestinal perforation.
HPyV-6 and 7 were discovered in 2010 [54] and have been identified in a wide range of clinical samples of healthy subjects, transplant recipients, and symptomatic immunocompetent patients [55–59]. They have been detected mostly in skin specimens of non-transplanted individuals and transplanted recipients with or without dermatological diseases, but the association with clinical manifestation is not established [55, 57, 59–61]. The reported seroprevalence rates of HPyV6 and HPyV7 in immunocompetent and immunocompromised adults varies from 69 to 84% and 35 to 72%, respectively [3]. The transmission route, tropism, pathogenic mechanisms, and potential association with human diseases are still not established. HPyV-6 DNA prevalence in healthy blood donors is 0.1% and 0.6% in kidney transplant recipients [3], while HPyV-7 has been detected in lung transplant recipients [3], yet no obvious clinical manifestations are associated with them. We report persistent HPyV-6/7 viremia in plasma samples of 2/25 allo-HSCT recipients over several months. Further investigations are needed to determine their pathogenicity.
Rubella virus was our most unexpected finding, yet the rubella reads for both patients mapped to different regions along the genome (rubella virus genome coverage of 3.69% and 5.47% for patients Ge14 and Ge22, respectively) and mNGS results were confirmed by specific rRT-PCR in several samples over a period of 39 and 3 days for patients Ge14 and Ge22, respectively.
Although rubella can persist in in vitro and animal models [62–64], it is not known to persist after vaccination or natural infection in humans, except in vaccinated immuno-deficient children [65–68]. Chronic rubella infection has also been hypothesized as causing Fuch’s heterochromic iridocyclitis, although the pathophysiology remains unknown [69, 70]. We found rubella sequences with low VLs in two patients, each with a distinct strain: a vaccine strain and a Chinese strain that was found in a patient who previously lived in China. Macrophages and keratinocytes are potential sites for rubella persistence [66], but retrospectively screened skin samples from one patient gave negative results. Both patients were seropositive before transplantation. Patients with GvHD frequently become seronegative for measles and rubella within 2 years after allo-HSCT [71]. Identification of the usual vaccine strain and a Chinese strain in a native Chinese, strongly argues for reactivation, in line with antibody loss after transplantation. Yet, we noted a decreased rubella IgG titer in one of both patients at the time of viremia, compared to the pre-transplant titers. Gonzalez et al. reported the case of a child who developed fulminant hepatitis after stem cell transplantation despite prior vaccination [72]. The hypothesis raised by the authors of a primary infection from a recently vaccinated contact implies that circulating vaccine strains in the population could be an issue for immunocompromised patients with waning antibodies. Whether rubella persistence could trigger GvHD after transplantation and where the viral reservoir would be are open questions.
A recent trial identified ruxolitinib as a second-line treatment for steroid-refractory GvHD, which has a poor prognosis and no approved clearly beneficial treatment [14, 73]: in the study, about 1/3 patients experienced a grade 3 infection, highlighting the importance of monitoring patients for infections. Our study reveals that some viral infections were overlooked by standard procedures, which may indicate that the 30% of infection risk associated with ruxolitinib could be underestimated, and raises the question of including mNGS analysis in the management of high-risk patients.
Among the 7 patients with clinically unrecognized viral sequences, most sequences were identified a few weeks before and, persisted until, patients’ deaths. Although neither the pathogenic nature of the viruses nor the clear associations with patient outcomes are proven, the identification of these viral sequences in patients’ blood during severe GvHD is relevant and reflects the altered immune response; monitoring these infections could help adjust immunosuppressive therapies. Among these patients, with nearly daily blood sample collection, such strategies could routinely be actionable by pooling plasma samples (overcoming transient viremia problems), with the aim of excluding disseminated infections before increasing immunosuppression, and unmasking a viral infection mimicking the GvHD syndrome.
The identification of HAstV and bufavirus in digestive tracts of patients with digestive GvHD may merely reflect the patient’s gut virome, but identification of enteric viruses in blood samples could indicate a disseminated infection that is triggered by GvHD inflammation or immunosuppressive treatment, which may require treatment adaptation.
These viral infections cannot be considered innocent bystanders. Most of the identified viruses can be shed asymptomatically, but certainly lead to organ disease under conditions where they become opportunistic pathogens, potentially causing unrecognized clinical features; they can also lead to a clinical exacerbation. The particular immunologic state of our population may influence this delicate balance between an indolent virus and its clinical impact.
A major limitation of this study is the small monocentric cohort. Additionally, including only allo-HSCT recipients with steroid-refractory/dependent GvHD precluded generalization of the results to all allo-HSCT recipients. Furthermore, we lacked control patients without GvHD. Despite the numerous viral infections revealed by mNGS, whether these are specific to patients with GvHD or to those treated with ruxolitinib, and if there is an association with clinical manifestations and/or an impact on the immune state of these patients, remains to be determined by appropriate studies. Notably, according to the comparison with routine diagnostic results and confirmatory r(RT-)PCR, our mNGS pipeline is accurate, although with a lower sensitivity compared to specific quantitative real-time PCR assays used in most routine laboratories.
Conclusions
Blood analysis of patients with steroid-refractory/dependent GvHD revealed clinically unrecognized viral sequences in 28% of patients, including rubella virus, novel protoparvoviruses, HPyV-6/7, Usutu virus, and HAstV-MLB2. These viruses have been described in humans, but rarely reported as causes of disease in allo-HSCT patients, or have unknown pathogenicity. Rubella virus identifications imply possible re-emergence from past infection or vaccination. Further investigations are needed to understand the clinical significance of these infections.
Supplementary Information
Additional file 1: Table S1. Detailed mNGS results per patient for the 25 adult allo-HSCT patients. Table S2. Comparison of mNGS results on the pooled plasma samples and of the routine r(RT-)PCR results on the corresponding plasma samples of the 25 patients. Figure S1. Boxplot of mapped reads of DNA viruses and corresponding mRNA detection with mNGS. The vertical axis represents the number of mapped reads. The horizontal axis represents all identified viral sequences of DNA viruses (left panel) and corresponding mRNA sequences (right panel). The numbers on the horizontal axis represent the number of patients in which sequences of each virus were identified. Abbreviations: HSV-1: herpes simplex 1 virus; CMV: cytomegalovirus; EBV: Epstein-Barr virus; TTMDV: torque teno midivirus; TTMV: torque teno minivirus; TTV: torque teno virus.
Publisher’s Note
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L. Kaiser and D. L. Vu contributed equally to this work.
Acknowledgements
The authors would like to thank Fiona Pigny for technical assistance and Erik Boehm for editorial assistance.
Authors’ contributions
MCZ, DLV, SC, and LK designed the research project. GV, MD, FL, and SC performed the mNGS and sequence analysis and r(RT-)PCR assays. VB, TAM, and JAL performed the biopsies histological examination. CVD, SML, and YC contributed to the interpretation of data regarding transplantation. MCZ, DLV, and SC collected and interpreted the data and wrote the first draft of the manuscript. All other authors revised and commented on the manuscript. The authors read and approved the final manuscript.
Funding
This work was supported by the “Projets Recherche et Développement (PRD)” of Geneva University Hospitals (grant number PRD 17-2019-I) and the Swiss National Science Foundation (grant number 320030_179507).
Availability of data and materials
The datasets generated and/or analyzed during the current study are available in the Dryad repository (10.5061/dryad.0k6djh9xp). The raw sequence data were deposited in the NCBI Sequence Read Archive under BioProject accession number PRJNA641787.
Ethics approval and consent to participate
The study protocol was approved by the Geneva Cantonal Ethics Commission (project #2019-00511).
Consent for publication
Not applicable
Competing interests
The authors declare that they have no competing interests. | CYCLOSPORINE, MYCOPHENOLATE MOFETIL, TACROLIMUS | DrugsGivenReaction | CC BY | 33487167 | 18,939,834 | 2021-01-24 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Systemic mycosis'. | Unmasking viral sequences by metagenomic next-generation sequencing in adult human blood samples during steroid-refractory/dependent graft-versus-host disease.
Viral infections are common complications following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Allo-HSCT recipients with steroid-refractory/dependent graft-versus-host disease (GvHD) are highly immunosuppressed and are more vulnerable to infections with weakly pathogenic or commensal viruses. Here, twenty-five adult allo-HSCT recipients from 2016 to 2019 with acute or chronic steroid-refractory/dependent GvHD were enrolled in a prospective cohort at Geneva University Hospitals. We performed metagenomics next-generation sequencing (mNGS) analysis using a validated pipeline and de novo analysis on pooled routine plasma samples collected throughout the period of intensive steroid treatment or second-line GvHD therapy to identify weakly pathogenic, commensal, and unexpected viruses.
Median duration of intensive immunosuppression was 5.1 months (IQR 5.5). GvHD-related mortality rate was 36%. mNGS analysis detected viral nucleotide sequences in 24/25 patients. Sequences of ≥ 3 distinct viruses were detected in 16/25 patients; Anelloviridae (24/25) and human pegivirus-1 (9/25) were the most prevalent. In 7 patients with fatal outcomes, viral sequences not assessed by routine investigations were identified with mNGS and confirmed by RT-PCR. These cases included Usutu virus (1), rubella virus (1 vaccine strain and 1 wild-type), novel human astrovirus (HAstV) MLB2 (1), classic HAstV (1), human polyomavirus 6 and 7 (2), cutavirus (1), and bufavirus (1).
Clinically unrecognized viral infections were identified in 28% of highly immunocompromised allo-HSCT recipients with steroid-refractory/dependent GvHD in consecutive samples. These identified viruses have all been previously described in humans, but have poorly understood clinical significance. Rubella virus identification raises the possibility of re-emergence from past infections or vaccinations, or re-infection. Video abstract.
Background
Viral primary infections and reactivations are common complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and are associated with significant morbidity and mortality [1, 2]. Current routine clinical surveillance molecular assays detect specific nucleotide sequences targeting usual culprits including Epstein-Barr virus (EBV), cytomegalovirus (CMV), BK polyomavirus (BKPyV), and adenovirus [3]. Metagenomic next-generation sequencing’s (mNGS) unbiased approach broadens viral infection diagnosis, theoretically detecting “all” viral nucleotide sequences or viral infections present [4–7], and is increasingly used in clinical investigations [8]. Allo-HSCT recipients suffering from steroid-refractory/dependent acute or chronic graft-versus-host disease (GvHD) are highly immunosuppressed patients; GvHD immune dysregulation, mucosal barrier alteration [9–13], and multiple prolonged immunosuppressive treatments create a permissive environment for opportunistic viral infections [10, 11, 14]. These clinically unrecognized viral infections can present with limited symptoms/atypical manifestations and lead to intermittent or prolonged viremia [3]. Given the nonspecific clinical features of GvHD and some viral infections, viral infections may remain clinically unrecognized due to limitations of clinical molecular assays.
We hypothesized that some viral infections, which would normally remain undiagnosed with common clinical assays, occur during intense immunosuppressive therapy in steroid-refractory/dependent GvHD. This study aimed to identify viruses that are not routinely searched by RT-PCR routine assays in clinical practice, due to the lack of knowledge. Therefore, we used mNGS on pooled plasma samples of adult allo-HSCT patients with steroid-refractory/dependent acute or chronic GvHD to look for viruses that could be missed by biased technology.
Methods
Setting, study population, and design
This observational study was conducted at the Geneva University Hospitals (HUG), Switzerland. The study protocol was approved by the Geneva Cantonal Ethics Commission (project #2019-00511). Inclusion criteria were adult patients who received an allo-HSCT from 1 January 2016 to 31 December 2018 at the HUG, who were enrolled in the local monocentric infectious disease cohort of allo-HSCT patients, and who developed steroid-refractory/dependent acute or chronic GvHD. All included patients provided written consent before enrollment. The only exclusion criteria was the lack of informed written consent.
Plasma samples were prospectively collected during clinical management after allo-HSCT and stored in the Laboratory of Virology, HUG. We performed mNGS analysis on pooled plasma samples of each patient, collected throughout the period of intensive steroid treatment or second-line GvHD therapy.
Definitions
Steroid-refractory/dependent acute and chronic GvHD were defined according to the position statement of the GvHD experts in Schoemans et al. [15].
Microbiological methods
mNGS and sequence analysis
Each pool (corresponding to 4 to 10 plasma samples from each patient) was prepared to obtain a final volume of 220 μl. Pools were then centrifuged at 10,000×g for 10 min to remove cells. Two-hundred microliters of cell-free supernatant were treated with 20 μl of Turbo DNAse (2 U/μl) + 24 μl of 10x TURBO DNase Buffer (Ambion, Rotkreuz, Switzerland), according to the manufacturer’s instructions. Then, the whole volume was divided into two tubes of 120 μl each. One tube was then used for each of the two nucleic acid extraction procedures. Indeed, virus genome extractions were done using two previously published protocols in parallel [16], namely the RNA and DNA protocols optimized for the detection of RNA and DNA viral sequences, respectively.
For the RNA protocol, nucleic acids were extracted with TRIzol (Invitrogen, Carlsbad, CA, USA). Ribosomal RNA was removed (Ribo-Zero Gold depletion kit (Illumina, San Diego, USA) before libraries’ preparation (TruSeq total RNA preparation protocol (Illumina)). Libraries’ concentrations and sizes were analyzed using the Qubit (Life Technologies, Carlsbad, CA, USA) and the 2200 TapeStation instruments (Agilent, SantaClara, CA, USA), respectively. Each library was loaded individually in a single lane on the HiSeq 4000 platform (Illumina) using the 2 × 100-bp protocol with dual-indexing. The mean total number of read pairs obtained per pool was 328,936,594.84 (range 252,670,103 to 385,257,539).
For the DNA protocol, nucleic acids were extracted with the NucliSens easyMAG magnetic bead system (bioMérieux, Geneva, Switzerland). As previously published [16], double-stranded DNA synthesis was done with the DNA polymerase I, Large Fragment (Klenow) (New England BioLabs, Ipswich, MA, USA)). Libraries were prepared using the Nextera XT (Illumina) protocol. Libraries’ concentrations and sizes were analyzed using the Qubit (Life Technologies) and the 2200 TapeStation instruments (Agilent), respectively. Each library was loaded individually in a single lane on the HiSeq 4000 platform (Illumina) using the 2 × 100-bp protocol with dual-indexing. The mean total number of read pairs obtained per pool was 301,393,033.48 (range 122,939,325 to 377,758,795).
To check for potential contaminating viral sequences from environment or experimental reagents [17], four negative controls (i.e., Neg1-4) were submitted to the whole mNGS procedure. To assess the mNGS process efficiency, positive controls underwent the whole mNGS procedure (canine distemper virus (CDV)-spiked samples and a baculovirus (GenScript, Piscataway, NJ, USA) harboring 793 nucleotides of the CDV fusion gene were used as positive controls for the RNA and DNA protocols, respectively).
Paired reads were quality filtered using Trimmomatic [18]. Reads mapped against the human genome and transcriptome (hg38, gencode.V23) were removed using SNAP [19]. Remaining reads were analyzed using two methods in parallel as previously described [20]: (1) by a pipeline that used virusscan 1.0 (https://github.com/sib-swiss/virusscan) to map reads against the Virosaurus database (version V90v_2018_11) (https://viralzone.expasy.org/8676), which is designed to report vertebrate viruses, and (2) by de novo assembly. Only viruses with ≥ 300 nucleotides of coverage were reported. The raw sequence data were deposited in the NCBI Sequence Read Archive under BioProject accession number PRJNA641787.
Sequences were considered clinically recognized viruses if they corresponded to a virus known to reactivate in/be frequently found among allo-HSCT recipients [2, 4] or if the patient had a known chronic viral infection and clinically unrecognized viruses if not.
Confirmatory real-time (reverse transcription-)polymerase chain reaction (r(RT-)PCR) assays
Clinically unrecognized mNGS findings were confirmed on unpooled plasma by specific semi-quantitative or quantitative r(RT-)PCR assays as previously published; additional specimens (including plasma, cerebrospinal fluid, bronchoalveolar lavage (BAL) fluids, nasopharyngeal swabs, native urines, stools suspension, tissue biopsies or bone marrow) were tested when available and pertinent. Quantitative r(RT-)PCR assays were done for Mamastrovirus 1 (classical) using the updated human astrovirus (HAstV) combination [21], Mamastrovirus 6 (MLB2) using the MLB2 assay [22], Usutu virus [23], and bufavirus using the BuV (NS1) assay [24]. Semi-quantitative r(RT-)PCR assays were done for cutavirus using the CuV (VP2) assay [24], human polyomavirus (HPyV) 6 using the VP2 assay [25], HPyV-7 using the VP2 assay [25], and rubella virus [26].
Nucleic acids from plasma, cerebrospinal fluid, BAL fluids, nasopharyngeal swabs, urine, stools resuspended in PBS, and bone marrow were extracted individually from 190 μL of each specimen, spiked with 10 μL of standardized CDV as internal control [27], using the NucliSENS easyMAG (bioMérieux, Geneva, Switzerland) nucleic acid kit, according to the manufacturer’s instructions, and eluted in 25 μL. DNA and RNA were extracted from tissue biopsies using the QIAamp DNA FFPE Tissue Kit (Qiagen, Hombrechtikon, Switzerland) and High Pure FFPET RNA isolation kit (Roche Applied Sciences, Indianapolis, IN, USA), respectively, following the manufacturer’s instructions. For RNA viruses, the rRT-PCR assays were performed using the one-step QuantiTect Probe RT-PCR Kit (Qiagen, Hombrechtikon, Switzerland) in a StepOne Plus instrument (Applied Biosystems, Rotkreuz, Switzerland). For DNA viruses, the rPCR assays were performed using the TaqMan Universal PCR Master Mix (Applied Biosystems) in a StepOne Plus instrument (Applied Biosystems) for cutavirus and bufavirus or in a QuantStudio 5 instrument (Applied Biosystems) for HPyV6 and 7.
For quantitative r(RT)-PCR assays, standard curves and lower limit of quantifications (LOQ) were assessed using 10-fold serial dilutions of specific RNA oligonucleotides (Mamastrovirus 1 (classical) and 6 (MLB2): LOQ = 1.25E4 and 1.25E3 RNA copies/ml of plasma, respectively), RNA transcript (Usutu virus: LOQ = 1.32E2 RNA copies/ml of plasma), DNA oligonucleotides (bufavirus: LOQ = 1.32E3 DNA copies/ml of plasma), or plasmids (HPyV6 and 7: LOQ = 2.63E2 DNA copies/ml of plasma each) containing the target sequences.
Statistical analysis
Categorical variables were described by counts and percentages. Continuous variables were expressed as mean and standard deviation or median and interquartile range.
Results
Patient characteristics
We identified 25 adult allo-HSCT recipients with acute or chronic steroid-refractory/dependent GvHD. Table 1 shows the patient’s characteristics. The median duration of intensive immunosuppression was 5.1 months (IQR 5.5), and 22/25 patients received ruxolitinib. At the time of writing, fifteen patients have died, with 9 considered as GvHD-related.
Table 1 Patients’ characteristics (25 allo-HSCT patients)
Total
n = 25
Demographics
Sex (male), n (%) 16 (64.0)
Age, median (IQR) 58.0 (25.0)
Allo-HSCT considered in the analysis,
n
(%)
First 23 (92.0)
Second 2 (8.0)
Transplant source,
n
(%)
Bone marrow 5 (20)
Peripheral blood cells 20 (80)
Underlying disease,
n
(%)
Acute myeloid leukemia 10 (40.0)
Lymphoid malignancy 6 (24.0)
MDS/MDPS 3 (12.0)
Acute lymphoid leukemia 2 (8.0)
Othera 4 (16.0)
Risk score,
n
(%)
Low 0 (0)
Intermediate 18 (72.0)
High 7 (28.0)
Donor sex, M,
n
(%) 7 (28.0)
Donor age, median (IQR) 36 (16.5)
Donor match,
n
(%)
Donor-related 10 (40.0)
CMV donor/recipient constellation,
n
(%)
+/+ 12 (48.0)
−/+ 1 (4.0)
+/− 7 (28.0)
−/− 5 (20.0)
CMV prophylaxis, n (%) 1 (4.0)
Conditioning,
n
(%)
Myeloablative conditioning 5 (20.0)
GvHD prophylaxis,
n
(%)
Calcineurin inhibitor 24 (96.0)
Mycophenolate mofetil 17 (68.0)
Methotrexate 7 (28.0)
GvHD organ,
n
(%)
Digestive tract 17 (68.0)
Skin 15 (60.0)
Mouth 4 (16.0)
Liver 7 (28.0)
Lung 5 (20.0)
Eyes 2 (8.0)
Musculoskeletal 1 (4.0)
GvHD grade or severity,
n
(%)
Grade
2 9 (36.0)
3 3 (12.0)
4 6 (24.0)
Moderate 6 (24.0)
Severe 7 (28.0)
GvHD treatment,
n
(%)
Corticosteroids 24 (96.0)
Ruxolitinib 22 (88.0)
Calcineurin inhibitor 21 (84.0)
Mycophenolate mofetil 12 (48.0)
Photopheresis 12 (48.0)
Budenoside 5 (20.0)
Sirolimus 3 (12.0)
Tocilizumab 2 (8.0)
Otherb 6 (24.0)
Death,
n
(%) 15 (60.0)
Median delay from allo-HSCT, months (IQR) 11.2 (15.8)
One patient could have multiple GvHD prophylaxis and treatment, multiple organs with GvHD and multiple grades of severity. CMV prophylaxis: one patient (patient Ge24) received letermovir during the period of intensive steroid treatment or second-line GvHD therapy. GvHD grade refers to acute GvHD, GvHD severity refers to chronic GvHD. In two patients, there was no information on grade/severity. Only organs with grade GvHD ≥ 2 or severity ≥ moderate are reported
Abbreviations: IQR interquartile range, allo-HSCT allogeneic hematopoietic stem cell transplantation, MDS/MDPS myelodysplasic syndrome/myelodysplasic proliferative syndrome, ATG anti-thymocyte globulin
aOther includes: multiple myeloma (n = 2), chronic myeloid leukemia (n = 1) and mixed acute leukemia (n = 1)
bOther includes: azithromycine, montelukast, prolastin, vedolisumab, nilotinib, basilixumab, ibrutinib, and/or methotrexate
Viral sequences identified with mNGS and confirmatory analyses
The mNGS analysis revealed viral nucleotide sequences in all patients except Ge18 (24/25). In 16/25 patients, ≥ 3 distinct viral species were detected (Fig. 1). Figure 2 depicts the prevalence of each identified virus, and Table S1 provides detailed mNGS characteristics.
Fig. 1 Grid plot of viral sequences identified with mNGS in pooled plasma samples (25 allo-HSCT patients). Each line corresponds to viral sequences assigned to one virus; the bottom line corresponds to mNGS negative (Neg1-4) and positive (Pos1/2 DNA/RNA) control samples. Each column corresponds to one pool of plasma sample (one patient). Colors represent the approximate number of reads matching virus genome detected in each pool of plasma samples. *Since they were detected in one negative control, human papillomavirus sequences were considered as likely contaminant. # cross-contamination. Abbreviations: HAstV human astrovirus, TTV torque teno virus, TTMV torque teno minivirus, TTMDV torque teno midivirus, HSV-1 herpes simplex 1 virus, EBV Epstein-Barr virus, CMV cytomegalovirus, CTRL control
Fig. 2 Prevalence of viruses identified with mNGS in pooled plasma samples (25 allo-HSCT recipients). The vertical axis represents all identified viral sequences. The horizontal axis represents the number of patients in which sequences of each virus were identified. Abbreviations: TTV torque teno virus, TTMV torque teno minivirus, CMV cytomegalovirus, TTMDV torque teno midivirus, EBV Epstein-Barr virus, HSV-1 herpes simplex 1 virus, HAstV human astrovirus
Anelloviridae (torque teno virus (TTV), torque teno minivirus (TTMV) and torque teno midivirus (TTMDV)) and human pegivirus-1 (HPgV-1) were the most prevalent with sequences detected in 24/25 and 9/25 patients, respectively.
Other detected DNA viruses included BK polyomavirus (BKPyV) (7/25), CMV (5/25), and JC polyomavirus (JCPyV) (4/25), and also herpes simplex virus 1 (HSV-1), EBV, hepatitis B virus (HBV), bufavirus, cutavirus, and HPyV-6/7, each detected once (1/25). Except HPgV-1, the detected RNA viruses were less prevalent than DNA viruses and were HAstV (Mamastrovirus 1 and 6) and rubella virus, both detected twice (2/25), and also hepatitis E (HEV) and Usutu viruses, both detected once (1/25). The de novo analysis did not reveal other relevant sequences. Interestingly, sequences for TTV (11/24), CMV (3/5), EBV (1/1), and HBV (1/1) were detected in both DNA and RNA libraries, suggesting active viral replication (Figure S1).
Clinically recognized viral sequences
Although not routinely searched in clinical practice, Anelloviridae and HPgV-1 sequences were identified in 96% and 36% of patients and were classified among clinically recognized viral sequences as they are known to be highly prevalent among immunocompromised patients. In 14/25 patients, mNGS analysis identified sequences of latent DNA viruses known to reactivate in transplant recipients (EBV, CMV, HSV-1, BKPyV, JCPyV, HBV). At the RNA level, HEV was identified once.
The r(RT-)PCR assays performed during routine investigations confirmed the mNGS analysis (Table S2): patient Ge05 had a chronic HEV infection, and patient Ge14 had chronic HBV and cutaneous HSV-1 infections, and HSV-1 viremia. BKPyV and JCPyV were not systematically screened and were only revealed by mNGS analysis. However, BKPyV was screened in patient Ge06 and detected at low viral loads (VL) (1.41E2 and 1.44E3 copies/ml) in two plasma samples collected a few days apart from those included for mNGS analysis. In 12/25 patients, CMV and EBV were detected only by rPCR at low VL; no other expected virus was detected by routine molecular assays.
Clinically unrecognized viral sequences
We found clinically unrecognized sequences belonging to either rare and/or recently identified viruses (HAstV MLB2, Usutu virus, bufavirus, cutavirus, HPyV-6, and HPyV-7) or those not routinely assessed alongside GvHD (classic HAstV and rubella virus) in 7/25 patients, whose characteristics are detailed in Table 2.
Table 2 Clinical characteristics of 7 patients with clinically unrecognized viral sequences
Patient’s code Age, gender Underlying disease GvHD organ GvHD treatmentsa Outcome
Ge02 61, M Lymphoma Digestive, skin CSA, tacrolimus, corticosteroids, sirolimus, budenoside, photopheresis Death (GvHD-related)
Ge05 23, M Lymphoma Digestive, skin, lung CSA, MMF, tacrolimus, corticosteroids Death
Ge07 60, M ALL Digestive Tacrolimus, corticosteroids, photopheresis Death
Ge09 65, M AML Liver, digestiveb CSA, corticosteroids, tocilizumab Death
Ge12 44, M MM Digestive, liver CSA, corticosteroids, basiliximab, MMF Death
Ge14 31, M AML Digestive, liver Corticosteroids Death
Ge22 68, M MDPS Digestive, skin CSA, tacrolimus, corticosteroids, vedolisumab, prolastin Death
Age at the time of transplantation
Abbreviations: GvHD graft-versus-host disease, M male, ALL acute lymphoid leukemia, AML acute myeloid leukemia, MM multiple myeloma, MDPS myelodysplasic proliferative syndrome, CSA cyclosporine A, MMF mycophenolate mofetil
aAll patients had ruxolitinib as part of the GvHD treatment
bDigestive GvHD was not confirmed by biopsies
mNGS identifications of these clinically unrecognized viral sequences were confirmed by r(RT-)PCR in unpooled plasma samples. Whenever available during/after the period of sample selection, additional specimens and/or tissue biopsies were screened over a median period of 7.1 weeks (IQR 25.3). These findings are shown in Table 3.
Table 3 mNGS and r(RT-)PCR results of 7 patients with clinically unrecognized viral sequences
Viral species detected with mNGS Viral species confirmed with r(RT)-PCR assays
Patient’s code Virus Plasma, n (pos/total) Time period (days) Estimated viral load (mean log10 copies/ml plasma or CT values) Other positive biological specimen
Ge02 HPyV7 14/14 279 4.75 BM, BAL
Ge05 Usutu virus 2/5 7 4.66 –
Ge07 Cutavirus 6/10 98 37.9 Skin
Ge09 Bufavirus 6/12 81 3.73 Stools, duodenum
Ge12 Novel human astrovirus MLB2 2/6 14 3.24 Intestine, colon, BM
Ge14 Rubella virus 3/5 39 37.9 –
Classic human astrovirus 5/11 25 5.56 –
HPyV6 11/11 74 3.76 –
Ge22 Rubella virus 2/8 3 36.7 –
Pos/total corresponds to the number of positive samples on the total of screened samples. Time period corresponds to the time period during which samplings were found positive. CT values above 40 were considered negative. CT values are indicated in italics
Abbreviations: BM bone marrow, BAL bronchoalveolar lavage, CT cycle threshold
Brief clinical description of patients harboring clinically unrecognized viral sequences
Ge02: HPyV-7
A 61-year-old male, transplanted for lymphoma, developed digestive and skin GvHD; intensive immunosuppression for GvHD lasted from 12 to 16 months after transplantation (4-month sample period), when the patient died from a post-transplant EBV-related lymphoma disease. Beginning 9 months before death, we found HPyV-7 in all screened plasma samples. In addition, HPyV-7 was also found in a BAL and a bone marrow sample collected 8 months after transplantation (2.8 log10 DNA copies/ml and CT value 28, respectively).
Ge05: Usutu virus
A 23-year-old male, transplanted for lymphoma, developed digestive skin and lung GvHD; intensive immunosuppression for GvHD lasted from 1 to 24 months after transplantation (22-month sample period), when the patient died from a disseminated fungal infection and GvHD. We found Usutu virus in 2 plasma samples collected 7 days apart, a few days after a blood transfusion, and 1.5 months before death.
Ge07: cutavirus
A 60-year-old male, transplanted for acute lymphoblastic leukemia, developed digestive GvHD; intensive immunosuppression for GvHD lasted from 6 to 8 months after transplantation (2-month sample period), when the patient died from a disseminated fungal infection and GvHD. We found cutavirus in a skin biopsy performed 3 weeks before transplantation (CT of 35) and at low plasma VL for 3 months before death. Autopsy results confirmed digestive GvHD and a disseminated mold infection.
Ge09: bufavirus
A 65-year-old male, transplanted for acute myeloid leukemia (AML), developed liver GvHD; intensive immunosuppression for GvHD lasted from 5 to 7 months after transplantation (2 month sample period), when the patient died from GvHD. We detected bufavirus RNA in several plasma samples taken over 2 months before death. In addition, bufavirus was also found in stool samples collected the day of and 1.5 months after transplantation, at CT values of 38.2 and 34.7, respectively, and in a duodenal biopsy performed 5 months after transplantation (CT value 27.3), which revealed chronic duodenitis.
Ge12: HAstV MLB2
A 44-year-old male, transplanted for multiple myeloma, developed a digestive and liver GvHD; intensive immunosuppression for GvHD lasted from 15 days to 2 months after transplantation (2-month sample period), when the patient died from the GvHD. We detected HAstV MLB2 RNA in two plasma samples collected 14 days apart and shortly before death, in a colonic biopsy performed few days before death (CT value 27.9), and in several intestine, colonic, and bone marrow autopsy samples (mean CT values 25.8, 27.6, 28, respectively). Autopsy results confirmed liver and digestive GvHD and revealed chronic pulmonary GvHD.
Ge14: rubella virus, classic HAstV, HPyV-6
A 31-year-old male of Chinese origin, transplanted for AML, developed digestive and liver GvHD; intensive immunosuppression for GvHD lasted 9–11 months after transplantation (3-month sample period), when the patient died from an acute intestinal perforation in the context of recurrent digestive GvHD. In several plasma samples starting 1 month before death, we found classic HAstV RNA and low VLs of a wild-type Chinese rubella strain. HPyV-6 DNA was also persistently found in plasma samples starting 2 months before death. The patient was seropositive for rubella before transplantation.
Ge22: rubella virus
A 68-year-old Portuguese male, transplanted for myelodysplastic syndrome, developed digestive and skin GvHD; intensive immunosuppression for GvHD lasted from 4 to 6 months after transplantation (6-week sample period), when the patient died from GvHD. Two plasma samples were positive for rubella-vaccine RNA at low VLs. The patient was seropositive before transplantation.
Discussion
We analyzed viral sequences by mNGS in pooled plasma samples of 25 adult allo-HSCT patients with severe steroid-refractory/dependent GvHD. Viral nucleotide sequences were found in 96% of patients, and 64% of patients had ≥ 3 distinct viral species. Besides commensal (Anelloviridae and HPgV-1) and latent (EBV, CMV, HSV-1, BKPyV, JCPyV) viruses known to be highly prevalent/reactivate in allo-HSCT recipients, 28% of patients had clinically unrecognized viral sequences that are rarely/never reported in allo-HSCT patients, with unknown pathogenicity (bufavirus, cutavirus, HPyV-6/7, novel HAstV-MLB2, classic HAstV, rubella virus, and Usutu virus). Chronic HBV and HEV infections were also confirmed by mNGS in two patients.
Anelloviridae (TTV, TTMV, and TTMDV) were the most prevalent in this study, concordant with the high TTV viremia rate identified among allo-HSCT recipients [28–31]. The high TTV, TTMV, and TTMDV co-detection rate has been previously described [30]. Chronic anelloviruses infection/re-infection is common, but disease associations remain undetermined [32]. Among allo-HSCT recipients, two studies failed to demonstrate any association between TTV viremia and immune-related complication or other viral reactivations [28, 33], while a third reported higher TTV viremia in patients receiving corticosteroids for GvHD [29]. A recent study found higher TTV VL at 100 days post-transplantation predicts worse overall survival, and a higher risk of acute GvHD and infections [34]. Finally, a mNGS study revealed increased detection rates and number of Anelloviridae sequences in stool samples of allo-HSCT recipients several weeks after developing digestive GvHD [5], suggesting a consequence of GvHD-associated inflammation and/or immunosuppressive therapy. Altogether, these data suggest that TTV viremia could be a potential immunosuppression-marker, requiring further investigation.
HPgV-1 (a Flaviviridae [35]) viremia occurs in 1–4% of blood donors in developed countries [36] and up to 30% of allo-HSCT recipients but has not been associated with clinical consequences [3, 4]. Given the interaction of HPgV-1 with the immune system [37], the effect of persistent HPgV-1 viremia requires deeper investigation.
We found four species of HPyV (JCPyV, BKPyV, HPyV-6/7), with JCPyV viremia occurring in 16% of allo-HSCT recipients, agreeing with studies where concomitant use of multiple immunosuppressive treatments was associated with increased persistent viremia risk—although progressive multifocal leucoencephalopathy was rare [38]. In another study, JCPyV DNA detection rate in plasma decreased from 4/22 to 1/22 patients at 3 and 12–18 months after transplantation, respectively, while viremia was not linked to any clinical manifestation [39]. Our study’s BKPyV prevalence (28%) was lower than the 54% of another study [40]. Notably, our patients did not develop hemorrhagic cystitis.
Contamination or other bioinformatics errors were excluded for each of the clinically unrecognized viral sequences, by confirming the mNGS-identified viral sequences using r(RT-)PCR on blood and non-blood samples at different time-points. These assays found cutavirus (60%) and bufavirus (50%), two Protoparvoviruses, in plasma samples at low VL. Interestingly, available skin and digestive biopsy tissues, previously described as putative primary infection sites [24, 41, 42], were positive by PCR at or shortly before transplantation, indicating viral latency and reactivation under immunosuppressive conditions. Bufavirus was first discovered in stool samples of children in 2012, and the stool prevalence is about 0.3–4.1%, although high seroprevalence was identified in some countries [41, 42]. Bufavirus was recovered in stools of subjects with digestive symptoms, but not in asymptomatic controls [41]. Whether bufavirus influences syndromes attributed to digestive GvHD remains unknown. Cutavirus was discovered in 2016 in stools of diarrheic children in Brazil with a prevalence of about 1–1.6%, and curiously, some associations were made with cutaneous T cell lymphoma [24, 41]. To our knowledge, cutavirus and bufavirus viremia have not been described before.
Usutu virus (a Flaviviridae) is an arbovirus, endemic in Africa and several European countries, that frequently co-circulates with West Nile virus [43–45]. The virus enzootic cycle involves birds (main reservoir) and ornithophilic mosquitos (vectors); humans are incidental and dead-end hosts [43]. Less than 50 documented cases of acute Usutu virus infections have been reported in humans, most of them corresponding to the identification of Usutu virus genome in donated blood samples [45]. Human Usutu virus infection can be asymptomatic or associated with various clinical manifestations, including fever, rash, and neurological manifestations; the virus genome was detected in some cases in CSF or blood samples [43, 45, 46]. The virus can infect neurons, astrocytes, microglia cells, and induced pluripotent stem cell (IPSc)-derived human neuronal stem cells, with a reduction in cell proliferation, induction of antiviral response, and apoptosis [47]. In our study, Usutu virus was transiently identified shortly after a blood transfusion, but retrospective blood bag testing was impossible. Although blood transmission has not been described, screening over ≥ 130,000 blood donations revealed 38 positive donors [48, 49]. Although overt clinical consequences are absent in our patient, this flavivirus is known to cause occasional complications [45] and cannot be disregarded. If transmission occurred by transfusion, it is possible that only remnant RNA was transmitted, not infectious virus.
Astroviruses are well-recognized enteric viruses infecting mainly children, elderly, and immunocompromised patients [50]. HAstV MLB2 was identified a decade ago [51], and since then, it has been demonstrated that it is circulating in every continent [50]. In addition, it is associated with systemic and central nervous system infections [7, 52] and has been identified in stool samples of asymptomatic children [53]. In our mNGS study, classic HAstV was found in plasma samples of a patient with digestive GvHD shortly before death, and HAstV MLB2 was found at low VL in plasma samples of a patient with diarrhea due to digestive GvHD. In the latter, autopsy confirmed the presence of HAstV MLB2 RNA in several intestinal and colonic samples at significant VLs. The presence of astrovirus MLB2 in the digestive tract of the patient is thus evident, and HAstV viremia plausibly came from an intestinal spillover in the context of the GvHD and intestinal perforation.
HPyV-6 and 7 were discovered in 2010 [54] and have been identified in a wide range of clinical samples of healthy subjects, transplant recipients, and symptomatic immunocompetent patients [55–59]. They have been detected mostly in skin specimens of non-transplanted individuals and transplanted recipients with or without dermatological diseases, but the association with clinical manifestation is not established [55, 57, 59–61]. The reported seroprevalence rates of HPyV6 and HPyV7 in immunocompetent and immunocompromised adults varies from 69 to 84% and 35 to 72%, respectively [3]. The transmission route, tropism, pathogenic mechanisms, and potential association with human diseases are still not established. HPyV-6 DNA prevalence in healthy blood donors is 0.1% and 0.6% in kidney transplant recipients [3], while HPyV-7 has been detected in lung transplant recipients [3], yet no obvious clinical manifestations are associated with them. We report persistent HPyV-6/7 viremia in plasma samples of 2/25 allo-HSCT recipients over several months. Further investigations are needed to determine their pathogenicity.
Rubella virus was our most unexpected finding, yet the rubella reads for both patients mapped to different regions along the genome (rubella virus genome coverage of 3.69% and 5.47% for patients Ge14 and Ge22, respectively) and mNGS results were confirmed by specific rRT-PCR in several samples over a period of 39 and 3 days for patients Ge14 and Ge22, respectively.
Although rubella can persist in in vitro and animal models [62–64], it is not known to persist after vaccination or natural infection in humans, except in vaccinated immuno-deficient children [65–68]. Chronic rubella infection has also been hypothesized as causing Fuch’s heterochromic iridocyclitis, although the pathophysiology remains unknown [69, 70]. We found rubella sequences with low VLs in two patients, each with a distinct strain: a vaccine strain and a Chinese strain that was found in a patient who previously lived in China. Macrophages and keratinocytes are potential sites for rubella persistence [66], but retrospectively screened skin samples from one patient gave negative results. Both patients were seropositive before transplantation. Patients with GvHD frequently become seronegative for measles and rubella within 2 years after allo-HSCT [71]. Identification of the usual vaccine strain and a Chinese strain in a native Chinese, strongly argues for reactivation, in line with antibody loss after transplantation. Yet, we noted a decreased rubella IgG titer in one of both patients at the time of viremia, compared to the pre-transplant titers. Gonzalez et al. reported the case of a child who developed fulminant hepatitis after stem cell transplantation despite prior vaccination [72]. The hypothesis raised by the authors of a primary infection from a recently vaccinated contact implies that circulating vaccine strains in the population could be an issue for immunocompromised patients with waning antibodies. Whether rubella persistence could trigger GvHD after transplantation and where the viral reservoir would be are open questions.
A recent trial identified ruxolitinib as a second-line treatment for steroid-refractory GvHD, which has a poor prognosis and no approved clearly beneficial treatment [14, 73]: in the study, about 1/3 patients experienced a grade 3 infection, highlighting the importance of monitoring patients for infections. Our study reveals that some viral infections were overlooked by standard procedures, which may indicate that the 30% of infection risk associated with ruxolitinib could be underestimated, and raises the question of including mNGS analysis in the management of high-risk patients.
Among the 7 patients with clinically unrecognized viral sequences, most sequences were identified a few weeks before and, persisted until, patients’ deaths. Although neither the pathogenic nature of the viruses nor the clear associations with patient outcomes are proven, the identification of these viral sequences in patients’ blood during severe GvHD is relevant and reflects the altered immune response; monitoring these infections could help adjust immunosuppressive therapies. Among these patients, with nearly daily blood sample collection, such strategies could routinely be actionable by pooling plasma samples (overcoming transient viremia problems), with the aim of excluding disseminated infections before increasing immunosuppression, and unmasking a viral infection mimicking the GvHD syndrome.
The identification of HAstV and bufavirus in digestive tracts of patients with digestive GvHD may merely reflect the patient’s gut virome, but identification of enteric viruses in blood samples could indicate a disseminated infection that is triggered by GvHD inflammation or immunosuppressive treatment, which may require treatment adaptation.
These viral infections cannot be considered innocent bystanders. Most of the identified viruses can be shed asymptomatically, but certainly lead to organ disease under conditions where they become opportunistic pathogens, potentially causing unrecognized clinical features; they can also lead to a clinical exacerbation. The particular immunologic state of our population may influence this delicate balance between an indolent virus and its clinical impact.
A major limitation of this study is the small monocentric cohort. Additionally, including only allo-HSCT recipients with steroid-refractory/dependent GvHD precluded generalization of the results to all allo-HSCT recipients. Furthermore, we lacked control patients without GvHD. Despite the numerous viral infections revealed by mNGS, whether these are specific to patients with GvHD or to those treated with ruxolitinib, and if there is an association with clinical manifestations and/or an impact on the immune state of these patients, remains to be determined by appropriate studies. Notably, according to the comparison with routine diagnostic results and confirmatory r(RT-)PCR, our mNGS pipeline is accurate, although with a lower sensitivity compared to specific quantitative real-time PCR assays used in most routine laboratories.
Conclusions
Blood analysis of patients with steroid-refractory/dependent GvHD revealed clinically unrecognized viral sequences in 28% of patients, including rubella virus, novel protoparvoviruses, HPyV-6/7, Usutu virus, and HAstV-MLB2. These viruses have been described in humans, but rarely reported as causes of disease in allo-HSCT patients, or have unknown pathogenicity. Rubella virus identifications imply possible re-emergence from past infection or vaccination. Further investigations are needed to understand the clinical significance of these infections.
Supplementary Information
Additional file 1: Table S1. Detailed mNGS results per patient for the 25 adult allo-HSCT patients. Table S2. Comparison of mNGS results on the pooled plasma samples and of the routine r(RT-)PCR results on the corresponding plasma samples of the 25 patients. Figure S1. Boxplot of mapped reads of DNA viruses and corresponding mRNA detection with mNGS. The vertical axis represents the number of mapped reads. The horizontal axis represents all identified viral sequences of DNA viruses (left panel) and corresponding mRNA sequences (right panel). The numbers on the horizontal axis represent the number of patients in which sequences of each virus were identified. Abbreviations: HSV-1: herpes simplex 1 virus; CMV: cytomegalovirus; EBV: Epstein-Barr virus; TTMDV: torque teno midivirus; TTMV: torque teno minivirus; TTV: torque teno virus.
Publisher’s Note
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L. Kaiser and D. L. Vu contributed equally to this work.
Acknowledgements
The authors would like to thank Fiona Pigny for technical assistance and Erik Boehm for editorial assistance.
Authors’ contributions
MCZ, DLV, SC, and LK designed the research project. GV, MD, FL, and SC performed the mNGS and sequence analysis and r(RT-)PCR assays. VB, TAM, and JAL performed the biopsies histological examination. CVD, SML, and YC contributed to the interpretation of data regarding transplantation. MCZ, DLV, and SC collected and interpreted the data and wrote the first draft of the manuscript. All other authors revised and commented on the manuscript. The authors read and approved the final manuscript.
Funding
This work was supported by the “Projets Recherche et Développement (PRD)” of Geneva University Hospitals (grant number PRD 17-2019-I) and the Swiss National Science Foundation (grant number 320030_179507).
Availability of data and materials
The datasets generated and/or analyzed during the current study are available in the Dryad repository (10.5061/dryad.0k6djh9xp). The raw sequence data were deposited in the NCBI Sequence Read Archive under BioProject accession number PRJNA641787.
Ethics approval and consent to participate
The study protocol was approved by the Geneva Cantonal Ethics Commission (project #2019-00511).
Consent for publication
Not applicable
Competing interests
The authors declare that they have no competing interests. | CYCLOSPORINE, MYCOPHENOLATE MOFETIL, TACROLIMUS | DrugsGivenReaction | CC BY | 33487167 | 18,939,834 | 2021-01-24 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Viral infection'. | Unmasking viral sequences by metagenomic next-generation sequencing in adult human blood samples during steroid-refractory/dependent graft-versus-host disease.
Viral infections are common complications following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Allo-HSCT recipients with steroid-refractory/dependent graft-versus-host disease (GvHD) are highly immunosuppressed and are more vulnerable to infections with weakly pathogenic or commensal viruses. Here, twenty-five adult allo-HSCT recipients from 2016 to 2019 with acute or chronic steroid-refractory/dependent GvHD were enrolled in a prospective cohort at Geneva University Hospitals. We performed metagenomics next-generation sequencing (mNGS) analysis using a validated pipeline and de novo analysis on pooled routine plasma samples collected throughout the period of intensive steroid treatment or second-line GvHD therapy to identify weakly pathogenic, commensal, and unexpected viruses.
Median duration of intensive immunosuppression was 5.1 months (IQR 5.5). GvHD-related mortality rate was 36%. mNGS analysis detected viral nucleotide sequences in 24/25 patients. Sequences of ≥ 3 distinct viruses were detected in 16/25 patients; Anelloviridae (24/25) and human pegivirus-1 (9/25) were the most prevalent. In 7 patients with fatal outcomes, viral sequences not assessed by routine investigations were identified with mNGS and confirmed by RT-PCR. These cases included Usutu virus (1), rubella virus (1 vaccine strain and 1 wild-type), novel human astrovirus (HAstV) MLB2 (1), classic HAstV (1), human polyomavirus 6 and 7 (2), cutavirus (1), and bufavirus (1).
Clinically unrecognized viral infections were identified in 28% of highly immunocompromised allo-HSCT recipients with steroid-refractory/dependent GvHD in consecutive samples. These identified viruses have all been previously described in humans, but have poorly understood clinical significance. Rubella virus identification raises the possibility of re-emergence from past infections or vaccinations, or re-infection. Video abstract.
Background
Viral primary infections and reactivations are common complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and are associated with significant morbidity and mortality [1, 2]. Current routine clinical surveillance molecular assays detect specific nucleotide sequences targeting usual culprits including Epstein-Barr virus (EBV), cytomegalovirus (CMV), BK polyomavirus (BKPyV), and adenovirus [3]. Metagenomic next-generation sequencing’s (mNGS) unbiased approach broadens viral infection diagnosis, theoretically detecting “all” viral nucleotide sequences or viral infections present [4–7], and is increasingly used in clinical investigations [8]. Allo-HSCT recipients suffering from steroid-refractory/dependent acute or chronic graft-versus-host disease (GvHD) are highly immunosuppressed patients; GvHD immune dysregulation, mucosal barrier alteration [9–13], and multiple prolonged immunosuppressive treatments create a permissive environment for opportunistic viral infections [10, 11, 14]. These clinically unrecognized viral infections can present with limited symptoms/atypical manifestations and lead to intermittent or prolonged viremia [3]. Given the nonspecific clinical features of GvHD and some viral infections, viral infections may remain clinically unrecognized due to limitations of clinical molecular assays.
We hypothesized that some viral infections, which would normally remain undiagnosed with common clinical assays, occur during intense immunosuppressive therapy in steroid-refractory/dependent GvHD. This study aimed to identify viruses that are not routinely searched by RT-PCR routine assays in clinical practice, due to the lack of knowledge. Therefore, we used mNGS on pooled plasma samples of adult allo-HSCT patients with steroid-refractory/dependent acute or chronic GvHD to look for viruses that could be missed by biased technology.
Methods
Setting, study population, and design
This observational study was conducted at the Geneva University Hospitals (HUG), Switzerland. The study protocol was approved by the Geneva Cantonal Ethics Commission (project #2019-00511). Inclusion criteria were adult patients who received an allo-HSCT from 1 January 2016 to 31 December 2018 at the HUG, who were enrolled in the local monocentric infectious disease cohort of allo-HSCT patients, and who developed steroid-refractory/dependent acute or chronic GvHD. All included patients provided written consent before enrollment. The only exclusion criteria was the lack of informed written consent.
Plasma samples were prospectively collected during clinical management after allo-HSCT and stored in the Laboratory of Virology, HUG. We performed mNGS analysis on pooled plasma samples of each patient, collected throughout the period of intensive steroid treatment or second-line GvHD therapy.
Definitions
Steroid-refractory/dependent acute and chronic GvHD were defined according to the position statement of the GvHD experts in Schoemans et al. [15].
Microbiological methods
mNGS and sequence analysis
Each pool (corresponding to 4 to 10 plasma samples from each patient) was prepared to obtain a final volume of 220 μl. Pools were then centrifuged at 10,000×g for 10 min to remove cells. Two-hundred microliters of cell-free supernatant were treated with 20 μl of Turbo DNAse (2 U/μl) + 24 μl of 10x TURBO DNase Buffer (Ambion, Rotkreuz, Switzerland), according to the manufacturer’s instructions. Then, the whole volume was divided into two tubes of 120 μl each. One tube was then used for each of the two nucleic acid extraction procedures. Indeed, virus genome extractions were done using two previously published protocols in parallel [16], namely the RNA and DNA protocols optimized for the detection of RNA and DNA viral sequences, respectively.
For the RNA protocol, nucleic acids were extracted with TRIzol (Invitrogen, Carlsbad, CA, USA). Ribosomal RNA was removed (Ribo-Zero Gold depletion kit (Illumina, San Diego, USA) before libraries’ preparation (TruSeq total RNA preparation protocol (Illumina)). Libraries’ concentrations and sizes were analyzed using the Qubit (Life Technologies, Carlsbad, CA, USA) and the 2200 TapeStation instruments (Agilent, SantaClara, CA, USA), respectively. Each library was loaded individually in a single lane on the HiSeq 4000 platform (Illumina) using the 2 × 100-bp protocol with dual-indexing. The mean total number of read pairs obtained per pool was 328,936,594.84 (range 252,670,103 to 385,257,539).
For the DNA protocol, nucleic acids were extracted with the NucliSens easyMAG magnetic bead system (bioMérieux, Geneva, Switzerland). As previously published [16], double-stranded DNA synthesis was done with the DNA polymerase I, Large Fragment (Klenow) (New England BioLabs, Ipswich, MA, USA)). Libraries were prepared using the Nextera XT (Illumina) protocol. Libraries’ concentrations and sizes were analyzed using the Qubit (Life Technologies) and the 2200 TapeStation instruments (Agilent), respectively. Each library was loaded individually in a single lane on the HiSeq 4000 platform (Illumina) using the 2 × 100-bp protocol with dual-indexing. The mean total number of read pairs obtained per pool was 301,393,033.48 (range 122,939,325 to 377,758,795).
To check for potential contaminating viral sequences from environment or experimental reagents [17], four negative controls (i.e., Neg1-4) were submitted to the whole mNGS procedure. To assess the mNGS process efficiency, positive controls underwent the whole mNGS procedure (canine distemper virus (CDV)-spiked samples and a baculovirus (GenScript, Piscataway, NJ, USA) harboring 793 nucleotides of the CDV fusion gene were used as positive controls for the RNA and DNA protocols, respectively).
Paired reads were quality filtered using Trimmomatic [18]. Reads mapped against the human genome and transcriptome (hg38, gencode.V23) were removed using SNAP [19]. Remaining reads were analyzed using two methods in parallel as previously described [20]: (1) by a pipeline that used virusscan 1.0 (https://github.com/sib-swiss/virusscan) to map reads against the Virosaurus database (version V90v_2018_11) (https://viralzone.expasy.org/8676), which is designed to report vertebrate viruses, and (2) by de novo assembly. Only viruses with ≥ 300 nucleotides of coverage were reported. The raw sequence data were deposited in the NCBI Sequence Read Archive under BioProject accession number PRJNA641787.
Sequences were considered clinically recognized viruses if they corresponded to a virus known to reactivate in/be frequently found among allo-HSCT recipients [2, 4] or if the patient had a known chronic viral infection and clinically unrecognized viruses if not.
Confirmatory real-time (reverse transcription-)polymerase chain reaction (r(RT-)PCR) assays
Clinically unrecognized mNGS findings were confirmed on unpooled plasma by specific semi-quantitative or quantitative r(RT-)PCR assays as previously published; additional specimens (including plasma, cerebrospinal fluid, bronchoalveolar lavage (BAL) fluids, nasopharyngeal swabs, native urines, stools suspension, tissue biopsies or bone marrow) were tested when available and pertinent. Quantitative r(RT-)PCR assays were done for Mamastrovirus 1 (classical) using the updated human astrovirus (HAstV) combination [21], Mamastrovirus 6 (MLB2) using the MLB2 assay [22], Usutu virus [23], and bufavirus using the BuV (NS1) assay [24]. Semi-quantitative r(RT-)PCR assays were done for cutavirus using the CuV (VP2) assay [24], human polyomavirus (HPyV) 6 using the VP2 assay [25], HPyV-7 using the VP2 assay [25], and rubella virus [26].
Nucleic acids from plasma, cerebrospinal fluid, BAL fluids, nasopharyngeal swabs, urine, stools resuspended in PBS, and bone marrow were extracted individually from 190 μL of each specimen, spiked with 10 μL of standardized CDV as internal control [27], using the NucliSENS easyMAG (bioMérieux, Geneva, Switzerland) nucleic acid kit, according to the manufacturer’s instructions, and eluted in 25 μL. DNA and RNA were extracted from tissue biopsies using the QIAamp DNA FFPE Tissue Kit (Qiagen, Hombrechtikon, Switzerland) and High Pure FFPET RNA isolation kit (Roche Applied Sciences, Indianapolis, IN, USA), respectively, following the manufacturer’s instructions. For RNA viruses, the rRT-PCR assays were performed using the one-step QuantiTect Probe RT-PCR Kit (Qiagen, Hombrechtikon, Switzerland) in a StepOne Plus instrument (Applied Biosystems, Rotkreuz, Switzerland). For DNA viruses, the rPCR assays were performed using the TaqMan Universal PCR Master Mix (Applied Biosystems) in a StepOne Plus instrument (Applied Biosystems) for cutavirus and bufavirus or in a QuantStudio 5 instrument (Applied Biosystems) for HPyV6 and 7.
For quantitative r(RT)-PCR assays, standard curves and lower limit of quantifications (LOQ) were assessed using 10-fold serial dilutions of specific RNA oligonucleotides (Mamastrovirus 1 (classical) and 6 (MLB2): LOQ = 1.25E4 and 1.25E3 RNA copies/ml of plasma, respectively), RNA transcript (Usutu virus: LOQ = 1.32E2 RNA copies/ml of plasma), DNA oligonucleotides (bufavirus: LOQ = 1.32E3 DNA copies/ml of plasma), or plasmids (HPyV6 and 7: LOQ = 2.63E2 DNA copies/ml of plasma each) containing the target sequences.
Statistical analysis
Categorical variables were described by counts and percentages. Continuous variables were expressed as mean and standard deviation or median and interquartile range.
Results
Patient characteristics
We identified 25 adult allo-HSCT recipients with acute or chronic steroid-refractory/dependent GvHD. Table 1 shows the patient’s characteristics. The median duration of intensive immunosuppression was 5.1 months (IQR 5.5), and 22/25 patients received ruxolitinib. At the time of writing, fifteen patients have died, with 9 considered as GvHD-related.
Table 1 Patients’ characteristics (25 allo-HSCT patients)
Total
n = 25
Demographics
Sex (male), n (%) 16 (64.0)
Age, median (IQR) 58.0 (25.0)
Allo-HSCT considered in the analysis,
n
(%)
First 23 (92.0)
Second 2 (8.0)
Transplant source,
n
(%)
Bone marrow 5 (20)
Peripheral blood cells 20 (80)
Underlying disease,
n
(%)
Acute myeloid leukemia 10 (40.0)
Lymphoid malignancy 6 (24.0)
MDS/MDPS 3 (12.0)
Acute lymphoid leukemia 2 (8.0)
Othera 4 (16.0)
Risk score,
n
(%)
Low 0 (0)
Intermediate 18 (72.0)
High 7 (28.0)
Donor sex, M,
n
(%) 7 (28.0)
Donor age, median (IQR) 36 (16.5)
Donor match,
n
(%)
Donor-related 10 (40.0)
CMV donor/recipient constellation,
n
(%)
+/+ 12 (48.0)
−/+ 1 (4.0)
+/− 7 (28.0)
−/− 5 (20.0)
CMV prophylaxis, n (%) 1 (4.0)
Conditioning,
n
(%)
Myeloablative conditioning 5 (20.0)
GvHD prophylaxis,
n
(%)
Calcineurin inhibitor 24 (96.0)
Mycophenolate mofetil 17 (68.0)
Methotrexate 7 (28.0)
GvHD organ,
n
(%)
Digestive tract 17 (68.0)
Skin 15 (60.0)
Mouth 4 (16.0)
Liver 7 (28.0)
Lung 5 (20.0)
Eyes 2 (8.0)
Musculoskeletal 1 (4.0)
GvHD grade or severity,
n
(%)
Grade
2 9 (36.0)
3 3 (12.0)
4 6 (24.0)
Moderate 6 (24.0)
Severe 7 (28.0)
GvHD treatment,
n
(%)
Corticosteroids 24 (96.0)
Ruxolitinib 22 (88.0)
Calcineurin inhibitor 21 (84.0)
Mycophenolate mofetil 12 (48.0)
Photopheresis 12 (48.0)
Budenoside 5 (20.0)
Sirolimus 3 (12.0)
Tocilizumab 2 (8.0)
Otherb 6 (24.0)
Death,
n
(%) 15 (60.0)
Median delay from allo-HSCT, months (IQR) 11.2 (15.8)
One patient could have multiple GvHD prophylaxis and treatment, multiple organs with GvHD and multiple grades of severity. CMV prophylaxis: one patient (patient Ge24) received letermovir during the period of intensive steroid treatment or second-line GvHD therapy. GvHD grade refers to acute GvHD, GvHD severity refers to chronic GvHD. In two patients, there was no information on grade/severity. Only organs with grade GvHD ≥ 2 or severity ≥ moderate are reported
Abbreviations: IQR interquartile range, allo-HSCT allogeneic hematopoietic stem cell transplantation, MDS/MDPS myelodysplasic syndrome/myelodysplasic proliferative syndrome, ATG anti-thymocyte globulin
aOther includes: multiple myeloma (n = 2), chronic myeloid leukemia (n = 1) and mixed acute leukemia (n = 1)
bOther includes: azithromycine, montelukast, prolastin, vedolisumab, nilotinib, basilixumab, ibrutinib, and/or methotrexate
Viral sequences identified with mNGS and confirmatory analyses
The mNGS analysis revealed viral nucleotide sequences in all patients except Ge18 (24/25). In 16/25 patients, ≥ 3 distinct viral species were detected (Fig. 1). Figure 2 depicts the prevalence of each identified virus, and Table S1 provides detailed mNGS characteristics.
Fig. 1 Grid plot of viral sequences identified with mNGS in pooled plasma samples (25 allo-HSCT patients). Each line corresponds to viral sequences assigned to one virus; the bottom line corresponds to mNGS negative (Neg1-4) and positive (Pos1/2 DNA/RNA) control samples. Each column corresponds to one pool of plasma sample (one patient). Colors represent the approximate number of reads matching virus genome detected in each pool of plasma samples. *Since they were detected in one negative control, human papillomavirus sequences were considered as likely contaminant. # cross-contamination. Abbreviations: HAstV human astrovirus, TTV torque teno virus, TTMV torque teno minivirus, TTMDV torque teno midivirus, HSV-1 herpes simplex 1 virus, EBV Epstein-Barr virus, CMV cytomegalovirus, CTRL control
Fig. 2 Prevalence of viruses identified with mNGS in pooled plasma samples (25 allo-HSCT recipients). The vertical axis represents all identified viral sequences. The horizontal axis represents the number of patients in which sequences of each virus were identified. Abbreviations: TTV torque teno virus, TTMV torque teno minivirus, CMV cytomegalovirus, TTMDV torque teno midivirus, EBV Epstein-Barr virus, HSV-1 herpes simplex 1 virus, HAstV human astrovirus
Anelloviridae (torque teno virus (TTV), torque teno minivirus (TTMV) and torque teno midivirus (TTMDV)) and human pegivirus-1 (HPgV-1) were the most prevalent with sequences detected in 24/25 and 9/25 patients, respectively.
Other detected DNA viruses included BK polyomavirus (BKPyV) (7/25), CMV (5/25), and JC polyomavirus (JCPyV) (4/25), and also herpes simplex virus 1 (HSV-1), EBV, hepatitis B virus (HBV), bufavirus, cutavirus, and HPyV-6/7, each detected once (1/25). Except HPgV-1, the detected RNA viruses were less prevalent than DNA viruses and were HAstV (Mamastrovirus 1 and 6) and rubella virus, both detected twice (2/25), and also hepatitis E (HEV) and Usutu viruses, both detected once (1/25). The de novo analysis did not reveal other relevant sequences. Interestingly, sequences for TTV (11/24), CMV (3/5), EBV (1/1), and HBV (1/1) were detected in both DNA and RNA libraries, suggesting active viral replication (Figure S1).
Clinically recognized viral sequences
Although not routinely searched in clinical practice, Anelloviridae and HPgV-1 sequences were identified in 96% and 36% of patients and were classified among clinically recognized viral sequences as they are known to be highly prevalent among immunocompromised patients. In 14/25 patients, mNGS analysis identified sequences of latent DNA viruses known to reactivate in transplant recipients (EBV, CMV, HSV-1, BKPyV, JCPyV, HBV). At the RNA level, HEV was identified once.
The r(RT-)PCR assays performed during routine investigations confirmed the mNGS analysis (Table S2): patient Ge05 had a chronic HEV infection, and patient Ge14 had chronic HBV and cutaneous HSV-1 infections, and HSV-1 viremia. BKPyV and JCPyV were not systematically screened and were only revealed by mNGS analysis. However, BKPyV was screened in patient Ge06 and detected at low viral loads (VL) (1.41E2 and 1.44E3 copies/ml) in two plasma samples collected a few days apart from those included for mNGS analysis. In 12/25 patients, CMV and EBV were detected only by rPCR at low VL; no other expected virus was detected by routine molecular assays.
Clinically unrecognized viral sequences
We found clinically unrecognized sequences belonging to either rare and/or recently identified viruses (HAstV MLB2, Usutu virus, bufavirus, cutavirus, HPyV-6, and HPyV-7) or those not routinely assessed alongside GvHD (classic HAstV and rubella virus) in 7/25 patients, whose characteristics are detailed in Table 2.
Table 2 Clinical characteristics of 7 patients with clinically unrecognized viral sequences
Patient’s code Age, gender Underlying disease GvHD organ GvHD treatmentsa Outcome
Ge02 61, M Lymphoma Digestive, skin CSA, tacrolimus, corticosteroids, sirolimus, budenoside, photopheresis Death (GvHD-related)
Ge05 23, M Lymphoma Digestive, skin, lung CSA, MMF, tacrolimus, corticosteroids Death
Ge07 60, M ALL Digestive Tacrolimus, corticosteroids, photopheresis Death
Ge09 65, M AML Liver, digestiveb CSA, corticosteroids, tocilizumab Death
Ge12 44, M MM Digestive, liver CSA, corticosteroids, basiliximab, MMF Death
Ge14 31, M AML Digestive, liver Corticosteroids Death
Ge22 68, M MDPS Digestive, skin CSA, tacrolimus, corticosteroids, vedolisumab, prolastin Death
Age at the time of transplantation
Abbreviations: GvHD graft-versus-host disease, M male, ALL acute lymphoid leukemia, AML acute myeloid leukemia, MM multiple myeloma, MDPS myelodysplasic proliferative syndrome, CSA cyclosporine A, MMF mycophenolate mofetil
aAll patients had ruxolitinib as part of the GvHD treatment
bDigestive GvHD was not confirmed by biopsies
mNGS identifications of these clinically unrecognized viral sequences were confirmed by r(RT-)PCR in unpooled plasma samples. Whenever available during/after the period of sample selection, additional specimens and/or tissue biopsies were screened over a median period of 7.1 weeks (IQR 25.3). These findings are shown in Table 3.
Table 3 mNGS and r(RT-)PCR results of 7 patients with clinically unrecognized viral sequences
Viral species detected with mNGS Viral species confirmed with r(RT)-PCR assays
Patient’s code Virus Plasma, n (pos/total) Time period (days) Estimated viral load (mean log10 copies/ml plasma or CT values) Other positive biological specimen
Ge02 HPyV7 14/14 279 4.75 BM, BAL
Ge05 Usutu virus 2/5 7 4.66 –
Ge07 Cutavirus 6/10 98 37.9 Skin
Ge09 Bufavirus 6/12 81 3.73 Stools, duodenum
Ge12 Novel human astrovirus MLB2 2/6 14 3.24 Intestine, colon, BM
Ge14 Rubella virus 3/5 39 37.9 –
Classic human astrovirus 5/11 25 5.56 –
HPyV6 11/11 74 3.76 –
Ge22 Rubella virus 2/8 3 36.7 –
Pos/total corresponds to the number of positive samples on the total of screened samples. Time period corresponds to the time period during which samplings were found positive. CT values above 40 were considered negative. CT values are indicated in italics
Abbreviations: BM bone marrow, BAL bronchoalveolar lavage, CT cycle threshold
Brief clinical description of patients harboring clinically unrecognized viral sequences
Ge02: HPyV-7
A 61-year-old male, transplanted for lymphoma, developed digestive and skin GvHD; intensive immunosuppression for GvHD lasted from 12 to 16 months after transplantation (4-month sample period), when the patient died from a post-transplant EBV-related lymphoma disease. Beginning 9 months before death, we found HPyV-7 in all screened plasma samples. In addition, HPyV-7 was also found in a BAL and a bone marrow sample collected 8 months after transplantation (2.8 log10 DNA copies/ml and CT value 28, respectively).
Ge05: Usutu virus
A 23-year-old male, transplanted for lymphoma, developed digestive skin and lung GvHD; intensive immunosuppression for GvHD lasted from 1 to 24 months after transplantation (22-month sample period), when the patient died from a disseminated fungal infection and GvHD. We found Usutu virus in 2 plasma samples collected 7 days apart, a few days after a blood transfusion, and 1.5 months before death.
Ge07: cutavirus
A 60-year-old male, transplanted for acute lymphoblastic leukemia, developed digestive GvHD; intensive immunosuppression for GvHD lasted from 6 to 8 months after transplantation (2-month sample period), when the patient died from a disseminated fungal infection and GvHD. We found cutavirus in a skin biopsy performed 3 weeks before transplantation (CT of 35) and at low plasma VL for 3 months before death. Autopsy results confirmed digestive GvHD and a disseminated mold infection.
Ge09: bufavirus
A 65-year-old male, transplanted for acute myeloid leukemia (AML), developed liver GvHD; intensive immunosuppression for GvHD lasted from 5 to 7 months after transplantation (2 month sample period), when the patient died from GvHD. We detected bufavirus RNA in several plasma samples taken over 2 months before death. In addition, bufavirus was also found in stool samples collected the day of and 1.5 months after transplantation, at CT values of 38.2 and 34.7, respectively, and in a duodenal biopsy performed 5 months after transplantation (CT value 27.3), which revealed chronic duodenitis.
Ge12: HAstV MLB2
A 44-year-old male, transplanted for multiple myeloma, developed a digestive and liver GvHD; intensive immunosuppression for GvHD lasted from 15 days to 2 months after transplantation (2-month sample period), when the patient died from the GvHD. We detected HAstV MLB2 RNA in two plasma samples collected 14 days apart and shortly before death, in a colonic biopsy performed few days before death (CT value 27.9), and in several intestine, colonic, and bone marrow autopsy samples (mean CT values 25.8, 27.6, 28, respectively). Autopsy results confirmed liver and digestive GvHD and revealed chronic pulmonary GvHD.
Ge14: rubella virus, classic HAstV, HPyV-6
A 31-year-old male of Chinese origin, transplanted for AML, developed digestive and liver GvHD; intensive immunosuppression for GvHD lasted 9–11 months after transplantation (3-month sample period), when the patient died from an acute intestinal perforation in the context of recurrent digestive GvHD. In several plasma samples starting 1 month before death, we found classic HAstV RNA and low VLs of a wild-type Chinese rubella strain. HPyV-6 DNA was also persistently found in plasma samples starting 2 months before death. The patient was seropositive for rubella before transplantation.
Ge22: rubella virus
A 68-year-old Portuguese male, transplanted for myelodysplastic syndrome, developed digestive and skin GvHD; intensive immunosuppression for GvHD lasted from 4 to 6 months after transplantation (6-week sample period), when the patient died from GvHD. Two plasma samples were positive for rubella-vaccine RNA at low VLs. The patient was seropositive before transplantation.
Discussion
We analyzed viral sequences by mNGS in pooled plasma samples of 25 adult allo-HSCT patients with severe steroid-refractory/dependent GvHD. Viral nucleotide sequences were found in 96% of patients, and 64% of patients had ≥ 3 distinct viral species. Besides commensal (Anelloviridae and HPgV-1) and latent (EBV, CMV, HSV-1, BKPyV, JCPyV) viruses known to be highly prevalent/reactivate in allo-HSCT recipients, 28% of patients had clinically unrecognized viral sequences that are rarely/never reported in allo-HSCT patients, with unknown pathogenicity (bufavirus, cutavirus, HPyV-6/7, novel HAstV-MLB2, classic HAstV, rubella virus, and Usutu virus). Chronic HBV and HEV infections were also confirmed by mNGS in two patients.
Anelloviridae (TTV, TTMV, and TTMDV) were the most prevalent in this study, concordant with the high TTV viremia rate identified among allo-HSCT recipients [28–31]. The high TTV, TTMV, and TTMDV co-detection rate has been previously described [30]. Chronic anelloviruses infection/re-infection is common, but disease associations remain undetermined [32]. Among allo-HSCT recipients, two studies failed to demonstrate any association between TTV viremia and immune-related complication or other viral reactivations [28, 33], while a third reported higher TTV viremia in patients receiving corticosteroids for GvHD [29]. A recent study found higher TTV VL at 100 days post-transplantation predicts worse overall survival, and a higher risk of acute GvHD and infections [34]. Finally, a mNGS study revealed increased detection rates and number of Anelloviridae sequences in stool samples of allo-HSCT recipients several weeks after developing digestive GvHD [5], suggesting a consequence of GvHD-associated inflammation and/or immunosuppressive therapy. Altogether, these data suggest that TTV viremia could be a potential immunosuppression-marker, requiring further investigation.
HPgV-1 (a Flaviviridae [35]) viremia occurs in 1–4% of blood donors in developed countries [36] and up to 30% of allo-HSCT recipients but has not been associated with clinical consequences [3, 4]. Given the interaction of HPgV-1 with the immune system [37], the effect of persistent HPgV-1 viremia requires deeper investigation.
We found four species of HPyV (JCPyV, BKPyV, HPyV-6/7), with JCPyV viremia occurring in 16% of allo-HSCT recipients, agreeing with studies where concomitant use of multiple immunosuppressive treatments was associated with increased persistent viremia risk—although progressive multifocal leucoencephalopathy was rare [38]. In another study, JCPyV DNA detection rate in plasma decreased from 4/22 to 1/22 patients at 3 and 12–18 months after transplantation, respectively, while viremia was not linked to any clinical manifestation [39]. Our study’s BKPyV prevalence (28%) was lower than the 54% of another study [40]. Notably, our patients did not develop hemorrhagic cystitis.
Contamination or other bioinformatics errors were excluded for each of the clinically unrecognized viral sequences, by confirming the mNGS-identified viral sequences using r(RT-)PCR on blood and non-blood samples at different time-points. These assays found cutavirus (60%) and bufavirus (50%), two Protoparvoviruses, in plasma samples at low VL. Interestingly, available skin and digestive biopsy tissues, previously described as putative primary infection sites [24, 41, 42], were positive by PCR at or shortly before transplantation, indicating viral latency and reactivation under immunosuppressive conditions. Bufavirus was first discovered in stool samples of children in 2012, and the stool prevalence is about 0.3–4.1%, although high seroprevalence was identified in some countries [41, 42]. Bufavirus was recovered in stools of subjects with digestive symptoms, but not in asymptomatic controls [41]. Whether bufavirus influences syndromes attributed to digestive GvHD remains unknown. Cutavirus was discovered in 2016 in stools of diarrheic children in Brazil with a prevalence of about 1–1.6%, and curiously, some associations were made with cutaneous T cell lymphoma [24, 41]. To our knowledge, cutavirus and bufavirus viremia have not been described before.
Usutu virus (a Flaviviridae) is an arbovirus, endemic in Africa and several European countries, that frequently co-circulates with West Nile virus [43–45]. The virus enzootic cycle involves birds (main reservoir) and ornithophilic mosquitos (vectors); humans are incidental and dead-end hosts [43]. Less than 50 documented cases of acute Usutu virus infections have been reported in humans, most of them corresponding to the identification of Usutu virus genome in donated blood samples [45]. Human Usutu virus infection can be asymptomatic or associated with various clinical manifestations, including fever, rash, and neurological manifestations; the virus genome was detected in some cases in CSF or blood samples [43, 45, 46]. The virus can infect neurons, astrocytes, microglia cells, and induced pluripotent stem cell (IPSc)-derived human neuronal stem cells, with a reduction in cell proliferation, induction of antiviral response, and apoptosis [47]. In our study, Usutu virus was transiently identified shortly after a blood transfusion, but retrospective blood bag testing was impossible. Although blood transmission has not been described, screening over ≥ 130,000 blood donations revealed 38 positive donors [48, 49]. Although overt clinical consequences are absent in our patient, this flavivirus is known to cause occasional complications [45] and cannot be disregarded. If transmission occurred by transfusion, it is possible that only remnant RNA was transmitted, not infectious virus.
Astroviruses are well-recognized enteric viruses infecting mainly children, elderly, and immunocompromised patients [50]. HAstV MLB2 was identified a decade ago [51], and since then, it has been demonstrated that it is circulating in every continent [50]. In addition, it is associated with systemic and central nervous system infections [7, 52] and has been identified in stool samples of asymptomatic children [53]. In our mNGS study, classic HAstV was found in plasma samples of a patient with digestive GvHD shortly before death, and HAstV MLB2 was found at low VL in plasma samples of a patient with diarrhea due to digestive GvHD. In the latter, autopsy confirmed the presence of HAstV MLB2 RNA in several intestinal and colonic samples at significant VLs. The presence of astrovirus MLB2 in the digestive tract of the patient is thus evident, and HAstV viremia plausibly came from an intestinal spillover in the context of the GvHD and intestinal perforation.
HPyV-6 and 7 were discovered in 2010 [54] and have been identified in a wide range of clinical samples of healthy subjects, transplant recipients, and symptomatic immunocompetent patients [55–59]. They have been detected mostly in skin specimens of non-transplanted individuals and transplanted recipients with or without dermatological diseases, but the association with clinical manifestation is not established [55, 57, 59–61]. The reported seroprevalence rates of HPyV6 and HPyV7 in immunocompetent and immunocompromised adults varies from 69 to 84% and 35 to 72%, respectively [3]. The transmission route, tropism, pathogenic mechanisms, and potential association with human diseases are still not established. HPyV-6 DNA prevalence in healthy blood donors is 0.1% and 0.6% in kidney transplant recipients [3], while HPyV-7 has been detected in lung transplant recipients [3], yet no obvious clinical manifestations are associated with them. We report persistent HPyV-6/7 viremia in plasma samples of 2/25 allo-HSCT recipients over several months. Further investigations are needed to determine their pathogenicity.
Rubella virus was our most unexpected finding, yet the rubella reads for both patients mapped to different regions along the genome (rubella virus genome coverage of 3.69% and 5.47% for patients Ge14 and Ge22, respectively) and mNGS results were confirmed by specific rRT-PCR in several samples over a period of 39 and 3 days for patients Ge14 and Ge22, respectively.
Although rubella can persist in in vitro and animal models [62–64], it is not known to persist after vaccination or natural infection in humans, except in vaccinated immuno-deficient children [65–68]. Chronic rubella infection has also been hypothesized as causing Fuch’s heterochromic iridocyclitis, although the pathophysiology remains unknown [69, 70]. We found rubella sequences with low VLs in two patients, each with a distinct strain: a vaccine strain and a Chinese strain that was found in a patient who previously lived in China. Macrophages and keratinocytes are potential sites for rubella persistence [66], but retrospectively screened skin samples from one patient gave negative results. Both patients were seropositive before transplantation. Patients with GvHD frequently become seronegative for measles and rubella within 2 years after allo-HSCT [71]. Identification of the usual vaccine strain and a Chinese strain in a native Chinese, strongly argues for reactivation, in line with antibody loss after transplantation. Yet, we noted a decreased rubella IgG titer in one of both patients at the time of viremia, compared to the pre-transplant titers. Gonzalez et al. reported the case of a child who developed fulminant hepatitis after stem cell transplantation despite prior vaccination [72]. The hypothesis raised by the authors of a primary infection from a recently vaccinated contact implies that circulating vaccine strains in the population could be an issue for immunocompromised patients with waning antibodies. Whether rubella persistence could trigger GvHD after transplantation and where the viral reservoir would be are open questions.
A recent trial identified ruxolitinib as a second-line treatment for steroid-refractory GvHD, which has a poor prognosis and no approved clearly beneficial treatment [14, 73]: in the study, about 1/3 patients experienced a grade 3 infection, highlighting the importance of monitoring patients for infections. Our study reveals that some viral infections were overlooked by standard procedures, which may indicate that the 30% of infection risk associated with ruxolitinib could be underestimated, and raises the question of including mNGS analysis in the management of high-risk patients.
Among the 7 patients with clinically unrecognized viral sequences, most sequences were identified a few weeks before and, persisted until, patients’ deaths. Although neither the pathogenic nature of the viruses nor the clear associations with patient outcomes are proven, the identification of these viral sequences in patients’ blood during severe GvHD is relevant and reflects the altered immune response; monitoring these infections could help adjust immunosuppressive therapies. Among these patients, with nearly daily blood sample collection, such strategies could routinely be actionable by pooling plasma samples (overcoming transient viremia problems), with the aim of excluding disseminated infections before increasing immunosuppression, and unmasking a viral infection mimicking the GvHD syndrome.
The identification of HAstV and bufavirus in digestive tracts of patients with digestive GvHD may merely reflect the patient’s gut virome, but identification of enteric viruses in blood samples could indicate a disseminated infection that is triggered by GvHD inflammation or immunosuppressive treatment, which may require treatment adaptation.
These viral infections cannot be considered innocent bystanders. Most of the identified viruses can be shed asymptomatically, but certainly lead to organ disease under conditions where they become opportunistic pathogens, potentially causing unrecognized clinical features; they can also lead to a clinical exacerbation. The particular immunologic state of our population may influence this delicate balance between an indolent virus and its clinical impact.
A major limitation of this study is the small monocentric cohort. Additionally, including only allo-HSCT recipients with steroid-refractory/dependent GvHD precluded generalization of the results to all allo-HSCT recipients. Furthermore, we lacked control patients without GvHD. Despite the numerous viral infections revealed by mNGS, whether these are specific to patients with GvHD or to those treated with ruxolitinib, and if there is an association with clinical manifestations and/or an impact on the immune state of these patients, remains to be determined by appropriate studies. Notably, according to the comparison with routine diagnostic results and confirmatory r(RT-)PCR, our mNGS pipeline is accurate, although with a lower sensitivity compared to specific quantitative real-time PCR assays used in most routine laboratories.
Conclusions
Blood analysis of patients with steroid-refractory/dependent GvHD revealed clinically unrecognized viral sequences in 28% of patients, including rubella virus, novel protoparvoviruses, HPyV-6/7, Usutu virus, and HAstV-MLB2. These viruses have been described in humans, but rarely reported as causes of disease in allo-HSCT patients, or have unknown pathogenicity. Rubella virus identifications imply possible re-emergence from past infection or vaccination. Further investigations are needed to understand the clinical significance of these infections.
Supplementary Information
Additional file 1: Table S1. Detailed mNGS results per patient for the 25 adult allo-HSCT patients. Table S2. Comparison of mNGS results on the pooled plasma samples and of the routine r(RT-)PCR results on the corresponding plasma samples of the 25 patients. Figure S1. Boxplot of mapped reads of DNA viruses and corresponding mRNA detection with mNGS. The vertical axis represents the number of mapped reads. The horizontal axis represents all identified viral sequences of DNA viruses (left panel) and corresponding mRNA sequences (right panel). The numbers on the horizontal axis represent the number of patients in which sequences of each virus were identified. Abbreviations: HSV-1: herpes simplex 1 virus; CMV: cytomegalovirus; EBV: Epstein-Barr virus; TTMDV: torque teno midivirus; TTMV: torque teno minivirus; TTV: torque teno virus.
Publisher’s Note
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L. Kaiser and D. L. Vu contributed equally to this work.
Acknowledgements
The authors would like to thank Fiona Pigny for technical assistance and Erik Boehm for editorial assistance.
Authors’ contributions
MCZ, DLV, SC, and LK designed the research project. GV, MD, FL, and SC performed the mNGS and sequence analysis and r(RT-)PCR assays. VB, TAM, and JAL performed the biopsies histological examination. CVD, SML, and YC contributed to the interpretation of data regarding transplantation. MCZ, DLV, and SC collected and interpreted the data and wrote the first draft of the manuscript. All other authors revised and commented on the manuscript. The authors read and approved the final manuscript.
Funding
This work was supported by the “Projets Recherche et Développement (PRD)” of Geneva University Hospitals (grant number PRD 17-2019-I) and the Swiss National Science Foundation (grant number 320030_179507).
Availability of data and materials
The datasets generated and/or analyzed during the current study are available in the Dryad repository (10.5061/dryad.0k6djh9xp). The raw sequence data were deposited in the NCBI Sequence Read Archive under BioProject accession number PRJNA641787.
Ethics approval and consent to participate
The study protocol was approved by the Geneva Cantonal Ethics Commission (project #2019-00511).
Consent for publication
Not applicable
Competing interests
The authors declare that they have no competing interests. | CYCLOSPORINE, MYCOPHENOLATE MOFETIL, TACROLIMUS | DrugsGivenReaction | CC BY | 33487167 | 18,939,834 | 2021-01-24 |
What was the dosage of drug 'CYCLOSPORINE'? | Unmasking viral sequences by metagenomic next-generation sequencing in adult human blood samples during steroid-refractory/dependent graft-versus-host disease.
Viral infections are common complications following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Allo-HSCT recipients with steroid-refractory/dependent graft-versus-host disease (GvHD) are highly immunosuppressed and are more vulnerable to infections with weakly pathogenic or commensal viruses. Here, twenty-five adult allo-HSCT recipients from 2016 to 2019 with acute or chronic steroid-refractory/dependent GvHD were enrolled in a prospective cohort at Geneva University Hospitals. We performed metagenomics next-generation sequencing (mNGS) analysis using a validated pipeline and de novo analysis on pooled routine plasma samples collected throughout the period of intensive steroid treatment or second-line GvHD therapy to identify weakly pathogenic, commensal, and unexpected viruses.
Median duration of intensive immunosuppression was 5.1 months (IQR 5.5). GvHD-related mortality rate was 36%. mNGS analysis detected viral nucleotide sequences in 24/25 patients. Sequences of ≥ 3 distinct viruses were detected in 16/25 patients; Anelloviridae (24/25) and human pegivirus-1 (9/25) were the most prevalent. In 7 patients with fatal outcomes, viral sequences not assessed by routine investigations were identified with mNGS and confirmed by RT-PCR. These cases included Usutu virus (1), rubella virus (1 vaccine strain and 1 wild-type), novel human astrovirus (HAstV) MLB2 (1), classic HAstV (1), human polyomavirus 6 and 7 (2), cutavirus (1), and bufavirus (1).
Clinically unrecognized viral infections were identified in 28% of highly immunocompromised allo-HSCT recipients with steroid-refractory/dependent GvHD in consecutive samples. These identified viruses have all been previously described in humans, but have poorly understood clinical significance. Rubella virus identification raises the possibility of re-emergence from past infections or vaccinations, or re-infection. Video abstract.
Background
Viral primary infections and reactivations are common complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and are associated with significant morbidity and mortality [1, 2]. Current routine clinical surveillance molecular assays detect specific nucleotide sequences targeting usual culprits including Epstein-Barr virus (EBV), cytomegalovirus (CMV), BK polyomavirus (BKPyV), and adenovirus [3]. Metagenomic next-generation sequencing’s (mNGS) unbiased approach broadens viral infection diagnosis, theoretically detecting “all” viral nucleotide sequences or viral infections present [4–7], and is increasingly used in clinical investigations [8]. Allo-HSCT recipients suffering from steroid-refractory/dependent acute or chronic graft-versus-host disease (GvHD) are highly immunosuppressed patients; GvHD immune dysregulation, mucosal barrier alteration [9–13], and multiple prolonged immunosuppressive treatments create a permissive environment for opportunistic viral infections [10, 11, 14]. These clinically unrecognized viral infections can present with limited symptoms/atypical manifestations and lead to intermittent or prolonged viremia [3]. Given the nonspecific clinical features of GvHD and some viral infections, viral infections may remain clinically unrecognized due to limitations of clinical molecular assays.
We hypothesized that some viral infections, which would normally remain undiagnosed with common clinical assays, occur during intense immunosuppressive therapy in steroid-refractory/dependent GvHD. This study aimed to identify viruses that are not routinely searched by RT-PCR routine assays in clinical practice, due to the lack of knowledge. Therefore, we used mNGS on pooled plasma samples of adult allo-HSCT patients with steroid-refractory/dependent acute or chronic GvHD to look for viruses that could be missed by biased technology.
Methods
Setting, study population, and design
This observational study was conducted at the Geneva University Hospitals (HUG), Switzerland. The study protocol was approved by the Geneva Cantonal Ethics Commission (project #2019-00511). Inclusion criteria were adult patients who received an allo-HSCT from 1 January 2016 to 31 December 2018 at the HUG, who were enrolled in the local monocentric infectious disease cohort of allo-HSCT patients, and who developed steroid-refractory/dependent acute or chronic GvHD. All included patients provided written consent before enrollment. The only exclusion criteria was the lack of informed written consent.
Plasma samples were prospectively collected during clinical management after allo-HSCT and stored in the Laboratory of Virology, HUG. We performed mNGS analysis on pooled plasma samples of each patient, collected throughout the period of intensive steroid treatment or second-line GvHD therapy.
Definitions
Steroid-refractory/dependent acute and chronic GvHD were defined according to the position statement of the GvHD experts in Schoemans et al. [15].
Microbiological methods
mNGS and sequence analysis
Each pool (corresponding to 4 to 10 plasma samples from each patient) was prepared to obtain a final volume of 220 μl. Pools were then centrifuged at 10,000×g for 10 min to remove cells. Two-hundred microliters of cell-free supernatant were treated with 20 μl of Turbo DNAse (2 U/μl) + 24 μl of 10x TURBO DNase Buffer (Ambion, Rotkreuz, Switzerland), according to the manufacturer’s instructions. Then, the whole volume was divided into two tubes of 120 μl each. One tube was then used for each of the two nucleic acid extraction procedures. Indeed, virus genome extractions were done using two previously published protocols in parallel [16], namely the RNA and DNA protocols optimized for the detection of RNA and DNA viral sequences, respectively.
For the RNA protocol, nucleic acids were extracted with TRIzol (Invitrogen, Carlsbad, CA, USA). Ribosomal RNA was removed (Ribo-Zero Gold depletion kit (Illumina, San Diego, USA) before libraries’ preparation (TruSeq total RNA preparation protocol (Illumina)). Libraries’ concentrations and sizes were analyzed using the Qubit (Life Technologies, Carlsbad, CA, USA) and the 2200 TapeStation instruments (Agilent, SantaClara, CA, USA), respectively. Each library was loaded individually in a single lane on the HiSeq 4000 platform (Illumina) using the 2 × 100-bp protocol with dual-indexing. The mean total number of read pairs obtained per pool was 328,936,594.84 (range 252,670,103 to 385,257,539).
For the DNA protocol, nucleic acids were extracted with the NucliSens easyMAG magnetic bead system (bioMérieux, Geneva, Switzerland). As previously published [16], double-stranded DNA synthesis was done with the DNA polymerase I, Large Fragment (Klenow) (New England BioLabs, Ipswich, MA, USA)). Libraries were prepared using the Nextera XT (Illumina) protocol. Libraries’ concentrations and sizes were analyzed using the Qubit (Life Technologies) and the 2200 TapeStation instruments (Agilent), respectively. Each library was loaded individually in a single lane on the HiSeq 4000 platform (Illumina) using the 2 × 100-bp protocol with dual-indexing. The mean total number of read pairs obtained per pool was 301,393,033.48 (range 122,939,325 to 377,758,795).
To check for potential contaminating viral sequences from environment or experimental reagents [17], four negative controls (i.e., Neg1-4) were submitted to the whole mNGS procedure. To assess the mNGS process efficiency, positive controls underwent the whole mNGS procedure (canine distemper virus (CDV)-spiked samples and a baculovirus (GenScript, Piscataway, NJ, USA) harboring 793 nucleotides of the CDV fusion gene were used as positive controls for the RNA and DNA protocols, respectively).
Paired reads were quality filtered using Trimmomatic [18]. Reads mapped against the human genome and transcriptome (hg38, gencode.V23) were removed using SNAP [19]. Remaining reads were analyzed using two methods in parallel as previously described [20]: (1) by a pipeline that used virusscan 1.0 (https://github.com/sib-swiss/virusscan) to map reads against the Virosaurus database (version V90v_2018_11) (https://viralzone.expasy.org/8676), which is designed to report vertebrate viruses, and (2) by de novo assembly. Only viruses with ≥ 300 nucleotides of coverage were reported. The raw sequence data were deposited in the NCBI Sequence Read Archive under BioProject accession number PRJNA641787.
Sequences were considered clinically recognized viruses if they corresponded to a virus known to reactivate in/be frequently found among allo-HSCT recipients [2, 4] or if the patient had a known chronic viral infection and clinically unrecognized viruses if not.
Confirmatory real-time (reverse transcription-)polymerase chain reaction (r(RT-)PCR) assays
Clinically unrecognized mNGS findings were confirmed on unpooled plasma by specific semi-quantitative or quantitative r(RT-)PCR assays as previously published; additional specimens (including plasma, cerebrospinal fluid, bronchoalveolar lavage (BAL) fluids, nasopharyngeal swabs, native urines, stools suspension, tissue biopsies or bone marrow) were tested when available and pertinent. Quantitative r(RT-)PCR assays were done for Mamastrovirus 1 (classical) using the updated human astrovirus (HAstV) combination [21], Mamastrovirus 6 (MLB2) using the MLB2 assay [22], Usutu virus [23], and bufavirus using the BuV (NS1) assay [24]. Semi-quantitative r(RT-)PCR assays were done for cutavirus using the CuV (VP2) assay [24], human polyomavirus (HPyV) 6 using the VP2 assay [25], HPyV-7 using the VP2 assay [25], and rubella virus [26].
Nucleic acids from plasma, cerebrospinal fluid, BAL fluids, nasopharyngeal swabs, urine, stools resuspended in PBS, and bone marrow were extracted individually from 190 μL of each specimen, spiked with 10 μL of standardized CDV as internal control [27], using the NucliSENS easyMAG (bioMérieux, Geneva, Switzerland) nucleic acid kit, according to the manufacturer’s instructions, and eluted in 25 μL. DNA and RNA were extracted from tissue biopsies using the QIAamp DNA FFPE Tissue Kit (Qiagen, Hombrechtikon, Switzerland) and High Pure FFPET RNA isolation kit (Roche Applied Sciences, Indianapolis, IN, USA), respectively, following the manufacturer’s instructions. For RNA viruses, the rRT-PCR assays were performed using the one-step QuantiTect Probe RT-PCR Kit (Qiagen, Hombrechtikon, Switzerland) in a StepOne Plus instrument (Applied Biosystems, Rotkreuz, Switzerland). For DNA viruses, the rPCR assays were performed using the TaqMan Universal PCR Master Mix (Applied Biosystems) in a StepOne Plus instrument (Applied Biosystems) for cutavirus and bufavirus or in a QuantStudio 5 instrument (Applied Biosystems) for HPyV6 and 7.
For quantitative r(RT)-PCR assays, standard curves and lower limit of quantifications (LOQ) were assessed using 10-fold serial dilutions of specific RNA oligonucleotides (Mamastrovirus 1 (classical) and 6 (MLB2): LOQ = 1.25E4 and 1.25E3 RNA copies/ml of plasma, respectively), RNA transcript (Usutu virus: LOQ = 1.32E2 RNA copies/ml of plasma), DNA oligonucleotides (bufavirus: LOQ = 1.32E3 DNA copies/ml of plasma), or plasmids (HPyV6 and 7: LOQ = 2.63E2 DNA copies/ml of plasma each) containing the target sequences.
Statistical analysis
Categorical variables were described by counts and percentages. Continuous variables were expressed as mean and standard deviation or median and interquartile range.
Results
Patient characteristics
We identified 25 adult allo-HSCT recipients with acute or chronic steroid-refractory/dependent GvHD. Table 1 shows the patient’s characteristics. The median duration of intensive immunosuppression was 5.1 months (IQR 5.5), and 22/25 patients received ruxolitinib. At the time of writing, fifteen patients have died, with 9 considered as GvHD-related.
Table 1 Patients’ characteristics (25 allo-HSCT patients)
Total
n = 25
Demographics
Sex (male), n (%) 16 (64.0)
Age, median (IQR) 58.0 (25.0)
Allo-HSCT considered in the analysis,
n
(%)
First 23 (92.0)
Second 2 (8.0)
Transplant source,
n
(%)
Bone marrow 5 (20)
Peripheral blood cells 20 (80)
Underlying disease,
n
(%)
Acute myeloid leukemia 10 (40.0)
Lymphoid malignancy 6 (24.0)
MDS/MDPS 3 (12.0)
Acute lymphoid leukemia 2 (8.0)
Othera 4 (16.0)
Risk score,
n
(%)
Low 0 (0)
Intermediate 18 (72.0)
High 7 (28.0)
Donor sex, M,
n
(%) 7 (28.0)
Donor age, median (IQR) 36 (16.5)
Donor match,
n
(%)
Donor-related 10 (40.0)
CMV donor/recipient constellation,
n
(%)
+/+ 12 (48.0)
−/+ 1 (4.0)
+/− 7 (28.0)
−/− 5 (20.0)
CMV prophylaxis, n (%) 1 (4.0)
Conditioning,
n
(%)
Myeloablative conditioning 5 (20.0)
GvHD prophylaxis,
n
(%)
Calcineurin inhibitor 24 (96.0)
Mycophenolate mofetil 17 (68.0)
Methotrexate 7 (28.0)
GvHD organ,
n
(%)
Digestive tract 17 (68.0)
Skin 15 (60.0)
Mouth 4 (16.0)
Liver 7 (28.0)
Lung 5 (20.0)
Eyes 2 (8.0)
Musculoskeletal 1 (4.0)
GvHD grade or severity,
n
(%)
Grade
2 9 (36.0)
3 3 (12.0)
4 6 (24.0)
Moderate 6 (24.0)
Severe 7 (28.0)
GvHD treatment,
n
(%)
Corticosteroids 24 (96.0)
Ruxolitinib 22 (88.0)
Calcineurin inhibitor 21 (84.0)
Mycophenolate mofetil 12 (48.0)
Photopheresis 12 (48.0)
Budenoside 5 (20.0)
Sirolimus 3 (12.0)
Tocilizumab 2 (8.0)
Otherb 6 (24.0)
Death,
n
(%) 15 (60.0)
Median delay from allo-HSCT, months (IQR) 11.2 (15.8)
One patient could have multiple GvHD prophylaxis and treatment, multiple organs with GvHD and multiple grades of severity. CMV prophylaxis: one patient (patient Ge24) received letermovir during the period of intensive steroid treatment or second-line GvHD therapy. GvHD grade refers to acute GvHD, GvHD severity refers to chronic GvHD. In two patients, there was no information on grade/severity. Only organs with grade GvHD ≥ 2 or severity ≥ moderate are reported
Abbreviations: IQR interquartile range, allo-HSCT allogeneic hematopoietic stem cell transplantation, MDS/MDPS myelodysplasic syndrome/myelodysplasic proliferative syndrome, ATG anti-thymocyte globulin
aOther includes: multiple myeloma (n = 2), chronic myeloid leukemia (n = 1) and mixed acute leukemia (n = 1)
bOther includes: azithromycine, montelukast, prolastin, vedolisumab, nilotinib, basilixumab, ibrutinib, and/or methotrexate
Viral sequences identified with mNGS and confirmatory analyses
The mNGS analysis revealed viral nucleotide sequences in all patients except Ge18 (24/25). In 16/25 patients, ≥ 3 distinct viral species were detected (Fig. 1). Figure 2 depicts the prevalence of each identified virus, and Table S1 provides detailed mNGS characteristics.
Fig. 1 Grid plot of viral sequences identified with mNGS in pooled plasma samples (25 allo-HSCT patients). Each line corresponds to viral sequences assigned to one virus; the bottom line corresponds to mNGS negative (Neg1-4) and positive (Pos1/2 DNA/RNA) control samples. Each column corresponds to one pool of plasma sample (one patient). Colors represent the approximate number of reads matching virus genome detected in each pool of plasma samples. *Since they were detected in one negative control, human papillomavirus sequences were considered as likely contaminant. # cross-contamination. Abbreviations: HAstV human astrovirus, TTV torque teno virus, TTMV torque teno minivirus, TTMDV torque teno midivirus, HSV-1 herpes simplex 1 virus, EBV Epstein-Barr virus, CMV cytomegalovirus, CTRL control
Fig. 2 Prevalence of viruses identified with mNGS in pooled plasma samples (25 allo-HSCT recipients). The vertical axis represents all identified viral sequences. The horizontal axis represents the number of patients in which sequences of each virus were identified. Abbreviations: TTV torque teno virus, TTMV torque teno minivirus, CMV cytomegalovirus, TTMDV torque teno midivirus, EBV Epstein-Barr virus, HSV-1 herpes simplex 1 virus, HAstV human astrovirus
Anelloviridae (torque teno virus (TTV), torque teno minivirus (TTMV) and torque teno midivirus (TTMDV)) and human pegivirus-1 (HPgV-1) were the most prevalent with sequences detected in 24/25 and 9/25 patients, respectively.
Other detected DNA viruses included BK polyomavirus (BKPyV) (7/25), CMV (5/25), and JC polyomavirus (JCPyV) (4/25), and also herpes simplex virus 1 (HSV-1), EBV, hepatitis B virus (HBV), bufavirus, cutavirus, and HPyV-6/7, each detected once (1/25). Except HPgV-1, the detected RNA viruses were less prevalent than DNA viruses and were HAstV (Mamastrovirus 1 and 6) and rubella virus, both detected twice (2/25), and also hepatitis E (HEV) and Usutu viruses, both detected once (1/25). The de novo analysis did not reveal other relevant sequences. Interestingly, sequences for TTV (11/24), CMV (3/5), EBV (1/1), and HBV (1/1) were detected in both DNA and RNA libraries, suggesting active viral replication (Figure S1).
Clinically recognized viral sequences
Although not routinely searched in clinical practice, Anelloviridae and HPgV-1 sequences were identified in 96% and 36% of patients and were classified among clinically recognized viral sequences as they are known to be highly prevalent among immunocompromised patients. In 14/25 patients, mNGS analysis identified sequences of latent DNA viruses known to reactivate in transplant recipients (EBV, CMV, HSV-1, BKPyV, JCPyV, HBV). At the RNA level, HEV was identified once.
The r(RT-)PCR assays performed during routine investigations confirmed the mNGS analysis (Table S2): patient Ge05 had a chronic HEV infection, and patient Ge14 had chronic HBV and cutaneous HSV-1 infections, and HSV-1 viremia. BKPyV and JCPyV were not systematically screened and were only revealed by mNGS analysis. However, BKPyV was screened in patient Ge06 and detected at low viral loads (VL) (1.41E2 and 1.44E3 copies/ml) in two plasma samples collected a few days apart from those included for mNGS analysis. In 12/25 patients, CMV and EBV were detected only by rPCR at low VL; no other expected virus was detected by routine molecular assays.
Clinically unrecognized viral sequences
We found clinically unrecognized sequences belonging to either rare and/or recently identified viruses (HAstV MLB2, Usutu virus, bufavirus, cutavirus, HPyV-6, and HPyV-7) or those not routinely assessed alongside GvHD (classic HAstV and rubella virus) in 7/25 patients, whose characteristics are detailed in Table 2.
Table 2 Clinical characteristics of 7 patients with clinically unrecognized viral sequences
Patient’s code Age, gender Underlying disease GvHD organ GvHD treatmentsa Outcome
Ge02 61, M Lymphoma Digestive, skin CSA, tacrolimus, corticosteroids, sirolimus, budenoside, photopheresis Death (GvHD-related)
Ge05 23, M Lymphoma Digestive, skin, lung CSA, MMF, tacrolimus, corticosteroids Death
Ge07 60, M ALL Digestive Tacrolimus, corticosteroids, photopheresis Death
Ge09 65, M AML Liver, digestiveb CSA, corticosteroids, tocilizumab Death
Ge12 44, M MM Digestive, liver CSA, corticosteroids, basiliximab, MMF Death
Ge14 31, M AML Digestive, liver Corticosteroids Death
Ge22 68, M MDPS Digestive, skin CSA, tacrolimus, corticosteroids, vedolisumab, prolastin Death
Age at the time of transplantation
Abbreviations: GvHD graft-versus-host disease, M male, ALL acute lymphoid leukemia, AML acute myeloid leukemia, MM multiple myeloma, MDPS myelodysplasic proliferative syndrome, CSA cyclosporine A, MMF mycophenolate mofetil
aAll patients had ruxolitinib as part of the GvHD treatment
bDigestive GvHD was not confirmed by biopsies
mNGS identifications of these clinically unrecognized viral sequences were confirmed by r(RT-)PCR in unpooled plasma samples. Whenever available during/after the period of sample selection, additional specimens and/or tissue biopsies were screened over a median period of 7.1 weeks (IQR 25.3). These findings are shown in Table 3.
Table 3 mNGS and r(RT-)PCR results of 7 patients with clinically unrecognized viral sequences
Viral species detected with mNGS Viral species confirmed with r(RT)-PCR assays
Patient’s code Virus Plasma, n (pos/total) Time period (days) Estimated viral load (mean log10 copies/ml plasma or CT values) Other positive biological specimen
Ge02 HPyV7 14/14 279 4.75 BM, BAL
Ge05 Usutu virus 2/5 7 4.66 –
Ge07 Cutavirus 6/10 98 37.9 Skin
Ge09 Bufavirus 6/12 81 3.73 Stools, duodenum
Ge12 Novel human astrovirus MLB2 2/6 14 3.24 Intestine, colon, BM
Ge14 Rubella virus 3/5 39 37.9 –
Classic human astrovirus 5/11 25 5.56 –
HPyV6 11/11 74 3.76 –
Ge22 Rubella virus 2/8 3 36.7 –
Pos/total corresponds to the number of positive samples on the total of screened samples. Time period corresponds to the time period during which samplings were found positive. CT values above 40 were considered negative. CT values are indicated in italics
Abbreviations: BM bone marrow, BAL bronchoalveolar lavage, CT cycle threshold
Brief clinical description of patients harboring clinically unrecognized viral sequences
Ge02: HPyV-7
A 61-year-old male, transplanted for lymphoma, developed digestive and skin GvHD; intensive immunosuppression for GvHD lasted from 12 to 16 months after transplantation (4-month sample period), when the patient died from a post-transplant EBV-related lymphoma disease. Beginning 9 months before death, we found HPyV-7 in all screened plasma samples. In addition, HPyV-7 was also found in a BAL and a bone marrow sample collected 8 months after transplantation (2.8 log10 DNA copies/ml and CT value 28, respectively).
Ge05: Usutu virus
A 23-year-old male, transplanted for lymphoma, developed digestive skin and lung GvHD; intensive immunosuppression for GvHD lasted from 1 to 24 months after transplantation (22-month sample period), when the patient died from a disseminated fungal infection and GvHD. We found Usutu virus in 2 plasma samples collected 7 days apart, a few days after a blood transfusion, and 1.5 months before death.
Ge07: cutavirus
A 60-year-old male, transplanted for acute lymphoblastic leukemia, developed digestive GvHD; intensive immunosuppression for GvHD lasted from 6 to 8 months after transplantation (2-month sample period), when the patient died from a disseminated fungal infection and GvHD. We found cutavirus in a skin biopsy performed 3 weeks before transplantation (CT of 35) and at low plasma VL for 3 months before death. Autopsy results confirmed digestive GvHD and a disseminated mold infection.
Ge09: bufavirus
A 65-year-old male, transplanted for acute myeloid leukemia (AML), developed liver GvHD; intensive immunosuppression for GvHD lasted from 5 to 7 months after transplantation (2 month sample period), when the patient died from GvHD. We detected bufavirus RNA in several plasma samples taken over 2 months before death. In addition, bufavirus was also found in stool samples collected the day of and 1.5 months after transplantation, at CT values of 38.2 and 34.7, respectively, and in a duodenal biopsy performed 5 months after transplantation (CT value 27.3), which revealed chronic duodenitis.
Ge12: HAstV MLB2
A 44-year-old male, transplanted for multiple myeloma, developed a digestive and liver GvHD; intensive immunosuppression for GvHD lasted from 15 days to 2 months after transplantation (2-month sample period), when the patient died from the GvHD. We detected HAstV MLB2 RNA in two plasma samples collected 14 days apart and shortly before death, in a colonic biopsy performed few days before death (CT value 27.9), and in several intestine, colonic, and bone marrow autopsy samples (mean CT values 25.8, 27.6, 28, respectively). Autopsy results confirmed liver and digestive GvHD and revealed chronic pulmonary GvHD.
Ge14: rubella virus, classic HAstV, HPyV-6
A 31-year-old male of Chinese origin, transplanted for AML, developed digestive and liver GvHD; intensive immunosuppression for GvHD lasted 9–11 months after transplantation (3-month sample period), when the patient died from an acute intestinal perforation in the context of recurrent digestive GvHD. In several plasma samples starting 1 month before death, we found classic HAstV RNA and low VLs of a wild-type Chinese rubella strain. HPyV-6 DNA was also persistently found in plasma samples starting 2 months before death. The patient was seropositive for rubella before transplantation.
Ge22: rubella virus
A 68-year-old Portuguese male, transplanted for myelodysplastic syndrome, developed digestive and skin GvHD; intensive immunosuppression for GvHD lasted from 4 to 6 months after transplantation (6-week sample period), when the patient died from GvHD. Two plasma samples were positive for rubella-vaccine RNA at low VLs. The patient was seropositive before transplantation.
Discussion
We analyzed viral sequences by mNGS in pooled plasma samples of 25 adult allo-HSCT patients with severe steroid-refractory/dependent GvHD. Viral nucleotide sequences were found in 96% of patients, and 64% of patients had ≥ 3 distinct viral species. Besides commensal (Anelloviridae and HPgV-1) and latent (EBV, CMV, HSV-1, BKPyV, JCPyV) viruses known to be highly prevalent/reactivate in allo-HSCT recipients, 28% of patients had clinically unrecognized viral sequences that are rarely/never reported in allo-HSCT patients, with unknown pathogenicity (bufavirus, cutavirus, HPyV-6/7, novel HAstV-MLB2, classic HAstV, rubella virus, and Usutu virus). Chronic HBV and HEV infections were also confirmed by mNGS in two patients.
Anelloviridae (TTV, TTMV, and TTMDV) were the most prevalent in this study, concordant with the high TTV viremia rate identified among allo-HSCT recipients [28–31]. The high TTV, TTMV, and TTMDV co-detection rate has been previously described [30]. Chronic anelloviruses infection/re-infection is common, but disease associations remain undetermined [32]. Among allo-HSCT recipients, two studies failed to demonstrate any association between TTV viremia and immune-related complication or other viral reactivations [28, 33], while a third reported higher TTV viremia in patients receiving corticosteroids for GvHD [29]. A recent study found higher TTV VL at 100 days post-transplantation predicts worse overall survival, and a higher risk of acute GvHD and infections [34]. Finally, a mNGS study revealed increased detection rates and number of Anelloviridae sequences in stool samples of allo-HSCT recipients several weeks after developing digestive GvHD [5], suggesting a consequence of GvHD-associated inflammation and/or immunosuppressive therapy. Altogether, these data suggest that TTV viremia could be a potential immunosuppression-marker, requiring further investigation.
HPgV-1 (a Flaviviridae [35]) viremia occurs in 1–4% of blood donors in developed countries [36] and up to 30% of allo-HSCT recipients but has not been associated with clinical consequences [3, 4]. Given the interaction of HPgV-1 with the immune system [37], the effect of persistent HPgV-1 viremia requires deeper investigation.
We found four species of HPyV (JCPyV, BKPyV, HPyV-6/7), with JCPyV viremia occurring in 16% of allo-HSCT recipients, agreeing with studies where concomitant use of multiple immunosuppressive treatments was associated with increased persistent viremia risk—although progressive multifocal leucoencephalopathy was rare [38]. In another study, JCPyV DNA detection rate in plasma decreased from 4/22 to 1/22 patients at 3 and 12–18 months after transplantation, respectively, while viremia was not linked to any clinical manifestation [39]. Our study’s BKPyV prevalence (28%) was lower than the 54% of another study [40]. Notably, our patients did not develop hemorrhagic cystitis.
Contamination or other bioinformatics errors were excluded for each of the clinically unrecognized viral sequences, by confirming the mNGS-identified viral sequences using r(RT-)PCR on blood and non-blood samples at different time-points. These assays found cutavirus (60%) and bufavirus (50%), two Protoparvoviruses, in plasma samples at low VL. Interestingly, available skin and digestive biopsy tissues, previously described as putative primary infection sites [24, 41, 42], were positive by PCR at or shortly before transplantation, indicating viral latency and reactivation under immunosuppressive conditions. Bufavirus was first discovered in stool samples of children in 2012, and the stool prevalence is about 0.3–4.1%, although high seroprevalence was identified in some countries [41, 42]. Bufavirus was recovered in stools of subjects with digestive symptoms, but not in asymptomatic controls [41]. Whether bufavirus influences syndromes attributed to digestive GvHD remains unknown. Cutavirus was discovered in 2016 in stools of diarrheic children in Brazil with a prevalence of about 1–1.6%, and curiously, some associations were made with cutaneous T cell lymphoma [24, 41]. To our knowledge, cutavirus and bufavirus viremia have not been described before.
Usutu virus (a Flaviviridae) is an arbovirus, endemic in Africa and several European countries, that frequently co-circulates with West Nile virus [43–45]. The virus enzootic cycle involves birds (main reservoir) and ornithophilic mosquitos (vectors); humans are incidental and dead-end hosts [43]. Less than 50 documented cases of acute Usutu virus infections have been reported in humans, most of them corresponding to the identification of Usutu virus genome in donated blood samples [45]. Human Usutu virus infection can be asymptomatic or associated with various clinical manifestations, including fever, rash, and neurological manifestations; the virus genome was detected in some cases in CSF or blood samples [43, 45, 46]. The virus can infect neurons, astrocytes, microglia cells, and induced pluripotent stem cell (IPSc)-derived human neuronal stem cells, with a reduction in cell proliferation, induction of antiviral response, and apoptosis [47]. In our study, Usutu virus was transiently identified shortly after a blood transfusion, but retrospective blood bag testing was impossible. Although blood transmission has not been described, screening over ≥ 130,000 blood donations revealed 38 positive donors [48, 49]. Although overt clinical consequences are absent in our patient, this flavivirus is known to cause occasional complications [45] and cannot be disregarded. If transmission occurred by transfusion, it is possible that only remnant RNA was transmitted, not infectious virus.
Astroviruses are well-recognized enteric viruses infecting mainly children, elderly, and immunocompromised patients [50]. HAstV MLB2 was identified a decade ago [51], and since then, it has been demonstrated that it is circulating in every continent [50]. In addition, it is associated with systemic and central nervous system infections [7, 52] and has been identified in stool samples of asymptomatic children [53]. In our mNGS study, classic HAstV was found in plasma samples of a patient with digestive GvHD shortly before death, and HAstV MLB2 was found at low VL in plasma samples of a patient with diarrhea due to digestive GvHD. In the latter, autopsy confirmed the presence of HAstV MLB2 RNA in several intestinal and colonic samples at significant VLs. The presence of astrovirus MLB2 in the digestive tract of the patient is thus evident, and HAstV viremia plausibly came from an intestinal spillover in the context of the GvHD and intestinal perforation.
HPyV-6 and 7 were discovered in 2010 [54] and have been identified in a wide range of clinical samples of healthy subjects, transplant recipients, and symptomatic immunocompetent patients [55–59]. They have been detected mostly in skin specimens of non-transplanted individuals and transplanted recipients with or without dermatological diseases, but the association with clinical manifestation is not established [55, 57, 59–61]. The reported seroprevalence rates of HPyV6 and HPyV7 in immunocompetent and immunocompromised adults varies from 69 to 84% and 35 to 72%, respectively [3]. The transmission route, tropism, pathogenic mechanisms, and potential association with human diseases are still not established. HPyV-6 DNA prevalence in healthy blood donors is 0.1% and 0.6% in kidney transplant recipients [3], while HPyV-7 has been detected in lung transplant recipients [3], yet no obvious clinical manifestations are associated with them. We report persistent HPyV-6/7 viremia in plasma samples of 2/25 allo-HSCT recipients over several months. Further investigations are needed to determine their pathogenicity.
Rubella virus was our most unexpected finding, yet the rubella reads for both patients mapped to different regions along the genome (rubella virus genome coverage of 3.69% and 5.47% for patients Ge14 and Ge22, respectively) and mNGS results were confirmed by specific rRT-PCR in several samples over a period of 39 and 3 days for patients Ge14 and Ge22, respectively.
Although rubella can persist in in vitro and animal models [62–64], it is not known to persist after vaccination or natural infection in humans, except in vaccinated immuno-deficient children [65–68]. Chronic rubella infection has also been hypothesized as causing Fuch’s heterochromic iridocyclitis, although the pathophysiology remains unknown [69, 70]. We found rubella sequences with low VLs in two patients, each with a distinct strain: a vaccine strain and a Chinese strain that was found in a patient who previously lived in China. Macrophages and keratinocytes are potential sites for rubella persistence [66], but retrospectively screened skin samples from one patient gave negative results. Both patients were seropositive before transplantation. Patients with GvHD frequently become seronegative for measles and rubella within 2 years after allo-HSCT [71]. Identification of the usual vaccine strain and a Chinese strain in a native Chinese, strongly argues for reactivation, in line with antibody loss after transplantation. Yet, we noted a decreased rubella IgG titer in one of both patients at the time of viremia, compared to the pre-transplant titers. Gonzalez et al. reported the case of a child who developed fulminant hepatitis after stem cell transplantation despite prior vaccination [72]. The hypothesis raised by the authors of a primary infection from a recently vaccinated contact implies that circulating vaccine strains in the population could be an issue for immunocompromised patients with waning antibodies. Whether rubella persistence could trigger GvHD after transplantation and where the viral reservoir would be are open questions.
A recent trial identified ruxolitinib as a second-line treatment for steroid-refractory GvHD, which has a poor prognosis and no approved clearly beneficial treatment [14, 73]: in the study, about 1/3 patients experienced a grade 3 infection, highlighting the importance of monitoring patients for infections. Our study reveals that some viral infections were overlooked by standard procedures, which may indicate that the 30% of infection risk associated with ruxolitinib could be underestimated, and raises the question of including mNGS analysis in the management of high-risk patients.
Among the 7 patients with clinically unrecognized viral sequences, most sequences were identified a few weeks before and, persisted until, patients’ deaths. Although neither the pathogenic nature of the viruses nor the clear associations with patient outcomes are proven, the identification of these viral sequences in patients’ blood during severe GvHD is relevant and reflects the altered immune response; monitoring these infections could help adjust immunosuppressive therapies. Among these patients, with nearly daily blood sample collection, such strategies could routinely be actionable by pooling plasma samples (overcoming transient viremia problems), with the aim of excluding disseminated infections before increasing immunosuppression, and unmasking a viral infection mimicking the GvHD syndrome.
The identification of HAstV and bufavirus in digestive tracts of patients with digestive GvHD may merely reflect the patient’s gut virome, but identification of enteric viruses in blood samples could indicate a disseminated infection that is triggered by GvHD inflammation or immunosuppressive treatment, which may require treatment adaptation.
These viral infections cannot be considered innocent bystanders. Most of the identified viruses can be shed asymptomatically, but certainly lead to organ disease under conditions where they become opportunistic pathogens, potentially causing unrecognized clinical features; they can also lead to a clinical exacerbation. The particular immunologic state of our population may influence this delicate balance between an indolent virus and its clinical impact.
A major limitation of this study is the small monocentric cohort. Additionally, including only allo-HSCT recipients with steroid-refractory/dependent GvHD precluded generalization of the results to all allo-HSCT recipients. Furthermore, we lacked control patients without GvHD. Despite the numerous viral infections revealed by mNGS, whether these are specific to patients with GvHD or to those treated with ruxolitinib, and if there is an association with clinical manifestations and/or an impact on the immune state of these patients, remains to be determined by appropriate studies. Notably, according to the comparison with routine diagnostic results and confirmatory r(RT-)PCR, our mNGS pipeline is accurate, although with a lower sensitivity compared to specific quantitative real-time PCR assays used in most routine laboratories.
Conclusions
Blood analysis of patients with steroid-refractory/dependent GvHD revealed clinically unrecognized viral sequences in 28% of patients, including rubella virus, novel protoparvoviruses, HPyV-6/7, Usutu virus, and HAstV-MLB2. These viruses have been described in humans, but rarely reported as causes of disease in allo-HSCT patients, or have unknown pathogenicity. Rubella virus identifications imply possible re-emergence from past infection or vaccination. Further investigations are needed to understand the clinical significance of these infections.
Supplementary Information
Additional file 1: Table S1. Detailed mNGS results per patient for the 25 adult allo-HSCT patients. Table S2. Comparison of mNGS results on the pooled plasma samples and of the routine r(RT-)PCR results on the corresponding plasma samples of the 25 patients. Figure S1. Boxplot of mapped reads of DNA viruses and corresponding mRNA detection with mNGS. The vertical axis represents the number of mapped reads. The horizontal axis represents all identified viral sequences of DNA viruses (left panel) and corresponding mRNA sequences (right panel). The numbers on the horizontal axis represent the number of patients in which sequences of each virus were identified. Abbreviations: HSV-1: herpes simplex 1 virus; CMV: cytomegalovirus; EBV: Epstein-Barr virus; TTMDV: torque teno midivirus; TTMV: torque teno minivirus; TTV: torque teno virus.
Publisher’s Note
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L. Kaiser and D. L. Vu contributed equally to this work.
Acknowledgements
The authors would like to thank Fiona Pigny for technical assistance and Erik Boehm for editorial assistance.
Authors’ contributions
MCZ, DLV, SC, and LK designed the research project. GV, MD, FL, and SC performed the mNGS and sequence analysis and r(RT-)PCR assays. VB, TAM, and JAL performed the biopsies histological examination. CVD, SML, and YC contributed to the interpretation of data regarding transplantation. MCZ, DLV, and SC collected and interpreted the data and wrote the first draft of the manuscript. All other authors revised and commented on the manuscript. The authors read and approved the final manuscript.
Funding
This work was supported by the “Projets Recherche et Développement (PRD)” of Geneva University Hospitals (grant number PRD 17-2019-I) and the Swiss National Science Foundation (grant number 320030_179507).
Availability of data and materials
The datasets generated and/or analyzed during the current study are available in the Dryad repository (10.5061/dryad.0k6djh9xp). The raw sequence data were deposited in the NCBI Sequence Read Archive under BioProject accession number PRJNA641787.
Ethics approval and consent to participate
The study protocol was approved by the Geneva Cantonal Ethics Commission (project #2019-00511).
Consent for publication
Not applicable
Competing interests
The authors declare that they have no competing interests. | UNK UNK, UNKNOWN FREQ. | DrugDosageText | CC BY | 33487167 | 18,939,834 | 2021-01-24 |
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