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What was the dosage of drug 'ACETAMINOPHEN\HYDROCODONE'? | Amniotic membrane transplantation in a 2-month-old infant with toxic epidermal necrolysis.
To report a case of 2-month-old boy with Stevens-Johnson syndrome (SJS)/Toxic epidermal necrolysis (TEN) and ocular involvement that was successfully treated with cryopreserved amniotic membrane transplantation (AMT).
A 2-month-old otherwise healthy boy was referred to Boston Children's Hospital with extensive rash and desquamation concerning for SJS/TEN. A skin biopsy was performed which showed full-thickness epidermal necrosis. AMT was performed at the bedside under general anesthesia. A combination of tobramycin and dexamethasone ointment was prescribed four times per day. On reassessment two weeks following AMT, the entire ocular surface had healed with no signs of conjunctival and/or corneal inflammation or ulceration.
To the best of our knowledge, our case represents the youngest patient with SJS/TEN to be managed by AMT and one of very few cases where acetaminophen is suspected to be the offending agent. This case highlights the efficacy of AMT at such a young age and feasibility of performing the procedure at bedside in these patients It also highlights that SJS/TEN can develop at such young age.
1 Introduction
Stevens-Johnson syndrome (SJS) and its more severe variant toxic epidermal necrolysis (TEN) are serious life-threatening conditions that involve wide spread skin and mucous membrane destruction.1,2 We present a case of 2 month old boy with Stevens-Johnson syndrome/Toxic epidermal necrolysis and ocular involvement that was successfully treated with cryopreserved amniotic membrane transplantation (AMT).
2 Case report
A 2-month-old otherwise healthy boy was referred to Boston Children's Hospital with extensive rash and desquamation concerning for SJS/TEN. One week prior to presentation, he developed non-specific viral prodromal symptoms including fever to102.6 F (39.2 °C), decreased urine output, emesis and decreased appetite. There was no history of any allergies. Family history was only significant for Sjögren's syndrome for his mother and recent pneumonia actively treated with azithromycin for the patient's older sister. A full sepsis work-up at outside hospital was performed and was negative. The patient was empirically started on acyclovir, vancomycin, ceftriaxone and acetaminophen. One day later, he developed a diffuse maculopapular rash with vesicles and desquamation involving head, trunk, upper and lower extremities (Fig. 1). The patient developed acute respiratory failure for which he was sedated and nasally intubated. At that time, he was transferred to Boston Children's Hospital with skin detachment involving more than 40% of his total body surface area (TBSA). A skin biopsy was performed which showed full-thickness epidermal necrosis. The adjacent epidermis demonstrated basal layer vacuolization and scattered dyskeratotic cells (Fig. 2). Special stains were performed including periodic acid Schiff (PAS), gram stain and Grocott-Gomori's (or Gömöri) methenamine silver which were all negative. No immunoreactivity was detected with IgG, IgA, IgM, C3 and fibrin. These findings were consistent with diagnosis of SJS/TEN. Systemic intravenous immunoglobulin (IVIG) was initiated.Fig. 1 External photo showing diffuse maculopapular rash with skin desquamation and epidermal detachment involving head, trunk and upper extremities with bilateral macerated upper and lower eye lids.
Fig. 1Fig. 2 Histopathology showing A-full thickness epidermal necrosis and separation (black arrow). B- The adjacent epidermis demonstrated scattered dyskeratotic cells (a) and basal layer vacuolization (b).
Fig. 2
Ocular evaluation by a senior faculty member at the time of initial presentation to our institution showed bilateral desquamated upper and lower eye lids (Fig. 1), mild conjunctival injection and bilateral corneal epithelial defects. No conjunctival staining was detected at that time. The anterior chamber was quiet bilaterally, the pupils were equal, round, regular and reactive to light. Dilated fundus examination disclosed normal disc, vessels, macula, and periphery. Erythromycin ointment and artificial tears were prescribed for the corneal epithelial defects which healed in two days. Five days later, diffuse perilimbal conjunctival staining was noted with early mild symblepharon formation nasally and temporally. AMT was performed at the bedside under general anesthesia using our previously described technique.3 In summary, intravenous tubing was used to create bolsters and a symblepharon ring, the diameter of which was estimated based on the distance between the superior and inferior orbital rims. A 5 × 5cm AM piece was then placed as a continuous sheet over the ocular surface. The symblepharon ring was inserted to push the AM into the fornices. Finally, the AM was anchored to the skin with 6–0 polypropylene sutures over the bolsters. A combination of tobramycin and dexamethasone ointment was prescribed four times per day. On reassessment two weeks following AMT, the entire ocular surface had healed with no signs of conjunctival and/or corneal inflammation or ulceration. There was no evidence of limbal stem cell deficiency, and the tobramycin/dexamethasone drops were gradually tapered. The general condition of the patient continued to improve with signs of skin re-epithelization (Fig. 3). At the last follow-up, 2 months later, ocular examination showed normal anterior segment with no evidence of lid margin keratinization, entropion, trichiasis or any other complication (Fig. 4). Further follow-up visits have been scheduled for early detection of late complications.Fig. 3 External photo taken 2 weeks after initial presentation showing marked improvement in the patient's general condition with continued skin re-epithelization.
Fig. 3Fig. 4 External photo taken after discharge showing complete healing of lid desquamation and normal anterior segment.
Fig. 4
3 Discussion
Ocular involvement in SJS/TEN occurs in 84% of patients during the acute stage, especially those with epidermal detachment >10% of TBSA.4 Our patient had more than 40% of TBSA involved, therefore it is better classified as TEN rather than SJS. Atypical cases of SJS/TEN may initially present with ocular signs only.5 Prompt diagnosis of ocular surface inflammation and early intervention are essential to avoid cicatricial keratoconjunctivitis and limbal stem cell deficiency that may lead to vision threatening complications. AMT performed in the first week after ocular involvement has been reported to be an effective treatment modality due to anti-inflammatory and anti-scarring effects mediated by anti-inflammatory cytokines, including interleukin-10 and anti-inflammatory protease inhibitors such as alpha 1 antitrypsin inhibitor. This can subsequently facilitate rapid epithelial healing preventing long-term ocular morbidity during the chronic stage.3,6, 7, 8 We present a rare case of TEN in a very young patient (2 months) that was successfully managed with AMT. The triggering factor for SJS/TEN in our case remained unclear, however it may be multifactorial. It may be a viral infection based on the history of fever and sick contact with pneumonia (patient's older sister). Our patient received acetaminophen one day before development of maculopapular rash and desquamation which raise the possibility that it may be one of the factors that lead to TEN. It has been previously reported to be associated with SJS/TEN with few reports in the literature, however it was started together with vancomycin, ceftriaxone and acyclovir and any one of them may be the triggering agent.9,10 Neonatal lupus presenting as TEN-like syndrome was considered initially given mother's history of Sjögren's syndrome, however the skin biopsy and overall clinical picture was consistent with TEN. Long-term follow-up of these cases is essential for early detection of complications. Catt and colleagues retrospectively evaluated the ocular manifestations of pediatric SJS/TEN and reported that the median time for development of corneal opacification was 4 months, of limbal stem cell deficiency was 7 months and of corneal neovascularization was 10 months after admission.11
To the best of our knowledge our case represents the youngest patient with SJS/TEN to be managed by AMT and one of very few cases where acetaminophen is suspected to be the offending agent. This case highlights the efficacy of AMT at such a young age and feasibility of performing the procedure at bedside in these patients It also highlights that SJS/TEN can develop at such young age.
Patient consent
Written informed consent was obtained from the patient's legal guardian.
Authorship
All authors attest that they meet the current ICMJE criteria for authorship.
Funding
Children's Hospital Ophthalmology Foundation, Inc.
Declaration of competing interest
The following authors have no financial disclosures:
Abdelrahman M. Elhusseiny, Ryan Gise, Christina Scelfo, Iason Mantagos.
Acknowledgment
None. | UNKNOWN | DrugDosageText | CC BY-NC-ND | 33521381 | 18,940,084 | 2021-03 |
What was the dosage of drug 'ACYCLOVIR'? | Amniotic membrane transplantation in a 2-month-old infant with toxic epidermal necrolysis.
To report a case of 2-month-old boy with Stevens-Johnson syndrome (SJS)/Toxic epidermal necrolysis (TEN) and ocular involvement that was successfully treated with cryopreserved amniotic membrane transplantation (AMT).
A 2-month-old otherwise healthy boy was referred to Boston Children's Hospital with extensive rash and desquamation concerning for SJS/TEN. A skin biopsy was performed which showed full-thickness epidermal necrosis. AMT was performed at the bedside under general anesthesia. A combination of tobramycin and dexamethasone ointment was prescribed four times per day. On reassessment two weeks following AMT, the entire ocular surface had healed with no signs of conjunctival and/or corneal inflammation or ulceration.
To the best of our knowledge, our case represents the youngest patient with SJS/TEN to be managed by AMT and one of very few cases where acetaminophen is suspected to be the offending agent. This case highlights the efficacy of AMT at such a young age and feasibility of performing the procedure at bedside in these patients It also highlights that SJS/TEN can develop at such young age.
1 Introduction
Stevens-Johnson syndrome (SJS) and its more severe variant toxic epidermal necrolysis (TEN) are serious life-threatening conditions that involve wide spread skin and mucous membrane destruction.1,2 We present a case of 2 month old boy with Stevens-Johnson syndrome/Toxic epidermal necrolysis and ocular involvement that was successfully treated with cryopreserved amniotic membrane transplantation (AMT).
2 Case report
A 2-month-old otherwise healthy boy was referred to Boston Children's Hospital with extensive rash and desquamation concerning for SJS/TEN. One week prior to presentation, he developed non-specific viral prodromal symptoms including fever to102.6 F (39.2 °C), decreased urine output, emesis and decreased appetite. There was no history of any allergies. Family history was only significant for Sjögren's syndrome for his mother and recent pneumonia actively treated with azithromycin for the patient's older sister. A full sepsis work-up at outside hospital was performed and was negative. The patient was empirically started on acyclovir, vancomycin, ceftriaxone and acetaminophen. One day later, he developed a diffuse maculopapular rash with vesicles and desquamation involving head, trunk, upper and lower extremities (Fig. 1). The patient developed acute respiratory failure for which he was sedated and nasally intubated. At that time, he was transferred to Boston Children's Hospital with skin detachment involving more than 40% of his total body surface area (TBSA). A skin biopsy was performed which showed full-thickness epidermal necrosis. The adjacent epidermis demonstrated basal layer vacuolization and scattered dyskeratotic cells (Fig. 2). Special stains were performed including periodic acid Schiff (PAS), gram stain and Grocott-Gomori's (or Gömöri) methenamine silver which were all negative. No immunoreactivity was detected with IgG, IgA, IgM, C3 and fibrin. These findings were consistent with diagnosis of SJS/TEN. Systemic intravenous immunoglobulin (IVIG) was initiated.Fig. 1 External photo showing diffuse maculopapular rash with skin desquamation and epidermal detachment involving head, trunk and upper extremities with bilateral macerated upper and lower eye lids.
Fig. 1Fig. 2 Histopathology showing A-full thickness epidermal necrosis and separation (black arrow). B- The adjacent epidermis demonstrated scattered dyskeratotic cells (a) and basal layer vacuolization (b).
Fig. 2
Ocular evaluation by a senior faculty member at the time of initial presentation to our institution showed bilateral desquamated upper and lower eye lids (Fig. 1), mild conjunctival injection and bilateral corneal epithelial defects. No conjunctival staining was detected at that time. The anterior chamber was quiet bilaterally, the pupils were equal, round, regular and reactive to light. Dilated fundus examination disclosed normal disc, vessels, macula, and periphery. Erythromycin ointment and artificial tears were prescribed for the corneal epithelial defects which healed in two days. Five days later, diffuse perilimbal conjunctival staining was noted with early mild symblepharon formation nasally and temporally. AMT was performed at the bedside under general anesthesia using our previously described technique.3 In summary, intravenous tubing was used to create bolsters and a symblepharon ring, the diameter of which was estimated based on the distance between the superior and inferior orbital rims. A 5 × 5cm AM piece was then placed as a continuous sheet over the ocular surface. The symblepharon ring was inserted to push the AM into the fornices. Finally, the AM was anchored to the skin with 6–0 polypropylene sutures over the bolsters. A combination of tobramycin and dexamethasone ointment was prescribed four times per day. On reassessment two weeks following AMT, the entire ocular surface had healed with no signs of conjunctival and/or corneal inflammation or ulceration. There was no evidence of limbal stem cell deficiency, and the tobramycin/dexamethasone drops were gradually tapered. The general condition of the patient continued to improve with signs of skin re-epithelization (Fig. 3). At the last follow-up, 2 months later, ocular examination showed normal anterior segment with no evidence of lid margin keratinization, entropion, trichiasis or any other complication (Fig. 4). Further follow-up visits have been scheduled for early detection of late complications.Fig. 3 External photo taken 2 weeks after initial presentation showing marked improvement in the patient's general condition with continued skin re-epithelization.
Fig. 3Fig. 4 External photo taken after discharge showing complete healing of lid desquamation and normal anterior segment.
Fig. 4
3 Discussion
Ocular involvement in SJS/TEN occurs in 84% of patients during the acute stage, especially those with epidermal detachment >10% of TBSA.4 Our patient had more than 40% of TBSA involved, therefore it is better classified as TEN rather than SJS. Atypical cases of SJS/TEN may initially present with ocular signs only.5 Prompt diagnosis of ocular surface inflammation and early intervention are essential to avoid cicatricial keratoconjunctivitis and limbal stem cell deficiency that may lead to vision threatening complications. AMT performed in the first week after ocular involvement has been reported to be an effective treatment modality due to anti-inflammatory and anti-scarring effects mediated by anti-inflammatory cytokines, including interleukin-10 and anti-inflammatory protease inhibitors such as alpha 1 antitrypsin inhibitor. This can subsequently facilitate rapid epithelial healing preventing long-term ocular morbidity during the chronic stage.3,6, 7, 8 We present a rare case of TEN in a very young patient (2 months) that was successfully managed with AMT. The triggering factor for SJS/TEN in our case remained unclear, however it may be multifactorial. It may be a viral infection based on the history of fever and sick contact with pneumonia (patient's older sister). Our patient received acetaminophen one day before development of maculopapular rash and desquamation which raise the possibility that it may be one of the factors that lead to TEN. It has been previously reported to be associated with SJS/TEN with few reports in the literature, however it was started together with vancomycin, ceftriaxone and acyclovir and any one of them may be the triggering agent.9,10 Neonatal lupus presenting as TEN-like syndrome was considered initially given mother's history of Sjögren's syndrome, however the skin biopsy and overall clinical picture was consistent with TEN. Long-term follow-up of these cases is essential for early detection of complications. Catt and colleagues retrospectively evaluated the ocular manifestations of pediatric SJS/TEN and reported that the median time for development of corneal opacification was 4 months, of limbal stem cell deficiency was 7 months and of corneal neovascularization was 10 months after admission.11
To the best of our knowledge our case represents the youngest patient with SJS/TEN to be managed by AMT and one of very few cases where acetaminophen is suspected to be the offending agent. This case highlights the efficacy of AMT at such a young age and feasibility of performing the procedure at bedside in these patients It also highlights that SJS/TEN can develop at such young age.
Patient consent
Written informed consent was obtained from the patient's legal guardian.
Authorship
All authors attest that they meet the current ICMJE criteria for authorship.
Funding
Children's Hospital Ophthalmology Foundation, Inc.
Declaration of competing interest
The following authors have no financial disclosures:
Abdelrahman M. Elhusseiny, Ryan Gise, Christina Scelfo, Iason Mantagos.
Acknowledgment
None. | UNKNOWN | DrugDosageText | CC BY-NC-ND | 33521381 | 18,940,084 | 2021-03 |
What was the dosage of drug 'CEFTRIAXONE'? | Amniotic membrane transplantation in a 2-month-old infant with toxic epidermal necrolysis.
To report a case of 2-month-old boy with Stevens-Johnson syndrome (SJS)/Toxic epidermal necrolysis (TEN) and ocular involvement that was successfully treated with cryopreserved amniotic membrane transplantation (AMT).
A 2-month-old otherwise healthy boy was referred to Boston Children's Hospital with extensive rash and desquamation concerning for SJS/TEN. A skin biopsy was performed which showed full-thickness epidermal necrosis. AMT was performed at the bedside under general anesthesia. A combination of tobramycin and dexamethasone ointment was prescribed four times per day. On reassessment two weeks following AMT, the entire ocular surface had healed with no signs of conjunctival and/or corneal inflammation or ulceration.
To the best of our knowledge, our case represents the youngest patient with SJS/TEN to be managed by AMT and one of very few cases where acetaminophen is suspected to be the offending agent. This case highlights the efficacy of AMT at such a young age and feasibility of performing the procedure at bedside in these patients It also highlights that SJS/TEN can develop at such young age.
1 Introduction
Stevens-Johnson syndrome (SJS) and its more severe variant toxic epidermal necrolysis (TEN) are serious life-threatening conditions that involve wide spread skin and mucous membrane destruction.1,2 We present a case of 2 month old boy with Stevens-Johnson syndrome/Toxic epidermal necrolysis and ocular involvement that was successfully treated with cryopreserved amniotic membrane transplantation (AMT).
2 Case report
A 2-month-old otherwise healthy boy was referred to Boston Children's Hospital with extensive rash and desquamation concerning for SJS/TEN. One week prior to presentation, he developed non-specific viral prodromal symptoms including fever to102.6 F (39.2 °C), decreased urine output, emesis and decreased appetite. There was no history of any allergies. Family history was only significant for Sjögren's syndrome for his mother and recent pneumonia actively treated with azithromycin for the patient's older sister. A full sepsis work-up at outside hospital was performed and was negative. The patient was empirically started on acyclovir, vancomycin, ceftriaxone and acetaminophen. One day later, he developed a diffuse maculopapular rash with vesicles and desquamation involving head, trunk, upper and lower extremities (Fig. 1). The patient developed acute respiratory failure for which he was sedated and nasally intubated. At that time, he was transferred to Boston Children's Hospital with skin detachment involving more than 40% of his total body surface area (TBSA). A skin biopsy was performed which showed full-thickness epidermal necrosis. The adjacent epidermis demonstrated basal layer vacuolization and scattered dyskeratotic cells (Fig. 2). Special stains were performed including periodic acid Schiff (PAS), gram stain and Grocott-Gomori's (or Gömöri) methenamine silver which were all negative. No immunoreactivity was detected with IgG, IgA, IgM, C3 and fibrin. These findings were consistent with diagnosis of SJS/TEN. Systemic intravenous immunoglobulin (IVIG) was initiated.Fig. 1 External photo showing diffuse maculopapular rash with skin desquamation and epidermal detachment involving head, trunk and upper extremities with bilateral macerated upper and lower eye lids.
Fig. 1Fig. 2 Histopathology showing A-full thickness epidermal necrosis and separation (black arrow). B- The adjacent epidermis demonstrated scattered dyskeratotic cells (a) and basal layer vacuolization (b).
Fig. 2
Ocular evaluation by a senior faculty member at the time of initial presentation to our institution showed bilateral desquamated upper and lower eye lids (Fig. 1), mild conjunctival injection and bilateral corneal epithelial defects. No conjunctival staining was detected at that time. The anterior chamber was quiet bilaterally, the pupils were equal, round, regular and reactive to light. Dilated fundus examination disclosed normal disc, vessels, macula, and periphery. Erythromycin ointment and artificial tears were prescribed for the corneal epithelial defects which healed in two days. Five days later, diffuse perilimbal conjunctival staining was noted with early mild symblepharon formation nasally and temporally. AMT was performed at the bedside under general anesthesia using our previously described technique.3 In summary, intravenous tubing was used to create bolsters and a symblepharon ring, the diameter of which was estimated based on the distance between the superior and inferior orbital rims. A 5 × 5cm AM piece was then placed as a continuous sheet over the ocular surface. The symblepharon ring was inserted to push the AM into the fornices. Finally, the AM was anchored to the skin with 6–0 polypropylene sutures over the bolsters. A combination of tobramycin and dexamethasone ointment was prescribed four times per day. On reassessment two weeks following AMT, the entire ocular surface had healed with no signs of conjunctival and/or corneal inflammation or ulceration. There was no evidence of limbal stem cell deficiency, and the tobramycin/dexamethasone drops were gradually tapered. The general condition of the patient continued to improve with signs of skin re-epithelization (Fig. 3). At the last follow-up, 2 months later, ocular examination showed normal anterior segment with no evidence of lid margin keratinization, entropion, trichiasis or any other complication (Fig. 4). Further follow-up visits have been scheduled for early detection of late complications.Fig. 3 External photo taken 2 weeks after initial presentation showing marked improvement in the patient's general condition with continued skin re-epithelization.
Fig. 3Fig. 4 External photo taken after discharge showing complete healing of lid desquamation and normal anterior segment.
Fig. 4
3 Discussion
Ocular involvement in SJS/TEN occurs in 84% of patients during the acute stage, especially those with epidermal detachment >10% of TBSA.4 Our patient had more than 40% of TBSA involved, therefore it is better classified as TEN rather than SJS. Atypical cases of SJS/TEN may initially present with ocular signs only.5 Prompt diagnosis of ocular surface inflammation and early intervention are essential to avoid cicatricial keratoconjunctivitis and limbal stem cell deficiency that may lead to vision threatening complications. AMT performed in the first week after ocular involvement has been reported to be an effective treatment modality due to anti-inflammatory and anti-scarring effects mediated by anti-inflammatory cytokines, including interleukin-10 and anti-inflammatory protease inhibitors such as alpha 1 antitrypsin inhibitor. This can subsequently facilitate rapid epithelial healing preventing long-term ocular morbidity during the chronic stage.3,6, 7, 8 We present a rare case of TEN in a very young patient (2 months) that was successfully managed with AMT. The triggering factor for SJS/TEN in our case remained unclear, however it may be multifactorial. It may be a viral infection based on the history of fever and sick contact with pneumonia (patient's older sister). Our patient received acetaminophen one day before development of maculopapular rash and desquamation which raise the possibility that it may be one of the factors that lead to TEN. It has been previously reported to be associated with SJS/TEN with few reports in the literature, however it was started together with vancomycin, ceftriaxone and acyclovir and any one of them may be the triggering agent.9,10 Neonatal lupus presenting as TEN-like syndrome was considered initially given mother's history of Sjögren's syndrome, however the skin biopsy and overall clinical picture was consistent with TEN. Long-term follow-up of these cases is essential for early detection of complications. Catt and colleagues retrospectively evaluated the ocular manifestations of pediatric SJS/TEN and reported that the median time for development of corneal opacification was 4 months, of limbal stem cell deficiency was 7 months and of corneal neovascularization was 10 months after admission.11
To the best of our knowledge our case represents the youngest patient with SJS/TEN to be managed by AMT and one of very few cases where acetaminophen is suspected to be the offending agent. This case highlights the efficacy of AMT at such a young age and feasibility of performing the procedure at bedside in these patients It also highlights that SJS/TEN can develop at such young age.
Patient consent
Written informed consent was obtained from the patient's legal guardian.
Authorship
All authors attest that they meet the current ICMJE criteria for authorship.
Funding
Children's Hospital Ophthalmology Foundation, Inc.
Declaration of competing interest
The following authors have no financial disclosures:
Abdelrahman M. Elhusseiny, Ryan Gise, Christina Scelfo, Iason Mantagos.
Acknowledgment
None. | UNKNOWN | DrugDosageText | CC BY-NC-ND | 33521381 | 18,940,084 | 2021-03 |
What was the dosage of drug 'VANCOMYCIN'? | Amniotic membrane transplantation in a 2-month-old infant with toxic epidermal necrolysis.
To report a case of 2-month-old boy with Stevens-Johnson syndrome (SJS)/Toxic epidermal necrolysis (TEN) and ocular involvement that was successfully treated with cryopreserved amniotic membrane transplantation (AMT).
A 2-month-old otherwise healthy boy was referred to Boston Children's Hospital with extensive rash and desquamation concerning for SJS/TEN. A skin biopsy was performed which showed full-thickness epidermal necrosis. AMT was performed at the bedside under general anesthesia. A combination of tobramycin and dexamethasone ointment was prescribed four times per day. On reassessment two weeks following AMT, the entire ocular surface had healed with no signs of conjunctival and/or corneal inflammation or ulceration.
To the best of our knowledge, our case represents the youngest patient with SJS/TEN to be managed by AMT and one of very few cases where acetaminophen is suspected to be the offending agent. This case highlights the efficacy of AMT at such a young age and feasibility of performing the procedure at bedside in these patients It also highlights that SJS/TEN can develop at such young age.
1 Introduction
Stevens-Johnson syndrome (SJS) and its more severe variant toxic epidermal necrolysis (TEN) are serious life-threatening conditions that involve wide spread skin and mucous membrane destruction.1,2 We present a case of 2 month old boy with Stevens-Johnson syndrome/Toxic epidermal necrolysis and ocular involvement that was successfully treated with cryopreserved amniotic membrane transplantation (AMT).
2 Case report
A 2-month-old otherwise healthy boy was referred to Boston Children's Hospital with extensive rash and desquamation concerning for SJS/TEN. One week prior to presentation, he developed non-specific viral prodromal symptoms including fever to102.6 F (39.2 °C), decreased urine output, emesis and decreased appetite. There was no history of any allergies. Family history was only significant for Sjögren's syndrome for his mother and recent pneumonia actively treated with azithromycin for the patient's older sister. A full sepsis work-up at outside hospital was performed and was negative. The patient was empirically started on acyclovir, vancomycin, ceftriaxone and acetaminophen. One day later, he developed a diffuse maculopapular rash with vesicles and desquamation involving head, trunk, upper and lower extremities (Fig. 1). The patient developed acute respiratory failure for which he was sedated and nasally intubated. At that time, he was transferred to Boston Children's Hospital with skin detachment involving more than 40% of his total body surface area (TBSA). A skin biopsy was performed which showed full-thickness epidermal necrosis. The adjacent epidermis demonstrated basal layer vacuolization and scattered dyskeratotic cells (Fig. 2). Special stains were performed including periodic acid Schiff (PAS), gram stain and Grocott-Gomori's (or Gömöri) methenamine silver which were all negative. No immunoreactivity was detected with IgG, IgA, IgM, C3 and fibrin. These findings were consistent with diagnosis of SJS/TEN. Systemic intravenous immunoglobulin (IVIG) was initiated.Fig. 1 External photo showing diffuse maculopapular rash with skin desquamation and epidermal detachment involving head, trunk and upper extremities with bilateral macerated upper and lower eye lids.
Fig. 1Fig. 2 Histopathology showing A-full thickness epidermal necrosis and separation (black arrow). B- The adjacent epidermis demonstrated scattered dyskeratotic cells (a) and basal layer vacuolization (b).
Fig. 2
Ocular evaluation by a senior faculty member at the time of initial presentation to our institution showed bilateral desquamated upper and lower eye lids (Fig. 1), mild conjunctival injection and bilateral corneal epithelial defects. No conjunctival staining was detected at that time. The anterior chamber was quiet bilaterally, the pupils were equal, round, regular and reactive to light. Dilated fundus examination disclosed normal disc, vessels, macula, and periphery. Erythromycin ointment and artificial tears were prescribed for the corneal epithelial defects which healed in two days. Five days later, diffuse perilimbal conjunctival staining was noted with early mild symblepharon formation nasally and temporally. AMT was performed at the bedside under general anesthesia using our previously described technique.3 In summary, intravenous tubing was used to create bolsters and a symblepharon ring, the diameter of which was estimated based on the distance between the superior and inferior orbital rims. A 5 × 5cm AM piece was then placed as a continuous sheet over the ocular surface. The symblepharon ring was inserted to push the AM into the fornices. Finally, the AM was anchored to the skin with 6–0 polypropylene sutures over the bolsters. A combination of tobramycin and dexamethasone ointment was prescribed four times per day. On reassessment two weeks following AMT, the entire ocular surface had healed with no signs of conjunctival and/or corneal inflammation or ulceration. There was no evidence of limbal stem cell deficiency, and the tobramycin/dexamethasone drops were gradually tapered. The general condition of the patient continued to improve with signs of skin re-epithelization (Fig. 3). At the last follow-up, 2 months later, ocular examination showed normal anterior segment with no evidence of lid margin keratinization, entropion, trichiasis or any other complication (Fig. 4). Further follow-up visits have been scheduled for early detection of late complications.Fig. 3 External photo taken 2 weeks after initial presentation showing marked improvement in the patient's general condition with continued skin re-epithelization.
Fig. 3Fig. 4 External photo taken after discharge showing complete healing of lid desquamation and normal anterior segment.
Fig. 4
3 Discussion
Ocular involvement in SJS/TEN occurs in 84% of patients during the acute stage, especially those with epidermal detachment >10% of TBSA.4 Our patient had more than 40% of TBSA involved, therefore it is better classified as TEN rather than SJS. Atypical cases of SJS/TEN may initially present with ocular signs only.5 Prompt diagnosis of ocular surface inflammation and early intervention are essential to avoid cicatricial keratoconjunctivitis and limbal stem cell deficiency that may lead to vision threatening complications. AMT performed in the first week after ocular involvement has been reported to be an effective treatment modality due to anti-inflammatory and anti-scarring effects mediated by anti-inflammatory cytokines, including interleukin-10 and anti-inflammatory protease inhibitors such as alpha 1 antitrypsin inhibitor. This can subsequently facilitate rapid epithelial healing preventing long-term ocular morbidity during the chronic stage.3,6, 7, 8 We present a rare case of TEN in a very young patient (2 months) that was successfully managed with AMT. The triggering factor for SJS/TEN in our case remained unclear, however it may be multifactorial. It may be a viral infection based on the history of fever and sick contact with pneumonia (patient's older sister). Our patient received acetaminophen one day before development of maculopapular rash and desquamation which raise the possibility that it may be one of the factors that lead to TEN. It has been previously reported to be associated with SJS/TEN with few reports in the literature, however it was started together with vancomycin, ceftriaxone and acyclovir and any one of them may be the triggering agent.9,10 Neonatal lupus presenting as TEN-like syndrome was considered initially given mother's history of Sjögren's syndrome, however the skin biopsy and overall clinical picture was consistent with TEN. Long-term follow-up of these cases is essential for early detection of complications. Catt and colleagues retrospectively evaluated the ocular manifestations of pediatric SJS/TEN and reported that the median time for development of corneal opacification was 4 months, of limbal stem cell deficiency was 7 months and of corneal neovascularization was 10 months after admission.11
To the best of our knowledge our case represents the youngest patient with SJS/TEN to be managed by AMT and one of very few cases where acetaminophen is suspected to be the offending agent. This case highlights the efficacy of AMT at such a young age and feasibility of performing the procedure at bedside in these patients It also highlights that SJS/TEN can develop at such young age.
Patient consent
Written informed consent was obtained from the patient's legal guardian.
Authorship
All authors attest that they meet the current ICMJE criteria for authorship.
Funding
Children's Hospital Ophthalmology Foundation, Inc.
Declaration of competing interest
The following authors have no financial disclosures:
Abdelrahman M. Elhusseiny, Ryan Gise, Christina Scelfo, Iason Mantagos.
Acknowledgment
None. | UNKNOWN | DrugDosageText | CC BY-NC-ND | 33521381 | 18,940,084 | 2021-03 |
What was the outcome of reaction 'Conjunctival ulcer'? | Amniotic membrane transplantation in a 2-month-old infant with toxic epidermal necrolysis.
To report a case of 2-month-old boy with Stevens-Johnson syndrome (SJS)/Toxic epidermal necrolysis (TEN) and ocular involvement that was successfully treated with cryopreserved amniotic membrane transplantation (AMT).
A 2-month-old otherwise healthy boy was referred to Boston Children's Hospital with extensive rash and desquamation concerning for SJS/TEN. A skin biopsy was performed which showed full-thickness epidermal necrosis. AMT was performed at the bedside under general anesthesia. A combination of tobramycin and dexamethasone ointment was prescribed four times per day. On reassessment two weeks following AMT, the entire ocular surface had healed with no signs of conjunctival and/or corneal inflammation or ulceration.
To the best of our knowledge, our case represents the youngest patient with SJS/TEN to be managed by AMT and one of very few cases where acetaminophen is suspected to be the offending agent. This case highlights the efficacy of AMT at such a young age and feasibility of performing the procedure at bedside in these patients It also highlights that SJS/TEN can develop at such young age.
1 Introduction
Stevens-Johnson syndrome (SJS) and its more severe variant toxic epidermal necrolysis (TEN) are serious life-threatening conditions that involve wide spread skin and mucous membrane destruction.1,2 We present a case of 2 month old boy with Stevens-Johnson syndrome/Toxic epidermal necrolysis and ocular involvement that was successfully treated with cryopreserved amniotic membrane transplantation (AMT).
2 Case report
A 2-month-old otherwise healthy boy was referred to Boston Children's Hospital with extensive rash and desquamation concerning for SJS/TEN. One week prior to presentation, he developed non-specific viral prodromal symptoms including fever to102.6 F (39.2 °C), decreased urine output, emesis and decreased appetite. There was no history of any allergies. Family history was only significant for Sjögren's syndrome for his mother and recent pneumonia actively treated with azithromycin for the patient's older sister. A full sepsis work-up at outside hospital was performed and was negative. The patient was empirically started on acyclovir, vancomycin, ceftriaxone and acetaminophen. One day later, he developed a diffuse maculopapular rash with vesicles and desquamation involving head, trunk, upper and lower extremities (Fig. 1). The patient developed acute respiratory failure for which he was sedated and nasally intubated. At that time, he was transferred to Boston Children's Hospital with skin detachment involving more than 40% of his total body surface area (TBSA). A skin biopsy was performed which showed full-thickness epidermal necrosis. The adjacent epidermis demonstrated basal layer vacuolization and scattered dyskeratotic cells (Fig. 2). Special stains were performed including periodic acid Schiff (PAS), gram stain and Grocott-Gomori's (or Gömöri) methenamine silver which were all negative. No immunoreactivity was detected with IgG, IgA, IgM, C3 and fibrin. These findings were consistent with diagnosis of SJS/TEN. Systemic intravenous immunoglobulin (IVIG) was initiated.Fig. 1 External photo showing diffuse maculopapular rash with skin desquamation and epidermal detachment involving head, trunk and upper extremities with bilateral macerated upper and lower eye lids.
Fig. 1Fig. 2 Histopathology showing A-full thickness epidermal necrosis and separation (black arrow). B- The adjacent epidermis demonstrated scattered dyskeratotic cells (a) and basal layer vacuolization (b).
Fig. 2
Ocular evaluation by a senior faculty member at the time of initial presentation to our institution showed bilateral desquamated upper and lower eye lids (Fig. 1), mild conjunctival injection and bilateral corneal epithelial defects. No conjunctival staining was detected at that time. The anterior chamber was quiet bilaterally, the pupils were equal, round, regular and reactive to light. Dilated fundus examination disclosed normal disc, vessels, macula, and periphery. Erythromycin ointment and artificial tears were prescribed for the corneal epithelial defects which healed in two days. Five days later, diffuse perilimbal conjunctival staining was noted with early mild symblepharon formation nasally and temporally. AMT was performed at the bedside under general anesthesia using our previously described technique.3 In summary, intravenous tubing was used to create bolsters and a symblepharon ring, the diameter of which was estimated based on the distance between the superior and inferior orbital rims. A 5 × 5cm AM piece was then placed as a continuous sheet over the ocular surface. The symblepharon ring was inserted to push the AM into the fornices. Finally, the AM was anchored to the skin with 6–0 polypropylene sutures over the bolsters. A combination of tobramycin and dexamethasone ointment was prescribed four times per day. On reassessment two weeks following AMT, the entire ocular surface had healed with no signs of conjunctival and/or corneal inflammation or ulceration. There was no evidence of limbal stem cell deficiency, and the tobramycin/dexamethasone drops were gradually tapered. The general condition of the patient continued to improve with signs of skin re-epithelization (Fig. 3). At the last follow-up, 2 months later, ocular examination showed normal anterior segment with no evidence of lid margin keratinization, entropion, trichiasis or any other complication (Fig. 4). Further follow-up visits have been scheduled for early detection of late complications.Fig. 3 External photo taken 2 weeks after initial presentation showing marked improvement in the patient's general condition with continued skin re-epithelization.
Fig. 3Fig. 4 External photo taken after discharge showing complete healing of lid desquamation and normal anterior segment.
Fig. 4
3 Discussion
Ocular involvement in SJS/TEN occurs in 84% of patients during the acute stage, especially those with epidermal detachment >10% of TBSA.4 Our patient had more than 40% of TBSA involved, therefore it is better classified as TEN rather than SJS. Atypical cases of SJS/TEN may initially present with ocular signs only.5 Prompt diagnosis of ocular surface inflammation and early intervention are essential to avoid cicatricial keratoconjunctivitis and limbal stem cell deficiency that may lead to vision threatening complications. AMT performed in the first week after ocular involvement has been reported to be an effective treatment modality due to anti-inflammatory and anti-scarring effects mediated by anti-inflammatory cytokines, including interleukin-10 and anti-inflammatory protease inhibitors such as alpha 1 antitrypsin inhibitor. This can subsequently facilitate rapid epithelial healing preventing long-term ocular morbidity during the chronic stage.3,6, 7, 8 We present a rare case of TEN in a very young patient (2 months) that was successfully managed with AMT. The triggering factor for SJS/TEN in our case remained unclear, however it may be multifactorial. It may be a viral infection based on the history of fever and sick contact with pneumonia (patient's older sister). Our patient received acetaminophen one day before development of maculopapular rash and desquamation which raise the possibility that it may be one of the factors that lead to TEN. It has been previously reported to be associated with SJS/TEN with few reports in the literature, however it was started together with vancomycin, ceftriaxone and acyclovir and any one of them may be the triggering agent.9,10 Neonatal lupus presenting as TEN-like syndrome was considered initially given mother's history of Sjögren's syndrome, however the skin biopsy and overall clinical picture was consistent with TEN. Long-term follow-up of these cases is essential for early detection of complications. Catt and colleagues retrospectively evaluated the ocular manifestations of pediatric SJS/TEN and reported that the median time for development of corneal opacification was 4 months, of limbal stem cell deficiency was 7 months and of corneal neovascularization was 10 months after admission.11
To the best of our knowledge our case represents the youngest patient with SJS/TEN to be managed by AMT and one of very few cases where acetaminophen is suspected to be the offending agent. This case highlights the efficacy of AMT at such a young age and feasibility of performing the procedure at bedside in these patients It also highlights that SJS/TEN can develop at such young age.
Patient consent
Written informed consent was obtained from the patient's legal guardian.
Authorship
All authors attest that they meet the current ICMJE criteria for authorship.
Funding
Children's Hospital Ophthalmology Foundation, Inc.
Declaration of competing interest
The following authors have no financial disclosures:
Abdelrahman M. Elhusseiny, Ryan Gise, Christina Scelfo, Iason Mantagos.
Acknowledgment
None. | Recovered | ReactionOutcome | CC BY-NC-ND | 33521381 | 18,940,084 | 2021-03 |
What was the outcome of reaction 'Stevens-Johnson syndrome'? | Amniotic membrane transplantation in a 2-month-old infant with toxic epidermal necrolysis.
To report a case of 2-month-old boy with Stevens-Johnson syndrome (SJS)/Toxic epidermal necrolysis (TEN) and ocular involvement that was successfully treated with cryopreserved amniotic membrane transplantation (AMT).
A 2-month-old otherwise healthy boy was referred to Boston Children's Hospital with extensive rash and desquamation concerning for SJS/TEN. A skin biopsy was performed which showed full-thickness epidermal necrosis. AMT was performed at the bedside under general anesthesia. A combination of tobramycin and dexamethasone ointment was prescribed four times per day. On reassessment two weeks following AMT, the entire ocular surface had healed with no signs of conjunctival and/or corneal inflammation or ulceration.
To the best of our knowledge, our case represents the youngest patient with SJS/TEN to be managed by AMT and one of very few cases where acetaminophen is suspected to be the offending agent. This case highlights the efficacy of AMT at such a young age and feasibility of performing the procedure at bedside in these patients It also highlights that SJS/TEN can develop at such young age.
1 Introduction
Stevens-Johnson syndrome (SJS) and its more severe variant toxic epidermal necrolysis (TEN) are serious life-threatening conditions that involve wide spread skin and mucous membrane destruction.1,2 We present a case of 2 month old boy with Stevens-Johnson syndrome/Toxic epidermal necrolysis and ocular involvement that was successfully treated with cryopreserved amniotic membrane transplantation (AMT).
2 Case report
A 2-month-old otherwise healthy boy was referred to Boston Children's Hospital with extensive rash and desquamation concerning for SJS/TEN. One week prior to presentation, he developed non-specific viral prodromal symptoms including fever to102.6 F (39.2 °C), decreased urine output, emesis and decreased appetite. There was no history of any allergies. Family history was only significant for Sjögren's syndrome for his mother and recent pneumonia actively treated with azithromycin for the patient's older sister. A full sepsis work-up at outside hospital was performed and was negative. The patient was empirically started on acyclovir, vancomycin, ceftriaxone and acetaminophen. One day later, he developed a diffuse maculopapular rash with vesicles and desquamation involving head, trunk, upper and lower extremities (Fig. 1). The patient developed acute respiratory failure for which he was sedated and nasally intubated. At that time, he was transferred to Boston Children's Hospital with skin detachment involving more than 40% of his total body surface area (TBSA). A skin biopsy was performed which showed full-thickness epidermal necrosis. The adjacent epidermis demonstrated basal layer vacuolization and scattered dyskeratotic cells (Fig. 2). Special stains were performed including periodic acid Schiff (PAS), gram stain and Grocott-Gomori's (or Gömöri) methenamine silver which were all negative. No immunoreactivity was detected with IgG, IgA, IgM, C3 and fibrin. These findings were consistent with diagnosis of SJS/TEN. Systemic intravenous immunoglobulin (IVIG) was initiated.Fig. 1 External photo showing diffuse maculopapular rash with skin desquamation and epidermal detachment involving head, trunk and upper extremities with bilateral macerated upper and lower eye lids.
Fig. 1Fig. 2 Histopathology showing A-full thickness epidermal necrosis and separation (black arrow). B- The adjacent epidermis demonstrated scattered dyskeratotic cells (a) and basal layer vacuolization (b).
Fig. 2
Ocular evaluation by a senior faculty member at the time of initial presentation to our institution showed bilateral desquamated upper and lower eye lids (Fig. 1), mild conjunctival injection and bilateral corneal epithelial defects. No conjunctival staining was detected at that time. The anterior chamber was quiet bilaterally, the pupils were equal, round, regular and reactive to light. Dilated fundus examination disclosed normal disc, vessels, macula, and periphery. Erythromycin ointment and artificial tears were prescribed for the corneal epithelial defects which healed in two days. Five days later, diffuse perilimbal conjunctival staining was noted with early mild symblepharon formation nasally and temporally. AMT was performed at the bedside under general anesthesia using our previously described technique.3 In summary, intravenous tubing was used to create bolsters and a symblepharon ring, the diameter of which was estimated based on the distance between the superior and inferior orbital rims. A 5 × 5cm AM piece was then placed as a continuous sheet over the ocular surface. The symblepharon ring was inserted to push the AM into the fornices. Finally, the AM was anchored to the skin with 6–0 polypropylene sutures over the bolsters. A combination of tobramycin and dexamethasone ointment was prescribed four times per day. On reassessment two weeks following AMT, the entire ocular surface had healed with no signs of conjunctival and/or corneal inflammation or ulceration. There was no evidence of limbal stem cell deficiency, and the tobramycin/dexamethasone drops were gradually tapered. The general condition of the patient continued to improve with signs of skin re-epithelization (Fig. 3). At the last follow-up, 2 months later, ocular examination showed normal anterior segment with no evidence of lid margin keratinization, entropion, trichiasis or any other complication (Fig. 4). Further follow-up visits have been scheduled for early detection of late complications.Fig. 3 External photo taken 2 weeks after initial presentation showing marked improvement in the patient's general condition with continued skin re-epithelization.
Fig. 3Fig. 4 External photo taken after discharge showing complete healing of lid desquamation and normal anterior segment.
Fig. 4
3 Discussion
Ocular involvement in SJS/TEN occurs in 84% of patients during the acute stage, especially those with epidermal detachment >10% of TBSA.4 Our patient had more than 40% of TBSA involved, therefore it is better classified as TEN rather than SJS. Atypical cases of SJS/TEN may initially present with ocular signs only.5 Prompt diagnosis of ocular surface inflammation and early intervention are essential to avoid cicatricial keratoconjunctivitis and limbal stem cell deficiency that may lead to vision threatening complications. AMT performed in the first week after ocular involvement has been reported to be an effective treatment modality due to anti-inflammatory and anti-scarring effects mediated by anti-inflammatory cytokines, including interleukin-10 and anti-inflammatory protease inhibitors such as alpha 1 antitrypsin inhibitor. This can subsequently facilitate rapid epithelial healing preventing long-term ocular morbidity during the chronic stage.3,6, 7, 8 We present a rare case of TEN in a very young patient (2 months) that was successfully managed with AMT. The triggering factor for SJS/TEN in our case remained unclear, however it may be multifactorial. It may be a viral infection based on the history of fever and sick contact with pneumonia (patient's older sister). Our patient received acetaminophen one day before development of maculopapular rash and desquamation which raise the possibility that it may be one of the factors that lead to TEN. It has been previously reported to be associated with SJS/TEN with few reports in the literature, however it was started together with vancomycin, ceftriaxone and acyclovir and any one of them may be the triggering agent.9,10 Neonatal lupus presenting as TEN-like syndrome was considered initially given mother's history of Sjögren's syndrome, however the skin biopsy and overall clinical picture was consistent with TEN. Long-term follow-up of these cases is essential for early detection of complications. Catt and colleagues retrospectively evaluated the ocular manifestations of pediatric SJS/TEN and reported that the median time for development of corneal opacification was 4 months, of limbal stem cell deficiency was 7 months and of corneal neovascularization was 10 months after admission.11
To the best of our knowledge our case represents the youngest patient with SJS/TEN to be managed by AMT and one of very few cases where acetaminophen is suspected to be the offending agent. This case highlights the efficacy of AMT at such a young age and feasibility of performing the procedure at bedside in these patients It also highlights that SJS/TEN can develop at such young age.
Patient consent
Written informed consent was obtained from the patient's legal guardian.
Authorship
All authors attest that they meet the current ICMJE criteria for authorship.
Funding
Children's Hospital Ophthalmology Foundation, Inc.
Declaration of competing interest
The following authors have no financial disclosures:
Abdelrahman M. Elhusseiny, Ryan Gise, Christina Scelfo, Iason Mantagos.
Acknowledgment
None. | Recovered | ReactionOutcome | CC BY-NC-ND | 33521381 | 18,898,525 | 2021-03 |
What was the outcome of reaction 'Ulcerative keratitis'? | Amniotic membrane transplantation in a 2-month-old infant with toxic epidermal necrolysis.
To report a case of 2-month-old boy with Stevens-Johnson syndrome (SJS)/Toxic epidermal necrolysis (TEN) and ocular involvement that was successfully treated with cryopreserved amniotic membrane transplantation (AMT).
A 2-month-old otherwise healthy boy was referred to Boston Children's Hospital with extensive rash and desquamation concerning for SJS/TEN. A skin biopsy was performed which showed full-thickness epidermal necrosis. AMT was performed at the bedside under general anesthesia. A combination of tobramycin and dexamethasone ointment was prescribed four times per day. On reassessment two weeks following AMT, the entire ocular surface had healed with no signs of conjunctival and/or corneal inflammation or ulceration.
To the best of our knowledge, our case represents the youngest patient with SJS/TEN to be managed by AMT and one of very few cases where acetaminophen is suspected to be the offending agent. This case highlights the efficacy of AMT at such a young age and feasibility of performing the procedure at bedside in these patients It also highlights that SJS/TEN can develop at such young age.
1 Introduction
Stevens-Johnson syndrome (SJS) and its more severe variant toxic epidermal necrolysis (TEN) are serious life-threatening conditions that involve wide spread skin and mucous membrane destruction.1,2 We present a case of 2 month old boy with Stevens-Johnson syndrome/Toxic epidermal necrolysis and ocular involvement that was successfully treated with cryopreserved amniotic membrane transplantation (AMT).
2 Case report
A 2-month-old otherwise healthy boy was referred to Boston Children's Hospital with extensive rash and desquamation concerning for SJS/TEN. One week prior to presentation, he developed non-specific viral prodromal symptoms including fever to102.6 F (39.2 °C), decreased urine output, emesis and decreased appetite. There was no history of any allergies. Family history was only significant for Sjögren's syndrome for his mother and recent pneumonia actively treated with azithromycin for the patient's older sister. A full sepsis work-up at outside hospital was performed and was negative. The patient was empirically started on acyclovir, vancomycin, ceftriaxone and acetaminophen. One day later, he developed a diffuse maculopapular rash with vesicles and desquamation involving head, trunk, upper and lower extremities (Fig. 1). The patient developed acute respiratory failure for which he was sedated and nasally intubated. At that time, he was transferred to Boston Children's Hospital with skin detachment involving more than 40% of his total body surface area (TBSA). A skin biopsy was performed which showed full-thickness epidermal necrosis. The adjacent epidermis demonstrated basal layer vacuolization and scattered dyskeratotic cells (Fig. 2). Special stains were performed including periodic acid Schiff (PAS), gram stain and Grocott-Gomori's (or Gömöri) methenamine silver which were all negative. No immunoreactivity was detected with IgG, IgA, IgM, C3 and fibrin. These findings were consistent with diagnosis of SJS/TEN. Systemic intravenous immunoglobulin (IVIG) was initiated.Fig. 1 External photo showing diffuse maculopapular rash with skin desquamation and epidermal detachment involving head, trunk and upper extremities with bilateral macerated upper and lower eye lids.
Fig. 1Fig. 2 Histopathology showing A-full thickness epidermal necrosis and separation (black arrow). B- The adjacent epidermis demonstrated scattered dyskeratotic cells (a) and basal layer vacuolization (b).
Fig. 2
Ocular evaluation by a senior faculty member at the time of initial presentation to our institution showed bilateral desquamated upper and lower eye lids (Fig. 1), mild conjunctival injection and bilateral corneal epithelial defects. No conjunctival staining was detected at that time. The anterior chamber was quiet bilaterally, the pupils were equal, round, regular and reactive to light. Dilated fundus examination disclosed normal disc, vessels, macula, and periphery. Erythromycin ointment and artificial tears were prescribed for the corneal epithelial defects which healed in two days. Five days later, diffuse perilimbal conjunctival staining was noted with early mild symblepharon formation nasally and temporally. AMT was performed at the bedside under general anesthesia using our previously described technique.3 In summary, intravenous tubing was used to create bolsters and a symblepharon ring, the diameter of which was estimated based on the distance between the superior and inferior orbital rims. A 5 × 5cm AM piece was then placed as a continuous sheet over the ocular surface. The symblepharon ring was inserted to push the AM into the fornices. Finally, the AM was anchored to the skin with 6–0 polypropylene sutures over the bolsters. A combination of tobramycin and dexamethasone ointment was prescribed four times per day. On reassessment two weeks following AMT, the entire ocular surface had healed with no signs of conjunctival and/or corneal inflammation or ulceration. There was no evidence of limbal stem cell deficiency, and the tobramycin/dexamethasone drops were gradually tapered. The general condition of the patient continued to improve with signs of skin re-epithelization (Fig. 3). At the last follow-up, 2 months later, ocular examination showed normal anterior segment with no evidence of lid margin keratinization, entropion, trichiasis or any other complication (Fig. 4). Further follow-up visits have been scheduled for early detection of late complications.Fig. 3 External photo taken 2 weeks after initial presentation showing marked improvement in the patient's general condition with continued skin re-epithelization.
Fig. 3Fig. 4 External photo taken after discharge showing complete healing of lid desquamation and normal anterior segment.
Fig. 4
3 Discussion
Ocular involvement in SJS/TEN occurs in 84% of patients during the acute stage, especially those with epidermal detachment >10% of TBSA.4 Our patient had more than 40% of TBSA involved, therefore it is better classified as TEN rather than SJS. Atypical cases of SJS/TEN may initially present with ocular signs only.5 Prompt diagnosis of ocular surface inflammation and early intervention are essential to avoid cicatricial keratoconjunctivitis and limbal stem cell deficiency that may lead to vision threatening complications. AMT performed in the first week after ocular involvement has been reported to be an effective treatment modality due to anti-inflammatory and anti-scarring effects mediated by anti-inflammatory cytokines, including interleukin-10 and anti-inflammatory protease inhibitors such as alpha 1 antitrypsin inhibitor. This can subsequently facilitate rapid epithelial healing preventing long-term ocular morbidity during the chronic stage.3,6, 7, 8 We present a rare case of TEN in a very young patient (2 months) that was successfully managed with AMT. The triggering factor for SJS/TEN in our case remained unclear, however it may be multifactorial. It may be a viral infection based on the history of fever and sick contact with pneumonia (patient's older sister). Our patient received acetaminophen one day before development of maculopapular rash and desquamation which raise the possibility that it may be one of the factors that lead to TEN. It has been previously reported to be associated with SJS/TEN with few reports in the literature, however it was started together with vancomycin, ceftriaxone and acyclovir and any one of them may be the triggering agent.9,10 Neonatal lupus presenting as TEN-like syndrome was considered initially given mother's history of Sjögren's syndrome, however the skin biopsy and overall clinical picture was consistent with TEN. Long-term follow-up of these cases is essential for early detection of complications. Catt and colleagues retrospectively evaluated the ocular manifestations of pediatric SJS/TEN and reported that the median time for development of corneal opacification was 4 months, of limbal stem cell deficiency was 7 months and of corneal neovascularization was 10 months after admission.11
To the best of our knowledge our case represents the youngest patient with SJS/TEN to be managed by AMT and one of very few cases where acetaminophen is suspected to be the offending agent. This case highlights the efficacy of AMT at such a young age and feasibility of performing the procedure at bedside in these patients It also highlights that SJS/TEN can develop at such young age.
Patient consent
Written informed consent was obtained from the patient's legal guardian.
Authorship
All authors attest that they meet the current ICMJE criteria for authorship.
Funding
Children's Hospital Ophthalmology Foundation, Inc.
Declaration of competing interest
The following authors have no financial disclosures:
Abdelrahman M. Elhusseiny, Ryan Gise, Christina Scelfo, Iason Mantagos.
Acknowledgment
None. | Recovered | ReactionOutcome | CC BY-NC-ND | 33521381 | 18,940,084 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Atrial flutter'. | Atrial Flutter in Patient With Critical COVID-19: Beneficial Effects of Rhythm Control on Respiratory Distress.
We report the case of a patient critically ill with coronavirus disease-2019 (COVID-19) in which atrial flutter with high ventricular response rate occurred, contributing to worsening of the respiratory distress. After failure of noninvasive rate and rhythm control strategies, successful transcatheter ablation was performed and the respiratory distress of the patient improved. (Level of Difficulty: Beginner.).
Coronavirus disease-2019 (COVID-19) has important implications for the cardiovascular system, including the onset of arrhythmias (1). Furthermore, arrhythmias may contribute to deteriorating respiratory distress, establishing a vicious circle.
We report the case of a 61-year-old man admitted to the hospital with dyspnea, cough, and fever (39°C). Blood pressure was 120/60 mm Hg and oxygen saturation level was 89% with respiratory rate of 33 breaths per minute. The acute deterioration of respiratory distress needed invasive ventilation and the patient was promptly intubated. High-resolution computed tomography showed bilateral severe interstitial pneumonia with “crazy paving” aspects (Figure 1A). At admission, the electrocardiogram showed sinus tachycardia of 100 beats/min. The nasopharyngeal swab detected severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) viral RNA. After 9 days the patient improved and was downgraded to noninvasive ventilation with helmet. The following day, the respiratory distress worsened and atrial flutter with high ventricular response rate occurred (Figure 1B). The echocardiogram showed left ventricular ejection fraction of 50%, mild right atrial dilatation, and signs of increased left ventricular filling pressures (mean averaged E/e′ was 16). An external electrical cardioversion initially restored sinus rhythm but atrial flutter relapsed early. A second cardioversion was attempted with intravenous amiodarone; sinus rhythm lasted only few hours and then atrial flutter started again. Due to the failure of rhythm, rate control strategy with prolonged intravenous full dose of metoprolol, verapamil, and digoxin was attempted but was equally ineffective. The persistent ventricular rate of 150 beats/min contributed to deterioration of the respiratory status, raising the issue of reverting to invasive mechanical ventilation. Therefore, after extensive multidisciplinary team discussion, we decided to perform transcatheter ablation of atrial flutter to achieve rhythm control. In addition to the difficulties of invasive procedure for a patient with COVID-19, we were well aware of two other problems: 1) the patient with helmet is normally seated but has to remain supine during the whole procedure, which, therefore, needs to be as fast as possible; and 2) the use of fluoroscopy is challenging by the presence of the helmet. Our option was for a zero fluoroscopy procedure, using a three-dimensional electroanatomic mapping system (EnSite Precision, Abbott, St. Paul, Minnesota) (2). Recommendations from international consensus were followed to ensure patient safety and minimize healthcare professional exposure (3). The only people allowed in the operative room with full protection, including FFP3 face mask, surgical gown, double gloves, and face shield, were a senior electrophysiologist, 2 anesthesiologists, and a specialized nurse. Double right femoral venous access was used, and the patient was maintained supine, ventilated with noninvasive helmet (Figure 1D). Endocardial mapping confirmed a cavo-tricuspid isthmus-dependent atrial flutter that was treated with radiofrequency ablation, restoring sinus rhythm. Bidirectional conduction block across the cavo-tricuspid isthmus was confirmed using activation map pacing from the coronary sinus ostium (Figure 1D) and from the lateral wall of right atrium. Procedural time including preparation of the patient was < 1 h. With the restoration of sinus rhythm (Figure 1E), the respiratory status improved, the oxygen saturation rapidly increased from 84% to 98%, and the patient was feeling better. This case highlights the contribution of atrial flutter with high ventricular response rate to respiratory deterioration in patients with COVID-19 and the beneficial role of rhythm control achieved with transcatheter ablation (with ad hoc precautions). The efficacy of medical therapy for rate or rhythm control of atrial flutter in critically ill patients is generally low for several reasons, including the trigger constituted by the underlying disease, the organism response, or the concomitant treatments. Furthermore, using amiodarone for rhythm control has potentially severe adverse effects of pulmonary toxicity (direct cytotoxicity and hypersensitivity reaction) and it should be used with caution in patients with respiratory distress. Transcatheter ablation is relatively simple and the most effective treatment to maintain sinus rhythm in atrial flutter, but, thus far, there are no specific data in the setting of COVID-19.Figure 1 Transcatheter Ablation of Atrial Flutter in a Critically Ill COVID-19 Patient
(A) High-resolution computed tomography showing bilateral interstitial pneumonia with “crazy paving” pattern. (B) Surface 12-lead electrocardiogram showing typical atrial flutter with high ventricular rate. (C) Non-fluoroscopic three-dimensional electroanatomic map of right atrium in caudal left anterior oblique and right anterior oblique view. Note signs of radiofrequency erogation in cavo-tricuspid isthmus (white and red dots) and the color-coded map shows counterclockwise block of the isthmus pacing from coronary sinus ostium. (D) Supine position of the patient with noninvasive ventilation helmet in electrophysiology laboratory and fluoroscopy system outside the operating field. (E) Post-operative 12-lead electrocardiogram showing sinus rhythm. COVID-19 = coronavirus disease–2019.
Author Disclosures
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center. | AMIODARONE, DIGOXIN, METOPROLOL, VERAPAMIL HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33521679 | 18,907,095 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Atrial Flutter in Patient With Critical COVID-19: Beneficial Effects of Rhythm Control on Respiratory Distress.
We report the case of a patient critically ill with coronavirus disease-2019 (COVID-19) in which atrial flutter with high ventricular response rate occurred, contributing to worsening of the respiratory distress. After failure of noninvasive rate and rhythm control strategies, successful transcatheter ablation was performed and the respiratory distress of the patient improved. (Level of Difficulty: Beginner.).
Coronavirus disease-2019 (COVID-19) has important implications for the cardiovascular system, including the onset of arrhythmias (1). Furthermore, arrhythmias may contribute to deteriorating respiratory distress, establishing a vicious circle.
We report the case of a 61-year-old man admitted to the hospital with dyspnea, cough, and fever (39°C). Blood pressure was 120/60 mm Hg and oxygen saturation level was 89% with respiratory rate of 33 breaths per minute. The acute deterioration of respiratory distress needed invasive ventilation and the patient was promptly intubated. High-resolution computed tomography showed bilateral severe interstitial pneumonia with “crazy paving” aspects (Figure 1A). At admission, the electrocardiogram showed sinus tachycardia of 100 beats/min. The nasopharyngeal swab detected severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) viral RNA. After 9 days the patient improved and was downgraded to noninvasive ventilation with helmet. The following day, the respiratory distress worsened and atrial flutter with high ventricular response rate occurred (Figure 1B). The echocardiogram showed left ventricular ejection fraction of 50%, mild right atrial dilatation, and signs of increased left ventricular filling pressures (mean averaged E/e′ was 16). An external electrical cardioversion initially restored sinus rhythm but atrial flutter relapsed early. A second cardioversion was attempted with intravenous amiodarone; sinus rhythm lasted only few hours and then atrial flutter started again. Due to the failure of rhythm, rate control strategy with prolonged intravenous full dose of metoprolol, verapamil, and digoxin was attempted but was equally ineffective. The persistent ventricular rate of 150 beats/min contributed to deterioration of the respiratory status, raising the issue of reverting to invasive mechanical ventilation. Therefore, after extensive multidisciplinary team discussion, we decided to perform transcatheter ablation of atrial flutter to achieve rhythm control. In addition to the difficulties of invasive procedure for a patient with COVID-19, we were well aware of two other problems: 1) the patient with helmet is normally seated but has to remain supine during the whole procedure, which, therefore, needs to be as fast as possible; and 2) the use of fluoroscopy is challenging by the presence of the helmet. Our option was for a zero fluoroscopy procedure, using a three-dimensional electroanatomic mapping system (EnSite Precision, Abbott, St. Paul, Minnesota) (2). Recommendations from international consensus were followed to ensure patient safety and minimize healthcare professional exposure (3). The only people allowed in the operative room with full protection, including FFP3 face mask, surgical gown, double gloves, and face shield, were a senior electrophysiologist, 2 anesthesiologists, and a specialized nurse. Double right femoral venous access was used, and the patient was maintained supine, ventilated with noninvasive helmet (Figure 1D). Endocardial mapping confirmed a cavo-tricuspid isthmus-dependent atrial flutter that was treated with radiofrequency ablation, restoring sinus rhythm. Bidirectional conduction block across the cavo-tricuspid isthmus was confirmed using activation map pacing from the coronary sinus ostium (Figure 1D) and from the lateral wall of right atrium. Procedural time including preparation of the patient was < 1 h. With the restoration of sinus rhythm (Figure 1E), the respiratory status improved, the oxygen saturation rapidly increased from 84% to 98%, and the patient was feeling better. This case highlights the contribution of atrial flutter with high ventricular response rate to respiratory deterioration in patients with COVID-19 and the beneficial role of rhythm control achieved with transcatheter ablation (with ad hoc precautions). The efficacy of medical therapy for rate or rhythm control of atrial flutter in critically ill patients is generally low for several reasons, including the trigger constituted by the underlying disease, the organism response, or the concomitant treatments. Furthermore, using amiodarone for rhythm control has potentially severe adverse effects of pulmonary toxicity (direct cytotoxicity and hypersensitivity reaction) and it should be used with caution in patients with respiratory distress. Transcatheter ablation is relatively simple and the most effective treatment to maintain sinus rhythm in atrial flutter, but, thus far, there are no specific data in the setting of COVID-19.Figure 1 Transcatheter Ablation of Atrial Flutter in a Critically Ill COVID-19 Patient
(A) High-resolution computed tomography showing bilateral interstitial pneumonia with “crazy paving” pattern. (B) Surface 12-lead electrocardiogram showing typical atrial flutter with high ventricular rate. (C) Non-fluoroscopic three-dimensional electroanatomic map of right atrium in caudal left anterior oblique and right anterior oblique view. Note signs of radiofrequency erogation in cavo-tricuspid isthmus (white and red dots) and the color-coded map shows counterclockwise block of the isthmus pacing from coronary sinus ostium. (D) Supine position of the patient with noninvasive ventilation helmet in electrophysiology laboratory and fluoroscopy system outside the operating field. (E) Post-operative 12-lead electrocardiogram showing sinus rhythm. COVID-19 = coronavirus disease–2019.
Author Disclosures
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center. | AMIODARONE, DIGOXIN, METOPROLOL, VERAPAMIL HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33521679 | 18,907,095 | 2021-01 |
What was the administration route of drug 'AMIODARONE'? | Atrial Flutter in Patient With Critical COVID-19: Beneficial Effects of Rhythm Control on Respiratory Distress.
We report the case of a patient critically ill with coronavirus disease-2019 (COVID-19) in which atrial flutter with high ventricular response rate occurred, contributing to worsening of the respiratory distress. After failure of noninvasive rate and rhythm control strategies, successful transcatheter ablation was performed and the respiratory distress of the patient improved. (Level of Difficulty: Beginner.).
Coronavirus disease-2019 (COVID-19) has important implications for the cardiovascular system, including the onset of arrhythmias (1). Furthermore, arrhythmias may contribute to deteriorating respiratory distress, establishing a vicious circle.
We report the case of a 61-year-old man admitted to the hospital with dyspnea, cough, and fever (39°C). Blood pressure was 120/60 mm Hg and oxygen saturation level was 89% with respiratory rate of 33 breaths per minute. The acute deterioration of respiratory distress needed invasive ventilation and the patient was promptly intubated. High-resolution computed tomography showed bilateral severe interstitial pneumonia with “crazy paving” aspects (Figure 1A). At admission, the electrocardiogram showed sinus tachycardia of 100 beats/min. The nasopharyngeal swab detected severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) viral RNA. After 9 days the patient improved and was downgraded to noninvasive ventilation with helmet. The following day, the respiratory distress worsened and atrial flutter with high ventricular response rate occurred (Figure 1B). The echocardiogram showed left ventricular ejection fraction of 50%, mild right atrial dilatation, and signs of increased left ventricular filling pressures (mean averaged E/e′ was 16). An external electrical cardioversion initially restored sinus rhythm but atrial flutter relapsed early. A second cardioversion was attempted with intravenous amiodarone; sinus rhythm lasted only few hours and then atrial flutter started again. Due to the failure of rhythm, rate control strategy with prolonged intravenous full dose of metoprolol, verapamil, and digoxin was attempted but was equally ineffective. The persistent ventricular rate of 150 beats/min contributed to deterioration of the respiratory status, raising the issue of reverting to invasive mechanical ventilation. Therefore, after extensive multidisciplinary team discussion, we decided to perform transcatheter ablation of atrial flutter to achieve rhythm control. In addition to the difficulties of invasive procedure for a patient with COVID-19, we were well aware of two other problems: 1) the patient with helmet is normally seated but has to remain supine during the whole procedure, which, therefore, needs to be as fast as possible; and 2) the use of fluoroscopy is challenging by the presence of the helmet. Our option was for a zero fluoroscopy procedure, using a three-dimensional electroanatomic mapping system (EnSite Precision, Abbott, St. Paul, Minnesota) (2). Recommendations from international consensus were followed to ensure patient safety and minimize healthcare professional exposure (3). The only people allowed in the operative room with full protection, including FFP3 face mask, surgical gown, double gloves, and face shield, were a senior electrophysiologist, 2 anesthesiologists, and a specialized nurse. Double right femoral venous access was used, and the patient was maintained supine, ventilated with noninvasive helmet (Figure 1D). Endocardial mapping confirmed a cavo-tricuspid isthmus-dependent atrial flutter that was treated with radiofrequency ablation, restoring sinus rhythm. Bidirectional conduction block across the cavo-tricuspid isthmus was confirmed using activation map pacing from the coronary sinus ostium (Figure 1D) and from the lateral wall of right atrium. Procedural time including preparation of the patient was < 1 h. With the restoration of sinus rhythm (Figure 1E), the respiratory status improved, the oxygen saturation rapidly increased from 84% to 98%, and the patient was feeling better. This case highlights the contribution of atrial flutter with high ventricular response rate to respiratory deterioration in patients with COVID-19 and the beneficial role of rhythm control achieved with transcatheter ablation (with ad hoc precautions). The efficacy of medical therapy for rate or rhythm control of atrial flutter in critically ill patients is generally low for several reasons, including the trigger constituted by the underlying disease, the organism response, or the concomitant treatments. Furthermore, using amiodarone for rhythm control has potentially severe adverse effects of pulmonary toxicity (direct cytotoxicity and hypersensitivity reaction) and it should be used with caution in patients with respiratory distress. Transcatheter ablation is relatively simple and the most effective treatment to maintain sinus rhythm in atrial flutter, but, thus far, there are no specific data in the setting of COVID-19.Figure 1 Transcatheter Ablation of Atrial Flutter in a Critically Ill COVID-19 Patient
(A) High-resolution computed tomography showing bilateral interstitial pneumonia with “crazy paving” pattern. (B) Surface 12-lead electrocardiogram showing typical atrial flutter with high ventricular rate. (C) Non-fluoroscopic three-dimensional electroanatomic map of right atrium in caudal left anterior oblique and right anterior oblique view. Note signs of radiofrequency erogation in cavo-tricuspid isthmus (white and red dots) and the color-coded map shows counterclockwise block of the isthmus pacing from coronary sinus ostium. (D) Supine position of the patient with noninvasive ventilation helmet in electrophysiology laboratory and fluoroscopy system outside the operating field. (E) Post-operative 12-lead electrocardiogram showing sinus rhythm. COVID-19 = coronavirus disease–2019.
Author Disclosures
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33521679 | 18,907,095 | 2021-01 |
What was the administration route of drug 'METOPROLOL'? | Atrial Flutter in Patient With Critical COVID-19: Beneficial Effects of Rhythm Control on Respiratory Distress.
We report the case of a patient critically ill with coronavirus disease-2019 (COVID-19) in which atrial flutter with high ventricular response rate occurred, contributing to worsening of the respiratory distress. After failure of noninvasive rate and rhythm control strategies, successful transcatheter ablation was performed and the respiratory distress of the patient improved. (Level of Difficulty: Beginner.).
Coronavirus disease-2019 (COVID-19) has important implications for the cardiovascular system, including the onset of arrhythmias (1). Furthermore, arrhythmias may contribute to deteriorating respiratory distress, establishing a vicious circle.
We report the case of a 61-year-old man admitted to the hospital with dyspnea, cough, and fever (39°C). Blood pressure was 120/60 mm Hg and oxygen saturation level was 89% with respiratory rate of 33 breaths per minute. The acute deterioration of respiratory distress needed invasive ventilation and the patient was promptly intubated. High-resolution computed tomography showed bilateral severe interstitial pneumonia with “crazy paving” aspects (Figure 1A). At admission, the electrocardiogram showed sinus tachycardia of 100 beats/min. The nasopharyngeal swab detected severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) viral RNA. After 9 days the patient improved and was downgraded to noninvasive ventilation with helmet. The following day, the respiratory distress worsened and atrial flutter with high ventricular response rate occurred (Figure 1B). The echocardiogram showed left ventricular ejection fraction of 50%, mild right atrial dilatation, and signs of increased left ventricular filling pressures (mean averaged E/e′ was 16). An external electrical cardioversion initially restored sinus rhythm but atrial flutter relapsed early. A second cardioversion was attempted with intravenous amiodarone; sinus rhythm lasted only few hours and then atrial flutter started again. Due to the failure of rhythm, rate control strategy with prolonged intravenous full dose of metoprolol, verapamil, and digoxin was attempted but was equally ineffective. The persistent ventricular rate of 150 beats/min contributed to deterioration of the respiratory status, raising the issue of reverting to invasive mechanical ventilation. Therefore, after extensive multidisciplinary team discussion, we decided to perform transcatheter ablation of atrial flutter to achieve rhythm control. In addition to the difficulties of invasive procedure for a patient with COVID-19, we were well aware of two other problems: 1) the patient with helmet is normally seated but has to remain supine during the whole procedure, which, therefore, needs to be as fast as possible; and 2) the use of fluoroscopy is challenging by the presence of the helmet. Our option was for a zero fluoroscopy procedure, using a three-dimensional electroanatomic mapping system (EnSite Precision, Abbott, St. Paul, Minnesota) (2). Recommendations from international consensus were followed to ensure patient safety and minimize healthcare professional exposure (3). The only people allowed in the operative room with full protection, including FFP3 face mask, surgical gown, double gloves, and face shield, were a senior electrophysiologist, 2 anesthesiologists, and a specialized nurse. Double right femoral venous access was used, and the patient was maintained supine, ventilated with noninvasive helmet (Figure 1D). Endocardial mapping confirmed a cavo-tricuspid isthmus-dependent atrial flutter that was treated with radiofrequency ablation, restoring sinus rhythm. Bidirectional conduction block across the cavo-tricuspid isthmus was confirmed using activation map pacing from the coronary sinus ostium (Figure 1D) and from the lateral wall of right atrium. Procedural time including preparation of the patient was < 1 h. With the restoration of sinus rhythm (Figure 1E), the respiratory status improved, the oxygen saturation rapidly increased from 84% to 98%, and the patient was feeling better. This case highlights the contribution of atrial flutter with high ventricular response rate to respiratory deterioration in patients with COVID-19 and the beneficial role of rhythm control achieved with transcatheter ablation (with ad hoc precautions). The efficacy of medical therapy for rate or rhythm control of atrial flutter in critically ill patients is generally low for several reasons, including the trigger constituted by the underlying disease, the organism response, or the concomitant treatments. Furthermore, using amiodarone for rhythm control has potentially severe adverse effects of pulmonary toxicity (direct cytotoxicity and hypersensitivity reaction) and it should be used with caution in patients with respiratory distress. Transcatheter ablation is relatively simple and the most effective treatment to maintain sinus rhythm in atrial flutter, but, thus far, there are no specific data in the setting of COVID-19.Figure 1 Transcatheter Ablation of Atrial Flutter in a Critically Ill COVID-19 Patient
(A) High-resolution computed tomography showing bilateral interstitial pneumonia with “crazy paving” pattern. (B) Surface 12-lead electrocardiogram showing typical atrial flutter with high ventricular rate. (C) Non-fluoroscopic three-dimensional electroanatomic map of right atrium in caudal left anterior oblique and right anterior oblique view. Note signs of radiofrequency erogation in cavo-tricuspid isthmus (white and red dots) and the color-coded map shows counterclockwise block of the isthmus pacing from coronary sinus ostium. (D) Supine position of the patient with noninvasive ventilation helmet in electrophysiology laboratory and fluoroscopy system outside the operating field. (E) Post-operative 12-lead electrocardiogram showing sinus rhythm. COVID-19 = coronavirus disease–2019.
Author Disclosures
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC-ND | 33521679 | 18,907,095 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Dehydration'. | Diabetes insipidus secondary to nivolumab-induced neurohypophysitis and pituitary metastasis.
A 62-year-old patient with metastatic hypopharyngeal carcinoma underwent treatment with nivolumab, following which he developed symptoms suggestive of diabetes insipidus. Nivolumab was stopped and therapy with methylprednisolone was started. During corticosteroid therapy, the patient presented himself in poor health condition with fungal infection and glycemic decompensation. Methylprednisolone dose was tapered off, leading to the resolution of mycosis and the restoration of glycemic compensation, nevertheless polyuria and polydipsia persisted. Increase in urine osmolarity after desmopressin administration was made diagnosing central diabetes insipidus as a possibility. The neuroradiological data by pituitary MRI scan with gadolinium was compatible with coexistence of metastatic localization and infundibulo-neurohypophysitis secondary to therapy with nivolumab. To define the exact etiology of the pituitary pathology, histological confirmation would have been necessary; however, unfortunately, it was not possible. In the absence of histological confirmation, we believe it is likely that both pathologies coexisted.
A remarkable risk of endocrine immune-related adverse events (irAEs) during therapy with checkpoint inhibitors exsists. In order to ensure maximum efficiency in the recognition and treatment of endocrine iRAes related to immune checkpoint inhibitors, multidisciplinary management of oncological patients is critical. The pituitary syndrome in oncological patients who underwent immunotherapy represents a challenge in the differential diagnosis between pituitary metastasis and drug-induced hypophysitis. This is the first case, described in the literature of diabetes insipidus in a patient suffering from nivolumab-induced infundibulo-neurohypophysitis and anterohypophyseal metastasis.
Background
The introduction of immune checkpoint inhibitors into oncological clinical practice has revolutionized the treatment of various neoplastic diseases. These drugs awaken the anti-tumor immune response by interrupting the inhibitory signal pathways and promote immune-mediated elimination of cancer cells. The targets of these therapies include CTLA-4 (cytotoxic T-lymphocyte associated protein-4), PD1 (programmed cell death protein-1) and PD-L1 (programmed death ligand-1). This mechanism is also the basis of immune-related adverse events (iRAes), due to the inhibition of immune-checkpoints that reinforce normal physiological barriers against autoimmunity (1). The main adverse events affect the skin, the gastrointestinal, musculoskeletal and endocrine systems. The main endocrinological manifestations are represented by thyroid dysfunction and hypophysitis. The involvement of the posterior pituitary, and consequent diabetes insipidus is exceptional, but not impossible (2, 3, 4). Pituitary metastasis is a rare complication of advanced malignancy; however, almost every cancer type can metastasize to the pituitary fossa. Diabetes insipidus is common among patients with pituitary metastasis (5).
Case presentation
We present the case of a 62-year-old patient with metastatic hypopharyngeal carcinoma undergoing treatment with Nivolumab (anti- PD1 MAB), following which he developed central diabetes insipidus. In 2002, the patient, with a history of heavy smoking and in the absence of other comorbidities, received the diagnosis of hypopharyngeal carcinoma and was treated with chemotherapy (platinum and fluorine) and surgery. In 2016, relapse on the lingual body developed, and due to the inoperability of the lesion, chemotherapy with cisplatin, 5-fluorouracil and erbitux was provided. In 2017, PET showed lung disease with massive metastatic adenopathies in almost all mediastinal lymph node stations. It was decided to carry out a re-challenge with platinum with evidence in January 2019 of reduction of lung and lymph node lesions. The CT of May 2019 showed a progression of pathology upon which the oncologist decided to start therapy with vivolumab (240 mg biweekly). After about 5 weeks of treatment (before the fourth cycle of therapy), the patient reported sudden onset of polyuria and polydipsia. The endocrine tests he underwent (Table 1) suggested the presence of hypophysitis as a result of mild hyperprolactinemia (19.8 ng/mL) and hypogonadotropic hypogonadism, in association with symptoms suggestive of diabetes insipidus. Moreover, the routine laboratory investigations (Table 2) revealed dehydration (hypercalcemia, hypernatremia, hyperkalemia) and impaired fasting glucose (blood glucose: 116 mg/dL); glycated hemoglobin (HbA1c) and oral glucose tolerance test (OGTT) were not sought. Considered the onset of a possible hypophysitis, the oncologist stopped nivolumab temporarily and started therapy with methylprednisolone 64 mg/day and requested endocrinological advice. After about 10 days of corticosteroid therapy, the patient was hospitalized in the endocrinology department. He presented in a poor health condition, in a state of dehydration and with a severe fungal infection of the oral cavity. Asthenia persisted, while he did not complain of visual field deficits. The patient reported persistence of polyuria and polydipsia (about 8 L/day), which did not change following the introduction of corticosteroid therapy. Blood chemistry tests showed glycemic decompensation (glucose: 320 mg/dL) with plasma hyperosmolality (303 mOsm/kg) and urine hyposmolarity (158 mmol/L).
Table 1 Laboratory values after 5 weeks of oncological treatment.
Hormone Result Reference values
TSH, µUI/mL 1.00 0.55–4.78
FT3, pg/mL 3.12 2–4.2
FT4, pg/mL 1.25 0.8–1.7
Testosterone, ng/mL 0.5 1.39–9.13
LH, mUI/mL 3.0 1.4–18.1
FSH, mUI/mL 2.7 4.5–9.3
Prolactin, ng/mL 19.8 2.1–17.7
ACTH, µg/dL 19.2 5.27–22.45
Cortisol, pg/mL 20.4 10–60
Table 2 Blood count and biochemistry test after 5 weeks of oncological treatment.
Blood count and biochemistry test Result Reference values
WBC, × 103/μL 11.25 4.3–10.5
RBC, × 106/μL 5.50 4.2–5.8
Hemoglobin, g/dL 16.1 12–17.5
Hematocrit, % 50.5 37–52
MCV, flL 91.8 80–99
MCH, pg 29.3 27–32
MCHC, g/dL 31.9 33–37
RDW, % 15.1 11.5–14.5
Platelets, × 103/μL 205 130–400
Neutrophils, × 103/μL 8.30 1.9–8
Lymphocytes, × 103/μL 1.86 0.9–5.2
Monocytes, × 103/μL 0.88 0.2–1
Eosinophils, × 103/μL 0.15 0–0.8
Basophils, × 103/μL 0.07 0–0.2
Glucose, mg/dL 116 60–100
BUN, mg/dL 9 5–25
Creatinine, mg/dL 0.8 0.6–1.2
Sodium, mEq/L 150 136–146
Potassium, mEq/L 5.3 3.5–5.1
Calcium, mg/dL 11.2 8.8–10.6
Magnesium, mg/dL 2.5 1.8–2.6
Uricemia, mg/dL 4.5 3.5–7.2
Proteins, g/dL 7.6 6.6–8.3
Albumin, g/dL 4.4 3.5–5.2
Total bilirubin, mg/dL 0.5 0.2–1.1
Direct bilirubin, mg/dL 0.1 0.1–0.4
Indirect bilirubin, mg/dL 0.4 0.2–0.8
LDH, U/L 274 0–248
AST, U/L 26 5–45
ALT, U/L 36 5–55
GGT, U/ L 30 10–50
Cholinesterase, U/L 5439 4500–11 400
ALP, U/L 118 30–120
Sideremia, μg/dL 67 70–180
Investigation
Pituitary hormonal function was assessed (Table 3) and frank hypogonadotropic hypogonadism and mild hyperprolactinemia were confirmed. The low TSH value was compatible with concomitant corticosteroid therapy (6). To complete the study of glycemic decompensation, HbA1c (7.7%), C-peptide (0.73 ng/mL, reference value: 0.5–2) and antibodies against glutamic acid decarboxylase (<5 IU/mL) and anti IA2 (<10 IU/mL) were assessed. The autoimmune origin was therefore excluded and diagnosis of metasteroid diabetes mellitus was made. It was treated with insulin therapy. During the hospitalization, methylprednisolone dose was tapered off, leading to the resolution of mycosis (which was also due to antifungal therapy) and the restoration of glycemic compensation with progressive reduction in the dose of insulin, until full discontinuation. Once normalization of blood glucose levels was obtained, the patient reported improvement in symptoms of polyuria and polydipsia, which however persisted albeit to a lesser extent (water balance: IN 4.5 L – OUT 5.5 L). The patient was affected by the polyuria–polydipsia syndrome (water intake > 3 L/day and diuresis > 40–50 mL/kg/day), and it was, therefore, necessary to define the etiology. Because of the technical limitations of the ADH assay (7), and the impossibility of copeptin dosage in our clinical laboratory, we assessed urine osmolarity and plasma osmolality. After just 2 h of fluid restriction, the onset of hypernatremia contraindicated the water deprivation test’s prosecution. Psychogenic polyuria was ruled out due to the presence of low urine osmolarity in association with high plasma osmolality. Afterwards, we decided to evaluate the response to the administration of desmopressin 2 μg s.c. In Table 4 you can see the values of natremia, plasma osmolality and urine osmolarity before and after the administration of the drug. An increase of 146% in urine osmolarity after desmopressin allowed us to rule out nephrogenic diabetes insipidus and has made diagnosing central diabetes insipidus possible (8). Anti-pituitary antibody and anti-rabphilin 3A antibody were not available in our laboratory, therefore they haven’t been investigated.
Table 3 Laboratory values during treatment with corticosteroid, after nivolumab discontinuation.
Hormone/antibody Result Reference values
TSH, µUI/mL 0.147 0.89–1.76
FT4, ng/dL 1.22 0.55–4.78
TGAb, U/mL 17.10 <60
TPOAb, U/mL 38.30 <60
Testosterone, ng/dL <20.0 181–758
LH, mUI/mL 0.4 0.8–7.6
FSH, mUI/mL 0.6 0.7–11.1
Prolactin, ng/mL 18.6 2.5–17.0
GH, ng/mL 0.4 <10
IGF-1, ng/mL 109 43–220
ACTH, pg/mL 6 0–46
Cortisol, µg/dL 20.3 4.3–22.4
Table 4 Plasma osmolality and urine osmolarity before and after desmopressin administration.
Sampling time Natremia (mEq/L) Plasma osmolality (mOsm/Kg) Urine osmolarity (mmol/L) Change in urine (osmolarity)
Before desmopressin
7:00 h 146 300 176 –
Desmopressin 2 µg s.c. injection: 10:00 h
12:30 h 142 294 353 +100%
15:30 h – – 430 +144%
At this point, pituitary MRI scan with gadolinium was performed. The radiological report showed a pituitary stalk substantially in axis, with marked and widespread thickening, up to about 6 mm, associated hyperintensity and contrast enhancement. Neurohypophysis hyperintensity was not displayed. A roundish formation of about 7 mm in diameter, substantially isointense with respect to the remaining glandular parenchyma in pre-contrast T1- and T2-weighted images and tenuously hypointense in post-contrast image, was observed at the posterior adenohypophyseal portion, in the median-paramedian area. The lesion seemed to cause focal interruption of the sellar floor (Fig. 1). In addition to the MRI examination of the pituitary, post-contrast axial DWI and 3D-T1-FFE sequences were acquired on the entire brain with documented presence of multiple contrast medium enhancement lesions located in the supra and sub-tentorial regions and in both cerebellar hemispheres (Fig. 2). The neuroradiological data were therefore compatible both with clinical suspicion of metastatic localization and with the hypothesis of hypophysitis secondary to therapy with nivolumab.
Figure 1 Pre-contrast (A) and postcontrast T1-weighted sagittal (B) and coronal (C) MR image demonstrates a diffuse enlargement of the pituitary stalk. The pituitary gland shows heterogenous enhancement due to a hypotense lesion, causing focal destruction of the sellar floor.
Figure 2 Post-contrast T1-weighted MR image of the brain demonstrates multiple metastatic lesions at the grey-white matter junction in the frontal lobe (A) and in the midbrain, close to the Sylvian aqueduct (B).
Treatment
The patient underwent replacement therapy with DDVAP sublingual tablets 60 μg in divided dose twice daily, with normalization of the water balance (2 L in balance).
Nine days after hospitalization, the patient was discharged with the following diagnosis ‘Partial hypopituitarism (diabetes insipidus and hypogonadism) secondary to probable nivolumab-induced infundibulo-neurohypophysitis and anterohypophyseal metastasis, in a patient suffering from metastatic hypopharyngeal carcinoma; multiple cerebral and cerebellar new on-set metastases and metasteroid diabetes mellitus’. The patient was started on replacement therapy with DDVAP sublingual tablets 60 μg in divided dose twice daily, 2% testosterone gel 4 puffs/day and methylprednisolone dose was tapered off until 4 mg, pending execution of ACTH test to evaluate the possible suppression of the hypothalamic–pituitary–adrenal axis. As the pituitary impairment was well compensated by the replacement therapy, no contraindication was given to the resumption of nivolumab therapy with necessary monitoring of the residual pituitary function.
Outcome and follow-up
The patient was re-evaluated by the oncologist and underwent total body CT scan for disease re- staging. In addition to the already known secondary malignancy in the lung, new-onset adrenal, pancreatic, skeletal metastases and peritoneal carcinosis were found.
Due to poor response to nivolumab therapy and rapid disease progression, treatment was stopped permanently. The patient died about 50 days after hospital discharge.
Discussion
The hypophysitis is an adverse event more characteristic of anti-CTLA4, and only to a lesser extent than anti-PD1. Patients with immune therapy-induced hypophysitis mostly present with multiple hormonal deficits, mainly of thyrotropin (84%), corticotropin (80%) and gonadotropins (76%); the involvement of the posterior pituitary is exceptional (2). So far, there are only two case reports described in the literature about anti PDL1 (3) and anti PD1- related central diabetes insipidus (4). The average time to onset of endocrinological side effects is 9 weeks from the start of treatment (with a range from 5 to 36 weeks). Considering the high incidence of these adverse events following therapy with immune-checkpoint, it is essential to research any clinical signs suggestive of iRAes before each cycle of therapy; when a suggestive symtom is found, it is essential to evaluate hormonal tests to identify endocrinopathy (9). In general, the oncological clinical practice involves the administration of high-dose corticosteroids for most iRAes. As regards specifically the pituitary, a recent consensus has highlighted how the use of high-dose corticosteroids is to be reserved exclusively for cases of adrenal crisis, severe headache and visual field deficit (10). In fact, corticosteroid therapy would be able to resolve the signs of local inflammation, but not the hormonal deficit. In addition, high-dose therapy would be responsible for major complications, some serious enough to require hospitalization (11). To confirm this, our patient had not received any benefit from corticosteroid therapy, but his general health condition worsened as a result of diabetes mellitus, dehydration and fungal infection onset. Besides the patient suffered from impaired fasting glucose, and glucocorticoid treatment precipitated a pre-diabetes condition. The etiology of diabetes mellitus in our patient under both corticosteroids and immune-checkpoint inhibitors treatment, was, at first, uncertain. In fact, among the autoimmune adverse events typical of immune-checkpoints inhibitors, there is also diabetes mellitus (12). The autoimmune form of origin was however excluded due to the absence of autoimmunity, the pancreatic reserve and the normalization of blood glucose levels following the steroid tapering.
The persistence of polyuria and polydipsia led us to investigate the origin of the polyuria–polydipsia syndrome, confirming the diagnosis of diabetes insipidus following the evaluation of plasma osmolality and urine osmolarity before and after DDVAP.
The diabetes insipidus in our patient could have been mainly due to two causes: the presence of metastases in the pituitary region or the onset of hypophysitis secondary to nivolumab therapy.
A recent observational retrospective study assessed the clinical, biochemical and radiological differences in patients with neoplastic and non-neoplastic pituitary stalk pathology. Statistically significant differences were found for the greater preponderance of diabetes insipidus and hypogonadism in subjects suffering from neoplastic pathology compared to those suffering from non-neoplastic pathology; with regard to radiological images, the features that have reached statistical significance were the thickness of the stalk and the heterogeneity of the contrast enhancement after administration of contrast agent. Specifically, all thickenings greater than 9.1 mm in diameter in the post-contrast coronal section in the upper part of the stalk and greater than 5.6 in the coronal section in the lower part were confirmed as neoplastic with a sensitivity of 100% (13). Our patient had biochemical and radiological characteristics consistent with the coexistence of neurohypophysitis (stalk thickness 6 mm, hyperintensity under the Gadolinium enhancement, and no evidence of neurohypophysis hyperintensity) and pituitary metastasis (roundish formation, at the posterior adenohypophyseal portion, causing focal interruption of the sellar floor). To define the exact etiology of the pituitary pathology, histological confirmation through biopsy sampling would have been necessary; however, because of the patient’s critical health condition, it was not possible to perform. In the absence of histological confirmation, we believe it is likely that both could have played a role in the onset of diabetes insipidus secondary to the pituitary stalk interruption syndrome, as a result of metastatic compression and drug therapy-induced hypophysitis.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Patient consent
Informed consent was obtained from the patient for publication of this report.
Author contribution statement
All the authors have contributed to the writing and editing of this manuscript and the physician responsible for the patient is one of the authors. | METHYLPREDNISOLONE, NIVOLUMAB | DrugsGivenReaction | CC BY-NC-ND | 33522491 | 19,074,871 | 2021-01-27 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Diabetes mellitus'. | Diabetes insipidus secondary to nivolumab-induced neurohypophysitis and pituitary metastasis.
A 62-year-old patient with metastatic hypopharyngeal carcinoma underwent treatment with nivolumab, following which he developed symptoms suggestive of diabetes insipidus. Nivolumab was stopped and therapy with methylprednisolone was started. During corticosteroid therapy, the patient presented himself in poor health condition with fungal infection and glycemic decompensation. Methylprednisolone dose was tapered off, leading to the resolution of mycosis and the restoration of glycemic compensation, nevertheless polyuria and polydipsia persisted. Increase in urine osmolarity after desmopressin administration was made diagnosing central diabetes insipidus as a possibility. The neuroradiological data by pituitary MRI scan with gadolinium was compatible with coexistence of metastatic localization and infundibulo-neurohypophysitis secondary to therapy with nivolumab. To define the exact etiology of the pituitary pathology, histological confirmation would have been necessary; however, unfortunately, it was not possible. In the absence of histological confirmation, we believe it is likely that both pathologies coexisted.
A remarkable risk of endocrine immune-related adverse events (irAEs) during therapy with checkpoint inhibitors exsists. In order to ensure maximum efficiency in the recognition and treatment of endocrine iRAes related to immune checkpoint inhibitors, multidisciplinary management of oncological patients is critical. The pituitary syndrome in oncological patients who underwent immunotherapy represents a challenge in the differential diagnosis between pituitary metastasis and drug-induced hypophysitis. This is the first case, described in the literature of diabetes insipidus in a patient suffering from nivolumab-induced infundibulo-neurohypophysitis and anterohypophyseal metastasis.
Background
The introduction of immune checkpoint inhibitors into oncological clinical practice has revolutionized the treatment of various neoplastic diseases. These drugs awaken the anti-tumor immune response by interrupting the inhibitory signal pathways and promote immune-mediated elimination of cancer cells. The targets of these therapies include CTLA-4 (cytotoxic T-lymphocyte associated protein-4), PD1 (programmed cell death protein-1) and PD-L1 (programmed death ligand-1). This mechanism is also the basis of immune-related adverse events (iRAes), due to the inhibition of immune-checkpoints that reinforce normal physiological barriers against autoimmunity (1). The main adverse events affect the skin, the gastrointestinal, musculoskeletal and endocrine systems. The main endocrinological manifestations are represented by thyroid dysfunction and hypophysitis. The involvement of the posterior pituitary, and consequent diabetes insipidus is exceptional, but not impossible (2, 3, 4). Pituitary metastasis is a rare complication of advanced malignancy; however, almost every cancer type can metastasize to the pituitary fossa. Diabetes insipidus is common among patients with pituitary metastasis (5).
Case presentation
We present the case of a 62-year-old patient with metastatic hypopharyngeal carcinoma undergoing treatment with Nivolumab (anti- PD1 MAB), following which he developed central diabetes insipidus. In 2002, the patient, with a history of heavy smoking and in the absence of other comorbidities, received the diagnosis of hypopharyngeal carcinoma and was treated with chemotherapy (platinum and fluorine) and surgery. In 2016, relapse on the lingual body developed, and due to the inoperability of the lesion, chemotherapy with cisplatin, 5-fluorouracil and erbitux was provided. In 2017, PET showed lung disease with massive metastatic adenopathies in almost all mediastinal lymph node stations. It was decided to carry out a re-challenge with platinum with evidence in January 2019 of reduction of lung and lymph node lesions. The CT of May 2019 showed a progression of pathology upon which the oncologist decided to start therapy with vivolumab (240 mg biweekly). After about 5 weeks of treatment (before the fourth cycle of therapy), the patient reported sudden onset of polyuria and polydipsia. The endocrine tests he underwent (Table 1) suggested the presence of hypophysitis as a result of mild hyperprolactinemia (19.8 ng/mL) and hypogonadotropic hypogonadism, in association with symptoms suggestive of diabetes insipidus. Moreover, the routine laboratory investigations (Table 2) revealed dehydration (hypercalcemia, hypernatremia, hyperkalemia) and impaired fasting glucose (blood glucose: 116 mg/dL); glycated hemoglobin (HbA1c) and oral glucose tolerance test (OGTT) were not sought. Considered the onset of a possible hypophysitis, the oncologist stopped nivolumab temporarily and started therapy with methylprednisolone 64 mg/day and requested endocrinological advice. After about 10 days of corticosteroid therapy, the patient was hospitalized in the endocrinology department. He presented in a poor health condition, in a state of dehydration and with a severe fungal infection of the oral cavity. Asthenia persisted, while he did not complain of visual field deficits. The patient reported persistence of polyuria and polydipsia (about 8 L/day), which did not change following the introduction of corticosteroid therapy. Blood chemistry tests showed glycemic decompensation (glucose: 320 mg/dL) with plasma hyperosmolality (303 mOsm/kg) and urine hyposmolarity (158 mmol/L).
Table 1 Laboratory values after 5 weeks of oncological treatment.
Hormone Result Reference values
TSH, µUI/mL 1.00 0.55–4.78
FT3, pg/mL 3.12 2–4.2
FT4, pg/mL 1.25 0.8–1.7
Testosterone, ng/mL 0.5 1.39–9.13
LH, mUI/mL 3.0 1.4–18.1
FSH, mUI/mL 2.7 4.5–9.3
Prolactin, ng/mL 19.8 2.1–17.7
ACTH, µg/dL 19.2 5.27–22.45
Cortisol, pg/mL 20.4 10–60
Table 2 Blood count and biochemistry test after 5 weeks of oncological treatment.
Blood count and biochemistry test Result Reference values
WBC, × 103/μL 11.25 4.3–10.5
RBC, × 106/μL 5.50 4.2–5.8
Hemoglobin, g/dL 16.1 12–17.5
Hematocrit, % 50.5 37–52
MCV, flL 91.8 80–99
MCH, pg 29.3 27–32
MCHC, g/dL 31.9 33–37
RDW, % 15.1 11.5–14.5
Platelets, × 103/μL 205 130–400
Neutrophils, × 103/μL 8.30 1.9–8
Lymphocytes, × 103/μL 1.86 0.9–5.2
Monocytes, × 103/μL 0.88 0.2–1
Eosinophils, × 103/μL 0.15 0–0.8
Basophils, × 103/μL 0.07 0–0.2
Glucose, mg/dL 116 60–100
BUN, mg/dL 9 5–25
Creatinine, mg/dL 0.8 0.6–1.2
Sodium, mEq/L 150 136–146
Potassium, mEq/L 5.3 3.5–5.1
Calcium, mg/dL 11.2 8.8–10.6
Magnesium, mg/dL 2.5 1.8–2.6
Uricemia, mg/dL 4.5 3.5–7.2
Proteins, g/dL 7.6 6.6–8.3
Albumin, g/dL 4.4 3.5–5.2
Total bilirubin, mg/dL 0.5 0.2–1.1
Direct bilirubin, mg/dL 0.1 0.1–0.4
Indirect bilirubin, mg/dL 0.4 0.2–0.8
LDH, U/L 274 0–248
AST, U/L 26 5–45
ALT, U/L 36 5–55
GGT, U/ L 30 10–50
Cholinesterase, U/L 5439 4500–11 400
ALP, U/L 118 30–120
Sideremia, μg/dL 67 70–180
Investigation
Pituitary hormonal function was assessed (Table 3) and frank hypogonadotropic hypogonadism and mild hyperprolactinemia were confirmed. The low TSH value was compatible with concomitant corticosteroid therapy (6). To complete the study of glycemic decompensation, HbA1c (7.7%), C-peptide (0.73 ng/mL, reference value: 0.5–2) and antibodies against glutamic acid decarboxylase (<5 IU/mL) and anti IA2 (<10 IU/mL) were assessed. The autoimmune origin was therefore excluded and diagnosis of metasteroid diabetes mellitus was made. It was treated with insulin therapy. During the hospitalization, methylprednisolone dose was tapered off, leading to the resolution of mycosis (which was also due to antifungal therapy) and the restoration of glycemic compensation with progressive reduction in the dose of insulin, until full discontinuation. Once normalization of blood glucose levels was obtained, the patient reported improvement in symptoms of polyuria and polydipsia, which however persisted albeit to a lesser extent (water balance: IN 4.5 L – OUT 5.5 L). The patient was affected by the polyuria–polydipsia syndrome (water intake > 3 L/day and diuresis > 40–50 mL/kg/day), and it was, therefore, necessary to define the etiology. Because of the technical limitations of the ADH assay (7), and the impossibility of copeptin dosage in our clinical laboratory, we assessed urine osmolarity and plasma osmolality. After just 2 h of fluid restriction, the onset of hypernatremia contraindicated the water deprivation test’s prosecution. Psychogenic polyuria was ruled out due to the presence of low urine osmolarity in association with high plasma osmolality. Afterwards, we decided to evaluate the response to the administration of desmopressin 2 μg s.c. In Table 4 you can see the values of natremia, plasma osmolality and urine osmolarity before and after the administration of the drug. An increase of 146% in urine osmolarity after desmopressin allowed us to rule out nephrogenic diabetes insipidus and has made diagnosing central diabetes insipidus possible (8). Anti-pituitary antibody and anti-rabphilin 3A antibody were not available in our laboratory, therefore they haven’t been investigated.
Table 3 Laboratory values during treatment with corticosteroid, after nivolumab discontinuation.
Hormone/antibody Result Reference values
TSH, µUI/mL 0.147 0.89–1.76
FT4, ng/dL 1.22 0.55–4.78
TGAb, U/mL 17.10 <60
TPOAb, U/mL 38.30 <60
Testosterone, ng/dL <20.0 181–758
LH, mUI/mL 0.4 0.8–7.6
FSH, mUI/mL 0.6 0.7–11.1
Prolactin, ng/mL 18.6 2.5–17.0
GH, ng/mL 0.4 <10
IGF-1, ng/mL 109 43–220
ACTH, pg/mL 6 0–46
Cortisol, µg/dL 20.3 4.3–22.4
Table 4 Plasma osmolality and urine osmolarity before and after desmopressin administration.
Sampling time Natremia (mEq/L) Plasma osmolality (mOsm/Kg) Urine osmolarity (mmol/L) Change in urine (osmolarity)
Before desmopressin
7:00 h 146 300 176 –
Desmopressin 2 µg s.c. injection: 10:00 h
12:30 h 142 294 353 +100%
15:30 h – – 430 +144%
At this point, pituitary MRI scan with gadolinium was performed. The radiological report showed a pituitary stalk substantially in axis, with marked and widespread thickening, up to about 6 mm, associated hyperintensity and contrast enhancement. Neurohypophysis hyperintensity was not displayed. A roundish formation of about 7 mm in diameter, substantially isointense with respect to the remaining glandular parenchyma in pre-contrast T1- and T2-weighted images and tenuously hypointense in post-contrast image, was observed at the posterior adenohypophyseal portion, in the median-paramedian area. The lesion seemed to cause focal interruption of the sellar floor (Fig. 1). In addition to the MRI examination of the pituitary, post-contrast axial DWI and 3D-T1-FFE sequences were acquired on the entire brain with documented presence of multiple contrast medium enhancement lesions located in the supra and sub-tentorial regions and in both cerebellar hemispheres (Fig. 2). The neuroradiological data were therefore compatible both with clinical suspicion of metastatic localization and with the hypothesis of hypophysitis secondary to therapy with nivolumab.
Figure 1 Pre-contrast (A) and postcontrast T1-weighted sagittal (B) and coronal (C) MR image demonstrates a diffuse enlargement of the pituitary stalk. The pituitary gland shows heterogenous enhancement due to a hypotense lesion, causing focal destruction of the sellar floor.
Figure 2 Post-contrast T1-weighted MR image of the brain demonstrates multiple metastatic lesions at the grey-white matter junction in the frontal lobe (A) and in the midbrain, close to the Sylvian aqueduct (B).
Treatment
The patient underwent replacement therapy with DDVAP sublingual tablets 60 μg in divided dose twice daily, with normalization of the water balance (2 L in balance).
Nine days after hospitalization, the patient was discharged with the following diagnosis ‘Partial hypopituitarism (diabetes insipidus and hypogonadism) secondary to probable nivolumab-induced infundibulo-neurohypophysitis and anterohypophyseal metastasis, in a patient suffering from metastatic hypopharyngeal carcinoma; multiple cerebral and cerebellar new on-set metastases and metasteroid diabetes mellitus’. The patient was started on replacement therapy with DDVAP sublingual tablets 60 μg in divided dose twice daily, 2% testosterone gel 4 puffs/day and methylprednisolone dose was tapered off until 4 mg, pending execution of ACTH test to evaluate the possible suppression of the hypothalamic–pituitary–adrenal axis. As the pituitary impairment was well compensated by the replacement therapy, no contraindication was given to the resumption of nivolumab therapy with necessary monitoring of the residual pituitary function.
Outcome and follow-up
The patient was re-evaluated by the oncologist and underwent total body CT scan for disease re- staging. In addition to the already known secondary malignancy in the lung, new-onset adrenal, pancreatic, skeletal metastases and peritoneal carcinosis were found.
Due to poor response to nivolumab therapy and rapid disease progression, treatment was stopped permanently. The patient died about 50 days after hospital discharge.
Discussion
The hypophysitis is an adverse event more characteristic of anti-CTLA4, and only to a lesser extent than anti-PD1. Patients with immune therapy-induced hypophysitis mostly present with multiple hormonal deficits, mainly of thyrotropin (84%), corticotropin (80%) and gonadotropins (76%); the involvement of the posterior pituitary is exceptional (2). So far, there are only two case reports described in the literature about anti PDL1 (3) and anti PD1- related central diabetes insipidus (4). The average time to onset of endocrinological side effects is 9 weeks from the start of treatment (with a range from 5 to 36 weeks). Considering the high incidence of these adverse events following therapy with immune-checkpoint, it is essential to research any clinical signs suggestive of iRAes before each cycle of therapy; when a suggestive symtom is found, it is essential to evaluate hormonal tests to identify endocrinopathy (9). In general, the oncological clinical practice involves the administration of high-dose corticosteroids for most iRAes. As regards specifically the pituitary, a recent consensus has highlighted how the use of high-dose corticosteroids is to be reserved exclusively for cases of adrenal crisis, severe headache and visual field deficit (10). In fact, corticosteroid therapy would be able to resolve the signs of local inflammation, but not the hormonal deficit. In addition, high-dose therapy would be responsible for major complications, some serious enough to require hospitalization (11). To confirm this, our patient had not received any benefit from corticosteroid therapy, but his general health condition worsened as a result of diabetes mellitus, dehydration and fungal infection onset. Besides the patient suffered from impaired fasting glucose, and glucocorticoid treatment precipitated a pre-diabetes condition. The etiology of diabetes mellitus in our patient under both corticosteroids and immune-checkpoint inhibitors treatment, was, at first, uncertain. In fact, among the autoimmune adverse events typical of immune-checkpoints inhibitors, there is also diabetes mellitus (12). The autoimmune form of origin was however excluded due to the absence of autoimmunity, the pancreatic reserve and the normalization of blood glucose levels following the steroid tapering.
The persistence of polyuria and polydipsia led us to investigate the origin of the polyuria–polydipsia syndrome, confirming the diagnosis of diabetes insipidus following the evaluation of plasma osmolality and urine osmolarity before and after DDVAP.
The diabetes insipidus in our patient could have been mainly due to two causes: the presence of metastases in the pituitary region or the onset of hypophysitis secondary to nivolumab therapy.
A recent observational retrospective study assessed the clinical, biochemical and radiological differences in patients with neoplastic and non-neoplastic pituitary stalk pathology. Statistically significant differences were found for the greater preponderance of diabetes insipidus and hypogonadism in subjects suffering from neoplastic pathology compared to those suffering from non-neoplastic pathology; with regard to radiological images, the features that have reached statistical significance were the thickness of the stalk and the heterogeneity of the contrast enhancement after administration of contrast agent. Specifically, all thickenings greater than 9.1 mm in diameter in the post-contrast coronal section in the upper part of the stalk and greater than 5.6 in the coronal section in the lower part were confirmed as neoplastic with a sensitivity of 100% (13). Our patient had biochemical and radiological characteristics consistent with the coexistence of neurohypophysitis (stalk thickness 6 mm, hyperintensity under the Gadolinium enhancement, and no evidence of neurohypophysis hyperintensity) and pituitary metastasis (roundish formation, at the posterior adenohypophyseal portion, causing focal interruption of the sellar floor). To define the exact etiology of the pituitary pathology, histological confirmation through biopsy sampling would have been necessary; however, because of the patient’s critical health condition, it was not possible to perform. In the absence of histological confirmation, we believe it is likely that both could have played a role in the onset of diabetes insipidus secondary to the pituitary stalk interruption syndrome, as a result of metastatic compression and drug therapy-induced hypophysitis.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Patient consent
Informed consent was obtained from the patient for publication of this report.
Author contribution statement
All the authors have contributed to the writing and editing of this manuscript and the physician responsible for the patient is one of the authors. | METHYLPREDNISOLONE, NIVOLUMAB | DrugsGivenReaction | CC BY-NC-ND | 33522491 | 19,074,871 | 2021-01-27 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Diabetic metabolic decompensation'. | Diabetes insipidus secondary to nivolumab-induced neurohypophysitis and pituitary metastasis.
A 62-year-old patient with metastatic hypopharyngeal carcinoma underwent treatment with nivolumab, following which he developed symptoms suggestive of diabetes insipidus. Nivolumab was stopped and therapy with methylprednisolone was started. During corticosteroid therapy, the patient presented himself in poor health condition with fungal infection and glycemic decompensation. Methylprednisolone dose was tapered off, leading to the resolution of mycosis and the restoration of glycemic compensation, nevertheless polyuria and polydipsia persisted. Increase in urine osmolarity after desmopressin administration was made diagnosing central diabetes insipidus as a possibility. The neuroradiological data by pituitary MRI scan with gadolinium was compatible with coexistence of metastatic localization and infundibulo-neurohypophysitis secondary to therapy with nivolumab. To define the exact etiology of the pituitary pathology, histological confirmation would have been necessary; however, unfortunately, it was not possible. In the absence of histological confirmation, we believe it is likely that both pathologies coexisted.
A remarkable risk of endocrine immune-related adverse events (irAEs) during therapy with checkpoint inhibitors exsists. In order to ensure maximum efficiency in the recognition and treatment of endocrine iRAes related to immune checkpoint inhibitors, multidisciplinary management of oncological patients is critical. The pituitary syndrome in oncological patients who underwent immunotherapy represents a challenge in the differential diagnosis between pituitary metastasis and drug-induced hypophysitis. This is the first case, described in the literature of diabetes insipidus in a patient suffering from nivolumab-induced infundibulo-neurohypophysitis and anterohypophyseal metastasis.
Background
The introduction of immune checkpoint inhibitors into oncological clinical practice has revolutionized the treatment of various neoplastic diseases. These drugs awaken the anti-tumor immune response by interrupting the inhibitory signal pathways and promote immune-mediated elimination of cancer cells. The targets of these therapies include CTLA-4 (cytotoxic T-lymphocyte associated protein-4), PD1 (programmed cell death protein-1) and PD-L1 (programmed death ligand-1). This mechanism is also the basis of immune-related adverse events (iRAes), due to the inhibition of immune-checkpoints that reinforce normal physiological barriers against autoimmunity (1). The main adverse events affect the skin, the gastrointestinal, musculoskeletal and endocrine systems. The main endocrinological manifestations are represented by thyroid dysfunction and hypophysitis. The involvement of the posterior pituitary, and consequent diabetes insipidus is exceptional, but not impossible (2, 3, 4). Pituitary metastasis is a rare complication of advanced malignancy; however, almost every cancer type can metastasize to the pituitary fossa. Diabetes insipidus is common among patients with pituitary metastasis (5).
Case presentation
We present the case of a 62-year-old patient with metastatic hypopharyngeal carcinoma undergoing treatment with Nivolumab (anti- PD1 MAB), following which he developed central diabetes insipidus. In 2002, the patient, with a history of heavy smoking and in the absence of other comorbidities, received the diagnosis of hypopharyngeal carcinoma and was treated with chemotherapy (platinum and fluorine) and surgery. In 2016, relapse on the lingual body developed, and due to the inoperability of the lesion, chemotherapy with cisplatin, 5-fluorouracil and erbitux was provided. In 2017, PET showed lung disease with massive metastatic adenopathies in almost all mediastinal lymph node stations. It was decided to carry out a re-challenge with platinum with evidence in January 2019 of reduction of lung and lymph node lesions. The CT of May 2019 showed a progression of pathology upon which the oncologist decided to start therapy with vivolumab (240 mg biweekly). After about 5 weeks of treatment (before the fourth cycle of therapy), the patient reported sudden onset of polyuria and polydipsia. The endocrine tests he underwent (Table 1) suggested the presence of hypophysitis as a result of mild hyperprolactinemia (19.8 ng/mL) and hypogonadotropic hypogonadism, in association with symptoms suggestive of diabetes insipidus. Moreover, the routine laboratory investigations (Table 2) revealed dehydration (hypercalcemia, hypernatremia, hyperkalemia) and impaired fasting glucose (blood glucose: 116 mg/dL); glycated hemoglobin (HbA1c) and oral glucose tolerance test (OGTT) were not sought. Considered the onset of a possible hypophysitis, the oncologist stopped nivolumab temporarily and started therapy with methylprednisolone 64 mg/day and requested endocrinological advice. After about 10 days of corticosteroid therapy, the patient was hospitalized in the endocrinology department. He presented in a poor health condition, in a state of dehydration and with a severe fungal infection of the oral cavity. Asthenia persisted, while he did not complain of visual field deficits. The patient reported persistence of polyuria and polydipsia (about 8 L/day), which did not change following the introduction of corticosteroid therapy. Blood chemistry tests showed glycemic decompensation (glucose: 320 mg/dL) with plasma hyperosmolality (303 mOsm/kg) and urine hyposmolarity (158 mmol/L).
Table 1 Laboratory values after 5 weeks of oncological treatment.
Hormone Result Reference values
TSH, µUI/mL 1.00 0.55–4.78
FT3, pg/mL 3.12 2–4.2
FT4, pg/mL 1.25 0.8–1.7
Testosterone, ng/mL 0.5 1.39–9.13
LH, mUI/mL 3.0 1.4–18.1
FSH, mUI/mL 2.7 4.5–9.3
Prolactin, ng/mL 19.8 2.1–17.7
ACTH, µg/dL 19.2 5.27–22.45
Cortisol, pg/mL 20.4 10–60
Table 2 Blood count and biochemistry test after 5 weeks of oncological treatment.
Blood count and biochemistry test Result Reference values
WBC, × 103/μL 11.25 4.3–10.5
RBC, × 106/μL 5.50 4.2–5.8
Hemoglobin, g/dL 16.1 12–17.5
Hematocrit, % 50.5 37–52
MCV, flL 91.8 80–99
MCH, pg 29.3 27–32
MCHC, g/dL 31.9 33–37
RDW, % 15.1 11.5–14.5
Platelets, × 103/μL 205 130–400
Neutrophils, × 103/μL 8.30 1.9–8
Lymphocytes, × 103/μL 1.86 0.9–5.2
Monocytes, × 103/μL 0.88 0.2–1
Eosinophils, × 103/μL 0.15 0–0.8
Basophils, × 103/μL 0.07 0–0.2
Glucose, mg/dL 116 60–100
BUN, mg/dL 9 5–25
Creatinine, mg/dL 0.8 0.6–1.2
Sodium, mEq/L 150 136–146
Potassium, mEq/L 5.3 3.5–5.1
Calcium, mg/dL 11.2 8.8–10.6
Magnesium, mg/dL 2.5 1.8–2.6
Uricemia, mg/dL 4.5 3.5–7.2
Proteins, g/dL 7.6 6.6–8.3
Albumin, g/dL 4.4 3.5–5.2
Total bilirubin, mg/dL 0.5 0.2–1.1
Direct bilirubin, mg/dL 0.1 0.1–0.4
Indirect bilirubin, mg/dL 0.4 0.2–0.8
LDH, U/L 274 0–248
AST, U/L 26 5–45
ALT, U/L 36 5–55
GGT, U/ L 30 10–50
Cholinesterase, U/L 5439 4500–11 400
ALP, U/L 118 30–120
Sideremia, μg/dL 67 70–180
Investigation
Pituitary hormonal function was assessed (Table 3) and frank hypogonadotropic hypogonadism and mild hyperprolactinemia were confirmed. The low TSH value was compatible with concomitant corticosteroid therapy (6). To complete the study of glycemic decompensation, HbA1c (7.7%), C-peptide (0.73 ng/mL, reference value: 0.5–2) and antibodies against glutamic acid decarboxylase (<5 IU/mL) and anti IA2 (<10 IU/mL) were assessed. The autoimmune origin was therefore excluded and diagnosis of metasteroid diabetes mellitus was made. It was treated with insulin therapy. During the hospitalization, methylprednisolone dose was tapered off, leading to the resolution of mycosis (which was also due to antifungal therapy) and the restoration of glycemic compensation with progressive reduction in the dose of insulin, until full discontinuation. Once normalization of blood glucose levels was obtained, the patient reported improvement in symptoms of polyuria and polydipsia, which however persisted albeit to a lesser extent (water balance: IN 4.5 L – OUT 5.5 L). The patient was affected by the polyuria–polydipsia syndrome (water intake > 3 L/day and diuresis > 40–50 mL/kg/day), and it was, therefore, necessary to define the etiology. Because of the technical limitations of the ADH assay (7), and the impossibility of copeptin dosage in our clinical laboratory, we assessed urine osmolarity and plasma osmolality. After just 2 h of fluid restriction, the onset of hypernatremia contraindicated the water deprivation test’s prosecution. Psychogenic polyuria was ruled out due to the presence of low urine osmolarity in association with high plasma osmolality. Afterwards, we decided to evaluate the response to the administration of desmopressin 2 μg s.c. In Table 4 you can see the values of natremia, plasma osmolality and urine osmolarity before and after the administration of the drug. An increase of 146% in urine osmolarity after desmopressin allowed us to rule out nephrogenic diabetes insipidus and has made diagnosing central diabetes insipidus possible (8). Anti-pituitary antibody and anti-rabphilin 3A antibody were not available in our laboratory, therefore they haven’t been investigated.
Table 3 Laboratory values during treatment with corticosteroid, after nivolumab discontinuation.
Hormone/antibody Result Reference values
TSH, µUI/mL 0.147 0.89–1.76
FT4, ng/dL 1.22 0.55–4.78
TGAb, U/mL 17.10 <60
TPOAb, U/mL 38.30 <60
Testosterone, ng/dL <20.0 181–758
LH, mUI/mL 0.4 0.8–7.6
FSH, mUI/mL 0.6 0.7–11.1
Prolactin, ng/mL 18.6 2.5–17.0
GH, ng/mL 0.4 <10
IGF-1, ng/mL 109 43–220
ACTH, pg/mL 6 0–46
Cortisol, µg/dL 20.3 4.3–22.4
Table 4 Plasma osmolality and urine osmolarity before and after desmopressin administration.
Sampling time Natremia (mEq/L) Plasma osmolality (mOsm/Kg) Urine osmolarity (mmol/L) Change in urine (osmolarity)
Before desmopressin
7:00 h 146 300 176 –
Desmopressin 2 µg s.c. injection: 10:00 h
12:30 h 142 294 353 +100%
15:30 h – – 430 +144%
At this point, pituitary MRI scan with gadolinium was performed. The radiological report showed a pituitary stalk substantially in axis, with marked and widespread thickening, up to about 6 mm, associated hyperintensity and contrast enhancement. Neurohypophysis hyperintensity was not displayed. A roundish formation of about 7 mm in diameter, substantially isointense with respect to the remaining glandular parenchyma in pre-contrast T1- and T2-weighted images and tenuously hypointense in post-contrast image, was observed at the posterior adenohypophyseal portion, in the median-paramedian area. The lesion seemed to cause focal interruption of the sellar floor (Fig. 1). In addition to the MRI examination of the pituitary, post-contrast axial DWI and 3D-T1-FFE sequences were acquired on the entire brain with documented presence of multiple contrast medium enhancement lesions located in the supra and sub-tentorial regions and in both cerebellar hemispheres (Fig. 2). The neuroradiological data were therefore compatible both with clinical suspicion of metastatic localization and with the hypothesis of hypophysitis secondary to therapy with nivolumab.
Figure 1 Pre-contrast (A) and postcontrast T1-weighted sagittal (B) and coronal (C) MR image demonstrates a diffuse enlargement of the pituitary stalk. The pituitary gland shows heterogenous enhancement due to a hypotense lesion, causing focal destruction of the sellar floor.
Figure 2 Post-contrast T1-weighted MR image of the brain demonstrates multiple metastatic lesions at the grey-white matter junction in the frontal lobe (A) and in the midbrain, close to the Sylvian aqueduct (B).
Treatment
The patient underwent replacement therapy with DDVAP sublingual tablets 60 μg in divided dose twice daily, with normalization of the water balance (2 L in balance).
Nine days after hospitalization, the patient was discharged with the following diagnosis ‘Partial hypopituitarism (diabetes insipidus and hypogonadism) secondary to probable nivolumab-induced infundibulo-neurohypophysitis and anterohypophyseal metastasis, in a patient suffering from metastatic hypopharyngeal carcinoma; multiple cerebral and cerebellar new on-set metastases and metasteroid diabetes mellitus’. The patient was started on replacement therapy with DDVAP sublingual tablets 60 μg in divided dose twice daily, 2% testosterone gel 4 puffs/day and methylprednisolone dose was tapered off until 4 mg, pending execution of ACTH test to evaluate the possible suppression of the hypothalamic–pituitary–adrenal axis. As the pituitary impairment was well compensated by the replacement therapy, no contraindication was given to the resumption of nivolumab therapy with necessary monitoring of the residual pituitary function.
Outcome and follow-up
The patient was re-evaluated by the oncologist and underwent total body CT scan for disease re- staging. In addition to the already known secondary malignancy in the lung, new-onset adrenal, pancreatic, skeletal metastases and peritoneal carcinosis were found.
Due to poor response to nivolumab therapy and rapid disease progression, treatment was stopped permanently. The patient died about 50 days after hospital discharge.
Discussion
The hypophysitis is an adverse event more characteristic of anti-CTLA4, and only to a lesser extent than anti-PD1. Patients with immune therapy-induced hypophysitis mostly present with multiple hormonal deficits, mainly of thyrotropin (84%), corticotropin (80%) and gonadotropins (76%); the involvement of the posterior pituitary is exceptional (2). So far, there are only two case reports described in the literature about anti PDL1 (3) and anti PD1- related central diabetes insipidus (4). The average time to onset of endocrinological side effects is 9 weeks from the start of treatment (with a range from 5 to 36 weeks). Considering the high incidence of these adverse events following therapy with immune-checkpoint, it is essential to research any clinical signs suggestive of iRAes before each cycle of therapy; when a suggestive symtom is found, it is essential to evaluate hormonal tests to identify endocrinopathy (9). In general, the oncological clinical practice involves the administration of high-dose corticosteroids for most iRAes. As regards specifically the pituitary, a recent consensus has highlighted how the use of high-dose corticosteroids is to be reserved exclusively for cases of adrenal crisis, severe headache and visual field deficit (10). In fact, corticosteroid therapy would be able to resolve the signs of local inflammation, but not the hormonal deficit. In addition, high-dose therapy would be responsible for major complications, some serious enough to require hospitalization (11). To confirm this, our patient had not received any benefit from corticosteroid therapy, but his general health condition worsened as a result of diabetes mellitus, dehydration and fungal infection onset. Besides the patient suffered from impaired fasting glucose, and glucocorticoid treatment precipitated a pre-diabetes condition. The etiology of diabetes mellitus in our patient under both corticosteroids and immune-checkpoint inhibitors treatment, was, at first, uncertain. In fact, among the autoimmune adverse events typical of immune-checkpoints inhibitors, there is also diabetes mellitus (12). The autoimmune form of origin was however excluded due to the absence of autoimmunity, the pancreatic reserve and the normalization of blood glucose levels following the steroid tapering.
The persistence of polyuria and polydipsia led us to investigate the origin of the polyuria–polydipsia syndrome, confirming the diagnosis of diabetes insipidus following the evaluation of plasma osmolality and urine osmolarity before and after DDVAP.
The diabetes insipidus in our patient could have been mainly due to two causes: the presence of metastases in the pituitary region or the onset of hypophysitis secondary to nivolumab therapy.
A recent observational retrospective study assessed the clinical, biochemical and radiological differences in patients with neoplastic and non-neoplastic pituitary stalk pathology. Statistically significant differences were found for the greater preponderance of diabetes insipidus and hypogonadism in subjects suffering from neoplastic pathology compared to those suffering from non-neoplastic pathology; with regard to radiological images, the features that have reached statistical significance were the thickness of the stalk and the heterogeneity of the contrast enhancement after administration of contrast agent. Specifically, all thickenings greater than 9.1 mm in diameter in the post-contrast coronal section in the upper part of the stalk and greater than 5.6 in the coronal section in the lower part were confirmed as neoplastic with a sensitivity of 100% (13). Our patient had biochemical and radiological characteristics consistent with the coexistence of neurohypophysitis (stalk thickness 6 mm, hyperintensity under the Gadolinium enhancement, and no evidence of neurohypophysis hyperintensity) and pituitary metastasis (roundish formation, at the posterior adenohypophyseal portion, causing focal interruption of the sellar floor). To define the exact etiology of the pituitary pathology, histological confirmation through biopsy sampling would have been necessary; however, because of the patient’s critical health condition, it was not possible to perform. In the absence of histological confirmation, we believe it is likely that both could have played a role in the onset of diabetes insipidus secondary to the pituitary stalk interruption syndrome, as a result of metastatic compression and drug therapy-induced hypophysitis.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Patient consent
Informed consent was obtained from the patient for publication of this report.
Author contribution statement
All the authors have contributed to the writing and editing of this manuscript and the physician responsible for the patient is one of the authors. | METHYLPREDNISOLONE | DrugsGivenReaction | CC BY-NC-ND | 33522491 | 19,107,271 | 2021-01-27 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Diabetes insipidus secondary to nivolumab-induced neurohypophysitis and pituitary metastasis.
A 62-year-old patient with metastatic hypopharyngeal carcinoma underwent treatment with nivolumab, following which he developed symptoms suggestive of diabetes insipidus. Nivolumab was stopped and therapy with methylprednisolone was started. During corticosteroid therapy, the patient presented himself in poor health condition with fungal infection and glycemic decompensation. Methylprednisolone dose was tapered off, leading to the resolution of mycosis and the restoration of glycemic compensation, nevertheless polyuria and polydipsia persisted. Increase in urine osmolarity after desmopressin administration was made diagnosing central diabetes insipidus as a possibility. The neuroradiological data by pituitary MRI scan with gadolinium was compatible with coexistence of metastatic localization and infundibulo-neurohypophysitis secondary to therapy with nivolumab. To define the exact etiology of the pituitary pathology, histological confirmation would have been necessary; however, unfortunately, it was not possible. In the absence of histological confirmation, we believe it is likely that both pathologies coexisted.
A remarkable risk of endocrine immune-related adverse events (irAEs) during therapy with checkpoint inhibitors exsists. In order to ensure maximum efficiency in the recognition and treatment of endocrine iRAes related to immune checkpoint inhibitors, multidisciplinary management of oncological patients is critical. The pituitary syndrome in oncological patients who underwent immunotherapy represents a challenge in the differential diagnosis between pituitary metastasis and drug-induced hypophysitis. This is the first case, described in the literature of diabetes insipidus in a patient suffering from nivolumab-induced infundibulo-neurohypophysitis and anterohypophyseal metastasis.
Background
The introduction of immune checkpoint inhibitors into oncological clinical practice has revolutionized the treatment of various neoplastic diseases. These drugs awaken the anti-tumor immune response by interrupting the inhibitory signal pathways and promote immune-mediated elimination of cancer cells. The targets of these therapies include CTLA-4 (cytotoxic T-lymphocyte associated protein-4), PD1 (programmed cell death protein-1) and PD-L1 (programmed death ligand-1). This mechanism is also the basis of immune-related adverse events (iRAes), due to the inhibition of immune-checkpoints that reinforce normal physiological barriers against autoimmunity (1). The main adverse events affect the skin, the gastrointestinal, musculoskeletal and endocrine systems. The main endocrinological manifestations are represented by thyroid dysfunction and hypophysitis. The involvement of the posterior pituitary, and consequent diabetes insipidus is exceptional, but not impossible (2, 3, 4). Pituitary metastasis is a rare complication of advanced malignancy; however, almost every cancer type can metastasize to the pituitary fossa. Diabetes insipidus is common among patients with pituitary metastasis (5).
Case presentation
We present the case of a 62-year-old patient with metastatic hypopharyngeal carcinoma undergoing treatment with Nivolumab (anti- PD1 MAB), following which he developed central diabetes insipidus. In 2002, the patient, with a history of heavy smoking and in the absence of other comorbidities, received the diagnosis of hypopharyngeal carcinoma and was treated with chemotherapy (platinum and fluorine) and surgery. In 2016, relapse on the lingual body developed, and due to the inoperability of the lesion, chemotherapy with cisplatin, 5-fluorouracil and erbitux was provided. In 2017, PET showed lung disease with massive metastatic adenopathies in almost all mediastinal lymph node stations. It was decided to carry out a re-challenge with platinum with evidence in January 2019 of reduction of lung and lymph node lesions. The CT of May 2019 showed a progression of pathology upon which the oncologist decided to start therapy with vivolumab (240 mg biweekly). After about 5 weeks of treatment (before the fourth cycle of therapy), the patient reported sudden onset of polyuria and polydipsia. The endocrine tests he underwent (Table 1) suggested the presence of hypophysitis as a result of mild hyperprolactinemia (19.8 ng/mL) and hypogonadotropic hypogonadism, in association with symptoms suggestive of diabetes insipidus. Moreover, the routine laboratory investigations (Table 2) revealed dehydration (hypercalcemia, hypernatremia, hyperkalemia) and impaired fasting glucose (blood glucose: 116 mg/dL); glycated hemoglobin (HbA1c) and oral glucose tolerance test (OGTT) were not sought. Considered the onset of a possible hypophysitis, the oncologist stopped nivolumab temporarily and started therapy with methylprednisolone 64 mg/day and requested endocrinological advice. After about 10 days of corticosteroid therapy, the patient was hospitalized in the endocrinology department. He presented in a poor health condition, in a state of dehydration and with a severe fungal infection of the oral cavity. Asthenia persisted, while he did not complain of visual field deficits. The patient reported persistence of polyuria and polydipsia (about 8 L/day), which did not change following the introduction of corticosteroid therapy. Blood chemistry tests showed glycemic decompensation (glucose: 320 mg/dL) with plasma hyperosmolality (303 mOsm/kg) and urine hyposmolarity (158 mmol/L).
Table 1 Laboratory values after 5 weeks of oncological treatment.
Hormone Result Reference values
TSH, µUI/mL 1.00 0.55–4.78
FT3, pg/mL 3.12 2–4.2
FT4, pg/mL 1.25 0.8–1.7
Testosterone, ng/mL 0.5 1.39–9.13
LH, mUI/mL 3.0 1.4–18.1
FSH, mUI/mL 2.7 4.5–9.3
Prolactin, ng/mL 19.8 2.1–17.7
ACTH, µg/dL 19.2 5.27–22.45
Cortisol, pg/mL 20.4 10–60
Table 2 Blood count and biochemistry test after 5 weeks of oncological treatment.
Blood count and biochemistry test Result Reference values
WBC, × 103/μL 11.25 4.3–10.5
RBC, × 106/μL 5.50 4.2–5.8
Hemoglobin, g/dL 16.1 12–17.5
Hematocrit, % 50.5 37–52
MCV, flL 91.8 80–99
MCH, pg 29.3 27–32
MCHC, g/dL 31.9 33–37
RDW, % 15.1 11.5–14.5
Platelets, × 103/μL 205 130–400
Neutrophils, × 103/μL 8.30 1.9–8
Lymphocytes, × 103/μL 1.86 0.9–5.2
Monocytes, × 103/μL 0.88 0.2–1
Eosinophils, × 103/μL 0.15 0–0.8
Basophils, × 103/μL 0.07 0–0.2
Glucose, mg/dL 116 60–100
BUN, mg/dL 9 5–25
Creatinine, mg/dL 0.8 0.6–1.2
Sodium, mEq/L 150 136–146
Potassium, mEq/L 5.3 3.5–5.1
Calcium, mg/dL 11.2 8.8–10.6
Magnesium, mg/dL 2.5 1.8–2.6
Uricemia, mg/dL 4.5 3.5–7.2
Proteins, g/dL 7.6 6.6–8.3
Albumin, g/dL 4.4 3.5–5.2
Total bilirubin, mg/dL 0.5 0.2–1.1
Direct bilirubin, mg/dL 0.1 0.1–0.4
Indirect bilirubin, mg/dL 0.4 0.2–0.8
LDH, U/L 274 0–248
AST, U/L 26 5–45
ALT, U/L 36 5–55
GGT, U/ L 30 10–50
Cholinesterase, U/L 5439 4500–11 400
ALP, U/L 118 30–120
Sideremia, μg/dL 67 70–180
Investigation
Pituitary hormonal function was assessed (Table 3) and frank hypogonadotropic hypogonadism and mild hyperprolactinemia were confirmed. The low TSH value was compatible with concomitant corticosteroid therapy (6). To complete the study of glycemic decompensation, HbA1c (7.7%), C-peptide (0.73 ng/mL, reference value: 0.5–2) and antibodies against glutamic acid decarboxylase (<5 IU/mL) and anti IA2 (<10 IU/mL) were assessed. The autoimmune origin was therefore excluded and diagnosis of metasteroid diabetes mellitus was made. It was treated with insulin therapy. During the hospitalization, methylprednisolone dose was tapered off, leading to the resolution of mycosis (which was also due to antifungal therapy) and the restoration of glycemic compensation with progressive reduction in the dose of insulin, until full discontinuation. Once normalization of blood glucose levels was obtained, the patient reported improvement in symptoms of polyuria and polydipsia, which however persisted albeit to a lesser extent (water balance: IN 4.5 L – OUT 5.5 L). The patient was affected by the polyuria–polydipsia syndrome (water intake > 3 L/day and diuresis > 40–50 mL/kg/day), and it was, therefore, necessary to define the etiology. Because of the technical limitations of the ADH assay (7), and the impossibility of copeptin dosage in our clinical laboratory, we assessed urine osmolarity and plasma osmolality. After just 2 h of fluid restriction, the onset of hypernatremia contraindicated the water deprivation test’s prosecution. Psychogenic polyuria was ruled out due to the presence of low urine osmolarity in association with high plasma osmolality. Afterwards, we decided to evaluate the response to the administration of desmopressin 2 μg s.c. In Table 4 you can see the values of natremia, plasma osmolality and urine osmolarity before and after the administration of the drug. An increase of 146% in urine osmolarity after desmopressin allowed us to rule out nephrogenic diabetes insipidus and has made diagnosing central diabetes insipidus possible (8). Anti-pituitary antibody and anti-rabphilin 3A antibody were not available in our laboratory, therefore they haven’t been investigated.
Table 3 Laboratory values during treatment with corticosteroid, after nivolumab discontinuation.
Hormone/antibody Result Reference values
TSH, µUI/mL 0.147 0.89–1.76
FT4, ng/dL 1.22 0.55–4.78
TGAb, U/mL 17.10 <60
TPOAb, U/mL 38.30 <60
Testosterone, ng/dL <20.0 181–758
LH, mUI/mL 0.4 0.8–7.6
FSH, mUI/mL 0.6 0.7–11.1
Prolactin, ng/mL 18.6 2.5–17.0
GH, ng/mL 0.4 <10
IGF-1, ng/mL 109 43–220
ACTH, pg/mL 6 0–46
Cortisol, µg/dL 20.3 4.3–22.4
Table 4 Plasma osmolality and urine osmolarity before and after desmopressin administration.
Sampling time Natremia (mEq/L) Plasma osmolality (mOsm/Kg) Urine osmolarity (mmol/L) Change in urine (osmolarity)
Before desmopressin
7:00 h 146 300 176 –
Desmopressin 2 µg s.c. injection: 10:00 h
12:30 h 142 294 353 +100%
15:30 h – – 430 +144%
At this point, pituitary MRI scan with gadolinium was performed. The radiological report showed a pituitary stalk substantially in axis, with marked and widespread thickening, up to about 6 mm, associated hyperintensity and contrast enhancement. Neurohypophysis hyperintensity was not displayed. A roundish formation of about 7 mm in diameter, substantially isointense with respect to the remaining glandular parenchyma in pre-contrast T1- and T2-weighted images and tenuously hypointense in post-contrast image, was observed at the posterior adenohypophyseal portion, in the median-paramedian area. The lesion seemed to cause focal interruption of the sellar floor (Fig. 1). In addition to the MRI examination of the pituitary, post-contrast axial DWI and 3D-T1-FFE sequences were acquired on the entire brain with documented presence of multiple contrast medium enhancement lesions located in the supra and sub-tentorial regions and in both cerebellar hemispheres (Fig. 2). The neuroradiological data were therefore compatible both with clinical suspicion of metastatic localization and with the hypothesis of hypophysitis secondary to therapy with nivolumab.
Figure 1 Pre-contrast (A) and postcontrast T1-weighted sagittal (B) and coronal (C) MR image demonstrates a diffuse enlargement of the pituitary stalk. The pituitary gland shows heterogenous enhancement due to a hypotense lesion, causing focal destruction of the sellar floor.
Figure 2 Post-contrast T1-weighted MR image of the brain demonstrates multiple metastatic lesions at the grey-white matter junction in the frontal lobe (A) and in the midbrain, close to the Sylvian aqueduct (B).
Treatment
The patient underwent replacement therapy with DDVAP sublingual tablets 60 μg in divided dose twice daily, with normalization of the water balance (2 L in balance).
Nine days after hospitalization, the patient was discharged with the following diagnosis ‘Partial hypopituitarism (diabetes insipidus and hypogonadism) secondary to probable nivolumab-induced infundibulo-neurohypophysitis and anterohypophyseal metastasis, in a patient suffering from metastatic hypopharyngeal carcinoma; multiple cerebral and cerebellar new on-set metastases and metasteroid diabetes mellitus’. The patient was started on replacement therapy with DDVAP sublingual tablets 60 μg in divided dose twice daily, 2% testosterone gel 4 puffs/day and methylprednisolone dose was tapered off until 4 mg, pending execution of ACTH test to evaluate the possible suppression of the hypothalamic–pituitary–adrenal axis. As the pituitary impairment was well compensated by the replacement therapy, no contraindication was given to the resumption of nivolumab therapy with necessary monitoring of the residual pituitary function.
Outcome and follow-up
The patient was re-evaluated by the oncologist and underwent total body CT scan for disease re- staging. In addition to the already known secondary malignancy in the lung, new-onset adrenal, pancreatic, skeletal metastases and peritoneal carcinosis were found.
Due to poor response to nivolumab therapy and rapid disease progression, treatment was stopped permanently. The patient died about 50 days after hospital discharge.
Discussion
The hypophysitis is an adverse event more characteristic of anti-CTLA4, and only to a lesser extent than anti-PD1. Patients with immune therapy-induced hypophysitis mostly present with multiple hormonal deficits, mainly of thyrotropin (84%), corticotropin (80%) and gonadotropins (76%); the involvement of the posterior pituitary is exceptional (2). So far, there are only two case reports described in the literature about anti PDL1 (3) and anti PD1- related central diabetes insipidus (4). The average time to onset of endocrinological side effects is 9 weeks from the start of treatment (with a range from 5 to 36 weeks). Considering the high incidence of these adverse events following therapy with immune-checkpoint, it is essential to research any clinical signs suggestive of iRAes before each cycle of therapy; when a suggestive symtom is found, it is essential to evaluate hormonal tests to identify endocrinopathy (9). In general, the oncological clinical practice involves the administration of high-dose corticosteroids for most iRAes. As regards specifically the pituitary, a recent consensus has highlighted how the use of high-dose corticosteroids is to be reserved exclusively for cases of adrenal crisis, severe headache and visual field deficit (10). In fact, corticosteroid therapy would be able to resolve the signs of local inflammation, but not the hormonal deficit. In addition, high-dose therapy would be responsible for major complications, some serious enough to require hospitalization (11). To confirm this, our patient had not received any benefit from corticosteroid therapy, but his general health condition worsened as a result of diabetes mellitus, dehydration and fungal infection onset. Besides the patient suffered from impaired fasting glucose, and glucocorticoid treatment precipitated a pre-diabetes condition. The etiology of diabetes mellitus in our patient under both corticosteroids and immune-checkpoint inhibitors treatment, was, at first, uncertain. In fact, among the autoimmune adverse events typical of immune-checkpoints inhibitors, there is also diabetes mellitus (12). The autoimmune form of origin was however excluded due to the absence of autoimmunity, the pancreatic reserve and the normalization of blood glucose levels following the steroid tapering.
The persistence of polyuria and polydipsia led us to investigate the origin of the polyuria–polydipsia syndrome, confirming the diagnosis of diabetes insipidus following the evaluation of plasma osmolality and urine osmolarity before and after DDVAP.
The diabetes insipidus in our patient could have been mainly due to two causes: the presence of metastases in the pituitary region or the onset of hypophysitis secondary to nivolumab therapy.
A recent observational retrospective study assessed the clinical, biochemical and radiological differences in patients with neoplastic and non-neoplastic pituitary stalk pathology. Statistically significant differences were found for the greater preponderance of diabetes insipidus and hypogonadism in subjects suffering from neoplastic pathology compared to those suffering from non-neoplastic pathology; with regard to radiological images, the features that have reached statistical significance were the thickness of the stalk and the heterogeneity of the contrast enhancement after administration of contrast agent. Specifically, all thickenings greater than 9.1 mm in diameter in the post-contrast coronal section in the upper part of the stalk and greater than 5.6 in the coronal section in the lower part were confirmed as neoplastic with a sensitivity of 100% (13). Our patient had biochemical and radiological characteristics consistent with the coexistence of neurohypophysitis (stalk thickness 6 mm, hyperintensity under the Gadolinium enhancement, and no evidence of neurohypophysis hyperintensity) and pituitary metastasis (roundish formation, at the posterior adenohypophyseal portion, causing focal interruption of the sellar floor). To define the exact etiology of the pituitary pathology, histological confirmation through biopsy sampling would have been necessary; however, because of the patient’s critical health condition, it was not possible to perform. In the absence of histological confirmation, we believe it is likely that both could have played a role in the onset of diabetes insipidus secondary to the pituitary stalk interruption syndrome, as a result of metastatic compression and drug therapy-induced hypophysitis.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Patient consent
Informed consent was obtained from the patient for publication of this report.
Author contribution statement
All the authors have contributed to the writing and editing of this manuscript and the physician responsible for the patient is one of the authors. | METHYLPREDNISOLONE, NIVOLUMAB | DrugsGivenReaction | CC BY-NC-ND | 33522491 | 19,074,871 | 2021-01-27 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Steroid diabetes'. | Diabetes insipidus secondary to nivolumab-induced neurohypophysitis and pituitary metastasis.
A 62-year-old patient with metastatic hypopharyngeal carcinoma underwent treatment with nivolumab, following which he developed symptoms suggestive of diabetes insipidus. Nivolumab was stopped and therapy with methylprednisolone was started. During corticosteroid therapy, the patient presented himself in poor health condition with fungal infection and glycemic decompensation. Methylprednisolone dose was tapered off, leading to the resolution of mycosis and the restoration of glycemic compensation, nevertheless polyuria and polydipsia persisted. Increase in urine osmolarity after desmopressin administration was made diagnosing central diabetes insipidus as a possibility. The neuroradiological data by pituitary MRI scan with gadolinium was compatible with coexistence of metastatic localization and infundibulo-neurohypophysitis secondary to therapy with nivolumab. To define the exact etiology of the pituitary pathology, histological confirmation would have been necessary; however, unfortunately, it was not possible. In the absence of histological confirmation, we believe it is likely that both pathologies coexisted.
A remarkable risk of endocrine immune-related adverse events (irAEs) during therapy with checkpoint inhibitors exsists. In order to ensure maximum efficiency in the recognition and treatment of endocrine iRAes related to immune checkpoint inhibitors, multidisciplinary management of oncological patients is critical. The pituitary syndrome in oncological patients who underwent immunotherapy represents a challenge in the differential diagnosis between pituitary metastasis and drug-induced hypophysitis. This is the first case, described in the literature of diabetes insipidus in a patient suffering from nivolumab-induced infundibulo-neurohypophysitis and anterohypophyseal metastasis.
Background
The introduction of immune checkpoint inhibitors into oncological clinical practice has revolutionized the treatment of various neoplastic diseases. These drugs awaken the anti-tumor immune response by interrupting the inhibitory signal pathways and promote immune-mediated elimination of cancer cells. The targets of these therapies include CTLA-4 (cytotoxic T-lymphocyte associated protein-4), PD1 (programmed cell death protein-1) and PD-L1 (programmed death ligand-1). This mechanism is also the basis of immune-related adverse events (iRAes), due to the inhibition of immune-checkpoints that reinforce normal physiological barriers against autoimmunity (1). The main adverse events affect the skin, the gastrointestinal, musculoskeletal and endocrine systems. The main endocrinological manifestations are represented by thyroid dysfunction and hypophysitis. The involvement of the posterior pituitary, and consequent diabetes insipidus is exceptional, but not impossible (2, 3, 4). Pituitary metastasis is a rare complication of advanced malignancy; however, almost every cancer type can metastasize to the pituitary fossa. Diabetes insipidus is common among patients with pituitary metastasis (5).
Case presentation
We present the case of a 62-year-old patient with metastatic hypopharyngeal carcinoma undergoing treatment with Nivolumab (anti- PD1 MAB), following which he developed central diabetes insipidus. In 2002, the patient, with a history of heavy smoking and in the absence of other comorbidities, received the diagnosis of hypopharyngeal carcinoma and was treated with chemotherapy (platinum and fluorine) and surgery. In 2016, relapse on the lingual body developed, and due to the inoperability of the lesion, chemotherapy with cisplatin, 5-fluorouracil and erbitux was provided. In 2017, PET showed lung disease with massive metastatic adenopathies in almost all mediastinal lymph node stations. It was decided to carry out a re-challenge with platinum with evidence in January 2019 of reduction of lung and lymph node lesions. The CT of May 2019 showed a progression of pathology upon which the oncologist decided to start therapy with vivolumab (240 mg biweekly). After about 5 weeks of treatment (before the fourth cycle of therapy), the patient reported sudden onset of polyuria and polydipsia. The endocrine tests he underwent (Table 1) suggested the presence of hypophysitis as a result of mild hyperprolactinemia (19.8 ng/mL) and hypogonadotropic hypogonadism, in association with symptoms suggestive of diabetes insipidus. Moreover, the routine laboratory investigations (Table 2) revealed dehydration (hypercalcemia, hypernatremia, hyperkalemia) and impaired fasting glucose (blood glucose: 116 mg/dL); glycated hemoglobin (HbA1c) and oral glucose tolerance test (OGTT) were not sought. Considered the onset of a possible hypophysitis, the oncologist stopped nivolumab temporarily and started therapy with methylprednisolone 64 mg/day and requested endocrinological advice. After about 10 days of corticosteroid therapy, the patient was hospitalized in the endocrinology department. He presented in a poor health condition, in a state of dehydration and with a severe fungal infection of the oral cavity. Asthenia persisted, while he did not complain of visual field deficits. The patient reported persistence of polyuria and polydipsia (about 8 L/day), which did not change following the introduction of corticosteroid therapy. Blood chemistry tests showed glycemic decompensation (glucose: 320 mg/dL) with plasma hyperosmolality (303 mOsm/kg) and urine hyposmolarity (158 mmol/L).
Table 1 Laboratory values after 5 weeks of oncological treatment.
Hormone Result Reference values
TSH, µUI/mL 1.00 0.55–4.78
FT3, pg/mL 3.12 2–4.2
FT4, pg/mL 1.25 0.8–1.7
Testosterone, ng/mL 0.5 1.39–9.13
LH, mUI/mL 3.0 1.4–18.1
FSH, mUI/mL 2.7 4.5–9.3
Prolactin, ng/mL 19.8 2.1–17.7
ACTH, µg/dL 19.2 5.27–22.45
Cortisol, pg/mL 20.4 10–60
Table 2 Blood count and biochemistry test after 5 weeks of oncological treatment.
Blood count and biochemistry test Result Reference values
WBC, × 103/μL 11.25 4.3–10.5
RBC, × 106/μL 5.50 4.2–5.8
Hemoglobin, g/dL 16.1 12–17.5
Hematocrit, % 50.5 37–52
MCV, flL 91.8 80–99
MCH, pg 29.3 27–32
MCHC, g/dL 31.9 33–37
RDW, % 15.1 11.5–14.5
Platelets, × 103/μL 205 130–400
Neutrophils, × 103/μL 8.30 1.9–8
Lymphocytes, × 103/μL 1.86 0.9–5.2
Monocytes, × 103/μL 0.88 0.2–1
Eosinophils, × 103/μL 0.15 0–0.8
Basophils, × 103/μL 0.07 0–0.2
Glucose, mg/dL 116 60–100
BUN, mg/dL 9 5–25
Creatinine, mg/dL 0.8 0.6–1.2
Sodium, mEq/L 150 136–146
Potassium, mEq/L 5.3 3.5–5.1
Calcium, mg/dL 11.2 8.8–10.6
Magnesium, mg/dL 2.5 1.8–2.6
Uricemia, mg/dL 4.5 3.5–7.2
Proteins, g/dL 7.6 6.6–8.3
Albumin, g/dL 4.4 3.5–5.2
Total bilirubin, mg/dL 0.5 0.2–1.1
Direct bilirubin, mg/dL 0.1 0.1–0.4
Indirect bilirubin, mg/dL 0.4 0.2–0.8
LDH, U/L 274 0–248
AST, U/L 26 5–45
ALT, U/L 36 5–55
GGT, U/ L 30 10–50
Cholinesterase, U/L 5439 4500–11 400
ALP, U/L 118 30–120
Sideremia, μg/dL 67 70–180
Investigation
Pituitary hormonal function was assessed (Table 3) and frank hypogonadotropic hypogonadism and mild hyperprolactinemia were confirmed. The low TSH value was compatible with concomitant corticosteroid therapy (6). To complete the study of glycemic decompensation, HbA1c (7.7%), C-peptide (0.73 ng/mL, reference value: 0.5–2) and antibodies against glutamic acid decarboxylase (<5 IU/mL) and anti IA2 (<10 IU/mL) were assessed. The autoimmune origin was therefore excluded and diagnosis of metasteroid diabetes mellitus was made. It was treated with insulin therapy. During the hospitalization, methylprednisolone dose was tapered off, leading to the resolution of mycosis (which was also due to antifungal therapy) and the restoration of glycemic compensation with progressive reduction in the dose of insulin, until full discontinuation. Once normalization of blood glucose levels was obtained, the patient reported improvement in symptoms of polyuria and polydipsia, which however persisted albeit to a lesser extent (water balance: IN 4.5 L – OUT 5.5 L). The patient was affected by the polyuria–polydipsia syndrome (water intake > 3 L/day and diuresis > 40–50 mL/kg/day), and it was, therefore, necessary to define the etiology. Because of the technical limitations of the ADH assay (7), and the impossibility of copeptin dosage in our clinical laboratory, we assessed urine osmolarity and plasma osmolality. After just 2 h of fluid restriction, the onset of hypernatremia contraindicated the water deprivation test’s prosecution. Psychogenic polyuria was ruled out due to the presence of low urine osmolarity in association with high plasma osmolality. Afterwards, we decided to evaluate the response to the administration of desmopressin 2 μg s.c. In Table 4 you can see the values of natremia, plasma osmolality and urine osmolarity before and after the administration of the drug. An increase of 146% in urine osmolarity after desmopressin allowed us to rule out nephrogenic diabetes insipidus and has made diagnosing central diabetes insipidus possible (8). Anti-pituitary antibody and anti-rabphilin 3A antibody were not available in our laboratory, therefore they haven’t been investigated.
Table 3 Laboratory values during treatment with corticosteroid, after nivolumab discontinuation.
Hormone/antibody Result Reference values
TSH, µUI/mL 0.147 0.89–1.76
FT4, ng/dL 1.22 0.55–4.78
TGAb, U/mL 17.10 <60
TPOAb, U/mL 38.30 <60
Testosterone, ng/dL <20.0 181–758
LH, mUI/mL 0.4 0.8–7.6
FSH, mUI/mL 0.6 0.7–11.1
Prolactin, ng/mL 18.6 2.5–17.0
GH, ng/mL 0.4 <10
IGF-1, ng/mL 109 43–220
ACTH, pg/mL 6 0–46
Cortisol, µg/dL 20.3 4.3–22.4
Table 4 Plasma osmolality and urine osmolarity before and after desmopressin administration.
Sampling time Natremia (mEq/L) Plasma osmolality (mOsm/Kg) Urine osmolarity (mmol/L) Change in urine (osmolarity)
Before desmopressin
7:00 h 146 300 176 –
Desmopressin 2 µg s.c. injection: 10:00 h
12:30 h 142 294 353 +100%
15:30 h – – 430 +144%
At this point, pituitary MRI scan with gadolinium was performed. The radiological report showed a pituitary stalk substantially in axis, with marked and widespread thickening, up to about 6 mm, associated hyperintensity and contrast enhancement. Neurohypophysis hyperintensity was not displayed. A roundish formation of about 7 mm in diameter, substantially isointense with respect to the remaining glandular parenchyma in pre-contrast T1- and T2-weighted images and tenuously hypointense in post-contrast image, was observed at the posterior adenohypophyseal portion, in the median-paramedian area. The lesion seemed to cause focal interruption of the sellar floor (Fig. 1). In addition to the MRI examination of the pituitary, post-contrast axial DWI and 3D-T1-FFE sequences were acquired on the entire brain with documented presence of multiple contrast medium enhancement lesions located in the supra and sub-tentorial regions and in both cerebellar hemispheres (Fig. 2). The neuroradiological data were therefore compatible both with clinical suspicion of metastatic localization and with the hypothesis of hypophysitis secondary to therapy with nivolumab.
Figure 1 Pre-contrast (A) and postcontrast T1-weighted sagittal (B) and coronal (C) MR image demonstrates a diffuse enlargement of the pituitary stalk. The pituitary gland shows heterogenous enhancement due to a hypotense lesion, causing focal destruction of the sellar floor.
Figure 2 Post-contrast T1-weighted MR image of the brain demonstrates multiple metastatic lesions at the grey-white matter junction in the frontal lobe (A) and in the midbrain, close to the Sylvian aqueduct (B).
Treatment
The patient underwent replacement therapy with DDVAP sublingual tablets 60 μg in divided dose twice daily, with normalization of the water balance (2 L in balance).
Nine days after hospitalization, the patient was discharged with the following diagnosis ‘Partial hypopituitarism (diabetes insipidus and hypogonadism) secondary to probable nivolumab-induced infundibulo-neurohypophysitis and anterohypophyseal metastasis, in a patient suffering from metastatic hypopharyngeal carcinoma; multiple cerebral and cerebellar new on-set metastases and metasteroid diabetes mellitus’. The patient was started on replacement therapy with DDVAP sublingual tablets 60 μg in divided dose twice daily, 2% testosterone gel 4 puffs/day and methylprednisolone dose was tapered off until 4 mg, pending execution of ACTH test to evaluate the possible suppression of the hypothalamic–pituitary–adrenal axis. As the pituitary impairment was well compensated by the replacement therapy, no contraindication was given to the resumption of nivolumab therapy with necessary monitoring of the residual pituitary function.
Outcome and follow-up
The patient was re-evaluated by the oncologist and underwent total body CT scan for disease re- staging. In addition to the already known secondary malignancy in the lung, new-onset adrenal, pancreatic, skeletal metastases and peritoneal carcinosis were found.
Due to poor response to nivolumab therapy and rapid disease progression, treatment was stopped permanently. The patient died about 50 days after hospital discharge.
Discussion
The hypophysitis is an adverse event more characteristic of anti-CTLA4, and only to a lesser extent than anti-PD1. Patients with immune therapy-induced hypophysitis mostly present with multiple hormonal deficits, mainly of thyrotropin (84%), corticotropin (80%) and gonadotropins (76%); the involvement of the posterior pituitary is exceptional (2). So far, there are only two case reports described in the literature about anti PDL1 (3) and anti PD1- related central diabetes insipidus (4). The average time to onset of endocrinological side effects is 9 weeks from the start of treatment (with a range from 5 to 36 weeks). Considering the high incidence of these adverse events following therapy with immune-checkpoint, it is essential to research any clinical signs suggestive of iRAes before each cycle of therapy; when a suggestive symtom is found, it is essential to evaluate hormonal tests to identify endocrinopathy (9). In general, the oncological clinical practice involves the administration of high-dose corticosteroids for most iRAes. As regards specifically the pituitary, a recent consensus has highlighted how the use of high-dose corticosteroids is to be reserved exclusively for cases of adrenal crisis, severe headache and visual field deficit (10). In fact, corticosteroid therapy would be able to resolve the signs of local inflammation, but not the hormonal deficit. In addition, high-dose therapy would be responsible for major complications, some serious enough to require hospitalization (11). To confirm this, our patient had not received any benefit from corticosteroid therapy, but his general health condition worsened as a result of diabetes mellitus, dehydration and fungal infection onset. Besides the patient suffered from impaired fasting glucose, and glucocorticoid treatment precipitated a pre-diabetes condition. The etiology of diabetes mellitus in our patient under both corticosteroids and immune-checkpoint inhibitors treatment, was, at first, uncertain. In fact, among the autoimmune adverse events typical of immune-checkpoints inhibitors, there is also diabetes mellitus (12). The autoimmune form of origin was however excluded due to the absence of autoimmunity, the pancreatic reserve and the normalization of blood glucose levels following the steroid tapering.
The persistence of polyuria and polydipsia led us to investigate the origin of the polyuria–polydipsia syndrome, confirming the diagnosis of diabetes insipidus following the evaluation of plasma osmolality and urine osmolarity before and after DDVAP.
The diabetes insipidus in our patient could have been mainly due to two causes: the presence of metastases in the pituitary region or the onset of hypophysitis secondary to nivolumab therapy.
A recent observational retrospective study assessed the clinical, biochemical and radiological differences in patients with neoplastic and non-neoplastic pituitary stalk pathology. Statistically significant differences were found for the greater preponderance of diabetes insipidus and hypogonadism in subjects suffering from neoplastic pathology compared to those suffering from non-neoplastic pathology; with regard to radiological images, the features that have reached statistical significance were the thickness of the stalk and the heterogeneity of the contrast enhancement after administration of contrast agent. Specifically, all thickenings greater than 9.1 mm in diameter in the post-contrast coronal section in the upper part of the stalk and greater than 5.6 in the coronal section in the lower part were confirmed as neoplastic with a sensitivity of 100% (13). Our patient had biochemical and radiological characteristics consistent with the coexistence of neurohypophysitis (stalk thickness 6 mm, hyperintensity under the Gadolinium enhancement, and no evidence of neurohypophysis hyperintensity) and pituitary metastasis (roundish formation, at the posterior adenohypophyseal portion, causing focal interruption of the sellar floor). To define the exact etiology of the pituitary pathology, histological confirmation through biopsy sampling would have been necessary; however, because of the patient’s critical health condition, it was not possible to perform. In the absence of histological confirmation, we believe it is likely that both could have played a role in the onset of diabetes insipidus secondary to the pituitary stalk interruption syndrome, as a result of metastatic compression and drug therapy-induced hypophysitis.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Patient consent
Informed consent was obtained from the patient for publication of this report.
Author contribution statement
All the authors have contributed to the writing and editing of this manuscript and the physician responsible for the patient is one of the authors. | METHYLPREDNISOLONE | DrugsGivenReaction | CC BY-NC-ND | 33522491 | 19,107,271 | 2021-01-27 |
What was the outcome of reaction 'Dehydration'? | Diabetes insipidus secondary to nivolumab-induced neurohypophysitis and pituitary metastasis.
A 62-year-old patient with metastatic hypopharyngeal carcinoma underwent treatment with nivolumab, following which he developed symptoms suggestive of diabetes insipidus. Nivolumab was stopped and therapy with methylprednisolone was started. During corticosteroid therapy, the patient presented himself in poor health condition with fungal infection and glycemic decompensation. Methylprednisolone dose was tapered off, leading to the resolution of mycosis and the restoration of glycemic compensation, nevertheless polyuria and polydipsia persisted. Increase in urine osmolarity after desmopressin administration was made diagnosing central diabetes insipidus as a possibility. The neuroradiological data by pituitary MRI scan with gadolinium was compatible with coexistence of metastatic localization and infundibulo-neurohypophysitis secondary to therapy with nivolumab. To define the exact etiology of the pituitary pathology, histological confirmation would have been necessary; however, unfortunately, it was not possible. In the absence of histological confirmation, we believe it is likely that both pathologies coexisted.
A remarkable risk of endocrine immune-related adverse events (irAEs) during therapy with checkpoint inhibitors exsists. In order to ensure maximum efficiency in the recognition and treatment of endocrine iRAes related to immune checkpoint inhibitors, multidisciplinary management of oncological patients is critical. The pituitary syndrome in oncological patients who underwent immunotherapy represents a challenge in the differential diagnosis between pituitary metastasis and drug-induced hypophysitis. This is the first case, described in the literature of diabetes insipidus in a patient suffering from nivolumab-induced infundibulo-neurohypophysitis and anterohypophyseal metastasis.
Background
The introduction of immune checkpoint inhibitors into oncological clinical practice has revolutionized the treatment of various neoplastic diseases. These drugs awaken the anti-tumor immune response by interrupting the inhibitory signal pathways and promote immune-mediated elimination of cancer cells. The targets of these therapies include CTLA-4 (cytotoxic T-lymphocyte associated protein-4), PD1 (programmed cell death protein-1) and PD-L1 (programmed death ligand-1). This mechanism is also the basis of immune-related adverse events (iRAes), due to the inhibition of immune-checkpoints that reinforce normal physiological barriers against autoimmunity (1). The main adverse events affect the skin, the gastrointestinal, musculoskeletal and endocrine systems. The main endocrinological manifestations are represented by thyroid dysfunction and hypophysitis. The involvement of the posterior pituitary, and consequent diabetes insipidus is exceptional, but not impossible (2, 3, 4). Pituitary metastasis is a rare complication of advanced malignancy; however, almost every cancer type can metastasize to the pituitary fossa. Diabetes insipidus is common among patients with pituitary metastasis (5).
Case presentation
We present the case of a 62-year-old patient with metastatic hypopharyngeal carcinoma undergoing treatment with Nivolumab (anti- PD1 MAB), following which he developed central diabetes insipidus. In 2002, the patient, with a history of heavy smoking and in the absence of other comorbidities, received the diagnosis of hypopharyngeal carcinoma and was treated with chemotherapy (platinum and fluorine) and surgery. In 2016, relapse on the lingual body developed, and due to the inoperability of the lesion, chemotherapy with cisplatin, 5-fluorouracil and erbitux was provided. In 2017, PET showed lung disease with massive metastatic adenopathies in almost all mediastinal lymph node stations. It was decided to carry out a re-challenge with platinum with evidence in January 2019 of reduction of lung and lymph node lesions. The CT of May 2019 showed a progression of pathology upon which the oncologist decided to start therapy with vivolumab (240 mg biweekly). After about 5 weeks of treatment (before the fourth cycle of therapy), the patient reported sudden onset of polyuria and polydipsia. The endocrine tests he underwent (Table 1) suggested the presence of hypophysitis as a result of mild hyperprolactinemia (19.8 ng/mL) and hypogonadotropic hypogonadism, in association with symptoms suggestive of diabetes insipidus. Moreover, the routine laboratory investigations (Table 2) revealed dehydration (hypercalcemia, hypernatremia, hyperkalemia) and impaired fasting glucose (blood glucose: 116 mg/dL); glycated hemoglobin (HbA1c) and oral glucose tolerance test (OGTT) were not sought. Considered the onset of a possible hypophysitis, the oncologist stopped nivolumab temporarily and started therapy with methylprednisolone 64 mg/day and requested endocrinological advice. After about 10 days of corticosteroid therapy, the patient was hospitalized in the endocrinology department. He presented in a poor health condition, in a state of dehydration and with a severe fungal infection of the oral cavity. Asthenia persisted, while he did not complain of visual field deficits. The patient reported persistence of polyuria and polydipsia (about 8 L/day), which did not change following the introduction of corticosteroid therapy. Blood chemistry tests showed glycemic decompensation (glucose: 320 mg/dL) with plasma hyperosmolality (303 mOsm/kg) and urine hyposmolarity (158 mmol/L).
Table 1 Laboratory values after 5 weeks of oncological treatment.
Hormone Result Reference values
TSH, µUI/mL 1.00 0.55–4.78
FT3, pg/mL 3.12 2–4.2
FT4, pg/mL 1.25 0.8–1.7
Testosterone, ng/mL 0.5 1.39–9.13
LH, mUI/mL 3.0 1.4–18.1
FSH, mUI/mL 2.7 4.5–9.3
Prolactin, ng/mL 19.8 2.1–17.7
ACTH, µg/dL 19.2 5.27–22.45
Cortisol, pg/mL 20.4 10–60
Table 2 Blood count and biochemistry test after 5 weeks of oncological treatment.
Blood count and biochemistry test Result Reference values
WBC, × 103/μL 11.25 4.3–10.5
RBC, × 106/μL 5.50 4.2–5.8
Hemoglobin, g/dL 16.1 12–17.5
Hematocrit, % 50.5 37–52
MCV, flL 91.8 80–99
MCH, pg 29.3 27–32
MCHC, g/dL 31.9 33–37
RDW, % 15.1 11.5–14.5
Platelets, × 103/μL 205 130–400
Neutrophils, × 103/μL 8.30 1.9–8
Lymphocytes, × 103/μL 1.86 0.9–5.2
Monocytes, × 103/μL 0.88 0.2–1
Eosinophils, × 103/μL 0.15 0–0.8
Basophils, × 103/μL 0.07 0–0.2
Glucose, mg/dL 116 60–100
BUN, mg/dL 9 5–25
Creatinine, mg/dL 0.8 0.6–1.2
Sodium, mEq/L 150 136–146
Potassium, mEq/L 5.3 3.5–5.1
Calcium, mg/dL 11.2 8.8–10.6
Magnesium, mg/dL 2.5 1.8–2.6
Uricemia, mg/dL 4.5 3.5–7.2
Proteins, g/dL 7.6 6.6–8.3
Albumin, g/dL 4.4 3.5–5.2
Total bilirubin, mg/dL 0.5 0.2–1.1
Direct bilirubin, mg/dL 0.1 0.1–0.4
Indirect bilirubin, mg/dL 0.4 0.2–0.8
LDH, U/L 274 0–248
AST, U/L 26 5–45
ALT, U/L 36 5–55
GGT, U/ L 30 10–50
Cholinesterase, U/L 5439 4500–11 400
ALP, U/L 118 30–120
Sideremia, μg/dL 67 70–180
Investigation
Pituitary hormonal function was assessed (Table 3) and frank hypogonadotropic hypogonadism and mild hyperprolactinemia were confirmed. The low TSH value was compatible with concomitant corticosteroid therapy (6). To complete the study of glycemic decompensation, HbA1c (7.7%), C-peptide (0.73 ng/mL, reference value: 0.5–2) and antibodies against glutamic acid decarboxylase (<5 IU/mL) and anti IA2 (<10 IU/mL) were assessed. The autoimmune origin was therefore excluded and diagnosis of metasteroid diabetes mellitus was made. It was treated with insulin therapy. During the hospitalization, methylprednisolone dose was tapered off, leading to the resolution of mycosis (which was also due to antifungal therapy) and the restoration of glycemic compensation with progressive reduction in the dose of insulin, until full discontinuation. Once normalization of blood glucose levels was obtained, the patient reported improvement in symptoms of polyuria and polydipsia, which however persisted albeit to a lesser extent (water balance: IN 4.5 L – OUT 5.5 L). The patient was affected by the polyuria–polydipsia syndrome (water intake > 3 L/day and diuresis > 40–50 mL/kg/day), and it was, therefore, necessary to define the etiology. Because of the technical limitations of the ADH assay (7), and the impossibility of copeptin dosage in our clinical laboratory, we assessed urine osmolarity and plasma osmolality. After just 2 h of fluid restriction, the onset of hypernatremia contraindicated the water deprivation test’s prosecution. Psychogenic polyuria was ruled out due to the presence of low urine osmolarity in association with high plasma osmolality. Afterwards, we decided to evaluate the response to the administration of desmopressin 2 μg s.c. In Table 4 you can see the values of natremia, plasma osmolality and urine osmolarity before and after the administration of the drug. An increase of 146% in urine osmolarity after desmopressin allowed us to rule out nephrogenic diabetes insipidus and has made diagnosing central diabetes insipidus possible (8). Anti-pituitary antibody and anti-rabphilin 3A antibody were not available in our laboratory, therefore they haven’t been investigated.
Table 3 Laboratory values during treatment with corticosteroid, after nivolumab discontinuation.
Hormone/antibody Result Reference values
TSH, µUI/mL 0.147 0.89–1.76
FT4, ng/dL 1.22 0.55–4.78
TGAb, U/mL 17.10 <60
TPOAb, U/mL 38.30 <60
Testosterone, ng/dL <20.0 181–758
LH, mUI/mL 0.4 0.8–7.6
FSH, mUI/mL 0.6 0.7–11.1
Prolactin, ng/mL 18.6 2.5–17.0
GH, ng/mL 0.4 <10
IGF-1, ng/mL 109 43–220
ACTH, pg/mL 6 0–46
Cortisol, µg/dL 20.3 4.3–22.4
Table 4 Plasma osmolality and urine osmolarity before and after desmopressin administration.
Sampling time Natremia (mEq/L) Plasma osmolality (mOsm/Kg) Urine osmolarity (mmol/L) Change in urine (osmolarity)
Before desmopressin
7:00 h 146 300 176 –
Desmopressin 2 µg s.c. injection: 10:00 h
12:30 h 142 294 353 +100%
15:30 h – – 430 +144%
At this point, pituitary MRI scan with gadolinium was performed. The radiological report showed a pituitary stalk substantially in axis, with marked and widespread thickening, up to about 6 mm, associated hyperintensity and contrast enhancement. Neurohypophysis hyperintensity was not displayed. A roundish formation of about 7 mm in diameter, substantially isointense with respect to the remaining glandular parenchyma in pre-contrast T1- and T2-weighted images and tenuously hypointense in post-contrast image, was observed at the posterior adenohypophyseal portion, in the median-paramedian area. The lesion seemed to cause focal interruption of the sellar floor (Fig. 1). In addition to the MRI examination of the pituitary, post-contrast axial DWI and 3D-T1-FFE sequences were acquired on the entire brain with documented presence of multiple contrast medium enhancement lesions located in the supra and sub-tentorial regions and in both cerebellar hemispheres (Fig. 2). The neuroradiological data were therefore compatible both with clinical suspicion of metastatic localization and with the hypothesis of hypophysitis secondary to therapy with nivolumab.
Figure 1 Pre-contrast (A) and postcontrast T1-weighted sagittal (B) and coronal (C) MR image demonstrates a diffuse enlargement of the pituitary stalk. The pituitary gland shows heterogenous enhancement due to a hypotense lesion, causing focal destruction of the sellar floor.
Figure 2 Post-contrast T1-weighted MR image of the brain demonstrates multiple metastatic lesions at the grey-white matter junction in the frontal lobe (A) and in the midbrain, close to the Sylvian aqueduct (B).
Treatment
The patient underwent replacement therapy with DDVAP sublingual tablets 60 μg in divided dose twice daily, with normalization of the water balance (2 L in balance).
Nine days after hospitalization, the patient was discharged with the following diagnosis ‘Partial hypopituitarism (diabetes insipidus and hypogonadism) secondary to probable nivolumab-induced infundibulo-neurohypophysitis and anterohypophyseal metastasis, in a patient suffering from metastatic hypopharyngeal carcinoma; multiple cerebral and cerebellar new on-set metastases and metasteroid diabetes mellitus’. The patient was started on replacement therapy with DDVAP sublingual tablets 60 μg in divided dose twice daily, 2% testosterone gel 4 puffs/day and methylprednisolone dose was tapered off until 4 mg, pending execution of ACTH test to evaluate the possible suppression of the hypothalamic–pituitary–adrenal axis. As the pituitary impairment was well compensated by the replacement therapy, no contraindication was given to the resumption of nivolumab therapy with necessary monitoring of the residual pituitary function.
Outcome and follow-up
The patient was re-evaluated by the oncologist and underwent total body CT scan for disease re- staging. In addition to the already known secondary malignancy in the lung, new-onset adrenal, pancreatic, skeletal metastases and peritoneal carcinosis were found.
Due to poor response to nivolumab therapy and rapid disease progression, treatment was stopped permanently. The patient died about 50 days after hospital discharge.
Discussion
The hypophysitis is an adverse event more characteristic of anti-CTLA4, and only to a lesser extent than anti-PD1. Patients with immune therapy-induced hypophysitis mostly present with multiple hormonal deficits, mainly of thyrotropin (84%), corticotropin (80%) and gonadotropins (76%); the involvement of the posterior pituitary is exceptional (2). So far, there are only two case reports described in the literature about anti PDL1 (3) and anti PD1- related central diabetes insipidus (4). The average time to onset of endocrinological side effects is 9 weeks from the start of treatment (with a range from 5 to 36 weeks). Considering the high incidence of these adverse events following therapy with immune-checkpoint, it is essential to research any clinical signs suggestive of iRAes before each cycle of therapy; when a suggestive symtom is found, it is essential to evaluate hormonal tests to identify endocrinopathy (9). In general, the oncological clinical practice involves the administration of high-dose corticosteroids for most iRAes. As regards specifically the pituitary, a recent consensus has highlighted how the use of high-dose corticosteroids is to be reserved exclusively for cases of adrenal crisis, severe headache and visual field deficit (10). In fact, corticosteroid therapy would be able to resolve the signs of local inflammation, but not the hormonal deficit. In addition, high-dose therapy would be responsible for major complications, some serious enough to require hospitalization (11). To confirm this, our patient had not received any benefit from corticosteroid therapy, but his general health condition worsened as a result of diabetes mellitus, dehydration and fungal infection onset. Besides the patient suffered from impaired fasting glucose, and glucocorticoid treatment precipitated a pre-diabetes condition. The etiology of diabetes mellitus in our patient under both corticosteroids and immune-checkpoint inhibitors treatment, was, at first, uncertain. In fact, among the autoimmune adverse events typical of immune-checkpoints inhibitors, there is also diabetes mellitus (12). The autoimmune form of origin was however excluded due to the absence of autoimmunity, the pancreatic reserve and the normalization of blood glucose levels following the steroid tapering.
The persistence of polyuria and polydipsia led us to investigate the origin of the polyuria–polydipsia syndrome, confirming the diagnosis of diabetes insipidus following the evaluation of plasma osmolality and urine osmolarity before and after DDVAP.
The diabetes insipidus in our patient could have been mainly due to two causes: the presence of metastases in the pituitary region or the onset of hypophysitis secondary to nivolumab therapy.
A recent observational retrospective study assessed the clinical, biochemical and radiological differences in patients with neoplastic and non-neoplastic pituitary stalk pathology. Statistically significant differences were found for the greater preponderance of diabetes insipidus and hypogonadism in subjects suffering from neoplastic pathology compared to those suffering from non-neoplastic pathology; with regard to radiological images, the features that have reached statistical significance were the thickness of the stalk and the heterogeneity of the contrast enhancement after administration of contrast agent. Specifically, all thickenings greater than 9.1 mm in diameter in the post-contrast coronal section in the upper part of the stalk and greater than 5.6 in the coronal section in the lower part were confirmed as neoplastic with a sensitivity of 100% (13). Our patient had biochemical and radiological characteristics consistent with the coexistence of neurohypophysitis (stalk thickness 6 mm, hyperintensity under the Gadolinium enhancement, and no evidence of neurohypophysis hyperintensity) and pituitary metastasis (roundish formation, at the posterior adenohypophyseal portion, causing focal interruption of the sellar floor). To define the exact etiology of the pituitary pathology, histological confirmation through biopsy sampling would have been necessary; however, because of the patient’s critical health condition, it was not possible to perform. In the absence of histological confirmation, we believe it is likely that both could have played a role in the onset of diabetes insipidus secondary to the pituitary stalk interruption syndrome, as a result of metastatic compression and drug therapy-induced hypophysitis.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Patient consent
Informed consent was obtained from the patient for publication of this report.
Author contribution statement
All the authors have contributed to the writing and editing of this manuscript and the physician responsible for the patient is one of the authors. | Recovering | ReactionOutcome | CC BY-NC-ND | 33522491 | 19,074,871 | 2021-01-27 |
What was the outcome of reaction 'Diabetes mellitus'? | Diabetes insipidus secondary to nivolumab-induced neurohypophysitis and pituitary metastasis.
A 62-year-old patient with metastatic hypopharyngeal carcinoma underwent treatment with nivolumab, following which he developed symptoms suggestive of diabetes insipidus. Nivolumab was stopped and therapy with methylprednisolone was started. During corticosteroid therapy, the patient presented himself in poor health condition with fungal infection and glycemic decompensation. Methylprednisolone dose was tapered off, leading to the resolution of mycosis and the restoration of glycemic compensation, nevertheless polyuria and polydipsia persisted. Increase in urine osmolarity after desmopressin administration was made diagnosing central diabetes insipidus as a possibility. The neuroradiological data by pituitary MRI scan with gadolinium was compatible with coexistence of metastatic localization and infundibulo-neurohypophysitis secondary to therapy with nivolumab. To define the exact etiology of the pituitary pathology, histological confirmation would have been necessary; however, unfortunately, it was not possible. In the absence of histological confirmation, we believe it is likely that both pathologies coexisted.
A remarkable risk of endocrine immune-related adverse events (irAEs) during therapy with checkpoint inhibitors exsists. In order to ensure maximum efficiency in the recognition and treatment of endocrine iRAes related to immune checkpoint inhibitors, multidisciplinary management of oncological patients is critical. The pituitary syndrome in oncological patients who underwent immunotherapy represents a challenge in the differential diagnosis between pituitary metastasis and drug-induced hypophysitis. This is the first case, described in the literature of diabetes insipidus in a patient suffering from nivolumab-induced infundibulo-neurohypophysitis and anterohypophyseal metastasis.
Background
The introduction of immune checkpoint inhibitors into oncological clinical practice has revolutionized the treatment of various neoplastic diseases. These drugs awaken the anti-tumor immune response by interrupting the inhibitory signal pathways and promote immune-mediated elimination of cancer cells. The targets of these therapies include CTLA-4 (cytotoxic T-lymphocyte associated protein-4), PD1 (programmed cell death protein-1) and PD-L1 (programmed death ligand-1). This mechanism is also the basis of immune-related adverse events (iRAes), due to the inhibition of immune-checkpoints that reinforce normal physiological barriers against autoimmunity (1). The main adverse events affect the skin, the gastrointestinal, musculoskeletal and endocrine systems. The main endocrinological manifestations are represented by thyroid dysfunction and hypophysitis. The involvement of the posterior pituitary, and consequent diabetes insipidus is exceptional, but not impossible (2, 3, 4). Pituitary metastasis is a rare complication of advanced malignancy; however, almost every cancer type can metastasize to the pituitary fossa. Diabetes insipidus is common among patients with pituitary metastasis (5).
Case presentation
We present the case of a 62-year-old patient with metastatic hypopharyngeal carcinoma undergoing treatment with Nivolumab (anti- PD1 MAB), following which he developed central diabetes insipidus. In 2002, the patient, with a history of heavy smoking and in the absence of other comorbidities, received the diagnosis of hypopharyngeal carcinoma and was treated with chemotherapy (platinum and fluorine) and surgery. In 2016, relapse on the lingual body developed, and due to the inoperability of the lesion, chemotherapy with cisplatin, 5-fluorouracil and erbitux was provided. In 2017, PET showed lung disease with massive metastatic adenopathies in almost all mediastinal lymph node stations. It was decided to carry out a re-challenge with platinum with evidence in January 2019 of reduction of lung and lymph node lesions. The CT of May 2019 showed a progression of pathology upon which the oncologist decided to start therapy with vivolumab (240 mg biweekly). After about 5 weeks of treatment (before the fourth cycle of therapy), the patient reported sudden onset of polyuria and polydipsia. The endocrine tests he underwent (Table 1) suggested the presence of hypophysitis as a result of mild hyperprolactinemia (19.8 ng/mL) and hypogonadotropic hypogonadism, in association with symptoms suggestive of diabetes insipidus. Moreover, the routine laboratory investigations (Table 2) revealed dehydration (hypercalcemia, hypernatremia, hyperkalemia) and impaired fasting glucose (blood glucose: 116 mg/dL); glycated hemoglobin (HbA1c) and oral glucose tolerance test (OGTT) were not sought. Considered the onset of a possible hypophysitis, the oncologist stopped nivolumab temporarily and started therapy with methylprednisolone 64 mg/day and requested endocrinological advice. After about 10 days of corticosteroid therapy, the patient was hospitalized in the endocrinology department. He presented in a poor health condition, in a state of dehydration and with a severe fungal infection of the oral cavity. Asthenia persisted, while he did not complain of visual field deficits. The patient reported persistence of polyuria and polydipsia (about 8 L/day), which did not change following the introduction of corticosteroid therapy. Blood chemistry tests showed glycemic decompensation (glucose: 320 mg/dL) with plasma hyperosmolality (303 mOsm/kg) and urine hyposmolarity (158 mmol/L).
Table 1 Laboratory values after 5 weeks of oncological treatment.
Hormone Result Reference values
TSH, µUI/mL 1.00 0.55–4.78
FT3, pg/mL 3.12 2–4.2
FT4, pg/mL 1.25 0.8–1.7
Testosterone, ng/mL 0.5 1.39–9.13
LH, mUI/mL 3.0 1.4–18.1
FSH, mUI/mL 2.7 4.5–9.3
Prolactin, ng/mL 19.8 2.1–17.7
ACTH, µg/dL 19.2 5.27–22.45
Cortisol, pg/mL 20.4 10–60
Table 2 Blood count and biochemistry test after 5 weeks of oncological treatment.
Blood count and biochemistry test Result Reference values
WBC, × 103/μL 11.25 4.3–10.5
RBC, × 106/μL 5.50 4.2–5.8
Hemoglobin, g/dL 16.1 12–17.5
Hematocrit, % 50.5 37–52
MCV, flL 91.8 80–99
MCH, pg 29.3 27–32
MCHC, g/dL 31.9 33–37
RDW, % 15.1 11.5–14.5
Platelets, × 103/μL 205 130–400
Neutrophils, × 103/μL 8.30 1.9–8
Lymphocytes, × 103/μL 1.86 0.9–5.2
Monocytes, × 103/μL 0.88 0.2–1
Eosinophils, × 103/μL 0.15 0–0.8
Basophils, × 103/μL 0.07 0–0.2
Glucose, mg/dL 116 60–100
BUN, mg/dL 9 5–25
Creatinine, mg/dL 0.8 0.6–1.2
Sodium, mEq/L 150 136–146
Potassium, mEq/L 5.3 3.5–5.1
Calcium, mg/dL 11.2 8.8–10.6
Magnesium, mg/dL 2.5 1.8–2.6
Uricemia, mg/dL 4.5 3.5–7.2
Proteins, g/dL 7.6 6.6–8.3
Albumin, g/dL 4.4 3.5–5.2
Total bilirubin, mg/dL 0.5 0.2–1.1
Direct bilirubin, mg/dL 0.1 0.1–0.4
Indirect bilirubin, mg/dL 0.4 0.2–0.8
LDH, U/L 274 0–248
AST, U/L 26 5–45
ALT, U/L 36 5–55
GGT, U/ L 30 10–50
Cholinesterase, U/L 5439 4500–11 400
ALP, U/L 118 30–120
Sideremia, μg/dL 67 70–180
Investigation
Pituitary hormonal function was assessed (Table 3) and frank hypogonadotropic hypogonadism and mild hyperprolactinemia were confirmed. The low TSH value was compatible with concomitant corticosteroid therapy (6). To complete the study of glycemic decompensation, HbA1c (7.7%), C-peptide (0.73 ng/mL, reference value: 0.5–2) and antibodies against glutamic acid decarboxylase (<5 IU/mL) and anti IA2 (<10 IU/mL) were assessed. The autoimmune origin was therefore excluded and diagnosis of metasteroid diabetes mellitus was made. It was treated with insulin therapy. During the hospitalization, methylprednisolone dose was tapered off, leading to the resolution of mycosis (which was also due to antifungal therapy) and the restoration of glycemic compensation with progressive reduction in the dose of insulin, until full discontinuation. Once normalization of blood glucose levels was obtained, the patient reported improvement in symptoms of polyuria and polydipsia, which however persisted albeit to a lesser extent (water balance: IN 4.5 L – OUT 5.5 L). The patient was affected by the polyuria–polydipsia syndrome (water intake > 3 L/day and diuresis > 40–50 mL/kg/day), and it was, therefore, necessary to define the etiology. Because of the technical limitations of the ADH assay (7), and the impossibility of copeptin dosage in our clinical laboratory, we assessed urine osmolarity and plasma osmolality. After just 2 h of fluid restriction, the onset of hypernatremia contraindicated the water deprivation test’s prosecution. Psychogenic polyuria was ruled out due to the presence of low urine osmolarity in association with high plasma osmolality. Afterwards, we decided to evaluate the response to the administration of desmopressin 2 μg s.c. In Table 4 you can see the values of natremia, plasma osmolality and urine osmolarity before and after the administration of the drug. An increase of 146% in urine osmolarity after desmopressin allowed us to rule out nephrogenic diabetes insipidus and has made diagnosing central diabetes insipidus possible (8). Anti-pituitary antibody and anti-rabphilin 3A antibody were not available in our laboratory, therefore they haven’t been investigated.
Table 3 Laboratory values during treatment with corticosteroid, after nivolumab discontinuation.
Hormone/antibody Result Reference values
TSH, µUI/mL 0.147 0.89–1.76
FT4, ng/dL 1.22 0.55–4.78
TGAb, U/mL 17.10 <60
TPOAb, U/mL 38.30 <60
Testosterone, ng/dL <20.0 181–758
LH, mUI/mL 0.4 0.8–7.6
FSH, mUI/mL 0.6 0.7–11.1
Prolactin, ng/mL 18.6 2.5–17.0
GH, ng/mL 0.4 <10
IGF-1, ng/mL 109 43–220
ACTH, pg/mL 6 0–46
Cortisol, µg/dL 20.3 4.3–22.4
Table 4 Plasma osmolality and urine osmolarity before and after desmopressin administration.
Sampling time Natremia (mEq/L) Plasma osmolality (mOsm/Kg) Urine osmolarity (mmol/L) Change in urine (osmolarity)
Before desmopressin
7:00 h 146 300 176 –
Desmopressin 2 µg s.c. injection: 10:00 h
12:30 h 142 294 353 +100%
15:30 h – – 430 +144%
At this point, pituitary MRI scan with gadolinium was performed. The radiological report showed a pituitary stalk substantially in axis, with marked and widespread thickening, up to about 6 mm, associated hyperintensity and contrast enhancement. Neurohypophysis hyperintensity was not displayed. A roundish formation of about 7 mm in diameter, substantially isointense with respect to the remaining glandular parenchyma in pre-contrast T1- and T2-weighted images and tenuously hypointense in post-contrast image, was observed at the posterior adenohypophyseal portion, in the median-paramedian area. The lesion seemed to cause focal interruption of the sellar floor (Fig. 1). In addition to the MRI examination of the pituitary, post-contrast axial DWI and 3D-T1-FFE sequences were acquired on the entire brain with documented presence of multiple contrast medium enhancement lesions located in the supra and sub-tentorial regions and in both cerebellar hemispheres (Fig. 2). The neuroradiological data were therefore compatible both with clinical suspicion of metastatic localization and with the hypothesis of hypophysitis secondary to therapy with nivolumab.
Figure 1 Pre-contrast (A) and postcontrast T1-weighted sagittal (B) and coronal (C) MR image demonstrates a diffuse enlargement of the pituitary stalk. The pituitary gland shows heterogenous enhancement due to a hypotense lesion, causing focal destruction of the sellar floor.
Figure 2 Post-contrast T1-weighted MR image of the brain demonstrates multiple metastatic lesions at the grey-white matter junction in the frontal lobe (A) and in the midbrain, close to the Sylvian aqueduct (B).
Treatment
The patient underwent replacement therapy with DDVAP sublingual tablets 60 μg in divided dose twice daily, with normalization of the water balance (2 L in balance).
Nine days after hospitalization, the patient was discharged with the following diagnosis ‘Partial hypopituitarism (diabetes insipidus and hypogonadism) secondary to probable nivolumab-induced infundibulo-neurohypophysitis and anterohypophyseal metastasis, in a patient suffering from metastatic hypopharyngeal carcinoma; multiple cerebral and cerebellar new on-set metastases and metasteroid diabetes mellitus’. The patient was started on replacement therapy with DDVAP sublingual tablets 60 μg in divided dose twice daily, 2% testosterone gel 4 puffs/day and methylprednisolone dose was tapered off until 4 mg, pending execution of ACTH test to evaluate the possible suppression of the hypothalamic–pituitary–adrenal axis. As the pituitary impairment was well compensated by the replacement therapy, no contraindication was given to the resumption of nivolumab therapy with necessary monitoring of the residual pituitary function.
Outcome and follow-up
The patient was re-evaluated by the oncologist and underwent total body CT scan for disease re- staging. In addition to the already known secondary malignancy in the lung, new-onset adrenal, pancreatic, skeletal metastases and peritoneal carcinosis were found.
Due to poor response to nivolumab therapy and rapid disease progression, treatment was stopped permanently. The patient died about 50 days after hospital discharge.
Discussion
The hypophysitis is an adverse event more characteristic of anti-CTLA4, and only to a lesser extent than anti-PD1. Patients with immune therapy-induced hypophysitis mostly present with multiple hormonal deficits, mainly of thyrotropin (84%), corticotropin (80%) and gonadotropins (76%); the involvement of the posterior pituitary is exceptional (2). So far, there are only two case reports described in the literature about anti PDL1 (3) and anti PD1- related central diabetes insipidus (4). The average time to onset of endocrinological side effects is 9 weeks from the start of treatment (with a range from 5 to 36 weeks). Considering the high incidence of these adverse events following therapy with immune-checkpoint, it is essential to research any clinical signs suggestive of iRAes before each cycle of therapy; when a suggestive symtom is found, it is essential to evaluate hormonal tests to identify endocrinopathy (9). In general, the oncological clinical practice involves the administration of high-dose corticosteroids for most iRAes. As regards specifically the pituitary, a recent consensus has highlighted how the use of high-dose corticosteroids is to be reserved exclusively for cases of adrenal crisis, severe headache and visual field deficit (10). In fact, corticosteroid therapy would be able to resolve the signs of local inflammation, but not the hormonal deficit. In addition, high-dose therapy would be responsible for major complications, some serious enough to require hospitalization (11). To confirm this, our patient had not received any benefit from corticosteroid therapy, but his general health condition worsened as a result of diabetes mellitus, dehydration and fungal infection onset. Besides the patient suffered from impaired fasting glucose, and glucocorticoid treatment precipitated a pre-diabetes condition. The etiology of diabetes mellitus in our patient under both corticosteroids and immune-checkpoint inhibitors treatment, was, at first, uncertain. In fact, among the autoimmune adverse events typical of immune-checkpoints inhibitors, there is also diabetes mellitus (12). The autoimmune form of origin was however excluded due to the absence of autoimmunity, the pancreatic reserve and the normalization of blood glucose levels following the steroid tapering.
The persistence of polyuria and polydipsia led us to investigate the origin of the polyuria–polydipsia syndrome, confirming the diagnosis of diabetes insipidus following the evaluation of plasma osmolality and urine osmolarity before and after DDVAP.
The diabetes insipidus in our patient could have been mainly due to two causes: the presence of metastases in the pituitary region or the onset of hypophysitis secondary to nivolumab therapy.
A recent observational retrospective study assessed the clinical, biochemical and radiological differences in patients with neoplastic and non-neoplastic pituitary stalk pathology. Statistically significant differences were found for the greater preponderance of diabetes insipidus and hypogonadism in subjects suffering from neoplastic pathology compared to those suffering from non-neoplastic pathology; with regard to radiological images, the features that have reached statistical significance were the thickness of the stalk and the heterogeneity of the contrast enhancement after administration of contrast agent. Specifically, all thickenings greater than 9.1 mm in diameter in the post-contrast coronal section in the upper part of the stalk and greater than 5.6 in the coronal section in the lower part were confirmed as neoplastic with a sensitivity of 100% (13). Our patient had biochemical and radiological characteristics consistent with the coexistence of neurohypophysitis (stalk thickness 6 mm, hyperintensity under the Gadolinium enhancement, and no evidence of neurohypophysis hyperintensity) and pituitary metastasis (roundish formation, at the posterior adenohypophyseal portion, causing focal interruption of the sellar floor). To define the exact etiology of the pituitary pathology, histological confirmation through biopsy sampling would have been necessary; however, because of the patient’s critical health condition, it was not possible to perform. In the absence of histological confirmation, we believe it is likely that both could have played a role in the onset of diabetes insipidus secondary to the pituitary stalk interruption syndrome, as a result of metastatic compression and drug therapy-induced hypophysitis.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Patient consent
Informed consent was obtained from the patient for publication of this report.
Author contribution statement
All the authors have contributed to the writing and editing of this manuscript and the physician responsible for the patient is one of the authors. | Recovering | ReactionOutcome | CC BY-NC-ND | 33522491 | 19,074,871 | 2021-01-27 |
What was the outcome of reaction 'Diabetic metabolic decompensation'? | Diabetes insipidus secondary to nivolumab-induced neurohypophysitis and pituitary metastasis.
A 62-year-old patient with metastatic hypopharyngeal carcinoma underwent treatment with nivolumab, following which he developed symptoms suggestive of diabetes insipidus. Nivolumab was stopped and therapy with methylprednisolone was started. During corticosteroid therapy, the patient presented himself in poor health condition with fungal infection and glycemic decompensation. Methylprednisolone dose was tapered off, leading to the resolution of mycosis and the restoration of glycemic compensation, nevertheless polyuria and polydipsia persisted. Increase in urine osmolarity after desmopressin administration was made diagnosing central diabetes insipidus as a possibility. The neuroradiological data by pituitary MRI scan with gadolinium was compatible with coexistence of metastatic localization and infundibulo-neurohypophysitis secondary to therapy with nivolumab. To define the exact etiology of the pituitary pathology, histological confirmation would have been necessary; however, unfortunately, it was not possible. In the absence of histological confirmation, we believe it is likely that both pathologies coexisted.
A remarkable risk of endocrine immune-related adverse events (irAEs) during therapy with checkpoint inhibitors exsists. In order to ensure maximum efficiency in the recognition and treatment of endocrine iRAes related to immune checkpoint inhibitors, multidisciplinary management of oncological patients is critical. The pituitary syndrome in oncological patients who underwent immunotherapy represents a challenge in the differential diagnosis between pituitary metastasis and drug-induced hypophysitis. This is the first case, described in the literature of diabetes insipidus in a patient suffering from nivolumab-induced infundibulo-neurohypophysitis and anterohypophyseal metastasis.
Background
The introduction of immune checkpoint inhibitors into oncological clinical practice has revolutionized the treatment of various neoplastic diseases. These drugs awaken the anti-tumor immune response by interrupting the inhibitory signal pathways and promote immune-mediated elimination of cancer cells. The targets of these therapies include CTLA-4 (cytotoxic T-lymphocyte associated protein-4), PD1 (programmed cell death protein-1) and PD-L1 (programmed death ligand-1). This mechanism is also the basis of immune-related adverse events (iRAes), due to the inhibition of immune-checkpoints that reinforce normal physiological barriers against autoimmunity (1). The main adverse events affect the skin, the gastrointestinal, musculoskeletal and endocrine systems. The main endocrinological manifestations are represented by thyroid dysfunction and hypophysitis. The involvement of the posterior pituitary, and consequent diabetes insipidus is exceptional, but not impossible (2, 3, 4). Pituitary metastasis is a rare complication of advanced malignancy; however, almost every cancer type can metastasize to the pituitary fossa. Diabetes insipidus is common among patients with pituitary metastasis (5).
Case presentation
We present the case of a 62-year-old patient with metastatic hypopharyngeal carcinoma undergoing treatment with Nivolumab (anti- PD1 MAB), following which he developed central diabetes insipidus. In 2002, the patient, with a history of heavy smoking and in the absence of other comorbidities, received the diagnosis of hypopharyngeal carcinoma and was treated with chemotherapy (platinum and fluorine) and surgery. In 2016, relapse on the lingual body developed, and due to the inoperability of the lesion, chemotherapy with cisplatin, 5-fluorouracil and erbitux was provided. In 2017, PET showed lung disease with massive metastatic adenopathies in almost all mediastinal lymph node stations. It was decided to carry out a re-challenge with platinum with evidence in January 2019 of reduction of lung and lymph node lesions. The CT of May 2019 showed a progression of pathology upon which the oncologist decided to start therapy with vivolumab (240 mg biweekly). After about 5 weeks of treatment (before the fourth cycle of therapy), the patient reported sudden onset of polyuria and polydipsia. The endocrine tests he underwent (Table 1) suggested the presence of hypophysitis as a result of mild hyperprolactinemia (19.8 ng/mL) and hypogonadotropic hypogonadism, in association with symptoms suggestive of diabetes insipidus. Moreover, the routine laboratory investigations (Table 2) revealed dehydration (hypercalcemia, hypernatremia, hyperkalemia) and impaired fasting glucose (blood glucose: 116 mg/dL); glycated hemoglobin (HbA1c) and oral glucose tolerance test (OGTT) were not sought. Considered the onset of a possible hypophysitis, the oncologist stopped nivolumab temporarily and started therapy with methylprednisolone 64 mg/day and requested endocrinological advice. After about 10 days of corticosteroid therapy, the patient was hospitalized in the endocrinology department. He presented in a poor health condition, in a state of dehydration and with a severe fungal infection of the oral cavity. Asthenia persisted, while he did not complain of visual field deficits. The patient reported persistence of polyuria and polydipsia (about 8 L/day), which did not change following the introduction of corticosteroid therapy. Blood chemistry tests showed glycemic decompensation (glucose: 320 mg/dL) with plasma hyperosmolality (303 mOsm/kg) and urine hyposmolarity (158 mmol/L).
Table 1 Laboratory values after 5 weeks of oncological treatment.
Hormone Result Reference values
TSH, µUI/mL 1.00 0.55–4.78
FT3, pg/mL 3.12 2–4.2
FT4, pg/mL 1.25 0.8–1.7
Testosterone, ng/mL 0.5 1.39–9.13
LH, mUI/mL 3.0 1.4–18.1
FSH, mUI/mL 2.7 4.5–9.3
Prolactin, ng/mL 19.8 2.1–17.7
ACTH, µg/dL 19.2 5.27–22.45
Cortisol, pg/mL 20.4 10–60
Table 2 Blood count and biochemistry test after 5 weeks of oncological treatment.
Blood count and biochemistry test Result Reference values
WBC, × 103/μL 11.25 4.3–10.5
RBC, × 106/μL 5.50 4.2–5.8
Hemoglobin, g/dL 16.1 12–17.5
Hematocrit, % 50.5 37–52
MCV, flL 91.8 80–99
MCH, pg 29.3 27–32
MCHC, g/dL 31.9 33–37
RDW, % 15.1 11.5–14.5
Platelets, × 103/μL 205 130–400
Neutrophils, × 103/μL 8.30 1.9–8
Lymphocytes, × 103/μL 1.86 0.9–5.2
Monocytes, × 103/μL 0.88 0.2–1
Eosinophils, × 103/μL 0.15 0–0.8
Basophils, × 103/μL 0.07 0–0.2
Glucose, mg/dL 116 60–100
BUN, mg/dL 9 5–25
Creatinine, mg/dL 0.8 0.6–1.2
Sodium, mEq/L 150 136–146
Potassium, mEq/L 5.3 3.5–5.1
Calcium, mg/dL 11.2 8.8–10.6
Magnesium, mg/dL 2.5 1.8–2.6
Uricemia, mg/dL 4.5 3.5–7.2
Proteins, g/dL 7.6 6.6–8.3
Albumin, g/dL 4.4 3.5–5.2
Total bilirubin, mg/dL 0.5 0.2–1.1
Direct bilirubin, mg/dL 0.1 0.1–0.4
Indirect bilirubin, mg/dL 0.4 0.2–0.8
LDH, U/L 274 0–248
AST, U/L 26 5–45
ALT, U/L 36 5–55
GGT, U/ L 30 10–50
Cholinesterase, U/L 5439 4500–11 400
ALP, U/L 118 30–120
Sideremia, μg/dL 67 70–180
Investigation
Pituitary hormonal function was assessed (Table 3) and frank hypogonadotropic hypogonadism and mild hyperprolactinemia were confirmed. The low TSH value was compatible with concomitant corticosteroid therapy (6). To complete the study of glycemic decompensation, HbA1c (7.7%), C-peptide (0.73 ng/mL, reference value: 0.5–2) and antibodies against glutamic acid decarboxylase (<5 IU/mL) and anti IA2 (<10 IU/mL) were assessed. The autoimmune origin was therefore excluded and diagnosis of metasteroid diabetes mellitus was made. It was treated with insulin therapy. During the hospitalization, methylprednisolone dose was tapered off, leading to the resolution of mycosis (which was also due to antifungal therapy) and the restoration of glycemic compensation with progressive reduction in the dose of insulin, until full discontinuation. Once normalization of blood glucose levels was obtained, the patient reported improvement in symptoms of polyuria and polydipsia, which however persisted albeit to a lesser extent (water balance: IN 4.5 L – OUT 5.5 L). The patient was affected by the polyuria–polydipsia syndrome (water intake > 3 L/day and diuresis > 40–50 mL/kg/day), and it was, therefore, necessary to define the etiology. Because of the technical limitations of the ADH assay (7), and the impossibility of copeptin dosage in our clinical laboratory, we assessed urine osmolarity and plasma osmolality. After just 2 h of fluid restriction, the onset of hypernatremia contraindicated the water deprivation test’s prosecution. Psychogenic polyuria was ruled out due to the presence of low urine osmolarity in association with high plasma osmolality. Afterwards, we decided to evaluate the response to the administration of desmopressin 2 μg s.c. In Table 4 you can see the values of natremia, plasma osmolality and urine osmolarity before and after the administration of the drug. An increase of 146% in urine osmolarity after desmopressin allowed us to rule out nephrogenic diabetes insipidus and has made diagnosing central diabetes insipidus possible (8). Anti-pituitary antibody and anti-rabphilin 3A antibody were not available in our laboratory, therefore they haven’t been investigated.
Table 3 Laboratory values during treatment with corticosteroid, after nivolumab discontinuation.
Hormone/antibody Result Reference values
TSH, µUI/mL 0.147 0.89–1.76
FT4, ng/dL 1.22 0.55–4.78
TGAb, U/mL 17.10 <60
TPOAb, U/mL 38.30 <60
Testosterone, ng/dL <20.0 181–758
LH, mUI/mL 0.4 0.8–7.6
FSH, mUI/mL 0.6 0.7–11.1
Prolactin, ng/mL 18.6 2.5–17.0
GH, ng/mL 0.4 <10
IGF-1, ng/mL 109 43–220
ACTH, pg/mL 6 0–46
Cortisol, µg/dL 20.3 4.3–22.4
Table 4 Plasma osmolality and urine osmolarity before and after desmopressin administration.
Sampling time Natremia (mEq/L) Plasma osmolality (mOsm/Kg) Urine osmolarity (mmol/L) Change in urine (osmolarity)
Before desmopressin
7:00 h 146 300 176 –
Desmopressin 2 µg s.c. injection: 10:00 h
12:30 h 142 294 353 +100%
15:30 h – – 430 +144%
At this point, pituitary MRI scan with gadolinium was performed. The radiological report showed a pituitary stalk substantially in axis, with marked and widespread thickening, up to about 6 mm, associated hyperintensity and contrast enhancement. Neurohypophysis hyperintensity was not displayed. A roundish formation of about 7 mm in diameter, substantially isointense with respect to the remaining glandular parenchyma in pre-contrast T1- and T2-weighted images and tenuously hypointense in post-contrast image, was observed at the posterior adenohypophyseal portion, in the median-paramedian area. The lesion seemed to cause focal interruption of the sellar floor (Fig. 1). In addition to the MRI examination of the pituitary, post-contrast axial DWI and 3D-T1-FFE sequences were acquired on the entire brain with documented presence of multiple contrast medium enhancement lesions located in the supra and sub-tentorial regions and in both cerebellar hemispheres (Fig. 2). The neuroradiological data were therefore compatible both with clinical suspicion of metastatic localization and with the hypothesis of hypophysitis secondary to therapy with nivolumab.
Figure 1 Pre-contrast (A) and postcontrast T1-weighted sagittal (B) and coronal (C) MR image demonstrates a diffuse enlargement of the pituitary stalk. The pituitary gland shows heterogenous enhancement due to a hypotense lesion, causing focal destruction of the sellar floor.
Figure 2 Post-contrast T1-weighted MR image of the brain demonstrates multiple metastatic lesions at the grey-white matter junction in the frontal lobe (A) and in the midbrain, close to the Sylvian aqueduct (B).
Treatment
The patient underwent replacement therapy with DDVAP sublingual tablets 60 μg in divided dose twice daily, with normalization of the water balance (2 L in balance).
Nine days after hospitalization, the patient was discharged with the following diagnosis ‘Partial hypopituitarism (diabetes insipidus and hypogonadism) secondary to probable nivolumab-induced infundibulo-neurohypophysitis and anterohypophyseal metastasis, in a patient suffering from metastatic hypopharyngeal carcinoma; multiple cerebral and cerebellar new on-set metastases and metasteroid diabetes mellitus’. The patient was started on replacement therapy with DDVAP sublingual tablets 60 μg in divided dose twice daily, 2% testosterone gel 4 puffs/day and methylprednisolone dose was tapered off until 4 mg, pending execution of ACTH test to evaluate the possible suppression of the hypothalamic–pituitary–adrenal axis. As the pituitary impairment was well compensated by the replacement therapy, no contraindication was given to the resumption of nivolumab therapy with necessary monitoring of the residual pituitary function.
Outcome and follow-up
The patient was re-evaluated by the oncologist and underwent total body CT scan for disease re- staging. In addition to the already known secondary malignancy in the lung, new-onset adrenal, pancreatic, skeletal metastases and peritoneal carcinosis were found.
Due to poor response to nivolumab therapy and rapid disease progression, treatment was stopped permanently. The patient died about 50 days after hospital discharge.
Discussion
The hypophysitis is an adverse event more characteristic of anti-CTLA4, and only to a lesser extent than anti-PD1. Patients with immune therapy-induced hypophysitis mostly present with multiple hormonal deficits, mainly of thyrotropin (84%), corticotropin (80%) and gonadotropins (76%); the involvement of the posterior pituitary is exceptional (2). So far, there are only two case reports described in the literature about anti PDL1 (3) and anti PD1- related central diabetes insipidus (4). The average time to onset of endocrinological side effects is 9 weeks from the start of treatment (with a range from 5 to 36 weeks). Considering the high incidence of these adverse events following therapy with immune-checkpoint, it is essential to research any clinical signs suggestive of iRAes before each cycle of therapy; when a suggestive symtom is found, it is essential to evaluate hormonal tests to identify endocrinopathy (9). In general, the oncological clinical practice involves the administration of high-dose corticosteroids for most iRAes. As regards specifically the pituitary, a recent consensus has highlighted how the use of high-dose corticosteroids is to be reserved exclusively for cases of adrenal crisis, severe headache and visual field deficit (10). In fact, corticosteroid therapy would be able to resolve the signs of local inflammation, but not the hormonal deficit. In addition, high-dose therapy would be responsible for major complications, some serious enough to require hospitalization (11). To confirm this, our patient had not received any benefit from corticosteroid therapy, but his general health condition worsened as a result of diabetes mellitus, dehydration and fungal infection onset. Besides the patient suffered from impaired fasting glucose, and glucocorticoid treatment precipitated a pre-diabetes condition. The etiology of diabetes mellitus in our patient under both corticosteroids and immune-checkpoint inhibitors treatment, was, at first, uncertain. In fact, among the autoimmune adverse events typical of immune-checkpoints inhibitors, there is also diabetes mellitus (12). The autoimmune form of origin was however excluded due to the absence of autoimmunity, the pancreatic reserve and the normalization of blood glucose levels following the steroid tapering.
The persistence of polyuria and polydipsia led us to investigate the origin of the polyuria–polydipsia syndrome, confirming the diagnosis of diabetes insipidus following the evaluation of plasma osmolality and urine osmolarity before and after DDVAP.
The diabetes insipidus in our patient could have been mainly due to two causes: the presence of metastases in the pituitary region or the onset of hypophysitis secondary to nivolumab therapy.
A recent observational retrospective study assessed the clinical, biochemical and radiological differences in patients with neoplastic and non-neoplastic pituitary stalk pathology. Statistically significant differences were found for the greater preponderance of diabetes insipidus and hypogonadism in subjects suffering from neoplastic pathology compared to those suffering from non-neoplastic pathology; with regard to radiological images, the features that have reached statistical significance were the thickness of the stalk and the heterogeneity of the contrast enhancement after administration of contrast agent. Specifically, all thickenings greater than 9.1 mm in diameter in the post-contrast coronal section in the upper part of the stalk and greater than 5.6 in the coronal section in the lower part were confirmed as neoplastic with a sensitivity of 100% (13). Our patient had biochemical and radiological characteristics consistent with the coexistence of neurohypophysitis (stalk thickness 6 mm, hyperintensity under the Gadolinium enhancement, and no evidence of neurohypophysis hyperintensity) and pituitary metastasis (roundish formation, at the posterior adenohypophyseal portion, causing focal interruption of the sellar floor). To define the exact etiology of the pituitary pathology, histological confirmation through biopsy sampling would have been necessary; however, because of the patient’s critical health condition, it was not possible to perform. In the absence of histological confirmation, we believe it is likely that both could have played a role in the onset of diabetes insipidus secondary to the pituitary stalk interruption syndrome, as a result of metastatic compression and drug therapy-induced hypophysitis.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Patient consent
Informed consent was obtained from the patient for publication of this report.
Author contribution statement
All the authors have contributed to the writing and editing of this manuscript and the physician responsible for the patient is one of the authors. | Recovered | ReactionOutcome | CC BY-NC-ND | 33522491 | 19,107,271 | 2021-01-27 |
What was the outcome of reaction 'Oral fungal infection'? | Diabetes insipidus secondary to nivolumab-induced neurohypophysitis and pituitary metastasis.
A 62-year-old patient with metastatic hypopharyngeal carcinoma underwent treatment with nivolumab, following which he developed symptoms suggestive of diabetes insipidus. Nivolumab was stopped and therapy with methylprednisolone was started. During corticosteroid therapy, the patient presented himself in poor health condition with fungal infection and glycemic decompensation. Methylprednisolone dose was tapered off, leading to the resolution of mycosis and the restoration of glycemic compensation, nevertheless polyuria and polydipsia persisted. Increase in urine osmolarity after desmopressin administration was made diagnosing central diabetes insipidus as a possibility. The neuroradiological data by pituitary MRI scan with gadolinium was compatible with coexistence of metastatic localization and infundibulo-neurohypophysitis secondary to therapy with nivolumab. To define the exact etiology of the pituitary pathology, histological confirmation would have been necessary; however, unfortunately, it was not possible. In the absence of histological confirmation, we believe it is likely that both pathologies coexisted.
A remarkable risk of endocrine immune-related adverse events (irAEs) during therapy with checkpoint inhibitors exsists. In order to ensure maximum efficiency in the recognition and treatment of endocrine iRAes related to immune checkpoint inhibitors, multidisciplinary management of oncological patients is critical. The pituitary syndrome in oncological patients who underwent immunotherapy represents a challenge in the differential diagnosis between pituitary metastasis and drug-induced hypophysitis. This is the first case, described in the literature of diabetes insipidus in a patient suffering from nivolumab-induced infundibulo-neurohypophysitis and anterohypophyseal metastasis.
Background
The introduction of immune checkpoint inhibitors into oncological clinical practice has revolutionized the treatment of various neoplastic diseases. These drugs awaken the anti-tumor immune response by interrupting the inhibitory signal pathways and promote immune-mediated elimination of cancer cells. The targets of these therapies include CTLA-4 (cytotoxic T-lymphocyte associated protein-4), PD1 (programmed cell death protein-1) and PD-L1 (programmed death ligand-1). This mechanism is also the basis of immune-related adverse events (iRAes), due to the inhibition of immune-checkpoints that reinforce normal physiological barriers against autoimmunity (1). The main adverse events affect the skin, the gastrointestinal, musculoskeletal and endocrine systems. The main endocrinological manifestations are represented by thyroid dysfunction and hypophysitis. The involvement of the posterior pituitary, and consequent diabetes insipidus is exceptional, but not impossible (2, 3, 4). Pituitary metastasis is a rare complication of advanced malignancy; however, almost every cancer type can metastasize to the pituitary fossa. Diabetes insipidus is common among patients with pituitary metastasis (5).
Case presentation
We present the case of a 62-year-old patient with metastatic hypopharyngeal carcinoma undergoing treatment with Nivolumab (anti- PD1 MAB), following which he developed central diabetes insipidus. In 2002, the patient, with a history of heavy smoking and in the absence of other comorbidities, received the diagnosis of hypopharyngeal carcinoma and was treated with chemotherapy (platinum and fluorine) and surgery. In 2016, relapse on the lingual body developed, and due to the inoperability of the lesion, chemotherapy with cisplatin, 5-fluorouracil and erbitux was provided. In 2017, PET showed lung disease with massive metastatic adenopathies in almost all mediastinal lymph node stations. It was decided to carry out a re-challenge with platinum with evidence in January 2019 of reduction of lung and lymph node lesions. The CT of May 2019 showed a progression of pathology upon which the oncologist decided to start therapy with vivolumab (240 mg biweekly). After about 5 weeks of treatment (before the fourth cycle of therapy), the patient reported sudden onset of polyuria and polydipsia. The endocrine tests he underwent (Table 1) suggested the presence of hypophysitis as a result of mild hyperprolactinemia (19.8 ng/mL) and hypogonadotropic hypogonadism, in association with symptoms suggestive of diabetes insipidus. Moreover, the routine laboratory investigations (Table 2) revealed dehydration (hypercalcemia, hypernatremia, hyperkalemia) and impaired fasting glucose (blood glucose: 116 mg/dL); glycated hemoglobin (HbA1c) and oral glucose tolerance test (OGTT) were not sought. Considered the onset of a possible hypophysitis, the oncologist stopped nivolumab temporarily and started therapy with methylprednisolone 64 mg/day and requested endocrinological advice. After about 10 days of corticosteroid therapy, the patient was hospitalized in the endocrinology department. He presented in a poor health condition, in a state of dehydration and with a severe fungal infection of the oral cavity. Asthenia persisted, while he did not complain of visual field deficits. The patient reported persistence of polyuria and polydipsia (about 8 L/day), which did not change following the introduction of corticosteroid therapy. Blood chemistry tests showed glycemic decompensation (glucose: 320 mg/dL) with plasma hyperosmolality (303 mOsm/kg) and urine hyposmolarity (158 mmol/L).
Table 1 Laboratory values after 5 weeks of oncological treatment.
Hormone Result Reference values
TSH, µUI/mL 1.00 0.55–4.78
FT3, pg/mL 3.12 2–4.2
FT4, pg/mL 1.25 0.8–1.7
Testosterone, ng/mL 0.5 1.39–9.13
LH, mUI/mL 3.0 1.4–18.1
FSH, mUI/mL 2.7 4.5–9.3
Prolactin, ng/mL 19.8 2.1–17.7
ACTH, µg/dL 19.2 5.27–22.45
Cortisol, pg/mL 20.4 10–60
Table 2 Blood count and biochemistry test after 5 weeks of oncological treatment.
Blood count and biochemistry test Result Reference values
WBC, × 103/μL 11.25 4.3–10.5
RBC, × 106/μL 5.50 4.2–5.8
Hemoglobin, g/dL 16.1 12–17.5
Hematocrit, % 50.5 37–52
MCV, flL 91.8 80–99
MCH, pg 29.3 27–32
MCHC, g/dL 31.9 33–37
RDW, % 15.1 11.5–14.5
Platelets, × 103/μL 205 130–400
Neutrophils, × 103/μL 8.30 1.9–8
Lymphocytes, × 103/μL 1.86 0.9–5.2
Monocytes, × 103/μL 0.88 0.2–1
Eosinophils, × 103/μL 0.15 0–0.8
Basophils, × 103/μL 0.07 0–0.2
Glucose, mg/dL 116 60–100
BUN, mg/dL 9 5–25
Creatinine, mg/dL 0.8 0.6–1.2
Sodium, mEq/L 150 136–146
Potassium, mEq/L 5.3 3.5–5.1
Calcium, mg/dL 11.2 8.8–10.6
Magnesium, mg/dL 2.5 1.8–2.6
Uricemia, mg/dL 4.5 3.5–7.2
Proteins, g/dL 7.6 6.6–8.3
Albumin, g/dL 4.4 3.5–5.2
Total bilirubin, mg/dL 0.5 0.2–1.1
Direct bilirubin, mg/dL 0.1 0.1–0.4
Indirect bilirubin, mg/dL 0.4 0.2–0.8
LDH, U/L 274 0–248
AST, U/L 26 5–45
ALT, U/L 36 5–55
GGT, U/ L 30 10–50
Cholinesterase, U/L 5439 4500–11 400
ALP, U/L 118 30–120
Sideremia, μg/dL 67 70–180
Investigation
Pituitary hormonal function was assessed (Table 3) and frank hypogonadotropic hypogonadism and mild hyperprolactinemia were confirmed. The low TSH value was compatible with concomitant corticosteroid therapy (6). To complete the study of glycemic decompensation, HbA1c (7.7%), C-peptide (0.73 ng/mL, reference value: 0.5–2) and antibodies against glutamic acid decarboxylase (<5 IU/mL) and anti IA2 (<10 IU/mL) were assessed. The autoimmune origin was therefore excluded and diagnosis of metasteroid diabetes mellitus was made. It was treated with insulin therapy. During the hospitalization, methylprednisolone dose was tapered off, leading to the resolution of mycosis (which was also due to antifungal therapy) and the restoration of glycemic compensation with progressive reduction in the dose of insulin, until full discontinuation. Once normalization of blood glucose levels was obtained, the patient reported improvement in symptoms of polyuria and polydipsia, which however persisted albeit to a lesser extent (water balance: IN 4.5 L – OUT 5.5 L). The patient was affected by the polyuria–polydipsia syndrome (water intake > 3 L/day and diuresis > 40–50 mL/kg/day), and it was, therefore, necessary to define the etiology. Because of the technical limitations of the ADH assay (7), and the impossibility of copeptin dosage in our clinical laboratory, we assessed urine osmolarity and plasma osmolality. After just 2 h of fluid restriction, the onset of hypernatremia contraindicated the water deprivation test’s prosecution. Psychogenic polyuria was ruled out due to the presence of low urine osmolarity in association with high plasma osmolality. Afterwards, we decided to evaluate the response to the administration of desmopressin 2 μg s.c. In Table 4 you can see the values of natremia, plasma osmolality and urine osmolarity before and after the administration of the drug. An increase of 146% in urine osmolarity after desmopressin allowed us to rule out nephrogenic diabetes insipidus and has made diagnosing central diabetes insipidus possible (8). Anti-pituitary antibody and anti-rabphilin 3A antibody were not available in our laboratory, therefore they haven’t been investigated.
Table 3 Laboratory values during treatment with corticosteroid, after nivolumab discontinuation.
Hormone/antibody Result Reference values
TSH, µUI/mL 0.147 0.89–1.76
FT4, ng/dL 1.22 0.55–4.78
TGAb, U/mL 17.10 <60
TPOAb, U/mL 38.30 <60
Testosterone, ng/dL <20.0 181–758
LH, mUI/mL 0.4 0.8–7.6
FSH, mUI/mL 0.6 0.7–11.1
Prolactin, ng/mL 18.6 2.5–17.0
GH, ng/mL 0.4 <10
IGF-1, ng/mL 109 43–220
ACTH, pg/mL 6 0–46
Cortisol, µg/dL 20.3 4.3–22.4
Table 4 Plasma osmolality and urine osmolarity before and after desmopressin administration.
Sampling time Natremia (mEq/L) Plasma osmolality (mOsm/Kg) Urine osmolarity (mmol/L) Change in urine (osmolarity)
Before desmopressin
7:00 h 146 300 176 –
Desmopressin 2 µg s.c. injection: 10:00 h
12:30 h 142 294 353 +100%
15:30 h – – 430 +144%
At this point, pituitary MRI scan with gadolinium was performed. The radiological report showed a pituitary stalk substantially in axis, with marked and widespread thickening, up to about 6 mm, associated hyperintensity and contrast enhancement. Neurohypophysis hyperintensity was not displayed. A roundish formation of about 7 mm in diameter, substantially isointense with respect to the remaining glandular parenchyma in pre-contrast T1- and T2-weighted images and tenuously hypointense in post-contrast image, was observed at the posterior adenohypophyseal portion, in the median-paramedian area. The lesion seemed to cause focal interruption of the sellar floor (Fig. 1). In addition to the MRI examination of the pituitary, post-contrast axial DWI and 3D-T1-FFE sequences were acquired on the entire brain with documented presence of multiple contrast medium enhancement lesions located in the supra and sub-tentorial regions and in both cerebellar hemispheres (Fig. 2). The neuroradiological data were therefore compatible both with clinical suspicion of metastatic localization and with the hypothesis of hypophysitis secondary to therapy with nivolumab.
Figure 1 Pre-contrast (A) and postcontrast T1-weighted sagittal (B) and coronal (C) MR image demonstrates a diffuse enlargement of the pituitary stalk. The pituitary gland shows heterogenous enhancement due to a hypotense lesion, causing focal destruction of the sellar floor.
Figure 2 Post-contrast T1-weighted MR image of the brain demonstrates multiple metastatic lesions at the grey-white matter junction in the frontal lobe (A) and in the midbrain, close to the Sylvian aqueduct (B).
Treatment
The patient underwent replacement therapy with DDVAP sublingual tablets 60 μg in divided dose twice daily, with normalization of the water balance (2 L in balance).
Nine days after hospitalization, the patient was discharged with the following diagnosis ‘Partial hypopituitarism (diabetes insipidus and hypogonadism) secondary to probable nivolumab-induced infundibulo-neurohypophysitis and anterohypophyseal metastasis, in a patient suffering from metastatic hypopharyngeal carcinoma; multiple cerebral and cerebellar new on-set metastases and metasteroid diabetes mellitus’. The patient was started on replacement therapy with DDVAP sublingual tablets 60 μg in divided dose twice daily, 2% testosterone gel 4 puffs/day and methylprednisolone dose was tapered off until 4 mg, pending execution of ACTH test to evaluate the possible suppression of the hypothalamic–pituitary–adrenal axis. As the pituitary impairment was well compensated by the replacement therapy, no contraindication was given to the resumption of nivolumab therapy with necessary monitoring of the residual pituitary function.
Outcome and follow-up
The patient was re-evaluated by the oncologist and underwent total body CT scan for disease re- staging. In addition to the already known secondary malignancy in the lung, new-onset adrenal, pancreatic, skeletal metastases and peritoneal carcinosis were found.
Due to poor response to nivolumab therapy and rapid disease progression, treatment was stopped permanently. The patient died about 50 days after hospital discharge.
Discussion
The hypophysitis is an adverse event more characteristic of anti-CTLA4, and only to a lesser extent than anti-PD1. Patients with immune therapy-induced hypophysitis mostly present with multiple hormonal deficits, mainly of thyrotropin (84%), corticotropin (80%) and gonadotropins (76%); the involvement of the posterior pituitary is exceptional (2). So far, there are only two case reports described in the literature about anti PDL1 (3) and anti PD1- related central diabetes insipidus (4). The average time to onset of endocrinological side effects is 9 weeks from the start of treatment (with a range from 5 to 36 weeks). Considering the high incidence of these adverse events following therapy with immune-checkpoint, it is essential to research any clinical signs suggestive of iRAes before each cycle of therapy; when a suggestive symtom is found, it is essential to evaluate hormonal tests to identify endocrinopathy (9). In general, the oncological clinical practice involves the administration of high-dose corticosteroids for most iRAes. As regards specifically the pituitary, a recent consensus has highlighted how the use of high-dose corticosteroids is to be reserved exclusively for cases of adrenal crisis, severe headache and visual field deficit (10). In fact, corticosteroid therapy would be able to resolve the signs of local inflammation, but not the hormonal deficit. In addition, high-dose therapy would be responsible for major complications, some serious enough to require hospitalization (11). To confirm this, our patient had not received any benefit from corticosteroid therapy, but his general health condition worsened as a result of diabetes mellitus, dehydration and fungal infection onset. Besides the patient suffered from impaired fasting glucose, and glucocorticoid treatment precipitated a pre-diabetes condition. The etiology of diabetes mellitus in our patient under both corticosteroids and immune-checkpoint inhibitors treatment, was, at first, uncertain. In fact, among the autoimmune adverse events typical of immune-checkpoints inhibitors, there is also diabetes mellitus (12). The autoimmune form of origin was however excluded due to the absence of autoimmunity, the pancreatic reserve and the normalization of blood glucose levels following the steroid tapering.
The persistence of polyuria and polydipsia led us to investigate the origin of the polyuria–polydipsia syndrome, confirming the diagnosis of diabetes insipidus following the evaluation of plasma osmolality and urine osmolarity before and after DDVAP.
The diabetes insipidus in our patient could have been mainly due to two causes: the presence of metastases in the pituitary region or the onset of hypophysitis secondary to nivolumab therapy.
A recent observational retrospective study assessed the clinical, biochemical and radiological differences in patients with neoplastic and non-neoplastic pituitary stalk pathology. Statistically significant differences were found for the greater preponderance of diabetes insipidus and hypogonadism in subjects suffering from neoplastic pathology compared to those suffering from non-neoplastic pathology; with regard to radiological images, the features that have reached statistical significance were the thickness of the stalk and the heterogeneity of the contrast enhancement after administration of contrast agent. Specifically, all thickenings greater than 9.1 mm in diameter in the post-contrast coronal section in the upper part of the stalk and greater than 5.6 in the coronal section in the lower part were confirmed as neoplastic with a sensitivity of 100% (13). Our patient had biochemical and radiological characteristics consistent with the coexistence of neurohypophysitis (stalk thickness 6 mm, hyperintensity under the Gadolinium enhancement, and no evidence of neurohypophysis hyperintensity) and pituitary metastasis (roundish formation, at the posterior adenohypophyseal portion, causing focal interruption of the sellar floor). To define the exact etiology of the pituitary pathology, histological confirmation through biopsy sampling would have been necessary; however, because of the patient’s critical health condition, it was not possible to perform. In the absence of histological confirmation, we believe it is likely that both could have played a role in the onset of diabetes insipidus secondary to the pituitary stalk interruption syndrome, as a result of metastatic compression and drug therapy-induced hypophysitis.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Patient consent
Informed consent was obtained from the patient for publication of this report.
Author contribution statement
All the authors have contributed to the writing and editing of this manuscript and the physician responsible for the patient is one of the authors. | Recovered | ReactionOutcome | CC BY-NC-ND | 33522491 | 19,074,871 | 2021-01-27 |
What was the outcome of reaction 'Steroid diabetes'? | Diabetes insipidus secondary to nivolumab-induced neurohypophysitis and pituitary metastasis.
A 62-year-old patient with metastatic hypopharyngeal carcinoma underwent treatment with nivolumab, following which he developed symptoms suggestive of diabetes insipidus. Nivolumab was stopped and therapy with methylprednisolone was started. During corticosteroid therapy, the patient presented himself in poor health condition with fungal infection and glycemic decompensation. Methylprednisolone dose was tapered off, leading to the resolution of mycosis and the restoration of glycemic compensation, nevertheless polyuria and polydipsia persisted. Increase in urine osmolarity after desmopressin administration was made diagnosing central diabetes insipidus as a possibility. The neuroradiological data by pituitary MRI scan with gadolinium was compatible with coexistence of metastatic localization and infundibulo-neurohypophysitis secondary to therapy with nivolumab. To define the exact etiology of the pituitary pathology, histological confirmation would have been necessary; however, unfortunately, it was not possible. In the absence of histological confirmation, we believe it is likely that both pathologies coexisted.
A remarkable risk of endocrine immune-related adverse events (irAEs) during therapy with checkpoint inhibitors exsists. In order to ensure maximum efficiency in the recognition and treatment of endocrine iRAes related to immune checkpoint inhibitors, multidisciplinary management of oncological patients is critical. The pituitary syndrome in oncological patients who underwent immunotherapy represents a challenge in the differential diagnosis between pituitary metastasis and drug-induced hypophysitis. This is the first case, described in the literature of diabetes insipidus in a patient suffering from nivolumab-induced infundibulo-neurohypophysitis and anterohypophyseal metastasis.
Background
The introduction of immune checkpoint inhibitors into oncological clinical practice has revolutionized the treatment of various neoplastic diseases. These drugs awaken the anti-tumor immune response by interrupting the inhibitory signal pathways and promote immune-mediated elimination of cancer cells. The targets of these therapies include CTLA-4 (cytotoxic T-lymphocyte associated protein-4), PD1 (programmed cell death protein-1) and PD-L1 (programmed death ligand-1). This mechanism is also the basis of immune-related adverse events (iRAes), due to the inhibition of immune-checkpoints that reinforce normal physiological barriers against autoimmunity (1). The main adverse events affect the skin, the gastrointestinal, musculoskeletal and endocrine systems. The main endocrinological manifestations are represented by thyroid dysfunction and hypophysitis. The involvement of the posterior pituitary, and consequent diabetes insipidus is exceptional, but not impossible (2, 3, 4). Pituitary metastasis is a rare complication of advanced malignancy; however, almost every cancer type can metastasize to the pituitary fossa. Diabetes insipidus is common among patients with pituitary metastasis (5).
Case presentation
We present the case of a 62-year-old patient with metastatic hypopharyngeal carcinoma undergoing treatment with Nivolumab (anti- PD1 MAB), following which he developed central diabetes insipidus. In 2002, the patient, with a history of heavy smoking and in the absence of other comorbidities, received the diagnosis of hypopharyngeal carcinoma and was treated with chemotherapy (platinum and fluorine) and surgery. In 2016, relapse on the lingual body developed, and due to the inoperability of the lesion, chemotherapy with cisplatin, 5-fluorouracil and erbitux was provided. In 2017, PET showed lung disease with massive metastatic adenopathies in almost all mediastinal lymph node stations. It was decided to carry out a re-challenge with platinum with evidence in January 2019 of reduction of lung and lymph node lesions. The CT of May 2019 showed a progression of pathology upon which the oncologist decided to start therapy with vivolumab (240 mg biweekly). After about 5 weeks of treatment (before the fourth cycle of therapy), the patient reported sudden onset of polyuria and polydipsia. The endocrine tests he underwent (Table 1) suggested the presence of hypophysitis as a result of mild hyperprolactinemia (19.8 ng/mL) and hypogonadotropic hypogonadism, in association with symptoms suggestive of diabetes insipidus. Moreover, the routine laboratory investigations (Table 2) revealed dehydration (hypercalcemia, hypernatremia, hyperkalemia) and impaired fasting glucose (blood glucose: 116 mg/dL); glycated hemoglobin (HbA1c) and oral glucose tolerance test (OGTT) were not sought. Considered the onset of a possible hypophysitis, the oncologist stopped nivolumab temporarily and started therapy with methylprednisolone 64 mg/day and requested endocrinological advice. After about 10 days of corticosteroid therapy, the patient was hospitalized in the endocrinology department. He presented in a poor health condition, in a state of dehydration and with a severe fungal infection of the oral cavity. Asthenia persisted, while he did not complain of visual field deficits. The patient reported persistence of polyuria and polydipsia (about 8 L/day), which did not change following the introduction of corticosteroid therapy. Blood chemistry tests showed glycemic decompensation (glucose: 320 mg/dL) with plasma hyperosmolality (303 mOsm/kg) and urine hyposmolarity (158 mmol/L).
Table 1 Laboratory values after 5 weeks of oncological treatment.
Hormone Result Reference values
TSH, µUI/mL 1.00 0.55–4.78
FT3, pg/mL 3.12 2–4.2
FT4, pg/mL 1.25 0.8–1.7
Testosterone, ng/mL 0.5 1.39–9.13
LH, mUI/mL 3.0 1.4–18.1
FSH, mUI/mL 2.7 4.5–9.3
Prolactin, ng/mL 19.8 2.1–17.7
ACTH, µg/dL 19.2 5.27–22.45
Cortisol, pg/mL 20.4 10–60
Table 2 Blood count and biochemistry test after 5 weeks of oncological treatment.
Blood count and biochemistry test Result Reference values
WBC, × 103/μL 11.25 4.3–10.5
RBC, × 106/μL 5.50 4.2–5.8
Hemoglobin, g/dL 16.1 12–17.5
Hematocrit, % 50.5 37–52
MCV, flL 91.8 80–99
MCH, pg 29.3 27–32
MCHC, g/dL 31.9 33–37
RDW, % 15.1 11.5–14.5
Platelets, × 103/μL 205 130–400
Neutrophils, × 103/μL 8.30 1.9–8
Lymphocytes, × 103/μL 1.86 0.9–5.2
Monocytes, × 103/μL 0.88 0.2–1
Eosinophils, × 103/μL 0.15 0–0.8
Basophils, × 103/μL 0.07 0–0.2
Glucose, mg/dL 116 60–100
BUN, mg/dL 9 5–25
Creatinine, mg/dL 0.8 0.6–1.2
Sodium, mEq/L 150 136–146
Potassium, mEq/L 5.3 3.5–5.1
Calcium, mg/dL 11.2 8.8–10.6
Magnesium, mg/dL 2.5 1.8–2.6
Uricemia, mg/dL 4.5 3.5–7.2
Proteins, g/dL 7.6 6.6–8.3
Albumin, g/dL 4.4 3.5–5.2
Total bilirubin, mg/dL 0.5 0.2–1.1
Direct bilirubin, mg/dL 0.1 0.1–0.4
Indirect bilirubin, mg/dL 0.4 0.2–0.8
LDH, U/L 274 0–248
AST, U/L 26 5–45
ALT, U/L 36 5–55
GGT, U/ L 30 10–50
Cholinesterase, U/L 5439 4500–11 400
ALP, U/L 118 30–120
Sideremia, μg/dL 67 70–180
Investigation
Pituitary hormonal function was assessed (Table 3) and frank hypogonadotropic hypogonadism and mild hyperprolactinemia were confirmed. The low TSH value was compatible with concomitant corticosteroid therapy (6). To complete the study of glycemic decompensation, HbA1c (7.7%), C-peptide (0.73 ng/mL, reference value: 0.5–2) and antibodies against glutamic acid decarboxylase (<5 IU/mL) and anti IA2 (<10 IU/mL) were assessed. The autoimmune origin was therefore excluded and diagnosis of metasteroid diabetes mellitus was made. It was treated with insulin therapy. During the hospitalization, methylprednisolone dose was tapered off, leading to the resolution of mycosis (which was also due to antifungal therapy) and the restoration of glycemic compensation with progressive reduction in the dose of insulin, until full discontinuation. Once normalization of blood glucose levels was obtained, the patient reported improvement in symptoms of polyuria and polydipsia, which however persisted albeit to a lesser extent (water balance: IN 4.5 L – OUT 5.5 L). The patient was affected by the polyuria–polydipsia syndrome (water intake > 3 L/day and diuresis > 40–50 mL/kg/day), and it was, therefore, necessary to define the etiology. Because of the technical limitations of the ADH assay (7), and the impossibility of copeptin dosage in our clinical laboratory, we assessed urine osmolarity and plasma osmolality. After just 2 h of fluid restriction, the onset of hypernatremia contraindicated the water deprivation test’s prosecution. Psychogenic polyuria was ruled out due to the presence of low urine osmolarity in association with high plasma osmolality. Afterwards, we decided to evaluate the response to the administration of desmopressin 2 μg s.c. In Table 4 you can see the values of natremia, plasma osmolality and urine osmolarity before and after the administration of the drug. An increase of 146% in urine osmolarity after desmopressin allowed us to rule out nephrogenic diabetes insipidus and has made diagnosing central diabetes insipidus possible (8). Anti-pituitary antibody and anti-rabphilin 3A antibody were not available in our laboratory, therefore they haven’t been investigated.
Table 3 Laboratory values during treatment with corticosteroid, after nivolumab discontinuation.
Hormone/antibody Result Reference values
TSH, µUI/mL 0.147 0.89–1.76
FT4, ng/dL 1.22 0.55–4.78
TGAb, U/mL 17.10 <60
TPOAb, U/mL 38.30 <60
Testosterone, ng/dL <20.0 181–758
LH, mUI/mL 0.4 0.8–7.6
FSH, mUI/mL 0.6 0.7–11.1
Prolactin, ng/mL 18.6 2.5–17.0
GH, ng/mL 0.4 <10
IGF-1, ng/mL 109 43–220
ACTH, pg/mL 6 0–46
Cortisol, µg/dL 20.3 4.3–22.4
Table 4 Plasma osmolality and urine osmolarity before and after desmopressin administration.
Sampling time Natremia (mEq/L) Plasma osmolality (mOsm/Kg) Urine osmolarity (mmol/L) Change in urine (osmolarity)
Before desmopressin
7:00 h 146 300 176 –
Desmopressin 2 µg s.c. injection: 10:00 h
12:30 h 142 294 353 +100%
15:30 h – – 430 +144%
At this point, pituitary MRI scan with gadolinium was performed. The radiological report showed a pituitary stalk substantially in axis, with marked and widespread thickening, up to about 6 mm, associated hyperintensity and contrast enhancement. Neurohypophysis hyperintensity was not displayed. A roundish formation of about 7 mm in diameter, substantially isointense with respect to the remaining glandular parenchyma in pre-contrast T1- and T2-weighted images and tenuously hypointense in post-contrast image, was observed at the posterior adenohypophyseal portion, in the median-paramedian area. The lesion seemed to cause focal interruption of the sellar floor (Fig. 1). In addition to the MRI examination of the pituitary, post-contrast axial DWI and 3D-T1-FFE sequences were acquired on the entire brain with documented presence of multiple contrast medium enhancement lesions located in the supra and sub-tentorial regions and in both cerebellar hemispheres (Fig. 2). The neuroradiological data were therefore compatible both with clinical suspicion of metastatic localization and with the hypothesis of hypophysitis secondary to therapy with nivolumab.
Figure 1 Pre-contrast (A) and postcontrast T1-weighted sagittal (B) and coronal (C) MR image demonstrates a diffuse enlargement of the pituitary stalk. The pituitary gland shows heterogenous enhancement due to a hypotense lesion, causing focal destruction of the sellar floor.
Figure 2 Post-contrast T1-weighted MR image of the brain demonstrates multiple metastatic lesions at the grey-white matter junction in the frontal lobe (A) and in the midbrain, close to the Sylvian aqueduct (B).
Treatment
The patient underwent replacement therapy with DDVAP sublingual tablets 60 μg in divided dose twice daily, with normalization of the water balance (2 L in balance).
Nine days after hospitalization, the patient was discharged with the following diagnosis ‘Partial hypopituitarism (diabetes insipidus and hypogonadism) secondary to probable nivolumab-induced infundibulo-neurohypophysitis and anterohypophyseal metastasis, in a patient suffering from metastatic hypopharyngeal carcinoma; multiple cerebral and cerebellar new on-set metastases and metasteroid diabetes mellitus’. The patient was started on replacement therapy with DDVAP sublingual tablets 60 μg in divided dose twice daily, 2% testosterone gel 4 puffs/day and methylprednisolone dose was tapered off until 4 mg, pending execution of ACTH test to evaluate the possible suppression of the hypothalamic–pituitary–adrenal axis. As the pituitary impairment was well compensated by the replacement therapy, no contraindication was given to the resumption of nivolumab therapy with necessary monitoring of the residual pituitary function.
Outcome and follow-up
The patient was re-evaluated by the oncologist and underwent total body CT scan for disease re- staging. In addition to the already known secondary malignancy in the lung, new-onset adrenal, pancreatic, skeletal metastases and peritoneal carcinosis were found.
Due to poor response to nivolumab therapy and rapid disease progression, treatment was stopped permanently. The patient died about 50 days after hospital discharge.
Discussion
The hypophysitis is an adverse event more characteristic of anti-CTLA4, and only to a lesser extent than anti-PD1. Patients with immune therapy-induced hypophysitis mostly present with multiple hormonal deficits, mainly of thyrotropin (84%), corticotropin (80%) and gonadotropins (76%); the involvement of the posterior pituitary is exceptional (2). So far, there are only two case reports described in the literature about anti PDL1 (3) and anti PD1- related central diabetes insipidus (4). The average time to onset of endocrinological side effects is 9 weeks from the start of treatment (with a range from 5 to 36 weeks). Considering the high incidence of these adverse events following therapy with immune-checkpoint, it is essential to research any clinical signs suggestive of iRAes before each cycle of therapy; when a suggestive symtom is found, it is essential to evaluate hormonal tests to identify endocrinopathy (9). In general, the oncological clinical practice involves the administration of high-dose corticosteroids for most iRAes. As regards specifically the pituitary, a recent consensus has highlighted how the use of high-dose corticosteroids is to be reserved exclusively for cases of adrenal crisis, severe headache and visual field deficit (10). In fact, corticosteroid therapy would be able to resolve the signs of local inflammation, but not the hormonal deficit. In addition, high-dose therapy would be responsible for major complications, some serious enough to require hospitalization (11). To confirm this, our patient had not received any benefit from corticosteroid therapy, but his general health condition worsened as a result of diabetes mellitus, dehydration and fungal infection onset. Besides the patient suffered from impaired fasting glucose, and glucocorticoid treatment precipitated a pre-diabetes condition. The etiology of diabetes mellitus in our patient under both corticosteroids and immune-checkpoint inhibitors treatment, was, at first, uncertain. In fact, among the autoimmune adverse events typical of immune-checkpoints inhibitors, there is also diabetes mellitus (12). The autoimmune form of origin was however excluded due to the absence of autoimmunity, the pancreatic reserve and the normalization of blood glucose levels following the steroid tapering.
The persistence of polyuria and polydipsia led us to investigate the origin of the polyuria–polydipsia syndrome, confirming the diagnosis of diabetes insipidus following the evaluation of plasma osmolality and urine osmolarity before and after DDVAP.
The diabetes insipidus in our patient could have been mainly due to two causes: the presence of metastases in the pituitary region or the onset of hypophysitis secondary to nivolumab therapy.
A recent observational retrospective study assessed the clinical, biochemical and radiological differences in patients with neoplastic and non-neoplastic pituitary stalk pathology. Statistically significant differences were found for the greater preponderance of diabetes insipidus and hypogonadism in subjects suffering from neoplastic pathology compared to those suffering from non-neoplastic pathology; with regard to radiological images, the features that have reached statistical significance were the thickness of the stalk and the heterogeneity of the contrast enhancement after administration of contrast agent. Specifically, all thickenings greater than 9.1 mm in diameter in the post-contrast coronal section in the upper part of the stalk and greater than 5.6 in the coronal section in the lower part were confirmed as neoplastic with a sensitivity of 100% (13). Our patient had biochemical and radiological characteristics consistent with the coexistence of neurohypophysitis (stalk thickness 6 mm, hyperintensity under the Gadolinium enhancement, and no evidence of neurohypophysis hyperintensity) and pituitary metastasis (roundish formation, at the posterior adenohypophyseal portion, causing focal interruption of the sellar floor). To define the exact etiology of the pituitary pathology, histological confirmation through biopsy sampling would have been necessary; however, because of the patient’s critical health condition, it was not possible to perform. In the absence of histological confirmation, we believe it is likely that both could have played a role in the onset of diabetes insipidus secondary to the pituitary stalk interruption syndrome, as a result of metastatic compression and drug therapy-induced hypophysitis.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Patient consent
Informed consent was obtained from the patient for publication of this report.
Author contribution statement
All the authors have contributed to the writing and editing of this manuscript and the physician responsible for the patient is one of the authors. | Recovered | ReactionOutcome | CC BY-NC-ND | 33522491 | 19,107,271 | 2021-01-27 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Diabetes mellitus inadequate control'. | New-onset diabetes after kidney transplantation revealing HNF1B-associated disease.
Molecular alterations of the transcription factor hepatocyte nuclear factor 1B (HNF1B) are associated with systemic disease, with kidney disease and maturity-onset diabetes of the young (MODY) as the most characteristic manifestations. Other features comprise pancreatic exocrine insufficiency, liver and biliary anomalies, and genital tract malformations. HNF1B-associated disease is clinically heterogeneous, and therefore the diagnosis is challenging. The authors describe the case of a 19-year-old man with new-onset diabetes after kidney transplantation (NODAT). The kidney disease presented during fetal life as bilateral hyperechogenic kidneys. Renal function progressively deteriorated during childhood, and at the age of 19, the patient was submitted to a living-kidney transplant. Two weeks after transplant, NODAT developed. Given the young age and normal body weight, NODAT was unexpected, and the possibility of HNF1B-associated disease was considered. Screening for mutations in HNF1B was undertaken, and a known mutation was found. As this case highlights, HNF1B-associated disease should be considered when NODAT unexpectedly develops in young kidney transplant recipients with a suggestive renal disease.
HNF1B anomalies are associated with systemic disease, including kidney disease, diabetes mellitus, pancreatic exocrine insufficiency, liver test abnormalities and genital tract malformations. Phenotype is variable and there are no pathognomonic manifestations, but kidney disease appears to be the most common feature and diabetes the most frequent extra-renal phenotype. Spontaneous gene alterations are common, and the lack of family history should not exclude the diagnosis. HNF1B defects should be considered when NODAT develops in a young adult kidney transplant recipient with a suggestive kidney disease and without extensive risk factors for diabetes. The most appropriate treatment for HNF1B-associated diabetes is not established, but immunosuppressive therapy superimposed on a beta-cell dysfunction seems to determine the need for insulin therapy after a variable period. Immunosupressive regimens free of calcineurin inhibitors should be considered in patients with HNF1B-associated disease to minimize the risk of developing NODAT.
Background
Since the first description of an HNF1B mutation associated with early-onset diabetes in 1997, the knowledge of HNF1B genetic changes has evolved significantly, and it is currently known that HNF1B anomalies are associated with a systemic disease with marked phenotypic variability (1). The diagnosis of HNF1B-associated disease is challenging, and many cases likely remain undetected or misdiagnosed. The authors describe the case of a young male with a previously unrecognized HNF1B mutation that developed NODAT after kidney transplantation, which triggered the diagnosis of HNF1B-associated disease.
Case presentation
A 19-year-old man was referred to our clinic because of new-onset diabetes after kidney transplantation (NODAT). Two weeks after transplantation, routine blood analysis revealed marked hyperglycemia (up to 17.2 mmol/L). He denied catabolic symptoms, and there was no evidence of ketoacidosis. Through childhood, blood glucose levels were normal, with fasting blood glucose levels ranging from 4.2 to 5.2 mmol/L, with no trend of deterioration over time. His body weight was 55 kg and BMI 21.5 kg/m2. Kidney disease was suspected on a routine fetal ultrasonographic scan (US) performed at 20 weeks’ gestation, revealing bilateral hyperechogenic kidneys. After birth, the US demonstrated hyperechogenic kidneys with small cysts, and plasma creatinine was abnormally elevated. The patient was the first child of non-consanguineous and healthy parents, which pointed to autosomal recessive polycystic kidney disease (ARPKD). Thereafter, renal function progressively deteriorated. By the age of 18, plasma creatinine level was 433.2 μmol/L (corresponding to a glomerular filtrate rate (GFR) of 15.9 mL/min/1.73 m2). One year later, the patient received a living kidney transplant from his 52-year-old father. There was no morphological abnormality on the father’s kidney, and his renal function was normal. The procedure was complicated by partial graft necrosis. At hospital discharge, plasma creatinine level was 185.6 μmol/L (GFR: 44.3 mL/min/1.73 m2). At that time, the immunosuppressive regimen comprised tacrolimus 15 mg/day, mycophenolate mofetil 2000 mg/day, and prednisolone 15 mg/day.
Investigation
Given the patient’s young age and normal body weight, and the absence of other major risk factors, the development of NODAT was unexpected. A history of diabetes was noted in the patient’s maternal grandmother and uncle, with no other known relevant family history, including kidney disease (Fig. 1). Fasting C-peptide was 1.3 nmol/L (normal range: 0.4 – 1.5 nmol/L). Islet autoantibodies, including GADA, ICA, IA-2A, and ZnT8A, were all negative. US pancreatic evaluation was normal. The association of diabetes with such kidney morphological abnormalities raised the possibility of maturity-onset diabetes of the young (MODY) type 5 and hepatocyte nuclear factor 1B (HNF1B) gene defects. Screening for mutations in the HNF1B gene was undertaken and a known missense heterozygous mutation (p.S148L, c.443 C>T) in exon 2 was found. So far, it was not possible to perform genetic testing on any other family member, but the family was referred for genetic counseling. Regarding other manifestations, the patient had no complaints suggestive of exocrine dysfunction, liver enzymes were normal over the years (both alanine aminotransferase and aspartate aminotransferase persistently below the upper limit of the normal range, both before and after transplantation), and there was no clinical evidence of genital tract malformations.
Figure 1 Family pedigree of the patient showing the affected patient (proband) and other affected family members with diabetes.
Treatment
Insulin therapy was started with a long-acting analog (0.16 UI/kg/day). The insulin dose was progressively reduced, following reductions in tacrolimus and prednisolone doses. Five months after NODAT diagnosis, insulin was switched to a dipeptidyl peptidase 4 (DPP-4) inhibitor. At that time, the patient was under tacrolimus 8 mg/day and prednisolone 5 mg/day. However, the patient stopped it a few weeks later due to vomiting. As glycated hemoglobin (HbA1c) remained below 6.5%, the patient was kept without medication. However, 16 months later, HbA1c increased to 6.9%. Therefore, sitagliptin 25 mg/day was resumed, with good tolerance. Nevertheless, HbA1c progressively increased to 8% in the following 8 months (Fig. 2). Renal function slowly deteriorated, with plasma creatinine level ranging between 185.6 and 229.8 μmol/L (GFR range: 34– 44 mL/min/1.73 m2). At that time, the patient was under tacrolimus 6 mg/day and prednisolone 5 mg/day. After discussing the therapeutic options, therapy was switched to liraglutide, which was progressively titrated to 1.8 mg/day.
Figure 2 Evolution of the patient’s glycemic control after NODAT diagnosis.
Outcome and follow-up
Two months after liraglutide introduction, HbA1c dropped to 6.7%. However, glycemic control again deteriorated, and HbA1c increased up to 10.9% (Fig. 1). Immunosuppressive therapy doses were unchanged, but the patient reported less physical activity. Plasma creatinine level was 224.5 μmol/L, corresponding to a GFR of 35.2 mL/min/1.73 m2. At this time, liraglutide was stopped, and insulin with a long-acting analog (0.14 UI/kg/day) was resumed. Two months later, glycemic control slightly improved. Insulin therapy will be maintained, and treatment management will continue as considered appropriate.
Discussion
HNF1B is involved in the embryogenesis and tissue-specific gene expression of several organs, including the kidney, pancreas, liver, and genital tract. Even though HNF1B mutations were first associated with MODY, it is currently known that HNF1B anomalies result in a systemic disease that follows the expression of HNF1B (1). The most frequently described manifestations include kidney disease, early-onset diabetes, pancreatic exocrine insufficiency, liver dysfunction, and genital tract malformations. Notably, there is marked phenotypic variability, suggesting that other genetic or environmental factors might modify the pattern and severity of the disease (1).
The prevalence of HNF1B-associated disease is unknown. The mean overall detection rate of HNF1B defects in cohorts of patients with kidney disease was 19% (1). By contrast, they are a rare cause of MODY, accounting for less than 1% of the cases (1). As most cohorts were pre-selected for kidney disease and/or diabetes, the frequency of these and other clinical features is unclear.
Genetic changes in the HNF1B gene comprise either heterozygous intragenic mutations or gene deletions. Although HNF1B-associated disease is inherited in an autosomal-dominant manner, spontaneous genetic changes are common, which explains the frequent absence of a family history of kidney disease or diabetes (1). Given the family history of diabetes in this patient, we hypothesize that the mutation was inherited.
Kidney disease appears to be the most common manifestation, but considerable variation is found in its phenotype and severity (2, 3, 4). Cystic disease is the predominant morphological manifestation in both children and adults (2, 3). As observed in this patient, kidney disease can present during fetal life as bilateral hyperechogenic kidneys of normal or slightly increased size (5). Tubular transport abnormalities can also be present, and hypomagnesemia is a common and distinctive feature (1, 3). Hyperuricemia and early-onset gout are also observed. Importantly, renal function is frequently impaired, and up to 20% of patients progress to end-stage renal disease (3).
Given the role of HNF1B in pancreatic development, HNF1B-associated disease can present with pancreatic hypoplasia, and both endocrine and exocrine dysfunction can occur (1). Diabetes is considered as the most frequent extra-renal phenotype. In the largest cohort described to date (3), Dubois-Laforgue et al. reported diabetes in 82% of 194 patients. Diabetes is usually of early-onset (median age 20 years), but it can be found at any age from the neonatal period to late middle age (1). Clinical presentation seems highly variable, including ketoacidosis (3). The pathophysiology of HNF1B-associated diabetes has not been definitively established. Both beta-cell dysfunction and reduced hepatic insulin sensitivity have been implicated (1). Beta-cell dysfunction, resulting in reduced insulin secretion, may be a consequence of pancreatic hypoplasia and beta-cell mass reduction. However, primary functional abnormalities in insulin secretion must also occur, as pancreatic hypoplasia and endocrine dysfunction do not completely correlate (6).
As this case demonstrates, HNF1B-associated diabetes can present as NODAT. In this patient, it was the association of an unexpected NODAT and the kidney disease that triggered the diagnosis. The frequency of NODAT in HNF1B-associated disease is unknown. It is suggested that HNF1B defects determine a genetic susceptibility to NODAT, as the reduced insulin secretory capacity of beta-cell is unmasked by the immunosuppressive drugs (7, 8). Faguer et al.(9) hypothesized that immunosuppressive therapy may switch off residual HNF1B expression and thus potentiate beta-cell dysfunction. Combining clinical data and in vitro experiments, these authors suggested that calcineurin inhibitors (CNI) induce a downregulation of the nonmutated allele, mimicking HNF1B biallelic inactivation. In this patient, given the deterioration of renal function, immunosuppressive regimens avoiding CNI were not considered. However, consideringthat immunosuppressive regimens free of CNI may minimize the deterioration of NODAT, if the patient’s glycemic control remains above the target, the possibility of such a regiment will be discussed. Whether all kidney transplant recipients will ultimately develop diabetes is unknown. Interestingly, Waller et al. (8) reported the case of a boy with a previously unrecognized HNF1B mutation in which NODAT regressed after transplant nephrectomy and cyclosporine and steroid withdrawal. It is not clear whether NODAT has a distinctive presentation in patients with HNF1B-associated disease. Some authors highlighted its very early onset after transplantation, as occurred in this case, but this was not seen in all patients reported.
The most appropriate treatment for HNF1B-associated diabetes is not established. In keeping with the hypothesis of beta-cell dysfunction, the majority of patients are treated with insulin (3). However, residual insulin secretion has been demonstrated, and some authors argue that insulin treatment can be delayed for a few years (3). The choice for a DPP-4 inhibitor was based on the patient characteristics (normal weight and post-transplantation kidney status) and an only slightly elevated HbA1c value. Also, there was the aim of simplifying the therapeutic regimen, switching to an oral agent. Even though our patient remained without any treatment for more than a year, glycemic control eventually deteriorated. The initial response to liraglutide was impressive, but glycemic control worsened again, and insulin therapy was required 6 months later. We hypothesize that the patient’s young age and normal body weight, in addition to the absence of major pancreatic morphological abnormalities, contributed to the initial glycemic control. However, the immunosuppressive therapy possibly limited an extended response to non-insulin agents, and so insulin therapy was resumed nearly 3 years after diabetes diagnosis. As far as we know, there is no data on treatment of HNF1B-associated diabetes with glucagon-like peptide-1 receptor agonists. Whether patients with HNF1B-associated diabetes not receiving calcineurin inhibitors respond to these agents remains to be elucidated.
Other reported manifestations of HNF1B-disease include abnormal liver function, usually manifesting as an asymptomatic rise in liver enzymes; biliary anomalies presenting as bile duct cysts; and various genital tract malformations (3). Of note, the clinical spectrum of the disease seems to be expanding (1, 6). At this time, there is no evidence of any of these additional features in this patient.
In conclusion, HNF1B-associated disease is remarkable for its marked phenotypic variability and the high rate of de novo cases. The diagnosis is challenging and many cases likely remain undetected or misdiagnosed. However, the right diagnosis is essential to provide the best care to both patients and their relatives. We believe the most important step for diagnosis of HNF1B-associated disease is to first recognize this possibility. Findings such as hypomagnesemia or pancreatic structural anomalies can support the indication for genetic testing (10). Additionally, an HNF1B score using a weight combination of clinical features has been proposed for selecting patients for HNF1B testing (4). Finally, as the case we present highlights, HNF1B-associated disease should be considered when NODAT unexpectedly develops in young kidney transplant recipients with a suggestive kidney disease. Even though the most appropriate treatment for HNF1B-associated diabetes is not established, immunosuppressive therapy superimposed on a beta-cell dysfunction seems to determine the need for insulin therapy after a variable period.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this case report.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Patient consent
Written informed consent has been obtained from the patient for publication of the submitted article and accompanying images.
Author contribution statement
Both authors were involved in the management of the patient, and in the writing and editing of the manuscript. | INSULIN NOS, PREDNISOLONE, SITAGLIPTIN PHOSPHATE, TACROLIMUS | DrugsGivenReaction | CC BY-NC-ND | 33522494 | 19,046,333 | 2021-01-27 |
What is the weight of the patient? | New-onset diabetes after kidney transplantation revealing HNF1B-associated disease.
Molecular alterations of the transcription factor hepatocyte nuclear factor 1B (HNF1B) are associated with systemic disease, with kidney disease and maturity-onset diabetes of the young (MODY) as the most characteristic manifestations. Other features comprise pancreatic exocrine insufficiency, liver and biliary anomalies, and genital tract malformations. HNF1B-associated disease is clinically heterogeneous, and therefore the diagnosis is challenging. The authors describe the case of a 19-year-old man with new-onset diabetes after kidney transplantation (NODAT). The kidney disease presented during fetal life as bilateral hyperechogenic kidneys. Renal function progressively deteriorated during childhood, and at the age of 19, the patient was submitted to a living-kidney transplant. Two weeks after transplant, NODAT developed. Given the young age and normal body weight, NODAT was unexpected, and the possibility of HNF1B-associated disease was considered. Screening for mutations in HNF1B was undertaken, and a known mutation was found. As this case highlights, HNF1B-associated disease should be considered when NODAT unexpectedly develops in young kidney transplant recipients with a suggestive renal disease.
HNF1B anomalies are associated with systemic disease, including kidney disease, diabetes mellitus, pancreatic exocrine insufficiency, liver test abnormalities and genital tract malformations. Phenotype is variable and there are no pathognomonic manifestations, but kidney disease appears to be the most common feature and diabetes the most frequent extra-renal phenotype. Spontaneous gene alterations are common, and the lack of family history should not exclude the diagnosis. HNF1B defects should be considered when NODAT develops in a young adult kidney transplant recipient with a suggestive kidney disease and without extensive risk factors for diabetes. The most appropriate treatment for HNF1B-associated diabetes is not established, but immunosuppressive therapy superimposed on a beta-cell dysfunction seems to determine the need for insulin therapy after a variable period. Immunosupressive regimens free of calcineurin inhibitors should be considered in patients with HNF1B-associated disease to minimize the risk of developing NODAT.
Background
Since the first description of an HNF1B mutation associated with early-onset diabetes in 1997, the knowledge of HNF1B genetic changes has evolved significantly, and it is currently known that HNF1B anomalies are associated with a systemic disease with marked phenotypic variability (1). The diagnosis of HNF1B-associated disease is challenging, and many cases likely remain undetected or misdiagnosed. The authors describe the case of a young male with a previously unrecognized HNF1B mutation that developed NODAT after kidney transplantation, which triggered the diagnosis of HNF1B-associated disease.
Case presentation
A 19-year-old man was referred to our clinic because of new-onset diabetes after kidney transplantation (NODAT). Two weeks after transplantation, routine blood analysis revealed marked hyperglycemia (up to 17.2 mmol/L). He denied catabolic symptoms, and there was no evidence of ketoacidosis. Through childhood, blood glucose levels were normal, with fasting blood glucose levels ranging from 4.2 to 5.2 mmol/L, with no trend of deterioration over time. His body weight was 55 kg and BMI 21.5 kg/m2. Kidney disease was suspected on a routine fetal ultrasonographic scan (US) performed at 20 weeks’ gestation, revealing bilateral hyperechogenic kidneys. After birth, the US demonstrated hyperechogenic kidneys with small cysts, and plasma creatinine was abnormally elevated. The patient was the first child of non-consanguineous and healthy parents, which pointed to autosomal recessive polycystic kidney disease (ARPKD). Thereafter, renal function progressively deteriorated. By the age of 18, plasma creatinine level was 433.2 μmol/L (corresponding to a glomerular filtrate rate (GFR) of 15.9 mL/min/1.73 m2). One year later, the patient received a living kidney transplant from his 52-year-old father. There was no morphological abnormality on the father’s kidney, and his renal function was normal. The procedure was complicated by partial graft necrosis. At hospital discharge, plasma creatinine level was 185.6 μmol/L (GFR: 44.3 mL/min/1.73 m2). At that time, the immunosuppressive regimen comprised tacrolimus 15 mg/day, mycophenolate mofetil 2000 mg/day, and prednisolone 15 mg/day.
Investigation
Given the patient’s young age and normal body weight, and the absence of other major risk factors, the development of NODAT was unexpected. A history of diabetes was noted in the patient’s maternal grandmother and uncle, with no other known relevant family history, including kidney disease (Fig. 1). Fasting C-peptide was 1.3 nmol/L (normal range: 0.4 – 1.5 nmol/L). Islet autoantibodies, including GADA, ICA, IA-2A, and ZnT8A, were all negative. US pancreatic evaluation was normal. The association of diabetes with such kidney morphological abnormalities raised the possibility of maturity-onset diabetes of the young (MODY) type 5 and hepatocyte nuclear factor 1B (HNF1B) gene defects. Screening for mutations in the HNF1B gene was undertaken and a known missense heterozygous mutation (p.S148L, c.443 C>T) in exon 2 was found. So far, it was not possible to perform genetic testing on any other family member, but the family was referred for genetic counseling. Regarding other manifestations, the patient had no complaints suggestive of exocrine dysfunction, liver enzymes were normal over the years (both alanine aminotransferase and aspartate aminotransferase persistently below the upper limit of the normal range, both before and after transplantation), and there was no clinical evidence of genital tract malformations.
Figure 1 Family pedigree of the patient showing the affected patient (proband) and other affected family members with diabetes.
Treatment
Insulin therapy was started with a long-acting analog (0.16 UI/kg/day). The insulin dose was progressively reduced, following reductions in tacrolimus and prednisolone doses. Five months after NODAT diagnosis, insulin was switched to a dipeptidyl peptidase 4 (DPP-4) inhibitor. At that time, the patient was under tacrolimus 8 mg/day and prednisolone 5 mg/day. However, the patient stopped it a few weeks later due to vomiting. As glycated hemoglobin (HbA1c) remained below 6.5%, the patient was kept without medication. However, 16 months later, HbA1c increased to 6.9%. Therefore, sitagliptin 25 mg/day was resumed, with good tolerance. Nevertheless, HbA1c progressively increased to 8% in the following 8 months (Fig. 2). Renal function slowly deteriorated, with plasma creatinine level ranging between 185.6 and 229.8 μmol/L (GFR range: 34– 44 mL/min/1.73 m2). At that time, the patient was under tacrolimus 6 mg/day and prednisolone 5 mg/day. After discussing the therapeutic options, therapy was switched to liraglutide, which was progressively titrated to 1.8 mg/day.
Figure 2 Evolution of the patient’s glycemic control after NODAT diagnosis.
Outcome and follow-up
Two months after liraglutide introduction, HbA1c dropped to 6.7%. However, glycemic control again deteriorated, and HbA1c increased up to 10.9% (Fig. 1). Immunosuppressive therapy doses were unchanged, but the patient reported less physical activity. Plasma creatinine level was 224.5 μmol/L, corresponding to a GFR of 35.2 mL/min/1.73 m2. At this time, liraglutide was stopped, and insulin with a long-acting analog (0.14 UI/kg/day) was resumed. Two months later, glycemic control slightly improved. Insulin therapy will be maintained, and treatment management will continue as considered appropriate.
Discussion
HNF1B is involved in the embryogenesis and tissue-specific gene expression of several organs, including the kidney, pancreas, liver, and genital tract. Even though HNF1B mutations were first associated with MODY, it is currently known that HNF1B anomalies result in a systemic disease that follows the expression of HNF1B (1). The most frequently described manifestations include kidney disease, early-onset diabetes, pancreatic exocrine insufficiency, liver dysfunction, and genital tract malformations. Notably, there is marked phenotypic variability, suggesting that other genetic or environmental factors might modify the pattern and severity of the disease (1).
The prevalence of HNF1B-associated disease is unknown. The mean overall detection rate of HNF1B defects in cohorts of patients with kidney disease was 19% (1). By contrast, they are a rare cause of MODY, accounting for less than 1% of the cases (1). As most cohorts were pre-selected for kidney disease and/or diabetes, the frequency of these and other clinical features is unclear.
Genetic changes in the HNF1B gene comprise either heterozygous intragenic mutations or gene deletions. Although HNF1B-associated disease is inherited in an autosomal-dominant manner, spontaneous genetic changes are common, which explains the frequent absence of a family history of kidney disease or diabetes (1). Given the family history of diabetes in this patient, we hypothesize that the mutation was inherited.
Kidney disease appears to be the most common manifestation, but considerable variation is found in its phenotype and severity (2, 3, 4). Cystic disease is the predominant morphological manifestation in both children and adults (2, 3). As observed in this patient, kidney disease can present during fetal life as bilateral hyperechogenic kidneys of normal or slightly increased size (5). Tubular transport abnormalities can also be present, and hypomagnesemia is a common and distinctive feature (1, 3). Hyperuricemia and early-onset gout are also observed. Importantly, renal function is frequently impaired, and up to 20% of patients progress to end-stage renal disease (3).
Given the role of HNF1B in pancreatic development, HNF1B-associated disease can present with pancreatic hypoplasia, and both endocrine and exocrine dysfunction can occur (1). Diabetes is considered as the most frequent extra-renal phenotype. In the largest cohort described to date (3), Dubois-Laforgue et al. reported diabetes in 82% of 194 patients. Diabetes is usually of early-onset (median age 20 years), but it can be found at any age from the neonatal period to late middle age (1). Clinical presentation seems highly variable, including ketoacidosis (3). The pathophysiology of HNF1B-associated diabetes has not been definitively established. Both beta-cell dysfunction and reduced hepatic insulin sensitivity have been implicated (1). Beta-cell dysfunction, resulting in reduced insulin secretion, may be a consequence of pancreatic hypoplasia and beta-cell mass reduction. However, primary functional abnormalities in insulin secretion must also occur, as pancreatic hypoplasia and endocrine dysfunction do not completely correlate (6).
As this case demonstrates, HNF1B-associated diabetes can present as NODAT. In this patient, it was the association of an unexpected NODAT and the kidney disease that triggered the diagnosis. The frequency of NODAT in HNF1B-associated disease is unknown. It is suggested that HNF1B defects determine a genetic susceptibility to NODAT, as the reduced insulin secretory capacity of beta-cell is unmasked by the immunosuppressive drugs (7, 8). Faguer et al.(9) hypothesized that immunosuppressive therapy may switch off residual HNF1B expression and thus potentiate beta-cell dysfunction. Combining clinical data and in vitro experiments, these authors suggested that calcineurin inhibitors (CNI) induce a downregulation of the nonmutated allele, mimicking HNF1B biallelic inactivation. In this patient, given the deterioration of renal function, immunosuppressive regimens avoiding CNI were not considered. However, consideringthat immunosuppressive regimens free of CNI may minimize the deterioration of NODAT, if the patient’s glycemic control remains above the target, the possibility of such a regiment will be discussed. Whether all kidney transplant recipients will ultimately develop diabetes is unknown. Interestingly, Waller et al. (8) reported the case of a boy with a previously unrecognized HNF1B mutation in which NODAT regressed after transplant nephrectomy and cyclosporine and steroid withdrawal. It is not clear whether NODAT has a distinctive presentation in patients with HNF1B-associated disease. Some authors highlighted its very early onset after transplantation, as occurred in this case, but this was not seen in all patients reported.
The most appropriate treatment for HNF1B-associated diabetes is not established. In keeping with the hypothesis of beta-cell dysfunction, the majority of patients are treated with insulin (3). However, residual insulin secretion has been demonstrated, and some authors argue that insulin treatment can be delayed for a few years (3). The choice for a DPP-4 inhibitor was based on the patient characteristics (normal weight and post-transplantation kidney status) and an only slightly elevated HbA1c value. Also, there was the aim of simplifying the therapeutic regimen, switching to an oral agent. Even though our patient remained without any treatment for more than a year, glycemic control eventually deteriorated. The initial response to liraglutide was impressive, but glycemic control worsened again, and insulin therapy was required 6 months later. We hypothesize that the patient’s young age and normal body weight, in addition to the absence of major pancreatic morphological abnormalities, contributed to the initial glycemic control. However, the immunosuppressive therapy possibly limited an extended response to non-insulin agents, and so insulin therapy was resumed nearly 3 years after diabetes diagnosis. As far as we know, there is no data on treatment of HNF1B-associated diabetes with glucagon-like peptide-1 receptor agonists. Whether patients with HNF1B-associated diabetes not receiving calcineurin inhibitors respond to these agents remains to be elucidated.
Other reported manifestations of HNF1B-disease include abnormal liver function, usually manifesting as an asymptomatic rise in liver enzymes; biliary anomalies presenting as bile duct cysts; and various genital tract malformations (3). Of note, the clinical spectrum of the disease seems to be expanding (1, 6). At this time, there is no evidence of any of these additional features in this patient.
In conclusion, HNF1B-associated disease is remarkable for its marked phenotypic variability and the high rate of de novo cases. The diagnosis is challenging and many cases likely remain undetected or misdiagnosed. However, the right diagnosis is essential to provide the best care to both patients and their relatives. We believe the most important step for diagnosis of HNF1B-associated disease is to first recognize this possibility. Findings such as hypomagnesemia or pancreatic structural anomalies can support the indication for genetic testing (10). Additionally, an HNF1B score using a weight combination of clinical features has been proposed for selecting patients for HNF1B testing (4). Finally, as the case we present highlights, HNF1B-associated disease should be considered when NODAT unexpectedly develops in young kidney transplant recipients with a suggestive kidney disease. Even though the most appropriate treatment for HNF1B-associated diabetes is not established, immunosuppressive therapy superimposed on a beta-cell dysfunction seems to determine the need for insulin therapy after a variable period.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this case report.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Patient consent
Written informed consent has been obtained from the patient for publication of the submitted article and accompanying images.
Author contribution statement
Both authors were involved in the management of the patient, and in the writing and editing of the manuscript. | 55 kg. | Weight | CC BY-NC-ND | 33522494 | 19,046,333 | 2021-01-27 |
What was the administration route of drug 'SITAGLIPTIN PHOSPHATE'? | New-onset diabetes after kidney transplantation revealing HNF1B-associated disease.
Molecular alterations of the transcription factor hepatocyte nuclear factor 1B (HNF1B) are associated with systemic disease, with kidney disease and maturity-onset diabetes of the young (MODY) as the most characteristic manifestations. Other features comprise pancreatic exocrine insufficiency, liver and biliary anomalies, and genital tract malformations. HNF1B-associated disease is clinically heterogeneous, and therefore the diagnosis is challenging. The authors describe the case of a 19-year-old man with new-onset diabetes after kidney transplantation (NODAT). The kidney disease presented during fetal life as bilateral hyperechogenic kidneys. Renal function progressively deteriorated during childhood, and at the age of 19, the patient was submitted to a living-kidney transplant. Two weeks after transplant, NODAT developed. Given the young age and normal body weight, NODAT was unexpected, and the possibility of HNF1B-associated disease was considered. Screening for mutations in HNF1B was undertaken, and a known mutation was found. As this case highlights, HNF1B-associated disease should be considered when NODAT unexpectedly develops in young kidney transplant recipients with a suggestive renal disease.
HNF1B anomalies are associated with systemic disease, including kidney disease, diabetes mellitus, pancreatic exocrine insufficiency, liver test abnormalities and genital tract malformations. Phenotype is variable and there are no pathognomonic manifestations, but kidney disease appears to be the most common feature and diabetes the most frequent extra-renal phenotype. Spontaneous gene alterations are common, and the lack of family history should not exclude the diagnosis. HNF1B defects should be considered when NODAT develops in a young adult kidney transplant recipient with a suggestive kidney disease and without extensive risk factors for diabetes. The most appropriate treatment for HNF1B-associated diabetes is not established, but immunosuppressive therapy superimposed on a beta-cell dysfunction seems to determine the need for insulin therapy after a variable period. Immunosupressive regimens free of calcineurin inhibitors should be considered in patients with HNF1B-associated disease to minimize the risk of developing NODAT.
Background
Since the first description of an HNF1B mutation associated with early-onset diabetes in 1997, the knowledge of HNF1B genetic changes has evolved significantly, and it is currently known that HNF1B anomalies are associated with a systemic disease with marked phenotypic variability (1). The diagnosis of HNF1B-associated disease is challenging, and many cases likely remain undetected or misdiagnosed. The authors describe the case of a young male with a previously unrecognized HNF1B mutation that developed NODAT after kidney transplantation, which triggered the diagnosis of HNF1B-associated disease.
Case presentation
A 19-year-old man was referred to our clinic because of new-onset diabetes after kidney transplantation (NODAT). Two weeks after transplantation, routine blood analysis revealed marked hyperglycemia (up to 17.2 mmol/L). He denied catabolic symptoms, and there was no evidence of ketoacidosis. Through childhood, blood glucose levels were normal, with fasting blood glucose levels ranging from 4.2 to 5.2 mmol/L, with no trend of deterioration over time. His body weight was 55 kg and BMI 21.5 kg/m2. Kidney disease was suspected on a routine fetal ultrasonographic scan (US) performed at 20 weeks’ gestation, revealing bilateral hyperechogenic kidneys. After birth, the US demonstrated hyperechogenic kidneys with small cysts, and plasma creatinine was abnormally elevated. The patient was the first child of non-consanguineous and healthy parents, which pointed to autosomal recessive polycystic kidney disease (ARPKD). Thereafter, renal function progressively deteriorated. By the age of 18, plasma creatinine level was 433.2 μmol/L (corresponding to a glomerular filtrate rate (GFR) of 15.9 mL/min/1.73 m2). One year later, the patient received a living kidney transplant from his 52-year-old father. There was no morphological abnormality on the father’s kidney, and his renal function was normal. The procedure was complicated by partial graft necrosis. At hospital discharge, plasma creatinine level was 185.6 μmol/L (GFR: 44.3 mL/min/1.73 m2). At that time, the immunosuppressive regimen comprised tacrolimus 15 mg/day, mycophenolate mofetil 2000 mg/day, and prednisolone 15 mg/day.
Investigation
Given the patient’s young age and normal body weight, and the absence of other major risk factors, the development of NODAT was unexpected. A history of diabetes was noted in the patient’s maternal grandmother and uncle, with no other known relevant family history, including kidney disease (Fig. 1). Fasting C-peptide was 1.3 nmol/L (normal range: 0.4 – 1.5 nmol/L). Islet autoantibodies, including GADA, ICA, IA-2A, and ZnT8A, were all negative. US pancreatic evaluation was normal. The association of diabetes with such kidney morphological abnormalities raised the possibility of maturity-onset diabetes of the young (MODY) type 5 and hepatocyte nuclear factor 1B (HNF1B) gene defects. Screening for mutations in the HNF1B gene was undertaken and a known missense heterozygous mutation (p.S148L, c.443 C>T) in exon 2 was found. So far, it was not possible to perform genetic testing on any other family member, but the family was referred for genetic counseling. Regarding other manifestations, the patient had no complaints suggestive of exocrine dysfunction, liver enzymes were normal over the years (both alanine aminotransferase and aspartate aminotransferase persistently below the upper limit of the normal range, both before and after transplantation), and there was no clinical evidence of genital tract malformations.
Figure 1 Family pedigree of the patient showing the affected patient (proband) and other affected family members with diabetes.
Treatment
Insulin therapy was started with a long-acting analog (0.16 UI/kg/day). The insulin dose was progressively reduced, following reductions in tacrolimus and prednisolone doses. Five months after NODAT diagnosis, insulin was switched to a dipeptidyl peptidase 4 (DPP-4) inhibitor. At that time, the patient was under tacrolimus 8 mg/day and prednisolone 5 mg/day. However, the patient stopped it a few weeks later due to vomiting. As glycated hemoglobin (HbA1c) remained below 6.5%, the patient was kept without medication. However, 16 months later, HbA1c increased to 6.9%. Therefore, sitagliptin 25 mg/day was resumed, with good tolerance. Nevertheless, HbA1c progressively increased to 8% in the following 8 months (Fig. 2). Renal function slowly deteriorated, with plasma creatinine level ranging between 185.6 and 229.8 μmol/L (GFR range: 34– 44 mL/min/1.73 m2). At that time, the patient was under tacrolimus 6 mg/day and prednisolone 5 mg/day. After discussing the therapeutic options, therapy was switched to liraglutide, which was progressively titrated to 1.8 mg/day.
Figure 2 Evolution of the patient’s glycemic control after NODAT diagnosis.
Outcome and follow-up
Two months after liraglutide introduction, HbA1c dropped to 6.7%. However, glycemic control again deteriorated, and HbA1c increased up to 10.9% (Fig. 1). Immunosuppressive therapy doses were unchanged, but the patient reported less physical activity. Plasma creatinine level was 224.5 μmol/L, corresponding to a GFR of 35.2 mL/min/1.73 m2. At this time, liraglutide was stopped, and insulin with a long-acting analog (0.14 UI/kg/day) was resumed. Two months later, glycemic control slightly improved. Insulin therapy will be maintained, and treatment management will continue as considered appropriate.
Discussion
HNF1B is involved in the embryogenesis and tissue-specific gene expression of several organs, including the kidney, pancreas, liver, and genital tract. Even though HNF1B mutations were first associated with MODY, it is currently known that HNF1B anomalies result in a systemic disease that follows the expression of HNF1B (1). The most frequently described manifestations include kidney disease, early-onset diabetes, pancreatic exocrine insufficiency, liver dysfunction, and genital tract malformations. Notably, there is marked phenotypic variability, suggesting that other genetic or environmental factors might modify the pattern and severity of the disease (1).
The prevalence of HNF1B-associated disease is unknown. The mean overall detection rate of HNF1B defects in cohorts of patients with kidney disease was 19% (1). By contrast, they are a rare cause of MODY, accounting for less than 1% of the cases (1). As most cohorts were pre-selected for kidney disease and/or diabetes, the frequency of these and other clinical features is unclear.
Genetic changes in the HNF1B gene comprise either heterozygous intragenic mutations or gene deletions. Although HNF1B-associated disease is inherited in an autosomal-dominant manner, spontaneous genetic changes are common, which explains the frequent absence of a family history of kidney disease or diabetes (1). Given the family history of diabetes in this patient, we hypothesize that the mutation was inherited.
Kidney disease appears to be the most common manifestation, but considerable variation is found in its phenotype and severity (2, 3, 4). Cystic disease is the predominant morphological manifestation in both children and adults (2, 3). As observed in this patient, kidney disease can present during fetal life as bilateral hyperechogenic kidneys of normal or slightly increased size (5). Tubular transport abnormalities can also be present, and hypomagnesemia is a common and distinctive feature (1, 3). Hyperuricemia and early-onset gout are also observed. Importantly, renal function is frequently impaired, and up to 20% of patients progress to end-stage renal disease (3).
Given the role of HNF1B in pancreatic development, HNF1B-associated disease can present with pancreatic hypoplasia, and both endocrine and exocrine dysfunction can occur (1). Diabetes is considered as the most frequent extra-renal phenotype. In the largest cohort described to date (3), Dubois-Laforgue et al. reported diabetes in 82% of 194 patients. Diabetes is usually of early-onset (median age 20 years), but it can be found at any age from the neonatal period to late middle age (1). Clinical presentation seems highly variable, including ketoacidosis (3). The pathophysiology of HNF1B-associated diabetes has not been definitively established. Both beta-cell dysfunction and reduced hepatic insulin sensitivity have been implicated (1). Beta-cell dysfunction, resulting in reduced insulin secretion, may be a consequence of pancreatic hypoplasia and beta-cell mass reduction. However, primary functional abnormalities in insulin secretion must also occur, as pancreatic hypoplasia and endocrine dysfunction do not completely correlate (6).
As this case demonstrates, HNF1B-associated diabetes can present as NODAT. In this patient, it was the association of an unexpected NODAT and the kidney disease that triggered the diagnosis. The frequency of NODAT in HNF1B-associated disease is unknown. It is suggested that HNF1B defects determine a genetic susceptibility to NODAT, as the reduced insulin secretory capacity of beta-cell is unmasked by the immunosuppressive drugs (7, 8). Faguer et al.(9) hypothesized that immunosuppressive therapy may switch off residual HNF1B expression and thus potentiate beta-cell dysfunction. Combining clinical data and in vitro experiments, these authors suggested that calcineurin inhibitors (CNI) induce a downregulation of the nonmutated allele, mimicking HNF1B biallelic inactivation. In this patient, given the deterioration of renal function, immunosuppressive regimens avoiding CNI were not considered. However, consideringthat immunosuppressive regimens free of CNI may minimize the deterioration of NODAT, if the patient’s glycemic control remains above the target, the possibility of such a regiment will be discussed. Whether all kidney transplant recipients will ultimately develop diabetes is unknown. Interestingly, Waller et al. (8) reported the case of a boy with a previously unrecognized HNF1B mutation in which NODAT regressed after transplant nephrectomy and cyclosporine and steroid withdrawal. It is not clear whether NODAT has a distinctive presentation in patients with HNF1B-associated disease. Some authors highlighted its very early onset after transplantation, as occurred in this case, but this was not seen in all patients reported.
The most appropriate treatment for HNF1B-associated diabetes is not established. In keeping with the hypothesis of beta-cell dysfunction, the majority of patients are treated with insulin (3). However, residual insulin secretion has been demonstrated, and some authors argue that insulin treatment can be delayed for a few years (3). The choice for a DPP-4 inhibitor was based on the patient characteristics (normal weight and post-transplantation kidney status) and an only slightly elevated HbA1c value. Also, there was the aim of simplifying the therapeutic regimen, switching to an oral agent. Even though our patient remained without any treatment for more than a year, glycemic control eventually deteriorated. The initial response to liraglutide was impressive, but glycemic control worsened again, and insulin therapy was required 6 months later. We hypothesize that the patient’s young age and normal body weight, in addition to the absence of major pancreatic morphological abnormalities, contributed to the initial glycemic control. However, the immunosuppressive therapy possibly limited an extended response to non-insulin agents, and so insulin therapy was resumed nearly 3 years after diabetes diagnosis. As far as we know, there is no data on treatment of HNF1B-associated diabetes with glucagon-like peptide-1 receptor agonists. Whether patients with HNF1B-associated diabetes not receiving calcineurin inhibitors respond to these agents remains to be elucidated.
Other reported manifestations of HNF1B-disease include abnormal liver function, usually manifesting as an asymptomatic rise in liver enzymes; biliary anomalies presenting as bile duct cysts; and various genital tract malformations (3). Of note, the clinical spectrum of the disease seems to be expanding (1, 6). At this time, there is no evidence of any of these additional features in this patient.
In conclusion, HNF1B-associated disease is remarkable for its marked phenotypic variability and the high rate of de novo cases. The diagnosis is challenging and many cases likely remain undetected or misdiagnosed. However, the right diagnosis is essential to provide the best care to both patients and their relatives. We believe the most important step for diagnosis of HNF1B-associated disease is to first recognize this possibility. Findings such as hypomagnesemia or pancreatic structural anomalies can support the indication for genetic testing (10). Additionally, an HNF1B score using a weight combination of clinical features has been proposed for selecting patients for HNF1B testing (4). Finally, as the case we present highlights, HNF1B-associated disease should be considered when NODAT unexpectedly develops in young kidney transplant recipients with a suggestive kidney disease. Even though the most appropriate treatment for HNF1B-associated diabetes is not established, immunosuppressive therapy superimposed on a beta-cell dysfunction seems to determine the need for insulin therapy after a variable period.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this case report.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Patient consent
Written informed consent has been obtained from the patient for publication of the submitted article and accompanying images.
Author contribution statement
Both authors were involved in the management of the patient, and in the writing and editing of the manuscript. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33522494 | 19,046,333 | 2021-01-27 |
What was the dosage of drug 'INSULIN NOS'? | New-onset diabetes after kidney transplantation revealing HNF1B-associated disease.
Molecular alterations of the transcription factor hepatocyte nuclear factor 1B (HNF1B) are associated with systemic disease, with kidney disease and maturity-onset diabetes of the young (MODY) as the most characteristic manifestations. Other features comprise pancreatic exocrine insufficiency, liver and biliary anomalies, and genital tract malformations. HNF1B-associated disease is clinically heterogeneous, and therefore the diagnosis is challenging. The authors describe the case of a 19-year-old man with new-onset diabetes after kidney transplantation (NODAT). The kidney disease presented during fetal life as bilateral hyperechogenic kidneys. Renal function progressively deteriorated during childhood, and at the age of 19, the patient was submitted to a living-kidney transplant. Two weeks after transplant, NODAT developed. Given the young age and normal body weight, NODAT was unexpected, and the possibility of HNF1B-associated disease was considered. Screening for mutations in HNF1B was undertaken, and a known mutation was found. As this case highlights, HNF1B-associated disease should be considered when NODAT unexpectedly develops in young kidney transplant recipients with a suggestive renal disease.
HNF1B anomalies are associated with systemic disease, including kidney disease, diabetes mellitus, pancreatic exocrine insufficiency, liver test abnormalities and genital tract malformations. Phenotype is variable and there are no pathognomonic manifestations, but kidney disease appears to be the most common feature and diabetes the most frequent extra-renal phenotype. Spontaneous gene alterations are common, and the lack of family history should not exclude the diagnosis. HNF1B defects should be considered when NODAT develops in a young adult kidney transplant recipient with a suggestive kidney disease and without extensive risk factors for diabetes. The most appropriate treatment for HNF1B-associated diabetes is not established, but immunosuppressive therapy superimposed on a beta-cell dysfunction seems to determine the need for insulin therapy after a variable period. Immunosupressive regimens free of calcineurin inhibitors should be considered in patients with HNF1B-associated disease to minimize the risk of developing NODAT.
Background
Since the first description of an HNF1B mutation associated with early-onset diabetes in 1997, the knowledge of HNF1B genetic changes has evolved significantly, and it is currently known that HNF1B anomalies are associated with a systemic disease with marked phenotypic variability (1). The diagnosis of HNF1B-associated disease is challenging, and many cases likely remain undetected or misdiagnosed. The authors describe the case of a young male with a previously unrecognized HNF1B mutation that developed NODAT after kidney transplantation, which triggered the diagnosis of HNF1B-associated disease.
Case presentation
A 19-year-old man was referred to our clinic because of new-onset diabetes after kidney transplantation (NODAT). Two weeks after transplantation, routine blood analysis revealed marked hyperglycemia (up to 17.2 mmol/L). He denied catabolic symptoms, and there was no evidence of ketoacidosis. Through childhood, blood glucose levels were normal, with fasting blood glucose levels ranging from 4.2 to 5.2 mmol/L, with no trend of deterioration over time. His body weight was 55 kg and BMI 21.5 kg/m2. Kidney disease was suspected on a routine fetal ultrasonographic scan (US) performed at 20 weeks’ gestation, revealing bilateral hyperechogenic kidneys. After birth, the US demonstrated hyperechogenic kidneys with small cysts, and plasma creatinine was abnormally elevated. The patient was the first child of non-consanguineous and healthy parents, which pointed to autosomal recessive polycystic kidney disease (ARPKD). Thereafter, renal function progressively deteriorated. By the age of 18, plasma creatinine level was 433.2 μmol/L (corresponding to a glomerular filtrate rate (GFR) of 15.9 mL/min/1.73 m2). One year later, the patient received a living kidney transplant from his 52-year-old father. There was no morphological abnormality on the father’s kidney, and his renal function was normal. The procedure was complicated by partial graft necrosis. At hospital discharge, plasma creatinine level was 185.6 μmol/L (GFR: 44.3 mL/min/1.73 m2). At that time, the immunosuppressive regimen comprised tacrolimus 15 mg/day, mycophenolate mofetil 2000 mg/day, and prednisolone 15 mg/day.
Investigation
Given the patient’s young age and normal body weight, and the absence of other major risk factors, the development of NODAT was unexpected. A history of diabetes was noted in the patient’s maternal grandmother and uncle, with no other known relevant family history, including kidney disease (Fig. 1). Fasting C-peptide was 1.3 nmol/L (normal range: 0.4 – 1.5 nmol/L). Islet autoantibodies, including GADA, ICA, IA-2A, and ZnT8A, were all negative. US pancreatic evaluation was normal. The association of diabetes with such kidney morphological abnormalities raised the possibility of maturity-onset diabetes of the young (MODY) type 5 and hepatocyte nuclear factor 1B (HNF1B) gene defects. Screening for mutations in the HNF1B gene was undertaken and a known missense heterozygous mutation (p.S148L, c.443 C>T) in exon 2 was found. So far, it was not possible to perform genetic testing on any other family member, but the family was referred for genetic counseling. Regarding other manifestations, the patient had no complaints suggestive of exocrine dysfunction, liver enzymes were normal over the years (both alanine aminotransferase and aspartate aminotransferase persistently below the upper limit of the normal range, both before and after transplantation), and there was no clinical evidence of genital tract malformations.
Figure 1 Family pedigree of the patient showing the affected patient (proband) and other affected family members with diabetes.
Treatment
Insulin therapy was started with a long-acting analog (0.16 UI/kg/day). The insulin dose was progressively reduced, following reductions in tacrolimus and prednisolone doses. Five months after NODAT diagnosis, insulin was switched to a dipeptidyl peptidase 4 (DPP-4) inhibitor. At that time, the patient was under tacrolimus 8 mg/day and prednisolone 5 mg/day. However, the patient stopped it a few weeks later due to vomiting. As glycated hemoglobin (HbA1c) remained below 6.5%, the patient was kept without medication. However, 16 months later, HbA1c increased to 6.9%. Therefore, sitagliptin 25 mg/day was resumed, with good tolerance. Nevertheless, HbA1c progressively increased to 8% in the following 8 months (Fig. 2). Renal function slowly deteriorated, with plasma creatinine level ranging between 185.6 and 229.8 μmol/L (GFR range: 34– 44 mL/min/1.73 m2). At that time, the patient was under tacrolimus 6 mg/day and prednisolone 5 mg/day. After discussing the therapeutic options, therapy was switched to liraglutide, which was progressively titrated to 1.8 mg/day.
Figure 2 Evolution of the patient’s glycemic control after NODAT diagnosis.
Outcome and follow-up
Two months after liraglutide introduction, HbA1c dropped to 6.7%. However, glycemic control again deteriorated, and HbA1c increased up to 10.9% (Fig. 1). Immunosuppressive therapy doses were unchanged, but the patient reported less physical activity. Plasma creatinine level was 224.5 μmol/L, corresponding to a GFR of 35.2 mL/min/1.73 m2. At this time, liraglutide was stopped, and insulin with a long-acting analog (0.14 UI/kg/day) was resumed. Two months later, glycemic control slightly improved. Insulin therapy will be maintained, and treatment management will continue as considered appropriate.
Discussion
HNF1B is involved in the embryogenesis and tissue-specific gene expression of several organs, including the kidney, pancreas, liver, and genital tract. Even though HNF1B mutations were first associated with MODY, it is currently known that HNF1B anomalies result in a systemic disease that follows the expression of HNF1B (1). The most frequently described manifestations include kidney disease, early-onset diabetes, pancreatic exocrine insufficiency, liver dysfunction, and genital tract malformations. Notably, there is marked phenotypic variability, suggesting that other genetic or environmental factors might modify the pattern and severity of the disease (1).
The prevalence of HNF1B-associated disease is unknown. The mean overall detection rate of HNF1B defects in cohorts of patients with kidney disease was 19% (1). By contrast, they are a rare cause of MODY, accounting for less than 1% of the cases (1). As most cohorts were pre-selected for kidney disease and/or diabetes, the frequency of these and other clinical features is unclear.
Genetic changes in the HNF1B gene comprise either heterozygous intragenic mutations or gene deletions. Although HNF1B-associated disease is inherited in an autosomal-dominant manner, spontaneous genetic changes are common, which explains the frequent absence of a family history of kidney disease or diabetes (1). Given the family history of diabetes in this patient, we hypothesize that the mutation was inherited.
Kidney disease appears to be the most common manifestation, but considerable variation is found in its phenotype and severity (2, 3, 4). Cystic disease is the predominant morphological manifestation in both children and adults (2, 3). As observed in this patient, kidney disease can present during fetal life as bilateral hyperechogenic kidneys of normal or slightly increased size (5). Tubular transport abnormalities can also be present, and hypomagnesemia is a common and distinctive feature (1, 3). Hyperuricemia and early-onset gout are also observed. Importantly, renal function is frequently impaired, and up to 20% of patients progress to end-stage renal disease (3).
Given the role of HNF1B in pancreatic development, HNF1B-associated disease can present with pancreatic hypoplasia, and both endocrine and exocrine dysfunction can occur (1). Diabetes is considered as the most frequent extra-renal phenotype. In the largest cohort described to date (3), Dubois-Laforgue et al. reported diabetes in 82% of 194 patients. Diabetes is usually of early-onset (median age 20 years), but it can be found at any age from the neonatal period to late middle age (1). Clinical presentation seems highly variable, including ketoacidosis (3). The pathophysiology of HNF1B-associated diabetes has not been definitively established. Both beta-cell dysfunction and reduced hepatic insulin sensitivity have been implicated (1). Beta-cell dysfunction, resulting in reduced insulin secretion, may be a consequence of pancreatic hypoplasia and beta-cell mass reduction. However, primary functional abnormalities in insulin secretion must also occur, as pancreatic hypoplasia and endocrine dysfunction do not completely correlate (6).
As this case demonstrates, HNF1B-associated diabetes can present as NODAT. In this patient, it was the association of an unexpected NODAT and the kidney disease that triggered the diagnosis. The frequency of NODAT in HNF1B-associated disease is unknown. It is suggested that HNF1B defects determine a genetic susceptibility to NODAT, as the reduced insulin secretory capacity of beta-cell is unmasked by the immunosuppressive drugs (7, 8). Faguer et al.(9) hypothesized that immunosuppressive therapy may switch off residual HNF1B expression and thus potentiate beta-cell dysfunction. Combining clinical data and in vitro experiments, these authors suggested that calcineurin inhibitors (CNI) induce a downregulation of the nonmutated allele, mimicking HNF1B biallelic inactivation. In this patient, given the deterioration of renal function, immunosuppressive regimens avoiding CNI were not considered. However, consideringthat immunosuppressive regimens free of CNI may minimize the deterioration of NODAT, if the patient’s glycemic control remains above the target, the possibility of such a regiment will be discussed. Whether all kidney transplant recipients will ultimately develop diabetes is unknown. Interestingly, Waller et al. (8) reported the case of a boy with a previously unrecognized HNF1B mutation in which NODAT regressed after transplant nephrectomy and cyclosporine and steroid withdrawal. It is not clear whether NODAT has a distinctive presentation in patients with HNF1B-associated disease. Some authors highlighted its very early onset after transplantation, as occurred in this case, but this was not seen in all patients reported.
The most appropriate treatment for HNF1B-associated diabetes is not established. In keeping with the hypothesis of beta-cell dysfunction, the majority of patients are treated with insulin (3). However, residual insulin secretion has been demonstrated, and some authors argue that insulin treatment can be delayed for a few years (3). The choice for a DPP-4 inhibitor was based on the patient characteristics (normal weight and post-transplantation kidney status) and an only slightly elevated HbA1c value. Also, there was the aim of simplifying the therapeutic regimen, switching to an oral agent. Even though our patient remained without any treatment for more than a year, glycemic control eventually deteriorated. The initial response to liraglutide was impressive, but glycemic control worsened again, and insulin therapy was required 6 months later. We hypothesize that the patient’s young age and normal body weight, in addition to the absence of major pancreatic morphological abnormalities, contributed to the initial glycemic control. However, the immunosuppressive therapy possibly limited an extended response to non-insulin agents, and so insulin therapy was resumed nearly 3 years after diabetes diagnosis. As far as we know, there is no data on treatment of HNF1B-associated diabetes with glucagon-like peptide-1 receptor agonists. Whether patients with HNF1B-associated diabetes not receiving calcineurin inhibitors respond to these agents remains to be elucidated.
Other reported manifestations of HNF1B-disease include abnormal liver function, usually manifesting as an asymptomatic rise in liver enzymes; biliary anomalies presenting as bile duct cysts; and various genital tract malformations (3). Of note, the clinical spectrum of the disease seems to be expanding (1, 6). At this time, there is no evidence of any of these additional features in this patient.
In conclusion, HNF1B-associated disease is remarkable for its marked phenotypic variability and the high rate of de novo cases. The diagnosis is challenging and many cases likely remain undetected or misdiagnosed. However, the right diagnosis is essential to provide the best care to both patients and their relatives. We believe the most important step for diagnosis of HNF1B-associated disease is to first recognize this possibility. Findings such as hypomagnesemia or pancreatic structural anomalies can support the indication for genetic testing (10). Additionally, an HNF1B score using a weight combination of clinical features has been proposed for selecting patients for HNF1B testing (4). Finally, as the case we present highlights, HNF1B-associated disease should be considered when NODAT unexpectedly develops in young kidney transplant recipients with a suggestive kidney disease. Even though the most appropriate treatment for HNF1B-associated diabetes is not established, immunosuppressive therapy superimposed on a beta-cell dysfunction seems to determine the need for insulin therapy after a variable period.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this case report.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Patient consent
Written informed consent has been obtained from the patient for publication of the submitted article and accompanying images.
Author contribution statement
Both authors were involved in the management of the patient, and in the writing and editing of the manuscript. | 0.16 INTERNATIONAL UNIT/KILOGRAM, QD | DrugDosageText | CC BY-NC-ND | 33522494 | 19,046,333 | 2021-01-27 |
What was the dosage of drug 'PREDNISOLONE'? | New-onset diabetes after kidney transplantation revealing HNF1B-associated disease.
Molecular alterations of the transcription factor hepatocyte nuclear factor 1B (HNF1B) are associated with systemic disease, with kidney disease and maturity-onset diabetes of the young (MODY) as the most characteristic manifestations. Other features comprise pancreatic exocrine insufficiency, liver and biliary anomalies, and genital tract malformations. HNF1B-associated disease is clinically heterogeneous, and therefore the diagnosis is challenging. The authors describe the case of a 19-year-old man with new-onset diabetes after kidney transplantation (NODAT). The kidney disease presented during fetal life as bilateral hyperechogenic kidneys. Renal function progressively deteriorated during childhood, and at the age of 19, the patient was submitted to a living-kidney transplant. Two weeks after transplant, NODAT developed. Given the young age and normal body weight, NODAT was unexpected, and the possibility of HNF1B-associated disease was considered. Screening for mutations in HNF1B was undertaken, and a known mutation was found. As this case highlights, HNF1B-associated disease should be considered when NODAT unexpectedly develops in young kidney transplant recipients with a suggestive renal disease.
HNF1B anomalies are associated with systemic disease, including kidney disease, diabetes mellitus, pancreatic exocrine insufficiency, liver test abnormalities and genital tract malformations. Phenotype is variable and there are no pathognomonic manifestations, but kidney disease appears to be the most common feature and diabetes the most frequent extra-renal phenotype. Spontaneous gene alterations are common, and the lack of family history should not exclude the diagnosis. HNF1B defects should be considered when NODAT develops in a young adult kidney transplant recipient with a suggestive kidney disease and without extensive risk factors for diabetes. The most appropriate treatment for HNF1B-associated diabetes is not established, but immunosuppressive therapy superimposed on a beta-cell dysfunction seems to determine the need for insulin therapy after a variable period. Immunosupressive regimens free of calcineurin inhibitors should be considered in patients with HNF1B-associated disease to minimize the risk of developing NODAT.
Background
Since the first description of an HNF1B mutation associated with early-onset diabetes in 1997, the knowledge of HNF1B genetic changes has evolved significantly, and it is currently known that HNF1B anomalies are associated with a systemic disease with marked phenotypic variability (1). The diagnosis of HNF1B-associated disease is challenging, and many cases likely remain undetected or misdiagnosed. The authors describe the case of a young male with a previously unrecognized HNF1B mutation that developed NODAT after kidney transplantation, which triggered the diagnosis of HNF1B-associated disease.
Case presentation
A 19-year-old man was referred to our clinic because of new-onset diabetes after kidney transplantation (NODAT). Two weeks after transplantation, routine blood analysis revealed marked hyperglycemia (up to 17.2 mmol/L). He denied catabolic symptoms, and there was no evidence of ketoacidosis. Through childhood, blood glucose levels were normal, with fasting blood glucose levels ranging from 4.2 to 5.2 mmol/L, with no trend of deterioration over time. His body weight was 55 kg and BMI 21.5 kg/m2. Kidney disease was suspected on a routine fetal ultrasonographic scan (US) performed at 20 weeks’ gestation, revealing bilateral hyperechogenic kidneys. After birth, the US demonstrated hyperechogenic kidneys with small cysts, and plasma creatinine was abnormally elevated. The patient was the first child of non-consanguineous and healthy parents, which pointed to autosomal recessive polycystic kidney disease (ARPKD). Thereafter, renal function progressively deteriorated. By the age of 18, plasma creatinine level was 433.2 μmol/L (corresponding to a glomerular filtrate rate (GFR) of 15.9 mL/min/1.73 m2). One year later, the patient received a living kidney transplant from his 52-year-old father. There was no morphological abnormality on the father’s kidney, and his renal function was normal. The procedure was complicated by partial graft necrosis. At hospital discharge, plasma creatinine level was 185.6 μmol/L (GFR: 44.3 mL/min/1.73 m2). At that time, the immunosuppressive regimen comprised tacrolimus 15 mg/day, mycophenolate mofetil 2000 mg/day, and prednisolone 15 mg/day.
Investigation
Given the patient’s young age and normal body weight, and the absence of other major risk factors, the development of NODAT was unexpected. A history of diabetes was noted in the patient’s maternal grandmother and uncle, with no other known relevant family history, including kidney disease (Fig. 1). Fasting C-peptide was 1.3 nmol/L (normal range: 0.4 – 1.5 nmol/L). Islet autoantibodies, including GADA, ICA, IA-2A, and ZnT8A, were all negative. US pancreatic evaluation was normal. The association of diabetes with such kidney morphological abnormalities raised the possibility of maturity-onset diabetes of the young (MODY) type 5 and hepatocyte nuclear factor 1B (HNF1B) gene defects. Screening for mutations in the HNF1B gene was undertaken and a known missense heterozygous mutation (p.S148L, c.443 C>T) in exon 2 was found. So far, it was not possible to perform genetic testing on any other family member, but the family was referred for genetic counseling. Regarding other manifestations, the patient had no complaints suggestive of exocrine dysfunction, liver enzymes were normal over the years (both alanine aminotransferase and aspartate aminotransferase persistently below the upper limit of the normal range, both before and after transplantation), and there was no clinical evidence of genital tract malformations.
Figure 1 Family pedigree of the patient showing the affected patient (proband) and other affected family members with diabetes.
Treatment
Insulin therapy was started with a long-acting analog (0.16 UI/kg/day). The insulin dose was progressively reduced, following reductions in tacrolimus and prednisolone doses. Five months after NODAT diagnosis, insulin was switched to a dipeptidyl peptidase 4 (DPP-4) inhibitor. At that time, the patient was under tacrolimus 8 mg/day and prednisolone 5 mg/day. However, the patient stopped it a few weeks later due to vomiting. As glycated hemoglobin (HbA1c) remained below 6.5%, the patient was kept without medication. However, 16 months later, HbA1c increased to 6.9%. Therefore, sitagliptin 25 mg/day was resumed, with good tolerance. Nevertheless, HbA1c progressively increased to 8% in the following 8 months (Fig. 2). Renal function slowly deteriorated, with plasma creatinine level ranging between 185.6 and 229.8 μmol/L (GFR range: 34– 44 mL/min/1.73 m2). At that time, the patient was under tacrolimus 6 mg/day and prednisolone 5 mg/day. After discussing the therapeutic options, therapy was switched to liraglutide, which was progressively titrated to 1.8 mg/day.
Figure 2 Evolution of the patient’s glycemic control after NODAT diagnosis.
Outcome and follow-up
Two months after liraglutide introduction, HbA1c dropped to 6.7%. However, glycemic control again deteriorated, and HbA1c increased up to 10.9% (Fig. 1). Immunosuppressive therapy doses were unchanged, but the patient reported less physical activity. Plasma creatinine level was 224.5 μmol/L, corresponding to a GFR of 35.2 mL/min/1.73 m2. At this time, liraglutide was stopped, and insulin with a long-acting analog (0.14 UI/kg/day) was resumed. Two months later, glycemic control slightly improved. Insulin therapy will be maintained, and treatment management will continue as considered appropriate.
Discussion
HNF1B is involved in the embryogenesis and tissue-specific gene expression of several organs, including the kidney, pancreas, liver, and genital tract. Even though HNF1B mutations were first associated with MODY, it is currently known that HNF1B anomalies result in a systemic disease that follows the expression of HNF1B (1). The most frequently described manifestations include kidney disease, early-onset diabetes, pancreatic exocrine insufficiency, liver dysfunction, and genital tract malformations. Notably, there is marked phenotypic variability, suggesting that other genetic or environmental factors might modify the pattern and severity of the disease (1).
The prevalence of HNF1B-associated disease is unknown. The mean overall detection rate of HNF1B defects in cohorts of patients with kidney disease was 19% (1). By contrast, they are a rare cause of MODY, accounting for less than 1% of the cases (1). As most cohorts were pre-selected for kidney disease and/or diabetes, the frequency of these and other clinical features is unclear.
Genetic changes in the HNF1B gene comprise either heterozygous intragenic mutations or gene deletions. Although HNF1B-associated disease is inherited in an autosomal-dominant manner, spontaneous genetic changes are common, which explains the frequent absence of a family history of kidney disease or diabetes (1). Given the family history of diabetes in this patient, we hypothesize that the mutation was inherited.
Kidney disease appears to be the most common manifestation, but considerable variation is found in its phenotype and severity (2, 3, 4). Cystic disease is the predominant morphological manifestation in both children and adults (2, 3). As observed in this patient, kidney disease can present during fetal life as bilateral hyperechogenic kidneys of normal or slightly increased size (5). Tubular transport abnormalities can also be present, and hypomagnesemia is a common and distinctive feature (1, 3). Hyperuricemia and early-onset gout are also observed. Importantly, renal function is frequently impaired, and up to 20% of patients progress to end-stage renal disease (3).
Given the role of HNF1B in pancreatic development, HNF1B-associated disease can present with pancreatic hypoplasia, and both endocrine and exocrine dysfunction can occur (1). Diabetes is considered as the most frequent extra-renal phenotype. In the largest cohort described to date (3), Dubois-Laforgue et al. reported diabetes in 82% of 194 patients. Diabetes is usually of early-onset (median age 20 years), but it can be found at any age from the neonatal period to late middle age (1). Clinical presentation seems highly variable, including ketoacidosis (3). The pathophysiology of HNF1B-associated diabetes has not been definitively established. Both beta-cell dysfunction and reduced hepatic insulin sensitivity have been implicated (1). Beta-cell dysfunction, resulting in reduced insulin secretion, may be a consequence of pancreatic hypoplasia and beta-cell mass reduction. However, primary functional abnormalities in insulin secretion must also occur, as pancreatic hypoplasia and endocrine dysfunction do not completely correlate (6).
As this case demonstrates, HNF1B-associated diabetes can present as NODAT. In this patient, it was the association of an unexpected NODAT and the kidney disease that triggered the diagnosis. The frequency of NODAT in HNF1B-associated disease is unknown. It is suggested that HNF1B defects determine a genetic susceptibility to NODAT, as the reduced insulin secretory capacity of beta-cell is unmasked by the immunosuppressive drugs (7, 8). Faguer et al.(9) hypothesized that immunosuppressive therapy may switch off residual HNF1B expression and thus potentiate beta-cell dysfunction. Combining clinical data and in vitro experiments, these authors suggested that calcineurin inhibitors (CNI) induce a downregulation of the nonmutated allele, mimicking HNF1B biallelic inactivation. In this patient, given the deterioration of renal function, immunosuppressive regimens avoiding CNI were not considered. However, consideringthat immunosuppressive regimens free of CNI may minimize the deterioration of NODAT, if the patient’s glycemic control remains above the target, the possibility of such a regiment will be discussed. Whether all kidney transplant recipients will ultimately develop diabetes is unknown. Interestingly, Waller et al. (8) reported the case of a boy with a previously unrecognized HNF1B mutation in which NODAT regressed after transplant nephrectomy and cyclosporine and steroid withdrawal. It is not clear whether NODAT has a distinctive presentation in patients with HNF1B-associated disease. Some authors highlighted its very early onset after transplantation, as occurred in this case, but this was not seen in all patients reported.
The most appropriate treatment for HNF1B-associated diabetes is not established. In keeping with the hypothesis of beta-cell dysfunction, the majority of patients are treated with insulin (3). However, residual insulin secretion has been demonstrated, and some authors argue that insulin treatment can be delayed for a few years (3). The choice for a DPP-4 inhibitor was based on the patient characteristics (normal weight and post-transplantation kidney status) and an only slightly elevated HbA1c value. Also, there was the aim of simplifying the therapeutic regimen, switching to an oral agent. Even though our patient remained without any treatment for more than a year, glycemic control eventually deteriorated. The initial response to liraglutide was impressive, but glycemic control worsened again, and insulin therapy was required 6 months later. We hypothesize that the patient’s young age and normal body weight, in addition to the absence of major pancreatic morphological abnormalities, contributed to the initial glycemic control. However, the immunosuppressive therapy possibly limited an extended response to non-insulin agents, and so insulin therapy was resumed nearly 3 years after diabetes diagnosis. As far as we know, there is no data on treatment of HNF1B-associated diabetes with glucagon-like peptide-1 receptor agonists. Whether patients with HNF1B-associated diabetes not receiving calcineurin inhibitors respond to these agents remains to be elucidated.
Other reported manifestations of HNF1B-disease include abnormal liver function, usually manifesting as an asymptomatic rise in liver enzymes; biliary anomalies presenting as bile duct cysts; and various genital tract malformations (3). Of note, the clinical spectrum of the disease seems to be expanding (1, 6). At this time, there is no evidence of any of these additional features in this patient.
In conclusion, HNF1B-associated disease is remarkable for its marked phenotypic variability and the high rate of de novo cases. The diagnosis is challenging and many cases likely remain undetected or misdiagnosed. However, the right diagnosis is essential to provide the best care to both patients and their relatives. We believe the most important step for diagnosis of HNF1B-associated disease is to first recognize this possibility. Findings such as hypomagnesemia or pancreatic structural anomalies can support the indication for genetic testing (10). Additionally, an HNF1B score using a weight combination of clinical features has been proposed for selecting patients for HNF1B testing (4). Finally, as the case we present highlights, HNF1B-associated disease should be considered when NODAT unexpectedly develops in young kidney transplant recipients with a suggestive kidney disease. Even though the most appropriate treatment for HNF1B-associated diabetes is not established, immunosuppressive therapy superimposed on a beta-cell dysfunction seems to determine the need for insulin therapy after a variable period.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this case report.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Patient consent
Written informed consent has been obtained from the patient for publication of the submitted article and accompanying images.
Author contribution statement
Both authors were involved in the management of the patient, and in the writing and editing of the manuscript. | 5 MILLIGRAM, QD | DrugDosageText | CC BY-NC-ND | 33522494 | 19,046,333 | 2021-01-27 |
What was the dosage of drug 'SITAGLIPTIN PHOSPHATE'? | New-onset diabetes after kidney transplantation revealing HNF1B-associated disease.
Molecular alterations of the transcription factor hepatocyte nuclear factor 1B (HNF1B) are associated with systemic disease, with kidney disease and maturity-onset diabetes of the young (MODY) as the most characteristic manifestations. Other features comprise pancreatic exocrine insufficiency, liver and biliary anomalies, and genital tract malformations. HNF1B-associated disease is clinically heterogeneous, and therefore the diagnosis is challenging. The authors describe the case of a 19-year-old man with new-onset diabetes after kidney transplantation (NODAT). The kidney disease presented during fetal life as bilateral hyperechogenic kidneys. Renal function progressively deteriorated during childhood, and at the age of 19, the patient was submitted to a living-kidney transplant. Two weeks after transplant, NODAT developed. Given the young age and normal body weight, NODAT was unexpected, and the possibility of HNF1B-associated disease was considered. Screening for mutations in HNF1B was undertaken, and a known mutation was found. As this case highlights, HNF1B-associated disease should be considered when NODAT unexpectedly develops in young kidney transplant recipients with a suggestive renal disease.
HNF1B anomalies are associated with systemic disease, including kidney disease, diabetes mellitus, pancreatic exocrine insufficiency, liver test abnormalities and genital tract malformations. Phenotype is variable and there are no pathognomonic manifestations, but kidney disease appears to be the most common feature and diabetes the most frequent extra-renal phenotype. Spontaneous gene alterations are common, and the lack of family history should not exclude the diagnosis. HNF1B defects should be considered when NODAT develops in a young adult kidney transplant recipient with a suggestive kidney disease and without extensive risk factors for diabetes. The most appropriate treatment for HNF1B-associated diabetes is not established, but immunosuppressive therapy superimposed on a beta-cell dysfunction seems to determine the need for insulin therapy after a variable period. Immunosupressive regimens free of calcineurin inhibitors should be considered in patients with HNF1B-associated disease to minimize the risk of developing NODAT.
Background
Since the first description of an HNF1B mutation associated with early-onset diabetes in 1997, the knowledge of HNF1B genetic changes has evolved significantly, and it is currently known that HNF1B anomalies are associated with a systemic disease with marked phenotypic variability (1). The diagnosis of HNF1B-associated disease is challenging, and many cases likely remain undetected or misdiagnosed. The authors describe the case of a young male with a previously unrecognized HNF1B mutation that developed NODAT after kidney transplantation, which triggered the diagnosis of HNF1B-associated disease.
Case presentation
A 19-year-old man was referred to our clinic because of new-onset diabetes after kidney transplantation (NODAT). Two weeks after transplantation, routine blood analysis revealed marked hyperglycemia (up to 17.2 mmol/L). He denied catabolic symptoms, and there was no evidence of ketoacidosis. Through childhood, blood glucose levels were normal, with fasting blood glucose levels ranging from 4.2 to 5.2 mmol/L, with no trend of deterioration over time. His body weight was 55 kg and BMI 21.5 kg/m2. Kidney disease was suspected on a routine fetal ultrasonographic scan (US) performed at 20 weeks’ gestation, revealing bilateral hyperechogenic kidneys. After birth, the US demonstrated hyperechogenic kidneys with small cysts, and plasma creatinine was abnormally elevated. The patient was the first child of non-consanguineous and healthy parents, which pointed to autosomal recessive polycystic kidney disease (ARPKD). Thereafter, renal function progressively deteriorated. By the age of 18, plasma creatinine level was 433.2 μmol/L (corresponding to a glomerular filtrate rate (GFR) of 15.9 mL/min/1.73 m2). One year later, the patient received a living kidney transplant from his 52-year-old father. There was no morphological abnormality on the father’s kidney, and his renal function was normal. The procedure was complicated by partial graft necrosis. At hospital discharge, plasma creatinine level was 185.6 μmol/L (GFR: 44.3 mL/min/1.73 m2). At that time, the immunosuppressive regimen comprised tacrolimus 15 mg/day, mycophenolate mofetil 2000 mg/day, and prednisolone 15 mg/day.
Investigation
Given the patient’s young age and normal body weight, and the absence of other major risk factors, the development of NODAT was unexpected. A history of diabetes was noted in the patient’s maternal grandmother and uncle, with no other known relevant family history, including kidney disease (Fig. 1). Fasting C-peptide was 1.3 nmol/L (normal range: 0.4 – 1.5 nmol/L). Islet autoantibodies, including GADA, ICA, IA-2A, and ZnT8A, were all negative. US pancreatic evaluation was normal. The association of diabetes with such kidney morphological abnormalities raised the possibility of maturity-onset diabetes of the young (MODY) type 5 and hepatocyte nuclear factor 1B (HNF1B) gene defects. Screening for mutations in the HNF1B gene was undertaken and a known missense heterozygous mutation (p.S148L, c.443 C>T) in exon 2 was found. So far, it was not possible to perform genetic testing on any other family member, but the family was referred for genetic counseling. Regarding other manifestations, the patient had no complaints suggestive of exocrine dysfunction, liver enzymes were normal over the years (both alanine aminotransferase and aspartate aminotransferase persistently below the upper limit of the normal range, both before and after transplantation), and there was no clinical evidence of genital tract malformations.
Figure 1 Family pedigree of the patient showing the affected patient (proband) and other affected family members with diabetes.
Treatment
Insulin therapy was started with a long-acting analog (0.16 UI/kg/day). The insulin dose was progressively reduced, following reductions in tacrolimus and prednisolone doses. Five months after NODAT diagnosis, insulin was switched to a dipeptidyl peptidase 4 (DPP-4) inhibitor. At that time, the patient was under tacrolimus 8 mg/day and prednisolone 5 mg/day. However, the patient stopped it a few weeks later due to vomiting. As glycated hemoglobin (HbA1c) remained below 6.5%, the patient was kept without medication. However, 16 months later, HbA1c increased to 6.9%. Therefore, sitagliptin 25 mg/day was resumed, with good tolerance. Nevertheless, HbA1c progressively increased to 8% in the following 8 months (Fig. 2). Renal function slowly deteriorated, with plasma creatinine level ranging between 185.6 and 229.8 μmol/L (GFR range: 34– 44 mL/min/1.73 m2). At that time, the patient was under tacrolimus 6 mg/day and prednisolone 5 mg/day. After discussing the therapeutic options, therapy was switched to liraglutide, which was progressively titrated to 1.8 mg/day.
Figure 2 Evolution of the patient’s glycemic control after NODAT diagnosis.
Outcome and follow-up
Two months after liraglutide introduction, HbA1c dropped to 6.7%. However, glycemic control again deteriorated, and HbA1c increased up to 10.9% (Fig. 1). Immunosuppressive therapy doses were unchanged, but the patient reported less physical activity. Plasma creatinine level was 224.5 μmol/L, corresponding to a GFR of 35.2 mL/min/1.73 m2. At this time, liraglutide was stopped, and insulin with a long-acting analog (0.14 UI/kg/day) was resumed. Two months later, glycemic control slightly improved. Insulin therapy will be maintained, and treatment management will continue as considered appropriate.
Discussion
HNF1B is involved in the embryogenesis and tissue-specific gene expression of several organs, including the kidney, pancreas, liver, and genital tract. Even though HNF1B mutations were first associated with MODY, it is currently known that HNF1B anomalies result in a systemic disease that follows the expression of HNF1B (1). The most frequently described manifestations include kidney disease, early-onset diabetes, pancreatic exocrine insufficiency, liver dysfunction, and genital tract malformations. Notably, there is marked phenotypic variability, suggesting that other genetic or environmental factors might modify the pattern and severity of the disease (1).
The prevalence of HNF1B-associated disease is unknown. The mean overall detection rate of HNF1B defects in cohorts of patients with kidney disease was 19% (1). By contrast, they are a rare cause of MODY, accounting for less than 1% of the cases (1). As most cohorts were pre-selected for kidney disease and/or diabetes, the frequency of these and other clinical features is unclear.
Genetic changes in the HNF1B gene comprise either heterozygous intragenic mutations or gene deletions. Although HNF1B-associated disease is inherited in an autosomal-dominant manner, spontaneous genetic changes are common, which explains the frequent absence of a family history of kidney disease or diabetes (1). Given the family history of diabetes in this patient, we hypothesize that the mutation was inherited.
Kidney disease appears to be the most common manifestation, but considerable variation is found in its phenotype and severity (2, 3, 4). Cystic disease is the predominant morphological manifestation in both children and adults (2, 3). As observed in this patient, kidney disease can present during fetal life as bilateral hyperechogenic kidneys of normal or slightly increased size (5). Tubular transport abnormalities can also be present, and hypomagnesemia is a common and distinctive feature (1, 3). Hyperuricemia and early-onset gout are also observed. Importantly, renal function is frequently impaired, and up to 20% of patients progress to end-stage renal disease (3).
Given the role of HNF1B in pancreatic development, HNF1B-associated disease can present with pancreatic hypoplasia, and both endocrine and exocrine dysfunction can occur (1). Diabetes is considered as the most frequent extra-renal phenotype. In the largest cohort described to date (3), Dubois-Laforgue et al. reported diabetes in 82% of 194 patients. Diabetes is usually of early-onset (median age 20 years), but it can be found at any age from the neonatal period to late middle age (1). Clinical presentation seems highly variable, including ketoacidosis (3). The pathophysiology of HNF1B-associated diabetes has not been definitively established. Both beta-cell dysfunction and reduced hepatic insulin sensitivity have been implicated (1). Beta-cell dysfunction, resulting in reduced insulin secretion, may be a consequence of pancreatic hypoplasia and beta-cell mass reduction. However, primary functional abnormalities in insulin secretion must also occur, as pancreatic hypoplasia and endocrine dysfunction do not completely correlate (6).
As this case demonstrates, HNF1B-associated diabetes can present as NODAT. In this patient, it was the association of an unexpected NODAT and the kidney disease that triggered the diagnosis. The frequency of NODAT in HNF1B-associated disease is unknown. It is suggested that HNF1B defects determine a genetic susceptibility to NODAT, as the reduced insulin secretory capacity of beta-cell is unmasked by the immunosuppressive drugs (7, 8). Faguer et al.(9) hypothesized that immunosuppressive therapy may switch off residual HNF1B expression and thus potentiate beta-cell dysfunction. Combining clinical data and in vitro experiments, these authors suggested that calcineurin inhibitors (CNI) induce a downregulation of the nonmutated allele, mimicking HNF1B biallelic inactivation. In this patient, given the deterioration of renal function, immunosuppressive regimens avoiding CNI were not considered. However, consideringthat immunosuppressive regimens free of CNI may minimize the deterioration of NODAT, if the patient’s glycemic control remains above the target, the possibility of such a regiment will be discussed. Whether all kidney transplant recipients will ultimately develop diabetes is unknown. Interestingly, Waller et al. (8) reported the case of a boy with a previously unrecognized HNF1B mutation in which NODAT regressed after transplant nephrectomy and cyclosporine and steroid withdrawal. It is not clear whether NODAT has a distinctive presentation in patients with HNF1B-associated disease. Some authors highlighted its very early onset after transplantation, as occurred in this case, but this was not seen in all patients reported.
The most appropriate treatment for HNF1B-associated diabetes is not established. In keeping with the hypothesis of beta-cell dysfunction, the majority of patients are treated with insulin (3). However, residual insulin secretion has been demonstrated, and some authors argue that insulin treatment can be delayed for a few years (3). The choice for a DPP-4 inhibitor was based on the patient characteristics (normal weight and post-transplantation kidney status) and an only slightly elevated HbA1c value. Also, there was the aim of simplifying the therapeutic regimen, switching to an oral agent. Even though our patient remained without any treatment for more than a year, glycemic control eventually deteriorated. The initial response to liraglutide was impressive, but glycemic control worsened again, and insulin therapy was required 6 months later. We hypothesize that the patient’s young age and normal body weight, in addition to the absence of major pancreatic morphological abnormalities, contributed to the initial glycemic control. However, the immunosuppressive therapy possibly limited an extended response to non-insulin agents, and so insulin therapy was resumed nearly 3 years after diabetes diagnosis. As far as we know, there is no data on treatment of HNF1B-associated diabetes with glucagon-like peptide-1 receptor agonists. Whether patients with HNF1B-associated diabetes not receiving calcineurin inhibitors respond to these agents remains to be elucidated.
Other reported manifestations of HNF1B-disease include abnormal liver function, usually manifesting as an asymptomatic rise in liver enzymes; biliary anomalies presenting as bile duct cysts; and various genital tract malformations (3). Of note, the clinical spectrum of the disease seems to be expanding (1, 6). At this time, there is no evidence of any of these additional features in this patient.
In conclusion, HNF1B-associated disease is remarkable for its marked phenotypic variability and the high rate of de novo cases. The diagnosis is challenging and many cases likely remain undetected or misdiagnosed. However, the right diagnosis is essential to provide the best care to both patients and their relatives. We believe the most important step for diagnosis of HNF1B-associated disease is to first recognize this possibility. Findings such as hypomagnesemia or pancreatic structural anomalies can support the indication for genetic testing (10). Additionally, an HNF1B score using a weight combination of clinical features has been proposed for selecting patients for HNF1B testing (4). Finally, as the case we present highlights, HNF1B-associated disease should be considered when NODAT unexpectedly develops in young kidney transplant recipients with a suggestive kidney disease. Even though the most appropriate treatment for HNF1B-associated diabetes is not established, immunosuppressive therapy superimposed on a beta-cell dysfunction seems to determine the need for insulin therapy after a variable period.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this case report.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Patient consent
Written informed consent has been obtained from the patient for publication of the submitted article and accompanying images.
Author contribution statement
Both authors were involved in the management of the patient, and in the writing and editing of the manuscript. | 25 MILLIGRAM, QD | DrugDosageText | CC BY-NC-ND | 33522494 | 19,046,333 | 2021-01-27 |
What was the dosage of drug 'TACROLIMUS'? | New-onset diabetes after kidney transplantation revealing HNF1B-associated disease.
Molecular alterations of the transcription factor hepatocyte nuclear factor 1B (HNF1B) are associated with systemic disease, with kidney disease and maturity-onset diabetes of the young (MODY) as the most characteristic manifestations. Other features comprise pancreatic exocrine insufficiency, liver and biliary anomalies, and genital tract malformations. HNF1B-associated disease is clinically heterogeneous, and therefore the diagnosis is challenging. The authors describe the case of a 19-year-old man with new-onset diabetes after kidney transplantation (NODAT). The kidney disease presented during fetal life as bilateral hyperechogenic kidneys. Renal function progressively deteriorated during childhood, and at the age of 19, the patient was submitted to a living-kidney transplant. Two weeks after transplant, NODAT developed. Given the young age and normal body weight, NODAT was unexpected, and the possibility of HNF1B-associated disease was considered. Screening for mutations in HNF1B was undertaken, and a known mutation was found. As this case highlights, HNF1B-associated disease should be considered when NODAT unexpectedly develops in young kidney transplant recipients with a suggestive renal disease.
HNF1B anomalies are associated with systemic disease, including kidney disease, diabetes mellitus, pancreatic exocrine insufficiency, liver test abnormalities and genital tract malformations. Phenotype is variable and there are no pathognomonic manifestations, but kidney disease appears to be the most common feature and diabetes the most frequent extra-renal phenotype. Spontaneous gene alterations are common, and the lack of family history should not exclude the diagnosis. HNF1B defects should be considered when NODAT develops in a young adult kidney transplant recipient with a suggestive kidney disease and without extensive risk factors for diabetes. The most appropriate treatment for HNF1B-associated diabetes is not established, but immunosuppressive therapy superimposed on a beta-cell dysfunction seems to determine the need for insulin therapy after a variable period. Immunosupressive regimens free of calcineurin inhibitors should be considered in patients with HNF1B-associated disease to minimize the risk of developing NODAT.
Background
Since the first description of an HNF1B mutation associated with early-onset diabetes in 1997, the knowledge of HNF1B genetic changes has evolved significantly, and it is currently known that HNF1B anomalies are associated with a systemic disease with marked phenotypic variability (1). The diagnosis of HNF1B-associated disease is challenging, and many cases likely remain undetected or misdiagnosed. The authors describe the case of a young male with a previously unrecognized HNF1B mutation that developed NODAT after kidney transplantation, which triggered the diagnosis of HNF1B-associated disease.
Case presentation
A 19-year-old man was referred to our clinic because of new-onset diabetes after kidney transplantation (NODAT). Two weeks after transplantation, routine blood analysis revealed marked hyperglycemia (up to 17.2 mmol/L). He denied catabolic symptoms, and there was no evidence of ketoacidosis. Through childhood, blood glucose levels were normal, with fasting blood glucose levels ranging from 4.2 to 5.2 mmol/L, with no trend of deterioration over time. His body weight was 55 kg and BMI 21.5 kg/m2. Kidney disease was suspected on a routine fetal ultrasonographic scan (US) performed at 20 weeks’ gestation, revealing bilateral hyperechogenic kidneys. After birth, the US demonstrated hyperechogenic kidneys with small cysts, and plasma creatinine was abnormally elevated. The patient was the first child of non-consanguineous and healthy parents, which pointed to autosomal recessive polycystic kidney disease (ARPKD). Thereafter, renal function progressively deteriorated. By the age of 18, plasma creatinine level was 433.2 μmol/L (corresponding to a glomerular filtrate rate (GFR) of 15.9 mL/min/1.73 m2). One year later, the patient received a living kidney transplant from his 52-year-old father. There was no morphological abnormality on the father’s kidney, and his renal function was normal. The procedure was complicated by partial graft necrosis. At hospital discharge, plasma creatinine level was 185.6 μmol/L (GFR: 44.3 mL/min/1.73 m2). At that time, the immunosuppressive regimen comprised tacrolimus 15 mg/day, mycophenolate mofetil 2000 mg/day, and prednisolone 15 mg/day.
Investigation
Given the patient’s young age and normal body weight, and the absence of other major risk factors, the development of NODAT was unexpected. A history of diabetes was noted in the patient’s maternal grandmother and uncle, with no other known relevant family history, including kidney disease (Fig. 1). Fasting C-peptide was 1.3 nmol/L (normal range: 0.4 – 1.5 nmol/L). Islet autoantibodies, including GADA, ICA, IA-2A, and ZnT8A, were all negative. US pancreatic evaluation was normal. The association of diabetes with such kidney morphological abnormalities raised the possibility of maturity-onset diabetes of the young (MODY) type 5 and hepatocyte nuclear factor 1B (HNF1B) gene defects. Screening for mutations in the HNF1B gene was undertaken and a known missense heterozygous mutation (p.S148L, c.443 C>T) in exon 2 was found. So far, it was not possible to perform genetic testing on any other family member, but the family was referred for genetic counseling. Regarding other manifestations, the patient had no complaints suggestive of exocrine dysfunction, liver enzymes were normal over the years (both alanine aminotransferase and aspartate aminotransferase persistently below the upper limit of the normal range, both before and after transplantation), and there was no clinical evidence of genital tract malformations.
Figure 1 Family pedigree of the patient showing the affected patient (proband) and other affected family members with diabetes.
Treatment
Insulin therapy was started with a long-acting analog (0.16 UI/kg/day). The insulin dose was progressively reduced, following reductions in tacrolimus and prednisolone doses. Five months after NODAT diagnosis, insulin was switched to a dipeptidyl peptidase 4 (DPP-4) inhibitor. At that time, the patient was under tacrolimus 8 mg/day and prednisolone 5 mg/day. However, the patient stopped it a few weeks later due to vomiting. As glycated hemoglobin (HbA1c) remained below 6.5%, the patient was kept without medication. However, 16 months later, HbA1c increased to 6.9%. Therefore, sitagliptin 25 mg/day was resumed, with good tolerance. Nevertheless, HbA1c progressively increased to 8% in the following 8 months (Fig. 2). Renal function slowly deteriorated, with plasma creatinine level ranging between 185.6 and 229.8 μmol/L (GFR range: 34– 44 mL/min/1.73 m2). At that time, the patient was under tacrolimus 6 mg/day and prednisolone 5 mg/day. After discussing the therapeutic options, therapy was switched to liraglutide, which was progressively titrated to 1.8 mg/day.
Figure 2 Evolution of the patient’s glycemic control after NODAT diagnosis.
Outcome and follow-up
Two months after liraglutide introduction, HbA1c dropped to 6.7%. However, glycemic control again deteriorated, and HbA1c increased up to 10.9% (Fig. 1). Immunosuppressive therapy doses were unchanged, but the patient reported less physical activity. Plasma creatinine level was 224.5 μmol/L, corresponding to a GFR of 35.2 mL/min/1.73 m2. At this time, liraglutide was stopped, and insulin with a long-acting analog (0.14 UI/kg/day) was resumed. Two months later, glycemic control slightly improved. Insulin therapy will be maintained, and treatment management will continue as considered appropriate.
Discussion
HNF1B is involved in the embryogenesis and tissue-specific gene expression of several organs, including the kidney, pancreas, liver, and genital tract. Even though HNF1B mutations were first associated with MODY, it is currently known that HNF1B anomalies result in a systemic disease that follows the expression of HNF1B (1). The most frequently described manifestations include kidney disease, early-onset diabetes, pancreatic exocrine insufficiency, liver dysfunction, and genital tract malformations. Notably, there is marked phenotypic variability, suggesting that other genetic or environmental factors might modify the pattern and severity of the disease (1).
The prevalence of HNF1B-associated disease is unknown. The mean overall detection rate of HNF1B defects in cohorts of patients with kidney disease was 19% (1). By contrast, they are a rare cause of MODY, accounting for less than 1% of the cases (1). As most cohorts were pre-selected for kidney disease and/or diabetes, the frequency of these and other clinical features is unclear.
Genetic changes in the HNF1B gene comprise either heterozygous intragenic mutations or gene deletions. Although HNF1B-associated disease is inherited in an autosomal-dominant manner, spontaneous genetic changes are common, which explains the frequent absence of a family history of kidney disease or diabetes (1). Given the family history of diabetes in this patient, we hypothesize that the mutation was inherited.
Kidney disease appears to be the most common manifestation, but considerable variation is found in its phenotype and severity (2, 3, 4). Cystic disease is the predominant morphological manifestation in both children and adults (2, 3). As observed in this patient, kidney disease can present during fetal life as bilateral hyperechogenic kidneys of normal or slightly increased size (5). Tubular transport abnormalities can also be present, and hypomagnesemia is a common and distinctive feature (1, 3). Hyperuricemia and early-onset gout are also observed. Importantly, renal function is frequently impaired, and up to 20% of patients progress to end-stage renal disease (3).
Given the role of HNF1B in pancreatic development, HNF1B-associated disease can present with pancreatic hypoplasia, and both endocrine and exocrine dysfunction can occur (1). Diabetes is considered as the most frequent extra-renal phenotype. In the largest cohort described to date (3), Dubois-Laforgue et al. reported diabetes in 82% of 194 patients. Diabetes is usually of early-onset (median age 20 years), but it can be found at any age from the neonatal period to late middle age (1). Clinical presentation seems highly variable, including ketoacidosis (3). The pathophysiology of HNF1B-associated diabetes has not been definitively established. Both beta-cell dysfunction and reduced hepatic insulin sensitivity have been implicated (1). Beta-cell dysfunction, resulting in reduced insulin secretion, may be a consequence of pancreatic hypoplasia and beta-cell mass reduction. However, primary functional abnormalities in insulin secretion must also occur, as pancreatic hypoplasia and endocrine dysfunction do not completely correlate (6).
As this case demonstrates, HNF1B-associated diabetes can present as NODAT. In this patient, it was the association of an unexpected NODAT and the kidney disease that triggered the diagnosis. The frequency of NODAT in HNF1B-associated disease is unknown. It is suggested that HNF1B defects determine a genetic susceptibility to NODAT, as the reduced insulin secretory capacity of beta-cell is unmasked by the immunosuppressive drugs (7, 8). Faguer et al.(9) hypothesized that immunosuppressive therapy may switch off residual HNF1B expression and thus potentiate beta-cell dysfunction. Combining clinical data and in vitro experiments, these authors suggested that calcineurin inhibitors (CNI) induce a downregulation of the nonmutated allele, mimicking HNF1B biallelic inactivation. In this patient, given the deterioration of renal function, immunosuppressive regimens avoiding CNI were not considered. However, consideringthat immunosuppressive regimens free of CNI may minimize the deterioration of NODAT, if the patient’s glycemic control remains above the target, the possibility of such a regiment will be discussed. Whether all kidney transplant recipients will ultimately develop diabetes is unknown. Interestingly, Waller et al. (8) reported the case of a boy with a previously unrecognized HNF1B mutation in which NODAT regressed after transplant nephrectomy and cyclosporine and steroid withdrawal. It is not clear whether NODAT has a distinctive presentation in patients with HNF1B-associated disease. Some authors highlighted its very early onset after transplantation, as occurred in this case, but this was not seen in all patients reported.
The most appropriate treatment for HNF1B-associated diabetes is not established. In keeping with the hypothesis of beta-cell dysfunction, the majority of patients are treated with insulin (3). However, residual insulin secretion has been demonstrated, and some authors argue that insulin treatment can be delayed for a few years (3). The choice for a DPP-4 inhibitor was based on the patient characteristics (normal weight and post-transplantation kidney status) and an only slightly elevated HbA1c value. Also, there was the aim of simplifying the therapeutic regimen, switching to an oral agent. Even though our patient remained without any treatment for more than a year, glycemic control eventually deteriorated. The initial response to liraglutide was impressive, but glycemic control worsened again, and insulin therapy was required 6 months later. We hypothesize that the patient’s young age and normal body weight, in addition to the absence of major pancreatic morphological abnormalities, contributed to the initial glycemic control. However, the immunosuppressive therapy possibly limited an extended response to non-insulin agents, and so insulin therapy was resumed nearly 3 years after diabetes diagnosis. As far as we know, there is no data on treatment of HNF1B-associated diabetes with glucagon-like peptide-1 receptor agonists. Whether patients with HNF1B-associated diabetes not receiving calcineurin inhibitors respond to these agents remains to be elucidated.
Other reported manifestations of HNF1B-disease include abnormal liver function, usually manifesting as an asymptomatic rise in liver enzymes; biliary anomalies presenting as bile duct cysts; and various genital tract malformations (3). Of note, the clinical spectrum of the disease seems to be expanding (1, 6). At this time, there is no evidence of any of these additional features in this patient.
In conclusion, HNF1B-associated disease is remarkable for its marked phenotypic variability and the high rate of de novo cases. The diagnosis is challenging and many cases likely remain undetected or misdiagnosed. However, the right diagnosis is essential to provide the best care to both patients and their relatives. We believe the most important step for diagnosis of HNF1B-associated disease is to first recognize this possibility. Findings such as hypomagnesemia or pancreatic structural anomalies can support the indication for genetic testing (10). Additionally, an HNF1B score using a weight combination of clinical features has been proposed for selecting patients for HNF1B testing (4). Finally, as the case we present highlights, HNF1B-associated disease should be considered when NODAT unexpectedly develops in young kidney transplant recipients with a suggestive kidney disease. Even though the most appropriate treatment for HNF1B-associated diabetes is not established, immunosuppressive therapy superimposed on a beta-cell dysfunction seems to determine the need for insulin therapy after a variable period.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this case report.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Patient consent
Written informed consent has been obtained from the patient for publication of the submitted article and accompanying images.
Author contribution statement
Both authors were involved in the management of the patient, and in the writing and editing of the manuscript. | 8 MILLIGRAM, QD | DrugDosageText | CC BY-NC-ND | 33522494 | 19,046,333 | 2021-01-27 |
What was the outcome of reaction 'Diabetes mellitus inadequate control'? | New-onset diabetes after kidney transplantation revealing HNF1B-associated disease.
Molecular alterations of the transcription factor hepatocyte nuclear factor 1B (HNF1B) are associated with systemic disease, with kidney disease and maturity-onset diabetes of the young (MODY) as the most characteristic manifestations. Other features comprise pancreatic exocrine insufficiency, liver and biliary anomalies, and genital tract malformations. HNF1B-associated disease is clinically heterogeneous, and therefore the diagnosis is challenging. The authors describe the case of a 19-year-old man with new-onset diabetes after kidney transplantation (NODAT). The kidney disease presented during fetal life as bilateral hyperechogenic kidneys. Renal function progressively deteriorated during childhood, and at the age of 19, the patient was submitted to a living-kidney transplant. Two weeks after transplant, NODAT developed. Given the young age and normal body weight, NODAT was unexpected, and the possibility of HNF1B-associated disease was considered. Screening for mutations in HNF1B was undertaken, and a known mutation was found. As this case highlights, HNF1B-associated disease should be considered when NODAT unexpectedly develops in young kidney transplant recipients with a suggestive renal disease.
HNF1B anomalies are associated with systemic disease, including kidney disease, diabetes mellitus, pancreatic exocrine insufficiency, liver test abnormalities and genital tract malformations. Phenotype is variable and there are no pathognomonic manifestations, but kidney disease appears to be the most common feature and diabetes the most frequent extra-renal phenotype. Spontaneous gene alterations are common, and the lack of family history should not exclude the diagnosis. HNF1B defects should be considered when NODAT develops in a young adult kidney transplant recipient with a suggestive kidney disease and without extensive risk factors for diabetes. The most appropriate treatment for HNF1B-associated diabetes is not established, but immunosuppressive therapy superimposed on a beta-cell dysfunction seems to determine the need for insulin therapy after a variable period. Immunosupressive regimens free of calcineurin inhibitors should be considered in patients with HNF1B-associated disease to minimize the risk of developing NODAT.
Background
Since the first description of an HNF1B mutation associated with early-onset diabetes in 1997, the knowledge of HNF1B genetic changes has evolved significantly, and it is currently known that HNF1B anomalies are associated with a systemic disease with marked phenotypic variability (1). The diagnosis of HNF1B-associated disease is challenging, and many cases likely remain undetected or misdiagnosed. The authors describe the case of a young male with a previously unrecognized HNF1B mutation that developed NODAT after kidney transplantation, which triggered the diagnosis of HNF1B-associated disease.
Case presentation
A 19-year-old man was referred to our clinic because of new-onset diabetes after kidney transplantation (NODAT). Two weeks after transplantation, routine blood analysis revealed marked hyperglycemia (up to 17.2 mmol/L). He denied catabolic symptoms, and there was no evidence of ketoacidosis. Through childhood, blood glucose levels were normal, with fasting blood glucose levels ranging from 4.2 to 5.2 mmol/L, with no trend of deterioration over time. His body weight was 55 kg and BMI 21.5 kg/m2. Kidney disease was suspected on a routine fetal ultrasonographic scan (US) performed at 20 weeks’ gestation, revealing bilateral hyperechogenic kidneys. After birth, the US demonstrated hyperechogenic kidneys with small cysts, and plasma creatinine was abnormally elevated. The patient was the first child of non-consanguineous and healthy parents, which pointed to autosomal recessive polycystic kidney disease (ARPKD). Thereafter, renal function progressively deteriorated. By the age of 18, plasma creatinine level was 433.2 μmol/L (corresponding to a glomerular filtrate rate (GFR) of 15.9 mL/min/1.73 m2). One year later, the patient received a living kidney transplant from his 52-year-old father. There was no morphological abnormality on the father’s kidney, and his renal function was normal. The procedure was complicated by partial graft necrosis. At hospital discharge, plasma creatinine level was 185.6 μmol/L (GFR: 44.3 mL/min/1.73 m2). At that time, the immunosuppressive regimen comprised tacrolimus 15 mg/day, mycophenolate mofetil 2000 mg/day, and prednisolone 15 mg/day.
Investigation
Given the patient’s young age and normal body weight, and the absence of other major risk factors, the development of NODAT was unexpected. A history of diabetes was noted in the patient’s maternal grandmother and uncle, with no other known relevant family history, including kidney disease (Fig. 1). Fasting C-peptide was 1.3 nmol/L (normal range: 0.4 – 1.5 nmol/L). Islet autoantibodies, including GADA, ICA, IA-2A, and ZnT8A, were all negative. US pancreatic evaluation was normal. The association of diabetes with such kidney morphological abnormalities raised the possibility of maturity-onset diabetes of the young (MODY) type 5 and hepatocyte nuclear factor 1B (HNF1B) gene defects. Screening for mutations in the HNF1B gene was undertaken and a known missense heterozygous mutation (p.S148L, c.443 C>T) in exon 2 was found. So far, it was not possible to perform genetic testing on any other family member, but the family was referred for genetic counseling. Regarding other manifestations, the patient had no complaints suggestive of exocrine dysfunction, liver enzymes were normal over the years (both alanine aminotransferase and aspartate aminotransferase persistently below the upper limit of the normal range, both before and after transplantation), and there was no clinical evidence of genital tract malformations.
Figure 1 Family pedigree of the patient showing the affected patient (proband) and other affected family members with diabetes.
Treatment
Insulin therapy was started with a long-acting analog (0.16 UI/kg/day). The insulin dose was progressively reduced, following reductions in tacrolimus and prednisolone doses. Five months after NODAT diagnosis, insulin was switched to a dipeptidyl peptidase 4 (DPP-4) inhibitor. At that time, the patient was under tacrolimus 8 mg/day and prednisolone 5 mg/day. However, the patient stopped it a few weeks later due to vomiting. As glycated hemoglobin (HbA1c) remained below 6.5%, the patient was kept without medication. However, 16 months later, HbA1c increased to 6.9%. Therefore, sitagliptin 25 mg/day was resumed, with good tolerance. Nevertheless, HbA1c progressively increased to 8% in the following 8 months (Fig. 2). Renal function slowly deteriorated, with plasma creatinine level ranging between 185.6 and 229.8 μmol/L (GFR range: 34– 44 mL/min/1.73 m2). At that time, the patient was under tacrolimus 6 mg/day and prednisolone 5 mg/day. After discussing the therapeutic options, therapy was switched to liraglutide, which was progressively titrated to 1.8 mg/day.
Figure 2 Evolution of the patient’s glycemic control after NODAT diagnosis.
Outcome and follow-up
Two months after liraglutide introduction, HbA1c dropped to 6.7%. However, glycemic control again deteriorated, and HbA1c increased up to 10.9% (Fig. 1). Immunosuppressive therapy doses were unchanged, but the patient reported less physical activity. Plasma creatinine level was 224.5 μmol/L, corresponding to a GFR of 35.2 mL/min/1.73 m2. At this time, liraglutide was stopped, and insulin with a long-acting analog (0.14 UI/kg/day) was resumed. Two months later, glycemic control slightly improved. Insulin therapy will be maintained, and treatment management will continue as considered appropriate.
Discussion
HNF1B is involved in the embryogenesis and tissue-specific gene expression of several organs, including the kidney, pancreas, liver, and genital tract. Even though HNF1B mutations were first associated with MODY, it is currently known that HNF1B anomalies result in a systemic disease that follows the expression of HNF1B (1). The most frequently described manifestations include kidney disease, early-onset diabetes, pancreatic exocrine insufficiency, liver dysfunction, and genital tract malformations. Notably, there is marked phenotypic variability, suggesting that other genetic or environmental factors might modify the pattern and severity of the disease (1).
The prevalence of HNF1B-associated disease is unknown. The mean overall detection rate of HNF1B defects in cohorts of patients with kidney disease was 19% (1). By contrast, they are a rare cause of MODY, accounting for less than 1% of the cases (1). As most cohorts were pre-selected for kidney disease and/or diabetes, the frequency of these and other clinical features is unclear.
Genetic changes in the HNF1B gene comprise either heterozygous intragenic mutations or gene deletions. Although HNF1B-associated disease is inherited in an autosomal-dominant manner, spontaneous genetic changes are common, which explains the frequent absence of a family history of kidney disease or diabetes (1). Given the family history of diabetes in this patient, we hypothesize that the mutation was inherited.
Kidney disease appears to be the most common manifestation, but considerable variation is found in its phenotype and severity (2, 3, 4). Cystic disease is the predominant morphological manifestation in both children and adults (2, 3). As observed in this patient, kidney disease can present during fetal life as bilateral hyperechogenic kidneys of normal or slightly increased size (5). Tubular transport abnormalities can also be present, and hypomagnesemia is a common and distinctive feature (1, 3). Hyperuricemia and early-onset gout are also observed. Importantly, renal function is frequently impaired, and up to 20% of patients progress to end-stage renal disease (3).
Given the role of HNF1B in pancreatic development, HNF1B-associated disease can present with pancreatic hypoplasia, and both endocrine and exocrine dysfunction can occur (1). Diabetes is considered as the most frequent extra-renal phenotype. In the largest cohort described to date (3), Dubois-Laforgue et al. reported diabetes in 82% of 194 patients. Diabetes is usually of early-onset (median age 20 years), but it can be found at any age from the neonatal period to late middle age (1). Clinical presentation seems highly variable, including ketoacidosis (3). The pathophysiology of HNF1B-associated diabetes has not been definitively established. Both beta-cell dysfunction and reduced hepatic insulin sensitivity have been implicated (1). Beta-cell dysfunction, resulting in reduced insulin secretion, may be a consequence of pancreatic hypoplasia and beta-cell mass reduction. However, primary functional abnormalities in insulin secretion must also occur, as pancreatic hypoplasia and endocrine dysfunction do not completely correlate (6).
As this case demonstrates, HNF1B-associated diabetes can present as NODAT. In this patient, it was the association of an unexpected NODAT and the kidney disease that triggered the diagnosis. The frequency of NODAT in HNF1B-associated disease is unknown. It is suggested that HNF1B defects determine a genetic susceptibility to NODAT, as the reduced insulin secretory capacity of beta-cell is unmasked by the immunosuppressive drugs (7, 8). Faguer et al.(9) hypothesized that immunosuppressive therapy may switch off residual HNF1B expression and thus potentiate beta-cell dysfunction. Combining clinical data and in vitro experiments, these authors suggested that calcineurin inhibitors (CNI) induce a downregulation of the nonmutated allele, mimicking HNF1B biallelic inactivation. In this patient, given the deterioration of renal function, immunosuppressive regimens avoiding CNI were not considered. However, consideringthat immunosuppressive regimens free of CNI may minimize the deterioration of NODAT, if the patient’s glycemic control remains above the target, the possibility of such a regiment will be discussed. Whether all kidney transplant recipients will ultimately develop diabetes is unknown. Interestingly, Waller et al. (8) reported the case of a boy with a previously unrecognized HNF1B mutation in which NODAT regressed after transplant nephrectomy and cyclosporine and steroid withdrawal. It is not clear whether NODAT has a distinctive presentation in patients with HNF1B-associated disease. Some authors highlighted its very early onset after transplantation, as occurred in this case, but this was not seen in all patients reported.
The most appropriate treatment for HNF1B-associated diabetes is not established. In keeping with the hypothesis of beta-cell dysfunction, the majority of patients are treated with insulin (3). However, residual insulin secretion has been demonstrated, and some authors argue that insulin treatment can be delayed for a few years (3). The choice for a DPP-4 inhibitor was based on the patient characteristics (normal weight and post-transplantation kidney status) and an only slightly elevated HbA1c value. Also, there was the aim of simplifying the therapeutic regimen, switching to an oral agent. Even though our patient remained without any treatment for more than a year, glycemic control eventually deteriorated. The initial response to liraglutide was impressive, but glycemic control worsened again, and insulin therapy was required 6 months later. We hypothesize that the patient’s young age and normal body weight, in addition to the absence of major pancreatic morphological abnormalities, contributed to the initial glycemic control. However, the immunosuppressive therapy possibly limited an extended response to non-insulin agents, and so insulin therapy was resumed nearly 3 years after diabetes diagnosis. As far as we know, there is no data on treatment of HNF1B-associated diabetes with glucagon-like peptide-1 receptor agonists. Whether patients with HNF1B-associated diabetes not receiving calcineurin inhibitors respond to these agents remains to be elucidated.
Other reported manifestations of HNF1B-disease include abnormal liver function, usually manifesting as an asymptomatic rise in liver enzymes; biliary anomalies presenting as bile duct cysts; and various genital tract malformations (3). Of note, the clinical spectrum of the disease seems to be expanding (1, 6). At this time, there is no evidence of any of these additional features in this patient.
In conclusion, HNF1B-associated disease is remarkable for its marked phenotypic variability and the high rate of de novo cases. The diagnosis is challenging and many cases likely remain undetected or misdiagnosed. However, the right diagnosis is essential to provide the best care to both patients and their relatives. We believe the most important step for diagnosis of HNF1B-associated disease is to first recognize this possibility. Findings such as hypomagnesemia or pancreatic structural anomalies can support the indication for genetic testing (10). Additionally, an HNF1B score using a weight combination of clinical features has been proposed for selecting patients for HNF1B testing (4). Finally, as the case we present highlights, HNF1B-associated disease should be considered when NODAT unexpectedly develops in young kidney transplant recipients with a suggestive kidney disease. Even though the most appropriate treatment for HNF1B-associated diabetes is not established, immunosuppressive therapy superimposed on a beta-cell dysfunction seems to determine the need for insulin therapy after a variable period.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this case report.
Funding
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Patient consent
Written informed consent has been obtained from the patient for publication of the submitted article and accompanying images.
Author contribution statement
Both authors were involved in the management of the patient, and in the writing and editing of the manuscript. | Recovered | ReactionOutcome | CC BY-NC-ND | 33522494 | 19,046,333 | 2021-01-27 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Tumour lysis syndrome'. | A phase Ib, open-label, dose-escalation trial of the anti-CD37 monoclonal antibody, BI 836826, in combination with gemcitabine and oxaliplatin in patients with relapsed/refractory diffuse large B-cell lymphoma.
Background BI 836826 is a chimeric mouse-human monoclonal antibody directed against human CD37, a transmembrane protein expressed on mature B lymphocytes. This open-label, phase I dose-escalation trial (NCT02624492) was conducted to determine the maximum tolerated dose (MTD), safety/tolerability, and preliminary efficacy of BI 836826 in combination with gemcitabine and oxaliplatin in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Methods Eligible patients received intravenous infusions of BI 836826 on day 8 and gemcitabine 1000 mg/m2 plus oxaliplatin 100 mg/m2 on day 1, for up to six 14-day treatment cycles. Dose escalation followed the standard 3 + 3 design. Results Of 21 treated patients, 17 had relapsed/refractory DLBCL and four had follicular lymphoma transformed to DLBCL. BI 836826 dosing started at 25 mg and proceeded through 50 mg and 100 mg. Two dose-limiting toxicities (DLTs) occurred during cycle 1, both grade 4 thrombocytopenia lasting > 7 days, affecting 1/6 evaluable patients (17%) in both the 50 mg and 100 mg cohorts. Due to early termination of the study, the MTD was not determined. The most common adverse events related to BI 836826 treatment were neutropenia (52%), thrombocytopenia (48%), and anemia (48%). Eight patients (38%) experienced BI 836826-related infusion-related reactions (two grade 3). Overall objective response rate was 38%, including two patients (10%) with complete remission and six patients (29%) with partial remission. Conclusions BI 836826 in combination with GemOx was generally well tolerated but did not exceed the MTD at doses up to 100 mg given every 14 days.
Introduction
Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma (NHL) and accounts for approximately 30–40% of new NHL cases [1, 2]. The current standard of care for front-line treatment of DLBCL is immunochemotherapy: rituximab plus the multi-agent chemotherapy cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) [3]. Up to 40% of patients relapse or become refractory to R-CHOP. However, despite years of intensive research into alternative front-line treatments, R-CHOP or R-CHOP-like therapies remain the standard of care. Poor response rates to front-line treatment have been associated with various prognostic factors, including clinical characteristic indices (International Prognosis Index [IPI], Revised-IPI [R-IPI], and NCCN-IPI) [4–6], high expression of certain tumor markers (e.g. β2-microglobulin), molecular rearrangements of oncogenes (e.g. MYC, BCL2), or cell of origin classification (e.g. activated B-cell-like origin) [7, 8]. Patients who are refractory to, or relapse after, first-line immunochemotherapy generally receive high dose chemotherapy followed by autologous stem cell transplant (ASCT) [9, 10]. However, outcomes following salvage treatment are generally poor. For instance, in the retrospective SCHOLAR-1 study of 636 patients with refractory DLBCL, the response rate to subsequent therapy was only 26% with median overall survival (OS) of 6.3 months [11]. Moreover, anti-CD20 based immunochemotherapy regimens appear to have low efficacy in the salvage setting. In the phase III CORAL trial, 3-year event-free survival in patients with relapsed/refractory DLBCL treated with R-ICE (rituximab, ifosfamide, carboplatin, etoposide) or R-DHAP (rituximab, dexamethasone, cytarabine, cisplatin) was 37% overall and only 21% in patients previously treated with rituximab [12]. Only 50% of patients could proceed to ASCT [13]. Thus, more effective salvage strategies for patients with relapsed or refractory disease after front-line immunochemotherapy are needed [2].
CD37 is a tetraspanin protein that is highly expressed on mature B lymphocytes and lymphoid neoplasms [14–16]. It appears to have multiple physiological functions, including regulation of apoptosis/survival signaling [17], B/T cell interaction [18], and T-cell proliferation [19]. Early clinical studies of anti-CD37 agents [20–22] have demonstrated that it is a viable therapeutic target in B cell NHL.
BI 836826 is a chimeric Fc-engineered immunoglobulin G1 (IgG1) monoclonal antibody directed against human CD37 [23]. In transgenic mice and cynomolgous monkeys, BI 836826 dose-dependently depleted peripheral B cells, and significantly suppressed tumor growth in a mouse B-cell lymphoma xenograft model [23]. In phase I studies, BI 836826 demonstrated acceptable tolerability and anti-tumor activity in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) [24] and in patients with relapsed/refractory B-cell NHL [25]. As gemcitabine and oxaliplatin (GemOx), with or without rituximab, is a treatment option in patients with ASCT-ineligible relapsed/refractory DLBCL [26, 27], we investigated the feasibility of combining BI 836826 and GemOx in this phase I, dose escalation study.
Patients and methods
Patients
Eligible patients were aged 18 years or older and had histologically confirmed relapsed/refractory DLBCL (including transformed follicular lymphoma). ‘Relapsed’ was defined as the appearance of any new lesion after attainment of an initial complete response (CR) and ‘refractory’ was defined as < 50% decrease in lesion size with prior anti-lymphoma treatment in the absence of new lesion development. All patients had previously been treated with an anti-CD20 monoclonal antibody in combination with anthracycline-containing chemotherapy and were either ineligible for high dose therapy and ASCT or had relapsed/progressed after an autologous/allogeneic stem cell transplant. Allogeneic stem cell transplant performed at least 6 months prior to study entry was permitted if patients did not require immunosuppressive treatment and had no evidence of active graft-versus-host disease. Patients were required to have Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, acceptable organ function, and a screening CT scan with involvement of at least one bi-dimensional lesion/node of > 1.5 cm.
Key exclusion criteria were: prior history of malignancy other than DLBCL; known central nervous system involvement; and receipt of anti-lymphoma treatment either within 14 days or, in the case of an investigational agent, less than five half-lives of the investigational drug, prior to the first dose of the current trial medication.
The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines, and the study protocol was approved by the Institutional Review Boards or Independent Ethics Committees of all participating institutions. Written informed consent was obtained from all patients.
Study design and treatment
This was an open-label, multicenter phase Ib dose-escalation trial conducted to determine the maximum tolerated dose (MTD), safety/tolerability, and preliminary efficacy of BI 836826 in combination with GemOx in patients with relapsed/refractory DLBCL (NCT02624492). BI 836826 (starting dose of 25 mg) was administered as an intravenous infusion on day 8 of each 14-day cycle, while gemcitabine (1000 mg/m2) and oxaliplatin (100 mg/m2) were given intravenously on day 1 of each cycle. Patients received a maximum of six treatment cycles; each cycle could be delayed by up to 14 days in cases of toxicity.
Paracetamol, antihistamine and glucocorticoid premedication to mitigate infusion-related reactions (IRRs) was administered 30–120 minutes prior to all BI 836826 infusions. Supportive care including blood products and growth factors were permitted according to local guidelines; prophylactic anti-infective agents were also allowed. Dose escalation was conducted according to the standard 3 + 3 design and was planned to continue until the MTD of BI 836926 in combination with GemOx was reached. BI 836826 dose increments of 50, 100, 150 and 200 mg were planned.
Study assessments
The primary endpoints were the MTD and the number of patients with dose-limiting toxicities (DLTs) during the MTD evaluation period (cycle 1). The MTD was defined as the highest dose for which the number of patients with DLTs was no more than 17% during the MTD evaluation period (cycle 1).
DLTs included both non-hematologic and hematologic adverse events (AEs) considered related to any trial medication. This included any non-hematologic grade ≥ 3 AEs except for: laboratory abnormalities that could be corrected with treatment within 48 h; nausea, vomiting, or diarrhea that resolved within 48 h with adequate treatment; neuropathy considered related to oxaliplatin; or IRRs. Hematologic DLTs were: grade 4 neutropenia lasting > 7 days despite growth factor support; any febrile neutropenia that did not resolve within 48 h with appropriate treatment; grade 4 thrombocytopenia lasting > 7 days or grade 3/4 thrombocytopenia with clinically significant bleeding; failure to recover platelets ≥ 75 × 109/L by 4 weeks after the start of the cycle; and failure to recover neutrophils ≥ 1.0 × 109/L by 4 weeks after start of the cycle. Other safety assessments included the incidence and severity of AEs graded according to the Common Toxicity Criteria for Adverse Events (CTCAE, version 4.0) and changes in laboratory parameters.
The secondary endpoint was investigator-assessed best overall response according to International Working Group criteria for non-Hodgkin lymphoma [28] with refined evaluation of the PET scan using the 5-point scale [29].Tumor size reduction was analyzed as best percentage change from baseline in the sum of the product of the longest perpendicular diameters (SPD) based on imaging data. Pharmacokinetic analysis was planned but was not conducted.
Statistical methods
No formal statistical testing was undertaken. The number of patients with DLTs and the best overall response was summarized by descriptive statistics.
Results
Patients and treatment exposure
Thirty-five patients were enrolled and 21 treated at seven centers in Belgium, Italy and Spain between March 10, 2016 and March 16, 2018. All patients were white and 48% were male (Table 1). Median age was 54.0 years (range 22 to 86), and 57%, 33% and 10% of patients had a baseline ECOG performance score of 0, 1 and 2, respectively. Of the 21 patients, 17 (81%) had pure DLBCL and four (19%) had follicular lymphoma transformed to DLBCL. Lymphoma was considered relapsed for 33% of patients, refractory for 38%, and progressive for 29%. All patients had previously received systemic therapy, with most having received one, two, or four previous therapies (33%, 29%, and 29% of patients, respectively); 71% had progressed following the last therapy.Table 1 Patient demographics
BI 836826 dosea
25 mg
(n = 5) 50 mg
(n = 8) 100 mg
(n = 8) Total
(N = 21)
Male, n (%) 1 (20.0) 4 (50.0) 5 (62.5) 10 (47.6)
Race, n (%)
White 5 (100.0) 8 (100.0) 8 (100.0) 21 (100.0)
Median age, years (range) 77.0 (22–86) 51.0 (41–78) 53.5 (42–77) 54.0 (22–86)
ECOG PS at baseline, n (%)
0 5 (100.0) 4 (50.0) 3 (37.5) 12 (57.1)
1 0 2 (25.0) 5 (62.5) 7 (33.3)
2 0 2 (25.0) 0 2 (9.5)
Ann Arbor stage at screening, n (%)
II 0 1 (12.5) 0 1 (4.8)
III 0 2 (25.0) 3 (37.5) 5 (23.8)
IV 5 (100.0) 5 (62.5) 5 (62.5) 15 (71.4)
Mean time from first diagnosis, years (SD) 4.4 (3.8) 5.1 (7.5) 2.9 (3.7) 4.1 (5.4)
Median number of prior therapies (range) 2.0 (1–4) 2.0 (1–4) 3.0 (1–6) 2.0 (1–6)
Prior therapy, n (%)
Radiotherapy 2 (40.0) 1 (12.5) 1 (12.5) 4 (19.0)
Stem cell transplant 2 (40.0) 2 (25.0) 3 (37.5) 7 (33.3)
Surgery 0 2 (25.0) 1 (12.5) 3 (14.3)
Progression since last systemic therapy, n (%) 5 (100.0) 7 (87.5) 3 (37.5) 15 (71.4)
aGiven every 14 days in combination with gemcitabine 1000 mg/m2 and oxaliplatin 100 mg/m2
ECOG PS Eastern Cooperative Oncology Group Performance Status, SD standard deviation
The best response to previous therapy was CR in five patients (23.8%), partial remission (PR) in two patients (9.5%), and stable disease (SD) in two patients (9.5%); 10 patients (47.6%) had progressive disease (PD); the status of two patients (9.5%) was unknown or missing. Important protocol deviations were noted for seven patients, three of whom had more than one protocol deviation: entrance criteria were not met for 6 patients (efficacy-related criteria for four patients, trial diagnosis for one patient, and safety criteria for one patient), administration of trial medication was delayed for three patients, and prohibited medication was administered for one patient (Supplementary Table 1).
All 21 patients discontinued the trial, with10 patients (48%) completing the maximum of six treatment cycles. Of the 11 patients who discontinued before completing six cycles, six (29%) discontinued due to AEs, and 5 (24%) discontinued due to disease progression. Two patients did not receive a complete infusion of BI 836826: one died of tumor lysis syndrome after a single dose of GemOx and did not receive any BI 836826, while a second had an interruption of the first BI 836826 infusion due to an IRR. This patient received 10 mg out of 25 mg BI 836826 and permanently discontinued trial drug.
MTD and DLTs
BI 836826 dosing in combination with GemOx started at 25 mg and proceeded through 50 mg and 100 mg cohorts. Six patients were replaced and hence excluded from the MTD evaluation set. Two DLTs occurred during the MTD evaluation period (cycle 1), both grade 4 thrombocytopenia lasting > 7 days, affecting one of six evaluable patients (17%) in the 50 mg dosing cohort, and one of six evaluable patients (17%) in the 100 mg cohort. Due to a strategic decision by the sponsor, the trial was prematurely discontinued, and no further patients were enrolled after the 100 mg dose cohort. Consequently, the MTD of BI 836826 in combination with GemOx was not established.
Safety
All patients experienced at least one AE during the on-treatment period of the trial, most commonly neutropenia (n = 16 [79%]), thrombocytopenia (n = 15 [71%]) and anemia (n = 14 [67%]). Sixteen patients (76%) experienced at least one AE deemed to be related to BI 836826 by the Investigator; the most frequent were (any grade/grade 3/4) neutropenia (52/38%), anemia (48/29%), thrombocytopenia (48/43%; Table 2). Eight patients (38%) experienced a treatment-related IRR, of which two (10%) were grade 3. Two patients (10%) had grade 4 neutropenia and a concomitant infection; both infections were of grade 2. One patient had grade 4 thrombocytopenia and concomitant bleeding, a single episode of grade 2 melena. The most common non-hematological AEs considered related to BI 836826 included pyrexia (n = 2 [9.5%]), asthenia (n = 2 [9.5%]), chills, cough, dizziness, nausea and vomiting (all n = 1 [4.8%]), which were either grade 1 or grade 2.Table 2 AEs considered related to BI 836826 occurring in ≥ 2 patients
Any-grade
n (%) Grade 3/4
n (%)
Any treatment-related AEs 16 (76.2) 12 (57.1)
Neutropenia 11 (52.4) 10 (47.6)
Anemia 10 (47.6) 6 (28.6)
Thrombocytopenia 10 (47.6) 9 (42.9)
Infusion-related reaction 8 (38.1) 2 (9.5)
Decreased white blood cell count 7 (33.3) 7 (33.3)
Increased AST 2 (9.5) 0
Increased GGT 2 (9.5) 1 (4.8)
Asthenia 2 (9.5) 0
Pyrexia 2 (9.5) 0
Decreased platelet count 1 (4.8) 1 (4.8)
Pancytopenia 1 (4.8) 1 (4.8)
Increased ALT 1 (4.8) 0
Chills 1 (4.8) 0
Cough 1 (4.8) 0
Dizziness 1 (4.8) 0
Hyperuricemia 1 (4.8) 0
Nausea 1 (4.8) 0
Vomiting 1 (4.8) 0
ALT alanine aminotransferase, AST aspartate aminotransferase, GGT gamma-glutamyl transferase
During the entire on-treatment period, seven patients experienced AEs that were consistent with the definition of a DLT. Thrombocytopenia (5 patients [24%]) was the only event reported for more than two patients.Six patients experienced a total of eight AEs leading to permanent discontinuation of last study medication: thrombocytopenia (two cases), neutropenia, Aspergillus infection, pneumonia, decreased white blood cell count, IRR, and tumor lysis syndrome (one case each).
Overall, 12 patients were reported with serious AEs (57%), of which only thrombocytopenia (4 patients [19%]) and IRR (3 patients [14%]) occurred in more than two patients. Three patients died during the study; however, no deaths were attributed to BI 836826. The case of tumor lysis syndrome was considered related to GemOx as the patient had not yet received BI 836926; the remaining two deaths were attributed to disease progression and Aspergillus infection.
Efficacy
The objective response rate was 38%, including two patients (10%) with complete remission and six patients (29%) with partial remission (Table 3). Six patients (29%) experienced stable disease, and three patients (14%) had progressive disease. Four patients did not have a response assessment. Patients with baseline and at least one post-baseline disease assessment were evaluated for best change in SPD from baseline in lymph nodes, or organ or extra-lymphatic nodules based on PET/CT scan. The median best percentage change was − 31.3% (range –100 to 41%) for 15 patients with baseline lymph nodules and − 78% (range − 89% to − 28%) for five patients with extra-lymphatic disease nodules. In one patient with baseline liver nodules, change from baseline was − 38%, while two patients with baseline spleen nodules had changes of − 100% and − 45%.Table 3 Best overall response in patients receiving BI 836826 plus GemOx
BI 836826 dose
Patients with response, n (%) 25 mg
(n = 5) 50 mg
(n = 8) 100 mg
(n = 8) Total
(n = 21)
Complete remission 1 (20.0) 0 1 (12.5) 2 (9.5)
Partial remission 2 (40.0) 3 (37.5) 1 (12.5) 6 (28.6)
Stable disease 2 (40.0) 1 (12.5) 3 (37.5) 6 (28.6)
Progressive disease 0 2 (25.0) 1 (12.5) 3 (14.3)
Missing 0 2 (25.0) 2 (25.0) 4 (19.0)
GemOx gemcitabine 1000 mg/m2 and oxaliplatin 100 mg/m2
Discussion
In this phase I, dose-finding study in patients with relapsed/refractory DLBCL, BI 836826 in combination with GemOx was generally well tolerated. The MTD was not established, as the trial was prematurely discontinued following the termination of the BI 836826 clinical development program. The MTD was not exceeded at the doses tested (50 and 100 mg given every 14 days).
Adverse events associated with BI 836826 administration were predominantly hematological, which is to be expected in this population, and in keeping with prior studies of BI 836826 in patients with B-cell malignancies [24, 30]. Grade 3/4 hematological AEs were more common in this study than with BI 836826 monotherapy [24, 30], most likely due to the additive effect of GemOx. One DLT of grade 4 thrombocytopenia lasting > 7 days was recorded in each of the 50 mg and 100 mg dosing cohorts. As CD37 has been identified on megakaryocytes and platelets [31, 32], this may be the result of the direct action of BI 836826 on these cells, or may be related to the myelotoxic effects of gemcitabine and oxaliplatin [33, 34]. It is possible that the myelosuppressive effect of combination therapy was exacerbated by administering BI 836826 on day 8 of each cycle, corresponding with the nadir of hematological toxicity due to GemOx. Therefore, hematological toxicity could potentially be less severe with an alternative treatment schedule. However, the tested treatment schedule was based on modelling that evaluated different timings for the BI 836826 and GemOx administrations. The modelling showed that dosing BI 836826 after GemOx at the cytopenia nadir would actually shorten hematological toxicity compared to administering the drugs together, which was predicted to deepen and extend the cytopenia. Of note, the overall incidence of treatment-related IRRs (any-grade, 38%; grade 3/4, 10%) was lower than in a previous study of BI 836826 in patients with relapsed/refractory chronic lymphocytic leukemia (any-grade, 70%; grade 3/4, 8%) [24], and comparable to that seen in Caucasian patients with relapsed/refractory B-cell NHL (any-grade, 41%; grade 3/4, 8%) [30].
The overall response rate in this study was 38%. Few published data on the use of GemOx alone in DLBCL are available for comparison. In a retrospective study of GemOx with/without rituximab in 44 patients with relapsed/refractory aggressive lymphoma, overall response rate was 43%, including 30% CR [27], while an overall response rate of 61%, with 44% CR, was reported in a study of 49 patients with relapsed/refractory DLBCL who received rituximab plus GemOx [26]. However, considerable hematological toxicity was observed in both studies, with 73% of patients experiencing grade ≥ 3 neutropenia and 44% experiencing grade 3 thrombocytopenia in the latter study.
Although the clinical development of BI 836826 has been terminated for strategic reasons, the findings from this study suggest that CD37-based therapy for DLBCL can be safely combined with established chemotherapy regimens. A number of anti-CD37 therapies are currently being investigated for the treatment of B-cell NHL [20–22, 35–37], including radioimmunotherapy. Of note, a phase Ib study of the novel agent lutetium (177Lu)-lilotomabsatetraxetan (Betalutin®) in ASCT-ineligible patients with relapsed/refractory DLBCL is currently in progress (NCT02658968), and results from this and other ongoing clinical trials may provide new hope for DLBCL patients faced with limited options.
Supplementary Information
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Acknowledgements
We thank the patients, their families, and all of the investigators who participated in these studies. The authors were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development, and have approved the final version.
Author contributions
Anne-Marie Quinson, Valérie Belsack and Carmelo Carlo-Stella contributed to the study conception and design. Material preparation and data collection were performed by Monica Balzarotti, Massimo Magagnoli, Miguel Ángel Canales, Paolo Corradini, Carlos Grande, Juan-Manuel Sancho, Francesco Zaja and Carmelo Carlo-Stella. Data analysis were performed by Anne-Marie Quinson, Valérie Belsack and Daniela Maier. The first draft of the manuscript was written by Anne-Marie Quinson, Valérie Belsack, Monica Balzarotti and Carmelo Carlo-Stella. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
The conduct of this research, study design, data collection, and analysis was financially supported by Boehringer Ingelheim. Medical writing assistance, funded by Boehringer Ingelheim, was provided by Lynn Pritchard, DPhil, of GeoMed, an Ashfield company, part of UDG Healthcare plc, during the preparation of this manuscript.
Data Availability
The clinical study report (including appendices, but without line listings) and other clinical documents related to this study may be accessed on request. Prior to providing access, the documents and data will be examined, and, if necessary, redacted and de-identified to protect the personal data of study participants and personnel, and to respect the boundaries of the informed consent of the study participants. See https://trials.boehringer-ingelheim.com/data_sharing/sharing.html#accordion-1-2 for further details. Bona fide, qualified scientific and medical researchers may request access to de-identified, analyzable patient-level study data, together with documentation describing the structure and content of the datasets. Researchers should use https://clinicalstudydatarequest.com/ to request access to raw data from this study.
Compliance with ethical standards
Conflict of interest
Miguel Ángel Canales received speaker honoraria from Amgen, Janssen, Roche, Sandoz, Takeda; consulting fees from Celgene, Gilead, iQone, Janssen, Karyopharm, Novartis, Roche, Sandoz, Sanofi; and support for CME from Gilead, Janssen, Novartis, Roche, Sandoz, Sanofi.
Paolo Corradini received honoraria as a lecturer from AbbVie, Amgen, Celgene, Gilead/Kite, Janssen, Jazz Pharmaceutics, Novartis, Roche, Sanofi, Sandoz, Takeda, and consulting fees from AbbVie, ADC Therapeutics, Amgen, Celgene, Daiichi Sankyo, Gilead, Incyte, Janssen, Kite, KiowaKirin, Novartis, Roche, Sanofi, Servier and Takeda.
Francesco Zaja received honoraria from Novartis, Amgen, Janssen, Takeda, Celgene, Abbvie, Roche, Mundipharma and Grifols.
Juan-Manuel Sancho received advisory council or committee fees from Roche, Gilead, Janssen, Celgene, Incyte, Celltrion, Novartis, and honoraria as a speaker from Roche, Gilead, Janssen, Celgene, Incyte, Takeda, Novartis, Sanofi and Servier.
Anne-Marie Quinson, Valérie Belsack and Daniela Maier are employees of Boehringer Ingelheim.
Carmelo Carlo-Stella received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Servier, Amgen, Janssen Oncology, Sanofi, ADC Therapeutics, Novartis, and AstraZeneca; provided consultancy to Boehringer Ingelheim, Genenta Science, Sanofi, ADC Therapeutics, and received research funding from Rhizen Pharmaceuticals.
Monica Balzarotti, Massimo Magagnoli and Carlos Grande report no conflict of interest.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | GEMCITABINE HYDROCHLORIDE, OXALIPLATIN | DrugsGivenReaction | CC BY | 33523334 | 18,904,482 | 2021-08 |
What was the administration route of drug 'GEMCITABINE HYDROCHLORIDE'? | A phase Ib, open-label, dose-escalation trial of the anti-CD37 monoclonal antibody, BI 836826, in combination with gemcitabine and oxaliplatin in patients with relapsed/refractory diffuse large B-cell lymphoma.
Background BI 836826 is a chimeric mouse-human monoclonal antibody directed against human CD37, a transmembrane protein expressed on mature B lymphocytes. This open-label, phase I dose-escalation trial (NCT02624492) was conducted to determine the maximum tolerated dose (MTD), safety/tolerability, and preliminary efficacy of BI 836826 in combination with gemcitabine and oxaliplatin in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Methods Eligible patients received intravenous infusions of BI 836826 on day 8 and gemcitabine 1000 mg/m2 plus oxaliplatin 100 mg/m2 on day 1, for up to six 14-day treatment cycles. Dose escalation followed the standard 3 + 3 design. Results Of 21 treated patients, 17 had relapsed/refractory DLBCL and four had follicular lymphoma transformed to DLBCL. BI 836826 dosing started at 25 mg and proceeded through 50 mg and 100 mg. Two dose-limiting toxicities (DLTs) occurred during cycle 1, both grade 4 thrombocytopenia lasting > 7 days, affecting 1/6 evaluable patients (17%) in both the 50 mg and 100 mg cohorts. Due to early termination of the study, the MTD was not determined. The most common adverse events related to BI 836826 treatment were neutropenia (52%), thrombocytopenia (48%), and anemia (48%). Eight patients (38%) experienced BI 836826-related infusion-related reactions (two grade 3). Overall objective response rate was 38%, including two patients (10%) with complete remission and six patients (29%) with partial remission. Conclusions BI 836826 in combination with GemOx was generally well tolerated but did not exceed the MTD at doses up to 100 mg given every 14 days.
Introduction
Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma (NHL) and accounts for approximately 30–40% of new NHL cases [1, 2]. The current standard of care for front-line treatment of DLBCL is immunochemotherapy: rituximab plus the multi-agent chemotherapy cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) [3]. Up to 40% of patients relapse or become refractory to R-CHOP. However, despite years of intensive research into alternative front-line treatments, R-CHOP or R-CHOP-like therapies remain the standard of care. Poor response rates to front-line treatment have been associated with various prognostic factors, including clinical characteristic indices (International Prognosis Index [IPI], Revised-IPI [R-IPI], and NCCN-IPI) [4–6], high expression of certain tumor markers (e.g. β2-microglobulin), molecular rearrangements of oncogenes (e.g. MYC, BCL2), or cell of origin classification (e.g. activated B-cell-like origin) [7, 8]. Patients who are refractory to, or relapse after, first-line immunochemotherapy generally receive high dose chemotherapy followed by autologous stem cell transplant (ASCT) [9, 10]. However, outcomes following salvage treatment are generally poor. For instance, in the retrospective SCHOLAR-1 study of 636 patients with refractory DLBCL, the response rate to subsequent therapy was only 26% with median overall survival (OS) of 6.3 months [11]. Moreover, anti-CD20 based immunochemotherapy regimens appear to have low efficacy in the salvage setting. In the phase III CORAL trial, 3-year event-free survival in patients with relapsed/refractory DLBCL treated with R-ICE (rituximab, ifosfamide, carboplatin, etoposide) or R-DHAP (rituximab, dexamethasone, cytarabine, cisplatin) was 37% overall and only 21% in patients previously treated with rituximab [12]. Only 50% of patients could proceed to ASCT [13]. Thus, more effective salvage strategies for patients with relapsed or refractory disease after front-line immunochemotherapy are needed [2].
CD37 is a tetraspanin protein that is highly expressed on mature B lymphocytes and lymphoid neoplasms [14–16]. It appears to have multiple physiological functions, including regulation of apoptosis/survival signaling [17], B/T cell interaction [18], and T-cell proliferation [19]. Early clinical studies of anti-CD37 agents [20–22] have demonstrated that it is a viable therapeutic target in B cell NHL.
BI 836826 is a chimeric Fc-engineered immunoglobulin G1 (IgG1) monoclonal antibody directed against human CD37 [23]. In transgenic mice and cynomolgous monkeys, BI 836826 dose-dependently depleted peripheral B cells, and significantly suppressed tumor growth in a mouse B-cell lymphoma xenograft model [23]. In phase I studies, BI 836826 demonstrated acceptable tolerability and anti-tumor activity in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) [24] and in patients with relapsed/refractory B-cell NHL [25]. As gemcitabine and oxaliplatin (GemOx), with or without rituximab, is a treatment option in patients with ASCT-ineligible relapsed/refractory DLBCL [26, 27], we investigated the feasibility of combining BI 836826 and GemOx in this phase I, dose escalation study.
Patients and methods
Patients
Eligible patients were aged 18 years or older and had histologically confirmed relapsed/refractory DLBCL (including transformed follicular lymphoma). ‘Relapsed’ was defined as the appearance of any new lesion after attainment of an initial complete response (CR) and ‘refractory’ was defined as < 50% decrease in lesion size with prior anti-lymphoma treatment in the absence of new lesion development. All patients had previously been treated with an anti-CD20 monoclonal antibody in combination with anthracycline-containing chemotherapy and were either ineligible for high dose therapy and ASCT or had relapsed/progressed after an autologous/allogeneic stem cell transplant. Allogeneic stem cell transplant performed at least 6 months prior to study entry was permitted if patients did not require immunosuppressive treatment and had no evidence of active graft-versus-host disease. Patients were required to have Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, acceptable organ function, and a screening CT scan with involvement of at least one bi-dimensional lesion/node of > 1.5 cm.
Key exclusion criteria were: prior history of malignancy other than DLBCL; known central nervous system involvement; and receipt of anti-lymphoma treatment either within 14 days or, in the case of an investigational agent, less than five half-lives of the investigational drug, prior to the first dose of the current trial medication.
The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines, and the study protocol was approved by the Institutional Review Boards or Independent Ethics Committees of all participating institutions. Written informed consent was obtained from all patients.
Study design and treatment
This was an open-label, multicenter phase Ib dose-escalation trial conducted to determine the maximum tolerated dose (MTD), safety/tolerability, and preliminary efficacy of BI 836826 in combination with GemOx in patients with relapsed/refractory DLBCL (NCT02624492). BI 836826 (starting dose of 25 mg) was administered as an intravenous infusion on day 8 of each 14-day cycle, while gemcitabine (1000 mg/m2) and oxaliplatin (100 mg/m2) were given intravenously on day 1 of each cycle. Patients received a maximum of six treatment cycles; each cycle could be delayed by up to 14 days in cases of toxicity.
Paracetamol, antihistamine and glucocorticoid premedication to mitigate infusion-related reactions (IRRs) was administered 30–120 minutes prior to all BI 836826 infusions. Supportive care including blood products and growth factors were permitted according to local guidelines; prophylactic anti-infective agents were also allowed. Dose escalation was conducted according to the standard 3 + 3 design and was planned to continue until the MTD of BI 836926 in combination with GemOx was reached. BI 836826 dose increments of 50, 100, 150 and 200 mg were planned.
Study assessments
The primary endpoints were the MTD and the number of patients with dose-limiting toxicities (DLTs) during the MTD evaluation period (cycle 1). The MTD was defined as the highest dose for which the number of patients with DLTs was no more than 17% during the MTD evaluation period (cycle 1).
DLTs included both non-hematologic and hematologic adverse events (AEs) considered related to any trial medication. This included any non-hematologic grade ≥ 3 AEs except for: laboratory abnormalities that could be corrected with treatment within 48 h; nausea, vomiting, or diarrhea that resolved within 48 h with adequate treatment; neuropathy considered related to oxaliplatin; or IRRs. Hematologic DLTs were: grade 4 neutropenia lasting > 7 days despite growth factor support; any febrile neutropenia that did not resolve within 48 h with appropriate treatment; grade 4 thrombocytopenia lasting > 7 days or grade 3/4 thrombocytopenia with clinically significant bleeding; failure to recover platelets ≥ 75 × 109/L by 4 weeks after the start of the cycle; and failure to recover neutrophils ≥ 1.0 × 109/L by 4 weeks after start of the cycle. Other safety assessments included the incidence and severity of AEs graded according to the Common Toxicity Criteria for Adverse Events (CTCAE, version 4.0) and changes in laboratory parameters.
The secondary endpoint was investigator-assessed best overall response according to International Working Group criteria for non-Hodgkin lymphoma [28] with refined evaluation of the PET scan using the 5-point scale [29].Tumor size reduction was analyzed as best percentage change from baseline in the sum of the product of the longest perpendicular diameters (SPD) based on imaging data. Pharmacokinetic analysis was planned but was not conducted.
Statistical methods
No formal statistical testing was undertaken. The number of patients with DLTs and the best overall response was summarized by descriptive statistics.
Results
Patients and treatment exposure
Thirty-five patients were enrolled and 21 treated at seven centers in Belgium, Italy and Spain between March 10, 2016 and March 16, 2018. All patients were white and 48% were male (Table 1). Median age was 54.0 years (range 22 to 86), and 57%, 33% and 10% of patients had a baseline ECOG performance score of 0, 1 and 2, respectively. Of the 21 patients, 17 (81%) had pure DLBCL and four (19%) had follicular lymphoma transformed to DLBCL. Lymphoma was considered relapsed for 33% of patients, refractory for 38%, and progressive for 29%. All patients had previously received systemic therapy, with most having received one, two, or four previous therapies (33%, 29%, and 29% of patients, respectively); 71% had progressed following the last therapy.Table 1 Patient demographics
BI 836826 dosea
25 mg
(n = 5) 50 mg
(n = 8) 100 mg
(n = 8) Total
(N = 21)
Male, n (%) 1 (20.0) 4 (50.0) 5 (62.5) 10 (47.6)
Race, n (%)
White 5 (100.0) 8 (100.0) 8 (100.0) 21 (100.0)
Median age, years (range) 77.0 (22–86) 51.0 (41–78) 53.5 (42–77) 54.0 (22–86)
ECOG PS at baseline, n (%)
0 5 (100.0) 4 (50.0) 3 (37.5) 12 (57.1)
1 0 2 (25.0) 5 (62.5) 7 (33.3)
2 0 2 (25.0) 0 2 (9.5)
Ann Arbor stage at screening, n (%)
II 0 1 (12.5) 0 1 (4.8)
III 0 2 (25.0) 3 (37.5) 5 (23.8)
IV 5 (100.0) 5 (62.5) 5 (62.5) 15 (71.4)
Mean time from first diagnosis, years (SD) 4.4 (3.8) 5.1 (7.5) 2.9 (3.7) 4.1 (5.4)
Median number of prior therapies (range) 2.0 (1–4) 2.0 (1–4) 3.0 (1–6) 2.0 (1–6)
Prior therapy, n (%)
Radiotherapy 2 (40.0) 1 (12.5) 1 (12.5) 4 (19.0)
Stem cell transplant 2 (40.0) 2 (25.0) 3 (37.5) 7 (33.3)
Surgery 0 2 (25.0) 1 (12.5) 3 (14.3)
Progression since last systemic therapy, n (%) 5 (100.0) 7 (87.5) 3 (37.5) 15 (71.4)
aGiven every 14 days in combination with gemcitabine 1000 mg/m2 and oxaliplatin 100 mg/m2
ECOG PS Eastern Cooperative Oncology Group Performance Status, SD standard deviation
The best response to previous therapy was CR in five patients (23.8%), partial remission (PR) in two patients (9.5%), and stable disease (SD) in two patients (9.5%); 10 patients (47.6%) had progressive disease (PD); the status of two patients (9.5%) was unknown or missing. Important protocol deviations were noted for seven patients, three of whom had more than one protocol deviation: entrance criteria were not met for 6 patients (efficacy-related criteria for four patients, trial diagnosis for one patient, and safety criteria for one patient), administration of trial medication was delayed for three patients, and prohibited medication was administered for one patient (Supplementary Table 1).
All 21 patients discontinued the trial, with10 patients (48%) completing the maximum of six treatment cycles. Of the 11 patients who discontinued before completing six cycles, six (29%) discontinued due to AEs, and 5 (24%) discontinued due to disease progression. Two patients did not receive a complete infusion of BI 836826: one died of tumor lysis syndrome after a single dose of GemOx and did not receive any BI 836826, while a second had an interruption of the first BI 836826 infusion due to an IRR. This patient received 10 mg out of 25 mg BI 836826 and permanently discontinued trial drug.
MTD and DLTs
BI 836826 dosing in combination with GemOx started at 25 mg and proceeded through 50 mg and 100 mg cohorts. Six patients were replaced and hence excluded from the MTD evaluation set. Two DLTs occurred during the MTD evaluation period (cycle 1), both grade 4 thrombocytopenia lasting > 7 days, affecting one of six evaluable patients (17%) in the 50 mg dosing cohort, and one of six evaluable patients (17%) in the 100 mg cohort. Due to a strategic decision by the sponsor, the trial was prematurely discontinued, and no further patients were enrolled after the 100 mg dose cohort. Consequently, the MTD of BI 836826 in combination with GemOx was not established.
Safety
All patients experienced at least one AE during the on-treatment period of the trial, most commonly neutropenia (n = 16 [79%]), thrombocytopenia (n = 15 [71%]) and anemia (n = 14 [67%]). Sixteen patients (76%) experienced at least one AE deemed to be related to BI 836826 by the Investigator; the most frequent were (any grade/grade 3/4) neutropenia (52/38%), anemia (48/29%), thrombocytopenia (48/43%; Table 2). Eight patients (38%) experienced a treatment-related IRR, of which two (10%) were grade 3. Two patients (10%) had grade 4 neutropenia and a concomitant infection; both infections were of grade 2. One patient had grade 4 thrombocytopenia and concomitant bleeding, a single episode of grade 2 melena. The most common non-hematological AEs considered related to BI 836826 included pyrexia (n = 2 [9.5%]), asthenia (n = 2 [9.5%]), chills, cough, dizziness, nausea and vomiting (all n = 1 [4.8%]), which were either grade 1 or grade 2.Table 2 AEs considered related to BI 836826 occurring in ≥ 2 patients
Any-grade
n (%) Grade 3/4
n (%)
Any treatment-related AEs 16 (76.2) 12 (57.1)
Neutropenia 11 (52.4) 10 (47.6)
Anemia 10 (47.6) 6 (28.6)
Thrombocytopenia 10 (47.6) 9 (42.9)
Infusion-related reaction 8 (38.1) 2 (9.5)
Decreased white blood cell count 7 (33.3) 7 (33.3)
Increased AST 2 (9.5) 0
Increased GGT 2 (9.5) 1 (4.8)
Asthenia 2 (9.5) 0
Pyrexia 2 (9.5) 0
Decreased platelet count 1 (4.8) 1 (4.8)
Pancytopenia 1 (4.8) 1 (4.8)
Increased ALT 1 (4.8) 0
Chills 1 (4.8) 0
Cough 1 (4.8) 0
Dizziness 1 (4.8) 0
Hyperuricemia 1 (4.8) 0
Nausea 1 (4.8) 0
Vomiting 1 (4.8) 0
ALT alanine aminotransferase, AST aspartate aminotransferase, GGT gamma-glutamyl transferase
During the entire on-treatment period, seven patients experienced AEs that were consistent with the definition of a DLT. Thrombocytopenia (5 patients [24%]) was the only event reported for more than two patients.Six patients experienced a total of eight AEs leading to permanent discontinuation of last study medication: thrombocytopenia (two cases), neutropenia, Aspergillus infection, pneumonia, decreased white blood cell count, IRR, and tumor lysis syndrome (one case each).
Overall, 12 patients were reported with serious AEs (57%), of which only thrombocytopenia (4 patients [19%]) and IRR (3 patients [14%]) occurred in more than two patients. Three patients died during the study; however, no deaths were attributed to BI 836826. The case of tumor lysis syndrome was considered related to GemOx as the patient had not yet received BI 836926; the remaining two deaths were attributed to disease progression and Aspergillus infection.
Efficacy
The objective response rate was 38%, including two patients (10%) with complete remission and six patients (29%) with partial remission (Table 3). Six patients (29%) experienced stable disease, and three patients (14%) had progressive disease. Four patients did not have a response assessment. Patients with baseline and at least one post-baseline disease assessment were evaluated for best change in SPD from baseline in lymph nodes, or organ or extra-lymphatic nodules based on PET/CT scan. The median best percentage change was − 31.3% (range –100 to 41%) for 15 patients with baseline lymph nodules and − 78% (range − 89% to − 28%) for five patients with extra-lymphatic disease nodules. In one patient with baseline liver nodules, change from baseline was − 38%, while two patients with baseline spleen nodules had changes of − 100% and − 45%.Table 3 Best overall response in patients receiving BI 836826 plus GemOx
BI 836826 dose
Patients with response, n (%) 25 mg
(n = 5) 50 mg
(n = 8) 100 mg
(n = 8) Total
(n = 21)
Complete remission 1 (20.0) 0 1 (12.5) 2 (9.5)
Partial remission 2 (40.0) 3 (37.5) 1 (12.5) 6 (28.6)
Stable disease 2 (40.0) 1 (12.5) 3 (37.5) 6 (28.6)
Progressive disease 0 2 (25.0) 1 (12.5) 3 (14.3)
Missing 0 2 (25.0) 2 (25.0) 4 (19.0)
GemOx gemcitabine 1000 mg/m2 and oxaliplatin 100 mg/m2
Discussion
In this phase I, dose-finding study in patients with relapsed/refractory DLBCL, BI 836826 in combination with GemOx was generally well tolerated. The MTD was not established, as the trial was prematurely discontinued following the termination of the BI 836826 clinical development program. The MTD was not exceeded at the doses tested (50 and 100 mg given every 14 days).
Adverse events associated with BI 836826 administration were predominantly hematological, which is to be expected in this population, and in keeping with prior studies of BI 836826 in patients with B-cell malignancies [24, 30]. Grade 3/4 hematological AEs were more common in this study than with BI 836826 monotherapy [24, 30], most likely due to the additive effect of GemOx. One DLT of grade 4 thrombocytopenia lasting > 7 days was recorded in each of the 50 mg and 100 mg dosing cohorts. As CD37 has been identified on megakaryocytes and platelets [31, 32], this may be the result of the direct action of BI 836826 on these cells, or may be related to the myelotoxic effects of gemcitabine and oxaliplatin [33, 34]. It is possible that the myelosuppressive effect of combination therapy was exacerbated by administering BI 836826 on day 8 of each cycle, corresponding with the nadir of hematological toxicity due to GemOx. Therefore, hematological toxicity could potentially be less severe with an alternative treatment schedule. However, the tested treatment schedule was based on modelling that evaluated different timings for the BI 836826 and GemOx administrations. The modelling showed that dosing BI 836826 after GemOx at the cytopenia nadir would actually shorten hematological toxicity compared to administering the drugs together, which was predicted to deepen and extend the cytopenia. Of note, the overall incidence of treatment-related IRRs (any-grade, 38%; grade 3/4, 10%) was lower than in a previous study of BI 836826 in patients with relapsed/refractory chronic lymphocytic leukemia (any-grade, 70%; grade 3/4, 8%) [24], and comparable to that seen in Caucasian patients with relapsed/refractory B-cell NHL (any-grade, 41%; grade 3/4, 8%) [30].
The overall response rate in this study was 38%. Few published data on the use of GemOx alone in DLBCL are available for comparison. In a retrospective study of GemOx with/without rituximab in 44 patients with relapsed/refractory aggressive lymphoma, overall response rate was 43%, including 30% CR [27], while an overall response rate of 61%, with 44% CR, was reported in a study of 49 patients with relapsed/refractory DLBCL who received rituximab plus GemOx [26]. However, considerable hematological toxicity was observed in both studies, with 73% of patients experiencing grade ≥ 3 neutropenia and 44% experiencing grade 3 thrombocytopenia in the latter study.
Although the clinical development of BI 836826 has been terminated for strategic reasons, the findings from this study suggest that CD37-based therapy for DLBCL can be safely combined with established chemotherapy regimens. A number of anti-CD37 therapies are currently being investigated for the treatment of B-cell NHL [20–22, 35–37], including radioimmunotherapy. Of note, a phase Ib study of the novel agent lutetium (177Lu)-lilotomabsatetraxetan (Betalutin®) in ASCT-ineligible patients with relapsed/refractory DLBCL is currently in progress (NCT02658968), and results from this and other ongoing clinical trials may provide new hope for DLBCL patients faced with limited options.
Supplementary Information
ESM 1 (PDF 8 kb)
Acknowledgements
We thank the patients, their families, and all of the investigators who participated in these studies. The authors were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development, and have approved the final version.
Author contributions
Anne-Marie Quinson, Valérie Belsack and Carmelo Carlo-Stella contributed to the study conception and design. Material preparation and data collection were performed by Monica Balzarotti, Massimo Magagnoli, Miguel Ángel Canales, Paolo Corradini, Carlos Grande, Juan-Manuel Sancho, Francesco Zaja and Carmelo Carlo-Stella. Data analysis were performed by Anne-Marie Quinson, Valérie Belsack and Daniela Maier. The first draft of the manuscript was written by Anne-Marie Quinson, Valérie Belsack, Monica Balzarotti and Carmelo Carlo-Stella. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
The conduct of this research, study design, data collection, and analysis was financially supported by Boehringer Ingelheim. Medical writing assistance, funded by Boehringer Ingelheim, was provided by Lynn Pritchard, DPhil, of GeoMed, an Ashfield company, part of UDG Healthcare plc, during the preparation of this manuscript.
Data Availability
The clinical study report (including appendices, but without line listings) and other clinical documents related to this study may be accessed on request. Prior to providing access, the documents and data will be examined, and, if necessary, redacted and de-identified to protect the personal data of study participants and personnel, and to respect the boundaries of the informed consent of the study participants. See https://trials.boehringer-ingelheim.com/data_sharing/sharing.html#accordion-1-2 for further details. Bona fide, qualified scientific and medical researchers may request access to de-identified, analyzable patient-level study data, together with documentation describing the structure and content of the datasets. Researchers should use https://clinicalstudydatarequest.com/ to request access to raw data from this study.
Compliance with ethical standards
Conflict of interest
Miguel Ángel Canales received speaker honoraria from Amgen, Janssen, Roche, Sandoz, Takeda; consulting fees from Celgene, Gilead, iQone, Janssen, Karyopharm, Novartis, Roche, Sandoz, Sanofi; and support for CME from Gilead, Janssen, Novartis, Roche, Sandoz, Sanofi.
Paolo Corradini received honoraria as a lecturer from AbbVie, Amgen, Celgene, Gilead/Kite, Janssen, Jazz Pharmaceutics, Novartis, Roche, Sanofi, Sandoz, Takeda, and consulting fees from AbbVie, ADC Therapeutics, Amgen, Celgene, Daiichi Sankyo, Gilead, Incyte, Janssen, Kite, KiowaKirin, Novartis, Roche, Sanofi, Servier and Takeda.
Francesco Zaja received honoraria from Novartis, Amgen, Janssen, Takeda, Celgene, Abbvie, Roche, Mundipharma and Grifols.
Juan-Manuel Sancho received advisory council or committee fees from Roche, Gilead, Janssen, Celgene, Incyte, Celltrion, Novartis, and honoraria as a speaker from Roche, Gilead, Janssen, Celgene, Incyte, Takeda, Novartis, Sanofi and Servier.
Anne-Marie Quinson, Valérie Belsack and Daniela Maier are employees of Boehringer Ingelheim.
Carmelo Carlo-Stella received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Servier, Amgen, Janssen Oncology, Sanofi, ADC Therapeutics, Novartis, and AstraZeneca; provided consultancy to Boehringer Ingelheim, Genenta Science, Sanofi, ADC Therapeutics, and received research funding from Rhizen Pharmaceuticals.
Monica Balzarotti, Massimo Magagnoli and Carlos Grande report no conflict of interest.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33523334 | 18,904,482 | 2021-08 |
What was the administration route of drug 'OXALIPLATIN'? | A phase Ib, open-label, dose-escalation trial of the anti-CD37 monoclonal antibody, BI 836826, in combination with gemcitabine and oxaliplatin in patients with relapsed/refractory diffuse large B-cell lymphoma.
Background BI 836826 is a chimeric mouse-human monoclonal antibody directed against human CD37, a transmembrane protein expressed on mature B lymphocytes. This open-label, phase I dose-escalation trial (NCT02624492) was conducted to determine the maximum tolerated dose (MTD), safety/tolerability, and preliminary efficacy of BI 836826 in combination with gemcitabine and oxaliplatin in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Methods Eligible patients received intravenous infusions of BI 836826 on day 8 and gemcitabine 1000 mg/m2 plus oxaliplatin 100 mg/m2 on day 1, for up to six 14-day treatment cycles. Dose escalation followed the standard 3 + 3 design. Results Of 21 treated patients, 17 had relapsed/refractory DLBCL and four had follicular lymphoma transformed to DLBCL. BI 836826 dosing started at 25 mg and proceeded through 50 mg and 100 mg. Two dose-limiting toxicities (DLTs) occurred during cycle 1, both grade 4 thrombocytopenia lasting > 7 days, affecting 1/6 evaluable patients (17%) in both the 50 mg and 100 mg cohorts. Due to early termination of the study, the MTD was not determined. The most common adverse events related to BI 836826 treatment were neutropenia (52%), thrombocytopenia (48%), and anemia (48%). Eight patients (38%) experienced BI 836826-related infusion-related reactions (two grade 3). Overall objective response rate was 38%, including two patients (10%) with complete remission and six patients (29%) with partial remission. Conclusions BI 836826 in combination with GemOx was generally well tolerated but did not exceed the MTD at doses up to 100 mg given every 14 days.
Introduction
Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma (NHL) and accounts for approximately 30–40% of new NHL cases [1, 2]. The current standard of care for front-line treatment of DLBCL is immunochemotherapy: rituximab plus the multi-agent chemotherapy cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) [3]. Up to 40% of patients relapse or become refractory to R-CHOP. However, despite years of intensive research into alternative front-line treatments, R-CHOP or R-CHOP-like therapies remain the standard of care. Poor response rates to front-line treatment have been associated with various prognostic factors, including clinical characteristic indices (International Prognosis Index [IPI], Revised-IPI [R-IPI], and NCCN-IPI) [4–6], high expression of certain tumor markers (e.g. β2-microglobulin), molecular rearrangements of oncogenes (e.g. MYC, BCL2), or cell of origin classification (e.g. activated B-cell-like origin) [7, 8]. Patients who are refractory to, or relapse after, first-line immunochemotherapy generally receive high dose chemotherapy followed by autologous stem cell transplant (ASCT) [9, 10]. However, outcomes following salvage treatment are generally poor. For instance, in the retrospective SCHOLAR-1 study of 636 patients with refractory DLBCL, the response rate to subsequent therapy was only 26% with median overall survival (OS) of 6.3 months [11]. Moreover, anti-CD20 based immunochemotherapy regimens appear to have low efficacy in the salvage setting. In the phase III CORAL trial, 3-year event-free survival in patients with relapsed/refractory DLBCL treated with R-ICE (rituximab, ifosfamide, carboplatin, etoposide) or R-DHAP (rituximab, dexamethasone, cytarabine, cisplatin) was 37% overall and only 21% in patients previously treated with rituximab [12]. Only 50% of patients could proceed to ASCT [13]. Thus, more effective salvage strategies for patients with relapsed or refractory disease after front-line immunochemotherapy are needed [2].
CD37 is a tetraspanin protein that is highly expressed on mature B lymphocytes and lymphoid neoplasms [14–16]. It appears to have multiple physiological functions, including regulation of apoptosis/survival signaling [17], B/T cell interaction [18], and T-cell proliferation [19]. Early clinical studies of anti-CD37 agents [20–22] have demonstrated that it is a viable therapeutic target in B cell NHL.
BI 836826 is a chimeric Fc-engineered immunoglobulin G1 (IgG1) monoclonal antibody directed against human CD37 [23]. In transgenic mice and cynomolgous monkeys, BI 836826 dose-dependently depleted peripheral B cells, and significantly suppressed tumor growth in a mouse B-cell lymphoma xenograft model [23]. In phase I studies, BI 836826 demonstrated acceptable tolerability and anti-tumor activity in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) [24] and in patients with relapsed/refractory B-cell NHL [25]. As gemcitabine and oxaliplatin (GemOx), with or without rituximab, is a treatment option in patients with ASCT-ineligible relapsed/refractory DLBCL [26, 27], we investigated the feasibility of combining BI 836826 and GemOx in this phase I, dose escalation study.
Patients and methods
Patients
Eligible patients were aged 18 years or older and had histologically confirmed relapsed/refractory DLBCL (including transformed follicular lymphoma). ‘Relapsed’ was defined as the appearance of any new lesion after attainment of an initial complete response (CR) and ‘refractory’ was defined as < 50% decrease in lesion size with prior anti-lymphoma treatment in the absence of new lesion development. All patients had previously been treated with an anti-CD20 monoclonal antibody in combination with anthracycline-containing chemotherapy and were either ineligible for high dose therapy and ASCT or had relapsed/progressed after an autologous/allogeneic stem cell transplant. Allogeneic stem cell transplant performed at least 6 months prior to study entry was permitted if patients did not require immunosuppressive treatment and had no evidence of active graft-versus-host disease. Patients were required to have Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, acceptable organ function, and a screening CT scan with involvement of at least one bi-dimensional lesion/node of > 1.5 cm.
Key exclusion criteria were: prior history of malignancy other than DLBCL; known central nervous system involvement; and receipt of anti-lymphoma treatment either within 14 days or, in the case of an investigational agent, less than five half-lives of the investigational drug, prior to the first dose of the current trial medication.
The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines, and the study protocol was approved by the Institutional Review Boards or Independent Ethics Committees of all participating institutions. Written informed consent was obtained from all patients.
Study design and treatment
This was an open-label, multicenter phase Ib dose-escalation trial conducted to determine the maximum tolerated dose (MTD), safety/tolerability, and preliminary efficacy of BI 836826 in combination with GemOx in patients with relapsed/refractory DLBCL (NCT02624492). BI 836826 (starting dose of 25 mg) was administered as an intravenous infusion on day 8 of each 14-day cycle, while gemcitabine (1000 mg/m2) and oxaliplatin (100 mg/m2) were given intravenously on day 1 of each cycle. Patients received a maximum of six treatment cycles; each cycle could be delayed by up to 14 days in cases of toxicity.
Paracetamol, antihistamine and glucocorticoid premedication to mitigate infusion-related reactions (IRRs) was administered 30–120 minutes prior to all BI 836826 infusions. Supportive care including blood products and growth factors were permitted according to local guidelines; prophylactic anti-infective agents were also allowed. Dose escalation was conducted according to the standard 3 + 3 design and was planned to continue until the MTD of BI 836926 in combination with GemOx was reached. BI 836826 dose increments of 50, 100, 150 and 200 mg were planned.
Study assessments
The primary endpoints were the MTD and the number of patients with dose-limiting toxicities (DLTs) during the MTD evaluation period (cycle 1). The MTD was defined as the highest dose for which the number of patients with DLTs was no more than 17% during the MTD evaluation period (cycle 1).
DLTs included both non-hematologic and hematologic adverse events (AEs) considered related to any trial medication. This included any non-hematologic grade ≥ 3 AEs except for: laboratory abnormalities that could be corrected with treatment within 48 h; nausea, vomiting, or diarrhea that resolved within 48 h with adequate treatment; neuropathy considered related to oxaliplatin; or IRRs. Hematologic DLTs were: grade 4 neutropenia lasting > 7 days despite growth factor support; any febrile neutropenia that did not resolve within 48 h with appropriate treatment; grade 4 thrombocytopenia lasting > 7 days or grade 3/4 thrombocytopenia with clinically significant bleeding; failure to recover platelets ≥ 75 × 109/L by 4 weeks after the start of the cycle; and failure to recover neutrophils ≥ 1.0 × 109/L by 4 weeks after start of the cycle. Other safety assessments included the incidence and severity of AEs graded according to the Common Toxicity Criteria for Adverse Events (CTCAE, version 4.0) and changes in laboratory parameters.
The secondary endpoint was investigator-assessed best overall response according to International Working Group criteria for non-Hodgkin lymphoma [28] with refined evaluation of the PET scan using the 5-point scale [29].Tumor size reduction was analyzed as best percentage change from baseline in the sum of the product of the longest perpendicular diameters (SPD) based on imaging data. Pharmacokinetic analysis was planned but was not conducted.
Statistical methods
No formal statistical testing was undertaken. The number of patients with DLTs and the best overall response was summarized by descriptive statistics.
Results
Patients and treatment exposure
Thirty-five patients were enrolled and 21 treated at seven centers in Belgium, Italy and Spain between March 10, 2016 and March 16, 2018. All patients were white and 48% were male (Table 1). Median age was 54.0 years (range 22 to 86), and 57%, 33% and 10% of patients had a baseline ECOG performance score of 0, 1 and 2, respectively. Of the 21 patients, 17 (81%) had pure DLBCL and four (19%) had follicular lymphoma transformed to DLBCL. Lymphoma was considered relapsed for 33% of patients, refractory for 38%, and progressive for 29%. All patients had previously received systemic therapy, with most having received one, two, or four previous therapies (33%, 29%, and 29% of patients, respectively); 71% had progressed following the last therapy.Table 1 Patient demographics
BI 836826 dosea
25 mg
(n = 5) 50 mg
(n = 8) 100 mg
(n = 8) Total
(N = 21)
Male, n (%) 1 (20.0) 4 (50.0) 5 (62.5) 10 (47.6)
Race, n (%)
White 5 (100.0) 8 (100.0) 8 (100.0) 21 (100.0)
Median age, years (range) 77.0 (22–86) 51.0 (41–78) 53.5 (42–77) 54.0 (22–86)
ECOG PS at baseline, n (%)
0 5 (100.0) 4 (50.0) 3 (37.5) 12 (57.1)
1 0 2 (25.0) 5 (62.5) 7 (33.3)
2 0 2 (25.0) 0 2 (9.5)
Ann Arbor stage at screening, n (%)
II 0 1 (12.5) 0 1 (4.8)
III 0 2 (25.0) 3 (37.5) 5 (23.8)
IV 5 (100.0) 5 (62.5) 5 (62.5) 15 (71.4)
Mean time from first diagnosis, years (SD) 4.4 (3.8) 5.1 (7.5) 2.9 (3.7) 4.1 (5.4)
Median number of prior therapies (range) 2.0 (1–4) 2.0 (1–4) 3.0 (1–6) 2.0 (1–6)
Prior therapy, n (%)
Radiotherapy 2 (40.0) 1 (12.5) 1 (12.5) 4 (19.0)
Stem cell transplant 2 (40.0) 2 (25.0) 3 (37.5) 7 (33.3)
Surgery 0 2 (25.0) 1 (12.5) 3 (14.3)
Progression since last systemic therapy, n (%) 5 (100.0) 7 (87.5) 3 (37.5) 15 (71.4)
aGiven every 14 days in combination with gemcitabine 1000 mg/m2 and oxaliplatin 100 mg/m2
ECOG PS Eastern Cooperative Oncology Group Performance Status, SD standard deviation
The best response to previous therapy was CR in five patients (23.8%), partial remission (PR) in two patients (9.5%), and stable disease (SD) in two patients (9.5%); 10 patients (47.6%) had progressive disease (PD); the status of two patients (9.5%) was unknown or missing. Important protocol deviations were noted for seven patients, three of whom had more than one protocol deviation: entrance criteria were not met for 6 patients (efficacy-related criteria for four patients, trial diagnosis for one patient, and safety criteria for one patient), administration of trial medication was delayed for three patients, and prohibited medication was administered for one patient (Supplementary Table 1).
All 21 patients discontinued the trial, with10 patients (48%) completing the maximum of six treatment cycles. Of the 11 patients who discontinued before completing six cycles, six (29%) discontinued due to AEs, and 5 (24%) discontinued due to disease progression. Two patients did not receive a complete infusion of BI 836826: one died of tumor lysis syndrome after a single dose of GemOx and did not receive any BI 836826, while a second had an interruption of the first BI 836826 infusion due to an IRR. This patient received 10 mg out of 25 mg BI 836826 and permanently discontinued trial drug.
MTD and DLTs
BI 836826 dosing in combination with GemOx started at 25 mg and proceeded through 50 mg and 100 mg cohorts. Six patients were replaced and hence excluded from the MTD evaluation set. Two DLTs occurred during the MTD evaluation period (cycle 1), both grade 4 thrombocytopenia lasting > 7 days, affecting one of six evaluable patients (17%) in the 50 mg dosing cohort, and one of six evaluable patients (17%) in the 100 mg cohort. Due to a strategic decision by the sponsor, the trial was prematurely discontinued, and no further patients were enrolled after the 100 mg dose cohort. Consequently, the MTD of BI 836826 in combination with GemOx was not established.
Safety
All patients experienced at least one AE during the on-treatment period of the trial, most commonly neutropenia (n = 16 [79%]), thrombocytopenia (n = 15 [71%]) and anemia (n = 14 [67%]). Sixteen patients (76%) experienced at least one AE deemed to be related to BI 836826 by the Investigator; the most frequent were (any grade/grade 3/4) neutropenia (52/38%), anemia (48/29%), thrombocytopenia (48/43%; Table 2). Eight patients (38%) experienced a treatment-related IRR, of which two (10%) were grade 3. Two patients (10%) had grade 4 neutropenia and a concomitant infection; both infections were of grade 2. One patient had grade 4 thrombocytopenia and concomitant bleeding, a single episode of grade 2 melena. The most common non-hematological AEs considered related to BI 836826 included pyrexia (n = 2 [9.5%]), asthenia (n = 2 [9.5%]), chills, cough, dizziness, nausea and vomiting (all n = 1 [4.8%]), which were either grade 1 or grade 2.Table 2 AEs considered related to BI 836826 occurring in ≥ 2 patients
Any-grade
n (%) Grade 3/4
n (%)
Any treatment-related AEs 16 (76.2) 12 (57.1)
Neutropenia 11 (52.4) 10 (47.6)
Anemia 10 (47.6) 6 (28.6)
Thrombocytopenia 10 (47.6) 9 (42.9)
Infusion-related reaction 8 (38.1) 2 (9.5)
Decreased white blood cell count 7 (33.3) 7 (33.3)
Increased AST 2 (9.5) 0
Increased GGT 2 (9.5) 1 (4.8)
Asthenia 2 (9.5) 0
Pyrexia 2 (9.5) 0
Decreased platelet count 1 (4.8) 1 (4.8)
Pancytopenia 1 (4.8) 1 (4.8)
Increased ALT 1 (4.8) 0
Chills 1 (4.8) 0
Cough 1 (4.8) 0
Dizziness 1 (4.8) 0
Hyperuricemia 1 (4.8) 0
Nausea 1 (4.8) 0
Vomiting 1 (4.8) 0
ALT alanine aminotransferase, AST aspartate aminotransferase, GGT gamma-glutamyl transferase
During the entire on-treatment period, seven patients experienced AEs that were consistent with the definition of a DLT. Thrombocytopenia (5 patients [24%]) was the only event reported for more than two patients.Six patients experienced a total of eight AEs leading to permanent discontinuation of last study medication: thrombocytopenia (two cases), neutropenia, Aspergillus infection, pneumonia, decreased white blood cell count, IRR, and tumor lysis syndrome (one case each).
Overall, 12 patients were reported with serious AEs (57%), of which only thrombocytopenia (4 patients [19%]) and IRR (3 patients [14%]) occurred in more than two patients. Three patients died during the study; however, no deaths were attributed to BI 836826. The case of tumor lysis syndrome was considered related to GemOx as the patient had not yet received BI 836926; the remaining two deaths were attributed to disease progression and Aspergillus infection.
Efficacy
The objective response rate was 38%, including two patients (10%) with complete remission and six patients (29%) with partial remission (Table 3). Six patients (29%) experienced stable disease, and three patients (14%) had progressive disease. Four patients did not have a response assessment. Patients with baseline and at least one post-baseline disease assessment were evaluated for best change in SPD from baseline in lymph nodes, or organ or extra-lymphatic nodules based on PET/CT scan. The median best percentage change was − 31.3% (range –100 to 41%) for 15 patients with baseline lymph nodules and − 78% (range − 89% to − 28%) for five patients with extra-lymphatic disease nodules. In one patient with baseline liver nodules, change from baseline was − 38%, while two patients with baseline spleen nodules had changes of − 100% and − 45%.Table 3 Best overall response in patients receiving BI 836826 plus GemOx
BI 836826 dose
Patients with response, n (%) 25 mg
(n = 5) 50 mg
(n = 8) 100 mg
(n = 8) Total
(n = 21)
Complete remission 1 (20.0) 0 1 (12.5) 2 (9.5)
Partial remission 2 (40.0) 3 (37.5) 1 (12.5) 6 (28.6)
Stable disease 2 (40.0) 1 (12.5) 3 (37.5) 6 (28.6)
Progressive disease 0 2 (25.0) 1 (12.5) 3 (14.3)
Missing 0 2 (25.0) 2 (25.0) 4 (19.0)
GemOx gemcitabine 1000 mg/m2 and oxaliplatin 100 mg/m2
Discussion
In this phase I, dose-finding study in patients with relapsed/refractory DLBCL, BI 836826 in combination with GemOx was generally well tolerated. The MTD was not established, as the trial was prematurely discontinued following the termination of the BI 836826 clinical development program. The MTD was not exceeded at the doses tested (50 and 100 mg given every 14 days).
Adverse events associated with BI 836826 administration were predominantly hematological, which is to be expected in this population, and in keeping with prior studies of BI 836826 in patients with B-cell malignancies [24, 30]. Grade 3/4 hematological AEs were more common in this study than with BI 836826 monotherapy [24, 30], most likely due to the additive effect of GemOx. One DLT of grade 4 thrombocytopenia lasting > 7 days was recorded in each of the 50 mg and 100 mg dosing cohorts. As CD37 has been identified on megakaryocytes and platelets [31, 32], this may be the result of the direct action of BI 836826 on these cells, or may be related to the myelotoxic effects of gemcitabine and oxaliplatin [33, 34]. It is possible that the myelosuppressive effect of combination therapy was exacerbated by administering BI 836826 on day 8 of each cycle, corresponding with the nadir of hematological toxicity due to GemOx. Therefore, hematological toxicity could potentially be less severe with an alternative treatment schedule. However, the tested treatment schedule was based on modelling that evaluated different timings for the BI 836826 and GemOx administrations. The modelling showed that dosing BI 836826 after GemOx at the cytopenia nadir would actually shorten hematological toxicity compared to administering the drugs together, which was predicted to deepen and extend the cytopenia. Of note, the overall incidence of treatment-related IRRs (any-grade, 38%; grade 3/4, 10%) was lower than in a previous study of BI 836826 in patients with relapsed/refractory chronic lymphocytic leukemia (any-grade, 70%; grade 3/4, 8%) [24], and comparable to that seen in Caucasian patients with relapsed/refractory B-cell NHL (any-grade, 41%; grade 3/4, 8%) [30].
The overall response rate in this study was 38%. Few published data on the use of GemOx alone in DLBCL are available for comparison. In a retrospective study of GemOx with/without rituximab in 44 patients with relapsed/refractory aggressive lymphoma, overall response rate was 43%, including 30% CR [27], while an overall response rate of 61%, with 44% CR, was reported in a study of 49 patients with relapsed/refractory DLBCL who received rituximab plus GemOx [26]. However, considerable hematological toxicity was observed in both studies, with 73% of patients experiencing grade ≥ 3 neutropenia and 44% experiencing grade 3 thrombocytopenia in the latter study.
Although the clinical development of BI 836826 has been terminated for strategic reasons, the findings from this study suggest that CD37-based therapy for DLBCL can be safely combined with established chemotherapy regimens. A number of anti-CD37 therapies are currently being investigated for the treatment of B-cell NHL [20–22, 35–37], including radioimmunotherapy. Of note, a phase Ib study of the novel agent lutetium (177Lu)-lilotomabsatetraxetan (Betalutin®) in ASCT-ineligible patients with relapsed/refractory DLBCL is currently in progress (NCT02658968), and results from this and other ongoing clinical trials may provide new hope for DLBCL patients faced with limited options.
Supplementary Information
ESM 1 (PDF 8 kb)
Acknowledgements
We thank the patients, their families, and all of the investigators who participated in these studies. The authors were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development, and have approved the final version.
Author contributions
Anne-Marie Quinson, Valérie Belsack and Carmelo Carlo-Stella contributed to the study conception and design. Material preparation and data collection were performed by Monica Balzarotti, Massimo Magagnoli, Miguel Ángel Canales, Paolo Corradini, Carlos Grande, Juan-Manuel Sancho, Francesco Zaja and Carmelo Carlo-Stella. Data analysis were performed by Anne-Marie Quinson, Valérie Belsack and Daniela Maier. The first draft of the manuscript was written by Anne-Marie Quinson, Valérie Belsack, Monica Balzarotti and Carmelo Carlo-Stella. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
The conduct of this research, study design, data collection, and analysis was financially supported by Boehringer Ingelheim. Medical writing assistance, funded by Boehringer Ingelheim, was provided by Lynn Pritchard, DPhil, of GeoMed, an Ashfield company, part of UDG Healthcare plc, during the preparation of this manuscript.
Data Availability
The clinical study report (including appendices, but without line listings) and other clinical documents related to this study may be accessed on request. Prior to providing access, the documents and data will be examined, and, if necessary, redacted and de-identified to protect the personal data of study participants and personnel, and to respect the boundaries of the informed consent of the study participants. See https://trials.boehringer-ingelheim.com/data_sharing/sharing.html#accordion-1-2 for further details. Bona fide, qualified scientific and medical researchers may request access to de-identified, analyzable patient-level study data, together with documentation describing the structure and content of the datasets. Researchers should use https://clinicalstudydatarequest.com/ to request access to raw data from this study.
Compliance with ethical standards
Conflict of interest
Miguel Ángel Canales received speaker honoraria from Amgen, Janssen, Roche, Sandoz, Takeda; consulting fees from Celgene, Gilead, iQone, Janssen, Karyopharm, Novartis, Roche, Sandoz, Sanofi; and support for CME from Gilead, Janssen, Novartis, Roche, Sandoz, Sanofi.
Paolo Corradini received honoraria as a lecturer from AbbVie, Amgen, Celgene, Gilead/Kite, Janssen, Jazz Pharmaceutics, Novartis, Roche, Sanofi, Sandoz, Takeda, and consulting fees from AbbVie, ADC Therapeutics, Amgen, Celgene, Daiichi Sankyo, Gilead, Incyte, Janssen, Kite, KiowaKirin, Novartis, Roche, Sanofi, Servier and Takeda.
Francesco Zaja received honoraria from Novartis, Amgen, Janssen, Takeda, Celgene, Abbvie, Roche, Mundipharma and Grifols.
Juan-Manuel Sancho received advisory council or committee fees from Roche, Gilead, Janssen, Celgene, Incyte, Celltrion, Novartis, and honoraria as a speaker from Roche, Gilead, Janssen, Celgene, Incyte, Takeda, Novartis, Sanofi and Servier.
Anne-Marie Quinson, Valérie Belsack and Daniela Maier are employees of Boehringer Ingelheim.
Carmelo Carlo-Stella received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Servier, Amgen, Janssen Oncology, Sanofi, ADC Therapeutics, Novartis, and AstraZeneca; provided consultancy to Boehringer Ingelheim, Genenta Science, Sanofi, ADC Therapeutics, and received research funding from Rhizen Pharmaceuticals.
Monica Balzarotti, Massimo Magagnoli and Carlos Grande report no conflict of interest.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33523334 | 18,904,482 | 2021-08 |
What was the dosage of drug 'GEMCITABINE HYDROCHLORIDE'? | A phase Ib, open-label, dose-escalation trial of the anti-CD37 monoclonal antibody, BI 836826, in combination with gemcitabine and oxaliplatin in patients with relapsed/refractory diffuse large B-cell lymphoma.
Background BI 836826 is a chimeric mouse-human monoclonal antibody directed against human CD37, a transmembrane protein expressed on mature B lymphocytes. This open-label, phase I dose-escalation trial (NCT02624492) was conducted to determine the maximum tolerated dose (MTD), safety/tolerability, and preliminary efficacy of BI 836826 in combination with gemcitabine and oxaliplatin in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Methods Eligible patients received intravenous infusions of BI 836826 on day 8 and gemcitabine 1000 mg/m2 plus oxaliplatin 100 mg/m2 on day 1, for up to six 14-day treatment cycles. Dose escalation followed the standard 3 + 3 design. Results Of 21 treated patients, 17 had relapsed/refractory DLBCL and four had follicular lymphoma transformed to DLBCL. BI 836826 dosing started at 25 mg and proceeded through 50 mg and 100 mg. Two dose-limiting toxicities (DLTs) occurred during cycle 1, both grade 4 thrombocytopenia lasting > 7 days, affecting 1/6 evaluable patients (17%) in both the 50 mg and 100 mg cohorts. Due to early termination of the study, the MTD was not determined. The most common adverse events related to BI 836826 treatment were neutropenia (52%), thrombocytopenia (48%), and anemia (48%). Eight patients (38%) experienced BI 836826-related infusion-related reactions (two grade 3). Overall objective response rate was 38%, including two patients (10%) with complete remission and six patients (29%) with partial remission. Conclusions BI 836826 in combination with GemOx was generally well tolerated but did not exceed the MTD at doses up to 100 mg given every 14 days.
Introduction
Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma (NHL) and accounts for approximately 30–40% of new NHL cases [1, 2]. The current standard of care for front-line treatment of DLBCL is immunochemotherapy: rituximab plus the multi-agent chemotherapy cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) [3]. Up to 40% of patients relapse or become refractory to R-CHOP. However, despite years of intensive research into alternative front-line treatments, R-CHOP or R-CHOP-like therapies remain the standard of care. Poor response rates to front-line treatment have been associated with various prognostic factors, including clinical characteristic indices (International Prognosis Index [IPI], Revised-IPI [R-IPI], and NCCN-IPI) [4–6], high expression of certain tumor markers (e.g. β2-microglobulin), molecular rearrangements of oncogenes (e.g. MYC, BCL2), or cell of origin classification (e.g. activated B-cell-like origin) [7, 8]. Patients who are refractory to, or relapse after, first-line immunochemotherapy generally receive high dose chemotherapy followed by autologous stem cell transplant (ASCT) [9, 10]. However, outcomes following salvage treatment are generally poor. For instance, in the retrospective SCHOLAR-1 study of 636 patients with refractory DLBCL, the response rate to subsequent therapy was only 26% with median overall survival (OS) of 6.3 months [11]. Moreover, anti-CD20 based immunochemotherapy regimens appear to have low efficacy in the salvage setting. In the phase III CORAL trial, 3-year event-free survival in patients with relapsed/refractory DLBCL treated with R-ICE (rituximab, ifosfamide, carboplatin, etoposide) or R-DHAP (rituximab, dexamethasone, cytarabine, cisplatin) was 37% overall and only 21% in patients previously treated with rituximab [12]. Only 50% of patients could proceed to ASCT [13]. Thus, more effective salvage strategies for patients with relapsed or refractory disease after front-line immunochemotherapy are needed [2].
CD37 is a tetraspanin protein that is highly expressed on mature B lymphocytes and lymphoid neoplasms [14–16]. It appears to have multiple physiological functions, including regulation of apoptosis/survival signaling [17], B/T cell interaction [18], and T-cell proliferation [19]. Early clinical studies of anti-CD37 agents [20–22] have demonstrated that it is a viable therapeutic target in B cell NHL.
BI 836826 is a chimeric Fc-engineered immunoglobulin G1 (IgG1) monoclonal antibody directed against human CD37 [23]. In transgenic mice and cynomolgous monkeys, BI 836826 dose-dependently depleted peripheral B cells, and significantly suppressed tumor growth in a mouse B-cell lymphoma xenograft model [23]. In phase I studies, BI 836826 demonstrated acceptable tolerability and anti-tumor activity in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) [24] and in patients with relapsed/refractory B-cell NHL [25]. As gemcitabine and oxaliplatin (GemOx), with or without rituximab, is a treatment option in patients with ASCT-ineligible relapsed/refractory DLBCL [26, 27], we investigated the feasibility of combining BI 836826 and GemOx in this phase I, dose escalation study.
Patients and methods
Patients
Eligible patients were aged 18 years or older and had histologically confirmed relapsed/refractory DLBCL (including transformed follicular lymphoma). ‘Relapsed’ was defined as the appearance of any new lesion after attainment of an initial complete response (CR) and ‘refractory’ was defined as < 50% decrease in lesion size with prior anti-lymphoma treatment in the absence of new lesion development. All patients had previously been treated with an anti-CD20 monoclonal antibody in combination with anthracycline-containing chemotherapy and were either ineligible for high dose therapy and ASCT or had relapsed/progressed after an autologous/allogeneic stem cell transplant. Allogeneic stem cell transplant performed at least 6 months prior to study entry was permitted if patients did not require immunosuppressive treatment and had no evidence of active graft-versus-host disease. Patients were required to have Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, acceptable organ function, and a screening CT scan with involvement of at least one bi-dimensional lesion/node of > 1.5 cm.
Key exclusion criteria were: prior history of malignancy other than DLBCL; known central nervous system involvement; and receipt of anti-lymphoma treatment either within 14 days or, in the case of an investigational agent, less than five half-lives of the investigational drug, prior to the first dose of the current trial medication.
The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines, and the study protocol was approved by the Institutional Review Boards or Independent Ethics Committees of all participating institutions. Written informed consent was obtained from all patients.
Study design and treatment
This was an open-label, multicenter phase Ib dose-escalation trial conducted to determine the maximum tolerated dose (MTD), safety/tolerability, and preliminary efficacy of BI 836826 in combination with GemOx in patients with relapsed/refractory DLBCL (NCT02624492). BI 836826 (starting dose of 25 mg) was administered as an intravenous infusion on day 8 of each 14-day cycle, while gemcitabine (1000 mg/m2) and oxaliplatin (100 mg/m2) were given intravenously on day 1 of each cycle. Patients received a maximum of six treatment cycles; each cycle could be delayed by up to 14 days in cases of toxicity.
Paracetamol, antihistamine and glucocorticoid premedication to mitigate infusion-related reactions (IRRs) was administered 30–120 minutes prior to all BI 836826 infusions. Supportive care including blood products and growth factors were permitted according to local guidelines; prophylactic anti-infective agents were also allowed. Dose escalation was conducted according to the standard 3 + 3 design and was planned to continue until the MTD of BI 836926 in combination with GemOx was reached. BI 836826 dose increments of 50, 100, 150 and 200 mg were planned.
Study assessments
The primary endpoints were the MTD and the number of patients with dose-limiting toxicities (DLTs) during the MTD evaluation period (cycle 1). The MTD was defined as the highest dose for which the number of patients with DLTs was no more than 17% during the MTD evaluation period (cycle 1).
DLTs included both non-hematologic and hematologic adverse events (AEs) considered related to any trial medication. This included any non-hematologic grade ≥ 3 AEs except for: laboratory abnormalities that could be corrected with treatment within 48 h; nausea, vomiting, or diarrhea that resolved within 48 h with adequate treatment; neuropathy considered related to oxaliplatin; or IRRs. Hematologic DLTs were: grade 4 neutropenia lasting > 7 days despite growth factor support; any febrile neutropenia that did not resolve within 48 h with appropriate treatment; grade 4 thrombocytopenia lasting > 7 days or grade 3/4 thrombocytopenia with clinically significant bleeding; failure to recover platelets ≥ 75 × 109/L by 4 weeks after the start of the cycle; and failure to recover neutrophils ≥ 1.0 × 109/L by 4 weeks after start of the cycle. Other safety assessments included the incidence and severity of AEs graded according to the Common Toxicity Criteria for Adverse Events (CTCAE, version 4.0) and changes in laboratory parameters.
The secondary endpoint was investigator-assessed best overall response according to International Working Group criteria for non-Hodgkin lymphoma [28] with refined evaluation of the PET scan using the 5-point scale [29].Tumor size reduction was analyzed as best percentage change from baseline in the sum of the product of the longest perpendicular diameters (SPD) based on imaging data. Pharmacokinetic analysis was planned but was not conducted.
Statistical methods
No formal statistical testing was undertaken. The number of patients with DLTs and the best overall response was summarized by descriptive statistics.
Results
Patients and treatment exposure
Thirty-five patients were enrolled and 21 treated at seven centers in Belgium, Italy and Spain between March 10, 2016 and March 16, 2018. All patients were white and 48% were male (Table 1). Median age was 54.0 years (range 22 to 86), and 57%, 33% and 10% of patients had a baseline ECOG performance score of 0, 1 and 2, respectively. Of the 21 patients, 17 (81%) had pure DLBCL and four (19%) had follicular lymphoma transformed to DLBCL. Lymphoma was considered relapsed for 33% of patients, refractory for 38%, and progressive for 29%. All patients had previously received systemic therapy, with most having received one, two, or four previous therapies (33%, 29%, and 29% of patients, respectively); 71% had progressed following the last therapy.Table 1 Patient demographics
BI 836826 dosea
25 mg
(n = 5) 50 mg
(n = 8) 100 mg
(n = 8) Total
(N = 21)
Male, n (%) 1 (20.0) 4 (50.0) 5 (62.5) 10 (47.6)
Race, n (%)
White 5 (100.0) 8 (100.0) 8 (100.0) 21 (100.0)
Median age, years (range) 77.0 (22–86) 51.0 (41–78) 53.5 (42–77) 54.0 (22–86)
ECOG PS at baseline, n (%)
0 5 (100.0) 4 (50.0) 3 (37.5) 12 (57.1)
1 0 2 (25.0) 5 (62.5) 7 (33.3)
2 0 2 (25.0) 0 2 (9.5)
Ann Arbor stage at screening, n (%)
II 0 1 (12.5) 0 1 (4.8)
III 0 2 (25.0) 3 (37.5) 5 (23.8)
IV 5 (100.0) 5 (62.5) 5 (62.5) 15 (71.4)
Mean time from first diagnosis, years (SD) 4.4 (3.8) 5.1 (7.5) 2.9 (3.7) 4.1 (5.4)
Median number of prior therapies (range) 2.0 (1–4) 2.0 (1–4) 3.0 (1–6) 2.0 (1–6)
Prior therapy, n (%)
Radiotherapy 2 (40.0) 1 (12.5) 1 (12.5) 4 (19.0)
Stem cell transplant 2 (40.0) 2 (25.0) 3 (37.5) 7 (33.3)
Surgery 0 2 (25.0) 1 (12.5) 3 (14.3)
Progression since last systemic therapy, n (%) 5 (100.0) 7 (87.5) 3 (37.5) 15 (71.4)
aGiven every 14 days in combination with gemcitabine 1000 mg/m2 and oxaliplatin 100 mg/m2
ECOG PS Eastern Cooperative Oncology Group Performance Status, SD standard deviation
The best response to previous therapy was CR in five patients (23.8%), partial remission (PR) in two patients (9.5%), and stable disease (SD) in two patients (9.5%); 10 patients (47.6%) had progressive disease (PD); the status of two patients (9.5%) was unknown or missing. Important protocol deviations were noted for seven patients, three of whom had more than one protocol deviation: entrance criteria were not met for 6 patients (efficacy-related criteria for four patients, trial diagnosis for one patient, and safety criteria for one patient), administration of trial medication was delayed for three patients, and prohibited medication was administered for one patient (Supplementary Table 1).
All 21 patients discontinued the trial, with10 patients (48%) completing the maximum of six treatment cycles. Of the 11 patients who discontinued before completing six cycles, six (29%) discontinued due to AEs, and 5 (24%) discontinued due to disease progression. Two patients did not receive a complete infusion of BI 836826: one died of tumor lysis syndrome after a single dose of GemOx and did not receive any BI 836826, while a second had an interruption of the first BI 836826 infusion due to an IRR. This patient received 10 mg out of 25 mg BI 836826 and permanently discontinued trial drug.
MTD and DLTs
BI 836826 dosing in combination with GemOx started at 25 mg and proceeded through 50 mg and 100 mg cohorts. Six patients were replaced and hence excluded from the MTD evaluation set. Two DLTs occurred during the MTD evaluation period (cycle 1), both grade 4 thrombocytopenia lasting > 7 days, affecting one of six evaluable patients (17%) in the 50 mg dosing cohort, and one of six evaluable patients (17%) in the 100 mg cohort. Due to a strategic decision by the sponsor, the trial was prematurely discontinued, and no further patients were enrolled after the 100 mg dose cohort. Consequently, the MTD of BI 836826 in combination with GemOx was not established.
Safety
All patients experienced at least one AE during the on-treatment period of the trial, most commonly neutropenia (n = 16 [79%]), thrombocytopenia (n = 15 [71%]) and anemia (n = 14 [67%]). Sixteen patients (76%) experienced at least one AE deemed to be related to BI 836826 by the Investigator; the most frequent were (any grade/grade 3/4) neutropenia (52/38%), anemia (48/29%), thrombocytopenia (48/43%; Table 2). Eight patients (38%) experienced a treatment-related IRR, of which two (10%) were grade 3. Two patients (10%) had grade 4 neutropenia and a concomitant infection; both infections were of grade 2. One patient had grade 4 thrombocytopenia and concomitant bleeding, a single episode of grade 2 melena. The most common non-hematological AEs considered related to BI 836826 included pyrexia (n = 2 [9.5%]), asthenia (n = 2 [9.5%]), chills, cough, dizziness, nausea and vomiting (all n = 1 [4.8%]), which were either grade 1 or grade 2.Table 2 AEs considered related to BI 836826 occurring in ≥ 2 patients
Any-grade
n (%) Grade 3/4
n (%)
Any treatment-related AEs 16 (76.2) 12 (57.1)
Neutropenia 11 (52.4) 10 (47.6)
Anemia 10 (47.6) 6 (28.6)
Thrombocytopenia 10 (47.6) 9 (42.9)
Infusion-related reaction 8 (38.1) 2 (9.5)
Decreased white blood cell count 7 (33.3) 7 (33.3)
Increased AST 2 (9.5) 0
Increased GGT 2 (9.5) 1 (4.8)
Asthenia 2 (9.5) 0
Pyrexia 2 (9.5) 0
Decreased platelet count 1 (4.8) 1 (4.8)
Pancytopenia 1 (4.8) 1 (4.8)
Increased ALT 1 (4.8) 0
Chills 1 (4.8) 0
Cough 1 (4.8) 0
Dizziness 1 (4.8) 0
Hyperuricemia 1 (4.8) 0
Nausea 1 (4.8) 0
Vomiting 1 (4.8) 0
ALT alanine aminotransferase, AST aspartate aminotransferase, GGT gamma-glutamyl transferase
During the entire on-treatment period, seven patients experienced AEs that were consistent with the definition of a DLT. Thrombocytopenia (5 patients [24%]) was the only event reported for more than two patients.Six patients experienced a total of eight AEs leading to permanent discontinuation of last study medication: thrombocytopenia (two cases), neutropenia, Aspergillus infection, pneumonia, decreased white blood cell count, IRR, and tumor lysis syndrome (one case each).
Overall, 12 patients were reported with serious AEs (57%), of which only thrombocytopenia (4 patients [19%]) and IRR (3 patients [14%]) occurred in more than two patients. Three patients died during the study; however, no deaths were attributed to BI 836826. The case of tumor lysis syndrome was considered related to GemOx as the patient had not yet received BI 836926; the remaining two deaths were attributed to disease progression and Aspergillus infection.
Efficacy
The objective response rate was 38%, including two patients (10%) with complete remission and six patients (29%) with partial remission (Table 3). Six patients (29%) experienced stable disease, and three patients (14%) had progressive disease. Four patients did not have a response assessment. Patients with baseline and at least one post-baseline disease assessment were evaluated for best change in SPD from baseline in lymph nodes, or organ or extra-lymphatic nodules based on PET/CT scan. The median best percentage change was − 31.3% (range –100 to 41%) for 15 patients with baseline lymph nodules and − 78% (range − 89% to − 28%) for five patients with extra-lymphatic disease nodules. In one patient with baseline liver nodules, change from baseline was − 38%, while two patients with baseline spleen nodules had changes of − 100% and − 45%.Table 3 Best overall response in patients receiving BI 836826 plus GemOx
BI 836826 dose
Patients with response, n (%) 25 mg
(n = 5) 50 mg
(n = 8) 100 mg
(n = 8) Total
(n = 21)
Complete remission 1 (20.0) 0 1 (12.5) 2 (9.5)
Partial remission 2 (40.0) 3 (37.5) 1 (12.5) 6 (28.6)
Stable disease 2 (40.0) 1 (12.5) 3 (37.5) 6 (28.6)
Progressive disease 0 2 (25.0) 1 (12.5) 3 (14.3)
Missing 0 2 (25.0) 2 (25.0) 4 (19.0)
GemOx gemcitabine 1000 mg/m2 and oxaliplatin 100 mg/m2
Discussion
In this phase I, dose-finding study in patients with relapsed/refractory DLBCL, BI 836826 in combination with GemOx was generally well tolerated. The MTD was not established, as the trial was prematurely discontinued following the termination of the BI 836826 clinical development program. The MTD was not exceeded at the doses tested (50 and 100 mg given every 14 days).
Adverse events associated with BI 836826 administration were predominantly hematological, which is to be expected in this population, and in keeping with prior studies of BI 836826 in patients with B-cell malignancies [24, 30]. Grade 3/4 hematological AEs were more common in this study than with BI 836826 monotherapy [24, 30], most likely due to the additive effect of GemOx. One DLT of grade 4 thrombocytopenia lasting > 7 days was recorded in each of the 50 mg and 100 mg dosing cohorts. As CD37 has been identified on megakaryocytes and platelets [31, 32], this may be the result of the direct action of BI 836826 on these cells, or may be related to the myelotoxic effects of gemcitabine and oxaliplatin [33, 34]. It is possible that the myelosuppressive effect of combination therapy was exacerbated by administering BI 836826 on day 8 of each cycle, corresponding with the nadir of hematological toxicity due to GemOx. Therefore, hematological toxicity could potentially be less severe with an alternative treatment schedule. However, the tested treatment schedule was based on modelling that evaluated different timings for the BI 836826 and GemOx administrations. The modelling showed that dosing BI 836826 after GemOx at the cytopenia nadir would actually shorten hematological toxicity compared to administering the drugs together, which was predicted to deepen and extend the cytopenia. Of note, the overall incidence of treatment-related IRRs (any-grade, 38%; grade 3/4, 10%) was lower than in a previous study of BI 836826 in patients with relapsed/refractory chronic lymphocytic leukemia (any-grade, 70%; grade 3/4, 8%) [24], and comparable to that seen in Caucasian patients with relapsed/refractory B-cell NHL (any-grade, 41%; grade 3/4, 8%) [30].
The overall response rate in this study was 38%. Few published data on the use of GemOx alone in DLBCL are available for comparison. In a retrospective study of GemOx with/without rituximab in 44 patients with relapsed/refractory aggressive lymphoma, overall response rate was 43%, including 30% CR [27], while an overall response rate of 61%, with 44% CR, was reported in a study of 49 patients with relapsed/refractory DLBCL who received rituximab plus GemOx [26]. However, considerable hematological toxicity was observed in both studies, with 73% of patients experiencing grade ≥ 3 neutropenia and 44% experiencing grade 3 thrombocytopenia in the latter study.
Although the clinical development of BI 836826 has been terminated for strategic reasons, the findings from this study suggest that CD37-based therapy for DLBCL can be safely combined with established chemotherapy regimens. A number of anti-CD37 therapies are currently being investigated for the treatment of B-cell NHL [20–22, 35–37], including radioimmunotherapy. Of note, a phase Ib study of the novel agent lutetium (177Lu)-lilotomabsatetraxetan (Betalutin®) in ASCT-ineligible patients with relapsed/refractory DLBCL is currently in progress (NCT02658968), and results from this and other ongoing clinical trials may provide new hope for DLBCL patients faced with limited options.
Supplementary Information
ESM 1 (PDF 8 kb)
Acknowledgements
We thank the patients, their families, and all of the investigators who participated in these studies. The authors were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development, and have approved the final version.
Author contributions
Anne-Marie Quinson, Valérie Belsack and Carmelo Carlo-Stella contributed to the study conception and design. Material preparation and data collection were performed by Monica Balzarotti, Massimo Magagnoli, Miguel Ángel Canales, Paolo Corradini, Carlos Grande, Juan-Manuel Sancho, Francesco Zaja and Carmelo Carlo-Stella. Data analysis were performed by Anne-Marie Quinson, Valérie Belsack and Daniela Maier. The first draft of the manuscript was written by Anne-Marie Quinson, Valérie Belsack, Monica Balzarotti and Carmelo Carlo-Stella. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
The conduct of this research, study design, data collection, and analysis was financially supported by Boehringer Ingelheim. Medical writing assistance, funded by Boehringer Ingelheim, was provided by Lynn Pritchard, DPhil, of GeoMed, an Ashfield company, part of UDG Healthcare plc, during the preparation of this manuscript.
Data Availability
The clinical study report (including appendices, but without line listings) and other clinical documents related to this study may be accessed on request. Prior to providing access, the documents and data will be examined, and, if necessary, redacted and de-identified to protect the personal data of study participants and personnel, and to respect the boundaries of the informed consent of the study participants. See https://trials.boehringer-ingelheim.com/data_sharing/sharing.html#accordion-1-2 for further details. Bona fide, qualified scientific and medical researchers may request access to de-identified, analyzable patient-level study data, together with documentation describing the structure and content of the datasets. Researchers should use https://clinicalstudydatarequest.com/ to request access to raw data from this study.
Compliance with ethical standards
Conflict of interest
Miguel Ángel Canales received speaker honoraria from Amgen, Janssen, Roche, Sandoz, Takeda; consulting fees from Celgene, Gilead, iQone, Janssen, Karyopharm, Novartis, Roche, Sandoz, Sanofi; and support for CME from Gilead, Janssen, Novartis, Roche, Sandoz, Sanofi.
Paolo Corradini received honoraria as a lecturer from AbbVie, Amgen, Celgene, Gilead/Kite, Janssen, Jazz Pharmaceutics, Novartis, Roche, Sanofi, Sandoz, Takeda, and consulting fees from AbbVie, ADC Therapeutics, Amgen, Celgene, Daiichi Sankyo, Gilead, Incyte, Janssen, Kite, KiowaKirin, Novartis, Roche, Sanofi, Servier and Takeda.
Francesco Zaja received honoraria from Novartis, Amgen, Janssen, Takeda, Celgene, Abbvie, Roche, Mundipharma and Grifols.
Juan-Manuel Sancho received advisory council or committee fees from Roche, Gilead, Janssen, Celgene, Incyte, Celltrion, Novartis, and honoraria as a speaker from Roche, Gilead, Janssen, Celgene, Incyte, Takeda, Novartis, Sanofi and Servier.
Anne-Marie Quinson, Valérie Belsack and Daniela Maier are employees of Boehringer Ingelheim.
Carmelo Carlo-Stella received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Servier, Amgen, Janssen Oncology, Sanofi, ADC Therapeutics, Novartis, and AstraZeneca; provided consultancy to Boehringer Ingelheim, Genenta Science, Sanofi, ADC Therapeutics, and received research funding from Rhizen Pharmaceuticals.
Monica Balzarotti, Massimo Magagnoli and Carlos Grande report no conflict of interest.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | 1000 MG/M2, ON DAY 1 OF EACH 14-DAY CYCLE | DrugDosageText | CC BY | 33523334 | 18,904,482 | 2021-08 |
What was the dosage of drug 'OXALIPLATIN'? | A phase Ib, open-label, dose-escalation trial of the anti-CD37 monoclonal antibody, BI 836826, in combination with gemcitabine and oxaliplatin in patients with relapsed/refractory diffuse large B-cell lymphoma.
Background BI 836826 is a chimeric mouse-human monoclonal antibody directed against human CD37, a transmembrane protein expressed on mature B lymphocytes. This open-label, phase I dose-escalation trial (NCT02624492) was conducted to determine the maximum tolerated dose (MTD), safety/tolerability, and preliminary efficacy of BI 836826 in combination with gemcitabine and oxaliplatin in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Methods Eligible patients received intravenous infusions of BI 836826 on day 8 and gemcitabine 1000 mg/m2 plus oxaliplatin 100 mg/m2 on day 1, for up to six 14-day treatment cycles. Dose escalation followed the standard 3 + 3 design. Results Of 21 treated patients, 17 had relapsed/refractory DLBCL and four had follicular lymphoma transformed to DLBCL. BI 836826 dosing started at 25 mg and proceeded through 50 mg and 100 mg. Two dose-limiting toxicities (DLTs) occurred during cycle 1, both grade 4 thrombocytopenia lasting > 7 days, affecting 1/6 evaluable patients (17%) in both the 50 mg and 100 mg cohorts. Due to early termination of the study, the MTD was not determined. The most common adverse events related to BI 836826 treatment were neutropenia (52%), thrombocytopenia (48%), and anemia (48%). Eight patients (38%) experienced BI 836826-related infusion-related reactions (two grade 3). Overall objective response rate was 38%, including two patients (10%) with complete remission and six patients (29%) with partial remission. Conclusions BI 836826 in combination with GemOx was generally well tolerated but did not exceed the MTD at doses up to 100 mg given every 14 days.
Introduction
Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma (NHL) and accounts for approximately 30–40% of new NHL cases [1, 2]. The current standard of care for front-line treatment of DLBCL is immunochemotherapy: rituximab plus the multi-agent chemotherapy cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) [3]. Up to 40% of patients relapse or become refractory to R-CHOP. However, despite years of intensive research into alternative front-line treatments, R-CHOP or R-CHOP-like therapies remain the standard of care. Poor response rates to front-line treatment have been associated with various prognostic factors, including clinical characteristic indices (International Prognosis Index [IPI], Revised-IPI [R-IPI], and NCCN-IPI) [4–6], high expression of certain tumor markers (e.g. β2-microglobulin), molecular rearrangements of oncogenes (e.g. MYC, BCL2), or cell of origin classification (e.g. activated B-cell-like origin) [7, 8]. Patients who are refractory to, or relapse after, first-line immunochemotherapy generally receive high dose chemotherapy followed by autologous stem cell transplant (ASCT) [9, 10]. However, outcomes following salvage treatment are generally poor. For instance, in the retrospective SCHOLAR-1 study of 636 patients with refractory DLBCL, the response rate to subsequent therapy was only 26% with median overall survival (OS) of 6.3 months [11]. Moreover, anti-CD20 based immunochemotherapy regimens appear to have low efficacy in the salvage setting. In the phase III CORAL trial, 3-year event-free survival in patients with relapsed/refractory DLBCL treated with R-ICE (rituximab, ifosfamide, carboplatin, etoposide) or R-DHAP (rituximab, dexamethasone, cytarabine, cisplatin) was 37% overall and only 21% in patients previously treated with rituximab [12]. Only 50% of patients could proceed to ASCT [13]. Thus, more effective salvage strategies for patients with relapsed or refractory disease after front-line immunochemotherapy are needed [2].
CD37 is a tetraspanin protein that is highly expressed on mature B lymphocytes and lymphoid neoplasms [14–16]. It appears to have multiple physiological functions, including regulation of apoptosis/survival signaling [17], B/T cell interaction [18], and T-cell proliferation [19]. Early clinical studies of anti-CD37 agents [20–22] have demonstrated that it is a viable therapeutic target in B cell NHL.
BI 836826 is a chimeric Fc-engineered immunoglobulin G1 (IgG1) monoclonal antibody directed against human CD37 [23]. In transgenic mice and cynomolgous monkeys, BI 836826 dose-dependently depleted peripheral B cells, and significantly suppressed tumor growth in a mouse B-cell lymphoma xenograft model [23]. In phase I studies, BI 836826 demonstrated acceptable tolerability and anti-tumor activity in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) [24] and in patients with relapsed/refractory B-cell NHL [25]. As gemcitabine and oxaliplatin (GemOx), with or without rituximab, is a treatment option in patients with ASCT-ineligible relapsed/refractory DLBCL [26, 27], we investigated the feasibility of combining BI 836826 and GemOx in this phase I, dose escalation study.
Patients and methods
Patients
Eligible patients were aged 18 years or older and had histologically confirmed relapsed/refractory DLBCL (including transformed follicular lymphoma). ‘Relapsed’ was defined as the appearance of any new lesion after attainment of an initial complete response (CR) and ‘refractory’ was defined as < 50% decrease in lesion size with prior anti-lymphoma treatment in the absence of new lesion development. All patients had previously been treated with an anti-CD20 monoclonal antibody in combination with anthracycline-containing chemotherapy and were either ineligible for high dose therapy and ASCT or had relapsed/progressed after an autologous/allogeneic stem cell transplant. Allogeneic stem cell transplant performed at least 6 months prior to study entry was permitted if patients did not require immunosuppressive treatment and had no evidence of active graft-versus-host disease. Patients were required to have Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, acceptable organ function, and a screening CT scan with involvement of at least one bi-dimensional lesion/node of > 1.5 cm.
Key exclusion criteria were: prior history of malignancy other than DLBCL; known central nervous system involvement; and receipt of anti-lymphoma treatment either within 14 days or, in the case of an investigational agent, less than five half-lives of the investigational drug, prior to the first dose of the current trial medication.
The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines, and the study protocol was approved by the Institutional Review Boards or Independent Ethics Committees of all participating institutions. Written informed consent was obtained from all patients.
Study design and treatment
This was an open-label, multicenter phase Ib dose-escalation trial conducted to determine the maximum tolerated dose (MTD), safety/tolerability, and preliminary efficacy of BI 836826 in combination with GemOx in patients with relapsed/refractory DLBCL (NCT02624492). BI 836826 (starting dose of 25 mg) was administered as an intravenous infusion on day 8 of each 14-day cycle, while gemcitabine (1000 mg/m2) and oxaliplatin (100 mg/m2) were given intravenously on day 1 of each cycle. Patients received a maximum of six treatment cycles; each cycle could be delayed by up to 14 days in cases of toxicity.
Paracetamol, antihistamine and glucocorticoid premedication to mitigate infusion-related reactions (IRRs) was administered 30–120 minutes prior to all BI 836826 infusions. Supportive care including blood products and growth factors were permitted according to local guidelines; prophylactic anti-infective agents were also allowed. Dose escalation was conducted according to the standard 3 + 3 design and was planned to continue until the MTD of BI 836926 in combination with GemOx was reached. BI 836826 dose increments of 50, 100, 150 and 200 mg were planned.
Study assessments
The primary endpoints were the MTD and the number of patients with dose-limiting toxicities (DLTs) during the MTD evaluation period (cycle 1). The MTD was defined as the highest dose for which the number of patients with DLTs was no more than 17% during the MTD evaluation period (cycle 1).
DLTs included both non-hematologic and hematologic adverse events (AEs) considered related to any trial medication. This included any non-hematologic grade ≥ 3 AEs except for: laboratory abnormalities that could be corrected with treatment within 48 h; nausea, vomiting, or diarrhea that resolved within 48 h with adequate treatment; neuropathy considered related to oxaliplatin; or IRRs. Hematologic DLTs were: grade 4 neutropenia lasting > 7 days despite growth factor support; any febrile neutropenia that did not resolve within 48 h with appropriate treatment; grade 4 thrombocytopenia lasting > 7 days or grade 3/4 thrombocytopenia with clinically significant bleeding; failure to recover platelets ≥ 75 × 109/L by 4 weeks after the start of the cycle; and failure to recover neutrophils ≥ 1.0 × 109/L by 4 weeks after start of the cycle. Other safety assessments included the incidence and severity of AEs graded according to the Common Toxicity Criteria for Adverse Events (CTCAE, version 4.0) and changes in laboratory parameters.
The secondary endpoint was investigator-assessed best overall response according to International Working Group criteria for non-Hodgkin lymphoma [28] with refined evaluation of the PET scan using the 5-point scale [29].Tumor size reduction was analyzed as best percentage change from baseline in the sum of the product of the longest perpendicular diameters (SPD) based on imaging data. Pharmacokinetic analysis was planned but was not conducted.
Statistical methods
No formal statistical testing was undertaken. The number of patients with DLTs and the best overall response was summarized by descriptive statistics.
Results
Patients and treatment exposure
Thirty-five patients were enrolled and 21 treated at seven centers in Belgium, Italy and Spain between March 10, 2016 and March 16, 2018. All patients were white and 48% were male (Table 1). Median age was 54.0 years (range 22 to 86), and 57%, 33% and 10% of patients had a baseline ECOG performance score of 0, 1 and 2, respectively. Of the 21 patients, 17 (81%) had pure DLBCL and four (19%) had follicular lymphoma transformed to DLBCL. Lymphoma was considered relapsed for 33% of patients, refractory for 38%, and progressive for 29%. All patients had previously received systemic therapy, with most having received one, two, or four previous therapies (33%, 29%, and 29% of patients, respectively); 71% had progressed following the last therapy.Table 1 Patient demographics
BI 836826 dosea
25 mg
(n = 5) 50 mg
(n = 8) 100 mg
(n = 8) Total
(N = 21)
Male, n (%) 1 (20.0) 4 (50.0) 5 (62.5) 10 (47.6)
Race, n (%)
White 5 (100.0) 8 (100.0) 8 (100.0) 21 (100.0)
Median age, years (range) 77.0 (22–86) 51.0 (41–78) 53.5 (42–77) 54.0 (22–86)
ECOG PS at baseline, n (%)
0 5 (100.0) 4 (50.0) 3 (37.5) 12 (57.1)
1 0 2 (25.0) 5 (62.5) 7 (33.3)
2 0 2 (25.0) 0 2 (9.5)
Ann Arbor stage at screening, n (%)
II 0 1 (12.5) 0 1 (4.8)
III 0 2 (25.0) 3 (37.5) 5 (23.8)
IV 5 (100.0) 5 (62.5) 5 (62.5) 15 (71.4)
Mean time from first diagnosis, years (SD) 4.4 (3.8) 5.1 (7.5) 2.9 (3.7) 4.1 (5.4)
Median number of prior therapies (range) 2.0 (1–4) 2.0 (1–4) 3.0 (1–6) 2.0 (1–6)
Prior therapy, n (%)
Radiotherapy 2 (40.0) 1 (12.5) 1 (12.5) 4 (19.0)
Stem cell transplant 2 (40.0) 2 (25.0) 3 (37.5) 7 (33.3)
Surgery 0 2 (25.0) 1 (12.5) 3 (14.3)
Progression since last systemic therapy, n (%) 5 (100.0) 7 (87.5) 3 (37.5) 15 (71.4)
aGiven every 14 days in combination with gemcitabine 1000 mg/m2 and oxaliplatin 100 mg/m2
ECOG PS Eastern Cooperative Oncology Group Performance Status, SD standard deviation
The best response to previous therapy was CR in five patients (23.8%), partial remission (PR) in two patients (9.5%), and stable disease (SD) in two patients (9.5%); 10 patients (47.6%) had progressive disease (PD); the status of two patients (9.5%) was unknown or missing. Important protocol deviations were noted for seven patients, three of whom had more than one protocol deviation: entrance criteria were not met for 6 patients (efficacy-related criteria for four patients, trial diagnosis for one patient, and safety criteria for one patient), administration of trial medication was delayed for three patients, and prohibited medication was administered for one patient (Supplementary Table 1).
All 21 patients discontinued the trial, with10 patients (48%) completing the maximum of six treatment cycles. Of the 11 patients who discontinued before completing six cycles, six (29%) discontinued due to AEs, and 5 (24%) discontinued due to disease progression. Two patients did not receive a complete infusion of BI 836826: one died of tumor lysis syndrome after a single dose of GemOx and did not receive any BI 836826, while a second had an interruption of the first BI 836826 infusion due to an IRR. This patient received 10 mg out of 25 mg BI 836826 and permanently discontinued trial drug.
MTD and DLTs
BI 836826 dosing in combination with GemOx started at 25 mg and proceeded through 50 mg and 100 mg cohorts. Six patients were replaced and hence excluded from the MTD evaluation set. Two DLTs occurred during the MTD evaluation period (cycle 1), both grade 4 thrombocytopenia lasting > 7 days, affecting one of six evaluable patients (17%) in the 50 mg dosing cohort, and one of six evaluable patients (17%) in the 100 mg cohort. Due to a strategic decision by the sponsor, the trial was prematurely discontinued, and no further patients were enrolled after the 100 mg dose cohort. Consequently, the MTD of BI 836826 in combination with GemOx was not established.
Safety
All patients experienced at least one AE during the on-treatment period of the trial, most commonly neutropenia (n = 16 [79%]), thrombocytopenia (n = 15 [71%]) and anemia (n = 14 [67%]). Sixteen patients (76%) experienced at least one AE deemed to be related to BI 836826 by the Investigator; the most frequent were (any grade/grade 3/4) neutropenia (52/38%), anemia (48/29%), thrombocytopenia (48/43%; Table 2). Eight patients (38%) experienced a treatment-related IRR, of which two (10%) were grade 3. Two patients (10%) had grade 4 neutropenia and a concomitant infection; both infections were of grade 2. One patient had grade 4 thrombocytopenia and concomitant bleeding, a single episode of grade 2 melena. The most common non-hematological AEs considered related to BI 836826 included pyrexia (n = 2 [9.5%]), asthenia (n = 2 [9.5%]), chills, cough, dizziness, nausea and vomiting (all n = 1 [4.8%]), which were either grade 1 or grade 2.Table 2 AEs considered related to BI 836826 occurring in ≥ 2 patients
Any-grade
n (%) Grade 3/4
n (%)
Any treatment-related AEs 16 (76.2) 12 (57.1)
Neutropenia 11 (52.4) 10 (47.6)
Anemia 10 (47.6) 6 (28.6)
Thrombocytopenia 10 (47.6) 9 (42.9)
Infusion-related reaction 8 (38.1) 2 (9.5)
Decreased white blood cell count 7 (33.3) 7 (33.3)
Increased AST 2 (9.5) 0
Increased GGT 2 (9.5) 1 (4.8)
Asthenia 2 (9.5) 0
Pyrexia 2 (9.5) 0
Decreased platelet count 1 (4.8) 1 (4.8)
Pancytopenia 1 (4.8) 1 (4.8)
Increased ALT 1 (4.8) 0
Chills 1 (4.8) 0
Cough 1 (4.8) 0
Dizziness 1 (4.8) 0
Hyperuricemia 1 (4.8) 0
Nausea 1 (4.8) 0
Vomiting 1 (4.8) 0
ALT alanine aminotransferase, AST aspartate aminotransferase, GGT gamma-glutamyl transferase
During the entire on-treatment period, seven patients experienced AEs that were consistent with the definition of a DLT. Thrombocytopenia (5 patients [24%]) was the only event reported for more than two patients.Six patients experienced a total of eight AEs leading to permanent discontinuation of last study medication: thrombocytopenia (two cases), neutropenia, Aspergillus infection, pneumonia, decreased white blood cell count, IRR, and tumor lysis syndrome (one case each).
Overall, 12 patients were reported with serious AEs (57%), of which only thrombocytopenia (4 patients [19%]) and IRR (3 patients [14%]) occurred in more than two patients. Three patients died during the study; however, no deaths were attributed to BI 836826. The case of tumor lysis syndrome was considered related to GemOx as the patient had not yet received BI 836926; the remaining two deaths were attributed to disease progression and Aspergillus infection.
Efficacy
The objective response rate was 38%, including two patients (10%) with complete remission and six patients (29%) with partial remission (Table 3). Six patients (29%) experienced stable disease, and three patients (14%) had progressive disease. Four patients did not have a response assessment. Patients with baseline and at least one post-baseline disease assessment were evaluated for best change in SPD from baseline in lymph nodes, or organ or extra-lymphatic nodules based on PET/CT scan. The median best percentage change was − 31.3% (range –100 to 41%) for 15 patients with baseline lymph nodules and − 78% (range − 89% to − 28%) for five patients with extra-lymphatic disease nodules. In one patient with baseline liver nodules, change from baseline was − 38%, while two patients with baseline spleen nodules had changes of − 100% and − 45%.Table 3 Best overall response in patients receiving BI 836826 plus GemOx
BI 836826 dose
Patients with response, n (%) 25 mg
(n = 5) 50 mg
(n = 8) 100 mg
(n = 8) Total
(n = 21)
Complete remission 1 (20.0) 0 1 (12.5) 2 (9.5)
Partial remission 2 (40.0) 3 (37.5) 1 (12.5) 6 (28.6)
Stable disease 2 (40.0) 1 (12.5) 3 (37.5) 6 (28.6)
Progressive disease 0 2 (25.0) 1 (12.5) 3 (14.3)
Missing 0 2 (25.0) 2 (25.0) 4 (19.0)
GemOx gemcitabine 1000 mg/m2 and oxaliplatin 100 mg/m2
Discussion
In this phase I, dose-finding study in patients with relapsed/refractory DLBCL, BI 836826 in combination with GemOx was generally well tolerated. The MTD was not established, as the trial was prematurely discontinued following the termination of the BI 836826 clinical development program. The MTD was not exceeded at the doses tested (50 and 100 mg given every 14 days).
Adverse events associated with BI 836826 administration were predominantly hematological, which is to be expected in this population, and in keeping with prior studies of BI 836826 in patients with B-cell malignancies [24, 30]. Grade 3/4 hematological AEs were more common in this study than with BI 836826 monotherapy [24, 30], most likely due to the additive effect of GemOx. One DLT of grade 4 thrombocytopenia lasting > 7 days was recorded in each of the 50 mg and 100 mg dosing cohorts. As CD37 has been identified on megakaryocytes and platelets [31, 32], this may be the result of the direct action of BI 836826 on these cells, or may be related to the myelotoxic effects of gemcitabine and oxaliplatin [33, 34]. It is possible that the myelosuppressive effect of combination therapy was exacerbated by administering BI 836826 on day 8 of each cycle, corresponding with the nadir of hematological toxicity due to GemOx. Therefore, hematological toxicity could potentially be less severe with an alternative treatment schedule. However, the tested treatment schedule was based on modelling that evaluated different timings for the BI 836826 and GemOx administrations. The modelling showed that dosing BI 836826 after GemOx at the cytopenia nadir would actually shorten hematological toxicity compared to administering the drugs together, which was predicted to deepen and extend the cytopenia. Of note, the overall incidence of treatment-related IRRs (any-grade, 38%; grade 3/4, 10%) was lower than in a previous study of BI 836826 in patients with relapsed/refractory chronic lymphocytic leukemia (any-grade, 70%; grade 3/4, 8%) [24], and comparable to that seen in Caucasian patients with relapsed/refractory B-cell NHL (any-grade, 41%; grade 3/4, 8%) [30].
The overall response rate in this study was 38%. Few published data on the use of GemOx alone in DLBCL are available for comparison. In a retrospective study of GemOx with/without rituximab in 44 patients with relapsed/refractory aggressive lymphoma, overall response rate was 43%, including 30% CR [27], while an overall response rate of 61%, with 44% CR, was reported in a study of 49 patients with relapsed/refractory DLBCL who received rituximab plus GemOx [26]. However, considerable hematological toxicity was observed in both studies, with 73% of patients experiencing grade ≥ 3 neutropenia and 44% experiencing grade 3 thrombocytopenia in the latter study.
Although the clinical development of BI 836826 has been terminated for strategic reasons, the findings from this study suggest that CD37-based therapy for DLBCL can be safely combined with established chemotherapy regimens. A number of anti-CD37 therapies are currently being investigated for the treatment of B-cell NHL [20–22, 35–37], including radioimmunotherapy. Of note, a phase Ib study of the novel agent lutetium (177Lu)-lilotomabsatetraxetan (Betalutin®) in ASCT-ineligible patients with relapsed/refractory DLBCL is currently in progress (NCT02658968), and results from this and other ongoing clinical trials may provide new hope for DLBCL patients faced with limited options.
Supplementary Information
ESM 1 (PDF 8 kb)
Acknowledgements
We thank the patients, their families, and all of the investigators who participated in these studies. The authors were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development, and have approved the final version.
Author contributions
Anne-Marie Quinson, Valérie Belsack and Carmelo Carlo-Stella contributed to the study conception and design. Material preparation and data collection were performed by Monica Balzarotti, Massimo Magagnoli, Miguel Ángel Canales, Paolo Corradini, Carlos Grande, Juan-Manuel Sancho, Francesco Zaja and Carmelo Carlo-Stella. Data analysis were performed by Anne-Marie Quinson, Valérie Belsack and Daniela Maier. The first draft of the manuscript was written by Anne-Marie Quinson, Valérie Belsack, Monica Balzarotti and Carmelo Carlo-Stella. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
The conduct of this research, study design, data collection, and analysis was financially supported by Boehringer Ingelheim. Medical writing assistance, funded by Boehringer Ingelheim, was provided by Lynn Pritchard, DPhil, of GeoMed, an Ashfield company, part of UDG Healthcare plc, during the preparation of this manuscript.
Data Availability
The clinical study report (including appendices, but without line listings) and other clinical documents related to this study may be accessed on request. Prior to providing access, the documents and data will be examined, and, if necessary, redacted and de-identified to protect the personal data of study participants and personnel, and to respect the boundaries of the informed consent of the study participants. See https://trials.boehringer-ingelheim.com/data_sharing/sharing.html#accordion-1-2 for further details. Bona fide, qualified scientific and medical researchers may request access to de-identified, analyzable patient-level study data, together with documentation describing the structure and content of the datasets. Researchers should use https://clinicalstudydatarequest.com/ to request access to raw data from this study.
Compliance with ethical standards
Conflict of interest
Miguel Ángel Canales received speaker honoraria from Amgen, Janssen, Roche, Sandoz, Takeda; consulting fees from Celgene, Gilead, iQone, Janssen, Karyopharm, Novartis, Roche, Sandoz, Sanofi; and support for CME from Gilead, Janssen, Novartis, Roche, Sandoz, Sanofi.
Paolo Corradini received honoraria as a lecturer from AbbVie, Amgen, Celgene, Gilead/Kite, Janssen, Jazz Pharmaceutics, Novartis, Roche, Sanofi, Sandoz, Takeda, and consulting fees from AbbVie, ADC Therapeutics, Amgen, Celgene, Daiichi Sankyo, Gilead, Incyte, Janssen, Kite, KiowaKirin, Novartis, Roche, Sanofi, Servier and Takeda.
Francesco Zaja received honoraria from Novartis, Amgen, Janssen, Takeda, Celgene, Abbvie, Roche, Mundipharma and Grifols.
Juan-Manuel Sancho received advisory council or committee fees from Roche, Gilead, Janssen, Celgene, Incyte, Celltrion, Novartis, and honoraria as a speaker from Roche, Gilead, Janssen, Celgene, Incyte, Takeda, Novartis, Sanofi and Servier.
Anne-Marie Quinson, Valérie Belsack and Daniela Maier are employees of Boehringer Ingelheim.
Carmelo Carlo-Stella received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Servier, Amgen, Janssen Oncology, Sanofi, ADC Therapeutics, Novartis, and AstraZeneca; provided consultancy to Boehringer Ingelheim, Genenta Science, Sanofi, ADC Therapeutics, and received research funding from Rhizen Pharmaceuticals.
Monica Balzarotti, Massimo Magagnoli and Carlos Grande report no conflict of interest.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Publisher’s note
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What was the outcome of reaction 'Tumour lysis syndrome'? | A phase Ib, open-label, dose-escalation trial of the anti-CD37 monoclonal antibody, BI 836826, in combination with gemcitabine and oxaliplatin in patients with relapsed/refractory diffuse large B-cell lymphoma.
Background BI 836826 is a chimeric mouse-human monoclonal antibody directed against human CD37, a transmembrane protein expressed on mature B lymphocytes. This open-label, phase I dose-escalation trial (NCT02624492) was conducted to determine the maximum tolerated dose (MTD), safety/tolerability, and preliminary efficacy of BI 836826 in combination with gemcitabine and oxaliplatin in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Methods Eligible patients received intravenous infusions of BI 836826 on day 8 and gemcitabine 1000 mg/m2 plus oxaliplatin 100 mg/m2 on day 1, for up to six 14-day treatment cycles. Dose escalation followed the standard 3 + 3 design. Results Of 21 treated patients, 17 had relapsed/refractory DLBCL and four had follicular lymphoma transformed to DLBCL. BI 836826 dosing started at 25 mg and proceeded through 50 mg and 100 mg. Two dose-limiting toxicities (DLTs) occurred during cycle 1, both grade 4 thrombocytopenia lasting > 7 days, affecting 1/6 evaluable patients (17%) in both the 50 mg and 100 mg cohorts. Due to early termination of the study, the MTD was not determined. The most common adverse events related to BI 836826 treatment were neutropenia (52%), thrombocytopenia (48%), and anemia (48%). Eight patients (38%) experienced BI 836826-related infusion-related reactions (two grade 3). Overall objective response rate was 38%, including two patients (10%) with complete remission and six patients (29%) with partial remission. Conclusions BI 836826 in combination with GemOx was generally well tolerated but did not exceed the MTD at doses up to 100 mg given every 14 days.
Introduction
Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma (NHL) and accounts for approximately 30–40% of new NHL cases [1, 2]. The current standard of care for front-line treatment of DLBCL is immunochemotherapy: rituximab plus the multi-agent chemotherapy cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) [3]. Up to 40% of patients relapse or become refractory to R-CHOP. However, despite years of intensive research into alternative front-line treatments, R-CHOP or R-CHOP-like therapies remain the standard of care. Poor response rates to front-line treatment have been associated with various prognostic factors, including clinical characteristic indices (International Prognosis Index [IPI], Revised-IPI [R-IPI], and NCCN-IPI) [4–6], high expression of certain tumor markers (e.g. β2-microglobulin), molecular rearrangements of oncogenes (e.g. MYC, BCL2), or cell of origin classification (e.g. activated B-cell-like origin) [7, 8]. Patients who are refractory to, or relapse after, first-line immunochemotherapy generally receive high dose chemotherapy followed by autologous stem cell transplant (ASCT) [9, 10]. However, outcomes following salvage treatment are generally poor. For instance, in the retrospective SCHOLAR-1 study of 636 patients with refractory DLBCL, the response rate to subsequent therapy was only 26% with median overall survival (OS) of 6.3 months [11]. Moreover, anti-CD20 based immunochemotherapy regimens appear to have low efficacy in the salvage setting. In the phase III CORAL trial, 3-year event-free survival in patients with relapsed/refractory DLBCL treated with R-ICE (rituximab, ifosfamide, carboplatin, etoposide) or R-DHAP (rituximab, dexamethasone, cytarabine, cisplatin) was 37% overall and only 21% in patients previously treated with rituximab [12]. Only 50% of patients could proceed to ASCT [13]. Thus, more effective salvage strategies for patients with relapsed or refractory disease after front-line immunochemotherapy are needed [2].
CD37 is a tetraspanin protein that is highly expressed on mature B lymphocytes and lymphoid neoplasms [14–16]. It appears to have multiple physiological functions, including regulation of apoptosis/survival signaling [17], B/T cell interaction [18], and T-cell proliferation [19]. Early clinical studies of anti-CD37 agents [20–22] have demonstrated that it is a viable therapeutic target in B cell NHL.
BI 836826 is a chimeric Fc-engineered immunoglobulin G1 (IgG1) monoclonal antibody directed against human CD37 [23]. In transgenic mice and cynomolgous monkeys, BI 836826 dose-dependently depleted peripheral B cells, and significantly suppressed tumor growth in a mouse B-cell lymphoma xenograft model [23]. In phase I studies, BI 836826 demonstrated acceptable tolerability and anti-tumor activity in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) [24] and in patients with relapsed/refractory B-cell NHL [25]. As gemcitabine and oxaliplatin (GemOx), with or without rituximab, is a treatment option in patients with ASCT-ineligible relapsed/refractory DLBCL [26, 27], we investigated the feasibility of combining BI 836826 and GemOx in this phase I, dose escalation study.
Patients and methods
Patients
Eligible patients were aged 18 years or older and had histologically confirmed relapsed/refractory DLBCL (including transformed follicular lymphoma). ‘Relapsed’ was defined as the appearance of any new lesion after attainment of an initial complete response (CR) and ‘refractory’ was defined as < 50% decrease in lesion size with prior anti-lymphoma treatment in the absence of new lesion development. All patients had previously been treated with an anti-CD20 monoclonal antibody in combination with anthracycline-containing chemotherapy and were either ineligible for high dose therapy and ASCT or had relapsed/progressed after an autologous/allogeneic stem cell transplant. Allogeneic stem cell transplant performed at least 6 months prior to study entry was permitted if patients did not require immunosuppressive treatment and had no evidence of active graft-versus-host disease. Patients were required to have Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, acceptable organ function, and a screening CT scan with involvement of at least one bi-dimensional lesion/node of > 1.5 cm.
Key exclusion criteria were: prior history of malignancy other than DLBCL; known central nervous system involvement; and receipt of anti-lymphoma treatment either within 14 days or, in the case of an investigational agent, less than five half-lives of the investigational drug, prior to the first dose of the current trial medication.
The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines, and the study protocol was approved by the Institutional Review Boards or Independent Ethics Committees of all participating institutions. Written informed consent was obtained from all patients.
Study design and treatment
This was an open-label, multicenter phase Ib dose-escalation trial conducted to determine the maximum tolerated dose (MTD), safety/tolerability, and preliminary efficacy of BI 836826 in combination with GemOx in patients with relapsed/refractory DLBCL (NCT02624492). BI 836826 (starting dose of 25 mg) was administered as an intravenous infusion on day 8 of each 14-day cycle, while gemcitabine (1000 mg/m2) and oxaliplatin (100 mg/m2) were given intravenously on day 1 of each cycle. Patients received a maximum of six treatment cycles; each cycle could be delayed by up to 14 days in cases of toxicity.
Paracetamol, antihistamine and glucocorticoid premedication to mitigate infusion-related reactions (IRRs) was administered 30–120 minutes prior to all BI 836826 infusions. Supportive care including blood products and growth factors were permitted according to local guidelines; prophylactic anti-infective agents were also allowed. Dose escalation was conducted according to the standard 3 + 3 design and was planned to continue until the MTD of BI 836926 in combination with GemOx was reached. BI 836826 dose increments of 50, 100, 150 and 200 mg were planned.
Study assessments
The primary endpoints were the MTD and the number of patients with dose-limiting toxicities (DLTs) during the MTD evaluation period (cycle 1). The MTD was defined as the highest dose for which the number of patients with DLTs was no more than 17% during the MTD evaluation period (cycle 1).
DLTs included both non-hematologic and hematologic adverse events (AEs) considered related to any trial medication. This included any non-hematologic grade ≥ 3 AEs except for: laboratory abnormalities that could be corrected with treatment within 48 h; nausea, vomiting, or diarrhea that resolved within 48 h with adequate treatment; neuropathy considered related to oxaliplatin; or IRRs. Hematologic DLTs were: grade 4 neutropenia lasting > 7 days despite growth factor support; any febrile neutropenia that did not resolve within 48 h with appropriate treatment; grade 4 thrombocytopenia lasting > 7 days or grade 3/4 thrombocytopenia with clinically significant bleeding; failure to recover platelets ≥ 75 × 109/L by 4 weeks after the start of the cycle; and failure to recover neutrophils ≥ 1.0 × 109/L by 4 weeks after start of the cycle. Other safety assessments included the incidence and severity of AEs graded according to the Common Toxicity Criteria for Adverse Events (CTCAE, version 4.0) and changes in laboratory parameters.
The secondary endpoint was investigator-assessed best overall response according to International Working Group criteria for non-Hodgkin lymphoma [28] with refined evaluation of the PET scan using the 5-point scale [29].Tumor size reduction was analyzed as best percentage change from baseline in the sum of the product of the longest perpendicular diameters (SPD) based on imaging data. Pharmacokinetic analysis was planned but was not conducted.
Statistical methods
No formal statistical testing was undertaken. The number of patients with DLTs and the best overall response was summarized by descriptive statistics.
Results
Patients and treatment exposure
Thirty-five patients were enrolled and 21 treated at seven centers in Belgium, Italy and Spain between March 10, 2016 and March 16, 2018. All patients were white and 48% were male (Table 1). Median age was 54.0 years (range 22 to 86), and 57%, 33% and 10% of patients had a baseline ECOG performance score of 0, 1 and 2, respectively. Of the 21 patients, 17 (81%) had pure DLBCL and four (19%) had follicular lymphoma transformed to DLBCL. Lymphoma was considered relapsed for 33% of patients, refractory for 38%, and progressive for 29%. All patients had previously received systemic therapy, with most having received one, two, or four previous therapies (33%, 29%, and 29% of patients, respectively); 71% had progressed following the last therapy.Table 1 Patient demographics
BI 836826 dosea
25 mg
(n = 5) 50 mg
(n = 8) 100 mg
(n = 8) Total
(N = 21)
Male, n (%) 1 (20.0) 4 (50.0) 5 (62.5) 10 (47.6)
Race, n (%)
White 5 (100.0) 8 (100.0) 8 (100.0) 21 (100.0)
Median age, years (range) 77.0 (22–86) 51.0 (41–78) 53.5 (42–77) 54.0 (22–86)
ECOG PS at baseline, n (%)
0 5 (100.0) 4 (50.0) 3 (37.5) 12 (57.1)
1 0 2 (25.0) 5 (62.5) 7 (33.3)
2 0 2 (25.0) 0 2 (9.5)
Ann Arbor stage at screening, n (%)
II 0 1 (12.5) 0 1 (4.8)
III 0 2 (25.0) 3 (37.5) 5 (23.8)
IV 5 (100.0) 5 (62.5) 5 (62.5) 15 (71.4)
Mean time from first diagnosis, years (SD) 4.4 (3.8) 5.1 (7.5) 2.9 (3.7) 4.1 (5.4)
Median number of prior therapies (range) 2.0 (1–4) 2.0 (1–4) 3.0 (1–6) 2.0 (1–6)
Prior therapy, n (%)
Radiotherapy 2 (40.0) 1 (12.5) 1 (12.5) 4 (19.0)
Stem cell transplant 2 (40.0) 2 (25.0) 3 (37.5) 7 (33.3)
Surgery 0 2 (25.0) 1 (12.5) 3 (14.3)
Progression since last systemic therapy, n (%) 5 (100.0) 7 (87.5) 3 (37.5) 15 (71.4)
aGiven every 14 days in combination with gemcitabine 1000 mg/m2 and oxaliplatin 100 mg/m2
ECOG PS Eastern Cooperative Oncology Group Performance Status, SD standard deviation
The best response to previous therapy was CR in five patients (23.8%), partial remission (PR) in two patients (9.5%), and stable disease (SD) in two patients (9.5%); 10 patients (47.6%) had progressive disease (PD); the status of two patients (9.5%) was unknown or missing. Important protocol deviations were noted for seven patients, three of whom had more than one protocol deviation: entrance criteria were not met for 6 patients (efficacy-related criteria for four patients, trial diagnosis for one patient, and safety criteria for one patient), administration of trial medication was delayed for three patients, and prohibited medication was administered for one patient (Supplementary Table 1).
All 21 patients discontinued the trial, with10 patients (48%) completing the maximum of six treatment cycles. Of the 11 patients who discontinued before completing six cycles, six (29%) discontinued due to AEs, and 5 (24%) discontinued due to disease progression. Two patients did not receive a complete infusion of BI 836826: one died of tumor lysis syndrome after a single dose of GemOx and did not receive any BI 836826, while a second had an interruption of the first BI 836826 infusion due to an IRR. This patient received 10 mg out of 25 mg BI 836826 and permanently discontinued trial drug.
MTD and DLTs
BI 836826 dosing in combination with GemOx started at 25 mg and proceeded through 50 mg and 100 mg cohorts. Six patients were replaced and hence excluded from the MTD evaluation set. Two DLTs occurred during the MTD evaluation period (cycle 1), both grade 4 thrombocytopenia lasting > 7 days, affecting one of six evaluable patients (17%) in the 50 mg dosing cohort, and one of six evaluable patients (17%) in the 100 mg cohort. Due to a strategic decision by the sponsor, the trial was prematurely discontinued, and no further patients were enrolled after the 100 mg dose cohort. Consequently, the MTD of BI 836826 in combination with GemOx was not established.
Safety
All patients experienced at least one AE during the on-treatment period of the trial, most commonly neutropenia (n = 16 [79%]), thrombocytopenia (n = 15 [71%]) and anemia (n = 14 [67%]). Sixteen patients (76%) experienced at least one AE deemed to be related to BI 836826 by the Investigator; the most frequent were (any grade/grade 3/4) neutropenia (52/38%), anemia (48/29%), thrombocytopenia (48/43%; Table 2). Eight patients (38%) experienced a treatment-related IRR, of which two (10%) were grade 3. Two patients (10%) had grade 4 neutropenia and a concomitant infection; both infections were of grade 2. One patient had grade 4 thrombocytopenia and concomitant bleeding, a single episode of grade 2 melena. The most common non-hematological AEs considered related to BI 836826 included pyrexia (n = 2 [9.5%]), asthenia (n = 2 [9.5%]), chills, cough, dizziness, nausea and vomiting (all n = 1 [4.8%]), which were either grade 1 or grade 2.Table 2 AEs considered related to BI 836826 occurring in ≥ 2 patients
Any-grade
n (%) Grade 3/4
n (%)
Any treatment-related AEs 16 (76.2) 12 (57.1)
Neutropenia 11 (52.4) 10 (47.6)
Anemia 10 (47.6) 6 (28.6)
Thrombocytopenia 10 (47.6) 9 (42.9)
Infusion-related reaction 8 (38.1) 2 (9.5)
Decreased white blood cell count 7 (33.3) 7 (33.3)
Increased AST 2 (9.5) 0
Increased GGT 2 (9.5) 1 (4.8)
Asthenia 2 (9.5) 0
Pyrexia 2 (9.5) 0
Decreased platelet count 1 (4.8) 1 (4.8)
Pancytopenia 1 (4.8) 1 (4.8)
Increased ALT 1 (4.8) 0
Chills 1 (4.8) 0
Cough 1 (4.8) 0
Dizziness 1 (4.8) 0
Hyperuricemia 1 (4.8) 0
Nausea 1 (4.8) 0
Vomiting 1 (4.8) 0
ALT alanine aminotransferase, AST aspartate aminotransferase, GGT gamma-glutamyl transferase
During the entire on-treatment period, seven patients experienced AEs that were consistent with the definition of a DLT. Thrombocytopenia (5 patients [24%]) was the only event reported for more than two patients.Six patients experienced a total of eight AEs leading to permanent discontinuation of last study medication: thrombocytopenia (two cases), neutropenia, Aspergillus infection, pneumonia, decreased white blood cell count, IRR, and tumor lysis syndrome (one case each).
Overall, 12 patients were reported with serious AEs (57%), of which only thrombocytopenia (4 patients [19%]) and IRR (3 patients [14%]) occurred in more than two patients. Three patients died during the study; however, no deaths were attributed to BI 836826. The case of tumor lysis syndrome was considered related to GemOx as the patient had not yet received BI 836926; the remaining two deaths were attributed to disease progression and Aspergillus infection.
Efficacy
The objective response rate was 38%, including two patients (10%) with complete remission and six patients (29%) with partial remission (Table 3). Six patients (29%) experienced stable disease, and three patients (14%) had progressive disease. Four patients did not have a response assessment. Patients with baseline and at least one post-baseline disease assessment were evaluated for best change in SPD from baseline in lymph nodes, or organ or extra-lymphatic nodules based on PET/CT scan. The median best percentage change was − 31.3% (range –100 to 41%) for 15 patients with baseline lymph nodules and − 78% (range − 89% to − 28%) for five patients with extra-lymphatic disease nodules. In one patient with baseline liver nodules, change from baseline was − 38%, while two patients with baseline spleen nodules had changes of − 100% and − 45%.Table 3 Best overall response in patients receiving BI 836826 plus GemOx
BI 836826 dose
Patients with response, n (%) 25 mg
(n = 5) 50 mg
(n = 8) 100 mg
(n = 8) Total
(n = 21)
Complete remission 1 (20.0) 0 1 (12.5) 2 (9.5)
Partial remission 2 (40.0) 3 (37.5) 1 (12.5) 6 (28.6)
Stable disease 2 (40.0) 1 (12.5) 3 (37.5) 6 (28.6)
Progressive disease 0 2 (25.0) 1 (12.5) 3 (14.3)
Missing 0 2 (25.0) 2 (25.0) 4 (19.0)
GemOx gemcitabine 1000 mg/m2 and oxaliplatin 100 mg/m2
Discussion
In this phase I, dose-finding study in patients with relapsed/refractory DLBCL, BI 836826 in combination with GemOx was generally well tolerated. The MTD was not established, as the trial was prematurely discontinued following the termination of the BI 836826 clinical development program. The MTD was not exceeded at the doses tested (50 and 100 mg given every 14 days).
Adverse events associated with BI 836826 administration were predominantly hematological, which is to be expected in this population, and in keeping with prior studies of BI 836826 in patients with B-cell malignancies [24, 30]. Grade 3/4 hematological AEs were more common in this study than with BI 836826 monotherapy [24, 30], most likely due to the additive effect of GemOx. One DLT of grade 4 thrombocytopenia lasting > 7 days was recorded in each of the 50 mg and 100 mg dosing cohorts. As CD37 has been identified on megakaryocytes and platelets [31, 32], this may be the result of the direct action of BI 836826 on these cells, or may be related to the myelotoxic effects of gemcitabine and oxaliplatin [33, 34]. It is possible that the myelosuppressive effect of combination therapy was exacerbated by administering BI 836826 on day 8 of each cycle, corresponding with the nadir of hematological toxicity due to GemOx. Therefore, hematological toxicity could potentially be less severe with an alternative treatment schedule. However, the tested treatment schedule was based on modelling that evaluated different timings for the BI 836826 and GemOx administrations. The modelling showed that dosing BI 836826 after GemOx at the cytopenia nadir would actually shorten hematological toxicity compared to administering the drugs together, which was predicted to deepen and extend the cytopenia. Of note, the overall incidence of treatment-related IRRs (any-grade, 38%; grade 3/4, 10%) was lower than in a previous study of BI 836826 in patients with relapsed/refractory chronic lymphocytic leukemia (any-grade, 70%; grade 3/4, 8%) [24], and comparable to that seen in Caucasian patients with relapsed/refractory B-cell NHL (any-grade, 41%; grade 3/4, 8%) [30].
The overall response rate in this study was 38%. Few published data on the use of GemOx alone in DLBCL are available for comparison. In a retrospective study of GemOx with/without rituximab in 44 patients with relapsed/refractory aggressive lymphoma, overall response rate was 43%, including 30% CR [27], while an overall response rate of 61%, with 44% CR, was reported in a study of 49 patients with relapsed/refractory DLBCL who received rituximab plus GemOx [26]. However, considerable hematological toxicity was observed in both studies, with 73% of patients experiencing grade ≥ 3 neutropenia and 44% experiencing grade 3 thrombocytopenia in the latter study.
Although the clinical development of BI 836826 has been terminated for strategic reasons, the findings from this study suggest that CD37-based therapy for DLBCL can be safely combined with established chemotherapy regimens. A number of anti-CD37 therapies are currently being investigated for the treatment of B-cell NHL [20–22, 35–37], including radioimmunotherapy. Of note, a phase Ib study of the novel agent lutetium (177Lu)-lilotomabsatetraxetan (Betalutin®) in ASCT-ineligible patients with relapsed/refractory DLBCL is currently in progress (NCT02658968), and results from this and other ongoing clinical trials may provide new hope for DLBCL patients faced with limited options.
Supplementary Information
ESM 1 (PDF 8 kb)
Acknowledgements
We thank the patients, their families, and all of the investigators who participated in these studies. The authors were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development, and have approved the final version.
Author contributions
Anne-Marie Quinson, Valérie Belsack and Carmelo Carlo-Stella contributed to the study conception and design. Material preparation and data collection were performed by Monica Balzarotti, Massimo Magagnoli, Miguel Ángel Canales, Paolo Corradini, Carlos Grande, Juan-Manuel Sancho, Francesco Zaja and Carmelo Carlo-Stella. Data analysis were performed by Anne-Marie Quinson, Valérie Belsack and Daniela Maier. The first draft of the manuscript was written by Anne-Marie Quinson, Valérie Belsack, Monica Balzarotti and Carmelo Carlo-Stella. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
The conduct of this research, study design, data collection, and analysis was financially supported by Boehringer Ingelheim. Medical writing assistance, funded by Boehringer Ingelheim, was provided by Lynn Pritchard, DPhil, of GeoMed, an Ashfield company, part of UDG Healthcare plc, during the preparation of this manuscript.
Data Availability
The clinical study report (including appendices, but without line listings) and other clinical documents related to this study may be accessed on request. Prior to providing access, the documents and data will be examined, and, if necessary, redacted and de-identified to protect the personal data of study participants and personnel, and to respect the boundaries of the informed consent of the study participants. See https://trials.boehringer-ingelheim.com/data_sharing/sharing.html#accordion-1-2 for further details. Bona fide, qualified scientific and medical researchers may request access to de-identified, analyzable patient-level study data, together with documentation describing the structure and content of the datasets. Researchers should use https://clinicalstudydatarequest.com/ to request access to raw data from this study.
Compliance with ethical standards
Conflict of interest
Miguel Ángel Canales received speaker honoraria from Amgen, Janssen, Roche, Sandoz, Takeda; consulting fees from Celgene, Gilead, iQone, Janssen, Karyopharm, Novartis, Roche, Sandoz, Sanofi; and support for CME from Gilead, Janssen, Novartis, Roche, Sandoz, Sanofi.
Paolo Corradini received honoraria as a lecturer from AbbVie, Amgen, Celgene, Gilead/Kite, Janssen, Jazz Pharmaceutics, Novartis, Roche, Sanofi, Sandoz, Takeda, and consulting fees from AbbVie, ADC Therapeutics, Amgen, Celgene, Daiichi Sankyo, Gilead, Incyte, Janssen, Kite, KiowaKirin, Novartis, Roche, Sanofi, Servier and Takeda.
Francesco Zaja received honoraria from Novartis, Amgen, Janssen, Takeda, Celgene, Abbvie, Roche, Mundipharma and Grifols.
Juan-Manuel Sancho received advisory council or committee fees from Roche, Gilead, Janssen, Celgene, Incyte, Celltrion, Novartis, and honoraria as a speaker from Roche, Gilead, Janssen, Celgene, Incyte, Takeda, Novartis, Sanofi and Servier.
Anne-Marie Quinson, Valérie Belsack and Daniela Maier are employees of Boehringer Ingelheim.
Carmelo Carlo-Stella received honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Servier, Amgen, Janssen Oncology, Sanofi, ADC Therapeutics, Novartis, and AstraZeneca; provided consultancy to Boehringer Ingelheim, Genenta Science, Sanofi, ADC Therapeutics, and received research funding from Rhizen Pharmaceuticals.
Monica Balzarotti, Massimo Magagnoli and Carlos Grande report no conflict of interest.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent
Informed consent was obtained from all individual participants included in the study.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Fatal | ReactionOutcome | CC BY | 33523334 | 18,904,482 | 2021-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypertension'. | Hematopoietic Stem Cell Transplantation Resolves the Immune Deficit Associated with STAT3-Dominant-Negative Hyper-IgE Syndrome.
Autosomal dominant hyper-IgE syndrome caused by dominant-negative loss-of-function mutations in signal transducer and activator of transcription factor 3 (STAT3) (STAT3-HIES) is a rare primary immunodeficiency with multisystem pathology. The quality of life in patients with STAT3-HIES is determined by not only the progressive, life-limiting pulmonary disease, but also significant skin disease including recurrent infections and abscesses requiring surgery. Our early report indicated that hematopoietic stem cell transplantation might not be effective in patients with STAT3-HIES, although a few subsequent reports have reported successful outcomes. We update on progress of our patient now with over 18 years of follow-up and report on an additional seven cases, all of whom have survived despite demonstrating significant disease-related pathology prior to transplant. We conclude that effective cure of the immunological aspects of the disease and stabilization of even severe lung involvement may be achieved by allogeneic hematopoietic stem cell transplantation. Recurrent skin infections and abscesses may be abolished. Donor TH17 cells may produce comparable levels of IL17A to healthy controls. The future challenge will be to determine which patients should best be offered this treatment and at what point in their disease history.
Introduction
Autosomal dominant hyper-IgE syndrome is a rare primary immunodeficiency (PID) with multisystem pathology [1], caused by dominant-negative loss-of-function (LOF) mutations in signal transducer and activator of transcription factor 3 (STAT3) [2, 3] (STAT3-HIES). STAT3 is integral to lymphocyte development and differentiation. STAT3-deficient humans and mice have impaired cellular and humoral immune responses [4, 5], explaining the diverse immunologic manifestations [2–4]. In the context of infection, there is poor differentiation of T lymphocytes into TH17 cells, resulting in low IL17 and IL22 production [6], which contributes to susceptibility to encapsulated organisms and fungi.
HSCT was initially reported as unsuccessful in STAT3-HIES by our group [7]. Based on this impression, supportive treatment has been largely adopted [1], but many patients develop severe life-limiting pulmonary disease. However, over the years, eight case reports of allogeneic hematopoietic stem cell transplant (HSCT) for STAT3-HIES have been published [7–12], three of them performed following the diagnosis of non-Hodgkin’s B cell lymphoma, which is a known complication of this primary immunodeficiency [8]. In these eight cases, five patients had received myeloablative conditioning regimens, while three had reduced-intensity conditioning. Seven patients, including two with Hodgkin’s lymphoma, were recently reported as alive and well 4–20 years following report of HSCT [13], while one patient had died from the pre-existing lymphoma post-transplant [10].
We initially reported failure of HSCT to resolve or cure the immune defect in our first patient. However, we now acknowledge that STAT3-HIES patients have experienced sustained benefit from HSCT. At the time of our report, the molecular cause of STAT3-HIES was unknown, and we based our statements on failure to normalize the serum IgE level and an apparent failure to change the immunological defect. We have now shown that the IL17A levels of that patient approaches normal (although not measured pre-transplant) and memory B-lymphocytes are present. We now report a series of eight patients successfully treated with HSCT in the UK, including the long-term follow up of our previously reported patient [7].
Methods
We conducted a retrospective review of medical records of STAT3-HIES patients from two UK transplant centers for PID. We included only patients with confirmed dominant-negative STAT3 mutations who have undergone allogeneic HSCT. We recorded pre-transplant co-morbidities, conditioning, outcome, and on-going co-morbidities in eight patients who received nine transplants.
In selected patients for whom samples were available, IL17A levels were measured by Luminex (Bio-Plex, Biorad, UK) [14], 24 hours after stimulation in whole blood (96 Costar-F plates, 1:5 diluted in RPMI) of healthy controls and patients. Stimulations were performed using PHA (Sigma-Aldrich, 10 μg/ml) and compared with unstimulated medium samples. Data were compared with historic controls, which had been stimulated under identical conditions. P values were calculated using the two-tailed Mann-Whitney test or the Wilcoxon matched pairs test, excluding the data of P5 before HSCT.
Parents, and, where appropriate, patients consented to the procedure and data collection.
Results
Transplants were performed between 1996 and 2019. Demographic data, genetic mutation, and pre-HSCT clinical status are summarized in Table 1. All patients had dominant loss-of-function mutations in STAT3 with a classical clinical phenotype, and all had significant lung or skin-related complications prior to HSCT.Table 1 Patient demographic features and pre- and post-HSCT clinical details
Patient no.; sex Age at HSCT (years) STAT3 Heterozygous mutation Skin disease Lung disease and PFTs Fractures; other skeletal disease Infection; other Issues
Pre-HSCT Post-HSCT Pre-HSCT Post-HSCT Pre-HSCT Post-HSCT Pre-HSCT Post-HSCT
1
M
7 c.1909 G>A p.V637M Yes Normal Left upper and lower lobectomies with bronchopleural fistula; bilateral bronchiectasis; chronic Aspergillus infection; pulmonary hypertension
FEV1 47%
FVC 51%
Stable appearance on CT: bronchiectasis persist
Nocturnal CPAP for lobar collapse post-scoliosis repair with limited exercise tolerance
FEV1 20%
FVC 23%
Yes 2 further fractures at 3–4 years post-HSCT
Development of scoliosis requiring spinal fusion
Staphylococcus aureus pericarditis -
2
F
6 c.1771 A>G p.K591E Yes Normal Recurrent Pseudomonas lung infection with cyst formation
Not done
Stable; no progression of pulmonary cysts
FEV1 95%
FVC 88%
No Development of scoliosis - Gonadal failure following myeloablative conditioning
Arterial hypertension
3
M
13 c.1144 C>T p.R382W Yes Normal Severe and recurrent pneumonia with bronchiectasis
FEV1 63%
FVC 70%
Stable appearance on CT
No further hemoptysis
FEV1 83%
FVC 71%
Yes No - ST segment elevation myocardial infarction aged 26 years (13 years post-HSCT)
4
M
14 c.1144 C>T p.R382W Yes
Pustular dermatitis
Dry skin, no infection Bronchiectasis with multi-cystic lung disease, leading to left lobectomy
FEV1 28%
FVC 26%
Significant improvement in pulmonary cystic disease and resolution in right lower lobe bronchial thickening on CT
FEV1 65%
FVC 74%
Yes No Staphylococcus aureus liver abscess Autoimmune neutropenia
5
F
17 c.1144 C>T p.R382W Yes
Persistent infected czema
Normal Pneumatocoele leading to left lobectomy
FEV1 53%
FVC 67%
Improvement in lung appearance on CT
FEV1 51%
FVC 67%
Yes No - Aspergillus perdicarditis at 7 months post-HSCT resolved by 16 months post-HSCT
6
M
18 c.1110 A>G D371_G380del Yes
Eczema, pustular dermatitis
Resolution of previous chronic infection Lung abscess; pulmonary TB
FEV1 89%
FVC 90%
Stable CXR changes
Not done
No
Retained primary dentition
Enterococcal septic arthritis with collapse of femoral head Recurrent Staphylococcus aureus liver abscess
Candida retroperitoneal lymphadenitis and liver abscess
Early gastrointestinal bleed in post-transplant period
Medication-related nephrotoxicity
6
2nd HSCT
18
7
M
13 c.1144 C>G p.R382G Yes
Multiple skin abscesses
Dry skin, no infection Minimal
FEV1 89%
FVC 90%
Improvement in symptoms and exercise tolerance
Not done
No
Retained primary dentition
No Osteomyelitis of mandible -
8
F
6 c.1144 C>T p.R382W Yes
Eczema, Multiple skin abscesses
Dry skin, no infection Severe bronchiectasis bilaterally with broncho-pulmonary aspergillosis
FEV1 84%
FVC 92%
Improvement in symptoms
FEV1 82.7%FVC 78.4%
No No - -
Details of conditioning regimen, cell source, and graft-versus-host disease (GvHD) prophylaxis are detailed in Table 2. One patient received conventional myeloablative conditioning, four received reduced-toxicity myeloablative conditioning, and three received reduced intensity conditioning, one of whom rejected and was successfully re-transplanted following a reduced-toxicity myeloablative regimen (patient six). All inoculi were matched at 10/10 HLA-loci, apart from the first product for patient six, which was a 9/10 match (DQ mismatch).Table 2 Patient transplant demographics
Patient Follow-up Cell source; HLA Match Conditioning regimen GvHD prophylaxis Acute GvHD Latest donor chimerism
1 6 years URD PBSC
10/10
Alemtuzumab 1mg/kg
Fludarabine 150mg/m2
Melphalan 140mg/m2
CSA
MMF
- CD15 55%
CD19 55%
CD3 86%
2 20 years URD BM
10/10
Alemtuzumab 1mg/kg busulphan 16mg/kg
Cyclophosphamide 200mg/kg
CSA Grade 1 skin WB 100%
3 11 years URD BM
10/10
Alemtuzumab 1mg/kg
Fludarabine 150mg/m2
Melphalan 140mg/kg
CSA
MMF
- WB 100%
4 3 years MSD PBSC
10/10
Alemtuzumab 1mg/kg
Treosulfan 42g/m2
Fludarabine150mg/m2
CSA
MMF
Grade 1 skin CD15 100%
CD19 100%
CD3 91%
5 3 years URD PBSC
10/10
Alemtuzumab 1mg/kg
Fludarabine 150mg/m2
Treosulphan 42g/m2
CSA
MMF
Grade 1 skin WB 100%
6 - Mismatched URD PBSC
9/10
(DQ mismatch)
Alemtuzumab 60mg
Fludarabine 150mg/m2
Melphalan 140mg/m2
CSA - Hyperacute rejection D+13
2 years URD BM
10/10
ATG Fludarabine 150mg/m2
Treosulphan 42g/m2
Thiotepa 10mg/kg
CSA
MMF
- WB 100%
7 20 months URD PBSC
10/10
Alemtuzumab 1mg/kg
Fludarabine 150mg/m2
Treosulphan 42g/m2
CSA
MMF
- WB 100%
8 15 months MSD BM
10/10
Alemtuzumab 1mg/kg
Fludarabine 150mg/m2
Treosulphan 42g/m2
CSA
MMF
- CD15 96%
CD19 94%
CD3 94%
All patients survived and no patient experienced significant GvHD. Seven patients had complete or high level (>90%) donor chimerism and one had partial chimerism; however, all had improvement in immune phenotype, with a reduction in clinical symptoms, halting of progression of lung disease and improvement in skin infections. Non-immune manifestations showed variable improvement, with one patient developing further fractures and two patients demonstrating worsening scoliosis post-transplant. One patient has recently had vasculopathy with an ST segment elevation myocardial infarction with ectatic coronary vasculature [12]. Patient clinical status post-HSCT are summarized in Table 3.Table 3 Patient immunological data pre- and post-HSCT
Patient IgE (kU/L) IVIG given Vaccine responses; CSM/Mem B lymphocytes (25–75th centile reference range) Antimicrobial prophylaxis post-HSCT
Pre-HSCT Post-HSCT Pre-HSCT Post-HSCT Pre-HSCT Post-HSCT
1 4007 1720 Yes No Normal tetanus, absent HiB and pneumococcus
-
Normal
-
Voriconazole; azithromycin
2 75,000 2641 Yes No Normal
-
Normal
CSM B 9% (9.2–18.9%)
Mem B 13% (13.4–21.4%)
Azithromycin
3 >6000 176 Yes No Normal
-
Normal
-
Doxycycline
4 81,097 11,813 Yes No Normal
CSM B 1% (3.3–9.6%)
Mem B 3% (4.6–10.2%)
Normal
CSM B 1% (3.3–9.6%)
Mem B 3% (4.6–10.2%)
Azithromycin
5 4487 1939 No No Normal
CSM B 1% (3.3–9.6%)
Mem B 3% (4.6–10.2%)
Normal
CSM B 2% (7.2–12.7%)
Mem B 7% (7.4–13.9%)
Posaconazole; nebulized amphotericin B; azithromycin
6 143,000 - Yes No Normal
CSM B 0.4% (3.3–9.6%)
-
-
-
7 >5000 1636 Yes No Normal
-
In progress
Mem B cells 1.6% (3.3–9.6%)
-
8 1880–11,756 392 Yes Yes Normal tetanus and HiB, absent PPSV23
CSM B 2.6% (5.2–12.1%)
(On Ig)
CSM B 3% (5.2–12.1%)
Mem B 2% (7.5–12.4%)
Azithromycin
Reference ranges of 25–75th centile for CSM and Mem B lymphocytes from Morbach et al. [15]
CSM class switched memory, HSCT hematopoietic stem cell transplantation
In the one patient (patient 5) for whom pre- and post-transplant IL17A levels were available, IL17A was higher post-transplant. For patients 2, 3, and 4, IL17A levels were present post-transplant, but lower than controls (Fig. 1).Fig. 1 IL17A levels in healthy controls and patients post-transplant. IL17A levels were measured by Luminex (Bio-Plex, Biorad, UK) 24 hours after stimulation in whole blood (96 Costar-F plates, 1:5 diluted in RPMI) of healthy controls (historical and contemporary) and patients (P2—blue diamonds, P3—blue triangles, P4—blue squares, P5 (pre and post HSCT) —blue circles). Stimulations were done using PHA (Sigma-Aldrich, 10 μg/ml) and compared with unstimulated medium samples (Med)
Patient 1 had significant pulmonary infection (complicated cystic bronchiectasis with Pseudomonas infection and widespread Aspergillus infection leading to pulmonary hypertension) with two lobectomies, complicated by development of bronchopleural fistula. He subsequently developed a Staphylococcus aureus pericarditis requiring surgical drainage, complicated by prolonged air leak. Transplantation at age 7 years was relatively uncomplicated. There was no viral re-activation, progression of chest lesions, or acute graft versus host disease. Six years post-transplant, his eczema had resolved and he was no longer getting significant respiratory infections. Immunoglobulin support has ceased, and normal vaccine and T-lymphocyte proliferative responses have been demonstrated. His scoliosis, exacerbated by his two previous left sided lobectomies, had deteriorated requiring spinal fusion surgery. Following this, his right lower airway integrity has been compromised, severely impairing his respiratory capacity. He now is reliant on overnight CPAP and can only ambulate short distances.
Patient 2 experienced frequent staphylococcal skin infections and cystic bronchiectasis infected with Pseudomonas, because of which transplantation was offered when aged 6 years. Despite 100% donor chimerism, the procedure was initially described as unsuccessful [7] because of continued elevated serum IgE. However, long-term follow-up confirmed sustained clinical improvement with no further respiratory or skin infections. Serum IgE levels diminished and remained reduced, and immunoglobulin support is no longer required. She developed thoracolumbar scoliosis, arterial hypertension, and gonadal failure. With 20 years follow-up, pulmonary status includes stable lingular bronchiectasis and non-progressive right upper lobe pulmonary cysts.
Patient 3 experienced frequent severe bronchopneumonias and progressive bronchiectasis despite immunoglobulin replacement, as well as osteopenia and lumbar vertebrae compression fractures. Transplantation at 13 years was relatively uneventful, and 13 years post-transplant, he demonstrates 100% donor chimerism with reduced serum IgE levels. Lung function has improved to normal values. Hemoptysis has stopped, and there is no computerized tomographic evidence of pulmonary disease progression. An increase in IL17A production after polyclonal stimulation was demonstrated post-HSCT (Fig. 2), and TH17 cells display normal response to IFN-γ and IL12 and normal IL12 production (data not shown). However, at 11 years post-HSCT, he sustained an anterior myocardial infarction, accompanied by classical clinical, electrocardiographic and biochemical signs and parameters. Angiography revealed proximal ectasia causing mid-vessel occlusion of his left anterior descending coronary artery but otherwise unobstructed coronary vessels. He was commenced on aspirin 75 mg for 3 months with rivaroxaban 2.5 mg BID for 3 years and clopidogrel 75 mg long term [12].Fig. 2 Pre- and post-transplant peripheral blood mononuclear cells demonstrate that IL17A is absent pre-transplant and present post-transplant (patient 3), with normal control and a negative control patient who has not been transplanted (p.V637M)
Patient 4 developed bronchiectasis, Staphylococcus aureus liver abscess, and recurrent skin abscesses. Severe multi-cystic and suppurative lung disease warranted left upper lobectomy. Following transplantation at age 14 years, repeat computerized tomography demonstrated significant widespread decrease in the number and size of previously reported large cysts, and there was a clinical improvement in the eczematous skin lesions. Post-transplant IL17A production was normal.
Patient 5 developed multiple abscesses and pneumatoceles during infancy leading to right upper lobectomy and broncho-pulmonary fistula at age 13 years. Pulmonary function was impaired prior to HSCT, aged 17 years. Non-invasive pulmonary Aspergillus infection persisted post-HSCT, treated with appropriate long-term anti-fungal therapy—at 7 months post-transplant, and Aspergillus pericarditis was diagnosed, which resolved with dual anti-fungal therapy by 16 months post-transplant. Thoracic computerized tomography demonstrated a dramatic improvement in lung appearance, and the residual right upper lobe cavity remained stable.
Patient 6 had persistent multiple skin infections with severe eczema and lymphadenitis through childhood and a single lung abscess. Additionally, a persistent Staphylococcus aureus hepatic abscess required surgical drainage on four occasions. Further to this, the patient required surgical excision of Candida albicans retroperitoneal lymphadenitis and a fungal liver abscess. The patient developed bowel perforation of unknown etiology at 6 years of age, before HSCT. An immune-mediated acute rejection of first graft was confirmed at day 13 post-transplant, followed by an autologous recovery. In this period, the patient experienced an enterococcal septic arthritis, with collapse of femoral head, gastrointestinal hemorrhage, and further episodes of fungal lymphadenitis. A second transplant procedure using a reduced toxicity treosulfan-based regimen was successful. The patient has good immune reconstitution and has ceased immunosuppression and immunoglobulin replacement.
Patient 7 was first referred to pediatric care at the age of 4 weeks due of eczema and skin infections, mainly on the face and scalp, from which Staphylococcus aureus was isolated and treated. Serum IgE levels were elevated prompting a diagnosis of Hyper IgE syndrome, confirmed genetically. The patient continued to have numerous recurrent skin abscesses, requiring drainage over 20 times per year despite antibiotic treatment and immunoglobulin replacement. He subsequently developed mandibular osteomyelitis. Pulmonary disease was limited to asthma only, with no significant infection. Transplant was uncomplicated, and at 20 months post-HSCT, his skin is much improved with no new infections. He has discontinued immunoglobulin and is awaiting vaccination.
Patient 8 presented as a neonate with staphylococcal skin infection and went on to develop recurrent skin infection, pneumonia, and otitis media. She demonstrated elevated serum IgE with poor pneumococcal antibody titers following vaccination and almost no TH17 cells. Her pulmonary disease progressed with findings of Aspergillus on bronchoalveolar lavage leading to a diagnosis of allergic bronchopulmonary aspergillosis, treated with antifungal therapy, corticosteroids, and anti-IgE monoclonal antibodies. She underwent HSCT aged 6 years with an uncomplicated course. One year post-HSCT, she reports only dry skin with no infection. Pulmonary function is stable and she is asymptomatic from cough or dyspnoea. Serum IgE has fallen to 392 kU/L. She remains on immunoglobulin replacement but has normal B lymphocyte numbers.
Discussion
Published data on the outcome of allogeneic HSCT for STAT3-HIES patients are limited, perhaps stemming from our initial report indicating non-utility [7]. A recent report by Oikonomopoulou et al. [13] summarizes the data of 7 patients transplanted between 1998 and 2018, one of which was the patient we originally reported in 2000 [7]. For three of these, the transplant indication was lymphoma [9, 10], and thus, although the STAT3-HIES was reported as cured, their transplant indication and management could be considered separately. The first of these patients died 6 months following transplant from interstitial pulmonary fibrosis, although with pre-existing abnormal immune parameters, including raised IgE, normalized post-transplant [10]. The other two patients, with follow up of 10 and 14 years, respectively, both with 100% donor chimerism, were reported to have normalized immunological parameters including a normalized proportion of TH17+ lymphocytes. Furthermore, other abnormalities associated with STAT3-HIES, including coarse facies and osteoporosis, were reported to have resolved, and there was no symptomatic development of STAT3-HIES-associated vasculopathy, although it is not clear if any screening was performed [9]. A further patient, transplanted because of a complicated infectious history, was reported after 42 months of follow-up. The patient had full donor chimerism and remained infection-free after discontinuing anti-microbial prophylaxis. Vaccine antibody responses were demonstrated and IgE normalized, STAT3 signaling was restored in hematopoietic-derived cells, and the percentage of Th17+ lymphocytes and central memory T lymphocytes to normal ranges was established [11]. Finally, 2 patients, transplanted for recurrent infection, were reported with 8 and 10 years of follow-up, respectively. Immunological parameters normalized and the infection frequency significantly diminished, but non-immunological features of STAT3-HIES remained, including a propensity to recurrent fractures and development of a new pneumatocele, associated with ≤50% donor chimerism [8].
Our current report extends follow-up of the initial patient to over 18 years and reports on a further 7 patients, one recently published in the context of new onset vasculopathy complications [12], thus contributing the largest series to date. Perhaps the most remarkable observation is that despite pre-transplant severe, progressive lung disease—itself a significant risk factor for HSCT outcome—as well as other significant pre-transplant sequelae, all patients in our series survived. Importantly, pulmonary disease has stabilized in all and improved in some, as demonstrated on clinical, functional, and radiological parameters (Table 1; Fig. 3). No peri-transplant pulmonary inflammatory complications were observed, unlike the post-HSCT course seen in many PID patients. GvHD was infrequent and insignificant. Notably, no patients have required further lung surgery post-HSCT. Most patients have remained on some antimicrobial prophylaxis, in view of treating physician concerns of recurrent infections in pre-existing bronchiectatic lungs—despite this, control of lung disease reported by patients has stabilized or improved. Aspergillus infection, likely from pre-existing colonization or infection, recurred through, or after transplantation in some, but did not cause the severe complications usually associated with transplant-associated aspergillosis. Other significant infections reduced in frequency or resolved completely, accepting that most patients remained on antimicrobial prophylaxis. Importantly, eczema improved in all patients and skin infections were abolished post-transplant.Fig. 3 Thoracic computerized tomography images from patient 4. a Images taken 1 year pre-transplant showing markedly abnormal lung parenchyma with large cysts, bullae, and cystic bronchiectasis particularly in the right lower lobe in association with cylindrical bronchiectasis, bronchial wall thickening, bronchocoeles, and reduced lung attenuation. b Images taken 1 year post-transplant showing several thin walled pulmonary “cysts,” similar to previous pre-transplant findings and are therefore most likely to result from previous infection and lung destruction. Some regions of parenchymal distortion and scarring are also similar. There is some bronchial dilatation and distortion in regions of scarring, but no convincing evidence of bronchiectasis
STAT3 plays an important part in normal endothelial cell biology [16], and endothelial dysfunction is known to contribute to initiation of transplant-related inflammatory complications [17]. It may be that the lack of severe post-HSCT inflammatory complications including acute graft-versus-host disease, observed in these patients and the previously reported cases, might be due to reduced endothelial cell upregulation, conferred by dominant negative STAT3-LOF mutations.
Although serum IgE levels remain above the adult reference range, they are substantially lower post-HSCT compared with pre-HSCT levels, although, in non-transplanted patients, IgE levels may fall over time [1]. More importantly, in those patients for whom data were available, normal TH17 function and associated cytokine responses are demonstrated (Fig. 1), confirming previous reports [8, 9, 11].
As expected, many extra-immune manifestations have not resolved post-HSCT, and patients retain coarse facial features, as well as bone-related complications, although it is noteworthy that only one patient has developed fractures post-transplantation. No patient has developed lymphoma to date. Critically, however, one patient (#3) recently experienced an anterior myocardial infarction, with evidence of thrombotic occlusion of dilated (ectatic) coronary vessels upon angiography. We estimated this patient’s 10-year risk of developing a heart attack or stroke, using the QRISK3 calculator, as 0.1%, which suggests that conventional cardiovascular risk factors were unlikely to account for the event, and disease-associated vasculopathy is more likely to be implicated [12]. Screening of coronary vasculature had not been performed prior to this event, and so it is unclear whether HSCT ameliorated, accelerated, or had no effect on these coronary vessels. Whether earlier HSCT will favorably alter the pre-disposition to vascular complications documented in these patients remains to be seen. Further research is required to establish the clinical significance of these wider complications of STAT3-HIES and capture the long-term impact of STAT3-HIES on patients’ quality of life across the spectrum of presentations.
Contrary to our previous assertion [7], this series, along with other published reports, further supports the notion that allogeneic HSCT can improve the immunological deficit, modify the pulmonary course in these patients, and improve the skin condition. The future challenge will be to identify which patients will benefit from early consideration of this therapy to prevent end-organ damage, reduce hospitalization and improve quality of life, as well as which conditioning regimen to use. The importance of complete or high donor chimerism is not established, and further work is required to determine optimum conditioning regimens and minimum effective donor chimerism level. Furthermore, it will be particularly important to determine whether HSCT can alter the risk of developing vascular anomalies, which may be associated with significant morbidity and mortality.
Author Contribution
ARG conceived the study. SCH, MAS, ARG, and CT collated and analyzed the data and wrote the manuscript; ZN, AW, PV, MJP, JM, AC, SJ, WAH, TJF, AJC, and MA provided clinical data; BG provided genetic analysis and flow cytometry data; RD and GB-M provided cytokine data; all authors contributed to writing of the manuscript and approved the final version.
Funding
CT is supported by The Job Research Foundation.
MJP is supported by the Welsh Clinical Academic Training (WCAT) programme and is a participant in the NIH Graduate Partnership Program.
BG receives support through the Deutsche Forschungsgemeinschaft (DFG) SFB1160/2_B5, under Germany’s Excellence Strategy (CIBSS—EXC-2189—Project ID 390939984, and RESIST—EXC 2155—Project ID 390874280); through the E-rare program of the EU, managed by the DFG, grant code GR1617/14-1/iPAD, and through the “Netzwerke Seltener Erkrankungen” of the German Ministry of Education and Research (BMBF), grant code: GAIN_ 01GM1910A. This work was supported in part by the Center for Chronic Immunodeficiency (CCI), Freiburg Center for Rare Diseases (FZSE).
Data availability
For further information please contact ARG: a.r.gennery@ncl.ac.uk.
Compliance with ethical standards
Ethics Approval and Consent to Participate
Not applicable
Consent for Publication
Not applicable
Competing Interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ALEMTUZUMAB, BUSULFAN, CYCLOPHOSPHAMIDE, CYCLOSPORINE | DrugsGivenReaction | CC BY | 33523338 | 19,824,297 | 2021-07 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypogonadism'. | Hematopoietic Stem Cell Transplantation Resolves the Immune Deficit Associated with STAT3-Dominant-Negative Hyper-IgE Syndrome.
Autosomal dominant hyper-IgE syndrome caused by dominant-negative loss-of-function mutations in signal transducer and activator of transcription factor 3 (STAT3) (STAT3-HIES) is a rare primary immunodeficiency with multisystem pathology. The quality of life in patients with STAT3-HIES is determined by not only the progressive, life-limiting pulmonary disease, but also significant skin disease including recurrent infections and abscesses requiring surgery. Our early report indicated that hematopoietic stem cell transplantation might not be effective in patients with STAT3-HIES, although a few subsequent reports have reported successful outcomes. We update on progress of our patient now with over 18 years of follow-up and report on an additional seven cases, all of whom have survived despite demonstrating significant disease-related pathology prior to transplant. We conclude that effective cure of the immunological aspects of the disease and stabilization of even severe lung involvement may be achieved by allogeneic hematopoietic stem cell transplantation. Recurrent skin infections and abscesses may be abolished. Donor TH17 cells may produce comparable levels of IL17A to healthy controls. The future challenge will be to determine which patients should best be offered this treatment and at what point in their disease history.
Introduction
Autosomal dominant hyper-IgE syndrome is a rare primary immunodeficiency (PID) with multisystem pathology [1], caused by dominant-negative loss-of-function (LOF) mutations in signal transducer and activator of transcription factor 3 (STAT3) [2, 3] (STAT3-HIES). STAT3 is integral to lymphocyte development and differentiation. STAT3-deficient humans and mice have impaired cellular and humoral immune responses [4, 5], explaining the diverse immunologic manifestations [2–4]. In the context of infection, there is poor differentiation of T lymphocytes into TH17 cells, resulting in low IL17 and IL22 production [6], which contributes to susceptibility to encapsulated organisms and fungi.
HSCT was initially reported as unsuccessful in STAT3-HIES by our group [7]. Based on this impression, supportive treatment has been largely adopted [1], but many patients develop severe life-limiting pulmonary disease. However, over the years, eight case reports of allogeneic hematopoietic stem cell transplant (HSCT) for STAT3-HIES have been published [7–12], three of them performed following the diagnosis of non-Hodgkin’s B cell lymphoma, which is a known complication of this primary immunodeficiency [8]. In these eight cases, five patients had received myeloablative conditioning regimens, while three had reduced-intensity conditioning. Seven patients, including two with Hodgkin’s lymphoma, were recently reported as alive and well 4–20 years following report of HSCT [13], while one patient had died from the pre-existing lymphoma post-transplant [10].
We initially reported failure of HSCT to resolve or cure the immune defect in our first patient. However, we now acknowledge that STAT3-HIES patients have experienced sustained benefit from HSCT. At the time of our report, the molecular cause of STAT3-HIES was unknown, and we based our statements on failure to normalize the serum IgE level and an apparent failure to change the immunological defect. We have now shown that the IL17A levels of that patient approaches normal (although not measured pre-transplant) and memory B-lymphocytes are present. We now report a series of eight patients successfully treated with HSCT in the UK, including the long-term follow up of our previously reported patient [7].
Methods
We conducted a retrospective review of medical records of STAT3-HIES patients from two UK transplant centers for PID. We included only patients with confirmed dominant-negative STAT3 mutations who have undergone allogeneic HSCT. We recorded pre-transplant co-morbidities, conditioning, outcome, and on-going co-morbidities in eight patients who received nine transplants.
In selected patients for whom samples were available, IL17A levels were measured by Luminex (Bio-Plex, Biorad, UK) [14], 24 hours after stimulation in whole blood (96 Costar-F plates, 1:5 diluted in RPMI) of healthy controls and patients. Stimulations were performed using PHA (Sigma-Aldrich, 10 μg/ml) and compared with unstimulated medium samples. Data were compared with historic controls, which had been stimulated under identical conditions. P values were calculated using the two-tailed Mann-Whitney test or the Wilcoxon matched pairs test, excluding the data of P5 before HSCT.
Parents, and, where appropriate, patients consented to the procedure and data collection.
Results
Transplants were performed between 1996 and 2019. Demographic data, genetic mutation, and pre-HSCT clinical status are summarized in Table 1. All patients had dominant loss-of-function mutations in STAT3 with a classical clinical phenotype, and all had significant lung or skin-related complications prior to HSCT.Table 1 Patient demographic features and pre- and post-HSCT clinical details
Patient no.; sex Age at HSCT (years) STAT3 Heterozygous mutation Skin disease Lung disease and PFTs Fractures; other skeletal disease Infection; other Issues
Pre-HSCT Post-HSCT Pre-HSCT Post-HSCT Pre-HSCT Post-HSCT Pre-HSCT Post-HSCT
1
M
7 c.1909 G>A p.V637M Yes Normal Left upper and lower lobectomies with bronchopleural fistula; bilateral bronchiectasis; chronic Aspergillus infection; pulmonary hypertension
FEV1 47%
FVC 51%
Stable appearance on CT: bronchiectasis persist
Nocturnal CPAP for lobar collapse post-scoliosis repair with limited exercise tolerance
FEV1 20%
FVC 23%
Yes 2 further fractures at 3–4 years post-HSCT
Development of scoliosis requiring spinal fusion
Staphylococcus aureus pericarditis -
2
F
6 c.1771 A>G p.K591E Yes Normal Recurrent Pseudomonas lung infection with cyst formation
Not done
Stable; no progression of pulmonary cysts
FEV1 95%
FVC 88%
No Development of scoliosis - Gonadal failure following myeloablative conditioning
Arterial hypertension
3
M
13 c.1144 C>T p.R382W Yes Normal Severe and recurrent pneumonia with bronchiectasis
FEV1 63%
FVC 70%
Stable appearance on CT
No further hemoptysis
FEV1 83%
FVC 71%
Yes No - ST segment elevation myocardial infarction aged 26 years (13 years post-HSCT)
4
M
14 c.1144 C>T p.R382W Yes
Pustular dermatitis
Dry skin, no infection Bronchiectasis with multi-cystic lung disease, leading to left lobectomy
FEV1 28%
FVC 26%
Significant improvement in pulmonary cystic disease and resolution in right lower lobe bronchial thickening on CT
FEV1 65%
FVC 74%
Yes No Staphylococcus aureus liver abscess Autoimmune neutropenia
5
F
17 c.1144 C>T p.R382W Yes
Persistent infected czema
Normal Pneumatocoele leading to left lobectomy
FEV1 53%
FVC 67%
Improvement in lung appearance on CT
FEV1 51%
FVC 67%
Yes No - Aspergillus perdicarditis at 7 months post-HSCT resolved by 16 months post-HSCT
6
M
18 c.1110 A>G D371_G380del Yes
Eczema, pustular dermatitis
Resolution of previous chronic infection Lung abscess; pulmonary TB
FEV1 89%
FVC 90%
Stable CXR changes
Not done
No
Retained primary dentition
Enterococcal septic arthritis with collapse of femoral head Recurrent Staphylococcus aureus liver abscess
Candida retroperitoneal lymphadenitis and liver abscess
Early gastrointestinal bleed in post-transplant period
Medication-related nephrotoxicity
6
2nd HSCT
18
7
M
13 c.1144 C>G p.R382G Yes
Multiple skin abscesses
Dry skin, no infection Minimal
FEV1 89%
FVC 90%
Improvement in symptoms and exercise tolerance
Not done
No
Retained primary dentition
No Osteomyelitis of mandible -
8
F
6 c.1144 C>T p.R382W Yes
Eczema, Multiple skin abscesses
Dry skin, no infection Severe bronchiectasis bilaterally with broncho-pulmonary aspergillosis
FEV1 84%
FVC 92%
Improvement in symptoms
FEV1 82.7%FVC 78.4%
No No - -
Details of conditioning regimen, cell source, and graft-versus-host disease (GvHD) prophylaxis are detailed in Table 2. One patient received conventional myeloablative conditioning, four received reduced-toxicity myeloablative conditioning, and three received reduced intensity conditioning, one of whom rejected and was successfully re-transplanted following a reduced-toxicity myeloablative regimen (patient six). All inoculi were matched at 10/10 HLA-loci, apart from the first product for patient six, which was a 9/10 match (DQ mismatch).Table 2 Patient transplant demographics
Patient Follow-up Cell source; HLA Match Conditioning regimen GvHD prophylaxis Acute GvHD Latest donor chimerism
1 6 years URD PBSC
10/10
Alemtuzumab 1mg/kg
Fludarabine 150mg/m2
Melphalan 140mg/m2
CSA
MMF
- CD15 55%
CD19 55%
CD3 86%
2 20 years URD BM
10/10
Alemtuzumab 1mg/kg busulphan 16mg/kg
Cyclophosphamide 200mg/kg
CSA Grade 1 skin WB 100%
3 11 years URD BM
10/10
Alemtuzumab 1mg/kg
Fludarabine 150mg/m2
Melphalan 140mg/kg
CSA
MMF
- WB 100%
4 3 years MSD PBSC
10/10
Alemtuzumab 1mg/kg
Treosulfan 42g/m2
Fludarabine150mg/m2
CSA
MMF
Grade 1 skin CD15 100%
CD19 100%
CD3 91%
5 3 years URD PBSC
10/10
Alemtuzumab 1mg/kg
Fludarabine 150mg/m2
Treosulphan 42g/m2
CSA
MMF
Grade 1 skin WB 100%
6 - Mismatched URD PBSC
9/10
(DQ mismatch)
Alemtuzumab 60mg
Fludarabine 150mg/m2
Melphalan 140mg/m2
CSA - Hyperacute rejection D+13
2 years URD BM
10/10
ATG Fludarabine 150mg/m2
Treosulphan 42g/m2
Thiotepa 10mg/kg
CSA
MMF
- WB 100%
7 20 months URD PBSC
10/10
Alemtuzumab 1mg/kg
Fludarabine 150mg/m2
Treosulphan 42g/m2
CSA
MMF
- WB 100%
8 15 months MSD BM
10/10
Alemtuzumab 1mg/kg
Fludarabine 150mg/m2
Treosulphan 42g/m2
CSA
MMF
- CD15 96%
CD19 94%
CD3 94%
All patients survived and no patient experienced significant GvHD. Seven patients had complete or high level (>90%) donor chimerism and one had partial chimerism; however, all had improvement in immune phenotype, with a reduction in clinical symptoms, halting of progression of lung disease and improvement in skin infections. Non-immune manifestations showed variable improvement, with one patient developing further fractures and two patients demonstrating worsening scoliosis post-transplant. One patient has recently had vasculopathy with an ST segment elevation myocardial infarction with ectatic coronary vasculature [12]. Patient clinical status post-HSCT are summarized in Table 3.Table 3 Patient immunological data pre- and post-HSCT
Patient IgE (kU/L) IVIG given Vaccine responses; CSM/Mem B lymphocytes (25–75th centile reference range) Antimicrobial prophylaxis post-HSCT
Pre-HSCT Post-HSCT Pre-HSCT Post-HSCT Pre-HSCT Post-HSCT
1 4007 1720 Yes No Normal tetanus, absent HiB and pneumococcus
-
Normal
-
Voriconazole; azithromycin
2 75,000 2641 Yes No Normal
-
Normal
CSM B 9% (9.2–18.9%)
Mem B 13% (13.4–21.4%)
Azithromycin
3 >6000 176 Yes No Normal
-
Normal
-
Doxycycline
4 81,097 11,813 Yes No Normal
CSM B 1% (3.3–9.6%)
Mem B 3% (4.6–10.2%)
Normal
CSM B 1% (3.3–9.6%)
Mem B 3% (4.6–10.2%)
Azithromycin
5 4487 1939 No No Normal
CSM B 1% (3.3–9.6%)
Mem B 3% (4.6–10.2%)
Normal
CSM B 2% (7.2–12.7%)
Mem B 7% (7.4–13.9%)
Posaconazole; nebulized amphotericin B; azithromycin
6 143,000 - Yes No Normal
CSM B 0.4% (3.3–9.6%)
-
-
-
7 >5000 1636 Yes No Normal
-
In progress
Mem B cells 1.6% (3.3–9.6%)
-
8 1880–11,756 392 Yes Yes Normal tetanus and HiB, absent PPSV23
CSM B 2.6% (5.2–12.1%)
(On Ig)
CSM B 3% (5.2–12.1%)
Mem B 2% (7.5–12.4%)
Azithromycin
Reference ranges of 25–75th centile for CSM and Mem B lymphocytes from Morbach et al. [15]
CSM class switched memory, HSCT hematopoietic stem cell transplantation
In the one patient (patient 5) for whom pre- and post-transplant IL17A levels were available, IL17A was higher post-transplant. For patients 2, 3, and 4, IL17A levels were present post-transplant, but lower than controls (Fig. 1).Fig. 1 IL17A levels in healthy controls and patients post-transplant. IL17A levels were measured by Luminex (Bio-Plex, Biorad, UK) 24 hours after stimulation in whole blood (96 Costar-F plates, 1:5 diluted in RPMI) of healthy controls (historical and contemporary) and patients (P2—blue diamonds, P3—blue triangles, P4—blue squares, P5 (pre and post HSCT) —blue circles). Stimulations were done using PHA (Sigma-Aldrich, 10 μg/ml) and compared with unstimulated medium samples (Med)
Patient 1 had significant pulmonary infection (complicated cystic bronchiectasis with Pseudomonas infection and widespread Aspergillus infection leading to pulmonary hypertension) with two lobectomies, complicated by development of bronchopleural fistula. He subsequently developed a Staphylococcus aureus pericarditis requiring surgical drainage, complicated by prolonged air leak. Transplantation at age 7 years was relatively uncomplicated. There was no viral re-activation, progression of chest lesions, or acute graft versus host disease. Six years post-transplant, his eczema had resolved and he was no longer getting significant respiratory infections. Immunoglobulin support has ceased, and normal vaccine and T-lymphocyte proliferative responses have been demonstrated. His scoliosis, exacerbated by his two previous left sided lobectomies, had deteriorated requiring spinal fusion surgery. Following this, his right lower airway integrity has been compromised, severely impairing his respiratory capacity. He now is reliant on overnight CPAP and can only ambulate short distances.
Patient 2 experienced frequent staphylococcal skin infections and cystic bronchiectasis infected with Pseudomonas, because of which transplantation was offered when aged 6 years. Despite 100% donor chimerism, the procedure was initially described as unsuccessful [7] because of continued elevated serum IgE. However, long-term follow-up confirmed sustained clinical improvement with no further respiratory or skin infections. Serum IgE levels diminished and remained reduced, and immunoglobulin support is no longer required. She developed thoracolumbar scoliosis, arterial hypertension, and gonadal failure. With 20 years follow-up, pulmonary status includes stable lingular bronchiectasis and non-progressive right upper lobe pulmonary cysts.
Patient 3 experienced frequent severe bronchopneumonias and progressive bronchiectasis despite immunoglobulin replacement, as well as osteopenia and lumbar vertebrae compression fractures. Transplantation at 13 years was relatively uneventful, and 13 years post-transplant, he demonstrates 100% donor chimerism with reduced serum IgE levels. Lung function has improved to normal values. Hemoptysis has stopped, and there is no computerized tomographic evidence of pulmonary disease progression. An increase in IL17A production after polyclonal stimulation was demonstrated post-HSCT (Fig. 2), and TH17 cells display normal response to IFN-γ and IL12 and normal IL12 production (data not shown). However, at 11 years post-HSCT, he sustained an anterior myocardial infarction, accompanied by classical clinical, electrocardiographic and biochemical signs and parameters. Angiography revealed proximal ectasia causing mid-vessel occlusion of his left anterior descending coronary artery but otherwise unobstructed coronary vessels. He was commenced on aspirin 75 mg for 3 months with rivaroxaban 2.5 mg BID for 3 years and clopidogrel 75 mg long term [12].Fig. 2 Pre- and post-transplant peripheral blood mononuclear cells demonstrate that IL17A is absent pre-transplant and present post-transplant (patient 3), with normal control and a negative control patient who has not been transplanted (p.V637M)
Patient 4 developed bronchiectasis, Staphylococcus aureus liver abscess, and recurrent skin abscesses. Severe multi-cystic and suppurative lung disease warranted left upper lobectomy. Following transplantation at age 14 years, repeat computerized tomography demonstrated significant widespread decrease in the number and size of previously reported large cysts, and there was a clinical improvement in the eczematous skin lesions. Post-transplant IL17A production was normal.
Patient 5 developed multiple abscesses and pneumatoceles during infancy leading to right upper lobectomy and broncho-pulmonary fistula at age 13 years. Pulmonary function was impaired prior to HSCT, aged 17 years. Non-invasive pulmonary Aspergillus infection persisted post-HSCT, treated with appropriate long-term anti-fungal therapy—at 7 months post-transplant, and Aspergillus pericarditis was diagnosed, which resolved with dual anti-fungal therapy by 16 months post-transplant. Thoracic computerized tomography demonstrated a dramatic improvement in lung appearance, and the residual right upper lobe cavity remained stable.
Patient 6 had persistent multiple skin infections with severe eczema and lymphadenitis through childhood and a single lung abscess. Additionally, a persistent Staphylococcus aureus hepatic abscess required surgical drainage on four occasions. Further to this, the patient required surgical excision of Candida albicans retroperitoneal lymphadenitis and a fungal liver abscess. The patient developed bowel perforation of unknown etiology at 6 years of age, before HSCT. An immune-mediated acute rejection of first graft was confirmed at day 13 post-transplant, followed by an autologous recovery. In this period, the patient experienced an enterococcal septic arthritis, with collapse of femoral head, gastrointestinal hemorrhage, and further episodes of fungal lymphadenitis. A second transplant procedure using a reduced toxicity treosulfan-based regimen was successful. The patient has good immune reconstitution and has ceased immunosuppression and immunoglobulin replacement.
Patient 7 was first referred to pediatric care at the age of 4 weeks due of eczema and skin infections, mainly on the face and scalp, from which Staphylococcus aureus was isolated and treated. Serum IgE levels were elevated prompting a diagnosis of Hyper IgE syndrome, confirmed genetically. The patient continued to have numerous recurrent skin abscesses, requiring drainage over 20 times per year despite antibiotic treatment and immunoglobulin replacement. He subsequently developed mandibular osteomyelitis. Pulmonary disease was limited to asthma only, with no significant infection. Transplant was uncomplicated, and at 20 months post-HSCT, his skin is much improved with no new infections. He has discontinued immunoglobulin and is awaiting vaccination.
Patient 8 presented as a neonate with staphylococcal skin infection and went on to develop recurrent skin infection, pneumonia, and otitis media. She demonstrated elevated serum IgE with poor pneumococcal antibody titers following vaccination and almost no TH17 cells. Her pulmonary disease progressed with findings of Aspergillus on bronchoalveolar lavage leading to a diagnosis of allergic bronchopulmonary aspergillosis, treated with antifungal therapy, corticosteroids, and anti-IgE monoclonal antibodies. She underwent HSCT aged 6 years with an uncomplicated course. One year post-HSCT, she reports only dry skin with no infection. Pulmonary function is stable and she is asymptomatic from cough or dyspnoea. Serum IgE has fallen to 392 kU/L. She remains on immunoglobulin replacement but has normal B lymphocyte numbers.
Discussion
Published data on the outcome of allogeneic HSCT for STAT3-HIES patients are limited, perhaps stemming from our initial report indicating non-utility [7]. A recent report by Oikonomopoulou et al. [13] summarizes the data of 7 patients transplanted between 1998 and 2018, one of which was the patient we originally reported in 2000 [7]. For three of these, the transplant indication was lymphoma [9, 10], and thus, although the STAT3-HIES was reported as cured, their transplant indication and management could be considered separately. The first of these patients died 6 months following transplant from interstitial pulmonary fibrosis, although with pre-existing abnormal immune parameters, including raised IgE, normalized post-transplant [10]. The other two patients, with follow up of 10 and 14 years, respectively, both with 100% donor chimerism, were reported to have normalized immunological parameters including a normalized proportion of TH17+ lymphocytes. Furthermore, other abnormalities associated with STAT3-HIES, including coarse facies and osteoporosis, were reported to have resolved, and there was no symptomatic development of STAT3-HIES-associated vasculopathy, although it is not clear if any screening was performed [9]. A further patient, transplanted because of a complicated infectious history, was reported after 42 months of follow-up. The patient had full donor chimerism and remained infection-free after discontinuing anti-microbial prophylaxis. Vaccine antibody responses were demonstrated and IgE normalized, STAT3 signaling was restored in hematopoietic-derived cells, and the percentage of Th17+ lymphocytes and central memory T lymphocytes to normal ranges was established [11]. Finally, 2 patients, transplanted for recurrent infection, were reported with 8 and 10 years of follow-up, respectively. Immunological parameters normalized and the infection frequency significantly diminished, but non-immunological features of STAT3-HIES remained, including a propensity to recurrent fractures and development of a new pneumatocele, associated with ≤50% donor chimerism [8].
Our current report extends follow-up of the initial patient to over 18 years and reports on a further 7 patients, one recently published in the context of new onset vasculopathy complications [12], thus contributing the largest series to date. Perhaps the most remarkable observation is that despite pre-transplant severe, progressive lung disease—itself a significant risk factor for HSCT outcome—as well as other significant pre-transplant sequelae, all patients in our series survived. Importantly, pulmonary disease has stabilized in all and improved in some, as demonstrated on clinical, functional, and radiological parameters (Table 1; Fig. 3). No peri-transplant pulmonary inflammatory complications were observed, unlike the post-HSCT course seen in many PID patients. GvHD was infrequent and insignificant. Notably, no patients have required further lung surgery post-HSCT. Most patients have remained on some antimicrobial prophylaxis, in view of treating physician concerns of recurrent infections in pre-existing bronchiectatic lungs—despite this, control of lung disease reported by patients has stabilized or improved. Aspergillus infection, likely from pre-existing colonization or infection, recurred through, or after transplantation in some, but did not cause the severe complications usually associated with transplant-associated aspergillosis. Other significant infections reduced in frequency or resolved completely, accepting that most patients remained on antimicrobial prophylaxis. Importantly, eczema improved in all patients and skin infections were abolished post-transplant.Fig. 3 Thoracic computerized tomography images from patient 4. a Images taken 1 year pre-transplant showing markedly abnormal lung parenchyma with large cysts, bullae, and cystic bronchiectasis particularly in the right lower lobe in association with cylindrical bronchiectasis, bronchial wall thickening, bronchocoeles, and reduced lung attenuation. b Images taken 1 year post-transplant showing several thin walled pulmonary “cysts,” similar to previous pre-transplant findings and are therefore most likely to result from previous infection and lung destruction. Some regions of parenchymal distortion and scarring are also similar. There is some bronchial dilatation and distortion in regions of scarring, but no convincing evidence of bronchiectasis
STAT3 plays an important part in normal endothelial cell biology [16], and endothelial dysfunction is known to contribute to initiation of transplant-related inflammatory complications [17]. It may be that the lack of severe post-HSCT inflammatory complications including acute graft-versus-host disease, observed in these patients and the previously reported cases, might be due to reduced endothelial cell upregulation, conferred by dominant negative STAT3-LOF mutations.
Although serum IgE levels remain above the adult reference range, they are substantially lower post-HSCT compared with pre-HSCT levels, although, in non-transplanted patients, IgE levels may fall over time [1]. More importantly, in those patients for whom data were available, normal TH17 function and associated cytokine responses are demonstrated (Fig. 1), confirming previous reports [8, 9, 11].
As expected, many extra-immune manifestations have not resolved post-HSCT, and patients retain coarse facial features, as well as bone-related complications, although it is noteworthy that only one patient has developed fractures post-transplantation. No patient has developed lymphoma to date. Critically, however, one patient (#3) recently experienced an anterior myocardial infarction, with evidence of thrombotic occlusion of dilated (ectatic) coronary vessels upon angiography. We estimated this patient’s 10-year risk of developing a heart attack or stroke, using the QRISK3 calculator, as 0.1%, which suggests that conventional cardiovascular risk factors were unlikely to account for the event, and disease-associated vasculopathy is more likely to be implicated [12]. Screening of coronary vasculature had not been performed prior to this event, and so it is unclear whether HSCT ameliorated, accelerated, or had no effect on these coronary vessels. Whether earlier HSCT will favorably alter the pre-disposition to vascular complications documented in these patients remains to be seen. Further research is required to establish the clinical significance of these wider complications of STAT3-HIES and capture the long-term impact of STAT3-HIES on patients’ quality of life across the spectrum of presentations.
Contrary to our previous assertion [7], this series, along with other published reports, further supports the notion that allogeneic HSCT can improve the immunological deficit, modify the pulmonary course in these patients, and improve the skin condition. The future challenge will be to identify which patients will benefit from early consideration of this therapy to prevent end-organ damage, reduce hospitalization and improve quality of life, as well as which conditioning regimen to use. The importance of complete or high donor chimerism is not established, and further work is required to determine optimum conditioning regimens and minimum effective donor chimerism level. Furthermore, it will be particularly important to determine whether HSCT can alter the risk of developing vascular anomalies, which may be associated with significant morbidity and mortality.
Author Contribution
ARG conceived the study. SCH, MAS, ARG, and CT collated and analyzed the data and wrote the manuscript; ZN, AW, PV, MJP, JM, AC, SJ, WAH, TJF, AJC, and MA provided clinical data; BG provided genetic analysis and flow cytometry data; RD and GB-M provided cytokine data; all authors contributed to writing of the manuscript and approved the final version.
Funding
CT is supported by The Job Research Foundation.
MJP is supported by the Welsh Clinical Academic Training (WCAT) programme and is a participant in the NIH Graduate Partnership Program.
BG receives support through the Deutsche Forschungsgemeinschaft (DFG) SFB1160/2_B5, under Germany’s Excellence Strategy (CIBSS—EXC-2189—Project ID 390939984, and RESIST—EXC 2155—Project ID 390874280); through the E-rare program of the EU, managed by the DFG, grant code GR1617/14-1/iPAD, and through the “Netzwerke Seltener Erkrankungen” of the German Ministry of Education and Research (BMBF), grant code: GAIN_ 01GM1910A. This work was supported in part by the Center for Chronic Immunodeficiency (CCI), Freiburg Center for Rare Diseases (FZSE).
Data availability
For further information please contact ARG: a.r.gennery@ncl.ac.uk.
Compliance with ethical standards
Ethics Approval and Consent to Participate
Not applicable
Consent for Publication
Not applicable
Competing Interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | ALEMTUZUMAB, BUSULFAN, CYCLOPHOSPHAMIDE, CYCLOSPORINE | DrugsGivenReaction | CC BY | 33523338 | 19,824,297 | 2021-07 |
What was the dosage of drug 'ALEMTUZUMAB'? | Hematopoietic Stem Cell Transplantation Resolves the Immune Deficit Associated with STAT3-Dominant-Negative Hyper-IgE Syndrome.
Autosomal dominant hyper-IgE syndrome caused by dominant-negative loss-of-function mutations in signal transducer and activator of transcription factor 3 (STAT3) (STAT3-HIES) is a rare primary immunodeficiency with multisystem pathology. The quality of life in patients with STAT3-HIES is determined by not only the progressive, life-limiting pulmonary disease, but also significant skin disease including recurrent infections and abscesses requiring surgery. Our early report indicated that hematopoietic stem cell transplantation might not be effective in patients with STAT3-HIES, although a few subsequent reports have reported successful outcomes. We update on progress of our patient now with over 18 years of follow-up and report on an additional seven cases, all of whom have survived despite demonstrating significant disease-related pathology prior to transplant. We conclude that effective cure of the immunological aspects of the disease and stabilization of even severe lung involvement may be achieved by allogeneic hematopoietic stem cell transplantation. Recurrent skin infections and abscesses may be abolished. Donor TH17 cells may produce comparable levels of IL17A to healthy controls. The future challenge will be to determine which patients should best be offered this treatment and at what point in their disease history.
Introduction
Autosomal dominant hyper-IgE syndrome is a rare primary immunodeficiency (PID) with multisystem pathology [1], caused by dominant-negative loss-of-function (LOF) mutations in signal transducer and activator of transcription factor 3 (STAT3) [2, 3] (STAT3-HIES). STAT3 is integral to lymphocyte development and differentiation. STAT3-deficient humans and mice have impaired cellular and humoral immune responses [4, 5], explaining the diverse immunologic manifestations [2–4]. In the context of infection, there is poor differentiation of T lymphocytes into TH17 cells, resulting in low IL17 and IL22 production [6], which contributes to susceptibility to encapsulated organisms and fungi.
HSCT was initially reported as unsuccessful in STAT3-HIES by our group [7]. Based on this impression, supportive treatment has been largely adopted [1], but many patients develop severe life-limiting pulmonary disease. However, over the years, eight case reports of allogeneic hematopoietic stem cell transplant (HSCT) for STAT3-HIES have been published [7–12], three of them performed following the diagnosis of non-Hodgkin’s B cell lymphoma, which is a known complication of this primary immunodeficiency [8]. In these eight cases, five patients had received myeloablative conditioning regimens, while three had reduced-intensity conditioning. Seven patients, including two with Hodgkin’s lymphoma, were recently reported as alive and well 4–20 years following report of HSCT [13], while one patient had died from the pre-existing lymphoma post-transplant [10].
We initially reported failure of HSCT to resolve or cure the immune defect in our first patient. However, we now acknowledge that STAT3-HIES patients have experienced sustained benefit from HSCT. At the time of our report, the molecular cause of STAT3-HIES was unknown, and we based our statements on failure to normalize the serum IgE level and an apparent failure to change the immunological defect. We have now shown that the IL17A levels of that patient approaches normal (although not measured pre-transplant) and memory B-lymphocytes are present. We now report a series of eight patients successfully treated with HSCT in the UK, including the long-term follow up of our previously reported patient [7].
Methods
We conducted a retrospective review of medical records of STAT3-HIES patients from two UK transplant centers for PID. We included only patients with confirmed dominant-negative STAT3 mutations who have undergone allogeneic HSCT. We recorded pre-transplant co-morbidities, conditioning, outcome, and on-going co-morbidities in eight patients who received nine transplants.
In selected patients for whom samples were available, IL17A levels were measured by Luminex (Bio-Plex, Biorad, UK) [14], 24 hours after stimulation in whole blood (96 Costar-F plates, 1:5 diluted in RPMI) of healthy controls and patients. Stimulations were performed using PHA (Sigma-Aldrich, 10 μg/ml) and compared with unstimulated medium samples. Data were compared with historic controls, which had been stimulated under identical conditions. P values were calculated using the two-tailed Mann-Whitney test or the Wilcoxon matched pairs test, excluding the data of P5 before HSCT.
Parents, and, where appropriate, patients consented to the procedure and data collection.
Results
Transplants were performed between 1996 and 2019. Demographic data, genetic mutation, and pre-HSCT clinical status are summarized in Table 1. All patients had dominant loss-of-function mutations in STAT3 with a classical clinical phenotype, and all had significant lung or skin-related complications prior to HSCT.Table 1 Patient demographic features and pre- and post-HSCT clinical details
Patient no.; sex Age at HSCT (years) STAT3 Heterozygous mutation Skin disease Lung disease and PFTs Fractures; other skeletal disease Infection; other Issues
Pre-HSCT Post-HSCT Pre-HSCT Post-HSCT Pre-HSCT Post-HSCT Pre-HSCT Post-HSCT
1
M
7 c.1909 G>A p.V637M Yes Normal Left upper and lower lobectomies with bronchopleural fistula; bilateral bronchiectasis; chronic Aspergillus infection; pulmonary hypertension
FEV1 47%
FVC 51%
Stable appearance on CT: bronchiectasis persist
Nocturnal CPAP for lobar collapse post-scoliosis repair with limited exercise tolerance
FEV1 20%
FVC 23%
Yes 2 further fractures at 3–4 years post-HSCT
Development of scoliosis requiring spinal fusion
Staphylococcus aureus pericarditis -
2
F
6 c.1771 A>G p.K591E Yes Normal Recurrent Pseudomonas lung infection with cyst formation
Not done
Stable; no progression of pulmonary cysts
FEV1 95%
FVC 88%
No Development of scoliosis - Gonadal failure following myeloablative conditioning
Arterial hypertension
3
M
13 c.1144 C>T p.R382W Yes Normal Severe and recurrent pneumonia with bronchiectasis
FEV1 63%
FVC 70%
Stable appearance on CT
No further hemoptysis
FEV1 83%
FVC 71%
Yes No - ST segment elevation myocardial infarction aged 26 years (13 years post-HSCT)
4
M
14 c.1144 C>T p.R382W Yes
Pustular dermatitis
Dry skin, no infection Bronchiectasis with multi-cystic lung disease, leading to left lobectomy
FEV1 28%
FVC 26%
Significant improvement in pulmonary cystic disease and resolution in right lower lobe bronchial thickening on CT
FEV1 65%
FVC 74%
Yes No Staphylococcus aureus liver abscess Autoimmune neutropenia
5
F
17 c.1144 C>T p.R382W Yes
Persistent infected czema
Normal Pneumatocoele leading to left lobectomy
FEV1 53%
FVC 67%
Improvement in lung appearance on CT
FEV1 51%
FVC 67%
Yes No - Aspergillus perdicarditis at 7 months post-HSCT resolved by 16 months post-HSCT
6
M
18 c.1110 A>G D371_G380del Yes
Eczema, pustular dermatitis
Resolution of previous chronic infection Lung abscess; pulmonary TB
FEV1 89%
FVC 90%
Stable CXR changes
Not done
No
Retained primary dentition
Enterococcal septic arthritis with collapse of femoral head Recurrent Staphylococcus aureus liver abscess
Candida retroperitoneal lymphadenitis and liver abscess
Early gastrointestinal bleed in post-transplant period
Medication-related nephrotoxicity
6
2nd HSCT
18
7
M
13 c.1144 C>G p.R382G Yes
Multiple skin abscesses
Dry skin, no infection Minimal
FEV1 89%
FVC 90%
Improvement in symptoms and exercise tolerance
Not done
No
Retained primary dentition
No Osteomyelitis of mandible -
8
F
6 c.1144 C>T p.R382W Yes
Eczema, Multiple skin abscesses
Dry skin, no infection Severe bronchiectasis bilaterally with broncho-pulmonary aspergillosis
FEV1 84%
FVC 92%
Improvement in symptoms
FEV1 82.7%FVC 78.4%
No No - -
Details of conditioning regimen, cell source, and graft-versus-host disease (GvHD) prophylaxis are detailed in Table 2. One patient received conventional myeloablative conditioning, four received reduced-toxicity myeloablative conditioning, and three received reduced intensity conditioning, one of whom rejected and was successfully re-transplanted following a reduced-toxicity myeloablative regimen (patient six). All inoculi were matched at 10/10 HLA-loci, apart from the first product for patient six, which was a 9/10 match (DQ mismatch).Table 2 Patient transplant demographics
Patient Follow-up Cell source; HLA Match Conditioning regimen GvHD prophylaxis Acute GvHD Latest donor chimerism
1 6 years URD PBSC
10/10
Alemtuzumab 1mg/kg
Fludarabine 150mg/m2
Melphalan 140mg/m2
CSA
MMF
- CD15 55%
CD19 55%
CD3 86%
2 20 years URD BM
10/10
Alemtuzumab 1mg/kg busulphan 16mg/kg
Cyclophosphamide 200mg/kg
CSA Grade 1 skin WB 100%
3 11 years URD BM
10/10
Alemtuzumab 1mg/kg
Fludarabine 150mg/m2
Melphalan 140mg/kg
CSA
MMF
- WB 100%
4 3 years MSD PBSC
10/10
Alemtuzumab 1mg/kg
Treosulfan 42g/m2
Fludarabine150mg/m2
CSA
MMF
Grade 1 skin CD15 100%
CD19 100%
CD3 91%
5 3 years URD PBSC
10/10
Alemtuzumab 1mg/kg
Fludarabine 150mg/m2
Treosulphan 42g/m2
CSA
MMF
Grade 1 skin WB 100%
6 - Mismatched URD PBSC
9/10
(DQ mismatch)
Alemtuzumab 60mg
Fludarabine 150mg/m2
Melphalan 140mg/m2
CSA - Hyperacute rejection D+13
2 years URD BM
10/10
ATG Fludarabine 150mg/m2
Treosulphan 42g/m2
Thiotepa 10mg/kg
CSA
MMF
- WB 100%
7 20 months URD PBSC
10/10
Alemtuzumab 1mg/kg
Fludarabine 150mg/m2
Treosulphan 42g/m2
CSA
MMF
- WB 100%
8 15 months MSD BM
10/10
Alemtuzumab 1mg/kg
Fludarabine 150mg/m2
Treosulphan 42g/m2
CSA
MMF
- CD15 96%
CD19 94%
CD3 94%
All patients survived and no patient experienced significant GvHD. Seven patients had complete or high level (>90%) donor chimerism and one had partial chimerism; however, all had improvement in immune phenotype, with a reduction in clinical symptoms, halting of progression of lung disease and improvement in skin infections. Non-immune manifestations showed variable improvement, with one patient developing further fractures and two patients demonstrating worsening scoliosis post-transplant. One patient has recently had vasculopathy with an ST segment elevation myocardial infarction with ectatic coronary vasculature [12]. Patient clinical status post-HSCT are summarized in Table 3.Table 3 Patient immunological data pre- and post-HSCT
Patient IgE (kU/L) IVIG given Vaccine responses; CSM/Mem B lymphocytes (25–75th centile reference range) Antimicrobial prophylaxis post-HSCT
Pre-HSCT Post-HSCT Pre-HSCT Post-HSCT Pre-HSCT Post-HSCT
1 4007 1720 Yes No Normal tetanus, absent HiB and pneumococcus
-
Normal
-
Voriconazole; azithromycin
2 75,000 2641 Yes No Normal
-
Normal
CSM B 9% (9.2–18.9%)
Mem B 13% (13.4–21.4%)
Azithromycin
3 >6000 176 Yes No Normal
-
Normal
-
Doxycycline
4 81,097 11,813 Yes No Normal
CSM B 1% (3.3–9.6%)
Mem B 3% (4.6–10.2%)
Normal
CSM B 1% (3.3–9.6%)
Mem B 3% (4.6–10.2%)
Azithromycin
5 4487 1939 No No Normal
CSM B 1% (3.3–9.6%)
Mem B 3% (4.6–10.2%)
Normal
CSM B 2% (7.2–12.7%)
Mem B 7% (7.4–13.9%)
Posaconazole; nebulized amphotericin B; azithromycin
6 143,000 - Yes No Normal
CSM B 0.4% (3.3–9.6%)
-
-
-
7 >5000 1636 Yes No Normal
-
In progress
Mem B cells 1.6% (3.3–9.6%)
-
8 1880–11,756 392 Yes Yes Normal tetanus and HiB, absent PPSV23
CSM B 2.6% (5.2–12.1%)
(On Ig)
CSM B 3% (5.2–12.1%)
Mem B 2% (7.5–12.4%)
Azithromycin
Reference ranges of 25–75th centile for CSM and Mem B lymphocytes from Morbach et al. [15]
CSM class switched memory, HSCT hematopoietic stem cell transplantation
In the one patient (patient 5) for whom pre- and post-transplant IL17A levels were available, IL17A was higher post-transplant. For patients 2, 3, and 4, IL17A levels were present post-transplant, but lower than controls (Fig. 1).Fig. 1 IL17A levels in healthy controls and patients post-transplant. IL17A levels were measured by Luminex (Bio-Plex, Biorad, UK) 24 hours after stimulation in whole blood (96 Costar-F plates, 1:5 diluted in RPMI) of healthy controls (historical and contemporary) and patients (P2—blue diamonds, P3—blue triangles, P4—blue squares, P5 (pre and post HSCT) —blue circles). Stimulations were done using PHA (Sigma-Aldrich, 10 μg/ml) and compared with unstimulated medium samples (Med)
Patient 1 had significant pulmonary infection (complicated cystic bronchiectasis with Pseudomonas infection and widespread Aspergillus infection leading to pulmonary hypertension) with two lobectomies, complicated by development of bronchopleural fistula. He subsequently developed a Staphylococcus aureus pericarditis requiring surgical drainage, complicated by prolonged air leak. Transplantation at age 7 years was relatively uncomplicated. There was no viral re-activation, progression of chest lesions, or acute graft versus host disease. Six years post-transplant, his eczema had resolved and he was no longer getting significant respiratory infections. Immunoglobulin support has ceased, and normal vaccine and T-lymphocyte proliferative responses have been demonstrated. His scoliosis, exacerbated by his two previous left sided lobectomies, had deteriorated requiring spinal fusion surgery. Following this, his right lower airway integrity has been compromised, severely impairing his respiratory capacity. He now is reliant on overnight CPAP and can only ambulate short distances.
Patient 2 experienced frequent staphylococcal skin infections and cystic bronchiectasis infected with Pseudomonas, because of which transplantation was offered when aged 6 years. Despite 100% donor chimerism, the procedure was initially described as unsuccessful [7] because of continued elevated serum IgE. However, long-term follow-up confirmed sustained clinical improvement with no further respiratory or skin infections. Serum IgE levels diminished and remained reduced, and immunoglobulin support is no longer required. She developed thoracolumbar scoliosis, arterial hypertension, and gonadal failure. With 20 years follow-up, pulmonary status includes stable lingular bronchiectasis and non-progressive right upper lobe pulmonary cysts.
Patient 3 experienced frequent severe bronchopneumonias and progressive bronchiectasis despite immunoglobulin replacement, as well as osteopenia and lumbar vertebrae compression fractures. Transplantation at 13 years was relatively uneventful, and 13 years post-transplant, he demonstrates 100% donor chimerism with reduced serum IgE levels. Lung function has improved to normal values. Hemoptysis has stopped, and there is no computerized tomographic evidence of pulmonary disease progression. An increase in IL17A production after polyclonal stimulation was demonstrated post-HSCT (Fig. 2), and TH17 cells display normal response to IFN-γ and IL12 and normal IL12 production (data not shown). However, at 11 years post-HSCT, he sustained an anterior myocardial infarction, accompanied by classical clinical, electrocardiographic and biochemical signs and parameters. Angiography revealed proximal ectasia causing mid-vessel occlusion of his left anterior descending coronary artery but otherwise unobstructed coronary vessels. He was commenced on aspirin 75 mg for 3 months with rivaroxaban 2.5 mg BID for 3 years and clopidogrel 75 mg long term [12].Fig. 2 Pre- and post-transplant peripheral blood mononuclear cells demonstrate that IL17A is absent pre-transplant and present post-transplant (patient 3), with normal control and a negative control patient who has not been transplanted (p.V637M)
Patient 4 developed bronchiectasis, Staphylococcus aureus liver abscess, and recurrent skin abscesses. Severe multi-cystic and suppurative lung disease warranted left upper lobectomy. Following transplantation at age 14 years, repeat computerized tomography demonstrated significant widespread decrease in the number and size of previously reported large cysts, and there was a clinical improvement in the eczematous skin lesions. Post-transplant IL17A production was normal.
Patient 5 developed multiple abscesses and pneumatoceles during infancy leading to right upper lobectomy and broncho-pulmonary fistula at age 13 years. Pulmonary function was impaired prior to HSCT, aged 17 years. Non-invasive pulmonary Aspergillus infection persisted post-HSCT, treated with appropriate long-term anti-fungal therapy—at 7 months post-transplant, and Aspergillus pericarditis was diagnosed, which resolved with dual anti-fungal therapy by 16 months post-transplant. Thoracic computerized tomography demonstrated a dramatic improvement in lung appearance, and the residual right upper lobe cavity remained stable.
Patient 6 had persistent multiple skin infections with severe eczema and lymphadenitis through childhood and a single lung abscess. Additionally, a persistent Staphylococcus aureus hepatic abscess required surgical drainage on four occasions. Further to this, the patient required surgical excision of Candida albicans retroperitoneal lymphadenitis and a fungal liver abscess. The patient developed bowel perforation of unknown etiology at 6 years of age, before HSCT. An immune-mediated acute rejection of first graft was confirmed at day 13 post-transplant, followed by an autologous recovery. In this period, the patient experienced an enterococcal septic arthritis, with collapse of femoral head, gastrointestinal hemorrhage, and further episodes of fungal lymphadenitis. A second transplant procedure using a reduced toxicity treosulfan-based regimen was successful. The patient has good immune reconstitution and has ceased immunosuppression and immunoglobulin replacement.
Patient 7 was first referred to pediatric care at the age of 4 weeks due of eczema and skin infections, mainly on the face and scalp, from which Staphylococcus aureus was isolated and treated. Serum IgE levels were elevated prompting a diagnosis of Hyper IgE syndrome, confirmed genetically. The patient continued to have numerous recurrent skin abscesses, requiring drainage over 20 times per year despite antibiotic treatment and immunoglobulin replacement. He subsequently developed mandibular osteomyelitis. Pulmonary disease was limited to asthma only, with no significant infection. Transplant was uncomplicated, and at 20 months post-HSCT, his skin is much improved with no new infections. He has discontinued immunoglobulin and is awaiting vaccination.
Patient 8 presented as a neonate with staphylococcal skin infection and went on to develop recurrent skin infection, pneumonia, and otitis media. She demonstrated elevated serum IgE with poor pneumococcal antibody titers following vaccination and almost no TH17 cells. Her pulmonary disease progressed with findings of Aspergillus on bronchoalveolar lavage leading to a diagnosis of allergic bronchopulmonary aspergillosis, treated with antifungal therapy, corticosteroids, and anti-IgE monoclonal antibodies. She underwent HSCT aged 6 years with an uncomplicated course. One year post-HSCT, she reports only dry skin with no infection. Pulmonary function is stable and she is asymptomatic from cough or dyspnoea. Serum IgE has fallen to 392 kU/L. She remains on immunoglobulin replacement but has normal B lymphocyte numbers.
Discussion
Published data on the outcome of allogeneic HSCT for STAT3-HIES patients are limited, perhaps stemming from our initial report indicating non-utility [7]. A recent report by Oikonomopoulou et al. [13] summarizes the data of 7 patients transplanted between 1998 and 2018, one of which was the patient we originally reported in 2000 [7]. For three of these, the transplant indication was lymphoma [9, 10], and thus, although the STAT3-HIES was reported as cured, their transplant indication and management could be considered separately. The first of these patients died 6 months following transplant from interstitial pulmonary fibrosis, although with pre-existing abnormal immune parameters, including raised IgE, normalized post-transplant [10]. The other two patients, with follow up of 10 and 14 years, respectively, both with 100% donor chimerism, were reported to have normalized immunological parameters including a normalized proportion of TH17+ lymphocytes. Furthermore, other abnormalities associated with STAT3-HIES, including coarse facies and osteoporosis, were reported to have resolved, and there was no symptomatic development of STAT3-HIES-associated vasculopathy, although it is not clear if any screening was performed [9]. A further patient, transplanted because of a complicated infectious history, was reported after 42 months of follow-up. The patient had full donor chimerism and remained infection-free after discontinuing anti-microbial prophylaxis. Vaccine antibody responses were demonstrated and IgE normalized, STAT3 signaling was restored in hematopoietic-derived cells, and the percentage of Th17+ lymphocytes and central memory T lymphocytes to normal ranges was established [11]. Finally, 2 patients, transplanted for recurrent infection, were reported with 8 and 10 years of follow-up, respectively. Immunological parameters normalized and the infection frequency significantly diminished, but non-immunological features of STAT3-HIES remained, including a propensity to recurrent fractures and development of a new pneumatocele, associated with ≤50% donor chimerism [8].
Our current report extends follow-up of the initial patient to over 18 years and reports on a further 7 patients, one recently published in the context of new onset vasculopathy complications [12], thus contributing the largest series to date. Perhaps the most remarkable observation is that despite pre-transplant severe, progressive lung disease—itself a significant risk factor for HSCT outcome—as well as other significant pre-transplant sequelae, all patients in our series survived. Importantly, pulmonary disease has stabilized in all and improved in some, as demonstrated on clinical, functional, and radiological parameters (Table 1; Fig. 3). No peri-transplant pulmonary inflammatory complications were observed, unlike the post-HSCT course seen in many PID patients. GvHD was infrequent and insignificant. Notably, no patients have required further lung surgery post-HSCT. Most patients have remained on some antimicrobial prophylaxis, in view of treating physician concerns of recurrent infections in pre-existing bronchiectatic lungs—despite this, control of lung disease reported by patients has stabilized or improved. Aspergillus infection, likely from pre-existing colonization or infection, recurred through, or after transplantation in some, but did not cause the severe complications usually associated with transplant-associated aspergillosis. Other significant infections reduced in frequency or resolved completely, accepting that most patients remained on antimicrobial prophylaxis. Importantly, eczema improved in all patients and skin infections were abolished post-transplant.Fig. 3 Thoracic computerized tomography images from patient 4. a Images taken 1 year pre-transplant showing markedly abnormal lung parenchyma with large cysts, bullae, and cystic bronchiectasis particularly in the right lower lobe in association with cylindrical bronchiectasis, bronchial wall thickening, bronchocoeles, and reduced lung attenuation. b Images taken 1 year post-transplant showing several thin walled pulmonary “cysts,” similar to previous pre-transplant findings and are therefore most likely to result from previous infection and lung destruction. Some regions of parenchymal distortion and scarring are also similar. There is some bronchial dilatation and distortion in regions of scarring, but no convincing evidence of bronchiectasis
STAT3 plays an important part in normal endothelial cell biology [16], and endothelial dysfunction is known to contribute to initiation of transplant-related inflammatory complications [17]. It may be that the lack of severe post-HSCT inflammatory complications including acute graft-versus-host disease, observed in these patients and the previously reported cases, might be due to reduced endothelial cell upregulation, conferred by dominant negative STAT3-LOF mutations.
Although serum IgE levels remain above the adult reference range, they are substantially lower post-HSCT compared with pre-HSCT levels, although, in non-transplanted patients, IgE levels may fall over time [1]. More importantly, in those patients for whom data were available, normal TH17 function and associated cytokine responses are demonstrated (Fig. 1), confirming previous reports [8, 9, 11].
As expected, many extra-immune manifestations have not resolved post-HSCT, and patients retain coarse facial features, as well as bone-related complications, although it is noteworthy that only one patient has developed fractures post-transplantation. No patient has developed lymphoma to date. Critically, however, one patient (#3) recently experienced an anterior myocardial infarction, with evidence of thrombotic occlusion of dilated (ectatic) coronary vessels upon angiography. We estimated this patient’s 10-year risk of developing a heart attack or stroke, using the QRISK3 calculator, as 0.1%, which suggests that conventional cardiovascular risk factors were unlikely to account for the event, and disease-associated vasculopathy is more likely to be implicated [12]. Screening of coronary vasculature had not been performed prior to this event, and so it is unclear whether HSCT ameliorated, accelerated, or had no effect on these coronary vessels. Whether earlier HSCT will favorably alter the pre-disposition to vascular complications documented in these patients remains to be seen. Further research is required to establish the clinical significance of these wider complications of STAT3-HIES and capture the long-term impact of STAT3-HIES on patients’ quality of life across the spectrum of presentations.
Contrary to our previous assertion [7], this series, along with other published reports, further supports the notion that allogeneic HSCT can improve the immunological deficit, modify the pulmonary course in these patients, and improve the skin condition. The future challenge will be to identify which patients will benefit from early consideration of this therapy to prevent end-organ damage, reduce hospitalization and improve quality of life, as well as which conditioning regimen to use. The importance of complete or high donor chimerism is not established, and further work is required to determine optimum conditioning regimens and minimum effective donor chimerism level. Furthermore, it will be particularly important to determine whether HSCT can alter the risk of developing vascular anomalies, which may be associated with significant morbidity and mortality.
Author Contribution
ARG conceived the study. SCH, MAS, ARG, and CT collated and analyzed the data and wrote the manuscript; ZN, AW, PV, MJP, JM, AC, SJ, WAH, TJF, AJC, and MA provided clinical data; BG provided genetic analysis and flow cytometry data; RD and GB-M provided cytokine data; all authors contributed to writing of the manuscript and approved the final version.
Funding
CT is supported by The Job Research Foundation.
MJP is supported by the Welsh Clinical Academic Training (WCAT) programme and is a participant in the NIH Graduate Partnership Program.
BG receives support through the Deutsche Forschungsgemeinschaft (DFG) SFB1160/2_B5, under Germany’s Excellence Strategy (CIBSS—EXC-2189—Project ID 390939984, and RESIST—EXC 2155—Project ID 390874280); through the E-rare program of the EU, managed by the DFG, grant code GR1617/14-1/iPAD, and through the “Netzwerke Seltener Erkrankungen” of the German Ministry of Education and Research (BMBF), grant code: GAIN_ 01GM1910A. This work was supported in part by the Center for Chronic Immunodeficiency (CCI), Freiburg Center for Rare Diseases (FZSE).
Data availability
For further information please contact ARG: a.r.gennery@ncl.ac.uk.
Compliance with ethical standards
Ethics Approval and Consent to Participate
Not applicable
Consent for Publication
Not applicable
Competing Interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | 1 MG/KG | DrugDosageText | CC BY | 33523338 | 19,824,297 | 2021-07 |
What was the dosage of drug 'BUSULFAN'? | Hematopoietic Stem Cell Transplantation Resolves the Immune Deficit Associated with STAT3-Dominant-Negative Hyper-IgE Syndrome.
Autosomal dominant hyper-IgE syndrome caused by dominant-negative loss-of-function mutations in signal transducer and activator of transcription factor 3 (STAT3) (STAT3-HIES) is a rare primary immunodeficiency with multisystem pathology. The quality of life in patients with STAT3-HIES is determined by not only the progressive, life-limiting pulmonary disease, but also significant skin disease including recurrent infections and abscesses requiring surgery. Our early report indicated that hematopoietic stem cell transplantation might not be effective in patients with STAT3-HIES, although a few subsequent reports have reported successful outcomes. We update on progress of our patient now with over 18 years of follow-up and report on an additional seven cases, all of whom have survived despite demonstrating significant disease-related pathology prior to transplant. We conclude that effective cure of the immunological aspects of the disease and stabilization of even severe lung involvement may be achieved by allogeneic hematopoietic stem cell transplantation. Recurrent skin infections and abscesses may be abolished. Donor TH17 cells may produce comparable levels of IL17A to healthy controls. The future challenge will be to determine which patients should best be offered this treatment and at what point in their disease history.
Introduction
Autosomal dominant hyper-IgE syndrome is a rare primary immunodeficiency (PID) with multisystem pathology [1], caused by dominant-negative loss-of-function (LOF) mutations in signal transducer and activator of transcription factor 3 (STAT3) [2, 3] (STAT3-HIES). STAT3 is integral to lymphocyte development and differentiation. STAT3-deficient humans and mice have impaired cellular and humoral immune responses [4, 5], explaining the diverse immunologic manifestations [2–4]. In the context of infection, there is poor differentiation of T lymphocytes into TH17 cells, resulting in low IL17 and IL22 production [6], which contributes to susceptibility to encapsulated organisms and fungi.
HSCT was initially reported as unsuccessful in STAT3-HIES by our group [7]. Based on this impression, supportive treatment has been largely adopted [1], but many patients develop severe life-limiting pulmonary disease. However, over the years, eight case reports of allogeneic hematopoietic stem cell transplant (HSCT) for STAT3-HIES have been published [7–12], three of them performed following the diagnosis of non-Hodgkin’s B cell lymphoma, which is a known complication of this primary immunodeficiency [8]. In these eight cases, five patients had received myeloablative conditioning regimens, while three had reduced-intensity conditioning. Seven patients, including two with Hodgkin’s lymphoma, were recently reported as alive and well 4–20 years following report of HSCT [13], while one patient had died from the pre-existing lymphoma post-transplant [10].
We initially reported failure of HSCT to resolve or cure the immune defect in our first patient. However, we now acknowledge that STAT3-HIES patients have experienced sustained benefit from HSCT. At the time of our report, the molecular cause of STAT3-HIES was unknown, and we based our statements on failure to normalize the serum IgE level and an apparent failure to change the immunological defect. We have now shown that the IL17A levels of that patient approaches normal (although not measured pre-transplant) and memory B-lymphocytes are present. We now report a series of eight patients successfully treated with HSCT in the UK, including the long-term follow up of our previously reported patient [7].
Methods
We conducted a retrospective review of medical records of STAT3-HIES patients from two UK transplant centers for PID. We included only patients with confirmed dominant-negative STAT3 mutations who have undergone allogeneic HSCT. We recorded pre-transplant co-morbidities, conditioning, outcome, and on-going co-morbidities in eight patients who received nine transplants.
In selected patients for whom samples were available, IL17A levels were measured by Luminex (Bio-Plex, Biorad, UK) [14], 24 hours after stimulation in whole blood (96 Costar-F plates, 1:5 diluted in RPMI) of healthy controls and patients. Stimulations were performed using PHA (Sigma-Aldrich, 10 μg/ml) and compared with unstimulated medium samples. Data were compared with historic controls, which had been stimulated under identical conditions. P values were calculated using the two-tailed Mann-Whitney test or the Wilcoxon matched pairs test, excluding the data of P5 before HSCT.
Parents, and, where appropriate, patients consented to the procedure and data collection.
Results
Transplants were performed between 1996 and 2019. Demographic data, genetic mutation, and pre-HSCT clinical status are summarized in Table 1. All patients had dominant loss-of-function mutations in STAT3 with a classical clinical phenotype, and all had significant lung or skin-related complications prior to HSCT.Table 1 Patient demographic features and pre- and post-HSCT clinical details
Patient no.; sex Age at HSCT (years) STAT3 Heterozygous mutation Skin disease Lung disease and PFTs Fractures; other skeletal disease Infection; other Issues
Pre-HSCT Post-HSCT Pre-HSCT Post-HSCT Pre-HSCT Post-HSCT Pre-HSCT Post-HSCT
1
M
7 c.1909 G>A p.V637M Yes Normal Left upper and lower lobectomies with bronchopleural fistula; bilateral bronchiectasis; chronic Aspergillus infection; pulmonary hypertension
FEV1 47%
FVC 51%
Stable appearance on CT: bronchiectasis persist
Nocturnal CPAP for lobar collapse post-scoliosis repair with limited exercise tolerance
FEV1 20%
FVC 23%
Yes 2 further fractures at 3–4 years post-HSCT
Development of scoliosis requiring spinal fusion
Staphylococcus aureus pericarditis -
2
F
6 c.1771 A>G p.K591E Yes Normal Recurrent Pseudomonas lung infection with cyst formation
Not done
Stable; no progression of pulmonary cysts
FEV1 95%
FVC 88%
No Development of scoliosis - Gonadal failure following myeloablative conditioning
Arterial hypertension
3
M
13 c.1144 C>T p.R382W Yes Normal Severe and recurrent pneumonia with bronchiectasis
FEV1 63%
FVC 70%
Stable appearance on CT
No further hemoptysis
FEV1 83%
FVC 71%
Yes No - ST segment elevation myocardial infarction aged 26 years (13 years post-HSCT)
4
M
14 c.1144 C>T p.R382W Yes
Pustular dermatitis
Dry skin, no infection Bronchiectasis with multi-cystic lung disease, leading to left lobectomy
FEV1 28%
FVC 26%
Significant improvement in pulmonary cystic disease and resolution in right lower lobe bronchial thickening on CT
FEV1 65%
FVC 74%
Yes No Staphylococcus aureus liver abscess Autoimmune neutropenia
5
F
17 c.1144 C>T p.R382W Yes
Persistent infected czema
Normal Pneumatocoele leading to left lobectomy
FEV1 53%
FVC 67%
Improvement in lung appearance on CT
FEV1 51%
FVC 67%
Yes No - Aspergillus perdicarditis at 7 months post-HSCT resolved by 16 months post-HSCT
6
M
18 c.1110 A>G D371_G380del Yes
Eczema, pustular dermatitis
Resolution of previous chronic infection Lung abscess; pulmonary TB
FEV1 89%
FVC 90%
Stable CXR changes
Not done
No
Retained primary dentition
Enterococcal septic arthritis with collapse of femoral head Recurrent Staphylococcus aureus liver abscess
Candida retroperitoneal lymphadenitis and liver abscess
Early gastrointestinal bleed in post-transplant period
Medication-related nephrotoxicity
6
2nd HSCT
18
7
M
13 c.1144 C>G p.R382G Yes
Multiple skin abscesses
Dry skin, no infection Minimal
FEV1 89%
FVC 90%
Improvement in symptoms and exercise tolerance
Not done
No
Retained primary dentition
No Osteomyelitis of mandible -
8
F
6 c.1144 C>T p.R382W Yes
Eczema, Multiple skin abscesses
Dry skin, no infection Severe bronchiectasis bilaterally with broncho-pulmonary aspergillosis
FEV1 84%
FVC 92%
Improvement in symptoms
FEV1 82.7%FVC 78.4%
No No - -
Details of conditioning regimen, cell source, and graft-versus-host disease (GvHD) prophylaxis are detailed in Table 2. One patient received conventional myeloablative conditioning, four received reduced-toxicity myeloablative conditioning, and three received reduced intensity conditioning, one of whom rejected and was successfully re-transplanted following a reduced-toxicity myeloablative regimen (patient six). All inoculi were matched at 10/10 HLA-loci, apart from the first product for patient six, which was a 9/10 match (DQ mismatch).Table 2 Patient transplant demographics
Patient Follow-up Cell source; HLA Match Conditioning regimen GvHD prophylaxis Acute GvHD Latest donor chimerism
1 6 years URD PBSC
10/10
Alemtuzumab 1mg/kg
Fludarabine 150mg/m2
Melphalan 140mg/m2
CSA
MMF
- CD15 55%
CD19 55%
CD3 86%
2 20 years URD BM
10/10
Alemtuzumab 1mg/kg busulphan 16mg/kg
Cyclophosphamide 200mg/kg
CSA Grade 1 skin WB 100%
3 11 years URD BM
10/10
Alemtuzumab 1mg/kg
Fludarabine 150mg/m2
Melphalan 140mg/kg
CSA
MMF
- WB 100%
4 3 years MSD PBSC
10/10
Alemtuzumab 1mg/kg
Treosulfan 42g/m2
Fludarabine150mg/m2
CSA
MMF
Grade 1 skin CD15 100%
CD19 100%
CD3 91%
5 3 years URD PBSC
10/10
Alemtuzumab 1mg/kg
Fludarabine 150mg/m2
Treosulphan 42g/m2
CSA
MMF
Grade 1 skin WB 100%
6 - Mismatched URD PBSC
9/10
(DQ mismatch)
Alemtuzumab 60mg
Fludarabine 150mg/m2
Melphalan 140mg/m2
CSA - Hyperacute rejection D+13
2 years URD BM
10/10
ATG Fludarabine 150mg/m2
Treosulphan 42g/m2
Thiotepa 10mg/kg
CSA
MMF
- WB 100%
7 20 months URD PBSC
10/10
Alemtuzumab 1mg/kg
Fludarabine 150mg/m2
Treosulphan 42g/m2
CSA
MMF
- WB 100%
8 15 months MSD BM
10/10
Alemtuzumab 1mg/kg
Fludarabine 150mg/m2
Treosulphan 42g/m2
CSA
MMF
- CD15 96%
CD19 94%
CD3 94%
All patients survived and no patient experienced significant GvHD. Seven patients had complete or high level (>90%) donor chimerism and one had partial chimerism; however, all had improvement in immune phenotype, with a reduction in clinical symptoms, halting of progression of lung disease and improvement in skin infections. Non-immune manifestations showed variable improvement, with one patient developing further fractures and two patients demonstrating worsening scoliosis post-transplant. One patient has recently had vasculopathy with an ST segment elevation myocardial infarction with ectatic coronary vasculature [12]. Patient clinical status post-HSCT are summarized in Table 3.Table 3 Patient immunological data pre- and post-HSCT
Patient IgE (kU/L) IVIG given Vaccine responses; CSM/Mem B lymphocytes (25–75th centile reference range) Antimicrobial prophylaxis post-HSCT
Pre-HSCT Post-HSCT Pre-HSCT Post-HSCT Pre-HSCT Post-HSCT
1 4007 1720 Yes No Normal tetanus, absent HiB and pneumococcus
-
Normal
-
Voriconazole; azithromycin
2 75,000 2641 Yes No Normal
-
Normal
CSM B 9% (9.2–18.9%)
Mem B 13% (13.4–21.4%)
Azithromycin
3 >6000 176 Yes No Normal
-
Normal
-
Doxycycline
4 81,097 11,813 Yes No Normal
CSM B 1% (3.3–9.6%)
Mem B 3% (4.6–10.2%)
Normal
CSM B 1% (3.3–9.6%)
Mem B 3% (4.6–10.2%)
Azithromycin
5 4487 1939 No No Normal
CSM B 1% (3.3–9.6%)
Mem B 3% (4.6–10.2%)
Normal
CSM B 2% (7.2–12.7%)
Mem B 7% (7.4–13.9%)
Posaconazole; nebulized amphotericin B; azithromycin
6 143,000 - Yes No Normal
CSM B 0.4% (3.3–9.6%)
-
-
-
7 >5000 1636 Yes No Normal
-
In progress
Mem B cells 1.6% (3.3–9.6%)
-
8 1880–11,756 392 Yes Yes Normal tetanus and HiB, absent PPSV23
CSM B 2.6% (5.2–12.1%)
(On Ig)
CSM B 3% (5.2–12.1%)
Mem B 2% (7.5–12.4%)
Azithromycin
Reference ranges of 25–75th centile for CSM and Mem B lymphocytes from Morbach et al. [15]
CSM class switched memory, HSCT hematopoietic stem cell transplantation
In the one patient (patient 5) for whom pre- and post-transplant IL17A levels were available, IL17A was higher post-transplant. For patients 2, 3, and 4, IL17A levels were present post-transplant, but lower than controls (Fig. 1).Fig. 1 IL17A levels in healthy controls and patients post-transplant. IL17A levels were measured by Luminex (Bio-Plex, Biorad, UK) 24 hours after stimulation in whole blood (96 Costar-F plates, 1:5 diluted in RPMI) of healthy controls (historical and contemporary) and patients (P2—blue diamonds, P3—blue triangles, P4—blue squares, P5 (pre and post HSCT) —blue circles). Stimulations were done using PHA (Sigma-Aldrich, 10 μg/ml) and compared with unstimulated medium samples (Med)
Patient 1 had significant pulmonary infection (complicated cystic bronchiectasis with Pseudomonas infection and widespread Aspergillus infection leading to pulmonary hypertension) with two lobectomies, complicated by development of bronchopleural fistula. He subsequently developed a Staphylococcus aureus pericarditis requiring surgical drainage, complicated by prolonged air leak. Transplantation at age 7 years was relatively uncomplicated. There was no viral re-activation, progression of chest lesions, or acute graft versus host disease. Six years post-transplant, his eczema had resolved and he was no longer getting significant respiratory infections. Immunoglobulin support has ceased, and normal vaccine and T-lymphocyte proliferative responses have been demonstrated. His scoliosis, exacerbated by his two previous left sided lobectomies, had deteriorated requiring spinal fusion surgery. Following this, his right lower airway integrity has been compromised, severely impairing his respiratory capacity. He now is reliant on overnight CPAP and can only ambulate short distances.
Patient 2 experienced frequent staphylococcal skin infections and cystic bronchiectasis infected with Pseudomonas, because of which transplantation was offered when aged 6 years. Despite 100% donor chimerism, the procedure was initially described as unsuccessful [7] because of continued elevated serum IgE. However, long-term follow-up confirmed sustained clinical improvement with no further respiratory or skin infections. Serum IgE levels diminished and remained reduced, and immunoglobulin support is no longer required. She developed thoracolumbar scoliosis, arterial hypertension, and gonadal failure. With 20 years follow-up, pulmonary status includes stable lingular bronchiectasis and non-progressive right upper lobe pulmonary cysts.
Patient 3 experienced frequent severe bronchopneumonias and progressive bronchiectasis despite immunoglobulin replacement, as well as osteopenia and lumbar vertebrae compression fractures. Transplantation at 13 years was relatively uneventful, and 13 years post-transplant, he demonstrates 100% donor chimerism with reduced serum IgE levels. Lung function has improved to normal values. Hemoptysis has stopped, and there is no computerized tomographic evidence of pulmonary disease progression. An increase in IL17A production after polyclonal stimulation was demonstrated post-HSCT (Fig. 2), and TH17 cells display normal response to IFN-γ and IL12 and normal IL12 production (data not shown). However, at 11 years post-HSCT, he sustained an anterior myocardial infarction, accompanied by classical clinical, electrocardiographic and biochemical signs and parameters. Angiography revealed proximal ectasia causing mid-vessel occlusion of his left anterior descending coronary artery but otherwise unobstructed coronary vessels. He was commenced on aspirin 75 mg for 3 months with rivaroxaban 2.5 mg BID for 3 years and clopidogrel 75 mg long term [12].Fig. 2 Pre- and post-transplant peripheral blood mononuclear cells demonstrate that IL17A is absent pre-transplant and present post-transplant (patient 3), with normal control and a negative control patient who has not been transplanted (p.V637M)
Patient 4 developed bronchiectasis, Staphylococcus aureus liver abscess, and recurrent skin abscesses. Severe multi-cystic and suppurative lung disease warranted left upper lobectomy. Following transplantation at age 14 years, repeat computerized tomography demonstrated significant widespread decrease in the number and size of previously reported large cysts, and there was a clinical improvement in the eczematous skin lesions. Post-transplant IL17A production was normal.
Patient 5 developed multiple abscesses and pneumatoceles during infancy leading to right upper lobectomy and broncho-pulmonary fistula at age 13 years. Pulmonary function was impaired prior to HSCT, aged 17 years. Non-invasive pulmonary Aspergillus infection persisted post-HSCT, treated with appropriate long-term anti-fungal therapy—at 7 months post-transplant, and Aspergillus pericarditis was diagnosed, which resolved with dual anti-fungal therapy by 16 months post-transplant. Thoracic computerized tomography demonstrated a dramatic improvement in lung appearance, and the residual right upper lobe cavity remained stable.
Patient 6 had persistent multiple skin infections with severe eczema and lymphadenitis through childhood and a single lung abscess. Additionally, a persistent Staphylococcus aureus hepatic abscess required surgical drainage on four occasions. Further to this, the patient required surgical excision of Candida albicans retroperitoneal lymphadenitis and a fungal liver abscess. The patient developed bowel perforation of unknown etiology at 6 years of age, before HSCT. An immune-mediated acute rejection of first graft was confirmed at day 13 post-transplant, followed by an autologous recovery. In this period, the patient experienced an enterococcal septic arthritis, with collapse of femoral head, gastrointestinal hemorrhage, and further episodes of fungal lymphadenitis. A second transplant procedure using a reduced toxicity treosulfan-based regimen was successful. The patient has good immune reconstitution and has ceased immunosuppression and immunoglobulin replacement.
Patient 7 was first referred to pediatric care at the age of 4 weeks due of eczema and skin infections, mainly on the face and scalp, from which Staphylococcus aureus was isolated and treated. Serum IgE levels were elevated prompting a diagnosis of Hyper IgE syndrome, confirmed genetically. The patient continued to have numerous recurrent skin abscesses, requiring drainage over 20 times per year despite antibiotic treatment and immunoglobulin replacement. He subsequently developed mandibular osteomyelitis. Pulmonary disease was limited to asthma only, with no significant infection. Transplant was uncomplicated, and at 20 months post-HSCT, his skin is much improved with no new infections. He has discontinued immunoglobulin and is awaiting vaccination.
Patient 8 presented as a neonate with staphylococcal skin infection and went on to develop recurrent skin infection, pneumonia, and otitis media. She demonstrated elevated serum IgE with poor pneumococcal antibody titers following vaccination and almost no TH17 cells. Her pulmonary disease progressed with findings of Aspergillus on bronchoalveolar lavage leading to a diagnosis of allergic bronchopulmonary aspergillosis, treated with antifungal therapy, corticosteroids, and anti-IgE monoclonal antibodies. She underwent HSCT aged 6 years with an uncomplicated course. One year post-HSCT, she reports only dry skin with no infection. Pulmonary function is stable and she is asymptomatic from cough or dyspnoea. Serum IgE has fallen to 392 kU/L. She remains on immunoglobulin replacement but has normal B lymphocyte numbers.
Discussion
Published data on the outcome of allogeneic HSCT for STAT3-HIES patients are limited, perhaps stemming from our initial report indicating non-utility [7]. A recent report by Oikonomopoulou et al. [13] summarizes the data of 7 patients transplanted between 1998 and 2018, one of which was the patient we originally reported in 2000 [7]. For three of these, the transplant indication was lymphoma [9, 10], and thus, although the STAT3-HIES was reported as cured, their transplant indication and management could be considered separately. The first of these patients died 6 months following transplant from interstitial pulmonary fibrosis, although with pre-existing abnormal immune parameters, including raised IgE, normalized post-transplant [10]. The other two patients, with follow up of 10 and 14 years, respectively, both with 100% donor chimerism, were reported to have normalized immunological parameters including a normalized proportion of TH17+ lymphocytes. Furthermore, other abnormalities associated with STAT3-HIES, including coarse facies and osteoporosis, were reported to have resolved, and there was no symptomatic development of STAT3-HIES-associated vasculopathy, although it is not clear if any screening was performed [9]. A further patient, transplanted because of a complicated infectious history, was reported after 42 months of follow-up. The patient had full donor chimerism and remained infection-free after discontinuing anti-microbial prophylaxis. Vaccine antibody responses were demonstrated and IgE normalized, STAT3 signaling was restored in hematopoietic-derived cells, and the percentage of Th17+ lymphocytes and central memory T lymphocytes to normal ranges was established [11]. Finally, 2 patients, transplanted for recurrent infection, were reported with 8 and 10 years of follow-up, respectively. Immunological parameters normalized and the infection frequency significantly diminished, but non-immunological features of STAT3-HIES remained, including a propensity to recurrent fractures and development of a new pneumatocele, associated with ≤50% donor chimerism [8].
Our current report extends follow-up of the initial patient to over 18 years and reports on a further 7 patients, one recently published in the context of new onset vasculopathy complications [12], thus contributing the largest series to date. Perhaps the most remarkable observation is that despite pre-transplant severe, progressive lung disease—itself a significant risk factor for HSCT outcome—as well as other significant pre-transplant sequelae, all patients in our series survived. Importantly, pulmonary disease has stabilized in all and improved in some, as demonstrated on clinical, functional, and radiological parameters (Table 1; Fig. 3). No peri-transplant pulmonary inflammatory complications were observed, unlike the post-HSCT course seen in many PID patients. GvHD was infrequent and insignificant. Notably, no patients have required further lung surgery post-HSCT. Most patients have remained on some antimicrobial prophylaxis, in view of treating physician concerns of recurrent infections in pre-existing bronchiectatic lungs—despite this, control of lung disease reported by patients has stabilized or improved. Aspergillus infection, likely from pre-existing colonization or infection, recurred through, or after transplantation in some, but did not cause the severe complications usually associated with transplant-associated aspergillosis. Other significant infections reduced in frequency or resolved completely, accepting that most patients remained on antimicrobial prophylaxis. Importantly, eczema improved in all patients and skin infections were abolished post-transplant.Fig. 3 Thoracic computerized tomography images from patient 4. a Images taken 1 year pre-transplant showing markedly abnormal lung parenchyma with large cysts, bullae, and cystic bronchiectasis particularly in the right lower lobe in association with cylindrical bronchiectasis, bronchial wall thickening, bronchocoeles, and reduced lung attenuation. b Images taken 1 year post-transplant showing several thin walled pulmonary “cysts,” similar to previous pre-transplant findings and are therefore most likely to result from previous infection and lung destruction. Some regions of parenchymal distortion and scarring are also similar. There is some bronchial dilatation and distortion in regions of scarring, but no convincing evidence of bronchiectasis
STAT3 plays an important part in normal endothelial cell biology [16], and endothelial dysfunction is known to contribute to initiation of transplant-related inflammatory complications [17]. It may be that the lack of severe post-HSCT inflammatory complications including acute graft-versus-host disease, observed in these patients and the previously reported cases, might be due to reduced endothelial cell upregulation, conferred by dominant negative STAT3-LOF mutations.
Although serum IgE levels remain above the adult reference range, they are substantially lower post-HSCT compared with pre-HSCT levels, although, in non-transplanted patients, IgE levels may fall over time [1]. More importantly, in those patients for whom data were available, normal TH17 function and associated cytokine responses are demonstrated (Fig. 1), confirming previous reports [8, 9, 11].
As expected, many extra-immune manifestations have not resolved post-HSCT, and patients retain coarse facial features, as well as bone-related complications, although it is noteworthy that only one patient has developed fractures post-transplantation. No patient has developed lymphoma to date. Critically, however, one patient (#3) recently experienced an anterior myocardial infarction, with evidence of thrombotic occlusion of dilated (ectatic) coronary vessels upon angiography. We estimated this patient’s 10-year risk of developing a heart attack or stroke, using the QRISK3 calculator, as 0.1%, which suggests that conventional cardiovascular risk factors were unlikely to account for the event, and disease-associated vasculopathy is more likely to be implicated [12]. Screening of coronary vasculature had not been performed prior to this event, and so it is unclear whether HSCT ameliorated, accelerated, or had no effect on these coronary vessels. Whether earlier HSCT will favorably alter the pre-disposition to vascular complications documented in these patients remains to be seen. Further research is required to establish the clinical significance of these wider complications of STAT3-HIES and capture the long-term impact of STAT3-HIES on patients’ quality of life across the spectrum of presentations.
Contrary to our previous assertion [7], this series, along with other published reports, further supports the notion that allogeneic HSCT can improve the immunological deficit, modify the pulmonary course in these patients, and improve the skin condition. The future challenge will be to identify which patients will benefit from early consideration of this therapy to prevent end-organ damage, reduce hospitalization and improve quality of life, as well as which conditioning regimen to use. The importance of complete or high donor chimerism is not established, and further work is required to determine optimum conditioning regimens and minimum effective donor chimerism level. Furthermore, it will be particularly important to determine whether HSCT can alter the risk of developing vascular anomalies, which may be associated with significant morbidity and mortality.
Author Contribution
ARG conceived the study. SCH, MAS, ARG, and CT collated and analyzed the data and wrote the manuscript; ZN, AW, PV, MJP, JM, AC, SJ, WAH, TJF, AJC, and MA provided clinical data; BG provided genetic analysis and flow cytometry data; RD and GB-M provided cytokine data; all authors contributed to writing of the manuscript and approved the final version.
Funding
CT is supported by The Job Research Foundation.
MJP is supported by the Welsh Clinical Academic Training (WCAT) programme and is a participant in the NIH Graduate Partnership Program.
BG receives support through the Deutsche Forschungsgemeinschaft (DFG) SFB1160/2_B5, under Germany’s Excellence Strategy (CIBSS—EXC-2189—Project ID 390939984, and RESIST—EXC 2155—Project ID 390874280); through the E-rare program of the EU, managed by the DFG, grant code GR1617/14-1/iPAD, and through the “Netzwerke Seltener Erkrankungen” of the German Ministry of Education and Research (BMBF), grant code: GAIN_ 01GM1910A. This work was supported in part by the Center for Chronic Immunodeficiency (CCI), Freiburg Center for Rare Diseases (FZSE).
Data availability
For further information please contact ARG: a.r.gennery@ncl.ac.uk.
Compliance with ethical standards
Ethics Approval and Consent to Participate
Not applicable
Consent for Publication
Not applicable
Competing Interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | 16 MG/KG | DrugDosageText | CC BY | 33523338 | 19,824,297 | 2021-07 |
What was the dosage of drug 'CYCLOPHOSPHAMIDE'? | Hematopoietic Stem Cell Transplantation Resolves the Immune Deficit Associated with STAT3-Dominant-Negative Hyper-IgE Syndrome.
Autosomal dominant hyper-IgE syndrome caused by dominant-negative loss-of-function mutations in signal transducer and activator of transcription factor 3 (STAT3) (STAT3-HIES) is a rare primary immunodeficiency with multisystem pathology. The quality of life in patients with STAT3-HIES is determined by not only the progressive, life-limiting pulmonary disease, but also significant skin disease including recurrent infections and abscesses requiring surgery. Our early report indicated that hematopoietic stem cell transplantation might not be effective in patients with STAT3-HIES, although a few subsequent reports have reported successful outcomes. We update on progress of our patient now with over 18 years of follow-up and report on an additional seven cases, all of whom have survived despite demonstrating significant disease-related pathology prior to transplant. We conclude that effective cure of the immunological aspects of the disease and stabilization of even severe lung involvement may be achieved by allogeneic hematopoietic stem cell transplantation. Recurrent skin infections and abscesses may be abolished. Donor TH17 cells may produce comparable levels of IL17A to healthy controls. The future challenge will be to determine which patients should best be offered this treatment and at what point in their disease history.
Introduction
Autosomal dominant hyper-IgE syndrome is a rare primary immunodeficiency (PID) with multisystem pathology [1], caused by dominant-negative loss-of-function (LOF) mutations in signal transducer and activator of transcription factor 3 (STAT3) [2, 3] (STAT3-HIES). STAT3 is integral to lymphocyte development and differentiation. STAT3-deficient humans and mice have impaired cellular and humoral immune responses [4, 5], explaining the diverse immunologic manifestations [2–4]. In the context of infection, there is poor differentiation of T lymphocytes into TH17 cells, resulting in low IL17 and IL22 production [6], which contributes to susceptibility to encapsulated organisms and fungi.
HSCT was initially reported as unsuccessful in STAT3-HIES by our group [7]. Based on this impression, supportive treatment has been largely adopted [1], but many patients develop severe life-limiting pulmonary disease. However, over the years, eight case reports of allogeneic hematopoietic stem cell transplant (HSCT) for STAT3-HIES have been published [7–12], three of them performed following the diagnosis of non-Hodgkin’s B cell lymphoma, which is a known complication of this primary immunodeficiency [8]. In these eight cases, five patients had received myeloablative conditioning regimens, while three had reduced-intensity conditioning. Seven patients, including two with Hodgkin’s lymphoma, were recently reported as alive and well 4–20 years following report of HSCT [13], while one patient had died from the pre-existing lymphoma post-transplant [10].
We initially reported failure of HSCT to resolve or cure the immune defect in our first patient. However, we now acknowledge that STAT3-HIES patients have experienced sustained benefit from HSCT. At the time of our report, the molecular cause of STAT3-HIES was unknown, and we based our statements on failure to normalize the serum IgE level and an apparent failure to change the immunological defect. We have now shown that the IL17A levels of that patient approaches normal (although not measured pre-transplant) and memory B-lymphocytes are present. We now report a series of eight patients successfully treated with HSCT in the UK, including the long-term follow up of our previously reported patient [7].
Methods
We conducted a retrospective review of medical records of STAT3-HIES patients from two UK transplant centers for PID. We included only patients with confirmed dominant-negative STAT3 mutations who have undergone allogeneic HSCT. We recorded pre-transplant co-morbidities, conditioning, outcome, and on-going co-morbidities in eight patients who received nine transplants.
In selected patients for whom samples were available, IL17A levels were measured by Luminex (Bio-Plex, Biorad, UK) [14], 24 hours after stimulation in whole blood (96 Costar-F plates, 1:5 diluted in RPMI) of healthy controls and patients. Stimulations were performed using PHA (Sigma-Aldrich, 10 μg/ml) and compared with unstimulated medium samples. Data were compared with historic controls, which had been stimulated under identical conditions. P values were calculated using the two-tailed Mann-Whitney test or the Wilcoxon matched pairs test, excluding the data of P5 before HSCT.
Parents, and, where appropriate, patients consented to the procedure and data collection.
Results
Transplants were performed between 1996 and 2019. Demographic data, genetic mutation, and pre-HSCT clinical status are summarized in Table 1. All patients had dominant loss-of-function mutations in STAT3 with a classical clinical phenotype, and all had significant lung or skin-related complications prior to HSCT.Table 1 Patient demographic features and pre- and post-HSCT clinical details
Patient no.; sex Age at HSCT (years) STAT3 Heterozygous mutation Skin disease Lung disease and PFTs Fractures; other skeletal disease Infection; other Issues
Pre-HSCT Post-HSCT Pre-HSCT Post-HSCT Pre-HSCT Post-HSCT Pre-HSCT Post-HSCT
1
M
7 c.1909 G>A p.V637M Yes Normal Left upper and lower lobectomies with bronchopleural fistula; bilateral bronchiectasis; chronic Aspergillus infection; pulmonary hypertension
FEV1 47%
FVC 51%
Stable appearance on CT: bronchiectasis persist
Nocturnal CPAP for lobar collapse post-scoliosis repair with limited exercise tolerance
FEV1 20%
FVC 23%
Yes 2 further fractures at 3–4 years post-HSCT
Development of scoliosis requiring spinal fusion
Staphylococcus aureus pericarditis -
2
F
6 c.1771 A>G p.K591E Yes Normal Recurrent Pseudomonas lung infection with cyst formation
Not done
Stable; no progression of pulmonary cysts
FEV1 95%
FVC 88%
No Development of scoliosis - Gonadal failure following myeloablative conditioning
Arterial hypertension
3
M
13 c.1144 C>T p.R382W Yes Normal Severe and recurrent pneumonia with bronchiectasis
FEV1 63%
FVC 70%
Stable appearance on CT
No further hemoptysis
FEV1 83%
FVC 71%
Yes No - ST segment elevation myocardial infarction aged 26 years (13 years post-HSCT)
4
M
14 c.1144 C>T p.R382W Yes
Pustular dermatitis
Dry skin, no infection Bronchiectasis with multi-cystic lung disease, leading to left lobectomy
FEV1 28%
FVC 26%
Significant improvement in pulmonary cystic disease and resolution in right lower lobe bronchial thickening on CT
FEV1 65%
FVC 74%
Yes No Staphylococcus aureus liver abscess Autoimmune neutropenia
5
F
17 c.1144 C>T p.R382W Yes
Persistent infected czema
Normal Pneumatocoele leading to left lobectomy
FEV1 53%
FVC 67%
Improvement in lung appearance on CT
FEV1 51%
FVC 67%
Yes No - Aspergillus perdicarditis at 7 months post-HSCT resolved by 16 months post-HSCT
6
M
18 c.1110 A>G D371_G380del Yes
Eczema, pustular dermatitis
Resolution of previous chronic infection Lung abscess; pulmonary TB
FEV1 89%
FVC 90%
Stable CXR changes
Not done
No
Retained primary dentition
Enterococcal septic arthritis with collapse of femoral head Recurrent Staphylococcus aureus liver abscess
Candida retroperitoneal lymphadenitis and liver abscess
Early gastrointestinal bleed in post-transplant period
Medication-related nephrotoxicity
6
2nd HSCT
18
7
M
13 c.1144 C>G p.R382G Yes
Multiple skin abscesses
Dry skin, no infection Minimal
FEV1 89%
FVC 90%
Improvement in symptoms and exercise tolerance
Not done
No
Retained primary dentition
No Osteomyelitis of mandible -
8
F
6 c.1144 C>T p.R382W Yes
Eczema, Multiple skin abscesses
Dry skin, no infection Severe bronchiectasis bilaterally with broncho-pulmonary aspergillosis
FEV1 84%
FVC 92%
Improvement in symptoms
FEV1 82.7%FVC 78.4%
No No - -
Details of conditioning regimen, cell source, and graft-versus-host disease (GvHD) prophylaxis are detailed in Table 2. One patient received conventional myeloablative conditioning, four received reduced-toxicity myeloablative conditioning, and three received reduced intensity conditioning, one of whom rejected and was successfully re-transplanted following a reduced-toxicity myeloablative regimen (patient six). All inoculi were matched at 10/10 HLA-loci, apart from the first product for patient six, which was a 9/10 match (DQ mismatch).Table 2 Patient transplant demographics
Patient Follow-up Cell source; HLA Match Conditioning regimen GvHD prophylaxis Acute GvHD Latest donor chimerism
1 6 years URD PBSC
10/10
Alemtuzumab 1mg/kg
Fludarabine 150mg/m2
Melphalan 140mg/m2
CSA
MMF
- CD15 55%
CD19 55%
CD3 86%
2 20 years URD BM
10/10
Alemtuzumab 1mg/kg busulphan 16mg/kg
Cyclophosphamide 200mg/kg
CSA Grade 1 skin WB 100%
3 11 years URD BM
10/10
Alemtuzumab 1mg/kg
Fludarabine 150mg/m2
Melphalan 140mg/kg
CSA
MMF
- WB 100%
4 3 years MSD PBSC
10/10
Alemtuzumab 1mg/kg
Treosulfan 42g/m2
Fludarabine150mg/m2
CSA
MMF
Grade 1 skin CD15 100%
CD19 100%
CD3 91%
5 3 years URD PBSC
10/10
Alemtuzumab 1mg/kg
Fludarabine 150mg/m2
Treosulphan 42g/m2
CSA
MMF
Grade 1 skin WB 100%
6 - Mismatched URD PBSC
9/10
(DQ mismatch)
Alemtuzumab 60mg
Fludarabine 150mg/m2
Melphalan 140mg/m2
CSA - Hyperacute rejection D+13
2 years URD BM
10/10
ATG Fludarabine 150mg/m2
Treosulphan 42g/m2
Thiotepa 10mg/kg
CSA
MMF
- WB 100%
7 20 months URD PBSC
10/10
Alemtuzumab 1mg/kg
Fludarabine 150mg/m2
Treosulphan 42g/m2
CSA
MMF
- WB 100%
8 15 months MSD BM
10/10
Alemtuzumab 1mg/kg
Fludarabine 150mg/m2
Treosulphan 42g/m2
CSA
MMF
- CD15 96%
CD19 94%
CD3 94%
All patients survived and no patient experienced significant GvHD. Seven patients had complete or high level (>90%) donor chimerism and one had partial chimerism; however, all had improvement in immune phenotype, with a reduction in clinical symptoms, halting of progression of lung disease and improvement in skin infections. Non-immune manifestations showed variable improvement, with one patient developing further fractures and two patients demonstrating worsening scoliosis post-transplant. One patient has recently had vasculopathy with an ST segment elevation myocardial infarction with ectatic coronary vasculature [12]. Patient clinical status post-HSCT are summarized in Table 3.Table 3 Patient immunological data pre- and post-HSCT
Patient IgE (kU/L) IVIG given Vaccine responses; CSM/Mem B lymphocytes (25–75th centile reference range) Antimicrobial prophylaxis post-HSCT
Pre-HSCT Post-HSCT Pre-HSCT Post-HSCT Pre-HSCT Post-HSCT
1 4007 1720 Yes No Normal tetanus, absent HiB and pneumococcus
-
Normal
-
Voriconazole; azithromycin
2 75,000 2641 Yes No Normal
-
Normal
CSM B 9% (9.2–18.9%)
Mem B 13% (13.4–21.4%)
Azithromycin
3 >6000 176 Yes No Normal
-
Normal
-
Doxycycline
4 81,097 11,813 Yes No Normal
CSM B 1% (3.3–9.6%)
Mem B 3% (4.6–10.2%)
Normal
CSM B 1% (3.3–9.6%)
Mem B 3% (4.6–10.2%)
Azithromycin
5 4487 1939 No No Normal
CSM B 1% (3.3–9.6%)
Mem B 3% (4.6–10.2%)
Normal
CSM B 2% (7.2–12.7%)
Mem B 7% (7.4–13.9%)
Posaconazole; nebulized amphotericin B; azithromycin
6 143,000 - Yes No Normal
CSM B 0.4% (3.3–9.6%)
-
-
-
7 >5000 1636 Yes No Normal
-
In progress
Mem B cells 1.6% (3.3–9.6%)
-
8 1880–11,756 392 Yes Yes Normal tetanus and HiB, absent PPSV23
CSM B 2.6% (5.2–12.1%)
(On Ig)
CSM B 3% (5.2–12.1%)
Mem B 2% (7.5–12.4%)
Azithromycin
Reference ranges of 25–75th centile for CSM and Mem B lymphocytes from Morbach et al. [15]
CSM class switched memory, HSCT hematopoietic stem cell transplantation
In the one patient (patient 5) for whom pre- and post-transplant IL17A levels were available, IL17A was higher post-transplant. For patients 2, 3, and 4, IL17A levels were present post-transplant, but lower than controls (Fig. 1).Fig. 1 IL17A levels in healthy controls and patients post-transplant. IL17A levels were measured by Luminex (Bio-Plex, Biorad, UK) 24 hours after stimulation in whole blood (96 Costar-F plates, 1:5 diluted in RPMI) of healthy controls (historical and contemporary) and patients (P2—blue diamonds, P3—blue triangles, P4—blue squares, P5 (pre and post HSCT) —blue circles). Stimulations were done using PHA (Sigma-Aldrich, 10 μg/ml) and compared with unstimulated medium samples (Med)
Patient 1 had significant pulmonary infection (complicated cystic bronchiectasis with Pseudomonas infection and widespread Aspergillus infection leading to pulmonary hypertension) with two lobectomies, complicated by development of bronchopleural fistula. He subsequently developed a Staphylococcus aureus pericarditis requiring surgical drainage, complicated by prolonged air leak. Transplantation at age 7 years was relatively uncomplicated. There was no viral re-activation, progression of chest lesions, or acute graft versus host disease. Six years post-transplant, his eczema had resolved and he was no longer getting significant respiratory infections. Immunoglobulin support has ceased, and normal vaccine and T-lymphocyte proliferative responses have been demonstrated. His scoliosis, exacerbated by his two previous left sided lobectomies, had deteriorated requiring spinal fusion surgery. Following this, his right lower airway integrity has been compromised, severely impairing his respiratory capacity. He now is reliant on overnight CPAP and can only ambulate short distances.
Patient 2 experienced frequent staphylococcal skin infections and cystic bronchiectasis infected with Pseudomonas, because of which transplantation was offered when aged 6 years. Despite 100% donor chimerism, the procedure was initially described as unsuccessful [7] because of continued elevated serum IgE. However, long-term follow-up confirmed sustained clinical improvement with no further respiratory or skin infections. Serum IgE levels diminished and remained reduced, and immunoglobulin support is no longer required. She developed thoracolumbar scoliosis, arterial hypertension, and gonadal failure. With 20 years follow-up, pulmonary status includes stable lingular bronchiectasis and non-progressive right upper lobe pulmonary cysts.
Patient 3 experienced frequent severe bronchopneumonias and progressive bronchiectasis despite immunoglobulin replacement, as well as osteopenia and lumbar vertebrae compression fractures. Transplantation at 13 years was relatively uneventful, and 13 years post-transplant, he demonstrates 100% donor chimerism with reduced serum IgE levels. Lung function has improved to normal values. Hemoptysis has stopped, and there is no computerized tomographic evidence of pulmonary disease progression. An increase in IL17A production after polyclonal stimulation was demonstrated post-HSCT (Fig. 2), and TH17 cells display normal response to IFN-γ and IL12 and normal IL12 production (data not shown). However, at 11 years post-HSCT, he sustained an anterior myocardial infarction, accompanied by classical clinical, electrocardiographic and biochemical signs and parameters. Angiography revealed proximal ectasia causing mid-vessel occlusion of his left anterior descending coronary artery but otherwise unobstructed coronary vessels. He was commenced on aspirin 75 mg for 3 months with rivaroxaban 2.5 mg BID for 3 years and clopidogrel 75 mg long term [12].Fig. 2 Pre- and post-transplant peripheral blood mononuclear cells demonstrate that IL17A is absent pre-transplant and present post-transplant (patient 3), with normal control and a negative control patient who has not been transplanted (p.V637M)
Patient 4 developed bronchiectasis, Staphylococcus aureus liver abscess, and recurrent skin abscesses. Severe multi-cystic and suppurative lung disease warranted left upper lobectomy. Following transplantation at age 14 years, repeat computerized tomography demonstrated significant widespread decrease in the number and size of previously reported large cysts, and there was a clinical improvement in the eczematous skin lesions. Post-transplant IL17A production was normal.
Patient 5 developed multiple abscesses and pneumatoceles during infancy leading to right upper lobectomy and broncho-pulmonary fistula at age 13 years. Pulmonary function was impaired prior to HSCT, aged 17 years. Non-invasive pulmonary Aspergillus infection persisted post-HSCT, treated with appropriate long-term anti-fungal therapy—at 7 months post-transplant, and Aspergillus pericarditis was diagnosed, which resolved with dual anti-fungal therapy by 16 months post-transplant. Thoracic computerized tomography demonstrated a dramatic improvement in lung appearance, and the residual right upper lobe cavity remained stable.
Patient 6 had persistent multiple skin infections with severe eczema and lymphadenitis through childhood and a single lung abscess. Additionally, a persistent Staphylococcus aureus hepatic abscess required surgical drainage on four occasions. Further to this, the patient required surgical excision of Candida albicans retroperitoneal lymphadenitis and a fungal liver abscess. The patient developed bowel perforation of unknown etiology at 6 years of age, before HSCT. An immune-mediated acute rejection of first graft was confirmed at day 13 post-transplant, followed by an autologous recovery. In this period, the patient experienced an enterococcal septic arthritis, with collapse of femoral head, gastrointestinal hemorrhage, and further episodes of fungal lymphadenitis. A second transplant procedure using a reduced toxicity treosulfan-based regimen was successful. The patient has good immune reconstitution and has ceased immunosuppression and immunoglobulin replacement.
Patient 7 was first referred to pediatric care at the age of 4 weeks due of eczema and skin infections, mainly on the face and scalp, from which Staphylococcus aureus was isolated and treated. Serum IgE levels were elevated prompting a diagnosis of Hyper IgE syndrome, confirmed genetically. The patient continued to have numerous recurrent skin abscesses, requiring drainage over 20 times per year despite antibiotic treatment and immunoglobulin replacement. He subsequently developed mandibular osteomyelitis. Pulmonary disease was limited to asthma only, with no significant infection. Transplant was uncomplicated, and at 20 months post-HSCT, his skin is much improved with no new infections. He has discontinued immunoglobulin and is awaiting vaccination.
Patient 8 presented as a neonate with staphylococcal skin infection and went on to develop recurrent skin infection, pneumonia, and otitis media. She demonstrated elevated serum IgE with poor pneumococcal antibody titers following vaccination and almost no TH17 cells. Her pulmonary disease progressed with findings of Aspergillus on bronchoalveolar lavage leading to a diagnosis of allergic bronchopulmonary aspergillosis, treated with antifungal therapy, corticosteroids, and anti-IgE monoclonal antibodies. She underwent HSCT aged 6 years with an uncomplicated course. One year post-HSCT, she reports only dry skin with no infection. Pulmonary function is stable and she is asymptomatic from cough or dyspnoea. Serum IgE has fallen to 392 kU/L. She remains on immunoglobulin replacement but has normal B lymphocyte numbers.
Discussion
Published data on the outcome of allogeneic HSCT for STAT3-HIES patients are limited, perhaps stemming from our initial report indicating non-utility [7]. A recent report by Oikonomopoulou et al. [13] summarizes the data of 7 patients transplanted between 1998 and 2018, one of which was the patient we originally reported in 2000 [7]. For three of these, the transplant indication was lymphoma [9, 10], and thus, although the STAT3-HIES was reported as cured, their transplant indication and management could be considered separately. The first of these patients died 6 months following transplant from interstitial pulmonary fibrosis, although with pre-existing abnormal immune parameters, including raised IgE, normalized post-transplant [10]. The other two patients, with follow up of 10 and 14 years, respectively, both with 100% donor chimerism, were reported to have normalized immunological parameters including a normalized proportion of TH17+ lymphocytes. Furthermore, other abnormalities associated with STAT3-HIES, including coarse facies and osteoporosis, were reported to have resolved, and there was no symptomatic development of STAT3-HIES-associated vasculopathy, although it is not clear if any screening was performed [9]. A further patient, transplanted because of a complicated infectious history, was reported after 42 months of follow-up. The patient had full donor chimerism and remained infection-free after discontinuing anti-microbial prophylaxis. Vaccine antibody responses were demonstrated and IgE normalized, STAT3 signaling was restored in hematopoietic-derived cells, and the percentage of Th17+ lymphocytes and central memory T lymphocytes to normal ranges was established [11]. Finally, 2 patients, transplanted for recurrent infection, were reported with 8 and 10 years of follow-up, respectively. Immunological parameters normalized and the infection frequency significantly diminished, but non-immunological features of STAT3-HIES remained, including a propensity to recurrent fractures and development of a new pneumatocele, associated with ≤50% donor chimerism [8].
Our current report extends follow-up of the initial patient to over 18 years and reports on a further 7 patients, one recently published in the context of new onset vasculopathy complications [12], thus contributing the largest series to date. Perhaps the most remarkable observation is that despite pre-transplant severe, progressive lung disease—itself a significant risk factor for HSCT outcome—as well as other significant pre-transplant sequelae, all patients in our series survived. Importantly, pulmonary disease has stabilized in all and improved in some, as demonstrated on clinical, functional, and radiological parameters (Table 1; Fig. 3). No peri-transplant pulmonary inflammatory complications were observed, unlike the post-HSCT course seen in many PID patients. GvHD was infrequent and insignificant. Notably, no patients have required further lung surgery post-HSCT. Most patients have remained on some antimicrobial prophylaxis, in view of treating physician concerns of recurrent infections in pre-existing bronchiectatic lungs—despite this, control of lung disease reported by patients has stabilized or improved. Aspergillus infection, likely from pre-existing colonization or infection, recurred through, or after transplantation in some, but did not cause the severe complications usually associated with transplant-associated aspergillosis. Other significant infections reduced in frequency or resolved completely, accepting that most patients remained on antimicrobial prophylaxis. Importantly, eczema improved in all patients and skin infections were abolished post-transplant.Fig. 3 Thoracic computerized tomography images from patient 4. a Images taken 1 year pre-transplant showing markedly abnormal lung parenchyma with large cysts, bullae, and cystic bronchiectasis particularly in the right lower lobe in association with cylindrical bronchiectasis, bronchial wall thickening, bronchocoeles, and reduced lung attenuation. b Images taken 1 year post-transplant showing several thin walled pulmonary “cysts,” similar to previous pre-transplant findings and are therefore most likely to result from previous infection and lung destruction. Some regions of parenchymal distortion and scarring are also similar. There is some bronchial dilatation and distortion in regions of scarring, but no convincing evidence of bronchiectasis
STAT3 plays an important part in normal endothelial cell biology [16], and endothelial dysfunction is known to contribute to initiation of transplant-related inflammatory complications [17]. It may be that the lack of severe post-HSCT inflammatory complications including acute graft-versus-host disease, observed in these patients and the previously reported cases, might be due to reduced endothelial cell upregulation, conferred by dominant negative STAT3-LOF mutations.
Although serum IgE levels remain above the adult reference range, they are substantially lower post-HSCT compared with pre-HSCT levels, although, in non-transplanted patients, IgE levels may fall over time [1]. More importantly, in those patients for whom data were available, normal TH17 function and associated cytokine responses are demonstrated (Fig. 1), confirming previous reports [8, 9, 11].
As expected, many extra-immune manifestations have not resolved post-HSCT, and patients retain coarse facial features, as well as bone-related complications, although it is noteworthy that only one patient has developed fractures post-transplantation. No patient has developed lymphoma to date. Critically, however, one patient (#3) recently experienced an anterior myocardial infarction, with evidence of thrombotic occlusion of dilated (ectatic) coronary vessels upon angiography. We estimated this patient’s 10-year risk of developing a heart attack or stroke, using the QRISK3 calculator, as 0.1%, which suggests that conventional cardiovascular risk factors were unlikely to account for the event, and disease-associated vasculopathy is more likely to be implicated [12]. Screening of coronary vasculature had not been performed prior to this event, and so it is unclear whether HSCT ameliorated, accelerated, or had no effect on these coronary vessels. Whether earlier HSCT will favorably alter the pre-disposition to vascular complications documented in these patients remains to be seen. Further research is required to establish the clinical significance of these wider complications of STAT3-HIES and capture the long-term impact of STAT3-HIES on patients’ quality of life across the spectrum of presentations.
Contrary to our previous assertion [7], this series, along with other published reports, further supports the notion that allogeneic HSCT can improve the immunological deficit, modify the pulmonary course in these patients, and improve the skin condition. The future challenge will be to identify which patients will benefit from early consideration of this therapy to prevent end-organ damage, reduce hospitalization and improve quality of life, as well as which conditioning regimen to use. The importance of complete or high donor chimerism is not established, and further work is required to determine optimum conditioning regimens and minimum effective donor chimerism level. Furthermore, it will be particularly important to determine whether HSCT can alter the risk of developing vascular anomalies, which may be associated with significant morbidity and mortality.
Author Contribution
ARG conceived the study. SCH, MAS, ARG, and CT collated and analyzed the data and wrote the manuscript; ZN, AW, PV, MJP, JM, AC, SJ, WAH, TJF, AJC, and MA provided clinical data; BG provided genetic analysis and flow cytometry data; RD and GB-M provided cytokine data; all authors contributed to writing of the manuscript and approved the final version.
Funding
CT is supported by The Job Research Foundation.
MJP is supported by the Welsh Clinical Academic Training (WCAT) programme and is a participant in the NIH Graduate Partnership Program.
BG receives support through the Deutsche Forschungsgemeinschaft (DFG) SFB1160/2_B5, under Germany’s Excellence Strategy (CIBSS—EXC-2189—Project ID 390939984, and RESIST—EXC 2155—Project ID 390874280); through the E-rare program of the EU, managed by the DFG, grant code GR1617/14-1/iPAD, and through the “Netzwerke Seltener Erkrankungen” of the German Ministry of Education and Research (BMBF), grant code: GAIN_ 01GM1910A. This work was supported in part by the Center for Chronic Immunodeficiency (CCI), Freiburg Center for Rare Diseases (FZSE).
Data availability
For further information please contact ARG: a.r.gennery@ncl.ac.uk.
Compliance with ethical standards
Ethics Approval and Consent to Participate
Not applicable
Consent for Publication
Not applicable
Competing Interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. | 200 MG/KG | DrugDosageText | CC BY | 33523338 | 19,824,297 | 2021-07 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Disease progression'. | Chest Computed Tomography Findings of Eight Patients With Covid-19 Diagnosis: Case Series.
COVID-19 is an infectious disease caused by the virus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and declared a pandemic on March 11, 2020, by the world health organization. In Turkey, the first cases began to appear on March 11, 2020. After the cases in China, the appearance of ground glass with or without consolidation in the posterior and periphery of the bilateral lung is determined as the main finding of COVID-19. In this article, we wanted to share the tomography findings of eight patients who were diagnosed with COVID-19 in our emergency department and who had lung involvement.
COVID-19 is an infectious disease caused by the virus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and declared a pandemic on March 11, 2020, by the world health organization. In Turkey, the first cases began to appear on March 11, 2020. The number of patients diagnosed with COVID-19 in our country and all over the world is increasing day by day.
The clinical spectrum of COVID-19 infection is broad. The cases can be seen as asymptomatic, mild upper respiratory disease, mild pneumonia, severe pneumonia, and respiratory failure (1). SARS-CoV-2 infects respiratory epithelial cells as a result of the interaction of the S protein on its own with the cell angiotensin-converting enzyme 2 receptor (1).
In the diagnosis of COVID-19, real-time reverse transcription-polymerase chain reaction (RT-PCR) of viral nucleic acid is accepted as the reference standard test. However, recent studies have addressed the importance of chest computed tomography (CT) examination in COVID-19 patients with false-negative RT-PCR results (2). The sensitivity of computed tomography has been reported to be 98% (2).
In the patient data in China, where the disease was first seen, most patients had bilateral lung involvement. Lung lesions were widely distributed posteriorly, peripherally, and subpleurally. Bilateral widespread ground glass appearance with bilateral consolidation and without consolidation is considered the main finding of COVID-19 (2, 3, 4, 5).
In our country, COVID-19 cases were seen later than in other countries. In this article, we wanted to share the tomography findings of our first patients who were diagnosed with COVID-19 in our emergency department and who had lung involvement.
Case Reports
Case 1
A forty-one-year-old male patient was admitted to the emergency department with complaints of fever, cough, and shortness of breath for five days. The patient had no comorbidity and contact history. RT-PCR test was positive. The laboratory values of the patient at the time of admission were as follows: White Blood Count (WBC) 10100 µ / L, Lymphocyte 1400 µ / L, C-reactive protein (CRP) 49.66 mg / L and lactate dehydrogenase (LDH) 176 IU / L. In the tomography of the patient; There were extensive areas of diffuse ground-glass opacities (GGO) accompanied by diffuse placement, with both lungs apparent in the subpleural areas (Fig 1). In the treatment, the patient was given hydroxychloroquine (2x400 mg / first day, 2x200 mg / 4 days), azithromycin ( 2x250 mg/ first day, 1x250 mg / 4 days), oseltamivir ( 2x75 mg / 5 days). The patient was admitted to the intensive care unit after the oxygen saturations decreased four days later and connected to the ventilator. In intensive care, the patient received treatment with Favipiravir (2x1200 mg / 5 days). The patient was treated in the hospital for 15 days, two days in the intensive care unit, and then discharged.
Figure 1. Images of the lungs in a 41-year-old man with a positive RT-PCR show multiple bilateral consolidations (red arrows) with surrounding GGO (yellow arrows).
Case 2
A sixty-four-year-old male patient was admitted to the emergency department with complaints of fever and cough for one day. He had hypertension. The patient’s wife was hospitalized with the diagnosis of COVID-19. In the laboratory values of the patient; WBC was 8600 µ / L, Lymphocyte 1900 µ / L, CRP 65.28 mg / and LDH 416 IU / L. Lung tomography showed diffuse ground-glass densities with diffuse location, more prominent in both lung lower lobes and peripheral areas (Fig 2). In the treatment, the patient was given hydroxychloroquine (2x400 mg / first day, 2x200 mg / 4 days), azithromycin (2x250 mg / first day, 1x250 mg / 4 days), oseltamivir (2x75 mg / 5 days). No additional treatment was given. The patient was discharged seven days later.
Figure 2. Typical CT imaging features for COVID-19. Unenhanced, thin-section axial (A- C) images of the lungs in a 64-year-old man with a positive RT-PCR show bilateral, multifocal rounded and peripheral GGO.
Case 3
A fifty-six-year-old male patient had complaints of cough, headache, and myalgia for two days. The patient had no additional diseases. The patient returned from Germany a week ago. The patient had no fever. The patient’s laboratory values were as follows: WBC 7900 µ / L, Lymphocyte 600 µ / L, CRP 196 mg / L and LDH 396 IU / L. Tomography showed bilateral peripheral ground-glass opacities and consolidations, more prominent in the upper-lower lobes (Fig 3). Hydroxychloroquine (2x400 mg / first day, 2x200 mg / 4 days), azithromycin (2x250 mg/ first day, 1x250 mg / 4 days), oseltamivir (2x75 mg / 5 days) were given in the treatment. The patient was discharged nine days later.
Figure 3. Typical CT imaging features for COVID-19. Unenhanced, thin-section axial images of the lungs in a 56-year-old man with a positive RT-PCR (A-C) show bilateral, multifocal and peripheral GGO (arrows) with superimposed interlobular septal thickening and visible intralobular lines (“crazy-paving”).
Case 4
Fifty-seven-year-old male patient admitted to the emergency department with the complaint of fever, cough, and shortness of breath for four days. The patient applied to another hospital six days ago, and the RT-PCR test was performed there. Hydroxychloroquine and oseltamivir were started because their tomography was compatible with SARS-CoV-2. When the patient was under follow-up at home, when the dyspnea progressed, he applied to our emergency room. He had no comorbidity. The patient’s RT-PCR test was positive. In tomography; In both lung parenchyma, there were areas and consolidations with more common ground-glass density in the upper lobes (Fig 4). The laboratory values of the patient were as follows; WBC 25.000 µ / TL), Lymphocyte 800 µ / L, CRP 350.71 mg / L, LDH 409 IU / L and Ferritin 669 ng / mL. The patient was hospitalized in the intensive care unit. Favipiravir ( 2x1600 mg first day, 2x600 mg / 7 days), hydroxychloroquine (2x200 mg / 5 days) and Tocilizumab (1x400 mg / day, one time) were started in the patient, whose oxygen saturation was 92%. Seven days later, the patient was removed from the intensive care unit and transferred to the regular clinic. The patient was discharged on the 14th day of hospitalization.
Figure 4. A 56-year-old male COVID-19 patient. CT scan shows a patchy GGO with an air bubble sign (red arrow) in the posterior segment of the upper right lobe.
Case 5
Sixty-four-year-old male patient admitted to the emergency department with the complaint of back pain for five days. The patient had no fever and cough complaints. A kidney was removed due to malignancy. He had contact with tourists from abroad. Tomography findings: The bilateral lower lobes have more prominent peripheral ground-glass opacities and consolidations (Fig 5). The laboratory values of the patient were as follows; WBC 4.500 µ / TL), Lymphocyte 700 µ / L, CRP 38.9 mg / L, and LDH 225 IU / L. The patient had a fever on the second day of hospitalization. The COVID-19 PCR test was positive. The patient was given hydroxychloroquine (2x400 mg / first day, 2x200 mg / 4 days), azithromycin (2x250 mg / first day, 1x250 mg / 4 days), oseltamivir (2x75 mg / 5 days). On the seventh day of hospitalization, the patient was started on favipiravir (2x1600 mg / first day, 2x600 mg / 4 days) and vitamin C (1x1 g). The patient was discharged from the hospital 14 days later.
Figure 5. Unenhanced axial images showing patchy GGO with nonrounded morphology and no specific distribution, in a case of COVID-19 pneumonia (A, B)
Case 6
Sixty-five-year-old male patient admitted with the complaint of cough, shortness of breath, and weakness for six days. The patient came from Mecca a week ago. There is no history of chronic disease. The patient had no fever. The patient’s WBC (10.4 10x3µ / L), CRP (261 mg / L) and LDH (301 IU / L) levels were high. The lymphocyte value was 600 µ / L. In the patient’s lung tomography; there were consolidations, and paving stone views bilaterally in the lower lobes with peripheral ground-glass opacities (Fig 6). RT-PCR test was positive. Hydroxychloroquine (f2x400 mg/first day dose, 2x200 mg / 4 days), azithromycin (2x250 mg/ first day, 1x250 mg / 4 days), oseltamivir (2x75 mg / 5 days) were given in the treatment. On the third day of his admission, Tocilizumab (1x400 mg/day, one time) was given when ferritin level increased (1745 ng / mL), and Favipiravir (2x1600 mg / first day, 2x600 mg / 4 days) was given when hypoxia developed. On the fourth day of hospitalization, D-dimer level (58.28 mg / L) increased, and Enoxaparin was given to the patient. The patient was discharged 11 days later.
Figure 6. Unenhanced, thin-section axial (A- B) images of the lungs in a 65-year-old man with a positive RT-PCR show bilateral, posterior, peripheral GGO and consolidation. Air bronchograms are noticeable in the left lung.
Case 7
A forty-six-year-old male patient admitted to the emergency room with a complaint of cough and fever for three days. The patient has uncontrolled diabetes mellitus. RT-PCR test was positive. He works as a security guard in the hospital. Laboratory values of the patient at admission were as follows: WBC 9.400 µ / L), Lymphocyte 1700 µ / L, CRP 135.97 mg / L, LDH 302 IU / L. In the CT; in both lung parenchyma, there are patchy areas, and peripheral ground-glass opacities in the upper and lower lobes (Fig 7). The patient was started on hydroxychloroquine (2x400 mg / first day, 2x200 mg / 4 days), azithromycin (2x250 mg/ first day, 1x250 mg / 4 days), oseltamivir (2x75 mg / 5 days). On the fifth day of hospitalization, Favipiravir was started when hypoxia appeared, and on the sixth day, Tocilizumab was started when Ferritin level increased to 2205 ng / mL. The patient was discharged after 17 days when the RT-PCR test became negative.
Figure 7. CT scan shows large areas of GGO in the right and left upper lobe with multiple small vascular enlargement (red arrows).
Case 8
Fifty-year-old male patient admitted to the emergency department with the complaint of cough and shortness of breath for five days. The patient had no fever, comorbidity, and a history of contact. Laboratory values of the patient at admission were as follows: WBC 5800 µ / L, Lymphocyte 1500 µ / L, CRP 5.84 mg / L, LDH 306 IU / L. CT scan showed bilateral peripheral ground-glass opacities, paving stone views, areas with reverse halo sign appearance, and consolidations especially in lower lobes (Fig 8). In the treatment, hydroxychloroquine (2x400 mg / first day, 2x200 mg / 4 days), azithromycin ( 2x250 mg/ first day, 1x250 mg / 4 days), oseltamivir (2x75 mg / 5 days) were given. RT-PCR test was positive. The patient was discharged five days later.
Figure 8. Image of the lungs in a 50-year-old man with a positive RT-PCR show bilateral a reversed halo sign (red arrows) in the superior segment of the right and left lower lobe.
Discussion
In the patient data in China, where the disease was first seen, most patients had bilateral lung involvement. Zhou et al. reported that 191 patients had consolidation in 59%, ground-glass opacity in 71%, and bilateral infiltration in 75% (1).
Heshoui et al. reported that the dominant lesion was ground-glass opacity with indeterminate margins, air bronchograms, smooth or irregular interlobular or septal thickening, and thickening of the adjacent pleura (3).
In a study conducted in Korea, COVID-19 pneumonia generally manifested as pure ground-glass opacity to mixed ground-glass opacity and consolidative lesions in the bilateral peripheral posterior lungs (4). The shape of the injuries is typically ill-defined and patched or nodular. Irregular-confluent lesions are primarily distributed throughout the pleura, while nodular lesions are mostly distributed along with the bronchovascular bundles (4).
The study of Xu et al. showed bilateral, multifocal ground-glass opacities, with peripheral distribution in patients with SARS-CoV-2 pneumonia. More than half of the patients had multilobar involvement, and lesions were more common in the lower lobes (6).
Bilateral diffuse multifocal ground-glass opacities and consolidations were observed as typical tomography findings in our cases. Reticular pattern, air bronchogram, vascular enlargement, pleural thickening, crazy paving pattern, air bubble sign, halo sign were the other tomographic findings that we detected in our cases. Our findings are consistent with previous studies and may be helpful in the early detection of SARS-CoV-2 pneumonia.
Conclusion
As a result, the appearance of ground glass with or without consolidation in the posterior and periphery of the bilateral lung is likely the main finding of COVID-19. RT-PCR results may delay and could be false negative so CT seems to be helpful in the early diagnosis.
Conflict of Interest
Each author declares that he or she has no commercial associations (e.g. consultancies, stock ownership, equity interest, patent/licensing arrangement etc.) that might pose a conflict of interest in connection with the submitted article. | HYDROXYCHLOROQUINE, OSELTAMIVIR | DrugsGivenReaction | CC BY-NC-SA | 33525256 | 19,213,503 | 2021-01-19 |
What was the dosage of drug 'HYDROXYCHLOROQUINE'? | Chest Computed Tomography Findings of Eight Patients With Covid-19 Diagnosis: Case Series.
COVID-19 is an infectious disease caused by the virus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and declared a pandemic on March 11, 2020, by the world health organization. In Turkey, the first cases began to appear on March 11, 2020. After the cases in China, the appearance of ground glass with or without consolidation in the posterior and periphery of the bilateral lung is determined as the main finding of COVID-19. In this article, we wanted to share the tomography findings of eight patients who were diagnosed with COVID-19 in our emergency department and who had lung involvement.
COVID-19 is an infectious disease caused by the virus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and declared a pandemic on March 11, 2020, by the world health organization. In Turkey, the first cases began to appear on March 11, 2020. The number of patients diagnosed with COVID-19 in our country and all over the world is increasing day by day.
The clinical spectrum of COVID-19 infection is broad. The cases can be seen as asymptomatic, mild upper respiratory disease, mild pneumonia, severe pneumonia, and respiratory failure (1). SARS-CoV-2 infects respiratory epithelial cells as a result of the interaction of the S protein on its own with the cell angiotensin-converting enzyme 2 receptor (1).
In the diagnosis of COVID-19, real-time reverse transcription-polymerase chain reaction (RT-PCR) of viral nucleic acid is accepted as the reference standard test. However, recent studies have addressed the importance of chest computed tomography (CT) examination in COVID-19 patients with false-negative RT-PCR results (2). The sensitivity of computed tomography has been reported to be 98% (2).
In the patient data in China, where the disease was first seen, most patients had bilateral lung involvement. Lung lesions were widely distributed posteriorly, peripherally, and subpleurally. Bilateral widespread ground glass appearance with bilateral consolidation and without consolidation is considered the main finding of COVID-19 (2, 3, 4, 5).
In our country, COVID-19 cases were seen later than in other countries. In this article, we wanted to share the tomography findings of our first patients who were diagnosed with COVID-19 in our emergency department and who had lung involvement.
Case Reports
Case 1
A forty-one-year-old male patient was admitted to the emergency department with complaints of fever, cough, and shortness of breath for five days. The patient had no comorbidity and contact history. RT-PCR test was positive. The laboratory values of the patient at the time of admission were as follows: White Blood Count (WBC) 10100 µ / L, Lymphocyte 1400 µ / L, C-reactive protein (CRP) 49.66 mg / L and lactate dehydrogenase (LDH) 176 IU / L. In the tomography of the patient; There were extensive areas of diffuse ground-glass opacities (GGO) accompanied by diffuse placement, with both lungs apparent in the subpleural areas (Fig 1). In the treatment, the patient was given hydroxychloroquine (2x400 mg / first day, 2x200 mg / 4 days), azithromycin ( 2x250 mg/ first day, 1x250 mg / 4 days), oseltamivir ( 2x75 mg / 5 days). The patient was admitted to the intensive care unit after the oxygen saturations decreased four days later and connected to the ventilator. In intensive care, the patient received treatment with Favipiravir (2x1200 mg / 5 days). The patient was treated in the hospital for 15 days, two days in the intensive care unit, and then discharged.
Figure 1. Images of the lungs in a 41-year-old man with a positive RT-PCR show multiple bilateral consolidations (red arrows) with surrounding GGO (yellow arrows).
Case 2
A sixty-four-year-old male patient was admitted to the emergency department with complaints of fever and cough for one day. He had hypertension. The patient’s wife was hospitalized with the diagnosis of COVID-19. In the laboratory values of the patient; WBC was 8600 µ / L, Lymphocyte 1900 µ / L, CRP 65.28 mg / and LDH 416 IU / L. Lung tomography showed diffuse ground-glass densities with diffuse location, more prominent in both lung lower lobes and peripheral areas (Fig 2). In the treatment, the patient was given hydroxychloroquine (2x400 mg / first day, 2x200 mg / 4 days), azithromycin (2x250 mg / first day, 1x250 mg / 4 days), oseltamivir (2x75 mg / 5 days). No additional treatment was given. The patient was discharged seven days later.
Figure 2. Typical CT imaging features for COVID-19. Unenhanced, thin-section axial (A- C) images of the lungs in a 64-year-old man with a positive RT-PCR show bilateral, multifocal rounded and peripheral GGO.
Case 3
A fifty-six-year-old male patient had complaints of cough, headache, and myalgia for two days. The patient had no additional diseases. The patient returned from Germany a week ago. The patient had no fever. The patient’s laboratory values were as follows: WBC 7900 µ / L, Lymphocyte 600 µ / L, CRP 196 mg / L and LDH 396 IU / L. Tomography showed bilateral peripheral ground-glass opacities and consolidations, more prominent in the upper-lower lobes (Fig 3). Hydroxychloroquine (2x400 mg / first day, 2x200 mg / 4 days), azithromycin (2x250 mg/ first day, 1x250 mg / 4 days), oseltamivir (2x75 mg / 5 days) were given in the treatment. The patient was discharged nine days later.
Figure 3. Typical CT imaging features for COVID-19. Unenhanced, thin-section axial images of the lungs in a 56-year-old man with a positive RT-PCR (A-C) show bilateral, multifocal and peripheral GGO (arrows) with superimposed interlobular septal thickening and visible intralobular lines (“crazy-paving”).
Case 4
Fifty-seven-year-old male patient admitted to the emergency department with the complaint of fever, cough, and shortness of breath for four days. The patient applied to another hospital six days ago, and the RT-PCR test was performed there. Hydroxychloroquine and oseltamivir were started because their tomography was compatible with SARS-CoV-2. When the patient was under follow-up at home, when the dyspnea progressed, he applied to our emergency room. He had no comorbidity. The patient’s RT-PCR test was positive. In tomography; In both lung parenchyma, there were areas and consolidations with more common ground-glass density in the upper lobes (Fig 4). The laboratory values of the patient were as follows; WBC 25.000 µ / TL), Lymphocyte 800 µ / L, CRP 350.71 mg / L, LDH 409 IU / L and Ferritin 669 ng / mL. The patient was hospitalized in the intensive care unit. Favipiravir ( 2x1600 mg first day, 2x600 mg / 7 days), hydroxychloroquine (2x200 mg / 5 days) and Tocilizumab (1x400 mg / day, one time) were started in the patient, whose oxygen saturation was 92%. Seven days later, the patient was removed from the intensive care unit and transferred to the regular clinic. The patient was discharged on the 14th day of hospitalization.
Figure 4. A 56-year-old male COVID-19 patient. CT scan shows a patchy GGO with an air bubble sign (red arrow) in the posterior segment of the upper right lobe.
Case 5
Sixty-four-year-old male patient admitted to the emergency department with the complaint of back pain for five days. The patient had no fever and cough complaints. A kidney was removed due to malignancy. He had contact with tourists from abroad. Tomography findings: The bilateral lower lobes have more prominent peripheral ground-glass opacities and consolidations (Fig 5). The laboratory values of the patient were as follows; WBC 4.500 µ / TL), Lymphocyte 700 µ / L, CRP 38.9 mg / L, and LDH 225 IU / L. The patient had a fever on the second day of hospitalization. The COVID-19 PCR test was positive. The patient was given hydroxychloroquine (2x400 mg / first day, 2x200 mg / 4 days), azithromycin (2x250 mg / first day, 1x250 mg / 4 days), oseltamivir (2x75 mg / 5 days). On the seventh day of hospitalization, the patient was started on favipiravir (2x1600 mg / first day, 2x600 mg / 4 days) and vitamin C (1x1 g). The patient was discharged from the hospital 14 days later.
Figure 5. Unenhanced axial images showing patchy GGO with nonrounded morphology and no specific distribution, in a case of COVID-19 pneumonia (A, B)
Case 6
Sixty-five-year-old male patient admitted with the complaint of cough, shortness of breath, and weakness for six days. The patient came from Mecca a week ago. There is no history of chronic disease. The patient had no fever. The patient’s WBC (10.4 10x3µ / L), CRP (261 mg / L) and LDH (301 IU / L) levels were high. The lymphocyte value was 600 µ / L. In the patient’s lung tomography; there were consolidations, and paving stone views bilaterally in the lower lobes with peripheral ground-glass opacities (Fig 6). RT-PCR test was positive. Hydroxychloroquine (f2x400 mg/first day dose, 2x200 mg / 4 days), azithromycin (2x250 mg/ first day, 1x250 mg / 4 days), oseltamivir (2x75 mg / 5 days) were given in the treatment. On the third day of his admission, Tocilizumab (1x400 mg/day, one time) was given when ferritin level increased (1745 ng / mL), and Favipiravir (2x1600 mg / first day, 2x600 mg / 4 days) was given when hypoxia developed. On the fourth day of hospitalization, D-dimer level (58.28 mg / L) increased, and Enoxaparin was given to the patient. The patient was discharged 11 days later.
Figure 6. Unenhanced, thin-section axial (A- B) images of the lungs in a 65-year-old man with a positive RT-PCR show bilateral, posterior, peripheral GGO and consolidation. Air bronchograms are noticeable in the left lung.
Case 7
A forty-six-year-old male patient admitted to the emergency room with a complaint of cough and fever for three days. The patient has uncontrolled diabetes mellitus. RT-PCR test was positive. He works as a security guard in the hospital. Laboratory values of the patient at admission were as follows: WBC 9.400 µ / L), Lymphocyte 1700 µ / L, CRP 135.97 mg / L, LDH 302 IU / L. In the CT; in both lung parenchyma, there are patchy areas, and peripheral ground-glass opacities in the upper and lower lobes (Fig 7). The patient was started on hydroxychloroquine (2x400 mg / first day, 2x200 mg / 4 days), azithromycin (2x250 mg/ first day, 1x250 mg / 4 days), oseltamivir (2x75 mg / 5 days). On the fifth day of hospitalization, Favipiravir was started when hypoxia appeared, and on the sixth day, Tocilizumab was started when Ferritin level increased to 2205 ng / mL. The patient was discharged after 17 days when the RT-PCR test became negative.
Figure 7. CT scan shows large areas of GGO in the right and left upper lobe with multiple small vascular enlargement (red arrows).
Case 8
Fifty-year-old male patient admitted to the emergency department with the complaint of cough and shortness of breath for five days. The patient had no fever, comorbidity, and a history of contact. Laboratory values of the patient at admission were as follows: WBC 5800 µ / L, Lymphocyte 1500 µ / L, CRP 5.84 mg / L, LDH 306 IU / L. CT scan showed bilateral peripheral ground-glass opacities, paving stone views, areas with reverse halo sign appearance, and consolidations especially in lower lobes (Fig 8). In the treatment, hydroxychloroquine (2x400 mg / first day, 2x200 mg / 4 days), azithromycin ( 2x250 mg/ first day, 1x250 mg / 4 days), oseltamivir (2x75 mg / 5 days) were given. RT-PCR test was positive. The patient was discharged five days later.
Figure 8. Image of the lungs in a 50-year-old man with a positive RT-PCR show bilateral a reversed halo sign (red arrows) in the superior segment of the right and left lower lobe.
Discussion
In the patient data in China, where the disease was first seen, most patients had bilateral lung involvement. Zhou et al. reported that 191 patients had consolidation in 59%, ground-glass opacity in 71%, and bilateral infiltration in 75% (1).
Heshoui et al. reported that the dominant lesion was ground-glass opacity with indeterminate margins, air bronchograms, smooth or irregular interlobular or septal thickening, and thickening of the adjacent pleura (3).
In a study conducted in Korea, COVID-19 pneumonia generally manifested as pure ground-glass opacity to mixed ground-glass opacity and consolidative lesions in the bilateral peripheral posterior lungs (4). The shape of the injuries is typically ill-defined and patched or nodular. Irregular-confluent lesions are primarily distributed throughout the pleura, while nodular lesions are mostly distributed along with the bronchovascular bundles (4).
The study of Xu et al. showed bilateral, multifocal ground-glass opacities, with peripheral distribution in patients with SARS-CoV-2 pneumonia. More than half of the patients had multilobar involvement, and lesions were more common in the lower lobes (6).
Bilateral diffuse multifocal ground-glass opacities and consolidations were observed as typical tomography findings in our cases. Reticular pattern, air bronchogram, vascular enlargement, pleural thickening, crazy paving pattern, air bubble sign, halo sign were the other tomographic findings that we detected in our cases. Our findings are consistent with previous studies and may be helpful in the early detection of SARS-CoV-2 pneumonia.
Conclusion
As a result, the appearance of ground glass with or without consolidation in the posterior and periphery of the bilateral lung is likely the main finding of COVID-19. RT-PCR results may delay and could be false negative so CT seems to be helpful in the early diagnosis.
Conflict of Interest
Each author declares that he or she has no commercial associations (e.g. consultancies, stock ownership, equity interest, patent/licensing arrangement etc.) that might pose a conflict of interest in connection with the submitted article. | 2 X 200 MG , UNK | DrugDosageText | CC BY-NC-SA | 33525256 | 19,213,503 | 2021-01-19 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardiac failure congestive'. | Maintaining infliximab induced clinical remission with azathioprine and 5-aminosalicylates in acute severe steroid-refractory ulcerative colitis has lower cost and high efficacy (MIRACLE): a multicenter study.
Infliximab (IFX) has been used to induce and maintain remission in patients with severe steroid-refractory ulcerative colitis (UC). Long-term use of biologics in developing countries is limited by high cost and frequent side effects. An optimal maintenance strategy in these patients needs to be established.
A retrospective analysis of maintenance of clinical remission with combination of azathioprine (AZA) and 5-aminosalicylates (5-ASA) in patients with severe steroidrefractory UC where IFX (5 mg/kg intravenously at weeks 0, 2, 6) had been used only as an induction therapy was done at 2 centers in India. Primary outcome was the proportion of patients maintaining corticosteroid-free sustained clinical remission (SCR) at the end of study period. Rates of relapse and cost of therapy were also analyzed.
Of the 137 patients who received rescue IFX induction therapy, 77 (56.2%) achieved clinical remission (mean age 34.81 ± 13.32 years, 68.83% males, median follow-up 4 years, range 3 months to 6 years) and were included. Cumulative corticosteroid-free SCR was maintained in 68%, 59%, 42%, and 35% patients at 1, 2, 4, and 6 years respectively. Sixty-seven relapses were observed in 33 patients. Majority of the relapses (45/67, 67.16%) occurred within first 2 years of follow-up. Two relapses were managed with re-induction with IFX, one required colectomy, whereas all other responded to repeat course(s) of corticosteroids. Annual per capita maintenance therapy with 5-ASA and AZA was cheaper by US$ 4,526 compared to maintaining remission with IFX.
Clinical remission achieved with IFX induction therapy in severe steroid-refractory UC can be sustained over long time with a combination of AZA and 5-ASA.
pmcINTRODUCTION
Ulcerative colitis (UC) is a chronic inflammatory disease of the colon with a relapsing remitting course [1]. Acute severe exacerbations of the disease develop in 15% to 20% of the patients, requiring hospitalization and treatment with intravenous (IV) corticosteroids [2]. Though corticosteroids are effective in a majority of patients with severe UC, they are not a panpharmacon. Up to one-third of patients with acute severe UC may fail to respond to therapy with IV corticosteroids and hence require rescue therapy with IV cyclosporin A (CsA)/infliximab (IFX) or colectomy [3-7]. In patients where IFX is used as rescue therapy, continuation of an 8 weekly dosing schedule has been recommended for maintenance of remission. However, up to 30% of patients may not be able to continue IFX in the long run due to adverse events or a secondary loss of response [8,9]. Furthermore, the continued use of biologics for maintenance of remission is not feasible in developing countries where the health insurance coverage is minimal, placing significant economic burden on the patients. To sustain clinical remission in these patients, alternative maintenance therapies need to be studied. We present a multicenter experience of use of combination therapy with azathioprine (AZA) and 5-aminosalicylates (5-ASA) for maintenance of clinical remission in patients with acute severe steroid-refractory UC who achieved clinical remission with IFX induction regimen and IFX was stopped thereafter.
METHODS
1. Setting
This was a retrospective analysis of database from 2 tertiary care centers in north India; Dayanand Medical College and Hospital, Ludhiana and All India Institute of Medical Sciences, New Delhi. Patients with acute severe steroid-refractory UC who received IFX as a rescue induction therapy and subsequently maintained on 5-ASA and AZA between August 2005 and December 2017 were enrolled. The study was approved by Institutional Ethics Committee (IEC Nos. DMCH/R & D/2020/23 and IECPG-599/24.10.19) of both the institutions and performed in accordance with the principles of the Declaration of Helsinki. Written informed consent was obtained.
2. Study Population
Adult (≥ 18 years) patients with acute severe UC (defined as 6 or more stools with blood and 1 or more of the following hemoglobin < 10.5 g/dL, erythrocyte sedimentation rate [ESR] > 30 mm/hr, fever > 37.8°C, or tachycardia > 90/min; the Truelove Witts criteria) refractory to IV hydrocortisone (300–400 mg/day administered in 3 divided doses, used for 5–7 days) were offered rescue therapy with either IFX (originator, induction protocol: 5 mg/kg at weeks 0, 2 and 6)/CsA (2 mg/kg infusion for 5 days, followed by oral CsA acting as bridge to thiopurines); or colectomy. The current study is a retrospective analysis of treatment outcomes of the patients who opted for IFX as a rescue therapy and achieved clinical remission. Clinical remission was defined as partial Mayo score ≤ 1 at week 10 [10].
AZA was introduced/continued in all patients, whether AZA naïve or experienced, at the time of first dose of IFX induction regime. The patients who achieved clinical remission were followed for maintenance of corticosteroid-free sustained clinical remission (SCR) with combination therapy of AZA and 5-ASA. Corticosteroid-free SCR was defined as partial Mayo score ≤ 1 with absence of diarrhea and blood in stools and without need for new courses of corticosteroids or any other systemic drug (CsA, biologics, or investigational drugs) [11]. 5-ASA was used in a dose of 3.6–4.8 g/day and the dose of AZA was maintained at 1.5–2 mg/kg/day. All the patients were followed at an interval of 8–12 weeks, or earlier in case of worsening of symptoms. Disease activity (partial Mayo score) and concomitant pharmacotherapy were recorded for each visit. Patients with adverse events necessitating drug withdrawal were excluded.
Relapse was defined as partial Mayo score ≥ 3 [12]. In case of relapse, stool examination for infections including Clostridioides difficile; and IgM serology and histology for cytomegalovirus were performed. The management protocols for each relapse, including use of corticosteroids, biologics (IFX), CsA or surgery, were noted.
Patients with failure to achieve clinical remission with IFX induction therapy, incomplete induction protocol, active or latent tuberculosis, hepatitis B, hepatitis C, human immunodeficiency virus (HIV), pathogens on stool culture, contraindication to IFX or AZA according to labelling recommendations, previous use of multiple biologics, Crohn’s colitis/inflammatory bowel disease (IBD)-unclassified, pregnancy or lactation, and patients with missing data were excluded.
3. Cost-Benefit Analysis
Cost-benefit analysis of AZA plus 5-ASA was done in comparison to IFX maintenance. The cost of drug used in analysis was based on maximum retail price of the drugs. Annual expenditure (including the cost involved in treatment of relapses, hospitalization, rescue therapy and surgery) were estimated and compared between the 2 approaches.
4. Clinical Outcomes
The primary outcome was maintenance of corticosteroid-free SCR during the follow-up. Secondary outcomes included assessment of rates of relapses and their management and cost-benefit analysis.
5. Statistical Analysis
Descriptive statistics were provided with mean and standard deviation, median and interquartile range for continuous variables and frequency and percentage for categorical variables. Log-rank test was used to investigate the factors affecting relapse after cessation of IFX therapy. Using the standard α=0.05 cutoff, P<0.05 was considered statistically significant. Cumulative relapse-free survival (corticosteroid-free SCR) was calculated using Kaplan-Meier survival analysis. All statistical analyses were performed using Stata 12 (StataCorp. 2011. Stata Statistical Software: Release 12; StataCorp LP, College Station, TX, USA).
RESULTS
A total of 137 patients with acute severe UC were treated with IFX for inducing remission during the study period. Twenty-three patients (17.1%) did not respond to IFX and underwent colectomy, 5 (3.7%) had adverse events (tuberculosis: n=3; congestive heart failure: n=2) and 32 (23.4%) either had adverse events/poor compliance with AZA or were lost to follow-up. The 77 patients (56.2%) who achieved clinical remission were followed (median, follow up 4 years; range, 3 months–6 years) for disease course (Fig. 1). These patients were maintained on 5-ASA (median, 4.8 g/day; range, 3.6–4.8 g/day) and AZA (median, 100 mg/day; range, 50–150 mg/day). IFX was stopped after the induction regimen. The baseline characteristics of these patients are listed in Table 1.
1. Corticosteroid-Free SCR
Seventy-seven patients (mean age, 34.81 ± 13.32 years; 68.83% of males, n=53) with acute severe steroid-refractory UC achieving clinical remission with IFX were followed up. The mean duration of corticosteroid-free SCR with 5-ASA and AZA was 2.70 ± 2.17 years (median, 1.5 years). The cumulative corticosteroid-free SCR at the end of follow-up (6 years) was 35%. The cumulative relapse-free survivals at 1, 2, and 4 years were 68%, 59%, and 42% respectively (Fig. 2).
2. Rates and Patterns of Relapse
Thirty-three patients (42.85%) suffered a total of 67 relapses over the entire follow-up period. Twelve (36.36%) of these 33 patients suffered > 1 relapses. Majority of the patients (n=27, 81.81%) relapsed within first 2 years of follow-up. Of the total 67 relapses, 64 (95.52%) were managed successfully with repeat courses of corticosteroids whereas 2 needed re-induction with IFX and 1 needed colectomy (Table 2). The factors that influenced corticosteroid-free SCR were evaluated. No significant effects of age, sex, disease duration, disease severity (Mayo score), disease extent, previous exposure to AZA and inflammatory markers (ESR, C-reactive protein, and albumin) were observed (Table 3).
3. Adverse Events
Eight patients had adverse events due to AZA (hepatotoxicity: n=4, pancreatitis: n=2, and leukopenia: n=2). Six of these discontinued AZA (hepatotoxicity: n=2, pancreatitis: n=2, and leukopenia: n=2) and were excluded from the analysis. Of these 6 patients, 2 underwent fecal microbiota transplantation, 1 was started on methotrexate and 3 patients shifted to complementary and alternative medicine. Two patients who had mildly elevated liver enzymes tolerated split dose AZA (AZA administered in 2 divided doses) and continued on therapy. None of the 2 patients who required re-induction with IFX had infusion reaction on re-induction infusions. Two patients died during the study period; 1due to surgical complications after colectomy and another due to myocardial infarction, unrelated to UC.
4. Cost-Benefit Analysis
Cost-benefit analysis was performed by comparing the therapeutic benefits (including the proportion of patients maintaining corticosteroid-free SCR and frequency of relapses) and costs incurred on the therapy. Comparisons were made for IFX used as maintenance therapy versus IFX used only for inducing remission and maintaining with 5-ASA and AZA. The relapse rates with IFX maintenance were derived from the existing literature reporting long-term efficacy of IFX. Annual costs were calculated based on absolute compliance to therapy, the number of relapses observed/expected and costs incurred on management of relapses. Maintenance therapy per capita per annum was cheaper by US$ 4,526 with 5-ASA and AZA as compared to maintaining remission with IFX (Table 4).
DISCUSSION
In acute severe UC, corticosteroids are the initially recommended drugs. However, a subset of patients is refractory to corticosteroids and need rescue therapy with IFX. Both ECCO (European Crohn’s and Colitis Organisation) and ACG (American College of Gastroenterology) guidelines recommend that remission achieved with IFX should be maintained with the same, either alone or in combination with thiopurines [13,14]. However, maintenance of remission with IFX every 8 weeks is difficult in real world settings in resource-limited countries like India. Apart from cost, there are safety concerns as the use of IFX in areas with high prevalence of tuberculosis carries a risk of reactivation, even in the absence of latent tuberculosis [15]. The present study highlights the role of combination therapy with AZA and 5-ASA as effective maintenance therapy for patients with severe steroid-refractory UC who required IFX as a rescue induction therapy. Cumulative corticosteroid-free SCR was achieved in 35% of patients at 6 years. A total of 67 relapses were observed in 33 patients. Majority of the relapses (45/67, 67.16%) occurred within first 2 years of follow-up. Two relapses were managed with re-induction with IFX, 1 required colectomy, whereas all other responded to repeat course(s) of corticosteroids.
Thiopurines are immunosuppressive agents with proven clinical efficacy and long-term safety in patients with IBD [16,17]. However, the primary obstacle to their use in an acute flare is their delayed onset of action. Therefore, IFX was used in the current study only to induce remission and rapidly decrease tumor necrosis factor (TNF)-α secretion; thereby normalizing dysregulated immunity, reducing intestinal inflammation, and restoring mucosal immune homeostasis [18-21]. The clinical remission achieved by IFX was subsequently maintained on AZA in combination with 5-ASA. A secondary loss of response is reported in nearly 30%–50% receiving maintenance therapy with IFX [22-24]. The ACT1 and ACT2 extension studies found that nearly 45% of patients had active disease at week 152 of follow-up [8]. Similarly, the cumulative rates of maintenance of remission with IFX monotherapy in single center studies from Belgium and Japan were also 68% at 3 years and 56.1% at 5 years, respectively [11,23].
IFX withdrawal after achieving remission has been attempted in patients with Crohn’s disease (CD), though not in UC [25,26]. In a retrospective analysis of patients with CD where IFX was withdrawn, 52% of patients remained in SCR after a median period of approximately 10 years [27]. The cumulative relapse-free survivals in our study, though in patients with UC, were 68%, 59%, 42%, and 35% patients at 1, 2, 4, and 6 years respectively.
The majority of episodes of relapse were seen in the first 2 years after initiation of 5-ASA and AZA. Most patients experiencing multiple relapses were also seen in the initial 2 years (Table 2, Fig. 2). A systematic review assessing relapse rates after discontinuation of anti-TNF treatment revealed a similar number of relapses at the end of 1 year (21.1%–39%), but relapse rates were much higher (37%–55.7%) at the end of 2 years [28]. Animal models of colitis have demonstrated that AZA induces production of interleukin 10 (IL-10) by T cells in cultures that are primed for > 6 days and not in early primed (< 2 days) cultures despite increasing concentrations of the drug [29]. AZA thus tilts the balance towards prominence of anti-inflammatory cytokines (decreased serum IL-6, IL-8, IL-17, TNF-α levels and increased IL-10, transforming growth factor β), after a lag period, and the frequency of relapses decreases with time. This could explain greater number of relapses in initial 2 years of follow-up. 5-ASA and AZA combination was well tolerated and only 6 patients, who were intolerant to AZA, had to stop thiopurines.
Patients who experienced relapses during long-term follow up in the current study rarely required a re-induction with IFX and could be managed with repeat course(s) of corticosteroids, suggesting that initial steroid refractoriness is not permanent. Even though a proportion of patients suffered repeated relapses over the period of follow-up (Table 2), majority of these subsequent relapses were also responsive to corticosteroids. Corticosteroids have both immunologic and anti-inflammatory properties, including inhibitory effects on nuclear factor-κB and activating protein-1 [30]. Resistance to corticosteroids is mediated by altered expression of transcription factors and/or cytokines. IL-2 has been shown to promote resistance to corticosteroids by reducing the nuclear translocation of glucocorticoid receptor. T cells from steroid-resistant individuals have been demonstrated to produce more IL-2 than T cells from steroid-sensitive individuals. Blocking IL-2 (via anti-IL-2 [basiliximab] or Janus kinase inhibitors [JAK1 and JAK3]) has been demonstrated to restore steroid sensitivity in vitro [31,32]. Thiopurines, especially AZA, have anti-proliferative effects that are mediated by direct inhibition of IL-2 and hence could help in re-establishment of response to corticosteroids [33]. AZA, along with 5-ASA, in the current study therefore may have resulted steroid responsiveness of the relapses occurring during follow up. The colectomy rate in our study was very low. However, colectomy could not be excluded in patients who were lost to follow-up.
The cost of AZA+5-ASA maintenance therapy (including the costs for management of relapses) was approximately INR 53,535 (US$ 733) per capita per year while maintenance with IFX alone would cost approximately INR 383,906 (US$ 5,259) per capita per year, which is nearly seven times higher. In a similar cost analysis of contemporary immunomodulatory and biologic strategies in CD, AZA monotherapy was found to be more cost effective than maintenance with IFX alone or IFX+AZA combination and it yielded similar quality-adjusted life years and rates of surgery [34].
This is the first study where IFX has been withdrawn after inducing remission in patients with UC. This is also the first study to document sustained benefit with use of combination of 5-ASA and AZA in maintaining remission achieved by IFX over a long time (up to 6 years). The limitations of our study include the lack of control group, retrospective analysis, high rates of attrition due to loss of follow-up (relapse and/or colectomy cannot be excluded in patients lost to follow-up) and use of clinical parameters to assess efficacy rather than a more precise end point like mucosal healing (endoscopy/biomarkers like fecal calprotectin). However, the present study documents AZA+5-ASA combination as an effective, safe and cost-beneficial alternative to maintain remission induced by IFX in acute severe steroid-refractory UC. Larger, prospective studies using the proposed regime are however needed.
To conclude, treatment strategies in resource constrained countries cannot match those followed in developed countries as the health care policies in these countries differ significantly. Induction of remission with IFX and subsequent maintenance with AZA and 5-ASA in patients with acute severe steroid-refractory UC seems to be an effective strategy, sustaining clinical remission over long term. Relapses occur on combination therapy of 5-ASA and AZA but vast majority of these relapses can be managed with repeat course(s) of corticosteroids.
Fig. 1. Flowchart of the patients in the current study. IFX, infliximab; AZA, azathioprine.
Fig. 2. Kaplan-Meier cumulative survival curve for corticosteroid-free sustained clinical remission (SCR).
Table 1. Baseline Characteristics of the Patients
Characteristics Value (n = 77)
Age (yr) 34.81 ± 13.32
Sex
Male 53 (68.83)
Female 24 (31.16)
Disease extent
E2 47 (61.03)
E3 30 (38.96)
Duration of disease (yr) 1.84 (0.25–17.00)
Total Mayo score (before IFX induction regimen) 8.87 ± 1.14
CRP (mg/L) 51.26 ± 64.14
ESR (mm/hr) 52.90 ± 20.18
Albumin (g/dL) 3.26 ± 0.85
Hemoglobin (g/dL) 9.98 ± 1.94
Previous AZA use
Experienced 27 (35.06)
Naïve 50 (64.93)
Values are presented as mean±standard deviation, number (%), or median (range).
E2, left-sided colitis; E3, pancolitis, IFX, infliximab; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; AZA, azathioprine.
Table 2. Patterns of Disease Relapse and Treatment
Year No. of patients with single relapse No. of patients with > 1 relapse No. of relapses
1 14a 8a 31
2 4b + 4a 2b + 1a 14
3 2b + 1a 2b + 1a 9
4 3b 2a 7
5 2a 1b 4
6 1b - 2
Total 67
Treatment Corticosteroids: 64 Infliximab: 2 (1 patient each in year 1 and 2) Colectomy: 1 (year 3)
a Patients with first relapse.
b Patients who also relapsed in previous years.
Table 3. Factors Influencing the Maintenance of Corticosteroid-Free Sustained Clinical Remission
Parameter Odds ratio 95% CI P-value
Age 1.00 0.97–1.03 0.74
Male sex 0.60 0.23–1.60 0.31
Disease duration 1.01 0.92–1.11 0.71
Disease extent E2 0.07 0.00–1.48 0.09
AZA naïve 0.68 0.24–1.90 0.47
Mayo score 1.13 0.74–1.71 0.56
Hemoglobin (g/dL) 1.01 0.77–1.32 0.92
ESR (mm/hr) 1.00 0.97–1.02 0.93
Albumin (g/L) 0.79 0.45–1.40 0.43
CRP (mg/L) 0.99 0.99–1.01 0.47
CI, confidence interval; E2, left-sided colitis; AZA, azathioprine; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein.
Table 4. Cost-Benefit Analysis (Annual) (n=77)
Maintenance therapy with 5-ASA+AZA INR (US$) Maintenance therapy with IFX INR (US$)
Number of days AZA +5-ASA consumed 365 Number of IFX doses needed per patient if used for maintenance of remission 6
Daily cost of AZA (100 mg/day) +5-ASA (4.8 g/day) 140 (1.91) Annual cost of IFX maintenance therapy for the entire cohort (C) 27,720,000 (3,79,726)
Annual cost of maintenance therapy with 5-ASA and AZA for the entire cohort (A) 39,34,700 (53,900) Cost of hospitalization and losses incurred due to absence from worka (D) 415,800 (5,695)
Total number of relapses observed at 1 year 31 Expected number of relapses on IFX therapy over the entire cohortb 19
Cost incurred on treatment of relapses with corticosteroids 7,500 (103) (n = 30, corticosteroids tapered over 16 weeks) - -
Cost incurred on treatment of relapses with IFX induction regimen 180,000 (2,465) (n = 1, IFX administered at a dose of 5 mg/kg at 0, 2, 6 weeks) - -
Cost incurred on colectomy - Cost incurred on treatment of relapse with colectomy in the entire cohortc (E) 1,425,000 (19,520)
Total cost incurred on management of relapses in the entire cohort (B) 187,500 (2,568)
Total cost incurred for the entire cohort (A+B) 4,122,200 (56,468) Total cost incurred for the entire cohort (C+D+E) 29,560,800 (404,942)
Average cost per person per year 53,535 (733) Average cost per person per year 383,906 (5,259)
All values are approximate 1US$ (INR 73). Annual cost difference per patient: INR 330,371 (US$ 4,526). Cohort size (n)=77; Cost of IFX originator: INR 20,000/100 mg; Cost of AZA 100 mg: INR 20; Cost of oral 5-ASA 4.8 g: INR 120; Cost of colectomy in a tertiary care center: INR 75,000; Costs calculated for average body weight of 60 kg.
a For a single day care admission approximate cost of hospitalization: INR 500 for a tertiary care hospital (data derived from World Health Organization report on Estimates of Unit Costs for Patient Services for India; available at https://www.who.int/choice/country/ind/cost/en/, accessed on October 18, 2020) and approximate loss of income due to absence from work: INR 370 (data derived from per capita income in India for 2018-2019; available at http://mospi.gov.in, accessed on October 18, 2020).
b Calculated considering average relapse rates of 25% and 30% at 1 year and 2 years respectively. [8,17,23,24]
c Biologics other than anti-tumor necrosis factor agents are not available in India, so the only therapeutic option for patient relapsing on IFX is colectomy.
5-ASA, 5-aminosalicylic acid; AZA, azathioprine; IFX, infliximab.
Funding Source
The authors received no financial support for the research, authorship, and/or publication of this article.
Conflict of Interest
Sood A is an editorial board member of the journal but was not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.
Author Contribution
Conceptualization: Mahajan R, Midha V, Sood A. Data curation: Kedia S, Kaur K, Sahu P, Singh D, Ahuja V. Formal analysis: Mahajan R, Singh A, Kaur K, Bansal N, Dharni K. Investigation: Mahajan R, Singh A, Kedia S, Kaur K, Singh D, Sood A. Methodology: Mahajan R, Singh A, Kedia S, Kaur K, Midha V, Sahu P, Mehta V, Kaushal S, Ahuja V, Sood A. Project administration: Mahajan R, Kedia S, Sood A. Resources: Midha V, Singh D, Sood A. Software: Singh A, Bansal N, Dharni K. Supervision: Mahajan R, Kedia S, Midha V, Ahuja V, Sood A. Visualization: Mahajan R, Singh A, Kedia S. Writing - original draft: Mahajan R, Singh A, Kedia S, Kaur K, Midha V, Sahu P, Mehta V, Ahuja V, Sood A. Writing - review & editing: Mahajan R, Singh A, Kedia S, Kaur K, Midha V, Sahu P, Mehta V, Bansal N, Dharni K, Kaushal S, Ahuja V, Sood A. Approval of final manuscript: all authors. | AZATHIOPRINE, INFLIXIMAB | DrugsGivenReaction | CC BY-NC | 33525859 | 18,907,208 | 2021-02-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Maintaining infliximab induced clinical remission with azathioprine and 5-aminosalicylates in acute severe steroid-refractory ulcerative colitis has lower cost and high efficacy (MIRACLE): a multicenter study.
Infliximab (IFX) has been used to induce and maintain remission in patients with severe steroid-refractory ulcerative colitis (UC). Long-term use of biologics in developing countries is limited by high cost and frequent side effects. An optimal maintenance strategy in these patients needs to be established.
A retrospective analysis of maintenance of clinical remission with combination of azathioprine (AZA) and 5-aminosalicylates (5-ASA) in patients with severe steroidrefractory UC where IFX (5 mg/kg intravenously at weeks 0, 2, 6) had been used only as an induction therapy was done at 2 centers in India. Primary outcome was the proportion of patients maintaining corticosteroid-free sustained clinical remission (SCR) at the end of study period. Rates of relapse and cost of therapy were also analyzed.
Of the 137 patients who received rescue IFX induction therapy, 77 (56.2%) achieved clinical remission (mean age 34.81 ± 13.32 years, 68.83% males, median follow-up 4 years, range 3 months to 6 years) and were included. Cumulative corticosteroid-free SCR was maintained in 68%, 59%, 42%, and 35% patients at 1, 2, 4, and 6 years respectively. Sixty-seven relapses were observed in 33 patients. Majority of the relapses (45/67, 67.16%) occurred within first 2 years of follow-up. Two relapses were managed with re-induction with IFX, one required colectomy, whereas all other responded to repeat course(s) of corticosteroids. Annual per capita maintenance therapy with 5-ASA and AZA was cheaper by US$ 4,526 compared to maintaining remission with IFX.
Clinical remission achieved with IFX induction therapy in severe steroid-refractory UC can be sustained over long time with a combination of AZA and 5-ASA.
pmcINTRODUCTION
Ulcerative colitis (UC) is a chronic inflammatory disease of the colon with a relapsing remitting course [1]. Acute severe exacerbations of the disease develop in 15% to 20% of the patients, requiring hospitalization and treatment with intravenous (IV) corticosteroids [2]. Though corticosteroids are effective in a majority of patients with severe UC, they are not a panpharmacon. Up to one-third of patients with acute severe UC may fail to respond to therapy with IV corticosteroids and hence require rescue therapy with IV cyclosporin A (CsA)/infliximab (IFX) or colectomy [3-7]. In patients where IFX is used as rescue therapy, continuation of an 8 weekly dosing schedule has been recommended for maintenance of remission. However, up to 30% of patients may not be able to continue IFX in the long run due to adverse events or a secondary loss of response [8,9]. Furthermore, the continued use of biologics for maintenance of remission is not feasible in developing countries where the health insurance coverage is minimal, placing significant economic burden on the patients. To sustain clinical remission in these patients, alternative maintenance therapies need to be studied. We present a multicenter experience of use of combination therapy with azathioprine (AZA) and 5-aminosalicylates (5-ASA) for maintenance of clinical remission in patients with acute severe steroid-refractory UC who achieved clinical remission with IFX induction regimen and IFX was stopped thereafter.
METHODS
1. Setting
This was a retrospective analysis of database from 2 tertiary care centers in north India; Dayanand Medical College and Hospital, Ludhiana and All India Institute of Medical Sciences, New Delhi. Patients with acute severe steroid-refractory UC who received IFX as a rescue induction therapy and subsequently maintained on 5-ASA and AZA between August 2005 and December 2017 were enrolled. The study was approved by Institutional Ethics Committee (IEC Nos. DMCH/R & D/2020/23 and IECPG-599/24.10.19) of both the institutions and performed in accordance with the principles of the Declaration of Helsinki. Written informed consent was obtained.
2. Study Population
Adult (≥ 18 years) patients with acute severe UC (defined as 6 or more stools with blood and 1 or more of the following hemoglobin < 10.5 g/dL, erythrocyte sedimentation rate [ESR] > 30 mm/hr, fever > 37.8°C, or tachycardia > 90/min; the Truelove Witts criteria) refractory to IV hydrocortisone (300–400 mg/day administered in 3 divided doses, used for 5–7 days) were offered rescue therapy with either IFX (originator, induction protocol: 5 mg/kg at weeks 0, 2 and 6)/CsA (2 mg/kg infusion for 5 days, followed by oral CsA acting as bridge to thiopurines); or colectomy. The current study is a retrospective analysis of treatment outcomes of the patients who opted for IFX as a rescue therapy and achieved clinical remission. Clinical remission was defined as partial Mayo score ≤ 1 at week 10 [10].
AZA was introduced/continued in all patients, whether AZA naïve or experienced, at the time of first dose of IFX induction regime. The patients who achieved clinical remission were followed for maintenance of corticosteroid-free sustained clinical remission (SCR) with combination therapy of AZA and 5-ASA. Corticosteroid-free SCR was defined as partial Mayo score ≤ 1 with absence of diarrhea and blood in stools and without need for new courses of corticosteroids or any other systemic drug (CsA, biologics, or investigational drugs) [11]. 5-ASA was used in a dose of 3.6–4.8 g/day and the dose of AZA was maintained at 1.5–2 mg/kg/day. All the patients were followed at an interval of 8–12 weeks, or earlier in case of worsening of symptoms. Disease activity (partial Mayo score) and concomitant pharmacotherapy were recorded for each visit. Patients with adverse events necessitating drug withdrawal were excluded.
Relapse was defined as partial Mayo score ≥ 3 [12]. In case of relapse, stool examination for infections including Clostridioides difficile; and IgM serology and histology for cytomegalovirus were performed. The management protocols for each relapse, including use of corticosteroids, biologics (IFX), CsA or surgery, were noted.
Patients with failure to achieve clinical remission with IFX induction therapy, incomplete induction protocol, active or latent tuberculosis, hepatitis B, hepatitis C, human immunodeficiency virus (HIV), pathogens on stool culture, contraindication to IFX or AZA according to labelling recommendations, previous use of multiple biologics, Crohn’s colitis/inflammatory bowel disease (IBD)-unclassified, pregnancy or lactation, and patients with missing data were excluded.
3. Cost-Benefit Analysis
Cost-benefit analysis of AZA plus 5-ASA was done in comparison to IFX maintenance. The cost of drug used in analysis was based on maximum retail price of the drugs. Annual expenditure (including the cost involved in treatment of relapses, hospitalization, rescue therapy and surgery) were estimated and compared between the 2 approaches.
4. Clinical Outcomes
The primary outcome was maintenance of corticosteroid-free SCR during the follow-up. Secondary outcomes included assessment of rates of relapses and their management and cost-benefit analysis.
5. Statistical Analysis
Descriptive statistics were provided with mean and standard deviation, median and interquartile range for continuous variables and frequency and percentage for categorical variables. Log-rank test was used to investigate the factors affecting relapse after cessation of IFX therapy. Using the standard α=0.05 cutoff, P<0.05 was considered statistically significant. Cumulative relapse-free survival (corticosteroid-free SCR) was calculated using Kaplan-Meier survival analysis. All statistical analyses were performed using Stata 12 (StataCorp. 2011. Stata Statistical Software: Release 12; StataCorp LP, College Station, TX, USA).
RESULTS
A total of 137 patients with acute severe UC were treated with IFX for inducing remission during the study period. Twenty-three patients (17.1%) did not respond to IFX and underwent colectomy, 5 (3.7%) had adverse events (tuberculosis: n=3; congestive heart failure: n=2) and 32 (23.4%) either had adverse events/poor compliance with AZA or were lost to follow-up. The 77 patients (56.2%) who achieved clinical remission were followed (median, follow up 4 years; range, 3 months–6 years) for disease course (Fig. 1). These patients were maintained on 5-ASA (median, 4.8 g/day; range, 3.6–4.8 g/day) and AZA (median, 100 mg/day; range, 50–150 mg/day). IFX was stopped after the induction regimen. The baseline characteristics of these patients are listed in Table 1.
1. Corticosteroid-Free SCR
Seventy-seven patients (mean age, 34.81 ± 13.32 years; 68.83% of males, n=53) with acute severe steroid-refractory UC achieving clinical remission with IFX were followed up. The mean duration of corticosteroid-free SCR with 5-ASA and AZA was 2.70 ± 2.17 years (median, 1.5 years). The cumulative corticosteroid-free SCR at the end of follow-up (6 years) was 35%. The cumulative relapse-free survivals at 1, 2, and 4 years were 68%, 59%, and 42% respectively (Fig. 2).
2. Rates and Patterns of Relapse
Thirty-three patients (42.85%) suffered a total of 67 relapses over the entire follow-up period. Twelve (36.36%) of these 33 patients suffered > 1 relapses. Majority of the patients (n=27, 81.81%) relapsed within first 2 years of follow-up. Of the total 67 relapses, 64 (95.52%) were managed successfully with repeat courses of corticosteroids whereas 2 needed re-induction with IFX and 1 needed colectomy (Table 2). The factors that influenced corticosteroid-free SCR were evaluated. No significant effects of age, sex, disease duration, disease severity (Mayo score), disease extent, previous exposure to AZA and inflammatory markers (ESR, C-reactive protein, and albumin) were observed (Table 3).
3. Adverse Events
Eight patients had adverse events due to AZA (hepatotoxicity: n=4, pancreatitis: n=2, and leukopenia: n=2). Six of these discontinued AZA (hepatotoxicity: n=2, pancreatitis: n=2, and leukopenia: n=2) and were excluded from the analysis. Of these 6 patients, 2 underwent fecal microbiota transplantation, 1 was started on methotrexate and 3 patients shifted to complementary and alternative medicine. Two patients who had mildly elevated liver enzymes tolerated split dose AZA (AZA administered in 2 divided doses) and continued on therapy. None of the 2 patients who required re-induction with IFX had infusion reaction on re-induction infusions. Two patients died during the study period; 1due to surgical complications after colectomy and another due to myocardial infarction, unrelated to UC.
4. Cost-Benefit Analysis
Cost-benefit analysis was performed by comparing the therapeutic benefits (including the proportion of patients maintaining corticosteroid-free SCR and frequency of relapses) and costs incurred on the therapy. Comparisons were made for IFX used as maintenance therapy versus IFX used only for inducing remission and maintaining with 5-ASA and AZA. The relapse rates with IFX maintenance were derived from the existing literature reporting long-term efficacy of IFX. Annual costs were calculated based on absolute compliance to therapy, the number of relapses observed/expected and costs incurred on management of relapses. Maintenance therapy per capita per annum was cheaper by US$ 4,526 with 5-ASA and AZA as compared to maintaining remission with IFX (Table 4).
DISCUSSION
In acute severe UC, corticosteroids are the initially recommended drugs. However, a subset of patients is refractory to corticosteroids and need rescue therapy with IFX. Both ECCO (European Crohn’s and Colitis Organisation) and ACG (American College of Gastroenterology) guidelines recommend that remission achieved with IFX should be maintained with the same, either alone or in combination with thiopurines [13,14]. However, maintenance of remission with IFX every 8 weeks is difficult in real world settings in resource-limited countries like India. Apart from cost, there are safety concerns as the use of IFX in areas with high prevalence of tuberculosis carries a risk of reactivation, even in the absence of latent tuberculosis [15]. The present study highlights the role of combination therapy with AZA and 5-ASA as effective maintenance therapy for patients with severe steroid-refractory UC who required IFX as a rescue induction therapy. Cumulative corticosteroid-free SCR was achieved in 35% of patients at 6 years. A total of 67 relapses were observed in 33 patients. Majority of the relapses (45/67, 67.16%) occurred within first 2 years of follow-up. Two relapses were managed with re-induction with IFX, 1 required colectomy, whereas all other responded to repeat course(s) of corticosteroids.
Thiopurines are immunosuppressive agents with proven clinical efficacy and long-term safety in patients with IBD [16,17]. However, the primary obstacle to their use in an acute flare is their delayed onset of action. Therefore, IFX was used in the current study only to induce remission and rapidly decrease tumor necrosis factor (TNF)-α secretion; thereby normalizing dysregulated immunity, reducing intestinal inflammation, and restoring mucosal immune homeostasis [18-21]. The clinical remission achieved by IFX was subsequently maintained on AZA in combination with 5-ASA. A secondary loss of response is reported in nearly 30%–50% receiving maintenance therapy with IFX [22-24]. The ACT1 and ACT2 extension studies found that nearly 45% of patients had active disease at week 152 of follow-up [8]. Similarly, the cumulative rates of maintenance of remission with IFX monotherapy in single center studies from Belgium and Japan were also 68% at 3 years and 56.1% at 5 years, respectively [11,23].
IFX withdrawal after achieving remission has been attempted in patients with Crohn’s disease (CD), though not in UC [25,26]. In a retrospective analysis of patients with CD where IFX was withdrawn, 52% of patients remained in SCR after a median period of approximately 10 years [27]. The cumulative relapse-free survivals in our study, though in patients with UC, were 68%, 59%, 42%, and 35% patients at 1, 2, 4, and 6 years respectively.
The majority of episodes of relapse were seen in the first 2 years after initiation of 5-ASA and AZA. Most patients experiencing multiple relapses were also seen in the initial 2 years (Table 2, Fig. 2). A systematic review assessing relapse rates after discontinuation of anti-TNF treatment revealed a similar number of relapses at the end of 1 year (21.1%–39%), but relapse rates were much higher (37%–55.7%) at the end of 2 years [28]. Animal models of colitis have demonstrated that AZA induces production of interleukin 10 (IL-10) by T cells in cultures that are primed for > 6 days and not in early primed (< 2 days) cultures despite increasing concentrations of the drug [29]. AZA thus tilts the balance towards prominence of anti-inflammatory cytokines (decreased serum IL-6, IL-8, IL-17, TNF-α levels and increased IL-10, transforming growth factor β), after a lag period, and the frequency of relapses decreases with time. This could explain greater number of relapses in initial 2 years of follow-up. 5-ASA and AZA combination was well tolerated and only 6 patients, who were intolerant to AZA, had to stop thiopurines.
Patients who experienced relapses during long-term follow up in the current study rarely required a re-induction with IFX and could be managed with repeat course(s) of corticosteroids, suggesting that initial steroid refractoriness is not permanent. Even though a proportion of patients suffered repeated relapses over the period of follow-up (Table 2), majority of these subsequent relapses were also responsive to corticosteroids. Corticosteroids have both immunologic and anti-inflammatory properties, including inhibitory effects on nuclear factor-κB and activating protein-1 [30]. Resistance to corticosteroids is mediated by altered expression of transcription factors and/or cytokines. IL-2 has been shown to promote resistance to corticosteroids by reducing the nuclear translocation of glucocorticoid receptor. T cells from steroid-resistant individuals have been demonstrated to produce more IL-2 than T cells from steroid-sensitive individuals. Blocking IL-2 (via anti-IL-2 [basiliximab] or Janus kinase inhibitors [JAK1 and JAK3]) has been demonstrated to restore steroid sensitivity in vitro [31,32]. Thiopurines, especially AZA, have anti-proliferative effects that are mediated by direct inhibition of IL-2 and hence could help in re-establishment of response to corticosteroids [33]. AZA, along with 5-ASA, in the current study therefore may have resulted steroid responsiveness of the relapses occurring during follow up. The colectomy rate in our study was very low. However, colectomy could not be excluded in patients who were lost to follow-up.
The cost of AZA+5-ASA maintenance therapy (including the costs for management of relapses) was approximately INR 53,535 (US$ 733) per capita per year while maintenance with IFX alone would cost approximately INR 383,906 (US$ 5,259) per capita per year, which is nearly seven times higher. In a similar cost analysis of contemporary immunomodulatory and biologic strategies in CD, AZA monotherapy was found to be more cost effective than maintenance with IFX alone or IFX+AZA combination and it yielded similar quality-adjusted life years and rates of surgery [34].
This is the first study where IFX has been withdrawn after inducing remission in patients with UC. This is also the first study to document sustained benefit with use of combination of 5-ASA and AZA in maintaining remission achieved by IFX over a long time (up to 6 years). The limitations of our study include the lack of control group, retrospective analysis, high rates of attrition due to loss of follow-up (relapse and/or colectomy cannot be excluded in patients lost to follow-up) and use of clinical parameters to assess efficacy rather than a more precise end point like mucosal healing (endoscopy/biomarkers like fecal calprotectin). However, the present study documents AZA+5-ASA combination as an effective, safe and cost-beneficial alternative to maintain remission induced by IFX in acute severe steroid-refractory UC. Larger, prospective studies using the proposed regime are however needed.
To conclude, treatment strategies in resource constrained countries cannot match those followed in developed countries as the health care policies in these countries differ significantly. Induction of remission with IFX and subsequent maintenance with AZA and 5-ASA in patients with acute severe steroid-refractory UC seems to be an effective strategy, sustaining clinical remission over long term. Relapses occur on combination therapy of 5-ASA and AZA but vast majority of these relapses can be managed with repeat course(s) of corticosteroids.
Fig. 1. Flowchart of the patients in the current study. IFX, infliximab; AZA, azathioprine.
Fig. 2. Kaplan-Meier cumulative survival curve for corticosteroid-free sustained clinical remission (SCR).
Table 1. Baseline Characteristics of the Patients
Characteristics Value (n = 77)
Age (yr) 34.81 ± 13.32
Sex
Male 53 (68.83)
Female 24 (31.16)
Disease extent
E2 47 (61.03)
E3 30 (38.96)
Duration of disease (yr) 1.84 (0.25–17.00)
Total Mayo score (before IFX induction regimen) 8.87 ± 1.14
CRP (mg/L) 51.26 ± 64.14
ESR (mm/hr) 52.90 ± 20.18
Albumin (g/dL) 3.26 ± 0.85
Hemoglobin (g/dL) 9.98 ± 1.94
Previous AZA use
Experienced 27 (35.06)
Naïve 50 (64.93)
Values are presented as mean±standard deviation, number (%), or median (range).
E2, left-sided colitis; E3, pancolitis, IFX, infliximab; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; AZA, azathioprine.
Table 2. Patterns of Disease Relapse and Treatment
Year No. of patients with single relapse No. of patients with > 1 relapse No. of relapses
1 14a 8a 31
2 4b + 4a 2b + 1a 14
3 2b + 1a 2b + 1a 9
4 3b 2a 7
5 2a 1b 4
6 1b - 2
Total 67
Treatment Corticosteroids: 64 Infliximab: 2 (1 patient each in year 1 and 2) Colectomy: 1 (year 3)
a Patients with first relapse.
b Patients who also relapsed in previous years.
Table 3. Factors Influencing the Maintenance of Corticosteroid-Free Sustained Clinical Remission
Parameter Odds ratio 95% CI P-value
Age 1.00 0.97–1.03 0.74
Male sex 0.60 0.23–1.60 0.31
Disease duration 1.01 0.92–1.11 0.71
Disease extent E2 0.07 0.00–1.48 0.09
AZA naïve 0.68 0.24–1.90 0.47
Mayo score 1.13 0.74–1.71 0.56
Hemoglobin (g/dL) 1.01 0.77–1.32 0.92
ESR (mm/hr) 1.00 0.97–1.02 0.93
Albumin (g/L) 0.79 0.45–1.40 0.43
CRP (mg/L) 0.99 0.99–1.01 0.47
CI, confidence interval; E2, left-sided colitis; AZA, azathioprine; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein.
Table 4. Cost-Benefit Analysis (Annual) (n=77)
Maintenance therapy with 5-ASA+AZA INR (US$) Maintenance therapy with IFX INR (US$)
Number of days AZA +5-ASA consumed 365 Number of IFX doses needed per patient if used for maintenance of remission 6
Daily cost of AZA (100 mg/day) +5-ASA (4.8 g/day) 140 (1.91) Annual cost of IFX maintenance therapy for the entire cohort (C) 27,720,000 (3,79,726)
Annual cost of maintenance therapy with 5-ASA and AZA for the entire cohort (A) 39,34,700 (53,900) Cost of hospitalization and losses incurred due to absence from worka (D) 415,800 (5,695)
Total number of relapses observed at 1 year 31 Expected number of relapses on IFX therapy over the entire cohortb 19
Cost incurred on treatment of relapses with corticosteroids 7,500 (103) (n = 30, corticosteroids tapered over 16 weeks) - -
Cost incurred on treatment of relapses with IFX induction regimen 180,000 (2,465) (n = 1, IFX administered at a dose of 5 mg/kg at 0, 2, 6 weeks) - -
Cost incurred on colectomy - Cost incurred on treatment of relapse with colectomy in the entire cohortc (E) 1,425,000 (19,520)
Total cost incurred on management of relapses in the entire cohort (B) 187,500 (2,568)
Total cost incurred for the entire cohort (A+B) 4,122,200 (56,468) Total cost incurred for the entire cohort (C+D+E) 29,560,800 (404,942)
Average cost per person per year 53,535 (733) Average cost per person per year 383,906 (5,259)
All values are approximate 1US$ (INR 73). Annual cost difference per patient: INR 330,371 (US$ 4,526). Cohort size (n)=77; Cost of IFX originator: INR 20,000/100 mg; Cost of AZA 100 mg: INR 20; Cost of oral 5-ASA 4.8 g: INR 120; Cost of colectomy in a tertiary care center: INR 75,000; Costs calculated for average body weight of 60 kg.
a For a single day care admission approximate cost of hospitalization: INR 500 for a tertiary care hospital (data derived from World Health Organization report on Estimates of Unit Costs for Patient Services for India; available at https://www.who.int/choice/country/ind/cost/en/, accessed on October 18, 2020) and approximate loss of income due to absence from work: INR 370 (data derived from per capita income in India for 2018-2019; available at http://mospi.gov.in, accessed on October 18, 2020).
b Calculated considering average relapse rates of 25% and 30% at 1 year and 2 years respectively. [8,17,23,24]
c Biologics other than anti-tumor necrosis factor agents are not available in India, so the only therapeutic option for patient relapsing on IFX is colectomy.
5-ASA, 5-aminosalicylic acid; AZA, azathioprine; IFX, infliximab.
Funding Source
The authors received no financial support for the research, authorship, and/or publication of this article.
Conflict of Interest
Sood A is an editorial board member of the journal but was not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.
Author Contribution
Conceptualization: Mahajan R, Midha V, Sood A. Data curation: Kedia S, Kaur K, Sahu P, Singh D, Ahuja V. Formal analysis: Mahajan R, Singh A, Kaur K, Bansal N, Dharni K. Investigation: Mahajan R, Singh A, Kedia S, Kaur K, Singh D, Sood A. Methodology: Mahajan R, Singh A, Kedia S, Kaur K, Midha V, Sahu P, Mehta V, Kaushal S, Ahuja V, Sood A. Project administration: Mahajan R, Kedia S, Sood A. Resources: Midha V, Singh D, Sood A. Software: Singh A, Bansal N, Dharni K. Supervision: Mahajan R, Kedia S, Midha V, Ahuja V, Sood A. Visualization: Mahajan R, Singh A, Kedia S. Writing - original draft: Mahajan R, Singh A, Kedia S, Kaur K, Midha V, Sahu P, Mehta V, Ahuja V, Sood A. Writing - review & editing: Mahajan R, Singh A, Kedia S, Kaur K, Midha V, Sahu P, Mehta V, Bansal N, Dharni K, Kaushal S, Ahuja V, Sood A. Approval of final manuscript: all authors. | AZATHIOPRINE, INFLIXIMAB | DrugsGivenReaction | CC BY-NC | 33525859 | 18,907,208 | 2021-02-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Tuberculosis'. | Maintaining infliximab induced clinical remission with azathioprine and 5-aminosalicylates in acute severe steroid-refractory ulcerative colitis has lower cost and high efficacy (MIRACLE): a multicenter study.
Infliximab (IFX) has been used to induce and maintain remission in patients with severe steroid-refractory ulcerative colitis (UC). Long-term use of biologics in developing countries is limited by high cost and frequent side effects. An optimal maintenance strategy in these patients needs to be established.
A retrospective analysis of maintenance of clinical remission with combination of azathioprine (AZA) and 5-aminosalicylates (5-ASA) in patients with severe steroidrefractory UC where IFX (5 mg/kg intravenously at weeks 0, 2, 6) had been used only as an induction therapy was done at 2 centers in India. Primary outcome was the proportion of patients maintaining corticosteroid-free sustained clinical remission (SCR) at the end of study period. Rates of relapse and cost of therapy were also analyzed.
Of the 137 patients who received rescue IFX induction therapy, 77 (56.2%) achieved clinical remission (mean age 34.81 ± 13.32 years, 68.83% males, median follow-up 4 years, range 3 months to 6 years) and were included. Cumulative corticosteroid-free SCR was maintained in 68%, 59%, 42%, and 35% patients at 1, 2, 4, and 6 years respectively. Sixty-seven relapses were observed in 33 patients. Majority of the relapses (45/67, 67.16%) occurred within first 2 years of follow-up. Two relapses were managed with re-induction with IFX, one required colectomy, whereas all other responded to repeat course(s) of corticosteroids. Annual per capita maintenance therapy with 5-ASA and AZA was cheaper by US$ 4,526 compared to maintaining remission with IFX.
Clinical remission achieved with IFX induction therapy in severe steroid-refractory UC can be sustained over long time with a combination of AZA and 5-ASA.
pmcINTRODUCTION
Ulcerative colitis (UC) is a chronic inflammatory disease of the colon with a relapsing remitting course [1]. Acute severe exacerbations of the disease develop in 15% to 20% of the patients, requiring hospitalization and treatment with intravenous (IV) corticosteroids [2]. Though corticosteroids are effective in a majority of patients with severe UC, they are not a panpharmacon. Up to one-third of patients with acute severe UC may fail to respond to therapy with IV corticosteroids and hence require rescue therapy with IV cyclosporin A (CsA)/infliximab (IFX) or colectomy [3-7]. In patients where IFX is used as rescue therapy, continuation of an 8 weekly dosing schedule has been recommended for maintenance of remission. However, up to 30% of patients may not be able to continue IFX in the long run due to adverse events or a secondary loss of response [8,9]. Furthermore, the continued use of biologics for maintenance of remission is not feasible in developing countries where the health insurance coverage is minimal, placing significant economic burden on the patients. To sustain clinical remission in these patients, alternative maintenance therapies need to be studied. We present a multicenter experience of use of combination therapy with azathioprine (AZA) and 5-aminosalicylates (5-ASA) for maintenance of clinical remission in patients with acute severe steroid-refractory UC who achieved clinical remission with IFX induction regimen and IFX was stopped thereafter.
METHODS
1. Setting
This was a retrospective analysis of database from 2 tertiary care centers in north India; Dayanand Medical College and Hospital, Ludhiana and All India Institute of Medical Sciences, New Delhi. Patients with acute severe steroid-refractory UC who received IFX as a rescue induction therapy and subsequently maintained on 5-ASA and AZA between August 2005 and December 2017 were enrolled. The study was approved by Institutional Ethics Committee (IEC Nos. DMCH/R & D/2020/23 and IECPG-599/24.10.19) of both the institutions and performed in accordance with the principles of the Declaration of Helsinki. Written informed consent was obtained.
2. Study Population
Adult (≥ 18 years) patients with acute severe UC (defined as 6 or more stools with blood and 1 or more of the following hemoglobin < 10.5 g/dL, erythrocyte sedimentation rate [ESR] > 30 mm/hr, fever > 37.8°C, or tachycardia > 90/min; the Truelove Witts criteria) refractory to IV hydrocortisone (300–400 mg/day administered in 3 divided doses, used for 5–7 days) were offered rescue therapy with either IFX (originator, induction protocol: 5 mg/kg at weeks 0, 2 and 6)/CsA (2 mg/kg infusion for 5 days, followed by oral CsA acting as bridge to thiopurines); or colectomy. The current study is a retrospective analysis of treatment outcomes of the patients who opted for IFX as a rescue therapy and achieved clinical remission. Clinical remission was defined as partial Mayo score ≤ 1 at week 10 [10].
AZA was introduced/continued in all patients, whether AZA naïve or experienced, at the time of first dose of IFX induction regime. The patients who achieved clinical remission were followed for maintenance of corticosteroid-free sustained clinical remission (SCR) with combination therapy of AZA and 5-ASA. Corticosteroid-free SCR was defined as partial Mayo score ≤ 1 with absence of diarrhea and blood in stools and without need for new courses of corticosteroids or any other systemic drug (CsA, biologics, or investigational drugs) [11]. 5-ASA was used in a dose of 3.6–4.8 g/day and the dose of AZA was maintained at 1.5–2 mg/kg/day. All the patients were followed at an interval of 8–12 weeks, or earlier in case of worsening of symptoms. Disease activity (partial Mayo score) and concomitant pharmacotherapy were recorded for each visit. Patients with adverse events necessitating drug withdrawal were excluded.
Relapse was defined as partial Mayo score ≥ 3 [12]. In case of relapse, stool examination for infections including Clostridioides difficile; and IgM serology and histology for cytomegalovirus were performed. The management protocols for each relapse, including use of corticosteroids, biologics (IFX), CsA or surgery, were noted.
Patients with failure to achieve clinical remission with IFX induction therapy, incomplete induction protocol, active or latent tuberculosis, hepatitis B, hepatitis C, human immunodeficiency virus (HIV), pathogens on stool culture, contraindication to IFX or AZA according to labelling recommendations, previous use of multiple biologics, Crohn’s colitis/inflammatory bowel disease (IBD)-unclassified, pregnancy or lactation, and patients with missing data were excluded.
3. Cost-Benefit Analysis
Cost-benefit analysis of AZA plus 5-ASA was done in comparison to IFX maintenance. The cost of drug used in analysis was based on maximum retail price of the drugs. Annual expenditure (including the cost involved in treatment of relapses, hospitalization, rescue therapy and surgery) were estimated and compared between the 2 approaches.
4. Clinical Outcomes
The primary outcome was maintenance of corticosteroid-free SCR during the follow-up. Secondary outcomes included assessment of rates of relapses and their management and cost-benefit analysis.
5. Statistical Analysis
Descriptive statistics were provided with mean and standard deviation, median and interquartile range for continuous variables and frequency and percentage for categorical variables. Log-rank test was used to investigate the factors affecting relapse after cessation of IFX therapy. Using the standard α=0.05 cutoff, P<0.05 was considered statistically significant. Cumulative relapse-free survival (corticosteroid-free SCR) was calculated using Kaplan-Meier survival analysis. All statistical analyses were performed using Stata 12 (StataCorp. 2011. Stata Statistical Software: Release 12; StataCorp LP, College Station, TX, USA).
RESULTS
A total of 137 patients with acute severe UC were treated with IFX for inducing remission during the study period. Twenty-three patients (17.1%) did not respond to IFX and underwent colectomy, 5 (3.7%) had adverse events (tuberculosis: n=3; congestive heart failure: n=2) and 32 (23.4%) either had adverse events/poor compliance with AZA or were lost to follow-up. The 77 patients (56.2%) who achieved clinical remission were followed (median, follow up 4 years; range, 3 months–6 years) for disease course (Fig. 1). These patients were maintained on 5-ASA (median, 4.8 g/day; range, 3.6–4.8 g/day) and AZA (median, 100 mg/day; range, 50–150 mg/day). IFX was stopped after the induction regimen. The baseline characteristics of these patients are listed in Table 1.
1. Corticosteroid-Free SCR
Seventy-seven patients (mean age, 34.81 ± 13.32 years; 68.83% of males, n=53) with acute severe steroid-refractory UC achieving clinical remission with IFX were followed up. The mean duration of corticosteroid-free SCR with 5-ASA and AZA was 2.70 ± 2.17 years (median, 1.5 years). The cumulative corticosteroid-free SCR at the end of follow-up (6 years) was 35%. The cumulative relapse-free survivals at 1, 2, and 4 years were 68%, 59%, and 42% respectively (Fig. 2).
2. Rates and Patterns of Relapse
Thirty-three patients (42.85%) suffered a total of 67 relapses over the entire follow-up period. Twelve (36.36%) of these 33 patients suffered > 1 relapses. Majority of the patients (n=27, 81.81%) relapsed within first 2 years of follow-up. Of the total 67 relapses, 64 (95.52%) were managed successfully with repeat courses of corticosteroids whereas 2 needed re-induction with IFX and 1 needed colectomy (Table 2). The factors that influenced corticosteroid-free SCR were evaluated. No significant effects of age, sex, disease duration, disease severity (Mayo score), disease extent, previous exposure to AZA and inflammatory markers (ESR, C-reactive protein, and albumin) were observed (Table 3).
3. Adverse Events
Eight patients had adverse events due to AZA (hepatotoxicity: n=4, pancreatitis: n=2, and leukopenia: n=2). Six of these discontinued AZA (hepatotoxicity: n=2, pancreatitis: n=2, and leukopenia: n=2) and were excluded from the analysis. Of these 6 patients, 2 underwent fecal microbiota transplantation, 1 was started on methotrexate and 3 patients shifted to complementary and alternative medicine. Two patients who had mildly elevated liver enzymes tolerated split dose AZA (AZA administered in 2 divided doses) and continued on therapy. None of the 2 patients who required re-induction with IFX had infusion reaction on re-induction infusions. Two patients died during the study period; 1due to surgical complications after colectomy and another due to myocardial infarction, unrelated to UC.
4. Cost-Benefit Analysis
Cost-benefit analysis was performed by comparing the therapeutic benefits (including the proportion of patients maintaining corticosteroid-free SCR and frequency of relapses) and costs incurred on the therapy. Comparisons were made for IFX used as maintenance therapy versus IFX used only for inducing remission and maintaining with 5-ASA and AZA. The relapse rates with IFX maintenance were derived from the existing literature reporting long-term efficacy of IFX. Annual costs were calculated based on absolute compliance to therapy, the number of relapses observed/expected and costs incurred on management of relapses. Maintenance therapy per capita per annum was cheaper by US$ 4,526 with 5-ASA and AZA as compared to maintaining remission with IFX (Table 4).
DISCUSSION
In acute severe UC, corticosteroids are the initially recommended drugs. However, a subset of patients is refractory to corticosteroids and need rescue therapy with IFX. Both ECCO (European Crohn’s and Colitis Organisation) and ACG (American College of Gastroenterology) guidelines recommend that remission achieved with IFX should be maintained with the same, either alone or in combination with thiopurines [13,14]. However, maintenance of remission with IFX every 8 weeks is difficult in real world settings in resource-limited countries like India. Apart from cost, there are safety concerns as the use of IFX in areas with high prevalence of tuberculosis carries a risk of reactivation, even in the absence of latent tuberculosis [15]. The present study highlights the role of combination therapy with AZA and 5-ASA as effective maintenance therapy for patients with severe steroid-refractory UC who required IFX as a rescue induction therapy. Cumulative corticosteroid-free SCR was achieved in 35% of patients at 6 years. A total of 67 relapses were observed in 33 patients. Majority of the relapses (45/67, 67.16%) occurred within first 2 years of follow-up. Two relapses were managed with re-induction with IFX, 1 required colectomy, whereas all other responded to repeat course(s) of corticosteroids.
Thiopurines are immunosuppressive agents with proven clinical efficacy and long-term safety in patients with IBD [16,17]. However, the primary obstacle to their use in an acute flare is their delayed onset of action. Therefore, IFX was used in the current study only to induce remission and rapidly decrease tumor necrosis factor (TNF)-α secretion; thereby normalizing dysregulated immunity, reducing intestinal inflammation, and restoring mucosal immune homeostasis [18-21]. The clinical remission achieved by IFX was subsequently maintained on AZA in combination with 5-ASA. A secondary loss of response is reported in nearly 30%–50% receiving maintenance therapy with IFX [22-24]. The ACT1 and ACT2 extension studies found that nearly 45% of patients had active disease at week 152 of follow-up [8]. Similarly, the cumulative rates of maintenance of remission with IFX monotherapy in single center studies from Belgium and Japan were also 68% at 3 years and 56.1% at 5 years, respectively [11,23].
IFX withdrawal after achieving remission has been attempted in patients with Crohn’s disease (CD), though not in UC [25,26]. In a retrospective analysis of patients with CD where IFX was withdrawn, 52% of patients remained in SCR after a median period of approximately 10 years [27]. The cumulative relapse-free survivals in our study, though in patients with UC, were 68%, 59%, 42%, and 35% patients at 1, 2, 4, and 6 years respectively.
The majority of episodes of relapse were seen in the first 2 years after initiation of 5-ASA and AZA. Most patients experiencing multiple relapses were also seen in the initial 2 years (Table 2, Fig. 2). A systematic review assessing relapse rates after discontinuation of anti-TNF treatment revealed a similar number of relapses at the end of 1 year (21.1%–39%), but relapse rates were much higher (37%–55.7%) at the end of 2 years [28]. Animal models of colitis have demonstrated that AZA induces production of interleukin 10 (IL-10) by T cells in cultures that are primed for > 6 days and not in early primed (< 2 days) cultures despite increasing concentrations of the drug [29]. AZA thus tilts the balance towards prominence of anti-inflammatory cytokines (decreased serum IL-6, IL-8, IL-17, TNF-α levels and increased IL-10, transforming growth factor β), after a lag period, and the frequency of relapses decreases with time. This could explain greater number of relapses in initial 2 years of follow-up. 5-ASA and AZA combination was well tolerated and only 6 patients, who were intolerant to AZA, had to stop thiopurines.
Patients who experienced relapses during long-term follow up in the current study rarely required a re-induction with IFX and could be managed with repeat course(s) of corticosteroids, suggesting that initial steroid refractoriness is not permanent. Even though a proportion of patients suffered repeated relapses over the period of follow-up (Table 2), majority of these subsequent relapses were also responsive to corticosteroids. Corticosteroids have both immunologic and anti-inflammatory properties, including inhibitory effects on nuclear factor-κB and activating protein-1 [30]. Resistance to corticosteroids is mediated by altered expression of transcription factors and/or cytokines. IL-2 has been shown to promote resistance to corticosteroids by reducing the nuclear translocation of glucocorticoid receptor. T cells from steroid-resistant individuals have been demonstrated to produce more IL-2 than T cells from steroid-sensitive individuals. Blocking IL-2 (via anti-IL-2 [basiliximab] or Janus kinase inhibitors [JAK1 and JAK3]) has been demonstrated to restore steroid sensitivity in vitro [31,32]. Thiopurines, especially AZA, have anti-proliferative effects that are mediated by direct inhibition of IL-2 and hence could help in re-establishment of response to corticosteroids [33]. AZA, along with 5-ASA, in the current study therefore may have resulted steroid responsiveness of the relapses occurring during follow up. The colectomy rate in our study was very low. However, colectomy could not be excluded in patients who were lost to follow-up.
The cost of AZA+5-ASA maintenance therapy (including the costs for management of relapses) was approximately INR 53,535 (US$ 733) per capita per year while maintenance with IFX alone would cost approximately INR 383,906 (US$ 5,259) per capita per year, which is nearly seven times higher. In a similar cost analysis of contemporary immunomodulatory and biologic strategies in CD, AZA monotherapy was found to be more cost effective than maintenance with IFX alone or IFX+AZA combination and it yielded similar quality-adjusted life years and rates of surgery [34].
This is the first study where IFX has been withdrawn after inducing remission in patients with UC. This is also the first study to document sustained benefit with use of combination of 5-ASA and AZA in maintaining remission achieved by IFX over a long time (up to 6 years). The limitations of our study include the lack of control group, retrospective analysis, high rates of attrition due to loss of follow-up (relapse and/or colectomy cannot be excluded in patients lost to follow-up) and use of clinical parameters to assess efficacy rather than a more precise end point like mucosal healing (endoscopy/biomarkers like fecal calprotectin). However, the present study documents AZA+5-ASA combination as an effective, safe and cost-beneficial alternative to maintain remission induced by IFX in acute severe steroid-refractory UC. Larger, prospective studies using the proposed regime are however needed.
To conclude, treatment strategies in resource constrained countries cannot match those followed in developed countries as the health care policies in these countries differ significantly. Induction of remission with IFX and subsequent maintenance with AZA and 5-ASA in patients with acute severe steroid-refractory UC seems to be an effective strategy, sustaining clinical remission over long term. Relapses occur on combination therapy of 5-ASA and AZA but vast majority of these relapses can be managed with repeat course(s) of corticosteroids.
Fig. 1. Flowchart of the patients in the current study. IFX, infliximab; AZA, azathioprine.
Fig. 2. Kaplan-Meier cumulative survival curve for corticosteroid-free sustained clinical remission (SCR).
Table 1. Baseline Characteristics of the Patients
Characteristics Value (n = 77)
Age (yr) 34.81 ± 13.32
Sex
Male 53 (68.83)
Female 24 (31.16)
Disease extent
E2 47 (61.03)
E3 30 (38.96)
Duration of disease (yr) 1.84 (0.25–17.00)
Total Mayo score (before IFX induction regimen) 8.87 ± 1.14
CRP (mg/L) 51.26 ± 64.14
ESR (mm/hr) 52.90 ± 20.18
Albumin (g/dL) 3.26 ± 0.85
Hemoglobin (g/dL) 9.98 ± 1.94
Previous AZA use
Experienced 27 (35.06)
Naïve 50 (64.93)
Values are presented as mean±standard deviation, number (%), or median (range).
E2, left-sided colitis; E3, pancolitis, IFX, infliximab; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; AZA, azathioprine.
Table 2. Patterns of Disease Relapse and Treatment
Year No. of patients with single relapse No. of patients with > 1 relapse No. of relapses
1 14a 8a 31
2 4b + 4a 2b + 1a 14
3 2b + 1a 2b + 1a 9
4 3b 2a 7
5 2a 1b 4
6 1b - 2
Total 67
Treatment Corticosteroids: 64 Infliximab: 2 (1 patient each in year 1 and 2) Colectomy: 1 (year 3)
a Patients with first relapse.
b Patients who also relapsed in previous years.
Table 3. Factors Influencing the Maintenance of Corticosteroid-Free Sustained Clinical Remission
Parameter Odds ratio 95% CI P-value
Age 1.00 0.97–1.03 0.74
Male sex 0.60 0.23–1.60 0.31
Disease duration 1.01 0.92–1.11 0.71
Disease extent E2 0.07 0.00–1.48 0.09
AZA naïve 0.68 0.24–1.90 0.47
Mayo score 1.13 0.74–1.71 0.56
Hemoglobin (g/dL) 1.01 0.77–1.32 0.92
ESR (mm/hr) 1.00 0.97–1.02 0.93
Albumin (g/L) 0.79 0.45–1.40 0.43
CRP (mg/L) 0.99 0.99–1.01 0.47
CI, confidence interval; E2, left-sided colitis; AZA, azathioprine; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein.
Table 4. Cost-Benefit Analysis (Annual) (n=77)
Maintenance therapy with 5-ASA+AZA INR (US$) Maintenance therapy with IFX INR (US$)
Number of days AZA +5-ASA consumed 365 Number of IFX doses needed per patient if used for maintenance of remission 6
Daily cost of AZA (100 mg/day) +5-ASA (4.8 g/day) 140 (1.91) Annual cost of IFX maintenance therapy for the entire cohort (C) 27,720,000 (3,79,726)
Annual cost of maintenance therapy with 5-ASA and AZA for the entire cohort (A) 39,34,700 (53,900) Cost of hospitalization and losses incurred due to absence from worka (D) 415,800 (5,695)
Total number of relapses observed at 1 year 31 Expected number of relapses on IFX therapy over the entire cohortb 19
Cost incurred on treatment of relapses with corticosteroids 7,500 (103) (n = 30, corticosteroids tapered over 16 weeks) - -
Cost incurred on treatment of relapses with IFX induction regimen 180,000 (2,465) (n = 1, IFX administered at a dose of 5 mg/kg at 0, 2, 6 weeks) - -
Cost incurred on colectomy - Cost incurred on treatment of relapse with colectomy in the entire cohortc (E) 1,425,000 (19,520)
Total cost incurred on management of relapses in the entire cohort (B) 187,500 (2,568)
Total cost incurred for the entire cohort (A+B) 4,122,200 (56,468) Total cost incurred for the entire cohort (C+D+E) 29,560,800 (404,942)
Average cost per person per year 53,535 (733) Average cost per person per year 383,906 (5,259)
All values are approximate 1US$ (INR 73). Annual cost difference per patient: INR 330,371 (US$ 4,526). Cohort size (n)=77; Cost of IFX originator: INR 20,000/100 mg; Cost of AZA 100 mg: INR 20; Cost of oral 5-ASA 4.8 g: INR 120; Cost of colectomy in a tertiary care center: INR 75,000; Costs calculated for average body weight of 60 kg.
a For a single day care admission approximate cost of hospitalization: INR 500 for a tertiary care hospital (data derived from World Health Organization report on Estimates of Unit Costs for Patient Services for India; available at https://www.who.int/choice/country/ind/cost/en/, accessed on October 18, 2020) and approximate loss of income due to absence from work: INR 370 (data derived from per capita income in India for 2018-2019; available at http://mospi.gov.in, accessed on October 18, 2020).
b Calculated considering average relapse rates of 25% and 30% at 1 year and 2 years respectively. [8,17,23,24]
c Biologics other than anti-tumor necrosis factor agents are not available in India, so the only therapeutic option for patient relapsing on IFX is colectomy.
5-ASA, 5-aminosalicylic acid; AZA, azathioprine; IFX, infliximab.
Funding Source
The authors received no financial support for the research, authorship, and/or publication of this article.
Conflict of Interest
Sood A is an editorial board member of the journal but was not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.
Author Contribution
Conceptualization: Mahajan R, Midha V, Sood A. Data curation: Kedia S, Kaur K, Sahu P, Singh D, Ahuja V. Formal analysis: Mahajan R, Singh A, Kaur K, Bansal N, Dharni K. Investigation: Mahajan R, Singh A, Kedia S, Kaur K, Singh D, Sood A. Methodology: Mahajan R, Singh A, Kedia S, Kaur K, Midha V, Sahu P, Mehta V, Kaushal S, Ahuja V, Sood A. Project administration: Mahajan R, Kedia S, Sood A. Resources: Midha V, Singh D, Sood A. Software: Singh A, Bansal N, Dharni K. Supervision: Mahajan R, Kedia S, Midha V, Ahuja V, Sood A. Visualization: Mahajan R, Singh A, Kedia S. Writing - original draft: Mahajan R, Singh A, Kedia S, Kaur K, Midha V, Sahu P, Mehta V, Ahuja V, Sood A. Writing - review & editing: Mahajan R, Singh A, Kedia S, Kaur K, Midha V, Sahu P, Mehta V, Bansal N, Dharni K, Kaushal S, Ahuja V, Sood A. Approval of final manuscript: all authors. | AZATHIOPRINE, INFLIXIMAB | DrugsGivenReaction | CC BY-NC | 33525859 | 18,907,208 | 2021-02-03 |
What was the administration route of drug 'INFLIXIMAB'? | Maintaining infliximab induced clinical remission with azathioprine and 5-aminosalicylates in acute severe steroid-refractory ulcerative colitis has lower cost and high efficacy (MIRACLE): a multicenter study.
Infliximab (IFX) has been used to induce and maintain remission in patients with severe steroid-refractory ulcerative colitis (UC). Long-term use of biologics in developing countries is limited by high cost and frequent side effects. An optimal maintenance strategy in these patients needs to be established.
A retrospective analysis of maintenance of clinical remission with combination of azathioprine (AZA) and 5-aminosalicylates (5-ASA) in patients with severe steroidrefractory UC where IFX (5 mg/kg intravenously at weeks 0, 2, 6) had been used only as an induction therapy was done at 2 centers in India. Primary outcome was the proportion of patients maintaining corticosteroid-free sustained clinical remission (SCR) at the end of study period. Rates of relapse and cost of therapy were also analyzed.
Of the 137 patients who received rescue IFX induction therapy, 77 (56.2%) achieved clinical remission (mean age 34.81 ± 13.32 years, 68.83% males, median follow-up 4 years, range 3 months to 6 years) and were included. Cumulative corticosteroid-free SCR was maintained in 68%, 59%, 42%, and 35% patients at 1, 2, 4, and 6 years respectively. Sixty-seven relapses were observed in 33 patients. Majority of the relapses (45/67, 67.16%) occurred within first 2 years of follow-up. Two relapses were managed with re-induction with IFX, one required colectomy, whereas all other responded to repeat course(s) of corticosteroids. Annual per capita maintenance therapy with 5-ASA and AZA was cheaper by US$ 4,526 compared to maintaining remission with IFX.
Clinical remission achieved with IFX induction therapy in severe steroid-refractory UC can be sustained over long time with a combination of AZA and 5-ASA.
pmcINTRODUCTION
Ulcerative colitis (UC) is a chronic inflammatory disease of the colon with a relapsing remitting course [1]. Acute severe exacerbations of the disease develop in 15% to 20% of the patients, requiring hospitalization and treatment with intravenous (IV) corticosteroids [2]. Though corticosteroids are effective in a majority of patients with severe UC, they are not a panpharmacon. Up to one-third of patients with acute severe UC may fail to respond to therapy with IV corticosteroids and hence require rescue therapy with IV cyclosporin A (CsA)/infliximab (IFX) or colectomy [3-7]. In patients where IFX is used as rescue therapy, continuation of an 8 weekly dosing schedule has been recommended for maintenance of remission. However, up to 30% of patients may not be able to continue IFX in the long run due to adverse events or a secondary loss of response [8,9]. Furthermore, the continued use of biologics for maintenance of remission is not feasible in developing countries where the health insurance coverage is minimal, placing significant economic burden on the patients. To sustain clinical remission in these patients, alternative maintenance therapies need to be studied. We present a multicenter experience of use of combination therapy with azathioprine (AZA) and 5-aminosalicylates (5-ASA) for maintenance of clinical remission in patients with acute severe steroid-refractory UC who achieved clinical remission with IFX induction regimen and IFX was stopped thereafter.
METHODS
1. Setting
This was a retrospective analysis of database from 2 tertiary care centers in north India; Dayanand Medical College and Hospital, Ludhiana and All India Institute of Medical Sciences, New Delhi. Patients with acute severe steroid-refractory UC who received IFX as a rescue induction therapy and subsequently maintained on 5-ASA and AZA between August 2005 and December 2017 were enrolled. The study was approved by Institutional Ethics Committee (IEC Nos. DMCH/R & D/2020/23 and IECPG-599/24.10.19) of both the institutions and performed in accordance with the principles of the Declaration of Helsinki. Written informed consent was obtained.
2. Study Population
Adult (≥ 18 years) patients with acute severe UC (defined as 6 or more stools with blood and 1 or more of the following hemoglobin < 10.5 g/dL, erythrocyte sedimentation rate [ESR] > 30 mm/hr, fever > 37.8°C, or tachycardia > 90/min; the Truelove Witts criteria) refractory to IV hydrocortisone (300–400 mg/day administered in 3 divided doses, used for 5–7 days) were offered rescue therapy with either IFX (originator, induction protocol: 5 mg/kg at weeks 0, 2 and 6)/CsA (2 mg/kg infusion for 5 days, followed by oral CsA acting as bridge to thiopurines); or colectomy. The current study is a retrospective analysis of treatment outcomes of the patients who opted for IFX as a rescue therapy and achieved clinical remission. Clinical remission was defined as partial Mayo score ≤ 1 at week 10 [10].
AZA was introduced/continued in all patients, whether AZA naïve or experienced, at the time of first dose of IFX induction regime. The patients who achieved clinical remission were followed for maintenance of corticosteroid-free sustained clinical remission (SCR) with combination therapy of AZA and 5-ASA. Corticosteroid-free SCR was defined as partial Mayo score ≤ 1 with absence of diarrhea and blood in stools and without need for new courses of corticosteroids or any other systemic drug (CsA, biologics, or investigational drugs) [11]. 5-ASA was used in a dose of 3.6–4.8 g/day and the dose of AZA was maintained at 1.5–2 mg/kg/day. All the patients were followed at an interval of 8–12 weeks, or earlier in case of worsening of symptoms. Disease activity (partial Mayo score) and concomitant pharmacotherapy were recorded for each visit. Patients with adverse events necessitating drug withdrawal were excluded.
Relapse was defined as partial Mayo score ≥ 3 [12]. In case of relapse, stool examination for infections including Clostridioides difficile; and IgM serology and histology for cytomegalovirus were performed. The management protocols for each relapse, including use of corticosteroids, biologics (IFX), CsA or surgery, were noted.
Patients with failure to achieve clinical remission with IFX induction therapy, incomplete induction protocol, active or latent tuberculosis, hepatitis B, hepatitis C, human immunodeficiency virus (HIV), pathogens on stool culture, contraindication to IFX or AZA according to labelling recommendations, previous use of multiple biologics, Crohn’s colitis/inflammatory bowel disease (IBD)-unclassified, pregnancy or lactation, and patients with missing data were excluded.
3. Cost-Benefit Analysis
Cost-benefit analysis of AZA plus 5-ASA was done in comparison to IFX maintenance. The cost of drug used in analysis was based on maximum retail price of the drugs. Annual expenditure (including the cost involved in treatment of relapses, hospitalization, rescue therapy and surgery) were estimated and compared between the 2 approaches.
4. Clinical Outcomes
The primary outcome was maintenance of corticosteroid-free SCR during the follow-up. Secondary outcomes included assessment of rates of relapses and their management and cost-benefit analysis.
5. Statistical Analysis
Descriptive statistics were provided with mean and standard deviation, median and interquartile range for continuous variables and frequency and percentage for categorical variables. Log-rank test was used to investigate the factors affecting relapse after cessation of IFX therapy. Using the standard α=0.05 cutoff, P<0.05 was considered statistically significant. Cumulative relapse-free survival (corticosteroid-free SCR) was calculated using Kaplan-Meier survival analysis. All statistical analyses were performed using Stata 12 (StataCorp. 2011. Stata Statistical Software: Release 12; StataCorp LP, College Station, TX, USA).
RESULTS
A total of 137 patients with acute severe UC were treated with IFX for inducing remission during the study period. Twenty-three patients (17.1%) did not respond to IFX and underwent colectomy, 5 (3.7%) had adverse events (tuberculosis: n=3; congestive heart failure: n=2) and 32 (23.4%) either had adverse events/poor compliance with AZA or were lost to follow-up. The 77 patients (56.2%) who achieved clinical remission were followed (median, follow up 4 years; range, 3 months–6 years) for disease course (Fig. 1). These patients were maintained on 5-ASA (median, 4.8 g/day; range, 3.6–4.8 g/day) and AZA (median, 100 mg/day; range, 50–150 mg/day). IFX was stopped after the induction regimen. The baseline characteristics of these patients are listed in Table 1.
1. Corticosteroid-Free SCR
Seventy-seven patients (mean age, 34.81 ± 13.32 years; 68.83% of males, n=53) with acute severe steroid-refractory UC achieving clinical remission with IFX were followed up. The mean duration of corticosteroid-free SCR with 5-ASA and AZA was 2.70 ± 2.17 years (median, 1.5 years). The cumulative corticosteroid-free SCR at the end of follow-up (6 years) was 35%. The cumulative relapse-free survivals at 1, 2, and 4 years were 68%, 59%, and 42% respectively (Fig. 2).
2. Rates and Patterns of Relapse
Thirty-three patients (42.85%) suffered a total of 67 relapses over the entire follow-up period. Twelve (36.36%) of these 33 patients suffered > 1 relapses. Majority of the patients (n=27, 81.81%) relapsed within first 2 years of follow-up. Of the total 67 relapses, 64 (95.52%) were managed successfully with repeat courses of corticosteroids whereas 2 needed re-induction with IFX and 1 needed colectomy (Table 2). The factors that influenced corticosteroid-free SCR were evaluated. No significant effects of age, sex, disease duration, disease severity (Mayo score), disease extent, previous exposure to AZA and inflammatory markers (ESR, C-reactive protein, and albumin) were observed (Table 3).
3. Adverse Events
Eight patients had adverse events due to AZA (hepatotoxicity: n=4, pancreatitis: n=2, and leukopenia: n=2). Six of these discontinued AZA (hepatotoxicity: n=2, pancreatitis: n=2, and leukopenia: n=2) and were excluded from the analysis. Of these 6 patients, 2 underwent fecal microbiota transplantation, 1 was started on methotrexate and 3 patients shifted to complementary and alternative medicine. Two patients who had mildly elevated liver enzymes tolerated split dose AZA (AZA administered in 2 divided doses) and continued on therapy. None of the 2 patients who required re-induction with IFX had infusion reaction on re-induction infusions. Two patients died during the study period; 1due to surgical complications after colectomy and another due to myocardial infarction, unrelated to UC.
4. Cost-Benefit Analysis
Cost-benefit analysis was performed by comparing the therapeutic benefits (including the proportion of patients maintaining corticosteroid-free SCR and frequency of relapses) and costs incurred on the therapy. Comparisons were made for IFX used as maintenance therapy versus IFX used only for inducing remission and maintaining with 5-ASA and AZA. The relapse rates with IFX maintenance were derived from the existing literature reporting long-term efficacy of IFX. Annual costs were calculated based on absolute compliance to therapy, the number of relapses observed/expected and costs incurred on management of relapses. Maintenance therapy per capita per annum was cheaper by US$ 4,526 with 5-ASA and AZA as compared to maintaining remission with IFX (Table 4).
DISCUSSION
In acute severe UC, corticosteroids are the initially recommended drugs. However, a subset of patients is refractory to corticosteroids and need rescue therapy with IFX. Both ECCO (European Crohn’s and Colitis Organisation) and ACG (American College of Gastroenterology) guidelines recommend that remission achieved with IFX should be maintained with the same, either alone or in combination with thiopurines [13,14]. However, maintenance of remission with IFX every 8 weeks is difficult in real world settings in resource-limited countries like India. Apart from cost, there are safety concerns as the use of IFX in areas with high prevalence of tuberculosis carries a risk of reactivation, even in the absence of latent tuberculosis [15]. The present study highlights the role of combination therapy with AZA and 5-ASA as effective maintenance therapy for patients with severe steroid-refractory UC who required IFX as a rescue induction therapy. Cumulative corticosteroid-free SCR was achieved in 35% of patients at 6 years. A total of 67 relapses were observed in 33 patients. Majority of the relapses (45/67, 67.16%) occurred within first 2 years of follow-up. Two relapses were managed with re-induction with IFX, 1 required colectomy, whereas all other responded to repeat course(s) of corticosteroids.
Thiopurines are immunosuppressive agents with proven clinical efficacy and long-term safety in patients with IBD [16,17]. However, the primary obstacle to their use in an acute flare is their delayed onset of action. Therefore, IFX was used in the current study only to induce remission and rapidly decrease tumor necrosis factor (TNF)-α secretion; thereby normalizing dysregulated immunity, reducing intestinal inflammation, and restoring mucosal immune homeostasis [18-21]. The clinical remission achieved by IFX was subsequently maintained on AZA in combination with 5-ASA. A secondary loss of response is reported in nearly 30%–50% receiving maintenance therapy with IFX [22-24]. The ACT1 and ACT2 extension studies found that nearly 45% of patients had active disease at week 152 of follow-up [8]. Similarly, the cumulative rates of maintenance of remission with IFX monotherapy in single center studies from Belgium and Japan were also 68% at 3 years and 56.1% at 5 years, respectively [11,23].
IFX withdrawal after achieving remission has been attempted in patients with Crohn’s disease (CD), though not in UC [25,26]. In a retrospective analysis of patients with CD where IFX was withdrawn, 52% of patients remained in SCR after a median period of approximately 10 years [27]. The cumulative relapse-free survivals in our study, though in patients with UC, were 68%, 59%, 42%, and 35% patients at 1, 2, 4, and 6 years respectively.
The majority of episodes of relapse were seen in the first 2 years after initiation of 5-ASA and AZA. Most patients experiencing multiple relapses were also seen in the initial 2 years (Table 2, Fig. 2). A systematic review assessing relapse rates after discontinuation of anti-TNF treatment revealed a similar number of relapses at the end of 1 year (21.1%–39%), but relapse rates were much higher (37%–55.7%) at the end of 2 years [28]. Animal models of colitis have demonstrated that AZA induces production of interleukin 10 (IL-10) by T cells in cultures that are primed for > 6 days and not in early primed (< 2 days) cultures despite increasing concentrations of the drug [29]. AZA thus tilts the balance towards prominence of anti-inflammatory cytokines (decreased serum IL-6, IL-8, IL-17, TNF-α levels and increased IL-10, transforming growth factor β), after a lag period, and the frequency of relapses decreases with time. This could explain greater number of relapses in initial 2 years of follow-up. 5-ASA and AZA combination was well tolerated and only 6 patients, who were intolerant to AZA, had to stop thiopurines.
Patients who experienced relapses during long-term follow up in the current study rarely required a re-induction with IFX and could be managed with repeat course(s) of corticosteroids, suggesting that initial steroid refractoriness is not permanent. Even though a proportion of patients suffered repeated relapses over the period of follow-up (Table 2), majority of these subsequent relapses were also responsive to corticosteroids. Corticosteroids have both immunologic and anti-inflammatory properties, including inhibitory effects on nuclear factor-κB and activating protein-1 [30]. Resistance to corticosteroids is mediated by altered expression of transcription factors and/or cytokines. IL-2 has been shown to promote resistance to corticosteroids by reducing the nuclear translocation of glucocorticoid receptor. T cells from steroid-resistant individuals have been demonstrated to produce more IL-2 than T cells from steroid-sensitive individuals. Blocking IL-2 (via anti-IL-2 [basiliximab] or Janus kinase inhibitors [JAK1 and JAK3]) has been demonstrated to restore steroid sensitivity in vitro [31,32]. Thiopurines, especially AZA, have anti-proliferative effects that are mediated by direct inhibition of IL-2 and hence could help in re-establishment of response to corticosteroids [33]. AZA, along with 5-ASA, in the current study therefore may have resulted steroid responsiveness of the relapses occurring during follow up. The colectomy rate in our study was very low. However, colectomy could not be excluded in patients who were lost to follow-up.
The cost of AZA+5-ASA maintenance therapy (including the costs for management of relapses) was approximately INR 53,535 (US$ 733) per capita per year while maintenance with IFX alone would cost approximately INR 383,906 (US$ 5,259) per capita per year, which is nearly seven times higher. In a similar cost analysis of contemporary immunomodulatory and biologic strategies in CD, AZA monotherapy was found to be more cost effective than maintenance with IFX alone or IFX+AZA combination and it yielded similar quality-adjusted life years and rates of surgery [34].
This is the first study where IFX has been withdrawn after inducing remission in patients with UC. This is also the first study to document sustained benefit with use of combination of 5-ASA and AZA in maintaining remission achieved by IFX over a long time (up to 6 years). The limitations of our study include the lack of control group, retrospective analysis, high rates of attrition due to loss of follow-up (relapse and/or colectomy cannot be excluded in patients lost to follow-up) and use of clinical parameters to assess efficacy rather than a more precise end point like mucosal healing (endoscopy/biomarkers like fecal calprotectin). However, the present study documents AZA+5-ASA combination as an effective, safe and cost-beneficial alternative to maintain remission induced by IFX in acute severe steroid-refractory UC. Larger, prospective studies using the proposed regime are however needed.
To conclude, treatment strategies in resource constrained countries cannot match those followed in developed countries as the health care policies in these countries differ significantly. Induction of remission with IFX and subsequent maintenance with AZA and 5-ASA in patients with acute severe steroid-refractory UC seems to be an effective strategy, sustaining clinical remission over long term. Relapses occur on combination therapy of 5-ASA and AZA but vast majority of these relapses can be managed with repeat course(s) of corticosteroids.
Fig. 1. Flowchart of the patients in the current study. IFX, infliximab; AZA, azathioprine.
Fig. 2. Kaplan-Meier cumulative survival curve for corticosteroid-free sustained clinical remission (SCR).
Table 1. Baseline Characteristics of the Patients
Characteristics Value (n = 77)
Age (yr) 34.81 ± 13.32
Sex
Male 53 (68.83)
Female 24 (31.16)
Disease extent
E2 47 (61.03)
E3 30 (38.96)
Duration of disease (yr) 1.84 (0.25–17.00)
Total Mayo score (before IFX induction regimen) 8.87 ± 1.14
CRP (mg/L) 51.26 ± 64.14
ESR (mm/hr) 52.90 ± 20.18
Albumin (g/dL) 3.26 ± 0.85
Hemoglobin (g/dL) 9.98 ± 1.94
Previous AZA use
Experienced 27 (35.06)
Naïve 50 (64.93)
Values are presented as mean±standard deviation, number (%), or median (range).
E2, left-sided colitis; E3, pancolitis, IFX, infliximab; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; AZA, azathioprine.
Table 2. Patterns of Disease Relapse and Treatment
Year No. of patients with single relapse No. of patients with > 1 relapse No. of relapses
1 14a 8a 31
2 4b + 4a 2b + 1a 14
3 2b + 1a 2b + 1a 9
4 3b 2a 7
5 2a 1b 4
6 1b - 2
Total 67
Treatment Corticosteroids: 64 Infliximab: 2 (1 patient each in year 1 and 2) Colectomy: 1 (year 3)
a Patients with first relapse.
b Patients who also relapsed in previous years.
Table 3. Factors Influencing the Maintenance of Corticosteroid-Free Sustained Clinical Remission
Parameter Odds ratio 95% CI P-value
Age 1.00 0.97–1.03 0.74
Male sex 0.60 0.23–1.60 0.31
Disease duration 1.01 0.92–1.11 0.71
Disease extent E2 0.07 0.00–1.48 0.09
AZA naïve 0.68 0.24–1.90 0.47
Mayo score 1.13 0.74–1.71 0.56
Hemoglobin (g/dL) 1.01 0.77–1.32 0.92
ESR (mm/hr) 1.00 0.97–1.02 0.93
Albumin (g/L) 0.79 0.45–1.40 0.43
CRP (mg/L) 0.99 0.99–1.01 0.47
CI, confidence interval; E2, left-sided colitis; AZA, azathioprine; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein.
Table 4. Cost-Benefit Analysis (Annual) (n=77)
Maintenance therapy with 5-ASA+AZA INR (US$) Maintenance therapy with IFX INR (US$)
Number of days AZA +5-ASA consumed 365 Number of IFX doses needed per patient if used for maintenance of remission 6
Daily cost of AZA (100 mg/day) +5-ASA (4.8 g/day) 140 (1.91) Annual cost of IFX maintenance therapy for the entire cohort (C) 27,720,000 (3,79,726)
Annual cost of maintenance therapy with 5-ASA and AZA for the entire cohort (A) 39,34,700 (53,900) Cost of hospitalization and losses incurred due to absence from worka (D) 415,800 (5,695)
Total number of relapses observed at 1 year 31 Expected number of relapses on IFX therapy over the entire cohortb 19
Cost incurred on treatment of relapses with corticosteroids 7,500 (103) (n = 30, corticosteroids tapered over 16 weeks) - -
Cost incurred on treatment of relapses with IFX induction regimen 180,000 (2,465) (n = 1, IFX administered at a dose of 5 mg/kg at 0, 2, 6 weeks) - -
Cost incurred on colectomy - Cost incurred on treatment of relapse with colectomy in the entire cohortc (E) 1,425,000 (19,520)
Total cost incurred on management of relapses in the entire cohort (B) 187,500 (2,568)
Total cost incurred for the entire cohort (A+B) 4,122,200 (56,468) Total cost incurred for the entire cohort (C+D+E) 29,560,800 (404,942)
Average cost per person per year 53,535 (733) Average cost per person per year 383,906 (5,259)
All values are approximate 1US$ (INR 73). Annual cost difference per patient: INR 330,371 (US$ 4,526). Cohort size (n)=77; Cost of IFX originator: INR 20,000/100 mg; Cost of AZA 100 mg: INR 20; Cost of oral 5-ASA 4.8 g: INR 120; Cost of colectomy in a tertiary care center: INR 75,000; Costs calculated for average body weight of 60 kg.
a For a single day care admission approximate cost of hospitalization: INR 500 for a tertiary care hospital (data derived from World Health Organization report on Estimates of Unit Costs for Patient Services for India; available at https://www.who.int/choice/country/ind/cost/en/, accessed on October 18, 2020) and approximate loss of income due to absence from work: INR 370 (data derived from per capita income in India for 2018-2019; available at http://mospi.gov.in, accessed on October 18, 2020).
b Calculated considering average relapse rates of 25% and 30% at 1 year and 2 years respectively. [8,17,23,24]
c Biologics other than anti-tumor necrosis factor agents are not available in India, so the only therapeutic option for patient relapsing on IFX is colectomy.
5-ASA, 5-aminosalicylic acid; AZA, azathioprine; IFX, infliximab.
Funding Source
The authors received no financial support for the research, authorship, and/or publication of this article.
Conflict of Interest
Sood A is an editorial board member of the journal but was not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.
Author Contribution
Conceptualization: Mahajan R, Midha V, Sood A. Data curation: Kedia S, Kaur K, Sahu P, Singh D, Ahuja V. Formal analysis: Mahajan R, Singh A, Kaur K, Bansal N, Dharni K. Investigation: Mahajan R, Singh A, Kedia S, Kaur K, Singh D, Sood A. Methodology: Mahajan R, Singh A, Kedia S, Kaur K, Midha V, Sahu P, Mehta V, Kaushal S, Ahuja V, Sood A. Project administration: Mahajan R, Kedia S, Sood A. Resources: Midha V, Singh D, Sood A. Software: Singh A, Bansal N, Dharni K. Supervision: Mahajan R, Kedia S, Midha V, Ahuja V, Sood A. Visualization: Mahajan R, Singh A, Kedia S. Writing - original draft: Mahajan R, Singh A, Kedia S, Kaur K, Midha V, Sahu P, Mehta V, Ahuja V, Sood A. Writing - review & editing: Mahajan R, Singh A, Kedia S, Kaur K, Midha V, Sahu P, Mehta V, Bansal N, Dharni K, Kaushal S, Ahuja V, Sood A. Approval of final manuscript: all authors. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33525859 | 18,907,208 | 2021-02-03 |
What was the dosage of drug 'INFLIXIMAB'? | Maintaining infliximab induced clinical remission with azathioprine and 5-aminosalicylates in acute severe steroid-refractory ulcerative colitis has lower cost and high efficacy (MIRACLE): a multicenter study.
Infliximab (IFX) has been used to induce and maintain remission in patients with severe steroid-refractory ulcerative colitis (UC). Long-term use of biologics in developing countries is limited by high cost and frequent side effects. An optimal maintenance strategy in these patients needs to be established.
A retrospective analysis of maintenance of clinical remission with combination of azathioprine (AZA) and 5-aminosalicylates (5-ASA) in patients with severe steroidrefractory UC where IFX (5 mg/kg intravenously at weeks 0, 2, 6) had been used only as an induction therapy was done at 2 centers in India. Primary outcome was the proportion of patients maintaining corticosteroid-free sustained clinical remission (SCR) at the end of study period. Rates of relapse and cost of therapy were also analyzed.
Of the 137 patients who received rescue IFX induction therapy, 77 (56.2%) achieved clinical remission (mean age 34.81 ± 13.32 years, 68.83% males, median follow-up 4 years, range 3 months to 6 years) and were included. Cumulative corticosteroid-free SCR was maintained in 68%, 59%, 42%, and 35% patients at 1, 2, 4, and 6 years respectively. Sixty-seven relapses were observed in 33 patients. Majority of the relapses (45/67, 67.16%) occurred within first 2 years of follow-up. Two relapses were managed with re-induction with IFX, one required colectomy, whereas all other responded to repeat course(s) of corticosteroids. Annual per capita maintenance therapy with 5-ASA and AZA was cheaper by US$ 4,526 compared to maintaining remission with IFX.
Clinical remission achieved with IFX induction therapy in severe steroid-refractory UC can be sustained over long time with a combination of AZA and 5-ASA.
pmcINTRODUCTION
Ulcerative colitis (UC) is a chronic inflammatory disease of the colon with a relapsing remitting course [1]. Acute severe exacerbations of the disease develop in 15% to 20% of the patients, requiring hospitalization and treatment with intravenous (IV) corticosteroids [2]. Though corticosteroids are effective in a majority of patients with severe UC, they are not a panpharmacon. Up to one-third of patients with acute severe UC may fail to respond to therapy with IV corticosteroids and hence require rescue therapy with IV cyclosporin A (CsA)/infliximab (IFX) or colectomy [3-7]. In patients where IFX is used as rescue therapy, continuation of an 8 weekly dosing schedule has been recommended for maintenance of remission. However, up to 30% of patients may not be able to continue IFX in the long run due to adverse events or a secondary loss of response [8,9]. Furthermore, the continued use of biologics for maintenance of remission is not feasible in developing countries where the health insurance coverage is minimal, placing significant economic burden on the patients. To sustain clinical remission in these patients, alternative maintenance therapies need to be studied. We present a multicenter experience of use of combination therapy with azathioprine (AZA) and 5-aminosalicylates (5-ASA) for maintenance of clinical remission in patients with acute severe steroid-refractory UC who achieved clinical remission with IFX induction regimen and IFX was stopped thereafter.
METHODS
1. Setting
This was a retrospective analysis of database from 2 tertiary care centers in north India; Dayanand Medical College and Hospital, Ludhiana and All India Institute of Medical Sciences, New Delhi. Patients with acute severe steroid-refractory UC who received IFX as a rescue induction therapy and subsequently maintained on 5-ASA and AZA between August 2005 and December 2017 were enrolled. The study was approved by Institutional Ethics Committee (IEC Nos. DMCH/R & D/2020/23 and IECPG-599/24.10.19) of both the institutions and performed in accordance with the principles of the Declaration of Helsinki. Written informed consent was obtained.
2. Study Population
Adult (≥ 18 years) patients with acute severe UC (defined as 6 or more stools with blood and 1 or more of the following hemoglobin < 10.5 g/dL, erythrocyte sedimentation rate [ESR] > 30 mm/hr, fever > 37.8°C, or tachycardia > 90/min; the Truelove Witts criteria) refractory to IV hydrocortisone (300–400 mg/day administered in 3 divided doses, used for 5–7 days) were offered rescue therapy with either IFX (originator, induction protocol: 5 mg/kg at weeks 0, 2 and 6)/CsA (2 mg/kg infusion for 5 days, followed by oral CsA acting as bridge to thiopurines); or colectomy. The current study is a retrospective analysis of treatment outcomes of the patients who opted for IFX as a rescue therapy and achieved clinical remission. Clinical remission was defined as partial Mayo score ≤ 1 at week 10 [10].
AZA was introduced/continued in all patients, whether AZA naïve or experienced, at the time of first dose of IFX induction regime. The patients who achieved clinical remission were followed for maintenance of corticosteroid-free sustained clinical remission (SCR) with combination therapy of AZA and 5-ASA. Corticosteroid-free SCR was defined as partial Mayo score ≤ 1 with absence of diarrhea and blood in stools and without need for new courses of corticosteroids or any other systemic drug (CsA, biologics, or investigational drugs) [11]. 5-ASA was used in a dose of 3.6–4.8 g/day and the dose of AZA was maintained at 1.5–2 mg/kg/day. All the patients were followed at an interval of 8–12 weeks, or earlier in case of worsening of symptoms. Disease activity (partial Mayo score) and concomitant pharmacotherapy were recorded for each visit. Patients with adverse events necessitating drug withdrawal were excluded.
Relapse was defined as partial Mayo score ≥ 3 [12]. In case of relapse, stool examination for infections including Clostridioides difficile; and IgM serology and histology for cytomegalovirus were performed. The management protocols for each relapse, including use of corticosteroids, biologics (IFX), CsA or surgery, were noted.
Patients with failure to achieve clinical remission with IFX induction therapy, incomplete induction protocol, active or latent tuberculosis, hepatitis B, hepatitis C, human immunodeficiency virus (HIV), pathogens on stool culture, contraindication to IFX or AZA according to labelling recommendations, previous use of multiple biologics, Crohn’s colitis/inflammatory bowel disease (IBD)-unclassified, pregnancy or lactation, and patients with missing data were excluded.
3. Cost-Benefit Analysis
Cost-benefit analysis of AZA plus 5-ASA was done in comparison to IFX maintenance. The cost of drug used in analysis was based on maximum retail price of the drugs. Annual expenditure (including the cost involved in treatment of relapses, hospitalization, rescue therapy and surgery) were estimated and compared between the 2 approaches.
4. Clinical Outcomes
The primary outcome was maintenance of corticosteroid-free SCR during the follow-up. Secondary outcomes included assessment of rates of relapses and their management and cost-benefit analysis.
5. Statistical Analysis
Descriptive statistics were provided with mean and standard deviation, median and interquartile range for continuous variables and frequency and percentage for categorical variables. Log-rank test was used to investigate the factors affecting relapse after cessation of IFX therapy. Using the standard α=0.05 cutoff, P<0.05 was considered statistically significant. Cumulative relapse-free survival (corticosteroid-free SCR) was calculated using Kaplan-Meier survival analysis. All statistical analyses were performed using Stata 12 (StataCorp. 2011. Stata Statistical Software: Release 12; StataCorp LP, College Station, TX, USA).
RESULTS
A total of 137 patients with acute severe UC were treated with IFX for inducing remission during the study period. Twenty-three patients (17.1%) did not respond to IFX and underwent colectomy, 5 (3.7%) had adverse events (tuberculosis: n=3; congestive heart failure: n=2) and 32 (23.4%) either had adverse events/poor compliance with AZA or were lost to follow-up. The 77 patients (56.2%) who achieved clinical remission were followed (median, follow up 4 years; range, 3 months–6 years) for disease course (Fig. 1). These patients were maintained on 5-ASA (median, 4.8 g/day; range, 3.6–4.8 g/day) and AZA (median, 100 mg/day; range, 50–150 mg/day). IFX was stopped after the induction regimen. The baseline characteristics of these patients are listed in Table 1.
1. Corticosteroid-Free SCR
Seventy-seven patients (mean age, 34.81 ± 13.32 years; 68.83% of males, n=53) with acute severe steroid-refractory UC achieving clinical remission with IFX were followed up. The mean duration of corticosteroid-free SCR with 5-ASA and AZA was 2.70 ± 2.17 years (median, 1.5 years). The cumulative corticosteroid-free SCR at the end of follow-up (6 years) was 35%. The cumulative relapse-free survivals at 1, 2, and 4 years were 68%, 59%, and 42% respectively (Fig. 2).
2. Rates and Patterns of Relapse
Thirty-three patients (42.85%) suffered a total of 67 relapses over the entire follow-up period. Twelve (36.36%) of these 33 patients suffered > 1 relapses. Majority of the patients (n=27, 81.81%) relapsed within first 2 years of follow-up. Of the total 67 relapses, 64 (95.52%) were managed successfully with repeat courses of corticosteroids whereas 2 needed re-induction with IFX and 1 needed colectomy (Table 2). The factors that influenced corticosteroid-free SCR were evaluated. No significant effects of age, sex, disease duration, disease severity (Mayo score), disease extent, previous exposure to AZA and inflammatory markers (ESR, C-reactive protein, and albumin) were observed (Table 3).
3. Adverse Events
Eight patients had adverse events due to AZA (hepatotoxicity: n=4, pancreatitis: n=2, and leukopenia: n=2). Six of these discontinued AZA (hepatotoxicity: n=2, pancreatitis: n=2, and leukopenia: n=2) and were excluded from the analysis. Of these 6 patients, 2 underwent fecal microbiota transplantation, 1 was started on methotrexate and 3 patients shifted to complementary and alternative medicine. Two patients who had mildly elevated liver enzymes tolerated split dose AZA (AZA administered in 2 divided doses) and continued on therapy. None of the 2 patients who required re-induction with IFX had infusion reaction on re-induction infusions. Two patients died during the study period; 1due to surgical complications after colectomy and another due to myocardial infarction, unrelated to UC.
4. Cost-Benefit Analysis
Cost-benefit analysis was performed by comparing the therapeutic benefits (including the proportion of patients maintaining corticosteroid-free SCR and frequency of relapses) and costs incurred on the therapy. Comparisons were made for IFX used as maintenance therapy versus IFX used only for inducing remission and maintaining with 5-ASA and AZA. The relapse rates with IFX maintenance were derived from the existing literature reporting long-term efficacy of IFX. Annual costs were calculated based on absolute compliance to therapy, the number of relapses observed/expected and costs incurred on management of relapses. Maintenance therapy per capita per annum was cheaper by US$ 4,526 with 5-ASA and AZA as compared to maintaining remission with IFX (Table 4).
DISCUSSION
In acute severe UC, corticosteroids are the initially recommended drugs. However, a subset of patients is refractory to corticosteroids and need rescue therapy with IFX. Both ECCO (European Crohn’s and Colitis Organisation) and ACG (American College of Gastroenterology) guidelines recommend that remission achieved with IFX should be maintained with the same, either alone or in combination with thiopurines [13,14]. However, maintenance of remission with IFX every 8 weeks is difficult in real world settings in resource-limited countries like India. Apart from cost, there are safety concerns as the use of IFX in areas with high prevalence of tuberculosis carries a risk of reactivation, even in the absence of latent tuberculosis [15]. The present study highlights the role of combination therapy with AZA and 5-ASA as effective maintenance therapy for patients with severe steroid-refractory UC who required IFX as a rescue induction therapy. Cumulative corticosteroid-free SCR was achieved in 35% of patients at 6 years. A total of 67 relapses were observed in 33 patients. Majority of the relapses (45/67, 67.16%) occurred within first 2 years of follow-up. Two relapses were managed with re-induction with IFX, 1 required colectomy, whereas all other responded to repeat course(s) of corticosteroids.
Thiopurines are immunosuppressive agents with proven clinical efficacy and long-term safety in patients with IBD [16,17]. However, the primary obstacle to their use in an acute flare is their delayed onset of action. Therefore, IFX was used in the current study only to induce remission and rapidly decrease tumor necrosis factor (TNF)-α secretion; thereby normalizing dysregulated immunity, reducing intestinal inflammation, and restoring mucosal immune homeostasis [18-21]. The clinical remission achieved by IFX was subsequently maintained on AZA in combination with 5-ASA. A secondary loss of response is reported in nearly 30%–50% receiving maintenance therapy with IFX [22-24]. The ACT1 and ACT2 extension studies found that nearly 45% of patients had active disease at week 152 of follow-up [8]. Similarly, the cumulative rates of maintenance of remission with IFX monotherapy in single center studies from Belgium and Japan were also 68% at 3 years and 56.1% at 5 years, respectively [11,23].
IFX withdrawal after achieving remission has been attempted in patients with Crohn’s disease (CD), though not in UC [25,26]. In a retrospective analysis of patients with CD where IFX was withdrawn, 52% of patients remained in SCR after a median period of approximately 10 years [27]. The cumulative relapse-free survivals in our study, though in patients with UC, were 68%, 59%, 42%, and 35% patients at 1, 2, 4, and 6 years respectively.
The majority of episodes of relapse were seen in the first 2 years after initiation of 5-ASA and AZA. Most patients experiencing multiple relapses were also seen in the initial 2 years (Table 2, Fig. 2). A systematic review assessing relapse rates after discontinuation of anti-TNF treatment revealed a similar number of relapses at the end of 1 year (21.1%–39%), but relapse rates were much higher (37%–55.7%) at the end of 2 years [28]. Animal models of colitis have demonstrated that AZA induces production of interleukin 10 (IL-10) by T cells in cultures that are primed for > 6 days and not in early primed (< 2 days) cultures despite increasing concentrations of the drug [29]. AZA thus tilts the balance towards prominence of anti-inflammatory cytokines (decreased serum IL-6, IL-8, IL-17, TNF-α levels and increased IL-10, transforming growth factor β), after a lag period, and the frequency of relapses decreases with time. This could explain greater number of relapses in initial 2 years of follow-up. 5-ASA and AZA combination was well tolerated and only 6 patients, who were intolerant to AZA, had to stop thiopurines.
Patients who experienced relapses during long-term follow up in the current study rarely required a re-induction with IFX and could be managed with repeat course(s) of corticosteroids, suggesting that initial steroid refractoriness is not permanent. Even though a proportion of patients suffered repeated relapses over the period of follow-up (Table 2), majority of these subsequent relapses were also responsive to corticosteroids. Corticosteroids have both immunologic and anti-inflammatory properties, including inhibitory effects on nuclear factor-κB and activating protein-1 [30]. Resistance to corticosteroids is mediated by altered expression of transcription factors and/or cytokines. IL-2 has been shown to promote resistance to corticosteroids by reducing the nuclear translocation of glucocorticoid receptor. T cells from steroid-resistant individuals have been demonstrated to produce more IL-2 than T cells from steroid-sensitive individuals. Blocking IL-2 (via anti-IL-2 [basiliximab] or Janus kinase inhibitors [JAK1 and JAK3]) has been demonstrated to restore steroid sensitivity in vitro [31,32]. Thiopurines, especially AZA, have anti-proliferative effects that are mediated by direct inhibition of IL-2 and hence could help in re-establishment of response to corticosteroids [33]. AZA, along with 5-ASA, in the current study therefore may have resulted steroid responsiveness of the relapses occurring during follow up. The colectomy rate in our study was very low. However, colectomy could not be excluded in patients who were lost to follow-up.
The cost of AZA+5-ASA maintenance therapy (including the costs for management of relapses) was approximately INR 53,535 (US$ 733) per capita per year while maintenance with IFX alone would cost approximately INR 383,906 (US$ 5,259) per capita per year, which is nearly seven times higher. In a similar cost analysis of contemporary immunomodulatory and biologic strategies in CD, AZA monotherapy was found to be more cost effective than maintenance with IFX alone or IFX+AZA combination and it yielded similar quality-adjusted life years and rates of surgery [34].
This is the first study where IFX has been withdrawn after inducing remission in patients with UC. This is also the first study to document sustained benefit with use of combination of 5-ASA and AZA in maintaining remission achieved by IFX over a long time (up to 6 years). The limitations of our study include the lack of control group, retrospective analysis, high rates of attrition due to loss of follow-up (relapse and/or colectomy cannot be excluded in patients lost to follow-up) and use of clinical parameters to assess efficacy rather than a more precise end point like mucosal healing (endoscopy/biomarkers like fecal calprotectin). However, the present study documents AZA+5-ASA combination as an effective, safe and cost-beneficial alternative to maintain remission induced by IFX in acute severe steroid-refractory UC. Larger, prospective studies using the proposed regime are however needed.
To conclude, treatment strategies in resource constrained countries cannot match those followed in developed countries as the health care policies in these countries differ significantly. Induction of remission with IFX and subsequent maintenance with AZA and 5-ASA in patients with acute severe steroid-refractory UC seems to be an effective strategy, sustaining clinical remission over long term. Relapses occur on combination therapy of 5-ASA and AZA but vast majority of these relapses can be managed with repeat course(s) of corticosteroids.
Fig. 1. Flowchart of the patients in the current study. IFX, infliximab; AZA, azathioprine.
Fig. 2. Kaplan-Meier cumulative survival curve for corticosteroid-free sustained clinical remission (SCR).
Table 1. Baseline Characteristics of the Patients
Characteristics Value (n = 77)
Age (yr) 34.81 ± 13.32
Sex
Male 53 (68.83)
Female 24 (31.16)
Disease extent
E2 47 (61.03)
E3 30 (38.96)
Duration of disease (yr) 1.84 (0.25–17.00)
Total Mayo score (before IFX induction regimen) 8.87 ± 1.14
CRP (mg/L) 51.26 ± 64.14
ESR (mm/hr) 52.90 ± 20.18
Albumin (g/dL) 3.26 ± 0.85
Hemoglobin (g/dL) 9.98 ± 1.94
Previous AZA use
Experienced 27 (35.06)
Naïve 50 (64.93)
Values are presented as mean±standard deviation, number (%), or median (range).
E2, left-sided colitis; E3, pancolitis, IFX, infliximab; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; AZA, azathioprine.
Table 2. Patterns of Disease Relapse and Treatment
Year No. of patients with single relapse No. of patients with > 1 relapse No. of relapses
1 14a 8a 31
2 4b + 4a 2b + 1a 14
3 2b + 1a 2b + 1a 9
4 3b 2a 7
5 2a 1b 4
6 1b - 2
Total 67
Treatment Corticosteroids: 64 Infliximab: 2 (1 patient each in year 1 and 2) Colectomy: 1 (year 3)
a Patients with first relapse.
b Patients who also relapsed in previous years.
Table 3. Factors Influencing the Maintenance of Corticosteroid-Free Sustained Clinical Remission
Parameter Odds ratio 95% CI P-value
Age 1.00 0.97–1.03 0.74
Male sex 0.60 0.23–1.60 0.31
Disease duration 1.01 0.92–1.11 0.71
Disease extent E2 0.07 0.00–1.48 0.09
AZA naïve 0.68 0.24–1.90 0.47
Mayo score 1.13 0.74–1.71 0.56
Hemoglobin (g/dL) 1.01 0.77–1.32 0.92
ESR (mm/hr) 1.00 0.97–1.02 0.93
Albumin (g/L) 0.79 0.45–1.40 0.43
CRP (mg/L) 0.99 0.99–1.01 0.47
CI, confidence interval; E2, left-sided colitis; AZA, azathioprine; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein.
Table 4. Cost-Benefit Analysis (Annual) (n=77)
Maintenance therapy with 5-ASA+AZA INR (US$) Maintenance therapy with IFX INR (US$)
Number of days AZA +5-ASA consumed 365 Number of IFX doses needed per patient if used for maintenance of remission 6
Daily cost of AZA (100 mg/day) +5-ASA (4.8 g/day) 140 (1.91) Annual cost of IFX maintenance therapy for the entire cohort (C) 27,720,000 (3,79,726)
Annual cost of maintenance therapy with 5-ASA and AZA for the entire cohort (A) 39,34,700 (53,900) Cost of hospitalization and losses incurred due to absence from worka (D) 415,800 (5,695)
Total number of relapses observed at 1 year 31 Expected number of relapses on IFX therapy over the entire cohortb 19
Cost incurred on treatment of relapses with corticosteroids 7,500 (103) (n = 30, corticosteroids tapered over 16 weeks) - -
Cost incurred on treatment of relapses with IFX induction regimen 180,000 (2,465) (n = 1, IFX administered at a dose of 5 mg/kg at 0, 2, 6 weeks) - -
Cost incurred on colectomy - Cost incurred on treatment of relapse with colectomy in the entire cohortc (E) 1,425,000 (19,520)
Total cost incurred on management of relapses in the entire cohort (B) 187,500 (2,568)
Total cost incurred for the entire cohort (A+B) 4,122,200 (56,468) Total cost incurred for the entire cohort (C+D+E) 29,560,800 (404,942)
Average cost per person per year 53,535 (733) Average cost per person per year 383,906 (5,259)
All values are approximate 1US$ (INR 73). Annual cost difference per patient: INR 330,371 (US$ 4,526). Cohort size (n)=77; Cost of IFX originator: INR 20,000/100 mg; Cost of AZA 100 mg: INR 20; Cost of oral 5-ASA 4.8 g: INR 120; Cost of colectomy in a tertiary care center: INR 75,000; Costs calculated for average body weight of 60 kg.
a For a single day care admission approximate cost of hospitalization: INR 500 for a tertiary care hospital (data derived from World Health Organization report on Estimates of Unit Costs for Patient Services for India; available at https://www.who.int/choice/country/ind/cost/en/, accessed on October 18, 2020) and approximate loss of income due to absence from work: INR 370 (data derived from per capita income in India for 2018-2019; available at http://mospi.gov.in, accessed on October 18, 2020).
b Calculated considering average relapse rates of 25% and 30% at 1 year and 2 years respectively. [8,17,23,24]
c Biologics other than anti-tumor necrosis factor agents are not available in India, so the only therapeutic option for patient relapsing on IFX is colectomy.
5-ASA, 5-aminosalicylic acid; AZA, azathioprine; IFX, infliximab.
Funding Source
The authors received no financial support for the research, authorship, and/or publication of this article.
Conflict of Interest
Sood A is an editorial board member of the journal but was not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.
Author Contribution
Conceptualization: Mahajan R, Midha V, Sood A. Data curation: Kedia S, Kaur K, Sahu P, Singh D, Ahuja V. Formal analysis: Mahajan R, Singh A, Kaur K, Bansal N, Dharni K. Investigation: Mahajan R, Singh A, Kedia S, Kaur K, Singh D, Sood A. Methodology: Mahajan R, Singh A, Kedia S, Kaur K, Midha V, Sahu P, Mehta V, Kaushal S, Ahuja V, Sood A. Project administration: Mahajan R, Kedia S, Sood A. Resources: Midha V, Singh D, Sood A. Software: Singh A, Bansal N, Dharni K. Supervision: Mahajan R, Kedia S, Midha V, Ahuja V, Sood A. Visualization: Mahajan R, Singh A, Kedia S. Writing - original draft: Mahajan R, Singh A, Kedia S, Kaur K, Midha V, Sahu P, Mehta V, Ahuja V, Sood A. Writing - review & editing: Mahajan R, Singh A, Kedia S, Kaur K, Midha V, Sahu P, Mehta V, Bansal N, Dharni K, Kaushal S, Ahuja V, Sood A. Approval of final manuscript: all authors. | AT WEEKS 0, 2 AND 6 | DrugDosageText | CC BY-NC | 33525859 | 18,907,208 | 2021-02-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acute respiratory failure'. | Chemotherapy-induced myasthenic crisis in thymoma treated with primary chemotherapy with curative intent on mechanical ventilation: a case report and review of the literature.
BACKGROUND
Thymoma is an uncommon cancer often associated with myasthenia gravis, an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced nonmetastatic thymoma, primary chemotherapy may be required to induce tumor shrinkage and to achieve radical resection. Cancer chemotherapy has been anecdotally reported as a trigger factor for worsening of myasthenia gravis in thymic epithelial cancers. The study of uncommon cases of chemotherapy-related myasthenic crisis is warranted to gain knowledge of clinical situations requiring intensive care support in the case of life-threatening respiratory failure.
METHODS
We report a case of an 18-year-old Caucasian woman with advanced Masaoka-Koga stage III type B2 thymoma and myasthenia gravis on treatment with pyridostigmine, steroids and intravenous immunoglobulins, who developed a myasthenic crisis 2 hours after initiation of cyclophosphamide/doxorubicin/cisplatin primary chemotherapy. Because of severe acute respiratory failure, emergency tracheal intubation, mechanical ventilation, and temporary (2 hours) discontinuation of chemotherapy were needed. Considering the curative intent of the multimodal therapeutic program, we elected to resume primary chemotherapy administration while the patient remained on mechanical ventilation. After 24 hours, the recovery of adequate respiratory function allowed successful weaning from respiratory support, and no further adverse events occurred. After 3 weeks, upon plasma exchange initiation with amelioration of myasthenic symptoms, a second course of chemotherapy was given, and in week 6, having documented partial tumor remission, the patient underwent radical surgery (R0) and then consolidation radiation therapy with 50.4 Gy in 28 fractions in weeks 15-20.
CONCLUSIONS
This case report, together with the only four available in a review of the literature, highlights that chemotherapy may carry the risk of myasthenic crisis in patients affected by thymoma and myasthenia gravis. To our knowledge, this is the first reported case of chemotherapy continuation on mechanical ventilation in a patient with chemotherapy-induced myasthenic crisis requiring tracheal intubation. The lesson learned from the present case is that, in selected cases of advanced thymoma, the paradoxical worsening of myasthenia gravis during chemotherapy should not be considered an absolute contraindication for the continuation of primary chemotherapy with curative intent.
Background
Thymoma is an uncommon epithelial cancer associated in nearly half of cases with myasthenia gravis (MG), an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced thymoma, primary chemotherapy is considered the standard of care, with the aim of achieving tumor shrinkage and facilitating radical surgery [1]. While several drugs are known to worsen MG, cancer chemotherapy has been anecdotally reported as a trigger event for myasthenic crisis (MC) in four case reports [2–6]. Here, we present a case of advanced thymoma treated with primary chemotherapy that caused an acute-onset MC requiring tracheal intubation and therapeutic plasma exchange (PEX), with relevant benefit from early resumption of anticancer treatment during mechanical ventilation.
Case presentation
Clinical presentation and diagnosis
An 18-year-old Caucasian woman with unremarkable medical history was admitted to the emergency room due to neurological symptoms. She presented with month-long worsening dysphagia, rhinolalia, bilateral ptosis, and skeletal muscle weakness. Signs of muscle fatigability were elicited at the physical exam and then confirmed by electromyography, consistently with neuromuscular junction disease. Blood tests were unremarkable with the exception of acetylcholine receptor antibodies (43 nmol/l, normal if < 0.5 nmol/l). Hence, MG class III, according to the Myasthenia Gravis Foundation of America (MGFA) scale, was diagnosed [7, 8]. Partial regression of symptoms to class II MG was achieved by oral administration of pyridostigmine 60 mg every 3 hours during the daytime, pyridostigmine sustained-release 180 mg orally before sleeping, prednisone 25 mg orally each day, and immunoglobulins 0.4 g/kg intravenously for 5 days [8, 9]. Chest computed tomography (CT) revealed a 12 cm anterior mediastinal mass suspicious for thymoma, with confirmed infiltration of the anterior chest wall, lung parenchyma, and pericardium at chest magnetic resonance imaging with contrast. CT-guided fine needle aspiration biopsy yielded a histological diagnosis of B2 thymoma [10]. Due to the young age, a family history of cancer was excluded. Physical exam was negative for signs of mediastinal syndrome and superficial lymph nodes. Metastatic disease was excluded by 18-fluorodeoxyglucose positron emission tomography (18FDG-PET). Patient imaging is shown in Fig. 1. Accordingly, the clinical stage was cT3 cN0 cM0 (Masaoka-Koga III) [11]. After multidisciplinary team discussion, the tumor was defined as unresectable, and the patient was offered primary chemotherapy with intravenous cyclophosphamide 500 mg/m2, doxorubicin 50 mg/m2 and cisplatin 50 mg/m2 (CAP regimen) on day 1 every 21 days [12]. Primary prophylaxis of chemotherapy-induced neutropenia was not planned due to the potential risk of worsening MG, without evidence about the safety of administering granulocyte colony-stimulating factor in unstable myasthenic patients [13]. Ovarian preservation by gonadotropin-releasing hormone analogue leuprorelin was preferred over oocyte retrieval to expedite the start of chemotherapy [14]. Standard pre-medication with intravenous administration of ondansetron 8 mg, dexamethasone 8 mg and saline was chosen [15].Fig. 1 Patient imaging. a Left chest X-ray with enlarged mediastinum (see arrow). b Chest computed tomography scan showing the mediastinal mass (see arrow). c
18PET-FDG limited radiotracer uptake in mediastinum
Chemotherapy-induced myasthenic crisis
Two hours after starting administration of the first course of chemotherapy, following doxorubicin bolus, the patient experienced sudden onset of acute dyspnea with severe respiratory failure (oxygen saturation 75% on room air), refractory to oxygen therapy and bolus hydrocortisone 500 mg and chlorphenamine 10 mg administered intravenously [16]. Physical exam was negative for bronchospasm with diminished vesicular breath sounds. Due to unstable clinical conditions and development of acute respiratory acidosis (pH 7.21, partial pressure of carbon dioxide 88 mmHg), tracheal intubation and mechanical ventilation in the intensive care unit (ICU) were needed. Urgent chest CT scan excluded acute cardiopulmonary events. Life-threatening MGFA class V MC was diagnosed, likely triggered by chemotherapy, thus classified as grade 4 according to the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) [8, 17]. Chemotherapy was held for 2 hours and then, considering its curative intent and in agreement with the family, it was resumed and fully administered during mechanical ventilation. After 24 hours, upon remission of MC and weaning from ventilation, the patient was extubated and could continue receiving MG treatment, together with starting PEX once every three days to control MG and prevent new crises (by replacing 1 plasma volume with 5% human albumin) [18]. In week 2, owing to CTCAE v5.0 grade 3 febrile neutropenia (absolute neutrophil count 60/mm3 and body temperature 38.4 °C), the patient was successfully treated with empirical piperacillin/tazobactam 4 g/0.5 g intravenously every 6 hours until recovery [19].
Curative treatment and outcome
After completing a second course of CAP chemotherapy with interposed PEX allowing symptom control, radiological assessment in week 6 documented objective partial response according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), with 33% tumor shrinkage (maximum diameter 8 versus 12 cm) [20]. This allowed us to perform radical (R0) extended thymectomy, left upper lung lobectomy and subtotal pericardiectomy, with histological diagnosis of Masaoka-Koga stage III type B2 [10, 11]. For patient histology, please see Fig. 2. The patient required early mediastinum and pleural cavity re-exploration due to postsurgical bleeding; persistent hypophonia developed due to postsurgical left vocal cord paralysis. A comparison of CT imaging at baseline and after surgery is shown in Fig. 3. As suggested for Masaoka-Koga stage III, radiotherapy of 50.4 Gy in 28 fractions was given as postoperative treatment in weeks 15–20 [1]. At the last follow-up visit, 6 months after surgery, the patient was in complete remission with gradually improving MGFA class I MG and mild persistent hypophonia [8]. Despite remarkable levels of psychological burden, the patient’s resilience and high-priority treatment goals were fundamental for successful coping.Fig. 2 Patient histology. a Hematoxylin and eosin (H&E; ×40 view) stained section of thymoma B2 according to WHO classification. b Same histological slice in ×100 view
Fig. 3 Chest computed tomography (CT) scan at baseline and after surgery. a Chest CT scan showing thymoma at baseline. b Postsurgical chest CT scan with no residual disease
Discussion and conclusions
According to the World Health Organization (WHO), thymoma is the most common variant of thymic epithelial tumors (66.3%), usually presenting with local invasion and seldom as metastatic disease [10, 21]. Overall, thymic epithelial tumors occur at a rate of 0.13–0.32 cases per 100,000 population at risk and are very uncommon in young adults [22, 23]. To our knowledge, the largest retrospective study regarding childhood thymic tumors (< 18 years) in Europe was able to identify only 36 cases during a 12-year period, confirming the extreme rarity of thymic cancer in children and adolescents [24]. Hence, the clinical case reported here has to be considered a peculiar presentation of early-onset thymoma (Fig. 4).Fig. 4 Age-specific incidence of thymic cancer by histological type. SEER*Stat Database: NPCR [National Program of Cancer Registries] and SEER [Surveillance, Epidemiology, and End Results] Incidence—U.S. Cancer Statistics Public Use Database, Nov 2017 submission (2001–2015). The green bar highlights the reported patient age interval (15–19 years)
Like thymoma, MG is extremely rare (0.17–2.13 per 100,000 person-years) [25]; however, it affects up to 30% of patients with thymoma [26]. The association of thymoma with MG has been related to the intratumoral generation of mature T cells, although the pathogenic mechanisms remain unclear [27]. MG has been found to be most commonly associated with B thymoma and confers favorable prognosis, since neuromuscular symptoms help in earlier detection of the tumor and thus less advanced stage at diagnosis. Nevertheless, concomitant MG should also be regarded as an adverse risk factor, since it can interfere with cancer treatment, being worsened by many drugs, and it reaches its maximum severity after thymectomy in a proportion of patients [28].
The case reported here, together with those published and summarized in Table 1 [3–6], highlights that chemotherapy is a realistic trigger event of MC in patients with thymoma and MG. The temporary association in all cases indicates a causative relation, and may hamper the continuation of chemotherapy that is a crucial element of multimodal treatment in cases not amenable to upfront radical surgery [1]. No biomarker is available to prove this relation, and clinical findings are crucial for the diagnosis of MC. Other differential diagnoses, such as infusion reaction to cancer chemotherapy, are less likely in the setting of prolonged respiratory failure. Here, a multidisciplinary approach was necessary, and involved neurologists for medical treatment and hematologists for a correct timing schedule of PEX sessions in order to avoid plasma drug displacement. It should be noted that we waited 72 hours from the end of chemotherapy before starting PEX, in order to preserve drug efficacy according to their half-life.Table 1. Comparison between present case and 4 other published cases
Fujiwara et al. [3] Qureshi et al. [4] Solak et al. [5] Ng et al. (6) Present case report
Sex Female Male Male Male Female
Age (year) 44 24 45 49 18
Histology B1 Thymoma (WHO) Thymoma Thymoma NE B2 thymoma (WHO)
Staging IVA (Masaoka-Koga) III (Masaoka-Koga) Advanced unresectable Advanced unresectable III (Masaoka-Koga)
AchR Ab level (nmol/l) 13 NE 74 NE 43
Chemotherapy regimen Primary CAMP Postoperative cisplatin and doxorubicin Single-agent cisplatin Doxorubicin, cisplatin, etoposide Primary CAP
Myasthenic crisis onset time During chemotherapy 8 hours after chemotherapy 1 week after chemotherapy A few hours after chemotherapy During chemotherapy
Tracheal intubation No Yes Yes Yes Yes
Plasma exchange No Yes Yes Yes Yes
Chemotherapy continuation in ICU No No No No Yes
Patient outcome after myasthenic crisis Alive Death Alive Alive Alive
AchR Ab acetylcholine receptor antibodies, CAMP cisplatin, doxorubicin, methylprednisolone, CAP cyclophosphamide, doxorubicin, cisplatin, ICU intensive care unit, NE not evaluable, WHO World Health Organization
To our knowledge, this is the first reported case of chemotherapy continuation despite the need for mechanical ventilation due to a chemotherapy-induced MC. Radical treatment was dependent on primary chemotherapy, as upfront surgery had already been ruled out. Besides, we could not confidently assume that, after MC resolution, the patient would have been able to receive further chemotherapy due to aggravation of symptoms. We conclude that special attention is warranted in patients with thymoma and MG with regard to the development of MC. Ideally, optimal control of myasthenic symptoms should be achieved before initiation of anticancer treatment. Nonetheless, chemotherapy-induced MC may complicate anticancer therapy administration, according to this evidence. We recommend that patients with thymoma and MG be hospitalized in tertiary medical centers for chemotherapy and that outpatient management be avoided. The lesson learned from the present case is that, in selected cases of advanced thymoma, paradoxical worsening of MG during chemotherapy should not be considered an absolute contraindication for continuation of primary chemotherapy with curative intent.
Abbreviations
CAPCisplatin, doxorubicin and cyclophosphamide
CTComputed tomography
CTCAE v5.0Common Terminology Criteria for Adverse Events version 5.0
GyGray
ICUIntensive Care Unit
MCMyasthenic crisis
MGMyasthenia gravis
MGFAMyasthenia Gravis Foundation of America
18PET-FDG18-Fluorodeoxyglucose positron emission tomography
PEXPlasma exchange
RECISTResponse Evaluation Criteria in Solid Tumours
WHOWorld Health Organization
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Fondazione Oncologia Niguarda Onlus for financial support.
Authors' contributions
GP, KB, FT, and SS were major contributors in writing the manuscript. KB, FT, GP, GM, GC, ASB, and SS provided clinical care. MP gave indication to and performed plasma exchange. AR and MT contributed to neoadjuvant treatment indication in a multidisciplinary team discussion and performed surgery. FL, AI, and ECA diagnosed thymoma and myasthenia and medically managed neurological symptoms. ASB and SS supervised oncological care and critically reviewed the case report. All authors read and approved the final manuscript.
Funding
This paper did not receive any specific grants from funding agencies in the public, commercial or not-for-profit sectors.
Ethics approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Availability of data and materials
Not applicable.
Competing interests
The authors declare that they have no competing interests. | CHLORPHENIRAMINE MALEATE, CISPLATIN, CYCLOPHOSPHAMIDE, DEXAMETHASONE, DOXORUBICIN, HYDROCORTISONE, ONDANSETRON, PREDNISONE, PYRIDOSTIGMINE, SODIUM CHLORIDE | DrugsGivenReaction | CC BY | 33526108 | 18,996,243 | 2021-02-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Chemotherapy-induced myasthenic crisis in thymoma treated with primary chemotherapy with curative intent on mechanical ventilation: a case report and review of the literature.
BACKGROUND
Thymoma is an uncommon cancer often associated with myasthenia gravis, an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced nonmetastatic thymoma, primary chemotherapy may be required to induce tumor shrinkage and to achieve radical resection. Cancer chemotherapy has been anecdotally reported as a trigger factor for worsening of myasthenia gravis in thymic epithelial cancers. The study of uncommon cases of chemotherapy-related myasthenic crisis is warranted to gain knowledge of clinical situations requiring intensive care support in the case of life-threatening respiratory failure.
METHODS
We report a case of an 18-year-old Caucasian woman with advanced Masaoka-Koga stage III type B2 thymoma and myasthenia gravis on treatment with pyridostigmine, steroids and intravenous immunoglobulins, who developed a myasthenic crisis 2 hours after initiation of cyclophosphamide/doxorubicin/cisplatin primary chemotherapy. Because of severe acute respiratory failure, emergency tracheal intubation, mechanical ventilation, and temporary (2 hours) discontinuation of chemotherapy were needed. Considering the curative intent of the multimodal therapeutic program, we elected to resume primary chemotherapy administration while the patient remained on mechanical ventilation. After 24 hours, the recovery of adequate respiratory function allowed successful weaning from respiratory support, and no further adverse events occurred. After 3 weeks, upon plasma exchange initiation with amelioration of myasthenic symptoms, a second course of chemotherapy was given, and in week 6, having documented partial tumor remission, the patient underwent radical surgery (R0) and then consolidation radiation therapy with 50.4 Gy in 28 fractions in weeks 15-20.
CONCLUSIONS
This case report, together with the only four available in a review of the literature, highlights that chemotherapy may carry the risk of myasthenic crisis in patients affected by thymoma and myasthenia gravis. To our knowledge, this is the first reported case of chemotherapy continuation on mechanical ventilation in a patient with chemotherapy-induced myasthenic crisis requiring tracheal intubation. The lesson learned from the present case is that, in selected cases of advanced thymoma, the paradoxical worsening of myasthenia gravis during chemotherapy should not be considered an absolute contraindication for the continuation of primary chemotherapy with curative intent.
Background
Thymoma is an uncommon epithelial cancer associated in nearly half of cases with myasthenia gravis (MG), an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced thymoma, primary chemotherapy is considered the standard of care, with the aim of achieving tumor shrinkage and facilitating radical surgery [1]. While several drugs are known to worsen MG, cancer chemotherapy has been anecdotally reported as a trigger event for myasthenic crisis (MC) in four case reports [2–6]. Here, we present a case of advanced thymoma treated with primary chemotherapy that caused an acute-onset MC requiring tracheal intubation and therapeutic plasma exchange (PEX), with relevant benefit from early resumption of anticancer treatment during mechanical ventilation.
Case presentation
Clinical presentation and diagnosis
An 18-year-old Caucasian woman with unremarkable medical history was admitted to the emergency room due to neurological symptoms. She presented with month-long worsening dysphagia, rhinolalia, bilateral ptosis, and skeletal muscle weakness. Signs of muscle fatigability were elicited at the physical exam and then confirmed by electromyography, consistently with neuromuscular junction disease. Blood tests were unremarkable with the exception of acetylcholine receptor antibodies (43 nmol/l, normal if < 0.5 nmol/l). Hence, MG class III, according to the Myasthenia Gravis Foundation of America (MGFA) scale, was diagnosed [7, 8]. Partial regression of symptoms to class II MG was achieved by oral administration of pyridostigmine 60 mg every 3 hours during the daytime, pyridostigmine sustained-release 180 mg orally before sleeping, prednisone 25 mg orally each day, and immunoglobulins 0.4 g/kg intravenously for 5 days [8, 9]. Chest computed tomography (CT) revealed a 12 cm anterior mediastinal mass suspicious for thymoma, with confirmed infiltration of the anterior chest wall, lung parenchyma, and pericardium at chest magnetic resonance imaging with contrast. CT-guided fine needle aspiration biopsy yielded a histological diagnosis of B2 thymoma [10]. Due to the young age, a family history of cancer was excluded. Physical exam was negative for signs of mediastinal syndrome and superficial lymph nodes. Metastatic disease was excluded by 18-fluorodeoxyglucose positron emission tomography (18FDG-PET). Patient imaging is shown in Fig. 1. Accordingly, the clinical stage was cT3 cN0 cM0 (Masaoka-Koga III) [11]. After multidisciplinary team discussion, the tumor was defined as unresectable, and the patient was offered primary chemotherapy with intravenous cyclophosphamide 500 mg/m2, doxorubicin 50 mg/m2 and cisplatin 50 mg/m2 (CAP regimen) on day 1 every 21 days [12]. Primary prophylaxis of chemotherapy-induced neutropenia was not planned due to the potential risk of worsening MG, without evidence about the safety of administering granulocyte colony-stimulating factor in unstable myasthenic patients [13]. Ovarian preservation by gonadotropin-releasing hormone analogue leuprorelin was preferred over oocyte retrieval to expedite the start of chemotherapy [14]. Standard pre-medication with intravenous administration of ondansetron 8 mg, dexamethasone 8 mg and saline was chosen [15].Fig. 1 Patient imaging. a Left chest X-ray with enlarged mediastinum (see arrow). b Chest computed tomography scan showing the mediastinal mass (see arrow). c
18PET-FDG limited radiotracer uptake in mediastinum
Chemotherapy-induced myasthenic crisis
Two hours after starting administration of the first course of chemotherapy, following doxorubicin bolus, the patient experienced sudden onset of acute dyspnea with severe respiratory failure (oxygen saturation 75% on room air), refractory to oxygen therapy and bolus hydrocortisone 500 mg and chlorphenamine 10 mg administered intravenously [16]. Physical exam was negative for bronchospasm with diminished vesicular breath sounds. Due to unstable clinical conditions and development of acute respiratory acidosis (pH 7.21, partial pressure of carbon dioxide 88 mmHg), tracheal intubation and mechanical ventilation in the intensive care unit (ICU) were needed. Urgent chest CT scan excluded acute cardiopulmonary events. Life-threatening MGFA class V MC was diagnosed, likely triggered by chemotherapy, thus classified as grade 4 according to the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) [8, 17]. Chemotherapy was held for 2 hours and then, considering its curative intent and in agreement with the family, it was resumed and fully administered during mechanical ventilation. After 24 hours, upon remission of MC and weaning from ventilation, the patient was extubated and could continue receiving MG treatment, together with starting PEX once every three days to control MG and prevent new crises (by replacing 1 plasma volume with 5% human albumin) [18]. In week 2, owing to CTCAE v5.0 grade 3 febrile neutropenia (absolute neutrophil count 60/mm3 and body temperature 38.4 °C), the patient was successfully treated with empirical piperacillin/tazobactam 4 g/0.5 g intravenously every 6 hours until recovery [19].
Curative treatment and outcome
After completing a second course of CAP chemotherapy with interposed PEX allowing symptom control, radiological assessment in week 6 documented objective partial response according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), with 33% tumor shrinkage (maximum diameter 8 versus 12 cm) [20]. This allowed us to perform radical (R0) extended thymectomy, left upper lung lobectomy and subtotal pericardiectomy, with histological diagnosis of Masaoka-Koga stage III type B2 [10, 11]. For patient histology, please see Fig. 2. The patient required early mediastinum and pleural cavity re-exploration due to postsurgical bleeding; persistent hypophonia developed due to postsurgical left vocal cord paralysis. A comparison of CT imaging at baseline and after surgery is shown in Fig. 3. As suggested for Masaoka-Koga stage III, radiotherapy of 50.4 Gy in 28 fractions was given as postoperative treatment in weeks 15–20 [1]. At the last follow-up visit, 6 months after surgery, the patient was in complete remission with gradually improving MGFA class I MG and mild persistent hypophonia [8]. Despite remarkable levels of psychological burden, the patient’s resilience and high-priority treatment goals were fundamental for successful coping.Fig. 2 Patient histology. a Hematoxylin and eosin (H&E; ×40 view) stained section of thymoma B2 according to WHO classification. b Same histological slice in ×100 view
Fig. 3 Chest computed tomography (CT) scan at baseline and after surgery. a Chest CT scan showing thymoma at baseline. b Postsurgical chest CT scan with no residual disease
Discussion and conclusions
According to the World Health Organization (WHO), thymoma is the most common variant of thymic epithelial tumors (66.3%), usually presenting with local invasion and seldom as metastatic disease [10, 21]. Overall, thymic epithelial tumors occur at a rate of 0.13–0.32 cases per 100,000 population at risk and are very uncommon in young adults [22, 23]. To our knowledge, the largest retrospective study regarding childhood thymic tumors (< 18 years) in Europe was able to identify only 36 cases during a 12-year period, confirming the extreme rarity of thymic cancer in children and adolescents [24]. Hence, the clinical case reported here has to be considered a peculiar presentation of early-onset thymoma (Fig. 4).Fig. 4 Age-specific incidence of thymic cancer by histological type. SEER*Stat Database: NPCR [National Program of Cancer Registries] and SEER [Surveillance, Epidemiology, and End Results] Incidence—U.S. Cancer Statistics Public Use Database, Nov 2017 submission (2001–2015). The green bar highlights the reported patient age interval (15–19 years)
Like thymoma, MG is extremely rare (0.17–2.13 per 100,000 person-years) [25]; however, it affects up to 30% of patients with thymoma [26]. The association of thymoma with MG has been related to the intratumoral generation of mature T cells, although the pathogenic mechanisms remain unclear [27]. MG has been found to be most commonly associated with B thymoma and confers favorable prognosis, since neuromuscular symptoms help in earlier detection of the tumor and thus less advanced stage at diagnosis. Nevertheless, concomitant MG should also be regarded as an adverse risk factor, since it can interfere with cancer treatment, being worsened by many drugs, and it reaches its maximum severity after thymectomy in a proportion of patients [28].
The case reported here, together with those published and summarized in Table 1 [3–6], highlights that chemotherapy is a realistic trigger event of MC in patients with thymoma and MG. The temporary association in all cases indicates a causative relation, and may hamper the continuation of chemotherapy that is a crucial element of multimodal treatment in cases not amenable to upfront radical surgery [1]. No biomarker is available to prove this relation, and clinical findings are crucial for the diagnosis of MC. Other differential diagnoses, such as infusion reaction to cancer chemotherapy, are less likely in the setting of prolonged respiratory failure. Here, a multidisciplinary approach was necessary, and involved neurologists for medical treatment and hematologists for a correct timing schedule of PEX sessions in order to avoid plasma drug displacement. It should be noted that we waited 72 hours from the end of chemotherapy before starting PEX, in order to preserve drug efficacy according to their half-life.Table 1. Comparison between present case and 4 other published cases
Fujiwara et al. [3] Qureshi et al. [4] Solak et al. [5] Ng et al. (6) Present case report
Sex Female Male Male Male Female
Age (year) 44 24 45 49 18
Histology B1 Thymoma (WHO) Thymoma Thymoma NE B2 thymoma (WHO)
Staging IVA (Masaoka-Koga) III (Masaoka-Koga) Advanced unresectable Advanced unresectable III (Masaoka-Koga)
AchR Ab level (nmol/l) 13 NE 74 NE 43
Chemotherapy regimen Primary CAMP Postoperative cisplatin and doxorubicin Single-agent cisplatin Doxorubicin, cisplatin, etoposide Primary CAP
Myasthenic crisis onset time During chemotherapy 8 hours after chemotherapy 1 week after chemotherapy A few hours after chemotherapy During chemotherapy
Tracheal intubation No Yes Yes Yes Yes
Plasma exchange No Yes Yes Yes Yes
Chemotherapy continuation in ICU No No No No Yes
Patient outcome after myasthenic crisis Alive Death Alive Alive Alive
AchR Ab acetylcholine receptor antibodies, CAMP cisplatin, doxorubicin, methylprednisolone, CAP cyclophosphamide, doxorubicin, cisplatin, ICU intensive care unit, NE not evaluable, WHO World Health Organization
To our knowledge, this is the first reported case of chemotherapy continuation despite the need for mechanical ventilation due to a chemotherapy-induced MC. Radical treatment was dependent on primary chemotherapy, as upfront surgery had already been ruled out. Besides, we could not confidently assume that, after MC resolution, the patient would have been able to receive further chemotherapy due to aggravation of symptoms. We conclude that special attention is warranted in patients with thymoma and MG with regard to the development of MC. Ideally, optimal control of myasthenic symptoms should be achieved before initiation of anticancer treatment. Nonetheless, chemotherapy-induced MC may complicate anticancer therapy administration, according to this evidence. We recommend that patients with thymoma and MG be hospitalized in tertiary medical centers for chemotherapy and that outpatient management be avoided. The lesson learned from the present case is that, in selected cases of advanced thymoma, paradoxical worsening of MG during chemotherapy should not be considered an absolute contraindication for continuation of primary chemotherapy with curative intent.
Abbreviations
CAPCisplatin, doxorubicin and cyclophosphamide
CTComputed tomography
CTCAE v5.0Common Terminology Criteria for Adverse Events version 5.0
GyGray
ICUIntensive Care Unit
MCMyasthenic crisis
MGMyasthenia gravis
MGFAMyasthenia Gravis Foundation of America
18PET-FDG18-Fluorodeoxyglucose positron emission tomography
PEXPlasma exchange
RECISTResponse Evaluation Criteria in Solid Tumours
WHOWorld Health Organization
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Fondazione Oncologia Niguarda Onlus for financial support.
Authors' contributions
GP, KB, FT, and SS were major contributors in writing the manuscript. KB, FT, GP, GM, GC, ASB, and SS provided clinical care. MP gave indication to and performed plasma exchange. AR and MT contributed to neoadjuvant treatment indication in a multidisciplinary team discussion and performed surgery. FL, AI, and ECA diagnosed thymoma and myasthenia and medically managed neurological symptoms. ASB and SS supervised oncological care and critically reviewed the case report. All authors read and approved the final manuscript.
Funding
This paper did not receive any specific grants from funding agencies in the public, commercial or not-for-profit sectors.
Ethics approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Availability of data and materials
Not applicable.
Competing interests
The authors declare that they have no competing interests. | CHLORPHENIRAMINE MALEATE, CISPLATIN, CYCLOPHOSPHAMIDE, DEXAMETHASONE, DOXORUBICIN, HYDROCORTISONE, ONDANSETRON, PREDNISONE, PYRIDOSTIGMINE, SODIUM CHLORIDE | DrugsGivenReaction | CC BY | 33526108 | 18,996,243 | 2021-02-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Dyspnoea'. | Chemotherapy-induced myasthenic crisis in thymoma treated with primary chemotherapy with curative intent on mechanical ventilation: a case report and review of the literature.
BACKGROUND
Thymoma is an uncommon cancer often associated with myasthenia gravis, an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced nonmetastatic thymoma, primary chemotherapy may be required to induce tumor shrinkage and to achieve radical resection. Cancer chemotherapy has been anecdotally reported as a trigger factor for worsening of myasthenia gravis in thymic epithelial cancers. The study of uncommon cases of chemotherapy-related myasthenic crisis is warranted to gain knowledge of clinical situations requiring intensive care support in the case of life-threatening respiratory failure.
METHODS
We report a case of an 18-year-old Caucasian woman with advanced Masaoka-Koga stage III type B2 thymoma and myasthenia gravis on treatment with pyridostigmine, steroids and intravenous immunoglobulins, who developed a myasthenic crisis 2 hours after initiation of cyclophosphamide/doxorubicin/cisplatin primary chemotherapy. Because of severe acute respiratory failure, emergency tracheal intubation, mechanical ventilation, and temporary (2 hours) discontinuation of chemotherapy were needed. Considering the curative intent of the multimodal therapeutic program, we elected to resume primary chemotherapy administration while the patient remained on mechanical ventilation. After 24 hours, the recovery of adequate respiratory function allowed successful weaning from respiratory support, and no further adverse events occurred. After 3 weeks, upon plasma exchange initiation with amelioration of myasthenic symptoms, a second course of chemotherapy was given, and in week 6, having documented partial tumor remission, the patient underwent radical surgery (R0) and then consolidation radiation therapy with 50.4 Gy in 28 fractions in weeks 15-20.
CONCLUSIONS
This case report, together with the only four available in a review of the literature, highlights that chemotherapy may carry the risk of myasthenic crisis in patients affected by thymoma and myasthenia gravis. To our knowledge, this is the first reported case of chemotherapy continuation on mechanical ventilation in a patient with chemotherapy-induced myasthenic crisis requiring tracheal intubation. The lesson learned from the present case is that, in selected cases of advanced thymoma, the paradoxical worsening of myasthenia gravis during chemotherapy should not be considered an absolute contraindication for the continuation of primary chemotherapy with curative intent.
Background
Thymoma is an uncommon epithelial cancer associated in nearly half of cases with myasthenia gravis (MG), an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced thymoma, primary chemotherapy is considered the standard of care, with the aim of achieving tumor shrinkage and facilitating radical surgery [1]. While several drugs are known to worsen MG, cancer chemotherapy has been anecdotally reported as a trigger event for myasthenic crisis (MC) in four case reports [2–6]. Here, we present a case of advanced thymoma treated with primary chemotherapy that caused an acute-onset MC requiring tracheal intubation and therapeutic plasma exchange (PEX), with relevant benefit from early resumption of anticancer treatment during mechanical ventilation.
Case presentation
Clinical presentation and diagnosis
An 18-year-old Caucasian woman with unremarkable medical history was admitted to the emergency room due to neurological symptoms. She presented with month-long worsening dysphagia, rhinolalia, bilateral ptosis, and skeletal muscle weakness. Signs of muscle fatigability were elicited at the physical exam and then confirmed by electromyography, consistently with neuromuscular junction disease. Blood tests were unremarkable with the exception of acetylcholine receptor antibodies (43 nmol/l, normal if < 0.5 nmol/l). Hence, MG class III, according to the Myasthenia Gravis Foundation of America (MGFA) scale, was diagnosed [7, 8]. Partial regression of symptoms to class II MG was achieved by oral administration of pyridostigmine 60 mg every 3 hours during the daytime, pyridostigmine sustained-release 180 mg orally before sleeping, prednisone 25 mg orally each day, and immunoglobulins 0.4 g/kg intravenously for 5 days [8, 9]. Chest computed tomography (CT) revealed a 12 cm anterior mediastinal mass suspicious for thymoma, with confirmed infiltration of the anterior chest wall, lung parenchyma, and pericardium at chest magnetic resonance imaging with contrast. CT-guided fine needle aspiration biopsy yielded a histological diagnosis of B2 thymoma [10]. Due to the young age, a family history of cancer was excluded. Physical exam was negative for signs of mediastinal syndrome and superficial lymph nodes. Metastatic disease was excluded by 18-fluorodeoxyglucose positron emission tomography (18FDG-PET). Patient imaging is shown in Fig. 1. Accordingly, the clinical stage was cT3 cN0 cM0 (Masaoka-Koga III) [11]. After multidisciplinary team discussion, the tumor was defined as unresectable, and the patient was offered primary chemotherapy with intravenous cyclophosphamide 500 mg/m2, doxorubicin 50 mg/m2 and cisplatin 50 mg/m2 (CAP regimen) on day 1 every 21 days [12]. Primary prophylaxis of chemotherapy-induced neutropenia was not planned due to the potential risk of worsening MG, without evidence about the safety of administering granulocyte colony-stimulating factor in unstable myasthenic patients [13]. Ovarian preservation by gonadotropin-releasing hormone analogue leuprorelin was preferred over oocyte retrieval to expedite the start of chemotherapy [14]. Standard pre-medication with intravenous administration of ondansetron 8 mg, dexamethasone 8 mg and saline was chosen [15].Fig. 1 Patient imaging. a Left chest X-ray with enlarged mediastinum (see arrow). b Chest computed tomography scan showing the mediastinal mass (see arrow). c
18PET-FDG limited radiotracer uptake in mediastinum
Chemotherapy-induced myasthenic crisis
Two hours after starting administration of the first course of chemotherapy, following doxorubicin bolus, the patient experienced sudden onset of acute dyspnea with severe respiratory failure (oxygen saturation 75% on room air), refractory to oxygen therapy and bolus hydrocortisone 500 mg and chlorphenamine 10 mg administered intravenously [16]. Physical exam was negative for bronchospasm with diminished vesicular breath sounds. Due to unstable clinical conditions and development of acute respiratory acidosis (pH 7.21, partial pressure of carbon dioxide 88 mmHg), tracheal intubation and mechanical ventilation in the intensive care unit (ICU) were needed. Urgent chest CT scan excluded acute cardiopulmonary events. Life-threatening MGFA class V MC was diagnosed, likely triggered by chemotherapy, thus classified as grade 4 according to the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) [8, 17]. Chemotherapy was held for 2 hours and then, considering its curative intent and in agreement with the family, it was resumed and fully administered during mechanical ventilation. After 24 hours, upon remission of MC and weaning from ventilation, the patient was extubated and could continue receiving MG treatment, together with starting PEX once every three days to control MG and prevent new crises (by replacing 1 plasma volume with 5% human albumin) [18]. In week 2, owing to CTCAE v5.0 grade 3 febrile neutropenia (absolute neutrophil count 60/mm3 and body temperature 38.4 °C), the patient was successfully treated with empirical piperacillin/tazobactam 4 g/0.5 g intravenously every 6 hours until recovery [19].
Curative treatment and outcome
After completing a second course of CAP chemotherapy with interposed PEX allowing symptom control, radiological assessment in week 6 documented objective partial response according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), with 33% tumor shrinkage (maximum diameter 8 versus 12 cm) [20]. This allowed us to perform radical (R0) extended thymectomy, left upper lung lobectomy and subtotal pericardiectomy, with histological diagnosis of Masaoka-Koga stage III type B2 [10, 11]. For patient histology, please see Fig. 2. The patient required early mediastinum and pleural cavity re-exploration due to postsurgical bleeding; persistent hypophonia developed due to postsurgical left vocal cord paralysis. A comparison of CT imaging at baseline and after surgery is shown in Fig. 3. As suggested for Masaoka-Koga stage III, radiotherapy of 50.4 Gy in 28 fractions was given as postoperative treatment in weeks 15–20 [1]. At the last follow-up visit, 6 months after surgery, the patient was in complete remission with gradually improving MGFA class I MG and mild persistent hypophonia [8]. Despite remarkable levels of psychological burden, the patient’s resilience and high-priority treatment goals were fundamental for successful coping.Fig. 2 Patient histology. a Hematoxylin and eosin (H&E; ×40 view) stained section of thymoma B2 according to WHO classification. b Same histological slice in ×100 view
Fig. 3 Chest computed tomography (CT) scan at baseline and after surgery. a Chest CT scan showing thymoma at baseline. b Postsurgical chest CT scan with no residual disease
Discussion and conclusions
According to the World Health Organization (WHO), thymoma is the most common variant of thymic epithelial tumors (66.3%), usually presenting with local invasion and seldom as metastatic disease [10, 21]. Overall, thymic epithelial tumors occur at a rate of 0.13–0.32 cases per 100,000 population at risk and are very uncommon in young adults [22, 23]. To our knowledge, the largest retrospective study regarding childhood thymic tumors (< 18 years) in Europe was able to identify only 36 cases during a 12-year period, confirming the extreme rarity of thymic cancer in children and adolescents [24]. Hence, the clinical case reported here has to be considered a peculiar presentation of early-onset thymoma (Fig. 4).Fig. 4 Age-specific incidence of thymic cancer by histological type. SEER*Stat Database: NPCR [National Program of Cancer Registries] and SEER [Surveillance, Epidemiology, and End Results] Incidence—U.S. Cancer Statistics Public Use Database, Nov 2017 submission (2001–2015). The green bar highlights the reported patient age interval (15–19 years)
Like thymoma, MG is extremely rare (0.17–2.13 per 100,000 person-years) [25]; however, it affects up to 30% of patients with thymoma [26]. The association of thymoma with MG has been related to the intratumoral generation of mature T cells, although the pathogenic mechanisms remain unclear [27]. MG has been found to be most commonly associated with B thymoma and confers favorable prognosis, since neuromuscular symptoms help in earlier detection of the tumor and thus less advanced stage at diagnosis. Nevertheless, concomitant MG should also be regarded as an adverse risk factor, since it can interfere with cancer treatment, being worsened by many drugs, and it reaches its maximum severity after thymectomy in a proportion of patients [28].
The case reported here, together with those published and summarized in Table 1 [3–6], highlights that chemotherapy is a realistic trigger event of MC in patients with thymoma and MG. The temporary association in all cases indicates a causative relation, and may hamper the continuation of chemotherapy that is a crucial element of multimodal treatment in cases not amenable to upfront radical surgery [1]. No biomarker is available to prove this relation, and clinical findings are crucial for the diagnosis of MC. Other differential diagnoses, such as infusion reaction to cancer chemotherapy, are less likely in the setting of prolonged respiratory failure. Here, a multidisciplinary approach was necessary, and involved neurologists for medical treatment and hematologists for a correct timing schedule of PEX sessions in order to avoid plasma drug displacement. It should be noted that we waited 72 hours from the end of chemotherapy before starting PEX, in order to preserve drug efficacy according to their half-life.Table 1. Comparison between present case and 4 other published cases
Fujiwara et al. [3] Qureshi et al. [4] Solak et al. [5] Ng et al. (6) Present case report
Sex Female Male Male Male Female
Age (year) 44 24 45 49 18
Histology B1 Thymoma (WHO) Thymoma Thymoma NE B2 thymoma (WHO)
Staging IVA (Masaoka-Koga) III (Masaoka-Koga) Advanced unresectable Advanced unresectable III (Masaoka-Koga)
AchR Ab level (nmol/l) 13 NE 74 NE 43
Chemotherapy regimen Primary CAMP Postoperative cisplatin and doxorubicin Single-agent cisplatin Doxorubicin, cisplatin, etoposide Primary CAP
Myasthenic crisis onset time During chemotherapy 8 hours after chemotherapy 1 week after chemotherapy A few hours after chemotherapy During chemotherapy
Tracheal intubation No Yes Yes Yes Yes
Plasma exchange No Yes Yes Yes Yes
Chemotherapy continuation in ICU No No No No Yes
Patient outcome after myasthenic crisis Alive Death Alive Alive Alive
AchR Ab acetylcholine receptor antibodies, CAMP cisplatin, doxorubicin, methylprednisolone, CAP cyclophosphamide, doxorubicin, cisplatin, ICU intensive care unit, NE not evaluable, WHO World Health Organization
To our knowledge, this is the first reported case of chemotherapy continuation despite the need for mechanical ventilation due to a chemotherapy-induced MC. Radical treatment was dependent on primary chemotherapy, as upfront surgery had already been ruled out. Besides, we could not confidently assume that, after MC resolution, the patient would have been able to receive further chemotherapy due to aggravation of symptoms. We conclude that special attention is warranted in patients with thymoma and MG with regard to the development of MC. Ideally, optimal control of myasthenic symptoms should be achieved before initiation of anticancer treatment. Nonetheless, chemotherapy-induced MC may complicate anticancer therapy administration, according to this evidence. We recommend that patients with thymoma and MG be hospitalized in tertiary medical centers for chemotherapy and that outpatient management be avoided. The lesson learned from the present case is that, in selected cases of advanced thymoma, paradoxical worsening of MG during chemotherapy should not be considered an absolute contraindication for continuation of primary chemotherapy with curative intent.
Abbreviations
CAPCisplatin, doxorubicin and cyclophosphamide
CTComputed tomography
CTCAE v5.0Common Terminology Criteria for Adverse Events version 5.0
GyGray
ICUIntensive Care Unit
MCMyasthenic crisis
MGMyasthenia gravis
MGFAMyasthenia Gravis Foundation of America
18PET-FDG18-Fluorodeoxyglucose positron emission tomography
PEXPlasma exchange
RECISTResponse Evaluation Criteria in Solid Tumours
WHOWorld Health Organization
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Fondazione Oncologia Niguarda Onlus for financial support.
Authors' contributions
GP, KB, FT, and SS were major contributors in writing the manuscript. KB, FT, GP, GM, GC, ASB, and SS provided clinical care. MP gave indication to and performed plasma exchange. AR and MT contributed to neoadjuvant treatment indication in a multidisciplinary team discussion and performed surgery. FL, AI, and ECA diagnosed thymoma and myasthenia and medically managed neurological symptoms. ASB and SS supervised oncological care and critically reviewed the case report. All authors read and approved the final manuscript.
Funding
This paper did not receive any specific grants from funding agencies in the public, commercial or not-for-profit sectors.
Ethics approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Availability of data and materials
Not applicable.
Competing interests
The authors declare that they have no competing interests. | CISPLATIN, CYCLOPHOSPHAMIDE, DEXAMETHASONE, DOXORUBICIN, LEUPROLIDE ACETATE, ONDANSETRON, PREDNISONE, PYRIDOSTIGMINE, SODIUM CHLORIDE | DrugsGivenReaction | CC BY | 33526108 | 18,959,226 | 2021-02-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Myasthenic syndrome'. | Chemotherapy-induced myasthenic crisis in thymoma treated with primary chemotherapy with curative intent on mechanical ventilation: a case report and review of the literature.
BACKGROUND
Thymoma is an uncommon cancer often associated with myasthenia gravis, an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced nonmetastatic thymoma, primary chemotherapy may be required to induce tumor shrinkage and to achieve radical resection. Cancer chemotherapy has been anecdotally reported as a trigger factor for worsening of myasthenia gravis in thymic epithelial cancers. The study of uncommon cases of chemotherapy-related myasthenic crisis is warranted to gain knowledge of clinical situations requiring intensive care support in the case of life-threatening respiratory failure.
METHODS
We report a case of an 18-year-old Caucasian woman with advanced Masaoka-Koga stage III type B2 thymoma and myasthenia gravis on treatment with pyridostigmine, steroids and intravenous immunoglobulins, who developed a myasthenic crisis 2 hours after initiation of cyclophosphamide/doxorubicin/cisplatin primary chemotherapy. Because of severe acute respiratory failure, emergency tracheal intubation, mechanical ventilation, and temporary (2 hours) discontinuation of chemotherapy were needed. Considering the curative intent of the multimodal therapeutic program, we elected to resume primary chemotherapy administration while the patient remained on mechanical ventilation. After 24 hours, the recovery of adequate respiratory function allowed successful weaning from respiratory support, and no further adverse events occurred. After 3 weeks, upon plasma exchange initiation with amelioration of myasthenic symptoms, a second course of chemotherapy was given, and in week 6, having documented partial tumor remission, the patient underwent radical surgery (R0) and then consolidation radiation therapy with 50.4 Gy in 28 fractions in weeks 15-20.
CONCLUSIONS
This case report, together with the only four available in a review of the literature, highlights that chemotherapy may carry the risk of myasthenic crisis in patients affected by thymoma and myasthenia gravis. To our knowledge, this is the first reported case of chemotherapy continuation on mechanical ventilation in a patient with chemotherapy-induced myasthenic crisis requiring tracheal intubation. The lesson learned from the present case is that, in selected cases of advanced thymoma, the paradoxical worsening of myasthenia gravis during chemotherapy should not be considered an absolute contraindication for the continuation of primary chemotherapy with curative intent.
Background
Thymoma is an uncommon epithelial cancer associated in nearly half of cases with myasthenia gravis (MG), an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced thymoma, primary chemotherapy is considered the standard of care, with the aim of achieving tumor shrinkage and facilitating radical surgery [1]. While several drugs are known to worsen MG, cancer chemotherapy has been anecdotally reported as a trigger event for myasthenic crisis (MC) in four case reports [2–6]. Here, we present a case of advanced thymoma treated with primary chemotherapy that caused an acute-onset MC requiring tracheal intubation and therapeutic plasma exchange (PEX), with relevant benefit from early resumption of anticancer treatment during mechanical ventilation.
Case presentation
Clinical presentation and diagnosis
An 18-year-old Caucasian woman with unremarkable medical history was admitted to the emergency room due to neurological symptoms. She presented with month-long worsening dysphagia, rhinolalia, bilateral ptosis, and skeletal muscle weakness. Signs of muscle fatigability were elicited at the physical exam and then confirmed by electromyography, consistently with neuromuscular junction disease. Blood tests were unremarkable with the exception of acetylcholine receptor antibodies (43 nmol/l, normal if < 0.5 nmol/l). Hence, MG class III, according to the Myasthenia Gravis Foundation of America (MGFA) scale, was diagnosed [7, 8]. Partial regression of symptoms to class II MG was achieved by oral administration of pyridostigmine 60 mg every 3 hours during the daytime, pyridostigmine sustained-release 180 mg orally before sleeping, prednisone 25 mg orally each day, and immunoglobulins 0.4 g/kg intravenously for 5 days [8, 9]. Chest computed tomography (CT) revealed a 12 cm anterior mediastinal mass suspicious for thymoma, with confirmed infiltration of the anterior chest wall, lung parenchyma, and pericardium at chest magnetic resonance imaging with contrast. CT-guided fine needle aspiration biopsy yielded a histological diagnosis of B2 thymoma [10]. Due to the young age, a family history of cancer was excluded. Physical exam was negative for signs of mediastinal syndrome and superficial lymph nodes. Metastatic disease was excluded by 18-fluorodeoxyglucose positron emission tomography (18FDG-PET). Patient imaging is shown in Fig. 1. Accordingly, the clinical stage was cT3 cN0 cM0 (Masaoka-Koga III) [11]. After multidisciplinary team discussion, the tumor was defined as unresectable, and the patient was offered primary chemotherapy with intravenous cyclophosphamide 500 mg/m2, doxorubicin 50 mg/m2 and cisplatin 50 mg/m2 (CAP regimen) on day 1 every 21 days [12]. Primary prophylaxis of chemotherapy-induced neutropenia was not planned due to the potential risk of worsening MG, without evidence about the safety of administering granulocyte colony-stimulating factor in unstable myasthenic patients [13]. Ovarian preservation by gonadotropin-releasing hormone analogue leuprorelin was preferred over oocyte retrieval to expedite the start of chemotherapy [14]. Standard pre-medication with intravenous administration of ondansetron 8 mg, dexamethasone 8 mg and saline was chosen [15].Fig. 1 Patient imaging. a Left chest X-ray with enlarged mediastinum (see arrow). b Chest computed tomography scan showing the mediastinal mass (see arrow). c
18PET-FDG limited radiotracer uptake in mediastinum
Chemotherapy-induced myasthenic crisis
Two hours after starting administration of the first course of chemotherapy, following doxorubicin bolus, the patient experienced sudden onset of acute dyspnea with severe respiratory failure (oxygen saturation 75% on room air), refractory to oxygen therapy and bolus hydrocortisone 500 mg and chlorphenamine 10 mg administered intravenously [16]. Physical exam was negative for bronchospasm with diminished vesicular breath sounds. Due to unstable clinical conditions and development of acute respiratory acidosis (pH 7.21, partial pressure of carbon dioxide 88 mmHg), tracheal intubation and mechanical ventilation in the intensive care unit (ICU) were needed. Urgent chest CT scan excluded acute cardiopulmonary events. Life-threatening MGFA class V MC was diagnosed, likely triggered by chemotherapy, thus classified as grade 4 according to the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) [8, 17]. Chemotherapy was held for 2 hours and then, considering its curative intent and in agreement with the family, it was resumed and fully administered during mechanical ventilation. After 24 hours, upon remission of MC and weaning from ventilation, the patient was extubated and could continue receiving MG treatment, together with starting PEX once every three days to control MG and prevent new crises (by replacing 1 plasma volume with 5% human albumin) [18]. In week 2, owing to CTCAE v5.0 grade 3 febrile neutropenia (absolute neutrophil count 60/mm3 and body temperature 38.4 °C), the patient was successfully treated with empirical piperacillin/tazobactam 4 g/0.5 g intravenously every 6 hours until recovery [19].
Curative treatment and outcome
After completing a second course of CAP chemotherapy with interposed PEX allowing symptom control, radiological assessment in week 6 documented objective partial response according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), with 33% tumor shrinkage (maximum diameter 8 versus 12 cm) [20]. This allowed us to perform radical (R0) extended thymectomy, left upper lung lobectomy and subtotal pericardiectomy, with histological diagnosis of Masaoka-Koga stage III type B2 [10, 11]. For patient histology, please see Fig. 2. The patient required early mediastinum and pleural cavity re-exploration due to postsurgical bleeding; persistent hypophonia developed due to postsurgical left vocal cord paralysis. A comparison of CT imaging at baseline and after surgery is shown in Fig. 3. As suggested for Masaoka-Koga stage III, radiotherapy of 50.4 Gy in 28 fractions was given as postoperative treatment in weeks 15–20 [1]. At the last follow-up visit, 6 months after surgery, the patient was in complete remission with gradually improving MGFA class I MG and mild persistent hypophonia [8]. Despite remarkable levels of psychological burden, the patient’s resilience and high-priority treatment goals were fundamental for successful coping.Fig. 2 Patient histology. a Hematoxylin and eosin (H&E; ×40 view) stained section of thymoma B2 according to WHO classification. b Same histological slice in ×100 view
Fig. 3 Chest computed tomography (CT) scan at baseline and after surgery. a Chest CT scan showing thymoma at baseline. b Postsurgical chest CT scan with no residual disease
Discussion and conclusions
According to the World Health Organization (WHO), thymoma is the most common variant of thymic epithelial tumors (66.3%), usually presenting with local invasion and seldom as metastatic disease [10, 21]. Overall, thymic epithelial tumors occur at a rate of 0.13–0.32 cases per 100,000 population at risk and are very uncommon in young adults [22, 23]. To our knowledge, the largest retrospective study regarding childhood thymic tumors (< 18 years) in Europe was able to identify only 36 cases during a 12-year period, confirming the extreme rarity of thymic cancer in children and adolescents [24]. Hence, the clinical case reported here has to be considered a peculiar presentation of early-onset thymoma (Fig. 4).Fig. 4 Age-specific incidence of thymic cancer by histological type. SEER*Stat Database: NPCR [National Program of Cancer Registries] and SEER [Surveillance, Epidemiology, and End Results] Incidence—U.S. Cancer Statistics Public Use Database, Nov 2017 submission (2001–2015). The green bar highlights the reported patient age interval (15–19 years)
Like thymoma, MG is extremely rare (0.17–2.13 per 100,000 person-years) [25]; however, it affects up to 30% of patients with thymoma [26]. The association of thymoma with MG has been related to the intratumoral generation of mature T cells, although the pathogenic mechanisms remain unclear [27]. MG has been found to be most commonly associated with B thymoma and confers favorable prognosis, since neuromuscular symptoms help in earlier detection of the tumor and thus less advanced stage at diagnosis. Nevertheless, concomitant MG should also be regarded as an adverse risk factor, since it can interfere with cancer treatment, being worsened by many drugs, and it reaches its maximum severity after thymectomy in a proportion of patients [28].
The case reported here, together with those published and summarized in Table 1 [3–6], highlights that chemotherapy is a realistic trigger event of MC in patients with thymoma and MG. The temporary association in all cases indicates a causative relation, and may hamper the continuation of chemotherapy that is a crucial element of multimodal treatment in cases not amenable to upfront radical surgery [1]. No biomarker is available to prove this relation, and clinical findings are crucial for the diagnosis of MC. Other differential diagnoses, such as infusion reaction to cancer chemotherapy, are less likely in the setting of prolonged respiratory failure. Here, a multidisciplinary approach was necessary, and involved neurologists for medical treatment and hematologists for a correct timing schedule of PEX sessions in order to avoid plasma drug displacement. It should be noted that we waited 72 hours from the end of chemotherapy before starting PEX, in order to preserve drug efficacy according to their half-life.Table 1. Comparison between present case and 4 other published cases
Fujiwara et al. [3] Qureshi et al. [4] Solak et al. [5] Ng et al. (6) Present case report
Sex Female Male Male Male Female
Age (year) 44 24 45 49 18
Histology B1 Thymoma (WHO) Thymoma Thymoma NE B2 thymoma (WHO)
Staging IVA (Masaoka-Koga) III (Masaoka-Koga) Advanced unresectable Advanced unresectable III (Masaoka-Koga)
AchR Ab level (nmol/l) 13 NE 74 NE 43
Chemotherapy regimen Primary CAMP Postoperative cisplatin and doxorubicin Single-agent cisplatin Doxorubicin, cisplatin, etoposide Primary CAP
Myasthenic crisis onset time During chemotherapy 8 hours after chemotherapy 1 week after chemotherapy A few hours after chemotherapy During chemotherapy
Tracheal intubation No Yes Yes Yes Yes
Plasma exchange No Yes Yes Yes Yes
Chemotherapy continuation in ICU No No No No Yes
Patient outcome after myasthenic crisis Alive Death Alive Alive Alive
AchR Ab acetylcholine receptor antibodies, CAMP cisplatin, doxorubicin, methylprednisolone, CAP cyclophosphamide, doxorubicin, cisplatin, ICU intensive care unit, NE not evaluable, WHO World Health Organization
To our knowledge, this is the first reported case of chemotherapy continuation despite the need for mechanical ventilation due to a chemotherapy-induced MC. Radical treatment was dependent on primary chemotherapy, as upfront surgery had already been ruled out. Besides, we could not confidently assume that, after MC resolution, the patient would have been able to receive further chemotherapy due to aggravation of symptoms. We conclude that special attention is warranted in patients with thymoma and MG with regard to the development of MC. Ideally, optimal control of myasthenic symptoms should be achieved before initiation of anticancer treatment. Nonetheless, chemotherapy-induced MC may complicate anticancer therapy administration, according to this evidence. We recommend that patients with thymoma and MG be hospitalized in tertiary medical centers for chemotherapy and that outpatient management be avoided. The lesson learned from the present case is that, in selected cases of advanced thymoma, paradoxical worsening of MG during chemotherapy should not be considered an absolute contraindication for continuation of primary chemotherapy with curative intent.
Abbreviations
CAPCisplatin, doxorubicin and cyclophosphamide
CTComputed tomography
CTCAE v5.0Common Terminology Criteria for Adverse Events version 5.0
GyGray
ICUIntensive Care Unit
MCMyasthenic crisis
MGMyasthenia gravis
MGFAMyasthenia Gravis Foundation of America
18PET-FDG18-Fluorodeoxyglucose positron emission tomography
PEXPlasma exchange
RECISTResponse Evaluation Criteria in Solid Tumours
WHOWorld Health Organization
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Fondazione Oncologia Niguarda Onlus for financial support.
Authors' contributions
GP, KB, FT, and SS were major contributors in writing the manuscript. KB, FT, GP, GM, GC, ASB, and SS provided clinical care. MP gave indication to and performed plasma exchange. AR and MT contributed to neoadjuvant treatment indication in a multidisciplinary team discussion and performed surgery. FL, AI, and ECA diagnosed thymoma and myasthenia and medically managed neurological symptoms. ASB and SS supervised oncological care and critically reviewed the case report. All authors read and approved the final manuscript.
Funding
This paper did not receive any specific grants from funding agencies in the public, commercial or not-for-profit sectors.
Ethics approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Availability of data and materials
Not applicable.
Competing interests
The authors declare that they have no competing interests. | CISPLATIN, CYCLOPHOSPHAMIDE, DOXORUBICIN HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33526108 | 18,898,875 | 2021-02-02 |
What is the weight of the patient? | Chemotherapy-induced myasthenic crisis in thymoma treated with primary chemotherapy with curative intent on mechanical ventilation: a case report and review of the literature.
BACKGROUND
Thymoma is an uncommon cancer often associated with myasthenia gravis, an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced nonmetastatic thymoma, primary chemotherapy may be required to induce tumor shrinkage and to achieve radical resection. Cancer chemotherapy has been anecdotally reported as a trigger factor for worsening of myasthenia gravis in thymic epithelial cancers. The study of uncommon cases of chemotherapy-related myasthenic crisis is warranted to gain knowledge of clinical situations requiring intensive care support in the case of life-threatening respiratory failure.
METHODS
We report a case of an 18-year-old Caucasian woman with advanced Masaoka-Koga stage III type B2 thymoma and myasthenia gravis on treatment with pyridostigmine, steroids and intravenous immunoglobulins, who developed a myasthenic crisis 2 hours after initiation of cyclophosphamide/doxorubicin/cisplatin primary chemotherapy. Because of severe acute respiratory failure, emergency tracheal intubation, mechanical ventilation, and temporary (2 hours) discontinuation of chemotherapy were needed. Considering the curative intent of the multimodal therapeutic program, we elected to resume primary chemotherapy administration while the patient remained on mechanical ventilation. After 24 hours, the recovery of adequate respiratory function allowed successful weaning from respiratory support, and no further adverse events occurred. After 3 weeks, upon plasma exchange initiation with amelioration of myasthenic symptoms, a second course of chemotherapy was given, and in week 6, having documented partial tumor remission, the patient underwent radical surgery (R0) and then consolidation radiation therapy with 50.4 Gy in 28 fractions in weeks 15-20.
CONCLUSIONS
This case report, together with the only four available in a review of the literature, highlights that chemotherapy may carry the risk of myasthenic crisis in patients affected by thymoma and myasthenia gravis. To our knowledge, this is the first reported case of chemotherapy continuation on mechanical ventilation in a patient with chemotherapy-induced myasthenic crisis requiring tracheal intubation. The lesson learned from the present case is that, in selected cases of advanced thymoma, the paradoxical worsening of myasthenia gravis during chemotherapy should not be considered an absolute contraindication for the continuation of primary chemotherapy with curative intent.
Background
Thymoma is an uncommon epithelial cancer associated in nearly half of cases with myasthenia gravis (MG), an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced thymoma, primary chemotherapy is considered the standard of care, with the aim of achieving tumor shrinkage and facilitating radical surgery [1]. While several drugs are known to worsen MG, cancer chemotherapy has been anecdotally reported as a trigger event for myasthenic crisis (MC) in four case reports [2–6]. Here, we present a case of advanced thymoma treated with primary chemotherapy that caused an acute-onset MC requiring tracheal intubation and therapeutic plasma exchange (PEX), with relevant benefit from early resumption of anticancer treatment during mechanical ventilation.
Case presentation
Clinical presentation and diagnosis
An 18-year-old Caucasian woman with unremarkable medical history was admitted to the emergency room due to neurological symptoms. She presented with month-long worsening dysphagia, rhinolalia, bilateral ptosis, and skeletal muscle weakness. Signs of muscle fatigability were elicited at the physical exam and then confirmed by electromyography, consistently with neuromuscular junction disease. Blood tests were unremarkable with the exception of acetylcholine receptor antibodies (43 nmol/l, normal if < 0.5 nmol/l). Hence, MG class III, according to the Myasthenia Gravis Foundation of America (MGFA) scale, was diagnosed [7, 8]. Partial regression of symptoms to class II MG was achieved by oral administration of pyridostigmine 60 mg every 3 hours during the daytime, pyridostigmine sustained-release 180 mg orally before sleeping, prednisone 25 mg orally each day, and immunoglobulins 0.4 g/kg intravenously for 5 days [8, 9]. Chest computed tomography (CT) revealed a 12 cm anterior mediastinal mass suspicious for thymoma, with confirmed infiltration of the anterior chest wall, lung parenchyma, and pericardium at chest magnetic resonance imaging with contrast. CT-guided fine needle aspiration biopsy yielded a histological diagnosis of B2 thymoma [10]. Due to the young age, a family history of cancer was excluded. Physical exam was negative for signs of mediastinal syndrome and superficial lymph nodes. Metastatic disease was excluded by 18-fluorodeoxyglucose positron emission tomography (18FDG-PET). Patient imaging is shown in Fig. 1. Accordingly, the clinical stage was cT3 cN0 cM0 (Masaoka-Koga III) [11]. After multidisciplinary team discussion, the tumor was defined as unresectable, and the patient was offered primary chemotherapy with intravenous cyclophosphamide 500 mg/m2, doxorubicin 50 mg/m2 and cisplatin 50 mg/m2 (CAP regimen) on day 1 every 21 days [12]. Primary prophylaxis of chemotherapy-induced neutropenia was not planned due to the potential risk of worsening MG, without evidence about the safety of administering granulocyte colony-stimulating factor in unstable myasthenic patients [13]. Ovarian preservation by gonadotropin-releasing hormone analogue leuprorelin was preferred over oocyte retrieval to expedite the start of chemotherapy [14]. Standard pre-medication with intravenous administration of ondansetron 8 mg, dexamethasone 8 mg and saline was chosen [15].Fig. 1 Patient imaging. a Left chest X-ray with enlarged mediastinum (see arrow). b Chest computed tomography scan showing the mediastinal mass (see arrow). c
18PET-FDG limited radiotracer uptake in mediastinum
Chemotherapy-induced myasthenic crisis
Two hours after starting administration of the first course of chemotherapy, following doxorubicin bolus, the patient experienced sudden onset of acute dyspnea with severe respiratory failure (oxygen saturation 75% on room air), refractory to oxygen therapy and bolus hydrocortisone 500 mg and chlorphenamine 10 mg administered intravenously [16]. Physical exam was negative for bronchospasm with diminished vesicular breath sounds. Due to unstable clinical conditions and development of acute respiratory acidosis (pH 7.21, partial pressure of carbon dioxide 88 mmHg), tracheal intubation and mechanical ventilation in the intensive care unit (ICU) were needed. Urgent chest CT scan excluded acute cardiopulmonary events. Life-threatening MGFA class V MC was diagnosed, likely triggered by chemotherapy, thus classified as grade 4 according to the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) [8, 17]. Chemotherapy was held for 2 hours and then, considering its curative intent and in agreement with the family, it was resumed and fully administered during mechanical ventilation. After 24 hours, upon remission of MC and weaning from ventilation, the patient was extubated and could continue receiving MG treatment, together with starting PEX once every three days to control MG and prevent new crises (by replacing 1 plasma volume with 5% human albumin) [18]. In week 2, owing to CTCAE v5.0 grade 3 febrile neutropenia (absolute neutrophil count 60/mm3 and body temperature 38.4 °C), the patient was successfully treated with empirical piperacillin/tazobactam 4 g/0.5 g intravenously every 6 hours until recovery [19].
Curative treatment and outcome
After completing a second course of CAP chemotherapy with interposed PEX allowing symptom control, radiological assessment in week 6 documented objective partial response according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), with 33% tumor shrinkage (maximum diameter 8 versus 12 cm) [20]. This allowed us to perform radical (R0) extended thymectomy, left upper lung lobectomy and subtotal pericardiectomy, with histological diagnosis of Masaoka-Koga stage III type B2 [10, 11]. For patient histology, please see Fig. 2. The patient required early mediastinum and pleural cavity re-exploration due to postsurgical bleeding; persistent hypophonia developed due to postsurgical left vocal cord paralysis. A comparison of CT imaging at baseline and after surgery is shown in Fig. 3. As suggested for Masaoka-Koga stage III, radiotherapy of 50.4 Gy in 28 fractions was given as postoperative treatment in weeks 15–20 [1]. At the last follow-up visit, 6 months after surgery, the patient was in complete remission with gradually improving MGFA class I MG and mild persistent hypophonia [8]. Despite remarkable levels of psychological burden, the patient’s resilience and high-priority treatment goals were fundamental for successful coping.Fig. 2 Patient histology. a Hematoxylin and eosin (H&E; ×40 view) stained section of thymoma B2 according to WHO classification. b Same histological slice in ×100 view
Fig. 3 Chest computed tomography (CT) scan at baseline and after surgery. a Chest CT scan showing thymoma at baseline. b Postsurgical chest CT scan with no residual disease
Discussion and conclusions
According to the World Health Organization (WHO), thymoma is the most common variant of thymic epithelial tumors (66.3%), usually presenting with local invasion and seldom as metastatic disease [10, 21]. Overall, thymic epithelial tumors occur at a rate of 0.13–0.32 cases per 100,000 population at risk and are very uncommon in young adults [22, 23]. To our knowledge, the largest retrospective study regarding childhood thymic tumors (< 18 years) in Europe was able to identify only 36 cases during a 12-year period, confirming the extreme rarity of thymic cancer in children and adolescents [24]. Hence, the clinical case reported here has to be considered a peculiar presentation of early-onset thymoma (Fig. 4).Fig. 4 Age-specific incidence of thymic cancer by histological type. SEER*Stat Database: NPCR [National Program of Cancer Registries] and SEER [Surveillance, Epidemiology, and End Results] Incidence—U.S. Cancer Statistics Public Use Database, Nov 2017 submission (2001–2015). The green bar highlights the reported patient age interval (15–19 years)
Like thymoma, MG is extremely rare (0.17–2.13 per 100,000 person-years) [25]; however, it affects up to 30% of patients with thymoma [26]. The association of thymoma with MG has been related to the intratumoral generation of mature T cells, although the pathogenic mechanisms remain unclear [27]. MG has been found to be most commonly associated with B thymoma and confers favorable prognosis, since neuromuscular symptoms help in earlier detection of the tumor and thus less advanced stage at diagnosis. Nevertheless, concomitant MG should also be regarded as an adverse risk factor, since it can interfere with cancer treatment, being worsened by many drugs, and it reaches its maximum severity after thymectomy in a proportion of patients [28].
The case reported here, together with those published and summarized in Table 1 [3–6], highlights that chemotherapy is a realistic trigger event of MC in patients with thymoma and MG. The temporary association in all cases indicates a causative relation, and may hamper the continuation of chemotherapy that is a crucial element of multimodal treatment in cases not amenable to upfront radical surgery [1]. No biomarker is available to prove this relation, and clinical findings are crucial for the diagnosis of MC. Other differential diagnoses, such as infusion reaction to cancer chemotherapy, are less likely in the setting of prolonged respiratory failure. Here, a multidisciplinary approach was necessary, and involved neurologists for medical treatment and hematologists for a correct timing schedule of PEX sessions in order to avoid plasma drug displacement. It should be noted that we waited 72 hours from the end of chemotherapy before starting PEX, in order to preserve drug efficacy according to their half-life.Table 1. Comparison between present case and 4 other published cases
Fujiwara et al. [3] Qureshi et al. [4] Solak et al. [5] Ng et al. (6) Present case report
Sex Female Male Male Male Female
Age (year) 44 24 45 49 18
Histology B1 Thymoma (WHO) Thymoma Thymoma NE B2 thymoma (WHO)
Staging IVA (Masaoka-Koga) III (Masaoka-Koga) Advanced unresectable Advanced unresectable III (Masaoka-Koga)
AchR Ab level (nmol/l) 13 NE 74 NE 43
Chemotherapy regimen Primary CAMP Postoperative cisplatin and doxorubicin Single-agent cisplatin Doxorubicin, cisplatin, etoposide Primary CAP
Myasthenic crisis onset time During chemotherapy 8 hours after chemotherapy 1 week after chemotherapy A few hours after chemotherapy During chemotherapy
Tracheal intubation No Yes Yes Yes Yes
Plasma exchange No Yes Yes Yes Yes
Chemotherapy continuation in ICU No No No No Yes
Patient outcome after myasthenic crisis Alive Death Alive Alive Alive
AchR Ab acetylcholine receptor antibodies, CAMP cisplatin, doxorubicin, methylprednisolone, CAP cyclophosphamide, doxorubicin, cisplatin, ICU intensive care unit, NE not evaluable, WHO World Health Organization
To our knowledge, this is the first reported case of chemotherapy continuation despite the need for mechanical ventilation due to a chemotherapy-induced MC. Radical treatment was dependent on primary chemotherapy, as upfront surgery had already been ruled out. Besides, we could not confidently assume that, after MC resolution, the patient would have been able to receive further chemotherapy due to aggravation of symptoms. We conclude that special attention is warranted in patients with thymoma and MG with regard to the development of MC. Ideally, optimal control of myasthenic symptoms should be achieved before initiation of anticancer treatment. Nonetheless, chemotherapy-induced MC may complicate anticancer therapy administration, according to this evidence. We recommend that patients with thymoma and MG be hospitalized in tertiary medical centers for chemotherapy and that outpatient management be avoided. The lesson learned from the present case is that, in selected cases of advanced thymoma, paradoxical worsening of MG during chemotherapy should not be considered an absolute contraindication for continuation of primary chemotherapy with curative intent.
Abbreviations
CAPCisplatin, doxorubicin and cyclophosphamide
CTComputed tomography
CTCAE v5.0Common Terminology Criteria for Adverse Events version 5.0
GyGray
ICUIntensive Care Unit
MCMyasthenic crisis
MGMyasthenia gravis
MGFAMyasthenia Gravis Foundation of America
18PET-FDG18-Fluorodeoxyglucose positron emission tomography
PEXPlasma exchange
RECISTResponse Evaluation Criteria in Solid Tumours
WHOWorld Health Organization
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Fondazione Oncologia Niguarda Onlus for financial support.
Authors' contributions
GP, KB, FT, and SS were major contributors in writing the manuscript. KB, FT, GP, GM, GC, ASB, and SS provided clinical care. MP gave indication to and performed plasma exchange. AR and MT contributed to neoadjuvant treatment indication in a multidisciplinary team discussion and performed surgery. FL, AI, and ECA diagnosed thymoma and myasthenia and medically managed neurological symptoms. ASB and SS supervised oncological care and critically reviewed the case report. All authors read and approved the final manuscript.
Funding
This paper did not receive any specific grants from funding agencies in the public, commercial or not-for-profit sectors.
Ethics approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Availability of data and materials
Not applicable.
Competing interests
The authors declare that they have no competing interests. | 55 kg. | Weight | CC BY | 33526108 | 18,898,005 | 2021-02-02 |
What was the administration route of drug 'CISPLATIN'? | Chemotherapy-induced myasthenic crisis in thymoma treated with primary chemotherapy with curative intent on mechanical ventilation: a case report and review of the literature.
BACKGROUND
Thymoma is an uncommon cancer often associated with myasthenia gravis, an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced nonmetastatic thymoma, primary chemotherapy may be required to induce tumor shrinkage and to achieve radical resection. Cancer chemotherapy has been anecdotally reported as a trigger factor for worsening of myasthenia gravis in thymic epithelial cancers. The study of uncommon cases of chemotherapy-related myasthenic crisis is warranted to gain knowledge of clinical situations requiring intensive care support in the case of life-threatening respiratory failure.
METHODS
We report a case of an 18-year-old Caucasian woman with advanced Masaoka-Koga stage III type B2 thymoma and myasthenia gravis on treatment with pyridostigmine, steroids and intravenous immunoglobulins, who developed a myasthenic crisis 2 hours after initiation of cyclophosphamide/doxorubicin/cisplatin primary chemotherapy. Because of severe acute respiratory failure, emergency tracheal intubation, mechanical ventilation, and temporary (2 hours) discontinuation of chemotherapy were needed. Considering the curative intent of the multimodal therapeutic program, we elected to resume primary chemotherapy administration while the patient remained on mechanical ventilation. After 24 hours, the recovery of adequate respiratory function allowed successful weaning from respiratory support, and no further adverse events occurred. After 3 weeks, upon plasma exchange initiation with amelioration of myasthenic symptoms, a second course of chemotherapy was given, and in week 6, having documented partial tumor remission, the patient underwent radical surgery (R0) and then consolidation radiation therapy with 50.4 Gy in 28 fractions in weeks 15-20.
CONCLUSIONS
This case report, together with the only four available in a review of the literature, highlights that chemotherapy may carry the risk of myasthenic crisis in patients affected by thymoma and myasthenia gravis. To our knowledge, this is the first reported case of chemotherapy continuation on mechanical ventilation in a patient with chemotherapy-induced myasthenic crisis requiring tracheal intubation. The lesson learned from the present case is that, in selected cases of advanced thymoma, the paradoxical worsening of myasthenia gravis during chemotherapy should not be considered an absolute contraindication for the continuation of primary chemotherapy with curative intent.
Background
Thymoma is an uncommon epithelial cancer associated in nearly half of cases with myasthenia gravis (MG), an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced thymoma, primary chemotherapy is considered the standard of care, with the aim of achieving tumor shrinkage and facilitating radical surgery [1]. While several drugs are known to worsen MG, cancer chemotherapy has been anecdotally reported as a trigger event for myasthenic crisis (MC) in four case reports [2–6]. Here, we present a case of advanced thymoma treated with primary chemotherapy that caused an acute-onset MC requiring tracheal intubation and therapeutic plasma exchange (PEX), with relevant benefit from early resumption of anticancer treatment during mechanical ventilation.
Case presentation
Clinical presentation and diagnosis
An 18-year-old Caucasian woman with unremarkable medical history was admitted to the emergency room due to neurological symptoms. She presented with month-long worsening dysphagia, rhinolalia, bilateral ptosis, and skeletal muscle weakness. Signs of muscle fatigability were elicited at the physical exam and then confirmed by electromyography, consistently with neuromuscular junction disease. Blood tests were unremarkable with the exception of acetylcholine receptor antibodies (43 nmol/l, normal if < 0.5 nmol/l). Hence, MG class III, according to the Myasthenia Gravis Foundation of America (MGFA) scale, was diagnosed [7, 8]. Partial regression of symptoms to class II MG was achieved by oral administration of pyridostigmine 60 mg every 3 hours during the daytime, pyridostigmine sustained-release 180 mg orally before sleeping, prednisone 25 mg orally each day, and immunoglobulins 0.4 g/kg intravenously for 5 days [8, 9]. Chest computed tomography (CT) revealed a 12 cm anterior mediastinal mass suspicious for thymoma, with confirmed infiltration of the anterior chest wall, lung parenchyma, and pericardium at chest magnetic resonance imaging with contrast. CT-guided fine needle aspiration biopsy yielded a histological diagnosis of B2 thymoma [10]. Due to the young age, a family history of cancer was excluded. Physical exam was negative for signs of mediastinal syndrome and superficial lymph nodes. Metastatic disease was excluded by 18-fluorodeoxyglucose positron emission tomography (18FDG-PET). Patient imaging is shown in Fig. 1. Accordingly, the clinical stage was cT3 cN0 cM0 (Masaoka-Koga III) [11]. After multidisciplinary team discussion, the tumor was defined as unresectable, and the patient was offered primary chemotherapy with intravenous cyclophosphamide 500 mg/m2, doxorubicin 50 mg/m2 and cisplatin 50 mg/m2 (CAP regimen) on day 1 every 21 days [12]. Primary prophylaxis of chemotherapy-induced neutropenia was not planned due to the potential risk of worsening MG, without evidence about the safety of administering granulocyte colony-stimulating factor in unstable myasthenic patients [13]. Ovarian preservation by gonadotropin-releasing hormone analogue leuprorelin was preferred over oocyte retrieval to expedite the start of chemotherapy [14]. Standard pre-medication with intravenous administration of ondansetron 8 mg, dexamethasone 8 mg and saline was chosen [15].Fig. 1 Patient imaging. a Left chest X-ray with enlarged mediastinum (see arrow). b Chest computed tomography scan showing the mediastinal mass (see arrow). c
18PET-FDG limited radiotracer uptake in mediastinum
Chemotherapy-induced myasthenic crisis
Two hours after starting administration of the first course of chemotherapy, following doxorubicin bolus, the patient experienced sudden onset of acute dyspnea with severe respiratory failure (oxygen saturation 75% on room air), refractory to oxygen therapy and bolus hydrocortisone 500 mg and chlorphenamine 10 mg administered intravenously [16]. Physical exam was negative for bronchospasm with diminished vesicular breath sounds. Due to unstable clinical conditions and development of acute respiratory acidosis (pH 7.21, partial pressure of carbon dioxide 88 mmHg), tracheal intubation and mechanical ventilation in the intensive care unit (ICU) were needed. Urgent chest CT scan excluded acute cardiopulmonary events. Life-threatening MGFA class V MC was diagnosed, likely triggered by chemotherapy, thus classified as grade 4 according to the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) [8, 17]. Chemotherapy was held for 2 hours and then, considering its curative intent and in agreement with the family, it was resumed and fully administered during mechanical ventilation. After 24 hours, upon remission of MC and weaning from ventilation, the patient was extubated and could continue receiving MG treatment, together with starting PEX once every three days to control MG and prevent new crises (by replacing 1 plasma volume with 5% human albumin) [18]. In week 2, owing to CTCAE v5.0 grade 3 febrile neutropenia (absolute neutrophil count 60/mm3 and body temperature 38.4 °C), the patient was successfully treated with empirical piperacillin/tazobactam 4 g/0.5 g intravenously every 6 hours until recovery [19].
Curative treatment and outcome
After completing a second course of CAP chemotherapy with interposed PEX allowing symptom control, radiological assessment in week 6 documented objective partial response according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), with 33% tumor shrinkage (maximum diameter 8 versus 12 cm) [20]. This allowed us to perform radical (R0) extended thymectomy, left upper lung lobectomy and subtotal pericardiectomy, with histological diagnosis of Masaoka-Koga stage III type B2 [10, 11]. For patient histology, please see Fig. 2. The patient required early mediastinum and pleural cavity re-exploration due to postsurgical bleeding; persistent hypophonia developed due to postsurgical left vocal cord paralysis. A comparison of CT imaging at baseline and after surgery is shown in Fig. 3. As suggested for Masaoka-Koga stage III, radiotherapy of 50.4 Gy in 28 fractions was given as postoperative treatment in weeks 15–20 [1]. At the last follow-up visit, 6 months after surgery, the patient was in complete remission with gradually improving MGFA class I MG and mild persistent hypophonia [8]. Despite remarkable levels of psychological burden, the patient’s resilience and high-priority treatment goals were fundamental for successful coping.Fig. 2 Patient histology. a Hematoxylin and eosin (H&E; ×40 view) stained section of thymoma B2 according to WHO classification. b Same histological slice in ×100 view
Fig. 3 Chest computed tomography (CT) scan at baseline and after surgery. a Chest CT scan showing thymoma at baseline. b Postsurgical chest CT scan with no residual disease
Discussion and conclusions
According to the World Health Organization (WHO), thymoma is the most common variant of thymic epithelial tumors (66.3%), usually presenting with local invasion and seldom as metastatic disease [10, 21]. Overall, thymic epithelial tumors occur at a rate of 0.13–0.32 cases per 100,000 population at risk and are very uncommon in young adults [22, 23]. To our knowledge, the largest retrospective study regarding childhood thymic tumors (< 18 years) in Europe was able to identify only 36 cases during a 12-year period, confirming the extreme rarity of thymic cancer in children and adolescents [24]. Hence, the clinical case reported here has to be considered a peculiar presentation of early-onset thymoma (Fig. 4).Fig. 4 Age-specific incidence of thymic cancer by histological type. SEER*Stat Database: NPCR [National Program of Cancer Registries] and SEER [Surveillance, Epidemiology, and End Results] Incidence—U.S. Cancer Statistics Public Use Database, Nov 2017 submission (2001–2015). The green bar highlights the reported patient age interval (15–19 years)
Like thymoma, MG is extremely rare (0.17–2.13 per 100,000 person-years) [25]; however, it affects up to 30% of patients with thymoma [26]. The association of thymoma with MG has been related to the intratumoral generation of mature T cells, although the pathogenic mechanisms remain unclear [27]. MG has been found to be most commonly associated with B thymoma and confers favorable prognosis, since neuromuscular symptoms help in earlier detection of the tumor and thus less advanced stage at diagnosis. Nevertheless, concomitant MG should also be regarded as an adverse risk factor, since it can interfere with cancer treatment, being worsened by many drugs, and it reaches its maximum severity after thymectomy in a proportion of patients [28].
The case reported here, together with those published and summarized in Table 1 [3–6], highlights that chemotherapy is a realistic trigger event of MC in patients with thymoma and MG. The temporary association in all cases indicates a causative relation, and may hamper the continuation of chemotherapy that is a crucial element of multimodal treatment in cases not amenable to upfront radical surgery [1]. No biomarker is available to prove this relation, and clinical findings are crucial for the diagnosis of MC. Other differential diagnoses, such as infusion reaction to cancer chemotherapy, are less likely in the setting of prolonged respiratory failure. Here, a multidisciplinary approach was necessary, and involved neurologists for medical treatment and hematologists for a correct timing schedule of PEX sessions in order to avoid plasma drug displacement. It should be noted that we waited 72 hours from the end of chemotherapy before starting PEX, in order to preserve drug efficacy according to their half-life.Table 1. Comparison between present case and 4 other published cases
Fujiwara et al. [3] Qureshi et al. [4] Solak et al. [5] Ng et al. (6) Present case report
Sex Female Male Male Male Female
Age (year) 44 24 45 49 18
Histology B1 Thymoma (WHO) Thymoma Thymoma NE B2 thymoma (WHO)
Staging IVA (Masaoka-Koga) III (Masaoka-Koga) Advanced unresectable Advanced unresectable III (Masaoka-Koga)
AchR Ab level (nmol/l) 13 NE 74 NE 43
Chemotherapy regimen Primary CAMP Postoperative cisplatin and doxorubicin Single-agent cisplatin Doxorubicin, cisplatin, etoposide Primary CAP
Myasthenic crisis onset time During chemotherapy 8 hours after chemotherapy 1 week after chemotherapy A few hours after chemotherapy During chemotherapy
Tracheal intubation No Yes Yes Yes Yes
Plasma exchange No Yes Yes Yes Yes
Chemotherapy continuation in ICU No No No No Yes
Patient outcome after myasthenic crisis Alive Death Alive Alive Alive
AchR Ab acetylcholine receptor antibodies, CAMP cisplatin, doxorubicin, methylprednisolone, CAP cyclophosphamide, doxorubicin, cisplatin, ICU intensive care unit, NE not evaluable, WHO World Health Organization
To our knowledge, this is the first reported case of chemotherapy continuation despite the need for mechanical ventilation due to a chemotherapy-induced MC. Radical treatment was dependent on primary chemotherapy, as upfront surgery had already been ruled out. Besides, we could not confidently assume that, after MC resolution, the patient would have been able to receive further chemotherapy due to aggravation of symptoms. We conclude that special attention is warranted in patients with thymoma and MG with regard to the development of MC. Ideally, optimal control of myasthenic symptoms should be achieved before initiation of anticancer treatment. Nonetheless, chemotherapy-induced MC may complicate anticancer therapy administration, according to this evidence. We recommend that patients with thymoma and MG be hospitalized in tertiary medical centers for chemotherapy and that outpatient management be avoided. The lesson learned from the present case is that, in selected cases of advanced thymoma, paradoxical worsening of MG during chemotherapy should not be considered an absolute contraindication for continuation of primary chemotherapy with curative intent.
Abbreviations
CAPCisplatin, doxorubicin and cyclophosphamide
CTComputed tomography
CTCAE v5.0Common Terminology Criteria for Adverse Events version 5.0
GyGray
ICUIntensive Care Unit
MCMyasthenic crisis
MGMyasthenia gravis
MGFAMyasthenia Gravis Foundation of America
18PET-FDG18-Fluorodeoxyglucose positron emission tomography
PEXPlasma exchange
RECISTResponse Evaluation Criteria in Solid Tumours
WHOWorld Health Organization
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Fondazione Oncologia Niguarda Onlus for financial support.
Authors' contributions
GP, KB, FT, and SS were major contributors in writing the manuscript. KB, FT, GP, GM, GC, ASB, and SS provided clinical care. MP gave indication to and performed plasma exchange. AR and MT contributed to neoadjuvant treatment indication in a multidisciplinary team discussion and performed surgery. FL, AI, and ECA diagnosed thymoma and myasthenia and medically managed neurological symptoms. ASB and SS supervised oncological care and critically reviewed the case report. All authors read and approved the final manuscript.
Funding
This paper did not receive any specific grants from funding agencies in the public, commercial or not-for-profit sectors.
Ethics approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Availability of data and materials
Not applicable.
Competing interests
The authors declare that they have no competing interests. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33526108 | 18,959,226 | 2021-02-02 |
What was the administration route of drug 'CYCLOPHOSPHAMIDE'? | Chemotherapy-induced myasthenic crisis in thymoma treated with primary chemotherapy with curative intent on mechanical ventilation: a case report and review of the literature.
BACKGROUND
Thymoma is an uncommon cancer often associated with myasthenia gravis, an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced nonmetastatic thymoma, primary chemotherapy may be required to induce tumor shrinkage and to achieve radical resection. Cancer chemotherapy has been anecdotally reported as a trigger factor for worsening of myasthenia gravis in thymic epithelial cancers. The study of uncommon cases of chemotherapy-related myasthenic crisis is warranted to gain knowledge of clinical situations requiring intensive care support in the case of life-threatening respiratory failure.
METHODS
We report a case of an 18-year-old Caucasian woman with advanced Masaoka-Koga stage III type B2 thymoma and myasthenia gravis on treatment with pyridostigmine, steroids and intravenous immunoglobulins, who developed a myasthenic crisis 2 hours after initiation of cyclophosphamide/doxorubicin/cisplatin primary chemotherapy. Because of severe acute respiratory failure, emergency tracheal intubation, mechanical ventilation, and temporary (2 hours) discontinuation of chemotherapy were needed. Considering the curative intent of the multimodal therapeutic program, we elected to resume primary chemotherapy administration while the patient remained on mechanical ventilation. After 24 hours, the recovery of adequate respiratory function allowed successful weaning from respiratory support, and no further adverse events occurred. After 3 weeks, upon plasma exchange initiation with amelioration of myasthenic symptoms, a second course of chemotherapy was given, and in week 6, having documented partial tumor remission, the patient underwent radical surgery (R0) and then consolidation radiation therapy with 50.4 Gy in 28 fractions in weeks 15-20.
CONCLUSIONS
This case report, together with the only four available in a review of the literature, highlights that chemotherapy may carry the risk of myasthenic crisis in patients affected by thymoma and myasthenia gravis. To our knowledge, this is the first reported case of chemotherapy continuation on mechanical ventilation in a patient with chemotherapy-induced myasthenic crisis requiring tracheal intubation. The lesson learned from the present case is that, in selected cases of advanced thymoma, the paradoxical worsening of myasthenia gravis during chemotherapy should not be considered an absolute contraindication for the continuation of primary chemotherapy with curative intent.
Background
Thymoma is an uncommon epithelial cancer associated in nearly half of cases with myasthenia gravis (MG), an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced thymoma, primary chemotherapy is considered the standard of care, with the aim of achieving tumor shrinkage and facilitating radical surgery [1]. While several drugs are known to worsen MG, cancer chemotherapy has been anecdotally reported as a trigger event for myasthenic crisis (MC) in four case reports [2–6]. Here, we present a case of advanced thymoma treated with primary chemotherapy that caused an acute-onset MC requiring tracheal intubation and therapeutic plasma exchange (PEX), with relevant benefit from early resumption of anticancer treatment during mechanical ventilation.
Case presentation
Clinical presentation and diagnosis
An 18-year-old Caucasian woman with unremarkable medical history was admitted to the emergency room due to neurological symptoms. She presented with month-long worsening dysphagia, rhinolalia, bilateral ptosis, and skeletal muscle weakness. Signs of muscle fatigability were elicited at the physical exam and then confirmed by electromyography, consistently with neuromuscular junction disease. Blood tests were unremarkable with the exception of acetylcholine receptor antibodies (43 nmol/l, normal if < 0.5 nmol/l). Hence, MG class III, according to the Myasthenia Gravis Foundation of America (MGFA) scale, was diagnosed [7, 8]. Partial regression of symptoms to class II MG was achieved by oral administration of pyridostigmine 60 mg every 3 hours during the daytime, pyridostigmine sustained-release 180 mg orally before sleeping, prednisone 25 mg orally each day, and immunoglobulins 0.4 g/kg intravenously for 5 days [8, 9]. Chest computed tomography (CT) revealed a 12 cm anterior mediastinal mass suspicious for thymoma, with confirmed infiltration of the anterior chest wall, lung parenchyma, and pericardium at chest magnetic resonance imaging with contrast. CT-guided fine needle aspiration biopsy yielded a histological diagnosis of B2 thymoma [10]. Due to the young age, a family history of cancer was excluded. Physical exam was negative for signs of mediastinal syndrome and superficial lymph nodes. Metastatic disease was excluded by 18-fluorodeoxyglucose positron emission tomography (18FDG-PET). Patient imaging is shown in Fig. 1. Accordingly, the clinical stage was cT3 cN0 cM0 (Masaoka-Koga III) [11]. After multidisciplinary team discussion, the tumor was defined as unresectable, and the patient was offered primary chemotherapy with intravenous cyclophosphamide 500 mg/m2, doxorubicin 50 mg/m2 and cisplatin 50 mg/m2 (CAP regimen) on day 1 every 21 days [12]. Primary prophylaxis of chemotherapy-induced neutropenia was not planned due to the potential risk of worsening MG, without evidence about the safety of administering granulocyte colony-stimulating factor in unstable myasthenic patients [13]. Ovarian preservation by gonadotropin-releasing hormone analogue leuprorelin was preferred over oocyte retrieval to expedite the start of chemotherapy [14]. Standard pre-medication with intravenous administration of ondansetron 8 mg, dexamethasone 8 mg and saline was chosen [15].Fig. 1 Patient imaging. a Left chest X-ray with enlarged mediastinum (see arrow). b Chest computed tomography scan showing the mediastinal mass (see arrow). c
18PET-FDG limited radiotracer uptake in mediastinum
Chemotherapy-induced myasthenic crisis
Two hours after starting administration of the first course of chemotherapy, following doxorubicin bolus, the patient experienced sudden onset of acute dyspnea with severe respiratory failure (oxygen saturation 75% on room air), refractory to oxygen therapy and bolus hydrocortisone 500 mg and chlorphenamine 10 mg administered intravenously [16]. Physical exam was negative for bronchospasm with diminished vesicular breath sounds. Due to unstable clinical conditions and development of acute respiratory acidosis (pH 7.21, partial pressure of carbon dioxide 88 mmHg), tracheal intubation and mechanical ventilation in the intensive care unit (ICU) were needed. Urgent chest CT scan excluded acute cardiopulmonary events. Life-threatening MGFA class V MC was diagnosed, likely triggered by chemotherapy, thus classified as grade 4 according to the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) [8, 17]. Chemotherapy was held for 2 hours and then, considering its curative intent and in agreement with the family, it was resumed and fully administered during mechanical ventilation. After 24 hours, upon remission of MC and weaning from ventilation, the patient was extubated and could continue receiving MG treatment, together with starting PEX once every three days to control MG and prevent new crises (by replacing 1 plasma volume with 5% human albumin) [18]. In week 2, owing to CTCAE v5.0 grade 3 febrile neutropenia (absolute neutrophil count 60/mm3 and body temperature 38.4 °C), the patient was successfully treated with empirical piperacillin/tazobactam 4 g/0.5 g intravenously every 6 hours until recovery [19].
Curative treatment and outcome
After completing a second course of CAP chemotherapy with interposed PEX allowing symptom control, radiological assessment in week 6 documented objective partial response according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), with 33% tumor shrinkage (maximum diameter 8 versus 12 cm) [20]. This allowed us to perform radical (R0) extended thymectomy, left upper lung lobectomy and subtotal pericardiectomy, with histological diagnosis of Masaoka-Koga stage III type B2 [10, 11]. For patient histology, please see Fig. 2. The patient required early mediastinum and pleural cavity re-exploration due to postsurgical bleeding; persistent hypophonia developed due to postsurgical left vocal cord paralysis. A comparison of CT imaging at baseline and after surgery is shown in Fig. 3. As suggested for Masaoka-Koga stage III, radiotherapy of 50.4 Gy in 28 fractions was given as postoperative treatment in weeks 15–20 [1]. At the last follow-up visit, 6 months after surgery, the patient was in complete remission with gradually improving MGFA class I MG and mild persistent hypophonia [8]. Despite remarkable levels of psychological burden, the patient’s resilience and high-priority treatment goals were fundamental for successful coping.Fig. 2 Patient histology. a Hematoxylin and eosin (H&E; ×40 view) stained section of thymoma B2 according to WHO classification. b Same histological slice in ×100 view
Fig. 3 Chest computed tomography (CT) scan at baseline and after surgery. a Chest CT scan showing thymoma at baseline. b Postsurgical chest CT scan with no residual disease
Discussion and conclusions
According to the World Health Organization (WHO), thymoma is the most common variant of thymic epithelial tumors (66.3%), usually presenting with local invasion and seldom as metastatic disease [10, 21]. Overall, thymic epithelial tumors occur at a rate of 0.13–0.32 cases per 100,000 population at risk and are very uncommon in young adults [22, 23]. To our knowledge, the largest retrospective study regarding childhood thymic tumors (< 18 years) in Europe was able to identify only 36 cases during a 12-year period, confirming the extreme rarity of thymic cancer in children and adolescents [24]. Hence, the clinical case reported here has to be considered a peculiar presentation of early-onset thymoma (Fig. 4).Fig. 4 Age-specific incidence of thymic cancer by histological type. SEER*Stat Database: NPCR [National Program of Cancer Registries] and SEER [Surveillance, Epidemiology, and End Results] Incidence—U.S. Cancer Statistics Public Use Database, Nov 2017 submission (2001–2015). The green bar highlights the reported patient age interval (15–19 years)
Like thymoma, MG is extremely rare (0.17–2.13 per 100,000 person-years) [25]; however, it affects up to 30% of patients with thymoma [26]. The association of thymoma with MG has been related to the intratumoral generation of mature T cells, although the pathogenic mechanisms remain unclear [27]. MG has been found to be most commonly associated with B thymoma and confers favorable prognosis, since neuromuscular symptoms help in earlier detection of the tumor and thus less advanced stage at diagnosis. Nevertheless, concomitant MG should also be regarded as an adverse risk factor, since it can interfere with cancer treatment, being worsened by many drugs, and it reaches its maximum severity after thymectomy in a proportion of patients [28].
The case reported here, together with those published and summarized in Table 1 [3–6], highlights that chemotherapy is a realistic trigger event of MC in patients with thymoma and MG. The temporary association in all cases indicates a causative relation, and may hamper the continuation of chemotherapy that is a crucial element of multimodal treatment in cases not amenable to upfront radical surgery [1]. No biomarker is available to prove this relation, and clinical findings are crucial for the diagnosis of MC. Other differential diagnoses, such as infusion reaction to cancer chemotherapy, are less likely in the setting of prolonged respiratory failure. Here, a multidisciplinary approach was necessary, and involved neurologists for medical treatment and hematologists for a correct timing schedule of PEX sessions in order to avoid plasma drug displacement. It should be noted that we waited 72 hours from the end of chemotherapy before starting PEX, in order to preserve drug efficacy according to their half-life.Table 1. Comparison between present case and 4 other published cases
Fujiwara et al. [3] Qureshi et al. [4] Solak et al. [5] Ng et al. (6) Present case report
Sex Female Male Male Male Female
Age (year) 44 24 45 49 18
Histology B1 Thymoma (WHO) Thymoma Thymoma NE B2 thymoma (WHO)
Staging IVA (Masaoka-Koga) III (Masaoka-Koga) Advanced unresectable Advanced unresectable III (Masaoka-Koga)
AchR Ab level (nmol/l) 13 NE 74 NE 43
Chemotherapy regimen Primary CAMP Postoperative cisplatin and doxorubicin Single-agent cisplatin Doxorubicin, cisplatin, etoposide Primary CAP
Myasthenic crisis onset time During chemotherapy 8 hours after chemotherapy 1 week after chemotherapy A few hours after chemotherapy During chemotherapy
Tracheal intubation No Yes Yes Yes Yes
Plasma exchange No Yes Yes Yes Yes
Chemotherapy continuation in ICU No No No No Yes
Patient outcome after myasthenic crisis Alive Death Alive Alive Alive
AchR Ab acetylcholine receptor antibodies, CAMP cisplatin, doxorubicin, methylprednisolone, CAP cyclophosphamide, doxorubicin, cisplatin, ICU intensive care unit, NE not evaluable, WHO World Health Organization
To our knowledge, this is the first reported case of chemotherapy continuation despite the need for mechanical ventilation due to a chemotherapy-induced MC. Radical treatment was dependent on primary chemotherapy, as upfront surgery had already been ruled out. Besides, we could not confidently assume that, after MC resolution, the patient would have been able to receive further chemotherapy due to aggravation of symptoms. We conclude that special attention is warranted in patients with thymoma and MG with regard to the development of MC. Ideally, optimal control of myasthenic symptoms should be achieved before initiation of anticancer treatment. Nonetheless, chemotherapy-induced MC may complicate anticancer therapy administration, according to this evidence. We recommend that patients with thymoma and MG be hospitalized in tertiary medical centers for chemotherapy and that outpatient management be avoided. The lesson learned from the present case is that, in selected cases of advanced thymoma, paradoxical worsening of MG during chemotherapy should not be considered an absolute contraindication for continuation of primary chemotherapy with curative intent.
Abbreviations
CAPCisplatin, doxorubicin and cyclophosphamide
CTComputed tomography
CTCAE v5.0Common Terminology Criteria for Adverse Events version 5.0
GyGray
ICUIntensive Care Unit
MCMyasthenic crisis
MGMyasthenia gravis
MGFAMyasthenia Gravis Foundation of America
18PET-FDG18-Fluorodeoxyglucose positron emission tomography
PEXPlasma exchange
RECISTResponse Evaluation Criteria in Solid Tumours
WHOWorld Health Organization
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Fondazione Oncologia Niguarda Onlus for financial support.
Authors' contributions
GP, KB, FT, and SS were major contributors in writing the manuscript. KB, FT, GP, GM, GC, ASB, and SS provided clinical care. MP gave indication to and performed plasma exchange. AR and MT contributed to neoadjuvant treatment indication in a multidisciplinary team discussion and performed surgery. FL, AI, and ECA diagnosed thymoma and myasthenia and medically managed neurological symptoms. ASB and SS supervised oncological care and critically reviewed the case report. All authors read and approved the final manuscript.
Funding
This paper did not receive any specific grants from funding agencies in the public, commercial or not-for-profit sectors.
Ethics approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Availability of data and materials
Not applicable.
Competing interests
The authors declare that they have no competing interests. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33526108 | 18,959,226 | 2021-02-02 |
What was the administration route of drug 'DEXAMETHASONE'? | Chemotherapy-induced myasthenic crisis in thymoma treated with primary chemotherapy with curative intent on mechanical ventilation: a case report and review of the literature.
BACKGROUND
Thymoma is an uncommon cancer often associated with myasthenia gravis, an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced nonmetastatic thymoma, primary chemotherapy may be required to induce tumor shrinkage and to achieve radical resection. Cancer chemotherapy has been anecdotally reported as a trigger factor for worsening of myasthenia gravis in thymic epithelial cancers. The study of uncommon cases of chemotherapy-related myasthenic crisis is warranted to gain knowledge of clinical situations requiring intensive care support in the case of life-threatening respiratory failure.
METHODS
We report a case of an 18-year-old Caucasian woman with advanced Masaoka-Koga stage III type B2 thymoma and myasthenia gravis on treatment with pyridostigmine, steroids and intravenous immunoglobulins, who developed a myasthenic crisis 2 hours after initiation of cyclophosphamide/doxorubicin/cisplatin primary chemotherapy. Because of severe acute respiratory failure, emergency tracheal intubation, mechanical ventilation, and temporary (2 hours) discontinuation of chemotherapy were needed. Considering the curative intent of the multimodal therapeutic program, we elected to resume primary chemotherapy administration while the patient remained on mechanical ventilation. After 24 hours, the recovery of adequate respiratory function allowed successful weaning from respiratory support, and no further adverse events occurred. After 3 weeks, upon plasma exchange initiation with amelioration of myasthenic symptoms, a second course of chemotherapy was given, and in week 6, having documented partial tumor remission, the patient underwent radical surgery (R0) and then consolidation radiation therapy with 50.4 Gy in 28 fractions in weeks 15-20.
CONCLUSIONS
This case report, together with the only four available in a review of the literature, highlights that chemotherapy may carry the risk of myasthenic crisis in patients affected by thymoma and myasthenia gravis. To our knowledge, this is the first reported case of chemotherapy continuation on mechanical ventilation in a patient with chemotherapy-induced myasthenic crisis requiring tracheal intubation. The lesson learned from the present case is that, in selected cases of advanced thymoma, the paradoxical worsening of myasthenia gravis during chemotherapy should not be considered an absolute contraindication for the continuation of primary chemotherapy with curative intent.
Background
Thymoma is an uncommon epithelial cancer associated in nearly half of cases with myasthenia gravis (MG), an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced thymoma, primary chemotherapy is considered the standard of care, with the aim of achieving tumor shrinkage and facilitating radical surgery [1]. While several drugs are known to worsen MG, cancer chemotherapy has been anecdotally reported as a trigger event for myasthenic crisis (MC) in four case reports [2–6]. Here, we present a case of advanced thymoma treated with primary chemotherapy that caused an acute-onset MC requiring tracheal intubation and therapeutic plasma exchange (PEX), with relevant benefit from early resumption of anticancer treatment during mechanical ventilation.
Case presentation
Clinical presentation and diagnosis
An 18-year-old Caucasian woman with unremarkable medical history was admitted to the emergency room due to neurological symptoms. She presented with month-long worsening dysphagia, rhinolalia, bilateral ptosis, and skeletal muscle weakness. Signs of muscle fatigability were elicited at the physical exam and then confirmed by electromyography, consistently with neuromuscular junction disease. Blood tests were unremarkable with the exception of acetylcholine receptor antibodies (43 nmol/l, normal if < 0.5 nmol/l). Hence, MG class III, according to the Myasthenia Gravis Foundation of America (MGFA) scale, was diagnosed [7, 8]. Partial regression of symptoms to class II MG was achieved by oral administration of pyridostigmine 60 mg every 3 hours during the daytime, pyridostigmine sustained-release 180 mg orally before sleeping, prednisone 25 mg orally each day, and immunoglobulins 0.4 g/kg intravenously for 5 days [8, 9]. Chest computed tomography (CT) revealed a 12 cm anterior mediastinal mass suspicious for thymoma, with confirmed infiltration of the anterior chest wall, lung parenchyma, and pericardium at chest magnetic resonance imaging with contrast. CT-guided fine needle aspiration biopsy yielded a histological diagnosis of B2 thymoma [10]. Due to the young age, a family history of cancer was excluded. Physical exam was negative for signs of mediastinal syndrome and superficial lymph nodes. Metastatic disease was excluded by 18-fluorodeoxyglucose positron emission tomography (18FDG-PET). Patient imaging is shown in Fig. 1. Accordingly, the clinical stage was cT3 cN0 cM0 (Masaoka-Koga III) [11]. After multidisciplinary team discussion, the tumor was defined as unresectable, and the patient was offered primary chemotherapy with intravenous cyclophosphamide 500 mg/m2, doxorubicin 50 mg/m2 and cisplatin 50 mg/m2 (CAP regimen) on day 1 every 21 days [12]. Primary prophylaxis of chemotherapy-induced neutropenia was not planned due to the potential risk of worsening MG, without evidence about the safety of administering granulocyte colony-stimulating factor in unstable myasthenic patients [13]. Ovarian preservation by gonadotropin-releasing hormone analogue leuprorelin was preferred over oocyte retrieval to expedite the start of chemotherapy [14]. Standard pre-medication with intravenous administration of ondansetron 8 mg, dexamethasone 8 mg and saline was chosen [15].Fig. 1 Patient imaging. a Left chest X-ray with enlarged mediastinum (see arrow). b Chest computed tomography scan showing the mediastinal mass (see arrow). c
18PET-FDG limited radiotracer uptake in mediastinum
Chemotherapy-induced myasthenic crisis
Two hours after starting administration of the first course of chemotherapy, following doxorubicin bolus, the patient experienced sudden onset of acute dyspnea with severe respiratory failure (oxygen saturation 75% on room air), refractory to oxygen therapy and bolus hydrocortisone 500 mg and chlorphenamine 10 mg administered intravenously [16]. Physical exam was negative for bronchospasm with diminished vesicular breath sounds. Due to unstable clinical conditions and development of acute respiratory acidosis (pH 7.21, partial pressure of carbon dioxide 88 mmHg), tracheal intubation and mechanical ventilation in the intensive care unit (ICU) were needed. Urgent chest CT scan excluded acute cardiopulmonary events. Life-threatening MGFA class V MC was diagnosed, likely triggered by chemotherapy, thus classified as grade 4 according to the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) [8, 17]. Chemotherapy was held for 2 hours and then, considering its curative intent and in agreement with the family, it was resumed and fully administered during mechanical ventilation. After 24 hours, upon remission of MC and weaning from ventilation, the patient was extubated and could continue receiving MG treatment, together with starting PEX once every three days to control MG and prevent new crises (by replacing 1 plasma volume with 5% human albumin) [18]. In week 2, owing to CTCAE v5.0 grade 3 febrile neutropenia (absolute neutrophil count 60/mm3 and body temperature 38.4 °C), the patient was successfully treated with empirical piperacillin/tazobactam 4 g/0.5 g intravenously every 6 hours until recovery [19].
Curative treatment and outcome
After completing a second course of CAP chemotherapy with interposed PEX allowing symptom control, radiological assessment in week 6 documented objective partial response according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), with 33% tumor shrinkage (maximum diameter 8 versus 12 cm) [20]. This allowed us to perform radical (R0) extended thymectomy, left upper lung lobectomy and subtotal pericardiectomy, with histological diagnosis of Masaoka-Koga stage III type B2 [10, 11]. For patient histology, please see Fig. 2. The patient required early mediastinum and pleural cavity re-exploration due to postsurgical bleeding; persistent hypophonia developed due to postsurgical left vocal cord paralysis. A comparison of CT imaging at baseline and after surgery is shown in Fig. 3. As suggested for Masaoka-Koga stage III, radiotherapy of 50.4 Gy in 28 fractions was given as postoperative treatment in weeks 15–20 [1]. At the last follow-up visit, 6 months after surgery, the patient was in complete remission with gradually improving MGFA class I MG and mild persistent hypophonia [8]. Despite remarkable levels of psychological burden, the patient’s resilience and high-priority treatment goals were fundamental for successful coping.Fig. 2 Patient histology. a Hematoxylin and eosin (H&E; ×40 view) stained section of thymoma B2 according to WHO classification. b Same histological slice in ×100 view
Fig. 3 Chest computed tomography (CT) scan at baseline and after surgery. a Chest CT scan showing thymoma at baseline. b Postsurgical chest CT scan with no residual disease
Discussion and conclusions
According to the World Health Organization (WHO), thymoma is the most common variant of thymic epithelial tumors (66.3%), usually presenting with local invasion and seldom as metastatic disease [10, 21]. Overall, thymic epithelial tumors occur at a rate of 0.13–0.32 cases per 100,000 population at risk and are very uncommon in young adults [22, 23]. To our knowledge, the largest retrospective study regarding childhood thymic tumors (< 18 years) in Europe was able to identify only 36 cases during a 12-year period, confirming the extreme rarity of thymic cancer in children and adolescents [24]. Hence, the clinical case reported here has to be considered a peculiar presentation of early-onset thymoma (Fig. 4).Fig. 4 Age-specific incidence of thymic cancer by histological type. SEER*Stat Database: NPCR [National Program of Cancer Registries] and SEER [Surveillance, Epidemiology, and End Results] Incidence—U.S. Cancer Statistics Public Use Database, Nov 2017 submission (2001–2015). The green bar highlights the reported patient age interval (15–19 years)
Like thymoma, MG is extremely rare (0.17–2.13 per 100,000 person-years) [25]; however, it affects up to 30% of patients with thymoma [26]. The association of thymoma with MG has been related to the intratumoral generation of mature T cells, although the pathogenic mechanisms remain unclear [27]. MG has been found to be most commonly associated with B thymoma and confers favorable prognosis, since neuromuscular symptoms help in earlier detection of the tumor and thus less advanced stage at diagnosis. Nevertheless, concomitant MG should also be regarded as an adverse risk factor, since it can interfere with cancer treatment, being worsened by many drugs, and it reaches its maximum severity after thymectomy in a proportion of patients [28].
The case reported here, together with those published and summarized in Table 1 [3–6], highlights that chemotherapy is a realistic trigger event of MC in patients with thymoma and MG. The temporary association in all cases indicates a causative relation, and may hamper the continuation of chemotherapy that is a crucial element of multimodal treatment in cases not amenable to upfront radical surgery [1]. No biomarker is available to prove this relation, and clinical findings are crucial for the diagnosis of MC. Other differential diagnoses, such as infusion reaction to cancer chemotherapy, are less likely in the setting of prolonged respiratory failure. Here, a multidisciplinary approach was necessary, and involved neurologists for medical treatment and hematologists for a correct timing schedule of PEX sessions in order to avoid plasma drug displacement. It should be noted that we waited 72 hours from the end of chemotherapy before starting PEX, in order to preserve drug efficacy according to their half-life.Table 1. Comparison between present case and 4 other published cases
Fujiwara et al. [3] Qureshi et al. [4] Solak et al. [5] Ng et al. (6) Present case report
Sex Female Male Male Male Female
Age (year) 44 24 45 49 18
Histology B1 Thymoma (WHO) Thymoma Thymoma NE B2 thymoma (WHO)
Staging IVA (Masaoka-Koga) III (Masaoka-Koga) Advanced unresectable Advanced unresectable III (Masaoka-Koga)
AchR Ab level (nmol/l) 13 NE 74 NE 43
Chemotherapy regimen Primary CAMP Postoperative cisplatin and doxorubicin Single-agent cisplatin Doxorubicin, cisplatin, etoposide Primary CAP
Myasthenic crisis onset time During chemotherapy 8 hours after chemotherapy 1 week after chemotherapy A few hours after chemotherapy During chemotherapy
Tracheal intubation No Yes Yes Yes Yes
Plasma exchange No Yes Yes Yes Yes
Chemotherapy continuation in ICU No No No No Yes
Patient outcome after myasthenic crisis Alive Death Alive Alive Alive
AchR Ab acetylcholine receptor antibodies, CAMP cisplatin, doxorubicin, methylprednisolone, CAP cyclophosphamide, doxorubicin, cisplatin, ICU intensive care unit, NE not evaluable, WHO World Health Organization
To our knowledge, this is the first reported case of chemotherapy continuation despite the need for mechanical ventilation due to a chemotherapy-induced MC. Radical treatment was dependent on primary chemotherapy, as upfront surgery had already been ruled out. Besides, we could not confidently assume that, after MC resolution, the patient would have been able to receive further chemotherapy due to aggravation of symptoms. We conclude that special attention is warranted in patients with thymoma and MG with regard to the development of MC. Ideally, optimal control of myasthenic symptoms should be achieved before initiation of anticancer treatment. Nonetheless, chemotherapy-induced MC may complicate anticancer therapy administration, according to this evidence. We recommend that patients with thymoma and MG be hospitalized in tertiary medical centers for chemotherapy and that outpatient management be avoided. The lesson learned from the present case is that, in selected cases of advanced thymoma, paradoxical worsening of MG during chemotherapy should not be considered an absolute contraindication for continuation of primary chemotherapy with curative intent.
Abbreviations
CAPCisplatin, doxorubicin and cyclophosphamide
CTComputed tomography
CTCAE v5.0Common Terminology Criteria for Adverse Events version 5.0
GyGray
ICUIntensive Care Unit
MCMyasthenic crisis
MGMyasthenia gravis
MGFAMyasthenia Gravis Foundation of America
18PET-FDG18-Fluorodeoxyglucose positron emission tomography
PEXPlasma exchange
RECISTResponse Evaluation Criteria in Solid Tumours
WHOWorld Health Organization
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Fondazione Oncologia Niguarda Onlus for financial support.
Authors' contributions
GP, KB, FT, and SS were major contributors in writing the manuscript. KB, FT, GP, GM, GC, ASB, and SS provided clinical care. MP gave indication to and performed plasma exchange. AR and MT contributed to neoadjuvant treatment indication in a multidisciplinary team discussion and performed surgery. FL, AI, and ECA diagnosed thymoma and myasthenia and medically managed neurological symptoms. ASB and SS supervised oncological care and critically reviewed the case report. All authors read and approved the final manuscript.
Funding
This paper did not receive any specific grants from funding agencies in the public, commercial or not-for-profit sectors.
Ethics approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Availability of data and materials
Not applicable.
Competing interests
The authors declare that they have no competing interests. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33526108 | 18,959,226 | 2021-02-02 |
What was the administration route of drug 'DOXORUBICIN HYDROCHLORIDE'? | Chemotherapy-induced myasthenic crisis in thymoma treated with primary chemotherapy with curative intent on mechanical ventilation: a case report and review of the literature.
BACKGROUND
Thymoma is an uncommon cancer often associated with myasthenia gravis, an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced nonmetastatic thymoma, primary chemotherapy may be required to induce tumor shrinkage and to achieve radical resection. Cancer chemotherapy has been anecdotally reported as a trigger factor for worsening of myasthenia gravis in thymic epithelial cancers. The study of uncommon cases of chemotherapy-related myasthenic crisis is warranted to gain knowledge of clinical situations requiring intensive care support in the case of life-threatening respiratory failure.
METHODS
We report a case of an 18-year-old Caucasian woman with advanced Masaoka-Koga stage III type B2 thymoma and myasthenia gravis on treatment with pyridostigmine, steroids and intravenous immunoglobulins, who developed a myasthenic crisis 2 hours after initiation of cyclophosphamide/doxorubicin/cisplatin primary chemotherapy. Because of severe acute respiratory failure, emergency tracheal intubation, mechanical ventilation, and temporary (2 hours) discontinuation of chemotherapy were needed. Considering the curative intent of the multimodal therapeutic program, we elected to resume primary chemotherapy administration while the patient remained on mechanical ventilation. After 24 hours, the recovery of adequate respiratory function allowed successful weaning from respiratory support, and no further adverse events occurred. After 3 weeks, upon plasma exchange initiation with amelioration of myasthenic symptoms, a second course of chemotherapy was given, and in week 6, having documented partial tumor remission, the patient underwent radical surgery (R0) and then consolidation radiation therapy with 50.4 Gy in 28 fractions in weeks 15-20.
CONCLUSIONS
This case report, together with the only four available in a review of the literature, highlights that chemotherapy may carry the risk of myasthenic crisis in patients affected by thymoma and myasthenia gravis. To our knowledge, this is the first reported case of chemotherapy continuation on mechanical ventilation in a patient with chemotherapy-induced myasthenic crisis requiring tracheal intubation. The lesson learned from the present case is that, in selected cases of advanced thymoma, the paradoxical worsening of myasthenia gravis during chemotherapy should not be considered an absolute contraindication for the continuation of primary chemotherapy with curative intent.
Background
Thymoma is an uncommon epithelial cancer associated in nearly half of cases with myasthenia gravis (MG), an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced thymoma, primary chemotherapy is considered the standard of care, with the aim of achieving tumor shrinkage and facilitating radical surgery [1]. While several drugs are known to worsen MG, cancer chemotherapy has been anecdotally reported as a trigger event for myasthenic crisis (MC) in four case reports [2–6]. Here, we present a case of advanced thymoma treated with primary chemotherapy that caused an acute-onset MC requiring tracheal intubation and therapeutic plasma exchange (PEX), with relevant benefit from early resumption of anticancer treatment during mechanical ventilation.
Case presentation
Clinical presentation and diagnosis
An 18-year-old Caucasian woman with unremarkable medical history was admitted to the emergency room due to neurological symptoms. She presented with month-long worsening dysphagia, rhinolalia, bilateral ptosis, and skeletal muscle weakness. Signs of muscle fatigability were elicited at the physical exam and then confirmed by electromyography, consistently with neuromuscular junction disease. Blood tests were unremarkable with the exception of acetylcholine receptor antibodies (43 nmol/l, normal if < 0.5 nmol/l). Hence, MG class III, according to the Myasthenia Gravis Foundation of America (MGFA) scale, was diagnosed [7, 8]. Partial regression of symptoms to class II MG was achieved by oral administration of pyridostigmine 60 mg every 3 hours during the daytime, pyridostigmine sustained-release 180 mg orally before sleeping, prednisone 25 mg orally each day, and immunoglobulins 0.4 g/kg intravenously for 5 days [8, 9]. Chest computed tomography (CT) revealed a 12 cm anterior mediastinal mass suspicious for thymoma, with confirmed infiltration of the anterior chest wall, lung parenchyma, and pericardium at chest magnetic resonance imaging with contrast. CT-guided fine needle aspiration biopsy yielded a histological diagnosis of B2 thymoma [10]. Due to the young age, a family history of cancer was excluded. Physical exam was negative for signs of mediastinal syndrome and superficial lymph nodes. Metastatic disease was excluded by 18-fluorodeoxyglucose positron emission tomography (18FDG-PET). Patient imaging is shown in Fig. 1. Accordingly, the clinical stage was cT3 cN0 cM0 (Masaoka-Koga III) [11]. After multidisciplinary team discussion, the tumor was defined as unresectable, and the patient was offered primary chemotherapy with intravenous cyclophosphamide 500 mg/m2, doxorubicin 50 mg/m2 and cisplatin 50 mg/m2 (CAP regimen) on day 1 every 21 days [12]. Primary prophylaxis of chemotherapy-induced neutropenia was not planned due to the potential risk of worsening MG, without evidence about the safety of administering granulocyte colony-stimulating factor in unstable myasthenic patients [13]. Ovarian preservation by gonadotropin-releasing hormone analogue leuprorelin was preferred over oocyte retrieval to expedite the start of chemotherapy [14]. Standard pre-medication with intravenous administration of ondansetron 8 mg, dexamethasone 8 mg and saline was chosen [15].Fig. 1 Patient imaging. a Left chest X-ray with enlarged mediastinum (see arrow). b Chest computed tomography scan showing the mediastinal mass (see arrow). c
18PET-FDG limited radiotracer uptake in mediastinum
Chemotherapy-induced myasthenic crisis
Two hours after starting administration of the first course of chemotherapy, following doxorubicin bolus, the patient experienced sudden onset of acute dyspnea with severe respiratory failure (oxygen saturation 75% on room air), refractory to oxygen therapy and bolus hydrocortisone 500 mg and chlorphenamine 10 mg administered intravenously [16]. Physical exam was negative for bronchospasm with diminished vesicular breath sounds. Due to unstable clinical conditions and development of acute respiratory acidosis (pH 7.21, partial pressure of carbon dioxide 88 mmHg), tracheal intubation and mechanical ventilation in the intensive care unit (ICU) were needed. Urgent chest CT scan excluded acute cardiopulmonary events. Life-threatening MGFA class V MC was diagnosed, likely triggered by chemotherapy, thus classified as grade 4 according to the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) [8, 17]. Chemotherapy was held for 2 hours and then, considering its curative intent and in agreement with the family, it was resumed and fully administered during mechanical ventilation. After 24 hours, upon remission of MC and weaning from ventilation, the patient was extubated and could continue receiving MG treatment, together with starting PEX once every three days to control MG and prevent new crises (by replacing 1 plasma volume with 5% human albumin) [18]. In week 2, owing to CTCAE v5.0 grade 3 febrile neutropenia (absolute neutrophil count 60/mm3 and body temperature 38.4 °C), the patient was successfully treated with empirical piperacillin/tazobactam 4 g/0.5 g intravenously every 6 hours until recovery [19].
Curative treatment and outcome
After completing a second course of CAP chemotherapy with interposed PEX allowing symptom control, radiological assessment in week 6 documented objective partial response according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), with 33% tumor shrinkage (maximum diameter 8 versus 12 cm) [20]. This allowed us to perform radical (R0) extended thymectomy, left upper lung lobectomy and subtotal pericardiectomy, with histological diagnosis of Masaoka-Koga stage III type B2 [10, 11]. For patient histology, please see Fig. 2. The patient required early mediastinum and pleural cavity re-exploration due to postsurgical bleeding; persistent hypophonia developed due to postsurgical left vocal cord paralysis. A comparison of CT imaging at baseline and after surgery is shown in Fig. 3. As suggested for Masaoka-Koga stage III, radiotherapy of 50.4 Gy in 28 fractions was given as postoperative treatment in weeks 15–20 [1]. At the last follow-up visit, 6 months after surgery, the patient was in complete remission with gradually improving MGFA class I MG and mild persistent hypophonia [8]. Despite remarkable levels of psychological burden, the patient’s resilience and high-priority treatment goals were fundamental for successful coping.Fig. 2 Patient histology. a Hematoxylin and eosin (H&E; ×40 view) stained section of thymoma B2 according to WHO classification. b Same histological slice in ×100 view
Fig. 3 Chest computed tomography (CT) scan at baseline and after surgery. a Chest CT scan showing thymoma at baseline. b Postsurgical chest CT scan with no residual disease
Discussion and conclusions
According to the World Health Organization (WHO), thymoma is the most common variant of thymic epithelial tumors (66.3%), usually presenting with local invasion and seldom as metastatic disease [10, 21]. Overall, thymic epithelial tumors occur at a rate of 0.13–0.32 cases per 100,000 population at risk and are very uncommon in young adults [22, 23]. To our knowledge, the largest retrospective study regarding childhood thymic tumors (< 18 years) in Europe was able to identify only 36 cases during a 12-year period, confirming the extreme rarity of thymic cancer in children and adolescents [24]. Hence, the clinical case reported here has to be considered a peculiar presentation of early-onset thymoma (Fig. 4).Fig. 4 Age-specific incidence of thymic cancer by histological type. SEER*Stat Database: NPCR [National Program of Cancer Registries] and SEER [Surveillance, Epidemiology, and End Results] Incidence—U.S. Cancer Statistics Public Use Database, Nov 2017 submission (2001–2015). The green bar highlights the reported patient age interval (15–19 years)
Like thymoma, MG is extremely rare (0.17–2.13 per 100,000 person-years) [25]; however, it affects up to 30% of patients with thymoma [26]. The association of thymoma with MG has been related to the intratumoral generation of mature T cells, although the pathogenic mechanisms remain unclear [27]. MG has been found to be most commonly associated with B thymoma and confers favorable prognosis, since neuromuscular symptoms help in earlier detection of the tumor and thus less advanced stage at diagnosis. Nevertheless, concomitant MG should also be regarded as an adverse risk factor, since it can interfere with cancer treatment, being worsened by many drugs, and it reaches its maximum severity after thymectomy in a proportion of patients [28].
The case reported here, together with those published and summarized in Table 1 [3–6], highlights that chemotherapy is a realistic trigger event of MC in patients with thymoma and MG. The temporary association in all cases indicates a causative relation, and may hamper the continuation of chemotherapy that is a crucial element of multimodal treatment in cases not amenable to upfront radical surgery [1]. No biomarker is available to prove this relation, and clinical findings are crucial for the diagnosis of MC. Other differential diagnoses, such as infusion reaction to cancer chemotherapy, are less likely in the setting of prolonged respiratory failure. Here, a multidisciplinary approach was necessary, and involved neurologists for medical treatment and hematologists for a correct timing schedule of PEX sessions in order to avoid plasma drug displacement. It should be noted that we waited 72 hours from the end of chemotherapy before starting PEX, in order to preserve drug efficacy according to their half-life.Table 1. Comparison between present case and 4 other published cases
Fujiwara et al. [3] Qureshi et al. [4] Solak et al. [5] Ng et al. (6) Present case report
Sex Female Male Male Male Female
Age (year) 44 24 45 49 18
Histology B1 Thymoma (WHO) Thymoma Thymoma NE B2 thymoma (WHO)
Staging IVA (Masaoka-Koga) III (Masaoka-Koga) Advanced unresectable Advanced unresectable III (Masaoka-Koga)
AchR Ab level (nmol/l) 13 NE 74 NE 43
Chemotherapy regimen Primary CAMP Postoperative cisplatin and doxorubicin Single-agent cisplatin Doxorubicin, cisplatin, etoposide Primary CAP
Myasthenic crisis onset time During chemotherapy 8 hours after chemotherapy 1 week after chemotherapy A few hours after chemotherapy During chemotherapy
Tracheal intubation No Yes Yes Yes Yes
Plasma exchange No Yes Yes Yes Yes
Chemotherapy continuation in ICU No No No No Yes
Patient outcome after myasthenic crisis Alive Death Alive Alive Alive
AchR Ab acetylcholine receptor antibodies, CAMP cisplatin, doxorubicin, methylprednisolone, CAP cyclophosphamide, doxorubicin, cisplatin, ICU intensive care unit, NE not evaluable, WHO World Health Organization
To our knowledge, this is the first reported case of chemotherapy continuation despite the need for mechanical ventilation due to a chemotherapy-induced MC. Radical treatment was dependent on primary chemotherapy, as upfront surgery had already been ruled out. Besides, we could not confidently assume that, after MC resolution, the patient would have been able to receive further chemotherapy due to aggravation of symptoms. We conclude that special attention is warranted in patients with thymoma and MG with regard to the development of MC. Ideally, optimal control of myasthenic symptoms should be achieved before initiation of anticancer treatment. Nonetheless, chemotherapy-induced MC may complicate anticancer therapy administration, according to this evidence. We recommend that patients with thymoma and MG be hospitalized in tertiary medical centers for chemotherapy and that outpatient management be avoided. The lesson learned from the present case is that, in selected cases of advanced thymoma, paradoxical worsening of MG during chemotherapy should not be considered an absolute contraindication for continuation of primary chemotherapy with curative intent.
Abbreviations
CAPCisplatin, doxorubicin and cyclophosphamide
CTComputed tomography
CTCAE v5.0Common Terminology Criteria for Adverse Events version 5.0
GyGray
ICUIntensive Care Unit
MCMyasthenic crisis
MGMyasthenia gravis
MGFAMyasthenia Gravis Foundation of America
18PET-FDG18-Fluorodeoxyglucose positron emission tomography
PEXPlasma exchange
RECISTResponse Evaluation Criteria in Solid Tumours
WHOWorld Health Organization
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Fondazione Oncologia Niguarda Onlus for financial support.
Authors' contributions
GP, KB, FT, and SS were major contributors in writing the manuscript. KB, FT, GP, GM, GC, ASB, and SS provided clinical care. MP gave indication to and performed plasma exchange. AR and MT contributed to neoadjuvant treatment indication in a multidisciplinary team discussion and performed surgery. FL, AI, and ECA diagnosed thymoma and myasthenia and medically managed neurological symptoms. ASB and SS supervised oncological care and critically reviewed the case report. All authors read and approved the final manuscript.
Funding
This paper did not receive any specific grants from funding agencies in the public, commercial or not-for-profit sectors.
Ethics approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Availability of data and materials
Not applicable.
Competing interests
The authors declare that they have no competing interests. | Intravenous bolus | DrugAdministrationRoute | CC BY | 33526108 | 18,898,875 | 2021-02-02 |
What was the administration route of drug 'DOXORUBICIN'? | Chemotherapy-induced myasthenic crisis in thymoma treated with primary chemotherapy with curative intent on mechanical ventilation: a case report and review of the literature.
BACKGROUND
Thymoma is an uncommon cancer often associated with myasthenia gravis, an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced nonmetastatic thymoma, primary chemotherapy may be required to induce tumor shrinkage and to achieve radical resection. Cancer chemotherapy has been anecdotally reported as a trigger factor for worsening of myasthenia gravis in thymic epithelial cancers. The study of uncommon cases of chemotherapy-related myasthenic crisis is warranted to gain knowledge of clinical situations requiring intensive care support in the case of life-threatening respiratory failure.
METHODS
We report a case of an 18-year-old Caucasian woman with advanced Masaoka-Koga stage III type B2 thymoma and myasthenia gravis on treatment with pyridostigmine, steroids and intravenous immunoglobulins, who developed a myasthenic crisis 2 hours after initiation of cyclophosphamide/doxorubicin/cisplatin primary chemotherapy. Because of severe acute respiratory failure, emergency tracheal intubation, mechanical ventilation, and temporary (2 hours) discontinuation of chemotherapy were needed. Considering the curative intent of the multimodal therapeutic program, we elected to resume primary chemotherapy administration while the patient remained on mechanical ventilation. After 24 hours, the recovery of adequate respiratory function allowed successful weaning from respiratory support, and no further adverse events occurred. After 3 weeks, upon plasma exchange initiation with amelioration of myasthenic symptoms, a second course of chemotherapy was given, and in week 6, having documented partial tumor remission, the patient underwent radical surgery (R0) and then consolidation radiation therapy with 50.4 Gy in 28 fractions in weeks 15-20.
CONCLUSIONS
This case report, together with the only four available in a review of the literature, highlights that chemotherapy may carry the risk of myasthenic crisis in patients affected by thymoma and myasthenia gravis. To our knowledge, this is the first reported case of chemotherapy continuation on mechanical ventilation in a patient with chemotherapy-induced myasthenic crisis requiring tracheal intubation. The lesson learned from the present case is that, in selected cases of advanced thymoma, the paradoxical worsening of myasthenia gravis during chemotherapy should not be considered an absolute contraindication for the continuation of primary chemotherapy with curative intent.
Background
Thymoma is an uncommon epithelial cancer associated in nearly half of cases with myasthenia gravis (MG), an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced thymoma, primary chemotherapy is considered the standard of care, with the aim of achieving tumor shrinkage and facilitating radical surgery [1]. While several drugs are known to worsen MG, cancer chemotherapy has been anecdotally reported as a trigger event for myasthenic crisis (MC) in four case reports [2–6]. Here, we present a case of advanced thymoma treated with primary chemotherapy that caused an acute-onset MC requiring tracheal intubation and therapeutic plasma exchange (PEX), with relevant benefit from early resumption of anticancer treatment during mechanical ventilation.
Case presentation
Clinical presentation and diagnosis
An 18-year-old Caucasian woman with unremarkable medical history was admitted to the emergency room due to neurological symptoms. She presented with month-long worsening dysphagia, rhinolalia, bilateral ptosis, and skeletal muscle weakness. Signs of muscle fatigability were elicited at the physical exam and then confirmed by electromyography, consistently with neuromuscular junction disease. Blood tests were unremarkable with the exception of acetylcholine receptor antibodies (43 nmol/l, normal if < 0.5 nmol/l). Hence, MG class III, according to the Myasthenia Gravis Foundation of America (MGFA) scale, was diagnosed [7, 8]. Partial regression of symptoms to class II MG was achieved by oral administration of pyridostigmine 60 mg every 3 hours during the daytime, pyridostigmine sustained-release 180 mg orally before sleeping, prednisone 25 mg orally each day, and immunoglobulins 0.4 g/kg intravenously for 5 days [8, 9]. Chest computed tomography (CT) revealed a 12 cm anterior mediastinal mass suspicious for thymoma, with confirmed infiltration of the anterior chest wall, lung parenchyma, and pericardium at chest magnetic resonance imaging with contrast. CT-guided fine needle aspiration biopsy yielded a histological diagnosis of B2 thymoma [10]. Due to the young age, a family history of cancer was excluded. Physical exam was negative for signs of mediastinal syndrome and superficial lymph nodes. Metastatic disease was excluded by 18-fluorodeoxyglucose positron emission tomography (18FDG-PET). Patient imaging is shown in Fig. 1. Accordingly, the clinical stage was cT3 cN0 cM0 (Masaoka-Koga III) [11]. After multidisciplinary team discussion, the tumor was defined as unresectable, and the patient was offered primary chemotherapy with intravenous cyclophosphamide 500 mg/m2, doxorubicin 50 mg/m2 and cisplatin 50 mg/m2 (CAP regimen) on day 1 every 21 days [12]. Primary prophylaxis of chemotherapy-induced neutropenia was not planned due to the potential risk of worsening MG, without evidence about the safety of administering granulocyte colony-stimulating factor in unstable myasthenic patients [13]. Ovarian preservation by gonadotropin-releasing hormone analogue leuprorelin was preferred over oocyte retrieval to expedite the start of chemotherapy [14]. Standard pre-medication with intravenous administration of ondansetron 8 mg, dexamethasone 8 mg and saline was chosen [15].Fig. 1 Patient imaging. a Left chest X-ray with enlarged mediastinum (see arrow). b Chest computed tomography scan showing the mediastinal mass (see arrow). c
18PET-FDG limited radiotracer uptake in mediastinum
Chemotherapy-induced myasthenic crisis
Two hours after starting administration of the first course of chemotherapy, following doxorubicin bolus, the patient experienced sudden onset of acute dyspnea with severe respiratory failure (oxygen saturation 75% on room air), refractory to oxygen therapy and bolus hydrocortisone 500 mg and chlorphenamine 10 mg administered intravenously [16]. Physical exam was negative for bronchospasm with diminished vesicular breath sounds. Due to unstable clinical conditions and development of acute respiratory acidosis (pH 7.21, partial pressure of carbon dioxide 88 mmHg), tracheal intubation and mechanical ventilation in the intensive care unit (ICU) were needed. Urgent chest CT scan excluded acute cardiopulmonary events. Life-threatening MGFA class V MC was diagnosed, likely triggered by chemotherapy, thus classified as grade 4 according to the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) [8, 17]. Chemotherapy was held for 2 hours and then, considering its curative intent and in agreement with the family, it was resumed and fully administered during mechanical ventilation. After 24 hours, upon remission of MC and weaning from ventilation, the patient was extubated and could continue receiving MG treatment, together with starting PEX once every three days to control MG and prevent new crises (by replacing 1 plasma volume with 5% human albumin) [18]. In week 2, owing to CTCAE v5.0 grade 3 febrile neutropenia (absolute neutrophil count 60/mm3 and body temperature 38.4 °C), the patient was successfully treated with empirical piperacillin/tazobactam 4 g/0.5 g intravenously every 6 hours until recovery [19].
Curative treatment and outcome
After completing a second course of CAP chemotherapy with interposed PEX allowing symptom control, radiological assessment in week 6 documented objective partial response according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), with 33% tumor shrinkage (maximum diameter 8 versus 12 cm) [20]. This allowed us to perform radical (R0) extended thymectomy, left upper lung lobectomy and subtotal pericardiectomy, with histological diagnosis of Masaoka-Koga stage III type B2 [10, 11]. For patient histology, please see Fig. 2. The patient required early mediastinum and pleural cavity re-exploration due to postsurgical bleeding; persistent hypophonia developed due to postsurgical left vocal cord paralysis. A comparison of CT imaging at baseline and after surgery is shown in Fig. 3. As suggested for Masaoka-Koga stage III, radiotherapy of 50.4 Gy in 28 fractions was given as postoperative treatment in weeks 15–20 [1]. At the last follow-up visit, 6 months after surgery, the patient was in complete remission with gradually improving MGFA class I MG and mild persistent hypophonia [8]. Despite remarkable levels of psychological burden, the patient’s resilience and high-priority treatment goals were fundamental for successful coping.Fig. 2 Patient histology. a Hematoxylin and eosin (H&E; ×40 view) stained section of thymoma B2 according to WHO classification. b Same histological slice in ×100 view
Fig. 3 Chest computed tomography (CT) scan at baseline and after surgery. a Chest CT scan showing thymoma at baseline. b Postsurgical chest CT scan with no residual disease
Discussion and conclusions
According to the World Health Organization (WHO), thymoma is the most common variant of thymic epithelial tumors (66.3%), usually presenting with local invasion and seldom as metastatic disease [10, 21]. Overall, thymic epithelial tumors occur at a rate of 0.13–0.32 cases per 100,000 population at risk and are very uncommon in young adults [22, 23]. To our knowledge, the largest retrospective study regarding childhood thymic tumors (< 18 years) in Europe was able to identify only 36 cases during a 12-year period, confirming the extreme rarity of thymic cancer in children and adolescents [24]. Hence, the clinical case reported here has to be considered a peculiar presentation of early-onset thymoma (Fig. 4).Fig. 4 Age-specific incidence of thymic cancer by histological type. SEER*Stat Database: NPCR [National Program of Cancer Registries] and SEER [Surveillance, Epidemiology, and End Results] Incidence—U.S. Cancer Statistics Public Use Database, Nov 2017 submission (2001–2015). The green bar highlights the reported patient age interval (15–19 years)
Like thymoma, MG is extremely rare (0.17–2.13 per 100,000 person-years) [25]; however, it affects up to 30% of patients with thymoma [26]. The association of thymoma with MG has been related to the intratumoral generation of mature T cells, although the pathogenic mechanisms remain unclear [27]. MG has been found to be most commonly associated with B thymoma and confers favorable prognosis, since neuromuscular symptoms help in earlier detection of the tumor and thus less advanced stage at diagnosis. Nevertheless, concomitant MG should also be regarded as an adverse risk factor, since it can interfere with cancer treatment, being worsened by many drugs, and it reaches its maximum severity after thymectomy in a proportion of patients [28].
The case reported here, together with those published and summarized in Table 1 [3–6], highlights that chemotherapy is a realistic trigger event of MC in patients with thymoma and MG. The temporary association in all cases indicates a causative relation, and may hamper the continuation of chemotherapy that is a crucial element of multimodal treatment in cases not amenable to upfront radical surgery [1]. No biomarker is available to prove this relation, and clinical findings are crucial for the diagnosis of MC. Other differential diagnoses, such as infusion reaction to cancer chemotherapy, are less likely in the setting of prolonged respiratory failure. Here, a multidisciplinary approach was necessary, and involved neurologists for medical treatment and hematologists for a correct timing schedule of PEX sessions in order to avoid plasma drug displacement. It should be noted that we waited 72 hours from the end of chemotherapy before starting PEX, in order to preserve drug efficacy according to their half-life.Table 1. Comparison between present case and 4 other published cases
Fujiwara et al. [3] Qureshi et al. [4] Solak et al. [5] Ng et al. (6) Present case report
Sex Female Male Male Male Female
Age (year) 44 24 45 49 18
Histology B1 Thymoma (WHO) Thymoma Thymoma NE B2 thymoma (WHO)
Staging IVA (Masaoka-Koga) III (Masaoka-Koga) Advanced unresectable Advanced unresectable III (Masaoka-Koga)
AchR Ab level (nmol/l) 13 NE 74 NE 43
Chemotherapy regimen Primary CAMP Postoperative cisplatin and doxorubicin Single-agent cisplatin Doxorubicin, cisplatin, etoposide Primary CAP
Myasthenic crisis onset time During chemotherapy 8 hours after chemotherapy 1 week after chemotherapy A few hours after chemotherapy During chemotherapy
Tracheal intubation No Yes Yes Yes Yes
Plasma exchange No Yes Yes Yes Yes
Chemotherapy continuation in ICU No No No No Yes
Patient outcome after myasthenic crisis Alive Death Alive Alive Alive
AchR Ab acetylcholine receptor antibodies, CAMP cisplatin, doxorubicin, methylprednisolone, CAP cyclophosphamide, doxorubicin, cisplatin, ICU intensive care unit, NE not evaluable, WHO World Health Organization
To our knowledge, this is the first reported case of chemotherapy continuation despite the need for mechanical ventilation due to a chemotherapy-induced MC. Radical treatment was dependent on primary chemotherapy, as upfront surgery had already been ruled out. Besides, we could not confidently assume that, after MC resolution, the patient would have been able to receive further chemotherapy due to aggravation of symptoms. We conclude that special attention is warranted in patients with thymoma and MG with regard to the development of MC. Ideally, optimal control of myasthenic symptoms should be achieved before initiation of anticancer treatment. Nonetheless, chemotherapy-induced MC may complicate anticancer therapy administration, according to this evidence. We recommend that patients with thymoma and MG be hospitalized in tertiary medical centers for chemotherapy and that outpatient management be avoided. The lesson learned from the present case is that, in selected cases of advanced thymoma, paradoxical worsening of MG during chemotherapy should not be considered an absolute contraindication for continuation of primary chemotherapy with curative intent.
Abbreviations
CAPCisplatin, doxorubicin and cyclophosphamide
CTComputed tomography
CTCAE v5.0Common Terminology Criteria for Adverse Events version 5.0
GyGray
ICUIntensive Care Unit
MCMyasthenic crisis
MGMyasthenia gravis
MGFAMyasthenia Gravis Foundation of America
18PET-FDG18-Fluorodeoxyglucose positron emission tomography
PEXPlasma exchange
RECISTResponse Evaluation Criteria in Solid Tumours
WHOWorld Health Organization
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Fondazione Oncologia Niguarda Onlus for financial support.
Authors' contributions
GP, KB, FT, and SS were major contributors in writing the manuscript. KB, FT, GP, GM, GC, ASB, and SS provided clinical care. MP gave indication to and performed plasma exchange. AR and MT contributed to neoadjuvant treatment indication in a multidisciplinary team discussion and performed surgery. FL, AI, and ECA diagnosed thymoma and myasthenia and medically managed neurological symptoms. ASB and SS supervised oncological care and critically reviewed the case report. All authors read and approved the final manuscript.
Funding
This paper did not receive any specific grants from funding agencies in the public, commercial or not-for-profit sectors.
Ethics approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Availability of data and materials
Not applicable.
Competing interests
The authors declare that they have no competing interests. | Intravenous bolus | DrugAdministrationRoute | CC BY | 33526108 | 18,959,226 | 2021-02-02 |
What was the administration route of drug 'HYDROCORTISONE'? | Chemotherapy-induced myasthenic crisis in thymoma treated with primary chemotherapy with curative intent on mechanical ventilation: a case report and review of the literature.
BACKGROUND
Thymoma is an uncommon cancer often associated with myasthenia gravis, an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced nonmetastatic thymoma, primary chemotherapy may be required to induce tumor shrinkage and to achieve radical resection. Cancer chemotherapy has been anecdotally reported as a trigger factor for worsening of myasthenia gravis in thymic epithelial cancers. The study of uncommon cases of chemotherapy-related myasthenic crisis is warranted to gain knowledge of clinical situations requiring intensive care support in the case of life-threatening respiratory failure.
METHODS
We report a case of an 18-year-old Caucasian woman with advanced Masaoka-Koga stage III type B2 thymoma and myasthenia gravis on treatment with pyridostigmine, steroids and intravenous immunoglobulins, who developed a myasthenic crisis 2 hours after initiation of cyclophosphamide/doxorubicin/cisplatin primary chemotherapy. Because of severe acute respiratory failure, emergency tracheal intubation, mechanical ventilation, and temporary (2 hours) discontinuation of chemotherapy were needed. Considering the curative intent of the multimodal therapeutic program, we elected to resume primary chemotherapy administration while the patient remained on mechanical ventilation. After 24 hours, the recovery of adequate respiratory function allowed successful weaning from respiratory support, and no further adverse events occurred. After 3 weeks, upon plasma exchange initiation with amelioration of myasthenic symptoms, a second course of chemotherapy was given, and in week 6, having documented partial tumor remission, the patient underwent radical surgery (R0) and then consolidation radiation therapy with 50.4 Gy in 28 fractions in weeks 15-20.
CONCLUSIONS
This case report, together with the only four available in a review of the literature, highlights that chemotherapy may carry the risk of myasthenic crisis in patients affected by thymoma and myasthenia gravis. To our knowledge, this is the first reported case of chemotherapy continuation on mechanical ventilation in a patient with chemotherapy-induced myasthenic crisis requiring tracheal intubation. The lesson learned from the present case is that, in selected cases of advanced thymoma, the paradoxical worsening of myasthenia gravis during chemotherapy should not be considered an absolute contraindication for the continuation of primary chemotherapy with curative intent.
Background
Thymoma is an uncommon epithelial cancer associated in nearly half of cases with myasthenia gravis (MG), an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced thymoma, primary chemotherapy is considered the standard of care, with the aim of achieving tumor shrinkage and facilitating radical surgery [1]. While several drugs are known to worsen MG, cancer chemotherapy has been anecdotally reported as a trigger event for myasthenic crisis (MC) in four case reports [2–6]. Here, we present a case of advanced thymoma treated with primary chemotherapy that caused an acute-onset MC requiring tracheal intubation and therapeutic plasma exchange (PEX), with relevant benefit from early resumption of anticancer treatment during mechanical ventilation.
Case presentation
Clinical presentation and diagnosis
An 18-year-old Caucasian woman with unremarkable medical history was admitted to the emergency room due to neurological symptoms. She presented with month-long worsening dysphagia, rhinolalia, bilateral ptosis, and skeletal muscle weakness. Signs of muscle fatigability were elicited at the physical exam and then confirmed by electromyography, consistently with neuromuscular junction disease. Blood tests were unremarkable with the exception of acetylcholine receptor antibodies (43 nmol/l, normal if < 0.5 nmol/l). Hence, MG class III, according to the Myasthenia Gravis Foundation of America (MGFA) scale, was diagnosed [7, 8]. Partial regression of symptoms to class II MG was achieved by oral administration of pyridostigmine 60 mg every 3 hours during the daytime, pyridostigmine sustained-release 180 mg orally before sleeping, prednisone 25 mg orally each day, and immunoglobulins 0.4 g/kg intravenously for 5 days [8, 9]. Chest computed tomography (CT) revealed a 12 cm anterior mediastinal mass suspicious for thymoma, with confirmed infiltration of the anterior chest wall, lung parenchyma, and pericardium at chest magnetic resonance imaging with contrast. CT-guided fine needle aspiration biopsy yielded a histological diagnosis of B2 thymoma [10]. Due to the young age, a family history of cancer was excluded. Physical exam was negative for signs of mediastinal syndrome and superficial lymph nodes. Metastatic disease was excluded by 18-fluorodeoxyglucose positron emission tomography (18FDG-PET). Patient imaging is shown in Fig. 1. Accordingly, the clinical stage was cT3 cN0 cM0 (Masaoka-Koga III) [11]. After multidisciplinary team discussion, the tumor was defined as unresectable, and the patient was offered primary chemotherapy with intravenous cyclophosphamide 500 mg/m2, doxorubicin 50 mg/m2 and cisplatin 50 mg/m2 (CAP regimen) on day 1 every 21 days [12]. Primary prophylaxis of chemotherapy-induced neutropenia was not planned due to the potential risk of worsening MG, without evidence about the safety of administering granulocyte colony-stimulating factor in unstable myasthenic patients [13]. Ovarian preservation by gonadotropin-releasing hormone analogue leuprorelin was preferred over oocyte retrieval to expedite the start of chemotherapy [14]. Standard pre-medication with intravenous administration of ondansetron 8 mg, dexamethasone 8 mg and saline was chosen [15].Fig. 1 Patient imaging. a Left chest X-ray with enlarged mediastinum (see arrow). b Chest computed tomography scan showing the mediastinal mass (see arrow). c
18PET-FDG limited radiotracer uptake in mediastinum
Chemotherapy-induced myasthenic crisis
Two hours after starting administration of the first course of chemotherapy, following doxorubicin bolus, the patient experienced sudden onset of acute dyspnea with severe respiratory failure (oxygen saturation 75% on room air), refractory to oxygen therapy and bolus hydrocortisone 500 mg and chlorphenamine 10 mg administered intravenously [16]. Physical exam was negative for bronchospasm with diminished vesicular breath sounds. Due to unstable clinical conditions and development of acute respiratory acidosis (pH 7.21, partial pressure of carbon dioxide 88 mmHg), tracheal intubation and mechanical ventilation in the intensive care unit (ICU) were needed. Urgent chest CT scan excluded acute cardiopulmonary events. Life-threatening MGFA class V MC was diagnosed, likely triggered by chemotherapy, thus classified as grade 4 according to the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) [8, 17]. Chemotherapy was held for 2 hours and then, considering its curative intent and in agreement with the family, it was resumed and fully administered during mechanical ventilation. After 24 hours, upon remission of MC and weaning from ventilation, the patient was extubated and could continue receiving MG treatment, together with starting PEX once every three days to control MG and prevent new crises (by replacing 1 plasma volume with 5% human albumin) [18]. In week 2, owing to CTCAE v5.0 grade 3 febrile neutropenia (absolute neutrophil count 60/mm3 and body temperature 38.4 °C), the patient was successfully treated with empirical piperacillin/tazobactam 4 g/0.5 g intravenously every 6 hours until recovery [19].
Curative treatment and outcome
After completing a second course of CAP chemotherapy with interposed PEX allowing symptom control, radiological assessment in week 6 documented objective partial response according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), with 33% tumor shrinkage (maximum diameter 8 versus 12 cm) [20]. This allowed us to perform radical (R0) extended thymectomy, left upper lung lobectomy and subtotal pericardiectomy, with histological diagnosis of Masaoka-Koga stage III type B2 [10, 11]. For patient histology, please see Fig. 2. The patient required early mediastinum and pleural cavity re-exploration due to postsurgical bleeding; persistent hypophonia developed due to postsurgical left vocal cord paralysis. A comparison of CT imaging at baseline and after surgery is shown in Fig. 3. As suggested for Masaoka-Koga stage III, radiotherapy of 50.4 Gy in 28 fractions was given as postoperative treatment in weeks 15–20 [1]. At the last follow-up visit, 6 months after surgery, the patient was in complete remission with gradually improving MGFA class I MG and mild persistent hypophonia [8]. Despite remarkable levels of psychological burden, the patient’s resilience and high-priority treatment goals were fundamental for successful coping.Fig. 2 Patient histology. a Hematoxylin and eosin (H&E; ×40 view) stained section of thymoma B2 according to WHO classification. b Same histological slice in ×100 view
Fig. 3 Chest computed tomography (CT) scan at baseline and after surgery. a Chest CT scan showing thymoma at baseline. b Postsurgical chest CT scan with no residual disease
Discussion and conclusions
According to the World Health Organization (WHO), thymoma is the most common variant of thymic epithelial tumors (66.3%), usually presenting with local invasion and seldom as metastatic disease [10, 21]. Overall, thymic epithelial tumors occur at a rate of 0.13–0.32 cases per 100,000 population at risk and are very uncommon in young adults [22, 23]. To our knowledge, the largest retrospective study regarding childhood thymic tumors (< 18 years) in Europe was able to identify only 36 cases during a 12-year period, confirming the extreme rarity of thymic cancer in children and adolescents [24]. Hence, the clinical case reported here has to be considered a peculiar presentation of early-onset thymoma (Fig. 4).Fig. 4 Age-specific incidence of thymic cancer by histological type. SEER*Stat Database: NPCR [National Program of Cancer Registries] and SEER [Surveillance, Epidemiology, and End Results] Incidence—U.S. Cancer Statistics Public Use Database, Nov 2017 submission (2001–2015). The green bar highlights the reported patient age interval (15–19 years)
Like thymoma, MG is extremely rare (0.17–2.13 per 100,000 person-years) [25]; however, it affects up to 30% of patients with thymoma [26]. The association of thymoma with MG has been related to the intratumoral generation of mature T cells, although the pathogenic mechanisms remain unclear [27]. MG has been found to be most commonly associated with B thymoma and confers favorable prognosis, since neuromuscular symptoms help in earlier detection of the tumor and thus less advanced stage at diagnosis. Nevertheless, concomitant MG should also be regarded as an adverse risk factor, since it can interfere with cancer treatment, being worsened by many drugs, and it reaches its maximum severity after thymectomy in a proportion of patients [28].
The case reported here, together with those published and summarized in Table 1 [3–6], highlights that chemotherapy is a realistic trigger event of MC in patients with thymoma and MG. The temporary association in all cases indicates a causative relation, and may hamper the continuation of chemotherapy that is a crucial element of multimodal treatment in cases not amenable to upfront radical surgery [1]. No biomarker is available to prove this relation, and clinical findings are crucial for the diagnosis of MC. Other differential diagnoses, such as infusion reaction to cancer chemotherapy, are less likely in the setting of prolonged respiratory failure. Here, a multidisciplinary approach was necessary, and involved neurologists for medical treatment and hematologists for a correct timing schedule of PEX sessions in order to avoid plasma drug displacement. It should be noted that we waited 72 hours from the end of chemotherapy before starting PEX, in order to preserve drug efficacy according to their half-life.Table 1. Comparison between present case and 4 other published cases
Fujiwara et al. [3] Qureshi et al. [4] Solak et al. [5] Ng et al. (6) Present case report
Sex Female Male Male Male Female
Age (year) 44 24 45 49 18
Histology B1 Thymoma (WHO) Thymoma Thymoma NE B2 thymoma (WHO)
Staging IVA (Masaoka-Koga) III (Masaoka-Koga) Advanced unresectable Advanced unresectable III (Masaoka-Koga)
AchR Ab level (nmol/l) 13 NE 74 NE 43
Chemotherapy regimen Primary CAMP Postoperative cisplatin and doxorubicin Single-agent cisplatin Doxorubicin, cisplatin, etoposide Primary CAP
Myasthenic crisis onset time During chemotherapy 8 hours after chemotherapy 1 week after chemotherapy A few hours after chemotherapy During chemotherapy
Tracheal intubation No Yes Yes Yes Yes
Plasma exchange No Yes Yes Yes Yes
Chemotherapy continuation in ICU No No No No Yes
Patient outcome after myasthenic crisis Alive Death Alive Alive Alive
AchR Ab acetylcholine receptor antibodies, CAMP cisplatin, doxorubicin, methylprednisolone, CAP cyclophosphamide, doxorubicin, cisplatin, ICU intensive care unit, NE not evaluable, WHO World Health Organization
To our knowledge, this is the first reported case of chemotherapy continuation despite the need for mechanical ventilation due to a chemotherapy-induced MC. Radical treatment was dependent on primary chemotherapy, as upfront surgery had already been ruled out. Besides, we could not confidently assume that, after MC resolution, the patient would have been able to receive further chemotherapy due to aggravation of symptoms. We conclude that special attention is warranted in patients with thymoma and MG with regard to the development of MC. Ideally, optimal control of myasthenic symptoms should be achieved before initiation of anticancer treatment. Nonetheless, chemotherapy-induced MC may complicate anticancer therapy administration, according to this evidence. We recommend that patients with thymoma and MG be hospitalized in tertiary medical centers for chemotherapy and that outpatient management be avoided. The lesson learned from the present case is that, in selected cases of advanced thymoma, paradoxical worsening of MG during chemotherapy should not be considered an absolute contraindication for continuation of primary chemotherapy with curative intent.
Abbreviations
CAPCisplatin, doxorubicin and cyclophosphamide
CTComputed tomography
CTCAE v5.0Common Terminology Criteria for Adverse Events version 5.0
GyGray
ICUIntensive Care Unit
MCMyasthenic crisis
MGMyasthenia gravis
MGFAMyasthenia Gravis Foundation of America
18PET-FDG18-Fluorodeoxyglucose positron emission tomography
PEXPlasma exchange
RECISTResponse Evaluation Criteria in Solid Tumours
WHOWorld Health Organization
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Fondazione Oncologia Niguarda Onlus for financial support.
Authors' contributions
GP, KB, FT, and SS were major contributors in writing the manuscript. KB, FT, GP, GM, GC, ASB, and SS provided clinical care. MP gave indication to and performed plasma exchange. AR and MT contributed to neoadjuvant treatment indication in a multidisciplinary team discussion and performed surgery. FL, AI, and ECA diagnosed thymoma and myasthenia and medically managed neurological symptoms. ASB and SS supervised oncological care and critically reviewed the case report. All authors read and approved the final manuscript.
Funding
This paper did not receive any specific grants from funding agencies in the public, commercial or not-for-profit sectors.
Ethics approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Availability of data and materials
Not applicable.
Competing interests
The authors declare that they have no competing interests. | Intravenous bolus | DrugAdministrationRoute | CC BY | 33526108 | 18,959,232 | 2021-02-02 |
What was the administration route of drug 'ONDANSETRON'? | Chemotherapy-induced myasthenic crisis in thymoma treated with primary chemotherapy with curative intent on mechanical ventilation: a case report and review of the literature.
BACKGROUND
Thymoma is an uncommon cancer often associated with myasthenia gravis, an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced nonmetastatic thymoma, primary chemotherapy may be required to induce tumor shrinkage and to achieve radical resection. Cancer chemotherapy has been anecdotally reported as a trigger factor for worsening of myasthenia gravis in thymic epithelial cancers. The study of uncommon cases of chemotherapy-related myasthenic crisis is warranted to gain knowledge of clinical situations requiring intensive care support in the case of life-threatening respiratory failure.
METHODS
We report a case of an 18-year-old Caucasian woman with advanced Masaoka-Koga stage III type B2 thymoma and myasthenia gravis on treatment with pyridostigmine, steroids and intravenous immunoglobulins, who developed a myasthenic crisis 2 hours after initiation of cyclophosphamide/doxorubicin/cisplatin primary chemotherapy. Because of severe acute respiratory failure, emergency tracheal intubation, mechanical ventilation, and temporary (2 hours) discontinuation of chemotherapy were needed. Considering the curative intent of the multimodal therapeutic program, we elected to resume primary chemotherapy administration while the patient remained on mechanical ventilation. After 24 hours, the recovery of adequate respiratory function allowed successful weaning from respiratory support, and no further adverse events occurred. After 3 weeks, upon plasma exchange initiation with amelioration of myasthenic symptoms, a second course of chemotherapy was given, and in week 6, having documented partial tumor remission, the patient underwent radical surgery (R0) and then consolidation radiation therapy with 50.4 Gy in 28 fractions in weeks 15-20.
CONCLUSIONS
This case report, together with the only four available in a review of the literature, highlights that chemotherapy may carry the risk of myasthenic crisis in patients affected by thymoma and myasthenia gravis. To our knowledge, this is the first reported case of chemotherapy continuation on mechanical ventilation in a patient with chemotherapy-induced myasthenic crisis requiring tracheal intubation. The lesson learned from the present case is that, in selected cases of advanced thymoma, the paradoxical worsening of myasthenia gravis during chemotherapy should not be considered an absolute contraindication for the continuation of primary chemotherapy with curative intent.
Background
Thymoma is an uncommon epithelial cancer associated in nearly half of cases with myasthenia gravis (MG), an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced thymoma, primary chemotherapy is considered the standard of care, with the aim of achieving tumor shrinkage and facilitating radical surgery [1]. While several drugs are known to worsen MG, cancer chemotherapy has been anecdotally reported as a trigger event for myasthenic crisis (MC) in four case reports [2–6]. Here, we present a case of advanced thymoma treated with primary chemotherapy that caused an acute-onset MC requiring tracheal intubation and therapeutic plasma exchange (PEX), with relevant benefit from early resumption of anticancer treatment during mechanical ventilation.
Case presentation
Clinical presentation and diagnosis
An 18-year-old Caucasian woman with unremarkable medical history was admitted to the emergency room due to neurological symptoms. She presented with month-long worsening dysphagia, rhinolalia, bilateral ptosis, and skeletal muscle weakness. Signs of muscle fatigability were elicited at the physical exam and then confirmed by electromyography, consistently with neuromuscular junction disease. Blood tests were unremarkable with the exception of acetylcholine receptor antibodies (43 nmol/l, normal if < 0.5 nmol/l). Hence, MG class III, according to the Myasthenia Gravis Foundation of America (MGFA) scale, was diagnosed [7, 8]. Partial regression of symptoms to class II MG was achieved by oral administration of pyridostigmine 60 mg every 3 hours during the daytime, pyridostigmine sustained-release 180 mg orally before sleeping, prednisone 25 mg orally each day, and immunoglobulins 0.4 g/kg intravenously for 5 days [8, 9]. Chest computed tomography (CT) revealed a 12 cm anterior mediastinal mass suspicious for thymoma, with confirmed infiltration of the anterior chest wall, lung parenchyma, and pericardium at chest magnetic resonance imaging with contrast. CT-guided fine needle aspiration biopsy yielded a histological diagnosis of B2 thymoma [10]. Due to the young age, a family history of cancer was excluded. Physical exam was negative for signs of mediastinal syndrome and superficial lymph nodes. Metastatic disease was excluded by 18-fluorodeoxyglucose positron emission tomography (18FDG-PET). Patient imaging is shown in Fig. 1. Accordingly, the clinical stage was cT3 cN0 cM0 (Masaoka-Koga III) [11]. After multidisciplinary team discussion, the tumor was defined as unresectable, and the patient was offered primary chemotherapy with intravenous cyclophosphamide 500 mg/m2, doxorubicin 50 mg/m2 and cisplatin 50 mg/m2 (CAP regimen) on day 1 every 21 days [12]. Primary prophylaxis of chemotherapy-induced neutropenia was not planned due to the potential risk of worsening MG, without evidence about the safety of administering granulocyte colony-stimulating factor in unstable myasthenic patients [13]. Ovarian preservation by gonadotropin-releasing hormone analogue leuprorelin was preferred over oocyte retrieval to expedite the start of chemotherapy [14]. Standard pre-medication with intravenous administration of ondansetron 8 mg, dexamethasone 8 mg and saline was chosen [15].Fig. 1 Patient imaging. a Left chest X-ray with enlarged mediastinum (see arrow). b Chest computed tomography scan showing the mediastinal mass (see arrow). c
18PET-FDG limited radiotracer uptake in mediastinum
Chemotherapy-induced myasthenic crisis
Two hours after starting administration of the first course of chemotherapy, following doxorubicin bolus, the patient experienced sudden onset of acute dyspnea with severe respiratory failure (oxygen saturation 75% on room air), refractory to oxygen therapy and bolus hydrocortisone 500 mg and chlorphenamine 10 mg administered intravenously [16]. Physical exam was negative for bronchospasm with diminished vesicular breath sounds. Due to unstable clinical conditions and development of acute respiratory acidosis (pH 7.21, partial pressure of carbon dioxide 88 mmHg), tracheal intubation and mechanical ventilation in the intensive care unit (ICU) were needed. Urgent chest CT scan excluded acute cardiopulmonary events. Life-threatening MGFA class V MC was diagnosed, likely triggered by chemotherapy, thus classified as grade 4 according to the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) [8, 17]. Chemotherapy was held for 2 hours and then, considering its curative intent and in agreement with the family, it was resumed and fully administered during mechanical ventilation. After 24 hours, upon remission of MC and weaning from ventilation, the patient was extubated and could continue receiving MG treatment, together with starting PEX once every three days to control MG and prevent new crises (by replacing 1 plasma volume with 5% human albumin) [18]. In week 2, owing to CTCAE v5.0 grade 3 febrile neutropenia (absolute neutrophil count 60/mm3 and body temperature 38.4 °C), the patient was successfully treated with empirical piperacillin/tazobactam 4 g/0.5 g intravenously every 6 hours until recovery [19].
Curative treatment and outcome
After completing a second course of CAP chemotherapy with interposed PEX allowing symptom control, radiological assessment in week 6 documented objective partial response according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), with 33% tumor shrinkage (maximum diameter 8 versus 12 cm) [20]. This allowed us to perform radical (R0) extended thymectomy, left upper lung lobectomy and subtotal pericardiectomy, with histological diagnosis of Masaoka-Koga stage III type B2 [10, 11]. For patient histology, please see Fig. 2. The patient required early mediastinum and pleural cavity re-exploration due to postsurgical bleeding; persistent hypophonia developed due to postsurgical left vocal cord paralysis. A comparison of CT imaging at baseline and after surgery is shown in Fig. 3. As suggested for Masaoka-Koga stage III, radiotherapy of 50.4 Gy in 28 fractions was given as postoperative treatment in weeks 15–20 [1]. At the last follow-up visit, 6 months after surgery, the patient was in complete remission with gradually improving MGFA class I MG and mild persistent hypophonia [8]. Despite remarkable levels of psychological burden, the patient’s resilience and high-priority treatment goals were fundamental for successful coping.Fig. 2 Patient histology. a Hematoxylin and eosin (H&E; ×40 view) stained section of thymoma B2 according to WHO classification. b Same histological slice in ×100 view
Fig. 3 Chest computed tomography (CT) scan at baseline and after surgery. a Chest CT scan showing thymoma at baseline. b Postsurgical chest CT scan with no residual disease
Discussion and conclusions
According to the World Health Organization (WHO), thymoma is the most common variant of thymic epithelial tumors (66.3%), usually presenting with local invasion and seldom as metastatic disease [10, 21]. Overall, thymic epithelial tumors occur at a rate of 0.13–0.32 cases per 100,000 population at risk and are very uncommon in young adults [22, 23]. To our knowledge, the largest retrospective study regarding childhood thymic tumors (< 18 years) in Europe was able to identify only 36 cases during a 12-year period, confirming the extreme rarity of thymic cancer in children and adolescents [24]. Hence, the clinical case reported here has to be considered a peculiar presentation of early-onset thymoma (Fig. 4).Fig. 4 Age-specific incidence of thymic cancer by histological type. SEER*Stat Database: NPCR [National Program of Cancer Registries] and SEER [Surveillance, Epidemiology, and End Results] Incidence—U.S. Cancer Statistics Public Use Database, Nov 2017 submission (2001–2015). The green bar highlights the reported patient age interval (15–19 years)
Like thymoma, MG is extremely rare (0.17–2.13 per 100,000 person-years) [25]; however, it affects up to 30% of patients with thymoma [26]. The association of thymoma with MG has been related to the intratumoral generation of mature T cells, although the pathogenic mechanisms remain unclear [27]. MG has been found to be most commonly associated with B thymoma and confers favorable prognosis, since neuromuscular symptoms help in earlier detection of the tumor and thus less advanced stage at diagnosis. Nevertheless, concomitant MG should also be regarded as an adverse risk factor, since it can interfere with cancer treatment, being worsened by many drugs, and it reaches its maximum severity after thymectomy in a proportion of patients [28].
The case reported here, together with those published and summarized in Table 1 [3–6], highlights that chemotherapy is a realistic trigger event of MC in patients with thymoma and MG. The temporary association in all cases indicates a causative relation, and may hamper the continuation of chemotherapy that is a crucial element of multimodal treatment in cases not amenable to upfront radical surgery [1]. No biomarker is available to prove this relation, and clinical findings are crucial for the diagnosis of MC. Other differential diagnoses, such as infusion reaction to cancer chemotherapy, are less likely in the setting of prolonged respiratory failure. Here, a multidisciplinary approach was necessary, and involved neurologists for medical treatment and hematologists for a correct timing schedule of PEX sessions in order to avoid plasma drug displacement. It should be noted that we waited 72 hours from the end of chemotherapy before starting PEX, in order to preserve drug efficacy according to their half-life.Table 1. Comparison between present case and 4 other published cases
Fujiwara et al. [3] Qureshi et al. [4] Solak et al. [5] Ng et al. (6) Present case report
Sex Female Male Male Male Female
Age (year) 44 24 45 49 18
Histology B1 Thymoma (WHO) Thymoma Thymoma NE B2 thymoma (WHO)
Staging IVA (Masaoka-Koga) III (Masaoka-Koga) Advanced unresectable Advanced unresectable III (Masaoka-Koga)
AchR Ab level (nmol/l) 13 NE 74 NE 43
Chemotherapy regimen Primary CAMP Postoperative cisplatin and doxorubicin Single-agent cisplatin Doxorubicin, cisplatin, etoposide Primary CAP
Myasthenic crisis onset time During chemotherapy 8 hours after chemotherapy 1 week after chemotherapy A few hours after chemotherapy During chemotherapy
Tracheal intubation No Yes Yes Yes Yes
Plasma exchange No Yes Yes Yes Yes
Chemotherapy continuation in ICU No No No No Yes
Patient outcome after myasthenic crisis Alive Death Alive Alive Alive
AchR Ab acetylcholine receptor antibodies, CAMP cisplatin, doxorubicin, methylprednisolone, CAP cyclophosphamide, doxorubicin, cisplatin, ICU intensive care unit, NE not evaluable, WHO World Health Organization
To our knowledge, this is the first reported case of chemotherapy continuation despite the need for mechanical ventilation due to a chemotherapy-induced MC. Radical treatment was dependent on primary chemotherapy, as upfront surgery had already been ruled out. Besides, we could not confidently assume that, after MC resolution, the patient would have been able to receive further chemotherapy due to aggravation of symptoms. We conclude that special attention is warranted in patients with thymoma and MG with regard to the development of MC. Ideally, optimal control of myasthenic symptoms should be achieved before initiation of anticancer treatment. Nonetheless, chemotherapy-induced MC may complicate anticancer therapy administration, according to this evidence. We recommend that patients with thymoma and MG be hospitalized in tertiary medical centers for chemotherapy and that outpatient management be avoided. The lesson learned from the present case is that, in selected cases of advanced thymoma, paradoxical worsening of MG during chemotherapy should not be considered an absolute contraindication for continuation of primary chemotherapy with curative intent.
Abbreviations
CAPCisplatin, doxorubicin and cyclophosphamide
CTComputed tomography
CTCAE v5.0Common Terminology Criteria for Adverse Events version 5.0
GyGray
ICUIntensive Care Unit
MCMyasthenic crisis
MGMyasthenia gravis
MGFAMyasthenia Gravis Foundation of America
18PET-FDG18-Fluorodeoxyglucose positron emission tomography
PEXPlasma exchange
RECISTResponse Evaluation Criteria in Solid Tumours
WHOWorld Health Organization
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Fondazione Oncologia Niguarda Onlus for financial support.
Authors' contributions
GP, KB, FT, and SS were major contributors in writing the manuscript. KB, FT, GP, GM, GC, ASB, and SS provided clinical care. MP gave indication to and performed plasma exchange. AR and MT contributed to neoadjuvant treatment indication in a multidisciplinary team discussion and performed surgery. FL, AI, and ECA diagnosed thymoma and myasthenia and medically managed neurological symptoms. ASB and SS supervised oncological care and critically reviewed the case report. All authors read and approved the final manuscript.
Funding
This paper did not receive any specific grants from funding agencies in the public, commercial or not-for-profit sectors.
Ethics approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Availability of data and materials
Not applicable.
Competing interests
The authors declare that they have no competing interests. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33526108 | 18,959,226 | 2021-02-02 |
What was the administration route of drug 'PREDNISONE'? | Chemotherapy-induced myasthenic crisis in thymoma treated with primary chemotherapy with curative intent on mechanical ventilation: a case report and review of the literature.
BACKGROUND
Thymoma is an uncommon cancer often associated with myasthenia gravis, an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced nonmetastatic thymoma, primary chemotherapy may be required to induce tumor shrinkage and to achieve radical resection. Cancer chemotherapy has been anecdotally reported as a trigger factor for worsening of myasthenia gravis in thymic epithelial cancers. The study of uncommon cases of chemotherapy-related myasthenic crisis is warranted to gain knowledge of clinical situations requiring intensive care support in the case of life-threatening respiratory failure.
METHODS
We report a case of an 18-year-old Caucasian woman with advanced Masaoka-Koga stage III type B2 thymoma and myasthenia gravis on treatment with pyridostigmine, steroids and intravenous immunoglobulins, who developed a myasthenic crisis 2 hours after initiation of cyclophosphamide/doxorubicin/cisplatin primary chemotherapy. Because of severe acute respiratory failure, emergency tracheal intubation, mechanical ventilation, and temporary (2 hours) discontinuation of chemotherapy were needed. Considering the curative intent of the multimodal therapeutic program, we elected to resume primary chemotherapy administration while the patient remained on mechanical ventilation. After 24 hours, the recovery of adequate respiratory function allowed successful weaning from respiratory support, and no further adverse events occurred. After 3 weeks, upon plasma exchange initiation with amelioration of myasthenic symptoms, a second course of chemotherapy was given, and in week 6, having documented partial tumor remission, the patient underwent radical surgery (R0) and then consolidation radiation therapy with 50.4 Gy in 28 fractions in weeks 15-20.
CONCLUSIONS
This case report, together with the only four available in a review of the literature, highlights that chemotherapy may carry the risk of myasthenic crisis in patients affected by thymoma and myasthenia gravis. To our knowledge, this is the first reported case of chemotherapy continuation on mechanical ventilation in a patient with chemotherapy-induced myasthenic crisis requiring tracheal intubation. The lesson learned from the present case is that, in selected cases of advanced thymoma, the paradoxical worsening of myasthenia gravis during chemotherapy should not be considered an absolute contraindication for the continuation of primary chemotherapy with curative intent.
Background
Thymoma is an uncommon epithelial cancer associated in nearly half of cases with myasthenia gravis (MG), an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced thymoma, primary chemotherapy is considered the standard of care, with the aim of achieving tumor shrinkage and facilitating radical surgery [1]. While several drugs are known to worsen MG, cancer chemotherapy has been anecdotally reported as a trigger event for myasthenic crisis (MC) in four case reports [2–6]. Here, we present a case of advanced thymoma treated with primary chemotherapy that caused an acute-onset MC requiring tracheal intubation and therapeutic plasma exchange (PEX), with relevant benefit from early resumption of anticancer treatment during mechanical ventilation.
Case presentation
Clinical presentation and diagnosis
An 18-year-old Caucasian woman with unremarkable medical history was admitted to the emergency room due to neurological symptoms. She presented with month-long worsening dysphagia, rhinolalia, bilateral ptosis, and skeletal muscle weakness. Signs of muscle fatigability were elicited at the physical exam and then confirmed by electromyography, consistently with neuromuscular junction disease. Blood tests were unremarkable with the exception of acetylcholine receptor antibodies (43 nmol/l, normal if < 0.5 nmol/l). Hence, MG class III, according to the Myasthenia Gravis Foundation of America (MGFA) scale, was diagnosed [7, 8]. Partial regression of symptoms to class II MG was achieved by oral administration of pyridostigmine 60 mg every 3 hours during the daytime, pyridostigmine sustained-release 180 mg orally before sleeping, prednisone 25 mg orally each day, and immunoglobulins 0.4 g/kg intravenously for 5 days [8, 9]. Chest computed tomography (CT) revealed a 12 cm anterior mediastinal mass suspicious for thymoma, with confirmed infiltration of the anterior chest wall, lung parenchyma, and pericardium at chest magnetic resonance imaging with contrast. CT-guided fine needle aspiration biopsy yielded a histological diagnosis of B2 thymoma [10]. Due to the young age, a family history of cancer was excluded. Physical exam was negative for signs of mediastinal syndrome and superficial lymph nodes. Metastatic disease was excluded by 18-fluorodeoxyglucose positron emission tomography (18FDG-PET). Patient imaging is shown in Fig. 1. Accordingly, the clinical stage was cT3 cN0 cM0 (Masaoka-Koga III) [11]. After multidisciplinary team discussion, the tumor was defined as unresectable, and the patient was offered primary chemotherapy with intravenous cyclophosphamide 500 mg/m2, doxorubicin 50 mg/m2 and cisplatin 50 mg/m2 (CAP regimen) on day 1 every 21 days [12]. Primary prophylaxis of chemotherapy-induced neutropenia was not planned due to the potential risk of worsening MG, without evidence about the safety of administering granulocyte colony-stimulating factor in unstable myasthenic patients [13]. Ovarian preservation by gonadotropin-releasing hormone analogue leuprorelin was preferred over oocyte retrieval to expedite the start of chemotherapy [14]. Standard pre-medication with intravenous administration of ondansetron 8 mg, dexamethasone 8 mg and saline was chosen [15].Fig. 1 Patient imaging. a Left chest X-ray with enlarged mediastinum (see arrow). b Chest computed tomography scan showing the mediastinal mass (see arrow). c
18PET-FDG limited radiotracer uptake in mediastinum
Chemotherapy-induced myasthenic crisis
Two hours after starting administration of the first course of chemotherapy, following doxorubicin bolus, the patient experienced sudden onset of acute dyspnea with severe respiratory failure (oxygen saturation 75% on room air), refractory to oxygen therapy and bolus hydrocortisone 500 mg and chlorphenamine 10 mg administered intravenously [16]. Physical exam was negative for bronchospasm with diminished vesicular breath sounds. Due to unstable clinical conditions and development of acute respiratory acidosis (pH 7.21, partial pressure of carbon dioxide 88 mmHg), tracheal intubation and mechanical ventilation in the intensive care unit (ICU) were needed. Urgent chest CT scan excluded acute cardiopulmonary events. Life-threatening MGFA class V MC was diagnosed, likely triggered by chemotherapy, thus classified as grade 4 according to the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) [8, 17]. Chemotherapy was held for 2 hours and then, considering its curative intent and in agreement with the family, it was resumed and fully administered during mechanical ventilation. After 24 hours, upon remission of MC and weaning from ventilation, the patient was extubated and could continue receiving MG treatment, together with starting PEX once every three days to control MG and prevent new crises (by replacing 1 plasma volume with 5% human albumin) [18]. In week 2, owing to CTCAE v5.0 grade 3 febrile neutropenia (absolute neutrophil count 60/mm3 and body temperature 38.4 °C), the patient was successfully treated with empirical piperacillin/tazobactam 4 g/0.5 g intravenously every 6 hours until recovery [19].
Curative treatment and outcome
After completing a second course of CAP chemotherapy with interposed PEX allowing symptom control, radiological assessment in week 6 documented objective partial response according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), with 33% tumor shrinkage (maximum diameter 8 versus 12 cm) [20]. This allowed us to perform radical (R0) extended thymectomy, left upper lung lobectomy and subtotal pericardiectomy, with histological diagnosis of Masaoka-Koga stage III type B2 [10, 11]. For patient histology, please see Fig. 2. The patient required early mediastinum and pleural cavity re-exploration due to postsurgical bleeding; persistent hypophonia developed due to postsurgical left vocal cord paralysis. A comparison of CT imaging at baseline and after surgery is shown in Fig. 3. As suggested for Masaoka-Koga stage III, radiotherapy of 50.4 Gy in 28 fractions was given as postoperative treatment in weeks 15–20 [1]. At the last follow-up visit, 6 months after surgery, the patient was in complete remission with gradually improving MGFA class I MG and mild persistent hypophonia [8]. Despite remarkable levels of psychological burden, the patient’s resilience and high-priority treatment goals were fundamental for successful coping.Fig. 2 Patient histology. a Hematoxylin and eosin (H&E; ×40 view) stained section of thymoma B2 according to WHO classification. b Same histological slice in ×100 view
Fig. 3 Chest computed tomography (CT) scan at baseline and after surgery. a Chest CT scan showing thymoma at baseline. b Postsurgical chest CT scan with no residual disease
Discussion and conclusions
According to the World Health Organization (WHO), thymoma is the most common variant of thymic epithelial tumors (66.3%), usually presenting with local invasion and seldom as metastatic disease [10, 21]. Overall, thymic epithelial tumors occur at a rate of 0.13–0.32 cases per 100,000 population at risk and are very uncommon in young adults [22, 23]. To our knowledge, the largest retrospective study regarding childhood thymic tumors (< 18 years) in Europe was able to identify only 36 cases during a 12-year period, confirming the extreme rarity of thymic cancer in children and adolescents [24]. Hence, the clinical case reported here has to be considered a peculiar presentation of early-onset thymoma (Fig. 4).Fig. 4 Age-specific incidence of thymic cancer by histological type. SEER*Stat Database: NPCR [National Program of Cancer Registries] and SEER [Surveillance, Epidemiology, and End Results] Incidence—U.S. Cancer Statistics Public Use Database, Nov 2017 submission (2001–2015). The green bar highlights the reported patient age interval (15–19 years)
Like thymoma, MG is extremely rare (0.17–2.13 per 100,000 person-years) [25]; however, it affects up to 30% of patients with thymoma [26]. The association of thymoma with MG has been related to the intratumoral generation of mature T cells, although the pathogenic mechanisms remain unclear [27]. MG has been found to be most commonly associated with B thymoma and confers favorable prognosis, since neuromuscular symptoms help in earlier detection of the tumor and thus less advanced stage at diagnosis. Nevertheless, concomitant MG should also be regarded as an adverse risk factor, since it can interfere with cancer treatment, being worsened by many drugs, and it reaches its maximum severity after thymectomy in a proportion of patients [28].
The case reported here, together with those published and summarized in Table 1 [3–6], highlights that chemotherapy is a realistic trigger event of MC in patients with thymoma and MG. The temporary association in all cases indicates a causative relation, and may hamper the continuation of chemotherapy that is a crucial element of multimodal treatment in cases not amenable to upfront radical surgery [1]. No biomarker is available to prove this relation, and clinical findings are crucial for the diagnosis of MC. Other differential diagnoses, such as infusion reaction to cancer chemotherapy, are less likely in the setting of prolonged respiratory failure. Here, a multidisciplinary approach was necessary, and involved neurologists for medical treatment and hematologists for a correct timing schedule of PEX sessions in order to avoid plasma drug displacement. It should be noted that we waited 72 hours from the end of chemotherapy before starting PEX, in order to preserve drug efficacy according to their half-life.Table 1. Comparison between present case and 4 other published cases
Fujiwara et al. [3] Qureshi et al. [4] Solak et al. [5] Ng et al. (6) Present case report
Sex Female Male Male Male Female
Age (year) 44 24 45 49 18
Histology B1 Thymoma (WHO) Thymoma Thymoma NE B2 thymoma (WHO)
Staging IVA (Masaoka-Koga) III (Masaoka-Koga) Advanced unresectable Advanced unresectable III (Masaoka-Koga)
AchR Ab level (nmol/l) 13 NE 74 NE 43
Chemotherapy regimen Primary CAMP Postoperative cisplatin and doxorubicin Single-agent cisplatin Doxorubicin, cisplatin, etoposide Primary CAP
Myasthenic crisis onset time During chemotherapy 8 hours after chemotherapy 1 week after chemotherapy A few hours after chemotherapy During chemotherapy
Tracheal intubation No Yes Yes Yes Yes
Plasma exchange No Yes Yes Yes Yes
Chemotherapy continuation in ICU No No No No Yes
Patient outcome after myasthenic crisis Alive Death Alive Alive Alive
AchR Ab acetylcholine receptor antibodies, CAMP cisplatin, doxorubicin, methylprednisolone, CAP cyclophosphamide, doxorubicin, cisplatin, ICU intensive care unit, NE not evaluable, WHO World Health Organization
To our knowledge, this is the first reported case of chemotherapy continuation despite the need for mechanical ventilation due to a chemotherapy-induced MC. Radical treatment was dependent on primary chemotherapy, as upfront surgery had already been ruled out. Besides, we could not confidently assume that, after MC resolution, the patient would have been able to receive further chemotherapy due to aggravation of symptoms. We conclude that special attention is warranted in patients with thymoma and MG with regard to the development of MC. Ideally, optimal control of myasthenic symptoms should be achieved before initiation of anticancer treatment. Nonetheless, chemotherapy-induced MC may complicate anticancer therapy administration, according to this evidence. We recommend that patients with thymoma and MG be hospitalized in tertiary medical centers for chemotherapy and that outpatient management be avoided. The lesson learned from the present case is that, in selected cases of advanced thymoma, paradoxical worsening of MG during chemotherapy should not be considered an absolute contraindication for continuation of primary chemotherapy with curative intent.
Abbreviations
CAPCisplatin, doxorubicin and cyclophosphamide
CTComputed tomography
CTCAE v5.0Common Terminology Criteria for Adverse Events version 5.0
GyGray
ICUIntensive Care Unit
MCMyasthenic crisis
MGMyasthenia gravis
MGFAMyasthenia Gravis Foundation of America
18PET-FDG18-Fluorodeoxyglucose positron emission tomography
PEXPlasma exchange
RECISTResponse Evaluation Criteria in Solid Tumours
WHOWorld Health Organization
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Fondazione Oncologia Niguarda Onlus for financial support.
Authors' contributions
GP, KB, FT, and SS were major contributors in writing the manuscript. KB, FT, GP, GM, GC, ASB, and SS provided clinical care. MP gave indication to and performed plasma exchange. AR and MT contributed to neoadjuvant treatment indication in a multidisciplinary team discussion and performed surgery. FL, AI, and ECA diagnosed thymoma and myasthenia and medically managed neurological symptoms. ASB and SS supervised oncological care and critically reviewed the case report. All authors read and approved the final manuscript.
Funding
This paper did not receive any specific grants from funding agencies in the public, commercial or not-for-profit sectors.
Ethics approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Availability of data and materials
Not applicable.
Competing interests
The authors declare that they have no competing interests. | Oral | DrugAdministrationRoute | CC BY | 33526108 | 18,959,226 | 2021-02-02 |
What was the administration route of drug 'PYRIDOSTIGMINE'? | Chemotherapy-induced myasthenic crisis in thymoma treated with primary chemotherapy with curative intent on mechanical ventilation: a case report and review of the literature.
BACKGROUND
Thymoma is an uncommon cancer often associated with myasthenia gravis, an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced nonmetastatic thymoma, primary chemotherapy may be required to induce tumor shrinkage and to achieve radical resection. Cancer chemotherapy has been anecdotally reported as a trigger factor for worsening of myasthenia gravis in thymic epithelial cancers. The study of uncommon cases of chemotherapy-related myasthenic crisis is warranted to gain knowledge of clinical situations requiring intensive care support in the case of life-threatening respiratory failure.
METHODS
We report a case of an 18-year-old Caucasian woman with advanced Masaoka-Koga stage III type B2 thymoma and myasthenia gravis on treatment with pyridostigmine, steroids and intravenous immunoglobulins, who developed a myasthenic crisis 2 hours after initiation of cyclophosphamide/doxorubicin/cisplatin primary chemotherapy. Because of severe acute respiratory failure, emergency tracheal intubation, mechanical ventilation, and temporary (2 hours) discontinuation of chemotherapy were needed. Considering the curative intent of the multimodal therapeutic program, we elected to resume primary chemotherapy administration while the patient remained on mechanical ventilation. After 24 hours, the recovery of adequate respiratory function allowed successful weaning from respiratory support, and no further adverse events occurred. After 3 weeks, upon plasma exchange initiation with amelioration of myasthenic symptoms, a second course of chemotherapy was given, and in week 6, having documented partial tumor remission, the patient underwent radical surgery (R0) and then consolidation radiation therapy with 50.4 Gy in 28 fractions in weeks 15-20.
CONCLUSIONS
This case report, together with the only four available in a review of the literature, highlights that chemotherapy may carry the risk of myasthenic crisis in patients affected by thymoma and myasthenia gravis. To our knowledge, this is the first reported case of chemotherapy continuation on mechanical ventilation in a patient with chemotherapy-induced myasthenic crisis requiring tracheal intubation. The lesson learned from the present case is that, in selected cases of advanced thymoma, the paradoxical worsening of myasthenia gravis during chemotherapy should not be considered an absolute contraindication for the continuation of primary chemotherapy with curative intent.
Background
Thymoma is an uncommon epithelial cancer associated in nearly half of cases with myasthenia gravis (MG), an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced thymoma, primary chemotherapy is considered the standard of care, with the aim of achieving tumor shrinkage and facilitating radical surgery [1]. While several drugs are known to worsen MG, cancer chemotherapy has been anecdotally reported as a trigger event for myasthenic crisis (MC) in four case reports [2–6]. Here, we present a case of advanced thymoma treated with primary chemotherapy that caused an acute-onset MC requiring tracheal intubation and therapeutic plasma exchange (PEX), with relevant benefit from early resumption of anticancer treatment during mechanical ventilation.
Case presentation
Clinical presentation and diagnosis
An 18-year-old Caucasian woman with unremarkable medical history was admitted to the emergency room due to neurological symptoms. She presented with month-long worsening dysphagia, rhinolalia, bilateral ptosis, and skeletal muscle weakness. Signs of muscle fatigability were elicited at the physical exam and then confirmed by electromyography, consistently with neuromuscular junction disease. Blood tests were unremarkable with the exception of acetylcholine receptor antibodies (43 nmol/l, normal if < 0.5 nmol/l). Hence, MG class III, according to the Myasthenia Gravis Foundation of America (MGFA) scale, was diagnosed [7, 8]. Partial regression of symptoms to class II MG was achieved by oral administration of pyridostigmine 60 mg every 3 hours during the daytime, pyridostigmine sustained-release 180 mg orally before sleeping, prednisone 25 mg orally each day, and immunoglobulins 0.4 g/kg intravenously for 5 days [8, 9]. Chest computed tomography (CT) revealed a 12 cm anterior mediastinal mass suspicious for thymoma, with confirmed infiltration of the anterior chest wall, lung parenchyma, and pericardium at chest magnetic resonance imaging with contrast. CT-guided fine needle aspiration biopsy yielded a histological diagnosis of B2 thymoma [10]. Due to the young age, a family history of cancer was excluded. Physical exam was negative for signs of mediastinal syndrome and superficial lymph nodes. Metastatic disease was excluded by 18-fluorodeoxyglucose positron emission tomography (18FDG-PET). Patient imaging is shown in Fig. 1. Accordingly, the clinical stage was cT3 cN0 cM0 (Masaoka-Koga III) [11]. After multidisciplinary team discussion, the tumor was defined as unresectable, and the patient was offered primary chemotherapy with intravenous cyclophosphamide 500 mg/m2, doxorubicin 50 mg/m2 and cisplatin 50 mg/m2 (CAP regimen) on day 1 every 21 days [12]. Primary prophylaxis of chemotherapy-induced neutropenia was not planned due to the potential risk of worsening MG, without evidence about the safety of administering granulocyte colony-stimulating factor in unstable myasthenic patients [13]. Ovarian preservation by gonadotropin-releasing hormone analogue leuprorelin was preferred over oocyte retrieval to expedite the start of chemotherapy [14]. Standard pre-medication with intravenous administration of ondansetron 8 mg, dexamethasone 8 mg and saline was chosen [15].Fig. 1 Patient imaging. a Left chest X-ray with enlarged mediastinum (see arrow). b Chest computed tomography scan showing the mediastinal mass (see arrow). c
18PET-FDG limited radiotracer uptake in mediastinum
Chemotherapy-induced myasthenic crisis
Two hours after starting administration of the first course of chemotherapy, following doxorubicin bolus, the patient experienced sudden onset of acute dyspnea with severe respiratory failure (oxygen saturation 75% on room air), refractory to oxygen therapy and bolus hydrocortisone 500 mg and chlorphenamine 10 mg administered intravenously [16]. Physical exam was negative for bronchospasm with diminished vesicular breath sounds. Due to unstable clinical conditions and development of acute respiratory acidosis (pH 7.21, partial pressure of carbon dioxide 88 mmHg), tracheal intubation and mechanical ventilation in the intensive care unit (ICU) were needed. Urgent chest CT scan excluded acute cardiopulmonary events. Life-threatening MGFA class V MC was diagnosed, likely triggered by chemotherapy, thus classified as grade 4 according to the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) [8, 17]. Chemotherapy was held for 2 hours and then, considering its curative intent and in agreement with the family, it was resumed and fully administered during mechanical ventilation. After 24 hours, upon remission of MC and weaning from ventilation, the patient was extubated and could continue receiving MG treatment, together with starting PEX once every three days to control MG and prevent new crises (by replacing 1 plasma volume with 5% human albumin) [18]. In week 2, owing to CTCAE v5.0 grade 3 febrile neutropenia (absolute neutrophil count 60/mm3 and body temperature 38.4 °C), the patient was successfully treated with empirical piperacillin/tazobactam 4 g/0.5 g intravenously every 6 hours until recovery [19].
Curative treatment and outcome
After completing a second course of CAP chemotherapy with interposed PEX allowing symptom control, radiological assessment in week 6 documented objective partial response according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), with 33% tumor shrinkage (maximum diameter 8 versus 12 cm) [20]. This allowed us to perform radical (R0) extended thymectomy, left upper lung lobectomy and subtotal pericardiectomy, with histological diagnosis of Masaoka-Koga stage III type B2 [10, 11]. For patient histology, please see Fig. 2. The patient required early mediastinum and pleural cavity re-exploration due to postsurgical bleeding; persistent hypophonia developed due to postsurgical left vocal cord paralysis. A comparison of CT imaging at baseline and after surgery is shown in Fig. 3. As suggested for Masaoka-Koga stage III, radiotherapy of 50.4 Gy in 28 fractions was given as postoperative treatment in weeks 15–20 [1]. At the last follow-up visit, 6 months after surgery, the patient was in complete remission with gradually improving MGFA class I MG and mild persistent hypophonia [8]. Despite remarkable levels of psychological burden, the patient’s resilience and high-priority treatment goals were fundamental for successful coping.Fig. 2 Patient histology. a Hematoxylin and eosin (H&E; ×40 view) stained section of thymoma B2 according to WHO classification. b Same histological slice in ×100 view
Fig. 3 Chest computed tomography (CT) scan at baseline and after surgery. a Chest CT scan showing thymoma at baseline. b Postsurgical chest CT scan with no residual disease
Discussion and conclusions
According to the World Health Organization (WHO), thymoma is the most common variant of thymic epithelial tumors (66.3%), usually presenting with local invasion and seldom as metastatic disease [10, 21]. Overall, thymic epithelial tumors occur at a rate of 0.13–0.32 cases per 100,000 population at risk and are very uncommon in young adults [22, 23]. To our knowledge, the largest retrospective study regarding childhood thymic tumors (< 18 years) in Europe was able to identify only 36 cases during a 12-year period, confirming the extreme rarity of thymic cancer in children and adolescents [24]. Hence, the clinical case reported here has to be considered a peculiar presentation of early-onset thymoma (Fig. 4).Fig. 4 Age-specific incidence of thymic cancer by histological type. SEER*Stat Database: NPCR [National Program of Cancer Registries] and SEER [Surveillance, Epidemiology, and End Results] Incidence—U.S. Cancer Statistics Public Use Database, Nov 2017 submission (2001–2015). The green bar highlights the reported patient age interval (15–19 years)
Like thymoma, MG is extremely rare (0.17–2.13 per 100,000 person-years) [25]; however, it affects up to 30% of patients with thymoma [26]. The association of thymoma with MG has been related to the intratumoral generation of mature T cells, although the pathogenic mechanisms remain unclear [27]. MG has been found to be most commonly associated with B thymoma and confers favorable prognosis, since neuromuscular symptoms help in earlier detection of the tumor and thus less advanced stage at diagnosis. Nevertheless, concomitant MG should also be regarded as an adverse risk factor, since it can interfere with cancer treatment, being worsened by many drugs, and it reaches its maximum severity after thymectomy in a proportion of patients [28].
The case reported here, together with those published and summarized in Table 1 [3–6], highlights that chemotherapy is a realistic trigger event of MC in patients with thymoma and MG. The temporary association in all cases indicates a causative relation, and may hamper the continuation of chemotherapy that is a crucial element of multimodal treatment in cases not amenable to upfront radical surgery [1]. No biomarker is available to prove this relation, and clinical findings are crucial for the diagnosis of MC. Other differential diagnoses, such as infusion reaction to cancer chemotherapy, are less likely in the setting of prolonged respiratory failure. Here, a multidisciplinary approach was necessary, and involved neurologists for medical treatment and hematologists for a correct timing schedule of PEX sessions in order to avoid plasma drug displacement. It should be noted that we waited 72 hours from the end of chemotherapy before starting PEX, in order to preserve drug efficacy according to their half-life.Table 1. Comparison between present case and 4 other published cases
Fujiwara et al. [3] Qureshi et al. [4] Solak et al. [5] Ng et al. (6) Present case report
Sex Female Male Male Male Female
Age (year) 44 24 45 49 18
Histology B1 Thymoma (WHO) Thymoma Thymoma NE B2 thymoma (WHO)
Staging IVA (Masaoka-Koga) III (Masaoka-Koga) Advanced unresectable Advanced unresectable III (Masaoka-Koga)
AchR Ab level (nmol/l) 13 NE 74 NE 43
Chemotherapy regimen Primary CAMP Postoperative cisplatin and doxorubicin Single-agent cisplatin Doxorubicin, cisplatin, etoposide Primary CAP
Myasthenic crisis onset time During chemotherapy 8 hours after chemotherapy 1 week after chemotherapy A few hours after chemotherapy During chemotherapy
Tracheal intubation No Yes Yes Yes Yes
Plasma exchange No Yes Yes Yes Yes
Chemotherapy continuation in ICU No No No No Yes
Patient outcome after myasthenic crisis Alive Death Alive Alive Alive
AchR Ab acetylcholine receptor antibodies, CAMP cisplatin, doxorubicin, methylprednisolone, CAP cyclophosphamide, doxorubicin, cisplatin, ICU intensive care unit, NE not evaluable, WHO World Health Organization
To our knowledge, this is the first reported case of chemotherapy continuation despite the need for mechanical ventilation due to a chemotherapy-induced MC. Radical treatment was dependent on primary chemotherapy, as upfront surgery had already been ruled out. Besides, we could not confidently assume that, after MC resolution, the patient would have been able to receive further chemotherapy due to aggravation of symptoms. We conclude that special attention is warranted in patients with thymoma and MG with regard to the development of MC. Ideally, optimal control of myasthenic symptoms should be achieved before initiation of anticancer treatment. Nonetheless, chemotherapy-induced MC may complicate anticancer therapy administration, according to this evidence. We recommend that patients with thymoma and MG be hospitalized in tertiary medical centers for chemotherapy and that outpatient management be avoided. The lesson learned from the present case is that, in selected cases of advanced thymoma, paradoxical worsening of MG during chemotherapy should not be considered an absolute contraindication for continuation of primary chemotherapy with curative intent.
Abbreviations
CAPCisplatin, doxorubicin and cyclophosphamide
CTComputed tomography
CTCAE v5.0Common Terminology Criteria for Adverse Events version 5.0
GyGray
ICUIntensive Care Unit
MCMyasthenic crisis
MGMyasthenia gravis
MGFAMyasthenia Gravis Foundation of America
18PET-FDG18-Fluorodeoxyglucose positron emission tomography
PEXPlasma exchange
RECISTResponse Evaluation Criteria in Solid Tumours
WHOWorld Health Organization
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Fondazione Oncologia Niguarda Onlus for financial support.
Authors' contributions
GP, KB, FT, and SS were major contributors in writing the manuscript. KB, FT, GP, GM, GC, ASB, and SS provided clinical care. MP gave indication to and performed plasma exchange. AR and MT contributed to neoadjuvant treatment indication in a multidisciplinary team discussion and performed surgery. FL, AI, and ECA diagnosed thymoma and myasthenia and medically managed neurological symptoms. ASB and SS supervised oncological care and critically reviewed the case report. All authors read and approved the final manuscript.
Funding
This paper did not receive any specific grants from funding agencies in the public, commercial or not-for-profit sectors.
Ethics approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Availability of data and materials
Not applicable.
Competing interests
The authors declare that they have no competing interests. | Oral | DrugAdministrationRoute | CC BY | 33526108 | 18,959,226 | 2021-02-02 |
What was the administration route of drug 'SODIUM CHLORIDE'? | Chemotherapy-induced myasthenic crisis in thymoma treated with primary chemotherapy with curative intent on mechanical ventilation: a case report and review of the literature.
BACKGROUND
Thymoma is an uncommon cancer often associated with myasthenia gravis, an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced nonmetastatic thymoma, primary chemotherapy may be required to induce tumor shrinkage and to achieve radical resection. Cancer chemotherapy has been anecdotally reported as a trigger factor for worsening of myasthenia gravis in thymic epithelial cancers. The study of uncommon cases of chemotherapy-related myasthenic crisis is warranted to gain knowledge of clinical situations requiring intensive care support in the case of life-threatening respiratory failure.
METHODS
We report a case of an 18-year-old Caucasian woman with advanced Masaoka-Koga stage III type B2 thymoma and myasthenia gravis on treatment with pyridostigmine, steroids and intravenous immunoglobulins, who developed a myasthenic crisis 2 hours after initiation of cyclophosphamide/doxorubicin/cisplatin primary chemotherapy. Because of severe acute respiratory failure, emergency tracheal intubation, mechanical ventilation, and temporary (2 hours) discontinuation of chemotherapy were needed. Considering the curative intent of the multimodal therapeutic program, we elected to resume primary chemotherapy administration while the patient remained on mechanical ventilation. After 24 hours, the recovery of adequate respiratory function allowed successful weaning from respiratory support, and no further adverse events occurred. After 3 weeks, upon plasma exchange initiation with amelioration of myasthenic symptoms, a second course of chemotherapy was given, and in week 6, having documented partial tumor remission, the patient underwent radical surgery (R0) and then consolidation radiation therapy with 50.4 Gy in 28 fractions in weeks 15-20.
CONCLUSIONS
This case report, together with the only four available in a review of the literature, highlights that chemotherapy may carry the risk of myasthenic crisis in patients affected by thymoma and myasthenia gravis. To our knowledge, this is the first reported case of chemotherapy continuation on mechanical ventilation in a patient with chemotherapy-induced myasthenic crisis requiring tracheal intubation. The lesson learned from the present case is that, in selected cases of advanced thymoma, the paradoxical worsening of myasthenia gravis during chemotherapy should not be considered an absolute contraindication for the continuation of primary chemotherapy with curative intent.
Background
Thymoma is an uncommon epithelial cancer associated in nearly half of cases with myasthenia gravis (MG), an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced thymoma, primary chemotherapy is considered the standard of care, with the aim of achieving tumor shrinkage and facilitating radical surgery [1]. While several drugs are known to worsen MG, cancer chemotherapy has been anecdotally reported as a trigger event for myasthenic crisis (MC) in four case reports [2–6]. Here, we present a case of advanced thymoma treated with primary chemotherapy that caused an acute-onset MC requiring tracheal intubation and therapeutic plasma exchange (PEX), with relevant benefit from early resumption of anticancer treatment during mechanical ventilation.
Case presentation
Clinical presentation and diagnosis
An 18-year-old Caucasian woman with unremarkable medical history was admitted to the emergency room due to neurological symptoms. She presented with month-long worsening dysphagia, rhinolalia, bilateral ptosis, and skeletal muscle weakness. Signs of muscle fatigability were elicited at the physical exam and then confirmed by electromyography, consistently with neuromuscular junction disease. Blood tests were unremarkable with the exception of acetylcholine receptor antibodies (43 nmol/l, normal if < 0.5 nmol/l). Hence, MG class III, according to the Myasthenia Gravis Foundation of America (MGFA) scale, was diagnosed [7, 8]. Partial regression of symptoms to class II MG was achieved by oral administration of pyridostigmine 60 mg every 3 hours during the daytime, pyridostigmine sustained-release 180 mg orally before sleeping, prednisone 25 mg orally each day, and immunoglobulins 0.4 g/kg intravenously for 5 days [8, 9]. Chest computed tomography (CT) revealed a 12 cm anterior mediastinal mass suspicious for thymoma, with confirmed infiltration of the anterior chest wall, lung parenchyma, and pericardium at chest magnetic resonance imaging with contrast. CT-guided fine needle aspiration biopsy yielded a histological diagnosis of B2 thymoma [10]. Due to the young age, a family history of cancer was excluded. Physical exam was negative for signs of mediastinal syndrome and superficial lymph nodes. Metastatic disease was excluded by 18-fluorodeoxyglucose positron emission tomography (18FDG-PET). Patient imaging is shown in Fig. 1. Accordingly, the clinical stage was cT3 cN0 cM0 (Masaoka-Koga III) [11]. After multidisciplinary team discussion, the tumor was defined as unresectable, and the patient was offered primary chemotherapy with intravenous cyclophosphamide 500 mg/m2, doxorubicin 50 mg/m2 and cisplatin 50 mg/m2 (CAP regimen) on day 1 every 21 days [12]. Primary prophylaxis of chemotherapy-induced neutropenia was not planned due to the potential risk of worsening MG, without evidence about the safety of administering granulocyte colony-stimulating factor in unstable myasthenic patients [13]. Ovarian preservation by gonadotropin-releasing hormone analogue leuprorelin was preferred over oocyte retrieval to expedite the start of chemotherapy [14]. Standard pre-medication with intravenous administration of ondansetron 8 mg, dexamethasone 8 mg and saline was chosen [15].Fig. 1 Patient imaging. a Left chest X-ray with enlarged mediastinum (see arrow). b Chest computed tomography scan showing the mediastinal mass (see arrow). c
18PET-FDG limited radiotracer uptake in mediastinum
Chemotherapy-induced myasthenic crisis
Two hours after starting administration of the first course of chemotherapy, following doxorubicin bolus, the patient experienced sudden onset of acute dyspnea with severe respiratory failure (oxygen saturation 75% on room air), refractory to oxygen therapy and bolus hydrocortisone 500 mg and chlorphenamine 10 mg administered intravenously [16]. Physical exam was negative for bronchospasm with diminished vesicular breath sounds. Due to unstable clinical conditions and development of acute respiratory acidosis (pH 7.21, partial pressure of carbon dioxide 88 mmHg), tracheal intubation and mechanical ventilation in the intensive care unit (ICU) were needed. Urgent chest CT scan excluded acute cardiopulmonary events. Life-threatening MGFA class V MC was diagnosed, likely triggered by chemotherapy, thus classified as grade 4 according to the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) [8, 17]. Chemotherapy was held for 2 hours and then, considering its curative intent and in agreement with the family, it was resumed and fully administered during mechanical ventilation. After 24 hours, upon remission of MC and weaning from ventilation, the patient was extubated and could continue receiving MG treatment, together with starting PEX once every three days to control MG and prevent new crises (by replacing 1 plasma volume with 5% human albumin) [18]. In week 2, owing to CTCAE v5.0 grade 3 febrile neutropenia (absolute neutrophil count 60/mm3 and body temperature 38.4 °C), the patient was successfully treated with empirical piperacillin/tazobactam 4 g/0.5 g intravenously every 6 hours until recovery [19].
Curative treatment and outcome
After completing a second course of CAP chemotherapy with interposed PEX allowing symptom control, radiological assessment in week 6 documented objective partial response according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), with 33% tumor shrinkage (maximum diameter 8 versus 12 cm) [20]. This allowed us to perform radical (R0) extended thymectomy, left upper lung lobectomy and subtotal pericardiectomy, with histological diagnosis of Masaoka-Koga stage III type B2 [10, 11]. For patient histology, please see Fig. 2. The patient required early mediastinum and pleural cavity re-exploration due to postsurgical bleeding; persistent hypophonia developed due to postsurgical left vocal cord paralysis. A comparison of CT imaging at baseline and after surgery is shown in Fig. 3. As suggested for Masaoka-Koga stage III, radiotherapy of 50.4 Gy in 28 fractions was given as postoperative treatment in weeks 15–20 [1]. At the last follow-up visit, 6 months after surgery, the patient was in complete remission with gradually improving MGFA class I MG and mild persistent hypophonia [8]. Despite remarkable levels of psychological burden, the patient’s resilience and high-priority treatment goals were fundamental for successful coping.Fig. 2 Patient histology. a Hematoxylin and eosin (H&E; ×40 view) stained section of thymoma B2 according to WHO classification. b Same histological slice in ×100 view
Fig. 3 Chest computed tomography (CT) scan at baseline and after surgery. a Chest CT scan showing thymoma at baseline. b Postsurgical chest CT scan with no residual disease
Discussion and conclusions
According to the World Health Organization (WHO), thymoma is the most common variant of thymic epithelial tumors (66.3%), usually presenting with local invasion and seldom as metastatic disease [10, 21]. Overall, thymic epithelial tumors occur at a rate of 0.13–0.32 cases per 100,000 population at risk and are very uncommon in young adults [22, 23]. To our knowledge, the largest retrospective study regarding childhood thymic tumors (< 18 years) in Europe was able to identify only 36 cases during a 12-year period, confirming the extreme rarity of thymic cancer in children and adolescents [24]. Hence, the clinical case reported here has to be considered a peculiar presentation of early-onset thymoma (Fig. 4).Fig. 4 Age-specific incidence of thymic cancer by histological type. SEER*Stat Database: NPCR [National Program of Cancer Registries] and SEER [Surveillance, Epidemiology, and End Results] Incidence—U.S. Cancer Statistics Public Use Database, Nov 2017 submission (2001–2015). The green bar highlights the reported patient age interval (15–19 years)
Like thymoma, MG is extremely rare (0.17–2.13 per 100,000 person-years) [25]; however, it affects up to 30% of patients with thymoma [26]. The association of thymoma with MG has been related to the intratumoral generation of mature T cells, although the pathogenic mechanisms remain unclear [27]. MG has been found to be most commonly associated with B thymoma and confers favorable prognosis, since neuromuscular symptoms help in earlier detection of the tumor and thus less advanced stage at diagnosis. Nevertheless, concomitant MG should also be regarded as an adverse risk factor, since it can interfere with cancer treatment, being worsened by many drugs, and it reaches its maximum severity after thymectomy in a proportion of patients [28].
The case reported here, together with those published and summarized in Table 1 [3–6], highlights that chemotherapy is a realistic trigger event of MC in patients with thymoma and MG. The temporary association in all cases indicates a causative relation, and may hamper the continuation of chemotherapy that is a crucial element of multimodal treatment in cases not amenable to upfront radical surgery [1]. No biomarker is available to prove this relation, and clinical findings are crucial for the diagnosis of MC. Other differential diagnoses, such as infusion reaction to cancer chemotherapy, are less likely in the setting of prolonged respiratory failure. Here, a multidisciplinary approach was necessary, and involved neurologists for medical treatment and hematologists for a correct timing schedule of PEX sessions in order to avoid plasma drug displacement. It should be noted that we waited 72 hours from the end of chemotherapy before starting PEX, in order to preserve drug efficacy according to their half-life.Table 1. Comparison between present case and 4 other published cases
Fujiwara et al. [3] Qureshi et al. [4] Solak et al. [5] Ng et al. (6) Present case report
Sex Female Male Male Male Female
Age (year) 44 24 45 49 18
Histology B1 Thymoma (WHO) Thymoma Thymoma NE B2 thymoma (WHO)
Staging IVA (Masaoka-Koga) III (Masaoka-Koga) Advanced unresectable Advanced unresectable III (Masaoka-Koga)
AchR Ab level (nmol/l) 13 NE 74 NE 43
Chemotherapy regimen Primary CAMP Postoperative cisplatin and doxorubicin Single-agent cisplatin Doxorubicin, cisplatin, etoposide Primary CAP
Myasthenic crisis onset time During chemotherapy 8 hours after chemotherapy 1 week after chemotherapy A few hours after chemotherapy During chemotherapy
Tracheal intubation No Yes Yes Yes Yes
Plasma exchange No Yes Yes Yes Yes
Chemotherapy continuation in ICU No No No No Yes
Patient outcome after myasthenic crisis Alive Death Alive Alive Alive
AchR Ab acetylcholine receptor antibodies, CAMP cisplatin, doxorubicin, methylprednisolone, CAP cyclophosphamide, doxorubicin, cisplatin, ICU intensive care unit, NE not evaluable, WHO World Health Organization
To our knowledge, this is the first reported case of chemotherapy continuation despite the need for mechanical ventilation due to a chemotherapy-induced MC. Radical treatment was dependent on primary chemotherapy, as upfront surgery had already been ruled out. Besides, we could not confidently assume that, after MC resolution, the patient would have been able to receive further chemotherapy due to aggravation of symptoms. We conclude that special attention is warranted in patients with thymoma and MG with regard to the development of MC. Ideally, optimal control of myasthenic symptoms should be achieved before initiation of anticancer treatment. Nonetheless, chemotherapy-induced MC may complicate anticancer therapy administration, according to this evidence. We recommend that patients with thymoma and MG be hospitalized in tertiary medical centers for chemotherapy and that outpatient management be avoided. The lesson learned from the present case is that, in selected cases of advanced thymoma, paradoxical worsening of MG during chemotherapy should not be considered an absolute contraindication for continuation of primary chemotherapy with curative intent.
Abbreviations
CAPCisplatin, doxorubicin and cyclophosphamide
CTComputed tomography
CTCAE v5.0Common Terminology Criteria for Adverse Events version 5.0
GyGray
ICUIntensive Care Unit
MCMyasthenic crisis
MGMyasthenia gravis
MGFAMyasthenia Gravis Foundation of America
18PET-FDG18-Fluorodeoxyglucose positron emission tomography
PEXPlasma exchange
RECISTResponse Evaluation Criteria in Solid Tumours
WHOWorld Health Organization
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Fondazione Oncologia Niguarda Onlus for financial support.
Authors' contributions
GP, KB, FT, and SS were major contributors in writing the manuscript. KB, FT, GP, GM, GC, ASB, and SS provided clinical care. MP gave indication to and performed plasma exchange. AR and MT contributed to neoadjuvant treatment indication in a multidisciplinary team discussion and performed surgery. FL, AI, and ECA diagnosed thymoma and myasthenia and medically managed neurological symptoms. ASB and SS supervised oncological care and critically reviewed the case report. All authors read and approved the final manuscript.
Funding
This paper did not receive any specific grants from funding agencies in the public, commercial or not-for-profit sectors.
Ethics approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Availability of data and materials
Not applicable.
Competing interests
The authors declare that they have no competing interests. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33526108 | 18,959,226 | 2021-02-02 |
What was the dosage of drug 'ALBUMIN HUMAN'? | Chemotherapy-induced myasthenic crisis in thymoma treated with primary chemotherapy with curative intent on mechanical ventilation: a case report and review of the literature.
BACKGROUND
Thymoma is an uncommon cancer often associated with myasthenia gravis, an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced nonmetastatic thymoma, primary chemotherapy may be required to induce tumor shrinkage and to achieve radical resection. Cancer chemotherapy has been anecdotally reported as a trigger factor for worsening of myasthenia gravis in thymic epithelial cancers. The study of uncommon cases of chemotherapy-related myasthenic crisis is warranted to gain knowledge of clinical situations requiring intensive care support in the case of life-threatening respiratory failure.
METHODS
We report a case of an 18-year-old Caucasian woman with advanced Masaoka-Koga stage III type B2 thymoma and myasthenia gravis on treatment with pyridostigmine, steroids and intravenous immunoglobulins, who developed a myasthenic crisis 2 hours after initiation of cyclophosphamide/doxorubicin/cisplatin primary chemotherapy. Because of severe acute respiratory failure, emergency tracheal intubation, mechanical ventilation, and temporary (2 hours) discontinuation of chemotherapy were needed. Considering the curative intent of the multimodal therapeutic program, we elected to resume primary chemotherapy administration while the patient remained on mechanical ventilation. After 24 hours, the recovery of adequate respiratory function allowed successful weaning from respiratory support, and no further adverse events occurred. After 3 weeks, upon plasma exchange initiation with amelioration of myasthenic symptoms, a second course of chemotherapy was given, and in week 6, having documented partial tumor remission, the patient underwent radical surgery (R0) and then consolidation radiation therapy with 50.4 Gy in 28 fractions in weeks 15-20.
CONCLUSIONS
This case report, together with the only four available in a review of the literature, highlights that chemotherapy may carry the risk of myasthenic crisis in patients affected by thymoma and myasthenia gravis. To our knowledge, this is the first reported case of chemotherapy continuation on mechanical ventilation in a patient with chemotherapy-induced myasthenic crisis requiring tracheal intubation. The lesson learned from the present case is that, in selected cases of advanced thymoma, the paradoxical worsening of myasthenia gravis during chemotherapy should not be considered an absolute contraindication for the continuation of primary chemotherapy with curative intent.
Background
Thymoma is an uncommon epithelial cancer associated in nearly half of cases with myasthenia gravis (MG), an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced thymoma, primary chemotherapy is considered the standard of care, with the aim of achieving tumor shrinkage and facilitating radical surgery [1]. While several drugs are known to worsen MG, cancer chemotherapy has been anecdotally reported as a trigger event for myasthenic crisis (MC) in four case reports [2–6]. Here, we present a case of advanced thymoma treated with primary chemotherapy that caused an acute-onset MC requiring tracheal intubation and therapeutic plasma exchange (PEX), with relevant benefit from early resumption of anticancer treatment during mechanical ventilation.
Case presentation
Clinical presentation and diagnosis
An 18-year-old Caucasian woman with unremarkable medical history was admitted to the emergency room due to neurological symptoms. She presented with month-long worsening dysphagia, rhinolalia, bilateral ptosis, and skeletal muscle weakness. Signs of muscle fatigability were elicited at the physical exam and then confirmed by electromyography, consistently with neuromuscular junction disease. Blood tests were unremarkable with the exception of acetylcholine receptor antibodies (43 nmol/l, normal if < 0.5 nmol/l). Hence, MG class III, according to the Myasthenia Gravis Foundation of America (MGFA) scale, was diagnosed [7, 8]. Partial regression of symptoms to class II MG was achieved by oral administration of pyridostigmine 60 mg every 3 hours during the daytime, pyridostigmine sustained-release 180 mg orally before sleeping, prednisone 25 mg orally each day, and immunoglobulins 0.4 g/kg intravenously for 5 days [8, 9]. Chest computed tomography (CT) revealed a 12 cm anterior mediastinal mass suspicious for thymoma, with confirmed infiltration of the anterior chest wall, lung parenchyma, and pericardium at chest magnetic resonance imaging with contrast. CT-guided fine needle aspiration biopsy yielded a histological diagnosis of B2 thymoma [10]. Due to the young age, a family history of cancer was excluded. Physical exam was negative for signs of mediastinal syndrome and superficial lymph nodes. Metastatic disease was excluded by 18-fluorodeoxyglucose positron emission tomography (18FDG-PET). Patient imaging is shown in Fig. 1. Accordingly, the clinical stage was cT3 cN0 cM0 (Masaoka-Koga III) [11]. After multidisciplinary team discussion, the tumor was defined as unresectable, and the patient was offered primary chemotherapy with intravenous cyclophosphamide 500 mg/m2, doxorubicin 50 mg/m2 and cisplatin 50 mg/m2 (CAP regimen) on day 1 every 21 days [12]. Primary prophylaxis of chemotherapy-induced neutropenia was not planned due to the potential risk of worsening MG, without evidence about the safety of administering granulocyte colony-stimulating factor in unstable myasthenic patients [13]. Ovarian preservation by gonadotropin-releasing hormone analogue leuprorelin was preferred over oocyte retrieval to expedite the start of chemotherapy [14]. Standard pre-medication with intravenous administration of ondansetron 8 mg, dexamethasone 8 mg and saline was chosen [15].Fig. 1 Patient imaging. a Left chest X-ray with enlarged mediastinum (see arrow). b Chest computed tomography scan showing the mediastinal mass (see arrow). c
18PET-FDG limited radiotracer uptake in mediastinum
Chemotherapy-induced myasthenic crisis
Two hours after starting administration of the first course of chemotherapy, following doxorubicin bolus, the patient experienced sudden onset of acute dyspnea with severe respiratory failure (oxygen saturation 75% on room air), refractory to oxygen therapy and bolus hydrocortisone 500 mg and chlorphenamine 10 mg administered intravenously [16]. Physical exam was negative for bronchospasm with diminished vesicular breath sounds. Due to unstable clinical conditions and development of acute respiratory acidosis (pH 7.21, partial pressure of carbon dioxide 88 mmHg), tracheal intubation and mechanical ventilation in the intensive care unit (ICU) were needed. Urgent chest CT scan excluded acute cardiopulmonary events. Life-threatening MGFA class V MC was diagnosed, likely triggered by chemotherapy, thus classified as grade 4 according to the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) [8, 17]. Chemotherapy was held for 2 hours and then, considering its curative intent and in agreement with the family, it was resumed and fully administered during mechanical ventilation. After 24 hours, upon remission of MC and weaning from ventilation, the patient was extubated and could continue receiving MG treatment, together with starting PEX once every three days to control MG and prevent new crises (by replacing 1 plasma volume with 5% human albumin) [18]. In week 2, owing to CTCAE v5.0 grade 3 febrile neutropenia (absolute neutrophil count 60/mm3 and body temperature 38.4 °C), the patient was successfully treated with empirical piperacillin/tazobactam 4 g/0.5 g intravenously every 6 hours until recovery [19].
Curative treatment and outcome
After completing a second course of CAP chemotherapy with interposed PEX allowing symptom control, radiological assessment in week 6 documented objective partial response according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), with 33% tumor shrinkage (maximum diameter 8 versus 12 cm) [20]. This allowed us to perform radical (R0) extended thymectomy, left upper lung lobectomy and subtotal pericardiectomy, with histological diagnosis of Masaoka-Koga stage III type B2 [10, 11]. For patient histology, please see Fig. 2. The patient required early mediastinum and pleural cavity re-exploration due to postsurgical bleeding; persistent hypophonia developed due to postsurgical left vocal cord paralysis. A comparison of CT imaging at baseline and after surgery is shown in Fig. 3. As suggested for Masaoka-Koga stage III, radiotherapy of 50.4 Gy in 28 fractions was given as postoperative treatment in weeks 15–20 [1]. At the last follow-up visit, 6 months after surgery, the patient was in complete remission with gradually improving MGFA class I MG and mild persistent hypophonia [8]. Despite remarkable levels of psychological burden, the patient’s resilience and high-priority treatment goals were fundamental for successful coping.Fig. 2 Patient histology. a Hematoxylin and eosin (H&E; ×40 view) stained section of thymoma B2 according to WHO classification. b Same histological slice in ×100 view
Fig. 3 Chest computed tomography (CT) scan at baseline and after surgery. a Chest CT scan showing thymoma at baseline. b Postsurgical chest CT scan with no residual disease
Discussion and conclusions
According to the World Health Organization (WHO), thymoma is the most common variant of thymic epithelial tumors (66.3%), usually presenting with local invasion and seldom as metastatic disease [10, 21]. Overall, thymic epithelial tumors occur at a rate of 0.13–0.32 cases per 100,000 population at risk and are very uncommon in young adults [22, 23]. To our knowledge, the largest retrospective study regarding childhood thymic tumors (< 18 years) in Europe was able to identify only 36 cases during a 12-year period, confirming the extreme rarity of thymic cancer in children and adolescents [24]. Hence, the clinical case reported here has to be considered a peculiar presentation of early-onset thymoma (Fig. 4).Fig. 4 Age-specific incidence of thymic cancer by histological type. SEER*Stat Database: NPCR [National Program of Cancer Registries] and SEER [Surveillance, Epidemiology, and End Results] Incidence—U.S. Cancer Statistics Public Use Database, Nov 2017 submission (2001–2015). The green bar highlights the reported patient age interval (15–19 years)
Like thymoma, MG is extremely rare (0.17–2.13 per 100,000 person-years) [25]; however, it affects up to 30% of patients with thymoma [26]. The association of thymoma with MG has been related to the intratumoral generation of mature T cells, although the pathogenic mechanisms remain unclear [27]. MG has been found to be most commonly associated with B thymoma and confers favorable prognosis, since neuromuscular symptoms help in earlier detection of the tumor and thus less advanced stage at diagnosis. Nevertheless, concomitant MG should also be regarded as an adverse risk factor, since it can interfere with cancer treatment, being worsened by many drugs, and it reaches its maximum severity after thymectomy in a proportion of patients [28].
The case reported here, together with those published and summarized in Table 1 [3–6], highlights that chemotherapy is a realistic trigger event of MC in patients with thymoma and MG. The temporary association in all cases indicates a causative relation, and may hamper the continuation of chemotherapy that is a crucial element of multimodal treatment in cases not amenable to upfront radical surgery [1]. No biomarker is available to prove this relation, and clinical findings are crucial for the diagnosis of MC. Other differential diagnoses, such as infusion reaction to cancer chemotherapy, are less likely in the setting of prolonged respiratory failure. Here, a multidisciplinary approach was necessary, and involved neurologists for medical treatment and hematologists for a correct timing schedule of PEX sessions in order to avoid plasma drug displacement. It should be noted that we waited 72 hours from the end of chemotherapy before starting PEX, in order to preserve drug efficacy according to their half-life.Table 1. Comparison between present case and 4 other published cases
Fujiwara et al. [3] Qureshi et al. [4] Solak et al. [5] Ng et al. (6) Present case report
Sex Female Male Male Male Female
Age (year) 44 24 45 49 18
Histology B1 Thymoma (WHO) Thymoma Thymoma NE B2 thymoma (WHO)
Staging IVA (Masaoka-Koga) III (Masaoka-Koga) Advanced unresectable Advanced unresectable III (Masaoka-Koga)
AchR Ab level (nmol/l) 13 NE 74 NE 43
Chemotherapy regimen Primary CAMP Postoperative cisplatin and doxorubicin Single-agent cisplatin Doxorubicin, cisplatin, etoposide Primary CAP
Myasthenic crisis onset time During chemotherapy 8 hours after chemotherapy 1 week after chemotherapy A few hours after chemotherapy During chemotherapy
Tracheal intubation No Yes Yes Yes Yes
Plasma exchange No Yes Yes Yes Yes
Chemotherapy continuation in ICU No No No No Yes
Patient outcome after myasthenic crisis Alive Death Alive Alive Alive
AchR Ab acetylcholine receptor antibodies, CAMP cisplatin, doxorubicin, methylprednisolone, CAP cyclophosphamide, doxorubicin, cisplatin, ICU intensive care unit, NE not evaluable, WHO World Health Organization
To our knowledge, this is the first reported case of chemotherapy continuation despite the need for mechanical ventilation due to a chemotherapy-induced MC. Radical treatment was dependent on primary chemotherapy, as upfront surgery had already been ruled out. Besides, we could not confidently assume that, after MC resolution, the patient would have been able to receive further chemotherapy due to aggravation of symptoms. We conclude that special attention is warranted in patients with thymoma and MG with regard to the development of MC. Ideally, optimal control of myasthenic symptoms should be achieved before initiation of anticancer treatment. Nonetheless, chemotherapy-induced MC may complicate anticancer therapy administration, according to this evidence. We recommend that patients with thymoma and MG be hospitalized in tertiary medical centers for chemotherapy and that outpatient management be avoided. The lesson learned from the present case is that, in selected cases of advanced thymoma, paradoxical worsening of MG during chemotherapy should not be considered an absolute contraindication for continuation of primary chemotherapy with curative intent.
Abbreviations
CAPCisplatin, doxorubicin and cyclophosphamide
CTComputed tomography
CTCAE v5.0Common Terminology Criteria for Adverse Events version 5.0
GyGray
ICUIntensive Care Unit
MCMyasthenic crisis
MGMyasthenia gravis
MGFAMyasthenia Gravis Foundation of America
18PET-FDG18-Fluorodeoxyglucose positron emission tomography
PEXPlasma exchange
RECISTResponse Evaluation Criteria in Solid Tumours
WHOWorld Health Organization
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Fondazione Oncologia Niguarda Onlus for financial support.
Authors' contributions
GP, KB, FT, and SS were major contributors in writing the manuscript. KB, FT, GP, GM, GC, ASB, and SS provided clinical care. MP gave indication to and performed plasma exchange. AR and MT contributed to neoadjuvant treatment indication in a multidisciplinary team discussion and performed surgery. FL, AI, and ECA diagnosed thymoma and myasthenia and medically managed neurological symptoms. ASB and SS supervised oncological care and critically reviewed the case report. All authors read and approved the final manuscript.
Funding
This paper did not receive any specific grants from funding agencies in the public, commercial or not-for-profit sectors.
Ethics approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Availability of data and materials
Not applicable.
Competing interests
The authors declare that they have no competing interests. | UNKNOWN, REPLACING 1 PLASMA VOLUME WITH 5% HUMAN ALBUMIN | DrugDosageText | CC BY | 33526108 | 18,959,232 | 2021-02-02 |
What was the dosage of drug 'DOXORUBICIN HYDROCHLORIDE'? | Chemotherapy-induced myasthenic crisis in thymoma treated with primary chemotherapy with curative intent on mechanical ventilation: a case report and review of the literature.
BACKGROUND
Thymoma is an uncommon cancer often associated with myasthenia gravis, an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced nonmetastatic thymoma, primary chemotherapy may be required to induce tumor shrinkage and to achieve radical resection. Cancer chemotherapy has been anecdotally reported as a trigger factor for worsening of myasthenia gravis in thymic epithelial cancers. The study of uncommon cases of chemotherapy-related myasthenic crisis is warranted to gain knowledge of clinical situations requiring intensive care support in the case of life-threatening respiratory failure.
METHODS
We report a case of an 18-year-old Caucasian woman with advanced Masaoka-Koga stage III type B2 thymoma and myasthenia gravis on treatment with pyridostigmine, steroids and intravenous immunoglobulins, who developed a myasthenic crisis 2 hours after initiation of cyclophosphamide/doxorubicin/cisplatin primary chemotherapy. Because of severe acute respiratory failure, emergency tracheal intubation, mechanical ventilation, and temporary (2 hours) discontinuation of chemotherapy were needed. Considering the curative intent of the multimodal therapeutic program, we elected to resume primary chemotherapy administration while the patient remained on mechanical ventilation. After 24 hours, the recovery of adequate respiratory function allowed successful weaning from respiratory support, and no further adverse events occurred. After 3 weeks, upon plasma exchange initiation with amelioration of myasthenic symptoms, a second course of chemotherapy was given, and in week 6, having documented partial tumor remission, the patient underwent radical surgery (R0) and then consolidation radiation therapy with 50.4 Gy in 28 fractions in weeks 15-20.
CONCLUSIONS
This case report, together with the only four available in a review of the literature, highlights that chemotherapy may carry the risk of myasthenic crisis in patients affected by thymoma and myasthenia gravis. To our knowledge, this is the first reported case of chemotherapy continuation on mechanical ventilation in a patient with chemotherapy-induced myasthenic crisis requiring tracheal intubation. The lesson learned from the present case is that, in selected cases of advanced thymoma, the paradoxical worsening of myasthenia gravis during chemotherapy should not be considered an absolute contraindication for the continuation of primary chemotherapy with curative intent.
Background
Thymoma is an uncommon epithelial cancer associated in nearly half of cases with myasthenia gravis (MG), an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced thymoma, primary chemotherapy is considered the standard of care, with the aim of achieving tumor shrinkage and facilitating radical surgery [1]. While several drugs are known to worsen MG, cancer chemotherapy has been anecdotally reported as a trigger event for myasthenic crisis (MC) in four case reports [2–6]. Here, we present a case of advanced thymoma treated with primary chemotherapy that caused an acute-onset MC requiring tracheal intubation and therapeutic plasma exchange (PEX), with relevant benefit from early resumption of anticancer treatment during mechanical ventilation.
Case presentation
Clinical presentation and diagnosis
An 18-year-old Caucasian woman with unremarkable medical history was admitted to the emergency room due to neurological symptoms. She presented with month-long worsening dysphagia, rhinolalia, bilateral ptosis, and skeletal muscle weakness. Signs of muscle fatigability were elicited at the physical exam and then confirmed by electromyography, consistently with neuromuscular junction disease. Blood tests were unremarkable with the exception of acetylcholine receptor antibodies (43 nmol/l, normal if < 0.5 nmol/l). Hence, MG class III, according to the Myasthenia Gravis Foundation of America (MGFA) scale, was diagnosed [7, 8]. Partial regression of symptoms to class II MG was achieved by oral administration of pyridostigmine 60 mg every 3 hours during the daytime, pyridostigmine sustained-release 180 mg orally before sleeping, prednisone 25 mg orally each day, and immunoglobulins 0.4 g/kg intravenously for 5 days [8, 9]. Chest computed tomography (CT) revealed a 12 cm anterior mediastinal mass suspicious for thymoma, with confirmed infiltration of the anterior chest wall, lung parenchyma, and pericardium at chest magnetic resonance imaging with contrast. CT-guided fine needle aspiration biopsy yielded a histological diagnosis of B2 thymoma [10]. Due to the young age, a family history of cancer was excluded. Physical exam was negative for signs of mediastinal syndrome and superficial lymph nodes. Metastatic disease was excluded by 18-fluorodeoxyglucose positron emission tomography (18FDG-PET). Patient imaging is shown in Fig. 1. Accordingly, the clinical stage was cT3 cN0 cM0 (Masaoka-Koga III) [11]. After multidisciplinary team discussion, the tumor was defined as unresectable, and the patient was offered primary chemotherapy with intravenous cyclophosphamide 500 mg/m2, doxorubicin 50 mg/m2 and cisplatin 50 mg/m2 (CAP regimen) on day 1 every 21 days [12]. Primary prophylaxis of chemotherapy-induced neutropenia was not planned due to the potential risk of worsening MG, without evidence about the safety of administering granulocyte colony-stimulating factor in unstable myasthenic patients [13]. Ovarian preservation by gonadotropin-releasing hormone analogue leuprorelin was preferred over oocyte retrieval to expedite the start of chemotherapy [14]. Standard pre-medication with intravenous administration of ondansetron 8 mg, dexamethasone 8 mg and saline was chosen [15].Fig. 1 Patient imaging. a Left chest X-ray with enlarged mediastinum (see arrow). b Chest computed tomography scan showing the mediastinal mass (see arrow). c
18PET-FDG limited radiotracer uptake in mediastinum
Chemotherapy-induced myasthenic crisis
Two hours after starting administration of the first course of chemotherapy, following doxorubicin bolus, the patient experienced sudden onset of acute dyspnea with severe respiratory failure (oxygen saturation 75% on room air), refractory to oxygen therapy and bolus hydrocortisone 500 mg and chlorphenamine 10 mg administered intravenously [16]. Physical exam was negative for bronchospasm with diminished vesicular breath sounds. Due to unstable clinical conditions and development of acute respiratory acidosis (pH 7.21, partial pressure of carbon dioxide 88 mmHg), tracheal intubation and mechanical ventilation in the intensive care unit (ICU) were needed. Urgent chest CT scan excluded acute cardiopulmonary events. Life-threatening MGFA class V MC was diagnosed, likely triggered by chemotherapy, thus classified as grade 4 according to the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) [8, 17]. Chemotherapy was held for 2 hours and then, considering its curative intent and in agreement with the family, it was resumed and fully administered during mechanical ventilation. After 24 hours, upon remission of MC and weaning from ventilation, the patient was extubated and could continue receiving MG treatment, together with starting PEX once every three days to control MG and prevent new crises (by replacing 1 plasma volume with 5% human albumin) [18]. In week 2, owing to CTCAE v5.0 grade 3 febrile neutropenia (absolute neutrophil count 60/mm3 and body temperature 38.4 °C), the patient was successfully treated with empirical piperacillin/tazobactam 4 g/0.5 g intravenously every 6 hours until recovery [19].
Curative treatment and outcome
After completing a second course of CAP chemotherapy with interposed PEX allowing symptom control, radiological assessment in week 6 documented objective partial response according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), with 33% tumor shrinkage (maximum diameter 8 versus 12 cm) [20]. This allowed us to perform radical (R0) extended thymectomy, left upper lung lobectomy and subtotal pericardiectomy, with histological diagnosis of Masaoka-Koga stage III type B2 [10, 11]. For patient histology, please see Fig. 2. The patient required early mediastinum and pleural cavity re-exploration due to postsurgical bleeding; persistent hypophonia developed due to postsurgical left vocal cord paralysis. A comparison of CT imaging at baseline and after surgery is shown in Fig. 3. As suggested for Masaoka-Koga stage III, radiotherapy of 50.4 Gy in 28 fractions was given as postoperative treatment in weeks 15–20 [1]. At the last follow-up visit, 6 months after surgery, the patient was in complete remission with gradually improving MGFA class I MG and mild persistent hypophonia [8]. Despite remarkable levels of psychological burden, the patient’s resilience and high-priority treatment goals were fundamental for successful coping.Fig. 2 Patient histology. a Hematoxylin and eosin (H&E; ×40 view) stained section of thymoma B2 according to WHO classification. b Same histological slice in ×100 view
Fig. 3 Chest computed tomography (CT) scan at baseline and after surgery. a Chest CT scan showing thymoma at baseline. b Postsurgical chest CT scan with no residual disease
Discussion and conclusions
According to the World Health Organization (WHO), thymoma is the most common variant of thymic epithelial tumors (66.3%), usually presenting with local invasion and seldom as metastatic disease [10, 21]. Overall, thymic epithelial tumors occur at a rate of 0.13–0.32 cases per 100,000 population at risk and are very uncommon in young adults [22, 23]. To our knowledge, the largest retrospective study regarding childhood thymic tumors (< 18 years) in Europe was able to identify only 36 cases during a 12-year period, confirming the extreme rarity of thymic cancer in children and adolescents [24]. Hence, the clinical case reported here has to be considered a peculiar presentation of early-onset thymoma (Fig. 4).Fig. 4 Age-specific incidence of thymic cancer by histological type. SEER*Stat Database: NPCR [National Program of Cancer Registries] and SEER [Surveillance, Epidemiology, and End Results] Incidence—U.S. Cancer Statistics Public Use Database, Nov 2017 submission (2001–2015). The green bar highlights the reported patient age interval (15–19 years)
Like thymoma, MG is extremely rare (0.17–2.13 per 100,000 person-years) [25]; however, it affects up to 30% of patients with thymoma [26]. The association of thymoma with MG has been related to the intratumoral generation of mature T cells, although the pathogenic mechanisms remain unclear [27]. MG has been found to be most commonly associated with B thymoma and confers favorable prognosis, since neuromuscular symptoms help in earlier detection of the tumor and thus less advanced stage at diagnosis. Nevertheless, concomitant MG should also be regarded as an adverse risk factor, since it can interfere with cancer treatment, being worsened by many drugs, and it reaches its maximum severity after thymectomy in a proportion of patients [28].
The case reported here, together with those published and summarized in Table 1 [3–6], highlights that chemotherapy is a realistic trigger event of MC in patients with thymoma and MG. The temporary association in all cases indicates a causative relation, and may hamper the continuation of chemotherapy that is a crucial element of multimodal treatment in cases not amenable to upfront radical surgery [1]. No biomarker is available to prove this relation, and clinical findings are crucial for the diagnosis of MC. Other differential diagnoses, such as infusion reaction to cancer chemotherapy, are less likely in the setting of prolonged respiratory failure. Here, a multidisciplinary approach was necessary, and involved neurologists for medical treatment and hematologists for a correct timing schedule of PEX sessions in order to avoid plasma drug displacement. It should be noted that we waited 72 hours from the end of chemotherapy before starting PEX, in order to preserve drug efficacy according to their half-life.Table 1. Comparison between present case and 4 other published cases
Fujiwara et al. [3] Qureshi et al. [4] Solak et al. [5] Ng et al. (6) Present case report
Sex Female Male Male Male Female
Age (year) 44 24 45 49 18
Histology B1 Thymoma (WHO) Thymoma Thymoma NE B2 thymoma (WHO)
Staging IVA (Masaoka-Koga) III (Masaoka-Koga) Advanced unresectable Advanced unresectable III (Masaoka-Koga)
AchR Ab level (nmol/l) 13 NE 74 NE 43
Chemotherapy regimen Primary CAMP Postoperative cisplatin and doxorubicin Single-agent cisplatin Doxorubicin, cisplatin, etoposide Primary CAP
Myasthenic crisis onset time During chemotherapy 8 hours after chemotherapy 1 week after chemotherapy A few hours after chemotherapy During chemotherapy
Tracheal intubation No Yes Yes Yes Yes
Plasma exchange No Yes Yes Yes Yes
Chemotherapy continuation in ICU No No No No Yes
Patient outcome after myasthenic crisis Alive Death Alive Alive Alive
AchR Ab acetylcholine receptor antibodies, CAMP cisplatin, doxorubicin, methylprednisolone, CAP cyclophosphamide, doxorubicin, cisplatin, ICU intensive care unit, NE not evaluable, WHO World Health Organization
To our knowledge, this is the first reported case of chemotherapy continuation despite the need for mechanical ventilation due to a chemotherapy-induced MC. Radical treatment was dependent on primary chemotherapy, as upfront surgery had already been ruled out. Besides, we could not confidently assume that, after MC resolution, the patient would have been able to receive further chemotherapy due to aggravation of symptoms. We conclude that special attention is warranted in patients with thymoma and MG with regard to the development of MC. Ideally, optimal control of myasthenic symptoms should be achieved before initiation of anticancer treatment. Nonetheless, chemotherapy-induced MC may complicate anticancer therapy administration, according to this evidence. We recommend that patients with thymoma and MG be hospitalized in tertiary medical centers for chemotherapy and that outpatient management be avoided. The lesson learned from the present case is that, in selected cases of advanced thymoma, paradoxical worsening of MG during chemotherapy should not be considered an absolute contraindication for continuation of primary chemotherapy with curative intent.
Abbreviations
CAPCisplatin, doxorubicin and cyclophosphamide
CTComputed tomography
CTCAE v5.0Common Terminology Criteria for Adverse Events version 5.0
GyGray
ICUIntensive Care Unit
MCMyasthenic crisis
MGMyasthenia gravis
MGFAMyasthenia Gravis Foundation of America
18PET-FDG18-Fluorodeoxyglucose positron emission tomography
PEXPlasma exchange
RECISTResponse Evaluation Criteria in Solid Tumours
WHOWorld Health Organization
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Fondazione Oncologia Niguarda Onlus for financial support.
Authors' contributions
GP, KB, FT, and SS were major contributors in writing the manuscript. KB, FT, GP, GM, GC, ASB, and SS provided clinical care. MP gave indication to and performed plasma exchange. AR and MT contributed to neoadjuvant treatment indication in a multidisciplinary team discussion and performed surgery. FL, AI, and ECA diagnosed thymoma and myasthenia and medically managed neurological symptoms. ASB and SS supervised oncological care and critically reviewed the case report. All authors read and approved the final manuscript.
Funding
This paper did not receive any specific grants from funding agencies in the public, commercial or not-for-profit sectors.
Ethics approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Availability of data and materials
Not applicable.
Competing interests
The authors declare that they have no competing interests. | 50 MG/M2, CYCLIC (DAY 1 EVERY 21 DAYS) | DrugDosageText | CC BY | 33526108 | 18,898,875 | 2021-02-02 |
What was the dosage of drug 'LEUPROLIDE ACETATE'? | Chemotherapy-induced myasthenic crisis in thymoma treated with primary chemotherapy with curative intent on mechanical ventilation: a case report and review of the literature.
BACKGROUND
Thymoma is an uncommon cancer often associated with myasthenia gravis, an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced nonmetastatic thymoma, primary chemotherapy may be required to induce tumor shrinkage and to achieve radical resection. Cancer chemotherapy has been anecdotally reported as a trigger factor for worsening of myasthenia gravis in thymic epithelial cancers. The study of uncommon cases of chemotherapy-related myasthenic crisis is warranted to gain knowledge of clinical situations requiring intensive care support in the case of life-threatening respiratory failure.
METHODS
We report a case of an 18-year-old Caucasian woman with advanced Masaoka-Koga stage III type B2 thymoma and myasthenia gravis on treatment with pyridostigmine, steroids and intravenous immunoglobulins, who developed a myasthenic crisis 2 hours after initiation of cyclophosphamide/doxorubicin/cisplatin primary chemotherapy. Because of severe acute respiratory failure, emergency tracheal intubation, mechanical ventilation, and temporary (2 hours) discontinuation of chemotherapy were needed. Considering the curative intent of the multimodal therapeutic program, we elected to resume primary chemotherapy administration while the patient remained on mechanical ventilation. After 24 hours, the recovery of adequate respiratory function allowed successful weaning from respiratory support, and no further adverse events occurred. After 3 weeks, upon plasma exchange initiation with amelioration of myasthenic symptoms, a second course of chemotherapy was given, and in week 6, having documented partial tumor remission, the patient underwent radical surgery (R0) and then consolidation radiation therapy with 50.4 Gy in 28 fractions in weeks 15-20.
CONCLUSIONS
This case report, together with the only four available in a review of the literature, highlights that chemotherapy may carry the risk of myasthenic crisis in patients affected by thymoma and myasthenia gravis. To our knowledge, this is the first reported case of chemotherapy continuation on mechanical ventilation in a patient with chemotherapy-induced myasthenic crisis requiring tracheal intubation. The lesson learned from the present case is that, in selected cases of advanced thymoma, the paradoxical worsening of myasthenia gravis during chemotherapy should not be considered an absolute contraindication for the continuation of primary chemotherapy with curative intent.
Background
Thymoma is an uncommon epithelial cancer associated in nearly half of cases with myasthenia gravis (MG), an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced thymoma, primary chemotherapy is considered the standard of care, with the aim of achieving tumor shrinkage and facilitating radical surgery [1]. While several drugs are known to worsen MG, cancer chemotherapy has been anecdotally reported as a trigger event for myasthenic crisis (MC) in four case reports [2–6]. Here, we present a case of advanced thymoma treated with primary chemotherapy that caused an acute-onset MC requiring tracheal intubation and therapeutic plasma exchange (PEX), with relevant benefit from early resumption of anticancer treatment during mechanical ventilation.
Case presentation
Clinical presentation and diagnosis
An 18-year-old Caucasian woman with unremarkable medical history was admitted to the emergency room due to neurological symptoms. She presented with month-long worsening dysphagia, rhinolalia, bilateral ptosis, and skeletal muscle weakness. Signs of muscle fatigability were elicited at the physical exam and then confirmed by electromyography, consistently with neuromuscular junction disease. Blood tests were unremarkable with the exception of acetylcholine receptor antibodies (43 nmol/l, normal if < 0.5 nmol/l). Hence, MG class III, according to the Myasthenia Gravis Foundation of America (MGFA) scale, was diagnosed [7, 8]. Partial regression of symptoms to class II MG was achieved by oral administration of pyridostigmine 60 mg every 3 hours during the daytime, pyridostigmine sustained-release 180 mg orally before sleeping, prednisone 25 mg orally each day, and immunoglobulins 0.4 g/kg intravenously for 5 days [8, 9]. Chest computed tomography (CT) revealed a 12 cm anterior mediastinal mass suspicious for thymoma, with confirmed infiltration of the anterior chest wall, lung parenchyma, and pericardium at chest magnetic resonance imaging with contrast. CT-guided fine needle aspiration biopsy yielded a histological diagnosis of B2 thymoma [10]. Due to the young age, a family history of cancer was excluded. Physical exam was negative for signs of mediastinal syndrome and superficial lymph nodes. Metastatic disease was excluded by 18-fluorodeoxyglucose positron emission tomography (18FDG-PET). Patient imaging is shown in Fig. 1. Accordingly, the clinical stage was cT3 cN0 cM0 (Masaoka-Koga III) [11]. After multidisciplinary team discussion, the tumor was defined as unresectable, and the patient was offered primary chemotherapy with intravenous cyclophosphamide 500 mg/m2, doxorubicin 50 mg/m2 and cisplatin 50 mg/m2 (CAP regimen) on day 1 every 21 days [12]. Primary prophylaxis of chemotherapy-induced neutropenia was not planned due to the potential risk of worsening MG, without evidence about the safety of administering granulocyte colony-stimulating factor in unstable myasthenic patients [13]. Ovarian preservation by gonadotropin-releasing hormone analogue leuprorelin was preferred over oocyte retrieval to expedite the start of chemotherapy [14]. Standard pre-medication with intravenous administration of ondansetron 8 mg, dexamethasone 8 mg and saline was chosen [15].Fig. 1 Patient imaging. a Left chest X-ray with enlarged mediastinum (see arrow). b Chest computed tomography scan showing the mediastinal mass (see arrow). c
18PET-FDG limited radiotracer uptake in mediastinum
Chemotherapy-induced myasthenic crisis
Two hours after starting administration of the first course of chemotherapy, following doxorubicin bolus, the patient experienced sudden onset of acute dyspnea with severe respiratory failure (oxygen saturation 75% on room air), refractory to oxygen therapy and bolus hydrocortisone 500 mg and chlorphenamine 10 mg administered intravenously [16]. Physical exam was negative for bronchospasm with diminished vesicular breath sounds. Due to unstable clinical conditions and development of acute respiratory acidosis (pH 7.21, partial pressure of carbon dioxide 88 mmHg), tracheal intubation and mechanical ventilation in the intensive care unit (ICU) were needed. Urgent chest CT scan excluded acute cardiopulmonary events. Life-threatening MGFA class V MC was diagnosed, likely triggered by chemotherapy, thus classified as grade 4 according to the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) [8, 17]. Chemotherapy was held for 2 hours and then, considering its curative intent and in agreement with the family, it was resumed and fully administered during mechanical ventilation. After 24 hours, upon remission of MC and weaning from ventilation, the patient was extubated and could continue receiving MG treatment, together with starting PEX once every three days to control MG and prevent new crises (by replacing 1 plasma volume with 5% human albumin) [18]. In week 2, owing to CTCAE v5.0 grade 3 febrile neutropenia (absolute neutrophil count 60/mm3 and body temperature 38.4 °C), the patient was successfully treated with empirical piperacillin/tazobactam 4 g/0.5 g intravenously every 6 hours until recovery [19].
Curative treatment and outcome
After completing a second course of CAP chemotherapy with interposed PEX allowing symptom control, radiological assessment in week 6 documented objective partial response according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), with 33% tumor shrinkage (maximum diameter 8 versus 12 cm) [20]. This allowed us to perform radical (R0) extended thymectomy, left upper lung lobectomy and subtotal pericardiectomy, with histological diagnosis of Masaoka-Koga stage III type B2 [10, 11]. For patient histology, please see Fig. 2. The patient required early mediastinum and pleural cavity re-exploration due to postsurgical bleeding; persistent hypophonia developed due to postsurgical left vocal cord paralysis. A comparison of CT imaging at baseline and after surgery is shown in Fig. 3. As suggested for Masaoka-Koga stage III, radiotherapy of 50.4 Gy in 28 fractions was given as postoperative treatment in weeks 15–20 [1]. At the last follow-up visit, 6 months after surgery, the patient was in complete remission with gradually improving MGFA class I MG and mild persistent hypophonia [8]. Despite remarkable levels of psychological burden, the patient’s resilience and high-priority treatment goals were fundamental for successful coping.Fig. 2 Patient histology. a Hematoxylin and eosin (H&E; ×40 view) stained section of thymoma B2 according to WHO classification. b Same histological slice in ×100 view
Fig. 3 Chest computed tomography (CT) scan at baseline and after surgery. a Chest CT scan showing thymoma at baseline. b Postsurgical chest CT scan with no residual disease
Discussion and conclusions
According to the World Health Organization (WHO), thymoma is the most common variant of thymic epithelial tumors (66.3%), usually presenting with local invasion and seldom as metastatic disease [10, 21]. Overall, thymic epithelial tumors occur at a rate of 0.13–0.32 cases per 100,000 population at risk and are very uncommon in young adults [22, 23]. To our knowledge, the largest retrospective study regarding childhood thymic tumors (< 18 years) in Europe was able to identify only 36 cases during a 12-year period, confirming the extreme rarity of thymic cancer in children and adolescents [24]. Hence, the clinical case reported here has to be considered a peculiar presentation of early-onset thymoma (Fig. 4).Fig. 4 Age-specific incidence of thymic cancer by histological type. SEER*Stat Database: NPCR [National Program of Cancer Registries] and SEER [Surveillance, Epidemiology, and End Results] Incidence—U.S. Cancer Statistics Public Use Database, Nov 2017 submission (2001–2015). The green bar highlights the reported patient age interval (15–19 years)
Like thymoma, MG is extremely rare (0.17–2.13 per 100,000 person-years) [25]; however, it affects up to 30% of patients with thymoma [26]. The association of thymoma with MG has been related to the intratumoral generation of mature T cells, although the pathogenic mechanisms remain unclear [27]. MG has been found to be most commonly associated with B thymoma and confers favorable prognosis, since neuromuscular symptoms help in earlier detection of the tumor and thus less advanced stage at diagnosis. Nevertheless, concomitant MG should also be regarded as an adverse risk factor, since it can interfere with cancer treatment, being worsened by many drugs, and it reaches its maximum severity after thymectomy in a proportion of patients [28].
The case reported here, together with those published and summarized in Table 1 [3–6], highlights that chemotherapy is a realistic trigger event of MC in patients with thymoma and MG. The temporary association in all cases indicates a causative relation, and may hamper the continuation of chemotherapy that is a crucial element of multimodal treatment in cases not amenable to upfront radical surgery [1]. No biomarker is available to prove this relation, and clinical findings are crucial for the diagnosis of MC. Other differential diagnoses, such as infusion reaction to cancer chemotherapy, are less likely in the setting of prolonged respiratory failure. Here, a multidisciplinary approach was necessary, and involved neurologists for medical treatment and hematologists for a correct timing schedule of PEX sessions in order to avoid plasma drug displacement. It should be noted that we waited 72 hours from the end of chemotherapy before starting PEX, in order to preserve drug efficacy according to their half-life.Table 1. Comparison between present case and 4 other published cases
Fujiwara et al. [3] Qureshi et al. [4] Solak et al. [5] Ng et al. (6) Present case report
Sex Female Male Male Male Female
Age (year) 44 24 45 49 18
Histology B1 Thymoma (WHO) Thymoma Thymoma NE B2 thymoma (WHO)
Staging IVA (Masaoka-Koga) III (Masaoka-Koga) Advanced unresectable Advanced unresectable III (Masaoka-Koga)
AchR Ab level (nmol/l) 13 NE 74 NE 43
Chemotherapy regimen Primary CAMP Postoperative cisplatin and doxorubicin Single-agent cisplatin Doxorubicin, cisplatin, etoposide Primary CAP
Myasthenic crisis onset time During chemotherapy 8 hours after chemotherapy 1 week after chemotherapy A few hours after chemotherapy During chemotherapy
Tracheal intubation No Yes Yes Yes Yes
Plasma exchange No Yes Yes Yes Yes
Chemotherapy continuation in ICU No No No No Yes
Patient outcome after myasthenic crisis Alive Death Alive Alive Alive
AchR Ab acetylcholine receptor antibodies, CAMP cisplatin, doxorubicin, methylprednisolone, CAP cyclophosphamide, doxorubicin, cisplatin, ICU intensive care unit, NE not evaluable, WHO World Health Organization
To our knowledge, this is the first reported case of chemotherapy continuation despite the need for mechanical ventilation due to a chemotherapy-induced MC. Radical treatment was dependent on primary chemotherapy, as upfront surgery had already been ruled out. Besides, we could not confidently assume that, after MC resolution, the patient would have been able to receive further chemotherapy due to aggravation of symptoms. We conclude that special attention is warranted in patients with thymoma and MG with regard to the development of MC. Ideally, optimal control of myasthenic symptoms should be achieved before initiation of anticancer treatment. Nonetheless, chemotherapy-induced MC may complicate anticancer therapy administration, according to this evidence. We recommend that patients with thymoma and MG be hospitalized in tertiary medical centers for chemotherapy and that outpatient management be avoided. The lesson learned from the present case is that, in selected cases of advanced thymoma, paradoxical worsening of MG during chemotherapy should not be considered an absolute contraindication for continuation of primary chemotherapy with curative intent.
Abbreviations
CAPCisplatin, doxorubicin and cyclophosphamide
CTComputed tomography
CTCAE v5.0Common Terminology Criteria for Adverse Events version 5.0
GyGray
ICUIntensive Care Unit
MCMyasthenic crisis
MGMyasthenia gravis
MGFAMyasthenia Gravis Foundation of America
18PET-FDG18-Fluorodeoxyglucose positron emission tomography
PEXPlasma exchange
RECISTResponse Evaluation Criteria in Solid Tumours
WHOWorld Health Organization
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Fondazione Oncologia Niguarda Onlus for financial support.
Authors' contributions
GP, KB, FT, and SS were major contributors in writing the manuscript. KB, FT, GP, GM, GC, ASB, and SS provided clinical care. MP gave indication to and performed plasma exchange. AR and MT contributed to neoadjuvant treatment indication in a multidisciplinary team discussion and performed surgery. FL, AI, and ECA diagnosed thymoma and myasthenia and medically managed neurological symptoms. ASB and SS supervised oncological care and critically reviewed the case report. All authors read and approved the final manuscript.
Funding
This paper did not receive any specific grants from funding agencies in the public, commercial or not-for-profit sectors.
Ethics approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Availability of data and materials
Not applicable.
Competing interests
The authors declare that they have no competing interests. | UNKNOWN | DrugDosageText | CC BY | 33526108 | 18,959,226 | 2021-02-02 |
What was the dosage of drug 'OXYGEN'? | Chemotherapy-induced myasthenic crisis in thymoma treated with primary chemotherapy with curative intent on mechanical ventilation: a case report and review of the literature.
BACKGROUND
Thymoma is an uncommon cancer often associated with myasthenia gravis, an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced nonmetastatic thymoma, primary chemotherapy may be required to induce tumor shrinkage and to achieve radical resection. Cancer chemotherapy has been anecdotally reported as a trigger factor for worsening of myasthenia gravis in thymic epithelial cancers. The study of uncommon cases of chemotherapy-related myasthenic crisis is warranted to gain knowledge of clinical situations requiring intensive care support in the case of life-threatening respiratory failure.
METHODS
We report a case of an 18-year-old Caucasian woman with advanced Masaoka-Koga stage III type B2 thymoma and myasthenia gravis on treatment with pyridostigmine, steroids and intravenous immunoglobulins, who developed a myasthenic crisis 2 hours after initiation of cyclophosphamide/doxorubicin/cisplatin primary chemotherapy. Because of severe acute respiratory failure, emergency tracheal intubation, mechanical ventilation, and temporary (2 hours) discontinuation of chemotherapy were needed. Considering the curative intent of the multimodal therapeutic program, we elected to resume primary chemotherapy administration while the patient remained on mechanical ventilation. After 24 hours, the recovery of adequate respiratory function allowed successful weaning from respiratory support, and no further adverse events occurred. After 3 weeks, upon plasma exchange initiation with amelioration of myasthenic symptoms, a second course of chemotherapy was given, and in week 6, having documented partial tumor remission, the patient underwent radical surgery (R0) and then consolidation radiation therapy with 50.4 Gy in 28 fractions in weeks 15-20.
CONCLUSIONS
This case report, together with the only four available in a review of the literature, highlights that chemotherapy may carry the risk of myasthenic crisis in patients affected by thymoma and myasthenia gravis. To our knowledge, this is the first reported case of chemotherapy continuation on mechanical ventilation in a patient with chemotherapy-induced myasthenic crisis requiring tracheal intubation. The lesson learned from the present case is that, in selected cases of advanced thymoma, the paradoxical worsening of myasthenia gravis during chemotherapy should not be considered an absolute contraindication for the continuation of primary chemotherapy with curative intent.
Background
Thymoma is an uncommon epithelial cancer associated in nearly half of cases with myasthenia gravis (MG), an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced thymoma, primary chemotherapy is considered the standard of care, with the aim of achieving tumor shrinkage and facilitating radical surgery [1]. While several drugs are known to worsen MG, cancer chemotherapy has been anecdotally reported as a trigger event for myasthenic crisis (MC) in four case reports [2–6]. Here, we present a case of advanced thymoma treated with primary chemotherapy that caused an acute-onset MC requiring tracheal intubation and therapeutic plasma exchange (PEX), with relevant benefit from early resumption of anticancer treatment during mechanical ventilation.
Case presentation
Clinical presentation and diagnosis
An 18-year-old Caucasian woman with unremarkable medical history was admitted to the emergency room due to neurological symptoms. She presented with month-long worsening dysphagia, rhinolalia, bilateral ptosis, and skeletal muscle weakness. Signs of muscle fatigability were elicited at the physical exam and then confirmed by electromyography, consistently with neuromuscular junction disease. Blood tests were unremarkable with the exception of acetylcholine receptor antibodies (43 nmol/l, normal if < 0.5 nmol/l). Hence, MG class III, according to the Myasthenia Gravis Foundation of America (MGFA) scale, was diagnosed [7, 8]. Partial regression of symptoms to class II MG was achieved by oral administration of pyridostigmine 60 mg every 3 hours during the daytime, pyridostigmine sustained-release 180 mg orally before sleeping, prednisone 25 mg orally each day, and immunoglobulins 0.4 g/kg intravenously for 5 days [8, 9]. Chest computed tomography (CT) revealed a 12 cm anterior mediastinal mass suspicious for thymoma, with confirmed infiltration of the anterior chest wall, lung parenchyma, and pericardium at chest magnetic resonance imaging with contrast. CT-guided fine needle aspiration biopsy yielded a histological diagnosis of B2 thymoma [10]. Due to the young age, a family history of cancer was excluded. Physical exam was negative for signs of mediastinal syndrome and superficial lymph nodes. Metastatic disease was excluded by 18-fluorodeoxyglucose positron emission tomography (18FDG-PET). Patient imaging is shown in Fig. 1. Accordingly, the clinical stage was cT3 cN0 cM0 (Masaoka-Koga III) [11]. After multidisciplinary team discussion, the tumor was defined as unresectable, and the patient was offered primary chemotherapy with intravenous cyclophosphamide 500 mg/m2, doxorubicin 50 mg/m2 and cisplatin 50 mg/m2 (CAP regimen) on day 1 every 21 days [12]. Primary prophylaxis of chemotherapy-induced neutropenia was not planned due to the potential risk of worsening MG, without evidence about the safety of administering granulocyte colony-stimulating factor in unstable myasthenic patients [13]. Ovarian preservation by gonadotropin-releasing hormone analogue leuprorelin was preferred over oocyte retrieval to expedite the start of chemotherapy [14]. Standard pre-medication with intravenous administration of ondansetron 8 mg, dexamethasone 8 mg and saline was chosen [15].Fig. 1 Patient imaging. a Left chest X-ray with enlarged mediastinum (see arrow). b Chest computed tomography scan showing the mediastinal mass (see arrow). c
18PET-FDG limited radiotracer uptake in mediastinum
Chemotherapy-induced myasthenic crisis
Two hours after starting administration of the first course of chemotherapy, following doxorubicin bolus, the patient experienced sudden onset of acute dyspnea with severe respiratory failure (oxygen saturation 75% on room air), refractory to oxygen therapy and bolus hydrocortisone 500 mg and chlorphenamine 10 mg administered intravenously [16]. Physical exam was negative for bronchospasm with diminished vesicular breath sounds. Due to unstable clinical conditions and development of acute respiratory acidosis (pH 7.21, partial pressure of carbon dioxide 88 mmHg), tracheal intubation and mechanical ventilation in the intensive care unit (ICU) were needed. Urgent chest CT scan excluded acute cardiopulmonary events. Life-threatening MGFA class V MC was diagnosed, likely triggered by chemotherapy, thus classified as grade 4 according to the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) [8, 17]. Chemotherapy was held for 2 hours and then, considering its curative intent and in agreement with the family, it was resumed and fully administered during mechanical ventilation. After 24 hours, upon remission of MC and weaning from ventilation, the patient was extubated and could continue receiving MG treatment, together with starting PEX once every three days to control MG and prevent new crises (by replacing 1 plasma volume with 5% human albumin) [18]. In week 2, owing to CTCAE v5.0 grade 3 febrile neutropenia (absolute neutrophil count 60/mm3 and body temperature 38.4 °C), the patient was successfully treated with empirical piperacillin/tazobactam 4 g/0.5 g intravenously every 6 hours until recovery [19].
Curative treatment and outcome
After completing a second course of CAP chemotherapy with interposed PEX allowing symptom control, radiological assessment in week 6 documented objective partial response according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), with 33% tumor shrinkage (maximum diameter 8 versus 12 cm) [20]. This allowed us to perform radical (R0) extended thymectomy, left upper lung lobectomy and subtotal pericardiectomy, with histological diagnosis of Masaoka-Koga stage III type B2 [10, 11]. For patient histology, please see Fig. 2. The patient required early mediastinum and pleural cavity re-exploration due to postsurgical bleeding; persistent hypophonia developed due to postsurgical left vocal cord paralysis. A comparison of CT imaging at baseline and after surgery is shown in Fig. 3. As suggested for Masaoka-Koga stage III, radiotherapy of 50.4 Gy in 28 fractions was given as postoperative treatment in weeks 15–20 [1]. At the last follow-up visit, 6 months after surgery, the patient was in complete remission with gradually improving MGFA class I MG and mild persistent hypophonia [8]. Despite remarkable levels of psychological burden, the patient’s resilience and high-priority treatment goals were fundamental for successful coping.Fig. 2 Patient histology. a Hematoxylin and eosin (H&E; ×40 view) stained section of thymoma B2 according to WHO classification. b Same histological slice in ×100 view
Fig. 3 Chest computed tomography (CT) scan at baseline and after surgery. a Chest CT scan showing thymoma at baseline. b Postsurgical chest CT scan with no residual disease
Discussion and conclusions
According to the World Health Organization (WHO), thymoma is the most common variant of thymic epithelial tumors (66.3%), usually presenting with local invasion and seldom as metastatic disease [10, 21]. Overall, thymic epithelial tumors occur at a rate of 0.13–0.32 cases per 100,000 population at risk and are very uncommon in young adults [22, 23]. To our knowledge, the largest retrospective study regarding childhood thymic tumors (< 18 years) in Europe was able to identify only 36 cases during a 12-year period, confirming the extreme rarity of thymic cancer in children and adolescents [24]. Hence, the clinical case reported here has to be considered a peculiar presentation of early-onset thymoma (Fig. 4).Fig. 4 Age-specific incidence of thymic cancer by histological type. SEER*Stat Database: NPCR [National Program of Cancer Registries] and SEER [Surveillance, Epidemiology, and End Results] Incidence—U.S. Cancer Statistics Public Use Database, Nov 2017 submission (2001–2015). The green bar highlights the reported patient age interval (15–19 years)
Like thymoma, MG is extremely rare (0.17–2.13 per 100,000 person-years) [25]; however, it affects up to 30% of patients with thymoma [26]. The association of thymoma with MG has been related to the intratumoral generation of mature T cells, although the pathogenic mechanisms remain unclear [27]. MG has been found to be most commonly associated with B thymoma and confers favorable prognosis, since neuromuscular symptoms help in earlier detection of the tumor and thus less advanced stage at diagnosis. Nevertheless, concomitant MG should also be regarded as an adverse risk factor, since it can interfere with cancer treatment, being worsened by many drugs, and it reaches its maximum severity after thymectomy in a proportion of patients [28].
The case reported here, together with those published and summarized in Table 1 [3–6], highlights that chemotherapy is a realistic trigger event of MC in patients with thymoma and MG. The temporary association in all cases indicates a causative relation, and may hamper the continuation of chemotherapy that is a crucial element of multimodal treatment in cases not amenable to upfront radical surgery [1]. No biomarker is available to prove this relation, and clinical findings are crucial for the diagnosis of MC. Other differential diagnoses, such as infusion reaction to cancer chemotherapy, are less likely in the setting of prolonged respiratory failure. Here, a multidisciplinary approach was necessary, and involved neurologists for medical treatment and hematologists for a correct timing schedule of PEX sessions in order to avoid plasma drug displacement. It should be noted that we waited 72 hours from the end of chemotherapy before starting PEX, in order to preserve drug efficacy according to their half-life.Table 1. Comparison between present case and 4 other published cases
Fujiwara et al. [3] Qureshi et al. [4] Solak et al. [5] Ng et al. (6) Present case report
Sex Female Male Male Male Female
Age (year) 44 24 45 49 18
Histology B1 Thymoma (WHO) Thymoma Thymoma NE B2 thymoma (WHO)
Staging IVA (Masaoka-Koga) III (Masaoka-Koga) Advanced unresectable Advanced unresectable III (Masaoka-Koga)
AchR Ab level (nmol/l) 13 NE 74 NE 43
Chemotherapy regimen Primary CAMP Postoperative cisplatin and doxorubicin Single-agent cisplatin Doxorubicin, cisplatin, etoposide Primary CAP
Myasthenic crisis onset time During chemotherapy 8 hours after chemotherapy 1 week after chemotherapy A few hours after chemotherapy During chemotherapy
Tracheal intubation No Yes Yes Yes Yes
Plasma exchange No Yes Yes Yes Yes
Chemotherapy continuation in ICU No No No No Yes
Patient outcome after myasthenic crisis Alive Death Alive Alive Alive
AchR Ab acetylcholine receptor antibodies, CAMP cisplatin, doxorubicin, methylprednisolone, CAP cyclophosphamide, doxorubicin, cisplatin, ICU intensive care unit, NE not evaluable, WHO World Health Organization
To our knowledge, this is the first reported case of chemotherapy continuation despite the need for mechanical ventilation due to a chemotherapy-induced MC. Radical treatment was dependent on primary chemotherapy, as upfront surgery had already been ruled out. Besides, we could not confidently assume that, after MC resolution, the patient would have been able to receive further chemotherapy due to aggravation of symptoms. We conclude that special attention is warranted in patients with thymoma and MG with regard to the development of MC. Ideally, optimal control of myasthenic symptoms should be achieved before initiation of anticancer treatment. Nonetheless, chemotherapy-induced MC may complicate anticancer therapy administration, according to this evidence. We recommend that patients with thymoma and MG be hospitalized in tertiary medical centers for chemotherapy and that outpatient management be avoided. The lesson learned from the present case is that, in selected cases of advanced thymoma, paradoxical worsening of MG during chemotherapy should not be considered an absolute contraindication for continuation of primary chemotherapy with curative intent.
Abbreviations
CAPCisplatin, doxorubicin and cyclophosphamide
CTComputed tomography
CTCAE v5.0Common Terminology Criteria for Adverse Events version 5.0
GyGray
ICUIntensive Care Unit
MCMyasthenic crisis
MGMyasthenia gravis
MGFAMyasthenia Gravis Foundation of America
18PET-FDG18-Fluorodeoxyglucose positron emission tomography
PEXPlasma exchange
RECISTResponse Evaluation Criteria in Solid Tumours
WHOWorld Health Organization
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Fondazione Oncologia Niguarda Onlus for financial support.
Authors' contributions
GP, KB, FT, and SS were major contributors in writing the manuscript. KB, FT, GP, GM, GC, ASB, and SS provided clinical care. MP gave indication to and performed plasma exchange. AR and MT contributed to neoadjuvant treatment indication in a multidisciplinary team discussion and performed surgery. FL, AI, and ECA diagnosed thymoma and myasthenia and medically managed neurological symptoms. ASB and SS supervised oncological care and critically reviewed the case report. All authors read and approved the final manuscript.
Funding
This paper did not receive any specific grants from funding agencies in the public, commercial or not-for-profit sectors.
Ethics approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Availability of data and materials
Not applicable.
Competing interests
The authors declare that they have no competing interests. | UNKNOWN | DrugDosageText | CC BY | 33526108 | 18,959,232 | 2021-02-02 |
What was the dosage of drug 'SODIUM CHLORIDE'? | Chemotherapy-induced myasthenic crisis in thymoma treated with primary chemotherapy with curative intent on mechanical ventilation: a case report and review of the literature.
BACKGROUND
Thymoma is an uncommon cancer often associated with myasthenia gravis, an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced nonmetastatic thymoma, primary chemotherapy may be required to induce tumor shrinkage and to achieve radical resection. Cancer chemotherapy has been anecdotally reported as a trigger factor for worsening of myasthenia gravis in thymic epithelial cancers. The study of uncommon cases of chemotherapy-related myasthenic crisis is warranted to gain knowledge of clinical situations requiring intensive care support in the case of life-threatening respiratory failure.
METHODS
We report a case of an 18-year-old Caucasian woman with advanced Masaoka-Koga stage III type B2 thymoma and myasthenia gravis on treatment with pyridostigmine, steroids and intravenous immunoglobulins, who developed a myasthenic crisis 2 hours after initiation of cyclophosphamide/doxorubicin/cisplatin primary chemotherapy. Because of severe acute respiratory failure, emergency tracheal intubation, mechanical ventilation, and temporary (2 hours) discontinuation of chemotherapy were needed. Considering the curative intent of the multimodal therapeutic program, we elected to resume primary chemotherapy administration while the patient remained on mechanical ventilation. After 24 hours, the recovery of adequate respiratory function allowed successful weaning from respiratory support, and no further adverse events occurred. After 3 weeks, upon plasma exchange initiation with amelioration of myasthenic symptoms, a second course of chemotherapy was given, and in week 6, having documented partial tumor remission, the patient underwent radical surgery (R0) and then consolidation radiation therapy with 50.4 Gy in 28 fractions in weeks 15-20.
CONCLUSIONS
This case report, together with the only four available in a review of the literature, highlights that chemotherapy may carry the risk of myasthenic crisis in patients affected by thymoma and myasthenia gravis. To our knowledge, this is the first reported case of chemotherapy continuation on mechanical ventilation in a patient with chemotherapy-induced myasthenic crisis requiring tracheal intubation. The lesson learned from the present case is that, in selected cases of advanced thymoma, the paradoxical worsening of myasthenia gravis during chemotherapy should not be considered an absolute contraindication for the continuation of primary chemotherapy with curative intent.
Background
Thymoma is an uncommon epithelial cancer associated in nearly half of cases with myasthenia gravis (MG), an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced thymoma, primary chemotherapy is considered the standard of care, with the aim of achieving tumor shrinkage and facilitating radical surgery [1]. While several drugs are known to worsen MG, cancer chemotherapy has been anecdotally reported as a trigger event for myasthenic crisis (MC) in four case reports [2–6]. Here, we present a case of advanced thymoma treated with primary chemotherapy that caused an acute-onset MC requiring tracheal intubation and therapeutic plasma exchange (PEX), with relevant benefit from early resumption of anticancer treatment during mechanical ventilation.
Case presentation
Clinical presentation and diagnosis
An 18-year-old Caucasian woman with unremarkable medical history was admitted to the emergency room due to neurological symptoms. She presented with month-long worsening dysphagia, rhinolalia, bilateral ptosis, and skeletal muscle weakness. Signs of muscle fatigability were elicited at the physical exam and then confirmed by electromyography, consistently with neuromuscular junction disease. Blood tests were unremarkable with the exception of acetylcholine receptor antibodies (43 nmol/l, normal if < 0.5 nmol/l). Hence, MG class III, according to the Myasthenia Gravis Foundation of America (MGFA) scale, was diagnosed [7, 8]. Partial regression of symptoms to class II MG was achieved by oral administration of pyridostigmine 60 mg every 3 hours during the daytime, pyridostigmine sustained-release 180 mg orally before sleeping, prednisone 25 mg orally each day, and immunoglobulins 0.4 g/kg intravenously for 5 days [8, 9]. Chest computed tomography (CT) revealed a 12 cm anterior mediastinal mass suspicious for thymoma, with confirmed infiltration of the anterior chest wall, lung parenchyma, and pericardium at chest magnetic resonance imaging with contrast. CT-guided fine needle aspiration biopsy yielded a histological diagnosis of B2 thymoma [10]. Due to the young age, a family history of cancer was excluded. Physical exam was negative for signs of mediastinal syndrome and superficial lymph nodes. Metastatic disease was excluded by 18-fluorodeoxyglucose positron emission tomography (18FDG-PET). Patient imaging is shown in Fig. 1. Accordingly, the clinical stage was cT3 cN0 cM0 (Masaoka-Koga III) [11]. After multidisciplinary team discussion, the tumor was defined as unresectable, and the patient was offered primary chemotherapy with intravenous cyclophosphamide 500 mg/m2, doxorubicin 50 mg/m2 and cisplatin 50 mg/m2 (CAP regimen) on day 1 every 21 days [12]. Primary prophylaxis of chemotherapy-induced neutropenia was not planned due to the potential risk of worsening MG, without evidence about the safety of administering granulocyte colony-stimulating factor in unstable myasthenic patients [13]. Ovarian preservation by gonadotropin-releasing hormone analogue leuprorelin was preferred over oocyte retrieval to expedite the start of chemotherapy [14]. Standard pre-medication with intravenous administration of ondansetron 8 mg, dexamethasone 8 mg and saline was chosen [15].Fig. 1 Patient imaging. a Left chest X-ray with enlarged mediastinum (see arrow). b Chest computed tomography scan showing the mediastinal mass (see arrow). c
18PET-FDG limited radiotracer uptake in mediastinum
Chemotherapy-induced myasthenic crisis
Two hours after starting administration of the first course of chemotherapy, following doxorubicin bolus, the patient experienced sudden onset of acute dyspnea with severe respiratory failure (oxygen saturation 75% on room air), refractory to oxygen therapy and bolus hydrocortisone 500 mg and chlorphenamine 10 mg administered intravenously [16]. Physical exam was negative for bronchospasm with diminished vesicular breath sounds. Due to unstable clinical conditions and development of acute respiratory acidosis (pH 7.21, partial pressure of carbon dioxide 88 mmHg), tracheal intubation and mechanical ventilation in the intensive care unit (ICU) were needed. Urgent chest CT scan excluded acute cardiopulmonary events. Life-threatening MGFA class V MC was diagnosed, likely triggered by chemotherapy, thus classified as grade 4 according to the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) [8, 17]. Chemotherapy was held for 2 hours and then, considering its curative intent and in agreement with the family, it was resumed and fully administered during mechanical ventilation. After 24 hours, upon remission of MC and weaning from ventilation, the patient was extubated and could continue receiving MG treatment, together with starting PEX once every three days to control MG and prevent new crises (by replacing 1 plasma volume with 5% human albumin) [18]. In week 2, owing to CTCAE v5.0 grade 3 febrile neutropenia (absolute neutrophil count 60/mm3 and body temperature 38.4 °C), the patient was successfully treated with empirical piperacillin/tazobactam 4 g/0.5 g intravenously every 6 hours until recovery [19].
Curative treatment and outcome
After completing a second course of CAP chemotherapy with interposed PEX allowing symptom control, radiological assessment in week 6 documented objective partial response according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), with 33% tumor shrinkage (maximum diameter 8 versus 12 cm) [20]. This allowed us to perform radical (R0) extended thymectomy, left upper lung lobectomy and subtotal pericardiectomy, with histological diagnosis of Masaoka-Koga stage III type B2 [10, 11]. For patient histology, please see Fig. 2. The patient required early mediastinum and pleural cavity re-exploration due to postsurgical bleeding; persistent hypophonia developed due to postsurgical left vocal cord paralysis. A comparison of CT imaging at baseline and after surgery is shown in Fig. 3. As suggested for Masaoka-Koga stage III, radiotherapy of 50.4 Gy in 28 fractions was given as postoperative treatment in weeks 15–20 [1]. At the last follow-up visit, 6 months after surgery, the patient was in complete remission with gradually improving MGFA class I MG and mild persistent hypophonia [8]. Despite remarkable levels of psychological burden, the patient’s resilience and high-priority treatment goals were fundamental for successful coping.Fig. 2 Patient histology. a Hematoxylin and eosin (H&E; ×40 view) stained section of thymoma B2 according to WHO classification. b Same histological slice in ×100 view
Fig. 3 Chest computed tomography (CT) scan at baseline and after surgery. a Chest CT scan showing thymoma at baseline. b Postsurgical chest CT scan with no residual disease
Discussion and conclusions
According to the World Health Organization (WHO), thymoma is the most common variant of thymic epithelial tumors (66.3%), usually presenting with local invasion and seldom as metastatic disease [10, 21]. Overall, thymic epithelial tumors occur at a rate of 0.13–0.32 cases per 100,000 population at risk and are very uncommon in young adults [22, 23]. To our knowledge, the largest retrospective study regarding childhood thymic tumors (< 18 years) in Europe was able to identify only 36 cases during a 12-year period, confirming the extreme rarity of thymic cancer in children and adolescents [24]. Hence, the clinical case reported here has to be considered a peculiar presentation of early-onset thymoma (Fig. 4).Fig. 4 Age-specific incidence of thymic cancer by histological type. SEER*Stat Database: NPCR [National Program of Cancer Registries] and SEER [Surveillance, Epidemiology, and End Results] Incidence—U.S. Cancer Statistics Public Use Database, Nov 2017 submission (2001–2015). The green bar highlights the reported patient age interval (15–19 years)
Like thymoma, MG is extremely rare (0.17–2.13 per 100,000 person-years) [25]; however, it affects up to 30% of patients with thymoma [26]. The association of thymoma with MG has been related to the intratumoral generation of mature T cells, although the pathogenic mechanisms remain unclear [27]. MG has been found to be most commonly associated with B thymoma and confers favorable prognosis, since neuromuscular symptoms help in earlier detection of the tumor and thus less advanced stage at diagnosis. Nevertheless, concomitant MG should also be regarded as an adverse risk factor, since it can interfere with cancer treatment, being worsened by many drugs, and it reaches its maximum severity after thymectomy in a proportion of patients [28].
The case reported here, together with those published and summarized in Table 1 [3–6], highlights that chemotherapy is a realistic trigger event of MC in patients with thymoma and MG. The temporary association in all cases indicates a causative relation, and may hamper the continuation of chemotherapy that is a crucial element of multimodal treatment in cases not amenable to upfront radical surgery [1]. No biomarker is available to prove this relation, and clinical findings are crucial for the diagnosis of MC. Other differential diagnoses, such as infusion reaction to cancer chemotherapy, are less likely in the setting of prolonged respiratory failure. Here, a multidisciplinary approach was necessary, and involved neurologists for medical treatment and hematologists for a correct timing schedule of PEX sessions in order to avoid plasma drug displacement. It should be noted that we waited 72 hours from the end of chemotherapy before starting PEX, in order to preserve drug efficacy according to their half-life.Table 1. Comparison between present case and 4 other published cases
Fujiwara et al. [3] Qureshi et al. [4] Solak et al. [5] Ng et al. (6) Present case report
Sex Female Male Male Male Female
Age (year) 44 24 45 49 18
Histology B1 Thymoma (WHO) Thymoma Thymoma NE B2 thymoma (WHO)
Staging IVA (Masaoka-Koga) III (Masaoka-Koga) Advanced unresectable Advanced unresectable III (Masaoka-Koga)
AchR Ab level (nmol/l) 13 NE 74 NE 43
Chemotherapy regimen Primary CAMP Postoperative cisplatin and doxorubicin Single-agent cisplatin Doxorubicin, cisplatin, etoposide Primary CAP
Myasthenic crisis onset time During chemotherapy 8 hours after chemotherapy 1 week after chemotherapy A few hours after chemotherapy During chemotherapy
Tracheal intubation No Yes Yes Yes Yes
Plasma exchange No Yes Yes Yes Yes
Chemotherapy continuation in ICU No No No No Yes
Patient outcome after myasthenic crisis Alive Death Alive Alive Alive
AchR Ab acetylcholine receptor antibodies, CAMP cisplatin, doxorubicin, methylprednisolone, CAP cyclophosphamide, doxorubicin, cisplatin, ICU intensive care unit, NE not evaluable, WHO World Health Organization
To our knowledge, this is the first reported case of chemotherapy continuation despite the need for mechanical ventilation due to a chemotherapy-induced MC. Radical treatment was dependent on primary chemotherapy, as upfront surgery had already been ruled out. Besides, we could not confidently assume that, after MC resolution, the patient would have been able to receive further chemotherapy due to aggravation of symptoms. We conclude that special attention is warranted in patients with thymoma and MG with regard to the development of MC. Ideally, optimal control of myasthenic symptoms should be achieved before initiation of anticancer treatment. Nonetheless, chemotherapy-induced MC may complicate anticancer therapy administration, according to this evidence. We recommend that patients with thymoma and MG be hospitalized in tertiary medical centers for chemotherapy and that outpatient management be avoided. The lesson learned from the present case is that, in selected cases of advanced thymoma, paradoxical worsening of MG during chemotherapy should not be considered an absolute contraindication for continuation of primary chemotherapy with curative intent.
Abbreviations
CAPCisplatin, doxorubicin and cyclophosphamide
CTComputed tomography
CTCAE v5.0Common Terminology Criteria for Adverse Events version 5.0
GyGray
ICUIntensive Care Unit
MCMyasthenic crisis
MGMyasthenia gravis
MGFAMyasthenia Gravis Foundation of America
18PET-FDG18-Fluorodeoxyglucose positron emission tomography
PEXPlasma exchange
RECISTResponse Evaluation Criteria in Solid Tumours
WHOWorld Health Organization
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Fondazione Oncologia Niguarda Onlus for financial support.
Authors' contributions
GP, KB, FT, and SS were major contributors in writing the manuscript. KB, FT, GP, GM, GC, ASB, and SS provided clinical care. MP gave indication to and performed plasma exchange. AR and MT contributed to neoadjuvant treatment indication in a multidisciplinary team discussion and performed surgery. FL, AI, and ECA diagnosed thymoma and myasthenia and medically managed neurological symptoms. ASB and SS supervised oncological care and critically reviewed the case report. All authors read and approved the final manuscript.
Funding
This paper did not receive any specific grants from funding agencies in the public, commercial or not-for-profit sectors.
Ethics approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Availability of data and materials
Not applicable.
Competing interests
The authors declare that they have no competing interests. | UNKNOWN | DrugDosageText | CC BY | 33526108 | 18,959,226 | 2021-02-02 |
What was the outcome of reaction 'Acute respiratory failure'? | Chemotherapy-induced myasthenic crisis in thymoma treated with primary chemotherapy with curative intent on mechanical ventilation: a case report and review of the literature.
BACKGROUND
Thymoma is an uncommon cancer often associated with myasthenia gravis, an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced nonmetastatic thymoma, primary chemotherapy may be required to induce tumor shrinkage and to achieve radical resection. Cancer chemotherapy has been anecdotally reported as a trigger factor for worsening of myasthenia gravis in thymic epithelial cancers. The study of uncommon cases of chemotherapy-related myasthenic crisis is warranted to gain knowledge of clinical situations requiring intensive care support in the case of life-threatening respiratory failure.
METHODS
We report a case of an 18-year-old Caucasian woman with advanced Masaoka-Koga stage III type B2 thymoma and myasthenia gravis on treatment with pyridostigmine, steroids and intravenous immunoglobulins, who developed a myasthenic crisis 2 hours after initiation of cyclophosphamide/doxorubicin/cisplatin primary chemotherapy. Because of severe acute respiratory failure, emergency tracheal intubation, mechanical ventilation, and temporary (2 hours) discontinuation of chemotherapy were needed. Considering the curative intent of the multimodal therapeutic program, we elected to resume primary chemotherapy administration while the patient remained on mechanical ventilation. After 24 hours, the recovery of adequate respiratory function allowed successful weaning from respiratory support, and no further adverse events occurred. After 3 weeks, upon plasma exchange initiation with amelioration of myasthenic symptoms, a second course of chemotherapy was given, and in week 6, having documented partial tumor remission, the patient underwent radical surgery (R0) and then consolidation radiation therapy with 50.4 Gy in 28 fractions in weeks 15-20.
CONCLUSIONS
This case report, together with the only four available in a review of the literature, highlights that chemotherapy may carry the risk of myasthenic crisis in patients affected by thymoma and myasthenia gravis. To our knowledge, this is the first reported case of chemotherapy continuation on mechanical ventilation in a patient with chemotherapy-induced myasthenic crisis requiring tracheal intubation. The lesson learned from the present case is that, in selected cases of advanced thymoma, the paradoxical worsening of myasthenia gravis during chemotherapy should not be considered an absolute contraindication for the continuation of primary chemotherapy with curative intent.
Background
Thymoma is an uncommon epithelial cancer associated in nearly half of cases with myasthenia gravis (MG), an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced thymoma, primary chemotherapy is considered the standard of care, with the aim of achieving tumor shrinkage and facilitating radical surgery [1]. While several drugs are known to worsen MG, cancer chemotherapy has been anecdotally reported as a trigger event for myasthenic crisis (MC) in four case reports [2–6]. Here, we present a case of advanced thymoma treated with primary chemotherapy that caused an acute-onset MC requiring tracheal intubation and therapeutic plasma exchange (PEX), with relevant benefit from early resumption of anticancer treatment during mechanical ventilation.
Case presentation
Clinical presentation and diagnosis
An 18-year-old Caucasian woman with unremarkable medical history was admitted to the emergency room due to neurological symptoms. She presented with month-long worsening dysphagia, rhinolalia, bilateral ptosis, and skeletal muscle weakness. Signs of muscle fatigability were elicited at the physical exam and then confirmed by electromyography, consistently with neuromuscular junction disease. Blood tests were unremarkable with the exception of acetylcholine receptor antibodies (43 nmol/l, normal if < 0.5 nmol/l). Hence, MG class III, according to the Myasthenia Gravis Foundation of America (MGFA) scale, was diagnosed [7, 8]. Partial regression of symptoms to class II MG was achieved by oral administration of pyridostigmine 60 mg every 3 hours during the daytime, pyridostigmine sustained-release 180 mg orally before sleeping, prednisone 25 mg orally each day, and immunoglobulins 0.4 g/kg intravenously for 5 days [8, 9]. Chest computed tomography (CT) revealed a 12 cm anterior mediastinal mass suspicious for thymoma, with confirmed infiltration of the anterior chest wall, lung parenchyma, and pericardium at chest magnetic resonance imaging with contrast. CT-guided fine needle aspiration biopsy yielded a histological diagnosis of B2 thymoma [10]. Due to the young age, a family history of cancer was excluded. Physical exam was negative for signs of mediastinal syndrome and superficial lymph nodes. Metastatic disease was excluded by 18-fluorodeoxyglucose positron emission tomography (18FDG-PET). Patient imaging is shown in Fig. 1. Accordingly, the clinical stage was cT3 cN0 cM0 (Masaoka-Koga III) [11]. After multidisciplinary team discussion, the tumor was defined as unresectable, and the patient was offered primary chemotherapy with intravenous cyclophosphamide 500 mg/m2, doxorubicin 50 mg/m2 and cisplatin 50 mg/m2 (CAP regimen) on day 1 every 21 days [12]. Primary prophylaxis of chemotherapy-induced neutropenia was not planned due to the potential risk of worsening MG, without evidence about the safety of administering granulocyte colony-stimulating factor in unstable myasthenic patients [13]. Ovarian preservation by gonadotropin-releasing hormone analogue leuprorelin was preferred over oocyte retrieval to expedite the start of chemotherapy [14]. Standard pre-medication with intravenous administration of ondansetron 8 mg, dexamethasone 8 mg and saline was chosen [15].Fig. 1 Patient imaging. a Left chest X-ray with enlarged mediastinum (see arrow). b Chest computed tomography scan showing the mediastinal mass (see arrow). c
18PET-FDG limited radiotracer uptake in mediastinum
Chemotherapy-induced myasthenic crisis
Two hours after starting administration of the first course of chemotherapy, following doxorubicin bolus, the patient experienced sudden onset of acute dyspnea with severe respiratory failure (oxygen saturation 75% on room air), refractory to oxygen therapy and bolus hydrocortisone 500 mg and chlorphenamine 10 mg administered intravenously [16]. Physical exam was negative for bronchospasm with diminished vesicular breath sounds. Due to unstable clinical conditions and development of acute respiratory acidosis (pH 7.21, partial pressure of carbon dioxide 88 mmHg), tracheal intubation and mechanical ventilation in the intensive care unit (ICU) were needed. Urgent chest CT scan excluded acute cardiopulmonary events. Life-threatening MGFA class V MC was diagnosed, likely triggered by chemotherapy, thus classified as grade 4 according to the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) [8, 17]. Chemotherapy was held for 2 hours and then, considering its curative intent and in agreement with the family, it was resumed and fully administered during mechanical ventilation. After 24 hours, upon remission of MC and weaning from ventilation, the patient was extubated and could continue receiving MG treatment, together with starting PEX once every three days to control MG and prevent new crises (by replacing 1 plasma volume with 5% human albumin) [18]. In week 2, owing to CTCAE v5.0 grade 3 febrile neutropenia (absolute neutrophil count 60/mm3 and body temperature 38.4 °C), the patient was successfully treated with empirical piperacillin/tazobactam 4 g/0.5 g intravenously every 6 hours until recovery [19].
Curative treatment and outcome
After completing a second course of CAP chemotherapy with interposed PEX allowing symptom control, radiological assessment in week 6 documented objective partial response according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), with 33% tumor shrinkage (maximum diameter 8 versus 12 cm) [20]. This allowed us to perform radical (R0) extended thymectomy, left upper lung lobectomy and subtotal pericardiectomy, with histological diagnosis of Masaoka-Koga stage III type B2 [10, 11]. For patient histology, please see Fig. 2. The patient required early mediastinum and pleural cavity re-exploration due to postsurgical bleeding; persistent hypophonia developed due to postsurgical left vocal cord paralysis. A comparison of CT imaging at baseline and after surgery is shown in Fig. 3. As suggested for Masaoka-Koga stage III, radiotherapy of 50.4 Gy in 28 fractions was given as postoperative treatment in weeks 15–20 [1]. At the last follow-up visit, 6 months after surgery, the patient was in complete remission with gradually improving MGFA class I MG and mild persistent hypophonia [8]. Despite remarkable levels of psychological burden, the patient’s resilience and high-priority treatment goals were fundamental for successful coping.Fig. 2 Patient histology. a Hematoxylin and eosin (H&E; ×40 view) stained section of thymoma B2 according to WHO classification. b Same histological slice in ×100 view
Fig. 3 Chest computed tomography (CT) scan at baseline and after surgery. a Chest CT scan showing thymoma at baseline. b Postsurgical chest CT scan with no residual disease
Discussion and conclusions
According to the World Health Organization (WHO), thymoma is the most common variant of thymic epithelial tumors (66.3%), usually presenting with local invasion and seldom as metastatic disease [10, 21]. Overall, thymic epithelial tumors occur at a rate of 0.13–0.32 cases per 100,000 population at risk and are very uncommon in young adults [22, 23]. To our knowledge, the largest retrospective study regarding childhood thymic tumors (< 18 years) in Europe was able to identify only 36 cases during a 12-year period, confirming the extreme rarity of thymic cancer in children and adolescents [24]. Hence, the clinical case reported here has to be considered a peculiar presentation of early-onset thymoma (Fig. 4).Fig. 4 Age-specific incidence of thymic cancer by histological type. SEER*Stat Database: NPCR [National Program of Cancer Registries] and SEER [Surveillance, Epidemiology, and End Results] Incidence—U.S. Cancer Statistics Public Use Database, Nov 2017 submission (2001–2015). The green bar highlights the reported patient age interval (15–19 years)
Like thymoma, MG is extremely rare (0.17–2.13 per 100,000 person-years) [25]; however, it affects up to 30% of patients with thymoma [26]. The association of thymoma with MG has been related to the intratumoral generation of mature T cells, although the pathogenic mechanisms remain unclear [27]. MG has been found to be most commonly associated with B thymoma and confers favorable prognosis, since neuromuscular symptoms help in earlier detection of the tumor and thus less advanced stage at diagnosis. Nevertheless, concomitant MG should also be regarded as an adverse risk factor, since it can interfere with cancer treatment, being worsened by many drugs, and it reaches its maximum severity after thymectomy in a proportion of patients [28].
The case reported here, together with those published and summarized in Table 1 [3–6], highlights that chemotherapy is a realistic trigger event of MC in patients with thymoma and MG. The temporary association in all cases indicates a causative relation, and may hamper the continuation of chemotherapy that is a crucial element of multimodal treatment in cases not amenable to upfront radical surgery [1]. No biomarker is available to prove this relation, and clinical findings are crucial for the diagnosis of MC. Other differential diagnoses, such as infusion reaction to cancer chemotherapy, are less likely in the setting of prolonged respiratory failure. Here, a multidisciplinary approach was necessary, and involved neurologists for medical treatment and hematologists for a correct timing schedule of PEX sessions in order to avoid plasma drug displacement. It should be noted that we waited 72 hours from the end of chemotherapy before starting PEX, in order to preserve drug efficacy according to their half-life.Table 1. Comparison between present case and 4 other published cases
Fujiwara et al. [3] Qureshi et al. [4] Solak et al. [5] Ng et al. (6) Present case report
Sex Female Male Male Male Female
Age (year) 44 24 45 49 18
Histology B1 Thymoma (WHO) Thymoma Thymoma NE B2 thymoma (WHO)
Staging IVA (Masaoka-Koga) III (Masaoka-Koga) Advanced unresectable Advanced unresectable III (Masaoka-Koga)
AchR Ab level (nmol/l) 13 NE 74 NE 43
Chemotherapy regimen Primary CAMP Postoperative cisplatin and doxorubicin Single-agent cisplatin Doxorubicin, cisplatin, etoposide Primary CAP
Myasthenic crisis onset time During chemotherapy 8 hours after chemotherapy 1 week after chemotherapy A few hours after chemotherapy During chemotherapy
Tracheal intubation No Yes Yes Yes Yes
Plasma exchange No Yes Yes Yes Yes
Chemotherapy continuation in ICU No No No No Yes
Patient outcome after myasthenic crisis Alive Death Alive Alive Alive
AchR Ab acetylcholine receptor antibodies, CAMP cisplatin, doxorubicin, methylprednisolone, CAP cyclophosphamide, doxorubicin, cisplatin, ICU intensive care unit, NE not evaluable, WHO World Health Organization
To our knowledge, this is the first reported case of chemotherapy continuation despite the need for mechanical ventilation due to a chemotherapy-induced MC. Radical treatment was dependent on primary chemotherapy, as upfront surgery had already been ruled out. Besides, we could not confidently assume that, after MC resolution, the patient would have been able to receive further chemotherapy due to aggravation of symptoms. We conclude that special attention is warranted in patients with thymoma and MG with regard to the development of MC. Ideally, optimal control of myasthenic symptoms should be achieved before initiation of anticancer treatment. Nonetheless, chemotherapy-induced MC may complicate anticancer therapy administration, according to this evidence. We recommend that patients with thymoma and MG be hospitalized in tertiary medical centers for chemotherapy and that outpatient management be avoided. The lesson learned from the present case is that, in selected cases of advanced thymoma, paradoxical worsening of MG during chemotherapy should not be considered an absolute contraindication for continuation of primary chemotherapy with curative intent.
Abbreviations
CAPCisplatin, doxorubicin and cyclophosphamide
CTComputed tomography
CTCAE v5.0Common Terminology Criteria for Adverse Events version 5.0
GyGray
ICUIntensive Care Unit
MCMyasthenic crisis
MGMyasthenia gravis
MGFAMyasthenia Gravis Foundation of America
18PET-FDG18-Fluorodeoxyglucose positron emission tomography
PEXPlasma exchange
RECISTResponse Evaluation Criteria in Solid Tumours
WHOWorld Health Organization
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Fondazione Oncologia Niguarda Onlus for financial support.
Authors' contributions
GP, KB, FT, and SS were major contributors in writing the manuscript. KB, FT, GP, GM, GC, ASB, and SS provided clinical care. MP gave indication to and performed plasma exchange. AR and MT contributed to neoadjuvant treatment indication in a multidisciplinary team discussion and performed surgery. FL, AI, and ECA diagnosed thymoma and myasthenia and medically managed neurological symptoms. ASB and SS supervised oncological care and critically reviewed the case report. All authors read and approved the final manuscript.
Funding
This paper did not receive any specific grants from funding agencies in the public, commercial or not-for-profit sectors.
Ethics approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Availability of data and materials
Not applicable.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33526108 | 18,996,243 | 2021-02-02 |
What was the outcome of reaction 'Dyspnoea'? | Chemotherapy-induced myasthenic crisis in thymoma treated with primary chemotherapy with curative intent on mechanical ventilation: a case report and review of the literature.
BACKGROUND
Thymoma is an uncommon cancer often associated with myasthenia gravis, an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced nonmetastatic thymoma, primary chemotherapy may be required to induce tumor shrinkage and to achieve radical resection. Cancer chemotherapy has been anecdotally reported as a trigger factor for worsening of myasthenia gravis in thymic epithelial cancers. The study of uncommon cases of chemotherapy-related myasthenic crisis is warranted to gain knowledge of clinical situations requiring intensive care support in the case of life-threatening respiratory failure.
METHODS
We report a case of an 18-year-old Caucasian woman with advanced Masaoka-Koga stage III type B2 thymoma and myasthenia gravis on treatment with pyridostigmine, steroids and intravenous immunoglobulins, who developed a myasthenic crisis 2 hours after initiation of cyclophosphamide/doxorubicin/cisplatin primary chemotherapy. Because of severe acute respiratory failure, emergency tracheal intubation, mechanical ventilation, and temporary (2 hours) discontinuation of chemotherapy were needed. Considering the curative intent of the multimodal therapeutic program, we elected to resume primary chemotherapy administration while the patient remained on mechanical ventilation. After 24 hours, the recovery of adequate respiratory function allowed successful weaning from respiratory support, and no further adverse events occurred. After 3 weeks, upon plasma exchange initiation with amelioration of myasthenic symptoms, a second course of chemotherapy was given, and in week 6, having documented partial tumor remission, the patient underwent radical surgery (R0) and then consolidation radiation therapy with 50.4 Gy in 28 fractions in weeks 15-20.
CONCLUSIONS
This case report, together with the only four available in a review of the literature, highlights that chemotherapy may carry the risk of myasthenic crisis in patients affected by thymoma and myasthenia gravis. To our knowledge, this is the first reported case of chemotherapy continuation on mechanical ventilation in a patient with chemotherapy-induced myasthenic crisis requiring tracheal intubation. The lesson learned from the present case is that, in selected cases of advanced thymoma, the paradoxical worsening of myasthenia gravis during chemotherapy should not be considered an absolute contraindication for the continuation of primary chemotherapy with curative intent.
Background
Thymoma is an uncommon epithelial cancer associated in nearly half of cases with myasthenia gravis (MG), an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced thymoma, primary chemotherapy is considered the standard of care, with the aim of achieving tumor shrinkage and facilitating radical surgery [1]. While several drugs are known to worsen MG, cancer chemotherapy has been anecdotally reported as a trigger event for myasthenic crisis (MC) in four case reports [2–6]. Here, we present a case of advanced thymoma treated with primary chemotherapy that caused an acute-onset MC requiring tracheal intubation and therapeutic plasma exchange (PEX), with relevant benefit from early resumption of anticancer treatment during mechanical ventilation.
Case presentation
Clinical presentation and diagnosis
An 18-year-old Caucasian woman with unremarkable medical history was admitted to the emergency room due to neurological symptoms. She presented with month-long worsening dysphagia, rhinolalia, bilateral ptosis, and skeletal muscle weakness. Signs of muscle fatigability were elicited at the physical exam and then confirmed by electromyography, consistently with neuromuscular junction disease. Blood tests were unremarkable with the exception of acetylcholine receptor antibodies (43 nmol/l, normal if < 0.5 nmol/l). Hence, MG class III, according to the Myasthenia Gravis Foundation of America (MGFA) scale, was diagnosed [7, 8]. Partial regression of symptoms to class II MG was achieved by oral administration of pyridostigmine 60 mg every 3 hours during the daytime, pyridostigmine sustained-release 180 mg orally before sleeping, prednisone 25 mg orally each day, and immunoglobulins 0.4 g/kg intravenously for 5 days [8, 9]. Chest computed tomography (CT) revealed a 12 cm anterior mediastinal mass suspicious for thymoma, with confirmed infiltration of the anterior chest wall, lung parenchyma, and pericardium at chest magnetic resonance imaging with contrast. CT-guided fine needle aspiration biopsy yielded a histological diagnosis of B2 thymoma [10]. Due to the young age, a family history of cancer was excluded. Physical exam was negative for signs of mediastinal syndrome and superficial lymph nodes. Metastatic disease was excluded by 18-fluorodeoxyglucose positron emission tomography (18FDG-PET). Patient imaging is shown in Fig. 1. Accordingly, the clinical stage was cT3 cN0 cM0 (Masaoka-Koga III) [11]. After multidisciplinary team discussion, the tumor was defined as unresectable, and the patient was offered primary chemotherapy with intravenous cyclophosphamide 500 mg/m2, doxorubicin 50 mg/m2 and cisplatin 50 mg/m2 (CAP regimen) on day 1 every 21 days [12]. Primary prophylaxis of chemotherapy-induced neutropenia was not planned due to the potential risk of worsening MG, without evidence about the safety of administering granulocyte colony-stimulating factor in unstable myasthenic patients [13]. Ovarian preservation by gonadotropin-releasing hormone analogue leuprorelin was preferred over oocyte retrieval to expedite the start of chemotherapy [14]. Standard pre-medication with intravenous administration of ondansetron 8 mg, dexamethasone 8 mg and saline was chosen [15].Fig. 1 Patient imaging. a Left chest X-ray with enlarged mediastinum (see arrow). b Chest computed tomography scan showing the mediastinal mass (see arrow). c
18PET-FDG limited radiotracer uptake in mediastinum
Chemotherapy-induced myasthenic crisis
Two hours after starting administration of the first course of chemotherapy, following doxorubicin bolus, the patient experienced sudden onset of acute dyspnea with severe respiratory failure (oxygen saturation 75% on room air), refractory to oxygen therapy and bolus hydrocortisone 500 mg and chlorphenamine 10 mg administered intravenously [16]. Physical exam was negative for bronchospasm with diminished vesicular breath sounds. Due to unstable clinical conditions and development of acute respiratory acidosis (pH 7.21, partial pressure of carbon dioxide 88 mmHg), tracheal intubation and mechanical ventilation in the intensive care unit (ICU) were needed. Urgent chest CT scan excluded acute cardiopulmonary events. Life-threatening MGFA class V MC was diagnosed, likely triggered by chemotherapy, thus classified as grade 4 according to the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) [8, 17]. Chemotherapy was held for 2 hours and then, considering its curative intent and in agreement with the family, it was resumed and fully administered during mechanical ventilation. After 24 hours, upon remission of MC and weaning from ventilation, the patient was extubated and could continue receiving MG treatment, together with starting PEX once every three days to control MG and prevent new crises (by replacing 1 plasma volume with 5% human albumin) [18]. In week 2, owing to CTCAE v5.0 grade 3 febrile neutropenia (absolute neutrophil count 60/mm3 and body temperature 38.4 °C), the patient was successfully treated with empirical piperacillin/tazobactam 4 g/0.5 g intravenously every 6 hours until recovery [19].
Curative treatment and outcome
After completing a second course of CAP chemotherapy with interposed PEX allowing symptom control, radiological assessment in week 6 documented objective partial response according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), with 33% tumor shrinkage (maximum diameter 8 versus 12 cm) [20]. This allowed us to perform radical (R0) extended thymectomy, left upper lung lobectomy and subtotal pericardiectomy, with histological diagnosis of Masaoka-Koga stage III type B2 [10, 11]. For patient histology, please see Fig. 2. The patient required early mediastinum and pleural cavity re-exploration due to postsurgical bleeding; persistent hypophonia developed due to postsurgical left vocal cord paralysis. A comparison of CT imaging at baseline and after surgery is shown in Fig. 3. As suggested for Masaoka-Koga stage III, radiotherapy of 50.4 Gy in 28 fractions was given as postoperative treatment in weeks 15–20 [1]. At the last follow-up visit, 6 months after surgery, the patient was in complete remission with gradually improving MGFA class I MG and mild persistent hypophonia [8]. Despite remarkable levels of psychological burden, the patient’s resilience and high-priority treatment goals were fundamental for successful coping.Fig. 2 Patient histology. a Hematoxylin and eosin (H&E; ×40 view) stained section of thymoma B2 according to WHO classification. b Same histological slice in ×100 view
Fig. 3 Chest computed tomography (CT) scan at baseline and after surgery. a Chest CT scan showing thymoma at baseline. b Postsurgical chest CT scan with no residual disease
Discussion and conclusions
According to the World Health Organization (WHO), thymoma is the most common variant of thymic epithelial tumors (66.3%), usually presenting with local invasion and seldom as metastatic disease [10, 21]. Overall, thymic epithelial tumors occur at a rate of 0.13–0.32 cases per 100,000 population at risk and are very uncommon in young adults [22, 23]. To our knowledge, the largest retrospective study regarding childhood thymic tumors (< 18 years) in Europe was able to identify only 36 cases during a 12-year period, confirming the extreme rarity of thymic cancer in children and adolescents [24]. Hence, the clinical case reported here has to be considered a peculiar presentation of early-onset thymoma (Fig. 4).Fig. 4 Age-specific incidence of thymic cancer by histological type. SEER*Stat Database: NPCR [National Program of Cancer Registries] and SEER [Surveillance, Epidemiology, and End Results] Incidence—U.S. Cancer Statistics Public Use Database, Nov 2017 submission (2001–2015). The green bar highlights the reported patient age interval (15–19 years)
Like thymoma, MG is extremely rare (0.17–2.13 per 100,000 person-years) [25]; however, it affects up to 30% of patients with thymoma [26]. The association of thymoma with MG has been related to the intratumoral generation of mature T cells, although the pathogenic mechanisms remain unclear [27]. MG has been found to be most commonly associated with B thymoma and confers favorable prognosis, since neuromuscular symptoms help in earlier detection of the tumor and thus less advanced stage at diagnosis. Nevertheless, concomitant MG should also be regarded as an adverse risk factor, since it can interfere with cancer treatment, being worsened by many drugs, and it reaches its maximum severity after thymectomy in a proportion of patients [28].
The case reported here, together with those published and summarized in Table 1 [3–6], highlights that chemotherapy is a realistic trigger event of MC in patients with thymoma and MG. The temporary association in all cases indicates a causative relation, and may hamper the continuation of chemotherapy that is a crucial element of multimodal treatment in cases not amenable to upfront radical surgery [1]. No biomarker is available to prove this relation, and clinical findings are crucial for the diagnosis of MC. Other differential diagnoses, such as infusion reaction to cancer chemotherapy, are less likely in the setting of prolonged respiratory failure. Here, a multidisciplinary approach was necessary, and involved neurologists for medical treatment and hematologists for a correct timing schedule of PEX sessions in order to avoid plasma drug displacement. It should be noted that we waited 72 hours from the end of chemotherapy before starting PEX, in order to preserve drug efficacy according to their half-life.Table 1. Comparison between present case and 4 other published cases
Fujiwara et al. [3] Qureshi et al. [4] Solak et al. [5] Ng et al. (6) Present case report
Sex Female Male Male Male Female
Age (year) 44 24 45 49 18
Histology B1 Thymoma (WHO) Thymoma Thymoma NE B2 thymoma (WHO)
Staging IVA (Masaoka-Koga) III (Masaoka-Koga) Advanced unresectable Advanced unresectable III (Masaoka-Koga)
AchR Ab level (nmol/l) 13 NE 74 NE 43
Chemotherapy regimen Primary CAMP Postoperative cisplatin and doxorubicin Single-agent cisplatin Doxorubicin, cisplatin, etoposide Primary CAP
Myasthenic crisis onset time During chemotherapy 8 hours after chemotherapy 1 week after chemotherapy A few hours after chemotherapy During chemotherapy
Tracheal intubation No Yes Yes Yes Yes
Plasma exchange No Yes Yes Yes Yes
Chemotherapy continuation in ICU No No No No Yes
Patient outcome after myasthenic crisis Alive Death Alive Alive Alive
AchR Ab acetylcholine receptor antibodies, CAMP cisplatin, doxorubicin, methylprednisolone, CAP cyclophosphamide, doxorubicin, cisplatin, ICU intensive care unit, NE not evaluable, WHO World Health Organization
To our knowledge, this is the first reported case of chemotherapy continuation despite the need for mechanical ventilation due to a chemotherapy-induced MC. Radical treatment was dependent on primary chemotherapy, as upfront surgery had already been ruled out. Besides, we could not confidently assume that, after MC resolution, the patient would have been able to receive further chemotherapy due to aggravation of symptoms. We conclude that special attention is warranted in patients with thymoma and MG with regard to the development of MC. Ideally, optimal control of myasthenic symptoms should be achieved before initiation of anticancer treatment. Nonetheless, chemotherapy-induced MC may complicate anticancer therapy administration, according to this evidence. We recommend that patients with thymoma and MG be hospitalized in tertiary medical centers for chemotherapy and that outpatient management be avoided. The lesson learned from the present case is that, in selected cases of advanced thymoma, paradoxical worsening of MG during chemotherapy should not be considered an absolute contraindication for continuation of primary chemotherapy with curative intent.
Abbreviations
CAPCisplatin, doxorubicin and cyclophosphamide
CTComputed tomography
CTCAE v5.0Common Terminology Criteria for Adverse Events version 5.0
GyGray
ICUIntensive Care Unit
MCMyasthenic crisis
MGMyasthenia gravis
MGFAMyasthenia Gravis Foundation of America
18PET-FDG18-Fluorodeoxyglucose positron emission tomography
PEXPlasma exchange
RECISTResponse Evaluation Criteria in Solid Tumours
WHOWorld Health Organization
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Fondazione Oncologia Niguarda Onlus for financial support.
Authors' contributions
GP, KB, FT, and SS were major contributors in writing the manuscript. KB, FT, GP, GM, GC, ASB, and SS provided clinical care. MP gave indication to and performed plasma exchange. AR and MT contributed to neoadjuvant treatment indication in a multidisciplinary team discussion and performed surgery. FL, AI, and ECA diagnosed thymoma and myasthenia and medically managed neurological symptoms. ASB and SS supervised oncological care and critically reviewed the case report. All authors read and approved the final manuscript.
Funding
This paper did not receive any specific grants from funding agencies in the public, commercial or not-for-profit sectors.
Ethics approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Availability of data and materials
Not applicable.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33526108 | 18,959,226 | 2021-02-02 |
What was the outcome of reaction 'Myasthenia gravis crisis'? | Chemotherapy-induced myasthenic crisis in thymoma treated with primary chemotherapy with curative intent on mechanical ventilation: a case report and review of the literature.
BACKGROUND
Thymoma is an uncommon cancer often associated with myasthenia gravis, an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced nonmetastatic thymoma, primary chemotherapy may be required to induce tumor shrinkage and to achieve radical resection. Cancer chemotherapy has been anecdotally reported as a trigger factor for worsening of myasthenia gravis in thymic epithelial cancers. The study of uncommon cases of chemotherapy-related myasthenic crisis is warranted to gain knowledge of clinical situations requiring intensive care support in the case of life-threatening respiratory failure.
METHODS
We report a case of an 18-year-old Caucasian woman with advanced Masaoka-Koga stage III type B2 thymoma and myasthenia gravis on treatment with pyridostigmine, steroids and intravenous immunoglobulins, who developed a myasthenic crisis 2 hours after initiation of cyclophosphamide/doxorubicin/cisplatin primary chemotherapy. Because of severe acute respiratory failure, emergency tracheal intubation, mechanical ventilation, and temporary (2 hours) discontinuation of chemotherapy were needed. Considering the curative intent of the multimodal therapeutic program, we elected to resume primary chemotherapy administration while the patient remained on mechanical ventilation. After 24 hours, the recovery of adequate respiratory function allowed successful weaning from respiratory support, and no further adverse events occurred. After 3 weeks, upon plasma exchange initiation with amelioration of myasthenic symptoms, a second course of chemotherapy was given, and in week 6, having documented partial tumor remission, the patient underwent radical surgery (R0) and then consolidation radiation therapy with 50.4 Gy in 28 fractions in weeks 15-20.
CONCLUSIONS
This case report, together with the only four available in a review of the literature, highlights that chemotherapy may carry the risk of myasthenic crisis in patients affected by thymoma and myasthenia gravis. To our knowledge, this is the first reported case of chemotherapy continuation on mechanical ventilation in a patient with chemotherapy-induced myasthenic crisis requiring tracheal intubation. The lesson learned from the present case is that, in selected cases of advanced thymoma, the paradoxical worsening of myasthenia gravis during chemotherapy should not be considered an absolute contraindication for the continuation of primary chemotherapy with curative intent.
Background
Thymoma is an uncommon epithelial cancer associated in nearly half of cases with myasthenia gravis (MG), an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced thymoma, primary chemotherapy is considered the standard of care, with the aim of achieving tumor shrinkage and facilitating radical surgery [1]. While several drugs are known to worsen MG, cancer chemotherapy has been anecdotally reported as a trigger event for myasthenic crisis (MC) in four case reports [2–6]. Here, we present a case of advanced thymoma treated with primary chemotherapy that caused an acute-onset MC requiring tracheal intubation and therapeutic plasma exchange (PEX), with relevant benefit from early resumption of anticancer treatment during mechanical ventilation.
Case presentation
Clinical presentation and diagnosis
An 18-year-old Caucasian woman with unremarkable medical history was admitted to the emergency room due to neurological symptoms. She presented with month-long worsening dysphagia, rhinolalia, bilateral ptosis, and skeletal muscle weakness. Signs of muscle fatigability were elicited at the physical exam and then confirmed by electromyography, consistently with neuromuscular junction disease. Blood tests were unremarkable with the exception of acetylcholine receptor antibodies (43 nmol/l, normal if < 0.5 nmol/l). Hence, MG class III, according to the Myasthenia Gravis Foundation of America (MGFA) scale, was diagnosed [7, 8]. Partial regression of symptoms to class II MG was achieved by oral administration of pyridostigmine 60 mg every 3 hours during the daytime, pyridostigmine sustained-release 180 mg orally before sleeping, prednisone 25 mg orally each day, and immunoglobulins 0.4 g/kg intravenously for 5 days [8, 9]. Chest computed tomography (CT) revealed a 12 cm anterior mediastinal mass suspicious for thymoma, with confirmed infiltration of the anterior chest wall, lung parenchyma, and pericardium at chest magnetic resonance imaging with contrast. CT-guided fine needle aspiration biopsy yielded a histological diagnosis of B2 thymoma [10]. Due to the young age, a family history of cancer was excluded. Physical exam was negative for signs of mediastinal syndrome and superficial lymph nodes. Metastatic disease was excluded by 18-fluorodeoxyglucose positron emission tomography (18FDG-PET). Patient imaging is shown in Fig. 1. Accordingly, the clinical stage was cT3 cN0 cM0 (Masaoka-Koga III) [11]. After multidisciplinary team discussion, the tumor was defined as unresectable, and the patient was offered primary chemotherapy with intravenous cyclophosphamide 500 mg/m2, doxorubicin 50 mg/m2 and cisplatin 50 mg/m2 (CAP regimen) on day 1 every 21 days [12]. Primary prophylaxis of chemotherapy-induced neutropenia was not planned due to the potential risk of worsening MG, without evidence about the safety of administering granulocyte colony-stimulating factor in unstable myasthenic patients [13]. Ovarian preservation by gonadotropin-releasing hormone analogue leuprorelin was preferred over oocyte retrieval to expedite the start of chemotherapy [14]. Standard pre-medication with intravenous administration of ondansetron 8 mg, dexamethasone 8 mg and saline was chosen [15].Fig. 1 Patient imaging. a Left chest X-ray with enlarged mediastinum (see arrow). b Chest computed tomography scan showing the mediastinal mass (see arrow). c
18PET-FDG limited radiotracer uptake in mediastinum
Chemotherapy-induced myasthenic crisis
Two hours after starting administration of the first course of chemotherapy, following doxorubicin bolus, the patient experienced sudden onset of acute dyspnea with severe respiratory failure (oxygen saturation 75% on room air), refractory to oxygen therapy and bolus hydrocortisone 500 mg and chlorphenamine 10 mg administered intravenously [16]. Physical exam was negative for bronchospasm with diminished vesicular breath sounds. Due to unstable clinical conditions and development of acute respiratory acidosis (pH 7.21, partial pressure of carbon dioxide 88 mmHg), tracheal intubation and mechanical ventilation in the intensive care unit (ICU) were needed. Urgent chest CT scan excluded acute cardiopulmonary events. Life-threatening MGFA class V MC was diagnosed, likely triggered by chemotherapy, thus classified as grade 4 according to the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) [8, 17]. Chemotherapy was held for 2 hours and then, considering its curative intent and in agreement with the family, it was resumed and fully administered during mechanical ventilation. After 24 hours, upon remission of MC and weaning from ventilation, the patient was extubated and could continue receiving MG treatment, together with starting PEX once every three days to control MG and prevent new crises (by replacing 1 plasma volume with 5% human albumin) [18]. In week 2, owing to CTCAE v5.0 grade 3 febrile neutropenia (absolute neutrophil count 60/mm3 and body temperature 38.4 °C), the patient was successfully treated with empirical piperacillin/tazobactam 4 g/0.5 g intravenously every 6 hours until recovery [19].
Curative treatment and outcome
After completing a second course of CAP chemotherapy with interposed PEX allowing symptom control, radiological assessment in week 6 documented objective partial response according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), with 33% tumor shrinkage (maximum diameter 8 versus 12 cm) [20]. This allowed us to perform radical (R0) extended thymectomy, left upper lung lobectomy and subtotal pericardiectomy, with histological diagnosis of Masaoka-Koga stage III type B2 [10, 11]. For patient histology, please see Fig. 2. The patient required early mediastinum and pleural cavity re-exploration due to postsurgical bleeding; persistent hypophonia developed due to postsurgical left vocal cord paralysis. A comparison of CT imaging at baseline and after surgery is shown in Fig. 3. As suggested for Masaoka-Koga stage III, radiotherapy of 50.4 Gy in 28 fractions was given as postoperative treatment in weeks 15–20 [1]. At the last follow-up visit, 6 months after surgery, the patient was in complete remission with gradually improving MGFA class I MG and mild persistent hypophonia [8]. Despite remarkable levels of psychological burden, the patient’s resilience and high-priority treatment goals were fundamental for successful coping.Fig. 2 Patient histology. a Hematoxylin and eosin (H&E; ×40 view) stained section of thymoma B2 according to WHO classification. b Same histological slice in ×100 view
Fig. 3 Chest computed tomography (CT) scan at baseline and after surgery. a Chest CT scan showing thymoma at baseline. b Postsurgical chest CT scan with no residual disease
Discussion and conclusions
According to the World Health Organization (WHO), thymoma is the most common variant of thymic epithelial tumors (66.3%), usually presenting with local invasion and seldom as metastatic disease [10, 21]. Overall, thymic epithelial tumors occur at a rate of 0.13–0.32 cases per 100,000 population at risk and are very uncommon in young adults [22, 23]. To our knowledge, the largest retrospective study regarding childhood thymic tumors (< 18 years) in Europe was able to identify only 36 cases during a 12-year period, confirming the extreme rarity of thymic cancer in children and adolescents [24]. Hence, the clinical case reported here has to be considered a peculiar presentation of early-onset thymoma (Fig. 4).Fig. 4 Age-specific incidence of thymic cancer by histological type. SEER*Stat Database: NPCR [National Program of Cancer Registries] and SEER [Surveillance, Epidemiology, and End Results] Incidence—U.S. Cancer Statistics Public Use Database, Nov 2017 submission (2001–2015). The green bar highlights the reported patient age interval (15–19 years)
Like thymoma, MG is extremely rare (0.17–2.13 per 100,000 person-years) [25]; however, it affects up to 30% of patients with thymoma [26]. The association of thymoma with MG has been related to the intratumoral generation of mature T cells, although the pathogenic mechanisms remain unclear [27]. MG has been found to be most commonly associated with B thymoma and confers favorable prognosis, since neuromuscular symptoms help in earlier detection of the tumor and thus less advanced stage at diagnosis. Nevertheless, concomitant MG should also be regarded as an adverse risk factor, since it can interfere with cancer treatment, being worsened by many drugs, and it reaches its maximum severity after thymectomy in a proportion of patients [28].
The case reported here, together with those published and summarized in Table 1 [3–6], highlights that chemotherapy is a realistic trigger event of MC in patients with thymoma and MG. The temporary association in all cases indicates a causative relation, and may hamper the continuation of chemotherapy that is a crucial element of multimodal treatment in cases not amenable to upfront radical surgery [1]. No biomarker is available to prove this relation, and clinical findings are crucial for the diagnosis of MC. Other differential diagnoses, such as infusion reaction to cancer chemotherapy, are less likely in the setting of prolonged respiratory failure. Here, a multidisciplinary approach was necessary, and involved neurologists for medical treatment and hematologists for a correct timing schedule of PEX sessions in order to avoid plasma drug displacement. It should be noted that we waited 72 hours from the end of chemotherapy before starting PEX, in order to preserve drug efficacy according to their half-life.Table 1. Comparison between present case and 4 other published cases
Fujiwara et al. [3] Qureshi et al. [4] Solak et al. [5] Ng et al. (6) Present case report
Sex Female Male Male Male Female
Age (year) 44 24 45 49 18
Histology B1 Thymoma (WHO) Thymoma Thymoma NE B2 thymoma (WHO)
Staging IVA (Masaoka-Koga) III (Masaoka-Koga) Advanced unresectable Advanced unresectable III (Masaoka-Koga)
AchR Ab level (nmol/l) 13 NE 74 NE 43
Chemotherapy regimen Primary CAMP Postoperative cisplatin and doxorubicin Single-agent cisplatin Doxorubicin, cisplatin, etoposide Primary CAP
Myasthenic crisis onset time During chemotherapy 8 hours after chemotherapy 1 week after chemotherapy A few hours after chemotherapy During chemotherapy
Tracheal intubation No Yes Yes Yes Yes
Plasma exchange No Yes Yes Yes Yes
Chemotherapy continuation in ICU No No No No Yes
Patient outcome after myasthenic crisis Alive Death Alive Alive Alive
AchR Ab acetylcholine receptor antibodies, CAMP cisplatin, doxorubicin, methylprednisolone, CAP cyclophosphamide, doxorubicin, cisplatin, ICU intensive care unit, NE not evaluable, WHO World Health Organization
To our knowledge, this is the first reported case of chemotherapy continuation despite the need for mechanical ventilation due to a chemotherapy-induced MC. Radical treatment was dependent on primary chemotherapy, as upfront surgery had already been ruled out. Besides, we could not confidently assume that, after MC resolution, the patient would have been able to receive further chemotherapy due to aggravation of symptoms. We conclude that special attention is warranted in patients with thymoma and MG with regard to the development of MC. Ideally, optimal control of myasthenic symptoms should be achieved before initiation of anticancer treatment. Nonetheless, chemotherapy-induced MC may complicate anticancer therapy administration, according to this evidence. We recommend that patients with thymoma and MG be hospitalized in tertiary medical centers for chemotherapy and that outpatient management be avoided. The lesson learned from the present case is that, in selected cases of advanced thymoma, paradoxical worsening of MG during chemotherapy should not be considered an absolute contraindication for continuation of primary chemotherapy with curative intent.
Abbreviations
CAPCisplatin, doxorubicin and cyclophosphamide
CTComputed tomography
CTCAE v5.0Common Terminology Criteria for Adverse Events version 5.0
GyGray
ICUIntensive Care Unit
MCMyasthenic crisis
MGMyasthenia gravis
MGFAMyasthenia Gravis Foundation of America
18PET-FDG18-Fluorodeoxyglucose positron emission tomography
PEXPlasma exchange
RECISTResponse Evaluation Criteria in Solid Tumours
WHOWorld Health Organization
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Fondazione Oncologia Niguarda Onlus for financial support.
Authors' contributions
GP, KB, FT, and SS were major contributors in writing the manuscript. KB, FT, GP, GM, GC, ASB, and SS provided clinical care. MP gave indication to and performed plasma exchange. AR and MT contributed to neoadjuvant treatment indication in a multidisciplinary team discussion and performed surgery. FL, AI, and ECA diagnosed thymoma and myasthenia and medically managed neurological symptoms. ASB and SS supervised oncological care and critically reviewed the case report. All authors read and approved the final manuscript.
Funding
This paper did not receive any specific grants from funding agencies in the public, commercial or not-for-profit sectors.
Ethics approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Availability of data and materials
Not applicable.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33526108 | 18,959,226 | 2021-02-02 |
What was the outcome of reaction 'Myasthenic syndrome'? | Chemotherapy-induced myasthenic crisis in thymoma treated with primary chemotherapy with curative intent on mechanical ventilation: a case report and review of the literature.
BACKGROUND
Thymoma is an uncommon cancer often associated with myasthenia gravis, an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced nonmetastatic thymoma, primary chemotherapy may be required to induce tumor shrinkage and to achieve radical resection. Cancer chemotherapy has been anecdotally reported as a trigger factor for worsening of myasthenia gravis in thymic epithelial cancers. The study of uncommon cases of chemotherapy-related myasthenic crisis is warranted to gain knowledge of clinical situations requiring intensive care support in the case of life-threatening respiratory failure.
METHODS
We report a case of an 18-year-old Caucasian woman with advanced Masaoka-Koga stage III type B2 thymoma and myasthenia gravis on treatment with pyridostigmine, steroids and intravenous immunoglobulins, who developed a myasthenic crisis 2 hours after initiation of cyclophosphamide/doxorubicin/cisplatin primary chemotherapy. Because of severe acute respiratory failure, emergency tracheal intubation, mechanical ventilation, and temporary (2 hours) discontinuation of chemotherapy were needed. Considering the curative intent of the multimodal therapeutic program, we elected to resume primary chemotherapy administration while the patient remained on mechanical ventilation. After 24 hours, the recovery of adequate respiratory function allowed successful weaning from respiratory support, and no further adverse events occurred. After 3 weeks, upon plasma exchange initiation with amelioration of myasthenic symptoms, a second course of chemotherapy was given, and in week 6, having documented partial tumor remission, the patient underwent radical surgery (R0) and then consolidation radiation therapy with 50.4 Gy in 28 fractions in weeks 15-20.
CONCLUSIONS
This case report, together with the only four available in a review of the literature, highlights that chemotherapy may carry the risk of myasthenic crisis in patients affected by thymoma and myasthenia gravis. To our knowledge, this is the first reported case of chemotherapy continuation on mechanical ventilation in a patient with chemotherapy-induced myasthenic crisis requiring tracheal intubation. The lesson learned from the present case is that, in selected cases of advanced thymoma, the paradoxical worsening of myasthenia gravis during chemotherapy should not be considered an absolute contraindication for the continuation of primary chemotherapy with curative intent.
Background
Thymoma is an uncommon epithelial cancer associated in nearly half of cases with myasthenia gravis (MG), an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced thymoma, primary chemotherapy is considered the standard of care, with the aim of achieving tumor shrinkage and facilitating radical surgery [1]. While several drugs are known to worsen MG, cancer chemotherapy has been anecdotally reported as a trigger event for myasthenic crisis (MC) in four case reports [2–6]. Here, we present a case of advanced thymoma treated with primary chemotherapy that caused an acute-onset MC requiring tracheal intubation and therapeutic plasma exchange (PEX), with relevant benefit from early resumption of anticancer treatment during mechanical ventilation.
Case presentation
Clinical presentation and diagnosis
An 18-year-old Caucasian woman with unremarkable medical history was admitted to the emergency room due to neurological symptoms. She presented with month-long worsening dysphagia, rhinolalia, bilateral ptosis, and skeletal muscle weakness. Signs of muscle fatigability were elicited at the physical exam and then confirmed by electromyography, consistently with neuromuscular junction disease. Blood tests were unremarkable with the exception of acetylcholine receptor antibodies (43 nmol/l, normal if < 0.5 nmol/l). Hence, MG class III, according to the Myasthenia Gravis Foundation of America (MGFA) scale, was diagnosed [7, 8]. Partial regression of symptoms to class II MG was achieved by oral administration of pyridostigmine 60 mg every 3 hours during the daytime, pyridostigmine sustained-release 180 mg orally before sleeping, prednisone 25 mg orally each day, and immunoglobulins 0.4 g/kg intravenously for 5 days [8, 9]. Chest computed tomography (CT) revealed a 12 cm anterior mediastinal mass suspicious for thymoma, with confirmed infiltration of the anterior chest wall, lung parenchyma, and pericardium at chest magnetic resonance imaging with contrast. CT-guided fine needle aspiration biopsy yielded a histological diagnosis of B2 thymoma [10]. Due to the young age, a family history of cancer was excluded. Physical exam was negative for signs of mediastinal syndrome and superficial lymph nodes. Metastatic disease was excluded by 18-fluorodeoxyglucose positron emission tomography (18FDG-PET). Patient imaging is shown in Fig. 1. Accordingly, the clinical stage was cT3 cN0 cM0 (Masaoka-Koga III) [11]. After multidisciplinary team discussion, the tumor was defined as unresectable, and the patient was offered primary chemotherapy with intravenous cyclophosphamide 500 mg/m2, doxorubicin 50 mg/m2 and cisplatin 50 mg/m2 (CAP regimen) on day 1 every 21 days [12]. Primary prophylaxis of chemotherapy-induced neutropenia was not planned due to the potential risk of worsening MG, without evidence about the safety of administering granulocyte colony-stimulating factor in unstable myasthenic patients [13]. Ovarian preservation by gonadotropin-releasing hormone analogue leuprorelin was preferred over oocyte retrieval to expedite the start of chemotherapy [14]. Standard pre-medication with intravenous administration of ondansetron 8 mg, dexamethasone 8 mg and saline was chosen [15].Fig. 1 Patient imaging. a Left chest X-ray with enlarged mediastinum (see arrow). b Chest computed tomography scan showing the mediastinal mass (see arrow). c
18PET-FDG limited radiotracer uptake in mediastinum
Chemotherapy-induced myasthenic crisis
Two hours after starting administration of the first course of chemotherapy, following doxorubicin bolus, the patient experienced sudden onset of acute dyspnea with severe respiratory failure (oxygen saturation 75% on room air), refractory to oxygen therapy and bolus hydrocortisone 500 mg and chlorphenamine 10 mg administered intravenously [16]. Physical exam was negative for bronchospasm with diminished vesicular breath sounds. Due to unstable clinical conditions and development of acute respiratory acidosis (pH 7.21, partial pressure of carbon dioxide 88 mmHg), tracheal intubation and mechanical ventilation in the intensive care unit (ICU) were needed. Urgent chest CT scan excluded acute cardiopulmonary events. Life-threatening MGFA class V MC was diagnosed, likely triggered by chemotherapy, thus classified as grade 4 according to the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) [8, 17]. Chemotherapy was held for 2 hours and then, considering its curative intent and in agreement with the family, it was resumed and fully administered during mechanical ventilation. After 24 hours, upon remission of MC and weaning from ventilation, the patient was extubated and could continue receiving MG treatment, together with starting PEX once every three days to control MG and prevent new crises (by replacing 1 plasma volume with 5% human albumin) [18]. In week 2, owing to CTCAE v5.0 grade 3 febrile neutropenia (absolute neutrophil count 60/mm3 and body temperature 38.4 °C), the patient was successfully treated with empirical piperacillin/tazobactam 4 g/0.5 g intravenously every 6 hours until recovery [19].
Curative treatment and outcome
After completing a second course of CAP chemotherapy with interposed PEX allowing symptom control, radiological assessment in week 6 documented objective partial response according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), with 33% tumor shrinkage (maximum diameter 8 versus 12 cm) [20]. This allowed us to perform radical (R0) extended thymectomy, left upper lung lobectomy and subtotal pericardiectomy, with histological diagnosis of Masaoka-Koga stage III type B2 [10, 11]. For patient histology, please see Fig. 2. The patient required early mediastinum and pleural cavity re-exploration due to postsurgical bleeding; persistent hypophonia developed due to postsurgical left vocal cord paralysis. A comparison of CT imaging at baseline and after surgery is shown in Fig. 3. As suggested for Masaoka-Koga stage III, radiotherapy of 50.4 Gy in 28 fractions was given as postoperative treatment in weeks 15–20 [1]. At the last follow-up visit, 6 months after surgery, the patient was in complete remission with gradually improving MGFA class I MG and mild persistent hypophonia [8]. Despite remarkable levels of psychological burden, the patient’s resilience and high-priority treatment goals were fundamental for successful coping.Fig. 2 Patient histology. a Hematoxylin and eosin (H&E; ×40 view) stained section of thymoma B2 according to WHO classification. b Same histological slice in ×100 view
Fig. 3 Chest computed tomography (CT) scan at baseline and after surgery. a Chest CT scan showing thymoma at baseline. b Postsurgical chest CT scan with no residual disease
Discussion and conclusions
According to the World Health Organization (WHO), thymoma is the most common variant of thymic epithelial tumors (66.3%), usually presenting with local invasion and seldom as metastatic disease [10, 21]. Overall, thymic epithelial tumors occur at a rate of 0.13–0.32 cases per 100,000 population at risk and are very uncommon in young adults [22, 23]. To our knowledge, the largest retrospective study regarding childhood thymic tumors (< 18 years) in Europe was able to identify only 36 cases during a 12-year period, confirming the extreme rarity of thymic cancer in children and adolescents [24]. Hence, the clinical case reported here has to be considered a peculiar presentation of early-onset thymoma (Fig. 4).Fig. 4 Age-specific incidence of thymic cancer by histological type. SEER*Stat Database: NPCR [National Program of Cancer Registries] and SEER [Surveillance, Epidemiology, and End Results] Incidence—U.S. Cancer Statistics Public Use Database, Nov 2017 submission (2001–2015). The green bar highlights the reported patient age interval (15–19 years)
Like thymoma, MG is extremely rare (0.17–2.13 per 100,000 person-years) [25]; however, it affects up to 30% of patients with thymoma [26]. The association of thymoma with MG has been related to the intratumoral generation of mature T cells, although the pathogenic mechanisms remain unclear [27]. MG has been found to be most commonly associated with B thymoma and confers favorable prognosis, since neuromuscular symptoms help in earlier detection of the tumor and thus less advanced stage at diagnosis. Nevertheless, concomitant MG should also be regarded as an adverse risk factor, since it can interfere with cancer treatment, being worsened by many drugs, and it reaches its maximum severity after thymectomy in a proportion of patients [28].
The case reported here, together with those published and summarized in Table 1 [3–6], highlights that chemotherapy is a realistic trigger event of MC in patients with thymoma and MG. The temporary association in all cases indicates a causative relation, and may hamper the continuation of chemotherapy that is a crucial element of multimodal treatment in cases not amenable to upfront radical surgery [1]. No biomarker is available to prove this relation, and clinical findings are crucial for the diagnosis of MC. Other differential diagnoses, such as infusion reaction to cancer chemotherapy, are less likely in the setting of prolonged respiratory failure. Here, a multidisciplinary approach was necessary, and involved neurologists for medical treatment and hematologists for a correct timing schedule of PEX sessions in order to avoid plasma drug displacement. It should be noted that we waited 72 hours from the end of chemotherapy before starting PEX, in order to preserve drug efficacy according to their half-life.Table 1. Comparison between present case and 4 other published cases
Fujiwara et al. [3] Qureshi et al. [4] Solak et al. [5] Ng et al. (6) Present case report
Sex Female Male Male Male Female
Age (year) 44 24 45 49 18
Histology B1 Thymoma (WHO) Thymoma Thymoma NE B2 thymoma (WHO)
Staging IVA (Masaoka-Koga) III (Masaoka-Koga) Advanced unresectable Advanced unresectable III (Masaoka-Koga)
AchR Ab level (nmol/l) 13 NE 74 NE 43
Chemotherapy regimen Primary CAMP Postoperative cisplatin and doxorubicin Single-agent cisplatin Doxorubicin, cisplatin, etoposide Primary CAP
Myasthenic crisis onset time During chemotherapy 8 hours after chemotherapy 1 week after chemotherapy A few hours after chemotherapy During chemotherapy
Tracheal intubation No Yes Yes Yes Yes
Plasma exchange No Yes Yes Yes Yes
Chemotherapy continuation in ICU No No No No Yes
Patient outcome after myasthenic crisis Alive Death Alive Alive Alive
AchR Ab acetylcholine receptor antibodies, CAMP cisplatin, doxorubicin, methylprednisolone, CAP cyclophosphamide, doxorubicin, cisplatin, ICU intensive care unit, NE not evaluable, WHO World Health Organization
To our knowledge, this is the first reported case of chemotherapy continuation despite the need for mechanical ventilation due to a chemotherapy-induced MC. Radical treatment was dependent on primary chemotherapy, as upfront surgery had already been ruled out. Besides, we could not confidently assume that, after MC resolution, the patient would have been able to receive further chemotherapy due to aggravation of symptoms. We conclude that special attention is warranted in patients with thymoma and MG with regard to the development of MC. Ideally, optimal control of myasthenic symptoms should be achieved before initiation of anticancer treatment. Nonetheless, chemotherapy-induced MC may complicate anticancer therapy administration, according to this evidence. We recommend that patients with thymoma and MG be hospitalized in tertiary medical centers for chemotherapy and that outpatient management be avoided. The lesson learned from the present case is that, in selected cases of advanced thymoma, paradoxical worsening of MG during chemotherapy should not be considered an absolute contraindication for continuation of primary chemotherapy with curative intent.
Abbreviations
CAPCisplatin, doxorubicin and cyclophosphamide
CTComputed tomography
CTCAE v5.0Common Terminology Criteria for Adverse Events version 5.0
GyGray
ICUIntensive Care Unit
MCMyasthenic crisis
MGMyasthenia gravis
MGFAMyasthenia Gravis Foundation of America
18PET-FDG18-Fluorodeoxyglucose positron emission tomography
PEXPlasma exchange
RECISTResponse Evaluation Criteria in Solid Tumours
WHOWorld Health Organization
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Fondazione Oncologia Niguarda Onlus for financial support.
Authors' contributions
GP, KB, FT, and SS were major contributors in writing the manuscript. KB, FT, GP, GM, GC, ASB, and SS provided clinical care. MP gave indication to and performed plasma exchange. AR and MT contributed to neoadjuvant treatment indication in a multidisciplinary team discussion and performed surgery. FL, AI, and ECA diagnosed thymoma and myasthenia and medically managed neurological symptoms. ASB and SS supervised oncological care and critically reviewed the case report. All authors read and approved the final manuscript.
Funding
This paper did not receive any specific grants from funding agencies in the public, commercial or not-for-profit sectors.
Ethics approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Availability of data and materials
Not applicable.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33526108 | 18,898,875 | 2021-02-02 |
What was the outcome of reaction 'Respiratory acidosis'? | Chemotherapy-induced myasthenic crisis in thymoma treated with primary chemotherapy with curative intent on mechanical ventilation: a case report and review of the literature.
BACKGROUND
Thymoma is an uncommon cancer often associated with myasthenia gravis, an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced nonmetastatic thymoma, primary chemotherapy may be required to induce tumor shrinkage and to achieve radical resection. Cancer chemotherapy has been anecdotally reported as a trigger factor for worsening of myasthenia gravis in thymic epithelial cancers. The study of uncommon cases of chemotherapy-related myasthenic crisis is warranted to gain knowledge of clinical situations requiring intensive care support in the case of life-threatening respiratory failure.
METHODS
We report a case of an 18-year-old Caucasian woman with advanced Masaoka-Koga stage III type B2 thymoma and myasthenia gravis on treatment with pyridostigmine, steroids and intravenous immunoglobulins, who developed a myasthenic crisis 2 hours after initiation of cyclophosphamide/doxorubicin/cisplatin primary chemotherapy. Because of severe acute respiratory failure, emergency tracheal intubation, mechanical ventilation, and temporary (2 hours) discontinuation of chemotherapy were needed. Considering the curative intent of the multimodal therapeutic program, we elected to resume primary chemotherapy administration while the patient remained on mechanical ventilation. After 24 hours, the recovery of adequate respiratory function allowed successful weaning from respiratory support, and no further adverse events occurred. After 3 weeks, upon plasma exchange initiation with amelioration of myasthenic symptoms, a second course of chemotherapy was given, and in week 6, having documented partial tumor remission, the patient underwent radical surgery (R0) and then consolidation radiation therapy with 50.4 Gy in 28 fractions in weeks 15-20.
CONCLUSIONS
This case report, together with the only four available in a review of the literature, highlights that chemotherapy may carry the risk of myasthenic crisis in patients affected by thymoma and myasthenia gravis. To our knowledge, this is the first reported case of chemotherapy continuation on mechanical ventilation in a patient with chemotherapy-induced myasthenic crisis requiring tracheal intubation. The lesson learned from the present case is that, in selected cases of advanced thymoma, the paradoxical worsening of myasthenia gravis during chemotherapy should not be considered an absolute contraindication for the continuation of primary chemotherapy with curative intent.
Background
Thymoma is an uncommon epithelial cancer associated in nearly half of cases with myasthenia gravis (MG), an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced thymoma, primary chemotherapy is considered the standard of care, with the aim of achieving tumor shrinkage and facilitating radical surgery [1]. While several drugs are known to worsen MG, cancer chemotherapy has been anecdotally reported as a trigger event for myasthenic crisis (MC) in four case reports [2–6]. Here, we present a case of advanced thymoma treated with primary chemotherapy that caused an acute-onset MC requiring tracheal intubation and therapeutic plasma exchange (PEX), with relevant benefit from early resumption of anticancer treatment during mechanical ventilation.
Case presentation
Clinical presentation and diagnosis
An 18-year-old Caucasian woman with unremarkable medical history was admitted to the emergency room due to neurological symptoms. She presented with month-long worsening dysphagia, rhinolalia, bilateral ptosis, and skeletal muscle weakness. Signs of muscle fatigability were elicited at the physical exam and then confirmed by electromyography, consistently with neuromuscular junction disease. Blood tests were unremarkable with the exception of acetylcholine receptor antibodies (43 nmol/l, normal if < 0.5 nmol/l). Hence, MG class III, according to the Myasthenia Gravis Foundation of America (MGFA) scale, was diagnosed [7, 8]. Partial regression of symptoms to class II MG was achieved by oral administration of pyridostigmine 60 mg every 3 hours during the daytime, pyridostigmine sustained-release 180 mg orally before sleeping, prednisone 25 mg orally each day, and immunoglobulins 0.4 g/kg intravenously for 5 days [8, 9]. Chest computed tomography (CT) revealed a 12 cm anterior mediastinal mass suspicious for thymoma, with confirmed infiltration of the anterior chest wall, lung parenchyma, and pericardium at chest magnetic resonance imaging with contrast. CT-guided fine needle aspiration biopsy yielded a histological diagnosis of B2 thymoma [10]. Due to the young age, a family history of cancer was excluded. Physical exam was negative for signs of mediastinal syndrome and superficial lymph nodes. Metastatic disease was excluded by 18-fluorodeoxyglucose positron emission tomography (18FDG-PET). Patient imaging is shown in Fig. 1. Accordingly, the clinical stage was cT3 cN0 cM0 (Masaoka-Koga III) [11]. After multidisciplinary team discussion, the tumor was defined as unresectable, and the patient was offered primary chemotherapy with intravenous cyclophosphamide 500 mg/m2, doxorubicin 50 mg/m2 and cisplatin 50 mg/m2 (CAP regimen) on day 1 every 21 days [12]. Primary prophylaxis of chemotherapy-induced neutropenia was not planned due to the potential risk of worsening MG, without evidence about the safety of administering granulocyte colony-stimulating factor in unstable myasthenic patients [13]. Ovarian preservation by gonadotropin-releasing hormone analogue leuprorelin was preferred over oocyte retrieval to expedite the start of chemotherapy [14]. Standard pre-medication with intravenous administration of ondansetron 8 mg, dexamethasone 8 mg and saline was chosen [15].Fig. 1 Patient imaging. a Left chest X-ray with enlarged mediastinum (see arrow). b Chest computed tomography scan showing the mediastinal mass (see arrow). c
18PET-FDG limited radiotracer uptake in mediastinum
Chemotherapy-induced myasthenic crisis
Two hours after starting administration of the first course of chemotherapy, following doxorubicin bolus, the patient experienced sudden onset of acute dyspnea with severe respiratory failure (oxygen saturation 75% on room air), refractory to oxygen therapy and bolus hydrocortisone 500 mg and chlorphenamine 10 mg administered intravenously [16]. Physical exam was negative for bronchospasm with diminished vesicular breath sounds. Due to unstable clinical conditions and development of acute respiratory acidosis (pH 7.21, partial pressure of carbon dioxide 88 mmHg), tracheal intubation and mechanical ventilation in the intensive care unit (ICU) were needed. Urgent chest CT scan excluded acute cardiopulmonary events. Life-threatening MGFA class V MC was diagnosed, likely triggered by chemotherapy, thus classified as grade 4 according to the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) [8, 17]. Chemotherapy was held for 2 hours and then, considering its curative intent and in agreement with the family, it was resumed and fully administered during mechanical ventilation. After 24 hours, upon remission of MC and weaning from ventilation, the patient was extubated and could continue receiving MG treatment, together with starting PEX once every three days to control MG and prevent new crises (by replacing 1 plasma volume with 5% human albumin) [18]. In week 2, owing to CTCAE v5.0 grade 3 febrile neutropenia (absolute neutrophil count 60/mm3 and body temperature 38.4 °C), the patient was successfully treated with empirical piperacillin/tazobactam 4 g/0.5 g intravenously every 6 hours until recovery [19].
Curative treatment and outcome
After completing a second course of CAP chemotherapy with interposed PEX allowing symptom control, radiological assessment in week 6 documented objective partial response according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), with 33% tumor shrinkage (maximum diameter 8 versus 12 cm) [20]. This allowed us to perform radical (R0) extended thymectomy, left upper lung lobectomy and subtotal pericardiectomy, with histological diagnosis of Masaoka-Koga stage III type B2 [10, 11]. For patient histology, please see Fig. 2. The patient required early mediastinum and pleural cavity re-exploration due to postsurgical bleeding; persistent hypophonia developed due to postsurgical left vocal cord paralysis. A comparison of CT imaging at baseline and after surgery is shown in Fig. 3. As suggested for Masaoka-Koga stage III, radiotherapy of 50.4 Gy in 28 fractions was given as postoperative treatment in weeks 15–20 [1]. At the last follow-up visit, 6 months after surgery, the patient was in complete remission with gradually improving MGFA class I MG and mild persistent hypophonia [8]. Despite remarkable levels of psychological burden, the patient’s resilience and high-priority treatment goals were fundamental for successful coping.Fig. 2 Patient histology. a Hematoxylin and eosin (H&E; ×40 view) stained section of thymoma B2 according to WHO classification. b Same histological slice in ×100 view
Fig. 3 Chest computed tomography (CT) scan at baseline and after surgery. a Chest CT scan showing thymoma at baseline. b Postsurgical chest CT scan with no residual disease
Discussion and conclusions
According to the World Health Organization (WHO), thymoma is the most common variant of thymic epithelial tumors (66.3%), usually presenting with local invasion and seldom as metastatic disease [10, 21]. Overall, thymic epithelial tumors occur at a rate of 0.13–0.32 cases per 100,000 population at risk and are very uncommon in young adults [22, 23]. To our knowledge, the largest retrospective study regarding childhood thymic tumors (< 18 years) in Europe was able to identify only 36 cases during a 12-year period, confirming the extreme rarity of thymic cancer in children and adolescents [24]. Hence, the clinical case reported here has to be considered a peculiar presentation of early-onset thymoma (Fig. 4).Fig. 4 Age-specific incidence of thymic cancer by histological type. SEER*Stat Database: NPCR [National Program of Cancer Registries] and SEER [Surveillance, Epidemiology, and End Results] Incidence—U.S. Cancer Statistics Public Use Database, Nov 2017 submission (2001–2015). The green bar highlights the reported patient age interval (15–19 years)
Like thymoma, MG is extremely rare (0.17–2.13 per 100,000 person-years) [25]; however, it affects up to 30% of patients with thymoma [26]. The association of thymoma with MG has been related to the intratumoral generation of mature T cells, although the pathogenic mechanisms remain unclear [27]. MG has been found to be most commonly associated with B thymoma and confers favorable prognosis, since neuromuscular symptoms help in earlier detection of the tumor and thus less advanced stage at diagnosis. Nevertheless, concomitant MG should also be regarded as an adverse risk factor, since it can interfere with cancer treatment, being worsened by many drugs, and it reaches its maximum severity after thymectomy in a proportion of patients [28].
The case reported here, together with those published and summarized in Table 1 [3–6], highlights that chemotherapy is a realistic trigger event of MC in patients with thymoma and MG. The temporary association in all cases indicates a causative relation, and may hamper the continuation of chemotherapy that is a crucial element of multimodal treatment in cases not amenable to upfront radical surgery [1]. No biomarker is available to prove this relation, and clinical findings are crucial for the diagnosis of MC. Other differential diagnoses, such as infusion reaction to cancer chemotherapy, are less likely in the setting of prolonged respiratory failure. Here, a multidisciplinary approach was necessary, and involved neurologists for medical treatment and hematologists for a correct timing schedule of PEX sessions in order to avoid plasma drug displacement. It should be noted that we waited 72 hours from the end of chemotherapy before starting PEX, in order to preserve drug efficacy according to their half-life.Table 1. Comparison between present case and 4 other published cases
Fujiwara et al. [3] Qureshi et al. [4] Solak et al. [5] Ng et al. (6) Present case report
Sex Female Male Male Male Female
Age (year) 44 24 45 49 18
Histology B1 Thymoma (WHO) Thymoma Thymoma NE B2 thymoma (WHO)
Staging IVA (Masaoka-Koga) III (Masaoka-Koga) Advanced unresectable Advanced unresectable III (Masaoka-Koga)
AchR Ab level (nmol/l) 13 NE 74 NE 43
Chemotherapy regimen Primary CAMP Postoperative cisplatin and doxorubicin Single-agent cisplatin Doxorubicin, cisplatin, etoposide Primary CAP
Myasthenic crisis onset time During chemotherapy 8 hours after chemotherapy 1 week after chemotherapy A few hours after chemotherapy During chemotherapy
Tracheal intubation No Yes Yes Yes Yes
Plasma exchange No Yes Yes Yes Yes
Chemotherapy continuation in ICU No No No No Yes
Patient outcome after myasthenic crisis Alive Death Alive Alive Alive
AchR Ab acetylcholine receptor antibodies, CAMP cisplatin, doxorubicin, methylprednisolone, CAP cyclophosphamide, doxorubicin, cisplatin, ICU intensive care unit, NE not evaluable, WHO World Health Organization
To our knowledge, this is the first reported case of chemotherapy continuation despite the need for mechanical ventilation due to a chemotherapy-induced MC. Radical treatment was dependent on primary chemotherapy, as upfront surgery had already been ruled out. Besides, we could not confidently assume that, after MC resolution, the patient would have been able to receive further chemotherapy due to aggravation of symptoms. We conclude that special attention is warranted in patients with thymoma and MG with regard to the development of MC. Ideally, optimal control of myasthenic symptoms should be achieved before initiation of anticancer treatment. Nonetheless, chemotherapy-induced MC may complicate anticancer therapy administration, according to this evidence. We recommend that patients with thymoma and MG be hospitalized in tertiary medical centers for chemotherapy and that outpatient management be avoided. The lesson learned from the present case is that, in selected cases of advanced thymoma, paradoxical worsening of MG during chemotherapy should not be considered an absolute contraindication for continuation of primary chemotherapy with curative intent.
Abbreviations
CAPCisplatin, doxorubicin and cyclophosphamide
CTComputed tomography
CTCAE v5.0Common Terminology Criteria for Adverse Events version 5.0
GyGray
ICUIntensive Care Unit
MCMyasthenic crisis
MGMyasthenia gravis
MGFAMyasthenia Gravis Foundation of America
18PET-FDG18-Fluorodeoxyglucose positron emission tomography
PEXPlasma exchange
RECISTResponse Evaluation Criteria in Solid Tumours
WHOWorld Health Organization
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Fondazione Oncologia Niguarda Onlus for financial support.
Authors' contributions
GP, KB, FT, and SS were major contributors in writing the manuscript. KB, FT, GP, GM, GC, ASB, and SS provided clinical care. MP gave indication to and performed plasma exchange. AR and MT contributed to neoadjuvant treatment indication in a multidisciplinary team discussion and performed surgery. FL, AI, and ECA diagnosed thymoma and myasthenia and medically managed neurological symptoms. ASB and SS supervised oncological care and critically reviewed the case report. All authors read and approved the final manuscript.
Funding
This paper did not receive any specific grants from funding agencies in the public, commercial or not-for-profit sectors.
Ethics approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Availability of data and materials
Not applicable.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33526108 | 18,959,226 | 2021-02-02 |
What was the outcome of reaction 'Respiratory failure'? | Chemotherapy-induced myasthenic crisis in thymoma treated with primary chemotherapy with curative intent on mechanical ventilation: a case report and review of the literature.
BACKGROUND
Thymoma is an uncommon cancer often associated with myasthenia gravis, an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced nonmetastatic thymoma, primary chemotherapy may be required to induce tumor shrinkage and to achieve radical resection. Cancer chemotherapy has been anecdotally reported as a trigger factor for worsening of myasthenia gravis in thymic epithelial cancers. The study of uncommon cases of chemotherapy-related myasthenic crisis is warranted to gain knowledge of clinical situations requiring intensive care support in the case of life-threatening respiratory failure.
METHODS
We report a case of an 18-year-old Caucasian woman with advanced Masaoka-Koga stage III type B2 thymoma and myasthenia gravis on treatment with pyridostigmine, steroids and intravenous immunoglobulins, who developed a myasthenic crisis 2 hours after initiation of cyclophosphamide/doxorubicin/cisplatin primary chemotherapy. Because of severe acute respiratory failure, emergency tracheal intubation, mechanical ventilation, and temporary (2 hours) discontinuation of chemotherapy were needed. Considering the curative intent of the multimodal therapeutic program, we elected to resume primary chemotherapy administration while the patient remained on mechanical ventilation. After 24 hours, the recovery of adequate respiratory function allowed successful weaning from respiratory support, and no further adverse events occurred. After 3 weeks, upon plasma exchange initiation with amelioration of myasthenic symptoms, a second course of chemotherapy was given, and in week 6, having documented partial tumor remission, the patient underwent radical surgery (R0) and then consolidation radiation therapy with 50.4 Gy in 28 fractions in weeks 15-20.
CONCLUSIONS
This case report, together with the only four available in a review of the literature, highlights that chemotherapy may carry the risk of myasthenic crisis in patients affected by thymoma and myasthenia gravis. To our knowledge, this is the first reported case of chemotherapy continuation on mechanical ventilation in a patient with chemotherapy-induced myasthenic crisis requiring tracheal intubation. The lesson learned from the present case is that, in selected cases of advanced thymoma, the paradoxical worsening of myasthenia gravis during chemotherapy should not be considered an absolute contraindication for the continuation of primary chemotherapy with curative intent.
Background
Thymoma is an uncommon epithelial cancer associated in nearly half of cases with myasthenia gravis (MG), an autoimmune disorder of the neuromuscular junction characterized by muscular fatigability. In patients with advanced thymoma, primary chemotherapy is considered the standard of care, with the aim of achieving tumor shrinkage and facilitating radical surgery [1]. While several drugs are known to worsen MG, cancer chemotherapy has been anecdotally reported as a trigger event for myasthenic crisis (MC) in four case reports [2–6]. Here, we present a case of advanced thymoma treated with primary chemotherapy that caused an acute-onset MC requiring tracheal intubation and therapeutic plasma exchange (PEX), with relevant benefit from early resumption of anticancer treatment during mechanical ventilation.
Case presentation
Clinical presentation and diagnosis
An 18-year-old Caucasian woman with unremarkable medical history was admitted to the emergency room due to neurological symptoms. She presented with month-long worsening dysphagia, rhinolalia, bilateral ptosis, and skeletal muscle weakness. Signs of muscle fatigability were elicited at the physical exam and then confirmed by electromyography, consistently with neuromuscular junction disease. Blood tests were unremarkable with the exception of acetylcholine receptor antibodies (43 nmol/l, normal if < 0.5 nmol/l). Hence, MG class III, according to the Myasthenia Gravis Foundation of America (MGFA) scale, was diagnosed [7, 8]. Partial regression of symptoms to class II MG was achieved by oral administration of pyridostigmine 60 mg every 3 hours during the daytime, pyridostigmine sustained-release 180 mg orally before sleeping, prednisone 25 mg orally each day, and immunoglobulins 0.4 g/kg intravenously for 5 days [8, 9]. Chest computed tomography (CT) revealed a 12 cm anterior mediastinal mass suspicious for thymoma, with confirmed infiltration of the anterior chest wall, lung parenchyma, and pericardium at chest magnetic resonance imaging with contrast. CT-guided fine needle aspiration biopsy yielded a histological diagnosis of B2 thymoma [10]. Due to the young age, a family history of cancer was excluded. Physical exam was negative for signs of mediastinal syndrome and superficial lymph nodes. Metastatic disease was excluded by 18-fluorodeoxyglucose positron emission tomography (18FDG-PET). Patient imaging is shown in Fig. 1. Accordingly, the clinical stage was cT3 cN0 cM0 (Masaoka-Koga III) [11]. After multidisciplinary team discussion, the tumor was defined as unresectable, and the patient was offered primary chemotherapy with intravenous cyclophosphamide 500 mg/m2, doxorubicin 50 mg/m2 and cisplatin 50 mg/m2 (CAP regimen) on day 1 every 21 days [12]. Primary prophylaxis of chemotherapy-induced neutropenia was not planned due to the potential risk of worsening MG, without evidence about the safety of administering granulocyte colony-stimulating factor in unstable myasthenic patients [13]. Ovarian preservation by gonadotropin-releasing hormone analogue leuprorelin was preferred over oocyte retrieval to expedite the start of chemotherapy [14]. Standard pre-medication with intravenous administration of ondansetron 8 mg, dexamethasone 8 mg and saline was chosen [15].Fig. 1 Patient imaging. a Left chest X-ray with enlarged mediastinum (see arrow). b Chest computed tomography scan showing the mediastinal mass (see arrow). c
18PET-FDG limited radiotracer uptake in mediastinum
Chemotherapy-induced myasthenic crisis
Two hours after starting administration of the first course of chemotherapy, following doxorubicin bolus, the patient experienced sudden onset of acute dyspnea with severe respiratory failure (oxygen saturation 75% on room air), refractory to oxygen therapy and bolus hydrocortisone 500 mg and chlorphenamine 10 mg administered intravenously [16]. Physical exam was negative for bronchospasm with diminished vesicular breath sounds. Due to unstable clinical conditions and development of acute respiratory acidosis (pH 7.21, partial pressure of carbon dioxide 88 mmHg), tracheal intubation and mechanical ventilation in the intensive care unit (ICU) were needed. Urgent chest CT scan excluded acute cardiopulmonary events. Life-threatening MGFA class V MC was diagnosed, likely triggered by chemotherapy, thus classified as grade 4 according to the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) [8, 17]. Chemotherapy was held for 2 hours and then, considering its curative intent and in agreement with the family, it was resumed and fully administered during mechanical ventilation. After 24 hours, upon remission of MC and weaning from ventilation, the patient was extubated and could continue receiving MG treatment, together with starting PEX once every three days to control MG and prevent new crises (by replacing 1 plasma volume with 5% human albumin) [18]. In week 2, owing to CTCAE v5.0 grade 3 febrile neutropenia (absolute neutrophil count 60/mm3 and body temperature 38.4 °C), the patient was successfully treated with empirical piperacillin/tazobactam 4 g/0.5 g intravenously every 6 hours until recovery [19].
Curative treatment and outcome
After completing a second course of CAP chemotherapy with interposed PEX allowing symptom control, radiological assessment in week 6 documented objective partial response according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), with 33% tumor shrinkage (maximum diameter 8 versus 12 cm) [20]. This allowed us to perform radical (R0) extended thymectomy, left upper lung lobectomy and subtotal pericardiectomy, with histological diagnosis of Masaoka-Koga stage III type B2 [10, 11]. For patient histology, please see Fig. 2. The patient required early mediastinum and pleural cavity re-exploration due to postsurgical bleeding; persistent hypophonia developed due to postsurgical left vocal cord paralysis. A comparison of CT imaging at baseline and after surgery is shown in Fig. 3. As suggested for Masaoka-Koga stage III, radiotherapy of 50.4 Gy in 28 fractions was given as postoperative treatment in weeks 15–20 [1]. At the last follow-up visit, 6 months after surgery, the patient was in complete remission with gradually improving MGFA class I MG and mild persistent hypophonia [8]. Despite remarkable levels of psychological burden, the patient’s resilience and high-priority treatment goals were fundamental for successful coping.Fig. 2 Patient histology. a Hematoxylin and eosin (H&E; ×40 view) stained section of thymoma B2 according to WHO classification. b Same histological slice in ×100 view
Fig. 3 Chest computed tomography (CT) scan at baseline and after surgery. a Chest CT scan showing thymoma at baseline. b Postsurgical chest CT scan with no residual disease
Discussion and conclusions
According to the World Health Organization (WHO), thymoma is the most common variant of thymic epithelial tumors (66.3%), usually presenting with local invasion and seldom as metastatic disease [10, 21]. Overall, thymic epithelial tumors occur at a rate of 0.13–0.32 cases per 100,000 population at risk and are very uncommon in young adults [22, 23]. To our knowledge, the largest retrospective study regarding childhood thymic tumors (< 18 years) in Europe was able to identify only 36 cases during a 12-year period, confirming the extreme rarity of thymic cancer in children and adolescents [24]. Hence, the clinical case reported here has to be considered a peculiar presentation of early-onset thymoma (Fig. 4).Fig. 4 Age-specific incidence of thymic cancer by histological type. SEER*Stat Database: NPCR [National Program of Cancer Registries] and SEER [Surveillance, Epidemiology, and End Results] Incidence—U.S. Cancer Statistics Public Use Database, Nov 2017 submission (2001–2015). The green bar highlights the reported patient age interval (15–19 years)
Like thymoma, MG is extremely rare (0.17–2.13 per 100,000 person-years) [25]; however, it affects up to 30% of patients with thymoma [26]. The association of thymoma with MG has been related to the intratumoral generation of mature T cells, although the pathogenic mechanisms remain unclear [27]. MG has been found to be most commonly associated with B thymoma and confers favorable prognosis, since neuromuscular symptoms help in earlier detection of the tumor and thus less advanced stage at diagnosis. Nevertheless, concomitant MG should also be regarded as an adverse risk factor, since it can interfere with cancer treatment, being worsened by many drugs, and it reaches its maximum severity after thymectomy in a proportion of patients [28].
The case reported here, together with those published and summarized in Table 1 [3–6], highlights that chemotherapy is a realistic trigger event of MC in patients with thymoma and MG. The temporary association in all cases indicates a causative relation, and may hamper the continuation of chemotherapy that is a crucial element of multimodal treatment in cases not amenable to upfront radical surgery [1]. No biomarker is available to prove this relation, and clinical findings are crucial for the diagnosis of MC. Other differential diagnoses, such as infusion reaction to cancer chemotherapy, are less likely in the setting of prolonged respiratory failure. Here, a multidisciplinary approach was necessary, and involved neurologists for medical treatment and hematologists for a correct timing schedule of PEX sessions in order to avoid plasma drug displacement. It should be noted that we waited 72 hours from the end of chemotherapy before starting PEX, in order to preserve drug efficacy according to their half-life.Table 1. Comparison between present case and 4 other published cases
Fujiwara et al. [3] Qureshi et al. [4] Solak et al. [5] Ng et al. (6) Present case report
Sex Female Male Male Male Female
Age (year) 44 24 45 49 18
Histology B1 Thymoma (WHO) Thymoma Thymoma NE B2 thymoma (WHO)
Staging IVA (Masaoka-Koga) III (Masaoka-Koga) Advanced unresectable Advanced unresectable III (Masaoka-Koga)
AchR Ab level (nmol/l) 13 NE 74 NE 43
Chemotherapy regimen Primary CAMP Postoperative cisplatin and doxorubicin Single-agent cisplatin Doxorubicin, cisplatin, etoposide Primary CAP
Myasthenic crisis onset time During chemotherapy 8 hours after chemotherapy 1 week after chemotherapy A few hours after chemotherapy During chemotherapy
Tracheal intubation No Yes Yes Yes Yes
Plasma exchange No Yes Yes Yes Yes
Chemotherapy continuation in ICU No No No No Yes
Patient outcome after myasthenic crisis Alive Death Alive Alive Alive
AchR Ab acetylcholine receptor antibodies, CAMP cisplatin, doxorubicin, methylprednisolone, CAP cyclophosphamide, doxorubicin, cisplatin, ICU intensive care unit, NE not evaluable, WHO World Health Organization
To our knowledge, this is the first reported case of chemotherapy continuation despite the need for mechanical ventilation due to a chemotherapy-induced MC. Radical treatment was dependent on primary chemotherapy, as upfront surgery had already been ruled out. Besides, we could not confidently assume that, after MC resolution, the patient would have been able to receive further chemotherapy due to aggravation of symptoms. We conclude that special attention is warranted in patients with thymoma and MG with regard to the development of MC. Ideally, optimal control of myasthenic symptoms should be achieved before initiation of anticancer treatment. Nonetheless, chemotherapy-induced MC may complicate anticancer therapy administration, according to this evidence. We recommend that patients with thymoma and MG be hospitalized in tertiary medical centers for chemotherapy and that outpatient management be avoided. The lesson learned from the present case is that, in selected cases of advanced thymoma, paradoxical worsening of MG during chemotherapy should not be considered an absolute contraindication for continuation of primary chemotherapy with curative intent.
Abbreviations
CAPCisplatin, doxorubicin and cyclophosphamide
CTComputed tomography
CTCAE v5.0Common Terminology Criteria for Adverse Events version 5.0
GyGray
ICUIntensive Care Unit
MCMyasthenic crisis
MGMyasthenia gravis
MGFAMyasthenia Gravis Foundation of America
18PET-FDG18-Fluorodeoxyglucose positron emission tomography
PEXPlasma exchange
RECISTResponse Evaluation Criteria in Solid Tumours
WHOWorld Health Organization
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We thank Fondazione Oncologia Niguarda Onlus for financial support.
Authors' contributions
GP, KB, FT, and SS were major contributors in writing the manuscript. KB, FT, GP, GM, GC, ASB, and SS provided clinical care. MP gave indication to and performed plasma exchange. AR and MT contributed to neoadjuvant treatment indication in a multidisciplinary team discussion and performed surgery. FL, AI, and ECA diagnosed thymoma and myasthenia and medically managed neurological symptoms. ASB and SS supervised oncological care and critically reviewed the case report. All authors read and approved the final manuscript.
Funding
This paper did not receive any specific grants from funding agencies in the public, commercial or not-for-profit sectors.
Ethics approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Availability of data and materials
Not applicable.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33526108 | 18,959,226 | 2021-02-02 |
What was the outcome of reaction 'COVID-19'? | SARS-CoV-2-specific humoral and cellular immunity in two renal transplants and two hemodialysis patients treated with convalescent plasma.
When patients with chronic kidney disease are infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) they can face two specific problems: virus-specific immune responses may be impaired and remdesivir, an antiviral drug described to shorten recovery, is contraindicated. Antiviral treatment with convalescent plasma (CP) could be an alternative treatment option. In this case report, we present two kidney transplant recipients and two hemodialysis patients who were infected with SARS-CoV-2 and received CP. Antibodies against the receptor-binding domain in the S1 subunit of the SARS-CoV-2 spike protein were determined sequentially by immunoglobulin G (IgG) enzyme-linked immunosorbent assay (ELISA) and neutralization assay and specific cellular responses by interferon-gamma ELISpot. Before treatment, in both kidney transplant recipients and one hemodialysis patient antibodies were undetectable by ELISA (ratio < 1.1), corresponding to low neutralizing antibody titers (≤1:40). ELISpot responses in the four patients were either weak or absent. After CP treatment, we observed an increase of SARS-CoV-2-specific antibodies (IgG ratio and neutralization titer) and of specific cellular responses. After intermittent clinical improvement, one kidney transplant recipient again developed typical symptoms on Day 12 after treatment and received a second cycle of CP treatment. Altogether, three patients clinically improved and could be discharged from the hospital. However, one 83-year-old multimorbid patient deceased. Our data suggest that the success of CP therapy may only be temporary in patients with chronic kidney disease; which requires close monitoring of viral load and antiviral immunity and possibly an adaptation of the treatment regimen.
1 INTRODUCTION
In patients with chronic kidney disease and infected with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) treatment can be complicated because their immune function is suppressed due to medication to prevent allograft rejection and/or the underlying kidney disease. Thereby, the formation of specific antibodies and of T‐cell immunity is impaired; which can result in a prolonged persistence of SARS‐CoV‐2 (for up to 2 months 1 ). Furthermore, remdesivir, an antiviral nucleoside analog that shortened the time to recovery in adults hospitalized with coronavirus 2019 (COVID‐19) disease, 2 is contraindicated in this special cohort. Antiviral treatment with convalescent plasma (CP) could be an alternative treatment option. Data on patients with chronic kidney disease infected with SARS‐CoV‐2 and receiving CP treatment are still limited. We are aware of only 14 described kidney transplant recipients who received CP. 3 , 4 , 5 , 6 , 7 Whereas clinical improvement after CP has been shown for all six kidney transplant recipients included in three studies, 3 , 4 , 5 in the fourth study 6 a mortality rate for solid organ recipients (including six with kidney allograft) in the range of recipients without CP treatment 8 , 9 , 10 was reported (23% 6 vs. 24%–32%, 8 , 9 , 10 respectively). In the fifth study describing HIV‐infected kidney transplant recipients 7 one of the two patients died after having received CP treatment. However, the previous reports did not present data on the course of SARS‐CoV‐2‐specific antibodies or cellular responses in the patients.
It was the aim of the current study to follow‐up up virus‐specific humoral and cellular immunity in patients with chronic kidney disease who were infected with SARS‐CoV‐2 and received CP therapy. We functionally analyzed the antibodies (by neutralization assay) and measured specific cellular responses by the highly sensitive ELISpot method, using various protein antigens of SARS‐CoV‐2 as specific stimuli. Finally, in one transplant recipient who again developed typical COVID‐19 symptoms after initial clinical improvement, we had the chance to modify the treatment regimen and to apply the second cycle of CP therapy.
2 MATERIALS AND METHODS
2.1 Patients and blood donors
The current case report includes two renal transplant recipients and two hemodialysis patients (Table 1) and their respective CP donors. Within the study period (July 27 to September 9, 2020), all SARS‐CoV‐2 infected renal transplant and hemodialysis patients with an estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73 m2 were included. The four patients included in the current study had chronic kidney disease according to the eGFR of 7–29 ml/min/1.73 m2. Both transplant recipients received tacrolimus, mycophenolate mofetil, and prednisone, both hemodialysis patients dexamethasone. The kidney transplant recipients were treated with prednisone to prevent organ rejection (which was not changed due to COVID‐19 infection), whereas the dialysis‐requiring patients were specifically treated with dexamethasone for 5 days to prevent an exaggerated immune response during COVID‐19 infection. Treatment with CP started when patients with chronic kidney disease without detectable immunoglobulin G (IgG) antibodies against SARS‐CoV‐2 showed increasing oxygen demand/clinical deterioration (RTX01, RTX02, and HD01) or when oxygen supply via nasal cannula was no longer sufficient in a patient with chronic kidney disease with detectable antibodies (HD02). One patient suffered from moderate (RTX02) and three from severe COVID‐19 disease. 11 More detailed information on the patients and the therapy used can be found in Table 1. One cycle of CP consisted of three units, separated with the Amicus™ (Fresenius Kabi), each containing 200–280 ml, which was applied at Days 1, 3, and 5. The study was approved by the local ethics committee (20‐9256‐BO for the patients and 20‐9225‐BO for the donors) and the study participants provided written informed consent. The procedures were in accordance with the institutional and national ethical standards as well as with the Helsinki Declaration of 1975, as revised in 2013. Four donors were selected based on their SARS‐CoV‐2 IgG ratio after polymerase chain reaction (PCR)‐confirmed SARS‐CoV‐2 infection and additional parameters like blood group and weight (Table 2). Details on the donor selection criteria have been described recently. 12
Table 1 Clinical characteristics of patients with chronic kidney disease
ID Sex/age/blood group CP intervala (days) CP units/cycles (Pre‐existing) comorbidity/cause of death COVID‐19 therapy Severity of COVID‐19 disease/outcome (discharge from hospitalb)
RTX01 F/63/O 3 6/2 RTX 1997 and 2001, chronic antibody‐mediated rejection, hypertension, asthma bronchial, reactive arthritis Oxygen administration via nasal cannula Severec/A (d28)
RTX02 F/62/A 13 3/1 RTX 14.08.2020 (13 days before SARS‐CoV‐2 infection), steroid‐induced diabetes, hypertension No oxygen necessary (minimum oxygen saturation 92%) Moderate (CT: pneumonia, but clinically asymptomatic)/A (d16)
HD01 F/83/A 4 2d/1 HD since 02/2012, type II diabetes, coronary heart disease, atrial fibrillation, apoplexy, acute event of fall (no evidence of stroke)/COVID‐19 pneumonia Oxygen administration first via nasal cannula, then 50–60 L/min high‐flow ventilation (FiO2 60%), dexamethasone Severec/D
HD02 F/78/O 7 3/1 HD since 01/2020, type II diabetes, hypertension, chronic obstructive pulmonary disease, adipositas Oxygen administration via nasal cannula, dexamethasone Severec/A (d8)
Abbreviations: A, alive; COVID, coronavirus; CP, convalescent plasma; CT, computed tomography; D, deceased; HD, hemodialysis; RTX, renal transplantation; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus 2.
a Interval between the onset of symptoms or positivity to SARS‐CoV‐2 polymerase chain reaction and treatment with CP.
b Discharge from hospital given as days after initiation of CP treatment.
c Oxygen supplementation but no mechanical ventilation.
d The patient deceased due to COVID‐19 pneumonia after having received two CP units.
John Wiley & Sons, Ltd.
This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.
Table 2 Characteristics of convalescent plasma donors
ID Sex Age Blood group Antibody ratio Neutralizing antibody titer HLA antibodies
D‐RTX01 F 55 O 5.83 1:1280 neg
D‐RTX02 M 53 A 7.33 1:320 neg
D‐HD01 M 40 A 10.44 1:160 neg
D‐HD02 F 48 O 3.39 1:320 neg
Abbreviations: D, donor; neg, negative.
John Wiley & Sons, Ltd.
This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.
2.2 Antibody enzyme‐linked immunosorbent assay
To assess SARS‐CoV‐2‐specific humoral immunity, IgG antibodies in donor and patient sera were determined by a CE marked anti‐SARS‐CoV‐2 IgG semi‐quantitative enzyme‐linked immunosorbent assay (ELISA; Euroimmun), according to the manufacturer's instructions. The ELISA plates were coated with recombinant SARS‐CoV‐2 spike (S) 1 protein (receptor binding domain). Serum samples were analyzed automatically at a 1:100 dilution, using the Immunomat™ (Virion\Serion). Results are given as a ratio (patient sample/control sample). An antibody ratio of ≥1.1 was considered positive, of ≥0.8 to <1.1 borderlines and of <0.8 negative.
2.3 Virus neutralization assay
The function of specific antibodies was measured by a cell‐culture based neutralization assay, using Vero E6 cells (ATCC® CRL‐1586™) and a clinical isolate of SARS‐CoV‐2 in a biosafety level 3 laboratory. 12 , 13 Neutralization capacity was determined by endpoint dilution assay, expressed as 50% tissue culture infective dose (TCID50)/ml. Serial dilutions (1:20 to 1:1280) of the respective sera were preincubated with 100 TCID50 of SARS‐CoV‐2 for 1 h at 37°C and added afterward to confluent Vero E6 cells cultured in 96‐well microtiter plates. On Day 3 after infection, the cells were stained with crystal violet (Roth) solved in 20% methanol (Merck) and the appearance of cytopathic effects (CPE) was analyzed by light microscopy. The neutralizing titer was defined as the reciprocal of the highest serum dilution at which no CPE breakthrough in any of the triplicate cultures was observed.
2.4 ELISpot assay
To assess SARS‐CoV‐2‐specific cellular immunity, we performed ELISpot assays, using peptide pools of the S1/S2 protein, the S1 protein, and the membrane (M) protein (PepTivator®, Miltenyi Biotec) and an S1 protein antigen of SARS‐CoV‐2 (Sino Biological). The peptide pools consist mainly of 15‐mer sequences with 11 amino acids overlap. We tested 250,000 peripheral blood mononuclear cells per cell culture and measured interferon‐gamma (IFN‐γ) production after 19 h, as published recently in detail. 12 Spot numbers were analyzed by an ELISpot reader (AID Fluorospot; Autoimmun Diagnostika GmbH). Mean values of duplicate cell cultures were considered. SARS‐CoV‐2‐specific spots were determined as stimulated minus nonstimulated (background) values (spots increment). We defined threefold higher SARS‐CoV‐2‐specific spots versus background together with at least three spots above background as a positive response. This cut‐off was set based on negative control values as specified previously. 12
3 RESULTS
In both kidney recipients and one hemodialysis patient with undetectable SARS‐CoV‐2‐specific IgG (ratio < 1.1) and low neutralizing antibody titers ( ≤ 1:40; RTX01, RTX02, and HD01; Table 1) we observed an increase of antibody titers (Figure 1A‐C). A 63‐year‐old female who was transplanted twice (RTX01) initially showed a clinical response to CP therapy, but at Day 12 again developed typical symptoms of COVID‐19 disease (fever and shortage of air; Figure 2A,B). Therefore, she received another cycle of CP therapy (from the same donor). SARS‐CoV‐2 antibodies increased after both CP cycles and SARS‐CoV‐2 viral load decreased (C t value to the PCR increased from 17.8 to 25.8 after the first and to 34.9 after the second CP cycle; Figure 2C). The patient could be discharged from the hospital on Day 28 after initiation of CP treatment. Since Day 13 after initiation of CP therapy oxygen supplementation via nasal cannula could be completely stopped and at Day 29 viral load became undetectable. The second kidney transplant recipient (RTX02), a 62‐year‐old female who received her graft 13 days before the detection of SARS‐CoV‐2 infection, also showed a decrease of the viral load (C t value to the PCR increased from 21.6 to 30.3 after the CP cycle and to 35.4 on Day 16 after initiation of CP treatment, when the patient was discharged from the hospital). On Day 39 after CP therapy, SARS‐CoV‐2 viral load became undetectable in the nasopharyngeal swab. The third patient, an 83‐year‐old multimorbid female (HD01), showed no clinical improvement despite increasing neutralizing antibody titers and decreasing C‐reactive protein and deceased due to COVID‐19 pneumonia on Day 4 after initiation of CP therapy. She had been on hemodialysis for 8 years, suffered from diabetes mellitus, coronary heart disease, had apoplexy in 2010, and an acute event of fall.
Figure 1 Course of specific humoral and cellular immunity in four patients with chronic kidney disease infected with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and receiving convalescent plasma treatment. Antibodies were determined by an S1 specific immunoglobulin G (IgG) enzyme‐linked immunosorbent assay (Euroimmun) and by cell‐culture based neutralization assay (NT titer). Cellular responses were analyzed by an interferon‐gamma (IFN‐γ) ELISpot assay, using peptide pools of the S1/S2, S1, and M protein and an S1 protein antigen as specific stimuli (depicted as S1/S2, S1, M, and S ELI). We here present data on two kidney transplant recipients (RTX01, RTX02) and two patients on hemodialysis (HD01, HD02) and compared their immune responses with those of the corresponding donors of convalescent plasma (CP; shaded area). SARS‐CoV‐2‐specific antibody data (IgG ratio and NT titer) are given on the left Y‐axis and ELISpot data on the right one. Horizontal dashed lines represent the cut‐off values for positive reactions (IgG ratio of 1.1 and NT titer of 1:20). Vertical dotted lines indicate the time points of convalescent plasma applications (CP1, CP2, and CP3). Related data points are connected. PBMC, peripheral blood mononuclear cells
Figure 2 Course of oxygen demand, C‐reactive protein, and severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) viral load in four patients with chronic kidney disease infected with SARS‐CoV‐2 and receiving convalescent plasma treatment. We here present data on two kidney transplant recipients (RTX01, RTX02) and two patients on hemodialysis (HD01, HD02) which were tested up to Day 39 after receiving convalescent plasma (CP). Vertical dotted lines indicate the time points of convalescent plasma applications (CP1, CP2, and CP3). Of note, only RTX01 received two cycles of CP while the remaining three patients received one cycle. A ct value of SARS‐CoV‐2 RNA > 40 was considered negative
The antibody ratios in these first three patients before the CP therapy were 0.15, 0.14, and 0.17, and the respective neutralizing antibody titers 1:20, <1:20, and 1:40. After CP therapy, antibodies in the patients reached a maximum ratio of 3.07, 2.19, and 3.70, corresponding to a neutralizing titer of up to 1:640, 1:160, and 1:640, respectively. In the donors, the antibody ratios were 5.83, 7.33, and 10.44, and the neutralizing titers 1:1280, 1:320, and 1:160, respectively.
The fourth patient, a 78‐year‐old female with pre‐existing antibodies (HD02), showed rapid clinical improvement and could be discharged from the hospital on Day 8 after initiation of CP treatment. Before CP treatment, SARS‐CoV‐2 was detectable by PCR at a low level (C t value of 31.1). On Day 14 after CP therapy, viral load was undetectable. The patient also showed an increase of specific immunity (ratio 5.96 → 7.01; neutralizing titer 1:640 → 1:1280; Figure 1D). However, SARS‐CoV‐2‐specific antibodies in the CP donor of the fourth patient were lower than in the patient (ratio: 3.39, neutralizing titer: 1:320).
Cellular immunity could be followed‐up by IFN‐γ ELISpot, using four different SARS‐CoV‐2‐specific antigens (peptide pools of the S1/S2, S1, and M protein and an S1 protein antigen). Before CP treatment, one patient was negative to the ELISpot (HD02) and three showed weak responses (RTX01, RTX02, and HD01). Three patients could be followed‐up after CP treatment. In these three patients, IFN‐γ production to the ELISpot intermittently increased, reaching a maximum at Days 6–14 after CP therapy.
4 DISCUSSION
Our data show an increase of specific humoral and cellular immunity in two kidney transplant recipients and two hemodialysis patients with SARS‐CoV‐2 infection after treatment with CP. This may represent the natural course of infection. However, the increase of immune responses occurred very close in time to the administration of CP; which suggests that there may be a causal relationship between treatment with CP and the increase in humoral and cellular immune responses. CP contains neutralizing antibodies as well as anti‐inflammatory cytokines and other immunomodulatory proteins. This combination could improve virus control in immunocompromised patients. 3 CP therapy thus could bridge the phase of acute COVID‐19 disease. However, presumably due to drug‐induced immunosuppression or impaired kidney function, the immune responses were not as long‐acting as expected. In one patient with two prior kidney transplantations (RTX01) two cycles of therapy were necessary for successful treatment. It can be supposed that the patient herself was unable to mount an adequate antibody response and that the passively transferred antibodies partly bound the virus that resides in the affected organs and in the respective lymphoid tissue. 14 Theoretically, it is possible that CP therapy mitigates the native humoral immune response and leaves an individual vulnerable to subsequent reinfection with SARS‐CoV‐2. 3 , 15 This phenomenon appears more likely in immunosuppressed versus otherwise healthy individuals. Concerning ELISpot data, we observed a maximum of IFN‐γ responses shortly after completion of the CP cycle. Of note, cellular immunity is regarded as important for recovery from SARS‐CoV‐2 infection 16 and appears as short‐lived in the current cohort. As CP therapy is a form of passive immunization, an increase in cellular responses is not expected at first glance. After an initial increase, IFN‐γ production decreased again, which could reflect the fact that proinflammatory immune responses shifted to anti‐inflammatory responses. 17 It has already been shown that there was a reduction in proinflammatory cytokines like IL‐6 and an increase in anti‐inflammatory cytokines after CP was administered. 18 , 19 , 20 Moreover, chronic kidney disease suppressed T‐cell function, which could impede long‐term protection against reinfection. 3 , 21
Three out of four patients with chronic kidney disease showed clinical improvement; which is in the range of previous reports. 3 , 4 , 5 , 6 However, due to the low patient number, it was beyond the aim of our study to answer the question of CP therapy was effective. This answer can only be given by large randomized clinical studies such as the Randomized Evaluation of COVID‐19 Therapy (RECOVERY) trial 22 ; which is currently underway.
In conclusion, our data suggest that despite an increase of SARS‐CoV‐2‐specific immunity the success of CP therapy may only be temporary in patients with chronic kidney disease. Thus, short‐term treatment control (monitoring of viral load and antiviral immunity) appears mandatory for this patient group. If necessary, the treatment regimen has to be adapted.
CONFLICT OF INTERESTS
The authors declare that there are no conflict of interests.
ETHICS STATEMENT
The study was approved by the local ethics committee (20‐9256‐BO for the patients and 20‐9225‐BO for the donors) and the study participants provided written informed consent.
AUTHOR CONTRIBUTIONS
Monika Lindemann, Adalbert Krawczyk, Veronika Lenz, Ulf Dittmer, Peter A. Horn, and Oliver Witzke conceived and designed the study. Laura Thümmler, Sina Schwarzkopf, Leonie Schipper, Maren Bormann, and Lukas van de Sand performed the experiments and analyzed the data. Sebastian Dolff, Margarethe Konik, Hana Rohn, Maximillian Platte, Marianne Breyer, Hannes Klump, Dietmar Knop, Veronika Lenz, Christian Temme, Peter A. Horn, and Oliver Witzke took care of the patients or convalescent plasma donors and participated in the collection and interpretation of data. Monika Lindemann had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analyses. Monika Lindemann, Adalbert Krawczyk, Sebastian Dolff, Peter A. Horn, and Oliver Witzke wrote the manuscript. All authors gave final approval of the manuscript.
ACKNOWLEDGEMENTS
This study was supported by the Stiftung Universitätsmedizin Essen (Adalbert Krawczyk) and the Rudolf Ackermann Foundation (Oliver Witzke). The authors would like to thank Babette Große‐Rhode and Martina Filipovic for their excellent technical assistance. The authors, furthermore, thank all volunteers for their participation and the donation of blood samples. Open Access funding enabled and organized by Projekt DEAL. | Recovered | ReactionOutcome | CC BY-NC-ND | 33527424 | 19,396,994 | 2021-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Candida infection'. | Two Cases of Fungemia after Endoscopic Variceal Obturation for Gastric Variceal Bleeding.
Fever is a common complication of endoscopic variceal obturation (EVO) therapy for gastric variceal bleeding. However, fungemia related to EVO therapy has not yet been reported. Herein, we report two cases of post-EVO fungemia in cirrhotic patients who underwent therapeutic EVO for gastric variceal bleeding. Both patients developed sustained high fever after repeated EVO procedures while on prophylactic antibiotic use. In both patients, blood cultures revealed yeast, and they were finally diagnosed with Candida infection. Candida is a common member of the intestinal flora; however, it can cause invasive infection with consequent poor prognosis in cirrhotic patients. The route of Candida invasion is unclear; however, repeated EVO may predispose patients to Candida infection, particularly those who are in the end stage of liver disease and receiving prophylactic antibiotics. Our cases highlight that repeated invasive procedures can increase the risk of fungal infections, and fungemia should be considered in the differential diagnosis of post-EVO fever.
INTRODUCTION
Fungal infections in cirrhotic patients have emerged as a life-threatening problem in the era of abundant use of broad spectrum antibiotics.1.2 The diagnosis of invasive fungal infections is often delayed with poor prognosis.13 Herein, we report two cases of fungemia in patients who were treated with therapeutic endoscopic variceal obturation (EVO) for acute gastric variceal bleeding.
CASE REPORT
Case 1
A 55-year-old man with a history of alcohol-related liver cirrhosis and type 2 diabetes mellitus presented to the emergency room (ER) with hematemesis. He reported a 30-year history of alcohol consumption (>150 g/day) and showed a lowgrade fever (38.1℃). Blood culture was done. Viral marker for hepatitis B or C was all negative, and abnormal laboratory data showed white blood cell count of 11.4×109/L, hemoglobin (Hb) of 12.4 g/dL, platelets of 34×109/L, International Normalized Ratio (INR) of 1.5, albumin of 3.1 g/dL, total bilirubin of 7.3 mg/dL, and glycated hemoglobin (HbA1c) of 10.6%. Abdominal computed tomography (CT) revealed liver cirrhosis without gastrorenal shunt. Child-Pugh Score (CPS) was classified as class C with a score of 10, and the model for end-stage liver disease (MELD) score was 18. Gastrofibroscopy revealed a large gastroesophageal varix with red-color sign on the posterior fundic wall (Fig. 1A). Three injections of a cyanoacrylate (0.5 mL) and lipiodol (0.5 mL) mixture [1 mL, 1 mL, and 0.5 mL (total 2.5 mL)] were done (Fig. 1B). Intravenous (IV) terlipressin, proton pump inhibitor, and prophylactic 3rd generation cephalosporin (ceftriaxone 2 g/day) were administered. Follow-up abdominopelvic CT revealed cyanoacrylate-lipiodol mixture in the varices without distant migration. After 2 days, additional EVO procedure was done for secondary prophylaxis with two injections (1 mL and 0.5 mL). From the following day, the subject developed high fever (38.7℃) that lasted for 5 days (Fig. 3A). Follow-up investigations including urinalysis, sputum cultures, chest radiography, and CT were unremarkable. Antibiotics were stepped up to piperacillin/tazobactam, and blood cultures were repeated every 1–2 days. The blood culture conducted at ER visit was negative; however, yeast was detected on the 6th day of blood culture conducted since the the day of high fever, and yeast was also detected in all subsequent follow-up cultures. Fever was immediately subsided, and the subject showed clinical improvement to IV fluconazole. Yeast was finally reported as Candida glabrata. We discontinued piperacillin/tazobactam. Fluconazole was switched to caspofungin for more than 14 days after negative conversion in the blood culture. The subject was discharged with complete improvement of symptoms.
Case 2
A 53-year-old woman with a history of alcoholic liver cirrhosis presented with melena and hematemesis. She reported a 30-year history of alcohol consumption (300 g of alcohol/week). She was alert and showed blood pressure of 81/53 mm Hg with heart rate of 75 bpm and hypothermia (35.4℃). Blood culture was immediately done. Viral marker for hepatitis B or C was all negative, and abnormal laboratory data showed in Hb of 7.6 g/dL, platelets of 86×109/L, total bilirubin of 4.1 mg/dL, albumin of 2.8 g/dL, and INR of 1.47. Abdominopelvic CT revealed liver cirrhosis with gastrorenal shunt. CPS was classified as class B with a score of 8, and MELD score was 16. Endoscopy revealed a large isolated gastric varix on the posterior fundic wall (Fig. 2A). Four injections of a cyanoacrylate (0.5 mL) and lipiodol (0.5 mL) mixture were done [1 mL, 1 mL, 0.5 mL, and 1 mL (total 3.5 mL)] (Fig. 2B). IV terlipressin, 2 g/day of ceftriaxone, and PPI were administered to the subject. Post-EVO abdominopelvic CT revealed cyanoacrylate-lipiodol mixture deposition the posterior fundic wall without evidence of embolism. Two additional EVO for secondary prophylaxis were done on day 2 and day 6 (one injection of 0.5 mL during the 1st session, two injections of 1 mL and 0.5 mL during the 2nd session). We attempted a plug-assisted retrograde transvenous obliteration procedure for the complete prophylactic treatment, but it was unsuccessful due to the huge diameter of gastrorenal shunt. On the third day after the 3rd EVO procedure, the subject developed high fever (38.8℃) (Fig. 3B). The blood culture conducted at ER visit had been reported as negative. Neutropenia was gradually progressed down to 0.63× 109/L during the high fever. We switched antibiotics from ceftriaxone to levofloxacin with the concern of drug fever or cytopenia. One pair of blood cultures revealed yeast on the seventh day of high fever (Fig. 3B). We immediately initiated IV fluconazole. Fever subsided after 3 days of fluconazole administration, and the causative organism was Candida albicans. During fluconazole administration, the subject received two additional EVO procedures for recurrent variceal bleeding (two injections of 0.5 mL during both sessions), without fever. Fluconazole was maintained for 15 days, and the subject was discharged without any symptoms.
We obtained informed consent from the patients regarding the reporting and publication of this case report.
DISCUSSION
Transient fever occurs in 90% of patients after EVO.45 Possible causes include abscess, distant embolism,6 and bacteremia.457 Isolated post-EVO bacteremia has been reported in 0–50% of cases,8 which can be caused by bacterial invasion through contaminated needle tips or by bacterial migration through a cyanoacrylate plug.59 Liberal use of prophylactic antibiotics exposes patients to gut dysbiosis and consequent bacterial or fungal infections.310 In particular, decompensated cirrhotic patients are vulnerable to fungal infection due to liberal use of PPI, and a few cases of fungal infections in end-stage liver disease were reported to be related to prophylactic antibiotics usage in patients with variceal bleeding.11 The prevalence of fungal infections in patients with cirrhosis were reported to be 4–20%,112 and mortality rates as high as 30–78%.1312 However, there has been little evidence for prophylactic antifungal treatment, and it is still not recommended.
Our two patients had high risks of opportunistic fungal infection such as excessive alcohol use, pancytopenia, and poorly controlled diabetes mellitus. Both cases had poor liver function with large size varix, and complete eradication of the feeding vessel was thought to be helpful in reducing the rebleeding risk.13141516 For complete obturation of a large varix, multiple injections of cyanoacrylate are required to restrict the amount of cyanoacrylate to less than 1.0 mL per injection and 3.0 mL for each session, considering the risks of embolism or ulcer formation.61718 Since cyanoacrylate causes acute endovascular necrosis and increased vascular permeability by foreign body reaction, repeated punctures with short intervals could increase the risk of microbial invasion and subsequent blood stream infection,19 which may contribute to candidemia. In particular, the risk of fungal infection may increase at the following EVO session due to the greater suppression of normal intestinal flora resulting from longer use of antibiotics and PPIs.
In both patients, there were no other signs indicating candida infection on urine and sputum cultures or chest x-ray. Both subjects did not have an intravascular or foley catheter, and there were no signs of esophageal or oral candidiasis in gastrofibroscopy. Therefore, we considered the possibility of blood stream infection of candida by repeated punctures at the EVO site. Focal invasion of candida through the ulcer occurring at the EVO site may cause candidemia, but it is known that the ulcer formation after EVO usually occurs about 1–3 months after the procedure.20 Therefore, the possibility of candida invasion through the ulcer of EVO site was considered to be low. Indeed, in both cases, ulcers at the EVO site were not observed in gastrofibroscopy until before candidemia was developed. Additionally, the whole stomach was evaluated again to exclude the possibility of other bleeding focus in every EVO procedure, and there were no findings that could be regarded as gastric candidiasis, such as multiple ulcers or ulcers with dirty margins. Therefore, we could exclude gastric candidiasis as the cause of candidemia.
In conclusion, fungemia should be carefully considered in post-EVO fever, especially in patients with high risks of opportunistic infection. The number of EVO sessions for secondary prophylaxis should be minimized in patients with liver cirrhosis.
ACKNOWLEDGEMENTS
This study was supported by a National Research Foundation of Korea grant from the Korean government (the Ministry of Education, Science and Technology, 2018R1D1A1B07048487).
The authors have no potential conflicts of interest to disclose.
AUTHOR CONTRIBUTIONS:
Conceptualization: Eileen L. Yoon.
Data curation: Eileen L. Yoon.
Funding acquisition: Eileen L. Yoon.
Investigation: Soo In Choi.
Resources: Eileen L. Yoon.
Supervision: Eileen L. Yoon.
Visualization: Soo In Choi.
Writing—original draft: Soo In Choi.
Writing—review & editing: Soo In Choi and Eileen L. Yoon.
Approval of final manuscript: all authors.
Fig. 1 Endoscopic findings of the patient described in Case 1. A: Initial endoscopic image showing a large GOV with red-color sign at the gastric fundus. B: Endoscopic image after 3 times of injections around the stigma. Wide arrow: suspicious bleeding stigma, Narrow arrow: injection sites. GOV, gastroesophageal varix.
Fig. 2 Endoscopic findings of the patient described in Case 2. A: Initial endoscopic image showing a large IGV at the gastric fundus. B: Endoscopic image after 4 times of injections at the EVO target. Wide arrow: suspicious bleeding stigma, Narrow arrow: injection sites. EVO, endoscopic variceal obturation; IGV, isolated gastric varix.
Fig. 3 Clinical course of the patient. A: Horizontal axis indicated the timeline of case 1 including EVO dates, period of antibiotic or antifungal agents use, and identificated culture period. Vertical axis indicated fever pattern of case 1. B: Horizontal axis indicated the timeline of case 2 including EVO dates, period of antibiotic or antifungal agents use, and identificated culture period. Vertical axis indicated fever pattern of case 2. EVO, endoscopic variceal obturation; PARTO, plug-assisted retrograde transvenous obliteration. | CEFTRIAXONE, ETHIODIZED OIL, LEVOFLOXACIN, TERLIPRESSIN | DrugsGivenReaction | CC BY-NC | 33527799 | 19,111,229 | 2021-02 |
What was the administration route of drug 'TERLIPRESSIN'? | Two Cases of Fungemia after Endoscopic Variceal Obturation for Gastric Variceal Bleeding.
Fever is a common complication of endoscopic variceal obturation (EVO) therapy for gastric variceal bleeding. However, fungemia related to EVO therapy has not yet been reported. Herein, we report two cases of post-EVO fungemia in cirrhotic patients who underwent therapeutic EVO for gastric variceal bleeding. Both patients developed sustained high fever after repeated EVO procedures while on prophylactic antibiotic use. In both patients, blood cultures revealed yeast, and they were finally diagnosed with Candida infection. Candida is a common member of the intestinal flora; however, it can cause invasive infection with consequent poor prognosis in cirrhotic patients. The route of Candida invasion is unclear; however, repeated EVO may predispose patients to Candida infection, particularly those who are in the end stage of liver disease and receiving prophylactic antibiotics. Our cases highlight that repeated invasive procedures can increase the risk of fungal infections, and fungemia should be considered in the differential diagnosis of post-EVO fever.
INTRODUCTION
Fungal infections in cirrhotic patients have emerged as a life-threatening problem in the era of abundant use of broad spectrum antibiotics.1.2 The diagnosis of invasive fungal infections is often delayed with poor prognosis.13 Herein, we report two cases of fungemia in patients who were treated with therapeutic endoscopic variceal obturation (EVO) for acute gastric variceal bleeding.
CASE REPORT
Case 1
A 55-year-old man with a history of alcohol-related liver cirrhosis and type 2 diabetes mellitus presented to the emergency room (ER) with hematemesis. He reported a 30-year history of alcohol consumption (>150 g/day) and showed a lowgrade fever (38.1℃). Blood culture was done. Viral marker for hepatitis B or C was all negative, and abnormal laboratory data showed white blood cell count of 11.4×109/L, hemoglobin (Hb) of 12.4 g/dL, platelets of 34×109/L, International Normalized Ratio (INR) of 1.5, albumin of 3.1 g/dL, total bilirubin of 7.3 mg/dL, and glycated hemoglobin (HbA1c) of 10.6%. Abdominal computed tomography (CT) revealed liver cirrhosis without gastrorenal shunt. Child-Pugh Score (CPS) was classified as class C with a score of 10, and the model for end-stage liver disease (MELD) score was 18. Gastrofibroscopy revealed a large gastroesophageal varix with red-color sign on the posterior fundic wall (Fig. 1A). Three injections of a cyanoacrylate (0.5 mL) and lipiodol (0.5 mL) mixture [1 mL, 1 mL, and 0.5 mL (total 2.5 mL)] were done (Fig. 1B). Intravenous (IV) terlipressin, proton pump inhibitor, and prophylactic 3rd generation cephalosporin (ceftriaxone 2 g/day) were administered. Follow-up abdominopelvic CT revealed cyanoacrylate-lipiodol mixture in the varices without distant migration. After 2 days, additional EVO procedure was done for secondary prophylaxis with two injections (1 mL and 0.5 mL). From the following day, the subject developed high fever (38.7℃) that lasted for 5 days (Fig. 3A). Follow-up investigations including urinalysis, sputum cultures, chest radiography, and CT were unremarkable. Antibiotics were stepped up to piperacillin/tazobactam, and blood cultures were repeated every 1–2 days. The blood culture conducted at ER visit was negative; however, yeast was detected on the 6th day of blood culture conducted since the the day of high fever, and yeast was also detected in all subsequent follow-up cultures. Fever was immediately subsided, and the subject showed clinical improvement to IV fluconazole. Yeast was finally reported as Candida glabrata. We discontinued piperacillin/tazobactam. Fluconazole was switched to caspofungin for more than 14 days after negative conversion in the blood culture. The subject was discharged with complete improvement of symptoms.
Case 2
A 53-year-old woman with a history of alcoholic liver cirrhosis presented with melena and hematemesis. She reported a 30-year history of alcohol consumption (300 g of alcohol/week). She was alert and showed blood pressure of 81/53 mm Hg with heart rate of 75 bpm and hypothermia (35.4℃). Blood culture was immediately done. Viral marker for hepatitis B or C was all negative, and abnormal laboratory data showed in Hb of 7.6 g/dL, platelets of 86×109/L, total bilirubin of 4.1 mg/dL, albumin of 2.8 g/dL, and INR of 1.47. Abdominopelvic CT revealed liver cirrhosis with gastrorenal shunt. CPS was classified as class B with a score of 8, and MELD score was 16. Endoscopy revealed a large isolated gastric varix on the posterior fundic wall (Fig. 2A). Four injections of a cyanoacrylate (0.5 mL) and lipiodol (0.5 mL) mixture were done [1 mL, 1 mL, 0.5 mL, and 1 mL (total 3.5 mL)] (Fig. 2B). IV terlipressin, 2 g/day of ceftriaxone, and PPI were administered to the subject. Post-EVO abdominopelvic CT revealed cyanoacrylate-lipiodol mixture deposition the posterior fundic wall without evidence of embolism. Two additional EVO for secondary prophylaxis were done on day 2 and day 6 (one injection of 0.5 mL during the 1st session, two injections of 1 mL and 0.5 mL during the 2nd session). We attempted a plug-assisted retrograde transvenous obliteration procedure for the complete prophylactic treatment, but it was unsuccessful due to the huge diameter of gastrorenal shunt. On the third day after the 3rd EVO procedure, the subject developed high fever (38.8℃) (Fig. 3B). The blood culture conducted at ER visit had been reported as negative. Neutropenia was gradually progressed down to 0.63× 109/L during the high fever. We switched antibiotics from ceftriaxone to levofloxacin with the concern of drug fever or cytopenia. One pair of blood cultures revealed yeast on the seventh day of high fever (Fig. 3B). We immediately initiated IV fluconazole. Fever subsided after 3 days of fluconazole administration, and the causative organism was Candida albicans. During fluconazole administration, the subject received two additional EVO procedures for recurrent variceal bleeding (two injections of 0.5 mL during both sessions), without fever. Fluconazole was maintained for 15 days, and the subject was discharged without any symptoms.
We obtained informed consent from the patients regarding the reporting and publication of this case report.
DISCUSSION
Transient fever occurs in 90% of patients after EVO.45 Possible causes include abscess, distant embolism,6 and bacteremia.457 Isolated post-EVO bacteremia has been reported in 0–50% of cases,8 which can be caused by bacterial invasion through contaminated needle tips or by bacterial migration through a cyanoacrylate plug.59 Liberal use of prophylactic antibiotics exposes patients to gut dysbiosis and consequent bacterial or fungal infections.310 In particular, decompensated cirrhotic patients are vulnerable to fungal infection due to liberal use of PPI, and a few cases of fungal infections in end-stage liver disease were reported to be related to prophylactic antibiotics usage in patients with variceal bleeding.11 The prevalence of fungal infections in patients with cirrhosis were reported to be 4–20%,112 and mortality rates as high as 30–78%.1312 However, there has been little evidence for prophylactic antifungal treatment, and it is still not recommended.
Our two patients had high risks of opportunistic fungal infection such as excessive alcohol use, pancytopenia, and poorly controlled diabetes mellitus. Both cases had poor liver function with large size varix, and complete eradication of the feeding vessel was thought to be helpful in reducing the rebleeding risk.13141516 For complete obturation of a large varix, multiple injections of cyanoacrylate are required to restrict the amount of cyanoacrylate to less than 1.0 mL per injection and 3.0 mL for each session, considering the risks of embolism or ulcer formation.61718 Since cyanoacrylate causes acute endovascular necrosis and increased vascular permeability by foreign body reaction, repeated punctures with short intervals could increase the risk of microbial invasion and subsequent blood stream infection,19 which may contribute to candidemia. In particular, the risk of fungal infection may increase at the following EVO session due to the greater suppression of normal intestinal flora resulting from longer use of antibiotics and PPIs.
In both patients, there were no other signs indicating candida infection on urine and sputum cultures or chest x-ray. Both subjects did not have an intravascular or foley catheter, and there were no signs of esophageal or oral candidiasis in gastrofibroscopy. Therefore, we considered the possibility of blood stream infection of candida by repeated punctures at the EVO site. Focal invasion of candida through the ulcer occurring at the EVO site may cause candidemia, but it is known that the ulcer formation after EVO usually occurs about 1–3 months after the procedure.20 Therefore, the possibility of candida invasion through the ulcer of EVO site was considered to be low. Indeed, in both cases, ulcers at the EVO site were not observed in gastrofibroscopy until before candidemia was developed. Additionally, the whole stomach was evaluated again to exclude the possibility of other bleeding focus in every EVO procedure, and there were no findings that could be regarded as gastric candidiasis, such as multiple ulcers or ulcers with dirty margins. Therefore, we could exclude gastric candidiasis as the cause of candidemia.
In conclusion, fungemia should be carefully considered in post-EVO fever, especially in patients with high risks of opportunistic infection. The number of EVO sessions for secondary prophylaxis should be minimized in patients with liver cirrhosis.
ACKNOWLEDGEMENTS
This study was supported by a National Research Foundation of Korea grant from the Korean government (the Ministry of Education, Science and Technology, 2018R1D1A1B07048487).
The authors have no potential conflicts of interest to disclose.
AUTHOR CONTRIBUTIONS:
Conceptualization: Eileen L. Yoon.
Data curation: Eileen L. Yoon.
Funding acquisition: Eileen L. Yoon.
Investigation: Soo In Choi.
Resources: Eileen L. Yoon.
Supervision: Eileen L. Yoon.
Visualization: Soo In Choi.
Writing—original draft: Soo In Choi.
Writing—review & editing: Soo In Choi and Eileen L. Yoon.
Approval of final manuscript: all authors.
Fig. 1 Endoscopic findings of the patient described in Case 1. A: Initial endoscopic image showing a large GOV with red-color sign at the gastric fundus. B: Endoscopic image after 3 times of injections around the stigma. Wide arrow: suspicious bleeding stigma, Narrow arrow: injection sites. GOV, gastroesophageal varix.
Fig. 2 Endoscopic findings of the patient described in Case 2. A: Initial endoscopic image showing a large IGV at the gastric fundus. B: Endoscopic image after 4 times of injections at the EVO target. Wide arrow: suspicious bleeding stigma, Narrow arrow: injection sites. EVO, endoscopic variceal obturation; IGV, isolated gastric varix.
Fig. 3 Clinical course of the patient. A: Horizontal axis indicated the timeline of case 1 including EVO dates, period of antibiotic or antifungal agents use, and identificated culture period. Vertical axis indicated fever pattern of case 1. B: Horizontal axis indicated the timeline of case 2 including EVO dates, period of antibiotic or antifungal agents use, and identificated culture period. Vertical axis indicated fever pattern of case 2. EVO, endoscopic variceal obturation; PARTO, plug-assisted retrograde transvenous obliteration. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33527799 | 19,111,229 | 2021-02 |
What was the outcome of reaction 'Candida infection'? | Two Cases of Fungemia after Endoscopic Variceal Obturation for Gastric Variceal Bleeding.
Fever is a common complication of endoscopic variceal obturation (EVO) therapy for gastric variceal bleeding. However, fungemia related to EVO therapy has not yet been reported. Herein, we report two cases of post-EVO fungemia in cirrhotic patients who underwent therapeutic EVO for gastric variceal bleeding. Both patients developed sustained high fever after repeated EVO procedures while on prophylactic antibiotic use. In both patients, blood cultures revealed yeast, and they were finally diagnosed with Candida infection. Candida is a common member of the intestinal flora; however, it can cause invasive infection with consequent poor prognosis in cirrhotic patients. The route of Candida invasion is unclear; however, repeated EVO may predispose patients to Candida infection, particularly those who are in the end stage of liver disease and receiving prophylactic antibiotics. Our cases highlight that repeated invasive procedures can increase the risk of fungal infections, and fungemia should be considered in the differential diagnosis of post-EVO fever.
INTRODUCTION
Fungal infections in cirrhotic patients have emerged as a life-threatening problem in the era of abundant use of broad spectrum antibiotics.1.2 The diagnosis of invasive fungal infections is often delayed with poor prognosis.13 Herein, we report two cases of fungemia in patients who were treated with therapeutic endoscopic variceal obturation (EVO) for acute gastric variceal bleeding.
CASE REPORT
Case 1
A 55-year-old man with a history of alcohol-related liver cirrhosis and type 2 diabetes mellitus presented to the emergency room (ER) with hematemesis. He reported a 30-year history of alcohol consumption (>150 g/day) and showed a lowgrade fever (38.1℃). Blood culture was done. Viral marker for hepatitis B or C was all negative, and abnormal laboratory data showed white blood cell count of 11.4×109/L, hemoglobin (Hb) of 12.4 g/dL, platelets of 34×109/L, International Normalized Ratio (INR) of 1.5, albumin of 3.1 g/dL, total bilirubin of 7.3 mg/dL, and glycated hemoglobin (HbA1c) of 10.6%. Abdominal computed tomography (CT) revealed liver cirrhosis without gastrorenal shunt. Child-Pugh Score (CPS) was classified as class C with a score of 10, and the model for end-stage liver disease (MELD) score was 18. Gastrofibroscopy revealed a large gastroesophageal varix with red-color sign on the posterior fundic wall (Fig. 1A). Three injections of a cyanoacrylate (0.5 mL) and lipiodol (0.5 mL) mixture [1 mL, 1 mL, and 0.5 mL (total 2.5 mL)] were done (Fig. 1B). Intravenous (IV) terlipressin, proton pump inhibitor, and prophylactic 3rd generation cephalosporin (ceftriaxone 2 g/day) were administered. Follow-up abdominopelvic CT revealed cyanoacrylate-lipiodol mixture in the varices without distant migration. After 2 days, additional EVO procedure was done for secondary prophylaxis with two injections (1 mL and 0.5 mL). From the following day, the subject developed high fever (38.7℃) that lasted for 5 days (Fig. 3A). Follow-up investigations including urinalysis, sputum cultures, chest radiography, and CT were unremarkable. Antibiotics were stepped up to piperacillin/tazobactam, and blood cultures were repeated every 1–2 days. The blood culture conducted at ER visit was negative; however, yeast was detected on the 6th day of blood culture conducted since the the day of high fever, and yeast was also detected in all subsequent follow-up cultures. Fever was immediately subsided, and the subject showed clinical improvement to IV fluconazole. Yeast was finally reported as Candida glabrata. We discontinued piperacillin/tazobactam. Fluconazole was switched to caspofungin for more than 14 days after negative conversion in the blood culture. The subject was discharged with complete improvement of symptoms.
Case 2
A 53-year-old woman with a history of alcoholic liver cirrhosis presented with melena and hematemesis. She reported a 30-year history of alcohol consumption (300 g of alcohol/week). She was alert and showed blood pressure of 81/53 mm Hg with heart rate of 75 bpm and hypothermia (35.4℃). Blood culture was immediately done. Viral marker for hepatitis B or C was all negative, and abnormal laboratory data showed in Hb of 7.6 g/dL, platelets of 86×109/L, total bilirubin of 4.1 mg/dL, albumin of 2.8 g/dL, and INR of 1.47. Abdominopelvic CT revealed liver cirrhosis with gastrorenal shunt. CPS was classified as class B with a score of 8, and MELD score was 16. Endoscopy revealed a large isolated gastric varix on the posterior fundic wall (Fig. 2A). Four injections of a cyanoacrylate (0.5 mL) and lipiodol (0.5 mL) mixture were done [1 mL, 1 mL, 0.5 mL, and 1 mL (total 3.5 mL)] (Fig. 2B). IV terlipressin, 2 g/day of ceftriaxone, and PPI were administered to the subject. Post-EVO abdominopelvic CT revealed cyanoacrylate-lipiodol mixture deposition the posterior fundic wall without evidence of embolism. Two additional EVO for secondary prophylaxis were done on day 2 and day 6 (one injection of 0.5 mL during the 1st session, two injections of 1 mL and 0.5 mL during the 2nd session). We attempted a plug-assisted retrograde transvenous obliteration procedure for the complete prophylactic treatment, but it was unsuccessful due to the huge diameter of gastrorenal shunt. On the third day after the 3rd EVO procedure, the subject developed high fever (38.8℃) (Fig. 3B). The blood culture conducted at ER visit had been reported as negative. Neutropenia was gradually progressed down to 0.63× 109/L during the high fever. We switched antibiotics from ceftriaxone to levofloxacin with the concern of drug fever or cytopenia. One pair of blood cultures revealed yeast on the seventh day of high fever (Fig. 3B). We immediately initiated IV fluconazole. Fever subsided after 3 days of fluconazole administration, and the causative organism was Candida albicans. During fluconazole administration, the subject received two additional EVO procedures for recurrent variceal bleeding (two injections of 0.5 mL during both sessions), without fever. Fluconazole was maintained for 15 days, and the subject was discharged without any symptoms.
We obtained informed consent from the patients regarding the reporting and publication of this case report.
DISCUSSION
Transient fever occurs in 90% of patients after EVO.45 Possible causes include abscess, distant embolism,6 and bacteremia.457 Isolated post-EVO bacteremia has been reported in 0–50% of cases,8 which can be caused by bacterial invasion through contaminated needle tips or by bacterial migration through a cyanoacrylate plug.59 Liberal use of prophylactic antibiotics exposes patients to gut dysbiosis and consequent bacterial or fungal infections.310 In particular, decompensated cirrhotic patients are vulnerable to fungal infection due to liberal use of PPI, and a few cases of fungal infections in end-stage liver disease were reported to be related to prophylactic antibiotics usage in patients with variceal bleeding.11 The prevalence of fungal infections in patients with cirrhosis were reported to be 4–20%,112 and mortality rates as high as 30–78%.1312 However, there has been little evidence for prophylactic antifungal treatment, and it is still not recommended.
Our two patients had high risks of opportunistic fungal infection such as excessive alcohol use, pancytopenia, and poorly controlled diabetes mellitus. Both cases had poor liver function with large size varix, and complete eradication of the feeding vessel was thought to be helpful in reducing the rebleeding risk.13141516 For complete obturation of a large varix, multiple injections of cyanoacrylate are required to restrict the amount of cyanoacrylate to less than 1.0 mL per injection and 3.0 mL for each session, considering the risks of embolism or ulcer formation.61718 Since cyanoacrylate causes acute endovascular necrosis and increased vascular permeability by foreign body reaction, repeated punctures with short intervals could increase the risk of microbial invasion and subsequent blood stream infection,19 which may contribute to candidemia. In particular, the risk of fungal infection may increase at the following EVO session due to the greater suppression of normal intestinal flora resulting from longer use of antibiotics and PPIs.
In both patients, there were no other signs indicating candida infection on urine and sputum cultures or chest x-ray. Both subjects did not have an intravascular or foley catheter, and there were no signs of esophageal or oral candidiasis in gastrofibroscopy. Therefore, we considered the possibility of blood stream infection of candida by repeated punctures at the EVO site. Focal invasion of candida through the ulcer occurring at the EVO site may cause candidemia, but it is known that the ulcer formation after EVO usually occurs about 1–3 months after the procedure.20 Therefore, the possibility of candida invasion through the ulcer of EVO site was considered to be low. Indeed, in both cases, ulcers at the EVO site were not observed in gastrofibroscopy until before candidemia was developed. Additionally, the whole stomach was evaluated again to exclude the possibility of other bleeding focus in every EVO procedure, and there were no findings that could be regarded as gastric candidiasis, such as multiple ulcers or ulcers with dirty margins. Therefore, we could exclude gastric candidiasis as the cause of candidemia.
In conclusion, fungemia should be carefully considered in post-EVO fever, especially in patients with high risks of opportunistic infection. The number of EVO sessions for secondary prophylaxis should be minimized in patients with liver cirrhosis.
ACKNOWLEDGEMENTS
This study was supported by a National Research Foundation of Korea grant from the Korean government (the Ministry of Education, Science and Technology, 2018R1D1A1B07048487).
The authors have no potential conflicts of interest to disclose.
AUTHOR CONTRIBUTIONS:
Conceptualization: Eileen L. Yoon.
Data curation: Eileen L. Yoon.
Funding acquisition: Eileen L. Yoon.
Investigation: Soo In Choi.
Resources: Eileen L. Yoon.
Supervision: Eileen L. Yoon.
Visualization: Soo In Choi.
Writing—original draft: Soo In Choi.
Writing—review & editing: Soo In Choi and Eileen L. Yoon.
Approval of final manuscript: all authors.
Fig. 1 Endoscopic findings of the patient described in Case 1. A: Initial endoscopic image showing a large GOV with red-color sign at the gastric fundus. B: Endoscopic image after 3 times of injections around the stigma. Wide arrow: suspicious bleeding stigma, Narrow arrow: injection sites. GOV, gastroesophageal varix.
Fig. 2 Endoscopic findings of the patient described in Case 2. A: Initial endoscopic image showing a large IGV at the gastric fundus. B: Endoscopic image after 4 times of injections at the EVO target. Wide arrow: suspicious bleeding stigma, Narrow arrow: injection sites. EVO, endoscopic variceal obturation; IGV, isolated gastric varix.
Fig. 3 Clinical course of the patient. A: Horizontal axis indicated the timeline of case 1 including EVO dates, period of antibiotic or antifungal agents use, and identificated culture period. Vertical axis indicated fever pattern of case 1. B: Horizontal axis indicated the timeline of case 2 including EVO dates, period of antibiotic or antifungal agents use, and identificated culture period. Vertical axis indicated fever pattern of case 2. EVO, endoscopic variceal obturation; PARTO, plug-assisted retrograde transvenous obliteration. | Recovered | ReactionOutcome | CC BY-NC | 33527799 | 19,111,229 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Chronic kidney disease'. | BK virus nephropathy in a heart transplant recipient.
BK virus nephropathy in kidney transplantation is widely recognized as an important cause of graft dysfunction and loss. In the case of transplants of organs other than kidney, BK virus nephropathy in native kidneys has been recognized as a cause of chronic kidney disease, which is related with immunosuppression; however, the diagnosis is usually late because the renal dysfunction is attributed to other causes, such as toxicity by anticalcineurinic drugs, interstitial nephritis due to medications, hemodynamic changes, diabetes, hypertension, etc. We report a case of BK virus nephropathy in a patient who underwent heart transplantation due to peripartum cardiomyopathy. The kidney biopsy reported active chronic tubulointerstitial nephritis associated with late stage polyomavirus nephritis and the blood viral load for BK virus was positive (logarithm 4.5). The immunosuppressive treatment was reduced, and after two years of follow-up, the patient had stable renal function with a serum creatinine of 2.5 mg/dL (GFR of 23.4 mL/min/1.73m2). We recommend that the BK virus be considered as a cause of renal dysfunction in heart transplant recipients, with the aim of detecting its replication in time to reduce immunosuppressive therapy before irreversible compromise of renal function may manifest.
pmcIntroduction
BK viruses are circular, double-stranded DNA viruses1 - 4 that typically cause asymptomatic infections in the pediatric population, persisting latent in the renal epithelium and lymphocytes with minimal episomal replication2 , 5 , 6. In immunosuppressed patients, this virus is associated with different complications, including BK virus nephropathy, ureteral stenosis, and hemorrhagic cystitis1 , 3 , 7.
At present, the exact route of transmission is not known, but it is believed that the virus is usually acquired via the air in childhood8. It is postulated that the BK virus enters the blood by infecting mononuclear cells that circulate through the tonsil tissue, allowing it to spread to distant sites, including the kidneys, spleen, thyroid, and pancreas5. Latent infection typically compromises the genitourinary tract, where it establishes a latency for life. Reactivation of the virus can occur in immunosuppressed patients, particularly in patients receiving immunosuppressive therapies6 , 9. BK virus nephropathy is recognized as an emerging problem in renal transplant recipients; approximately 30-50% of renal transplant patients present BK viruria one month after renal transplantation10 and 5-10% develop BK virus nephropathy, of which 50-80% develop renal graft failure9 , 11. The risk factors for the development of BK virus nephropathy include age over 50, male sex, rejection treatment, prolonged cold ischemia times, lymphocyte-depleting induction, and the use of immunosuppressants such as tacrolimus/mycophenolate12.
In recent years, cases of BK virus nephropathy have been reported in native kidneys of patients who have undergone bone marrow transplantation, as well as in transplantation of other non-renal solid organs, such as heart, liver, and lung10 , 13. We present here the case of a heart transplant patient who developed a BK virus nephropathy, with a late diagnosis of this complication resulting in advanced chronic kidney disease.
Clinical case
A 39-year-old woman with a diagnosis of peripartum cardiomyopathy who received a heart transplant in October 2014. She received induction with Basiliximab and methylprednisolone. In addition, she was given a maintenance treatment with extended-release tacrolimus XL, 7 mg daily, everolimus 1, twice daily, and prednisolone, 5 mg/day. She had two acute rejection episodes during the first year post-transplant, and was managed with pulse methylprednisolone, with good results. There was no history of kidney disease and her renal function was stable, with creatinine of 0.88 mg/dL and glomerular filtration rate (GFR) of 102 mL/min/1.73m2 during the first year post-transplant. Management was exclusively performed by the cardiac transplant group and routine monitoring of polyomavirus with viral load BK or urine cytology was not done. In 2016, she presented an elevation of serum creatinine up to 1.9 mg/dL, with a GFR of 32.6 mL/min/1.73m2. At that time, tacrolimus trough level was 7.2 ng/mL and everolimus, 5.2 ng/mL. Toxicity by anticalcineurinics was suspected; therefore, tacrolimus was reduced to 4 mg daily and creatinine value returned near to the baseline value (creatinine 1.25 mg/dL, GFR 54.1 mL/min/1.73m2); no kidney biopsy was performed. In March 2017, creatinine raised to 2.69 mg/dL, with a TFG of 21.4 mL/min/1.73m2, for which she was hospitalized. The patient stated she did not present any symptom. At physical examination, she was observed in good general condition, heart rate of 80 beats per minute, blood pressure of 130/90 mmHg, respiratory rate of 15 per minute, afebrile. Additional studies were conducted: ultrasound of the renal tract showed normal renal size, but increased echogenicity; urinary microscopy and culture analyses were negative, with no hematuria, pyuria or casts; echocardiogram with adequate cardiac function; serological tests for HIV, syphilis, hepatitis virus B and C were negative; tacrolimus trough level of 5.2 ng/mL, and everolimus of 5.98 ng/mL (Table 1). Management was initiated with intravenous hydration, and the dose of tacrolimus XL was decreased to 2 mg daily, but there was no improvement of kidney function; a kidney biopsy was planned.
Table 1 Laboratory tests results
Urine Tests
Density 1.005
Proteinuria Negative
Glycosuria Negative
Leukocytes 0-5
Erythrocytes 0-2
Bacteria Scarce
Test for infectious diseases
Bk virus, viral load (blood) 33800 copies/mL
AgS Hepatitis B Negative
Antibodies for hepatitis C Negative
Antibodies for human immunodeficiency virus Negative
Immunological Tests
Serological test for syphilis Negative
Antinuclear antibodies (ANAS) Negative
Antibodies anti-DNA Negative
Complement C3 y C4 Normal
Blood Tests
Sodium 140 mmol/L
Chloride 108 mmol/L
Potassium 3.68 mmol/L
Calcium 8.5 mg/dL
Phosphorus 3.3 mg/dL
Lactate dehydrogenase 188 U/L
Parathormone 81 pg/mL
CPK total 126 U/L
Albumin 4 g/dL
Hemoglobin 11.3 g/dL
Hematocrit 26.80%
Leukocytes 4900 mm3
Platelets 168000 mm3
Neutrophils 66%
Lymphocytes 20%
Echocardiography
Left ventricular ejection fraction: 60%
AgS: surface antigen.
The kidney biopsy revealed active chronic tubulointerstitial nephritis, associated with late stage polyomavirus nephritis (Figure 1). PCR for BK virus was performed and the result was positive at 33800 copies/mL in blood (logarithm 4.5). Tacrolimus was withdrawn; creatinine levels stabilized between 2.2 and 2.4 mg/dL, without further elevation in post-discharge controls. Her viral load started to decline until reaching undetectable values. Patient progress is summarized in Figures 2 and 3. The patient did not presented episodes of cardiac rejection at 3 years of follow-up; the last creatinine measure was 2.5 mg/dL, corresponding to a GFR of 23.4 mL/min/1.73m2.
Figure 1 Laboratory values during follow up.
Figure 2 BK viral load (number of copies).
Figure 3 Renal biopsy report: active chronic tubulointerstitial nephritis, with positive immunohistochemistry for SV40, consistent with stage C polyomavirus nephritis (arrows). Image courtesy of Department of Pathology, Fundación Santa Fe de Bogotá, Colombia.
Discussion
Polyomavirus nephropathy is a severe opportunistic infection that occurs in kidney transplant patients. In rare cases, it also affects the native kidneys of transplant recipients of other organs14, and it can lead to terminal chronic kidney disease of the native kidneys8. In recent years, the reporting of BK virus infection has increased in transplant recipients of heart, lung, liver, pancreas, and kidney plus pancreas8. In addition, there are reports of BK virus infection in the urinary system of bone marrow transplant recipients, in whom it manifests primarily with hemorrhagic cystitis8 , 15.
In the context of cardiac transplantation, BK virus infection of the urinary system has been reported mainly during rejection episodes, associated with an increase in immunosuppressant drugs. In some studies, BK viruria of up to 19% has been reported in heart transplant recipients, and viremia up to 5%, but BK virus nephropathy is unusual in this population. It has been suggested that additional damage to the native kidneys is required for the development of BK viral nephropathy8,16. Vigil D et al. reviewed the literature on heart transplants with BK virus infection. Eleven patients were reported, nine males, 81% of cases associated with rejection, of which 72% had terminal chronic kidney disease, with a mortality of 27%8. In the case reported here, the patient was a heart transplant recipient, with a previous episode of acute rejection, so she was strongly immunosuppressed. In addition, she presented a progressive increase in creatinine, initially attributed to toxicity by anticalcineurinics, but due to the poor response to the initial therapy, a renal biopsy was performed, and viral load was requested for BK virus, which was positive. These findings allowed the diagnosis of BK virus nephropathy, and due to the late diagnosis, the patient developed stage 4 chronic kidney disease12 , 17 , 18.
Detection of tubular or urothelial cells with inclusions of BK virus cells in urine is a useful tool for the diagnosis of this infection in the urinary system. These cells are known as Decoy cells for their similarity with tumor cells in Pap smears. Decoy cells have a sensitivity of 25% and a specificity of 84%12 but this study was not performed on the patient because initially this diagnosis was not considered. Electron microscopy in urine samples has a sensitivity and specificity of 100% but is not available in many centers12. Viral detection by PCR is a useful tool, widely available and with high sensitivity (100%) and specificity (78%) for diagnosis (PCR of the BK virus in urine: sensitivity 100%, specificity of 78%; PCR of the BK virus in blood: sensitivity of 100% and specificity 88%). It is also a useful prognostic parameter, since high levels of viruria or viremia correlate with the presence of BK virus nephropathy12.
Kidney biopsy is considered the "gold" diagnostic standard. It is usually indicated when viremia is greater than 10,000 copies/mL, with or without creatinine elevation, and with kidney dysfunction without recognizable cause12. In addition, immunohistochemistry for SV40 T antigen must be performed, which, when positive, allows to detect with high accuracy the viral infection. However, it should be taken into account that sometimes the infection is focal, so an insufficient renal biopsy may not detect the infection8 , 18 - 20. The original Banff classification recognizes three histological patterns: a first early stage without tubular cell necrosis (stage A); a second stage of active nephropathy with tubular cell necrosis (stage B); and a late third stage characterized by advanced fibrosis (stage C)21. This classification correlates with the risk of CKD progression, as stage A is an early stage without fibrosis and completely reversible, while stage C is usually irreversible, as in this patient's case.
Currently, there is no standard therapy for BK virus nephropathy8. Certain drugs have demonstrated antiviral properties in vitro (quinolones, leflunomide, cidofovir, statins), but they have not yet shown significant results in clinical studies12. Intravenous immunoglobulin, combined with the reduction of immunosuppressive therapy, may have some initial beneficial effect in the clearance of viremia, but it is followed by an increase in viremia and BK virus nephropathy22. In our patient, immunoglobulin was not prescribed, as the use of immunoglobulin in BK viral nephropathy is not currently approved in Colombia. The current therapeutic approach for BK virus infection consists in the reduction of immunosuppression or substitution of the different immunosuppressive pharmacological groups. Since the efficacy of BK viral nephropathy treatments is limited, conducting periodic screening tests in the period after transplantation or during rejection therapy are recommended to prevent this infection. In renal transplantation, the measurement of BK virus viral load in serum is recommended monthly from one to twelve months, and then every three months19. In other types of transplants, screening frequency has not yet been established. However, the systematic screening of viremia and BK viruria within post-transplant follow-up, especially in patients at high risk for this infection, may allow timely detection of the virus and an early modification of the immunosuppressive scheme to avoid chronic kidney damage12 , 17 , 23. In the case reported here, the treatment aimed to decrease immunosuppression by suspending the anticalcineurinic agent, which allowed to control the infection without rejection. The patient was already receiving a mammalian target of rapamycin inhibitor (MTOR) (everolimus), which was maintained to avoid rejection and because this drug has been attributed with antiviral properties, although in the case of BK virus ifection, its effectiveness is controversial18.
In summary, BK virus nephropathy in transplant patients other than kidney transplant recipients is a silent entity that can lead to chronic kidney disease with increased morbidity and mortality. We therefore propose to consider the BK virus infection as a cause of renal dysfunction in heart transplant recipients, with the aim of detecting its replication in time to reduce immunosuppressive therapy before irreversible impairment of renal function may manifest. | BASILIXIMAB, EVEROLIMUS, METHYLPREDNISOLONE, PREDNISOLONE, TACROLIMUS | DrugsGivenReaction | CC BY | 33527977 | 20,174,669 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Heart transplant rejection'. | BK virus nephropathy in a heart transplant recipient.
BK virus nephropathy in kidney transplantation is widely recognized as an important cause of graft dysfunction and loss. In the case of transplants of organs other than kidney, BK virus nephropathy in native kidneys has been recognized as a cause of chronic kidney disease, which is related with immunosuppression; however, the diagnosis is usually late because the renal dysfunction is attributed to other causes, such as toxicity by anticalcineurinic drugs, interstitial nephritis due to medications, hemodynamic changes, diabetes, hypertension, etc. We report a case of BK virus nephropathy in a patient who underwent heart transplantation due to peripartum cardiomyopathy. The kidney biopsy reported active chronic tubulointerstitial nephritis associated with late stage polyomavirus nephritis and the blood viral load for BK virus was positive (logarithm 4.5). The immunosuppressive treatment was reduced, and after two years of follow-up, the patient had stable renal function with a serum creatinine of 2.5 mg/dL (GFR of 23.4 mL/min/1.73m2). We recommend that the BK virus be considered as a cause of renal dysfunction in heart transplant recipients, with the aim of detecting its replication in time to reduce immunosuppressive therapy before irreversible compromise of renal function may manifest.
pmcIntroduction
BK viruses are circular, double-stranded DNA viruses1 - 4 that typically cause asymptomatic infections in the pediatric population, persisting latent in the renal epithelium and lymphocytes with minimal episomal replication2 , 5 , 6. In immunosuppressed patients, this virus is associated with different complications, including BK virus nephropathy, ureteral stenosis, and hemorrhagic cystitis1 , 3 , 7.
At present, the exact route of transmission is not known, but it is believed that the virus is usually acquired via the air in childhood8. It is postulated that the BK virus enters the blood by infecting mononuclear cells that circulate through the tonsil tissue, allowing it to spread to distant sites, including the kidneys, spleen, thyroid, and pancreas5. Latent infection typically compromises the genitourinary tract, where it establishes a latency for life. Reactivation of the virus can occur in immunosuppressed patients, particularly in patients receiving immunosuppressive therapies6 , 9. BK virus nephropathy is recognized as an emerging problem in renal transplant recipients; approximately 30-50% of renal transplant patients present BK viruria one month after renal transplantation10 and 5-10% develop BK virus nephropathy, of which 50-80% develop renal graft failure9 , 11. The risk factors for the development of BK virus nephropathy include age over 50, male sex, rejection treatment, prolonged cold ischemia times, lymphocyte-depleting induction, and the use of immunosuppressants such as tacrolimus/mycophenolate12.
In recent years, cases of BK virus nephropathy have been reported in native kidneys of patients who have undergone bone marrow transplantation, as well as in transplantation of other non-renal solid organs, such as heart, liver, and lung10 , 13. We present here the case of a heart transplant patient who developed a BK virus nephropathy, with a late diagnosis of this complication resulting in advanced chronic kidney disease.
Clinical case
A 39-year-old woman with a diagnosis of peripartum cardiomyopathy who received a heart transplant in October 2014. She received induction with Basiliximab and methylprednisolone. In addition, she was given a maintenance treatment with extended-release tacrolimus XL, 7 mg daily, everolimus 1, twice daily, and prednisolone, 5 mg/day. She had two acute rejection episodes during the first year post-transplant, and was managed with pulse methylprednisolone, with good results. There was no history of kidney disease and her renal function was stable, with creatinine of 0.88 mg/dL and glomerular filtration rate (GFR) of 102 mL/min/1.73m2 during the first year post-transplant. Management was exclusively performed by the cardiac transplant group and routine monitoring of polyomavirus with viral load BK or urine cytology was not done. In 2016, she presented an elevation of serum creatinine up to 1.9 mg/dL, with a GFR of 32.6 mL/min/1.73m2. At that time, tacrolimus trough level was 7.2 ng/mL and everolimus, 5.2 ng/mL. Toxicity by anticalcineurinics was suspected; therefore, tacrolimus was reduced to 4 mg daily and creatinine value returned near to the baseline value (creatinine 1.25 mg/dL, GFR 54.1 mL/min/1.73m2); no kidney biopsy was performed. In March 2017, creatinine raised to 2.69 mg/dL, with a TFG of 21.4 mL/min/1.73m2, for which she was hospitalized. The patient stated she did not present any symptom. At physical examination, she was observed in good general condition, heart rate of 80 beats per minute, blood pressure of 130/90 mmHg, respiratory rate of 15 per minute, afebrile. Additional studies were conducted: ultrasound of the renal tract showed normal renal size, but increased echogenicity; urinary microscopy and culture analyses were negative, with no hematuria, pyuria or casts; echocardiogram with adequate cardiac function; serological tests for HIV, syphilis, hepatitis virus B and C were negative; tacrolimus trough level of 5.2 ng/mL, and everolimus of 5.98 ng/mL (Table 1). Management was initiated with intravenous hydration, and the dose of tacrolimus XL was decreased to 2 mg daily, but there was no improvement of kidney function; a kidney biopsy was planned.
Table 1 Laboratory tests results
Urine Tests
Density 1.005
Proteinuria Negative
Glycosuria Negative
Leukocytes 0-5
Erythrocytes 0-2
Bacteria Scarce
Test for infectious diseases
Bk virus, viral load (blood) 33800 copies/mL
AgS Hepatitis B Negative
Antibodies for hepatitis C Negative
Antibodies for human immunodeficiency virus Negative
Immunological Tests
Serological test for syphilis Negative
Antinuclear antibodies (ANAS) Negative
Antibodies anti-DNA Negative
Complement C3 y C4 Normal
Blood Tests
Sodium 140 mmol/L
Chloride 108 mmol/L
Potassium 3.68 mmol/L
Calcium 8.5 mg/dL
Phosphorus 3.3 mg/dL
Lactate dehydrogenase 188 U/L
Parathormone 81 pg/mL
CPK total 126 U/L
Albumin 4 g/dL
Hemoglobin 11.3 g/dL
Hematocrit 26.80%
Leukocytes 4900 mm3
Platelets 168000 mm3
Neutrophils 66%
Lymphocytes 20%
Echocardiography
Left ventricular ejection fraction: 60%
AgS: surface antigen.
The kidney biopsy revealed active chronic tubulointerstitial nephritis, associated with late stage polyomavirus nephritis (Figure 1). PCR for BK virus was performed and the result was positive at 33800 copies/mL in blood (logarithm 4.5). Tacrolimus was withdrawn; creatinine levels stabilized between 2.2 and 2.4 mg/dL, without further elevation in post-discharge controls. Her viral load started to decline until reaching undetectable values. Patient progress is summarized in Figures 2 and 3. The patient did not presented episodes of cardiac rejection at 3 years of follow-up; the last creatinine measure was 2.5 mg/dL, corresponding to a GFR of 23.4 mL/min/1.73m2.
Figure 1 Laboratory values during follow up.
Figure 2 BK viral load (number of copies).
Figure 3 Renal biopsy report: active chronic tubulointerstitial nephritis, with positive immunohistochemistry for SV40, consistent with stage C polyomavirus nephritis (arrows). Image courtesy of Department of Pathology, Fundación Santa Fe de Bogotá, Colombia.
Discussion
Polyomavirus nephropathy is a severe opportunistic infection that occurs in kidney transplant patients. In rare cases, it also affects the native kidneys of transplant recipients of other organs14, and it can lead to terminal chronic kidney disease of the native kidneys8. In recent years, the reporting of BK virus infection has increased in transplant recipients of heart, lung, liver, pancreas, and kidney plus pancreas8. In addition, there are reports of BK virus infection in the urinary system of bone marrow transplant recipients, in whom it manifests primarily with hemorrhagic cystitis8 , 15.
In the context of cardiac transplantation, BK virus infection of the urinary system has been reported mainly during rejection episodes, associated with an increase in immunosuppressant drugs. In some studies, BK viruria of up to 19% has been reported in heart transplant recipients, and viremia up to 5%, but BK virus nephropathy is unusual in this population. It has been suggested that additional damage to the native kidneys is required for the development of BK viral nephropathy8,16. Vigil D et al. reviewed the literature on heart transplants with BK virus infection. Eleven patients were reported, nine males, 81% of cases associated with rejection, of which 72% had terminal chronic kidney disease, with a mortality of 27%8. In the case reported here, the patient was a heart transplant recipient, with a previous episode of acute rejection, so she was strongly immunosuppressed. In addition, she presented a progressive increase in creatinine, initially attributed to toxicity by anticalcineurinics, but due to the poor response to the initial therapy, a renal biopsy was performed, and viral load was requested for BK virus, which was positive. These findings allowed the diagnosis of BK virus nephropathy, and due to the late diagnosis, the patient developed stage 4 chronic kidney disease12 , 17 , 18.
Detection of tubular or urothelial cells with inclusions of BK virus cells in urine is a useful tool for the diagnosis of this infection in the urinary system. These cells are known as Decoy cells for their similarity with tumor cells in Pap smears. Decoy cells have a sensitivity of 25% and a specificity of 84%12 but this study was not performed on the patient because initially this diagnosis was not considered. Electron microscopy in urine samples has a sensitivity and specificity of 100% but is not available in many centers12. Viral detection by PCR is a useful tool, widely available and with high sensitivity (100%) and specificity (78%) for diagnosis (PCR of the BK virus in urine: sensitivity 100%, specificity of 78%; PCR of the BK virus in blood: sensitivity of 100% and specificity 88%). It is also a useful prognostic parameter, since high levels of viruria or viremia correlate with the presence of BK virus nephropathy12.
Kidney biopsy is considered the "gold" diagnostic standard. It is usually indicated when viremia is greater than 10,000 copies/mL, with or without creatinine elevation, and with kidney dysfunction without recognizable cause12. In addition, immunohistochemistry for SV40 T antigen must be performed, which, when positive, allows to detect with high accuracy the viral infection. However, it should be taken into account that sometimes the infection is focal, so an insufficient renal biopsy may not detect the infection8 , 18 - 20. The original Banff classification recognizes three histological patterns: a first early stage without tubular cell necrosis (stage A); a second stage of active nephropathy with tubular cell necrosis (stage B); and a late third stage characterized by advanced fibrosis (stage C)21. This classification correlates with the risk of CKD progression, as stage A is an early stage without fibrosis and completely reversible, while stage C is usually irreversible, as in this patient's case.
Currently, there is no standard therapy for BK virus nephropathy8. Certain drugs have demonstrated antiviral properties in vitro (quinolones, leflunomide, cidofovir, statins), but they have not yet shown significant results in clinical studies12. Intravenous immunoglobulin, combined with the reduction of immunosuppressive therapy, may have some initial beneficial effect in the clearance of viremia, but it is followed by an increase in viremia and BK virus nephropathy22. In our patient, immunoglobulin was not prescribed, as the use of immunoglobulin in BK viral nephropathy is not currently approved in Colombia. The current therapeutic approach for BK virus infection consists in the reduction of immunosuppression or substitution of the different immunosuppressive pharmacological groups. Since the efficacy of BK viral nephropathy treatments is limited, conducting periodic screening tests in the period after transplantation or during rejection therapy are recommended to prevent this infection. In renal transplantation, the measurement of BK virus viral load in serum is recommended monthly from one to twelve months, and then every three months19. In other types of transplants, screening frequency has not yet been established. However, the systematic screening of viremia and BK viruria within post-transplant follow-up, especially in patients at high risk for this infection, may allow timely detection of the virus and an early modification of the immunosuppressive scheme to avoid chronic kidney damage12 , 17 , 23. In the case reported here, the treatment aimed to decrease immunosuppression by suspending the anticalcineurinic agent, which allowed to control the infection without rejection. The patient was already receiving a mammalian target of rapamycin inhibitor (MTOR) (everolimus), which was maintained to avoid rejection and because this drug has been attributed with antiviral properties, although in the case of BK virus ifection, its effectiveness is controversial18.
In summary, BK virus nephropathy in transplant patients other than kidney transplant recipients is a silent entity that can lead to chronic kidney disease with increased morbidity and mortality. We therefore propose to consider the BK virus infection as a cause of renal dysfunction in heart transplant recipients, with the aim of detecting its replication in time to reduce immunosuppressive therapy before irreversible impairment of renal function may manifest. | BASILIXIMAB, EVEROLIMUS, METHYLPREDNISOLONE, PREDNISOLONE, TACROLIMUS | DrugsGivenReaction | CC BY | 33527977 | 20,169,062 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | BK virus nephropathy in a heart transplant recipient.
BK virus nephropathy in kidney transplantation is widely recognized as an important cause of graft dysfunction and loss. In the case of transplants of organs other than kidney, BK virus nephropathy in native kidneys has been recognized as a cause of chronic kidney disease, which is related with immunosuppression; however, the diagnosis is usually late because the renal dysfunction is attributed to other causes, such as toxicity by anticalcineurinic drugs, interstitial nephritis due to medications, hemodynamic changes, diabetes, hypertension, etc. We report a case of BK virus nephropathy in a patient who underwent heart transplantation due to peripartum cardiomyopathy. The kidney biopsy reported active chronic tubulointerstitial nephritis associated with late stage polyomavirus nephritis and the blood viral load for BK virus was positive (logarithm 4.5). The immunosuppressive treatment was reduced, and after two years of follow-up, the patient had stable renal function with a serum creatinine of 2.5 mg/dL (GFR of 23.4 mL/min/1.73m2). We recommend that the BK virus be considered as a cause of renal dysfunction in heart transplant recipients, with the aim of detecting its replication in time to reduce immunosuppressive therapy before irreversible compromise of renal function may manifest.
pmcIntroduction
BK viruses are circular, double-stranded DNA viruses1 - 4 that typically cause asymptomatic infections in the pediatric population, persisting latent in the renal epithelium and lymphocytes with minimal episomal replication2 , 5 , 6. In immunosuppressed patients, this virus is associated with different complications, including BK virus nephropathy, ureteral stenosis, and hemorrhagic cystitis1 , 3 , 7.
At present, the exact route of transmission is not known, but it is believed that the virus is usually acquired via the air in childhood8. It is postulated that the BK virus enters the blood by infecting mononuclear cells that circulate through the tonsil tissue, allowing it to spread to distant sites, including the kidneys, spleen, thyroid, and pancreas5. Latent infection typically compromises the genitourinary tract, where it establishes a latency for life. Reactivation of the virus can occur in immunosuppressed patients, particularly in patients receiving immunosuppressive therapies6 , 9. BK virus nephropathy is recognized as an emerging problem in renal transplant recipients; approximately 30-50% of renal transplant patients present BK viruria one month after renal transplantation10 and 5-10% develop BK virus nephropathy, of which 50-80% develop renal graft failure9 , 11. The risk factors for the development of BK virus nephropathy include age over 50, male sex, rejection treatment, prolonged cold ischemia times, lymphocyte-depleting induction, and the use of immunosuppressants such as tacrolimus/mycophenolate12.
In recent years, cases of BK virus nephropathy have been reported in native kidneys of patients who have undergone bone marrow transplantation, as well as in transplantation of other non-renal solid organs, such as heart, liver, and lung10 , 13. We present here the case of a heart transplant patient who developed a BK virus nephropathy, with a late diagnosis of this complication resulting in advanced chronic kidney disease.
Clinical case
A 39-year-old woman with a diagnosis of peripartum cardiomyopathy who received a heart transplant in October 2014. She received induction with Basiliximab and methylprednisolone. In addition, she was given a maintenance treatment with extended-release tacrolimus XL, 7 mg daily, everolimus 1, twice daily, and prednisolone, 5 mg/day. She had two acute rejection episodes during the first year post-transplant, and was managed with pulse methylprednisolone, with good results. There was no history of kidney disease and her renal function was stable, with creatinine of 0.88 mg/dL and glomerular filtration rate (GFR) of 102 mL/min/1.73m2 during the first year post-transplant. Management was exclusively performed by the cardiac transplant group and routine monitoring of polyomavirus with viral load BK or urine cytology was not done. In 2016, she presented an elevation of serum creatinine up to 1.9 mg/dL, with a GFR of 32.6 mL/min/1.73m2. At that time, tacrolimus trough level was 7.2 ng/mL and everolimus, 5.2 ng/mL. Toxicity by anticalcineurinics was suspected; therefore, tacrolimus was reduced to 4 mg daily and creatinine value returned near to the baseline value (creatinine 1.25 mg/dL, GFR 54.1 mL/min/1.73m2); no kidney biopsy was performed. In March 2017, creatinine raised to 2.69 mg/dL, with a TFG of 21.4 mL/min/1.73m2, for which she was hospitalized. The patient stated she did not present any symptom. At physical examination, she was observed in good general condition, heart rate of 80 beats per minute, blood pressure of 130/90 mmHg, respiratory rate of 15 per minute, afebrile. Additional studies were conducted: ultrasound of the renal tract showed normal renal size, but increased echogenicity; urinary microscopy and culture analyses were negative, with no hematuria, pyuria or casts; echocardiogram with adequate cardiac function; serological tests for HIV, syphilis, hepatitis virus B and C were negative; tacrolimus trough level of 5.2 ng/mL, and everolimus of 5.98 ng/mL (Table 1). Management was initiated with intravenous hydration, and the dose of tacrolimus XL was decreased to 2 mg daily, but there was no improvement of kidney function; a kidney biopsy was planned.
Table 1 Laboratory tests results
Urine Tests
Density 1.005
Proteinuria Negative
Glycosuria Negative
Leukocytes 0-5
Erythrocytes 0-2
Bacteria Scarce
Test for infectious diseases
Bk virus, viral load (blood) 33800 copies/mL
AgS Hepatitis B Negative
Antibodies for hepatitis C Negative
Antibodies for human immunodeficiency virus Negative
Immunological Tests
Serological test for syphilis Negative
Antinuclear antibodies (ANAS) Negative
Antibodies anti-DNA Negative
Complement C3 y C4 Normal
Blood Tests
Sodium 140 mmol/L
Chloride 108 mmol/L
Potassium 3.68 mmol/L
Calcium 8.5 mg/dL
Phosphorus 3.3 mg/dL
Lactate dehydrogenase 188 U/L
Parathormone 81 pg/mL
CPK total 126 U/L
Albumin 4 g/dL
Hemoglobin 11.3 g/dL
Hematocrit 26.80%
Leukocytes 4900 mm3
Platelets 168000 mm3
Neutrophils 66%
Lymphocytes 20%
Echocardiography
Left ventricular ejection fraction: 60%
AgS: surface antigen.
The kidney biopsy revealed active chronic tubulointerstitial nephritis, associated with late stage polyomavirus nephritis (Figure 1). PCR for BK virus was performed and the result was positive at 33800 copies/mL in blood (logarithm 4.5). Tacrolimus was withdrawn; creatinine levels stabilized between 2.2 and 2.4 mg/dL, without further elevation in post-discharge controls. Her viral load started to decline until reaching undetectable values. Patient progress is summarized in Figures 2 and 3. The patient did not presented episodes of cardiac rejection at 3 years of follow-up; the last creatinine measure was 2.5 mg/dL, corresponding to a GFR of 23.4 mL/min/1.73m2.
Figure 1 Laboratory values during follow up.
Figure 2 BK viral load (number of copies).
Figure 3 Renal biopsy report: active chronic tubulointerstitial nephritis, with positive immunohistochemistry for SV40, consistent with stage C polyomavirus nephritis (arrows). Image courtesy of Department of Pathology, Fundación Santa Fe de Bogotá, Colombia.
Discussion
Polyomavirus nephropathy is a severe opportunistic infection that occurs in kidney transplant patients. In rare cases, it also affects the native kidneys of transplant recipients of other organs14, and it can lead to terminal chronic kidney disease of the native kidneys8. In recent years, the reporting of BK virus infection has increased in transplant recipients of heart, lung, liver, pancreas, and kidney plus pancreas8. In addition, there are reports of BK virus infection in the urinary system of bone marrow transplant recipients, in whom it manifests primarily with hemorrhagic cystitis8 , 15.
In the context of cardiac transplantation, BK virus infection of the urinary system has been reported mainly during rejection episodes, associated with an increase in immunosuppressant drugs. In some studies, BK viruria of up to 19% has been reported in heart transplant recipients, and viremia up to 5%, but BK virus nephropathy is unusual in this population. It has been suggested that additional damage to the native kidneys is required for the development of BK viral nephropathy8,16. Vigil D et al. reviewed the literature on heart transplants with BK virus infection. Eleven patients were reported, nine males, 81% of cases associated with rejection, of which 72% had terminal chronic kidney disease, with a mortality of 27%8. In the case reported here, the patient was a heart transplant recipient, with a previous episode of acute rejection, so she was strongly immunosuppressed. In addition, she presented a progressive increase in creatinine, initially attributed to toxicity by anticalcineurinics, but due to the poor response to the initial therapy, a renal biopsy was performed, and viral load was requested for BK virus, which was positive. These findings allowed the diagnosis of BK virus nephropathy, and due to the late diagnosis, the patient developed stage 4 chronic kidney disease12 , 17 , 18.
Detection of tubular or urothelial cells with inclusions of BK virus cells in urine is a useful tool for the diagnosis of this infection in the urinary system. These cells are known as Decoy cells for their similarity with tumor cells in Pap smears. Decoy cells have a sensitivity of 25% and a specificity of 84%12 but this study was not performed on the patient because initially this diagnosis was not considered. Electron microscopy in urine samples has a sensitivity and specificity of 100% but is not available in many centers12. Viral detection by PCR is a useful tool, widely available and with high sensitivity (100%) and specificity (78%) for diagnosis (PCR of the BK virus in urine: sensitivity 100%, specificity of 78%; PCR of the BK virus in blood: sensitivity of 100% and specificity 88%). It is also a useful prognostic parameter, since high levels of viruria or viremia correlate with the presence of BK virus nephropathy12.
Kidney biopsy is considered the "gold" diagnostic standard. It is usually indicated when viremia is greater than 10,000 copies/mL, with or without creatinine elevation, and with kidney dysfunction without recognizable cause12. In addition, immunohistochemistry for SV40 T antigen must be performed, which, when positive, allows to detect with high accuracy the viral infection. However, it should be taken into account that sometimes the infection is focal, so an insufficient renal biopsy may not detect the infection8 , 18 - 20. The original Banff classification recognizes three histological patterns: a first early stage without tubular cell necrosis (stage A); a second stage of active nephropathy with tubular cell necrosis (stage B); and a late third stage characterized by advanced fibrosis (stage C)21. This classification correlates with the risk of CKD progression, as stage A is an early stage without fibrosis and completely reversible, while stage C is usually irreversible, as in this patient's case.
Currently, there is no standard therapy for BK virus nephropathy8. Certain drugs have demonstrated antiviral properties in vitro (quinolones, leflunomide, cidofovir, statins), but they have not yet shown significant results in clinical studies12. Intravenous immunoglobulin, combined with the reduction of immunosuppressive therapy, may have some initial beneficial effect in the clearance of viremia, but it is followed by an increase in viremia and BK virus nephropathy22. In our patient, immunoglobulin was not prescribed, as the use of immunoglobulin in BK viral nephropathy is not currently approved in Colombia. The current therapeutic approach for BK virus infection consists in the reduction of immunosuppression or substitution of the different immunosuppressive pharmacological groups. Since the efficacy of BK viral nephropathy treatments is limited, conducting periodic screening tests in the period after transplantation or during rejection therapy are recommended to prevent this infection. In renal transplantation, the measurement of BK virus viral load in serum is recommended monthly from one to twelve months, and then every three months19. In other types of transplants, screening frequency has not yet been established. However, the systematic screening of viremia and BK viruria within post-transplant follow-up, especially in patients at high risk for this infection, may allow timely detection of the virus and an early modification of the immunosuppressive scheme to avoid chronic kidney damage12 , 17 , 23. In the case reported here, the treatment aimed to decrease immunosuppression by suspending the anticalcineurinic agent, which allowed to control the infection without rejection. The patient was already receiving a mammalian target of rapamycin inhibitor (MTOR) (everolimus), which was maintained to avoid rejection and because this drug has been attributed with antiviral properties, although in the case of BK virus ifection, its effectiveness is controversial18.
In summary, BK virus nephropathy in transplant patients other than kidney transplant recipients is a silent entity that can lead to chronic kidney disease with increased morbidity and mortality. We therefore propose to consider the BK virus infection as a cause of renal dysfunction in heart transplant recipients, with the aim of detecting its replication in time to reduce immunosuppressive therapy before irreversible impairment of renal function may manifest. | EVEROLIMUS, METHYLPREDNISOLONE, PREDNISOLONE, TACROLIMUS | DrugsGivenReaction | CC BY | 33527977 | 20,112,608 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Renal impairment'. | BK virus nephropathy in a heart transplant recipient.
BK virus nephropathy in kidney transplantation is widely recognized as an important cause of graft dysfunction and loss. In the case of transplants of organs other than kidney, BK virus nephropathy in native kidneys has been recognized as a cause of chronic kidney disease, which is related with immunosuppression; however, the diagnosis is usually late because the renal dysfunction is attributed to other causes, such as toxicity by anticalcineurinic drugs, interstitial nephritis due to medications, hemodynamic changes, diabetes, hypertension, etc. We report a case of BK virus nephropathy in a patient who underwent heart transplantation due to peripartum cardiomyopathy. The kidney biopsy reported active chronic tubulointerstitial nephritis associated with late stage polyomavirus nephritis and the blood viral load for BK virus was positive (logarithm 4.5). The immunosuppressive treatment was reduced, and after two years of follow-up, the patient had stable renal function with a serum creatinine of 2.5 mg/dL (GFR of 23.4 mL/min/1.73m2). We recommend that the BK virus be considered as a cause of renal dysfunction in heart transplant recipients, with the aim of detecting its replication in time to reduce immunosuppressive therapy before irreversible compromise of renal function may manifest.
pmcIntroduction
BK viruses are circular, double-stranded DNA viruses1 - 4 that typically cause asymptomatic infections in the pediatric population, persisting latent in the renal epithelium and lymphocytes with minimal episomal replication2 , 5 , 6. In immunosuppressed patients, this virus is associated with different complications, including BK virus nephropathy, ureteral stenosis, and hemorrhagic cystitis1 , 3 , 7.
At present, the exact route of transmission is not known, but it is believed that the virus is usually acquired via the air in childhood8. It is postulated that the BK virus enters the blood by infecting mononuclear cells that circulate through the tonsil tissue, allowing it to spread to distant sites, including the kidneys, spleen, thyroid, and pancreas5. Latent infection typically compromises the genitourinary tract, where it establishes a latency for life. Reactivation of the virus can occur in immunosuppressed patients, particularly in patients receiving immunosuppressive therapies6 , 9. BK virus nephropathy is recognized as an emerging problem in renal transplant recipients; approximately 30-50% of renal transplant patients present BK viruria one month after renal transplantation10 and 5-10% develop BK virus nephropathy, of which 50-80% develop renal graft failure9 , 11. The risk factors for the development of BK virus nephropathy include age over 50, male sex, rejection treatment, prolonged cold ischemia times, lymphocyte-depleting induction, and the use of immunosuppressants such as tacrolimus/mycophenolate12.
In recent years, cases of BK virus nephropathy have been reported in native kidneys of patients who have undergone bone marrow transplantation, as well as in transplantation of other non-renal solid organs, such as heart, liver, and lung10 , 13. We present here the case of a heart transplant patient who developed a BK virus nephropathy, with a late diagnosis of this complication resulting in advanced chronic kidney disease.
Clinical case
A 39-year-old woman with a diagnosis of peripartum cardiomyopathy who received a heart transplant in October 2014. She received induction with Basiliximab and methylprednisolone. In addition, she was given a maintenance treatment with extended-release tacrolimus XL, 7 mg daily, everolimus 1, twice daily, and prednisolone, 5 mg/day. She had two acute rejection episodes during the first year post-transplant, and was managed with pulse methylprednisolone, with good results. There was no history of kidney disease and her renal function was stable, with creatinine of 0.88 mg/dL and glomerular filtration rate (GFR) of 102 mL/min/1.73m2 during the first year post-transplant. Management was exclusively performed by the cardiac transplant group and routine monitoring of polyomavirus with viral load BK or urine cytology was not done. In 2016, she presented an elevation of serum creatinine up to 1.9 mg/dL, with a GFR of 32.6 mL/min/1.73m2. At that time, tacrolimus trough level was 7.2 ng/mL and everolimus, 5.2 ng/mL. Toxicity by anticalcineurinics was suspected; therefore, tacrolimus was reduced to 4 mg daily and creatinine value returned near to the baseline value (creatinine 1.25 mg/dL, GFR 54.1 mL/min/1.73m2); no kidney biopsy was performed. In March 2017, creatinine raised to 2.69 mg/dL, with a TFG of 21.4 mL/min/1.73m2, for which she was hospitalized. The patient stated she did not present any symptom. At physical examination, she was observed in good general condition, heart rate of 80 beats per minute, blood pressure of 130/90 mmHg, respiratory rate of 15 per minute, afebrile. Additional studies were conducted: ultrasound of the renal tract showed normal renal size, but increased echogenicity; urinary microscopy and culture analyses were negative, with no hematuria, pyuria or casts; echocardiogram with adequate cardiac function; serological tests for HIV, syphilis, hepatitis virus B and C were negative; tacrolimus trough level of 5.2 ng/mL, and everolimus of 5.98 ng/mL (Table 1). Management was initiated with intravenous hydration, and the dose of tacrolimus XL was decreased to 2 mg daily, but there was no improvement of kidney function; a kidney biopsy was planned.
Table 1 Laboratory tests results
Urine Tests
Density 1.005
Proteinuria Negative
Glycosuria Negative
Leukocytes 0-5
Erythrocytes 0-2
Bacteria Scarce
Test for infectious diseases
Bk virus, viral load (blood) 33800 copies/mL
AgS Hepatitis B Negative
Antibodies for hepatitis C Negative
Antibodies for human immunodeficiency virus Negative
Immunological Tests
Serological test for syphilis Negative
Antinuclear antibodies (ANAS) Negative
Antibodies anti-DNA Negative
Complement C3 y C4 Normal
Blood Tests
Sodium 140 mmol/L
Chloride 108 mmol/L
Potassium 3.68 mmol/L
Calcium 8.5 mg/dL
Phosphorus 3.3 mg/dL
Lactate dehydrogenase 188 U/L
Parathormone 81 pg/mL
CPK total 126 U/L
Albumin 4 g/dL
Hemoglobin 11.3 g/dL
Hematocrit 26.80%
Leukocytes 4900 mm3
Platelets 168000 mm3
Neutrophils 66%
Lymphocytes 20%
Echocardiography
Left ventricular ejection fraction: 60%
AgS: surface antigen.
The kidney biopsy revealed active chronic tubulointerstitial nephritis, associated with late stage polyomavirus nephritis (Figure 1). PCR for BK virus was performed and the result was positive at 33800 copies/mL in blood (logarithm 4.5). Tacrolimus was withdrawn; creatinine levels stabilized between 2.2 and 2.4 mg/dL, without further elevation in post-discharge controls. Her viral load started to decline until reaching undetectable values. Patient progress is summarized in Figures 2 and 3. The patient did not presented episodes of cardiac rejection at 3 years of follow-up; the last creatinine measure was 2.5 mg/dL, corresponding to a GFR of 23.4 mL/min/1.73m2.
Figure 1 Laboratory values during follow up.
Figure 2 BK viral load (number of copies).
Figure 3 Renal biopsy report: active chronic tubulointerstitial nephritis, with positive immunohistochemistry for SV40, consistent with stage C polyomavirus nephritis (arrows). Image courtesy of Department of Pathology, Fundación Santa Fe de Bogotá, Colombia.
Discussion
Polyomavirus nephropathy is a severe opportunistic infection that occurs in kidney transplant patients. In rare cases, it also affects the native kidneys of transplant recipients of other organs14, and it can lead to terminal chronic kidney disease of the native kidneys8. In recent years, the reporting of BK virus infection has increased in transplant recipients of heart, lung, liver, pancreas, and kidney plus pancreas8. In addition, there are reports of BK virus infection in the urinary system of bone marrow transplant recipients, in whom it manifests primarily with hemorrhagic cystitis8 , 15.
In the context of cardiac transplantation, BK virus infection of the urinary system has been reported mainly during rejection episodes, associated with an increase in immunosuppressant drugs. In some studies, BK viruria of up to 19% has been reported in heart transplant recipients, and viremia up to 5%, but BK virus nephropathy is unusual in this population. It has been suggested that additional damage to the native kidneys is required for the development of BK viral nephropathy8,16. Vigil D et al. reviewed the literature on heart transplants with BK virus infection. Eleven patients were reported, nine males, 81% of cases associated with rejection, of which 72% had terminal chronic kidney disease, with a mortality of 27%8. In the case reported here, the patient was a heart transplant recipient, with a previous episode of acute rejection, so she was strongly immunosuppressed. In addition, she presented a progressive increase in creatinine, initially attributed to toxicity by anticalcineurinics, but due to the poor response to the initial therapy, a renal biopsy was performed, and viral load was requested for BK virus, which was positive. These findings allowed the diagnosis of BK virus nephropathy, and due to the late diagnosis, the patient developed stage 4 chronic kidney disease12 , 17 , 18.
Detection of tubular or urothelial cells with inclusions of BK virus cells in urine is a useful tool for the diagnosis of this infection in the urinary system. These cells are known as Decoy cells for their similarity with tumor cells in Pap smears. Decoy cells have a sensitivity of 25% and a specificity of 84%12 but this study was not performed on the patient because initially this diagnosis was not considered. Electron microscopy in urine samples has a sensitivity and specificity of 100% but is not available in many centers12. Viral detection by PCR is a useful tool, widely available and with high sensitivity (100%) and specificity (78%) for diagnosis (PCR of the BK virus in urine: sensitivity 100%, specificity of 78%; PCR of the BK virus in blood: sensitivity of 100% and specificity 88%). It is also a useful prognostic parameter, since high levels of viruria or viremia correlate with the presence of BK virus nephropathy12.
Kidney biopsy is considered the "gold" diagnostic standard. It is usually indicated when viremia is greater than 10,000 copies/mL, with or without creatinine elevation, and with kidney dysfunction without recognizable cause12. In addition, immunohistochemistry for SV40 T antigen must be performed, which, when positive, allows to detect with high accuracy the viral infection. However, it should be taken into account that sometimes the infection is focal, so an insufficient renal biopsy may not detect the infection8 , 18 - 20. The original Banff classification recognizes three histological patterns: a first early stage without tubular cell necrosis (stage A); a second stage of active nephropathy with tubular cell necrosis (stage B); and a late third stage characterized by advanced fibrosis (stage C)21. This classification correlates with the risk of CKD progression, as stage A is an early stage without fibrosis and completely reversible, while stage C is usually irreversible, as in this patient's case.
Currently, there is no standard therapy for BK virus nephropathy8. Certain drugs have demonstrated antiviral properties in vitro (quinolones, leflunomide, cidofovir, statins), but they have not yet shown significant results in clinical studies12. Intravenous immunoglobulin, combined with the reduction of immunosuppressive therapy, may have some initial beneficial effect in the clearance of viremia, but it is followed by an increase in viremia and BK virus nephropathy22. In our patient, immunoglobulin was not prescribed, as the use of immunoglobulin in BK viral nephropathy is not currently approved in Colombia. The current therapeutic approach for BK virus infection consists in the reduction of immunosuppression or substitution of the different immunosuppressive pharmacological groups. Since the efficacy of BK viral nephropathy treatments is limited, conducting periodic screening tests in the period after transplantation or during rejection therapy are recommended to prevent this infection. In renal transplantation, the measurement of BK virus viral load in serum is recommended monthly from one to twelve months, and then every three months19. In other types of transplants, screening frequency has not yet been established. However, the systematic screening of viremia and BK viruria within post-transplant follow-up, especially in patients at high risk for this infection, may allow timely detection of the virus and an early modification of the immunosuppressive scheme to avoid chronic kidney damage12 , 17 , 23. In the case reported here, the treatment aimed to decrease immunosuppression by suspending the anticalcineurinic agent, which allowed to control the infection without rejection. The patient was already receiving a mammalian target of rapamycin inhibitor (MTOR) (everolimus), which was maintained to avoid rejection and because this drug has been attributed with antiviral properties, although in the case of BK virus ifection, its effectiveness is controversial18.
In summary, BK virus nephropathy in transplant patients other than kidney transplant recipients is a silent entity that can lead to chronic kidney disease with increased morbidity and mortality. We therefore propose to consider the BK virus infection as a cause of renal dysfunction in heart transplant recipients, with the aim of detecting its replication in time to reduce immunosuppressive therapy before irreversible impairment of renal function may manifest. | BASILIXIMAB, EVEROLIMUS, METHYLPREDNISOLONE, PREDNISOLONE, TACROLIMUS | DrugsGivenReaction | CC BY | 33527977 | 20,174,669 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Toxicity to various agents'. | BK virus nephropathy in a heart transplant recipient.
BK virus nephropathy in kidney transplantation is widely recognized as an important cause of graft dysfunction and loss. In the case of transplants of organs other than kidney, BK virus nephropathy in native kidneys has been recognized as a cause of chronic kidney disease, which is related with immunosuppression; however, the diagnosis is usually late because the renal dysfunction is attributed to other causes, such as toxicity by anticalcineurinic drugs, interstitial nephritis due to medications, hemodynamic changes, diabetes, hypertension, etc. We report a case of BK virus nephropathy in a patient who underwent heart transplantation due to peripartum cardiomyopathy. The kidney biopsy reported active chronic tubulointerstitial nephritis associated with late stage polyomavirus nephritis and the blood viral load for BK virus was positive (logarithm 4.5). The immunosuppressive treatment was reduced, and after two years of follow-up, the patient had stable renal function with a serum creatinine of 2.5 mg/dL (GFR of 23.4 mL/min/1.73m2). We recommend that the BK virus be considered as a cause of renal dysfunction in heart transplant recipients, with the aim of detecting its replication in time to reduce immunosuppressive therapy before irreversible compromise of renal function may manifest.
pmcIntroduction
BK viruses are circular, double-stranded DNA viruses1 - 4 that typically cause asymptomatic infections in the pediatric population, persisting latent in the renal epithelium and lymphocytes with minimal episomal replication2 , 5 , 6. In immunosuppressed patients, this virus is associated with different complications, including BK virus nephropathy, ureteral stenosis, and hemorrhagic cystitis1 , 3 , 7.
At present, the exact route of transmission is not known, but it is believed that the virus is usually acquired via the air in childhood8. It is postulated that the BK virus enters the blood by infecting mononuclear cells that circulate through the tonsil tissue, allowing it to spread to distant sites, including the kidneys, spleen, thyroid, and pancreas5. Latent infection typically compromises the genitourinary tract, where it establishes a latency for life. Reactivation of the virus can occur in immunosuppressed patients, particularly in patients receiving immunosuppressive therapies6 , 9. BK virus nephropathy is recognized as an emerging problem in renal transplant recipients; approximately 30-50% of renal transplant patients present BK viruria one month after renal transplantation10 and 5-10% develop BK virus nephropathy, of which 50-80% develop renal graft failure9 , 11. The risk factors for the development of BK virus nephropathy include age over 50, male sex, rejection treatment, prolonged cold ischemia times, lymphocyte-depleting induction, and the use of immunosuppressants such as tacrolimus/mycophenolate12.
In recent years, cases of BK virus nephropathy have been reported in native kidneys of patients who have undergone bone marrow transplantation, as well as in transplantation of other non-renal solid organs, such as heart, liver, and lung10 , 13. We present here the case of a heart transplant patient who developed a BK virus nephropathy, with a late diagnosis of this complication resulting in advanced chronic kidney disease.
Clinical case
A 39-year-old woman with a diagnosis of peripartum cardiomyopathy who received a heart transplant in October 2014. She received induction with Basiliximab and methylprednisolone. In addition, she was given a maintenance treatment with extended-release tacrolimus XL, 7 mg daily, everolimus 1, twice daily, and prednisolone, 5 mg/day. She had two acute rejection episodes during the first year post-transplant, and was managed with pulse methylprednisolone, with good results. There was no history of kidney disease and her renal function was stable, with creatinine of 0.88 mg/dL and glomerular filtration rate (GFR) of 102 mL/min/1.73m2 during the first year post-transplant. Management was exclusively performed by the cardiac transplant group and routine monitoring of polyomavirus with viral load BK or urine cytology was not done. In 2016, she presented an elevation of serum creatinine up to 1.9 mg/dL, with a GFR of 32.6 mL/min/1.73m2. At that time, tacrolimus trough level was 7.2 ng/mL and everolimus, 5.2 ng/mL. Toxicity by anticalcineurinics was suspected; therefore, tacrolimus was reduced to 4 mg daily and creatinine value returned near to the baseline value (creatinine 1.25 mg/dL, GFR 54.1 mL/min/1.73m2); no kidney biopsy was performed. In March 2017, creatinine raised to 2.69 mg/dL, with a TFG of 21.4 mL/min/1.73m2, for which she was hospitalized. The patient stated she did not present any symptom. At physical examination, she was observed in good general condition, heart rate of 80 beats per minute, blood pressure of 130/90 mmHg, respiratory rate of 15 per minute, afebrile. Additional studies were conducted: ultrasound of the renal tract showed normal renal size, but increased echogenicity; urinary microscopy and culture analyses were negative, with no hematuria, pyuria or casts; echocardiogram with adequate cardiac function; serological tests for HIV, syphilis, hepatitis virus B and C were negative; tacrolimus trough level of 5.2 ng/mL, and everolimus of 5.98 ng/mL (Table 1). Management was initiated with intravenous hydration, and the dose of tacrolimus XL was decreased to 2 mg daily, but there was no improvement of kidney function; a kidney biopsy was planned.
Table 1 Laboratory tests results
Urine Tests
Density 1.005
Proteinuria Negative
Glycosuria Negative
Leukocytes 0-5
Erythrocytes 0-2
Bacteria Scarce
Test for infectious diseases
Bk virus, viral load (blood) 33800 copies/mL
AgS Hepatitis B Negative
Antibodies for hepatitis C Negative
Antibodies for human immunodeficiency virus Negative
Immunological Tests
Serological test for syphilis Negative
Antinuclear antibodies (ANAS) Negative
Antibodies anti-DNA Negative
Complement C3 y C4 Normal
Blood Tests
Sodium 140 mmol/L
Chloride 108 mmol/L
Potassium 3.68 mmol/L
Calcium 8.5 mg/dL
Phosphorus 3.3 mg/dL
Lactate dehydrogenase 188 U/L
Parathormone 81 pg/mL
CPK total 126 U/L
Albumin 4 g/dL
Hemoglobin 11.3 g/dL
Hematocrit 26.80%
Leukocytes 4900 mm3
Platelets 168000 mm3
Neutrophils 66%
Lymphocytes 20%
Echocardiography
Left ventricular ejection fraction: 60%
AgS: surface antigen.
The kidney biopsy revealed active chronic tubulointerstitial nephritis, associated with late stage polyomavirus nephritis (Figure 1). PCR for BK virus was performed and the result was positive at 33800 copies/mL in blood (logarithm 4.5). Tacrolimus was withdrawn; creatinine levels stabilized between 2.2 and 2.4 mg/dL, without further elevation in post-discharge controls. Her viral load started to decline until reaching undetectable values. Patient progress is summarized in Figures 2 and 3. The patient did not presented episodes of cardiac rejection at 3 years of follow-up; the last creatinine measure was 2.5 mg/dL, corresponding to a GFR of 23.4 mL/min/1.73m2.
Figure 1 Laboratory values during follow up.
Figure 2 BK viral load (number of copies).
Figure 3 Renal biopsy report: active chronic tubulointerstitial nephritis, with positive immunohistochemistry for SV40, consistent with stage C polyomavirus nephritis (arrows). Image courtesy of Department of Pathology, Fundación Santa Fe de Bogotá, Colombia.
Discussion
Polyomavirus nephropathy is a severe opportunistic infection that occurs in kidney transplant patients. In rare cases, it also affects the native kidneys of transplant recipients of other organs14, and it can lead to terminal chronic kidney disease of the native kidneys8. In recent years, the reporting of BK virus infection has increased in transplant recipients of heart, lung, liver, pancreas, and kidney plus pancreas8. In addition, there are reports of BK virus infection in the urinary system of bone marrow transplant recipients, in whom it manifests primarily with hemorrhagic cystitis8 , 15.
In the context of cardiac transplantation, BK virus infection of the urinary system has been reported mainly during rejection episodes, associated with an increase in immunosuppressant drugs. In some studies, BK viruria of up to 19% has been reported in heart transplant recipients, and viremia up to 5%, but BK virus nephropathy is unusual in this population. It has been suggested that additional damage to the native kidneys is required for the development of BK viral nephropathy8,16. Vigil D et al. reviewed the literature on heart transplants with BK virus infection. Eleven patients were reported, nine males, 81% of cases associated with rejection, of which 72% had terminal chronic kidney disease, with a mortality of 27%8. In the case reported here, the patient was a heart transplant recipient, with a previous episode of acute rejection, so she was strongly immunosuppressed. In addition, she presented a progressive increase in creatinine, initially attributed to toxicity by anticalcineurinics, but due to the poor response to the initial therapy, a renal biopsy was performed, and viral load was requested for BK virus, which was positive. These findings allowed the diagnosis of BK virus nephropathy, and due to the late diagnosis, the patient developed stage 4 chronic kidney disease12 , 17 , 18.
Detection of tubular or urothelial cells with inclusions of BK virus cells in urine is a useful tool for the diagnosis of this infection in the urinary system. These cells are known as Decoy cells for their similarity with tumor cells in Pap smears. Decoy cells have a sensitivity of 25% and a specificity of 84%12 but this study was not performed on the patient because initially this diagnosis was not considered. Electron microscopy in urine samples has a sensitivity and specificity of 100% but is not available in many centers12. Viral detection by PCR is a useful tool, widely available and with high sensitivity (100%) and specificity (78%) for diagnosis (PCR of the BK virus in urine: sensitivity 100%, specificity of 78%; PCR of the BK virus in blood: sensitivity of 100% and specificity 88%). It is also a useful prognostic parameter, since high levels of viruria or viremia correlate with the presence of BK virus nephropathy12.
Kidney biopsy is considered the "gold" diagnostic standard. It is usually indicated when viremia is greater than 10,000 copies/mL, with or without creatinine elevation, and with kidney dysfunction without recognizable cause12. In addition, immunohistochemistry for SV40 T antigen must be performed, which, when positive, allows to detect with high accuracy the viral infection. However, it should be taken into account that sometimes the infection is focal, so an insufficient renal biopsy may not detect the infection8 , 18 - 20. The original Banff classification recognizes three histological patterns: a first early stage without tubular cell necrosis (stage A); a second stage of active nephropathy with tubular cell necrosis (stage B); and a late third stage characterized by advanced fibrosis (stage C)21. This classification correlates with the risk of CKD progression, as stage A is an early stage without fibrosis and completely reversible, while stage C is usually irreversible, as in this patient's case.
Currently, there is no standard therapy for BK virus nephropathy8. Certain drugs have demonstrated antiviral properties in vitro (quinolones, leflunomide, cidofovir, statins), but they have not yet shown significant results in clinical studies12. Intravenous immunoglobulin, combined with the reduction of immunosuppressive therapy, may have some initial beneficial effect in the clearance of viremia, but it is followed by an increase in viremia and BK virus nephropathy22. In our patient, immunoglobulin was not prescribed, as the use of immunoglobulin in BK viral nephropathy is not currently approved in Colombia. The current therapeutic approach for BK virus infection consists in the reduction of immunosuppression or substitution of the different immunosuppressive pharmacological groups. Since the efficacy of BK viral nephropathy treatments is limited, conducting periodic screening tests in the period after transplantation or during rejection therapy are recommended to prevent this infection. In renal transplantation, the measurement of BK virus viral load in serum is recommended monthly from one to twelve months, and then every three months19. In other types of transplants, screening frequency has not yet been established. However, the systematic screening of viremia and BK viruria within post-transplant follow-up, especially in patients at high risk for this infection, may allow timely detection of the virus and an early modification of the immunosuppressive scheme to avoid chronic kidney damage12 , 17 , 23. In the case reported here, the treatment aimed to decrease immunosuppression by suspending the anticalcineurinic agent, which allowed to control the infection without rejection. The patient was already receiving a mammalian target of rapamycin inhibitor (MTOR) (everolimus), which was maintained to avoid rejection and because this drug has been attributed with antiviral properties, although in the case of BK virus ifection, its effectiveness is controversial18.
In summary, BK virus nephropathy in transplant patients other than kidney transplant recipients is a silent entity that can lead to chronic kidney disease with increased morbidity and mortality. We therefore propose to consider the BK virus infection as a cause of renal dysfunction in heart transplant recipients, with the aim of detecting its replication in time to reduce immunosuppressive therapy before irreversible impairment of renal function may manifest. | BASILIXIMAB, EVEROLIMUS, METHYLPREDNISOLONE, PREDNISOLONE, TACROLIMUS | DrugsGivenReaction | CC BY | 33527977 | 20,169,062 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Tubulointerstitial nephritis'. | BK virus nephropathy in a heart transplant recipient.
BK virus nephropathy in kidney transplantation is widely recognized as an important cause of graft dysfunction and loss. In the case of transplants of organs other than kidney, BK virus nephropathy in native kidneys has been recognized as a cause of chronic kidney disease, which is related with immunosuppression; however, the diagnosis is usually late because the renal dysfunction is attributed to other causes, such as toxicity by anticalcineurinic drugs, interstitial nephritis due to medications, hemodynamic changes, diabetes, hypertension, etc. We report a case of BK virus nephropathy in a patient who underwent heart transplantation due to peripartum cardiomyopathy. The kidney biopsy reported active chronic tubulointerstitial nephritis associated with late stage polyomavirus nephritis and the blood viral load for BK virus was positive (logarithm 4.5). The immunosuppressive treatment was reduced, and after two years of follow-up, the patient had stable renal function with a serum creatinine of 2.5 mg/dL (GFR of 23.4 mL/min/1.73m2). We recommend that the BK virus be considered as a cause of renal dysfunction in heart transplant recipients, with the aim of detecting its replication in time to reduce immunosuppressive therapy before irreversible compromise of renal function may manifest.
pmcIntroduction
BK viruses are circular, double-stranded DNA viruses1 - 4 that typically cause asymptomatic infections in the pediatric population, persisting latent in the renal epithelium and lymphocytes with minimal episomal replication2 , 5 , 6. In immunosuppressed patients, this virus is associated with different complications, including BK virus nephropathy, ureteral stenosis, and hemorrhagic cystitis1 , 3 , 7.
At present, the exact route of transmission is not known, but it is believed that the virus is usually acquired via the air in childhood8. It is postulated that the BK virus enters the blood by infecting mononuclear cells that circulate through the tonsil tissue, allowing it to spread to distant sites, including the kidneys, spleen, thyroid, and pancreas5. Latent infection typically compromises the genitourinary tract, where it establishes a latency for life. Reactivation of the virus can occur in immunosuppressed patients, particularly in patients receiving immunosuppressive therapies6 , 9. BK virus nephropathy is recognized as an emerging problem in renal transplant recipients; approximately 30-50% of renal transplant patients present BK viruria one month after renal transplantation10 and 5-10% develop BK virus nephropathy, of which 50-80% develop renal graft failure9 , 11. The risk factors for the development of BK virus nephropathy include age over 50, male sex, rejection treatment, prolonged cold ischemia times, lymphocyte-depleting induction, and the use of immunosuppressants such as tacrolimus/mycophenolate12.
In recent years, cases of BK virus nephropathy have been reported in native kidneys of patients who have undergone bone marrow transplantation, as well as in transplantation of other non-renal solid organs, such as heart, liver, and lung10 , 13. We present here the case of a heart transplant patient who developed a BK virus nephropathy, with a late diagnosis of this complication resulting in advanced chronic kidney disease.
Clinical case
A 39-year-old woman with a diagnosis of peripartum cardiomyopathy who received a heart transplant in October 2014. She received induction with Basiliximab and methylprednisolone. In addition, she was given a maintenance treatment with extended-release tacrolimus XL, 7 mg daily, everolimus 1, twice daily, and prednisolone, 5 mg/day. She had two acute rejection episodes during the first year post-transplant, and was managed with pulse methylprednisolone, with good results. There was no history of kidney disease and her renal function was stable, with creatinine of 0.88 mg/dL and glomerular filtration rate (GFR) of 102 mL/min/1.73m2 during the first year post-transplant. Management was exclusively performed by the cardiac transplant group and routine monitoring of polyomavirus with viral load BK or urine cytology was not done. In 2016, she presented an elevation of serum creatinine up to 1.9 mg/dL, with a GFR of 32.6 mL/min/1.73m2. At that time, tacrolimus trough level was 7.2 ng/mL and everolimus, 5.2 ng/mL. Toxicity by anticalcineurinics was suspected; therefore, tacrolimus was reduced to 4 mg daily and creatinine value returned near to the baseline value (creatinine 1.25 mg/dL, GFR 54.1 mL/min/1.73m2); no kidney biopsy was performed. In March 2017, creatinine raised to 2.69 mg/dL, with a TFG of 21.4 mL/min/1.73m2, for which she was hospitalized. The patient stated she did not present any symptom. At physical examination, she was observed in good general condition, heart rate of 80 beats per minute, blood pressure of 130/90 mmHg, respiratory rate of 15 per minute, afebrile. Additional studies were conducted: ultrasound of the renal tract showed normal renal size, but increased echogenicity; urinary microscopy and culture analyses were negative, with no hematuria, pyuria or casts; echocardiogram with adequate cardiac function; serological tests for HIV, syphilis, hepatitis virus B and C were negative; tacrolimus trough level of 5.2 ng/mL, and everolimus of 5.98 ng/mL (Table 1). Management was initiated with intravenous hydration, and the dose of tacrolimus XL was decreased to 2 mg daily, but there was no improvement of kidney function; a kidney biopsy was planned.
Table 1 Laboratory tests results
Urine Tests
Density 1.005
Proteinuria Negative
Glycosuria Negative
Leukocytes 0-5
Erythrocytes 0-2
Bacteria Scarce
Test for infectious diseases
Bk virus, viral load (blood) 33800 copies/mL
AgS Hepatitis B Negative
Antibodies for hepatitis C Negative
Antibodies for human immunodeficiency virus Negative
Immunological Tests
Serological test for syphilis Negative
Antinuclear antibodies (ANAS) Negative
Antibodies anti-DNA Negative
Complement C3 y C4 Normal
Blood Tests
Sodium 140 mmol/L
Chloride 108 mmol/L
Potassium 3.68 mmol/L
Calcium 8.5 mg/dL
Phosphorus 3.3 mg/dL
Lactate dehydrogenase 188 U/L
Parathormone 81 pg/mL
CPK total 126 U/L
Albumin 4 g/dL
Hemoglobin 11.3 g/dL
Hematocrit 26.80%
Leukocytes 4900 mm3
Platelets 168000 mm3
Neutrophils 66%
Lymphocytes 20%
Echocardiography
Left ventricular ejection fraction: 60%
AgS: surface antigen.
The kidney biopsy revealed active chronic tubulointerstitial nephritis, associated with late stage polyomavirus nephritis (Figure 1). PCR for BK virus was performed and the result was positive at 33800 copies/mL in blood (logarithm 4.5). Tacrolimus was withdrawn; creatinine levels stabilized between 2.2 and 2.4 mg/dL, without further elevation in post-discharge controls. Her viral load started to decline until reaching undetectable values. Patient progress is summarized in Figures 2 and 3. The patient did not presented episodes of cardiac rejection at 3 years of follow-up; the last creatinine measure was 2.5 mg/dL, corresponding to a GFR of 23.4 mL/min/1.73m2.
Figure 1 Laboratory values during follow up.
Figure 2 BK viral load (number of copies).
Figure 3 Renal biopsy report: active chronic tubulointerstitial nephritis, with positive immunohistochemistry for SV40, consistent with stage C polyomavirus nephritis (arrows). Image courtesy of Department of Pathology, Fundación Santa Fe de Bogotá, Colombia.
Discussion
Polyomavirus nephropathy is a severe opportunistic infection that occurs in kidney transplant patients. In rare cases, it also affects the native kidneys of transplant recipients of other organs14, and it can lead to terminal chronic kidney disease of the native kidneys8. In recent years, the reporting of BK virus infection has increased in transplant recipients of heart, lung, liver, pancreas, and kidney plus pancreas8. In addition, there are reports of BK virus infection in the urinary system of bone marrow transplant recipients, in whom it manifests primarily with hemorrhagic cystitis8 , 15.
In the context of cardiac transplantation, BK virus infection of the urinary system has been reported mainly during rejection episodes, associated with an increase in immunosuppressant drugs. In some studies, BK viruria of up to 19% has been reported in heart transplant recipients, and viremia up to 5%, but BK virus nephropathy is unusual in this population. It has been suggested that additional damage to the native kidneys is required for the development of BK viral nephropathy8,16. Vigil D et al. reviewed the literature on heart transplants with BK virus infection. Eleven patients were reported, nine males, 81% of cases associated with rejection, of which 72% had terminal chronic kidney disease, with a mortality of 27%8. In the case reported here, the patient was a heart transplant recipient, with a previous episode of acute rejection, so she was strongly immunosuppressed. In addition, she presented a progressive increase in creatinine, initially attributed to toxicity by anticalcineurinics, but due to the poor response to the initial therapy, a renal biopsy was performed, and viral load was requested for BK virus, which was positive. These findings allowed the diagnosis of BK virus nephropathy, and due to the late diagnosis, the patient developed stage 4 chronic kidney disease12 , 17 , 18.
Detection of tubular or urothelial cells with inclusions of BK virus cells in urine is a useful tool for the diagnosis of this infection in the urinary system. These cells are known as Decoy cells for their similarity with tumor cells in Pap smears. Decoy cells have a sensitivity of 25% and a specificity of 84%12 but this study was not performed on the patient because initially this diagnosis was not considered. Electron microscopy in urine samples has a sensitivity and specificity of 100% but is not available in many centers12. Viral detection by PCR is a useful tool, widely available and with high sensitivity (100%) and specificity (78%) for diagnosis (PCR of the BK virus in urine: sensitivity 100%, specificity of 78%; PCR of the BK virus in blood: sensitivity of 100% and specificity 88%). It is also a useful prognostic parameter, since high levels of viruria or viremia correlate with the presence of BK virus nephropathy12.
Kidney biopsy is considered the "gold" diagnostic standard. It is usually indicated when viremia is greater than 10,000 copies/mL, with or without creatinine elevation, and with kidney dysfunction without recognizable cause12. In addition, immunohistochemistry for SV40 T antigen must be performed, which, when positive, allows to detect with high accuracy the viral infection. However, it should be taken into account that sometimes the infection is focal, so an insufficient renal biopsy may not detect the infection8 , 18 - 20. The original Banff classification recognizes three histological patterns: a first early stage without tubular cell necrosis (stage A); a second stage of active nephropathy with tubular cell necrosis (stage B); and a late third stage characterized by advanced fibrosis (stage C)21. This classification correlates with the risk of CKD progression, as stage A is an early stage without fibrosis and completely reversible, while stage C is usually irreversible, as in this patient's case.
Currently, there is no standard therapy for BK virus nephropathy8. Certain drugs have demonstrated antiviral properties in vitro (quinolones, leflunomide, cidofovir, statins), but they have not yet shown significant results in clinical studies12. Intravenous immunoglobulin, combined with the reduction of immunosuppressive therapy, may have some initial beneficial effect in the clearance of viremia, but it is followed by an increase in viremia and BK virus nephropathy22. In our patient, immunoglobulin was not prescribed, as the use of immunoglobulin in BK viral nephropathy is not currently approved in Colombia. The current therapeutic approach for BK virus infection consists in the reduction of immunosuppression or substitution of the different immunosuppressive pharmacological groups. Since the efficacy of BK viral nephropathy treatments is limited, conducting periodic screening tests in the period after transplantation or during rejection therapy are recommended to prevent this infection. In renal transplantation, the measurement of BK virus viral load in serum is recommended monthly from one to twelve months, and then every three months19. In other types of transplants, screening frequency has not yet been established. However, the systematic screening of viremia and BK viruria within post-transplant follow-up, especially in patients at high risk for this infection, may allow timely detection of the virus and an early modification of the immunosuppressive scheme to avoid chronic kidney damage12 , 17 , 23. In the case reported here, the treatment aimed to decrease immunosuppression by suspending the anticalcineurinic agent, which allowed to control the infection without rejection. The patient was already receiving a mammalian target of rapamycin inhibitor (MTOR) (everolimus), which was maintained to avoid rejection and because this drug has been attributed with antiviral properties, although in the case of BK virus ifection, its effectiveness is controversial18.
In summary, BK virus nephropathy in transplant patients other than kidney transplant recipients is a silent entity that can lead to chronic kidney disease with increased morbidity and mortality. We therefore propose to consider the BK virus infection as a cause of renal dysfunction in heart transplant recipients, with the aim of detecting its replication in time to reduce immunosuppressive therapy before irreversible impairment of renal function may manifest. | BASILIXIMAB, EVEROLIMUS, METHYLPREDNISOLONE, PREDNISOLONE, TACROLIMUS | DrugsGivenReaction | CC BY | 33527977 | 20,174,669 | 2021 |
What was the dosage of drug 'BASILIXIMAB'? | BK virus nephropathy in a heart transplant recipient.
BK virus nephropathy in kidney transplantation is widely recognized as an important cause of graft dysfunction and loss. In the case of transplants of organs other than kidney, BK virus nephropathy in native kidneys has been recognized as a cause of chronic kidney disease, which is related with immunosuppression; however, the diagnosis is usually late because the renal dysfunction is attributed to other causes, such as toxicity by anticalcineurinic drugs, interstitial nephritis due to medications, hemodynamic changes, diabetes, hypertension, etc. We report a case of BK virus nephropathy in a patient who underwent heart transplantation due to peripartum cardiomyopathy. The kidney biopsy reported active chronic tubulointerstitial nephritis associated with late stage polyomavirus nephritis and the blood viral load for BK virus was positive (logarithm 4.5). The immunosuppressive treatment was reduced, and after two years of follow-up, the patient had stable renal function with a serum creatinine of 2.5 mg/dL (GFR of 23.4 mL/min/1.73m2). We recommend that the BK virus be considered as a cause of renal dysfunction in heart transplant recipients, with the aim of detecting its replication in time to reduce immunosuppressive therapy before irreversible compromise of renal function may manifest.
pmcIntroduction
BK viruses are circular, double-stranded DNA viruses1 - 4 that typically cause asymptomatic infections in the pediatric population, persisting latent in the renal epithelium and lymphocytes with minimal episomal replication2 , 5 , 6. In immunosuppressed patients, this virus is associated with different complications, including BK virus nephropathy, ureteral stenosis, and hemorrhagic cystitis1 , 3 , 7.
At present, the exact route of transmission is not known, but it is believed that the virus is usually acquired via the air in childhood8. It is postulated that the BK virus enters the blood by infecting mononuclear cells that circulate through the tonsil tissue, allowing it to spread to distant sites, including the kidneys, spleen, thyroid, and pancreas5. Latent infection typically compromises the genitourinary tract, where it establishes a latency for life. Reactivation of the virus can occur in immunosuppressed patients, particularly in patients receiving immunosuppressive therapies6 , 9. BK virus nephropathy is recognized as an emerging problem in renal transplant recipients; approximately 30-50% of renal transplant patients present BK viruria one month after renal transplantation10 and 5-10% develop BK virus nephropathy, of which 50-80% develop renal graft failure9 , 11. The risk factors for the development of BK virus nephropathy include age over 50, male sex, rejection treatment, prolonged cold ischemia times, lymphocyte-depleting induction, and the use of immunosuppressants such as tacrolimus/mycophenolate12.
In recent years, cases of BK virus nephropathy have been reported in native kidneys of patients who have undergone bone marrow transplantation, as well as in transplantation of other non-renal solid organs, such as heart, liver, and lung10 , 13. We present here the case of a heart transplant patient who developed a BK virus nephropathy, with a late diagnosis of this complication resulting in advanced chronic kidney disease.
Clinical case
A 39-year-old woman with a diagnosis of peripartum cardiomyopathy who received a heart transplant in October 2014. She received induction with Basiliximab and methylprednisolone. In addition, she was given a maintenance treatment with extended-release tacrolimus XL, 7 mg daily, everolimus 1, twice daily, and prednisolone, 5 mg/day. She had two acute rejection episodes during the first year post-transplant, and was managed with pulse methylprednisolone, with good results. There was no history of kidney disease and her renal function was stable, with creatinine of 0.88 mg/dL and glomerular filtration rate (GFR) of 102 mL/min/1.73m2 during the first year post-transplant. Management was exclusively performed by the cardiac transplant group and routine monitoring of polyomavirus with viral load BK or urine cytology was not done. In 2016, she presented an elevation of serum creatinine up to 1.9 mg/dL, with a GFR of 32.6 mL/min/1.73m2. At that time, tacrolimus trough level was 7.2 ng/mL and everolimus, 5.2 ng/mL. Toxicity by anticalcineurinics was suspected; therefore, tacrolimus was reduced to 4 mg daily and creatinine value returned near to the baseline value (creatinine 1.25 mg/dL, GFR 54.1 mL/min/1.73m2); no kidney biopsy was performed. In March 2017, creatinine raised to 2.69 mg/dL, with a TFG of 21.4 mL/min/1.73m2, for which she was hospitalized. The patient stated she did not present any symptom. At physical examination, she was observed in good general condition, heart rate of 80 beats per minute, blood pressure of 130/90 mmHg, respiratory rate of 15 per minute, afebrile. Additional studies were conducted: ultrasound of the renal tract showed normal renal size, but increased echogenicity; urinary microscopy and culture analyses were negative, with no hematuria, pyuria or casts; echocardiogram with adequate cardiac function; serological tests for HIV, syphilis, hepatitis virus B and C were negative; tacrolimus trough level of 5.2 ng/mL, and everolimus of 5.98 ng/mL (Table 1). Management was initiated with intravenous hydration, and the dose of tacrolimus XL was decreased to 2 mg daily, but there was no improvement of kidney function; a kidney biopsy was planned.
Table 1 Laboratory tests results
Urine Tests
Density 1.005
Proteinuria Negative
Glycosuria Negative
Leukocytes 0-5
Erythrocytes 0-2
Bacteria Scarce
Test for infectious diseases
Bk virus, viral load (blood) 33800 copies/mL
AgS Hepatitis B Negative
Antibodies for hepatitis C Negative
Antibodies for human immunodeficiency virus Negative
Immunological Tests
Serological test for syphilis Negative
Antinuclear antibodies (ANAS) Negative
Antibodies anti-DNA Negative
Complement C3 y C4 Normal
Blood Tests
Sodium 140 mmol/L
Chloride 108 mmol/L
Potassium 3.68 mmol/L
Calcium 8.5 mg/dL
Phosphorus 3.3 mg/dL
Lactate dehydrogenase 188 U/L
Parathormone 81 pg/mL
CPK total 126 U/L
Albumin 4 g/dL
Hemoglobin 11.3 g/dL
Hematocrit 26.80%
Leukocytes 4900 mm3
Platelets 168000 mm3
Neutrophils 66%
Lymphocytes 20%
Echocardiography
Left ventricular ejection fraction: 60%
AgS: surface antigen.
The kidney biopsy revealed active chronic tubulointerstitial nephritis, associated with late stage polyomavirus nephritis (Figure 1). PCR for BK virus was performed and the result was positive at 33800 copies/mL in blood (logarithm 4.5). Tacrolimus was withdrawn; creatinine levels stabilized between 2.2 and 2.4 mg/dL, without further elevation in post-discharge controls. Her viral load started to decline until reaching undetectable values. Patient progress is summarized in Figures 2 and 3. The patient did not presented episodes of cardiac rejection at 3 years of follow-up; the last creatinine measure was 2.5 mg/dL, corresponding to a GFR of 23.4 mL/min/1.73m2.
Figure 1 Laboratory values during follow up.
Figure 2 BK viral load (number of copies).
Figure 3 Renal biopsy report: active chronic tubulointerstitial nephritis, with positive immunohistochemistry for SV40, consistent with stage C polyomavirus nephritis (arrows). Image courtesy of Department of Pathology, Fundación Santa Fe de Bogotá, Colombia.
Discussion
Polyomavirus nephropathy is a severe opportunistic infection that occurs in kidney transplant patients. In rare cases, it also affects the native kidneys of transplant recipients of other organs14, and it can lead to terminal chronic kidney disease of the native kidneys8. In recent years, the reporting of BK virus infection has increased in transplant recipients of heart, lung, liver, pancreas, and kidney plus pancreas8. In addition, there are reports of BK virus infection in the urinary system of bone marrow transplant recipients, in whom it manifests primarily with hemorrhagic cystitis8 , 15.
In the context of cardiac transplantation, BK virus infection of the urinary system has been reported mainly during rejection episodes, associated with an increase in immunosuppressant drugs. In some studies, BK viruria of up to 19% has been reported in heart transplant recipients, and viremia up to 5%, but BK virus nephropathy is unusual in this population. It has been suggested that additional damage to the native kidneys is required for the development of BK viral nephropathy8,16. Vigil D et al. reviewed the literature on heart transplants with BK virus infection. Eleven patients were reported, nine males, 81% of cases associated with rejection, of which 72% had terminal chronic kidney disease, with a mortality of 27%8. In the case reported here, the patient was a heart transplant recipient, with a previous episode of acute rejection, so she was strongly immunosuppressed. In addition, she presented a progressive increase in creatinine, initially attributed to toxicity by anticalcineurinics, but due to the poor response to the initial therapy, a renal biopsy was performed, and viral load was requested for BK virus, which was positive. These findings allowed the diagnosis of BK virus nephropathy, and due to the late diagnosis, the patient developed stage 4 chronic kidney disease12 , 17 , 18.
Detection of tubular or urothelial cells with inclusions of BK virus cells in urine is a useful tool for the diagnosis of this infection in the urinary system. These cells are known as Decoy cells for their similarity with tumor cells in Pap smears. Decoy cells have a sensitivity of 25% and a specificity of 84%12 but this study was not performed on the patient because initially this diagnosis was not considered. Electron microscopy in urine samples has a sensitivity and specificity of 100% but is not available in many centers12. Viral detection by PCR is a useful tool, widely available and with high sensitivity (100%) and specificity (78%) for diagnosis (PCR of the BK virus in urine: sensitivity 100%, specificity of 78%; PCR of the BK virus in blood: sensitivity of 100% and specificity 88%). It is also a useful prognostic parameter, since high levels of viruria or viremia correlate with the presence of BK virus nephropathy12.
Kidney biopsy is considered the "gold" diagnostic standard. It is usually indicated when viremia is greater than 10,000 copies/mL, with or without creatinine elevation, and with kidney dysfunction without recognizable cause12. In addition, immunohistochemistry for SV40 T antigen must be performed, which, when positive, allows to detect with high accuracy the viral infection. However, it should be taken into account that sometimes the infection is focal, so an insufficient renal biopsy may not detect the infection8 , 18 - 20. The original Banff classification recognizes three histological patterns: a first early stage without tubular cell necrosis (stage A); a second stage of active nephropathy with tubular cell necrosis (stage B); and a late third stage characterized by advanced fibrosis (stage C)21. This classification correlates with the risk of CKD progression, as stage A is an early stage without fibrosis and completely reversible, while stage C is usually irreversible, as in this patient's case.
Currently, there is no standard therapy for BK virus nephropathy8. Certain drugs have demonstrated antiviral properties in vitro (quinolones, leflunomide, cidofovir, statins), but they have not yet shown significant results in clinical studies12. Intravenous immunoglobulin, combined with the reduction of immunosuppressive therapy, may have some initial beneficial effect in the clearance of viremia, but it is followed by an increase in viremia and BK virus nephropathy22. In our patient, immunoglobulin was not prescribed, as the use of immunoglobulin in BK viral nephropathy is not currently approved in Colombia. The current therapeutic approach for BK virus infection consists in the reduction of immunosuppression or substitution of the different immunosuppressive pharmacological groups. Since the efficacy of BK viral nephropathy treatments is limited, conducting periodic screening tests in the period after transplantation or during rejection therapy are recommended to prevent this infection. In renal transplantation, the measurement of BK virus viral load in serum is recommended monthly from one to twelve months, and then every three months19. In other types of transplants, screening frequency has not yet been established. However, the systematic screening of viremia and BK viruria within post-transplant follow-up, especially in patients at high risk for this infection, may allow timely detection of the virus and an early modification of the immunosuppressive scheme to avoid chronic kidney damage12 , 17 , 23. In the case reported here, the treatment aimed to decrease immunosuppression by suspending the anticalcineurinic agent, which allowed to control the infection without rejection. The patient was already receiving a mammalian target of rapamycin inhibitor (MTOR) (everolimus), which was maintained to avoid rejection and because this drug has been attributed with antiviral properties, although in the case of BK virus ifection, its effectiveness is controversial18.
In summary, BK virus nephropathy in transplant patients other than kidney transplant recipients is a silent entity that can lead to chronic kidney disease with increased morbidity and mortality. We therefore propose to consider the BK virus infection as a cause of renal dysfunction in heart transplant recipients, with the aim of detecting its replication in time to reduce immunosuppressive therapy before irreversible impairment of renal function may manifest. | UNK, (INDUCTION) | DrugDosageText | CC BY | 33527977 | 20,169,062 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Malignant neoplasm progression'. | KRAS-Mutated, Estrogen Receptor-Positive Low-Grade Serous Ovarian Cancer: Unraveling an Exceptional Response Mystery.
We report on a woman with aggressive estrogen receptor-positive, KRAS-mutated ovarian cancer who achieved a remarkable response to combination therapy with the MEK inhibitor (trametinib) and the aromatase inhibitor (letrozole), even though the disease had failed to respond to a combination of a PI3K inhibitor and different MEK inhibitor, as well as to trametinib and the estrogen modulator, tamoxifen, and to letrozole by itself. The mechanism of action for exceptional response was elucidated by in vitro experiments that demonstrated that the fact that tamoxifen can have an agonistic effect in addition to antagonist activity, whereas letrozole results only in estrogen depletion was crucial to the response achieved when letrozole was combined with an MEK inhibitor. Our current observations indicate that subtle variations in mechanisms of action of outwardly similar regimens may have a major impact on outcome and that such translational knowledge is critical for optimizing a precision medicine strategy. KEY POINTS: This report describes the remarkable response of a patient with KRAS-mutated, estrogen receptor-positive low-grade serous ovarian cancer treated with trametinib (MEK inhibitor) and letrozole (aromatase inhibitor), despite prior progression on similar agents including tamoxifen (estrogen modulator). In vitro investigation revealed that tamoxifen can have agonistic in addition to antagonistic effects, which could be the reason for the patient not responding to the combination of trametinib and tamoxifen. The current observations suggest that drugs with different mechanisms of action targeting the same receptor may have markedly different anticancer activity when used in combinations.
Introduction
Ovarian cancer is the second most common gynecologic malignancy and the most frequent cause of gynecologic cancer death in the U.S. [1, 2]. Serous ovarian cancer is generally classified into low‐ or high‐grade serous carcinoma [3]. Classification of low‐ versus high‐grade serous ovarian cancer is clinically important because patients with low‐grade serous ovarian cancer (LGSOC) are known to have better progression‐free survival compared with patients with high‐grade disease [4]. However, LGSOC is often resistant to cytotoxic agents (response rate [RR] of ~4%) [5].
Understanding the tumor grade is also important because there are molecular differences between low‐ and high‐grade serous carcinoma. Notably, LGSOC is less commonly associated with TP53 alterations compared with high‐grade carcinoma. Meanwhile, KRAS is altered in 20% to 40% of LGSOC, whereas this mutation is rare among high‐grade histology [5]. Moreover, overexpression of estrogen receptor (ER) and progesterone receptor (PR) are frequent in LGSOC (ER/PR overexpression: 43%–58% vs. 17%–27% for low and high grade, respectively) [6]. Attempts have been made to use antihormone therapy for ER/PR‐positive cancers and MEK inhibitor for KRAS mutant cancers; however, low response rates were observed with these treatment approaches (RR of 9% and 15%, respectively, when given as a single agent) [7, 8]. In some cases, one patient may have multiple molecular alterations that individually suggest different drug options [9, 10]. Previous work reveals that patient outcomes are better when biomarkers are concurrently targeted with different agents [9, 11].
Herein, we describe a patient with heavily pretreated, widely metastatic LGSOC with overexpression of ER by immunohistochemistry (PR negative) and with a KRAS G12V mutation as the sole genomic alteration detected by tissue and circulating cell‐free DNA (cfDNA) next‐generation sequencing. This patient experienced a dramatic and durable response (19+ months) to the combination of the aromatase inhibitor letrozole with the MEK inhibitor trametinib after a series of related regimens had failed. We performed translational experiments to demonstrate that differences in the mechanisms of action of the antiestrogen tamoxifen versus letrozole might explain the remarkable response to letrozole together with trametinib after primary failure of tamoxifen combined with trametinib or letrozole alone.
Patient Story
Case Report
A 28‐year‐old woman initially presented with right‐sided pelvic pain and underwent right‐sided salpingo‐oophorectomy. Pathology detected a serous low‐malignant‐potential tumor. One year later, the patient experienced left‐sided pelvic pain, and imaging studies revealed an adnexal mass, which prompted a hysterectomy with left salpingo‐oophorectomy. Pathology confirmed serous low‐malignant‐potential tumor. Three years after initial diagnosis, imaging revealed a hepatic lesion. The lesion was resected, and pathology showed metastatic LGSOC. Subsequently, the patient received carboplatin and paclitaxel (six cycles), followed by carboplatin, gemcitabine, and bevacizumab (seven cycles). A computed tomography scan performed 9 months after completion of chemotherapy revealed new, widely metastatic disease, and the patient subsequently underwent surgery for tumor debulking. Approximately 1 year later, the patient underwent five cycles of doxorubicin for recurrence. At progression, she sought treatment on a clinical trial with PI3K and MEK inhibitors (PF‐04691502, 130 mg i.v. weekly, and PD‐0325901 [mirdametinib], initially with 4 mg p.o. b.i.d. 3 weeks on, 1 week off; dose reduction was required to 2 mg p.o. b.i.d. 3 weeks on, 1 week off because of intolerable grade 2 rash), which she continued for approximately 1 year until progression. She was then referred to the Precision Medicine Clinic.
Molecular profiling of tissue next‐generation sequencing as well as cfDNA revealed a single alteration—KRAS G12V. Immunohistochemistry was positive for ER (2+, 75% positive) but negative for PR. The patient was started on the MEK inhibitor trametinib for the KRAS G12V mutation and tamoxifen for ER positivity. Unfortunately, serial imaging and cancer antigen 125 (CA125) assessments showed progression at 5 months, and treatment was stopped (Fig. 1A). She was lost to follow‐up for approximately 9 months, at which time she presented again with bulky pelvic masses and a rapidly rising CA125 level (Fig. 1A). Based on ER positivity, she was started on letrozole as monotherapy; however, after 3 months of therapy, she was found to have rising CA125 levels (>15,000 U/mL) with radiographic progression (Fig. 1A and B, left panel).
Figure 1 (A): Dynamic change in tumor marker (CA125) (blue line) and KRAS G12V cell‐free DNA (red dotted line) along with treatment course. (Note that the patient was lost to follow‐up for several months between treatments). (B): Computed tomography images before and after the combination of letrozole and trametinib. Reduction of solid tumor masses (arrows) and improvement in ascites (circles) were seen after the initiation of letrozole and trametinib. Therapy is ongoing at 19+ months. *, Over upper limit of detection (>15,000 U/mL). Abbreviations: CA125, cancer antigen 125; ND, not detected.
At that time, she was rechallenged with trametinib (for KRAS G12V) while continuing on letrozole. Surprisingly, after 2 months of therapy, the patient noted a reduction in abdominal pain and girth. Three months after the therapy began, CA125 level declined to 1,265 U/mL from >15,000 U/mL. KRAS G12V in cfDNA became undetectable. Restaging computed tomography scan performed 4 months after the initiation of letrozole and trametinib showed >50% tumor reduction (per RECIST version 1.1; Fig. 1A and B, right panel). She continues to do well with an ongoing progression‐free survival of 19+ months.
In Vitro Experiments: Combination of Estrogen Depletion with an MEK Inhibitor Sensitized ER‐Positive, RAS Pathway‐Activated Serous Ovarian Cancer Cell Lines Resistant to Tamoxifen and MEK Inhibitor Combination
Because both tamoxifen and letrozole target estrogen signaling, it was of interest to understand why our patient did not respond to tamoxifen combined with trametinib yet had an exceptional response to trametinib combined with letrozole. We considered that tamoxifen and letrozole have different mechanisms of action despite both targeting estrogen signaling. Tamoxifen is known to compete with 17β‐estradiol at the receptor site and to block the promotional role of 17β‐estradiol in breast cancer [12]. However, tamoxifen, can also act as a selective estrogen receptor modulator, and in some contexts, it can have partial agonist effects (i.e., mimicking the effects of estrogen) [13, 14, 15, 16]. In contrast, letrozole inhibits the enzyme aromatase and thereby reduces the production of estrogens; letrozole thereby acts purely as an estrogen antagonist [17].
We set out to experimentally determine whether we could reproduce the pattern of responsiveness seen in our patient. KRAS mutant/ER‐positive serous ovarian carcinoma models are not readily available. We therefore used two ER‐positive serous carcinoma cell lines (OVCAR 3 and SKOV 3) that are readily available. We hypothesized that the effects of the KRAS mutation reflected overactivation of the RAS signaling pathway, and for our experimental efforts we activated epidermal growth factor receptor (EGFR) to induce elevated levels of RAS signaling [18]. This would be consistent with our hypothesized mechanism (Fig. 2). We also used an ER‐negative cell line (OVCAR 5) as a control (supplemental online Methods).
Figure 2 Noncanonical and canonical ER signaling axis. We hypothesized that the partial agonist activity of tamoxifen versus the estrogen depletion effect of letrozole might explain the observed and widely different clinical responses [13, 14, 15, 16]. We also hypothesized that noncanonical ER signaling might be involved, in which MER can drive noncanonical ER signaling [13, 15, 23]. We constructed a map of the signaling pathway that comprises the described interactions, and we considered each of the treatment scenarios and responses. We found that our hypothesized mechanisms could potentially explain the diverging responses to tamoxifen and letrozole when combined with trametinib in a patient with hyperactivated RAS pathway signaling. (Scenario 1): MER‐driven noncanonical ER signaling and RAS signaling (replicating baseline condition of current case report). MER/E2 activates AKT and ER, which leads to cell growth. Activation of EGFR subsequently activates RAS/MAPK pathway, which also leads to growth signaling (similar to KRAS mutation). (Scenario 2): TMX functions as a partial agonist for MER‐driven noncanonical ER signaling. Thus, no inhibitory effect is seen on ER signaling. (Scenario 3): Combination treatment with tamoxifen and trametinib is not sufficient to halt the cell growth despite the successful inhibition of RAS/MEK pathway with trametinib because ER signaling is not adequately reduced with tamoxifen. (Scenario 4): Combination of estrogen depletion (mimicking treatment with letrozole) and trametinib successfully inhibits both ER and RAS signaling, thus leading to the inhibition of cell growth. (Scenario 5): Combination of estrogen depletion (mimicking treatment with letrozole) and erlotinib (EGFR inhibitor to reduce RAS activation) successfully reduces both ER and RAS signaling, thus leading to the inhibition of cell growth. Abbreviations: E2, estradiol; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; ER, estrogen receptor; MAPK, mitogen‐activated protein kinase; MEKi, MEK inhibitor; MER, membrane estrogen receptor; pAKT, phospho‐AKT; pER, phospho‐ER; TMX, tamoxifen.
We first tested if these cells were sensitive to estrogen depletion and found that all three cell lines grew just as well with estrogen depletion compared with when they were grown with estrogen (supplemental online Fig. 1A). Furthermore, we treated these cells with tamoxifen and found that they proliferated at approximately the same rate (supplemental online Fig. 1B). These observations suggest that targeting estrogen signaling alone with either estrogen depletion strategies (mimicking letrozole) or with a selective estrogen modulator (like tamoxifen) would be ineffective.
We then tested scenarios that replicated the patient's treatment schema. Cells were treated with trametinib, trametinib combined with tamoxifen, estrogen depletion, or estrogen depletion combined with trametinib. We found that ER‐positive cells maximally responded to estrogen depletion in combination with the MEK inhibitor trametinib. Interestingly, the ER‐negative cell line OVCAR 5 was sensitive to all treatments with MEK inhibition. No added benefit was observed when combining MEK inhibitor with tamoxifen or estradiol depletion (Fig. 3A). We hypothesized that the presence of ER may prove an alternate signaling pathway to survival when cells are treated with an MEK inhibitor.
Figure 3 Mechanism for tamoxifen and trametinib resistance in OVCAR 3 cells. (A): OVCAR 3 (estrogen receptor [ER]–positive), SKOV 3 (ER‐positive), and OVCAR 5 (ER‐negative) cells were stripped of hormone for 48 hours prior to seeding. Cell culture media contained hormone‐stripped FBS (which contains epidermal growth factor [EGF]) to maintain RAS/mitogen‐activated protein kinase (MAPK) signaling. Cells were treated with 10 nM 17β‐estradiol, 10 nM tamoxifen, and 20 nM trametinib in various combinations, as indicated, for 48 hours. Cell proliferation was measured by MTT assay. Data are representative of eight biological replicates. Histograms represent means, and error bars represent SD. Statistical significance is indicated and determined by one‐way ANOVA with post hoc Tukey's test. The results show that MEK inhibition in the presence of estrogen depletion was associated with significantly decreased growth in all three cell lines. However, MEK inhibition in the presence of estrogen had no effect among ER‐positive cell lines (OVCAR 3 and SKOV 3). On the contrary, MEK inhibition alone was sufficient to reduce the cell proliferation in the ER‐negative cell line (OVCAR 5). *p < .05. (B): OVCAR 3 cells (ER‐positive) were grown in hormone‐stripped cell culture media containing FBS (which contains EGF) for 48 hours prior to seeding. Cells were treated with 10 nM 17β‐estradiol, 10 nM tamoxifen, 20 nM trametinib, and 20 nM erlotinib in various combination, as indicated, for 48 hours. Cell proliferation was measured by MTT assay. Data are representative of eight biological replicates. Histograms represent means, and error bars represent SD. Statistical significance is indicated and determined by one‐way ANOVA with post hoc Tukey's test. The results show that MEK inhibition by trametinib in the presence of estrogen depletion was associated with decreased proliferation; however, if tamoxifen and MEK inhibition were given simultaneously, there was no decrease in proliferation (presumably because tamoxifen may have a partial agonist effect on ER). Similarly, erlotinib (to reduce RAS‐induced MAPK signaling) in combination with estrogen depletion led to decreased cell proliferation (Fig. 2). *p < .0001. (C): OVCAR 3 cells (ER‐positive) were grown in hormone‐stripped cell culture media containing FBS (which contains EGF) for 48 hours and then treated with 10 nM 17β‐estradiol, 10 nM tamoxifen, 20 nM trametinib, and 20 nM erlotinib in various combinations, as indicated, for 48 hours. Whole cell lysates were collected and analyzed by Western blot. Combination of trametinib or erlotinib along with estrogen depletion successfully reduced the phosphorylation of ERK, AKT, and ER. The same effects were not observed with tamoxifen alone or for tamoxifen in combination with trametinib (Fig. 2). Abbreviations: E2, estradiol; GAPDH, glyceraldehyde‐3‐phosphate dehydrogenase; MEKi, MEK inhibitor; pAKT, phospho‐AKT; pER, phospho‐ER, pERK, phosphor‐ERK; TMX, tamoxifen.
We then used trametinib, tamoxifen, estrogen, and erlotinib to deconstruct the signaling axis in OVCAR 3 cells. Cells grown in estrogen grew at comparable levels to cells grown with estrogen and tamoxifen (Fig. 3B). Furthermore, the estrogen and tamoxifen combination and single‐agent tamoxifen treatment did not show any reduction in ERK phosphorylation, ER phosphorylation, or AKT phosphorylation by Western blot (Fig. 3C). We propose that this occurs because tamoxifen can activate the membrane estrogen receptor (MER) to signal through AKT and phosphorylate ER (Fig. 2, Scenario 2). When cells were treated with trametinib, tamoxifen, and estrogen in combination, we observed no reduction in cell growth (Fig. 3B). However, significant reduction in phospho‐ERK signal was observed by Western blot, yet phospho‐ER and phospho‐AKT levels were unchanged (Fig. 3C). We propose that proliferation is maintained because MER can still promote growth signaling through AKT, and in turn, AKT phosphorylates ER to promote growth (Fig. 2, Scenario 3). Lastly, when cells were treated with trametinib or erlotinib in the absence of estrogen and tamoxifen, cellular growth was inhibited (Fig. 3B). Moreover, we observed a drastic reduction in phospho‐AKT, phospho‐ERK, and phospho‐ER by Western blot (Fig. 3C). We hypothesize that the growth inhibition occurs when ER activity is reduced because of upstream AKT and ERK being inhibited (Fig. 2, Scenarios 4 and 5).
Discussion
Herein, we unravel the biologic basis for an exceptional response to trametinib and letrozole that was unexpected in the context of prior rapid disease progression on trametinib and tamoxifen and on letrozole alone. Hence, two different therapeutic regimens that each targeted both the ER and MEK pathways produced remarkably different clinical effects. There are important lessons that emerge from consideration of this case: (a) the oncology dogma against revisiting prior failed drugs (in this case, trametinib and letrozole had each been given before) may not always hold true [19], even to the extent that two drugs that each failed were successful when given together; (b) drugs targeting the same receptor through different mechanisms may have disparate biologic impact that can be elucidated by bedside to bench interrogation; and (c) combination therapy affecting the estrogen receptor and MEK pathways may be beneficial in advanced cancer.
Antiestrogen is standard of care for ER‐positive breast cancer and may also be important in other malignancies [20]. In the context of excess mitogen‐activated protein kinase (MAPK) signaling (KRAS mutation in this case), the precise choice of antiestrogen therapy could be critical, as observed in both our patient and in our in vitro assays. The classic pathway of estrogen action is dependent on ERα and ERβ. Tamoxifen can act as an agonist in some tissues and as an antagonist in other tissues [16], providing one possible source for diverging behaviors between treatment with tamoxifen and letrozole. In addition, nonclassical mechanisms of steroid action may be dependent on MERs. The MER is a cell surface receptor that can activate the RAS and PI3K pathways [21]. We present evidence that proliferation in an in vitro context analogous to our patient's tumor relies upon MER‐mediated ERK and AKT signaling, which promotes phosphorylated nuclear ER. Inhibiting both MER (by estrogen depletion) and ERK pathways is necessary to halt proliferation and may justify the use of aromatase inhibitors rather than tamoxifen when MAPK activity is elevated. Of note, our study uses EGFR activation to activate RAS and its downstream signaling partners in order to phenocopy the effects of a KRAS mutation. However, EGFR can also have downstream consequences beyond those mediated by active RAS. Thus, although our experimental observations are consistent with our hypotheses and follow from consideration of described mechanisms of these drugs and biomarkers, alternative hypotheses could also be presented and could not be ruled out with the present study. Future studies could investigate patient‐derived xenografts from individuals with similar molecular characteristics to determine if they or their xenografts respond similarly. Furthermore, there are limited data describing the association between estrogen receptor positivity and KRAS mutation among LGSOC; this also requires further investigation.
In summary, we report a woman with aggressive ER‐positive, KRAS‐mutated LGSOC who achieved a remarkable response to combination therapy with the MEK inhibitor trametinib and aromatase inhibitor letrozole, even though the tumor had progressed on a combination of a PI3K inhibitor and different MEK inhibitor, as well as on trametinib itself and the selective estrogen receptor modulator tamoxifen, and on letrozole alone. The molecular mechanisms underlying this exceptional response were elucidated by in vitro modeling that demonstrated that the known partial agonist/antagonist mechanism of tamoxifen compared with the estrogen depletion of letrozole was likely the critical feature that explained the different responses to the combination of each agent with an MEK inhibitor. It has previously been suggested that customized combination therapy may be a key to achieving tumor control when there are important genomic co‐alterations [9, 10], especially when certain gene product pathways, such as KRAS or PI3K, are activated [22]. Our current observations indicate that drugs with subtly different mechanisms of action targeting the same receptor may have markedly different anticancer activity when used in combinations.
Author Contributions
Conception/design: Shumei Kato, Thomas McFall, Edward Stites, Razelle Kurzrock
Provision of study material or patients: Edward Stites, Razelle Kurzrock
Data analysis and interpretation: Shumei Kato, Thomas McFall, Kenta Takahashi, Kasey Bamel
Manuscript writing: Shumei Kato, Thomas McFall, Edward Stites, Razelle Kurzrock
Final approval of manuscript: Shumei Kato, Thomas McFall, Kenta Takahashi, Kasey Bamel, Sadakatsu Ikeda, Ramez N. Eskander, Steven Plaxe, Barbara Parker, Edward Stites, Razelle Kurzrock
Disclosures
Shumei Kato: Foundation Medicine (C/A), Roche (H); Barbara Parker: Pfizer, Novartis, Oncternal, Genentech (RF—institution), Merck (OI), Bioatla (C/A—spouse), EMD Serono (other—travel—spouse); Razelle Kurzrock: Incyte, Genentech, Merck Serono, Pfizer, Sequenom, Foundation Medicine, Guardant Health, Grifols, Konica Minolta (RF), LOXO, Pfizer, X‐Biotech, Actuate Therapeutics, Genentech, NeoMed (C/A), Roche (H), IDbyDNA, CureMatch, Inc. (OI), CureMatch, CureMetrix (SAB). The other authors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board
Supporting information
See http://www.TheOncologist.com for supplemental material available online.
Appendix S1. Supporting Information.
Click here for additional data file.
Figure S1
Click here for additional data file.
Acknowledgments
This work was supported in part by the Joan and Irwin Jacobs Fund and by the National Institutes of Health (grant NIH P30 CA023100 to R.K.) and by NIH K22CA216318 to E.S., NIH T32CA009370 to T.M., and NIH P30CA014195 to E.S. | LETROZOLE, TAMOXIFEN, TRAMETINIB | DrugsGivenReaction | CC BY-NC-ND | 33528846 | 19,137,424 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ovarian cancer'. | KRAS-Mutated, Estrogen Receptor-Positive Low-Grade Serous Ovarian Cancer: Unraveling an Exceptional Response Mystery.
We report on a woman with aggressive estrogen receptor-positive, KRAS-mutated ovarian cancer who achieved a remarkable response to combination therapy with the MEK inhibitor (trametinib) and the aromatase inhibitor (letrozole), even though the disease had failed to respond to a combination of a PI3K inhibitor and different MEK inhibitor, as well as to trametinib and the estrogen modulator, tamoxifen, and to letrozole by itself. The mechanism of action for exceptional response was elucidated by in vitro experiments that demonstrated that the fact that tamoxifen can have an agonistic effect in addition to antagonist activity, whereas letrozole results only in estrogen depletion was crucial to the response achieved when letrozole was combined with an MEK inhibitor. Our current observations indicate that subtle variations in mechanisms of action of outwardly similar regimens may have a major impact on outcome and that such translational knowledge is critical for optimizing a precision medicine strategy. KEY POINTS: This report describes the remarkable response of a patient with KRAS-mutated, estrogen receptor-positive low-grade serous ovarian cancer treated with trametinib (MEK inhibitor) and letrozole (aromatase inhibitor), despite prior progression on similar agents including tamoxifen (estrogen modulator). In vitro investigation revealed that tamoxifen can have agonistic in addition to antagonistic effects, which could be the reason for the patient not responding to the combination of trametinib and tamoxifen. The current observations suggest that drugs with different mechanisms of action targeting the same receptor may have markedly different anticancer activity when used in combinations.
Introduction
Ovarian cancer is the second most common gynecologic malignancy and the most frequent cause of gynecologic cancer death in the U.S. [1, 2]. Serous ovarian cancer is generally classified into low‐ or high‐grade serous carcinoma [3]. Classification of low‐ versus high‐grade serous ovarian cancer is clinically important because patients with low‐grade serous ovarian cancer (LGSOC) are known to have better progression‐free survival compared with patients with high‐grade disease [4]. However, LGSOC is often resistant to cytotoxic agents (response rate [RR] of ~4%) [5].
Understanding the tumor grade is also important because there are molecular differences between low‐ and high‐grade serous carcinoma. Notably, LGSOC is less commonly associated with TP53 alterations compared with high‐grade carcinoma. Meanwhile, KRAS is altered in 20% to 40% of LGSOC, whereas this mutation is rare among high‐grade histology [5]. Moreover, overexpression of estrogen receptor (ER) and progesterone receptor (PR) are frequent in LGSOC (ER/PR overexpression: 43%–58% vs. 17%–27% for low and high grade, respectively) [6]. Attempts have been made to use antihormone therapy for ER/PR‐positive cancers and MEK inhibitor for KRAS mutant cancers; however, low response rates were observed with these treatment approaches (RR of 9% and 15%, respectively, when given as a single agent) [7, 8]. In some cases, one patient may have multiple molecular alterations that individually suggest different drug options [9, 10]. Previous work reveals that patient outcomes are better when biomarkers are concurrently targeted with different agents [9, 11].
Herein, we describe a patient with heavily pretreated, widely metastatic LGSOC with overexpression of ER by immunohistochemistry (PR negative) and with a KRAS G12V mutation as the sole genomic alteration detected by tissue and circulating cell‐free DNA (cfDNA) next‐generation sequencing. This patient experienced a dramatic and durable response (19+ months) to the combination of the aromatase inhibitor letrozole with the MEK inhibitor trametinib after a series of related regimens had failed. We performed translational experiments to demonstrate that differences in the mechanisms of action of the antiestrogen tamoxifen versus letrozole might explain the remarkable response to letrozole together with trametinib after primary failure of tamoxifen combined with trametinib or letrozole alone.
Patient Story
Case Report
A 28‐year‐old woman initially presented with right‐sided pelvic pain and underwent right‐sided salpingo‐oophorectomy. Pathology detected a serous low‐malignant‐potential tumor. One year later, the patient experienced left‐sided pelvic pain, and imaging studies revealed an adnexal mass, which prompted a hysterectomy with left salpingo‐oophorectomy. Pathology confirmed serous low‐malignant‐potential tumor. Three years after initial diagnosis, imaging revealed a hepatic lesion. The lesion was resected, and pathology showed metastatic LGSOC. Subsequently, the patient received carboplatin and paclitaxel (six cycles), followed by carboplatin, gemcitabine, and bevacizumab (seven cycles). A computed tomography scan performed 9 months after completion of chemotherapy revealed new, widely metastatic disease, and the patient subsequently underwent surgery for tumor debulking. Approximately 1 year later, the patient underwent five cycles of doxorubicin for recurrence. At progression, she sought treatment on a clinical trial with PI3K and MEK inhibitors (PF‐04691502, 130 mg i.v. weekly, and PD‐0325901 [mirdametinib], initially with 4 mg p.o. b.i.d. 3 weeks on, 1 week off; dose reduction was required to 2 mg p.o. b.i.d. 3 weeks on, 1 week off because of intolerable grade 2 rash), which she continued for approximately 1 year until progression. She was then referred to the Precision Medicine Clinic.
Molecular profiling of tissue next‐generation sequencing as well as cfDNA revealed a single alteration—KRAS G12V. Immunohistochemistry was positive for ER (2+, 75% positive) but negative for PR. The patient was started on the MEK inhibitor trametinib for the KRAS G12V mutation and tamoxifen for ER positivity. Unfortunately, serial imaging and cancer antigen 125 (CA125) assessments showed progression at 5 months, and treatment was stopped (Fig. 1A). She was lost to follow‐up for approximately 9 months, at which time she presented again with bulky pelvic masses and a rapidly rising CA125 level (Fig. 1A). Based on ER positivity, she was started on letrozole as monotherapy; however, after 3 months of therapy, she was found to have rising CA125 levels (>15,000 U/mL) with radiographic progression (Fig. 1A and B, left panel).
Figure 1 (A): Dynamic change in tumor marker (CA125) (blue line) and KRAS G12V cell‐free DNA (red dotted line) along with treatment course. (Note that the patient was lost to follow‐up for several months between treatments). (B): Computed tomography images before and after the combination of letrozole and trametinib. Reduction of solid tumor masses (arrows) and improvement in ascites (circles) were seen after the initiation of letrozole and trametinib. Therapy is ongoing at 19+ months. *, Over upper limit of detection (>15,000 U/mL). Abbreviations: CA125, cancer antigen 125; ND, not detected.
At that time, she was rechallenged with trametinib (for KRAS G12V) while continuing on letrozole. Surprisingly, after 2 months of therapy, the patient noted a reduction in abdominal pain and girth. Three months after the therapy began, CA125 level declined to 1,265 U/mL from >15,000 U/mL. KRAS G12V in cfDNA became undetectable. Restaging computed tomography scan performed 4 months after the initiation of letrozole and trametinib showed >50% tumor reduction (per RECIST version 1.1; Fig. 1A and B, right panel). She continues to do well with an ongoing progression‐free survival of 19+ months.
In Vitro Experiments: Combination of Estrogen Depletion with an MEK Inhibitor Sensitized ER‐Positive, RAS Pathway‐Activated Serous Ovarian Cancer Cell Lines Resistant to Tamoxifen and MEK Inhibitor Combination
Because both tamoxifen and letrozole target estrogen signaling, it was of interest to understand why our patient did not respond to tamoxifen combined with trametinib yet had an exceptional response to trametinib combined with letrozole. We considered that tamoxifen and letrozole have different mechanisms of action despite both targeting estrogen signaling. Tamoxifen is known to compete with 17β‐estradiol at the receptor site and to block the promotional role of 17β‐estradiol in breast cancer [12]. However, tamoxifen, can also act as a selective estrogen receptor modulator, and in some contexts, it can have partial agonist effects (i.e., mimicking the effects of estrogen) [13, 14, 15, 16]. In contrast, letrozole inhibits the enzyme aromatase and thereby reduces the production of estrogens; letrozole thereby acts purely as an estrogen antagonist [17].
We set out to experimentally determine whether we could reproduce the pattern of responsiveness seen in our patient. KRAS mutant/ER‐positive serous ovarian carcinoma models are not readily available. We therefore used two ER‐positive serous carcinoma cell lines (OVCAR 3 and SKOV 3) that are readily available. We hypothesized that the effects of the KRAS mutation reflected overactivation of the RAS signaling pathway, and for our experimental efforts we activated epidermal growth factor receptor (EGFR) to induce elevated levels of RAS signaling [18]. This would be consistent with our hypothesized mechanism (Fig. 2). We also used an ER‐negative cell line (OVCAR 5) as a control (supplemental online Methods).
Figure 2 Noncanonical and canonical ER signaling axis. We hypothesized that the partial agonist activity of tamoxifen versus the estrogen depletion effect of letrozole might explain the observed and widely different clinical responses [13, 14, 15, 16]. We also hypothesized that noncanonical ER signaling might be involved, in which MER can drive noncanonical ER signaling [13, 15, 23]. We constructed a map of the signaling pathway that comprises the described interactions, and we considered each of the treatment scenarios and responses. We found that our hypothesized mechanisms could potentially explain the diverging responses to tamoxifen and letrozole when combined with trametinib in a patient with hyperactivated RAS pathway signaling. (Scenario 1): MER‐driven noncanonical ER signaling and RAS signaling (replicating baseline condition of current case report). MER/E2 activates AKT and ER, which leads to cell growth. Activation of EGFR subsequently activates RAS/MAPK pathway, which also leads to growth signaling (similar to KRAS mutation). (Scenario 2): TMX functions as a partial agonist for MER‐driven noncanonical ER signaling. Thus, no inhibitory effect is seen on ER signaling. (Scenario 3): Combination treatment with tamoxifen and trametinib is not sufficient to halt the cell growth despite the successful inhibition of RAS/MEK pathway with trametinib because ER signaling is not adequately reduced with tamoxifen. (Scenario 4): Combination of estrogen depletion (mimicking treatment with letrozole) and trametinib successfully inhibits both ER and RAS signaling, thus leading to the inhibition of cell growth. (Scenario 5): Combination of estrogen depletion (mimicking treatment with letrozole) and erlotinib (EGFR inhibitor to reduce RAS activation) successfully reduces both ER and RAS signaling, thus leading to the inhibition of cell growth. Abbreviations: E2, estradiol; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; ER, estrogen receptor; MAPK, mitogen‐activated protein kinase; MEKi, MEK inhibitor; MER, membrane estrogen receptor; pAKT, phospho‐AKT; pER, phospho‐ER; TMX, tamoxifen.
We first tested if these cells were sensitive to estrogen depletion and found that all three cell lines grew just as well with estrogen depletion compared with when they were grown with estrogen (supplemental online Fig. 1A). Furthermore, we treated these cells with tamoxifen and found that they proliferated at approximately the same rate (supplemental online Fig. 1B). These observations suggest that targeting estrogen signaling alone with either estrogen depletion strategies (mimicking letrozole) or with a selective estrogen modulator (like tamoxifen) would be ineffective.
We then tested scenarios that replicated the patient's treatment schema. Cells were treated with trametinib, trametinib combined with tamoxifen, estrogen depletion, or estrogen depletion combined with trametinib. We found that ER‐positive cells maximally responded to estrogen depletion in combination with the MEK inhibitor trametinib. Interestingly, the ER‐negative cell line OVCAR 5 was sensitive to all treatments with MEK inhibition. No added benefit was observed when combining MEK inhibitor with tamoxifen or estradiol depletion (Fig. 3A). We hypothesized that the presence of ER may prove an alternate signaling pathway to survival when cells are treated with an MEK inhibitor.
Figure 3 Mechanism for tamoxifen and trametinib resistance in OVCAR 3 cells. (A): OVCAR 3 (estrogen receptor [ER]–positive), SKOV 3 (ER‐positive), and OVCAR 5 (ER‐negative) cells were stripped of hormone for 48 hours prior to seeding. Cell culture media contained hormone‐stripped FBS (which contains epidermal growth factor [EGF]) to maintain RAS/mitogen‐activated protein kinase (MAPK) signaling. Cells were treated with 10 nM 17β‐estradiol, 10 nM tamoxifen, and 20 nM trametinib in various combinations, as indicated, for 48 hours. Cell proliferation was measured by MTT assay. Data are representative of eight biological replicates. Histograms represent means, and error bars represent SD. Statistical significance is indicated and determined by one‐way ANOVA with post hoc Tukey's test. The results show that MEK inhibition in the presence of estrogen depletion was associated with significantly decreased growth in all three cell lines. However, MEK inhibition in the presence of estrogen had no effect among ER‐positive cell lines (OVCAR 3 and SKOV 3). On the contrary, MEK inhibition alone was sufficient to reduce the cell proliferation in the ER‐negative cell line (OVCAR 5). *p < .05. (B): OVCAR 3 cells (ER‐positive) were grown in hormone‐stripped cell culture media containing FBS (which contains EGF) for 48 hours prior to seeding. Cells were treated with 10 nM 17β‐estradiol, 10 nM tamoxifen, 20 nM trametinib, and 20 nM erlotinib in various combination, as indicated, for 48 hours. Cell proliferation was measured by MTT assay. Data are representative of eight biological replicates. Histograms represent means, and error bars represent SD. Statistical significance is indicated and determined by one‐way ANOVA with post hoc Tukey's test. The results show that MEK inhibition by trametinib in the presence of estrogen depletion was associated with decreased proliferation; however, if tamoxifen and MEK inhibition were given simultaneously, there was no decrease in proliferation (presumably because tamoxifen may have a partial agonist effect on ER). Similarly, erlotinib (to reduce RAS‐induced MAPK signaling) in combination with estrogen depletion led to decreased cell proliferation (Fig. 2). *p < .0001. (C): OVCAR 3 cells (ER‐positive) were grown in hormone‐stripped cell culture media containing FBS (which contains EGF) for 48 hours and then treated with 10 nM 17β‐estradiol, 10 nM tamoxifen, 20 nM trametinib, and 20 nM erlotinib in various combinations, as indicated, for 48 hours. Whole cell lysates were collected and analyzed by Western blot. Combination of trametinib or erlotinib along with estrogen depletion successfully reduced the phosphorylation of ERK, AKT, and ER. The same effects were not observed with tamoxifen alone or for tamoxifen in combination with trametinib (Fig. 2). Abbreviations: E2, estradiol; GAPDH, glyceraldehyde‐3‐phosphate dehydrogenase; MEKi, MEK inhibitor; pAKT, phospho‐AKT; pER, phospho‐ER, pERK, phosphor‐ERK; TMX, tamoxifen.
We then used trametinib, tamoxifen, estrogen, and erlotinib to deconstruct the signaling axis in OVCAR 3 cells. Cells grown in estrogen grew at comparable levels to cells grown with estrogen and tamoxifen (Fig. 3B). Furthermore, the estrogen and tamoxifen combination and single‐agent tamoxifen treatment did not show any reduction in ERK phosphorylation, ER phosphorylation, or AKT phosphorylation by Western blot (Fig. 3C). We propose that this occurs because tamoxifen can activate the membrane estrogen receptor (MER) to signal through AKT and phosphorylate ER (Fig. 2, Scenario 2). When cells were treated with trametinib, tamoxifen, and estrogen in combination, we observed no reduction in cell growth (Fig. 3B). However, significant reduction in phospho‐ERK signal was observed by Western blot, yet phospho‐ER and phospho‐AKT levels were unchanged (Fig. 3C). We propose that proliferation is maintained because MER can still promote growth signaling through AKT, and in turn, AKT phosphorylates ER to promote growth (Fig. 2, Scenario 3). Lastly, when cells were treated with trametinib or erlotinib in the absence of estrogen and tamoxifen, cellular growth was inhibited (Fig. 3B). Moreover, we observed a drastic reduction in phospho‐AKT, phospho‐ERK, and phospho‐ER by Western blot (Fig. 3C). We hypothesize that the growth inhibition occurs when ER activity is reduced because of upstream AKT and ERK being inhibited (Fig. 2, Scenarios 4 and 5).
Discussion
Herein, we unravel the biologic basis for an exceptional response to trametinib and letrozole that was unexpected in the context of prior rapid disease progression on trametinib and tamoxifen and on letrozole alone. Hence, two different therapeutic regimens that each targeted both the ER and MEK pathways produced remarkably different clinical effects. There are important lessons that emerge from consideration of this case: (a) the oncology dogma against revisiting prior failed drugs (in this case, trametinib and letrozole had each been given before) may not always hold true [19], even to the extent that two drugs that each failed were successful when given together; (b) drugs targeting the same receptor through different mechanisms may have disparate biologic impact that can be elucidated by bedside to bench interrogation; and (c) combination therapy affecting the estrogen receptor and MEK pathways may be beneficial in advanced cancer.
Antiestrogen is standard of care for ER‐positive breast cancer and may also be important in other malignancies [20]. In the context of excess mitogen‐activated protein kinase (MAPK) signaling (KRAS mutation in this case), the precise choice of antiestrogen therapy could be critical, as observed in both our patient and in our in vitro assays. The classic pathway of estrogen action is dependent on ERα and ERβ. Tamoxifen can act as an agonist in some tissues and as an antagonist in other tissues [16], providing one possible source for diverging behaviors between treatment with tamoxifen and letrozole. In addition, nonclassical mechanisms of steroid action may be dependent on MERs. The MER is a cell surface receptor that can activate the RAS and PI3K pathways [21]. We present evidence that proliferation in an in vitro context analogous to our patient's tumor relies upon MER‐mediated ERK and AKT signaling, which promotes phosphorylated nuclear ER. Inhibiting both MER (by estrogen depletion) and ERK pathways is necessary to halt proliferation and may justify the use of aromatase inhibitors rather than tamoxifen when MAPK activity is elevated. Of note, our study uses EGFR activation to activate RAS and its downstream signaling partners in order to phenocopy the effects of a KRAS mutation. However, EGFR can also have downstream consequences beyond those mediated by active RAS. Thus, although our experimental observations are consistent with our hypotheses and follow from consideration of described mechanisms of these drugs and biomarkers, alternative hypotheses could also be presented and could not be ruled out with the present study. Future studies could investigate patient‐derived xenografts from individuals with similar molecular characteristics to determine if they or their xenografts respond similarly. Furthermore, there are limited data describing the association between estrogen receptor positivity and KRAS mutation among LGSOC; this also requires further investigation.
In summary, we report a woman with aggressive ER‐positive, KRAS‐mutated LGSOC who achieved a remarkable response to combination therapy with the MEK inhibitor trametinib and aromatase inhibitor letrozole, even though the tumor had progressed on a combination of a PI3K inhibitor and different MEK inhibitor, as well as on trametinib itself and the selective estrogen receptor modulator tamoxifen, and on letrozole alone. The molecular mechanisms underlying this exceptional response were elucidated by in vitro modeling that demonstrated that the known partial agonist/antagonist mechanism of tamoxifen compared with the estrogen depletion of letrozole was likely the critical feature that explained the different responses to the combination of each agent with an MEK inhibitor. It has previously been suggested that customized combination therapy may be a key to achieving tumor control when there are important genomic co‐alterations [9, 10], especially when certain gene product pathways, such as KRAS or PI3K, are activated [22]. Our current observations indicate that drugs with subtly different mechanisms of action targeting the same receptor may have markedly different anticancer activity when used in combinations.
Author Contributions
Conception/design: Shumei Kato, Thomas McFall, Edward Stites, Razelle Kurzrock
Provision of study material or patients: Edward Stites, Razelle Kurzrock
Data analysis and interpretation: Shumei Kato, Thomas McFall, Kenta Takahashi, Kasey Bamel
Manuscript writing: Shumei Kato, Thomas McFall, Edward Stites, Razelle Kurzrock
Final approval of manuscript: Shumei Kato, Thomas McFall, Kenta Takahashi, Kasey Bamel, Sadakatsu Ikeda, Ramez N. Eskander, Steven Plaxe, Barbara Parker, Edward Stites, Razelle Kurzrock
Disclosures
Shumei Kato: Foundation Medicine (C/A), Roche (H); Barbara Parker: Pfizer, Novartis, Oncternal, Genentech (RF—institution), Merck (OI), Bioatla (C/A—spouse), EMD Serono (other—travel—spouse); Razelle Kurzrock: Incyte, Genentech, Merck Serono, Pfizer, Sequenom, Foundation Medicine, Guardant Health, Grifols, Konica Minolta (RF), LOXO, Pfizer, X‐Biotech, Actuate Therapeutics, Genentech, NeoMed (C/A), Roche (H), IDbyDNA, CureMatch, Inc. (OI), CureMatch, CureMetrix (SAB). The other authors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board
Supporting information
See http://www.TheOncologist.com for supplemental material available online.
Appendix S1. Supporting Information.
Click here for additional data file.
Figure S1
Click here for additional data file.
Acknowledgments
This work was supported in part by the Joan and Irwin Jacobs Fund and by the National Institutes of Health (grant NIH P30 CA023100 to R.K.) and by NIH K22CA216318 to E.S., NIH T32CA009370 to T.M., and NIH P30CA014195 to E.S. | LETROZOLE, TAMOXIFEN, TRAMETINIB | DrugsGivenReaction | CC BY-NC-ND | 33528846 | 19,137,424 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'. | KRAS-Mutated, Estrogen Receptor-Positive Low-Grade Serous Ovarian Cancer: Unraveling an Exceptional Response Mystery.
We report on a woman with aggressive estrogen receptor-positive, KRAS-mutated ovarian cancer who achieved a remarkable response to combination therapy with the MEK inhibitor (trametinib) and the aromatase inhibitor (letrozole), even though the disease had failed to respond to a combination of a PI3K inhibitor and different MEK inhibitor, as well as to trametinib and the estrogen modulator, tamoxifen, and to letrozole by itself. The mechanism of action for exceptional response was elucidated by in vitro experiments that demonstrated that the fact that tamoxifen can have an agonistic effect in addition to antagonist activity, whereas letrozole results only in estrogen depletion was crucial to the response achieved when letrozole was combined with an MEK inhibitor. Our current observations indicate that subtle variations in mechanisms of action of outwardly similar regimens may have a major impact on outcome and that such translational knowledge is critical for optimizing a precision medicine strategy. KEY POINTS: This report describes the remarkable response of a patient with KRAS-mutated, estrogen receptor-positive low-grade serous ovarian cancer treated with trametinib (MEK inhibitor) and letrozole (aromatase inhibitor), despite prior progression on similar agents including tamoxifen (estrogen modulator). In vitro investigation revealed that tamoxifen can have agonistic in addition to antagonistic effects, which could be the reason for the patient not responding to the combination of trametinib and tamoxifen. The current observations suggest that drugs with different mechanisms of action targeting the same receptor may have markedly different anticancer activity when used in combinations.
Introduction
Ovarian cancer is the second most common gynecologic malignancy and the most frequent cause of gynecologic cancer death in the U.S. [1, 2]. Serous ovarian cancer is generally classified into low‐ or high‐grade serous carcinoma [3]. Classification of low‐ versus high‐grade serous ovarian cancer is clinically important because patients with low‐grade serous ovarian cancer (LGSOC) are known to have better progression‐free survival compared with patients with high‐grade disease [4]. However, LGSOC is often resistant to cytotoxic agents (response rate [RR] of ~4%) [5].
Understanding the tumor grade is also important because there are molecular differences between low‐ and high‐grade serous carcinoma. Notably, LGSOC is less commonly associated with TP53 alterations compared with high‐grade carcinoma. Meanwhile, KRAS is altered in 20% to 40% of LGSOC, whereas this mutation is rare among high‐grade histology [5]. Moreover, overexpression of estrogen receptor (ER) and progesterone receptor (PR) are frequent in LGSOC (ER/PR overexpression: 43%–58% vs. 17%–27% for low and high grade, respectively) [6]. Attempts have been made to use antihormone therapy for ER/PR‐positive cancers and MEK inhibitor for KRAS mutant cancers; however, low response rates were observed with these treatment approaches (RR of 9% and 15%, respectively, when given as a single agent) [7, 8]. In some cases, one patient may have multiple molecular alterations that individually suggest different drug options [9, 10]. Previous work reveals that patient outcomes are better when biomarkers are concurrently targeted with different agents [9, 11].
Herein, we describe a patient with heavily pretreated, widely metastatic LGSOC with overexpression of ER by immunohistochemistry (PR negative) and with a KRAS G12V mutation as the sole genomic alteration detected by tissue and circulating cell‐free DNA (cfDNA) next‐generation sequencing. This patient experienced a dramatic and durable response (19+ months) to the combination of the aromatase inhibitor letrozole with the MEK inhibitor trametinib after a series of related regimens had failed. We performed translational experiments to demonstrate that differences in the mechanisms of action of the antiestrogen tamoxifen versus letrozole might explain the remarkable response to letrozole together with trametinib after primary failure of tamoxifen combined with trametinib or letrozole alone.
Patient Story
Case Report
A 28‐year‐old woman initially presented with right‐sided pelvic pain and underwent right‐sided salpingo‐oophorectomy. Pathology detected a serous low‐malignant‐potential tumor. One year later, the patient experienced left‐sided pelvic pain, and imaging studies revealed an adnexal mass, which prompted a hysterectomy with left salpingo‐oophorectomy. Pathology confirmed serous low‐malignant‐potential tumor. Three years after initial diagnosis, imaging revealed a hepatic lesion. The lesion was resected, and pathology showed metastatic LGSOC. Subsequently, the patient received carboplatin and paclitaxel (six cycles), followed by carboplatin, gemcitabine, and bevacizumab (seven cycles). A computed tomography scan performed 9 months after completion of chemotherapy revealed new, widely metastatic disease, and the patient subsequently underwent surgery for tumor debulking. Approximately 1 year later, the patient underwent five cycles of doxorubicin for recurrence. At progression, she sought treatment on a clinical trial with PI3K and MEK inhibitors (PF‐04691502, 130 mg i.v. weekly, and PD‐0325901 [mirdametinib], initially with 4 mg p.o. b.i.d. 3 weeks on, 1 week off; dose reduction was required to 2 mg p.o. b.i.d. 3 weeks on, 1 week off because of intolerable grade 2 rash), which she continued for approximately 1 year until progression. She was then referred to the Precision Medicine Clinic.
Molecular profiling of tissue next‐generation sequencing as well as cfDNA revealed a single alteration—KRAS G12V. Immunohistochemistry was positive for ER (2+, 75% positive) but negative for PR. The patient was started on the MEK inhibitor trametinib for the KRAS G12V mutation and tamoxifen for ER positivity. Unfortunately, serial imaging and cancer antigen 125 (CA125) assessments showed progression at 5 months, and treatment was stopped (Fig. 1A). She was lost to follow‐up for approximately 9 months, at which time she presented again with bulky pelvic masses and a rapidly rising CA125 level (Fig. 1A). Based on ER positivity, she was started on letrozole as monotherapy; however, after 3 months of therapy, she was found to have rising CA125 levels (>15,000 U/mL) with radiographic progression (Fig. 1A and B, left panel).
Figure 1 (A): Dynamic change in tumor marker (CA125) (blue line) and KRAS G12V cell‐free DNA (red dotted line) along with treatment course. (Note that the patient was lost to follow‐up for several months between treatments). (B): Computed tomography images before and after the combination of letrozole and trametinib. Reduction of solid tumor masses (arrows) and improvement in ascites (circles) were seen after the initiation of letrozole and trametinib. Therapy is ongoing at 19+ months. *, Over upper limit of detection (>15,000 U/mL). Abbreviations: CA125, cancer antigen 125; ND, not detected.
At that time, she was rechallenged with trametinib (for KRAS G12V) while continuing on letrozole. Surprisingly, after 2 months of therapy, the patient noted a reduction in abdominal pain and girth. Three months after the therapy began, CA125 level declined to 1,265 U/mL from >15,000 U/mL. KRAS G12V in cfDNA became undetectable. Restaging computed tomography scan performed 4 months after the initiation of letrozole and trametinib showed >50% tumor reduction (per RECIST version 1.1; Fig. 1A and B, right panel). She continues to do well with an ongoing progression‐free survival of 19+ months.
In Vitro Experiments: Combination of Estrogen Depletion with an MEK Inhibitor Sensitized ER‐Positive, RAS Pathway‐Activated Serous Ovarian Cancer Cell Lines Resistant to Tamoxifen and MEK Inhibitor Combination
Because both tamoxifen and letrozole target estrogen signaling, it was of interest to understand why our patient did not respond to tamoxifen combined with trametinib yet had an exceptional response to trametinib combined with letrozole. We considered that tamoxifen and letrozole have different mechanisms of action despite both targeting estrogen signaling. Tamoxifen is known to compete with 17β‐estradiol at the receptor site and to block the promotional role of 17β‐estradiol in breast cancer [12]. However, tamoxifen, can also act as a selective estrogen receptor modulator, and in some contexts, it can have partial agonist effects (i.e., mimicking the effects of estrogen) [13, 14, 15, 16]. In contrast, letrozole inhibits the enzyme aromatase and thereby reduces the production of estrogens; letrozole thereby acts purely as an estrogen antagonist [17].
We set out to experimentally determine whether we could reproduce the pattern of responsiveness seen in our patient. KRAS mutant/ER‐positive serous ovarian carcinoma models are not readily available. We therefore used two ER‐positive serous carcinoma cell lines (OVCAR 3 and SKOV 3) that are readily available. We hypothesized that the effects of the KRAS mutation reflected overactivation of the RAS signaling pathway, and for our experimental efforts we activated epidermal growth factor receptor (EGFR) to induce elevated levels of RAS signaling [18]. This would be consistent with our hypothesized mechanism (Fig. 2). We also used an ER‐negative cell line (OVCAR 5) as a control (supplemental online Methods).
Figure 2 Noncanonical and canonical ER signaling axis. We hypothesized that the partial agonist activity of tamoxifen versus the estrogen depletion effect of letrozole might explain the observed and widely different clinical responses [13, 14, 15, 16]. We also hypothesized that noncanonical ER signaling might be involved, in which MER can drive noncanonical ER signaling [13, 15, 23]. We constructed a map of the signaling pathway that comprises the described interactions, and we considered each of the treatment scenarios and responses. We found that our hypothesized mechanisms could potentially explain the diverging responses to tamoxifen and letrozole when combined with trametinib in a patient with hyperactivated RAS pathway signaling. (Scenario 1): MER‐driven noncanonical ER signaling and RAS signaling (replicating baseline condition of current case report). MER/E2 activates AKT and ER, which leads to cell growth. Activation of EGFR subsequently activates RAS/MAPK pathway, which also leads to growth signaling (similar to KRAS mutation). (Scenario 2): TMX functions as a partial agonist for MER‐driven noncanonical ER signaling. Thus, no inhibitory effect is seen on ER signaling. (Scenario 3): Combination treatment with tamoxifen and trametinib is not sufficient to halt the cell growth despite the successful inhibition of RAS/MEK pathway with trametinib because ER signaling is not adequately reduced with tamoxifen. (Scenario 4): Combination of estrogen depletion (mimicking treatment with letrozole) and trametinib successfully inhibits both ER and RAS signaling, thus leading to the inhibition of cell growth. (Scenario 5): Combination of estrogen depletion (mimicking treatment with letrozole) and erlotinib (EGFR inhibitor to reduce RAS activation) successfully reduces both ER and RAS signaling, thus leading to the inhibition of cell growth. Abbreviations: E2, estradiol; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; ER, estrogen receptor; MAPK, mitogen‐activated protein kinase; MEKi, MEK inhibitor; MER, membrane estrogen receptor; pAKT, phospho‐AKT; pER, phospho‐ER; TMX, tamoxifen.
We first tested if these cells were sensitive to estrogen depletion and found that all three cell lines grew just as well with estrogen depletion compared with when they were grown with estrogen (supplemental online Fig. 1A). Furthermore, we treated these cells with tamoxifen and found that they proliferated at approximately the same rate (supplemental online Fig. 1B). These observations suggest that targeting estrogen signaling alone with either estrogen depletion strategies (mimicking letrozole) or with a selective estrogen modulator (like tamoxifen) would be ineffective.
We then tested scenarios that replicated the patient's treatment schema. Cells were treated with trametinib, trametinib combined with tamoxifen, estrogen depletion, or estrogen depletion combined with trametinib. We found that ER‐positive cells maximally responded to estrogen depletion in combination with the MEK inhibitor trametinib. Interestingly, the ER‐negative cell line OVCAR 5 was sensitive to all treatments with MEK inhibition. No added benefit was observed when combining MEK inhibitor with tamoxifen or estradiol depletion (Fig. 3A). We hypothesized that the presence of ER may prove an alternate signaling pathway to survival when cells are treated with an MEK inhibitor.
Figure 3 Mechanism for tamoxifen and trametinib resistance in OVCAR 3 cells. (A): OVCAR 3 (estrogen receptor [ER]–positive), SKOV 3 (ER‐positive), and OVCAR 5 (ER‐negative) cells were stripped of hormone for 48 hours prior to seeding. Cell culture media contained hormone‐stripped FBS (which contains epidermal growth factor [EGF]) to maintain RAS/mitogen‐activated protein kinase (MAPK) signaling. Cells were treated with 10 nM 17β‐estradiol, 10 nM tamoxifen, and 20 nM trametinib in various combinations, as indicated, for 48 hours. Cell proliferation was measured by MTT assay. Data are representative of eight biological replicates. Histograms represent means, and error bars represent SD. Statistical significance is indicated and determined by one‐way ANOVA with post hoc Tukey's test. The results show that MEK inhibition in the presence of estrogen depletion was associated with significantly decreased growth in all three cell lines. However, MEK inhibition in the presence of estrogen had no effect among ER‐positive cell lines (OVCAR 3 and SKOV 3). On the contrary, MEK inhibition alone was sufficient to reduce the cell proliferation in the ER‐negative cell line (OVCAR 5). *p < .05. (B): OVCAR 3 cells (ER‐positive) were grown in hormone‐stripped cell culture media containing FBS (which contains EGF) for 48 hours prior to seeding. Cells were treated with 10 nM 17β‐estradiol, 10 nM tamoxifen, 20 nM trametinib, and 20 nM erlotinib in various combination, as indicated, for 48 hours. Cell proliferation was measured by MTT assay. Data are representative of eight biological replicates. Histograms represent means, and error bars represent SD. Statistical significance is indicated and determined by one‐way ANOVA with post hoc Tukey's test. The results show that MEK inhibition by trametinib in the presence of estrogen depletion was associated with decreased proliferation; however, if tamoxifen and MEK inhibition were given simultaneously, there was no decrease in proliferation (presumably because tamoxifen may have a partial agonist effect on ER). Similarly, erlotinib (to reduce RAS‐induced MAPK signaling) in combination with estrogen depletion led to decreased cell proliferation (Fig. 2). *p < .0001. (C): OVCAR 3 cells (ER‐positive) were grown in hormone‐stripped cell culture media containing FBS (which contains EGF) for 48 hours and then treated with 10 nM 17β‐estradiol, 10 nM tamoxifen, 20 nM trametinib, and 20 nM erlotinib in various combinations, as indicated, for 48 hours. Whole cell lysates were collected and analyzed by Western blot. Combination of trametinib or erlotinib along with estrogen depletion successfully reduced the phosphorylation of ERK, AKT, and ER. The same effects were not observed with tamoxifen alone or for tamoxifen in combination with trametinib (Fig. 2). Abbreviations: E2, estradiol; GAPDH, glyceraldehyde‐3‐phosphate dehydrogenase; MEKi, MEK inhibitor; pAKT, phospho‐AKT; pER, phospho‐ER, pERK, phosphor‐ERK; TMX, tamoxifen.
We then used trametinib, tamoxifen, estrogen, and erlotinib to deconstruct the signaling axis in OVCAR 3 cells. Cells grown in estrogen grew at comparable levels to cells grown with estrogen and tamoxifen (Fig. 3B). Furthermore, the estrogen and tamoxifen combination and single‐agent tamoxifen treatment did not show any reduction in ERK phosphorylation, ER phosphorylation, or AKT phosphorylation by Western blot (Fig. 3C). We propose that this occurs because tamoxifen can activate the membrane estrogen receptor (MER) to signal through AKT and phosphorylate ER (Fig. 2, Scenario 2). When cells were treated with trametinib, tamoxifen, and estrogen in combination, we observed no reduction in cell growth (Fig. 3B). However, significant reduction in phospho‐ERK signal was observed by Western blot, yet phospho‐ER and phospho‐AKT levels were unchanged (Fig. 3C). We propose that proliferation is maintained because MER can still promote growth signaling through AKT, and in turn, AKT phosphorylates ER to promote growth (Fig. 2, Scenario 3). Lastly, when cells were treated with trametinib or erlotinib in the absence of estrogen and tamoxifen, cellular growth was inhibited (Fig. 3B). Moreover, we observed a drastic reduction in phospho‐AKT, phospho‐ERK, and phospho‐ER by Western blot (Fig. 3C). We hypothesize that the growth inhibition occurs when ER activity is reduced because of upstream AKT and ERK being inhibited (Fig. 2, Scenarios 4 and 5).
Discussion
Herein, we unravel the biologic basis for an exceptional response to trametinib and letrozole that was unexpected in the context of prior rapid disease progression on trametinib and tamoxifen and on letrozole alone. Hence, two different therapeutic regimens that each targeted both the ER and MEK pathways produced remarkably different clinical effects. There are important lessons that emerge from consideration of this case: (a) the oncology dogma against revisiting prior failed drugs (in this case, trametinib and letrozole had each been given before) may not always hold true [19], even to the extent that two drugs that each failed were successful when given together; (b) drugs targeting the same receptor through different mechanisms may have disparate biologic impact that can be elucidated by bedside to bench interrogation; and (c) combination therapy affecting the estrogen receptor and MEK pathways may be beneficial in advanced cancer.
Antiestrogen is standard of care for ER‐positive breast cancer and may also be important in other malignancies [20]. In the context of excess mitogen‐activated protein kinase (MAPK) signaling (KRAS mutation in this case), the precise choice of antiestrogen therapy could be critical, as observed in both our patient and in our in vitro assays. The classic pathway of estrogen action is dependent on ERα and ERβ. Tamoxifen can act as an agonist in some tissues and as an antagonist in other tissues [16], providing one possible source for diverging behaviors between treatment with tamoxifen and letrozole. In addition, nonclassical mechanisms of steroid action may be dependent on MERs. The MER is a cell surface receptor that can activate the RAS and PI3K pathways [21]. We present evidence that proliferation in an in vitro context analogous to our patient's tumor relies upon MER‐mediated ERK and AKT signaling, which promotes phosphorylated nuclear ER. Inhibiting both MER (by estrogen depletion) and ERK pathways is necessary to halt proliferation and may justify the use of aromatase inhibitors rather than tamoxifen when MAPK activity is elevated. Of note, our study uses EGFR activation to activate RAS and its downstream signaling partners in order to phenocopy the effects of a KRAS mutation. However, EGFR can also have downstream consequences beyond those mediated by active RAS. Thus, although our experimental observations are consistent with our hypotheses and follow from consideration of described mechanisms of these drugs and biomarkers, alternative hypotheses could also be presented and could not be ruled out with the present study. Future studies could investigate patient‐derived xenografts from individuals with similar molecular characteristics to determine if they or their xenografts respond similarly. Furthermore, there are limited data describing the association between estrogen receptor positivity and KRAS mutation among LGSOC; this also requires further investigation.
In summary, we report a woman with aggressive ER‐positive, KRAS‐mutated LGSOC who achieved a remarkable response to combination therapy with the MEK inhibitor trametinib and aromatase inhibitor letrozole, even though the tumor had progressed on a combination of a PI3K inhibitor and different MEK inhibitor, as well as on trametinib itself and the selective estrogen receptor modulator tamoxifen, and on letrozole alone. The molecular mechanisms underlying this exceptional response were elucidated by in vitro modeling that demonstrated that the known partial agonist/antagonist mechanism of tamoxifen compared with the estrogen depletion of letrozole was likely the critical feature that explained the different responses to the combination of each agent with an MEK inhibitor. It has previously been suggested that customized combination therapy may be a key to achieving tumor control when there are important genomic co‐alterations [9, 10], especially when certain gene product pathways, such as KRAS or PI3K, are activated [22]. Our current observations indicate that drugs with subtly different mechanisms of action targeting the same receptor may have markedly different anticancer activity when used in combinations.
Author Contributions
Conception/design: Shumei Kato, Thomas McFall, Edward Stites, Razelle Kurzrock
Provision of study material or patients: Edward Stites, Razelle Kurzrock
Data analysis and interpretation: Shumei Kato, Thomas McFall, Kenta Takahashi, Kasey Bamel
Manuscript writing: Shumei Kato, Thomas McFall, Edward Stites, Razelle Kurzrock
Final approval of manuscript: Shumei Kato, Thomas McFall, Kenta Takahashi, Kasey Bamel, Sadakatsu Ikeda, Ramez N. Eskander, Steven Plaxe, Barbara Parker, Edward Stites, Razelle Kurzrock
Disclosures
Shumei Kato: Foundation Medicine (C/A), Roche (H); Barbara Parker: Pfizer, Novartis, Oncternal, Genentech (RF—institution), Merck (OI), Bioatla (C/A—spouse), EMD Serono (other—travel—spouse); Razelle Kurzrock: Incyte, Genentech, Merck Serono, Pfizer, Sequenom, Foundation Medicine, Guardant Health, Grifols, Konica Minolta (RF), LOXO, Pfizer, X‐Biotech, Actuate Therapeutics, Genentech, NeoMed (C/A), Roche (H), IDbyDNA, CureMatch, Inc. (OI), CureMatch, CureMetrix (SAB). The other authors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board
Supporting information
See http://www.TheOncologist.com for supplemental material available online.
Appendix S1. Supporting Information.
Click here for additional data file.
Figure S1
Click here for additional data file.
Acknowledgments
This work was supported in part by the Joan and Irwin Jacobs Fund and by the National Institutes of Health (grant NIH P30 CA023100 to R.K.) and by NIH K22CA216318 to E.S., NIH T32CA009370 to T.M., and NIH P30CA014195 to E.S. | LETROZOLE, TAMOXIFEN, TRAMETINIB | DrugsGivenReaction | CC BY-NC-ND | 33528846 | 19,137,424 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Disorientation'. | A Young man with Peri-ictal water drinking.
Neuro-vegetative features have been linked to epilepsy arising from the temporal lobe, which can be seen during ictal events and play an important role in determining the focal side of the lesion. Among the rare known features is peri-ictal water drinking (PIWD). Here, we present the case of a 31-year-old male with refractory temporal epilepsy, having episodes of PIWD. The patient was considered a candidate for resective surgery and was investigated accordingly, including long-term video electroencephalogram (EEG), brain magnetic resonance imaging (MRI), and neuropsychology assessment, which pointed towards a lesioned temporal lobe over the non-dominant hemisphere. The patient had an excellent outcome following right anterior temporal lobectomy. The lateralization significance of PIWD has not yet been established definitively in the literature, partly due to a limited number of published cases. This case highlights the previously observed association between PIWD and the involvement of the non-dominant hemisphere in epilepsy patients.
The initial description of peri-ictal water drinking (PIWD) dates back to the early twentieth century with observations by William G. Lennox and Stanley Cobb.1 However, drinking water is a usual habitual action, so it is difficult for patients or witnesses to consider this behavior as part of ictal manifestation, which made PIWD largely underestimated. Neuro-vegetative features such as mydriasis, transient hypo- or hypertension, and an increase in heart rate are well known and occur quite frequently in temporal lobe seizures. Many other features are described and occur much less frequently, as is the case in PIWD.2 Review of the literature showed only a handful of studies looking into PIWD, and no definite evidence exists to answer all questions about its relevance to temporal lobe epilepsy (TLE); however, a possible lateralizing value has been hypothesized.3 We present a case of right symptomatic TLE secondary to mesial temporal sclerosis (MTS) with PIWD behavior episodes confirmed by ictal video-electroencephalogram (EEG) that was recorded in an epilepsy monitoring unit. We also reviewed the literature to evaluate the localization and lateralization significance of this manifestation in TLE.
Case Report
Patient information and clinical findings
A 31-year-old left-handed male known to have epilepsy since the age of 7 years presented to our epilepsy center at King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia. His seizures were characterized by palpitations and thirst followed by right-hand automatism. He reported partial intact awareness and orientation at first, but later he could not recall what had happened. No other seizure types or history of febrile convulsion were documented. The treatment regimen consisted of valproic acid and levetiracetam (1 g bid for each drug) with no seizure control. Clinical and neurological examinations were unremarkable.
Diagnostic assessment
The patient was admitted to our epilepsy center for preoperative evaluation, including video-EEG monitoring, brain magnetic resonance imaging (MRI), positron emission tomography (PET) scanning, and a neuropsychological assessment. The patient had 6 seizures during hospitalization secondary to the gradual discontinuation of antiepileptic drugs (AEDs). The episodes were characterized by sudden mild headaches, palpitations, and excessive drinking of water followed by left-hand dystonic contraction. During these episodes, he was able to speak and gave meaningful answers to questions; later, he became disoriented. Ictal EEG changes began 30 sec before clinical onset and showed a buildup of rhythmic theta activity over the right anterior and mid-temporal head regions (Figure 1A, B). No EEG changes were noted post-ictally. Brain MRI showed right mesial temporal sclerosis (Figure 2A, B), and a PET scan revealed hypometabolism in the right temporal lobe. Neuropsychological evaluation results were within normal limits.
Figure 1 Electroencephalogram (EEG) (A) Ictal EEG onset with rhythmic discharges started from the right temporal region; (B) High amplitude rhythmic discharges in the right temporal region (along with the beginning of ictal water drinking 30 seconds after EEG onset).
Figure 2 The coronal T2WI (A) and FLAIR (B) images showing right-sided mesial temporal sclerosis. Notice the increased signal and small hippocampus with loss of normal internal architecture of the right hippocampus and dilated right temporal horn.
Therapeutic intervention, follow-up, and outcome
The patient underwent a right anterior temporal resection. He was seizure-free at the one-year follow-up; however, he remained on AEDs. His follow-up EEG showed residual epileptic activity (Figure 3).
Figure 3 Time line figure of the presented case.
Discussion
The PIWD is an uncommon feature described in patients with lesional and non-lesional epilepsy of the temporal lobe. It is defined as a stereotyped action seen across all age groups during seizures or within 1 to 2 minutes of their onset.3 The described case in this report concerned lesional epilepsy of the temporal lobe as documented in neuroimaging over the right side with automatic PIWD during video-EEG documented seizures, confirming the ictal nature of this manifestation.
To date, 64 cases of epileptic seizures associated with PIWD have been reported.4 The rate of reported cases of PIWD seen in TLE ranged from 7% to 15.3%.2,3,5,6 It was observed in 15.3% of 386 seizures in 65 patients with focal epilepsy reported by Trinka et al3. In a study of 55 adult patients with TLE, PIWD was seen in 8 patients (14.5%).6 Janszky et al5 observed PIWD in 7% of 141 adult patients with TLE. Musilová et al2 reported PIWD in 14.4% of 380 seizures in 97 patients with TLE-associated vegetative signs.
Generally, favorable surgical outcomes have been described for TLE patients with PIWD. A case series published by Trinka et al.3 demonstrated a complete response to surgical treatment in 70% of the studied cohort (Wieser’s class I). Similar favorable results of surgery were seen with a group of patients studied by Szűcs et al.6 (Engel Class 1 or 2) with the outcome maintained for a few years of postoperative follow-up. Our patient was seizure-free at the one-year follow-up after surgery.
Normal drinking behavior is controlled by vascular volume and tissue osmolality. Information from peripheral receptors is processed in the hypothalamus and then conveyed to various brain structures that initiate a search for water and drink.7 Furthermore, the hippocampus and the amygdala are linked to the hypothalamus through several multi-synaptic pathways that are involved in the regulation of water balance and drinking behavior.8 Water-seeking behavior is triggered by the involvement of the hypothalamus, which is affected by abnormal electrical activity generated by the temporal lobe.9
The PIWD is thought to reflect involvement of the non-dominant hemisphere because neural networks involved in fluid balance, thirst, and water-seeking are normally asymmetrical and are likely more active in the non-dominant side.10 The lateralizing value of PIWD remains incompletely determined. Some studies have linked PIWD to significant lateralization to the non-dominant hemisphere in patients with TLE.2,3 Other reports could not demonstrate clear evidence for the lateralization value of PIWD.5,6 This uncertainty could be due to the rapid spread of epileptic discharges from the focal source of the seizures to the contralateral side of the temporal lobe, or it may be due simply to the few reported cases of PIWD.6
In conclusion, PIWD is a rare and important vegetative symptom of TLE that can be a valuable lateralizing sign to the non-dominant hemisphere. We report here a case of PIWD as a manifestation of TLE in the non-dominant hemisphere; however, the association of PIWD with a non-dominant hemisphere has not yet been definitively established in the literature. Given the significance of PIWD in planning surgical resection, a more comprehensive and powerful study with enrollment of more patients is needed. Furthermore, the lateralization could be supported and confirmed by invasive EEG recordings.
Acknowledgements
We would like to thank Dr. Alawi Al-Attas and Dr. Majed Alhameed for their kind support, guidance, and motivation to report this case. Also, I would like to thanks Dr. Eman Bakhsh, neuroradiologist consultant for reviewing the images of the patient, and Scribendi (www.scribendi.com) for English language editing.
Case Reports
Case reports will only be considered for unusual topics that add something new to the literature. All Case Reports should include at least one figure. Written informed consent for publication must accompany any photograph in which the subject can be identified. Figures should be submitted with a 300 dpi resolution when submitting electronically. The abstract should be unstructured, and the introductory section should always include the objective and reason why the author is presenting this particular case. References should be up to date, preferably not exceeding 15.
Disclosure. The authors declare no conflicting interests, support or funding from any drug company. | LEVETIRACETAM, VALPROIC ACID | DrugsGivenReaction | CC BY-NC-SA | 33530048 | 19,138,926 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | A Young man with Peri-ictal water drinking.
Neuro-vegetative features have been linked to epilepsy arising from the temporal lobe, which can be seen during ictal events and play an important role in determining the focal side of the lesion. Among the rare known features is peri-ictal water drinking (PIWD). Here, we present the case of a 31-year-old male with refractory temporal epilepsy, having episodes of PIWD. The patient was considered a candidate for resective surgery and was investigated accordingly, including long-term video electroencephalogram (EEG), brain magnetic resonance imaging (MRI), and neuropsychology assessment, which pointed towards a lesioned temporal lobe over the non-dominant hemisphere. The patient had an excellent outcome following right anterior temporal lobectomy. The lateralization significance of PIWD has not yet been established definitively in the literature, partly due to a limited number of published cases. This case highlights the previously observed association between PIWD and the involvement of the non-dominant hemisphere in epilepsy patients.
The initial description of peri-ictal water drinking (PIWD) dates back to the early twentieth century with observations by William G. Lennox and Stanley Cobb.1 However, drinking water is a usual habitual action, so it is difficult for patients or witnesses to consider this behavior as part of ictal manifestation, which made PIWD largely underestimated. Neuro-vegetative features such as mydriasis, transient hypo- or hypertension, and an increase in heart rate are well known and occur quite frequently in temporal lobe seizures. Many other features are described and occur much less frequently, as is the case in PIWD.2 Review of the literature showed only a handful of studies looking into PIWD, and no definite evidence exists to answer all questions about its relevance to temporal lobe epilepsy (TLE); however, a possible lateralizing value has been hypothesized.3 We present a case of right symptomatic TLE secondary to mesial temporal sclerosis (MTS) with PIWD behavior episodes confirmed by ictal video-electroencephalogram (EEG) that was recorded in an epilepsy monitoring unit. We also reviewed the literature to evaluate the localization and lateralization significance of this manifestation in TLE.
Case Report
Patient information and clinical findings
A 31-year-old left-handed male known to have epilepsy since the age of 7 years presented to our epilepsy center at King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia. His seizures were characterized by palpitations and thirst followed by right-hand automatism. He reported partial intact awareness and orientation at first, but later he could not recall what had happened. No other seizure types or history of febrile convulsion were documented. The treatment regimen consisted of valproic acid and levetiracetam (1 g bid for each drug) with no seizure control. Clinical and neurological examinations were unremarkable.
Diagnostic assessment
The patient was admitted to our epilepsy center for preoperative evaluation, including video-EEG monitoring, brain magnetic resonance imaging (MRI), positron emission tomography (PET) scanning, and a neuropsychological assessment. The patient had 6 seizures during hospitalization secondary to the gradual discontinuation of antiepileptic drugs (AEDs). The episodes were characterized by sudden mild headaches, palpitations, and excessive drinking of water followed by left-hand dystonic contraction. During these episodes, he was able to speak and gave meaningful answers to questions; later, he became disoriented. Ictal EEG changes began 30 sec before clinical onset and showed a buildup of rhythmic theta activity over the right anterior and mid-temporal head regions (Figure 1A, B). No EEG changes were noted post-ictally. Brain MRI showed right mesial temporal sclerosis (Figure 2A, B), and a PET scan revealed hypometabolism in the right temporal lobe. Neuropsychological evaluation results were within normal limits.
Figure 1 Electroencephalogram (EEG) (A) Ictal EEG onset with rhythmic discharges started from the right temporal region; (B) High amplitude rhythmic discharges in the right temporal region (along with the beginning of ictal water drinking 30 seconds after EEG onset).
Figure 2 The coronal T2WI (A) and FLAIR (B) images showing right-sided mesial temporal sclerosis. Notice the increased signal and small hippocampus with loss of normal internal architecture of the right hippocampus and dilated right temporal horn.
Therapeutic intervention, follow-up, and outcome
The patient underwent a right anterior temporal resection. He was seizure-free at the one-year follow-up; however, he remained on AEDs. His follow-up EEG showed residual epileptic activity (Figure 3).
Figure 3 Time line figure of the presented case.
Discussion
The PIWD is an uncommon feature described in patients with lesional and non-lesional epilepsy of the temporal lobe. It is defined as a stereotyped action seen across all age groups during seizures or within 1 to 2 minutes of their onset.3 The described case in this report concerned lesional epilepsy of the temporal lobe as documented in neuroimaging over the right side with automatic PIWD during video-EEG documented seizures, confirming the ictal nature of this manifestation.
To date, 64 cases of epileptic seizures associated with PIWD have been reported.4 The rate of reported cases of PIWD seen in TLE ranged from 7% to 15.3%.2,3,5,6 It was observed in 15.3% of 386 seizures in 65 patients with focal epilepsy reported by Trinka et al3. In a study of 55 adult patients with TLE, PIWD was seen in 8 patients (14.5%).6 Janszky et al5 observed PIWD in 7% of 141 adult patients with TLE. Musilová et al2 reported PIWD in 14.4% of 380 seizures in 97 patients with TLE-associated vegetative signs.
Generally, favorable surgical outcomes have been described for TLE patients with PIWD. A case series published by Trinka et al.3 demonstrated a complete response to surgical treatment in 70% of the studied cohort (Wieser’s class I). Similar favorable results of surgery were seen with a group of patients studied by Szűcs et al.6 (Engel Class 1 or 2) with the outcome maintained for a few years of postoperative follow-up. Our patient was seizure-free at the one-year follow-up after surgery.
Normal drinking behavior is controlled by vascular volume and tissue osmolality. Information from peripheral receptors is processed in the hypothalamus and then conveyed to various brain structures that initiate a search for water and drink.7 Furthermore, the hippocampus and the amygdala are linked to the hypothalamus through several multi-synaptic pathways that are involved in the regulation of water balance and drinking behavior.8 Water-seeking behavior is triggered by the involvement of the hypothalamus, which is affected by abnormal electrical activity generated by the temporal lobe.9
The PIWD is thought to reflect involvement of the non-dominant hemisphere because neural networks involved in fluid balance, thirst, and water-seeking are normally asymmetrical and are likely more active in the non-dominant side.10 The lateralizing value of PIWD remains incompletely determined. Some studies have linked PIWD to significant lateralization to the non-dominant hemisphere in patients with TLE.2,3 Other reports could not demonstrate clear evidence for the lateralization value of PIWD.5,6 This uncertainty could be due to the rapid spread of epileptic discharges from the focal source of the seizures to the contralateral side of the temporal lobe, or it may be due simply to the few reported cases of PIWD.6
In conclusion, PIWD is a rare and important vegetative symptom of TLE that can be a valuable lateralizing sign to the non-dominant hemisphere. We report here a case of PIWD as a manifestation of TLE in the non-dominant hemisphere; however, the association of PIWD with a non-dominant hemisphere has not yet been definitively established in the literature. Given the significance of PIWD in planning surgical resection, a more comprehensive and powerful study with enrollment of more patients is needed. Furthermore, the lateralization could be supported and confirmed by invasive EEG recordings.
Acknowledgements
We would like to thank Dr. Alawi Al-Attas and Dr. Majed Alhameed for their kind support, guidance, and motivation to report this case. Also, I would like to thanks Dr. Eman Bakhsh, neuroradiologist consultant for reviewing the images of the patient, and Scribendi (www.scribendi.com) for English language editing.
Case Reports
Case reports will only be considered for unusual topics that add something new to the literature. All Case Reports should include at least one figure. Written informed consent for publication must accompany any photograph in which the subject can be identified. Figures should be submitted with a 300 dpi resolution when submitting electronically. The abstract should be unstructured, and the introductory section should always include the objective and reason why the author is presenting this particular case. References should be up to date, preferably not exceeding 15.
Disclosure. The authors declare no conflicting interests, support or funding from any drug company. | LEVETIRACETAM, VALPROIC ACID | DrugsGivenReaction | CC BY-NC-SA | 33530048 | 19,149,896 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug withdrawal headache'. | A Young man with Peri-ictal water drinking.
Neuro-vegetative features have been linked to epilepsy arising from the temporal lobe, which can be seen during ictal events and play an important role in determining the focal side of the lesion. Among the rare known features is peri-ictal water drinking (PIWD). Here, we present the case of a 31-year-old male with refractory temporal epilepsy, having episodes of PIWD. The patient was considered a candidate for resective surgery and was investigated accordingly, including long-term video electroencephalogram (EEG), brain magnetic resonance imaging (MRI), and neuropsychology assessment, which pointed towards a lesioned temporal lobe over the non-dominant hemisphere. The patient had an excellent outcome following right anterior temporal lobectomy. The lateralization significance of PIWD has not yet been established definitively in the literature, partly due to a limited number of published cases. This case highlights the previously observed association between PIWD and the involvement of the non-dominant hemisphere in epilepsy patients.
The initial description of peri-ictal water drinking (PIWD) dates back to the early twentieth century with observations by William G. Lennox and Stanley Cobb.1 However, drinking water is a usual habitual action, so it is difficult for patients or witnesses to consider this behavior as part of ictal manifestation, which made PIWD largely underestimated. Neuro-vegetative features such as mydriasis, transient hypo- or hypertension, and an increase in heart rate are well known and occur quite frequently in temporal lobe seizures. Many other features are described and occur much less frequently, as is the case in PIWD.2 Review of the literature showed only a handful of studies looking into PIWD, and no definite evidence exists to answer all questions about its relevance to temporal lobe epilepsy (TLE); however, a possible lateralizing value has been hypothesized.3 We present a case of right symptomatic TLE secondary to mesial temporal sclerosis (MTS) with PIWD behavior episodes confirmed by ictal video-electroencephalogram (EEG) that was recorded in an epilepsy monitoring unit. We also reviewed the literature to evaluate the localization and lateralization significance of this manifestation in TLE.
Case Report
Patient information and clinical findings
A 31-year-old left-handed male known to have epilepsy since the age of 7 years presented to our epilepsy center at King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia. His seizures were characterized by palpitations and thirst followed by right-hand automatism. He reported partial intact awareness and orientation at first, but later he could not recall what had happened. No other seizure types or history of febrile convulsion were documented. The treatment regimen consisted of valproic acid and levetiracetam (1 g bid for each drug) with no seizure control. Clinical and neurological examinations were unremarkable.
Diagnostic assessment
The patient was admitted to our epilepsy center for preoperative evaluation, including video-EEG monitoring, brain magnetic resonance imaging (MRI), positron emission tomography (PET) scanning, and a neuropsychological assessment. The patient had 6 seizures during hospitalization secondary to the gradual discontinuation of antiepileptic drugs (AEDs). The episodes were characterized by sudden mild headaches, palpitations, and excessive drinking of water followed by left-hand dystonic contraction. During these episodes, he was able to speak and gave meaningful answers to questions; later, he became disoriented. Ictal EEG changes began 30 sec before clinical onset and showed a buildup of rhythmic theta activity over the right anterior and mid-temporal head regions (Figure 1A, B). No EEG changes were noted post-ictally. Brain MRI showed right mesial temporal sclerosis (Figure 2A, B), and a PET scan revealed hypometabolism in the right temporal lobe. Neuropsychological evaluation results were within normal limits.
Figure 1 Electroencephalogram (EEG) (A) Ictal EEG onset with rhythmic discharges started from the right temporal region; (B) High amplitude rhythmic discharges in the right temporal region (along with the beginning of ictal water drinking 30 seconds after EEG onset).
Figure 2 The coronal T2WI (A) and FLAIR (B) images showing right-sided mesial temporal sclerosis. Notice the increased signal and small hippocampus with loss of normal internal architecture of the right hippocampus and dilated right temporal horn.
Therapeutic intervention, follow-up, and outcome
The patient underwent a right anterior temporal resection. He was seizure-free at the one-year follow-up; however, he remained on AEDs. His follow-up EEG showed residual epileptic activity (Figure 3).
Figure 3 Time line figure of the presented case.
Discussion
The PIWD is an uncommon feature described in patients with lesional and non-lesional epilepsy of the temporal lobe. It is defined as a stereotyped action seen across all age groups during seizures or within 1 to 2 minutes of their onset.3 The described case in this report concerned lesional epilepsy of the temporal lobe as documented in neuroimaging over the right side with automatic PIWD during video-EEG documented seizures, confirming the ictal nature of this manifestation.
To date, 64 cases of epileptic seizures associated with PIWD have been reported.4 The rate of reported cases of PIWD seen in TLE ranged from 7% to 15.3%.2,3,5,6 It was observed in 15.3% of 386 seizures in 65 patients with focal epilepsy reported by Trinka et al3. In a study of 55 adult patients with TLE, PIWD was seen in 8 patients (14.5%).6 Janszky et al5 observed PIWD in 7% of 141 adult patients with TLE. Musilová et al2 reported PIWD in 14.4% of 380 seizures in 97 patients with TLE-associated vegetative signs.
Generally, favorable surgical outcomes have been described for TLE patients with PIWD. A case series published by Trinka et al.3 demonstrated a complete response to surgical treatment in 70% of the studied cohort (Wieser’s class I). Similar favorable results of surgery were seen with a group of patients studied by Szűcs et al.6 (Engel Class 1 or 2) with the outcome maintained for a few years of postoperative follow-up. Our patient was seizure-free at the one-year follow-up after surgery.
Normal drinking behavior is controlled by vascular volume and tissue osmolality. Information from peripheral receptors is processed in the hypothalamus and then conveyed to various brain structures that initiate a search for water and drink.7 Furthermore, the hippocampus and the amygdala are linked to the hypothalamus through several multi-synaptic pathways that are involved in the regulation of water balance and drinking behavior.8 Water-seeking behavior is triggered by the involvement of the hypothalamus, which is affected by abnormal electrical activity generated by the temporal lobe.9
The PIWD is thought to reflect involvement of the non-dominant hemisphere because neural networks involved in fluid balance, thirst, and water-seeking are normally asymmetrical and are likely more active in the non-dominant side.10 The lateralizing value of PIWD remains incompletely determined. Some studies have linked PIWD to significant lateralization to the non-dominant hemisphere in patients with TLE.2,3 Other reports could not demonstrate clear evidence for the lateralization value of PIWD.5,6 This uncertainty could be due to the rapid spread of epileptic discharges from the focal source of the seizures to the contralateral side of the temporal lobe, or it may be due simply to the few reported cases of PIWD.6
In conclusion, PIWD is a rare and important vegetative symptom of TLE that can be a valuable lateralizing sign to the non-dominant hemisphere. We report here a case of PIWD as a manifestation of TLE in the non-dominant hemisphere; however, the association of PIWD with a non-dominant hemisphere has not yet been definitively established in the literature. Given the significance of PIWD in planning surgical resection, a more comprehensive and powerful study with enrollment of more patients is needed. Furthermore, the lateralization could be supported and confirmed by invasive EEG recordings.
Acknowledgements
We would like to thank Dr. Alawi Al-Attas and Dr. Majed Alhameed for their kind support, guidance, and motivation to report this case. Also, I would like to thanks Dr. Eman Bakhsh, neuroradiologist consultant for reviewing the images of the patient, and Scribendi (www.scribendi.com) for English language editing.
Case Reports
Case reports will only be considered for unusual topics that add something new to the literature. All Case Reports should include at least one figure. Written informed consent for publication must accompany any photograph in which the subject can be identified. Figures should be submitted with a 300 dpi resolution when submitting electronically. The abstract should be unstructured, and the introductory section should always include the objective and reason why the author is presenting this particular case. References should be up to date, preferably not exceeding 15.
Disclosure. The authors declare no conflicting interests, support or funding from any drug company. | LEVETIRACETAM, VALPROIC ACID | DrugsGivenReaction | CC BY-NC-SA | 33530048 | 19,138,926 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Palpitations'. | A Young man with Peri-ictal water drinking.
Neuro-vegetative features have been linked to epilepsy arising from the temporal lobe, which can be seen during ictal events and play an important role in determining the focal side of the lesion. Among the rare known features is peri-ictal water drinking (PIWD). Here, we present the case of a 31-year-old male with refractory temporal epilepsy, having episodes of PIWD. The patient was considered a candidate for resective surgery and was investigated accordingly, including long-term video electroencephalogram (EEG), brain magnetic resonance imaging (MRI), and neuropsychology assessment, which pointed towards a lesioned temporal lobe over the non-dominant hemisphere. The patient had an excellent outcome following right anterior temporal lobectomy. The lateralization significance of PIWD has not yet been established definitively in the literature, partly due to a limited number of published cases. This case highlights the previously observed association between PIWD and the involvement of the non-dominant hemisphere in epilepsy patients.
The initial description of peri-ictal water drinking (PIWD) dates back to the early twentieth century with observations by William G. Lennox and Stanley Cobb.1 However, drinking water is a usual habitual action, so it is difficult for patients or witnesses to consider this behavior as part of ictal manifestation, which made PIWD largely underestimated. Neuro-vegetative features such as mydriasis, transient hypo- or hypertension, and an increase in heart rate are well known and occur quite frequently in temporal lobe seizures. Many other features are described and occur much less frequently, as is the case in PIWD.2 Review of the literature showed only a handful of studies looking into PIWD, and no definite evidence exists to answer all questions about its relevance to temporal lobe epilepsy (TLE); however, a possible lateralizing value has been hypothesized.3 We present a case of right symptomatic TLE secondary to mesial temporal sclerosis (MTS) with PIWD behavior episodes confirmed by ictal video-electroencephalogram (EEG) that was recorded in an epilepsy monitoring unit. We also reviewed the literature to evaluate the localization and lateralization significance of this manifestation in TLE.
Case Report
Patient information and clinical findings
A 31-year-old left-handed male known to have epilepsy since the age of 7 years presented to our epilepsy center at King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia. His seizures were characterized by palpitations and thirst followed by right-hand automatism. He reported partial intact awareness and orientation at first, but later he could not recall what had happened. No other seizure types or history of febrile convulsion were documented. The treatment regimen consisted of valproic acid and levetiracetam (1 g bid for each drug) with no seizure control. Clinical and neurological examinations were unremarkable.
Diagnostic assessment
The patient was admitted to our epilepsy center for preoperative evaluation, including video-EEG monitoring, brain magnetic resonance imaging (MRI), positron emission tomography (PET) scanning, and a neuropsychological assessment. The patient had 6 seizures during hospitalization secondary to the gradual discontinuation of antiepileptic drugs (AEDs). The episodes were characterized by sudden mild headaches, palpitations, and excessive drinking of water followed by left-hand dystonic contraction. During these episodes, he was able to speak and gave meaningful answers to questions; later, he became disoriented. Ictal EEG changes began 30 sec before clinical onset and showed a buildup of rhythmic theta activity over the right anterior and mid-temporal head regions (Figure 1A, B). No EEG changes were noted post-ictally. Brain MRI showed right mesial temporal sclerosis (Figure 2A, B), and a PET scan revealed hypometabolism in the right temporal lobe. Neuropsychological evaluation results were within normal limits.
Figure 1 Electroencephalogram (EEG) (A) Ictal EEG onset with rhythmic discharges started from the right temporal region; (B) High amplitude rhythmic discharges in the right temporal region (along with the beginning of ictal water drinking 30 seconds after EEG onset).
Figure 2 The coronal T2WI (A) and FLAIR (B) images showing right-sided mesial temporal sclerosis. Notice the increased signal and small hippocampus with loss of normal internal architecture of the right hippocampus and dilated right temporal horn.
Therapeutic intervention, follow-up, and outcome
The patient underwent a right anterior temporal resection. He was seizure-free at the one-year follow-up; however, he remained on AEDs. His follow-up EEG showed residual epileptic activity (Figure 3).
Figure 3 Time line figure of the presented case.
Discussion
The PIWD is an uncommon feature described in patients with lesional and non-lesional epilepsy of the temporal lobe. It is defined as a stereotyped action seen across all age groups during seizures or within 1 to 2 minutes of their onset.3 The described case in this report concerned lesional epilepsy of the temporal lobe as documented in neuroimaging over the right side with automatic PIWD during video-EEG documented seizures, confirming the ictal nature of this manifestation.
To date, 64 cases of epileptic seizures associated with PIWD have been reported.4 The rate of reported cases of PIWD seen in TLE ranged from 7% to 15.3%.2,3,5,6 It was observed in 15.3% of 386 seizures in 65 patients with focal epilepsy reported by Trinka et al3. In a study of 55 adult patients with TLE, PIWD was seen in 8 patients (14.5%).6 Janszky et al5 observed PIWD in 7% of 141 adult patients with TLE. Musilová et al2 reported PIWD in 14.4% of 380 seizures in 97 patients with TLE-associated vegetative signs.
Generally, favorable surgical outcomes have been described for TLE patients with PIWD. A case series published by Trinka et al.3 demonstrated a complete response to surgical treatment in 70% of the studied cohort (Wieser’s class I). Similar favorable results of surgery were seen with a group of patients studied by Szűcs et al.6 (Engel Class 1 or 2) with the outcome maintained for a few years of postoperative follow-up. Our patient was seizure-free at the one-year follow-up after surgery.
Normal drinking behavior is controlled by vascular volume and tissue osmolality. Information from peripheral receptors is processed in the hypothalamus and then conveyed to various brain structures that initiate a search for water and drink.7 Furthermore, the hippocampus and the amygdala are linked to the hypothalamus through several multi-synaptic pathways that are involved in the regulation of water balance and drinking behavior.8 Water-seeking behavior is triggered by the involvement of the hypothalamus, which is affected by abnormal electrical activity generated by the temporal lobe.9
The PIWD is thought to reflect involvement of the non-dominant hemisphere because neural networks involved in fluid balance, thirst, and water-seeking are normally asymmetrical and are likely more active in the non-dominant side.10 The lateralizing value of PIWD remains incompletely determined. Some studies have linked PIWD to significant lateralization to the non-dominant hemisphere in patients with TLE.2,3 Other reports could not demonstrate clear evidence for the lateralization value of PIWD.5,6 This uncertainty could be due to the rapid spread of epileptic discharges from the focal source of the seizures to the contralateral side of the temporal lobe, or it may be due simply to the few reported cases of PIWD.6
In conclusion, PIWD is a rare and important vegetative symptom of TLE that can be a valuable lateralizing sign to the non-dominant hemisphere. We report here a case of PIWD as a manifestation of TLE in the non-dominant hemisphere; however, the association of PIWD with a non-dominant hemisphere has not yet been definitively established in the literature. Given the significance of PIWD in planning surgical resection, a more comprehensive and powerful study with enrollment of more patients is needed. Furthermore, the lateralization could be supported and confirmed by invasive EEG recordings.
Acknowledgements
We would like to thank Dr. Alawi Al-Attas and Dr. Majed Alhameed for their kind support, guidance, and motivation to report this case. Also, I would like to thanks Dr. Eman Bakhsh, neuroradiologist consultant for reviewing the images of the patient, and Scribendi (www.scribendi.com) for English language editing.
Case Reports
Case reports will only be considered for unusual topics that add something new to the literature. All Case Reports should include at least one figure. Written informed consent for publication must accompany any photograph in which the subject can be identified. Figures should be submitted with a 300 dpi resolution when submitting electronically. The abstract should be unstructured, and the introductory section should always include the objective and reason why the author is presenting this particular case. References should be up to date, preferably not exceeding 15.
Disclosure. The authors declare no conflicting interests, support or funding from any drug company. | LEVETIRACETAM, VALPROIC ACID | DrugsGivenReaction | CC BY-NC-SA | 33530048 | 19,138,926 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Seizure'. | A Young man with Peri-ictal water drinking.
Neuro-vegetative features have been linked to epilepsy arising from the temporal lobe, which can be seen during ictal events and play an important role in determining the focal side of the lesion. Among the rare known features is peri-ictal water drinking (PIWD). Here, we present the case of a 31-year-old male with refractory temporal epilepsy, having episodes of PIWD. The patient was considered a candidate for resective surgery and was investigated accordingly, including long-term video electroencephalogram (EEG), brain magnetic resonance imaging (MRI), and neuropsychology assessment, which pointed towards a lesioned temporal lobe over the non-dominant hemisphere. The patient had an excellent outcome following right anterior temporal lobectomy. The lateralization significance of PIWD has not yet been established definitively in the literature, partly due to a limited number of published cases. This case highlights the previously observed association between PIWD and the involvement of the non-dominant hemisphere in epilepsy patients.
The initial description of peri-ictal water drinking (PIWD) dates back to the early twentieth century with observations by William G. Lennox and Stanley Cobb.1 However, drinking water is a usual habitual action, so it is difficult for patients or witnesses to consider this behavior as part of ictal manifestation, which made PIWD largely underestimated. Neuro-vegetative features such as mydriasis, transient hypo- or hypertension, and an increase in heart rate are well known and occur quite frequently in temporal lobe seizures. Many other features are described and occur much less frequently, as is the case in PIWD.2 Review of the literature showed only a handful of studies looking into PIWD, and no definite evidence exists to answer all questions about its relevance to temporal lobe epilepsy (TLE); however, a possible lateralizing value has been hypothesized.3 We present a case of right symptomatic TLE secondary to mesial temporal sclerosis (MTS) with PIWD behavior episodes confirmed by ictal video-electroencephalogram (EEG) that was recorded in an epilepsy monitoring unit. We also reviewed the literature to evaluate the localization and lateralization significance of this manifestation in TLE.
Case Report
Patient information and clinical findings
A 31-year-old left-handed male known to have epilepsy since the age of 7 years presented to our epilepsy center at King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia. His seizures were characterized by palpitations and thirst followed by right-hand automatism. He reported partial intact awareness and orientation at first, but later he could not recall what had happened. No other seizure types or history of febrile convulsion were documented. The treatment regimen consisted of valproic acid and levetiracetam (1 g bid for each drug) with no seizure control. Clinical and neurological examinations were unremarkable.
Diagnostic assessment
The patient was admitted to our epilepsy center for preoperative evaluation, including video-EEG monitoring, brain magnetic resonance imaging (MRI), positron emission tomography (PET) scanning, and a neuropsychological assessment. The patient had 6 seizures during hospitalization secondary to the gradual discontinuation of antiepileptic drugs (AEDs). The episodes were characterized by sudden mild headaches, palpitations, and excessive drinking of water followed by left-hand dystonic contraction. During these episodes, he was able to speak and gave meaningful answers to questions; later, he became disoriented. Ictal EEG changes began 30 sec before clinical onset and showed a buildup of rhythmic theta activity over the right anterior and mid-temporal head regions (Figure 1A, B). No EEG changes were noted post-ictally. Brain MRI showed right mesial temporal sclerosis (Figure 2A, B), and a PET scan revealed hypometabolism in the right temporal lobe. Neuropsychological evaluation results were within normal limits.
Figure 1 Electroencephalogram (EEG) (A) Ictal EEG onset with rhythmic discharges started from the right temporal region; (B) High amplitude rhythmic discharges in the right temporal region (along with the beginning of ictal water drinking 30 seconds after EEG onset).
Figure 2 The coronal T2WI (A) and FLAIR (B) images showing right-sided mesial temporal sclerosis. Notice the increased signal and small hippocampus with loss of normal internal architecture of the right hippocampus and dilated right temporal horn.
Therapeutic intervention, follow-up, and outcome
The patient underwent a right anterior temporal resection. He was seizure-free at the one-year follow-up; however, he remained on AEDs. His follow-up EEG showed residual epileptic activity (Figure 3).
Figure 3 Time line figure of the presented case.
Discussion
The PIWD is an uncommon feature described in patients with lesional and non-lesional epilepsy of the temporal lobe. It is defined as a stereotyped action seen across all age groups during seizures or within 1 to 2 minutes of their onset.3 The described case in this report concerned lesional epilepsy of the temporal lobe as documented in neuroimaging over the right side with automatic PIWD during video-EEG documented seizures, confirming the ictal nature of this manifestation.
To date, 64 cases of epileptic seizures associated with PIWD have been reported.4 The rate of reported cases of PIWD seen in TLE ranged from 7% to 15.3%.2,3,5,6 It was observed in 15.3% of 386 seizures in 65 patients with focal epilepsy reported by Trinka et al3. In a study of 55 adult patients with TLE, PIWD was seen in 8 patients (14.5%).6 Janszky et al5 observed PIWD in 7% of 141 adult patients with TLE. Musilová et al2 reported PIWD in 14.4% of 380 seizures in 97 patients with TLE-associated vegetative signs.
Generally, favorable surgical outcomes have been described for TLE patients with PIWD. A case series published by Trinka et al.3 demonstrated a complete response to surgical treatment in 70% of the studied cohort (Wieser’s class I). Similar favorable results of surgery were seen with a group of patients studied by Szűcs et al.6 (Engel Class 1 or 2) with the outcome maintained for a few years of postoperative follow-up. Our patient was seizure-free at the one-year follow-up after surgery.
Normal drinking behavior is controlled by vascular volume and tissue osmolality. Information from peripheral receptors is processed in the hypothalamus and then conveyed to various brain structures that initiate a search for water and drink.7 Furthermore, the hippocampus and the amygdala are linked to the hypothalamus through several multi-synaptic pathways that are involved in the regulation of water balance and drinking behavior.8 Water-seeking behavior is triggered by the involvement of the hypothalamus, which is affected by abnormal electrical activity generated by the temporal lobe.9
The PIWD is thought to reflect involvement of the non-dominant hemisphere because neural networks involved in fluid balance, thirst, and water-seeking are normally asymmetrical and are likely more active in the non-dominant side.10 The lateralizing value of PIWD remains incompletely determined. Some studies have linked PIWD to significant lateralization to the non-dominant hemisphere in patients with TLE.2,3 Other reports could not demonstrate clear evidence for the lateralization value of PIWD.5,6 This uncertainty could be due to the rapid spread of epileptic discharges from the focal source of the seizures to the contralateral side of the temporal lobe, or it may be due simply to the few reported cases of PIWD.6
In conclusion, PIWD is a rare and important vegetative symptom of TLE that can be a valuable lateralizing sign to the non-dominant hemisphere. We report here a case of PIWD as a manifestation of TLE in the non-dominant hemisphere; however, the association of PIWD with a non-dominant hemisphere has not yet been definitively established in the literature. Given the significance of PIWD in planning surgical resection, a more comprehensive and powerful study with enrollment of more patients is needed. Furthermore, the lateralization could be supported and confirmed by invasive EEG recordings.
Acknowledgements
We would like to thank Dr. Alawi Al-Attas and Dr. Majed Alhameed for their kind support, guidance, and motivation to report this case. Also, I would like to thanks Dr. Eman Bakhsh, neuroradiologist consultant for reviewing the images of the patient, and Scribendi (www.scribendi.com) for English language editing.
Case Reports
Case reports will only be considered for unusual topics that add something new to the literature. All Case Reports should include at least one figure. Written informed consent for publication must accompany any photograph in which the subject can be identified. Figures should be submitted with a 300 dpi resolution when submitting electronically. The abstract should be unstructured, and the introductory section should always include the objective and reason why the author is presenting this particular case. References should be up to date, preferably not exceeding 15.
Disclosure. The authors declare no conflicting interests, support or funding from any drug company. | LEVETIRACETAM, VALPROIC ACID | DrugsGivenReaction | CC BY-NC-SA | 33530048 | 19,138,926 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Withdrawal syndrome'. | A Young man with Peri-ictal water drinking.
Neuro-vegetative features have been linked to epilepsy arising from the temporal lobe, which can be seen during ictal events and play an important role in determining the focal side of the lesion. Among the rare known features is peri-ictal water drinking (PIWD). Here, we present the case of a 31-year-old male with refractory temporal epilepsy, having episodes of PIWD. The patient was considered a candidate for resective surgery and was investigated accordingly, including long-term video electroencephalogram (EEG), brain magnetic resonance imaging (MRI), and neuropsychology assessment, which pointed towards a lesioned temporal lobe over the non-dominant hemisphere. The patient had an excellent outcome following right anterior temporal lobectomy. The lateralization significance of PIWD has not yet been established definitively in the literature, partly due to a limited number of published cases. This case highlights the previously observed association between PIWD and the involvement of the non-dominant hemisphere in epilepsy patients.
The initial description of peri-ictal water drinking (PIWD) dates back to the early twentieth century with observations by William G. Lennox and Stanley Cobb.1 However, drinking water is a usual habitual action, so it is difficult for patients or witnesses to consider this behavior as part of ictal manifestation, which made PIWD largely underestimated. Neuro-vegetative features such as mydriasis, transient hypo- or hypertension, and an increase in heart rate are well known and occur quite frequently in temporal lobe seizures. Many other features are described and occur much less frequently, as is the case in PIWD.2 Review of the literature showed only a handful of studies looking into PIWD, and no definite evidence exists to answer all questions about its relevance to temporal lobe epilepsy (TLE); however, a possible lateralizing value has been hypothesized.3 We present a case of right symptomatic TLE secondary to mesial temporal sclerosis (MTS) with PIWD behavior episodes confirmed by ictal video-electroencephalogram (EEG) that was recorded in an epilepsy monitoring unit. We also reviewed the literature to evaluate the localization and lateralization significance of this manifestation in TLE.
Case Report
Patient information and clinical findings
A 31-year-old left-handed male known to have epilepsy since the age of 7 years presented to our epilepsy center at King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia. His seizures were characterized by palpitations and thirst followed by right-hand automatism. He reported partial intact awareness and orientation at first, but later he could not recall what had happened. No other seizure types or history of febrile convulsion were documented. The treatment regimen consisted of valproic acid and levetiracetam (1 g bid for each drug) with no seizure control. Clinical and neurological examinations were unremarkable.
Diagnostic assessment
The patient was admitted to our epilepsy center for preoperative evaluation, including video-EEG monitoring, brain magnetic resonance imaging (MRI), positron emission tomography (PET) scanning, and a neuropsychological assessment. The patient had 6 seizures during hospitalization secondary to the gradual discontinuation of antiepileptic drugs (AEDs). The episodes were characterized by sudden mild headaches, palpitations, and excessive drinking of water followed by left-hand dystonic contraction. During these episodes, he was able to speak and gave meaningful answers to questions; later, he became disoriented. Ictal EEG changes began 30 sec before clinical onset and showed a buildup of rhythmic theta activity over the right anterior and mid-temporal head regions (Figure 1A, B). No EEG changes were noted post-ictally. Brain MRI showed right mesial temporal sclerosis (Figure 2A, B), and a PET scan revealed hypometabolism in the right temporal lobe. Neuropsychological evaluation results were within normal limits.
Figure 1 Electroencephalogram (EEG) (A) Ictal EEG onset with rhythmic discharges started from the right temporal region; (B) High amplitude rhythmic discharges in the right temporal region (along with the beginning of ictal water drinking 30 seconds after EEG onset).
Figure 2 The coronal T2WI (A) and FLAIR (B) images showing right-sided mesial temporal sclerosis. Notice the increased signal and small hippocampus with loss of normal internal architecture of the right hippocampus and dilated right temporal horn.
Therapeutic intervention, follow-up, and outcome
The patient underwent a right anterior temporal resection. He was seizure-free at the one-year follow-up; however, he remained on AEDs. His follow-up EEG showed residual epileptic activity (Figure 3).
Figure 3 Time line figure of the presented case.
Discussion
The PIWD is an uncommon feature described in patients with lesional and non-lesional epilepsy of the temporal lobe. It is defined as a stereotyped action seen across all age groups during seizures or within 1 to 2 minutes of their onset.3 The described case in this report concerned lesional epilepsy of the temporal lobe as documented in neuroimaging over the right side with automatic PIWD during video-EEG documented seizures, confirming the ictal nature of this manifestation.
To date, 64 cases of epileptic seizures associated with PIWD have been reported.4 The rate of reported cases of PIWD seen in TLE ranged from 7% to 15.3%.2,3,5,6 It was observed in 15.3% of 386 seizures in 65 patients with focal epilepsy reported by Trinka et al3. In a study of 55 adult patients with TLE, PIWD was seen in 8 patients (14.5%).6 Janszky et al5 observed PIWD in 7% of 141 adult patients with TLE. Musilová et al2 reported PIWD in 14.4% of 380 seizures in 97 patients with TLE-associated vegetative signs.
Generally, favorable surgical outcomes have been described for TLE patients with PIWD. A case series published by Trinka et al.3 demonstrated a complete response to surgical treatment in 70% of the studied cohort (Wieser’s class I). Similar favorable results of surgery were seen with a group of patients studied by Szűcs et al.6 (Engel Class 1 or 2) with the outcome maintained for a few years of postoperative follow-up. Our patient was seizure-free at the one-year follow-up after surgery.
Normal drinking behavior is controlled by vascular volume and tissue osmolality. Information from peripheral receptors is processed in the hypothalamus and then conveyed to various brain structures that initiate a search for water and drink.7 Furthermore, the hippocampus and the amygdala are linked to the hypothalamus through several multi-synaptic pathways that are involved in the regulation of water balance and drinking behavior.8 Water-seeking behavior is triggered by the involvement of the hypothalamus, which is affected by abnormal electrical activity generated by the temporal lobe.9
The PIWD is thought to reflect involvement of the non-dominant hemisphere because neural networks involved in fluid balance, thirst, and water-seeking are normally asymmetrical and are likely more active in the non-dominant side.10 The lateralizing value of PIWD remains incompletely determined. Some studies have linked PIWD to significant lateralization to the non-dominant hemisphere in patients with TLE.2,3 Other reports could not demonstrate clear evidence for the lateralization value of PIWD.5,6 This uncertainty could be due to the rapid spread of epileptic discharges from the focal source of the seizures to the contralateral side of the temporal lobe, or it may be due simply to the few reported cases of PIWD.6
In conclusion, PIWD is a rare and important vegetative symptom of TLE that can be a valuable lateralizing sign to the non-dominant hemisphere. We report here a case of PIWD as a manifestation of TLE in the non-dominant hemisphere; however, the association of PIWD with a non-dominant hemisphere has not yet been definitively established in the literature. Given the significance of PIWD in planning surgical resection, a more comprehensive and powerful study with enrollment of more patients is needed. Furthermore, the lateralization could be supported and confirmed by invasive EEG recordings.
Acknowledgements
We would like to thank Dr. Alawi Al-Attas and Dr. Majed Alhameed for their kind support, guidance, and motivation to report this case. Also, I would like to thanks Dr. Eman Bakhsh, neuroradiologist consultant for reviewing the images of the patient, and Scribendi (www.scribendi.com) for English language editing.
Case Reports
Case reports will only be considered for unusual topics that add something new to the literature. All Case Reports should include at least one figure. Written informed consent for publication must accompany any photograph in which the subject can be identified. Figures should be submitted with a 300 dpi resolution when submitting electronically. The abstract should be unstructured, and the introductory section should always include the objective and reason why the author is presenting this particular case. References should be up to date, preferably not exceeding 15.
Disclosure. The authors declare no conflicting interests, support or funding from any drug company. | LEVETIRACETAM, VALPROIC ACID | DrugsGivenReaction | CC BY-NC-SA | 33530048 | 19,138,926 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Writer^s cramp'. | A Young man with Peri-ictal water drinking.
Neuro-vegetative features have been linked to epilepsy arising from the temporal lobe, which can be seen during ictal events and play an important role in determining the focal side of the lesion. Among the rare known features is peri-ictal water drinking (PIWD). Here, we present the case of a 31-year-old male with refractory temporal epilepsy, having episodes of PIWD. The patient was considered a candidate for resective surgery and was investigated accordingly, including long-term video electroencephalogram (EEG), brain magnetic resonance imaging (MRI), and neuropsychology assessment, which pointed towards a lesioned temporal lobe over the non-dominant hemisphere. The patient had an excellent outcome following right anterior temporal lobectomy. The lateralization significance of PIWD has not yet been established definitively in the literature, partly due to a limited number of published cases. This case highlights the previously observed association between PIWD and the involvement of the non-dominant hemisphere in epilepsy patients.
The initial description of peri-ictal water drinking (PIWD) dates back to the early twentieth century with observations by William G. Lennox and Stanley Cobb.1 However, drinking water is a usual habitual action, so it is difficult for patients or witnesses to consider this behavior as part of ictal manifestation, which made PIWD largely underestimated. Neuro-vegetative features such as mydriasis, transient hypo- or hypertension, and an increase in heart rate are well known and occur quite frequently in temporal lobe seizures. Many other features are described and occur much less frequently, as is the case in PIWD.2 Review of the literature showed only a handful of studies looking into PIWD, and no definite evidence exists to answer all questions about its relevance to temporal lobe epilepsy (TLE); however, a possible lateralizing value has been hypothesized.3 We present a case of right symptomatic TLE secondary to mesial temporal sclerosis (MTS) with PIWD behavior episodes confirmed by ictal video-electroencephalogram (EEG) that was recorded in an epilepsy monitoring unit. We also reviewed the literature to evaluate the localization and lateralization significance of this manifestation in TLE.
Case Report
Patient information and clinical findings
A 31-year-old left-handed male known to have epilepsy since the age of 7 years presented to our epilepsy center at King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia. His seizures were characterized by palpitations and thirst followed by right-hand automatism. He reported partial intact awareness and orientation at first, but later he could not recall what had happened. No other seizure types or history of febrile convulsion were documented. The treatment regimen consisted of valproic acid and levetiracetam (1 g bid for each drug) with no seizure control. Clinical and neurological examinations were unremarkable.
Diagnostic assessment
The patient was admitted to our epilepsy center for preoperative evaluation, including video-EEG monitoring, brain magnetic resonance imaging (MRI), positron emission tomography (PET) scanning, and a neuropsychological assessment. The patient had 6 seizures during hospitalization secondary to the gradual discontinuation of antiepileptic drugs (AEDs). The episodes were characterized by sudden mild headaches, palpitations, and excessive drinking of water followed by left-hand dystonic contraction. During these episodes, he was able to speak and gave meaningful answers to questions; later, he became disoriented. Ictal EEG changes began 30 sec before clinical onset and showed a buildup of rhythmic theta activity over the right anterior and mid-temporal head regions (Figure 1A, B). No EEG changes were noted post-ictally. Brain MRI showed right mesial temporal sclerosis (Figure 2A, B), and a PET scan revealed hypometabolism in the right temporal lobe. Neuropsychological evaluation results were within normal limits.
Figure 1 Electroencephalogram (EEG) (A) Ictal EEG onset with rhythmic discharges started from the right temporal region; (B) High amplitude rhythmic discharges in the right temporal region (along with the beginning of ictal water drinking 30 seconds after EEG onset).
Figure 2 The coronal T2WI (A) and FLAIR (B) images showing right-sided mesial temporal sclerosis. Notice the increased signal and small hippocampus with loss of normal internal architecture of the right hippocampus and dilated right temporal horn.
Therapeutic intervention, follow-up, and outcome
The patient underwent a right anterior temporal resection. He was seizure-free at the one-year follow-up; however, he remained on AEDs. His follow-up EEG showed residual epileptic activity (Figure 3).
Figure 3 Time line figure of the presented case.
Discussion
The PIWD is an uncommon feature described in patients with lesional and non-lesional epilepsy of the temporal lobe. It is defined as a stereotyped action seen across all age groups during seizures or within 1 to 2 minutes of their onset.3 The described case in this report concerned lesional epilepsy of the temporal lobe as documented in neuroimaging over the right side with automatic PIWD during video-EEG documented seizures, confirming the ictal nature of this manifestation.
To date, 64 cases of epileptic seizures associated with PIWD have been reported.4 The rate of reported cases of PIWD seen in TLE ranged from 7% to 15.3%.2,3,5,6 It was observed in 15.3% of 386 seizures in 65 patients with focal epilepsy reported by Trinka et al3. In a study of 55 adult patients with TLE, PIWD was seen in 8 patients (14.5%).6 Janszky et al5 observed PIWD in 7% of 141 adult patients with TLE. Musilová et al2 reported PIWD in 14.4% of 380 seizures in 97 patients with TLE-associated vegetative signs.
Generally, favorable surgical outcomes have been described for TLE patients with PIWD. A case series published by Trinka et al.3 demonstrated a complete response to surgical treatment in 70% of the studied cohort (Wieser’s class I). Similar favorable results of surgery were seen with a group of patients studied by Szűcs et al.6 (Engel Class 1 or 2) with the outcome maintained for a few years of postoperative follow-up. Our patient was seizure-free at the one-year follow-up after surgery.
Normal drinking behavior is controlled by vascular volume and tissue osmolality. Information from peripheral receptors is processed in the hypothalamus and then conveyed to various brain structures that initiate a search for water and drink.7 Furthermore, the hippocampus and the amygdala are linked to the hypothalamus through several multi-synaptic pathways that are involved in the regulation of water balance and drinking behavior.8 Water-seeking behavior is triggered by the involvement of the hypothalamus, which is affected by abnormal electrical activity generated by the temporal lobe.9
The PIWD is thought to reflect involvement of the non-dominant hemisphere because neural networks involved in fluid balance, thirst, and water-seeking are normally asymmetrical and are likely more active in the non-dominant side.10 The lateralizing value of PIWD remains incompletely determined. Some studies have linked PIWD to significant lateralization to the non-dominant hemisphere in patients with TLE.2,3 Other reports could not demonstrate clear evidence for the lateralization value of PIWD.5,6 This uncertainty could be due to the rapid spread of epileptic discharges from the focal source of the seizures to the contralateral side of the temporal lobe, or it may be due simply to the few reported cases of PIWD.6
In conclusion, PIWD is a rare and important vegetative symptom of TLE that can be a valuable lateralizing sign to the non-dominant hemisphere. We report here a case of PIWD as a manifestation of TLE in the non-dominant hemisphere; however, the association of PIWD with a non-dominant hemisphere has not yet been definitively established in the literature. Given the significance of PIWD in planning surgical resection, a more comprehensive and powerful study with enrollment of more patients is needed. Furthermore, the lateralization could be supported and confirmed by invasive EEG recordings.
Acknowledgements
We would like to thank Dr. Alawi Al-Attas and Dr. Majed Alhameed for their kind support, guidance, and motivation to report this case. Also, I would like to thanks Dr. Eman Bakhsh, neuroradiologist consultant for reviewing the images of the patient, and Scribendi (www.scribendi.com) for English language editing.
Case Reports
Case reports will only be considered for unusual topics that add something new to the literature. All Case Reports should include at least one figure. Written informed consent for publication must accompany any photograph in which the subject can be identified. Figures should be submitted with a 300 dpi resolution when submitting electronically. The abstract should be unstructured, and the introductory section should always include the objective and reason why the author is presenting this particular case. References should be up to date, preferably not exceeding 15.
Disclosure. The authors declare no conflicting interests, support or funding from any drug company. | LEVETIRACETAM, VALPROIC ACID | DrugsGivenReaction | CC BY-NC-SA | 33530048 | 19,138,926 | 2021-01 |
What was the outcome of reaction 'Seizure'? | A Young man with Peri-ictal water drinking.
Neuro-vegetative features have been linked to epilepsy arising from the temporal lobe, which can be seen during ictal events and play an important role in determining the focal side of the lesion. Among the rare known features is peri-ictal water drinking (PIWD). Here, we present the case of a 31-year-old male with refractory temporal epilepsy, having episodes of PIWD. The patient was considered a candidate for resective surgery and was investigated accordingly, including long-term video electroencephalogram (EEG), brain magnetic resonance imaging (MRI), and neuropsychology assessment, which pointed towards a lesioned temporal lobe over the non-dominant hemisphere. The patient had an excellent outcome following right anterior temporal lobectomy. The lateralization significance of PIWD has not yet been established definitively in the literature, partly due to a limited number of published cases. This case highlights the previously observed association between PIWD and the involvement of the non-dominant hemisphere in epilepsy patients.
The initial description of peri-ictal water drinking (PIWD) dates back to the early twentieth century with observations by William G. Lennox and Stanley Cobb.1 However, drinking water is a usual habitual action, so it is difficult for patients or witnesses to consider this behavior as part of ictal manifestation, which made PIWD largely underestimated. Neuro-vegetative features such as mydriasis, transient hypo- or hypertension, and an increase in heart rate are well known and occur quite frequently in temporal lobe seizures. Many other features are described and occur much less frequently, as is the case in PIWD.2 Review of the literature showed only a handful of studies looking into PIWD, and no definite evidence exists to answer all questions about its relevance to temporal lobe epilepsy (TLE); however, a possible lateralizing value has been hypothesized.3 We present a case of right symptomatic TLE secondary to mesial temporal sclerosis (MTS) with PIWD behavior episodes confirmed by ictal video-electroencephalogram (EEG) that was recorded in an epilepsy monitoring unit. We also reviewed the literature to evaluate the localization and lateralization significance of this manifestation in TLE.
Case Report
Patient information and clinical findings
A 31-year-old left-handed male known to have epilepsy since the age of 7 years presented to our epilepsy center at King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia. His seizures were characterized by palpitations and thirst followed by right-hand automatism. He reported partial intact awareness and orientation at first, but later he could not recall what had happened. No other seizure types or history of febrile convulsion were documented. The treatment regimen consisted of valproic acid and levetiracetam (1 g bid for each drug) with no seizure control. Clinical and neurological examinations were unremarkable.
Diagnostic assessment
The patient was admitted to our epilepsy center for preoperative evaluation, including video-EEG monitoring, brain magnetic resonance imaging (MRI), positron emission tomography (PET) scanning, and a neuropsychological assessment. The patient had 6 seizures during hospitalization secondary to the gradual discontinuation of antiepileptic drugs (AEDs). The episodes were characterized by sudden mild headaches, palpitations, and excessive drinking of water followed by left-hand dystonic contraction. During these episodes, he was able to speak and gave meaningful answers to questions; later, he became disoriented. Ictal EEG changes began 30 sec before clinical onset and showed a buildup of rhythmic theta activity over the right anterior and mid-temporal head regions (Figure 1A, B). No EEG changes were noted post-ictally. Brain MRI showed right mesial temporal sclerosis (Figure 2A, B), and a PET scan revealed hypometabolism in the right temporal lobe. Neuropsychological evaluation results were within normal limits.
Figure 1 Electroencephalogram (EEG) (A) Ictal EEG onset with rhythmic discharges started from the right temporal region; (B) High amplitude rhythmic discharges in the right temporal region (along with the beginning of ictal water drinking 30 seconds after EEG onset).
Figure 2 The coronal T2WI (A) and FLAIR (B) images showing right-sided mesial temporal sclerosis. Notice the increased signal and small hippocampus with loss of normal internal architecture of the right hippocampus and dilated right temporal horn.
Therapeutic intervention, follow-up, and outcome
The patient underwent a right anterior temporal resection. He was seizure-free at the one-year follow-up; however, he remained on AEDs. His follow-up EEG showed residual epileptic activity (Figure 3).
Figure 3 Time line figure of the presented case.
Discussion
The PIWD is an uncommon feature described in patients with lesional and non-lesional epilepsy of the temporal lobe. It is defined as a stereotyped action seen across all age groups during seizures or within 1 to 2 minutes of their onset.3 The described case in this report concerned lesional epilepsy of the temporal lobe as documented in neuroimaging over the right side with automatic PIWD during video-EEG documented seizures, confirming the ictal nature of this manifestation.
To date, 64 cases of epileptic seizures associated with PIWD have been reported.4 The rate of reported cases of PIWD seen in TLE ranged from 7% to 15.3%.2,3,5,6 It was observed in 15.3% of 386 seizures in 65 patients with focal epilepsy reported by Trinka et al3. In a study of 55 adult patients with TLE, PIWD was seen in 8 patients (14.5%).6 Janszky et al5 observed PIWD in 7% of 141 adult patients with TLE. Musilová et al2 reported PIWD in 14.4% of 380 seizures in 97 patients with TLE-associated vegetative signs.
Generally, favorable surgical outcomes have been described for TLE patients with PIWD. A case series published by Trinka et al.3 demonstrated a complete response to surgical treatment in 70% of the studied cohort (Wieser’s class I). Similar favorable results of surgery were seen with a group of patients studied by Szűcs et al.6 (Engel Class 1 or 2) with the outcome maintained for a few years of postoperative follow-up. Our patient was seizure-free at the one-year follow-up after surgery.
Normal drinking behavior is controlled by vascular volume and tissue osmolality. Information from peripheral receptors is processed in the hypothalamus and then conveyed to various brain structures that initiate a search for water and drink.7 Furthermore, the hippocampus and the amygdala are linked to the hypothalamus through several multi-synaptic pathways that are involved in the regulation of water balance and drinking behavior.8 Water-seeking behavior is triggered by the involvement of the hypothalamus, which is affected by abnormal electrical activity generated by the temporal lobe.9
The PIWD is thought to reflect involvement of the non-dominant hemisphere because neural networks involved in fluid balance, thirst, and water-seeking are normally asymmetrical and are likely more active in the non-dominant side.10 The lateralizing value of PIWD remains incompletely determined. Some studies have linked PIWD to significant lateralization to the non-dominant hemisphere in patients with TLE.2,3 Other reports could not demonstrate clear evidence for the lateralization value of PIWD.5,6 This uncertainty could be due to the rapid spread of epileptic discharges from the focal source of the seizures to the contralateral side of the temporal lobe, or it may be due simply to the few reported cases of PIWD.6
In conclusion, PIWD is a rare and important vegetative symptom of TLE that can be a valuable lateralizing sign to the non-dominant hemisphere. We report here a case of PIWD as a manifestation of TLE in the non-dominant hemisphere; however, the association of PIWD with a non-dominant hemisphere has not yet been definitively established in the literature. Given the significance of PIWD in planning surgical resection, a more comprehensive and powerful study with enrollment of more patients is needed. Furthermore, the lateralization could be supported and confirmed by invasive EEG recordings.
Acknowledgements
We would like to thank Dr. Alawi Al-Attas and Dr. Majed Alhameed for their kind support, guidance, and motivation to report this case. Also, I would like to thanks Dr. Eman Bakhsh, neuroradiologist consultant for reviewing the images of the patient, and Scribendi (www.scribendi.com) for English language editing.
Case Reports
Case reports will only be considered for unusual topics that add something new to the literature. All Case Reports should include at least one figure. Written informed consent for publication must accompany any photograph in which the subject can be identified. Figures should be submitted with a 300 dpi resolution when submitting electronically. The abstract should be unstructured, and the introductory section should always include the objective and reason why the author is presenting this particular case. References should be up to date, preferably not exceeding 15.
Disclosure. The authors declare no conflicting interests, support or funding from any drug company. | Recovering | ReactionOutcome | CC BY-NC-SA | 33530048 | 19,138,926 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypercalcaemia'. | Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy in Two Siblings: Same Mutations but Very Different Phenotypes.
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), caused by mutations in the AIRE gene, is mainly characterized by the triad of hypoparathyroidism, primary adrenocortical insufficiency and chronic mucocutaneous candidiasis, but can include many other manifestations, with no currently clear genotype-phenotype correlation. We present the clinical features of two siblings, a male and a female, with the same mutations in the AIRE gene associated with two very different phenotypes. Interestingly, the brother recently experienced COVID-19 infection with pneumonia, complicated by hypertension, hypokalemia and hypercalcemia. Although APECED is a monogenic disease, its expressiveness can be extremely different. In addition to the genetic basis, epigenetic and environmental factors might influence the phenotypic expression, although their exact role remains to be elucidated.
1. Background
Autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) is a rare monogenic disease, caused by mutations in the autoimmune regulator (AIRE) gene on chromosome 21 (21q22.3).
APECED is mainly known for the triad of hypoparathyroidism, primary adrenocortical insufficiency and chronic mucocutaneous candidiasis. The definite diagnosis of APECED requires one of the following three criteria: the presence of at least two out the three major clinical features or only one of the major components if a sibling has definite APECED or a disease-causing mutation in both alleles of the AIRE gene. [1]. However, many other manifestations have been described, including other endocrinopathy (hypergonadotropic hypogonadism, type 1 diabetes, autoimmune thyroid diseases, pituitary defects), gastrointestinal manifestations (autoimmune gastritis, autoimmune hepatitis, intestinal malabsorption, celiac disease), ectodermal abnormalities (keratitis, enamel dysplasia, vitiligo, alopecia, nail dystrophy) and others [1,2].
The major mutation found in Finns, i.e., the c.769C>T variant, and the 13 bp deletion in exon 8 (c.967–979del13), are the most common ones worldwide [1]. Currently, more than 100 pathogenic mutations have been described and recently new genetic variations have been added [3,4,5]. The AIRE gene plays an essential role in central tolerance. Mutations in the AIRE gene prevent the elimination of self-reactive T cells at the central level and induce a T regulatory cell (Treg) defect at peripheral levels, leading to the development of multiple autoimmune diseases at a young age [6,7].
Although APECED is the paradigm of a monogenic autoimmune disorder, it is characterized by a wide variability of the clinical expression. In the majority of studies, no genotype–phenotype correlation has been found, while several observations suggest that a partial genotype–phenotype correlation may exist for specific traits [6]. Therefore, clinical manifestations of APECED patients can vary, suggesting that other factors, such as environment, lifestyle, habits or other genetic mechanisms, might modulate the disease presentation [8]. In particular, disease-modifying genetic variants in APECED patients were recently supported by different findings in mice [9,10]. Recently, dominant-negative AIRE mutations involving the SAND or PHD-1 domains have been identified in patients presenting with much less severe APECED-like disease, indicating possible modulation of the phenotypic expression of common organ-specific autoimmune diseases [11].
Furthermore, the recent finding of important enhancer elements activated by nuclear factor κB (NF-κB) signaling that is necessary for AIRE gene expression, as well as the identification of further additional regulators, suggest that AIRE gene expression and its function are tightly regulated [11].
APECED syndrome could be potentially underdiagnosed or misdiagnosed due to its rarity, but also because of the variability in its presentation.
We report the case of two siblings with the same mutations in the AIRE gene but with very different phenotypes.
2. Case Reports
The girl (patient 1) in the first year of life developed oral candidiasis, onychodystrophy, transient transaminitis and hepatomegaly (with antinuclear antibodies -ANA- and actin smooth muscle antibodies -ASMA- positivity) and recurrent episodes of fever of unknown origin. At 1.6 years old, she presented a hypocalcemic tetanic crisis. The hematological exams were consistent with hypoparathyroidism, i.e., low blood calcium (1.42 mmol/L, normal range 2.3–2.8), high phosphorus (2.7 mmol/L, normal range 1.5–2) and low parathyroid hormone (PTH) (7.9 pg/mL, normal range 15–57). APECED was suspected and then confirmed by Sanger sequencing, which detected two compound heterozygous mutations in the AIRE gene, in exon 2 and exon 8, namely, NM_000383.4(AIRE):c.260T>C (p.Leu87Pro) and NM_000383.4(AIRE):c.967_979del (p.Leu323fs), respectively. Parental analysis showed that one mutation was inherited from the father and the other from the mother; by considering the absence of any signs or symptoms, no further laboratory investigations were performed.
Thereafter, she developed vitiligo, alopecia, enamel hypoplasia and autoimmune insulitis with positive glutamic acid decarboxylase (GADA) antibodies but no glycemic alteration, abdominal pain and bilateral swelling of the feet without radiographic abnormalities.
At 3.4 years old, for recurrent episodes of tetanic crisis and difficulty to maintain adequate serum calcium levels, notwithstanding the chronic therapy with calcium and calcitriol, she was enrolled in an experimental trial with recombinant human parathyroid hormone (rhPTH) (1–34). At 10 years of age, her height was 131.5 cm (10–25th percentile) with target height of 171 cm (90–97th percentile) and reduced growth velocity (3.3 cm/year, <3rd percentile) according to Tanner growth charts [12]; however, the dynamic growth hormone (GH) testing with Arginine did not show GH deficiency (GH values after arginine test of 11.4 ng/mL). At the age of 12, her abdominal pain worsened with chronic diarrhea and fat-soluble vitamin deficiencies were disclosed (vitamin A 0.21 mcg/mL, 25OH-vitamin D 14.6 ng/mL). The esophagogastroduodenoscopy (EGDS) and colonoscopy revealed macroscopical normal mucosa except for nodular duodenum; histological evaluation detected mild inflammatory infiltrate and voluminous lymphatic follicles in the duodenal bulb and in the rectum; immunohistochemistry of small and large bowel samples with chromogranin A staining showed the complete absence of enteroendocrine cells (EECs) in the stomach, duodenum and ileum, severe decrement of EECs in the ascending colon and normal expression in the rectum. From 13.6 years old, an estradiol-depot patch was placed for hypogonadism (estradiol < 5 pg/mL, anti-müllerian hormone 0.5 ng/mL, basal LH and FSH 0.4 U/L and 3.3 U/L, respectively, LH and FSH values after LHRH test 9.5 U/L and 18.8 U/L, respectively) Currently, patient 1 is 14 years old with height 146.7 cm (<3° percentile), but with catch-up growth (high velocity of 6.5 cm/year, > 97th percentile). Recently, she had SARS-CoV-2 asymptomatic infection.
The boy (patient 2) was evaluated for the first time at 6.4 years old, after his sister’s diagnosis. At the time of diagnosis, he had hypoparathyroidism with asymptomatic mild hypocalcemia, i.e., low blood calcium (1.07 mmol/L, normal range 2.3–2.8), high phosphorus (5.67 mmol/L, normal range 1.5–2) and low PTH (3 pg/mL, normal range 15–57), alopecia and mild oral candidiasis. The same compound heterozygous mutations in the AIRE gene identified in his sister were then detected. At 8.3 years old, for repeated episodes of hypocalcemic tetanic crisis despite therapy with calcium and calcitriol, rhPTH (1–34) treatment was started. Dermatitis rosaceiforme and severe acne were also present and a GADA-positive autoimmune insulitis, without glucose impairment, was then discovered. At 13.9 years old, hyponatremia linked to autoimmune adrenal insufficiency was detected during routine exams and therapy with hydrocortisone and fludrocortisone was started. Over time, he has shown regular growth and pubertal development: at the last evaluation at 19.8 years old, his height was 176.9 cm (50–75th percentile). At 19 years old, he developed COVID-19 pneumonia, treated with oxygen therapy through a nasal cannula, methylprednisolone (starting at 60 mg on the first day then down-titrated in the following days), antibiotics (azthromycin and ceftriaxone) and remdesivir. During the hospitalization, despite the discontinuation of fludrocortisone and the steroid tapering, he showed persistent hypertension (up to 200/120 mmHg) and hypokalemia. Antihypertensive therapy was started (with ramipril 10 mg/die and then, after discharge, amlodipine 10 mg/die and nebivolol 5 mg/die) with mild improvement of pressure values. Potassium chloride per os was added with subsequent normalization of serum potassium levels. He also developed hypercalcemia and hypercalciuria, requiring adjustments of treatment with calcium, calcitriol and rhPTH (1–34).
The main features of both patients are summarized in Table 1.
3. Discussion
The AIRE gene, pathogenetic for APECED, is expressed in thymic medullary epithelial cells where it induces the expression of a wide repertoire of peripheral tissue antigens that play a crucial role in central tolerance for the correct development of self-tolerance. Thus, the absence of AIRE expression results in an impaired clonal deletion of self-reactive thymocytes. Furthermore, there is now strong evidence for AIRE expression in peripheral tissues even though these levels are significantly lower than in thymic stromal cells [6].
The patients described here have two compound heterozygous mutations in the AIRE gene and one of these variants (i.e., 967–979 del13) is one of the most common in the literature, with variable prevalence in different populations of 71%, 53% and 48% in British, North American and Norwegian series, respectively [13,14,15].
The second mutation, NM_000383.4(AIRE):c.260T>C (p.Leu87Pro), has previously been described in a pediatric compound heterozygous patient with maternal inheritance, and paternal inheritance of the p.Leu323fs variant. The subject had a clinical diagnosis of APECED, with anti-omega antibodies and immunologic deregulation since birth. For the associated phenotype and the location within a region of the protein in which other single nucleotide variants produce lack of function alleles inhibiting proper dimerization of the AIRE protein, the mutation was classified as likely pathogenetic [16].
APECED is a recessive monogenic condition although, in a few cases, only one mutant allele of the AIRE gene has been reported in typical APECED patients, suggesting that the second mutation might be located in the regulatory regions of the gene [17].
As for the clinical features, chronic mucocutaneous candidiasis is usually the first of the main components to appear, even if APECED includes other ectodermal anomalies, as reported in the two cases presented, with different characteristics. Alopecia, which is usually localized (alopecia areata), as was seen in patient 1, can spread to the whole scalp (total alopecia), as it did in patient 2.
Hypoparathyroidism is the second most common major component of APECED and usually the first endocrine manifestation [1]. It should present with severe symptoms, as in patient 1, who had tetanic crisis. Treatment with oral calcium and vitamin D analogs represents the conventional treatments in children but they have to be modified frequently, based on body weight and intestinal absorption, and because they can lead to nephrocalcinosis due to hypercalciuria [18]. RhPTH (1–34) is an “off-label” treatment in pediatric ages, but in some clinical studies, it has allowed the maintenance of adequate levels of calcium and phosphate in the blood, to normalize urinary calcium excretion and to reduce tetanic episodes [18], as in our patients who needed high doses of oral calcium before RhPTH (1–34) treatment, and in which, particularly in patient 1, that treatment also led to a reduction of hypercalciuria. Its use over time in patient 1 was further justified by the important malabsorptive syndrome, which not only prevented the maintenance of plasma calcium values in the normal range, but also reduced growth.
The growth impairment reported in patient 1 can be determined by many causes, such as pubertal delay, malabsorption and chronic disease. It is noteworthy that hypogonadism was present only in patient 1, the female, thus confirming the different gender prevalence of this manifestation in APECED, with higher frequency in females [19]. Premature ovarian insufficiency develops in most patients with APECED, often before or shortly after menarche. In a recent study, it developed in 70% of patients at a median age of 16.0 years and in 71% of them before reaching adult height; therefore, timely initiation of hormone replacement therapy is important to ensure optimal pubertal development and growth [20].
In terms of gastrointestinal manifestations, patient 1 showed diarrhea, malabsorption and abdominal pain. Chronic diarrhea in APECED can be due to several causes, such as pancreatic exocrine insufficiency, autoimmune enteropathy (AE), lactose intolerance and celiac disease, as well as hypocalcemia [21]. Histological evaluation of the small bowel in typical AE reveals severe enteropathy with atrophy of the villi of the small intestine, crypt hyperplasia and infiltration of mononuclear cells in the lamina propria, while patients with APECED usually do not exhibit those features of AE, such as in our case, and the main or only finding being the loss of EECs and chromogranin A is considered a surrogate marker for these cells [22].
Primary adrenocortical insufficiency, present only in patient 2, most commonly appears after the other two main features, typically between 5 and 15 years of age [1], with symptoms such as fatigue, weight loss, hypotension, salt craving and increased skin pigmentation. Patient 2 showed incidental laboratory findings that suggested adrenal dysfunction, which was then confirmed by 21-hydroxylase antibody positivity with no sign nor symptoms. Therefore, a strict and regular follow-up allowed us to reach a precocious diagnosis, avoiding an adrenal crisis.
Autoimmune hepatitis affects about a fifth of patients and, fortunately, in most cases, it goes away without therapy after a few months [1]. Patient 1 presented with fever and liver enzyme abnormalities, hepatomegaly and ANA and ASMA positivity, but a liver biopsy was not performed for the resolution of signs and symptoms, leading us to consider autoimmune hepatitis as the most probable diagnosis, even without histological confirmation.
Although clinical type 1 diabetes occurs rarely in APECED, elevated titers of GADA are frequently found, as in the two patients presented, and could represent an epiphenomenon of autoimmune insulitis that usually does not lead to clinical manifestation of the disease [23], which is less frequent than in patients with other autoimmune diseases or in healthy children [24].
Patient 2 also had COVID-19 infection with pneumonia, complicated by hypertension, hypokalemia and hypercalcemia. Based on current data, there is no evidence that patients with adrenal insufficiency have an increased risk of contracting COVID-19 but they have a slightly increased overall risk of having infections and an overall increased mortality, possibly explained by an insufficient compensatory increase in the hydrocortisone dose at the time of the onset of an episode of infection. Thus, patients with adrenal insufficiency may be at higher risk of medical complications and eventually at increased mortality risk in the case of COVID-19 infection [25].
There are no significant data describing the effect of COVID-19 on APECED patients, which are certainly not typical examples of adrenal insufficiency, and our case showed different metabolic complications requiring different treatment adjustments, also concerning his chronic therapy for hypoparathyroidism.
The clinical variability of APECED and the absence of a clear genotype–phenotype correlation, also evidenced in our report of two cases with the same AIRE genotype but very different phenotypes, could indicate that, in addition to the failure of AIRE function, additional mechanisms may be involved, in a complex interaction between several genetic, epigenetic, immunological and/or environmental factors [26]. Some studies have investigated the effects of additional genetic loci, particularly the human leukocyte antigen (HLA) complex, limited to a few manifestations, but only a weak association has been observed between the HLA type and autoantibody specificities observed in APECED patients [6]. Infectious agents could act as a trigger for a self-reaction through various mechanisms in genetically susceptible subjects, but their role in the clinical expression of APECED has not been demonstrated. Since the AIRE gene also appears to be involved in the control of peripheral mechanisms for the maintenance of self-tolerance, a possible role of reduced peripheral tolerance has been hypothesized in the pathogenesis and clinical expression of APECED [26]. A decrease in CD4+CD25+ T regulatory cells (Tregs) has been reported in both adults and children with APECED, but the reduction in circulating Tregs could also be secondary to chronic fungal infection and their pathogenetic role is not defined [6]. Certainly, many factors may play a role in modulating the disease expression in our patients as well, but the current data did not find a definite reason for this variability.
Considering the multi-organ expressiveness of APECED disease, it is of utmost importance that pediatric endocrinologists or endocrinologists, who generally coordinate the multidisciplinary team of providers, have a deep awareness of the multifaceted manifestations and natural history of the disorder to set up a multidisciplinary follow-up, including immunologists, gastroenterologists and eventually other specialists, to promptly recognize and take of care of the development of new disease components or laboratory abnormalities which may appear throughout life [1].
4. Conclusions
APECED syndrome is a multisystemic disease, with different combinations of affected organs and autoantibody specificities, that certainly requires a multidisciplinary approach. The genotype does not predict the phenotype, even in siblings with the same mutations, and genetic, epigenetic and environmental factors may play a role. Therefore, further studies might identify new disease-modifying mechanisms or genes influencing the variable expressivity of APECED.
Acknowledgments
No grants have supported this work. Article processing charges (APC) were covered by Postgraduate School of Pediatrics, Department of Public Health and Pediatric Sciences, University of Turin.
Author Contributions
L.D.S., A.C. and R.B. conceived this article. A.C. and R.B. wrote the paper and carried out the reference search. P.M., G.T., M.P., P.L.C., D.M., F.L. and L.D.S. have followed the patients over the time and reviewed the manuscript. Each author approved the submitted version and agrees to be personally accountable for their own contribution and for ensuring that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved and documented in the literature. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
Ethical review and approval were waived for this study considering that patients were included in Piedmont Regional Network for Rare Disease which allows clinicians to use off-label drugs approved by the Italian National Health Service after obtaining informed consent, as for previous associated studies of teriparatide in APECED patients.
Informed Consent Statement
Informed consent has been obtained from the patient(s) to publish this paper.
Data Availability Statement
No primary datasets were produced in this study. Data sharing is not applicable to this article.
Conflicts of Interest
The authors declare no conflict of interest.
genes-12-00169-t001_Table 1 Table 1 Manifestations of two siblings affected by autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) disease: variability and similarities.
Manifestation Patient 1, Female, 14 Years Old Patient 2, Male, 19 Years Old
Hypoparathyroidism + +
Primary adrenocortical insufficiency − +
Chronic mucocutaneous candidiasis + +
Vitiligo + −
Alopecia + +
Enamel hypoplasia + −
Onicodystrophy + −
Rosaceiforme dermatisis and acne − +
Autoimmune hepatitis +/− −
Autoimmune insulitis + +
Diarrhea/intestinal malabsorption + −
Growth impairment + −
Pubertal delay + −
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | AMLODIPINE BESYLATE, AZITHROMYCIN, CALCITRIOL, CEFTRIAXONE, FLUDROCORTISONE, HYDROCORTISONE, METHYLPREDNISOLONE, NEBIVOLOL, POTASSIUM CHLORIDE, RAMIPRIL, REMDESIVIR | DrugsGivenReaction | CC BY | 33530632 | 20,098,464 | 2021-01-26 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypercalciuria'. | Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy in Two Siblings: Same Mutations but Very Different Phenotypes.
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), caused by mutations in the AIRE gene, is mainly characterized by the triad of hypoparathyroidism, primary adrenocortical insufficiency and chronic mucocutaneous candidiasis, but can include many other manifestations, with no currently clear genotype-phenotype correlation. We present the clinical features of two siblings, a male and a female, with the same mutations in the AIRE gene associated with two very different phenotypes. Interestingly, the brother recently experienced COVID-19 infection with pneumonia, complicated by hypertension, hypokalemia and hypercalcemia. Although APECED is a monogenic disease, its expressiveness can be extremely different. In addition to the genetic basis, epigenetic and environmental factors might influence the phenotypic expression, although their exact role remains to be elucidated.
1. Background
Autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) is a rare monogenic disease, caused by mutations in the autoimmune regulator (AIRE) gene on chromosome 21 (21q22.3).
APECED is mainly known for the triad of hypoparathyroidism, primary adrenocortical insufficiency and chronic mucocutaneous candidiasis. The definite diagnosis of APECED requires one of the following three criteria: the presence of at least two out the three major clinical features or only one of the major components if a sibling has definite APECED or a disease-causing mutation in both alleles of the AIRE gene. [1]. However, many other manifestations have been described, including other endocrinopathy (hypergonadotropic hypogonadism, type 1 diabetes, autoimmune thyroid diseases, pituitary defects), gastrointestinal manifestations (autoimmune gastritis, autoimmune hepatitis, intestinal malabsorption, celiac disease), ectodermal abnormalities (keratitis, enamel dysplasia, vitiligo, alopecia, nail dystrophy) and others [1,2].
The major mutation found in Finns, i.e., the c.769C>T variant, and the 13 bp deletion in exon 8 (c.967–979del13), are the most common ones worldwide [1]. Currently, more than 100 pathogenic mutations have been described and recently new genetic variations have been added [3,4,5]. The AIRE gene plays an essential role in central tolerance. Mutations in the AIRE gene prevent the elimination of self-reactive T cells at the central level and induce a T regulatory cell (Treg) defect at peripheral levels, leading to the development of multiple autoimmune diseases at a young age [6,7].
Although APECED is the paradigm of a monogenic autoimmune disorder, it is characterized by a wide variability of the clinical expression. In the majority of studies, no genotype–phenotype correlation has been found, while several observations suggest that a partial genotype–phenotype correlation may exist for specific traits [6]. Therefore, clinical manifestations of APECED patients can vary, suggesting that other factors, such as environment, lifestyle, habits or other genetic mechanisms, might modulate the disease presentation [8]. In particular, disease-modifying genetic variants in APECED patients were recently supported by different findings in mice [9,10]. Recently, dominant-negative AIRE mutations involving the SAND or PHD-1 domains have been identified in patients presenting with much less severe APECED-like disease, indicating possible modulation of the phenotypic expression of common organ-specific autoimmune diseases [11].
Furthermore, the recent finding of important enhancer elements activated by nuclear factor κB (NF-κB) signaling that is necessary for AIRE gene expression, as well as the identification of further additional regulators, suggest that AIRE gene expression and its function are tightly regulated [11].
APECED syndrome could be potentially underdiagnosed or misdiagnosed due to its rarity, but also because of the variability in its presentation.
We report the case of two siblings with the same mutations in the AIRE gene but with very different phenotypes.
2. Case Reports
The girl (patient 1) in the first year of life developed oral candidiasis, onychodystrophy, transient transaminitis and hepatomegaly (with antinuclear antibodies -ANA- and actin smooth muscle antibodies -ASMA- positivity) and recurrent episodes of fever of unknown origin. At 1.6 years old, she presented a hypocalcemic tetanic crisis. The hematological exams were consistent with hypoparathyroidism, i.e., low blood calcium (1.42 mmol/L, normal range 2.3–2.8), high phosphorus (2.7 mmol/L, normal range 1.5–2) and low parathyroid hormone (PTH) (7.9 pg/mL, normal range 15–57). APECED was suspected and then confirmed by Sanger sequencing, which detected two compound heterozygous mutations in the AIRE gene, in exon 2 and exon 8, namely, NM_000383.4(AIRE):c.260T>C (p.Leu87Pro) and NM_000383.4(AIRE):c.967_979del (p.Leu323fs), respectively. Parental analysis showed that one mutation was inherited from the father and the other from the mother; by considering the absence of any signs or symptoms, no further laboratory investigations were performed.
Thereafter, she developed vitiligo, alopecia, enamel hypoplasia and autoimmune insulitis with positive glutamic acid decarboxylase (GADA) antibodies but no glycemic alteration, abdominal pain and bilateral swelling of the feet without radiographic abnormalities.
At 3.4 years old, for recurrent episodes of tetanic crisis and difficulty to maintain adequate serum calcium levels, notwithstanding the chronic therapy with calcium and calcitriol, she was enrolled in an experimental trial with recombinant human parathyroid hormone (rhPTH) (1–34). At 10 years of age, her height was 131.5 cm (10–25th percentile) with target height of 171 cm (90–97th percentile) and reduced growth velocity (3.3 cm/year, <3rd percentile) according to Tanner growth charts [12]; however, the dynamic growth hormone (GH) testing with Arginine did not show GH deficiency (GH values after arginine test of 11.4 ng/mL). At the age of 12, her abdominal pain worsened with chronic diarrhea and fat-soluble vitamin deficiencies were disclosed (vitamin A 0.21 mcg/mL, 25OH-vitamin D 14.6 ng/mL). The esophagogastroduodenoscopy (EGDS) and colonoscopy revealed macroscopical normal mucosa except for nodular duodenum; histological evaluation detected mild inflammatory infiltrate and voluminous lymphatic follicles in the duodenal bulb and in the rectum; immunohistochemistry of small and large bowel samples with chromogranin A staining showed the complete absence of enteroendocrine cells (EECs) in the stomach, duodenum and ileum, severe decrement of EECs in the ascending colon and normal expression in the rectum. From 13.6 years old, an estradiol-depot patch was placed for hypogonadism (estradiol < 5 pg/mL, anti-müllerian hormone 0.5 ng/mL, basal LH and FSH 0.4 U/L and 3.3 U/L, respectively, LH and FSH values after LHRH test 9.5 U/L and 18.8 U/L, respectively) Currently, patient 1 is 14 years old with height 146.7 cm (<3° percentile), but with catch-up growth (high velocity of 6.5 cm/year, > 97th percentile). Recently, she had SARS-CoV-2 asymptomatic infection.
The boy (patient 2) was evaluated for the first time at 6.4 years old, after his sister’s diagnosis. At the time of diagnosis, he had hypoparathyroidism with asymptomatic mild hypocalcemia, i.e., low blood calcium (1.07 mmol/L, normal range 2.3–2.8), high phosphorus (5.67 mmol/L, normal range 1.5–2) and low PTH (3 pg/mL, normal range 15–57), alopecia and mild oral candidiasis. The same compound heterozygous mutations in the AIRE gene identified in his sister were then detected. At 8.3 years old, for repeated episodes of hypocalcemic tetanic crisis despite therapy with calcium and calcitriol, rhPTH (1–34) treatment was started. Dermatitis rosaceiforme and severe acne were also present and a GADA-positive autoimmune insulitis, without glucose impairment, was then discovered. At 13.9 years old, hyponatremia linked to autoimmune adrenal insufficiency was detected during routine exams and therapy with hydrocortisone and fludrocortisone was started. Over time, he has shown regular growth and pubertal development: at the last evaluation at 19.8 years old, his height was 176.9 cm (50–75th percentile). At 19 years old, he developed COVID-19 pneumonia, treated with oxygen therapy through a nasal cannula, methylprednisolone (starting at 60 mg on the first day then down-titrated in the following days), antibiotics (azthromycin and ceftriaxone) and remdesivir. During the hospitalization, despite the discontinuation of fludrocortisone and the steroid tapering, he showed persistent hypertension (up to 200/120 mmHg) and hypokalemia. Antihypertensive therapy was started (with ramipril 10 mg/die and then, after discharge, amlodipine 10 mg/die and nebivolol 5 mg/die) with mild improvement of pressure values. Potassium chloride per os was added with subsequent normalization of serum potassium levels. He also developed hypercalcemia and hypercalciuria, requiring adjustments of treatment with calcium, calcitriol and rhPTH (1–34).
The main features of both patients are summarized in Table 1.
3. Discussion
The AIRE gene, pathogenetic for APECED, is expressed in thymic medullary epithelial cells where it induces the expression of a wide repertoire of peripheral tissue antigens that play a crucial role in central tolerance for the correct development of self-tolerance. Thus, the absence of AIRE expression results in an impaired clonal deletion of self-reactive thymocytes. Furthermore, there is now strong evidence for AIRE expression in peripheral tissues even though these levels are significantly lower than in thymic stromal cells [6].
The patients described here have two compound heterozygous mutations in the AIRE gene and one of these variants (i.e., 967–979 del13) is one of the most common in the literature, with variable prevalence in different populations of 71%, 53% and 48% in British, North American and Norwegian series, respectively [13,14,15].
The second mutation, NM_000383.4(AIRE):c.260T>C (p.Leu87Pro), has previously been described in a pediatric compound heterozygous patient with maternal inheritance, and paternal inheritance of the p.Leu323fs variant. The subject had a clinical diagnosis of APECED, with anti-omega antibodies and immunologic deregulation since birth. For the associated phenotype and the location within a region of the protein in which other single nucleotide variants produce lack of function alleles inhibiting proper dimerization of the AIRE protein, the mutation was classified as likely pathogenetic [16].
APECED is a recessive monogenic condition although, in a few cases, only one mutant allele of the AIRE gene has been reported in typical APECED patients, suggesting that the second mutation might be located in the regulatory regions of the gene [17].
As for the clinical features, chronic mucocutaneous candidiasis is usually the first of the main components to appear, even if APECED includes other ectodermal anomalies, as reported in the two cases presented, with different characteristics. Alopecia, which is usually localized (alopecia areata), as was seen in patient 1, can spread to the whole scalp (total alopecia), as it did in patient 2.
Hypoparathyroidism is the second most common major component of APECED and usually the first endocrine manifestation [1]. It should present with severe symptoms, as in patient 1, who had tetanic crisis. Treatment with oral calcium and vitamin D analogs represents the conventional treatments in children but they have to be modified frequently, based on body weight and intestinal absorption, and because they can lead to nephrocalcinosis due to hypercalciuria [18]. RhPTH (1–34) is an “off-label” treatment in pediatric ages, but in some clinical studies, it has allowed the maintenance of adequate levels of calcium and phosphate in the blood, to normalize urinary calcium excretion and to reduce tetanic episodes [18], as in our patients who needed high doses of oral calcium before RhPTH (1–34) treatment, and in which, particularly in patient 1, that treatment also led to a reduction of hypercalciuria. Its use over time in patient 1 was further justified by the important malabsorptive syndrome, which not only prevented the maintenance of plasma calcium values in the normal range, but also reduced growth.
The growth impairment reported in patient 1 can be determined by many causes, such as pubertal delay, malabsorption and chronic disease. It is noteworthy that hypogonadism was present only in patient 1, the female, thus confirming the different gender prevalence of this manifestation in APECED, with higher frequency in females [19]. Premature ovarian insufficiency develops in most patients with APECED, often before or shortly after menarche. In a recent study, it developed in 70% of patients at a median age of 16.0 years and in 71% of them before reaching adult height; therefore, timely initiation of hormone replacement therapy is important to ensure optimal pubertal development and growth [20].
In terms of gastrointestinal manifestations, patient 1 showed diarrhea, malabsorption and abdominal pain. Chronic diarrhea in APECED can be due to several causes, such as pancreatic exocrine insufficiency, autoimmune enteropathy (AE), lactose intolerance and celiac disease, as well as hypocalcemia [21]. Histological evaluation of the small bowel in typical AE reveals severe enteropathy with atrophy of the villi of the small intestine, crypt hyperplasia and infiltration of mononuclear cells in the lamina propria, while patients with APECED usually do not exhibit those features of AE, such as in our case, and the main or only finding being the loss of EECs and chromogranin A is considered a surrogate marker for these cells [22].
Primary adrenocortical insufficiency, present only in patient 2, most commonly appears after the other two main features, typically between 5 and 15 years of age [1], with symptoms such as fatigue, weight loss, hypotension, salt craving and increased skin pigmentation. Patient 2 showed incidental laboratory findings that suggested adrenal dysfunction, which was then confirmed by 21-hydroxylase antibody positivity with no sign nor symptoms. Therefore, a strict and regular follow-up allowed us to reach a precocious diagnosis, avoiding an adrenal crisis.
Autoimmune hepatitis affects about a fifth of patients and, fortunately, in most cases, it goes away without therapy after a few months [1]. Patient 1 presented with fever and liver enzyme abnormalities, hepatomegaly and ANA and ASMA positivity, but a liver biopsy was not performed for the resolution of signs and symptoms, leading us to consider autoimmune hepatitis as the most probable diagnosis, even without histological confirmation.
Although clinical type 1 diabetes occurs rarely in APECED, elevated titers of GADA are frequently found, as in the two patients presented, and could represent an epiphenomenon of autoimmune insulitis that usually does not lead to clinical manifestation of the disease [23], which is less frequent than in patients with other autoimmune diseases or in healthy children [24].
Patient 2 also had COVID-19 infection with pneumonia, complicated by hypertension, hypokalemia and hypercalcemia. Based on current data, there is no evidence that patients with adrenal insufficiency have an increased risk of contracting COVID-19 but they have a slightly increased overall risk of having infections and an overall increased mortality, possibly explained by an insufficient compensatory increase in the hydrocortisone dose at the time of the onset of an episode of infection. Thus, patients with adrenal insufficiency may be at higher risk of medical complications and eventually at increased mortality risk in the case of COVID-19 infection [25].
There are no significant data describing the effect of COVID-19 on APECED patients, which are certainly not typical examples of adrenal insufficiency, and our case showed different metabolic complications requiring different treatment adjustments, also concerning his chronic therapy for hypoparathyroidism.
The clinical variability of APECED and the absence of a clear genotype–phenotype correlation, also evidenced in our report of two cases with the same AIRE genotype but very different phenotypes, could indicate that, in addition to the failure of AIRE function, additional mechanisms may be involved, in a complex interaction between several genetic, epigenetic, immunological and/or environmental factors [26]. Some studies have investigated the effects of additional genetic loci, particularly the human leukocyte antigen (HLA) complex, limited to a few manifestations, but only a weak association has been observed between the HLA type and autoantibody specificities observed in APECED patients [6]. Infectious agents could act as a trigger for a self-reaction through various mechanisms in genetically susceptible subjects, but their role in the clinical expression of APECED has not been demonstrated. Since the AIRE gene also appears to be involved in the control of peripheral mechanisms for the maintenance of self-tolerance, a possible role of reduced peripheral tolerance has been hypothesized in the pathogenesis and clinical expression of APECED [26]. A decrease in CD4+CD25+ T regulatory cells (Tregs) has been reported in both adults and children with APECED, but the reduction in circulating Tregs could also be secondary to chronic fungal infection and their pathogenetic role is not defined [6]. Certainly, many factors may play a role in modulating the disease expression in our patients as well, but the current data did not find a definite reason for this variability.
Considering the multi-organ expressiveness of APECED disease, it is of utmost importance that pediatric endocrinologists or endocrinologists, who generally coordinate the multidisciplinary team of providers, have a deep awareness of the multifaceted manifestations and natural history of the disorder to set up a multidisciplinary follow-up, including immunologists, gastroenterologists and eventually other specialists, to promptly recognize and take of care of the development of new disease components or laboratory abnormalities which may appear throughout life [1].
4. Conclusions
APECED syndrome is a multisystemic disease, with different combinations of affected organs and autoantibody specificities, that certainly requires a multidisciplinary approach. The genotype does not predict the phenotype, even in siblings with the same mutations, and genetic, epigenetic and environmental factors may play a role. Therefore, further studies might identify new disease-modifying mechanisms or genes influencing the variable expressivity of APECED.
Acknowledgments
No grants have supported this work. Article processing charges (APC) were covered by Postgraduate School of Pediatrics, Department of Public Health and Pediatric Sciences, University of Turin.
Author Contributions
L.D.S., A.C. and R.B. conceived this article. A.C. and R.B. wrote the paper and carried out the reference search. P.M., G.T., M.P., P.L.C., D.M., F.L. and L.D.S. have followed the patients over the time and reviewed the manuscript. Each author approved the submitted version and agrees to be personally accountable for their own contribution and for ensuring that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved and documented in the literature. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
Ethical review and approval were waived for this study considering that patients were included in Piedmont Regional Network for Rare Disease which allows clinicians to use off-label drugs approved by the Italian National Health Service after obtaining informed consent, as for previous associated studies of teriparatide in APECED patients.
Informed Consent Statement
Informed consent has been obtained from the patient(s) to publish this paper.
Data Availability Statement
No primary datasets were produced in this study. Data sharing is not applicable to this article.
Conflicts of Interest
The authors declare no conflict of interest.
genes-12-00169-t001_Table 1 Table 1 Manifestations of two siblings affected by autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) disease: variability and similarities.
Manifestation Patient 1, Female, 14 Years Old Patient 2, Male, 19 Years Old
Hypoparathyroidism + +
Primary adrenocortical insufficiency − +
Chronic mucocutaneous candidiasis + +
Vitiligo + −
Alopecia + +
Enamel hypoplasia + −
Onicodystrophy + −
Rosaceiforme dermatisis and acne − +
Autoimmune hepatitis +/− −
Autoimmune insulitis + +
Diarrhea/intestinal malabsorption + −
Growth impairment + −
Pubertal delay + −
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | AMLODIPINE BESYLATE, AZITHROMYCIN, CALCITRIOL, CEFTRIAXONE, FLUDROCORTISONE, HYDROCORTISONE, METHYLPREDNISOLONE, NEBIVOLOL, POTASSIUM CHLORIDE, RAMIPRIL, REMDESIVIR | DrugsGivenReaction | CC BY | 33530632 | 20,098,464 | 2021-01-26 |
What was the dosage of drug 'FLUDROCORTISONE'? | Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy in Two Siblings: Same Mutations but Very Different Phenotypes.
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), caused by mutations in the AIRE gene, is mainly characterized by the triad of hypoparathyroidism, primary adrenocortical insufficiency and chronic mucocutaneous candidiasis, but can include many other manifestations, with no currently clear genotype-phenotype correlation. We present the clinical features of two siblings, a male and a female, with the same mutations in the AIRE gene associated with two very different phenotypes. Interestingly, the brother recently experienced COVID-19 infection with pneumonia, complicated by hypertension, hypokalemia and hypercalcemia. Although APECED is a monogenic disease, its expressiveness can be extremely different. In addition to the genetic basis, epigenetic and environmental factors might influence the phenotypic expression, although their exact role remains to be elucidated.
1. Background
Autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) is a rare monogenic disease, caused by mutations in the autoimmune regulator (AIRE) gene on chromosome 21 (21q22.3).
APECED is mainly known for the triad of hypoparathyroidism, primary adrenocortical insufficiency and chronic mucocutaneous candidiasis. The definite diagnosis of APECED requires one of the following three criteria: the presence of at least two out the three major clinical features or only one of the major components if a sibling has definite APECED or a disease-causing mutation in both alleles of the AIRE gene. [1]. However, many other manifestations have been described, including other endocrinopathy (hypergonadotropic hypogonadism, type 1 diabetes, autoimmune thyroid diseases, pituitary defects), gastrointestinal manifestations (autoimmune gastritis, autoimmune hepatitis, intestinal malabsorption, celiac disease), ectodermal abnormalities (keratitis, enamel dysplasia, vitiligo, alopecia, nail dystrophy) and others [1,2].
The major mutation found in Finns, i.e., the c.769C>T variant, and the 13 bp deletion in exon 8 (c.967–979del13), are the most common ones worldwide [1]. Currently, more than 100 pathogenic mutations have been described and recently new genetic variations have been added [3,4,5]. The AIRE gene plays an essential role in central tolerance. Mutations in the AIRE gene prevent the elimination of self-reactive T cells at the central level and induce a T regulatory cell (Treg) defect at peripheral levels, leading to the development of multiple autoimmune diseases at a young age [6,7].
Although APECED is the paradigm of a monogenic autoimmune disorder, it is characterized by a wide variability of the clinical expression. In the majority of studies, no genotype–phenotype correlation has been found, while several observations suggest that a partial genotype–phenotype correlation may exist for specific traits [6]. Therefore, clinical manifestations of APECED patients can vary, suggesting that other factors, such as environment, lifestyle, habits or other genetic mechanisms, might modulate the disease presentation [8]. In particular, disease-modifying genetic variants in APECED patients were recently supported by different findings in mice [9,10]. Recently, dominant-negative AIRE mutations involving the SAND or PHD-1 domains have been identified in patients presenting with much less severe APECED-like disease, indicating possible modulation of the phenotypic expression of common organ-specific autoimmune diseases [11].
Furthermore, the recent finding of important enhancer elements activated by nuclear factor κB (NF-κB) signaling that is necessary for AIRE gene expression, as well as the identification of further additional regulators, suggest that AIRE gene expression and its function are tightly regulated [11].
APECED syndrome could be potentially underdiagnosed or misdiagnosed due to its rarity, but also because of the variability in its presentation.
We report the case of two siblings with the same mutations in the AIRE gene but with very different phenotypes.
2. Case Reports
The girl (patient 1) in the first year of life developed oral candidiasis, onychodystrophy, transient transaminitis and hepatomegaly (with antinuclear antibodies -ANA- and actin smooth muscle antibodies -ASMA- positivity) and recurrent episodes of fever of unknown origin. At 1.6 years old, she presented a hypocalcemic tetanic crisis. The hematological exams were consistent with hypoparathyroidism, i.e., low blood calcium (1.42 mmol/L, normal range 2.3–2.8), high phosphorus (2.7 mmol/L, normal range 1.5–2) and low parathyroid hormone (PTH) (7.9 pg/mL, normal range 15–57). APECED was suspected and then confirmed by Sanger sequencing, which detected two compound heterozygous mutations in the AIRE gene, in exon 2 and exon 8, namely, NM_000383.4(AIRE):c.260T>C (p.Leu87Pro) and NM_000383.4(AIRE):c.967_979del (p.Leu323fs), respectively. Parental analysis showed that one mutation was inherited from the father and the other from the mother; by considering the absence of any signs or symptoms, no further laboratory investigations were performed.
Thereafter, she developed vitiligo, alopecia, enamel hypoplasia and autoimmune insulitis with positive glutamic acid decarboxylase (GADA) antibodies but no glycemic alteration, abdominal pain and bilateral swelling of the feet without radiographic abnormalities.
At 3.4 years old, for recurrent episodes of tetanic crisis and difficulty to maintain adequate serum calcium levels, notwithstanding the chronic therapy with calcium and calcitriol, she was enrolled in an experimental trial with recombinant human parathyroid hormone (rhPTH) (1–34). At 10 years of age, her height was 131.5 cm (10–25th percentile) with target height of 171 cm (90–97th percentile) and reduced growth velocity (3.3 cm/year, <3rd percentile) according to Tanner growth charts [12]; however, the dynamic growth hormone (GH) testing with Arginine did not show GH deficiency (GH values after arginine test of 11.4 ng/mL). At the age of 12, her abdominal pain worsened with chronic diarrhea and fat-soluble vitamin deficiencies were disclosed (vitamin A 0.21 mcg/mL, 25OH-vitamin D 14.6 ng/mL). The esophagogastroduodenoscopy (EGDS) and colonoscopy revealed macroscopical normal mucosa except for nodular duodenum; histological evaluation detected mild inflammatory infiltrate and voluminous lymphatic follicles in the duodenal bulb and in the rectum; immunohistochemistry of small and large bowel samples with chromogranin A staining showed the complete absence of enteroendocrine cells (EECs) in the stomach, duodenum and ileum, severe decrement of EECs in the ascending colon and normal expression in the rectum. From 13.6 years old, an estradiol-depot patch was placed for hypogonadism (estradiol < 5 pg/mL, anti-müllerian hormone 0.5 ng/mL, basal LH and FSH 0.4 U/L and 3.3 U/L, respectively, LH and FSH values after LHRH test 9.5 U/L and 18.8 U/L, respectively) Currently, patient 1 is 14 years old with height 146.7 cm (<3° percentile), but with catch-up growth (high velocity of 6.5 cm/year, > 97th percentile). Recently, she had SARS-CoV-2 asymptomatic infection.
The boy (patient 2) was evaluated for the first time at 6.4 years old, after his sister’s diagnosis. At the time of diagnosis, he had hypoparathyroidism with asymptomatic mild hypocalcemia, i.e., low blood calcium (1.07 mmol/L, normal range 2.3–2.8), high phosphorus (5.67 mmol/L, normal range 1.5–2) and low PTH (3 pg/mL, normal range 15–57), alopecia and mild oral candidiasis. The same compound heterozygous mutations in the AIRE gene identified in his sister were then detected. At 8.3 years old, for repeated episodes of hypocalcemic tetanic crisis despite therapy with calcium and calcitriol, rhPTH (1–34) treatment was started. Dermatitis rosaceiforme and severe acne were also present and a GADA-positive autoimmune insulitis, without glucose impairment, was then discovered. At 13.9 years old, hyponatremia linked to autoimmune adrenal insufficiency was detected during routine exams and therapy with hydrocortisone and fludrocortisone was started. Over time, he has shown regular growth and pubertal development: at the last evaluation at 19.8 years old, his height was 176.9 cm (50–75th percentile). At 19 years old, he developed COVID-19 pneumonia, treated with oxygen therapy through a nasal cannula, methylprednisolone (starting at 60 mg on the first day then down-titrated in the following days), antibiotics (azthromycin and ceftriaxone) and remdesivir. During the hospitalization, despite the discontinuation of fludrocortisone and the steroid tapering, he showed persistent hypertension (up to 200/120 mmHg) and hypokalemia. Antihypertensive therapy was started (with ramipril 10 mg/die and then, after discharge, amlodipine 10 mg/die and nebivolol 5 mg/die) with mild improvement of pressure values. Potassium chloride per os was added with subsequent normalization of serum potassium levels. He also developed hypercalcemia and hypercalciuria, requiring adjustments of treatment with calcium, calcitriol and rhPTH (1–34).
The main features of both patients are summarized in Table 1.
3. Discussion
The AIRE gene, pathogenetic for APECED, is expressed in thymic medullary epithelial cells where it induces the expression of a wide repertoire of peripheral tissue antigens that play a crucial role in central tolerance for the correct development of self-tolerance. Thus, the absence of AIRE expression results in an impaired clonal deletion of self-reactive thymocytes. Furthermore, there is now strong evidence for AIRE expression in peripheral tissues even though these levels are significantly lower than in thymic stromal cells [6].
The patients described here have two compound heterozygous mutations in the AIRE gene and one of these variants (i.e., 967–979 del13) is one of the most common in the literature, with variable prevalence in different populations of 71%, 53% and 48% in British, North American and Norwegian series, respectively [13,14,15].
The second mutation, NM_000383.4(AIRE):c.260T>C (p.Leu87Pro), has previously been described in a pediatric compound heterozygous patient with maternal inheritance, and paternal inheritance of the p.Leu323fs variant. The subject had a clinical diagnosis of APECED, with anti-omega antibodies and immunologic deregulation since birth. For the associated phenotype and the location within a region of the protein in which other single nucleotide variants produce lack of function alleles inhibiting proper dimerization of the AIRE protein, the mutation was classified as likely pathogenetic [16].
APECED is a recessive monogenic condition although, in a few cases, only one mutant allele of the AIRE gene has been reported in typical APECED patients, suggesting that the second mutation might be located in the regulatory regions of the gene [17].
As for the clinical features, chronic mucocutaneous candidiasis is usually the first of the main components to appear, even if APECED includes other ectodermal anomalies, as reported in the two cases presented, with different characteristics. Alopecia, which is usually localized (alopecia areata), as was seen in patient 1, can spread to the whole scalp (total alopecia), as it did in patient 2.
Hypoparathyroidism is the second most common major component of APECED and usually the first endocrine manifestation [1]. It should present with severe symptoms, as in patient 1, who had tetanic crisis. Treatment with oral calcium and vitamin D analogs represents the conventional treatments in children but they have to be modified frequently, based on body weight and intestinal absorption, and because they can lead to nephrocalcinosis due to hypercalciuria [18]. RhPTH (1–34) is an “off-label” treatment in pediatric ages, but in some clinical studies, it has allowed the maintenance of adequate levels of calcium and phosphate in the blood, to normalize urinary calcium excretion and to reduce tetanic episodes [18], as in our patients who needed high doses of oral calcium before RhPTH (1–34) treatment, and in which, particularly in patient 1, that treatment also led to a reduction of hypercalciuria. Its use over time in patient 1 was further justified by the important malabsorptive syndrome, which not only prevented the maintenance of plasma calcium values in the normal range, but also reduced growth.
The growth impairment reported in patient 1 can be determined by many causes, such as pubertal delay, malabsorption and chronic disease. It is noteworthy that hypogonadism was present only in patient 1, the female, thus confirming the different gender prevalence of this manifestation in APECED, with higher frequency in females [19]. Premature ovarian insufficiency develops in most patients with APECED, often before or shortly after menarche. In a recent study, it developed in 70% of patients at a median age of 16.0 years and in 71% of them before reaching adult height; therefore, timely initiation of hormone replacement therapy is important to ensure optimal pubertal development and growth [20].
In terms of gastrointestinal manifestations, patient 1 showed diarrhea, malabsorption and abdominal pain. Chronic diarrhea in APECED can be due to several causes, such as pancreatic exocrine insufficiency, autoimmune enteropathy (AE), lactose intolerance and celiac disease, as well as hypocalcemia [21]. Histological evaluation of the small bowel in typical AE reveals severe enteropathy with atrophy of the villi of the small intestine, crypt hyperplasia and infiltration of mononuclear cells in the lamina propria, while patients with APECED usually do not exhibit those features of AE, such as in our case, and the main or only finding being the loss of EECs and chromogranin A is considered a surrogate marker for these cells [22].
Primary adrenocortical insufficiency, present only in patient 2, most commonly appears after the other two main features, typically between 5 and 15 years of age [1], with symptoms such as fatigue, weight loss, hypotension, salt craving and increased skin pigmentation. Patient 2 showed incidental laboratory findings that suggested adrenal dysfunction, which was then confirmed by 21-hydroxylase antibody positivity with no sign nor symptoms. Therefore, a strict and regular follow-up allowed us to reach a precocious diagnosis, avoiding an adrenal crisis.
Autoimmune hepatitis affects about a fifth of patients and, fortunately, in most cases, it goes away without therapy after a few months [1]. Patient 1 presented with fever and liver enzyme abnormalities, hepatomegaly and ANA and ASMA positivity, but a liver biopsy was not performed for the resolution of signs and symptoms, leading us to consider autoimmune hepatitis as the most probable diagnosis, even without histological confirmation.
Although clinical type 1 diabetes occurs rarely in APECED, elevated titers of GADA are frequently found, as in the two patients presented, and could represent an epiphenomenon of autoimmune insulitis that usually does not lead to clinical manifestation of the disease [23], which is less frequent than in patients with other autoimmune diseases or in healthy children [24].
Patient 2 also had COVID-19 infection with pneumonia, complicated by hypertension, hypokalemia and hypercalcemia. Based on current data, there is no evidence that patients with adrenal insufficiency have an increased risk of contracting COVID-19 but they have a slightly increased overall risk of having infections and an overall increased mortality, possibly explained by an insufficient compensatory increase in the hydrocortisone dose at the time of the onset of an episode of infection. Thus, patients with adrenal insufficiency may be at higher risk of medical complications and eventually at increased mortality risk in the case of COVID-19 infection [25].
There are no significant data describing the effect of COVID-19 on APECED patients, which are certainly not typical examples of adrenal insufficiency, and our case showed different metabolic complications requiring different treatment adjustments, also concerning his chronic therapy for hypoparathyroidism.
The clinical variability of APECED and the absence of a clear genotype–phenotype correlation, also evidenced in our report of two cases with the same AIRE genotype but very different phenotypes, could indicate that, in addition to the failure of AIRE function, additional mechanisms may be involved, in a complex interaction between several genetic, epigenetic, immunological and/or environmental factors [26]. Some studies have investigated the effects of additional genetic loci, particularly the human leukocyte antigen (HLA) complex, limited to a few manifestations, but only a weak association has been observed between the HLA type and autoantibody specificities observed in APECED patients [6]. Infectious agents could act as a trigger for a self-reaction through various mechanisms in genetically susceptible subjects, but their role in the clinical expression of APECED has not been demonstrated. Since the AIRE gene also appears to be involved in the control of peripheral mechanisms for the maintenance of self-tolerance, a possible role of reduced peripheral tolerance has been hypothesized in the pathogenesis and clinical expression of APECED [26]. A decrease in CD4+CD25+ T regulatory cells (Tregs) has been reported in both adults and children with APECED, but the reduction in circulating Tregs could also be secondary to chronic fungal infection and their pathogenetic role is not defined [6]. Certainly, many factors may play a role in modulating the disease expression in our patients as well, but the current data did not find a definite reason for this variability.
Considering the multi-organ expressiveness of APECED disease, it is of utmost importance that pediatric endocrinologists or endocrinologists, who generally coordinate the multidisciplinary team of providers, have a deep awareness of the multifaceted manifestations and natural history of the disorder to set up a multidisciplinary follow-up, including immunologists, gastroenterologists and eventually other specialists, to promptly recognize and take of care of the development of new disease components or laboratory abnormalities which may appear throughout life [1].
4. Conclusions
APECED syndrome is a multisystemic disease, with different combinations of affected organs and autoantibody specificities, that certainly requires a multidisciplinary approach. The genotype does not predict the phenotype, even in siblings with the same mutations, and genetic, epigenetic and environmental factors may play a role. Therefore, further studies might identify new disease-modifying mechanisms or genes influencing the variable expressivity of APECED.
Acknowledgments
No grants have supported this work. Article processing charges (APC) were covered by Postgraduate School of Pediatrics, Department of Public Health and Pediatric Sciences, University of Turin.
Author Contributions
L.D.S., A.C. and R.B. conceived this article. A.C. and R.B. wrote the paper and carried out the reference search. P.M., G.T., M.P., P.L.C., D.M., F.L. and L.D.S. have followed the patients over the time and reviewed the manuscript. Each author approved the submitted version and agrees to be personally accountable for their own contribution and for ensuring that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved and documented in the literature. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
Ethical review and approval were waived for this study considering that patients were included in Piedmont Regional Network for Rare Disease which allows clinicians to use off-label drugs approved by the Italian National Health Service after obtaining informed consent, as for previous associated studies of teriparatide in APECED patients.
Informed Consent Statement
Informed consent has been obtained from the patient(s) to publish this paper.
Data Availability Statement
No primary datasets were produced in this study. Data sharing is not applicable to this article.
Conflicts of Interest
The authors declare no conflict of interest.
genes-12-00169-t001_Table 1 Table 1 Manifestations of two siblings affected by autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) disease: variability and similarities.
Manifestation Patient 1, Female, 14 Years Old Patient 2, Male, 19 Years Old
Hypoparathyroidism + +
Primary adrenocortical insufficiency − +
Chronic mucocutaneous candidiasis + +
Vitiligo + −
Alopecia + +
Enamel hypoplasia + −
Onicodystrophy + −
Rosaceiforme dermatisis and acne − +
Autoimmune hepatitis +/− −
Autoimmune insulitis + +
Diarrhea/intestinal malabsorption + −
Growth impairment + −
Pubertal delay + −
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | AT 13.9 YEARS OLD | DrugDosageText | CC BY | 33530632 | 19,509,839 | 2021-01-26 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Abscess'. | Fatal acute-on-chronic liver failure in amiodarone-related steatohepatitis: a case report.
BACKGROUND
Amiodarone is an antiarrhythmic drug that has been recognized to induce hepatotoxicity. We report a case of acute-on-chronic liver failure (ACLF) in a patient who was receiving amiodarone for more than 2 years. The patient developed cirrhosis and suppurative microabscesses of the liver and died of progressive liver failure.
METHODS
A 69-year-old woman with risk factors for nonalcoholic fatty liver disease (NAFLD) was treated with oral amiodarone at a daily dose of 400 mg for more than 2 years, until she developed epigastralgia and vomiting. Initial laboratory findings included leukocytosis and elevated liver enzymes. Images of abdominal computed tomography scan revealed diffusely increased hepatic attenuation density (in contrast to decreased density in NAFLD), hepatomegaly, periportal edema, and ascites. Liver biopsy targeting the hotspot identified through positron emission tomography confirmed the diagnosis of amiodarone-associated chronic steatohepatitis and superimposed microabscesses. The patient died of progressive ACLF despite intensive supportive care.
CONCLUSIONS
Accumulation of amiodarone can result in chronic liver disease and pose an additional risk of ACLF following infection.
Background
Acute-on-chronic liver failure (ACLF) is a process of rapid deterioration in liver function occurring against a background of chronic liver disease characterized by multisystem organ failure, systemic inflammation, and high short-term mortality. Chronic liver disease is infrequently caused by potential hepatotoxic agents, such as amiodarone [1]. We report a rare case of ACLF caused by acute suppurative microabscesses superimposed on chronic drug-induced liver injury (DILI) associated with amiodarone.
Case presentation
A 69-year-old woman was admitted to our hospital for postprandial epigastralgia and vomiting for 2 weeks. She had a history of diabetes mellitus and hyperlipidemia, and she had undergone bypass surgery for coronary arterial disease 2.5 years previously. She had no alcohol consumption. Initial evaluation revealed distended abdomen, epigastric tenderness, neutrophilic leukocytosis (17.3 k/μL), elevated C-reactive protein, pyuria, liver panel abnormalities (i.e., hepatitis and conjugated hyperbilirubinemia), and coagulopathy. At presentation, the serum levels of aspartate transaminase (AST), alanine transaminase (ALT), total bilirubin, direct bilirubin, albumin, and international normalized ratio of prothrombin time were 226 U/L, 108 U/L, 11.72 mg/dL, 6.97 mg/dL, 2.1 g/dL, and 1.44, respectively. Two months before this admission, the serum levels of AST, ALT, total bilirubin, and direct bilirubin were 144 U/L, 131U/L, 0.64 mg/dL, and 0.21 mg/dL, respectively. The AST to platelet ratio index (APRI) score was 2.04, an increase from 1.23 in 2 years. A hepatopathy screening including viral hepatitis (hepatitis B, C, D, and E), auto-immune and hereditary liver disease was negative, except a document of remote hepatitis A infection. Computed tomography (CT) scanning disclosed hepatomegaly, periportal edema, and ascites (Fig. 1a, b). Notably, a diffuse increase in hepatic attenuation density, a hallmark of iron or amiodarone deposition, was observed. Amiodarone had been prescribed at a daily dose of 400 mg (estimated total cumulative dose exposure of 360 g) since the bypass surgery for tachyarrhythmia. Liver attenuation was approximately 50 Hounsfield units (HU) before exposure to amiodarone (Fig. 1c) and had increased one-fold by the following year. Amiodarone was discontinued upon admission. Broad-spectrum antibiotics were used to treat a documented vancomycin-resistant enterococcal urinary tract infection and other potential occult infections without significant clinical improvement. Leukocytosis persisted and a fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan 3 weeks after admission revealed multiple areas of active inflammation within the liver (Fig. 1d). The pathological findings of a targeted biopsy of the largest hot spot (Fig. 1d, arrow) in the FDG-PET scan revealed multifocal necrotizing suppurative microabscesses accompanied by aggregates of granulation tissue and histiocytes (Fig. 1e). No pathogen was observed on acid-fast, periodic-acid-Schiff, and Grocott's methenamine silver staining. Moreover, the liver parenchyma demonstrated cirrhosis and regenerative nodules associated with prominent periseptal ballooned hepatocytes containing numerous Mallory-Denk bodies (Fig. 1f). The changes of selective liver panels since the initial presentation were illustrated in Fig. 2. A rare presentation of ACLF was confirmed based on the findings of amiodarone-associated chronic steatohepatitis and superimposed microabscesses. The patient’s Chronic Liver Failure Consortium (CLIF-C) ACLF score was calculated to be 69.4, and the model for the end-stage liver disease (MELD) score was high (> 30), indicating an unfavorable outcome [2] (Fig. 3). The patient’s clinical condition deteriorated, and she died of progressive liver and renal failure.Fig. 1 Development and diagnosis of ACLF. a–c Serial changes in hepatic signal intensity on CT imaging. High attenuation (90–100 HU) following (a) the use of amiodarone and (b) periportal edema in ACLF. c Low attenuation (50 HU) of liver parenchyma 2 years prior to exposure to amiodarone. d FDG-PET scanning demonstrated focal hypermetabolic hepatic lesions in both lobes, with a maximum standardized uptake value of 8.8 (arrow). e, f Histopathological examination showed (e) suppurative microabscesses (dotted frame) and (f) numerous Mallory-Denk bodies in the periseptal hepatocytes
Fig. 2 Trends of liver function tests since the initial presentation. AST, aspartate transaminase; ALT, alanine transaminase; ALP, alkaline phosphatase; T-Bil, total bilirubin; D-Bil, direct bilirubin
Fig. 3 Trend of severity scores since the initial presentation. ACLF, acute-on-chronic liver failure; AD, acute decompensation; CLIF-C, Chronic Liver Failure Consortium; MELD, Model for End-stage Liver Disease
Discussion and conclusions
Amiodarone accounts for 1–3% of all DILIs, most commonly exhibiting a hepatocellular injury pattern, particularly in patients with older age, lower body surface area, and dyslipidemia [3]. Elevation of liver enzymes following high-dose intravenous infusion can occur and is mediated through direct hepatotoxicity, which is usually transient and self-reversible; by contrast, liver cirrhosis due to chronic use of low-dose amiodarone is caused by nonallergic idiosyncratic reactions of accumulation-related injury [4]. Amiodarone could induce lysosomal phospholipidosis, resulting in formation of Mallory-Denk bodies in the liver and inhibiting phagocytosis, the latter of which might impair macrophage function and contribute to ACLF progression as observed in the present case [5]. Steatohepatitis associated with amiodarone, through inhibition of the β-oxidation of free fatty acid in the mitochondria [4], exhibits high HU values, in contrast to hypointensity (low HU values) of the liver in nonalcoholic steatohepatitis associated with metabolic syndrome. However, additional hepatotoxicity by amiodarone on top of steatohepatitis related to her metabolic syndrome/insulin resistance is the most likely scenario of her chronic liver disease based on the above negative hepatopathy panel [6].
With the development of toxicity, no definite treatment exists for amiodarone-induced liver injury apart from drug discontinuation, and the mortality rate is as high as 60% at 5 months. The cumulative dose in our patient was 360 g over 2.5 years, close to the reported dose deemed sufficient to induce liver cirrhosis [7]. Together with acute inflammation and possibly macrophage dysfunction, we propose that amiodarone serves as a crucial contributor to the development of ACLF.
In conclusion, accumulation of amiodarone can result in chronic liver disease and pose an additional risk of developing ACLF following infections.
Abbreviations
ACLFacute-on-chronic liver failure
ALTalanine transaminase;
ASTaspartate transaminase
CLIF-Cchronic liver failure consortium
CTcomputed tomography
DILIdrug-induced liver injury
FDGfluorodeoxyglucose
HUhounsfield unit
MELDmodel for end-stage liver disease
PETposition emission tomography
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
None.
Authors’ contributions
WIJ analyzed and interpreted the patient data regarding the liver disease and the infection. TJH performed the histological examination of the liver. WIJ and HCM were major contributors in writing the manuscript. All authors read and approved the final manuscript.
Funding
Nil.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Waived.
Consent for publication
Written consent for publication from the next of kin was obtained.
Competing interests
Nothing to report. | AMIODARONE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33530924 | 18,942,904 | 2021-02-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acute on chronic liver failure'. | Fatal acute-on-chronic liver failure in amiodarone-related steatohepatitis: a case report.
BACKGROUND
Amiodarone is an antiarrhythmic drug that has been recognized to induce hepatotoxicity. We report a case of acute-on-chronic liver failure (ACLF) in a patient who was receiving amiodarone for more than 2 years. The patient developed cirrhosis and suppurative microabscesses of the liver and died of progressive liver failure.
METHODS
A 69-year-old woman with risk factors for nonalcoholic fatty liver disease (NAFLD) was treated with oral amiodarone at a daily dose of 400 mg for more than 2 years, until she developed epigastralgia and vomiting. Initial laboratory findings included leukocytosis and elevated liver enzymes. Images of abdominal computed tomography scan revealed diffusely increased hepatic attenuation density (in contrast to decreased density in NAFLD), hepatomegaly, periportal edema, and ascites. Liver biopsy targeting the hotspot identified through positron emission tomography confirmed the diagnosis of amiodarone-associated chronic steatohepatitis and superimposed microabscesses. The patient died of progressive ACLF despite intensive supportive care.
CONCLUSIONS
Accumulation of amiodarone can result in chronic liver disease and pose an additional risk of ACLF following infection.
Background
Acute-on-chronic liver failure (ACLF) is a process of rapid deterioration in liver function occurring against a background of chronic liver disease characterized by multisystem organ failure, systemic inflammation, and high short-term mortality. Chronic liver disease is infrequently caused by potential hepatotoxic agents, such as amiodarone [1]. We report a rare case of ACLF caused by acute suppurative microabscesses superimposed on chronic drug-induced liver injury (DILI) associated with amiodarone.
Case presentation
A 69-year-old woman was admitted to our hospital for postprandial epigastralgia and vomiting for 2 weeks. She had a history of diabetes mellitus and hyperlipidemia, and she had undergone bypass surgery for coronary arterial disease 2.5 years previously. She had no alcohol consumption. Initial evaluation revealed distended abdomen, epigastric tenderness, neutrophilic leukocytosis (17.3 k/μL), elevated C-reactive protein, pyuria, liver panel abnormalities (i.e., hepatitis and conjugated hyperbilirubinemia), and coagulopathy. At presentation, the serum levels of aspartate transaminase (AST), alanine transaminase (ALT), total bilirubin, direct bilirubin, albumin, and international normalized ratio of prothrombin time were 226 U/L, 108 U/L, 11.72 mg/dL, 6.97 mg/dL, 2.1 g/dL, and 1.44, respectively. Two months before this admission, the serum levels of AST, ALT, total bilirubin, and direct bilirubin were 144 U/L, 131U/L, 0.64 mg/dL, and 0.21 mg/dL, respectively. The AST to platelet ratio index (APRI) score was 2.04, an increase from 1.23 in 2 years. A hepatopathy screening including viral hepatitis (hepatitis B, C, D, and E), auto-immune and hereditary liver disease was negative, except a document of remote hepatitis A infection. Computed tomography (CT) scanning disclosed hepatomegaly, periportal edema, and ascites (Fig. 1a, b). Notably, a diffuse increase in hepatic attenuation density, a hallmark of iron or amiodarone deposition, was observed. Amiodarone had been prescribed at a daily dose of 400 mg (estimated total cumulative dose exposure of 360 g) since the bypass surgery for tachyarrhythmia. Liver attenuation was approximately 50 Hounsfield units (HU) before exposure to amiodarone (Fig. 1c) and had increased one-fold by the following year. Amiodarone was discontinued upon admission. Broad-spectrum antibiotics were used to treat a documented vancomycin-resistant enterococcal urinary tract infection and other potential occult infections without significant clinical improvement. Leukocytosis persisted and a fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan 3 weeks after admission revealed multiple areas of active inflammation within the liver (Fig. 1d). The pathological findings of a targeted biopsy of the largest hot spot (Fig. 1d, arrow) in the FDG-PET scan revealed multifocal necrotizing suppurative microabscesses accompanied by aggregates of granulation tissue and histiocytes (Fig. 1e). No pathogen was observed on acid-fast, periodic-acid-Schiff, and Grocott's methenamine silver staining. Moreover, the liver parenchyma demonstrated cirrhosis and regenerative nodules associated with prominent periseptal ballooned hepatocytes containing numerous Mallory-Denk bodies (Fig. 1f). The changes of selective liver panels since the initial presentation were illustrated in Fig. 2. A rare presentation of ACLF was confirmed based on the findings of amiodarone-associated chronic steatohepatitis and superimposed microabscesses. The patient’s Chronic Liver Failure Consortium (CLIF-C) ACLF score was calculated to be 69.4, and the model for the end-stage liver disease (MELD) score was high (> 30), indicating an unfavorable outcome [2] (Fig. 3). The patient’s clinical condition deteriorated, and she died of progressive liver and renal failure.Fig. 1 Development and diagnosis of ACLF. a–c Serial changes in hepatic signal intensity on CT imaging. High attenuation (90–100 HU) following (a) the use of amiodarone and (b) periportal edema in ACLF. c Low attenuation (50 HU) of liver parenchyma 2 years prior to exposure to amiodarone. d FDG-PET scanning demonstrated focal hypermetabolic hepatic lesions in both lobes, with a maximum standardized uptake value of 8.8 (arrow). e, f Histopathological examination showed (e) suppurative microabscesses (dotted frame) and (f) numerous Mallory-Denk bodies in the periseptal hepatocytes
Fig. 2 Trends of liver function tests since the initial presentation. AST, aspartate transaminase; ALT, alanine transaminase; ALP, alkaline phosphatase; T-Bil, total bilirubin; D-Bil, direct bilirubin
Fig. 3 Trend of severity scores since the initial presentation. ACLF, acute-on-chronic liver failure; AD, acute decompensation; CLIF-C, Chronic Liver Failure Consortium; MELD, Model for End-stage Liver Disease
Discussion and conclusions
Amiodarone accounts for 1–3% of all DILIs, most commonly exhibiting a hepatocellular injury pattern, particularly in patients with older age, lower body surface area, and dyslipidemia [3]. Elevation of liver enzymes following high-dose intravenous infusion can occur and is mediated through direct hepatotoxicity, which is usually transient and self-reversible; by contrast, liver cirrhosis due to chronic use of low-dose amiodarone is caused by nonallergic idiosyncratic reactions of accumulation-related injury [4]. Amiodarone could induce lysosomal phospholipidosis, resulting in formation of Mallory-Denk bodies in the liver and inhibiting phagocytosis, the latter of which might impair macrophage function and contribute to ACLF progression as observed in the present case [5]. Steatohepatitis associated with amiodarone, through inhibition of the β-oxidation of free fatty acid in the mitochondria [4], exhibits high HU values, in contrast to hypointensity (low HU values) of the liver in nonalcoholic steatohepatitis associated with metabolic syndrome. However, additional hepatotoxicity by amiodarone on top of steatohepatitis related to her metabolic syndrome/insulin resistance is the most likely scenario of her chronic liver disease based on the above negative hepatopathy panel [6].
With the development of toxicity, no definite treatment exists for amiodarone-induced liver injury apart from drug discontinuation, and the mortality rate is as high as 60% at 5 months. The cumulative dose in our patient was 360 g over 2.5 years, close to the reported dose deemed sufficient to induce liver cirrhosis [7]. Together with acute inflammation and possibly macrophage dysfunction, we propose that amiodarone serves as a crucial contributor to the development of ACLF.
In conclusion, accumulation of amiodarone can result in chronic liver disease and pose an additional risk of developing ACLF following infections.
Abbreviations
ACLFacute-on-chronic liver failure
ALTalanine transaminase;
ASTaspartate transaminase
CLIF-Cchronic liver failure consortium
CTcomputed tomography
DILIdrug-induced liver injury
FDGfluorodeoxyglucose
HUhounsfield unit
MELDmodel for end-stage liver disease
PETposition emission tomography
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
None.
Authors’ contributions
WIJ analyzed and interpreted the patient data regarding the liver disease and the infection. TJH performed the histological examination of the liver. WIJ and HCM were major contributors in writing the manuscript. All authors read and approved the final manuscript.
Funding
Nil.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
Waived.
Consent for publication
Written consent for publication from the next of kin was obtained.
Competing interests
Nothing to report. | AMIODARONE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33530924 | 18,942,904 | 2021-02-02 |
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