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What was the administration route of drug 'BENDAMUSTINE'? | Methicillin-resistant Staphylococcus aureus (MRSA) panniculitis in a patient undergoing stem cell mobilisation.
Methicillin-resistant Staphylococcus aureus (MRSA) can cause a wide range of skin infections, however MRSA panniculitis without bacteremia is a rare manifestation. Here, we report a woman in her 20s with relapsed Hodgkin lymphoma undergoing stem cell mobilisation who presented with bilateral subcutaneous nodules over her shins. Ultrasound scan of one nodule showed non-specific inflammatory changes. Punch biopsy of a nodule showed lobular panniculitis with Gram-positive cocci. Blood cultures were negative but a culture from the biopsy grew MRSA. She was started on doxycycline with improvement in her symptoms. This case serves as a reminder to consider infections as a cause of panniculitis in immunocompromised patients.
Background
Panniculitis usually presents as painful erythematous nodules or plaques and is characterised by inflammation of subcutaneous adipose tissue. Recognition, diagnosis and evaluation is challenging because of its rarity and myriad causes, including infection, malignancy, drugs and inflammatory conditions. Infectious panniculitis can occur primarily after direct inoculation or secondarily from hematogenous spread.1 We report a case of methicillin-resistant Staphylococcus aureus (MRSA) panniculitis.
Case presentation
A female in her 20s with relapsed Hodgkin lymphoma (HL) was referred to our centre for autologous stem cell transplantation. She was diagnosed with stage 2 HL in 2016 and underwent chemoradiotherapy, attaining complete remission. She relapsed in 2019 with a recurrent mediastinal mass and widespread lymphadenopathy. She underwent salvage chemotherapy with bendamustine and brentuximab (BB), which was uneventful except for a grade 1 cutaneous adverse drug reaction (CADR) to BB affecting 5% of her body surface area. This resolved with topical steroids and antihistamines. She had no other significant medical or surgical history. Medication on admission for stem cell harvesting included chlorpheniramine 4 mg two times per day, mometasone 0.1% lotion two times per day for her previous CADR and acyclovir 400 mg two times per day for prophylaxis against herpes zoster.
The patient went on to receive mobilisation chemotherapy with ifosfamide, carboplatin and etoposide. Pegfilgrastim was administered on days 5 and 11. On day 11, she was admitted with a fever of 38.3°C and pain in her legs. Examination revealed bilateral scattered tender, indurated subcutaneous nodules over her shins with mild overlying erythema, approximately 3–5 cm in diameter (figure 1). There was a residual dry scaly excoriated hyperpigmented rash from the previous CADR.
Figure 1 Photo of subcutaneous nodule on the lower limb.
Investigations
Investigations on admission showed a white cell count of 0.79×109/L, with neutrophils 0.56×109/L. Following admission, she was started on daily filgrastim due to her neutropaenia and low CD34+ count, which precluded successful mobilisation. C-reactive protein (CRP) was elevated at 74, and procalcitonin was 0.18. Blood cultures and a blood fungal culture were negative. An ultrasound scan of the leg nodule showed vague increased echogenicity and increased vascularity in the subcutaneous tissue with no evidence of abscess formation. A punch biopsy of the nodule confirmed lobular panniculitis with an inflammatory cell infiltrate composed of numerous neutrophils, mixed with lymphocytes, eosinophils, histiocytes and occasional multinucleated giant cells (figure 2A). Granulomas were not observed. No features of vasculitis were identified. Gram-positive cocci were present in the dermis and subcutis (figure 2B). No fungal organisms or acid-fast bacilli were seen on Grocott’s methenamine silver or Ziehl-Neelsen stains. Culture from the punch biopsy grew MRSA. Her antinuclear antibody titre was negative at <1:80. A tuberculosis quantiferon test was negative, and a chest radiograph was normal.
Figure 2 (A) Histology slide showing lobular panniculitis with an inflammatory cell infiltrate composed of numerous neutrophils, mixed with lymphocytes, eosinophils, histiocytes and occasional multinucleated giant cells. (B) Histology slide showing Gram-positive cocci.
Treatment
A diagnosis of infective panniculitis secondary to MRSA was made. She was started on doxycycline with resolution of her fever and nodules. Her filgrastim injections were continued till neutrophil recovery.
Outcome and follow-up
The patient unfortunately failed to mobilise peripheral blood stem cells but went on to have a successful bone marrow harvest with no evidence of microbial contamination of her cyropreserved stem cells. Her lower limb subcutaneous nodules also resolved completely without scarring nor atrophy following treatment with doxycycline.
DISCUSSION
Panniculitis can be classified as septal or lobular, with or without vasculitis. Histologically, infectious panniculitis presents as a neutrophilic predominant mixed inflammatory infiltrate with a lobular pattern of inflammation.2 Infective panniculitis can be caused by bacterial, mycobacterial, fungal, protozoal or viral infections. S. aureus is a skin commensal commonly responsible for primary cutaneous lesions such as folliculitis, carbuncles or cellulitis. Deeper pathology such as abscesses or rarely, panniculitis may result from haematogenous spread in bacteraemic patients,3 or following inoculation from primary superficial lesions. In our patient, repeated blood cultures were negative for S. aureus. Given this, we hypothesise that her prior CADR to BB chemotherapy resulted in weakened skin integrity, superficial inoculation and subsequent deep tissue infection which flared opportunistically when she was neutropaenic. To our knowledge, MRSA-induced panniculitis without bacteremia is rare. However, there have been a few reports of this phenomenon with Pseudomonas aeruginosa.4 5
We initially considered filgrastim-induced panniculitis as a differential. Filgrastim has been associated with several cutaneous reactions such as Sweet’s syndrome, pyoderma gangrenosum and vasculitis. A few cases have been reported in association with pegfilgrastim.6 Possible hypotheses include secondary cytokine production after filgrastim administration and neutrophil activation.7 In our patient, the temporal relationship between administration of pegfilgastrim and her symptoms initially led us to suspect pegfilgrastim as the cause of her panniculitis. However given her positive biopsy culture for MRSA, the presence of Gram-positive cocci in her dermis and subdermal layer, and clinical response to doxycycline despite being continued on filgrastim, we deemed this unlikely.
The site of the lesions, clinical context of HL and neutrophil-rich inflammatory infiltrate also raise the possibility of erythema nodosum. Erythema nodosum is usually idiopathic, but has also been associated with infection, drug, inflammatory condition or malignancy.8 Although this is classically a septal panniculitis,9 there can be histological overlap in some cases.10 Our patient's biopsy was in keeping with that of a lobular panniculitis. Her culture was positive for MRSA which is not a typical infection associated with erythema nodosum. In view of this and her quick response to doxycycline, we concluded erythema nodosum to be less probable.
The possibility of bacterial contamination during the biopsy procedure was also considered. MRSA is endemic in healthcare facilities,11 and patients who are colonised with MRSA may contaminate surrounding environmental surfaces.12 Our institution carries out active surveillance to identify MRSA-colonised patients. Our patient’s MRSA swabs (nasal, axilla and groin) were persistently negative. In addition, the procedure was done under aseptic technique, MRSA was cultured and demonstrated in histology specimens, and she improved following the institution of antimicrobial therapy. In light of this, bacterial contamination was considered unlikely.
Learning points
Infectious panniculitis due to Staphylococcus aureus in the absence of bacteraemia is extremely rare.
Careful workup including biopsy and culture is important to allow correct identification of aetiology and appropriate management.
Appropriate diagnosis allowed continued filgrastim injections so that her time-sensitive stem cell harvest could proceed.
Contributors: APYN drafted the manuscript. Y-LC and W-YJ reviewed and revised the manuscript. SBJW analysed the histology specimen.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY-NC | 33563686 | 19,224,532 | 2021-02-09 |
What was the administration route of drug 'MOMETASONE'? | Methicillin-resistant Staphylococcus aureus (MRSA) panniculitis in a patient undergoing stem cell mobilisation.
Methicillin-resistant Staphylococcus aureus (MRSA) can cause a wide range of skin infections, however MRSA panniculitis without bacteremia is a rare manifestation. Here, we report a woman in her 20s with relapsed Hodgkin lymphoma undergoing stem cell mobilisation who presented with bilateral subcutaneous nodules over her shins. Ultrasound scan of one nodule showed non-specific inflammatory changes. Punch biopsy of a nodule showed lobular panniculitis with Gram-positive cocci. Blood cultures were negative but a culture from the biopsy grew MRSA. She was started on doxycycline with improvement in her symptoms. This case serves as a reminder to consider infections as a cause of panniculitis in immunocompromised patients.
Background
Panniculitis usually presents as painful erythematous nodules or plaques and is characterised by inflammation of subcutaneous adipose tissue. Recognition, diagnosis and evaluation is challenging because of its rarity and myriad causes, including infection, malignancy, drugs and inflammatory conditions. Infectious panniculitis can occur primarily after direct inoculation or secondarily from hematogenous spread.1 We report a case of methicillin-resistant Staphylococcus aureus (MRSA) panniculitis.
Case presentation
A female in her 20s with relapsed Hodgkin lymphoma (HL) was referred to our centre for autologous stem cell transplantation. She was diagnosed with stage 2 HL in 2016 and underwent chemoradiotherapy, attaining complete remission. She relapsed in 2019 with a recurrent mediastinal mass and widespread lymphadenopathy. She underwent salvage chemotherapy with bendamustine and brentuximab (BB), which was uneventful except for a grade 1 cutaneous adverse drug reaction (CADR) to BB affecting 5% of her body surface area. This resolved with topical steroids and antihistamines. She had no other significant medical or surgical history. Medication on admission for stem cell harvesting included chlorpheniramine 4 mg two times per day, mometasone 0.1% lotion two times per day for her previous CADR and acyclovir 400 mg two times per day for prophylaxis against herpes zoster.
The patient went on to receive mobilisation chemotherapy with ifosfamide, carboplatin and etoposide. Pegfilgrastim was administered on days 5 and 11. On day 11, she was admitted with a fever of 38.3°C and pain in her legs. Examination revealed bilateral scattered tender, indurated subcutaneous nodules over her shins with mild overlying erythema, approximately 3–5 cm in diameter (figure 1). There was a residual dry scaly excoriated hyperpigmented rash from the previous CADR.
Figure 1 Photo of subcutaneous nodule on the lower limb.
Investigations
Investigations on admission showed a white cell count of 0.79×109/L, with neutrophils 0.56×109/L. Following admission, she was started on daily filgrastim due to her neutropaenia and low CD34+ count, which precluded successful mobilisation. C-reactive protein (CRP) was elevated at 74, and procalcitonin was 0.18. Blood cultures and a blood fungal culture were negative. An ultrasound scan of the leg nodule showed vague increased echogenicity and increased vascularity in the subcutaneous tissue with no evidence of abscess formation. A punch biopsy of the nodule confirmed lobular panniculitis with an inflammatory cell infiltrate composed of numerous neutrophils, mixed with lymphocytes, eosinophils, histiocytes and occasional multinucleated giant cells (figure 2A). Granulomas were not observed. No features of vasculitis were identified. Gram-positive cocci were present in the dermis and subcutis (figure 2B). No fungal organisms or acid-fast bacilli were seen on Grocott’s methenamine silver or Ziehl-Neelsen stains. Culture from the punch biopsy grew MRSA. Her antinuclear antibody titre was negative at <1:80. A tuberculosis quantiferon test was negative, and a chest radiograph was normal.
Figure 2 (A) Histology slide showing lobular panniculitis with an inflammatory cell infiltrate composed of numerous neutrophils, mixed with lymphocytes, eosinophils, histiocytes and occasional multinucleated giant cells. (B) Histology slide showing Gram-positive cocci.
Treatment
A diagnosis of infective panniculitis secondary to MRSA was made. She was started on doxycycline with resolution of her fever and nodules. Her filgrastim injections were continued till neutrophil recovery.
Outcome and follow-up
The patient unfortunately failed to mobilise peripheral blood stem cells but went on to have a successful bone marrow harvest with no evidence of microbial contamination of her cyropreserved stem cells. Her lower limb subcutaneous nodules also resolved completely without scarring nor atrophy following treatment with doxycycline.
DISCUSSION
Panniculitis can be classified as septal or lobular, with or without vasculitis. Histologically, infectious panniculitis presents as a neutrophilic predominant mixed inflammatory infiltrate with a lobular pattern of inflammation.2 Infective panniculitis can be caused by bacterial, mycobacterial, fungal, protozoal or viral infections. S. aureus is a skin commensal commonly responsible for primary cutaneous lesions such as folliculitis, carbuncles or cellulitis. Deeper pathology such as abscesses or rarely, panniculitis may result from haematogenous spread in bacteraemic patients,3 or following inoculation from primary superficial lesions. In our patient, repeated blood cultures were negative for S. aureus. Given this, we hypothesise that her prior CADR to BB chemotherapy resulted in weakened skin integrity, superficial inoculation and subsequent deep tissue infection which flared opportunistically when she was neutropaenic. To our knowledge, MRSA-induced panniculitis without bacteremia is rare. However, there have been a few reports of this phenomenon with Pseudomonas aeruginosa.4 5
We initially considered filgrastim-induced panniculitis as a differential. Filgrastim has been associated with several cutaneous reactions such as Sweet’s syndrome, pyoderma gangrenosum and vasculitis. A few cases have been reported in association with pegfilgrastim.6 Possible hypotheses include secondary cytokine production after filgrastim administration and neutrophil activation.7 In our patient, the temporal relationship between administration of pegfilgastrim and her symptoms initially led us to suspect pegfilgrastim as the cause of her panniculitis. However given her positive biopsy culture for MRSA, the presence of Gram-positive cocci in her dermis and subdermal layer, and clinical response to doxycycline despite being continued on filgrastim, we deemed this unlikely.
The site of the lesions, clinical context of HL and neutrophil-rich inflammatory infiltrate also raise the possibility of erythema nodosum. Erythema nodosum is usually idiopathic, but has also been associated with infection, drug, inflammatory condition or malignancy.8 Although this is classically a septal panniculitis,9 there can be histological overlap in some cases.10 Our patient's biopsy was in keeping with that of a lobular panniculitis. Her culture was positive for MRSA which is not a typical infection associated with erythema nodosum. In view of this and her quick response to doxycycline, we concluded erythema nodosum to be less probable.
The possibility of bacterial contamination during the biopsy procedure was also considered. MRSA is endemic in healthcare facilities,11 and patients who are colonised with MRSA may contaminate surrounding environmental surfaces.12 Our institution carries out active surveillance to identify MRSA-colonised patients. Our patient’s MRSA swabs (nasal, axilla and groin) were persistently negative. In addition, the procedure was done under aseptic technique, MRSA was cultured and demonstrated in histology specimens, and she improved following the institution of antimicrobial therapy. In light of this, bacterial contamination was considered unlikely.
Learning points
Infectious panniculitis due to Staphylococcus aureus in the absence of bacteraemia is extremely rare.
Careful workup including biopsy and culture is important to allow correct identification of aetiology and appropriate management.
Appropriate diagnosis allowed continued filgrastim injections so that her time-sensitive stem cell harvest could proceed.
Contributors: APYN drafted the manuscript. Y-LC and W-YJ reviewed and revised the manuscript. SBJW analysed the histology specimen.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Topical | DrugAdministrationRoute | CC BY-NC | 33563686 | 19,224,532 | 2021-02-09 |
What was the dosage of drug 'BENDAMUSTINE'? | Methicillin-resistant Staphylococcus aureus (MRSA) panniculitis in a patient undergoing stem cell mobilisation.
Methicillin-resistant Staphylococcus aureus (MRSA) can cause a wide range of skin infections, however MRSA panniculitis without bacteremia is a rare manifestation. Here, we report a woman in her 20s with relapsed Hodgkin lymphoma undergoing stem cell mobilisation who presented with bilateral subcutaneous nodules over her shins. Ultrasound scan of one nodule showed non-specific inflammatory changes. Punch biopsy of a nodule showed lobular panniculitis with Gram-positive cocci. Blood cultures were negative but a culture from the biopsy grew MRSA. She was started on doxycycline with improvement in her symptoms. This case serves as a reminder to consider infections as a cause of panniculitis in immunocompromised patients.
Background
Panniculitis usually presents as painful erythematous nodules or plaques and is characterised by inflammation of subcutaneous adipose tissue. Recognition, diagnosis and evaluation is challenging because of its rarity and myriad causes, including infection, malignancy, drugs and inflammatory conditions. Infectious panniculitis can occur primarily after direct inoculation or secondarily from hematogenous spread.1 We report a case of methicillin-resistant Staphylococcus aureus (MRSA) panniculitis.
Case presentation
A female in her 20s with relapsed Hodgkin lymphoma (HL) was referred to our centre for autologous stem cell transplantation. She was diagnosed with stage 2 HL in 2016 and underwent chemoradiotherapy, attaining complete remission. She relapsed in 2019 with a recurrent mediastinal mass and widespread lymphadenopathy. She underwent salvage chemotherapy with bendamustine and brentuximab (BB), which was uneventful except for a grade 1 cutaneous adverse drug reaction (CADR) to BB affecting 5% of her body surface area. This resolved with topical steroids and antihistamines. She had no other significant medical or surgical history. Medication on admission for stem cell harvesting included chlorpheniramine 4 mg two times per day, mometasone 0.1% lotion two times per day for her previous CADR and acyclovir 400 mg two times per day for prophylaxis against herpes zoster.
The patient went on to receive mobilisation chemotherapy with ifosfamide, carboplatin and etoposide. Pegfilgrastim was administered on days 5 and 11. On day 11, she was admitted with a fever of 38.3°C and pain in her legs. Examination revealed bilateral scattered tender, indurated subcutaneous nodules over her shins with mild overlying erythema, approximately 3–5 cm in diameter (figure 1). There was a residual dry scaly excoriated hyperpigmented rash from the previous CADR.
Figure 1 Photo of subcutaneous nodule on the lower limb.
Investigations
Investigations on admission showed a white cell count of 0.79×109/L, with neutrophils 0.56×109/L. Following admission, she was started on daily filgrastim due to her neutropaenia and low CD34+ count, which precluded successful mobilisation. C-reactive protein (CRP) was elevated at 74, and procalcitonin was 0.18. Blood cultures and a blood fungal culture were negative. An ultrasound scan of the leg nodule showed vague increased echogenicity and increased vascularity in the subcutaneous tissue with no evidence of abscess formation. A punch biopsy of the nodule confirmed lobular panniculitis with an inflammatory cell infiltrate composed of numerous neutrophils, mixed with lymphocytes, eosinophils, histiocytes and occasional multinucleated giant cells (figure 2A). Granulomas were not observed. No features of vasculitis were identified. Gram-positive cocci were present in the dermis and subcutis (figure 2B). No fungal organisms or acid-fast bacilli were seen on Grocott’s methenamine silver or Ziehl-Neelsen stains. Culture from the punch biopsy grew MRSA. Her antinuclear antibody titre was negative at <1:80. A tuberculosis quantiferon test was negative, and a chest radiograph was normal.
Figure 2 (A) Histology slide showing lobular panniculitis with an inflammatory cell infiltrate composed of numerous neutrophils, mixed with lymphocytes, eosinophils, histiocytes and occasional multinucleated giant cells. (B) Histology slide showing Gram-positive cocci.
Treatment
A diagnosis of infective panniculitis secondary to MRSA was made. She was started on doxycycline with resolution of her fever and nodules. Her filgrastim injections were continued till neutrophil recovery.
Outcome and follow-up
The patient unfortunately failed to mobilise peripheral blood stem cells but went on to have a successful bone marrow harvest with no evidence of microbial contamination of her cyropreserved stem cells. Her lower limb subcutaneous nodules also resolved completely without scarring nor atrophy following treatment with doxycycline.
DISCUSSION
Panniculitis can be classified as septal or lobular, with or without vasculitis. Histologically, infectious panniculitis presents as a neutrophilic predominant mixed inflammatory infiltrate with a lobular pattern of inflammation.2 Infective panniculitis can be caused by bacterial, mycobacterial, fungal, protozoal or viral infections. S. aureus is a skin commensal commonly responsible for primary cutaneous lesions such as folliculitis, carbuncles or cellulitis. Deeper pathology such as abscesses or rarely, panniculitis may result from haematogenous spread in bacteraemic patients,3 or following inoculation from primary superficial lesions. In our patient, repeated blood cultures were negative for S. aureus. Given this, we hypothesise that her prior CADR to BB chemotherapy resulted in weakened skin integrity, superficial inoculation and subsequent deep tissue infection which flared opportunistically when she was neutropaenic. To our knowledge, MRSA-induced panniculitis without bacteremia is rare. However, there have been a few reports of this phenomenon with Pseudomonas aeruginosa.4 5
We initially considered filgrastim-induced panniculitis as a differential. Filgrastim has been associated with several cutaneous reactions such as Sweet’s syndrome, pyoderma gangrenosum and vasculitis. A few cases have been reported in association with pegfilgrastim.6 Possible hypotheses include secondary cytokine production after filgrastim administration and neutrophil activation.7 In our patient, the temporal relationship between administration of pegfilgastrim and her symptoms initially led us to suspect pegfilgrastim as the cause of her panniculitis. However given her positive biopsy culture for MRSA, the presence of Gram-positive cocci in her dermis and subdermal layer, and clinical response to doxycycline despite being continued on filgrastim, we deemed this unlikely.
The site of the lesions, clinical context of HL and neutrophil-rich inflammatory infiltrate also raise the possibility of erythema nodosum. Erythema nodosum is usually idiopathic, but has also been associated with infection, drug, inflammatory condition or malignancy.8 Although this is classically a septal panniculitis,9 there can be histological overlap in some cases.10 Our patient's biopsy was in keeping with that of a lobular panniculitis. Her culture was positive for MRSA which is not a typical infection associated with erythema nodosum. In view of this and her quick response to doxycycline, we concluded erythema nodosum to be less probable.
The possibility of bacterial contamination during the biopsy procedure was also considered. MRSA is endemic in healthcare facilities,11 and patients who are colonised with MRSA may contaminate surrounding environmental surfaces.12 Our institution carries out active surveillance to identify MRSA-colonised patients. Our patient’s MRSA swabs (nasal, axilla and groin) were persistently negative. In addition, the procedure was done under aseptic technique, MRSA was cultured and demonstrated in histology specimens, and she improved following the institution of antimicrobial therapy. In light of this, bacterial contamination was considered unlikely.
Learning points
Infectious panniculitis due to Staphylococcus aureus in the absence of bacteraemia is extremely rare.
Careful workup including biopsy and culture is important to allow correct identification of aetiology and appropriate management.
Appropriate diagnosis allowed continued filgrastim injections so that her time-sensitive stem cell harvest could proceed.
Contributors: APYN drafted the manuscript. Y-LC and W-YJ reviewed and revised the manuscript. SBJW analysed the histology specimen.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | UNK UNK, CYCLIC | DrugDosageText | CC BY-NC | 33563686 | 19,224,532 | 2021-02-09 |
What was the dosage of drug 'FILGRASTIM'? | Methicillin-resistant Staphylococcus aureus (MRSA) panniculitis in a patient undergoing stem cell mobilisation.
Methicillin-resistant Staphylococcus aureus (MRSA) can cause a wide range of skin infections, however MRSA panniculitis without bacteremia is a rare manifestation. Here, we report a woman in her 20s with relapsed Hodgkin lymphoma undergoing stem cell mobilisation who presented with bilateral subcutaneous nodules over her shins. Ultrasound scan of one nodule showed non-specific inflammatory changes. Punch biopsy of a nodule showed lobular panniculitis with Gram-positive cocci. Blood cultures were negative but a culture from the biopsy grew MRSA. She was started on doxycycline with improvement in her symptoms. This case serves as a reminder to consider infections as a cause of panniculitis in immunocompromised patients.
Background
Panniculitis usually presents as painful erythematous nodules or plaques and is characterised by inflammation of subcutaneous adipose tissue. Recognition, diagnosis and evaluation is challenging because of its rarity and myriad causes, including infection, malignancy, drugs and inflammatory conditions. Infectious panniculitis can occur primarily after direct inoculation or secondarily from hematogenous spread.1 We report a case of methicillin-resistant Staphylococcus aureus (MRSA) panniculitis.
Case presentation
A female in her 20s with relapsed Hodgkin lymphoma (HL) was referred to our centre for autologous stem cell transplantation. She was diagnosed with stage 2 HL in 2016 and underwent chemoradiotherapy, attaining complete remission. She relapsed in 2019 with a recurrent mediastinal mass and widespread lymphadenopathy. She underwent salvage chemotherapy with bendamustine and brentuximab (BB), which was uneventful except for a grade 1 cutaneous adverse drug reaction (CADR) to BB affecting 5% of her body surface area. This resolved with topical steroids and antihistamines. She had no other significant medical or surgical history. Medication on admission for stem cell harvesting included chlorpheniramine 4 mg two times per day, mometasone 0.1% lotion two times per day for her previous CADR and acyclovir 400 mg two times per day for prophylaxis against herpes zoster.
The patient went on to receive mobilisation chemotherapy with ifosfamide, carboplatin and etoposide. Pegfilgrastim was administered on days 5 and 11. On day 11, she was admitted with a fever of 38.3°C and pain in her legs. Examination revealed bilateral scattered tender, indurated subcutaneous nodules over her shins with mild overlying erythema, approximately 3–5 cm in diameter (figure 1). There was a residual dry scaly excoriated hyperpigmented rash from the previous CADR.
Figure 1 Photo of subcutaneous nodule on the lower limb.
Investigations
Investigations on admission showed a white cell count of 0.79×109/L, with neutrophils 0.56×109/L. Following admission, she was started on daily filgrastim due to her neutropaenia and low CD34+ count, which precluded successful mobilisation. C-reactive protein (CRP) was elevated at 74, and procalcitonin was 0.18. Blood cultures and a blood fungal culture were negative. An ultrasound scan of the leg nodule showed vague increased echogenicity and increased vascularity in the subcutaneous tissue with no evidence of abscess formation. A punch biopsy of the nodule confirmed lobular panniculitis with an inflammatory cell infiltrate composed of numerous neutrophils, mixed with lymphocytes, eosinophils, histiocytes and occasional multinucleated giant cells (figure 2A). Granulomas were not observed. No features of vasculitis were identified. Gram-positive cocci were present in the dermis and subcutis (figure 2B). No fungal organisms or acid-fast bacilli were seen on Grocott’s methenamine silver or Ziehl-Neelsen stains. Culture from the punch biopsy grew MRSA. Her antinuclear antibody titre was negative at <1:80. A tuberculosis quantiferon test was negative, and a chest radiograph was normal.
Figure 2 (A) Histology slide showing lobular panniculitis with an inflammatory cell infiltrate composed of numerous neutrophils, mixed with lymphocytes, eosinophils, histiocytes and occasional multinucleated giant cells. (B) Histology slide showing Gram-positive cocci.
Treatment
A diagnosis of infective panniculitis secondary to MRSA was made. She was started on doxycycline with resolution of her fever and nodules. Her filgrastim injections were continued till neutrophil recovery.
Outcome and follow-up
The patient unfortunately failed to mobilise peripheral blood stem cells but went on to have a successful bone marrow harvest with no evidence of microbial contamination of her cyropreserved stem cells. Her lower limb subcutaneous nodules also resolved completely without scarring nor atrophy following treatment with doxycycline.
DISCUSSION
Panniculitis can be classified as septal or lobular, with or without vasculitis. Histologically, infectious panniculitis presents as a neutrophilic predominant mixed inflammatory infiltrate with a lobular pattern of inflammation.2 Infective panniculitis can be caused by bacterial, mycobacterial, fungal, protozoal or viral infections. S. aureus is a skin commensal commonly responsible for primary cutaneous lesions such as folliculitis, carbuncles or cellulitis. Deeper pathology such as abscesses or rarely, panniculitis may result from haematogenous spread in bacteraemic patients,3 or following inoculation from primary superficial lesions. In our patient, repeated blood cultures were negative for S. aureus. Given this, we hypothesise that her prior CADR to BB chemotherapy resulted in weakened skin integrity, superficial inoculation and subsequent deep tissue infection which flared opportunistically when she was neutropaenic. To our knowledge, MRSA-induced panniculitis without bacteremia is rare. However, there have been a few reports of this phenomenon with Pseudomonas aeruginosa.4 5
We initially considered filgrastim-induced panniculitis as a differential. Filgrastim has been associated with several cutaneous reactions such as Sweet’s syndrome, pyoderma gangrenosum and vasculitis. A few cases have been reported in association with pegfilgrastim.6 Possible hypotheses include secondary cytokine production after filgrastim administration and neutrophil activation.7 In our patient, the temporal relationship between administration of pegfilgastrim and her symptoms initially led us to suspect pegfilgrastim as the cause of her panniculitis. However given her positive biopsy culture for MRSA, the presence of Gram-positive cocci in her dermis and subdermal layer, and clinical response to doxycycline despite being continued on filgrastim, we deemed this unlikely.
The site of the lesions, clinical context of HL and neutrophil-rich inflammatory infiltrate also raise the possibility of erythema nodosum. Erythema nodosum is usually idiopathic, but has also been associated with infection, drug, inflammatory condition or malignancy.8 Although this is classically a septal panniculitis,9 there can be histological overlap in some cases.10 Our patient's biopsy was in keeping with that of a lobular panniculitis. Her culture was positive for MRSA which is not a typical infection associated with erythema nodosum. In view of this and her quick response to doxycycline, we concluded erythema nodosum to be less probable.
The possibility of bacterial contamination during the biopsy procedure was also considered. MRSA is endemic in healthcare facilities,11 and patients who are colonised with MRSA may contaminate surrounding environmental surfaces.12 Our institution carries out active surveillance to identify MRSA-colonised patients. Our patient’s MRSA swabs (nasal, axilla and groin) were persistently negative. In addition, the procedure was done under aseptic technique, MRSA was cultured and demonstrated in histology specimens, and she improved following the institution of antimicrobial therapy. In light of this, bacterial contamination was considered unlikely.
Learning points
Infectious panniculitis due to Staphylococcus aureus in the absence of bacteraemia is extremely rare.
Careful workup including biopsy and culture is important to allow correct identification of aetiology and appropriate management.
Appropriate diagnosis allowed continued filgrastim injections so that her time-sensitive stem cell harvest could proceed.
Contributors: APYN drafted the manuscript. Y-LC and W-YJ reviewed and revised the manuscript. SBJW analysed the histology specimen.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | DAILY | DrugDosageText | CC BY-NC | 33563686 | 19,019,075 | 2021-02-09 |
What was the dosage of drug 'MOMETASONE'? | Methicillin-resistant Staphylococcus aureus (MRSA) panniculitis in a patient undergoing stem cell mobilisation.
Methicillin-resistant Staphylococcus aureus (MRSA) can cause a wide range of skin infections, however MRSA panniculitis without bacteremia is a rare manifestation. Here, we report a woman in her 20s with relapsed Hodgkin lymphoma undergoing stem cell mobilisation who presented with bilateral subcutaneous nodules over her shins. Ultrasound scan of one nodule showed non-specific inflammatory changes. Punch biopsy of a nodule showed lobular panniculitis with Gram-positive cocci. Blood cultures were negative but a culture from the biopsy grew MRSA. She was started on doxycycline with improvement in her symptoms. This case serves as a reminder to consider infections as a cause of panniculitis in immunocompromised patients.
Background
Panniculitis usually presents as painful erythematous nodules or plaques and is characterised by inflammation of subcutaneous adipose tissue. Recognition, diagnosis and evaluation is challenging because of its rarity and myriad causes, including infection, malignancy, drugs and inflammatory conditions. Infectious panniculitis can occur primarily after direct inoculation or secondarily from hematogenous spread.1 We report a case of methicillin-resistant Staphylococcus aureus (MRSA) panniculitis.
Case presentation
A female in her 20s with relapsed Hodgkin lymphoma (HL) was referred to our centre for autologous stem cell transplantation. She was diagnosed with stage 2 HL in 2016 and underwent chemoradiotherapy, attaining complete remission. She relapsed in 2019 with a recurrent mediastinal mass and widespread lymphadenopathy. She underwent salvage chemotherapy with bendamustine and brentuximab (BB), which was uneventful except for a grade 1 cutaneous adverse drug reaction (CADR) to BB affecting 5% of her body surface area. This resolved with topical steroids and antihistamines. She had no other significant medical or surgical history. Medication on admission for stem cell harvesting included chlorpheniramine 4 mg two times per day, mometasone 0.1% lotion two times per day for her previous CADR and acyclovir 400 mg two times per day for prophylaxis against herpes zoster.
The patient went on to receive mobilisation chemotherapy with ifosfamide, carboplatin and etoposide. Pegfilgrastim was administered on days 5 and 11. On day 11, she was admitted with a fever of 38.3°C and pain in her legs. Examination revealed bilateral scattered tender, indurated subcutaneous nodules over her shins with mild overlying erythema, approximately 3–5 cm in diameter (figure 1). There was a residual dry scaly excoriated hyperpigmented rash from the previous CADR.
Figure 1 Photo of subcutaneous nodule on the lower limb.
Investigations
Investigations on admission showed a white cell count of 0.79×109/L, with neutrophils 0.56×109/L. Following admission, she was started on daily filgrastim due to her neutropaenia and low CD34+ count, which precluded successful mobilisation. C-reactive protein (CRP) was elevated at 74, and procalcitonin was 0.18. Blood cultures and a blood fungal culture were negative. An ultrasound scan of the leg nodule showed vague increased echogenicity and increased vascularity in the subcutaneous tissue with no evidence of abscess formation. A punch biopsy of the nodule confirmed lobular panniculitis with an inflammatory cell infiltrate composed of numerous neutrophils, mixed with lymphocytes, eosinophils, histiocytes and occasional multinucleated giant cells (figure 2A). Granulomas were not observed. No features of vasculitis were identified. Gram-positive cocci were present in the dermis and subcutis (figure 2B). No fungal organisms or acid-fast bacilli were seen on Grocott’s methenamine silver or Ziehl-Neelsen stains. Culture from the punch biopsy grew MRSA. Her antinuclear antibody titre was negative at <1:80. A tuberculosis quantiferon test was negative, and a chest radiograph was normal.
Figure 2 (A) Histology slide showing lobular panniculitis with an inflammatory cell infiltrate composed of numerous neutrophils, mixed with lymphocytes, eosinophils, histiocytes and occasional multinucleated giant cells. (B) Histology slide showing Gram-positive cocci.
Treatment
A diagnosis of infective panniculitis secondary to MRSA was made. She was started on doxycycline with resolution of her fever and nodules. Her filgrastim injections were continued till neutrophil recovery.
Outcome and follow-up
The patient unfortunately failed to mobilise peripheral blood stem cells but went on to have a successful bone marrow harvest with no evidence of microbial contamination of her cyropreserved stem cells. Her lower limb subcutaneous nodules also resolved completely without scarring nor atrophy following treatment with doxycycline.
DISCUSSION
Panniculitis can be classified as septal or lobular, with or without vasculitis. Histologically, infectious panniculitis presents as a neutrophilic predominant mixed inflammatory infiltrate with a lobular pattern of inflammation.2 Infective panniculitis can be caused by bacterial, mycobacterial, fungal, protozoal or viral infections. S. aureus is a skin commensal commonly responsible for primary cutaneous lesions such as folliculitis, carbuncles or cellulitis. Deeper pathology such as abscesses or rarely, panniculitis may result from haematogenous spread in bacteraemic patients,3 or following inoculation from primary superficial lesions. In our patient, repeated blood cultures were negative for S. aureus. Given this, we hypothesise that her prior CADR to BB chemotherapy resulted in weakened skin integrity, superficial inoculation and subsequent deep tissue infection which flared opportunistically when she was neutropaenic. To our knowledge, MRSA-induced panniculitis without bacteremia is rare. However, there have been a few reports of this phenomenon with Pseudomonas aeruginosa.4 5
We initially considered filgrastim-induced panniculitis as a differential. Filgrastim has been associated with several cutaneous reactions such as Sweet’s syndrome, pyoderma gangrenosum and vasculitis. A few cases have been reported in association with pegfilgrastim.6 Possible hypotheses include secondary cytokine production after filgrastim administration and neutrophil activation.7 In our patient, the temporal relationship between administration of pegfilgastrim and her symptoms initially led us to suspect pegfilgrastim as the cause of her panniculitis. However given her positive biopsy culture for MRSA, the presence of Gram-positive cocci in her dermis and subdermal layer, and clinical response to doxycycline despite being continued on filgrastim, we deemed this unlikely.
The site of the lesions, clinical context of HL and neutrophil-rich inflammatory infiltrate also raise the possibility of erythema nodosum. Erythema nodosum is usually idiopathic, but has also been associated with infection, drug, inflammatory condition or malignancy.8 Although this is classically a septal panniculitis,9 there can be histological overlap in some cases.10 Our patient's biopsy was in keeping with that of a lobular panniculitis. Her culture was positive for MRSA which is not a typical infection associated with erythema nodosum. In view of this and her quick response to doxycycline, we concluded erythema nodosum to be less probable.
The possibility of bacterial contamination during the biopsy procedure was also considered. MRSA is endemic in healthcare facilities,11 and patients who are colonised with MRSA may contaminate surrounding environmental surfaces.12 Our institution carries out active surveillance to identify MRSA-colonised patients. Our patient’s MRSA swabs (nasal, axilla and groin) were persistently negative. In addition, the procedure was done under aseptic technique, MRSA was cultured and demonstrated in histology specimens, and she improved following the institution of antimicrobial therapy. In light of this, bacterial contamination was considered unlikely.
Learning points
Infectious panniculitis due to Staphylococcus aureus in the absence of bacteraemia is extremely rare.
Careful workup including biopsy and culture is important to allow correct identification of aetiology and appropriate management.
Appropriate diagnosis allowed continued filgrastim injections so that her time-sensitive stem cell harvest could proceed.
Contributors: APYN drafted the manuscript. Y-LC and W-YJ reviewed and revised the manuscript. SBJW analysed the histology specimen.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | LOTION | DrugDosageText | CC BY-NC | 33563686 | 19,019,075 | 2021-02-09 |
What was the outcome of reaction 'Erythema'? | Methicillin-resistant Staphylococcus aureus (MRSA) panniculitis in a patient undergoing stem cell mobilisation.
Methicillin-resistant Staphylococcus aureus (MRSA) can cause a wide range of skin infections, however MRSA panniculitis without bacteremia is a rare manifestation. Here, we report a woman in her 20s with relapsed Hodgkin lymphoma undergoing stem cell mobilisation who presented with bilateral subcutaneous nodules over her shins. Ultrasound scan of one nodule showed non-specific inflammatory changes. Punch biopsy of a nodule showed lobular panniculitis with Gram-positive cocci. Blood cultures were negative but a culture from the biopsy grew MRSA. She was started on doxycycline with improvement in her symptoms. This case serves as a reminder to consider infections as a cause of panniculitis in immunocompromised patients.
Background
Panniculitis usually presents as painful erythematous nodules or plaques and is characterised by inflammation of subcutaneous adipose tissue. Recognition, diagnosis and evaluation is challenging because of its rarity and myriad causes, including infection, malignancy, drugs and inflammatory conditions. Infectious panniculitis can occur primarily after direct inoculation or secondarily from hematogenous spread.1 We report a case of methicillin-resistant Staphylococcus aureus (MRSA) panniculitis.
Case presentation
A female in her 20s with relapsed Hodgkin lymphoma (HL) was referred to our centre for autologous stem cell transplantation. She was diagnosed with stage 2 HL in 2016 and underwent chemoradiotherapy, attaining complete remission. She relapsed in 2019 with a recurrent mediastinal mass and widespread lymphadenopathy. She underwent salvage chemotherapy with bendamustine and brentuximab (BB), which was uneventful except for a grade 1 cutaneous adverse drug reaction (CADR) to BB affecting 5% of her body surface area. This resolved with topical steroids and antihistamines. She had no other significant medical or surgical history. Medication on admission for stem cell harvesting included chlorpheniramine 4 mg two times per day, mometasone 0.1% lotion two times per day for her previous CADR and acyclovir 400 mg two times per day for prophylaxis against herpes zoster.
The patient went on to receive mobilisation chemotherapy with ifosfamide, carboplatin and etoposide. Pegfilgrastim was administered on days 5 and 11. On day 11, she was admitted with a fever of 38.3°C and pain in her legs. Examination revealed bilateral scattered tender, indurated subcutaneous nodules over her shins with mild overlying erythema, approximately 3–5 cm in diameter (figure 1). There was a residual dry scaly excoriated hyperpigmented rash from the previous CADR.
Figure 1 Photo of subcutaneous nodule on the lower limb.
Investigations
Investigations on admission showed a white cell count of 0.79×109/L, with neutrophils 0.56×109/L. Following admission, she was started on daily filgrastim due to her neutropaenia and low CD34+ count, which precluded successful mobilisation. C-reactive protein (CRP) was elevated at 74, and procalcitonin was 0.18. Blood cultures and a blood fungal culture were negative. An ultrasound scan of the leg nodule showed vague increased echogenicity and increased vascularity in the subcutaneous tissue with no evidence of abscess formation. A punch biopsy of the nodule confirmed lobular panniculitis with an inflammatory cell infiltrate composed of numerous neutrophils, mixed with lymphocytes, eosinophils, histiocytes and occasional multinucleated giant cells (figure 2A). Granulomas were not observed. No features of vasculitis were identified. Gram-positive cocci were present in the dermis and subcutis (figure 2B). No fungal organisms or acid-fast bacilli were seen on Grocott’s methenamine silver or Ziehl-Neelsen stains. Culture from the punch biopsy grew MRSA. Her antinuclear antibody titre was negative at <1:80. A tuberculosis quantiferon test was negative, and a chest radiograph was normal.
Figure 2 (A) Histology slide showing lobular panniculitis with an inflammatory cell infiltrate composed of numerous neutrophils, mixed with lymphocytes, eosinophils, histiocytes and occasional multinucleated giant cells. (B) Histology slide showing Gram-positive cocci.
Treatment
A diagnosis of infective panniculitis secondary to MRSA was made. She was started on doxycycline with resolution of her fever and nodules. Her filgrastim injections were continued till neutrophil recovery.
Outcome and follow-up
The patient unfortunately failed to mobilise peripheral blood stem cells but went on to have a successful bone marrow harvest with no evidence of microbial contamination of her cyropreserved stem cells. Her lower limb subcutaneous nodules also resolved completely without scarring nor atrophy following treatment with doxycycline.
DISCUSSION
Panniculitis can be classified as septal or lobular, with or without vasculitis. Histologically, infectious panniculitis presents as a neutrophilic predominant mixed inflammatory infiltrate with a lobular pattern of inflammation.2 Infective panniculitis can be caused by bacterial, mycobacterial, fungal, protozoal or viral infections. S. aureus is a skin commensal commonly responsible for primary cutaneous lesions such as folliculitis, carbuncles or cellulitis. Deeper pathology such as abscesses or rarely, panniculitis may result from haematogenous spread in bacteraemic patients,3 or following inoculation from primary superficial lesions. In our patient, repeated blood cultures were negative for S. aureus. Given this, we hypothesise that her prior CADR to BB chemotherapy resulted in weakened skin integrity, superficial inoculation and subsequent deep tissue infection which flared opportunistically when she was neutropaenic. To our knowledge, MRSA-induced panniculitis without bacteremia is rare. However, there have been a few reports of this phenomenon with Pseudomonas aeruginosa.4 5
We initially considered filgrastim-induced panniculitis as a differential. Filgrastim has been associated with several cutaneous reactions such as Sweet’s syndrome, pyoderma gangrenosum and vasculitis. A few cases have been reported in association with pegfilgrastim.6 Possible hypotheses include secondary cytokine production after filgrastim administration and neutrophil activation.7 In our patient, the temporal relationship between administration of pegfilgastrim and her symptoms initially led us to suspect pegfilgrastim as the cause of her panniculitis. However given her positive biopsy culture for MRSA, the presence of Gram-positive cocci in her dermis and subdermal layer, and clinical response to doxycycline despite being continued on filgrastim, we deemed this unlikely.
The site of the lesions, clinical context of HL and neutrophil-rich inflammatory infiltrate also raise the possibility of erythema nodosum. Erythema nodosum is usually idiopathic, but has also been associated with infection, drug, inflammatory condition or malignancy.8 Although this is classically a septal panniculitis,9 there can be histological overlap in some cases.10 Our patient's biopsy was in keeping with that of a lobular panniculitis. Her culture was positive for MRSA which is not a typical infection associated with erythema nodosum. In view of this and her quick response to doxycycline, we concluded erythema nodosum to be less probable.
The possibility of bacterial contamination during the biopsy procedure was also considered. MRSA is endemic in healthcare facilities,11 and patients who are colonised with MRSA may contaminate surrounding environmental surfaces.12 Our institution carries out active surveillance to identify MRSA-colonised patients. Our patient’s MRSA swabs (nasal, axilla and groin) were persistently negative. In addition, the procedure was done under aseptic technique, MRSA was cultured and demonstrated in histology specimens, and she improved following the institution of antimicrobial therapy. In light of this, bacterial contamination was considered unlikely.
Learning points
Infectious panniculitis due to Staphylococcus aureus in the absence of bacteraemia is extremely rare.
Careful workup including biopsy and culture is important to allow correct identification of aetiology and appropriate management.
Appropriate diagnosis allowed continued filgrastim injections so that her time-sensitive stem cell harvest could proceed.
Contributors: APYN drafted the manuscript. Y-LC and W-YJ reviewed and revised the manuscript. SBJW analysed the histology specimen.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Recovered | ReactionOutcome | CC BY-NC | 33563686 | 19,224,532 | 2021-02-09 |
What was the outcome of reaction 'Pain in extremity'? | Methicillin-resistant Staphylococcus aureus (MRSA) panniculitis in a patient undergoing stem cell mobilisation.
Methicillin-resistant Staphylococcus aureus (MRSA) can cause a wide range of skin infections, however MRSA panniculitis without bacteremia is a rare manifestation. Here, we report a woman in her 20s with relapsed Hodgkin lymphoma undergoing stem cell mobilisation who presented with bilateral subcutaneous nodules over her shins. Ultrasound scan of one nodule showed non-specific inflammatory changes. Punch biopsy of a nodule showed lobular panniculitis with Gram-positive cocci. Blood cultures were negative but a culture from the biopsy grew MRSA. She was started on doxycycline with improvement in her symptoms. This case serves as a reminder to consider infections as a cause of panniculitis in immunocompromised patients.
Background
Panniculitis usually presents as painful erythematous nodules or plaques and is characterised by inflammation of subcutaneous adipose tissue. Recognition, diagnosis and evaluation is challenging because of its rarity and myriad causes, including infection, malignancy, drugs and inflammatory conditions. Infectious panniculitis can occur primarily after direct inoculation or secondarily from hematogenous spread.1 We report a case of methicillin-resistant Staphylococcus aureus (MRSA) panniculitis.
Case presentation
A female in her 20s with relapsed Hodgkin lymphoma (HL) was referred to our centre for autologous stem cell transplantation. She was diagnosed with stage 2 HL in 2016 and underwent chemoradiotherapy, attaining complete remission. She relapsed in 2019 with a recurrent mediastinal mass and widespread lymphadenopathy. She underwent salvage chemotherapy with bendamustine and brentuximab (BB), which was uneventful except for a grade 1 cutaneous adverse drug reaction (CADR) to BB affecting 5% of her body surface area. This resolved with topical steroids and antihistamines. She had no other significant medical or surgical history. Medication on admission for stem cell harvesting included chlorpheniramine 4 mg two times per day, mometasone 0.1% lotion two times per day for her previous CADR and acyclovir 400 mg two times per day for prophylaxis against herpes zoster.
The patient went on to receive mobilisation chemotherapy with ifosfamide, carboplatin and etoposide. Pegfilgrastim was administered on days 5 and 11. On day 11, she was admitted with a fever of 38.3°C and pain in her legs. Examination revealed bilateral scattered tender, indurated subcutaneous nodules over her shins with mild overlying erythema, approximately 3–5 cm in diameter (figure 1). There was a residual dry scaly excoriated hyperpigmented rash from the previous CADR.
Figure 1 Photo of subcutaneous nodule on the lower limb.
Investigations
Investigations on admission showed a white cell count of 0.79×109/L, with neutrophils 0.56×109/L. Following admission, she was started on daily filgrastim due to her neutropaenia and low CD34+ count, which precluded successful mobilisation. C-reactive protein (CRP) was elevated at 74, and procalcitonin was 0.18. Blood cultures and a blood fungal culture were negative. An ultrasound scan of the leg nodule showed vague increased echogenicity and increased vascularity in the subcutaneous tissue with no evidence of abscess formation. A punch biopsy of the nodule confirmed lobular panniculitis with an inflammatory cell infiltrate composed of numerous neutrophils, mixed with lymphocytes, eosinophils, histiocytes and occasional multinucleated giant cells (figure 2A). Granulomas were not observed. No features of vasculitis were identified. Gram-positive cocci were present in the dermis and subcutis (figure 2B). No fungal organisms or acid-fast bacilli were seen on Grocott’s methenamine silver or Ziehl-Neelsen stains. Culture from the punch biopsy grew MRSA. Her antinuclear antibody titre was negative at <1:80. A tuberculosis quantiferon test was negative, and a chest radiograph was normal.
Figure 2 (A) Histology slide showing lobular panniculitis with an inflammatory cell infiltrate composed of numerous neutrophils, mixed with lymphocytes, eosinophils, histiocytes and occasional multinucleated giant cells. (B) Histology slide showing Gram-positive cocci.
Treatment
A diagnosis of infective panniculitis secondary to MRSA was made. She was started on doxycycline with resolution of her fever and nodules. Her filgrastim injections were continued till neutrophil recovery.
Outcome and follow-up
The patient unfortunately failed to mobilise peripheral blood stem cells but went on to have a successful bone marrow harvest with no evidence of microbial contamination of her cyropreserved stem cells. Her lower limb subcutaneous nodules also resolved completely without scarring nor atrophy following treatment with doxycycline.
DISCUSSION
Panniculitis can be classified as septal or lobular, with or without vasculitis. Histologically, infectious panniculitis presents as a neutrophilic predominant mixed inflammatory infiltrate with a lobular pattern of inflammation.2 Infective panniculitis can be caused by bacterial, mycobacterial, fungal, protozoal or viral infections. S. aureus is a skin commensal commonly responsible for primary cutaneous lesions such as folliculitis, carbuncles or cellulitis. Deeper pathology such as abscesses or rarely, panniculitis may result from haematogenous spread in bacteraemic patients,3 or following inoculation from primary superficial lesions. In our patient, repeated blood cultures were negative for S. aureus. Given this, we hypothesise that her prior CADR to BB chemotherapy resulted in weakened skin integrity, superficial inoculation and subsequent deep tissue infection which flared opportunistically when she was neutropaenic. To our knowledge, MRSA-induced panniculitis without bacteremia is rare. However, there have been a few reports of this phenomenon with Pseudomonas aeruginosa.4 5
We initially considered filgrastim-induced panniculitis as a differential. Filgrastim has been associated with several cutaneous reactions such as Sweet’s syndrome, pyoderma gangrenosum and vasculitis. A few cases have been reported in association with pegfilgrastim.6 Possible hypotheses include secondary cytokine production after filgrastim administration and neutrophil activation.7 In our patient, the temporal relationship between administration of pegfilgastrim and her symptoms initially led us to suspect pegfilgrastim as the cause of her panniculitis. However given her positive biopsy culture for MRSA, the presence of Gram-positive cocci in her dermis and subdermal layer, and clinical response to doxycycline despite being continued on filgrastim, we deemed this unlikely.
The site of the lesions, clinical context of HL and neutrophil-rich inflammatory infiltrate also raise the possibility of erythema nodosum. Erythema nodosum is usually idiopathic, but has also been associated with infection, drug, inflammatory condition or malignancy.8 Although this is classically a septal panniculitis,9 there can be histological overlap in some cases.10 Our patient's biopsy was in keeping with that of a lobular panniculitis. Her culture was positive for MRSA which is not a typical infection associated with erythema nodosum. In view of this and her quick response to doxycycline, we concluded erythema nodosum to be less probable.
The possibility of bacterial contamination during the biopsy procedure was also considered. MRSA is endemic in healthcare facilities,11 and patients who are colonised with MRSA may contaminate surrounding environmental surfaces.12 Our institution carries out active surveillance to identify MRSA-colonised patients. Our patient’s MRSA swabs (nasal, axilla and groin) were persistently negative. In addition, the procedure was done under aseptic technique, MRSA was cultured and demonstrated in histology specimens, and she improved following the institution of antimicrobial therapy. In light of this, bacterial contamination was considered unlikely.
Learning points
Infectious panniculitis due to Staphylococcus aureus in the absence of bacteraemia is extremely rare.
Careful workup including biopsy and culture is important to allow correct identification of aetiology and appropriate management.
Appropriate diagnosis allowed continued filgrastim injections so that her time-sensitive stem cell harvest could proceed.
Contributors: APYN drafted the manuscript. Y-LC and W-YJ reviewed and revised the manuscript. SBJW analysed the histology specimen.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Recovered | ReactionOutcome | CC BY-NC | 33563686 | 19,224,532 | 2021-02-09 |
What was the outcome of reaction 'Panniculitis'? | Methicillin-resistant Staphylococcus aureus (MRSA) panniculitis in a patient undergoing stem cell mobilisation.
Methicillin-resistant Staphylococcus aureus (MRSA) can cause a wide range of skin infections, however MRSA panniculitis without bacteremia is a rare manifestation. Here, we report a woman in her 20s with relapsed Hodgkin lymphoma undergoing stem cell mobilisation who presented with bilateral subcutaneous nodules over her shins. Ultrasound scan of one nodule showed non-specific inflammatory changes. Punch biopsy of a nodule showed lobular panniculitis with Gram-positive cocci. Blood cultures were negative but a culture from the biopsy grew MRSA. She was started on doxycycline with improvement in her symptoms. This case serves as a reminder to consider infections as a cause of panniculitis in immunocompromised patients.
Background
Panniculitis usually presents as painful erythematous nodules or plaques and is characterised by inflammation of subcutaneous adipose tissue. Recognition, diagnosis and evaluation is challenging because of its rarity and myriad causes, including infection, malignancy, drugs and inflammatory conditions. Infectious panniculitis can occur primarily after direct inoculation or secondarily from hematogenous spread.1 We report a case of methicillin-resistant Staphylococcus aureus (MRSA) panniculitis.
Case presentation
A female in her 20s with relapsed Hodgkin lymphoma (HL) was referred to our centre for autologous stem cell transplantation. She was diagnosed with stage 2 HL in 2016 and underwent chemoradiotherapy, attaining complete remission. She relapsed in 2019 with a recurrent mediastinal mass and widespread lymphadenopathy. She underwent salvage chemotherapy with bendamustine and brentuximab (BB), which was uneventful except for a grade 1 cutaneous adverse drug reaction (CADR) to BB affecting 5% of her body surface area. This resolved with topical steroids and antihistamines. She had no other significant medical or surgical history. Medication on admission for stem cell harvesting included chlorpheniramine 4 mg two times per day, mometasone 0.1% lotion two times per day for her previous CADR and acyclovir 400 mg two times per day for prophylaxis against herpes zoster.
The patient went on to receive mobilisation chemotherapy with ifosfamide, carboplatin and etoposide. Pegfilgrastim was administered on days 5 and 11. On day 11, she was admitted with a fever of 38.3°C and pain in her legs. Examination revealed bilateral scattered tender, indurated subcutaneous nodules over her shins with mild overlying erythema, approximately 3–5 cm in diameter (figure 1). There was a residual dry scaly excoriated hyperpigmented rash from the previous CADR.
Figure 1 Photo of subcutaneous nodule on the lower limb.
Investigations
Investigations on admission showed a white cell count of 0.79×109/L, with neutrophils 0.56×109/L. Following admission, she was started on daily filgrastim due to her neutropaenia and low CD34+ count, which precluded successful mobilisation. C-reactive protein (CRP) was elevated at 74, and procalcitonin was 0.18. Blood cultures and a blood fungal culture were negative. An ultrasound scan of the leg nodule showed vague increased echogenicity and increased vascularity in the subcutaneous tissue with no evidence of abscess formation. A punch biopsy of the nodule confirmed lobular panniculitis with an inflammatory cell infiltrate composed of numerous neutrophils, mixed with lymphocytes, eosinophils, histiocytes and occasional multinucleated giant cells (figure 2A). Granulomas were not observed. No features of vasculitis were identified. Gram-positive cocci were present in the dermis and subcutis (figure 2B). No fungal organisms or acid-fast bacilli were seen on Grocott’s methenamine silver or Ziehl-Neelsen stains. Culture from the punch biopsy grew MRSA. Her antinuclear antibody titre was negative at <1:80. A tuberculosis quantiferon test was negative, and a chest radiograph was normal.
Figure 2 (A) Histology slide showing lobular panniculitis with an inflammatory cell infiltrate composed of numerous neutrophils, mixed with lymphocytes, eosinophils, histiocytes and occasional multinucleated giant cells. (B) Histology slide showing Gram-positive cocci.
Treatment
A diagnosis of infective panniculitis secondary to MRSA was made. She was started on doxycycline with resolution of her fever and nodules. Her filgrastim injections were continued till neutrophil recovery.
Outcome and follow-up
The patient unfortunately failed to mobilise peripheral blood stem cells but went on to have a successful bone marrow harvest with no evidence of microbial contamination of her cyropreserved stem cells. Her lower limb subcutaneous nodules also resolved completely without scarring nor atrophy following treatment with doxycycline.
DISCUSSION
Panniculitis can be classified as septal or lobular, with or without vasculitis. Histologically, infectious panniculitis presents as a neutrophilic predominant mixed inflammatory infiltrate with a lobular pattern of inflammation.2 Infective panniculitis can be caused by bacterial, mycobacterial, fungal, protozoal or viral infections. S. aureus is a skin commensal commonly responsible for primary cutaneous lesions such as folliculitis, carbuncles or cellulitis. Deeper pathology such as abscesses or rarely, panniculitis may result from haematogenous spread in bacteraemic patients,3 or following inoculation from primary superficial lesions. In our patient, repeated blood cultures were negative for S. aureus. Given this, we hypothesise that her prior CADR to BB chemotherapy resulted in weakened skin integrity, superficial inoculation and subsequent deep tissue infection which flared opportunistically when she was neutropaenic. To our knowledge, MRSA-induced panniculitis without bacteremia is rare. However, there have been a few reports of this phenomenon with Pseudomonas aeruginosa.4 5
We initially considered filgrastim-induced panniculitis as a differential. Filgrastim has been associated with several cutaneous reactions such as Sweet’s syndrome, pyoderma gangrenosum and vasculitis. A few cases have been reported in association with pegfilgrastim.6 Possible hypotheses include secondary cytokine production after filgrastim administration and neutrophil activation.7 In our patient, the temporal relationship between administration of pegfilgastrim and her symptoms initially led us to suspect pegfilgrastim as the cause of her panniculitis. However given her positive biopsy culture for MRSA, the presence of Gram-positive cocci in her dermis and subdermal layer, and clinical response to doxycycline despite being continued on filgrastim, we deemed this unlikely.
The site of the lesions, clinical context of HL and neutrophil-rich inflammatory infiltrate also raise the possibility of erythema nodosum. Erythema nodosum is usually idiopathic, but has also been associated with infection, drug, inflammatory condition or malignancy.8 Although this is classically a septal panniculitis,9 there can be histological overlap in some cases.10 Our patient's biopsy was in keeping with that of a lobular panniculitis. Her culture was positive for MRSA which is not a typical infection associated with erythema nodosum. In view of this and her quick response to doxycycline, we concluded erythema nodosum to be less probable.
The possibility of bacterial contamination during the biopsy procedure was also considered. MRSA is endemic in healthcare facilities,11 and patients who are colonised with MRSA may contaminate surrounding environmental surfaces.12 Our institution carries out active surveillance to identify MRSA-colonised patients. Our patient’s MRSA swabs (nasal, axilla and groin) were persistently negative. In addition, the procedure was done under aseptic technique, MRSA was cultured and demonstrated in histology specimens, and she improved following the institution of antimicrobial therapy. In light of this, bacterial contamination was considered unlikely.
Learning points
Infectious panniculitis due to Staphylococcus aureus in the absence of bacteraemia is extremely rare.
Careful workup including biopsy and culture is important to allow correct identification of aetiology and appropriate management.
Appropriate diagnosis allowed continued filgrastim injections so that her time-sensitive stem cell harvest could proceed.
Contributors: APYN drafted the manuscript. Y-LC and W-YJ reviewed and revised the manuscript. SBJW analysed the histology specimen.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Recovered | ReactionOutcome | CC BY-NC | 33563686 | 19,019,075 | 2021-02-09 |
What was the outcome of reaction 'Pyrexia'? | Methicillin-resistant Staphylococcus aureus (MRSA) panniculitis in a patient undergoing stem cell mobilisation.
Methicillin-resistant Staphylococcus aureus (MRSA) can cause a wide range of skin infections, however MRSA panniculitis without bacteremia is a rare manifestation. Here, we report a woman in her 20s with relapsed Hodgkin lymphoma undergoing stem cell mobilisation who presented with bilateral subcutaneous nodules over her shins. Ultrasound scan of one nodule showed non-specific inflammatory changes. Punch biopsy of a nodule showed lobular panniculitis with Gram-positive cocci. Blood cultures were negative but a culture from the biopsy grew MRSA. She was started on doxycycline with improvement in her symptoms. This case serves as a reminder to consider infections as a cause of panniculitis in immunocompromised patients.
Background
Panniculitis usually presents as painful erythematous nodules or plaques and is characterised by inflammation of subcutaneous adipose tissue. Recognition, diagnosis and evaluation is challenging because of its rarity and myriad causes, including infection, malignancy, drugs and inflammatory conditions. Infectious panniculitis can occur primarily after direct inoculation or secondarily from hematogenous spread.1 We report a case of methicillin-resistant Staphylococcus aureus (MRSA) panniculitis.
Case presentation
A female in her 20s with relapsed Hodgkin lymphoma (HL) was referred to our centre for autologous stem cell transplantation. She was diagnosed with stage 2 HL in 2016 and underwent chemoradiotherapy, attaining complete remission. She relapsed in 2019 with a recurrent mediastinal mass and widespread lymphadenopathy. She underwent salvage chemotherapy with bendamustine and brentuximab (BB), which was uneventful except for a grade 1 cutaneous adverse drug reaction (CADR) to BB affecting 5% of her body surface area. This resolved with topical steroids and antihistamines. She had no other significant medical or surgical history. Medication on admission for stem cell harvesting included chlorpheniramine 4 mg two times per day, mometasone 0.1% lotion two times per day for her previous CADR and acyclovir 400 mg two times per day for prophylaxis against herpes zoster.
The patient went on to receive mobilisation chemotherapy with ifosfamide, carboplatin and etoposide. Pegfilgrastim was administered on days 5 and 11. On day 11, she was admitted with a fever of 38.3°C and pain in her legs. Examination revealed bilateral scattered tender, indurated subcutaneous nodules over her shins with mild overlying erythema, approximately 3–5 cm in diameter (figure 1). There was a residual dry scaly excoriated hyperpigmented rash from the previous CADR.
Figure 1 Photo of subcutaneous nodule on the lower limb.
Investigations
Investigations on admission showed a white cell count of 0.79×109/L, with neutrophils 0.56×109/L. Following admission, she was started on daily filgrastim due to her neutropaenia and low CD34+ count, which precluded successful mobilisation. C-reactive protein (CRP) was elevated at 74, and procalcitonin was 0.18. Blood cultures and a blood fungal culture were negative. An ultrasound scan of the leg nodule showed vague increased echogenicity and increased vascularity in the subcutaneous tissue with no evidence of abscess formation. A punch biopsy of the nodule confirmed lobular panniculitis with an inflammatory cell infiltrate composed of numerous neutrophils, mixed with lymphocytes, eosinophils, histiocytes and occasional multinucleated giant cells (figure 2A). Granulomas were not observed. No features of vasculitis were identified. Gram-positive cocci were present in the dermis and subcutis (figure 2B). No fungal organisms or acid-fast bacilli were seen on Grocott’s methenamine silver or Ziehl-Neelsen stains. Culture from the punch biopsy grew MRSA. Her antinuclear antibody titre was negative at <1:80. A tuberculosis quantiferon test was negative, and a chest radiograph was normal.
Figure 2 (A) Histology slide showing lobular panniculitis with an inflammatory cell infiltrate composed of numerous neutrophils, mixed with lymphocytes, eosinophils, histiocytes and occasional multinucleated giant cells. (B) Histology slide showing Gram-positive cocci.
Treatment
A diagnosis of infective panniculitis secondary to MRSA was made. She was started on doxycycline with resolution of her fever and nodules. Her filgrastim injections were continued till neutrophil recovery.
Outcome and follow-up
The patient unfortunately failed to mobilise peripheral blood stem cells but went on to have a successful bone marrow harvest with no evidence of microbial contamination of her cyropreserved stem cells. Her lower limb subcutaneous nodules also resolved completely without scarring nor atrophy following treatment with doxycycline.
DISCUSSION
Panniculitis can be classified as septal or lobular, with or without vasculitis. Histologically, infectious panniculitis presents as a neutrophilic predominant mixed inflammatory infiltrate with a lobular pattern of inflammation.2 Infective panniculitis can be caused by bacterial, mycobacterial, fungal, protozoal or viral infections. S. aureus is a skin commensal commonly responsible for primary cutaneous lesions such as folliculitis, carbuncles or cellulitis. Deeper pathology such as abscesses or rarely, panniculitis may result from haematogenous spread in bacteraemic patients,3 or following inoculation from primary superficial lesions. In our patient, repeated blood cultures were negative for S. aureus. Given this, we hypothesise that her prior CADR to BB chemotherapy resulted in weakened skin integrity, superficial inoculation and subsequent deep tissue infection which flared opportunistically when she was neutropaenic. To our knowledge, MRSA-induced panniculitis without bacteremia is rare. However, there have been a few reports of this phenomenon with Pseudomonas aeruginosa.4 5
We initially considered filgrastim-induced panniculitis as a differential. Filgrastim has been associated with several cutaneous reactions such as Sweet’s syndrome, pyoderma gangrenosum and vasculitis. A few cases have been reported in association with pegfilgrastim.6 Possible hypotheses include secondary cytokine production after filgrastim administration and neutrophil activation.7 In our patient, the temporal relationship between administration of pegfilgastrim and her symptoms initially led us to suspect pegfilgrastim as the cause of her panniculitis. However given her positive biopsy culture for MRSA, the presence of Gram-positive cocci in her dermis and subdermal layer, and clinical response to doxycycline despite being continued on filgrastim, we deemed this unlikely.
The site of the lesions, clinical context of HL and neutrophil-rich inflammatory infiltrate also raise the possibility of erythema nodosum. Erythema nodosum is usually idiopathic, but has also been associated with infection, drug, inflammatory condition or malignancy.8 Although this is classically a septal panniculitis,9 there can be histological overlap in some cases.10 Our patient's biopsy was in keeping with that of a lobular panniculitis. Her culture was positive for MRSA which is not a typical infection associated with erythema nodosum. In view of this and her quick response to doxycycline, we concluded erythema nodosum to be less probable.
The possibility of bacterial contamination during the biopsy procedure was also considered. MRSA is endemic in healthcare facilities,11 and patients who are colonised with MRSA may contaminate surrounding environmental surfaces.12 Our institution carries out active surveillance to identify MRSA-colonised patients. Our patient’s MRSA swabs (nasal, axilla and groin) were persistently negative. In addition, the procedure was done under aseptic technique, MRSA was cultured and demonstrated in histology specimens, and she improved following the institution of antimicrobial therapy. In light of this, bacterial contamination was considered unlikely.
Learning points
Infectious panniculitis due to Staphylococcus aureus in the absence of bacteraemia is extremely rare.
Careful workup including biopsy and culture is important to allow correct identification of aetiology and appropriate management.
Appropriate diagnosis allowed continued filgrastim injections so that her time-sensitive stem cell harvest could proceed.
Contributors: APYN drafted the manuscript. Y-LC and W-YJ reviewed and revised the manuscript. SBJW analysed the histology specimen.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Recovered | ReactionOutcome | CC BY-NC | 33563686 | 19,224,532 | 2021-02-09 |
What was the outcome of reaction 'Skin mass'? | Methicillin-resistant Staphylococcus aureus (MRSA) panniculitis in a patient undergoing stem cell mobilisation.
Methicillin-resistant Staphylococcus aureus (MRSA) can cause a wide range of skin infections, however MRSA panniculitis without bacteremia is a rare manifestation. Here, we report a woman in her 20s with relapsed Hodgkin lymphoma undergoing stem cell mobilisation who presented with bilateral subcutaneous nodules over her shins. Ultrasound scan of one nodule showed non-specific inflammatory changes. Punch biopsy of a nodule showed lobular panniculitis with Gram-positive cocci. Blood cultures were negative but a culture from the biopsy grew MRSA. She was started on doxycycline with improvement in her symptoms. This case serves as a reminder to consider infections as a cause of panniculitis in immunocompromised patients.
Background
Panniculitis usually presents as painful erythematous nodules or plaques and is characterised by inflammation of subcutaneous adipose tissue. Recognition, diagnosis and evaluation is challenging because of its rarity and myriad causes, including infection, malignancy, drugs and inflammatory conditions. Infectious panniculitis can occur primarily after direct inoculation or secondarily from hematogenous spread.1 We report a case of methicillin-resistant Staphylococcus aureus (MRSA) panniculitis.
Case presentation
A female in her 20s with relapsed Hodgkin lymphoma (HL) was referred to our centre for autologous stem cell transplantation. She was diagnosed with stage 2 HL in 2016 and underwent chemoradiotherapy, attaining complete remission. She relapsed in 2019 with a recurrent mediastinal mass and widespread lymphadenopathy. She underwent salvage chemotherapy with bendamustine and brentuximab (BB), which was uneventful except for a grade 1 cutaneous adverse drug reaction (CADR) to BB affecting 5% of her body surface area. This resolved with topical steroids and antihistamines. She had no other significant medical or surgical history. Medication on admission for stem cell harvesting included chlorpheniramine 4 mg two times per day, mometasone 0.1% lotion two times per day for her previous CADR and acyclovir 400 mg two times per day for prophylaxis against herpes zoster.
The patient went on to receive mobilisation chemotherapy with ifosfamide, carboplatin and etoposide. Pegfilgrastim was administered on days 5 and 11. On day 11, she was admitted with a fever of 38.3°C and pain in her legs. Examination revealed bilateral scattered tender, indurated subcutaneous nodules over her shins with mild overlying erythema, approximately 3–5 cm in diameter (figure 1). There was a residual dry scaly excoriated hyperpigmented rash from the previous CADR.
Figure 1 Photo of subcutaneous nodule on the lower limb.
Investigations
Investigations on admission showed a white cell count of 0.79×109/L, with neutrophils 0.56×109/L. Following admission, she was started on daily filgrastim due to her neutropaenia and low CD34+ count, which precluded successful mobilisation. C-reactive protein (CRP) was elevated at 74, and procalcitonin was 0.18. Blood cultures and a blood fungal culture were negative. An ultrasound scan of the leg nodule showed vague increased echogenicity and increased vascularity in the subcutaneous tissue with no evidence of abscess formation. A punch biopsy of the nodule confirmed lobular panniculitis with an inflammatory cell infiltrate composed of numerous neutrophils, mixed with lymphocytes, eosinophils, histiocytes and occasional multinucleated giant cells (figure 2A). Granulomas were not observed. No features of vasculitis were identified. Gram-positive cocci were present in the dermis and subcutis (figure 2B). No fungal organisms or acid-fast bacilli were seen on Grocott’s methenamine silver or Ziehl-Neelsen stains. Culture from the punch biopsy grew MRSA. Her antinuclear antibody titre was negative at <1:80. A tuberculosis quantiferon test was negative, and a chest radiograph was normal.
Figure 2 (A) Histology slide showing lobular panniculitis with an inflammatory cell infiltrate composed of numerous neutrophils, mixed with lymphocytes, eosinophils, histiocytes and occasional multinucleated giant cells. (B) Histology slide showing Gram-positive cocci.
Treatment
A diagnosis of infective panniculitis secondary to MRSA was made. She was started on doxycycline with resolution of her fever and nodules. Her filgrastim injections were continued till neutrophil recovery.
Outcome and follow-up
The patient unfortunately failed to mobilise peripheral blood stem cells but went on to have a successful bone marrow harvest with no evidence of microbial contamination of her cyropreserved stem cells. Her lower limb subcutaneous nodules also resolved completely without scarring nor atrophy following treatment with doxycycline.
DISCUSSION
Panniculitis can be classified as septal or lobular, with or without vasculitis. Histologically, infectious panniculitis presents as a neutrophilic predominant mixed inflammatory infiltrate with a lobular pattern of inflammation.2 Infective panniculitis can be caused by bacterial, mycobacterial, fungal, protozoal or viral infections. S. aureus is a skin commensal commonly responsible for primary cutaneous lesions such as folliculitis, carbuncles or cellulitis. Deeper pathology such as abscesses or rarely, panniculitis may result from haematogenous spread in bacteraemic patients,3 or following inoculation from primary superficial lesions. In our patient, repeated blood cultures were negative for S. aureus. Given this, we hypothesise that her prior CADR to BB chemotherapy resulted in weakened skin integrity, superficial inoculation and subsequent deep tissue infection which flared opportunistically when she was neutropaenic. To our knowledge, MRSA-induced panniculitis without bacteremia is rare. However, there have been a few reports of this phenomenon with Pseudomonas aeruginosa.4 5
We initially considered filgrastim-induced panniculitis as a differential. Filgrastim has been associated with several cutaneous reactions such as Sweet’s syndrome, pyoderma gangrenosum and vasculitis. A few cases have been reported in association with pegfilgrastim.6 Possible hypotheses include secondary cytokine production after filgrastim administration and neutrophil activation.7 In our patient, the temporal relationship between administration of pegfilgastrim and her symptoms initially led us to suspect pegfilgrastim as the cause of her panniculitis. However given her positive biopsy culture for MRSA, the presence of Gram-positive cocci in her dermis and subdermal layer, and clinical response to doxycycline despite being continued on filgrastim, we deemed this unlikely.
The site of the lesions, clinical context of HL and neutrophil-rich inflammatory infiltrate also raise the possibility of erythema nodosum. Erythema nodosum is usually idiopathic, but has also been associated with infection, drug, inflammatory condition or malignancy.8 Although this is classically a septal panniculitis,9 there can be histological overlap in some cases.10 Our patient's biopsy was in keeping with that of a lobular panniculitis. Her culture was positive for MRSA which is not a typical infection associated with erythema nodosum. In view of this and her quick response to doxycycline, we concluded erythema nodosum to be less probable.
The possibility of bacterial contamination during the biopsy procedure was also considered. MRSA is endemic in healthcare facilities,11 and patients who are colonised with MRSA may contaminate surrounding environmental surfaces.12 Our institution carries out active surveillance to identify MRSA-colonised patients. Our patient’s MRSA swabs (nasal, axilla and groin) were persistently negative. In addition, the procedure was done under aseptic technique, MRSA was cultured and demonstrated in histology specimens, and she improved following the institution of antimicrobial therapy. In light of this, bacterial contamination was considered unlikely.
Learning points
Infectious panniculitis due to Staphylococcus aureus in the absence of bacteraemia is extremely rare.
Careful workup including biopsy and culture is important to allow correct identification of aetiology and appropriate management.
Appropriate diagnosis allowed continued filgrastim injections so that her time-sensitive stem cell harvest could proceed.
Contributors: APYN drafted the manuscript. Y-LC and W-YJ reviewed and revised the manuscript. SBJW analysed the histology specimen.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Recovered | ReactionOutcome | CC BY-NC | 33563686 | 19,224,532 | 2021-02-09 |
What was the outcome of reaction 'Skin reaction'? | Methicillin-resistant Staphylococcus aureus (MRSA) panniculitis in a patient undergoing stem cell mobilisation.
Methicillin-resistant Staphylococcus aureus (MRSA) can cause a wide range of skin infections, however MRSA panniculitis without bacteremia is a rare manifestation. Here, we report a woman in her 20s with relapsed Hodgkin lymphoma undergoing stem cell mobilisation who presented with bilateral subcutaneous nodules over her shins. Ultrasound scan of one nodule showed non-specific inflammatory changes. Punch biopsy of a nodule showed lobular panniculitis with Gram-positive cocci. Blood cultures were negative but a culture from the biopsy grew MRSA. She was started on doxycycline with improvement in her symptoms. This case serves as a reminder to consider infections as a cause of panniculitis in immunocompromised patients.
Background
Panniculitis usually presents as painful erythematous nodules or plaques and is characterised by inflammation of subcutaneous adipose tissue. Recognition, diagnosis and evaluation is challenging because of its rarity and myriad causes, including infection, malignancy, drugs and inflammatory conditions. Infectious panniculitis can occur primarily after direct inoculation or secondarily from hematogenous spread.1 We report a case of methicillin-resistant Staphylococcus aureus (MRSA) panniculitis.
Case presentation
A female in her 20s with relapsed Hodgkin lymphoma (HL) was referred to our centre for autologous stem cell transplantation. She was diagnosed with stage 2 HL in 2016 and underwent chemoradiotherapy, attaining complete remission. She relapsed in 2019 with a recurrent mediastinal mass and widespread lymphadenopathy. She underwent salvage chemotherapy with bendamustine and brentuximab (BB), which was uneventful except for a grade 1 cutaneous adverse drug reaction (CADR) to BB affecting 5% of her body surface area. This resolved with topical steroids and antihistamines. She had no other significant medical or surgical history. Medication on admission for stem cell harvesting included chlorpheniramine 4 mg two times per day, mometasone 0.1% lotion two times per day for her previous CADR and acyclovir 400 mg two times per day for prophylaxis against herpes zoster.
The patient went on to receive mobilisation chemotherapy with ifosfamide, carboplatin and etoposide. Pegfilgrastim was administered on days 5 and 11. On day 11, she was admitted with a fever of 38.3°C and pain in her legs. Examination revealed bilateral scattered tender, indurated subcutaneous nodules over her shins with mild overlying erythema, approximately 3–5 cm in diameter (figure 1). There was a residual dry scaly excoriated hyperpigmented rash from the previous CADR.
Figure 1 Photo of subcutaneous nodule on the lower limb.
Investigations
Investigations on admission showed a white cell count of 0.79×109/L, with neutrophils 0.56×109/L. Following admission, she was started on daily filgrastim due to her neutropaenia and low CD34+ count, which precluded successful mobilisation. C-reactive protein (CRP) was elevated at 74, and procalcitonin was 0.18. Blood cultures and a blood fungal culture were negative. An ultrasound scan of the leg nodule showed vague increased echogenicity and increased vascularity in the subcutaneous tissue with no evidence of abscess formation. A punch biopsy of the nodule confirmed lobular panniculitis with an inflammatory cell infiltrate composed of numerous neutrophils, mixed with lymphocytes, eosinophils, histiocytes and occasional multinucleated giant cells (figure 2A). Granulomas were not observed. No features of vasculitis were identified. Gram-positive cocci were present in the dermis and subcutis (figure 2B). No fungal organisms or acid-fast bacilli were seen on Grocott’s methenamine silver or Ziehl-Neelsen stains. Culture from the punch biopsy grew MRSA. Her antinuclear antibody titre was negative at <1:80. A tuberculosis quantiferon test was negative, and a chest radiograph was normal.
Figure 2 (A) Histology slide showing lobular panniculitis with an inflammatory cell infiltrate composed of numerous neutrophils, mixed with lymphocytes, eosinophils, histiocytes and occasional multinucleated giant cells. (B) Histology slide showing Gram-positive cocci.
Treatment
A diagnosis of infective panniculitis secondary to MRSA was made. She was started on doxycycline with resolution of her fever and nodules. Her filgrastim injections were continued till neutrophil recovery.
Outcome and follow-up
The patient unfortunately failed to mobilise peripheral blood stem cells but went on to have a successful bone marrow harvest with no evidence of microbial contamination of her cyropreserved stem cells. Her lower limb subcutaneous nodules also resolved completely without scarring nor atrophy following treatment with doxycycline.
DISCUSSION
Panniculitis can be classified as septal or lobular, with or without vasculitis. Histologically, infectious panniculitis presents as a neutrophilic predominant mixed inflammatory infiltrate with a lobular pattern of inflammation.2 Infective panniculitis can be caused by bacterial, mycobacterial, fungal, protozoal or viral infections. S. aureus is a skin commensal commonly responsible for primary cutaneous lesions such as folliculitis, carbuncles or cellulitis. Deeper pathology such as abscesses or rarely, panniculitis may result from haematogenous spread in bacteraemic patients,3 or following inoculation from primary superficial lesions. In our patient, repeated blood cultures were negative for S. aureus. Given this, we hypothesise that her prior CADR to BB chemotherapy resulted in weakened skin integrity, superficial inoculation and subsequent deep tissue infection which flared opportunistically when she was neutropaenic. To our knowledge, MRSA-induced panniculitis without bacteremia is rare. However, there have been a few reports of this phenomenon with Pseudomonas aeruginosa.4 5
We initially considered filgrastim-induced panniculitis as a differential. Filgrastim has been associated with several cutaneous reactions such as Sweet’s syndrome, pyoderma gangrenosum and vasculitis. A few cases have been reported in association with pegfilgrastim.6 Possible hypotheses include secondary cytokine production after filgrastim administration and neutrophil activation.7 In our patient, the temporal relationship between administration of pegfilgastrim and her symptoms initially led us to suspect pegfilgrastim as the cause of her panniculitis. However given her positive biopsy culture for MRSA, the presence of Gram-positive cocci in her dermis and subdermal layer, and clinical response to doxycycline despite being continued on filgrastim, we deemed this unlikely.
The site of the lesions, clinical context of HL and neutrophil-rich inflammatory infiltrate also raise the possibility of erythema nodosum. Erythema nodosum is usually idiopathic, but has also been associated with infection, drug, inflammatory condition or malignancy.8 Although this is classically a septal panniculitis,9 there can be histological overlap in some cases.10 Our patient's biopsy was in keeping with that of a lobular panniculitis. Her culture was positive for MRSA which is not a typical infection associated with erythema nodosum. In view of this and her quick response to doxycycline, we concluded erythema nodosum to be less probable.
The possibility of bacterial contamination during the biopsy procedure was also considered. MRSA is endemic in healthcare facilities,11 and patients who are colonised with MRSA may contaminate surrounding environmental surfaces.12 Our institution carries out active surveillance to identify MRSA-colonised patients. Our patient’s MRSA swabs (nasal, axilla and groin) were persistently negative. In addition, the procedure was done under aseptic technique, MRSA was cultured and demonstrated in histology specimens, and she improved following the institution of antimicrobial therapy. In light of this, bacterial contamination was considered unlikely.
Learning points
Infectious panniculitis due to Staphylococcus aureus in the absence of bacteraemia is extremely rare.
Careful workup including biopsy and culture is important to allow correct identification of aetiology and appropriate management.
Appropriate diagnosis allowed continued filgrastim injections so that her time-sensitive stem cell harvest could proceed.
Contributors: APYN drafted the manuscript. Y-LC and W-YJ reviewed and revised the manuscript. SBJW analysed the histology specimen.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Recovered | ReactionOutcome | CC BY-NC | 33563686 | 19,224,532 | 2021-02-09 |
What was the outcome of reaction 'Staphylococcal infection'? | Methicillin-resistant Staphylococcus aureus (MRSA) panniculitis in a patient undergoing stem cell mobilisation.
Methicillin-resistant Staphylococcus aureus (MRSA) can cause a wide range of skin infections, however MRSA panniculitis without bacteremia is a rare manifestation. Here, we report a woman in her 20s with relapsed Hodgkin lymphoma undergoing stem cell mobilisation who presented with bilateral subcutaneous nodules over her shins. Ultrasound scan of one nodule showed non-specific inflammatory changes. Punch biopsy of a nodule showed lobular panniculitis with Gram-positive cocci. Blood cultures were negative but a culture from the biopsy grew MRSA. She was started on doxycycline with improvement in her symptoms. This case serves as a reminder to consider infections as a cause of panniculitis in immunocompromised patients.
Background
Panniculitis usually presents as painful erythematous nodules or plaques and is characterised by inflammation of subcutaneous adipose tissue. Recognition, diagnosis and evaluation is challenging because of its rarity and myriad causes, including infection, malignancy, drugs and inflammatory conditions. Infectious panniculitis can occur primarily after direct inoculation or secondarily from hematogenous spread.1 We report a case of methicillin-resistant Staphylococcus aureus (MRSA) panniculitis.
Case presentation
A female in her 20s with relapsed Hodgkin lymphoma (HL) was referred to our centre for autologous stem cell transplantation. She was diagnosed with stage 2 HL in 2016 and underwent chemoradiotherapy, attaining complete remission. She relapsed in 2019 with a recurrent mediastinal mass and widespread lymphadenopathy. She underwent salvage chemotherapy with bendamustine and brentuximab (BB), which was uneventful except for a grade 1 cutaneous adverse drug reaction (CADR) to BB affecting 5% of her body surface area. This resolved with topical steroids and antihistamines. She had no other significant medical or surgical history. Medication on admission for stem cell harvesting included chlorpheniramine 4 mg two times per day, mometasone 0.1% lotion two times per day for her previous CADR and acyclovir 400 mg two times per day for prophylaxis against herpes zoster.
The patient went on to receive mobilisation chemotherapy with ifosfamide, carboplatin and etoposide. Pegfilgrastim was administered on days 5 and 11. On day 11, she was admitted with a fever of 38.3°C and pain in her legs. Examination revealed bilateral scattered tender, indurated subcutaneous nodules over her shins with mild overlying erythema, approximately 3–5 cm in diameter (figure 1). There was a residual dry scaly excoriated hyperpigmented rash from the previous CADR.
Figure 1 Photo of subcutaneous nodule on the lower limb.
Investigations
Investigations on admission showed a white cell count of 0.79×109/L, with neutrophils 0.56×109/L. Following admission, she was started on daily filgrastim due to her neutropaenia and low CD34+ count, which precluded successful mobilisation. C-reactive protein (CRP) was elevated at 74, and procalcitonin was 0.18. Blood cultures and a blood fungal culture were negative. An ultrasound scan of the leg nodule showed vague increased echogenicity and increased vascularity in the subcutaneous tissue with no evidence of abscess formation. A punch biopsy of the nodule confirmed lobular panniculitis with an inflammatory cell infiltrate composed of numerous neutrophils, mixed with lymphocytes, eosinophils, histiocytes and occasional multinucleated giant cells (figure 2A). Granulomas were not observed. No features of vasculitis were identified. Gram-positive cocci were present in the dermis and subcutis (figure 2B). No fungal organisms or acid-fast bacilli were seen on Grocott’s methenamine silver or Ziehl-Neelsen stains. Culture from the punch biopsy grew MRSA. Her antinuclear antibody titre was negative at <1:80. A tuberculosis quantiferon test was negative, and a chest radiograph was normal.
Figure 2 (A) Histology slide showing lobular panniculitis with an inflammatory cell infiltrate composed of numerous neutrophils, mixed with lymphocytes, eosinophils, histiocytes and occasional multinucleated giant cells. (B) Histology slide showing Gram-positive cocci.
Treatment
A diagnosis of infective panniculitis secondary to MRSA was made. She was started on doxycycline with resolution of her fever and nodules. Her filgrastim injections were continued till neutrophil recovery.
Outcome and follow-up
The patient unfortunately failed to mobilise peripheral blood stem cells but went on to have a successful bone marrow harvest with no evidence of microbial contamination of her cyropreserved stem cells. Her lower limb subcutaneous nodules also resolved completely without scarring nor atrophy following treatment with doxycycline.
DISCUSSION
Panniculitis can be classified as septal or lobular, with or without vasculitis. Histologically, infectious panniculitis presents as a neutrophilic predominant mixed inflammatory infiltrate with a lobular pattern of inflammation.2 Infective panniculitis can be caused by bacterial, mycobacterial, fungal, protozoal or viral infections. S. aureus is a skin commensal commonly responsible for primary cutaneous lesions such as folliculitis, carbuncles or cellulitis. Deeper pathology such as abscesses or rarely, panniculitis may result from haematogenous spread in bacteraemic patients,3 or following inoculation from primary superficial lesions. In our patient, repeated blood cultures were negative for S. aureus. Given this, we hypothesise that her prior CADR to BB chemotherapy resulted in weakened skin integrity, superficial inoculation and subsequent deep tissue infection which flared opportunistically when she was neutropaenic. To our knowledge, MRSA-induced panniculitis without bacteremia is rare. However, there have been a few reports of this phenomenon with Pseudomonas aeruginosa.4 5
We initially considered filgrastim-induced panniculitis as a differential. Filgrastim has been associated with several cutaneous reactions such as Sweet’s syndrome, pyoderma gangrenosum and vasculitis. A few cases have been reported in association with pegfilgrastim.6 Possible hypotheses include secondary cytokine production after filgrastim administration and neutrophil activation.7 In our patient, the temporal relationship between administration of pegfilgastrim and her symptoms initially led us to suspect pegfilgrastim as the cause of her panniculitis. However given her positive biopsy culture for MRSA, the presence of Gram-positive cocci in her dermis and subdermal layer, and clinical response to doxycycline despite being continued on filgrastim, we deemed this unlikely.
The site of the lesions, clinical context of HL and neutrophil-rich inflammatory infiltrate also raise the possibility of erythema nodosum. Erythema nodosum is usually idiopathic, but has also been associated with infection, drug, inflammatory condition or malignancy.8 Although this is classically a septal panniculitis,9 there can be histological overlap in some cases.10 Our patient's biopsy was in keeping with that of a lobular panniculitis. Her culture was positive for MRSA which is not a typical infection associated with erythema nodosum. In view of this and her quick response to doxycycline, we concluded erythema nodosum to be less probable.
The possibility of bacterial contamination during the biopsy procedure was also considered. MRSA is endemic in healthcare facilities,11 and patients who are colonised with MRSA may contaminate surrounding environmental surfaces.12 Our institution carries out active surveillance to identify MRSA-colonised patients. Our patient’s MRSA swabs (nasal, axilla and groin) were persistently negative. In addition, the procedure was done under aseptic technique, MRSA was cultured and demonstrated in histology specimens, and she improved following the institution of antimicrobial therapy. In light of this, bacterial contamination was considered unlikely.
Learning points
Infectious panniculitis due to Staphylococcus aureus in the absence of bacteraemia is extremely rare.
Careful workup including biopsy and culture is important to allow correct identification of aetiology and appropriate management.
Appropriate diagnosis allowed continued filgrastim injections so that her time-sensitive stem cell harvest could proceed.
Contributors: APYN drafted the manuscript. Y-LC and W-YJ reviewed and revised the manuscript. SBJW analysed the histology specimen.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None declared.
Patient consent for publication: Obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Recovered | ReactionOutcome | CC BY-NC | 33563686 | 19,019,075 | 2021-02-09 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardiac failure congestive'. | Fatal New-Onset Congestive Heart Failure Related to Adalimumab Use in a Patient with Relapsing Hidradenitis Suppurativa: A Case Report.
BACKGROUND Tumor necrosis factor (TNF)-alpha inhibitors are essential treatments in several inflammatory conditions such as hidradenitis suppurativa (HS). However, they are not without associated risks. In rare cases, new-onset and exacerbations of heart failure have been associated with their use. The purpose of this report is to raise awareness of the need for further study of adalimumab for this adverse effect, as well as to recognize the need for research to find new HS treatment modalities for better care of the broad patient population. CASE REPORT We report the case of a 67-year-old man with a history of severe HS and major depressive disorder who came to our hospital complaining of dyspnea, fatigue upon exertion, and lower-extremity edema of 2 weeks' evolution. Symptoms began after the re-initiation of adalimumab for his severe HS. During hospitalization, he was diagnosed with decompensated congestive heart failure (CHF). Extensive studies, looking for ischemic or infectious etiology, yielded negative results. Being aware of adalimumab's potential adverse effects, the team discontinued the medication as a probable cause of his condition. Unfortunately, the patient died secondary to heart failure and septicemia. CONCLUSIONS The unusual but potentially life-threatening appearance of heart failure secondary to adalimumab use merits thorough attention by primary care doctors and specialists. This adverse event's rare occurrence can underestimate the number of fatalities associated with adalimumab and congestive heart failure.
Background
Hidradenitis suppurativa (HS) is a chronic inflammatory disorder of the pilosebaceous unit, commonly found in inter-triginous areas, such as the axilla, inframammary area, and anogenital region. The inflammation is associated with deep, painful subcutaneous nodules, cysts, and abscesses. These lesions may form sinus tracts containing malodorous mucopuru-lent discharge. The constant inflammation in these areas has long-term consequences such as scarring, chronic pain, skin contractures, and possible disfigurement. Its pathophysiology is not well understood and is thought to be multifactorial. Studies have shown a mixture of components like genetic susceptibility, autoimmunity, hormonal dysregulation, and environmental factors such as smoking and obesity [1]. The trigger is thought to be the constant repetition of microtrauma from microbial factors that activate the innate immune system’s pro-inflammatory response [2]. Elevation of pro-inflammatory cytokines such as interleukin (IL) 1-beta, IL-17, and IL-23, as well as tumor necrosis factor (TNF) alpha, have been found on HS lesions, suggesting a dysregulation of the body’s adaptive immune response.
TNF-alpha also affects many other tissues, such as its widely studied effect on the myocardium. The pro-inflammatory cytokine alters the beta-adrenergic receptors in the myocardium, depressing cardiac inotropy. This leads to further inflammation and cardiac injury, ultimately producing congestive heart failure (CHF). Despite the evidence associating TNF-alpha with heart failure, inhibition of the cytokine has not achieved significant success. Reports have found that it worsens cardiovascular symptoms, leading to de novo or exacerbations of existing congestive heart failure [3]. Adalimumab, a TNF-alpha inhibitor, is the only FDA-approved biologic treatment for HS. In this case report, we present the case of a middle-aged man with severe HS treated with adalimumab who developed de novo CHF. We want to raise awareness of the potential adverse effects of HS treatment, specifically use of adalimumab. More investigation is warranted to further understand the patho-physiology and improve treatment.
Case Report
We report the case of a 67-year-old man who presented to the services of Manatí Medical Center with a chief complaint of fatigue upon exertion, dyspnea, and lower-extremity edema that had been progressively worsening for 2 weeks. His medical history was significant for a 30-year history of hidradenitis suppurativa (HS) Hurley stage III, hypertension, major depressive disorder, and a positive Mantoux test, treated with isoniazid 12 years ago. On physical exam, he was hypotensive, tachycardic, and tachypneic. On auscultation, a mild holosystolic murmur with S3 gallop was heard at the apex. Crackles and rales were appreciated in all lung fields, as well as bilateral lower-extremity edema. Additionally, there was mild ascites without abdominal tenderness or guarding. The patient was not confused at any point during history taking or physical exam.
Troponin levels remained constant at less than 0.015 ng/mL, CK-MB less than 1.00 mg/mL, and total creatinine kinase at 15 IU/L, all within normal limits. However, Pro-B natriuretic peptide was elevated at 77 660 pg/mL (normal levels are 5–125 pg/mL). The electrocardiogram showed sinus rhythm with no indication of acute ischemic changes or arrythmia. A chest X-ray showed marked Kerley B lines, enlarged cardiac silhouette, and bilateral pleural effusion, suggesting exacerbated congestive heart failure. He was admitted to the hospital the same day for clinical stabilization and further treatment.
During the hospital stay, various studies were performed to find the etiology of his CHF. The patient’s echocardiogram showed an ejection fraction (EF) of 20–25%, significantly different from a previous study done 2 months ago, which reported an EF of 50%, which also mentioned findings of global hypokinesis of the left ventricle with enlarged atria, left worse than right, and present mitral regurgitation. There were no changes indicating possible myocarditis or pericarditis. Findings of this study suggested new-onset decompensated congestive heart failure (CHF). Other diagnostic tools looking for ischemic and infectious etiology yielded negative results.
A chest CT scan without contrast showed bilateral pleural effusions with bibasilar compressive atelectasis and no evidence of pulmonary or infectious processes. There was also no evidence of an intra-abdominal emergent process on abdominal imaging. The patient did not have significant leukocytosis, with negative blood cultures and pleural fluid culture, suggesting there was no systemic infection or sepsis that may have caused the heart failure. The patient had no coronary disease or cardiovascular risk factors that could explain his symptoms’ severity and rapid progression. However, his clinical history revealed that he was re-initiated on adalimumab 2 months before this presentation. Therefore, adalimumab was discontinued as a precaution of potential cause, with an adverse drug reaction probability of 5.
Further investigation with his dermatologist revealed he first started adalimumab treatment 3 years ago with the standard HS regimen, beginning with subcutaneous 160 mg on the first day, and 80 mg on day 15. On day 29 and weekly thereafter, the dose was maintained at 40 mg. After 2 years of utilizing the medication with no complications, it was discontinued due to his lesions’ progression. However, even with alternate standard treatments and procedures, his condition had not stabilized. After various hospital admissions, adalimumab was re-initiated with the standard-dose regimen, as previously described. Once adalimumab was discontinued during this hospital stay, his health continued to decline, with worsening of symptoms. Unfortunately, the patient’s condition continued to worsen, increasing his hospital visits for symptom management. On the 8th day of hospitalization, he died due to de-compensated heart failure and septicemia.
Discussion
We report a case of new-acute onset CHF in a patient with severe HS who recently re-initiated adalimumab. Although not fully understood, there have been studies describing this adverse effect of TNF-alpha inhibitors. Initially, in various in vitro studies involving mice cardiac myocytes, it was reported that TNF-alpha inhibitors could improve CHF symptoms by reducing the inflammatory response. In practice, this would attenuate ventricular remodeling, fibrosis, and continuous cardiomyocyte apoptosis. However, there are no in vivo data that support these results [3]. A well-known clinical trial investigating the effects of TNF-inhibitors, specifically infliximab, against class III-IV heart failure was prematurely halted, concluding there was an increase in hospitalizations and deaths with a high infliximab dose of 10 mg/kg. At the lower dose of 5 mg/ kg, there was no evident benefit or relief of patients’ cardiac symptoms [4]. As a matter of fact, most of the cases reporting CHF as an adverse effect of TNF-inhibitors have been with long-term use well after the end of the trial.
In 2003, post-marketing reports from the FDA MedWatch system warned of an alarming rise of new and exacerbating CHF cases in patients stable on TNF-inhibitors for rheumatoid arthritis (RA) [5]. The data included patients on infliximab, etanercept, and adalimumab. Although RA increases cardiovascular risk and most of the patients had comorbid conditions, TNF-inhibitors presented an additive risk factor for the disease. Adalimumab itself had the least cases of CHF reported. The incidence of new cases among RA patients was 0.1%, which was comparable to the placebo group. The patient presented in our case report had an adverse drug reaction probability score of 5, which indicates the adverse effect was a probable effect of adalimumab. This score takes into consideration the timing of symptom onset after medication, literature describing the adverse effect, and exclusion of other possible causes known to cause the adverse effect [6].
While there are studies of TNF-inhibitors warning about new or exacerbated CHF, adalimumab specifically has not been extensively studied for this adverse effect. In 2012, a sizable long-term safety analysis regarding adalimumab on patients with systemic inflammatory diseases demonstrated 0.2 per 100 patient-years of serious CHF events [7]. It should be noted that the progression and outcome of the disease was not mentioned in their analysis. In the Cochrane review, a meta-analysis on adverse effects of biologics, there was no statistical significance regarding CHF due to TNF-inhibitors, as there was insufficient data and inconsistent definitions regarding the disease [8]. While the literature suggests it is an unusual risk, there has yet to be a meta-analysis discussing risk factors such as dosage, length of time, or re-initiation after a prolonged period leading to CHF occurrence.
With very few options for HS management, it is imperative to understand the relationship between TNF-inhibitors and cardiac myocytes. As previously stated, HS is known to be a systemic inflammatory condition with recorded elevated inflammatory cytokines, including interleukin (IL) 1-beta, IL-17, and IL-23, as well as tumor necrosis factor (TNF) alpha. This continuous inflammatory process leads to known comorbidities such as obesity and diabetes. As HS progresses, the comorbidity burden increases. A retrospective matched cohort study enrolled 5357 patients with mild and severe HS to learn what other conditions HS patients were more likely to develop. The study found that HS patients were 3 times more likely to develop inflammatory conditions compared to individuals without HS. In addition, individuals with severe forms of HS were found to have a 2-fold higher prevalence of metabolic and cardiovascular dysregulations, including congestive heart failure, compared to HS-free individuals. CHF developed in 2.9% of individuals with severe HS and in only 0.5% of HS-free individuals, regardless of treatment. While the data presented showed a comorbidity burden related to HS progression, the results were limited due to small sample size and inconsistent characterization of HS severity. Additionally, the study did not determine whether heart failure development was due to modifiable risk factors or due to the innate inflammatory cardiac damage [9].
As previously mentioned, there has been little research on HS compared to other cutaneous dermatoses. Overall, federal funding for HS in comparison with other inflammatory conditions has been minimal. In 2018, there were only 17 clinical trials dedicated to HS, with even less investigation of model therapies and possible adverse effects [10]. New treatment modalities for HS need to be investigated, as there is a lack of options for a broad patient population with various comorbid conditions. When caring for an individual with HS, awareness of medication effects is not the only way to ensure optimal care. Impairment of quality of life in individuals with HS leads to suboptimal psychological well-being [11]. In a recent meta-analysis, the prevalence of depression in patients with HS was 16.9%. These alarming facts need to be communicated to their primary care providers for prompt recognition of symptoms and urgent management. This intervention will also ensure optimal care.
Conclusions
Management of hidradenitis suppurativa is challenging, and a multimodality approach is usually required. With few treatment options, adalimumab is the only FDA-approved treatment efficacious enough for severe cases of HS. This report presents a fatal case of new-onset acute CHF in an individual re-initiated on adalimumab for severe HS. Understanding the mechanism of action of TNF-inhibitors and cardiovascular decline may help us prevent such cases. Moreover, awareness of CHF as an adverse effect of adalimumab is of utmost importance in primary care to prevent disease progression and fatalities. In addition, understanding the secondary complications of HS such as depression and anxiety will also improve care quality. Management of HS needs to consider many factors for it to be comprehensive and effective. More targeted research regarding new HS treatments is imperative to care for this disease’s broad population.
We wish to extend our gratitude to the Manatí Medical Center staff for their excellence in rendering high-quality patient care and graduate medical education, and the Family Medicine Residency Program to support scholastic achievement.
Conflict of Interest
None. | ADALIMUMAB | DrugsGivenReaction | CC BY-NC-ND | 33563886 | 18,905,508 | 2021-02-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardiac failure'. | Fatal New-Onset Congestive Heart Failure Related to Adalimumab Use in a Patient with Relapsing Hidradenitis Suppurativa: A Case Report.
BACKGROUND Tumor necrosis factor (TNF)-alpha inhibitors are essential treatments in several inflammatory conditions such as hidradenitis suppurativa (HS). However, they are not without associated risks. In rare cases, new-onset and exacerbations of heart failure have been associated with their use. The purpose of this report is to raise awareness of the need for further study of adalimumab for this adverse effect, as well as to recognize the need for research to find new HS treatment modalities for better care of the broad patient population. CASE REPORT We report the case of a 67-year-old man with a history of severe HS and major depressive disorder who came to our hospital complaining of dyspnea, fatigue upon exertion, and lower-extremity edema of 2 weeks' evolution. Symptoms began after the re-initiation of adalimumab for his severe HS. During hospitalization, he was diagnosed with decompensated congestive heart failure (CHF). Extensive studies, looking for ischemic or infectious etiology, yielded negative results. Being aware of adalimumab's potential adverse effects, the team discontinued the medication as a probable cause of his condition. Unfortunately, the patient died secondary to heart failure and septicemia. CONCLUSIONS The unusual but potentially life-threatening appearance of heart failure secondary to adalimumab use merits thorough attention by primary care doctors and specialists. This adverse event's rare occurrence can underestimate the number of fatalities associated with adalimumab and congestive heart failure.
Background
Hidradenitis suppurativa (HS) is a chronic inflammatory disorder of the pilosebaceous unit, commonly found in inter-triginous areas, such as the axilla, inframammary area, and anogenital region. The inflammation is associated with deep, painful subcutaneous nodules, cysts, and abscesses. These lesions may form sinus tracts containing malodorous mucopuru-lent discharge. The constant inflammation in these areas has long-term consequences such as scarring, chronic pain, skin contractures, and possible disfigurement. Its pathophysiology is not well understood and is thought to be multifactorial. Studies have shown a mixture of components like genetic susceptibility, autoimmunity, hormonal dysregulation, and environmental factors such as smoking and obesity [1]. The trigger is thought to be the constant repetition of microtrauma from microbial factors that activate the innate immune system’s pro-inflammatory response [2]. Elevation of pro-inflammatory cytokines such as interleukin (IL) 1-beta, IL-17, and IL-23, as well as tumor necrosis factor (TNF) alpha, have been found on HS lesions, suggesting a dysregulation of the body’s adaptive immune response.
TNF-alpha also affects many other tissues, such as its widely studied effect on the myocardium. The pro-inflammatory cytokine alters the beta-adrenergic receptors in the myocardium, depressing cardiac inotropy. This leads to further inflammation and cardiac injury, ultimately producing congestive heart failure (CHF). Despite the evidence associating TNF-alpha with heart failure, inhibition of the cytokine has not achieved significant success. Reports have found that it worsens cardiovascular symptoms, leading to de novo or exacerbations of existing congestive heart failure [3]. Adalimumab, a TNF-alpha inhibitor, is the only FDA-approved biologic treatment for HS. In this case report, we present the case of a middle-aged man with severe HS treated with adalimumab who developed de novo CHF. We want to raise awareness of the potential adverse effects of HS treatment, specifically use of adalimumab. More investigation is warranted to further understand the patho-physiology and improve treatment.
Case Report
We report the case of a 67-year-old man who presented to the services of Manatí Medical Center with a chief complaint of fatigue upon exertion, dyspnea, and lower-extremity edema that had been progressively worsening for 2 weeks. His medical history was significant for a 30-year history of hidradenitis suppurativa (HS) Hurley stage III, hypertension, major depressive disorder, and a positive Mantoux test, treated with isoniazid 12 years ago. On physical exam, he was hypotensive, tachycardic, and tachypneic. On auscultation, a mild holosystolic murmur with S3 gallop was heard at the apex. Crackles and rales were appreciated in all lung fields, as well as bilateral lower-extremity edema. Additionally, there was mild ascites without abdominal tenderness or guarding. The patient was not confused at any point during history taking or physical exam.
Troponin levels remained constant at less than 0.015 ng/mL, CK-MB less than 1.00 mg/mL, and total creatinine kinase at 15 IU/L, all within normal limits. However, Pro-B natriuretic peptide was elevated at 77 660 pg/mL (normal levels are 5–125 pg/mL). The electrocardiogram showed sinus rhythm with no indication of acute ischemic changes or arrythmia. A chest X-ray showed marked Kerley B lines, enlarged cardiac silhouette, and bilateral pleural effusion, suggesting exacerbated congestive heart failure. He was admitted to the hospital the same day for clinical stabilization and further treatment.
During the hospital stay, various studies were performed to find the etiology of his CHF. The patient’s echocardiogram showed an ejection fraction (EF) of 20–25%, significantly different from a previous study done 2 months ago, which reported an EF of 50%, which also mentioned findings of global hypokinesis of the left ventricle with enlarged atria, left worse than right, and present mitral regurgitation. There were no changes indicating possible myocarditis or pericarditis. Findings of this study suggested new-onset decompensated congestive heart failure (CHF). Other diagnostic tools looking for ischemic and infectious etiology yielded negative results.
A chest CT scan without contrast showed bilateral pleural effusions with bibasilar compressive atelectasis and no evidence of pulmonary or infectious processes. There was also no evidence of an intra-abdominal emergent process on abdominal imaging. The patient did not have significant leukocytosis, with negative blood cultures and pleural fluid culture, suggesting there was no systemic infection or sepsis that may have caused the heart failure. The patient had no coronary disease or cardiovascular risk factors that could explain his symptoms’ severity and rapid progression. However, his clinical history revealed that he was re-initiated on adalimumab 2 months before this presentation. Therefore, adalimumab was discontinued as a precaution of potential cause, with an adverse drug reaction probability of 5.
Further investigation with his dermatologist revealed he first started adalimumab treatment 3 years ago with the standard HS regimen, beginning with subcutaneous 160 mg on the first day, and 80 mg on day 15. On day 29 and weekly thereafter, the dose was maintained at 40 mg. After 2 years of utilizing the medication with no complications, it was discontinued due to his lesions’ progression. However, even with alternate standard treatments and procedures, his condition had not stabilized. After various hospital admissions, adalimumab was re-initiated with the standard-dose regimen, as previously described. Once adalimumab was discontinued during this hospital stay, his health continued to decline, with worsening of symptoms. Unfortunately, the patient’s condition continued to worsen, increasing his hospital visits for symptom management. On the 8th day of hospitalization, he died due to de-compensated heart failure and septicemia.
Discussion
We report a case of new-acute onset CHF in a patient with severe HS who recently re-initiated adalimumab. Although not fully understood, there have been studies describing this adverse effect of TNF-alpha inhibitors. Initially, in various in vitro studies involving mice cardiac myocytes, it was reported that TNF-alpha inhibitors could improve CHF symptoms by reducing the inflammatory response. In practice, this would attenuate ventricular remodeling, fibrosis, and continuous cardiomyocyte apoptosis. However, there are no in vivo data that support these results [3]. A well-known clinical trial investigating the effects of TNF-inhibitors, specifically infliximab, against class III-IV heart failure was prematurely halted, concluding there was an increase in hospitalizations and deaths with a high infliximab dose of 10 mg/kg. At the lower dose of 5 mg/ kg, there was no evident benefit or relief of patients’ cardiac symptoms [4]. As a matter of fact, most of the cases reporting CHF as an adverse effect of TNF-inhibitors have been with long-term use well after the end of the trial.
In 2003, post-marketing reports from the FDA MedWatch system warned of an alarming rise of new and exacerbating CHF cases in patients stable on TNF-inhibitors for rheumatoid arthritis (RA) [5]. The data included patients on infliximab, etanercept, and adalimumab. Although RA increases cardiovascular risk and most of the patients had comorbid conditions, TNF-inhibitors presented an additive risk factor for the disease. Adalimumab itself had the least cases of CHF reported. The incidence of new cases among RA patients was 0.1%, which was comparable to the placebo group. The patient presented in our case report had an adverse drug reaction probability score of 5, which indicates the adverse effect was a probable effect of adalimumab. This score takes into consideration the timing of symptom onset after medication, literature describing the adverse effect, and exclusion of other possible causes known to cause the adverse effect [6].
While there are studies of TNF-inhibitors warning about new or exacerbated CHF, adalimumab specifically has not been extensively studied for this adverse effect. In 2012, a sizable long-term safety analysis regarding adalimumab on patients with systemic inflammatory diseases demonstrated 0.2 per 100 patient-years of serious CHF events [7]. It should be noted that the progression and outcome of the disease was not mentioned in their analysis. In the Cochrane review, a meta-analysis on adverse effects of biologics, there was no statistical significance regarding CHF due to TNF-inhibitors, as there was insufficient data and inconsistent definitions regarding the disease [8]. While the literature suggests it is an unusual risk, there has yet to be a meta-analysis discussing risk factors such as dosage, length of time, or re-initiation after a prolonged period leading to CHF occurrence.
With very few options for HS management, it is imperative to understand the relationship between TNF-inhibitors and cardiac myocytes. As previously stated, HS is known to be a systemic inflammatory condition with recorded elevated inflammatory cytokines, including interleukin (IL) 1-beta, IL-17, and IL-23, as well as tumor necrosis factor (TNF) alpha. This continuous inflammatory process leads to known comorbidities such as obesity and diabetes. As HS progresses, the comorbidity burden increases. A retrospective matched cohort study enrolled 5357 patients with mild and severe HS to learn what other conditions HS patients were more likely to develop. The study found that HS patients were 3 times more likely to develop inflammatory conditions compared to individuals without HS. In addition, individuals with severe forms of HS were found to have a 2-fold higher prevalence of metabolic and cardiovascular dysregulations, including congestive heart failure, compared to HS-free individuals. CHF developed in 2.9% of individuals with severe HS and in only 0.5% of HS-free individuals, regardless of treatment. While the data presented showed a comorbidity burden related to HS progression, the results were limited due to small sample size and inconsistent characterization of HS severity. Additionally, the study did not determine whether heart failure development was due to modifiable risk factors or due to the innate inflammatory cardiac damage [9].
As previously mentioned, there has been little research on HS compared to other cutaneous dermatoses. Overall, federal funding for HS in comparison with other inflammatory conditions has been minimal. In 2018, there were only 17 clinical trials dedicated to HS, with even less investigation of model therapies and possible adverse effects [10]. New treatment modalities for HS need to be investigated, as there is a lack of options for a broad patient population with various comorbid conditions. When caring for an individual with HS, awareness of medication effects is not the only way to ensure optimal care. Impairment of quality of life in individuals with HS leads to suboptimal psychological well-being [11]. In a recent meta-analysis, the prevalence of depression in patients with HS was 16.9%. These alarming facts need to be communicated to their primary care providers for prompt recognition of symptoms and urgent management. This intervention will also ensure optimal care.
Conclusions
Management of hidradenitis suppurativa is challenging, and a multimodality approach is usually required. With few treatment options, adalimumab is the only FDA-approved treatment efficacious enough for severe cases of HS. This report presents a fatal case of new-onset acute CHF in an individual re-initiated on adalimumab for severe HS. Understanding the mechanism of action of TNF-inhibitors and cardiovascular decline may help us prevent such cases. Moreover, awareness of CHF as an adverse effect of adalimumab is of utmost importance in primary care to prevent disease progression and fatalities. In addition, understanding the secondary complications of HS such as depression and anxiety will also improve care quality. Management of HS needs to consider many factors for it to be comprehensive and effective. More targeted research regarding new HS treatments is imperative to care for this disease’s broad population.
We wish to extend our gratitude to the Manatí Medical Center staff for their excellence in rendering high-quality patient care and graduate medical education, and the Family Medicine Residency Program to support scholastic achievement.
Conflict of Interest
None. | ADALIMUMAB | DrugsGivenReaction | CC BY-NC-ND | 33563886 | 19,097,488 | 2021-02-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hidradenitis'. | Fatal New-Onset Congestive Heart Failure Related to Adalimumab Use in a Patient with Relapsing Hidradenitis Suppurativa: A Case Report.
BACKGROUND Tumor necrosis factor (TNF)-alpha inhibitors are essential treatments in several inflammatory conditions such as hidradenitis suppurativa (HS). However, they are not without associated risks. In rare cases, new-onset and exacerbations of heart failure have been associated with their use. The purpose of this report is to raise awareness of the need for further study of adalimumab for this adverse effect, as well as to recognize the need for research to find new HS treatment modalities for better care of the broad patient population. CASE REPORT We report the case of a 67-year-old man with a history of severe HS and major depressive disorder who came to our hospital complaining of dyspnea, fatigue upon exertion, and lower-extremity edema of 2 weeks' evolution. Symptoms began after the re-initiation of adalimumab for his severe HS. During hospitalization, he was diagnosed with decompensated congestive heart failure (CHF). Extensive studies, looking for ischemic or infectious etiology, yielded negative results. Being aware of adalimumab's potential adverse effects, the team discontinued the medication as a probable cause of his condition. Unfortunately, the patient died secondary to heart failure and septicemia. CONCLUSIONS The unusual but potentially life-threatening appearance of heart failure secondary to adalimumab use merits thorough attention by primary care doctors and specialists. This adverse event's rare occurrence can underestimate the number of fatalities associated with adalimumab and congestive heart failure.
Background
Hidradenitis suppurativa (HS) is a chronic inflammatory disorder of the pilosebaceous unit, commonly found in inter-triginous areas, such as the axilla, inframammary area, and anogenital region. The inflammation is associated with deep, painful subcutaneous nodules, cysts, and abscesses. These lesions may form sinus tracts containing malodorous mucopuru-lent discharge. The constant inflammation in these areas has long-term consequences such as scarring, chronic pain, skin contractures, and possible disfigurement. Its pathophysiology is not well understood and is thought to be multifactorial. Studies have shown a mixture of components like genetic susceptibility, autoimmunity, hormonal dysregulation, and environmental factors such as smoking and obesity [1]. The trigger is thought to be the constant repetition of microtrauma from microbial factors that activate the innate immune system’s pro-inflammatory response [2]. Elevation of pro-inflammatory cytokines such as interleukin (IL) 1-beta, IL-17, and IL-23, as well as tumor necrosis factor (TNF) alpha, have been found on HS lesions, suggesting a dysregulation of the body’s adaptive immune response.
TNF-alpha also affects many other tissues, such as its widely studied effect on the myocardium. The pro-inflammatory cytokine alters the beta-adrenergic receptors in the myocardium, depressing cardiac inotropy. This leads to further inflammation and cardiac injury, ultimately producing congestive heart failure (CHF). Despite the evidence associating TNF-alpha with heart failure, inhibition of the cytokine has not achieved significant success. Reports have found that it worsens cardiovascular symptoms, leading to de novo or exacerbations of existing congestive heart failure [3]. Adalimumab, a TNF-alpha inhibitor, is the only FDA-approved biologic treatment for HS. In this case report, we present the case of a middle-aged man with severe HS treated with adalimumab who developed de novo CHF. We want to raise awareness of the potential adverse effects of HS treatment, specifically use of adalimumab. More investigation is warranted to further understand the patho-physiology and improve treatment.
Case Report
We report the case of a 67-year-old man who presented to the services of Manatí Medical Center with a chief complaint of fatigue upon exertion, dyspnea, and lower-extremity edema that had been progressively worsening for 2 weeks. His medical history was significant for a 30-year history of hidradenitis suppurativa (HS) Hurley stage III, hypertension, major depressive disorder, and a positive Mantoux test, treated with isoniazid 12 years ago. On physical exam, he was hypotensive, tachycardic, and tachypneic. On auscultation, a mild holosystolic murmur with S3 gallop was heard at the apex. Crackles and rales were appreciated in all lung fields, as well as bilateral lower-extremity edema. Additionally, there was mild ascites without abdominal tenderness or guarding. The patient was not confused at any point during history taking or physical exam.
Troponin levels remained constant at less than 0.015 ng/mL, CK-MB less than 1.00 mg/mL, and total creatinine kinase at 15 IU/L, all within normal limits. However, Pro-B natriuretic peptide was elevated at 77 660 pg/mL (normal levels are 5–125 pg/mL). The electrocardiogram showed sinus rhythm with no indication of acute ischemic changes or arrythmia. A chest X-ray showed marked Kerley B lines, enlarged cardiac silhouette, and bilateral pleural effusion, suggesting exacerbated congestive heart failure. He was admitted to the hospital the same day for clinical stabilization and further treatment.
During the hospital stay, various studies were performed to find the etiology of his CHF. The patient’s echocardiogram showed an ejection fraction (EF) of 20–25%, significantly different from a previous study done 2 months ago, which reported an EF of 50%, which also mentioned findings of global hypokinesis of the left ventricle with enlarged atria, left worse than right, and present mitral regurgitation. There were no changes indicating possible myocarditis or pericarditis. Findings of this study suggested new-onset decompensated congestive heart failure (CHF). Other diagnostic tools looking for ischemic and infectious etiology yielded negative results.
A chest CT scan without contrast showed bilateral pleural effusions with bibasilar compressive atelectasis and no evidence of pulmonary or infectious processes. There was also no evidence of an intra-abdominal emergent process on abdominal imaging. The patient did not have significant leukocytosis, with negative blood cultures and pleural fluid culture, suggesting there was no systemic infection or sepsis that may have caused the heart failure. The patient had no coronary disease or cardiovascular risk factors that could explain his symptoms’ severity and rapid progression. However, his clinical history revealed that he was re-initiated on adalimumab 2 months before this presentation. Therefore, adalimumab was discontinued as a precaution of potential cause, with an adverse drug reaction probability of 5.
Further investigation with his dermatologist revealed he first started adalimumab treatment 3 years ago with the standard HS regimen, beginning with subcutaneous 160 mg on the first day, and 80 mg on day 15. On day 29 and weekly thereafter, the dose was maintained at 40 mg. After 2 years of utilizing the medication with no complications, it was discontinued due to his lesions’ progression. However, even with alternate standard treatments and procedures, his condition had not stabilized. After various hospital admissions, adalimumab was re-initiated with the standard-dose regimen, as previously described. Once adalimumab was discontinued during this hospital stay, his health continued to decline, with worsening of symptoms. Unfortunately, the patient’s condition continued to worsen, increasing his hospital visits for symptom management. On the 8th day of hospitalization, he died due to de-compensated heart failure and septicemia.
Discussion
We report a case of new-acute onset CHF in a patient with severe HS who recently re-initiated adalimumab. Although not fully understood, there have been studies describing this adverse effect of TNF-alpha inhibitors. Initially, in various in vitro studies involving mice cardiac myocytes, it was reported that TNF-alpha inhibitors could improve CHF symptoms by reducing the inflammatory response. In practice, this would attenuate ventricular remodeling, fibrosis, and continuous cardiomyocyte apoptosis. However, there are no in vivo data that support these results [3]. A well-known clinical trial investigating the effects of TNF-inhibitors, specifically infliximab, against class III-IV heart failure was prematurely halted, concluding there was an increase in hospitalizations and deaths with a high infliximab dose of 10 mg/kg. At the lower dose of 5 mg/ kg, there was no evident benefit or relief of patients’ cardiac symptoms [4]. As a matter of fact, most of the cases reporting CHF as an adverse effect of TNF-inhibitors have been with long-term use well after the end of the trial.
In 2003, post-marketing reports from the FDA MedWatch system warned of an alarming rise of new and exacerbating CHF cases in patients stable on TNF-inhibitors for rheumatoid arthritis (RA) [5]. The data included patients on infliximab, etanercept, and adalimumab. Although RA increases cardiovascular risk and most of the patients had comorbid conditions, TNF-inhibitors presented an additive risk factor for the disease. Adalimumab itself had the least cases of CHF reported. The incidence of new cases among RA patients was 0.1%, which was comparable to the placebo group. The patient presented in our case report had an adverse drug reaction probability score of 5, which indicates the adverse effect was a probable effect of adalimumab. This score takes into consideration the timing of symptom onset after medication, literature describing the adverse effect, and exclusion of other possible causes known to cause the adverse effect [6].
While there are studies of TNF-inhibitors warning about new or exacerbated CHF, adalimumab specifically has not been extensively studied for this adverse effect. In 2012, a sizable long-term safety analysis regarding adalimumab on patients with systemic inflammatory diseases demonstrated 0.2 per 100 patient-years of serious CHF events [7]. It should be noted that the progression and outcome of the disease was not mentioned in their analysis. In the Cochrane review, a meta-analysis on adverse effects of biologics, there was no statistical significance regarding CHF due to TNF-inhibitors, as there was insufficient data and inconsistent definitions regarding the disease [8]. While the literature suggests it is an unusual risk, there has yet to be a meta-analysis discussing risk factors such as dosage, length of time, or re-initiation after a prolonged period leading to CHF occurrence.
With very few options for HS management, it is imperative to understand the relationship between TNF-inhibitors and cardiac myocytes. As previously stated, HS is known to be a systemic inflammatory condition with recorded elevated inflammatory cytokines, including interleukin (IL) 1-beta, IL-17, and IL-23, as well as tumor necrosis factor (TNF) alpha. This continuous inflammatory process leads to known comorbidities such as obesity and diabetes. As HS progresses, the comorbidity burden increases. A retrospective matched cohort study enrolled 5357 patients with mild and severe HS to learn what other conditions HS patients were more likely to develop. The study found that HS patients were 3 times more likely to develop inflammatory conditions compared to individuals without HS. In addition, individuals with severe forms of HS were found to have a 2-fold higher prevalence of metabolic and cardiovascular dysregulations, including congestive heart failure, compared to HS-free individuals. CHF developed in 2.9% of individuals with severe HS and in only 0.5% of HS-free individuals, regardless of treatment. While the data presented showed a comorbidity burden related to HS progression, the results were limited due to small sample size and inconsistent characterization of HS severity. Additionally, the study did not determine whether heart failure development was due to modifiable risk factors or due to the innate inflammatory cardiac damage [9].
As previously mentioned, there has been little research on HS compared to other cutaneous dermatoses. Overall, federal funding for HS in comparison with other inflammatory conditions has been minimal. In 2018, there were only 17 clinical trials dedicated to HS, with even less investigation of model therapies and possible adverse effects [10]. New treatment modalities for HS need to be investigated, as there is a lack of options for a broad patient population with various comorbid conditions. When caring for an individual with HS, awareness of medication effects is not the only way to ensure optimal care. Impairment of quality of life in individuals with HS leads to suboptimal psychological well-being [11]. In a recent meta-analysis, the prevalence of depression in patients with HS was 16.9%. These alarming facts need to be communicated to their primary care providers for prompt recognition of symptoms and urgent management. This intervention will also ensure optimal care.
Conclusions
Management of hidradenitis suppurativa is challenging, and a multimodality approach is usually required. With few treatment options, adalimumab is the only FDA-approved treatment efficacious enough for severe cases of HS. This report presents a fatal case of new-onset acute CHF in an individual re-initiated on adalimumab for severe HS. Understanding the mechanism of action of TNF-inhibitors and cardiovascular decline may help us prevent such cases. Moreover, awareness of CHF as an adverse effect of adalimumab is of utmost importance in primary care to prevent disease progression and fatalities. In addition, understanding the secondary complications of HS such as depression and anxiety will also improve care quality. Management of HS needs to consider many factors for it to be comprehensive and effective. More targeted research regarding new HS treatments is imperative to care for this disease’s broad population.
We wish to extend our gratitude to the Manatí Medical Center staff for their excellence in rendering high-quality patient care and graduate medical education, and the Family Medicine Residency Program to support scholastic achievement.
Conflict of Interest
None. | ADALIMUMAB | DrugsGivenReaction | CC BY-NC-ND | 33563886 | 18,905,508 | 2021-02-10 |
What was the administration route of drug 'ADALIMUMAB'? | Fatal New-Onset Congestive Heart Failure Related to Adalimumab Use in a Patient with Relapsing Hidradenitis Suppurativa: A Case Report.
BACKGROUND Tumor necrosis factor (TNF)-alpha inhibitors are essential treatments in several inflammatory conditions such as hidradenitis suppurativa (HS). However, they are not without associated risks. In rare cases, new-onset and exacerbations of heart failure have been associated with their use. The purpose of this report is to raise awareness of the need for further study of adalimumab for this adverse effect, as well as to recognize the need for research to find new HS treatment modalities for better care of the broad patient population. CASE REPORT We report the case of a 67-year-old man with a history of severe HS and major depressive disorder who came to our hospital complaining of dyspnea, fatigue upon exertion, and lower-extremity edema of 2 weeks' evolution. Symptoms began after the re-initiation of adalimumab for his severe HS. During hospitalization, he was diagnosed with decompensated congestive heart failure (CHF). Extensive studies, looking for ischemic or infectious etiology, yielded negative results. Being aware of adalimumab's potential adverse effects, the team discontinued the medication as a probable cause of his condition. Unfortunately, the patient died secondary to heart failure and septicemia. CONCLUSIONS The unusual but potentially life-threatening appearance of heart failure secondary to adalimumab use merits thorough attention by primary care doctors and specialists. This adverse event's rare occurrence can underestimate the number of fatalities associated with adalimumab and congestive heart failure.
Background
Hidradenitis suppurativa (HS) is a chronic inflammatory disorder of the pilosebaceous unit, commonly found in inter-triginous areas, such as the axilla, inframammary area, and anogenital region. The inflammation is associated with deep, painful subcutaneous nodules, cysts, and abscesses. These lesions may form sinus tracts containing malodorous mucopuru-lent discharge. The constant inflammation in these areas has long-term consequences such as scarring, chronic pain, skin contractures, and possible disfigurement. Its pathophysiology is not well understood and is thought to be multifactorial. Studies have shown a mixture of components like genetic susceptibility, autoimmunity, hormonal dysregulation, and environmental factors such as smoking and obesity [1]. The trigger is thought to be the constant repetition of microtrauma from microbial factors that activate the innate immune system’s pro-inflammatory response [2]. Elevation of pro-inflammatory cytokines such as interleukin (IL) 1-beta, IL-17, and IL-23, as well as tumor necrosis factor (TNF) alpha, have been found on HS lesions, suggesting a dysregulation of the body’s adaptive immune response.
TNF-alpha also affects many other tissues, such as its widely studied effect on the myocardium. The pro-inflammatory cytokine alters the beta-adrenergic receptors in the myocardium, depressing cardiac inotropy. This leads to further inflammation and cardiac injury, ultimately producing congestive heart failure (CHF). Despite the evidence associating TNF-alpha with heart failure, inhibition of the cytokine has not achieved significant success. Reports have found that it worsens cardiovascular symptoms, leading to de novo or exacerbations of existing congestive heart failure [3]. Adalimumab, a TNF-alpha inhibitor, is the only FDA-approved biologic treatment for HS. In this case report, we present the case of a middle-aged man with severe HS treated with adalimumab who developed de novo CHF. We want to raise awareness of the potential adverse effects of HS treatment, specifically use of adalimumab. More investigation is warranted to further understand the patho-physiology and improve treatment.
Case Report
We report the case of a 67-year-old man who presented to the services of Manatí Medical Center with a chief complaint of fatigue upon exertion, dyspnea, and lower-extremity edema that had been progressively worsening for 2 weeks. His medical history was significant for a 30-year history of hidradenitis suppurativa (HS) Hurley stage III, hypertension, major depressive disorder, and a positive Mantoux test, treated with isoniazid 12 years ago. On physical exam, he was hypotensive, tachycardic, and tachypneic. On auscultation, a mild holosystolic murmur with S3 gallop was heard at the apex. Crackles and rales were appreciated in all lung fields, as well as bilateral lower-extremity edema. Additionally, there was mild ascites without abdominal tenderness or guarding. The patient was not confused at any point during history taking or physical exam.
Troponin levels remained constant at less than 0.015 ng/mL, CK-MB less than 1.00 mg/mL, and total creatinine kinase at 15 IU/L, all within normal limits. However, Pro-B natriuretic peptide was elevated at 77 660 pg/mL (normal levels are 5–125 pg/mL). The electrocardiogram showed sinus rhythm with no indication of acute ischemic changes or arrythmia. A chest X-ray showed marked Kerley B lines, enlarged cardiac silhouette, and bilateral pleural effusion, suggesting exacerbated congestive heart failure. He was admitted to the hospital the same day for clinical stabilization and further treatment.
During the hospital stay, various studies were performed to find the etiology of his CHF. The patient’s echocardiogram showed an ejection fraction (EF) of 20–25%, significantly different from a previous study done 2 months ago, which reported an EF of 50%, which also mentioned findings of global hypokinesis of the left ventricle with enlarged atria, left worse than right, and present mitral regurgitation. There were no changes indicating possible myocarditis or pericarditis. Findings of this study suggested new-onset decompensated congestive heart failure (CHF). Other diagnostic tools looking for ischemic and infectious etiology yielded negative results.
A chest CT scan without contrast showed bilateral pleural effusions with bibasilar compressive atelectasis and no evidence of pulmonary or infectious processes. There was also no evidence of an intra-abdominal emergent process on abdominal imaging. The patient did not have significant leukocytosis, with negative blood cultures and pleural fluid culture, suggesting there was no systemic infection or sepsis that may have caused the heart failure. The patient had no coronary disease or cardiovascular risk factors that could explain his symptoms’ severity and rapid progression. However, his clinical history revealed that he was re-initiated on adalimumab 2 months before this presentation. Therefore, adalimumab was discontinued as a precaution of potential cause, with an adverse drug reaction probability of 5.
Further investigation with his dermatologist revealed he first started adalimumab treatment 3 years ago with the standard HS regimen, beginning with subcutaneous 160 mg on the first day, and 80 mg on day 15. On day 29 and weekly thereafter, the dose was maintained at 40 mg. After 2 years of utilizing the medication with no complications, it was discontinued due to his lesions’ progression. However, even with alternate standard treatments and procedures, his condition had not stabilized. After various hospital admissions, adalimumab was re-initiated with the standard-dose regimen, as previously described. Once adalimumab was discontinued during this hospital stay, his health continued to decline, with worsening of symptoms. Unfortunately, the patient’s condition continued to worsen, increasing his hospital visits for symptom management. On the 8th day of hospitalization, he died due to de-compensated heart failure and septicemia.
Discussion
We report a case of new-acute onset CHF in a patient with severe HS who recently re-initiated adalimumab. Although not fully understood, there have been studies describing this adverse effect of TNF-alpha inhibitors. Initially, in various in vitro studies involving mice cardiac myocytes, it was reported that TNF-alpha inhibitors could improve CHF symptoms by reducing the inflammatory response. In practice, this would attenuate ventricular remodeling, fibrosis, and continuous cardiomyocyte apoptosis. However, there are no in vivo data that support these results [3]. A well-known clinical trial investigating the effects of TNF-inhibitors, specifically infliximab, against class III-IV heart failure was prematurely halted, concluding there was an increase in hospitalizations and deaths with a high infliximab dose of 10 mg/kg. At the lower dose of 5 mg/ kg, there was no evident benefit or relief of patients’ cardiac symptoms [4]. As a matter of fact, most of the cases reporting CHF as an adverse effect of TNF-inhibitors have been with long-term use well after the end of the trial.
In 2003, post-marketing reports from the FDA MedWatch system warned of an alarming rise of new and exacerbating CHF cases in patients stable on TNF-inhibitors for rheumatoid arthritis (RA) [5]. The data included patients on infliximab, etanercept, and adalimumab. Although RA increases cardiovascular risk and most of the patients had comorbid conditions, TNF-inhibitors presented an additive risk factor for the disease. Adalimumab itself had the least cases of CHF reported. The incidence of new cases among RA patients was 0.1%, which was comparable to the placebo group. The patient presented in our case report had an adverse drug reaction probability score of 5, which indicates the adverse effect was a probable effect of adalimumab. This score takes into consideration the timing of symptom onset after medication, literature describing the adverse effect, and exclusion of other possible causes known to cause the adverse effect [6].
While there are studies of TNF-inhibitors warning about new or exacerbated CHF, adalimumab specifically has not been extensively studied for this adverse effect. In 2012, a sizable long-term safety analysis regarding adalimumab on patients with systemic inflammatory diseases demonstrated 0.2 per 100 patient-years of serious CHF events [7]. It should be noted that the progression and outcome of the disease was not mentioned in their analysis. In the Cochrane review, a meta-analysis on adverse effects of biologics, there was no statistical significance regarding CHF due to TNF-inhibitors, as there was insufficient data and inconsistent definitions regarding the disease [8]. While the literature suggests it is an unusual risk, there has yet to be a meta-analysis discussing risk factors such as dosage, length of time, or re-initiation after a prolonged period leading to CHF occurrence.
With very few options for HS management, it is imperative to understand the relationship between TNF-inhibitors and cardiac myocytes. As previously stated, HS is known to be a systemic inflammatory condition with recorded elevated inflammatory cytokines, including interleukin (IL) 1-beta, IL-17, and IL-23, as well as tumor necrosis factor (TNF) alpha. This continuous inflammatory process leads to known comorbidities such as obesity and diabetes. As HS progresses, the comorbidity burden increases. A retrospective matched cohort study enrolled 5357 patients with mild and severe HS to learn what other conditions HS patients were more likely to develop. The study found that HS patients were 3 times more likely to develop inflammatory conditions compared to individuals without HS. In addition, individuals with severe forms of HS were found to have a 2-fold higher prevalence of metabolic and cardiovascular dysregulations, including congestive heart failure, compared to HS-free individuals. CHF developed in 2.9% of individuals with severe HS and in only 0.5% of HS-free individuals, regardless of treatment. While the data presented showed a comorbidity burden related to HS progression, the results were limited due to small sample size and inconsistent characterization of HS severity. Additionally, the study did not determine whether heart failure development was due to modifiable risk factors or due to the innate inflammatory cardiac damage [9].
As previously mentioned, there has been little research on HS compared to other cutaneous dermatoses. Overall, federal funding for HS in comparison with other inflammatory conditions has been minimal. In 2018, there were only 17 clinical trials dedicated to HS, with even less investigation of model therapies and possible adverse effects [10]. New treatment modalities for HS need to be investigated, as there is a lack of options for a broad patient population with various comorbid conditions. When caring for an individual with HS, awareness of medication effects is not the only way to ensure optimal care. Impairment of quality of life in individuals with HS leads to suboptimal psychological well-being [11]. In a recent meta-analysis, the prevalence of depression in patients with HS was 16.9%. These alarming facts need to be communicated to their primary care providers for prompt recognition of symptoms and urgent management. This intervention will also ensure optimal care.
Conclusions
Management of hidradenitis suppurativa is challenging, and a multimodality approach is usually required. With few treatment options, adalimumab is the only FDA-approved treatment efficacious enough for severe cases of HS. This report presents a fatal case of new-onset acute CHF in an individual re-initiated on adalimumab for severe HS. Understanding the mechanism of action of TNF-inhibitors and cardiovascular decline may help us prevent such cases. Moreover, awareness of CHF as an adverse effect of adalimumab is of utmost importance in primary care to prevent disease progression and fatalities. In addition, understanding the secondary complications of HS such as depression and anxiety will also improve care quality. Management of HS needs to consider many factors for it to be comprehensive and effective. More targeted research regarding new HS treatments is imperative to care for this disease’s broad population.
We wish to extend our gratitude to the Manatí Medical Center staff for their excellence in rendering high-quality patient care and graduate medical education, and the Family Medicine Residency Program to support scholastic achievement.
Conflict of Interest
None. | Subcutaneous | DrugAdministrationRoute | CC BY-NC-ND | 33563886 | 19,097,488 | 2021-02-10 |
What was the outcome of reaction 'Cardiac failure congestive'? | Fatal New-Onset Congestive Heart Failure Related to Adalimumab Use in a Patient with Relapsing Hidradenitis Suppurativa: A Case Report.
BACKGROUND Tumor necrosis factor (TNF)-alpha inhibitors are essential treatments in several inflammatory conditions such as hidradenitis suppurativa (HS). However, they are not without associated risks. In rare cases, new-onset and exacerbations of heart failure have been associated with their use. The purpose of this report is to raise awareness of the need for further study of adalimumab for this adverse effect, as well as to recognize the need for research to find new HS treatment modalities for better care of the broad patient population. CASE REPORT We report the case of a 67-year-old man with a history of severe HS and major depressive disorder who came to our hospital complaining of dyspnea, fatigue upon exertion, and lower-extremity edema of 2 weeks' evolution. Symptoms began after the re-initiation of adalimumab for his severe HS. During hospitalization, he was diagnosed with decompensated congestive heart failure (CHF). Extensive studies, looking for ischemic or infectious etiology, yielded negative results. Being aware of adalimumab's potential adverse effects, the team discontinued the medication as a probable cause of his condition. Unfortunately, the patient died secondary to heart failure and septicemia. CONCLUSIONS The unusual but potentially life-threatening appearance of heart failure secondary to adalimumab use merits thorough attention by primary care doctors and specialists. This adverse event's rare occurrence can underestimate the number of fatalities associated with adalimumab and congestive heart failure.
Background
Hidradenitis suppurativa (HS) is a chronic inflammatory disorder of the pilosebaceous unit, commonly found in inter-triginous areas, such as the axilla, inframammary area, and anogenital region. The inflammation is associated with deep, painful subcutaneous nodules, cysts, and abscesses. These lesions may form sinus tracts containing malodorous mucopuru-lent discharge. The constant inflammation in these areas has long-term consequences such as scarring, chronic pain, skin contractures, and possible disfigurement. Its pathophysiology is not well understood and is thought to be multifactorial. Studies have shown a mixture of components like genetic susceptibility, autoimmunity, hormonal dysregulation, and environmental factors such as smoking and obesity [1]. The trigger is thought to be the constant repetition of microtrauma from microbial factors that activate the innate immune system’s pro-inflammatory response [2]. Elevation of pro-inflammatory cytokines such as interleukin (IL) 1-beta, IL-17, and IL-23, as well as tumor necrosis factor (TNF) alpha, have been found on HS lesions, suggesting a dysregulation of the body’s adaptive immune response.
TNF-alpha also affects many other tissues, such as its widely studied effect on the myocardium. The pro-inflammatory cytokine alters the beta-adrenergic receptors in the myocardium, depressing cardiac inotropy. This leads to further inflammation and cardiac injury, ultimately producing congestive heart failure (CHF). Despite the evidence associating TNF-alpha with heart failure, inhibition of the cytokine has not achieved significant success. Reports have found that it worsens cardiovascular symptoms, leading to de novo or exacerbations of existing congestive heart failure [3]. Adalimumab, a TNF-alpha inhibitor, is the only FDA-approved biologic treatment for HS. In this case report, we present the case of a middle-aged man with severe HS treated with adalimumab who developed de novo CHF. We want to raise awareness of the potential adverse effects of HS treatment, specifically use of adalimumab. More investigation is warranted to further understand the patho-physiology and improve treatment.
Case Report
We report the case of a 67-year-old man who presented to the services of Manatí Medical Center with a chief complaint of fatigue upon exertion, dyspnea, and lower-extremity edema that had been progressively worsening for 2 weeks. His medical history was significant for a 30-year history of hidradenitis suppurativa (HS) Hurley stage III, hypertension, major depressive disorder, and a positive Mantoux test, treated with isoniazid 12 years ago. On physical exam, he was hypotensive, tachycardic, and tachypneic. On auscultation, a mild holosystolic murmur with S3 gallop was heard at the apex. Crackles and rales were appreciated in all lung fields, as well as bilateral lower-extremity edema. Additionally, there was mild ascites without abdominal tenderness or guarding. The patient was not confused at any point during history taking or physical exam.
Troponin levels remained constant at less than 0.015 ng/mL, CK-MB less than 1.00 mg/mL, and total creatinine kinase at 15 IU/L, all within normal limits. However, Pro-B natriuretic peptide was elevated at 77 660 pg/mL (normal levels are 5–125 pg/mL). The electrocardiogram showed sinus rhythm with no indication of acute ischemic changes or arrythmia. A chest X-ray showed marked Kerley B lines, enlarged cardiac silhouette, and bilateral pleural effusion, suggesting exacerbated congestive heart failure. He was admitted to the hospital the same day for clinical stabilization and further treatment.
During the hospital stay, various studies were performed to find the etiology of his CHF. The patient’s echocardiogram showed an ejection fraction (EF) of 20–25%, significantly different from a previous study done 2 months ago, which reported an EF of 50%, which also mentioned findings of global hypokinesis of the left ventricle with enlarged atria, left worse than right, and present mitral regurgitation. There were no changes indicating possible myocarditis or pericarditis. Findings of this study suggested new-onset decompensated congestive heart failure (CHF). Other diagnostic tools looking for ischemic and infectious etiology yielded negative results.
A chest CT scan without contrast showed bilateral pleural effusions with bibasilar compressive atelectasis and no evidence of pulmonary or infectious processes. There was also no evidence of an intra-abdominal emergent process on abdominal imaging. The patient did not have significant leukocytosis, with negative blood cultures and pleural fluid culture, suggesting there was no systemic infection or sepsis that may have caused the heart failure. The patient had no coronary disease or cardiovascular risk factors that could explain his symptoms’ severity and rapid progression. However, his clinical history revealed that he was re-initiated on adalimumab 2 months before this presentation. Therefore, adalimumab was discontinued as a precaution of potential cause, with an adverse drug reaction probability of 5.
Further investigation with his dermatologist revealed he first started adalimumab treatment 3 years ago with the standard HS regimen, beginning with subcutaneous 160 mg on the first day, and 80 mg on day 15. On day 29 and weekly thereafter, the dose was maintained at 40 mg. After 2 years of utilizing the medication with no complications, it was discontinued due to his lesions’ progression. However, even with alternate standard treatments and procedures, his condition had not stabilized. After various hospital admissions, adalimumab was re-initiated with the standard-dose regimen, as previously described. Once adalimumab was discontinued during this hospital stay, his health continued to decline, with worsening of symptoms. Unfortunately, the patient’s condition continued to worsen, increasing his hospital visits for symptom management. On the 8th day of hospitalization, he died due to de-compensated heart failure and septicemia.
Discussion
We report a case of new-acute onset CHF in a patient with severe HS who recently re-initiated adalimumab. Although not fully understood, there have been studies describing this adverse effect of TNF-alpha inhibitors. Initially, in various in vitro studies involving mice cardiac myocytes, it was reported that TNF-alpha inhibitors could improve CHF symptoms by reducing the inflammatory response. In practice, this would attenuate ventricular remodeling, fibrosis, and continuous cardiomyocyte apoptosis. However, there are no in vivo data that support these results [3]. A well-known clinical trial investigating the effects of TNF-inhibitors, specifically infliximab, against class III-IV heart failure was prematurely halted, concluding there was an increase in hospitalizations and deaths with a high infliximab dose of 10 mg/kg. At the lower dose of 5 mg/ kg, there was no evident benefit or relief of patients’ cardiac symptoms [4]. As a matter of fact, most of the cases reporting CHF as an adverse effect of TNF-inhibitors have been with long-term use well after the end of the trial.
In 2003, post-marketing reports from the FDA MedWatch system warned of an alarming rise of new and exacerbating CHF cases in patients stable on TNF-inhibitors for rheumatoid arthritis (RA) [5]. The data included patients on infliximab, etanercept, and adalimumab. Although RA increases cardiovascular risk and most of the patients had comorbid conditions, TNF-inhibitors presented an additive risk factor for the disease. Adalimumab itself had the least cases of CHF reported. The incidence of new cases among RA patients was 0.1%, which was comparable to the placebo group. The patient presented in our case report had an adverse drug reaction probability score of 5, which indicates the adverse effect was a probable effect of adalimumab. This score takes into consideration the timing of symptom onset after medication, literature describing the adverse effect, and exclusion of other possible causes known to cause the adverse effect [6].
While there are studies of TNF-inhibitors warning about new or exacerbated CHF, adalimumab specifically has not been extensively studied for this adverse effect. In 2012, a sizable long-term safety analysis regarding adalimumab on patients with systemic inflammatory diseases demonstrated 0.2 per 100 patient-years of serious CHF events [7]. It should be noted that the progression and outcome of the disease was not mentioned in their analysis. In the Cochrane review, a meta-analysis on adverse effects of biologics, there was no statistical significance regarding CHF due to TNF-inhibitors, as there was insufficient data and inconsistent definitions regarding the disease [8]. While the literature suggests it is an unusual risk, there has yet to be a meta-analysis discussing risk factors such as dosage, length of time, or re-initiation after a prolonged period leading to CHF occurrence.
With very few options for HS management, it is imperative to understand the relationship between TNF-inhibitors and cardiac myocytes. As previously stated, HS is known to be a systemic inflammatory condition with recorded elevated inflammatory cytokines, including interleukin (IL) 1-beta, IL-17, and IL-23, as well as tumor necrosis factor (TNF) alpha. This continuous inflammatory process leads to known comorbidities such as obesity and diabetes. As HS progresses, the comorbidity burden increases. A retrospective matched cohort study enrolled 5357 patients with mild and severe HS to learn what other conditions HS patients were more likely to develop. The study found that HS patients were 3 times more likely to develop inflammatory conditions compared to individuals without HS. In addition, individuals with severe forms of HS were found to have a 2-fold higher prevalence of metabolic and cardiovascular dysregulations, including congestive heart failure, compared to HS-free individuals. CHF developed in 2.9% of individuals with severe HS and in only 0.5% of HS-free individuals, regardless of treatment. While the data presented showed a comorbidity burden related to HS progression, the results were limited due to small sample size and inconsistent characterization of HS severity. Additionally, the study did not determine whether heart failure development was due to modifiable risk factors or due to the innate inflammatory cardiac damage [9].
As previously mentioned, there has been little research on HS compared to other cutaneous dermatoses. Overall, federal funding for HS in comparison with other inflammatory conditions has been minimal. In 2018, there were only 17 clinical trials dedicated to HS, with even less investigation of model therapies and possible adverse effects [10]. New treatment modalities for HS need to be investigated, as there is a lack of options for a broad patient population with various comorbid conditions. When caring for an individual with HS, awareness of medication effects is not the only way to ensure optimal care. Impairment of quality of life in individuals with HS leads to suboptimal psychological well-being [11]. In a recent meta-analysis, the prevalence of depression in patients with HS was 16.9%. These alarming facts need to be communicated to their primary care providers for prompt recognition of symptoms and urgent management. This intervention will also ensure optimal care.
Conclusions
Management of hidradenitis suppurativa is challenging, and a multimodality approach is usually required. With few treatment options, adalimumab is the only FDA-approved treatment efficacious enough for severe cases of HS. This report presents a fatal case of new-onset acute CHF in an individual re-initiated on adalimumab for severe HS. Understanding the mechanism of action of TNF-inhibitors and cardiovascular decline may help us prevent such cases. Moreover, awareness of CHF as an adverse effect of adalimumab is of utmost importance in primary care to prevent disease progression and fatalities. In addition, understanding the secondary complications of HS such as depression and anxiety will also improve care quality. Management of HS needs to consider many factors for it to be comprehensive and effective. More targeted research regarding new HS treatments is imperative to care for this disease’s broad population.
We wish to extend our gratitude to the Manatí Medical Center staff for their excellence in rendering high-quality patient care and graduate medical education, and the Family Medicine Residency Program to support scholastic achievement.
Conflict of Interest
None. | Fatal | ReactionOutcome | CC BY-NC-ND | 33563886 | 18,905,508 | 2021-02-10 |
What was the outcome of reaction 'Cardiac failure'? | Fatal New-Onset Congestive Heart Failure Related to Adalimumab Use in a Patient with Relapsing Hidradenitis Suppurativa: A Case Report.
BACKGROUND Tumor necrosis factor (TNF)-alpha inhibitors are essential treatments in several inflammatory conditions such as hidradenitis suppurativa (HS). However, they are not without associated risks. In rare cases, new-onset and exacerbations of heart failure have been associated with their use. The purpose of this report is to raise awareness of the need for further study of adalimumab for this adverse effect, as well as to recognize the need for research to find new HS treatment modalities for better care of the broad patient population. CASE REPORT We report the case of a 67-year-old man with a history of severe HS and major depressive disorder who came to our hospital complaining of dyspnea, fatigue upon exertion, and lower-extremity edema of 2 weeks' evolution. Symptoms began after the re-initiation of adalimumab for his severe HS. During hospitalization, he was diagnosed with decompensated congestive heart failure (CHF). Extensive studies, looking for ischemic or infectious etiology, yielded negative results. Being aware of adalimumab's potential adverse effects, the team discontinued the medication as a probable cause of his condition. Unfortunately, the patient died secondary to heart failure and septicemia. CONCLUSIONS The unusual but potentially life-threatening appearance of heart failure secondary to adalimumab use merits thorough attention by primary care doctors and specialists. This adverse event's rare occurrence can underestimate the number of fatalities associated with adalimumab and congestive heart failure.
Background
Hidradenitis suppurativa (HS) is a chronic inflammatory disorder of the pilosebaceous unit, commonly found in inter-triginous areas, such as the axilla, inframammary area, and anogenital region. The inflammation is associated with deep, painful subcutaneous nodules, cysts, and abscesses. These lesions may form sinus tracts containing malodorous mucopuru-lent discharge. The constant inflammation in these areas has long-term consequences such as scarring, chronic pain, skin contractures, and possible disfigurement. Its pathophysiology is not well understood and is thought to be multifactorial. Studies have shown a mixture of components like genetic susceptibility, autoimmunity, hormonal dysregulation, and environmental factors such as smoking and obesity [1]. The trigger is thought to be the constant repetition of microtrauma from microbial factors that activate the innate immune system’s pro-inflammatory response [2]. Elevation of pro-inflammatory cytokines such as interleukin (IL) 1-beta, IL-17, and IL-23, as well as tumor necrosis factor (TNF) alpha, have been found on HS lesions, suggesting a dysregulation of the body’s adaptive immune response.
TNF-alpha also affects many other tissues, such as its widely studied effect on the myocardium. The pro-inflammatory cytokine alters the beta-adrenergic receptors in the myocardium, depressing cardiac inotropy. This leads to further inflammation and cardiac injury, ultimately producing congestive heart failure (CHF). Despite the evidence associating TNF-alpha with heart failure, inhibition of the cytokine has not achieved significant success. Reports have found that it worsens cardiovascular symptoms, leading to de novo or exacerbations of existing congestive heart failure [3]. Adalimumab, a TNF-alpha inhibitor, is the only FDA-approved biologic treatment for HS. In this case report, we present the case of a middle-aged man with severe HS treated with adalimumab who developed de novo CHF. We want to raise awareness of the potential adverse effects of HS treatment, specifically use of adalimumab. More investigation is warranted to further understand the patho-physiology and improve treatment.
Case Report
We report the case of a 67-year-old man who presented to the services of Manatí Medical Center with a chief complaint of fatigue upon exertion, dyspnea, and lower-extremity edema that had been progressively worsening for 2 weeks. His medical history was significant for a 30-year history of hidradenitis suppurativa (HS) Hurley stage III, hypertension, major depressive disorder, and a positive Mantoux test, treated with isoniazid 12 years ago. On physical exam, he was hypotensive, tachycardic, and tachypneic. On auscultation, a mild holosystolic murmur with S3 gallop was heard at the apex. Crackles and rales were appreciated in all lung fields, as well as bilateral lower-extremity edema. Additionally, there was mild ascites without abdominal tenderness or guarding. The patient was not confused at any point during history taking or physical exam.
Troponin levels remained constant at less than 0.015 ng/mL, CK-MB less than 1.00 mg/mL, and total creatinine kinase at 15 IU/L, all within normal limits. However, Pro-B natriuretic peptide was elevated at 77 660 pg/mL (normal levels are 5–125 pg/mL). The electrocardiogram showed sinus rhythm with no indication of acute ischemic changes or arrythmia. A chest X-ray showed marked Kerley B lines, enlarged cardiac silhouette, and bilateral pleural effusion, suggesting exacerbated congestive heart failure. He was admitted to the hospital the same day for clinical stabilization and further treatment.
During the hospital stay, various studies were performed to find the etiology of his CHF. The patient’s echocardiogram showed an ejection fraction (EF) of 20–25%, significantly different from a previous study done 2 months ago, which reported an EF of 50%, which also mentioned findings of global hypokinesis of the left ventricle with enlarged atria, left worse than right, and present mitral regurgitation. There were no changes indicating possible myocarditis or pericarditis. Findings of this study suggested new-onset decompensated congestive heart failure (CHF). Other diagnostic tools looking for ischemic and infectious etiology yielded negative results.
A chest CT scan without contrast showed bilateral pleural effusions with bibasilar compressive atelectasis and no evidence of pulmonary or infectious processes. There was also no evidence of an intra-abdominal emergent process on abdominal imaging. The patient did not have significant leukocytosis, with negative blood cultures and pleural fluid culture, suggesting there was no systemic infection or sepsis that may have caused the heart failure. The patient had no coronary disease or cardiovascular risk factors that could explain his symptoms’ severity and rapid progression. However, his clinical history revealed that he was re-initiated on adalimumab 2 months before this presentation. Therefore, adalimumab was discontinued as a precaution of potential cause, with an adverse drug reaction probability of 5.
Further investigation with his dermatologist revealed he first started adalimumab treatment 3 years ago with the standard HS regimen, beginning with subcutaneous 160 mg on the first day, and 80 mg on day 15. On day 29 and weekly thereafter, the dose was maintained at 40 mg. After 2 years of utilizing the medication with no complications, it was discontinued due to his lesions’ progression. However, even with alternate standard treatments and procedures, his condition had not stabilized. After various hospital admissions, adalimumab was re-initiated with the standard-dose regimen, as previously described. Once adalimumab was discontinued during this hospital stay, his health continued to decline, with worsening of symptoms. Unfortunately, the patient’s condition continued to worsen, increasing his hospital visits for symptom management. On the 8th day of hospitalization, he died due to de-compensated heart failure and septicemia.
Discussion
We report a case of new-acute onset CHF in a patient with severe HS who recently re-initiated adalimumab. Although not fully understood, there have been studies describing this adverse effect of TNF-alpha inhibitors. Initially, in various in vitro studies involving mice cardiac myocytes, it was reported that TNF-alpha inhibitors could improve CHF symptoms by reducing the inflammatory response. In practice, this would attenuate ventricular remodeling, fibrosis, and continuous cardiomyocyte apoptosis. However, there are no in vivo data that support these results [3]. A well-known clinical trial investigating the effects of TNF-inhibitors, specifically infliximab, against class III-IV heart failure was prematurely halted, concluding there was an increase in hospitalizations and deaths with a high infliximab dose of 10 mg/kg. At the lower dose of 5 mg/ kg, there was no evident benefit or relief of patients’ cardiac symptoms [4]. As a matter of fact, most of the cases reporting CHF as an adverse effect of TNF-inhibitors have been with long-term use well after the end of the trial.
In 2003, post-marketing reports from the FDA MedWatch system warned of an alarming rise of new and exacerbating CHF cases in patients stable on TNF-inhibitors for rheumatoid arthritis (RA) [5]. The data included patients on infliximab, etanercept, and adalimumab. Although RA increases cardiovascular risk and most of the patients had comorbid conditions, TNF-inhibitors presented an additive risk factor for the disease. Adalimumab itself had the least cases of CHF reported. The incidence of new cases among RA patients was 0.1%, which was comparable to the placebo group. The patient presented in our case report had an adverse drug reaction probability score of 5, which indicates the adverse effect was a probable effect of adalimumab. This score takes into consideration the timing of symptom onset after medication, literature describing the adverse effect, and exclusion of other possible causes known to cause the adverse effect [6].
While there are studies of TNF-inhibitors warning about new or exacerbated CHF, adalimumab specifically has not been extensively studied for this adverse effect. In 2012, a sizable long-term safety analysis regarding adalimumab on patients with systemic inflammatory diseases demonstrated 0.2 per 100 patient-years of serious CHF events [7]. It should be noted that the progression and outcome of the disease was not mentioned in their analysis. In the Cochrane review, a meta-analysis on adverse effects of biologics, there was no statistical significance regarding CHF due to TNF-inhibitors, as there was insufficient data and inconsistent definitions regarding the disease [8]. While the literature suggests it is an unusual risk, there has yet to be a meta-analysis discussing risk factors such as dosage, length of time, or re-initiation after a prolonged period leading to CHF occurrence.
With very few options for HS management, it is imperative to understand the relationship between TNF-inhibitors and cardiac myocytes. As previously stated, HS is known to be a systemic inflammatory condition with recorded elevated inflammatory cytokines, including interleukin (IL) 1-beta, IL-17, and IL-23, as well as tumor necrosis factor (TNF) alpha. This continuous inflammatory process leads to known comorbidities such as obesity and diabetes. As HS progresses, the comorbidity burden increases. A retrospective matched cohort study enrolled 5357 patients with mild and severe HS to learn what other conditions HS patients were more likely to develop. The study found that HS patients were 3 times more likely to develop inflammatory conditions compared to individuals without HS. In addition, individuals with severe forms of HS were found to have a 2-fold higher prevalence of metabolic and cardiovascular dysregulations, including congestive heart failure, compared to HS-free individuals. CHF developed in 2.9% of individuals with severe HS and in only 0.5% of HS-free individuals, regardless of treatment. While the data presented showed a comorbidity burden related to HS progression, the results were limited due to small sample size and inconsistent characterization of HS severity. Additionally, the study did not determine whether heart failure development was due to modifiable risk factors or due to the innate inflammatory cardiac damage [9].
As previously mentioned, there has been little research on HS compared to other cutaneous dermatoses. Overall, federal funding for HS in comparison with other inflammatory conditions has been minimal. In 2018, there were only 17 clinical trials dedicated to HS, with even less investigation of model therapies and possible adverse effects [10]. New treatment modalities for HS need to be investigated, as there is a lack of options for a broad patient population with various comorbid conditions. When caring for an individual with HS, awareness of medication effects is not the only way to ensure optimal care. Impairment of quality of life in individuals with HS leads to suboptimal psychological well-being [11]. In a recent meta-analysis, the prevalence of depression in patients with HS was 16.9%. These alarming facts need to be communicated to their primary care providers for prompt recognition of symptoms and urgent management. This intervention will also ensure optimal care.
Conclusions
Management of hidradenitis suppurativa is challenging, and a multimodality approach is usually required. With few treatment options, adalimumab is the only FDA-approved treatment efficacious enough for severe cases of HS. This report presents a fatal case of new-onset acute CHF in an individual re-initiated on adalimumab for severe HS. Understanding the mechanism of action of TNF-inhibitors and cardiovascular decline may help us prevent such cases. Moreover, awareness of CHF as an adverse effect of adalimumab is of utmost importance in primary care to prevent disease progression and fatalities. In addition, understanding the secondary complications of HS such as depression and anxiety will also improve care quality. Management of HS needs to consider many factors for it to be comprehensive and effective. More targeted research regarding new HS treatments is imperative to care for this disease’s broad population.
We wish to extend our gratitude to the Manatí Medical Center staff for their excellence in rendering high-quality patient care and graduate medical education, and the Family Medicine Residency Program to support scholastic achievement.
Conflict of Interest
None. | Fatal | ReactionOutcome | CC BY-NC-ND | 33563886 | 19,097,488 | 2021-02-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Plasma cell myeloma recurrent'. | Phase 1 open-label study of panobinostat, lenalidomide, bortezomib + dexamethasone in relapsed and relapsed/refractory multiple myeloma.
Additional therapeutic options are needed for relapsed and refractory multiple myeloma (RRMM). We present data from a phase 1b, open-label, dose-escalation study (NCT01965353) of 20 patients with RRMM (median age: 63 years [range: 50-77]) and a median of four prior regimens (range: 2-14); 85% had refractory disease (lenalidomide [80%]; bortezomib [75%]; lenalidomide and bortezomib [50%]). Patients received a median of six cycles (range: 1-74) of panobinostat (10 or 15 mg), lenalidomide 15 mg, bortezomib 1 mg/m2, and dexamethasone 20 mg (pano-RVd). Median follow-up was ~14 months. Six dose-limiting toxicities were reported (mostly hematological); maximum tolerated dose of panobinostat (primary endpoint) was 10 mg. Most common adverse events (AEs) were diarrhea (60%) and peripheral neuropathy (60%); all grade 1/2. Grade 3/4 AEs occurred in 80% of patients and included decreased neutrophil (45%), platelet (25%) and white blood cell (25%) counts, anemia (25%) and hypophosphatemia (25%). No treatment-related discontinuations or mortality occurred. In evaluable patients (n = 18), overall response rate was 44%, and clinical benefit rate was 61%. Median duration of response was 9.2 months; progression-free survival was 7.4 months; overall survival was not reached. Pano-RVd proved generally well-tolerated and demonstrated potential to overcome lenalidomide and/or bortezomib resistance.
Introduction
Treatment of multiple myeloma (MM), an incurable plasma-cell neoplasm, has changed substantially in recent decades1. Rapidly evolving treatment standards have led to improvements in overall survival (OS), as well as the depth and duration of response (DOR)2–4. Nevertheless, most patients ultimately relapse and require subsequent lines of therapy, with the depth of response and DOR to each successive regimen typically decreasing over time1. However, different emerging classes of agents, which can be combined in triplet or even quadruplet regimens, have provided clinicians with several new therapeutic options for relapsed and refractory MM (RRMM) patients.
Histone deacetylase inhibitors (HDACis), which influence transcriptional activation and other nuclear events by increasing histone acetylation, have been developed in recent years as a treatment for RRMM1,5–7. Histone deacetylases (HDACs) are overexpressed in MM, leading to reduced expression of tumor suppressor genes and, consequently, increased growth and proliferation of tumor cells. Unsurprisingly, overexpression of class I HDACs is associated with a poorer prognosis in MM8.
Broad-spectrum HDACis can enhance the anti-MM activity of proteasome inhibitors through multiple non-mutually exclusive mechanisms, including the transcriptional repression of ubiquitin/proteasome pathway genes and drivers of tumor cell survival and treatment resistance9,10, as well as the inhibition of the aggresome, which is an alternative route for protein degradation11. Panobinostat is among the most potent HDACis in clinical development and the only HDACi approved for the treatment of RRMM, in combination with bortezomib and dexamethasone12,13. In the phase 2 PANORAMA 2 trial, heavily pre-treated, bortezomib-refractory patients with RRMM had an overall response rate (ORR) of 34.5% with panobinostat plus bortezomib and dexamethasone (pano-Vd), highlighting that the addition of panobinostat can overcome resistance to prior therapeutic agents, including bortezomib14. In the randomized phase 3 PANORAMA 1 study, pano-Vd significantly improved median progression-free survival (PFS) by 12.5 vs. 4.7 months (hazard ratio 0.47; 95% confidence interval [CI] 0.31, 0.72) in patients who had received ≥2 prior regimens including bortezomib and an immunomodulatory drug (IMiD), and nearly tripled the rate of complete response/near complete response, compared with placebo-Vd (22% vs. 8% for pano-Vd and placebo-Vd, respectively)5,6,15.
The optimal dose and schedule of pano-Vd was confirmed in the randomized phase 3 PANORAMA 3 trial as 20 mg thrice weekly; DOR with this regimen was 22.6 months and tolerability was improved with subcutaneous administration of bortezomib with only 11.5% of patients in the 20 mg TIW dosing group reporting grade 3/4 diarrhea compared with intravenous delivery of bortezomib, as was standard practice at the time of previous clinical trials.16
Broad-spectrum HDACis also enhance the anti-MM activity of IMiDs, such as lenalidomide, by suppressing diverse oncogenic transcriptional programs10, including the interferon regulatory factor-4/MYC axis17. In a phase 2 study of patients with RRMM, panobinostat plus lenalidomide and dexamethasone (pano-Rd) demonstrated an encouraging ORR (41%) and median PFS (7.1 months) in patients with high-risk, lenalidomide-refractory (81%), and/or bortezomib-refractory (52%) MM, suggesting that panobinostat is also able to overcome resistance to IMiDs.
These data provided the rationale for investigating the quadruplet regimen, panobinostat, lenalidomide, bortezomib and dexamethasone (pano-RVd), in heavily pre-treated patients, particularly in those refractory to proteasome inhibitors and/or IMiDs for whom additional therapy options are needed. Here, we report the findings of a phase 1b dose-escalation study of pano-RVd with extended follow-up.
Methods
Study design and objectives
This study was an open-label, multicenter, phase 1b, study of pano-RVd in RRMM (NCT01965353). Primary objectives were to identify the maximum tolerated dose (MTD) of panobinostat in combination with RVd and to evaluate the safety profile of pano-RVd. Secondary objectives were to evaluate ORR, DOR, time to progression (TTP), PFS and OS. A modified Fibonacci design was used, with 3–6 patients planned at each dose level followed by a dose-expansion phase with an additional ten patients to evaluate the tolerability of the MTD.
The study was conducted in accordance with the Declaration of Helsinki, US Code of Federal Regulations governing clinical study conduct, state laws and Dana-Farber/Harvard Cancer Center research policies and procedures. The institutional review board for each center approved the protocol and amendments. All patients provided written informed consent before enrollment.
Patient eligibility
Eligible patients were aged ≥18 years with measurable RRMM (2011 International Myeloma Working Group consensus)18, an Eastern Cooperative Oncology Group performance status <2, and had received ≥2 lines of therapy. Patients with primary refractory disease, prior HDACi treatment, creatinine clearance <45 mL/min, platelet count <75,000 cells/mm3, absolute neutrophil count <1500 cells/mm3, or hemoglobin level <8.0 g/dl at screening were excluded. Patients with ≥grade (G) 2 peripheral neuropathy (PN) or hepatic impairment (bilirubin > 1.5 × institutional upper limit of normal, or aspartate aminotransferase, alanine aminotransferase, or alkaline phosphatase >2 × institutional upper limit of normal) within 21 days of study therapy initiation were also excluded.
Treatments administered
Patients received oral panobinostat 10 mg or 15 mg plus subcutaneous bortezomib 1 mg/m2, oral lenalidomide 15 mg, and oral dexamethasone 20 mg in 21-day cycles per the schema in Fig. 1. After eight cycles, patients switched to a maintenance schedule, with reduced bortezomib and dexamethasone dosing. Treatment continued until disease progression, unacceptable toxicity, consent was withdrawn, or discontinuation was in the best interest of the patient. Doses could be held for up to 21 days or reduced to manage therapy-related adverse events (TRAEs).Fig. 1 Each cycle consisted of 21 days, patients received eight treatment cycles before switching to maintenance cycles.
Progression to the next higher dose level occurred, if appropriate, when the safety and tolerability of the prior dose level(s) had been determined at the end of the first cycle.
Necessary concomitant medications were allowed, except for those which may cause QTcF prolongation or induce torsades de pointes. Leukocyte growth factors were only administered during cycle 1 in the event of a dose-limiting toxicity (DLT) (if appropriate), but could be prescribed for severe neutropenia after cycle 1.
Dose escalation, MTD, and DLTs
A standard 3 + 3 dose-escalation schema was used (Supplementary Fig. S1). If ≥2 of 3 patients within a cohort experienced a DLT during the dose-escalation phase, the dose immediately below the current dose was defined as the MTD. The 3 + 3 schema was chosen, rather than an alternative methodologic phase 1 study design, due to the limited number of patients in the study and the fact that only three dose levels were planned. DLTs were assessed during the first cycle and defined as a QTcF interval >500 ms, or an absolute increase of >60 ms, a ≥ G3 non-hematological AE or a G4 hematological AE (including thrombocytopenia with platelets <25,000/mm3 on >1 occasion, or G4 neutropenia for >5 days and/or resulting in neutropenic fever on two occasions). Lymphopenia, an AE associated with bortezomib use, was not considered a DLT. Inability to take ≥75% of the planned study drug doses, or receive day 1 doses for cycle 2 due to a drug-related AE occurring in cycle 1, were also considered DLTs.
Assessments
AEs, graded using Cancer Therapy Evaluation Program Version 4 of the National Cancer Institute Common Terminology Criteria for Adverse Events19, were assessed throughout the study and for 30 days after completion of study therapy. Patients who discontinued for any reason other than disease progression were followed every three months until disease progression. Disease response/progression were assessed at the start of each treatment and maintenance cycle, at the end of study, and during the follow-up phase. Disease response was assessed locally using the International Myeloma Working Group Response Criteria18 with M-protein quantification and immunofixation in serum and 24-h urine samples, and serum-free light chain testing. OS was assessed every three months after disease progression.
Statistical analyses
Data cut-off was 24 January 2019. Descriptive statistics are provided for the reported outcomes. All participants who had received ≥1 dose of any study treatment were evaluated for AEs from treatment initiation. All patients who had received study treatment and had ≥1 follow-up assessment were included in the response evaluation. Only patients who responded to treatment (≥minimal response) were included in the DOR analysis. DOR, TTP, PFS, and OS were estimated using Kaplan–Meier methodology. DOR was measured as the time from initiation of first response to time of disease progression, death, or last follow-up (for those patients who had not progressed or died). TTP was defined as time from registration to progression or to last follow-up (for those who had not progressed). PFS was defined as the time from registration to disease progression, death, or last follow-up (for those who had not progressed or died). OS was defined as time from registration to death or last follow-up (for patients who had not died).
Results
Patient characteristics
Between November 2013 and October 2016, 20 patients were enrolled: median age was 63 years (range: 50–77), 70% male (Table 1). Cytogenetic data were available for 17 patients; two had t(4;14), and one had t(14;16). The median number of prior lines of treatment was four (range: 2–14); five patients had received >5 prior lines of treatment. Overall, 95% and 90% had been previously treated with bortezomib and lenalidomide, respectively. Most patients (n = 17, 85%) had refractory disease (lenalidomide [80%]; bortezomib [75%]; lenalidomide and bortezomib [50%]; dexamethasone [85%]).Table 1 Patient baseline characteristics.
Total population n = 20 (%)
Male 14 (70)
Race
Black/African American 4 (20)
White 15 (75)
Other 1 (5)
Age, median (range) 63 (50–77)
Age group
≤55 4 (20)
56–65 9 (45)
>65 7 (35)
Disease status
Relapsed 3 (15)
R/R 17 (85)
ECOG PS
0 9 (45)
1 11 (55)
ISS classification
I 5 (25)
II 7 (35)
III 7 (35)
Missing 1 (5)
Number of prior treatments, median (range) 4 (2–14)
Prior treatment
Bortezomib 19 (95)
Dexamethasone 20 (100)
Lenalidomide 18 (90)
Pomalidomide 15 (75)
Carfilzomib 0
Refractory to any prior treatment
Bortezomib 15 (75)
Dexamethasone 17 (85)
Lenalidomide 16 (80)
Refractory most recent prior treatment
Bortezomib 9 (45)
Dexamethasone 16 (80)
Lenalidomide 2 (10)
Prior autologous transplants
1 9 (45)
Cytogenetics
No FISH failure 17 (85)
t (4;14)a 2 (10)
t (14;16)b 1 (5)
ECOG PS Eastern Cooperative Oncology Group Performance Status, FISH fluorescence in situ hybridization, ISS International Staging System, R/R relapsed/refractory.
aMissing: n = 9.
bMissing: n = 10.
MTD and DLTs
Three patients were treated with panobinostat 10 mg; one experienced a DLT; per protocol, three additional patients were treated with panobinostat 10 mg. No further DLTs were reported, and the dose was escalated. Three patients were treated with panobinostat 15 mg; two experienced DLTs. One of these DLTs (syncope) was a pre-existing condition and not considered related to study treatment, thus, one additional patient was treated with panobinostat 15 mg; this patient subsequently experienced a DLT (thrombocytopenia). Therefore, 10 mg was defined as the MTD for panobinostat in the pano-RVd combination. In the expansion phase, ten patients were treated with pano-RVd with panobinostat dosed at 10 mg; two experienced a DLT. Overall, four patients experienced one DLT, one patient experienced two DLTs and one patient experienced three DLTs (Table 2).Table 2 Dose limiting toxicities.
n (panobinostat dose)
Decreased platelet count 3 (15 mg, n = 2; 10 mg, n = 1)
Decreased neutrophil count 2 (15 mg)
Fatigue 1 (15 mg)
Hyperglycemia 1 (10 mg)
Hypophosphatemia 1 (10 mg)
Syncope 1a (15 mg)
aNot related to treatment.
Treatment summary
Patients completed a median of six cycles (range: 1–74) (Supplementary Table S1). Three patients completed one cycle before withdrawing due to progressive disease. Eight patients completed all eight treatment cycles and ≥1 cycle of maintenance therapy. At the data cut-off date, one patient remained on treatment (Supplementary Fig. S2).
Safety and tolerability
All 20 patients experienced ≥1 TRAE. The distribution of worst overall TRAEs experienced was G1 (n = 1), G2 (n = 3), G3 (n = 11) or G4 (n = 5). The most common TRAEs included diarrhea (60%, all were G1/2), PN (60%), anemia (55%), fatigue (55%), neutropenia (55%), constipation (50%) and hypokalemia (50%) (Table 3). The median (95% CI) duration of neutropenia and thrombocytopenia AEs was 7 (4; 11) days and 8 (4; 11) days, respectively. Overall, 37 G3/4 TRAEs were reported; the most common were decreased neutrophil (45%), platelet (25%) and white blood cell (25%) counts; anemia (25%); and hypophosphatemia (25%). The rate of cardiac TRAEs was low (atrial fibrillation, n = 1; atrial flutter, n = 1; sinus bradycardia, n = 1; sinus tachycardia, n = 1; palpitations, n = 1; prolongation of QTcF interval, n = 1; heart racing, n = 1; chronic right bundle branch block, n = 1; ectopy and murmur n = 1), and all events were G1/2. No G3/4 diarrhea TRAEs were observed. The only reported G4 TRAEs were decreased platelet (25%) and white blood cell counts (5%). In total, nine serious AEs were experienced by six patients, including treatment-related hyperglycemia, decreased neutrophil count, fatigue, and decreased platelet count. TRAE rates were generally balanced in patients in patients <65 (n = 11) and ≥65 (n = 9) years old, although G4 thrombocytopenia TRAEs were more common in patients ≥65 years old.Table 3 AEs experienced by ≥20% of patients and all grade 4 AEs.
Total, n (%) Grade 1 Grade 2 Grade 3 Grade 4
(n = 20) n (%) n (%) n (%) n (%)
Blood and lymphatic system disorders
Anemia 11 (55) 2 (10) 4 (20) 5 (25) –
Neutrophil count decreased 11 (55) 1 (5) 1 (5) 9 (45) –
Platelet count decreased 9 (45) 4 (20) – – 5 (25)
White blood cell count decreased 7 (35) – 2 (10) 4 (20) 1 (5)
Blood and lymphatic system disorders – other 4 (20) 1 (5) 3 (15) – –
Bruising 4 (20) 4 (20) – – –
Cardiac disorders
Dizziness 5 (25) 4 (20) 1 (5) – –
Cardiac disorders – other 4 (20) 4 (20) – – –
Eye disorders
Eye disorders—other 4 (20) 2 (10) 2 (10) – –
Gastrointestinal disorders
Diarrhea 12 (60) 7 (35) 5 (25) – –
Constipation 10 (50) 6 (30) 4 (20) – –
Nausea 7 (35) 5 (25) 2 (10) – –
Gastrointestinal disorders—other 5 (25) 3 (15) 2 (10) – –
Dysgeusia 4 (20) 2 (10) 2 (10) – –
General disorders and administration site conditions
Fatigue 11 (55) 1 (5) 9 (45) 1 (5) –
Edema limbs 7 (35) 4 (20) 3 (15) – –
Infections and infestations
Upper respiratory infection 8 (40) – 8 (40) – –
Infections and infestations – other 6 (30) 2 (10) 2 (10) 2 (10) –
Investigations
Hypokalemia 10 (50) 8 (40) 2 (10) – –
Hypomagnesemia 8 (40) 8 (40) – – –
Hypophosphatemia 7 (35) 1 (5) 1 (5) 5 (25) –
Hypocalcemia 5 (25) 4 (20) 1 (5) – –
Hyponatremia 5 (25) 5 (25) – – –
Metabolism and nutrition disorders
Anorexia 7 (35) 5 (25) 2 (10) – –
Hyperglycemia 7 (35) 4 (20) 2 (10) 1 (5) –
Musculoskeletal and connective tissue disorders
Musculoskeletal and connective tissue disorder – other 4 (20) 2 (10) 2 (10) – –
Nervous system disorders
Peripheral sensory neuropathy 12 (60) 6 (30) 6 (30) – –
Psychiatric disorders
Insomnia 6 (30) 3 (15) 3 (15) – –
Respiratory, thoracic, and mediastinal disorders
Cough 6 (30) 1 (5) 5 (25) – –
Dyspnea 6 (30) 3 (15) 2 (10) 1 (5) –
AEs that were possibly, probably, or definitely related to any study treatments are reported. Each AE represents the highest grade for that AE per patient, so patients may be included in each row at most once.
AE adverse event.
There were no instances of treatment-related death or study discontinuation. Dose levels of lenalidomide, bortezomib, dexamethasone, and panobinostat were reduced in at least one cycle for three, six, six, and three patients, respectively. Dose reductions for panobinostat and lenalidomide only occurred in patients in the panobinostat 15 mg cohort. At least one cycle of the pano-RVd regimen was delayed in 18 patients. The most common reason for dose holds was AEs (73%), of which upper respiratory infection, decreased neutrophil count and peripheral sensory neuropathy were the most common (Supplementary Table S2). Reasons for treatment withdrawal included progressive disease (85%), death (5%) and autologous stem cell transplantation (5%).
Responses and outcomes
The median follow-up was ~14 months. Per protocol, two patients were not eligible for response evaluation; one died due to factors unrelated to study treatment 2 weeks after starting study treatment, and one withdrew from the study 3 days after starting treatment, due to rapid disease progression. In response-evaluable patients (n = 18), the rate of very good partial response or better was 17%, the ORR (≥partial response) was 44% (90% CI 24, 66) and the clinical benefit response rate (≥minimal response) was 61% (90% CI 39, 80) (Table 4). In patients refractory to both lenalidomide and bortezomib (n = 10), the ORR was 30% (90% CI 9, 61) and the clinical benefit rate was 50% (90% CI 22, 78). Median time-to-first response was approximately 1 month (range: 0.79–4.6), and the median DOR was 9.2 months (range: 2.1–50.4 months). At data cut-off, four patients had a DOR of at least 10 months, median (95% CI) TTP was 7.8 (7.2, not reached) months, median (95% CI) PFS was 7.4 (4.2, not reached) months (Fig. 2), and median (95% CI) OS had not been reached (13.5, not reached). In patients refractory to both lenalidomide and bortezomib, median (95% CI) DOR was 22.1 (9.2, not reached) months, median (95% CI) TTP and PFS were both 22.9 (0.9, not reached) months (Fig. 2), and median (95% CI) OS was not reached (6.8, not reached).Table 4 Patient responses.
All patients, N = 18a N (%) 90% CI
Stringent complete response 1 (6) NA
Complete response 0 (0) NA
Very good partial response 2 (11) NA
Partial response 5 (28) NA
Minimal response 3 (17) NA
Stable disease 7 (39) NA
Overall response rate (partial response or better) 8 (44) 24, 66
Clinical benefit rate (minimal response or better) 11 (61) 39, 80
Patients refractory to both lenalidomide and bortezomib, N = 10 N (%) 90% CI
Overall response rate (partial response or better) 3 (30) 9, 61
Clinical benefit rate (minimal response or better) 5 (50) 22, 78
CI confidence interval, NA not applicable. M-spike evaluation.
aNon evaluable: n = 2 (10%).
Fig. 2 Kaplan–Meier distributions of PFS in all 20 patients receiving pano-RVd and lenalidomide/bortezomib-refractory patients.
Len/Btz lenalidomide/bortezomib. Pano-RVd panobinostat/lenalidomide/bortezomib/dexamethasone, PFS progression free survival.
Discussion
Despite recent approvals of new therapeutic agents for RRMM, nearly all patients ultimately still experience disease relapse. The pano-RVd regimen investigated in this study provides a potential treatment option that can restore responses in heavily treated patients with refractory disease. The MTD of panobinostat in the pano-RVd regimen was 10 mg, dosed in a 2-weeks-on/1-week-off schedule, in combination with bortezomib 1 mg/m2, lenalidomide 15 mg and dexamethasone 20 mg. Although all patients experienced at least one TRAE, no patients discontinued therapy or were withdrawn from the study due to a TRAE. Importantly, this regimen demonstrated promising activity in RRMM patients, including those who were refractory to bortezomib and/or lenalidomide and had received a median of four prior lines of therapy. Furthermore, DOR, TTP, and PFS efficacy outcomes were favorable, even in patients refractory to both lenalidomide and bortezomib.
Most patients in the study were refractory to bortezomib or lenalidomide (75% and 80%, respectively) and 50% were refractory to both bortezomib and lenalidomide. The overall ORR of 44% and clinical benefit rate of 61% demonstrates that pano-RVd can provide disease control in patients previously treated with and resistant to lenalidomide and/or bortezomib, a finding that is consistent with previous studies involving panobinostat-containing regimens7,14. This observation is likely due to the unique epigenetic mechanism of action of panobinostat, which targets multiple pathways that contribute to high-risk biology in MM and abrogates resistance to more established agents caused by epigenetic changes9,10,20.
AEs commonly associated with regimens incorporating panobinostat, bortezomib, and/or lenalidomide include neutropenia, diarrhea, PN, and thrombocytopenia2,13,21. The most commonly reported TRAEs in this study included diarrhea and PN, which were all G1/2. This finding contrasts with the phase 3 PANORAMA 1 study in which 25% of patients experienced G3/4 diarrhea and 18% experienced G3/4 PN5,6. The toxicity profile differences observed between the present study and PANORAMA 1 may be related to the different method of bortezomib administration (subcutaneous vs. intravenous) and the reduced dose of panobinostat (10–15 mg vs. 20 mg). At the MTD for pano-RVd, G3/4 AEs were experienced by 80% of patients, the majority of which were hematological. This high percentage of G3/4 AEs reflects chemotherapy-related bone marrow suppression in the context of a four-drug treatment regimen administered to patients who had received a median of four prior lines of therapy22. Importantly, no patients were withdrawn because of TRAEs, and 40% of patients were able to receive maintenance therapy as part of the study, including one patient who had received 74 cycles at the time of data cut-off. Collectively, these data demonstrate that a reduced panobinostat dose (10 mg) can be effective and tolerated as part of a quadruplet regimen.
The reported patient response to pano-RVd is similar to outcomes reported with pano-Rd in the phase 2 study by Chari et al. (ORR 44% vs. 41%)7. However, the inclusion of bortezomib within the pano-RVd regimen resulted, as expected, in a higher rate of AEs, particularly neuropathy and thrombocytopenia. The two study populations were similar in terms of exposure to prior therapies, and percentage of patients refractory to bortezomib and lenalidomide at time of study entry. However, the studies had different approaches to dosing panobinostat7. In the pano-Rd study, panobinostat was dosed every other week, rather than the 2-weeks-on/1-week-off schedule in the current study. This alternative dosing schedule used by Chari et al. may have enabled patients to tolerate higher doses of study treatment.
Anticipation of overlapping toxicities, particularly bone marrow suppression, led to the dosing strategy in this study, in which both lenalidomide and bortezomib were dose reduced relative to standard dosing of these agents. In spite of this strategy, dose reduction of lenalidomide, bortezomib and dexamethasone was required in 15%, 30%, and 30% of patients, respectively, and at least one treatment delay was required in 90% of patients. However, these reductions in dose enabled longer-term administration of all four agents, which presumably contributed to the sustained responses observed in some patients.
The small sample size is an important limitation of this study and inherent to phase 1 studies in general. While patients had received a substantial number of prior therapies, they were also relatively young, and thus it will be important to ascertain whether this quadruplet regimen could be tolerated in elderly patients23. However, the similar rates of TRAEs observed in patients <65 and ≥65 years old suggest that, indeed, pano-RVd may be tolerated in fit elderly patients.
This study was not designed or powered to definitively evaluate efficacy. However, the exploratory data reported herein are promising. Of note, in a previous study, pano-RVd was shown to have a favorable safety and efficacy profile in the front-line setting24. Panobinostat has also been shown to be effective and well tolerated when administered 1-week-on/1-week-off in a 28-day cycle in combination with lenalidomide and dexamethasone7 or with carfilzomib25, and once-weekly administration of bortezomib has been shown to improve the safety profile while maintaining efficacy26–28. As such, it would be of interest to evaluate a modified dosing regimen of pano-RVd using a 28-day cycle in which panobinostat is administered 1-week-on/1-week-off, along with weekly bortezomib, as such an approach may reduce the rates of thrombocytopenia and PN, while maintaining efficacy, and so translate efficiently into real-world practice23.
The relative lack of significant patient exposure to more recently approved agents such as carfilzomib, daratumumab, and elotuzumab is also a potential limitation of the study. Nonetheless, the results highlight the ability of panobinostat to re-sensitize patients to agents which, in most instances, they had previously become refractory to and were resistant. These data underscore the utility of panobinostat as an oral therapy with a unique, multifaceted mechanism of action that can partner with other agents to overcome resistance and enhance treatment response. Given the use of continuous/treat-to-progression therapy as a standard of care in MM, patients are more likely to become refractory to multiple agents after fewer lines of therapy, pointing to the need for additional treatment options for RRMM. As the dose and schedule of panobinostat are optimized, regimens incorporating this agent, such as pano-RVd, may contribute to further improvements in patient outcomes by targeting patterns of resistance to IMiDs and/or PIs, as well as to other novel agents29.
Supplementary information
Supplementary Figures
Supplementary Table 1
Supplementary Table 2
Reproducibility checklist
This work was presented in part at the American Society of Clinical Oncology Annual Meeting, Chicago, June 2016, and the European Hematology Association Virtual Congress, June 2020.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
The online version contains supplementary material available at 10.1038/s41408-021-00407-5.
Acknowledgements
The authors thank all patients involved in the study, as well as investigators and research staff in participating institutions. The authors thank Cara Valvona, PhD, of Watermeadow Medical, part of Ashfield Healthcare, Witney, UK, for providing medical writing support, funded by Secura Bio, Inc. San Diego, US, in accordance with Good Publication Practice guidelines. Funding: Novartis Pharmaceuticals Corporation funded this study. Secura Bio, Inc. funded the publication of this manuscript, including medical writing support.
Author contributions
All authors were involved in data collection, analysis, and interpretation. All authors critically revised and approved the manuscript.
Data sharing statement
All data requests should be submitted to the corresponding author for consideration. Access to anonymized data may be granted following review.
Conflict of interest
J.P.L., J.M.R., K.C., K.M., D.W., and R.A.R. report no conflicts of interest. S.A.T. reports grants and personal fees from Celgene, grants and personal fees from Karyopharm, grants and personal fees from Sanofi, personal fees from Caelum, grants from Amgen, and grants from Janssen, outside the submitted work. C.S.M. discloses employment of a relative with Takeda; consultant/honoraria from Fate Therapeutics, Ionis Pharmaceuticals; past research funding from Novartis; as well as research funding outside the scope of this submitted work from Janssen/Johnson & Johnson, TEVA, EMD Serono, AbbVie, Karyopharm, Sanofi, and Arch Oncology. D.G. is a consultant to Secura Bio, Inc. P.G.R. reports grants from BMS, grants and honoraria (advisory committee member) from Oncopeptides, Celgene, Takeda, and Karyopharm; and honoraria (advisory committee member) from Janssen, Sanofi, and Secura Bio, Inc. outside the submitted work. | BORTEZOMIB, DEXAMETHASONE, LENALIDOMIDE, PANOBINOSTAT | DrugsGivenReaction | CC BY | 33563894 | 18,917,658 | 2021-02-05 |
What was the dosage of drug 'BORTEZOMIB'? | Phase 1 open-label study of panobinostat, lenalidomide, bortezomib + dexamethasone in relapsed and relapsed/refractory multiple myeloma.
Additional therapeutic options are needed for relapsed and refractory multiple myeloma (RRMM). We present data from a phase 1b, open-label, dose-escalation study (NCT01965353) of 20 patients with RRMM (median age: 63 years [range: 50-77]) and a median of four prior regimens (range: 2-14); 85% had refractory disease (lenalidomide [80%]; bortezomib [75%]; lenalidomide and bortezomib [50%]). Patients received a median of six cycles (range: 1-74) of panobinostat (10 or 15 mg), lenalidomide 15 mg, bortezomib 1 mg/m2, and dexamethasone 20 mg (pano-RVd). Median follow-up was ~14 months. Six dose-limiting toxicities were reported (mostly hematological); maximum tolerated dose of panobinostat (primary endpoint) was 10 mg. Most common adverse events (AEs) were diarrhea (60%) and peripheral neuropathy (60%); all grade 1/2. Grade 3/4 AEs occurred in 80% of patients and included decreased neutrophil (45%), platelet (25%) and white blood cell (25%) counts, anemia (25%) and hypophosphatemia (25%). No treatment-related discontinuations or mortality occurred. In evaluable patients (n = 18), overall response rate was 44%, and clinical benefit rate was 61%. Median duration of response was 9.2 months; progression-free survival was 7.4 months; overall survival was not reached. Pano-RVd proved generally well-tolerated and demonstrated potential to overcome lenalidomide and/or bortezomib resistance.
Introduction
Treatment of multiple myeloma (MM), an incurable plasma-cell neoplasm, has changed substantially in recent decades1. Rapidly evolving treatment standards have led to improvements in overall survival (OS), as well as the depth and duration of response (DOR)2–4. Nevertheless, most patients ultimately relapse and require subsequent lines of therapy, with the depth of response and DOR to each successive regimen typically decreasing over time1. However, different emerging classes of agents, which can be combined in triplet or even quadruplet regimens, have provided clinicians with several new therapeutic options for relapsed and refractory MM (RRMM) patients.
Histone deacetylase inhibitors (HDACis), which influence transcriptional activation and other nuclear events by increasing histone acetylation, have been developed in recent years as a treatment for RRMM1,5–7. Histone deacetylases (HDACs) are overexpressed in MM, leading to reduced expression of tumor suppressor genes and, consequently, increased growth and proliferation of tumor cells. Unsurprisingly, overexpression of class I HDACs is associated with a poorer prognosis in MM8.
Broad-spectrum HDACis can enhance the anti-MM activity of proteasome inhibitors through multiple non-mutually exclusive mechanisms, including the transcriptional repression of ubiquitin/proteasome pathway genes and drivers of tumor cell survival and treatment resistance9,10, as well as the inhibition of the aggresome, which is an alternative route for protein degradation11. Panobinostat is among the most potent HDACis in clinical development and the only HDACi approved for the treatment of RRMM, in combination with bortezomib and dexamethasone12,13. In the phase 2 PANORAMA 2 trial, heavily pre-treated, bortezomib-refractory patients with RRMM had an overall response rate (ORR) of 34.5% with panobinostat plus bortezomib and dexamethasone (pano-Vd), highlighting that the addition of panobinostat can overcome resistance to prior therapeutic agents, including bortezomib14. In the randomized phase 3 PANORAMA 1 study, pano-Vd significantly improved median progression-free survival (PFS) by 12.5 vs. 4.7 months (hazard ratio 0.47; 95% confidence interval [CI] 0.31, 0.72) in patients who had received ≥2 prior regimens including bortezomib and an immunomodulatory drug (IMiD), and nearly tripled the rate of complete response/near complete response, compared with placebo-Vd (22% vs. 8% for pano-Vd and placebo-Vd, respectively)5,6,15.
The optimal dose and schedule of pano-Vd was confirmed in the randomized phase 3 PANORAMA 3 trial as 20 mg thrice weekly; DOR with this regimen was 22.6 months and tolerability was improved with subcutaneous administration of bortezomib with only 11.5% of patients in the 20 mg TIW dosing group reporting grade 3/4 diarrhea compared with intravenous delivery of bortezomib, as was standard practice at the time of previous clinical trials.16
Broad-spectrum HDACis also enhance the anti-MM activity of IMiDs, such as lenalidomide, by suppressing diverse oncogenic transcriptional programs10, including the interferon regulatory factor-4/MYC axis17. In a phase 2 study of patients with RRMM, panobinostat plus lenalidomide and dexamethasone (pano-Rd) demonstrated an encouraging ORR (41%) and median PFS (7.1 months) in patients with high-risk, lenalidomide-refractory (81%), and/or bortezomib-refractory (52%) MM, suggesting that panobinostat is also able to overcome resistance to IMiDs.
These data provided the rationale for investigating the quadruplet regimen, panobinostat, lenalidomide, bortezomib and dexamethasone (pano-RVd), in heavily pre-treated patients, particularly in those refractory to proteasome inhibitors and/or IMiDs for whom additional therapy options are needed. Here, we report the findings of a phase 1b dose-escalation study of pano-RVd with extended follow-up.
Methods
Study design and objectives
This study was an open-label, multicenter, phase 1b, study of pano-RVd in RRMM (NCT01965353). Primary objectives were to identify the maximum tolerated dose (MTD) of panobinostat in combination with RVd and to evaluate the safety profile of pano-RVd. Secondary objectives were to evaluate ORR, DOR, time to progression (TTP), PFS and OS. A modified Fibonacci design was used, with 3–6 patients planned at each dose level followed by a dose-expansion phase with an additional ten patients to evaluate the tolerability of the MTD.
The study was conducted in accordance with the Declaration of Helsinki, US Code of Federal Regulations governing clinical study conduct, state laws and Dana-Farber/Harvard Cancer Center research policies and procedures. The institutional review board for each center approved the protocol and amendments. All patients provided written informed consent before enrollment.
Patient eligibility
Eligible patients were aged ≥18 years with measurable RRMM (2011 International Myeloma Working Group consensus)18, an Eastern Cooperative Oncology Group performance status <2, and had received ≥2 lines of therapy. Patients with primary refractory disease, prior HDACi treatment, creatinine clearance <45 mL/min, platelet count <75,000 cells/mm3, absolute neutrophil count <1500 cells/mm3, or hemoglobin level <8.0 g/dl at screening were excluded. Patients with ≥grade (G) 2 peripheral neuropathy (PN) or hepatic impairment (bilirubin > 1.5 × institutional upper limit of normal, or aspartate aminotransferase, alanine aminotransferase, or alkaline phosphatase >2 × institutional upper limit of normal) within 21 days of study therapy initiation were also excluded.
Treatments administered
Patients received oral panobinostat 10 mg or 15 mg plus subcutaneous bortezomib 1 mg/m2, oral lenalidomide 15 mg, and oral dexamethasone 20 mg in 21-day cycles per the schema in Fig. 1. After eight cycles, patients switched to a maintenance schedule, with reduced bortezomib and dexamethasone dosing. Treatment continued until disease progression, unacceptable toxicity, consent was withdrawn, or discontinuation was in the best interest of the patient. Doses could be held for up to 21 days or reduced to manage therapy-related adverse events (TRAEs).Fig. 1 Each cycle consisted of 21 days, patients received eight treatment cycles before switching to maintenance cycles.
Progression to the next higher dose level occurred, if appropriate, when the safety and tolerability of the prior dose level(s) had been determined at the end of the first cycle.
Necessary concomitant medications were allowed, except for those which may cause QTcF prolongation or induce torsades de pointes. Leukocyte growth factors were only administered during cycle 1 in the event of a dose-limiting toxicity (DLT) (if appropriate), but could be prescribed for severe neutropenia after cycle 1.
Dose escalation, MTD, and DLTs
A standard 3 + 3 dose-escalation schema was used (Supplementary Fig. S1). If ≥2 of 3 patients within a cohort experienced a DLT during the dose-escalation phase, the dose immediately below the current dose was defined as the MTD. The 3 + 3 schema was chosen, rather than an alternative methodologic phase 1 study design, due to the limited number of patients in the study and the fact that only three dose levels were planned. DLTs were assessed during the first cycle and defined as a QTcF interval >500 ms, or an absolute increase of >60 ms, a ≥ G3 non-hematological AE or a G4 hematological AE (including thrombocytopenia with platelets <25,000/mm3 on >1 occasion, or G4 neutropenia for >5 days and/or resulting in neutropenic fever on two occasions). Lymphopenia, an AE associated with bortezomib use, was not considered a DLT. Inability to take ≥75% of the planned study drug doses, or receive day 1 doses for cycle 2 due to a drug-related AE occurring in cycle 1, were also considered DLTs.
Assessments
AEs, graded using Cancer Therapy Evaluation Program Version 4 of the National Cancer Institute Common Terminology Criteria for Adverse Events19, were assessed throughout the study and for 30 days after completion of study therapy. Patients who discontinued for any reason other than disease progression were followed every three months until disease progression. Disease response/progression were assessed at the start of each treatment and maintenance cycle, at the end of study, and during the follow-up phase. Disease response was assessed locally using the International Myeloma Working Group Response Criteria18 with M-protein quantification and immunofixation in serum and 24-h urine samples, and serum-free light chain testing. OS was assessed every three months after disease progression.
Statistical analyses
Data cut-off was 24 January 2019. Descriptive statistics are provided for the reported outcomes. All participants who had received ≥1 dose of any study treatment were evaluated for AEs from treatment initiation. All patients who had received study treatment and had ≥1 follow-up assessment were included in the response evaluation. Only patients who responded to treatment (≥minimal response) were included in the DOR analysis. DOR, TTP, PFS, and OS were estimated using Kaplan–Meier methodology. DOR was measured as the time from initiation of first response to time of disease progression, death, or last follow-up (for those patients who had not progressed or died). TTP was defined as time from registration to progression or to last follow-up (for those who had not progressed). PFS was defined as the time from registration to disease progression, death, or last follow-up (for those who had not progressed or died). OS was defined as time from registration to death or last follow-up (for patients who had not died).
Results
Patient characteristics
Between November 2013 and October 2016, 20 patients were enrolled: median age was 63 years (range: 50–77), 70% male (Table 1). Cytogenetic data were available for 17 patients; two had t(4;14), and one had t(14;16). The median number of prior lines of treatment was four (range: 2–14); five patients had received >5 prior lines of treatment. Overall, 95% and 90% had been previously treated with bortezomib and lenalidomide, respectively. Most patients (n = 17, 85%) had refractory disease (lenalidomide [80%]; bortezomib [75%]; lenalidomide and bortezomib [50%]; dexamethasone [85%]).Table 1 Patient baseline characteristics.
Total population n = 20 (%)
Male 14 (70)
Race
Black/African American 4 (20)
White 15 (75)
Other 1 (5)
Age, median (range) 63 (50–77)
Age group
≤55 4 (20)
56–65 9 (45)
>65 7 (35)
Disease status
Relapsed 3 (15)
R/R 17 (85)
ECOG PS
0 9 (45)
1 11 (55)
ISS classification
I 5 (25)
II 7 (35)
III 7 (35)
Missing 1 (5)
Number of prior treatments, median (range) 4 (2–14)
Prior treatment
Bortezomib 19 (95)
Dexamethasone 20 (100)
Lenalidomide 18 (90)
Pomalidomide 15 (75)
Carfilzomib 0
Refractory to any prior treatment
Bortezomib 15 (75)
Dexamethasone 17 (85)
Lenalidomide 16 (80)
Refractory most recent prior treatment
Bortezomib 9 (45)
Dexamethasone 16 (80)
Lenalidomide 2 (10)
Prior autologous transplants
1 9 (45)
Cytogenetics
No FISH failure 17 (85)
t (4;14)a 2 (10)
t (14;16)b 1 (5)
ECOG PS Eastern Cooperative Oncology Group Performance Status, FISH fluorescence in situ hybridization, ISS International Staging System, R/R relapsed/refractory.
aMissing: n = 9.
bMissing: n = 10.
MTD and DLTs
Three patients were treated with panobinostat 10 mg; one experienced a DLT; per protocol, three additional patients were treated with panobinostat 10 mg. No further DLTs were reported, and the dose was escalated. Three patients were treated with panobinostat 15 mg; two experienced DLTs. One of these DLTs (syncope) was a pre-existing condition and not considered related to study treatment, thus, one additional patient was treated with panobinostat 15 mg; this patient subsequently experienced a DLT (thrombocytopenia). Therefore, 10 mg was defined as the MTD for panobinostat in the pano-RVd combination. In the expansion phase, ten patients were treated with pano-RVd with panobinostat dosed at 10 mg; two experienced a DLT. Overall, four patients experienced one DLT, one patient experienced two DLTs and one patient experienced three DLTs (Table 2).Table 2 Dose limiting toxicities.
n (panobinostat dose)
Decreased platelet count 3 (15 mg, n = 2; 10 mg, n = 1)
Decreased neutrophil count 2 (15 mg)
Fatigue 1 (15 mg)
Hyperglycemia 1 (10 mg)
Hypophosphatemia 1 (10 mg)
Syncope 1a (15 mg)
aNot related to treatment.
Treatment summary
Patients completed a median of six cycles (range: 1–74) (Supplementary Table S1). Three patients completed one cycle before withdrawing due to progressive disease. Eight patients completed all eight treatment cycles and ≥1 cycle of maintenance therapy. At the data cut-off date, one patient remained on treatment (Supplementary Fig. S2).
Safety and tolerability
All 20 patients experienced ≥1 TRAE. The distribution of worst overall TRAEs experienced was G1 (n = 1), G2 (n = 3), G3 (n = 11) or G4 (n = 5). The most common TRAEs included diarrhea (60%, all were G1/2), PN (60%), anemia (55%), fatigue (55%), neutropenia (55%), constipation (50%) and hypokalemia (50%) (Table 3). The median (95% CI) duration of neutropenia and thrombocytopenia AEs was 7 (4; 11) days and 8 (4; 11) days, respectively. Overall, 37 G3/4 TRAEs were reported; the most common were decreased neutrophil (45%), platelet (25%) and white blood cell (25%) counts; anemia (25%); and hypophosphatemia (25%). The rate of cardiac TRAEs was low (atrial fibrillation, n = 1; atrial flutter, n = 1; sinus bradycardia, n = 1; sinus tachycardia, n = 1; palpitations, n = 1; prolongation of QTcF interval, n = 1; heart racing, n = 1; chronic right bundle branch block, n = 1; ectopy and murmur n = 1), and all events were G1/2. No G3/4 diarrhea TRAEs were observed. The only reported G4 TRAEs were decreased platelet (25%) and white blood cell counts (5%). In total, nine serious AEs were experienced by six patients, including treatment-related hyperglycemia, decreased neutrophil count, fatigue, and decreased platelet count. TRAE rates were generally balanced in patients in patients <65 (n = 11) and ≥65 (n = 9) years old, although G4 thrombocytopenia TRAEs were more common in patients ≥65 years old.Table 3 AEs experienced by ≥20% of patients and all grade 4 AEs.
Total, n (%) Grade 1 Grade 2 Grade 3 Grade 4
(n = 20) n (%) n (%) n (%) n (%)
Blood and lymphatic system disorders
Anemia 11 (55) 2 (10) 4 (20) 5 (25) –
Neutrophil count decreased 11 (55) 1 (5) 1 (5) 9 (45) –
Platelet count decreased 9 (45) 4 (20) – – 5 (25)
White blood cell count decreased 7 (35) – 2 (10) 4 (20) 1 (5)
Blood and lymphatic system disorders – other 4 (20) 1 (5) 3 (15) – –
Bruising 4 (20) 4 (20) – – –
Cardiac disorders
Dizziness 5 (25) 4 (20) 1 (5) – –
Cardiac disorders – other 4 (20) 4 (20) – – –
Eye disorders
Eye disorders—other 4 (20) 2 (10) 2 (10) – –
Gastrointestinal disorders
Diarrhea 12 (60) 7 (35) 5 (25) – –
Constipation 10 (50) 6 (30) 4 (20) – –
Nausea 7 (35) 5 (25) 2 (10) – –
Gastrointestinal disorders—other 5 (25) 3 (15) 2 (10) – –
Dysgeusia 4 (20) 2 (10) 2 (10) – –
General disorders and administration site conditions
Fatigue 11 (55) 1 (5) 9 (45) 1 (5) –
Edema limbs 7 (35) 4 (20) 3 (15) – –
Infections and infestations
Upper respiratory infection 8 (40) – 8 (40) – –
Infections and infestations – other 6 (30) 2 (10) 2 (10) 2 (10) –
Investigations
Hypokalemia 10 (50) 8 (40) 2 (10) – –
Hypomagnesemia 8 (40) 8 (40) – – –
Hypophosphatemia 7 (35) 1 (5) 1 (5) 5 (25) –
Hypocalcemia 5 (25) 4 (20) 1 (5) – –
Hyponatremia 5 (25) 5 (25) – – –
Metabolism and nutrition disorders
Anorexia 7 (35) 5 (25) 2 (10) – –
Hyperglycemia 7 (35) 4 (20) 2 (10) 1 (5) –
Musculoskeletal and connective tissue disorders
Musculoskeletal and connective tissue disorder – other 4 (20) 2 (10) 2 (10) – –
Nervous system disorders
Peripheral sensory neuropathy 12 (60) 6 (30) 6 (30) – –
Psychiatric disorders
Insomnia 6 (30) 3 (15) 3 (15) – –
Respiratory, thoracic, and mediastinal disorders
Cough 6 (30) 1 (5) 5 (25) – –
Dyspnea 6 (30) 3 (15) 2 (10) 1 (5) –
AEs that were possibly, probably, or definitely related to any study treatments are reported. Each AE represents the highest grade for that AE per patient, so patients may be included in each row at most once.
AE adverse event.
There were no instances of treatment-related death or study discontinuation. Dose levels of lenalidomide, bortezomib, dexamethasone, and panobinostat were reduced in at least one cycle for three, six, six, and three patients, respectively. Dose reductions for panobinostat and lenalidomide only occurred in patients in the panobinostat 15 mg cohort. At least one cycle of the pano-RVd regimen was delayed in 18 patients. The most common reason for dose holds was AEs (73%), of which upper respiratory infection, decreased neutrophil count and peripheral sensory neuropathy were the most common (Supplementary Table S2). Reasons for treatment withdrawal included progressive disease (85%), death (5%) and autologous stem cell transplantation (5%).
Responses and outcomes
The median follow-up was ~14 months. Per protocol, two patients were not eligible for response evaluation; one died due to factors unrelated to study treatment 2 weeks after starting study treatment, and one withdrew from the study 3 days after starting treatment, due to rapid disease progression. In response-evaluable patients (n = 18), the rate of very good partial response or better was 17%, the ORR (≥partial response) was 44% (90% CI 24, 66) and the clinical benefit response rate (≥minimal response) was 61% (90% CI 39, 80) (Table 4). In patients refractory to both lenalidomide and bortezomib (n = 10), the ORR was 30% (90% CI 9, 61) and the clinical benefit rate was 50% (90% CI 22, 78). Median time-to-first response was approximately 1 month (range: 0.79–4.6), and the median DOR was 9.2 months (range: 2.1–50.4 months). At data cut-off, four patients had a DOR of at least 10 months, median (95% CI) TTP was 7.8 (7.2, not reached) months, median (95% CI) PFS was 7.4 (4.2, not reached) months (Fig. 2), and median (95% CI) OS had not been reached (13.5, not reached). In patients refractory to both lenalidomide and bortezomib, median (95% CI) DOR was 22.1 (9.2, not reached) months, median (95% CI) TTP and PFS were both 22.9 (0.9, not reached) months (Fig. 2), and median (95% CI) OS was not reached (6.8, not reached).Table 4 Patient responses.
All patients, N = 18a N (%) 90% CI
Stringent complete response 1 (6) NA
Complete response 0 (0) NA
Very good partial response 2 (11) NA
Partial response 5 (28) NA
Minimal response 3 (17) NA
Stable disease 7 (39) NA
Overall response rate (partial response or better) 8 (44) 24, 66
Clinical benefit rate (minimal response or better) 11 (61) 39, 80
Patients refractory to both lenalidomide and bortezomib, N = 10 N (%) 90% CI
Overall response rate (partial response or better) 3 (30) 9, 61
Clinical benefit rate (minimal response or better) 5 (50) 22, 78
CI confidence interval, NA not applicable. M-spike evaluation.
aNon evaluable: n = 2 (10%).
Fig. 2 Kaplan–Meier distributions of PFS in all 20 patients receiving pano-RVd and lenalidomide/bortezomib-refractory patients.
Len/Btz lenalidomide/bortezomib. Pano-RVd panobinostat/lenalidomide/bortezomib/dexamethasone, PFS progression free survival.
Discussion
Despite recent approvals of new therapeutic agents for RRMM, nearly all patients ultimately still experience disease relapse. The pano-RVd regimen investigated in this study provides a potential treatment option that can restore responses in heavily treated patients with refractory disease. The MTD of panobinostat in the pano-RVd regimen was 10 mg, dosed in a 2-weeks-on/1-week-off schedule, in combination with bortezomib 1 mg/m2, lenalidomide 15 mg and dexamethasone 20 mg. Although all patients experienced at least one TRAE, no patients discontinued therapy or were withdrawn from the study due to a TRAE. Importantly, this regimen demonstrated promising activity in RRMM patients, including those who were refractory to bortezomib and/or lenalidomide and had received a median of four prior lines of therapy. Furthermore, DOR, TTP, and PFS efficacy outcomes were favorable, even in patients refractory to both lenalidomide and bortezomib.
Most patients in the study were refractory to bortezomib or lenalidomide (75% and 80%, respectively) and 50% were refractory to both bortezomib and lenalidomide. The overall ORR of 44% and clinical benefit rate of 61% demonstrates that pano-RVd can provide disease control in patients previously treated with and resistant to lenalidomide and/or bortezomib, a finding that is consistent with previous studies involving panobinostat-containing regimens7,14. This observation is likely due to the unique epigenetic mechanism of action of panobinostat, which targets multiple pathways that contribute to high-risk biology in MM and abrogates resistance to more established agents caused by epigenetic changes9,10,20.
AEs commonly associated with regimens incorporating panobinostat, bortezomib, and/or lenalidomide include neutropenia, diarrhea, PN, and thrombocytopenia2,13,21. The most commonly reported TRAEs in this study included diarrhea and PN, which were all G1/2. This finding contrasts with the phase 3 PANORAMA 1 study in which 25% of patients experienced G3/4 diarrhea and 18% experienced G3/4 PN5,6. The toxicity profile differences observed between the present study and PANORAMA 1 may be related to the different method of bortezomib administration (subcutaneous vs. intravenous) and the reduced dose of panobinostat (10–15 mg vs. 20 mg). At the MTD for pano-RVd, G3/4 AEs were experienced by 80% of patients, the majority of which were hematological. This high percentage of G3/4 AEs reflects chemotherapy-related bone marrow suppression in the context of a four-drug treatment regimen administered to patients who had received a median of four prior lines of therapy22. Importantly, no patients were withdrawn because of TRAEs, and 40% of patients were able to receive maintenance therapy as part of the study, including one patient who had received 74 cycles at the time of data cut-off. Collectively, these data demonstrate that a reduced panobinostat dose (10 mg) can be effective and tolerated as part of a quadruplet regimen.
The reported patient response to pano-RVd is similar to outcomes reported with pano-Rd in the phase 2 study by Chari et al. (ORR 44% vs. 41%)7. However, the inclusion of bortezomib within the pano-RVd regimen resulted, as expected, in a higher rate of AEs, particularly neuropathy and thrombocytopenia. The two study populations were similar in terms of exposure to prior therapies, and percentage of patients refractory to bortezomib and lenalidomide at time of study entry. However, the studies had different approaches to dosing panobinostat7. In the pano-Rd study, panobinostat was dosed every other week, rather than the 2-weeks-on/1-week-off schedule in the current study. This alternative dosing schedule used by Chari et al. may have enabled patients to tolerate higher doses of study treatment.
Anticipation of overlapping toxicities, particularly bone marrow suppression, led to the dosing strategy in this study, in which both lenalidomide and bortezomib were dose reduced relative to standard dosing of these agents. In spite of this strategy, dose reduction of lenalidomide, bortezomib and dexamethasone was required in 15%, 30%, and 30% of patients, respectively, and at least one treatment delay was required in 90% of patients. However, these reductions in dose enabled longer-term administration of all four agents, which presumably contributed to the sustained responses observed in some patients.
The small sample size is an important limitation of this study and inherent to phase 1 studies in general. While patients had received a substantial number of prior therapies, they were also relatively young, and thus it will be important to ascertain whether this quadruplet regimen could be tolerated in elderly patients23. However, the similar rates of TRAEs observed in patients <65 and ≥65 years old suggest that, indeed, pano-RVd may be tolerated in fit elderly patients.
This study was not designed or powered to definitively evaluate efficacy. However, the exploratory data reported herein are promising. Of note, in a previous study, pano-RVd was shown to have a favorable safety and efficacy profile in the front-line setting24. Panobinostat has also been shown to be effective and well tolerated when administered 1-week-on/1-week-off in a 28-day cycle in combination with lenalidomide and dexamethasone7 or with carfilzomib25, and once-weekly administration of bortezomib has been shown to improve the safety profile while maintaining efficacy26–28. As such, it would be of interest to evaluate a modified dosing regimen of pano-RVd using a 28-day cycle in which panobinostat is administered 1-week-on/1-week-off, along with weekly bortezomib, as such an approach may reduce the rates of thrombocytopenia and PN, while maintaining efficacy, and so translate efficiently into real-world practice23.
The relative lack of significant patient exposure to more recently approved agents such as carfilzomib, daratumumab, and elotuzumab is also a potential limitation of the study. Nonetheless, the results highlight the ability of panobinostat to re-sensitize patients to agents which, in most instances, they had previously become refractory to and were resistant. These data underscore the utility of panobinostat as an oral therapy with a unique, multifaceted mechanism of action that can partner with other agents to overcome resistance and enhance treatment response. Given the use of continuous/treat-to-progression therapy as a standard of care in MM, patients are more likely to become refractory to multiple agents after fewer lines of therapy, pointing to the need for additional treatment options for RRMM. As the dose and schedule of panobinostat are optimized, regimens incorporating this agent, such as pano-RVd, may contribute to further improvements in patient outcomes by targeting patterns of resistance to IMiDs and/or PIs, as well as to other novel agents29.
Supplementary information
Supplementary Figures
Supplementary Table 1
Supplementary Table 2
Reproducibility checklist
This work was presented in part at the American Society of Clinical Oncology Annual Meeting, Chicago, June 2016, and the European Hematology Association Virtual Congress, June 2020.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
The online version contains supplementary material available at 10.1038/s41408-021-00407-5.
Acknowledgements
The authors thank all patients involved in the study, as well as investigators and research staff in participating institutions. The authors thank Cara Valvona, PhD, of Watermeadow Medical, part of Ashfield Healthcare, Witney, UK, for providing medical writing support, funded by Secura Bio, Inc. San Diego, US, in accordance with Good Publication Practice guidelines. Funding: Novartis Pharmaceuticals Corporation funded this study. Secura Bio, Inc. funded the publication of this manuscript, including medical writing support.
Author contributions
All authors were involved in data collection, analysis, and interpretation. All authors critically revised and approved the manuscript.
Data sharing statement
All data requests should be submitted to the corresponding author for consideration. Access to anonymized data may be granted following review.
Conflict of interest
J.P.L., J.M.R., K.C., K.M., D.W., and R.A.R. report no conflicts of interest. S.A.T. reports grants and personal fees from Celgene, grants and personal fees from Karyopharm, grants and personal fees from Sanofi, personal fees from Caelum, grants from Amgen, and grants from Janssen, outside the submitted work. C.S.M. discloses employment of a relative with Takeda; consultant/honoraria from Fate Therapeutics, Ionis Pharmaceuticals; past research funding from Novartis; as well as research funding outside the scope of this submitted work from Janssen/Johnson & Johnson, TEVA, EMD Serono, AbbVie, Karyopharm, Sanofi, and Arch Oncology. D.G. is a consultant to Secura Bio, Inc. P.G.R. reports grants from BMS, grants and honoraria (advisory committee member) from Oncopeptides, Celgene, Takeda, and Karyopharm; and honoraria (advisory committee member) from Janssen, Sanofi, and Secura Bio, Inc. outside the submitted work. | 1 MILLIGRAM/SQ. METER | DrugDosageText | CC BY | 33563894 | 18,917,658 | 2021-02-05 |
What was the dosage of drug 'DEXAMETHASONE'? | Phase 1 open-label study of panobinostat, lenalidomide, bortezomib + dexamethasone in relapsed and relapsed/refractory multiple myeloma.
Additional therapeutic options are needed for relapsed and refractory multiple myeloma (RRMM). We present data from a phase 1b, open-label, dose-escalation study (NCT01965353) of 20 patients with RRMM (median age: 63 years [range: 50-77]) and a median of four prior regimens (range: 2-14); 85% had refractory disease (lenalidomide [80%]; bortezomib [75%]; lenalidomide and bortezomib [50%]). Patients received a median of six cycles (range: 1-74) of panobinostat (10 or 15 mg), lenalidomide 15 mg, bortezomib 1 mg/m2, and dexamethasone 20 mg (pano-RVd). Median follow-up was ~14 months. Six dose-limiting toxicities were reported (mostly hematological); maximum tolerated dose of panobinostat (primary endpoint) was 10 mg. Most common adverse events (AEs) were diarrhea (60%) and peripheral neuropathy (60%); all grade 1/2. Grade 3/4 AEs occurred in 80% of patients and included decreased neutrophil (45%), platelet (25%) and white blood cell (25%) counts, anemia (25%) and hypophosphatemia (25%). No treatment-related discontinuations or mortality occurred. In evaluable patients (n = 18), overall response rate was 44%, and clinical benefit rate was 61%. Median duration of response was 9.2 months; progression-free survival was 7.4 months; overall survival was not reached. Pano-RVd proved generally well-tolerated and demonstrated potential to overcome lenalidomide and/or bortezomib resistance.
Introduction
Treatment of multiple myeloma (MM), an incurable plasma-cell neoplasm, has changed substantially in recent decades1. Rapidly evolving treatment standards have led to improvements in overall survival (OS), as well as the depth and duration of response (DOR)2–4. Nevertheless, most patients ultimately relapse and require subsequent lines of therapy, with the depth of response and DOR to each successive regimen typically decreasing over time1. However, different emerging classes of agents, which can be combined in triplet or even quadruplet regimens, have provided clinicians with several new therapeutic options for relapsed and refractory MM (RRMM) patients.
Histone deacetylase inhibitors (HDACis), which influence transcriptional activation and other nuclear events by increasing histone acetylation, have been developed in recent years as a treatment for RRMM1,5–7. Histone deacetylases (HDACs) are overexpressed in MM, leading to reduced expression of tumor suppressor genes and, consequently, increased growth and proliferation of tumor cells. Unsurprisingly, overexpression of class I HDACs is associated with a poorer prognosis in MM8.
Broad-spectrum HDACis can enhance the anti-MM activity of proteasome inhibitors through multiple non-mutually exclusive mechanisms, including the transcriptional repression of ubiquitin/proteasome pathway genes and drivers of tumor cell survival and treatment resistance9,10, as well as the inhibition of the aggresome, which is an alternative route for protein degradation11. Panobinostat is among the most potent HDACis in clinical development and the only HDACi approved for the treatment of RRMM, in combination with bortezomib and dexamethasone12,13. In the phase 2 PANORAMA 2 trial, heavily pre-treated, bortezomib-refractory patients with RRMM had an overall response rate (ORR) of 34.5% with panobinostat plus bortezomib and dexamethasone (pano-Vd), highlighting that the addition of panobinostat can overcome resistance to prior therapeutic agents, including bortezomib14. In the randomized phase 3 PANORAMA 1 study, pano-Vd significantly improved median progression-free survival (PFS) by 12.5 vs. 4.7 months (hazard ratio 0.47; 95% confidence interval [CI] 0.31, 0.72) in patients who had received ≥2 prior regimens including bortezomib and an immunomodulatory drug (IMiD), and nearly tripled the rate of complete response/near complete response, compared with placebo-Vd (22% vs. 8% for pano-Vd and placebo-Vd, respectively)5,6,15.
The optimal dose and schedule of pano-Vd was confirmed in the randomized phase 3 PANORAMA 3 trial as 20 mg thrice weekly; DOR with this regimen was 22.6 months and tolerability was improved with subcutaneous administration of bortezomib with only 11.5% of patients in the 20 mg TIW dosing group reporting grade 3/4 diarrhea compared with intravenous delivery of bortezomib, as was standard practice at the time of previous clinical trials.16
Broad-spectrum HDACis also enhance the anti-MM activity of IMiDs, such as lenalidomide, by suppressing diverse oncogenic transcriptional programs10, including the interferon regulatory factor-4/MYC axis17. In a phase 2 study of patients with RRMM, panobinostat plus lenalidomide and dexamethasone (pano-Rd) demonstrated an encouraging ORR (41%) and median PFS (7.1 months) in patients with high-risk, lenalidomide-refractory (81%), and/or bortezomib-refractory (52%) MM, suggesting that panobinostat is also able to overcome resistance to IMiDs.
These data provided the rationale for investigating the quadruplet regimen, panobinostat, lenalidomide, bortezomib and dexamethasone (pano-RVd), in heavily pre-treated patients, particularly in those refractory to proteasome inhibitors and/or IMiDs for whom additional therapy options are needed. Here, we report the findings of a phase 1b dose-escalation study of pano-RVd with extended follow-up.
Methods
Study design and objectives
This study was an open-label, multicenter, phase 1b, study of pano-RVd in RRMM (NCT01965353). Primary objectives were to identify the maximum tolerated dose (MTD) of panobinostat in combination with RVd and to evaluate the safety profile of pano-RVd. Secondary objectives were to evaluate ORR, DOR, time to progression (TTP), PFS and OS. A modified Fibonacci design was used, with 3–6 patients planned at each dose level followed by a dose-expansion phase with an additional ten patients to evaluate the tolerability of the MTD.
The study was conducted in accordance with the Declaration of Helsinki, US Code of Federal Regulations governing clinical study conduct, state laws and Dana-Farber/Harvard Cancer Center research policies and procedures. The institutional review board for each center approved the protocol and amendments. All patients provided written informed consent before enrollment.
Patient eligibility
Eligible patients were aged ≥18 years with measurable RRMM (2011 International Myeloma Working Group consensus)18, an Eastern Cooperative Oncology Group performance status <2, and had received ≥2 lines of therapy. Patients with primary refractory disease, prior HDACi treatment, creatinine clearance <45 mL/min, platelet count <75,000 cells/mm3, absolute neutrophil count <1500 cells/mm3, or hemoglobin level <8.0 g/dl at screening were excluded. Patients with ≥grade (G) 2 peripheral neuropathy (PN) or hepatic impairment (bilirubin > 1.5 × institutional upper limit of normal, or aspartate aminotransferase, alanine aminotransferase, or alkaline phosphatase >2 × institutional upper limit of normal) within 21 days of study therapy initiation were also excluded.
Treatments administered
Patients received oral panobinostat 10 mg or 15 mg plus subcutaneous bortezomib 1 mg/m2, oral lenalidomide 15 mg, and oral dexamethasone 20 mg in 21-day cycles per the schema in Fig. 1. After eight cycles, patients switched to a maintenance schedule, with reduced bortezomib and dexamethasone dosing. Treatment continued until disease progression, unacceptable toxicity, consent was withdrawn, or discontinuation was in the best interest of the patient. Doses could be held for up to 21 days or reduced to manage therapy-related adverse events (TRAEs).Fig. 1 Each cycle consisted of 21 days, patients received eight treatment cycles before switching to maintenance cycles.
Progression to the next higher dose level occurred, if appropriate, when the safety and tolerability of the prior dose level(s) had been determined at the end of the first cycle.
Necessary concomitant medications were allowed, except for those which may cause QTcF prolongation or induce torsades de pointes. Leukocyte growth factors were only administered during cycle 1 in the event of a dose-limiting toxicity (DLT) (if appropriate), but could be prescribed for severe neutropenia after cycle 1.
Dose escalation, MTD, and DLTs
A standard 3 + 3 dose-escalation schema was used (Supplementary Fig. S1). If ≥2 of 3 patients within a cohort experienced a DLT during the dose-escalation phase, the dose immediately below the current dose was defined as the MTD. The 3 + 3 schema was chosen, rather than an alternative methodologic phase 1 study design, due to the limited number of patients in the study and the fact that only three dose levels were planned. DLTs were assessed during the first cycle and defined as a QTcF interval >500 ms, or an absolute increase of >60 ms, a ≥ G3 non-hematological AE or a G4 hematological AE (including thrombocytopenia with platelets <25,000/mm3 on >1 occasion, or G4 neutropenia for >5 days and/or resulting in neutropenic fever on two occasions). Lymphopenia, an AE associated with bortezomib use, was not considered a DLT. Inability to take ≥75% of the planned study drug doses, or receive day 1 doses for cycle 2 due to a drug-related AE occurring in cycle 1, were also considered DLTs.
Assessments
AEs, graded using Cancer Therapy Evaluation Program Version 4 of the National Cancer Institute Common Terminology Criteria for Adverse Events19, were assessed throughout the study and for 30 days after completion of study therapy. Patients who discontinued for any reason other than disease progression were followed every three months until disease progression. Disease response/progression were assessed at the start of each treatment and maintenance cycle, at the end of study, and during the follow-up phase. Disease response was assessed locally using the International Myeloma Working Group Response Criteria18 with M-protein quantification and immunofixation in serum and 24-h urine samples, and serum-free light chain testing. OS was assessed every three months after disease progression.
Statistical analyses
Data cut-off was 24 January 2019. Descriptive statistics are provided for the reported outcomes. All participants who had received ≥1 dose of any study treatment were evaluated for AEs from treatment initiation. All patients who had received study treatment and had ≥1 follow-up assessment were included in the response evaluation. Only patients who responded to treatment (≥minimal response) were included in the DOR analysis. DOR, TTP, PFS, and OS were estimated using Kaplan–Meier methodology. DOR was measured as the time from initiation of first response to time of disease progression, death, or last follow-up (for those patients who had not progressed or died). TTP was defined as time from registration to progression or to last follow-up (for those who had not progressed). PFS was defined as the time from registration to disease progression, death, or last follow-up (for those who had not progressed or died). OS was defined as time from registration to death or last follow-up (for patients who had not died).
Results
Patient characteristics
Between November 2013 and October 2016, 20 patients were enrolled: median age was 63 years (range: 50–77), 70% male (Table 1). Cytogenetic data were available for 17 patients; two had t(4;14), and one had t(14;16). The median number of prior lines of treatment was four (range: 2–14); five patients had received >5 prior lines of treatment. Overall, 95% and 90% had been previously treated with bortezomib and lenalidomide, respectively. Most patients (n = 17, 85%) had refractory disease (lenalidomide [80%]; bortezomib [75%]; lenalidomide and bortezomib [50%]; dexamethasone [85%]).Table 1 Patient baseline characteristics.
Total population n = 20 (%)
Male 14 (70)
Race
Black/African American 4 (20)
White 15 (75)
Other 1 (5)
Age, median (range) 63 (50–77)
Age group
≤55 4 (20)
56–65 9 (45)
>65 7 (35)
Disease status
Relapsed 3 (15)
R/R 17 (85)
ECOG PS
0 9 (45)
1 11 (55)
ISS classification
I 5 (25)
II 7 (35)
III 7 (35)
Missing 1 (5)
Number of prior treatments, median (range) 4 (2–14)
Prior treatment
Bortezomib 19 (95)
Dexamethasone 20 (100)
Lenalidomide 18 (90)
Pomalidomide 15 (75)
Carfilzomib 0
Refractory to any prior treatment
Bortezomib 15 (75)
Dexamethasone 17 (85)
Lenalidomide 16 (80)
Refractory most recent prior treatment
Bortezomib 9 (45)
Dexamethasone 16 (80)
Lenalidomide 2 (10)
Prior autologous transplants
1 9 (45)
Cytogenetics
No FISH failure 17 (85)
t (4;14)a 2 (10)
t (14;16)b 1 (5)
ECOG PS Eastern Cooperative Oncology Group Performance Status, FISH fluorescence in situ hybridization, ISS International Staging System, R/R relapsed/refractory.
aMissing: n = 9.
bMissing: n = 10.
MTD and DLTs
Three patients were treated with panobinostat 10 mg; one experienced a DLT; per protocol, three additional patients were treated with panobinostat 10 mg. No further DLTs were reported, and the dose was escalated. Three patients were treated with panobinostat 15 mg; two experienced DLTs. One of these DLTs (syncope) was a pre-existing condition and not considered related to study treatment, thus, one additional patient was treated with panobinostat 15 mg; this patient subsequently experienced a DLT (thrombocytopenia). Therefore, 10 mg was defined as the MTD for panobinostat in the pano-RVd combination. In the expansion phase, ten patients were treated with pano-RVd with panobinostat dosed at 10 mg; two experienced a DLT. Overall, four patients experienced one DLT, one patient experienced two DLTs and one patient experienced three DLTs (Table 2).Table 2 Dose limiting toxicities.
n (panobinostat dose)
Decreased platelet count 3 (15 mg, n = 2; 10 mg, n = 1)
Decreased neutrophil count 2 (15 mg)
Fatigue 1 (15 mg)
Hyperglycemia 1 (10 mg)
Hypophosphatemia 1 (10 mg)
Syncope 1a (15 mg)
aNot related to treatment.
Treatment summary
Patients completed a median of six cycles (range: 1–74) (Supplementary Table S1). Three patients completed one cycle before withdrawing due to progressive disease. Eight patients completed all eight treatment cycles and ≥1 cycle of maintenance therapy. At the data cut-off date, one patient remained on treatment (Supplementary Fig. S2).
Safety and tolerability
All 20 patients experienced ≥1 TRAE. The distribution of worst overall TRAEs experienced was G1 (n = 1), G2 (n = 3), G3 (n = 11) or G4 (n = 5). The most common TRAEs included diarrhea (60%, all were G1/2), PN (60%), anemia (55%), fatigue (55%), neutropenia (55%), constipation (50%) and hypokalemia (50%) (Table 3). The median (95% CI) duration of neutropenia and thrombocytopenia AEs was 7 (4; 11) days and 8 (4; 11) days, respectively. Overall, 37 G3/4 TRAEs were reported; the most common were decreased neutrophil (45%), platelet (25%) and white blood cell (25%) counts; anemia (25%); and hypophosphatemia (25%). The rate of cardiac TRAEs was low (atrial fibrillation, n = 1; atrial flutter, n = 1; sinus bradycardia, n = 1; sinus tachycardia, n = 1; palpitations, n = 1; prolongation of QTcF interval, n = 1; heart racing, n = 1; chronic right bundle branch block, n = 1; ectopy and murmur n = 1), and all events were G1/2. No G3/4 diarrhea TRAEs were observed. The only reported G4 TRAEs were decreased platelet (25%) and white blood cell counts (5%). In total, nine serious AEs were experienced by six patients, including treatment-related hyperglycemia, decreased neutrophil count, fatigue, and decreased platelet count. TRAE rates were generally balanced in patients in patients <65 (n = 11) and ≥65 (n = 9) years old, although G4 thrombocytopenia TRAEs were more common in patients ≥65 years old.Table 3 AEs experienced by ≥20% of patients and all grade 4 AEs.
Total, n (%) Grade 1 Grade 2 Grade 3 Grade 4
(n = 20) n (%) n (%) n (%) n (%)
Blood and lymphatic system disorders
Anemia 11 (55) 2 (10) 4 (20) 5 (25) –
Neutrophil count decreased 11 (55) 1 (5) 1 (5) 9 (45) –
Platelet count decreased 9 (45) 4 (20) – – 5 (25)
White blood cell count decreased 7 (35) – 2 (10) 4 (20) 1 (5)
Blood and lymphatic system disorders – other 4 (20) 1 (5) 3 (15) – –
Bruising 4 (20) 4 (20) – – –
Cardiac disorders
Dizziness 5 (25) 4 (20) 1 (5) – –
Cardiac disorders – other 4 (20) 4 (20) – – –
Eye disorders
Eye disorders—other 4 (20) 2 (10) 2 (10) – –
Gastrointestinal disorders
Diarrhea 12 (60) 7 (35) 5 (25) – –
Constipation 10 (50) 6 (30) 4 (20) – –
Nausea 7 (35) 5 (25) 2 (10) – –
Gastrointestinal disorders—other 5 (25) 3 (15) 2 (10) – –
Dysgeusia 4 (20) 2 (10) 2 (10) – –
General disorders and administration site conditions
Fatigue 11 (55) 1 (5) 9 (45) 1 (5) –
Edema limbs 7 (35) 4 (20) 3 (15) – –
Infections and infestations
Upper respiratory infection 8 (40) – 8 (40) – –
Infections and infestations – other 6 (30) 2 (10) 2 (10) 2 (10) –
Investigations
Hypokalemia 10 (50) 8 (40) 2 (10) – –
Hypomagnesemia 8 (40) 8 (40) – – –
Hypophosphatemia 7 (35) 1 (5) 1 (5) 5 (25) –
Hypocalcemia 5 (25) 4 (20) 1 (5) – –
Hyponatremia 5 (25) 5 (25) – – –
Metabolism and nutrition disorders
Anorexia 7 (35) 5 (25) 2 (10) – –
Hyperglycemia 7 (35) 4 (20) 2 (10) 1 (5) –
Musculoskeletal and connective tissue disorders
Musculoskeletal and connective tissue disorder – other 4 (20) 2 (10) 2 (10) – –
Nervous system disorders
Peripheral sensory neuropathy 12 (60) 6 (30) 6 (30) – –
Psychiatric disorders
Insomnia 6 (30) 3 (15) 3 (15) – –
Respiratory, thoracic, and mediastinal disorders
Cough 6 (30) 1 (5) 5 (25) – –
Dyspnea 6 (30) 3 (15) 2 (10) 1 (5) –
AEs that were possibly, probably, or definitely related to any study treatments are reported. Each AE represents the highest grade for that AE per patient, so patients may be included in each row at most once.
AE adverse event.
There were no instances of treatment-related death or study discontinuation. Dose levels of lenalidomide, bortezomib, dexamethasone, and panobinostat were reduced in at least one cycle for three, six, six, and three patients, respectively. Dose reductions for panobinostat and lenalidomide only occurred in patients in the panobinostat 15 mg cohort. At least one cycle of the pano-RVd regimen was delayed in 18 patients. The most common reason for dose holds was AEs (73%), of which upper respiratory infection, decreased neutrophil count and peripheral sensory neuropathy were the most common (Supplementary Table S2). Reasons for treatment withdrawal included progressive disease (85%), death (5%) and autologous stem cell transplantation (5%).
Responses and outcomes
The median follow-up was ~14 months. Per protocol, two patients were not eligible for response evaluation; one died due to factors unrelated to study treatment 2 weeks after starting study treatment, and one withdrew from the study 3 days after starting treatment, due to rapid disease progression. In response-evaluable patients (n = 18), the rate of very good partial response or better was 17%, the ORR (≥partial response) was 44% (90% CI 24, 66) and the clinical benefit response rate (≥minimal response) was 61% (90% CI 39, 80) (Table 4). In patients refractory to both lenalidomide and bortezomib (n = 10), the ORR was 30% (90% CI 9, 61) and the clinical benefit rate was 50% (90% CI 22, 78). Median time-to-first response was approximately 1 month (range: 0.79–4.6), and the median DOR was 9.2 months (range: 2.1–50.4 months). At data cut-off, four patients had a DOR of at least 10 months, median (95% CI) TTP was 7.8 (7.2, not reached) months, median (95% CI) PFS was 7.4 (4.2, not reached) months (Fig. 2), and median (95% CI) OS had not been reached (13.5, not reached). In patients refractory to both lenalidomide and bortezomib, median (95% CI) DOR was 22.1 (9.2, not reached) months, median (95% CI) TTP and PFS were both 22.9 (0.9, not reached) months (Fig. 2), and median (95% CI) OS was not reached (6.8, not reached).Table 4 Patient responses.
All patients, N = 18a N (%) 90% CI
Stringent complete response 1 (6) NA
Complete response 0 (0) NA
Very good partial response 2 (11) NA
Partial response 5 (28) NA
Minimal response 3 (17) NA
Stable disease 7 (39) NA
Overall response rate (partial response or better) 8 (44) 24, 66
Clinical benefit rate (minimal response or better) 11 (61) 39, 80
Patients refractory to both lenalidomide and bortezomib, N = 10 N (%) 90% CI
Overall response rate (partial response or better) 3 (30) 9, 61
Clinical benefit rate (minimal response or better) 5 (50) 22, 78
CI confidence interval, NA not applicable. M-spike evaluation.
aNon evaluable: n = 2 (10%).
Fig. 2 Kaplan–Meier distributions of PFS in all 20 patients receiving pano-RVd and lenalidomide/bortezomib-refractory patients.
Len/Btz lenalidomide/bortezomib. Pano-RVd panobinostat/lenalidomide/bortezomib/dexamethasone, PFS progression free survival.
Discussion
Despite recent approvals of new therapeutic agents for RRMM, nearly all patients ultimately still experience disease relapse. The pano-RVd regimen investigated in this study provides a potential treatment option that can restore responses in heavily treated patients with refractory disease. The MTD of panobinostat in the pano-RVd regimen was 10 mg, dosed in a 2-weeks-on/1-week-off schedule, in combination with bortezomib 1 mg/m2, lenalidomide 15 mg and dexamethasone 20 mg. Although all patients experienced at least one TRAE, no patients discontinued therapy or were withdrawn from the study due to a TRAE. Importantly, this regimen demonstrated promising activity in RRMM patients, including those who were refractory to bortezomib and/or lenalidomide and had received a median of four prior lines of therapy. Furthermore, DOR, TTP, and PFS efficacy outcomes were favorable, even in patients refractory to both lenalidomide and bortezomib.
Most patients in the study were refractory to bortezomib or lenalidomide (75% and 80%, respectively) and 50% were refractory to both bortezomib and lenalidomide. The overall ORR of 44% and clinical benefit rate of 61% demonstrates that pano-RVd can provide disease control in patients previously treated with and resistant to lenalidomide and/or bortezomib, a finding that is consistent with previous studies involving panobinostat-containing regimens7,14. This observation is likely due to the unique epigenetic mechanism of action of panobinostat, which targets multiple pathways that contribute to high-risk biology in MM and abrogates resistance to more established agents caused by epigenetic changes9,10,20.
AEs commonly associated with regimens incorporating panobinostat, bortezomib, and/or lenalidomide include neutropenia, diarrhea, PN, and thrombocytopenia2,13,21. The most commonly reported TRAEs in this study included diarrhea and PN, which were all G1/2. This finding contrasts with the phase 3 PANORAMA 1 study in which 25% of patients experienced G3/4 diarrhea and 18% experienced G3/4 PN5,6. The toxicity profile differences observed between the present study and PANORAMA 1 may be related to the different method of bortezomib administration (subcutaneous vs. intravenous) and the reduced dose of panobinostat (10–15 mg vs. 20 mg). At the MTD for pano-RVd, G3/4 AEs were experienced by 80% of patients, the majority of which were hematological. This high percentage of G3/4 AEs reflects chemotherapy-related bone marrow suppression in the context of a four-drug treatment regimen administered to patients who had received a median of four prior lines of therapy22. Importantly, no patients were withdrawn because of TRAEs, and 40% of patients were able to receive maintenance therapy as part of the study, including one patient who had received 74 cycles at the time of data cut-off. Collectively, these data demonstrate that a reduced panobinostat dose (10 mg) can be effective and tolerated as part of a quadruplet regimen.
The reported patient response to pano-RVd is similar to outcomes reported with pano-Rd in the phase 2 study by Chari et al. (ORR 44% vs. 41%)7. However, the inclusion of bortezomib within the pano-RVd regimen resulted, as expected, in a higher rate of AEs, particularly neuropathy and thrombocytopenia. The two study populations were similar in terms of exposure to prior therapies, and percentage of patients refractory to bortezomib and lenalidomide at time of study entry. However, the studies had different approaches to dosing panobinostat7. In the pano-Rd study, panobinostat was dosed every other week, rather than the 2-weeks-on/1-week-off schedule in the current study. This alternative dosing schedule used by Chari et al. may have enabled patients to tolerate higher doses of study treatment.
Anticipation of overlapping toxicities, particularly bone marrow suppression, led to the dosing strategy in this study, in which both lenalidomide and bortezomib were dose reduced relative to standard dosing of these agents. In spite of this strategy, dose reduction of lenalidomide, bortezomib and dexamethasone was required in 15%, 30%, and 30% of patients, respectively, and at least one treatment delay was required in 90% of patients. However, these reductions in dose enabled longer-term administration of all four agents, which presumably contributed to the sustained responses observed in some patients.
The small sample size is an important limitation of this study and inherent to phase 1 studies in general. While patients had received a substantial number of prior therapies, they were also relatively young, and thus it will be important to ascertain whether this quadruplet regimen could be tolerated in elderly patients23. However, the similar rates of TRAEs observed in patients <65 and ≥65 years old suggest that, indeed, pano-RVd may be tolerated in fit elderly patients.
This study was not designed or powered to definitively evaluate efficacy. However, the exploratory data reported herein are promising. Of note, in a previous study, pano-RVd was shown to have a favorable safety and efficacy profile in the front-line setting24. Panobinostat has also been shown to be effective and well tolerated when administered 1-week-on/1-week-off in a 28-day cycle in combination with lenalidomide and dexamethasone7 or with carfilzomib25, and once-weekly administration of bortezomib has been shown to improve the safety profile while maintaining efficacy26–28. As such, it would be of interest to evaluate a modified dosing regimen of pano-RVd using a 28-day cycle in which panobinostat is administered 1-week-on/1-week-off, along with weekly bortezomib, as such an approach may reduce the rates of thrombocytopenia and PN, while maintaining efficacy, and so translate efficiently into real-world practice23.
The relative lack of significant patient exposure to more recently approved agents such as carfilzomib, daratumumab, and elotuzumab is also a potential limitation of the study. Nonetheless, the results highlight the ability of panobinostat to re-sensitize patients to agents which, in most instances, they had previously become refractory to and were resistant. These data underscore the utility of panobinostat as an oral therapy with a unique, multifaceted mechanism of action that can partner with other agents to overcome resistance and enhance treatment response. Given the use of continuous/treat-to-progression therapy as a standard of care in MM, patients are more likely to become refractory to multiple agents after fewer lines of therapy, pointing to the need for additional treatment options for RRMM. As the dose and schedule of panobinostat are optimized, regimens incorporating this agent, such as pano-RVd, may contribute to further improvements in patient outcomes by targeting patterns of resistance to IMiDs and/or PIs, as well as to other novel agents29.
Supplementary information
Supplementary Figures
Supplementary Table 1
Supplementary Table 2
Reproducibility checklist
This work was presented in part at the American Society of Clinical Oncology Annual Meeting, Chicago, June 2016, and the European Hematology Association Virtual Congress, June 2020.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
The online version contains supplementary material available at 10.1038/s41408-021-00407-5.
Acknowledgements
The authors thank all patients involved in the study, as well as investigators and research staff in participating institutions. The authors thank Cara Valvona, PhD, of Watermeadow Medical, part of Ashfield Healthcare, Witney, UK, for providing medical writing support, funded by Secura Bio, Inc. San Diego, US, in accordance with Good Publication Practice guidelines. Funding: Novartis Pharmaceuticals Corporation funded this study. Secura Bio, Inc. funded the publication of this manuscript, including medical writing support.
Author contributions
All authors were involved in data collection, analysis, and interpretation. All authors critically revised and approved the manuscript.
Data sharing statement
All data requests should be submitted to the corresponding author for consideration. Access to anonymized data may be granted following review.
Conflict of interest
J.P.L., J.M.R., K.C., K.M., D.W., and R.A.R. report no conflicts of interest. S.A.T. reports grants and personal fees from Celgene, grants and personal fees from Karyopharm, grants and personal fees from Sanofi, personal fees from Caelum, grants from Amgen, and grants from Janssen, outside the submitted work. C.S.M. discloses employment of a relative with Takeda; consultant/honoraria from Fate Therapeutics, Ionis Pharmaceuticals; past research funding from Novartis; as well as research funding outside the scope of this submitted work from Janssen/Johnson & Johnson, TEVA, EMD Serono, AbbVie, Karyopharm, Sanofi, and Arch Oncology. D.G. is a consultant to Secura Bio, Inc. P.G.R. reports grants from BMS, grants and honoraria (advisory committee member) from Oncopeptides, Celgene, Takeda, and Karyopharm; and honoraria (advisory committee member) from Janssen, Sanofi, and Secura Bio, Inc. outside the submitted work. | 20 MILLIGRAM | DrugDosageText | CC BY | 33563894 | 18,917,658 | 2021-02-05 |
What was the dosage of drug 'LENALIDOMIDE'? | Phase 1 open-label study of panobinostat, lenalidomide, bortezomib + dexamethasone in relapsed and relapsed/refractory multiple myeloma.
Additional therapeutic options are needed for relapsed and refractory multiple myeloma (RRMM). We present data from a phase 1b, open-label, dose-escalation study (NCT01965353) of 20 patients with RRMM (median age: 63 years [range: 50-77]) and a median of four prior regimens (range: 2-14); 85% had refractory disease (lenalidomide [80%]; bortezomib [75%]; lenalidomide and bortezomib [50%]). Patients received a median of six cycles (range: 1-74) of panobinostat (10 or 15 mg), lenalidomide 15 mg, bortezomib 1 mg/m2, and dexamethasone 20 mg (pano-RVd). Median follow-up was ~14 months. Six dose-limiting toxicities were reported (mostly hematological); maximum tolerated dose of panobinostat (primary endpoint) was 10 mg. Most common adverse events (AEs) were diarrhea (60%) and peripheral neuropathy (60%); all grade 1/2. Grade 3/4 AEs occurred in 80% of patients and included decreased neutrophil (45%), platelet (25%) and white blood cell (25%) counts, anemia (25%) and hypophosphatemia (25%). No treatment-related discontinuations or mortality occurred. In evaluable patients (n = 18), overall response rate was 44%, and clinical benefit rate was 61%. Median duration of response was 9.2 months; progression-free survival was 7.4 months; overall survival was not reached. Pano-RVd proved generally well-tolerated and demonstrated potential to overcome lenalidomide and/or bortezomib resistance.
Introduction
Treatment of multiple myeloma (MM), an incurable plasma-cell neoplasm, has changed substantially in recent decades1. Rapidly evolving treatment standards have led to improvements in overall survival (OS), as well as the depth and duration of response (DOR)2–4. Nevertheless, most patients ultimately relapse and require subsequent lines of therapy, with the depth of response and DOR to each successive regimen typically decreasing over time1. However, different emerging classes of agents, which can be combined in triplet or even quadruplet regimens, have provided clinicians with several new therapeutic options for relapsed and refractory MM (RRMM) patients.
Histone deacetylase inhibitors (HDACis), which influence transcriptional activation and other nuclear events by increasing histone acetylation, have been developed in recent years as a treatment for RRMM1,5–7. Histone deacetylases (HDACs) are overexpressed in MM, leading to reduced expression of tumor suppressor genes and, consequently, increased growth and proliferation of tumor cells. Unsurprisingly, overexpression of class I HDACs is associated with a poorer prognosis in MM8.
Broad-spectrum HDACis can enhance the anti-MM activity of proteasome inhibitors through multiple non-mutually exclusive mechanisms, including the transcriptional repression of ubiquitin/proteasome pathway genes and drivers of tumor cell survival and treatment resistance9,10, as well as the inhibition of the aggresome, which is an alternative route for protein degradation11. Panobinostat is among the most potent HDACis in clinical development and the only HDACi approved for the treatment of RRMM, in combination with bortezomib and dexamethasone12,13. In the phase 2 PANORAMA 2 trial, heavily pre-treated, bortezomib-refractory patients with RRMM had an overall response rate (ORR) of 34.5% with panobinostat plus bortezomib and dexamethasone (pano-Vd), highlighting that the addition of panobinostat can overcome resistance to prior therapeutic agents, including bortezomib14. In the randomized phase 3 PANORAMA 1 study, pano-Vd significantly improved median progression-free survival (PFS) by 12.5 vs. 4.7 months (hazard ratio 0.47; 95% confidence interval [CI] 0.31, 0.72) in patients who had received ≥2 prior regimens including bortezomib and an immunomodulatory drug (IMiD), and nearly tripled the rate of complete response/near complete response, compared with placebo-Vd (22% vs. 8% for pano-Vd and placebo-Vd, respectively)5,6,15.
The optimal dose and schedule of pano-Vd was confirmed in the randomized phase 3 PANORAMA 3 trial as 20 mg thrice weekly; DOR with this regimen was 22.6 months and tolerability was improved with subcutaneous administration of bortezomib with only 11.5% of patients in the 20 mg TIW dosing group reporting grade 3/4 diarrhea compared with intravenous delivery of bortezomib, as was standard practice at the time of previous clinical trials.16
Broad-spectrum HDACis also enhance the anti-MM activity of IMiDs, such as lenalidomide, by suppressing diverse oncogenic transcriptional programs10, including the interferon regulatory factor-4/MYC axis17. In a phase 2 study of patients with RRMM, panobinostat plus lenalidomide and dexamethasone (pano-Rd) demonstrated an encouraging ORR (41%) and median PFS (7.1 months) in patients with high-risk, lenalidomide-refractory (81%), and/or bortezomib-refractory (52%) MM, suggesting that panobinostat is also able to overcome resistance to IMiDs.
These data provided the rationale for investigating the quadruplet regimen, panobinostat, lenalidomide, bortezomib and dexamethasone (pano-RVd), in heavily pre-treated patients, particularly in those refractory to proteasome inhibitors and/or IMiDs for whom additional therapy options are needed. Here, we report the findings of a phase 1b dose-escalation study of pano-RVd with extended follow-up.
Methods
Study design and objectives
This study was an open-label, multicenter, phase 1b, study of pano-RVd in RRMM (NCT01965353). Primary objectives were to identify the maximum tolerated dose (MTD) of panobinostat in combination with RVd and to evaluate the safety profile of pano-RVd. Secondary objectives were to evaluate ORR, DOR, time to progression (TTP), PFS and OS. A modified Fibonacci design was used, with 3–6 patients planned at each dose level followed by a dose-expansion phase with an additional ten patients to evaluate the tolerability of the MTD.
The study was conducted in accordance with the Declaration of Helsinki, US Code of Federal Regulations governing clinical study conduct, state laws and Dana-Farber/Harvard Cancer Center research policies and procedures. The institutional review board for each center approved the protocol and amendments. All patients provided written informed consent before enrollment.
Patient eligibility
Eligible patients were aged ≥18 years with measurable RRMM (2011 International Myeloma Working Group consensus)18, an Eastern Cooperative Oncology Group performance status <2, and had received ≥2 lines of therapy. Patients with primary refractory disease, prior HDACi treatment, creatinine clearance <45 mL/min, platelet count <75,000 cells/mm3, absolute neutrophil count <1500 cells/mm3, or hemoglobin level <8.0 g/dl at screening were excluded. Patients with ≥grade (G) 2 peripheral neuropathy (PN) or hepatic impairment (bilirubin > 1.5 × institutional upper limit of normal, or aspartate aminotransferase, alanine aminotransferase, or alkaline phosphatase >2 × institutional upper limit of normal) within 21 days of study therapy initiation were also excluded.
Treatments administered
Patients received oral panobinostat 10 mg or 15 mg plus subcutaneous bortezomib 1 mg/m2, oral lenalidomide 15 mg, and oral dexamethasone 20 mg in 21-day cycles per the schema in Fig. 1. After eight cycles, patients switched to a maintenance schedule, with reduced bortezomib and dexamethasone dosing. Treatment continued until disease progression, unacceptable toxicity, consent was withdrawn, or discontinuation was in the best interest of the patient. Doses could be held for up to 21 days or reduced to manage therapy-related adverse events (TRAEs).Fig. 1 Each cycle consisted of 21 days, patients received eight treatment cycles before switching to maintenance cycles.
Progression to the next higher dose level occurred, if appropriate, when the safety and tolerability of the prior dose level(s) had been determined at the end of the first cycle.
Necessary concomitant medications were allowed, except for those which may cause QTcF prolongation or induce torsades de pointes. Leukocyte growth factors were only administered during cycle 1 in the event of a dose-limiting toxicity (DLT) (if appropriate), but could be prescribed for severe neutropenia after cycle 1.
Dose escalation, MTD, and DLTs
A standard 3 + 3 dose-escalation schema was used (Supplementary Fig. S1). If ≥2 of 3 patients within a cohort experienced a DLT during the dose-escalation phase, the dose immediately below the current dose was defined as the MTD. The 3 + 3 schema was chosen, rather than an alternative methodologic phase 1 study design, due to the limited number of patients in the study and the fact that only three dose levels were planned. DLTs were assessed during the first cycle and defined as a QTcF interval >500 ms, or an absolute increase of >60 ms, a ≥ G3 non-hematological AE or a G4 hematological AE (including thrombocytopenia with platelets <25,000/mm3 on >1 occasion, or G4 neutropenia for >5 days and/or resulting in neutropenic fever on two occasions). Lymphopenia, an AE associated with bortezomib use, was not considered a DLT. Inability to take ≥75% of the planned study drug doses, or receive day 1 doses for cycle 2 due to a drug-related AE occurring in cycle 1, were also considered DLTs.
Assessments
AEs, graded using Cancer Therapy Evaluation Program Version 4 of the National Cancer Institute Common Terminology Criteria for Adverse Events19, were assessed throughout the study and for 30 days after completion of study therapy. Patients who discontinued for any reason other than disease progression were followed every three months until disease progression. Disease response/progression were assessed at the start of each treatment and maintenance cycle, at the end of study, and during the follow-up phase. Disease response was assessed locally using the International Myeloma Working Group Response Criteria18 with M-protein quantification and immunofixation in serum and 24-h urine samples, and serum-free light chain testing. OS was assessed every three months after disease progression.
Statistical analyses
Data cut-off was 24 January 2019. Descriptive statistics are provided for the reported outcomes. All participants who had received ≥1 dose of any study treatment were evaluated for AEs from treatment initiation. All patients who had received study treatment and had ≥1 follow-up assessment were included in the response evaluation. Only patients who responded to treatment (≥minimal response) were included in the DOR analysis. DOR, TTP, PFS, and OS were estimated using Kaplan–Meier methodology. DOR was measured as the time from initiation of first response to time of disease progression, death, or last follow-up (for those patients who had not progressed or died). TTP was defined as time from registration to progression or to last follow-up (for those who had not progressed). PFS was defined as the time from registration to disease progression, death, or last follow-up (for those who had not progressed or died). OS was defined as time from registration to death or last follow-up (for patients who had not died).
Results
Patient characteristics
Between November 2013 and October 2016, 20 patients were enrolled: median age was 63 years (range: 50–77), 70% male (Table 1). Cytogenetic data were available for 17 patients; two had t(4;14), and one had t(14;16). The median number of prior lines of treatment was four (range: 2–14); five patients had received >5 prior lines of treatment. Overall, 95% and 90% had been previously treated with bortezomib and lenalidomide, respectively. Most patients (n = 17, 85%) had refractory disease (lenalidomide [80%]; bortezomib [75%]; lenalidomide and bortezomib [50%]; dexamethasone [85%]).Table 1 Patient baseline characteristics.
Total population n = 20 (%)
Male 14 (70)
Race
Black/African American 4 (20)
White 15 (75)
Other 1 (5)
Age, median (range) 63 (50–77)
Age group
≤55 4 (20)
56–65 9 (45)
>65 7 (35)
Disease status
Relapsed 3 (15)
R/R 17 (85)
ECOG PS
0 9 (45)
1 11 (55)
ISS classification
I 5 (25)
II 7 (35)
III 7 (35)
Missing 1 (5)
Number of prior treatments, median (range) 4 (2–14)
Prior treatment
Bortezomib 19 (95)
Dexamethasone 20 (100)
Lenalidomide 18 (90)
Pomalidomide 15 (75)
Carfilzomib 0
Refractory to any prior treatment
Bortezomib 15 (75)
Dexamethasone 17 (85)
Lenalidomide 16 (80)
Refractory most recent prior treatment
Bortezomib 9 (45)
Dexamethasone 16 (80)
Lenalidomide 2 (10)
Prior autologous transplants
1 9 (45)
Cytogenetics
No FISH failure 17 (85)
t (4;14)a 2 (10)
t (14;16)b 1 (5)
ECOG PS Eastern Cooperative Oncology Group Performance Status, FISH fluorescence in situ hybridization, ISS International Staging System, R/R relapsed/refractory.
aMissing: n = 9.
bMissing: n = 10.
MTD and DLTs
Three patients were treated with panobinostat 10 mg; one experienced a DLT; per protocol, three additional patients were treated with panobinostat 10 mg. No further DLTs were reported, and the dose was escalated. Three patients were treated with panobinostat 15 mg; two experienced DLTs. One of these DLTs (syncope) was a pre-existing condition and not considered related to study treatment, thus, one additional patient was treated with panobinostat 15 mg; this patient subsequently experienced a DLT (thrombocytopenia). Therefore, 10 mg was defined as the MTD for panobinostat in the pano-RVd combination. In the expansion phase, ten patients were treated with pano-RVd with panobinostat dosed at 10 mg; two experienced a DLT. Overall, four patients experienced one DLT, one patient experienced two DLTs and one patient experienced three DLTs (Table 2).Table 2 Dose limiting toxicities.
n (panobinostat dose)
Decreased platelet count 3 (15 mg, n = 2; 10 mg, n = 1)
Decreased neutrophil count 2 (15 mg)
Fatigue 1 (15 mg)
Hyperglycemia 1 (10 mg)
Hypophosphatemia 1 (10 mg)
Syncope 1a (15 mg)
aNot related to treatment.
Treatment summary
Patients completed a median of six cycles (range: 1–74) (Supplementary Table S1). Three patients completed one cycle before withdrawing due to progressive disease. Eight patients completed all eight treatment cycles and ≥1 cycle of maintenance therapy. At the data cut-off date, one patient remained on treatment (Supplementary Fig. S2).
Safety and tolerability
All 20 patients experienced ≥1 TRAE. The distribution of worst overall TRAEs experienced was G1 (n = 1), G2 (n = 3), G3 (n = 11) or G4 (n = 5). The most common TRAEs included diarrhea (60%, all were G1/2), PN (60%), anemia (55%), fatigue (55%), neutropenia (55%), constipation (50%) and hypokalemia (50%) (Table 3). The median (95% CI) duration of neutropenia and thrombocytopenia AEs was 7 (4; 11) days and 8 (4; 11) days, respectively. Overall, 37 G3/4 TRAEs were reported; the most common were decreased neutrophil (45%), platelet (25%) and white blood cell (25%) counts; anemia (25%); and hypophosphatemia (25%). The rate of cardiac TRAEs was low (atrial fibrillation, n = 1; atrial flutter, n = 1; sinus bradycardia, n = 1; sinus tachycardia, n = 1; palpitations, n = 1; prolongation of QTcF interval, n = 1; heart racing, n = 1; chronic right bundle branch block, n = 1; ectopy and murmur n = 1), and all events were G1/2. No G3/4 diarrhea TRAEs were observed. The only reported G4 TRAEs were decreased platelet (25%) and white blood cell counts (5%). In total, nine serious AEs were experienced by six patients, including treatment-related hyperglycemia, decreased neutrophil count, fatigue, and decreased platelet count. TRAE rates were generally balanced in patients in patients <65 (n = 11) and ≥65 (n = 9) years old, although G4 thrombocytopenia TRAEs were more common in patients ≥65 years old.Table 3 AEs experienced by ≥20% of patients and all grade 4 AEs.
Total, n (%) Grade 1 Grade 2 Grade 3 Grade 4
(n = 20) n (%) n (%) n (%) n (%)
Blood and lymphatic system disorders
Anemia 11 (55) 2 (10) 4 (20) 5 (25) –
Neutrophil count decreased 11 (55) 1 (5) 1 (5) 9 (45) –
Platelet count decreased 9 (45) 4 (20) – – 5 (25)
White blood cell count decreased 7 (35) – 2 (10) 4 (20) 1 (5)
Blood and lymphatic system disorders – other 4 (20) 1 (5) 3 (15) – –
Bruising 4 (20) 4 (20) – – –
Cardiac disorders
Dizziness 5 (25) 4 (20) 1 (5) – –
Cardiac disorders – other 4 (20) 4 (20) – – –
Eye disorders
Eye disorders—other 4 (20) 2 (10) 2 (10) – –
Gastrointestinal disorders
Diarrhea 12 (60) 7 (35) 5 (25) – –
Constipation 10 (50) 6 (30) 4 (20) – –
Nausea 7 (35) 5 (25) 2 (10) – –
Gastrointestinal disorders—other 5 (25) 3 (15) 2 (10) – –
Dysgeusia 4 (20) 2 (10) 2 (10) – –
General disorders and administration site conditions
Fatigue 11 (55) 1 (5) 9 (45) 1 (5) –
Edema limbs 7 (35) 4 (20) 3 (15) – –
Infections and infestations
Upper respiratory infection 8 (40) – 8 (40) – –
Infections and infestations – other 6 (30) 2 (10) 2 (10) 2 (10) –
Investigations
Hypokalemia 10 (50) 8 (40) 2 (10) – –
Hypomagnesemia 8 (40) 8 (40) – – –
Hypophosphatemia 7 (35) 1 (5) 1 (5) 5 (25) –
Hypocalcemia 5 (25) 4 (20) 1 (5) – –
Hyponatremia 5 (25) 5 (25) – – –
Metabolism and nutrition disorders
Anorexia 7 (35) 5 (25) 2 (10) – –
Hyperglycemia 7 (35) 4 (20) 2 (10) 1 (5) –
Musculoskeletal and connective tissue disorders
Musculoskeletal and connective tissue disorder – other 4 (20) 2 (10) 2 (10) – –
Nervous system disorders
Peripheral sensory neuropathy 12 (60) 6 (30) 6 (30) – –
Psychiatric disorders
Insomnia 6 (30) 3 (15) 3 (15) – –
Respiratory, thoracic, and mediastinal disorders
Cough 6 (30) 1 (5) 5 (25) – –
Dyspnea 6 (30) 3 (15) 2 (10) 1 (5) –
AEs that were possibly, probably, or definitely related to any study treatments are reported. Each AE represents the highest grade for that AE per patient, so patients may be included in each row at most once.
AE adverse event.
There were no instances of treatment-related death or study discontinuation. Dose levels of lenalidomide, bortezomib, dexamethasone, and panobinostat were reduced in at least one cycle for three, six, six, and three patients, respectively. Dose reductions for panobinostat and lenalidomide only occurred in patients in the panobinostat 15 mg cohort. At least one cycle of the pano-RVd regimen was delayed in 18 patients. The most common reason for dose holds was AEs (73%), of which upper respiratory infection, decreased neutrophil count and peripheral sensory neuropathy were the most common (Supplementary Table S2). Reasons for treatment withdrawal included progressive disease (85%), death (5%) and autologous stem cell transplantation (5%).
Responses and outcomes
The median follow-up was ~14 months. Per protocol, two patients were not eligible for response evaluation; one died due to factors unrelated to study treatment 2 weeks after starting study treatment, and one withdrew from the study 3 days after starting treatment, due to rapid disease progression. In response-evaluable patients (n = 18), the rate of very good partial response or better was 17%, the ORR (≥partial response) was 44% (90% CI 24, 66) and the clinical benefit response rate (≥minimal response) was 61% (90% CI 39, 80) (Table 4). In patients refractory to both lenalidomide and bortezomib (n = 10), the ORR was 30% (90% CI 9, 61) and the clinical benefit rate was 50% (90% CI 22, 78). Median time-to-first response was approximately 1 month (range: 0.79–4.6), and the median DOR was 9.2 months (range: 2.1–50.4 months). At data cut-off, four patients had a DOR of at least 10 months, median (95% CI) TTP was 7.8 (7.2, not reached) months, median (95% CI) PFS was 7.4 (4.2, not reached) months (Fig. 2), and median (95% CI) OS had not been reached (13.5, not reached). In patients refractory to both lenalidomide and bortezomib, median (95% CI) DOR was 22.1 (9.2, not reached) months, median (95% CI) TTP and PFS were both 22.9 (0.9, not reached) months (Fig. 2), and median (95% CI) OS was not reached (6.8, not reached).Table 4 Patient responses.
All patients, N = 18a N (%) 90% CI
Stringent complete response 1 (6) NA
Complete response 0 (0) NA
Very good partial response 2 (11) NA
Partial response 5 (28) NA
Minimal response 3 (17) NA
Stable disease 7 (39) NA
Overall response rate (partial response or better) 8 (44) 24, 66
Clinical benefit rate (minimal response or better) 11 (61) 39, 80
Patients refractory to both lenalidomide and bortezomib, N = 10 N (%) 90% CI
Overall response rate (partial response or better) 3 (30) 9, 61
Clinical benefit rate (minimal response or better) 5 (50) 22, 78
CI confidence interval, NA not applicable. M-spike evaluation.
aNon evaluable: n = 2 (10%).
Fig. 2 Kaplan–Meier distributions of PFS in all 20 patients receiving pano-RVd and lenalidomide/bortezomib-refractory patients.
Len/Btz lenalidomide/bortezomib. Pano-RVd panobinostat/lenalidomide/bortezomib/dexamethasone, PFS progression free survival.
Discussion
Despite recent approvals of new therapeutic agents for RRMM, nearly all patients ultimately still experience disease relapse. The pano-RVd regimen investigated in this study provides a potential treatment option that can restore responses in heavily treated patients with refractory disease. The MTD of panobinostat in the pano-RVd regimen was 10 mg, dosed in a 2-weeks-on/1-week-off schedule, in combination with bortezomib 1 mg/m2, lenalidomide 15 mg and dexamethasone 20 mg. Although all patients experienced at least one TRAE, no patients discontinued therapy or were withdrawn from the study due to a TRAE. Importantly, this regimen demonstrated promising activity in RRMM patients, including those who were refractory to bortezomib and/or lenalidomide and had received a median of four prior lines of therapy. Furthermore, DOR, TTP, and PFS efficacy outcomes were favorable, even in patients refractory to both lenalidomide and bortezomib.
Most patients in the study were refractory to bortezomib or lenalidomide (75% and 80%, respectively) and 50% were refractory to both bortezomib and lenalidomide. The overall ORR of 44% and clinical benefit rate of 61% demonstrates that pano-RVd can provide disease control in patients previously treated with and resistant to lenalidomide and/or bortezomib, a finding that is consistent with previous studies involving panobinostat-containing regimens7,14. This observation is likely due to the unique epigenetic mechanism of action of panobinostat, which targets multiple pathways that contribute to high-risk biology in MM and abrogates resistance to more established agents caused by epigenetic changes9,10,20.
AEs commonly associated with regimens incorporating panobinostat, bortezomib, and/or lenalidomide include neutropenia, diarrhea, PN, and thrombocytopenia2,13,21. The most commonly reported TRAEs in this study included diarrhea and PN, which were all G1/2. This finding contrasts with the phase 3 PANORAMA 1 study in which 25% of patients experienced G3/4 diarrhea and 18% experienced G3/4 PN5,6. The toxicity profile differences observed between the present study and PANORAMA 1 may be related to the different method of bortezomib administration (subcutaneous vs. intravenous) and the reduced dose of panobinostat (10–15 mg vs. 20 mg). At the MTD for pano-RVd, G3/4 AEs were experienced by 80% of patients, the majority of which were hematological. This high percentage of G3/4 AEs reflects chemotherapy-related bone marrow suppression in the context of a four-drug treatment regimen administered to patients who had received a median of four prior lines of therapy22. Importantly, no patients were withdrawn because of TRAEs, and 40% of patients were able to receive maintenance therapy as part of the study, including one patient who had received 74 cycles at the time of data cut-off. Collectively, these data demonstrate that a reduced panobinostat dose (10 mg) can be effective and tolerated as part of a quadruplet regimen.
The reported patient response to pano-RVd is similar to outcomes reported with pano-Rd in the phase 2 study by Chari et al. (ORR 44% vs. 41%)7. However, the inclusion of bortezomib within the pano-RVd regimen resulted, as expected, in a higher rate of AEs, particularly neuropathy and thrombocytopenia. The two study populations were similar in terms of exposure to prior therapies, and percentage of patients refractory to bortezomib and lenalidomide at time of study entry. However, the studies had different approaches to dosing panobinostat7. In the pano-Rd study, panobinostat was dosed every other week, rather than the 2-weeks-on/1-week-off schedule in the current study. This alternative dosing schedule used by Chari et al. may have enabled patients to tolerate higher doses of study treatment.
Anticipation of overlapping toxicities, particularly bone marrow suppression, led to the dosing strategy in this study, in which both lenalidomide and bortezomib were dose reduced relative to standard dosing of these agents. In spite of this strategy, dose reduction of lenalidomide, bortezomib and dexamethasone was required in 15%, 30%, and 30% of patients, respectively, and at least one treatment delay was required in 90% of patients. However, these reductions in dose enabled longer-term administration of all four agents, which presumably contributed to the sustained responses observed in some patients.
The small sample size is an important limitation of this study and inherent to phase 1 studies in general. While patients had received a substantial number of prior therapies, they were also relatively young, and thus it will be important to ascertain whether this quadruplet regimen could be tolerated in elderly patients23. However, the similar rates of TRAEs observed in patients <65 and ≥65 years old suggest that, indeed, pano-RVd may be tolerated in fit elderly patients.
This study was not designed or powered to definitively evaluate efficacy. However, the exploratory data reported herein are promising. Of note, in a previous study, pano-RVd was shown to have a favorable safety and efficacy profile in the front-line setting24. Panobinostat has also been shown to be effective and well tolerated when administered 1-week-on/1-week-off in a 28-day cycle in combination with lenalidomide and dexamethasone7 or with carfilzomib25, and once-weekly administration of bortezomib has been shown to improve the safety profile while maintaining efficacy26–28. As such, it would be of interest to evaluate a modified dosing regimen of pano-RVd using a 28-day cycle in which panobinostat is administered 1-week-on/1-week-off, along with weekly bortezomib, as such an approach may reduce the rates of thrombocytopenia and PN, while maintaining efficacy, and so translate efficiently into real-world practice23.
The relative lack of significant patient exposure to more recently approved agents such as carfilzomib, daratumumab, and elotuzumab is also a potential limitation of the study. Nonetheless, the results highlight the ability of panobinostat to re-sensitize patients to agents which, in most instances, they had previously become refractory to and were resistant. These data underscore the utility of panobinostat as an oral therapy with a unique, multifaceted mechanism of action that can partner with other agents to overcome resistance and enhance treatment response. Given the use of continuous/treat-to-progression therapy as a standard of care in MM, patients are more likely to become refractory to multiple agents after fewer lines of therapy, pointing to the need for additional treatment options for RRMM. As the dose and schedule of panobinostat are optimized, regimens incorporating this agent, such as pano-RVd, may contribute to further improvements in patient outcomes by targeting patterns of resistance to IMiDs and/or PIs, as well as to other novel agents29.
Supplementary information
Supplementary Figures
Supplementary Table 1
Supplementary Table 2
Reproducibility checklist
This work was presented in part at the American Society of Clinical Oncology Annual Meeting, Chicago, June 2016, and the European Hematology Association Virtual Congress, June 2020.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
The online version contains supplementary material available at 10.1038/s41408-021-00407-5.
Acknowledgements
The authors thank all patients involved in the study, as well as investigators and research staff in participating institutions. The authors thank Cara Valvona, PhD, of Watermeadow Medical, part of Ashfield Healthcare, Witney, UK, for providing medical writing support, funded by Secura Bio, Inc. San Diego, US, in accordance with Good Publication Practice guidelines. Funding: Novartis Pharmaceuticals Corporation funded this study. Secura Bio, Inc. funded the publication of this manuscript, including medical writing support.
Author contributions
All authors were involved in data collection, analysis, and interpretation. All authors critically revised and approved the manuscript.
Data sharing statement
All data requests should be submitted to the corresponding author for consideration. Access to anonymized data may be granted following review.
Conflict of interest
J.P.L., J.M.R., K.C., K.M., D.W., and R.A.R. report no conflicts of interest. S.A.T. reports grants and personal fees from Celgene, grants and personal fees from Karyopharm, grants and personal fees from Sanofi, personal fees from Caelum, grants from Amgen, and grants from Janssen, outside the submitted work. C.S.M. discloses employment of a relative with Takeda; consultant/honoraria from Fate Therapeutics, Ionis Pharmaceuticals; past research funding from Novartis; as well as research funding outside the scope of this submitted work from Janssen/Johnson & Johnson, TEVA, EMD Serono, AbbVie, Karyopharm, Sanofi, and Arch Oncology. D.G. is a consultant to Secura Bio, Inc. P.G.R. reports grants from BMS, grants and honoraria (advisory committee member) from Oncopeptides, Celgene, Takeda, and Karyopharm; and honoraria (advisory committee member) from Janssen, Sanofi, and Secura Bio, Inc. outside the submitted work. | 15 MILLIGRAM | DrugDosageText | CC BY | 33563894 | 18,917,658 | 2021-02-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Condition aggravated'. | Cutaneous Coinfection of Cytomegalovirus and Mycobacterium chelonae Accelerated by Immunosuppression.
A mildly diabetic 58-year-old male had traumatic ulceration on the left popliteal fossa, and the lesion progressed to a painful 6 cm deep ulcer. After surgical debridement and skin grafting, ulceration recurred. Pyoderma gangrenosum was clinically diagnosed after the first biopsy, indicating a noninfective ulcer. Immunosuppressive therapy (prednisolone and cyclosporine A) induced complete epithelialization in three months. Four months later, subcutaneous nonulcerated nodules appeared on the anterior area of the left lower leg. Subcutaneous induration progressed and ulceration recurred, so that immunosuppressive therapy continued for one year. Cytomegalovirus (CMV) viremia was detected, and the second biopsy demonstrated CMV inclusions of endothelial and perivascular cells in fibrosing septolobular panniculitis. Cyclosporine A was cancelled, prednisolone was tapered, and ganciclovir started. Viremia soon disappeared, but the lesion progressed to large induration with multiple ulcers measuring up to 3 cm. The third biopsy disclosed infection of Gram-positive mycobacteria, accompanying fat droplet-centered suppurative granulomas without CMV infection. Microbial culture identified Mycobacterium chelonae. Clarithromycin with thermotherapy was effective. A review of the second biopsy confirmed coinfection of CMV and Gram-positive mycobacteria. Immunostaining using a panel of anti-bacterial antibodies visualized the mycobacteria in the lesion. Positive findings were obtained with antibodies to Bacillus Calmette-Guérin, Bacillus cereus, MPT64 (Mycobacterium tuberculosis-specific 24 kDa secretory antigen), LAM (Mycobacterium tuberculosis-related lipoarabinomannan), and PAB (Propionibacterium acnes-specific lipoteichoic acid).
1. Introduction
Immunosuppressive conditions may provoke opportunistic skin infection of a variety of bacteria, fungi, and viruses [1, 2]. The present article describes a case of pyoderma gangrenosum on the left popliteal fossa, followed by immunosuppressive therapy-induced opportunistic dual skin infection of cytomegalovirus (CMV) and Mycobacterium chelonae on the left lower leg. Histopathological and immunohistochemical features of this rare combination of pathogens are detailed.
2. Case Report
A 58-year-old Japanese man slipped and fell on the road to have his left knee contused, resulting in a 1.5 cm sized shallow ulceration. The patient had suffered from hypertension and mild type 2 diabetes mellitus for two years, but no history of autoimmune disorders. Serum antibodies against insulin and glutamic acid decarboxylase were negative, excluding the possibility of type 1 diabetes mellitus. He had smoked 15 cigarettes per day for more than 40 years. Five months later, a painful skin ulcer, 6 cm in size, occurred on the inner side of the left popliteal fossa (at the same site of contusion). No pathogens were identified in the biopsy specimen, and microbial culture was negative. Surgical debridement and full-thickness grafting from the abdominal skin were performed by a plastic surgeon, but half of the skin flap was eventually impaired, leaving a 3 cm sized deep ulcer with severe pain. The patient was then consulted to dermatologists. Clinical findings, as well as the first biopsy features displaying nonspecific and noninfective ulcer, were consistent with pyoderma gangrenosum (Figure 1). The serum level of granulocyte colony-stimulating factor, a biomarker of pyoderma gangrenosum [3], was elevated to 48.1 pg/mL (reference value < 30 pg/mL). Administration of prednisolone (PSL) (20 mg/day) and cyclosporine A (CyA: 100 mg/day) started. In order to control exacerbation of the skin lesion, medication of PSL plus CyA was maintained, while PSL was gradually tapered to 10 mg/day. Complete epithelialization was achieved three months later.
Four months later, subcutaneous nonulcerated, painful nodules appeared on the anterior area of the left lower leg, 20 cm distal from the primary ulcer caused by pyoderma gangrenosum. Ulceration recurred, and subcutaneous induration soon progressed toward both the distal and proximal directions. Immunosuppressive therapy restarted, but the painful ulcer persisted for one year. At this point of time, CMV viremia was identified, and the second skin biopsy from one of the subcutaneous nodules identified CMV inclusions in the subcutaneous tissue with fibrosing septolobular panniculitis. The CMV antigens were immunohistochemically visualized in the viral inclusions with 1 : 200 diluted cocktail monoclonal antibodies, CCH2+DDG9, available from Agilent Technologies (Figure 2). Both endothelial cells and perivascular stromal cells were infected. The dermis was free of inflammation. CyA was cancelled, PSL was reduced to 5 mg/day, and instead, ganciclovir (900 mg/day) was administered. Viremia soon disappeared, but the lower leg lesion progressed to form multiple ulcers. The third skin biopsy disclosed that infection involved both the dermis and the subcutaneous fat tissue. Suppurative granulomas (small abscesses surrounded by epithelioid granulomas) were dispersed (Figure 3). Gram-positive acid-fast bacilli were identified in microabscesses and also in fat droplets surrounded by suppurative granulomas (Figure 4). Caseous necrosis was focally associated. Grocott stain gave negative results. CMV infection was no longer identified. The second skin biopsy was retrospectively reevaluated, and Gram-positive acid-fast bacilli were identified mainly in microabscesses and in fat droplets surrounded by suppurative granulomas, multifocally distributed in the inflamed subcutaneous tissue. The final diagnosis of the second biopsy was thus subcutaneous coinfection of CMV and nontuberculous mycobacteria.
Microbial culture on 2% Ogawa medium at 37°C identified rapidly growing nontuberculous mycobacteria. The bacteria were acid-fast and Gram-positive. Mycobacterium chelonae was identified by analyzing with Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS) by using the MALDI Biotyper (Bruker Japan Daltonics division, Yokohama) (Figure 5) [4]. The log score value for M. chelonae was more than 2.0 (2.208).
Clarithromycin administration (800 mg/day), combined with thermotherapy using disposal pocket body warmers for one hour twice a day, resulted in marked regression of the ulcers. PSL tapering induced subcutaneous nodularity with ulceration, and thus, clarithromycin treatment was kept to date. After chemotherapy for 15 months, epithelialization was almost achieved. Valganciclovir was administered when CMV viremia reappeared.
Metformin (an oral antidiabetic) and sitagliptin phosphate hydrate (a selective inhibitor of dipeptidyl peptidase-4) continued for controlling type 2 diabetes mellitus. Mitiglinide calcium hydrate (a stimulator of insulin secretion) was added after the appearance of the skin ulceration for one year. During the clinical course, the patient's blood glucose levels were persistently hyperglycemic, ranging from 106 to 186 mg/dL but without glycosuria. Mild proteinuria ranging from 15 to 100 mg/dL was noted, indicating the complication of stage 2 (early) diabetic nephropathy. His HbA1c levels ranged from 6.4 to 7.3% (standard levels: 4.1–6.2%). The patient thus suffered from mild and controlled diabetes mellitus.
For characterizing the mycobacteria colonizing the skin lesion in the second and third skin biopsy specimens, immunostaining using selected antibodies was performed, as indicated in Table 1. An amino acid polymer method (Simple Stain Max-PO, Nichirei Biosciences, Tokyo) was employed. As reported in the previous article describing a low-specificity and high-sensitivity immunostaining with widely cross-reactive antibacterial antisera [5], the mycobacteria were visualized in formalin-fixed, paraffin-embedded sections. The antibodies gave clearly positive signals in the cytoplasm of macrophages infiltrating in the lesion, in addition to long rods labeled with Gram and Ziehl-Neelsen stains. Figure 6 illustrates positive findings with rabbit antisera to Bacillus Calmette-Guérin (BCG) [6], Bacillus cereus [5], MPT64 (also called as protein Rv1980c, M. tuberculosis-specific 24 kDa secretory antigen) [7], and monoclonal antibodies to LAM (M. tuberculosis-related lipoarabinomannan) [8] and PAB (Propionibacterium acnes-specific lipoteichoic acid) [9]. Antiserum to Treponema pallidum gave weak immunoreactivity. Escherichia coli antigens were scarcely observed. The background staining was minimal.
3. Discussion
Opportunistic infection caused by a variety of bacteria, fungi, or viruses occurs in the skin under the immunosuppressive state such as acquired immunodeficiency syndrome (AIDS) and after the use of immunosuppressive agents [1, 2]. One of the authors (YT) described histopathological features of such conditions in a textbook entitled Pathology of Skin Infections published in 2013 [10]. We describe herein a case of cutaneous coinfection of CMV and M. chelonae, provoked by immunosuppressive therapy against pyoderma gangrenosum. The patient suffered from mild and controlled type 2 diabetes mellitus. Pyoderma gangrenosum is characterized by noninfectious autoimmune-type progressive skin ulceration [11], successfully treated with immunosuppressive agents [12].
Opportunistic skin infection of CMV is rare. CMV mainly affects vascular endothelial cells and perivascular stromal cells, and multifocal anogenital ulcerations are most frequently encountered in AIDS patients [13]. Cutaneous lesions with verrucous elevations [14] and septal panniculitis [15] have also been described in non-AIDS immunosuppressed patients. Since the skin ulcer remained unchanged after ganciclovir treatment, Grushchak et al. regarded CMV infection as a bystander phenomenon [16]. The skin lesion in the present case demonstrated features of septolobular panniculitis with CMV inclusions in endothelial and perivascular stromal cells, but the lesion progressed to form large induration with multiple ulcers after gancyclovir treatment. It is reasonable to consider the CMV infection as bystander incidence associated with nontuberculous mycobacteriosis. In other words, when CMV inclusions are noted in nodular or ulcerated skin lesions, primary causative microbes other than CMV should be searched under the microscope, as was so in the present case.
Varied nontuberculous mycobacteria affect the skin, including M. avium-intracellulare complex, M. marinum, M. ulcerans, M. fortuitum, and M. chelonae-abscessus complex [17, 18]. Reportedly, rapidly growing mycobacteria (RGM) form colonies on a common chocolate agar medium when the culture period is prolonged to two weeks or more [19].
M. chelonae was first isolated from the tortoise by Friedmann in 1902 [20]. M. chelonae belongs to nonchromogenic RGM (Runyon group IV), widely distributed in environmental water [21]. This zoonotic mycobacterium, categorized in M. chelonae-abscessus complex, causes opportunistic infection in the human skin, as well as infection in aquatic animals such as the reptiles and fish [22]. Of notice is that not only traumatic injuries but also surgical procedures make risk factors of human infection [23]. It is plausible that in the present case, medical disposals caused iatrogenic infection of the environmental pathogen. Immunosuppression and diabetic conditions accelerated opportunistic infection, as reported previously [17, 18, 22]. Microscopically, infection of RGM, including M. chelonae, provokes abscess-forming granulomas (suppurative granulomas): some lesions are recognized as abscess surrounded by abortive granuloma formation, while the others predominantly reveal epithelioid granulomas [24, 25]. Acid-fast bacilli are characteristically identified in the lipid droplets (vacuoles) often located in the center of suppurative granulomas. It is noteworthy that the bacilli are positively labeled with Gram stain: namely, Gram positivity is a feature of RGM [26].
The cell wall of mycobacteria contains voluminous mycolic acids, extremely long fatty acids, as molecular forms of mycolic acid-containing glycolipid such as trehalose dimycolate and trehalose monomycolate, giving lipophilic nature of mycobacteria [27]. RGM are characterized by the presence of an additional mycolate, glucose mycolate, on the cell wall [28]. Such biological features may be related to the lipid droplet-centered pattern of infection by RGM.
Lipid droplet-centered suppurative granulomas are commonly observed in granulomatous mastitis caused by a lipophilic bacterium, Corynebacterium kroppenstedtii [29]. The Gram-positive rods are uniquely clustered in the lipid droplets surrounded by suppurative granulomas. The histological features are quite similar to those of RGM infection. Unlike other corynebacteria, C. kroppenstedtii lacks mycolic acid but instead contains tuberculostearic acid in the cell wall [30]. It is understandable from both the microscopic appearance and the pharmacodynamic properties of antibiotics [31] that administration of lipophilic antibiotics is essential for treating not only granulomatous mastitis but also RGM infection. The treatment regimen for tuberculosis using hydrophilic antibiotics such as isoniazid, ethambuthol, pyrazinamide, and streptomycin is consistently ineffective for infection of RGM, which are usually resistant to lipophilic rifampicin [18]. In the present case, clarithromycin, a type of lipophilic macrolides, was effective, as has been reported so far [32, 33]. Thermotherapy was also useful [34], based on the biological features of the bacteria showing low optimal temperature (25–37°C) for growth [17, 18].
Immunohistochemical cross-reactivity of rabbit antisera against BCG and B. cereus was observed in the infected lesion. T. pallidum antiserum also showed weak cross-reactivity. Positive signals with low background staining were observed not only on the mycobacteria in the lipid droplets but also in the cytoplasm of macrophages, so that the detection sensitivity was very high [5]. Similar results were observed in granulomatous mastitis [29]. The visualization of microbes within the lesion is essentially important for making a histopathological diagnosis of infection [5]. Another important point of our findings includes the cross-reactivity of antibodies against MPT64, LAM, and PAB to M. chelonae. It has been reported that MPT64 and LAM are specific to M. tuberculosis, and PAB is solely expressed on Propionibacterium (Cutibacterium) acnes [7–9]. The P. acnes antigens were detected in granulomas of sarcoidosis [35]. The lipophilic bacteria in granulomatous mastitis also expressed LAM and PAB (Tsutsumi, unpublished observation). Such unexpected cross-reactivity should be cautious about applying the antibacterial antibodies as immunohistochemical probes, as has been described previously [5].
4. Conclusion
We reported here rare opportunistic skin coinfection of CMV and M. chelonae, a rapidly growing nontuberculous mycobacterium, after immunosuppressive therapy against pyoderma gangrenosum. It is of note that M. chelonae provoked suppurative granulomas with lipid droplet-centered colonization of Gram-positive and acid-fast rods. Unique immunohistochemical reactivities with a variety of antibacterial antibodies were applicable to visualizing the causative mycobacteria in the lesion.
Acknowledgments
The authors deeply thank Mr. Izumi Kurita, M.T., Clinical Laboratory Medicine, Shimada Municipal Hospital, Shimada, for identifying M. chelonae.
Consent
The patient gave written informed consent to publication of the case report.
Disclosure
The present address of Kentaro Odani is the Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto. The present address of Hideo Hashizume is the Department of Dermatology, Iwata City Hospital, Iwata, Shizuoka.
Conflicts of Interest
The authors do not have any conflict of interest in the present report.
Authors' Contributions
We declare that all the authors (1) made a substantial contribution to the concept of the case report or interpretation of data and (2) approved the version to be submitted. (3) Each author has participated sufficiently in the work to take public responsibility for appropriate portions of the content.
Figure 1 Pyoderma gangrenosum ((a) gross appearance of left lower thigh, (b) H&E). A demarcated deep ulcer, 4 cm in size, is observed. Fibrinous exudation is seen at the ulcer base, and erythematous change is associated around the ulcer (a). Microscopic features of the first biopsy specimen are nonspecific. Ulcer base is composed of fibrinous exudation and granulation tissue (b). Neither granulomatous reactions nor infectious agents are identified.
Figure 2 A subcutaneous nodule without ulceration ((a) gross appearance; (b) H&E, low-powered view; (c) H&E, high-powered view of the subcutaneous tissue, inset: immunostaining for CMV antigens). Subcutaneous nodularity with mild reddening is observed on the lower thigh near the original ulcer by pyoderma gangrenosum (arrow, (a)). A low-powered view of the second biopsy specimen demonstrates subcutaneous septolobular panniculitis (b). Endothelial cells and perivascular stromal cells with enlarged nuclei reveal intranuclear and cytoplasmic inclusions (c). Immunostaining for CMV antigens is clearly positive (inset).
Figure 3 A large nodular and indurated skin lesion with multiple ulcers ((a) gross appearance, (b) H&E, low-powered view, and (c) H&E, high-powered view of the dermis). Multiple ulcers, 2–3 cm in size, are formed in the irregular-shaped reddish induration (a). The third biopsy specimen reveals diffuse inflammatory infiltration in the dermis through subcutaneous tissue (b). Suppurative granuloma (abscess surrounded by epithelioid granuloma) is scattered in the lesion (c). No CMV inclusions are observed any longer.
Figure 4 Gram-positive acid-fast bacilli in the second (a–c) and third (d–f) biopsy specimens ((a, d) H&E, (b, e) Ziehl-Neelsen stain, and (c, f) Gram stain). Gram-positive acid-fast bacilli are multifocally clustered in microabscess (a–c) and also in fat droplets located in the center of suppurative granuloma (d–f). The bacteria are visible in the fat droplets even in H&E preparations (d). Such patterns of bacterial colonization are seen in both the second and third biopsy specimens.
Figure 5 Colonies of Mycobacterium chelonae on 2% Ogawa medium ((a) gross appearance, (b) Ziehl-Neelsen stain, (c) Gram stain, and (d) MALDI Biotyper analysis). Smooth-surfaced white (nonchromogenic) colonies are formed seven days after inoculation. The formalin-fixed, paraffin-embedded colonies display acid-fastness and Gram reactivity of the rods. By the MALDI biotyping analysis, the spectrum pattern indicates M. chelonae with the log score value of 2.208.
Figure 6 Immunohistochemical demonstration of varied bacterial antigens ((a) BCG, (b) Bacillus cereus, (c) Treponema pallidum, (d) MPT64, (e) LAM, and (f) PAB). The cytoplasm of macrophages infiltrating around the fat droplet exhibits clear cross-reactivity with varied bacterial antigens. Immunoreactivity of T. pallidum antigens is relatively weak.
Table 1 Antibodies used in the present study.
Target antigen Animal/clone Dilution Antigen retrieval Source
Bacillus Calmette-Guérin (BCG) Rabbit antiserum 1 : 10,000 None Agilent
MPT64 (RV1980C, 24 kDa protein) Rabbit antiserum 1 : 800 HIER in 10 mM CB (pH 6) Abcam
LAM (lipoarabinomannan) Mouse TMDU3 1 : 1,000 HIER in 10 mM CB (pH 6) MBL
PAB (Propionibacterium acnes-specific lipoteichoic acid) Mouse TMDU2 1 : 4,000 HIER in 10 mM CB (pH 6) MBL
Bacillus cereus Rabbit antiserum 1 : 500 HIER in 10 mM CB (pH 6) Abcam
Treponema pallidum Rabbit antiserum 1 : 1,000 HIER in 1 mM EDTA (pH 8) BM
Escherichia coli Rabbit antiserum 1 : 20,000 Proteinase K digestion Agilent
MPT: mycobacterial protein tuberculosis; HIER: heat-induced epitope retrieval; CB: citrate buffer; EDTA: ethylenediamine tetraacetic acid; Agilent: Agilent Technologies (Santa Clara, CA, USA); MBL: Medical and Biological Laboratories (Nagoya, Japan); Abcam: Abcam plc (Cambridge, UK); BM: Biocare Medical LLC (Pacheco, Philippines). | CYCLOSPORINE, METFORMIN HYDROCHLORIDE, MITIGLINIDE CALCIUM ANHYDROUS, PREDNISOLONE, SITAGLIPTIN PHOSPHATE | DrugsGivenReaction | CC BY | 33564484 | 19,706,871 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cytomegalovirus infection'. | Cutaneous Coinfection of Cytomegalovirus and Mycobacterium chelonae Accelerated by Immunosuppression.
A mildly diabetic 58-year-old male had traumatic ulceration on the left popliteal fossa, and the lesion progressed to a painful 6 cm deep ulcer. After surgical debridement and skin grafting, ulceration recurred. Pyoderma gangrenosum was clinically diagnosed after the first biopsy, indicating a noninfective ulcer. Immunosuppressive therapy (prednisolone and cyclosporine A) induced complete epithelialization in three months. Four months later, subcutaneous nonulcerated nodules appeared on the anterior area of the left lower leg. Subcutaneous induration progressed and ulceration recurred, so that immunosuppressive therapy continued for one year. Cytomegalovirus (CMV) viremia was detected, and the second biopsy demonstrated CMV inclusions of endothelial and perivascular cells in fibrosing septolobular panniculitis. Cyclosporine A was cancelled, prednisolone was tapered, and ganciclovir started. Viremia soon disappeared, but the lesion progressed to large induration with multiple ulcers measuring up to 3 cm. The third biopsy disclosed infection of Gram-positive mycobacteria, accompanying fat droplet-centered suppurative granulomas without CMV infection. Microbial culture identified Mycobacterium chelonae. Clarithromycin with thermotherapy was effective. A review of the second biopsy confirmed coinfection of CMV and Gram-positive mycobacteria. Immunostaining using a panel of anti-bacterial antibodies visualized the mycobacteria in the lesion. Positive findings were obtained with antibodies to Bacillus Calmette-Guérin, Bacillus cereus, MPT64 (Mycobacterium tuberculosis-specific 24 kDa secretory antigen), LAM (Mycobacterium tuberculosis-related lipoarabinomannan), and PAB (Propionibacterium acnes-specific lipoteichoic acid).
1. Introduction
Immunosuppressive conditions may provoke opportunistic skin infection of a variety of bacteria, fungi, and viruses [1, 2]. The present article describes a case of pyoderma gangrenosum on the left popliteal fossa, followed by immunosuppressive therapy-induced opportunistic dual skin infection of cytomegalovirus (CMV) and Mycobacterium chelonae on the left lower leg. Histopathological and immunohistochemical features of this rare combination of pathogens are detailed.
2. Case Report
A 58-year-old Japanese man slipped and fell on the road to have his left knee contused, resulting in a 1.5 cm sized shallow ulceration. The patient had suffered from hypertension and mild type 2 diabetes mellitus for two years, but no history of autoimmune disorders. Serum antibodies against insulin and glutamic acid decarboxylase were negative, excluding the possibility of type 1 diabetes mellitus. He had smoked 15 cigarettes per day for more than 40 years. Five months later, a painful skin ulcer, 6 cm in size, occurred on the inner side of the left popliteal fossa (at the same site of contusion). No pathogens were identified in the biopsy specimen, and microbial culture was negative. Surgical debridement and full-thickness grafting from the abdominal skin were performed by a plastic surgeon, but half of the skin flap was eventually impaired, leaving a 3 cm sized deep ulcer with severe pain. The patient was then consulted to dermatologists. Clinical findings, as well as the first biopsy features displaying nonspecific and noninfective ulcer, were consistent with pyoderma gangrenosum (Figure 1). The serum level of granulocyte colony-stimulating factor, a biomarker of pyoderma gangrenosum [3], was elevated to 48.1 pg/mL (reference value < 30 pg/mL). Administration of prednisolone (PSL) (20 mg/day) and cyclosporine A (CyA: 100 mg/day) started. In order to control exacerbation of the skin lesion, medication of PSL plus CyA was maintained, while PSL was gradually tapered to 10 mg/day. Complete epithelialization was achieved three months later.
Four months later, subcutaneous nonulcerated, painful nodules appeared on the anterior area of the left lower leg, 20 cm distal from the primary ulcer caused by pyoderma gangrenosum. Ulceration recurred, and subcutaneous induration soon progressed toward both the distal and proximal directions. Immunosuppressive therapy restarted, but the painful ulcer persisted for one year. At this point of time, CMV viremia was identified, and the second skin biopsy from one of the subcutaneous nodules identified CMV inclusions in the subcutaneous tissue with fibrosing septolobular panniculitis. The CMV antigens were immunohistochemically visualized in the viral inclusions with 1 : 200 diluted cocktail monoclonal antibodies, CCH2+DDG9, available from Agilent Technologies (Figure 2). Both endothelial cells and perivascular stromal cells were infected. The dermis was free of inflammation. CyA was cancelled, PSL was reduced to 5 mg/day, and instead, ganciclovir (900 mg/day) was administered. Viremia soon disappeared, but the lower leg lesion progressed to form multiple ulcers. The third skin biopsy disclosed that infection involved both the dermis and the subcutaneous fat tissue. Suppurative granulomas (small abscesses surrounded by epithelioid granulomas) were dispersed (Figure 3). Gram-positive acid-fast bacilli were identified in microabscesses and also in fat droplets surrounded by suppurative granulomas (Figure 4). Caseous necrosis was focally associated. Grocott stain gave negative results. CMV infection was no longer identified. The second skin biopsy was retrospectively reevaluated, and Gram-positive acid-fast bacilli were identified mainly in microabscesses and in fat droplets surrounded by suppurative granulomas, multifocally distributed in the inflamed subcutaneous tissue. The final diagnosis of the second biopsy was thus subcutaneous coinfection of CMV and nontuberculous mycobacteria.
Microbial culture on 2% Ogawa medium at 37°C identified rapidly growing nontuberculous mycobacteria. The bacteria were acid-fast and Gram-positive. Mycobacterium chelonae was identified by analyzing with Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS) by using the MALDI Biotyper (Bruker Japan Daltonics division, Yokohama) (Figure 5) [4]. The log score value for M. chelonae was more than 2.0 (2.208).
Clarithromycin administration (800 mg/day), combined with thermotherapy using disposal pocket body warmers for one hour twice a day, resulted in marked regression of the ulcers. PSL tapering induced subcutaneous nodularity with ulceration, and thus, clarithromycin treatment was kept to date. After chemotherapy for 15 months, epithelialization was almost achieved. Valganciclovir was administered when CMV viremia reappeared.
Metformin (an oral antidiabetic) and sitagliptin phosphate hydrate (a selective inhibitor of dipeptidyl peptidase-4) continued for controlling type 2 diabetes mellitus. Mitiglinide calcium hydrate (a stimulator of insulin secretion) was added after the appearance of the skin ulceration for one year. During the clinical course, the patient's blood glucose levels were persistently hyperglycemic, ranging from 106 to 186 mg/dL but without glycosuria. Mild proteinuria ranging from 15 to 100 mg/dL was noted, indicating the complication of stage 2 (early) diabetic nephropathy. His HbA1c levels ranged from 6.4 to 7.3% (standard levels: 4.1–6.2%). The patient thus suffered from mild and controlled diabetes mellitus.
For characterizing the mycobacteria colonizing the skin lesion in the second and third skin biopsy specimens, immunostaining using selected antibodies was performed, as indicated in Table 1. An amino acid polymer method (Simple Stain Max-PO, Nichirei Biosciences, Tokyo) was employed. As reported in the previous article describing a low-specificity and high-sensitivity immunostaining with widely cross-reactive antibacterial antisera [5], the mycobacteria were visualized in formalin-fixed, paraffin-embedded sections. The antibodies gave clearly positive signals in the cytoplasm of macrophages infiltrating in the lesion, in addition to long rods labeled with Gram and Ziehl-Neelsen stains. Figure 6 illustrates positive findings with rabbit antisera to Bacillus Calmette-Guérin (BCG) [6], Bacillus cereus [5], MPT64 (also called as protein Rv1980c, M. tuberculosis-specific 24 kDa secretory antigen) [7], and monoclonal antibodies to LAM (M. tuberculosis-related lipoarabinomannan) [8] and PAB (Propionibacterium acnes-specific lipoteichoic acid) [9]. Antiserum to Treponema pallidum gave weak immunoreactivity. Escherichia coli antigens were scarcely observed. The background staining was minimal.
3. Discussion
Opportunistic infection caused by a variety of bacteria, fungi, or viruses occurs in the skin under the immunosuppressive state such as acquired immunodeficiency syndrome (AIDS) and after the use of immunosuppressive agents [1, 2]. One of the authors (YT) described histopathological features of such conditions in a textbook entitled Pathology of Skin Infections published in 2013 [10]. We describe herein a case of cutaneous coinfection of CMV and M. chelonae, provoked by immunosuppressive therapy against pyoderma gangrenosum. The patient suffered from mild and controlled type 2 diabetes mellitus. Pyoderma gangrenosum is characterized by noninfectious autoimmune-type progressive skin ulceration [11], successfully treated with immunosuppressive agents [12].
Opportunistic skin infection of CMV is rare. CMV mainly affects vascular endothelial cells and perivascular stromal cells, and multifocal anogenital ulcerations are most frequently encountered in AIDS patients [13]. Cutaneous lesions with verrucous elevations [14] and septal panniculitis [15] have also been described in non-AIDS immunosuppressed patients. Since the skin ulcer remained unchanged after ganciclovir treatment, Grushchak et al. regarded CMV infection as a bystander phenomenon [16]. The skin lesion in the present case demonstrated features of septolobular panniculitis with CMV inclusions in endothelial and perivascular stromal cells, but the lesion progressed to form large induration with multiple ulcers after gancyclovir treatment. It is reasonable to consider the CMV infection as bystander incidence associated with nontuberculous mycobacteriosis. In other words, when CMV inclusions are noted in nodular or ulcerated skin lesions, primary causative microbes other than CMV should be searched under the microscope, as was so in the present case.
Varied nontuberculous mycobacteria affect the skin, including M. avium-intracellulare complex, M. marinum, M. ulcerans, M. fortuitum, and M. chelonae-abscessus complex [17, 18]. Reportedly, rapidly growing mycobacteria (RGM) form colonies on a common chocolate agar medium when the culture period is prolonged to two weeks or more [19].
M. chelonae was first isolated from the tortoise by Friedmann in 1902 [20]. M. chelonae belongs to nonchromogenic RGM (Runyon group IV), widely distributed in environmental water [21]. This zoonotic mycobacterium, categorized in M. chelonae-abscessus complex, causes opportunistic infection in the human skin, as well as infection in aquatic animals such as the reptiles and fish [22]. Of notice is that not only traumatic injuries but also surgical procedures make risk factors of human infection [23]. It is plausible that in the present case, medical disposals caused iatrogenic infection of the environmental pathogen. Immunosuppression and diabetic conditions accelerated opportunistic infection, as reported previously [17, 18, 22]. Microscopically, infection of RGM, including M. chelonae, provokes abscess-forming granulomas (suppurative granulomas): some lesions are recognized as abscess surrounded by abortive granuloma formation, while the others predominantly reveal epithelioid granulomas [24, 25]. Acid-fast bacilli are characteristically identified in the lipid droplets (vacuoles) often located in the center of suppurative granulomas. It is noteworthy that the bacilli are positively labeled with Gram stain: namely, Gram positivity is a feature of RGM [26].
The cell wall of mycobacteria contains voluminous mycolic acids, extremely long fatty acids, as molecular forms of mycolic acid-containing glycolipid such as trehalose dimycolate and trehalose monomycolate, giving lipophilic nature of mycobacteria [27]. RGM are characterized by the presence of an additional mycolate, glucose mycolate, on the cell wall [28]. Such biological features may be related to the lipid droplet-centered pattern of infection by RGM.
Lipid droplet-centered suppurative granulomas are commonly observed in granulomatous mastitis caused by a lipophilic bacterium, Corynebacterium kroppenstedtii [29]. The Gram-positive rods are uniquely clustered in the lipid droplets surrounded by suppurative granulomas. The histological features are quite similar to those of RGM infection. Unlike other corynebacteria, C. kroppenstedtii lacks mycolic acid but instead contains tuberculostearic acid in the cell wall [30]. It is understandable from both the microscopic appearance and the pharmacodynamic properties of antibiotics [31] that administration of lipophilic antibiotics is essential for treating not only granulomatous mastitis but also RGM infection. The treatment regimen for tuberculosis using hydrophilic antibiotics such as isoniazid, ethambuthol, pyrazinamide, and streptomycin is consistently ineffective for infection of RGM, which are usually resistant to lipophilic rifampicin [18]. In the present case, clarithromycin, a type of lipophilic macrolides, was effective, as has been reported so far [32, 33]. Thermotherapy was also useful [34], based on the biological features of the bacteria showing low optimal temperature (25–37°C) for growth [17, 18].
Immunohistochemical cross-reactivity of rabbit antisera against BCG and B. cereus was observed in the infected lesion. T. pallidum antiserum also showed weak cross-reactivity. Positive signals with low background staining were observed not only on the mycobacteria in the lipid droplets but also in the cytoplasm of macrophages, so that the detection sensitivity was very high [5]. Similar results were observed in granulomatous mastitis [29]. The visualization of microbes within the lesion is essentially important for making a histopathological diagnosis of infection [5]. Another important point of our findings includes the cross-reactivity of antibodies against MPT64, LAM, and PAB to M. chelonae. It has been reported that MPT64 and LAM are specific to M. tuberculosis, and PAB is solely expressed on Propionibacterium (Cutibacterium) acnes [7–9]. The P. acnes antigens were detected in granulomas of sarcoidosis [35]. The lipophilic bacteria in granulomatous mastitis also expressed LAM and PAB (Tsutsumi, unpublished observation). Such unexpected cross-reactivity should be cautious about applying the antibacterial antibodies as immunohistochemical probes, as has been described previously [5].
4. Conclusion
We reported here rare opportunistic skin coinfection of CMV and M. chelonae, a rapidly growing nontuberculous mycobacterium, after immunosuppressive therapy against pyoderma gangrenosum. It is of note that M. chelonae provoked suppurative granulomas with lipid droplet-centered colonization of Gram-positive and acid-fast rods. Unique immunohistochemical reactivities with a variety of antibacterial antibodies were applicable to visualizing the causative mycobacteria in the lesion.
Acknowledgments
The authors deeply thank Mr. Izumi Kurita, M.T., Clinical Laboratory Medicine, Shimada Municipal Hospital, Shimada, for identifying M. chelonae.
Consent
The patient gave written informed consent to publication of the case report.
Disclosure
The present address of Kentaro Odani is the Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto. The present address of Hideo Hashizume is the Department of Dermatology, Iwata City Hospital, Iwata, Shizuoka.
Conflicts of Interest
The authors do not have any conflict of interest in the present report.
Authors' Contributions
We declare that all the authors (1) made a substantial contribution to the concept of the case report or interpretation of data and (2) approved the version to be submitted. (3) Each author has participated sufficiently in the work to take public responsibility for appropriate portions of the content.
Figure 1 Pyoderma gangrenosum ((a) gross appearance of left lower thigh, (b) H&E). A demarcated deep ulcer, 4 cm in size, is observed. Fibrinous exudation is seen at the ulcer base, and erythematous change is associated around the ulcer (a). Microscopic features of the first biopsy specimen are nonspecific. Ulcer base is composed of fibrinous exudation and granulation tissue (b). Neither granulomatous reactions nor infectious agents are identified.
Figure 2 A subcutaneous nodule without ulceration ((a) gross appearance; (b) H&E, low-powered view; (c) H&E, high-powered view of the subcutaneous tissue, inset: immunostaining for CMV antigens). Subcutaneous nodularity with mild reddening is observed on the lower thigh near the original ulcer by pyoderma gangrenosum (arrow, (a)). A low-powered view of the second biopsy specimen demonstrates subcutaneous septolobular panniculitis (b). Endothelial cells and perivascular stromal cells with enlarged nuclei reveal intranuclear and cytoplasmic inclusions (c). Immunostaining for CMV antigens is clearly positive (inset).
Figure 3 A large nodular and indurated skin lesion with multiple ulcers ((a) gross appearance, (b) H&E, low-powered view, and (c) H&E, high-powered view of the dermis). Multiple ulcers, 2–3 cm in size, are formed in the irregular-shaped reddish induration (a). The third biopsy specimen reveals diffuse inflammatory infiltration in the dermis through subcutaneous tissue (b). Suppurative granuloma (abscess surrounded by epithelioid granuloma) is scattered in the lesion (c). No CMV inclusions are observed any longer.
Figure 4 Gram-positive acid-fast bacilli in the second (a–c) and third (d–f) biopsy specimens ((a, d) H&E, (b, e) Ziehl-Neelsen stain, and (c, f) Gram stain). Gram-positive acid-fast bacilli are multifocally clustered in microabscess (a–c) and also in fat droplets located in the center of suppurative granuloma (d–f). The bacteria are visible in the fat droplets even in H&E preparations (d). Such patterns of bacterial colonization are seen in both the second and third biopsy specimens.
Figure 5 Colonies of Mycobacterium chelonae on 2% Ogawa medium ((a) gross appearance, (b) Ziehl-Neelsen stain, (c) Gram stain, and (d) MALDI Biotyper analysis). Smooth-surfaced white (nonchromogenic) colonies are formed seven days after inoculation. The formalin-fixed, paraffin-embedded colonies display acid-fastness and Gram reactivity of the rods. By the MALDI biotyping analysis, the spectrum pattern indicates M. chelonae with the log score value of 2.208.
Figure 6 Immunohistochemical demonstration of varied bacterial antigens ((a) BCG, (b) Bacillus cereus, (c) Treponema pallidum, (d) MPT64, (e) LAM, and (f) PAB). The cytoplasm of macrophages infiltrating around the fat droplet exhibits clear cross-reactivity with varied bacterial antigens. Immunoreactivity of T. pallidum antigens is relatively weak.
Table 1 Antibodies used in the present study.
Target antigen Animal/clone Dilution Antigen retrieval Source
Bacillus Calmette-Guérin (BCG) Rabbit antiserum 1 : 10,000 None Agilent
MPT64 (RV1980C, 24 kDa protein) Rabbit antiserum 1 : 800 HIER in 10 mM CB (pH 6) Abcam
LAM (lipoarabinomannan) Mouse TMDU3 1 : 1,000 HIER in 10 mM CB (pH 6) MBL
PAB (Propionibacterium acnes-specific lipoteichoic acid) Mouse TMDU2 1 : 4,000 HIER in 10 mM CB (pH 6) MBL
Bacillus cereus Rabbit antiserum 1 : 500 HIER in 10 mM CB (pH 6) Abcam
Treponema pallidum Rabbit antiserum 1 : 1,000 HIER in 1 mM EDTA (pH 8) BM
Escherichia coli Rabbit antiserum 1 : 20,000 Proteinase K digestion Agilent
MPT: mycobacterial protein tuberculosis; HIER: heat-induced epitope retrieval; CB: citrate buffer; EDTA: ethylenediamine tetraacetic acid; Agilent: Agilent Technologies (Santa Clara, CA, USA); MBL: Medical and Biological Laboratories (Nagoya, Japan); Abcam: Abcam plc (Cambridge, UK); BM: Biocare Medical LLC (Pacheco, Philippines). | CYCLOSPORINE, METFORMIN HYDROCHLORIDE, MITIGLINIDE CALCIUM ANHYDROUS, PREDNISOLONE, SITAGLIPTIN PHOSPHATE | DrugsGivenReaction | CC BY | 33564484 | 19,706,871 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Mycobacterial infection'. | Cutaneous Coinfection of Cytomegalovirus and Mycobacterium chelonae Accelerated by Immunosuppression.
A mildly diabetic 58-year-old male had traumatic ulceration on the left popliteal fossa, and the lesion progressed to a painful 6 cm deep ulcer. After surgical debridement and skin grafting, ulceration recurred. Pyoderma gangrenosum was clinically diagnosed after the first biopsy, indicating a noninfective ulcer. Immunosuppressive therapy (prednisolone and cyclosporine A) induced complete epithelialization in three months. Four months later, subcutaneous nonulcerated nodules appeared on the anterior area of the left lower leg. Subcutaneous induration progressed and ulceration recurred, so that immunosuppressive therapy continued for one year. Cytomegalovirus (CMV) viremia was detected, and the second biopsy demonstrated CMV inclusions of endothelial and perivascular cells in fibrosing septolobular panniculitis. Cyclosporine A was cancelled, prednisolone was tapered, and ganciclovir started. Viremia soon disappeared, but the lesion progressed to large induration with multiple ulcers measuring up to 3 cm. The third biopsy disclosed infection of Gram-positive mycobacteria, accompanying fat droplet-centered suppurative granulomas without CMV infection. Microbial culture identified Mycobacterium chelonae. Clarithromycin with thermotherapy was effective. A review of the second biopsy confirmed coinfection of CMV and Gram-positive mycobacteria. Immunostaining using a panel of anti-bacterial antibodies visualized the mycobacteria in the lesion. Positive findings were obtained with antibodies to Bacillus Calmette-Guérin, Bacillus cereus, MPT64 (Mycobacterium tuberculosis-specific 24 kDa secretory antigen), LAM (Mycobacterium tuberculosis-related lipoarabinomannan), and PAB (Propionibacterium acnes-specific lipoteichoic acid).
1. Introduction
Immunosuppressive conditions may provoke opportunistic skin infection of a variety of bacteria, fungi, and viruses [1, 2]. The present article describes a case of pyoderma gangrenosum on the left popliteal fossa, followed by immunosuppressive therapy-induced opportunistic dual skin infection of cytomegalovirus (CMV) and Mycobacterium chelonae on the left lower leg. Histopathological and immunohistochemical features of this rare combination of pathogens are detailed.
2. Case Report
A 58-year-old Japanese man slipped and fell on the road to have his left knee contused, resulting in a 1.5 cm sized shallow ulceration. The patient had suffered from hypertension and mild type 2 diabetes mellitus for two years, but no history of autoimmune disorders. Serum antibodies against insulin and glutamic acid decarboxylase were negative, excluding the possibility of type 1 diabetes mellitus. He had smoked 15 cigarettes per day for more than 40 years. Five months later, a painful skin ulcer, 6 cm in size, occurred on the inner side of the left popliteal fossa (at the same site of contusion). No pathogens were identified in the biopsy specimen, and microbial culture was negative. Surgical debridement and full-thickness grafting from the abdominal skin were performed by a plastic surgeon, but half of the skin flap was eventually impaired, leaving a 3 cm sized deep ulcer with severe pain. The patient was then consulted to dermatologists. Clinical findings, as well as the first biopsy features displaying nonspecific and noninfective ulcer, were consistent with pyoderma gangrenosum (Figure 1). The serum level of granulocyte colony-stimulating factor, a biomarker of pyoderma gangrenosum [3], was elevated to 48.1 pg/mL (reference value < 30 pg/mL). Administration of prednisolone (PSL) (20 mg/day) and cyclosporine A (CyA: 100 mg/day) started. In order to control exacerbation of the skin lesion, medication of PSL plus CyA was maintained, while PSL was gradually tapered to 10 mg/day. Complete epithelialization was achieved three months later.
Four months later, subcutaneous nonulcerated, painful nodules appeared on the anterior area of the left lower leg, 20 cm distal from the primary ulcer caused by pyoderma gangrenosum. Ulceration recurred, and subcutaneous induration soon progressed toward both the distal and proximal directions. Immunosuppressive therapy restarted, but the painful ulcer persisted for one year. At this point of time, CMV viremia was identified, and the second skin biopsy from one of the subcutaneous nodules identified CMV inclusions in the subcutaneous tissue with fibrosing septolobular panniculitis. The CMV antigens were immunohistochemically visualized in the viral inclusions with 1 : 200 diluted cocktail monoclonal antibodies, CCH2+DDG9, available from Agilent Technologies (Figure 2). Both endothelial cells and perivascular stromal cells were infected. The dermis was free of inflammation. CyA was cancelled, PSL was reduced to 5 mg/day, and instead, ganciclovir (900 mg/day) was administered. Viremia soon disappeared, but the lower leg lesion progressed to form multiple ulcers. The third skin biopsy disclosed that infection involved both the dermis and the subcutaneous fat tissue. Suppurative granulomas (small abscesses surrounded by epithelioid granulomas) were dispersed (Figure 3). Gram-positive acid-fast bacilli were identified in microabscesses and also in fat droplets surrounded by suppurative granulomas (Figure 4). Caseous necrosis was focally associated. Grocott stain gave negative results. CMV infection was no longer identified. The second skin biopsy was retrospectively reevaluated, and Gram-positive acid-fast bacilli were identified mainly in microabscesses and in fat droplets surrounded by suppurative granulomas, multifocally distributed in the inflamed subcutaneous tissue. The final diagnosis of the second biopsy was thus subcutaneous coinfection of CMV and nontuberculous mycobacteria.
Microbial culture on 2% Ogawa medium at 37°C identified rapidly growing nontuberculous mycobacteria. The bacteria were acid-fast and Gram-positive. Mycobacterium chelonae was identified by analyzing with Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS) by using the MALDI Biotyper (Bruker Japan Daltonics division, Yokohama) (Figure 5) [4]. The log score value for M. chelonae was more than 2.0 (2.208).
Clarithromycin administration (800 mg/day), combined with thermotherapy using disposal pocket body warmers for one hour twice a day, resulted in marked regression of the ulcers. PSL tapering induced subcutaneous nodularity with ulceration, and thus, clarithromycin treatment was kept to date. After chemotherapy for 15 months, epithelialization was almost achieved. Valganciclovir was administered when CMV viremia reappeared.
Metformin (an oral antidiabetic) and sitagliptin phosphate hydrate (a selective inhibitor of dipeptidyl peptidase-4) continued for controlling type 2 diabetes mellitus. Mitiglinide calcium hydrate (a stimulator of insulin secretion) was added after the appearance of the skin ulceration for one year. During the clinical course, the patient's blood glucose levels were persistently hyperglycemic, ranging from 106 to 186 mg/dL but without glycosuria. Mild proteinuria ranging from 15 to 100 mg/dL was noted, indicating the complication of stage 2 (early) diabetic nephropathy. His HbA1c levels ranged from 6.4 to 7.3% (standard levels: 4.1–6.2%). The patient thus suffered from mild and controlled diabetes mellitus.
For characterizing the mycobacteria colonizing the skin lesion in the second and third skin biopsy specimens, immunostaining using selected antibodies was performed, as indicated in Table 1. An amino acid polymer method (Simple Stain Max-PO, Nichirei Biosciences, Tokyo) was employed. As reported in the previous article describing a low-specificity and high-sensitivity immunostaining with widely cross-reactive antibacterial antisera [5], the mycobacteria were visualized in formalin-fixed, paraffin-embedded sections. The antibodies gave clearly positive signals in the cytoplasm of macrophages infiltrating in the lesion, in addition to long rods labeled with Gram and Ziehl-Neelsen stains. Figure 6 illustrates positive findings with rabbit antisera to Bacillus Calmette-Guérin (BCG) [6], Bacillus cereus [5], MPT64 (also called as protein Rv1980c, M. tuberculosis-specific 24 kDa secretory antigen) [7], and monoclonal antibodies to LAM (M. tuberculosis-related lipoarabinomannan) [8] and PAB (Propionibacterium acnes-specific lipoteichoic acid) [9]. Antiserum to Treponema pallidum gave weak immunoreactivity. Escherichia coli antigens were scarcely observed. The background staining was minimal.
3. Discussion
Opportunistic infection caused by a variety of bacteria, fungi, or viruses occurs in the skin under the immunosuppressive state such as acquired immunodeficiency syndrome (AIDS) and after the use of immunosuppressive agents [1, 2]. One of the authors (YT) described histopathological features of such conditions in a textbook entitled Pathology of Skin Infections published in 2013 [10]. We describe herein a case of cutaneous coinfection of CMV and M. chelonae, provoked by immunosuppressive therapy against pyoderma gangrenosum. The patient suffered from mild and controlled type 2 diabetes mellitus. Pyoderma gangrenosum is characterized by noninfectious autoimmune-type progressive skin ulceration [11], successfully treated with immunosuppressive agents [12].
Opportunistic skin infection of CMV is rare. CMV mainly affects vascular endothelial cells and perivascular stromal cells, and multifocal anogenital ulcerations are most frequently encountered in AIDS patients [13]. Cutaneous lesions with verrucous elevations [14] and septal panniculitis [15] have also been described in non-AIDS immunosuppressed patients. Since the skin ulcer remained unchanged after ganciclovir treatment, Grushchak et al. regarded CMV infection as a bystander phenomenon [16]. The skin lesion in the present case demonstrated features of septolobular panniculitis with CMV inclusions in endothelial and perivascular stromal cells, but the lesion progressed to form large induration with multiple ulcers after gancyclovir treatment. It is reasonable to consider the CMV infection as bystander incidence associated with nontuberculous mycobacteriosis. In other words, when CMV inclusions are noted in nodular or ulcerated skin lesions, primary causative microbes other than CMV should be searched under the microscope, as was so in the present case.
Varied nontuberculous mycobacteria affect the skin, including M. avium-intracellulare complex, M. marinum, M. ulcerans, M. fortuitum, and M. chelonae-abscessus complex [17, 18]. Reportedly, rapidly growing mycobacteria (RGM) form colonies on a common chocolate agar medium when the culture period is prolonged to two weeks or more [19].
M. chelonae was first isolated from the tortoise by Friedmann in 1902 [20]. M. chelonae belongs to nonchromogenic RGM (Runyon group IV), widely distributed in environmental water [21]. This zoonotic mycobacterium, categorized in M. chelonae-abscessus complex, causes opportunistic infection in the human skin, as well as infection in aquatic animals such as the reptiles and fish [22]. Of notice is that not only traumatic injuries but also surgical procedures make risk factors of human infection [23]. It is plausible that in the present case, medical disposals caused iatrogenic infection of the environmental pathogen. Immunosuppression and diabetic conditions accelerated opportunistic infection, as reported previously [17, 18, 22]. Microscopically, infection of RGM, including M. chelonae, provokes abscess-forming granulomas (suppurative granulomas): some lesions are recognized as abscess surrounded by abortive granuloma formation, while the others predominantly reveal epithelioid granulomas [24, 25]. Acid-fast bacilli are characteristically identified in the lipid droplets (vacuoles) often located in the center of suppurative granulomas. It is noteworthy that the bacilli are positively labeled with Gram stain: namely, Gram positivity is a feature of RGM [26].
The cell wall of mycobacteria contains voluminous mycolic acids, extremely long fatty acids, as molecular forms of mycolic acid-containing glycolipid such as trehalose dimycolate and trehalose monomycolate, giving lipophilic nature of mycobacteria [27]. RGM are characterized by the presence of an additional mycolate, glucose mycolate, on the cell wall [28]. Such biological features may be related to the lipid droplet-centered pattern of infection by RGM.
Lipid droplet-centered suppurative granulomas are commonly observed in granulomatous mastitis caused by a lipophilic bacterium, Corynebacterium kroppenstedtii [29]. The Gram-positive rods are uniquely clustered in the lipid droplets surrounded by suppurative granulomas. The histological features are quite similar to those of RGM infection. Unlike other corynebacteria, C. kroppenstedtii lacks mycolic acid but instead contains tuberculostearic acid in the cell wall [30]. It is understandable from both the microscopic appearance and the pharmacodynamic properties of antibiotics [31] that administration of lipophilic antibiotics is essential for treating not only granulomatous mastitis but also RGM infection. The treatment regimen for tuberculosis using hydrophilic antibiotics such as isoniazid, ethambuthol, pyrazinamide, and streptomycin is consistently ineffective for infection of RGM, which are usually resistant to lipophilic rifampicin [18]. In the present case, clarithromycin, a type of lipophilic macrolides, was effective, as has been reported so far [32, 33]. Thermotherapy was also useful [34], based on the biological features of the bacteria showing low optimal temperature (25–37°C) for growth [17, 18].
Immunohistochemical cross-reactivity of rabbit antisera against BCG and B. cereus was observed in the infected lesion. T. pallidum antiserum also showed weak cross-reactivity. Positive signals with low background staining were observed not only on the mycobacteria in the lipid droplets but also in the cytoplasm of macrophages, so that the detection sensitivity was very high [5]. Similar results were observed in granulomatous mastitis [29]. The visualization of microbes within the lesion is essentially important for making a histopathological diagnosis of infection [5]. Another important point of our findings includes the cross-reactivity of antibodies against MPT64, LAM, and PAB to M. chelonae. It has been reported that MPT64 and LAM are specific to M. tuberculosis, and PAB is solely expressed on Propionibacterium (Cutibacterium) acnes [7–9]. The P. acnes antigens were detected in granulomas of sarcoidosis [35]. The lipophilic bacteria in granulomatous mastitis also expressed LAM and PAB (Tsutsumi, unpublished observation). Such unexpected cross-reactivity should be cautious about applying the antibacterial antibodies as immunohistochemical probes, as has been described previously [5].
4. Conclusion
We reported here rare opportunistic skin coinfection of CMV and M. chelonae, a rapidly growing nontuberculous mycobacterium, after immunosuppressive therapy against pyoderma gangrenosum. It is of note that M. chelonae provoked suppurative granulomas with lipid droplet-centered colonization of Gram-positive and acid-fast rods. Unique immunohistochemical reactivities with a variety of antibacterial antibodies were applicable to visualizing the causative mycobacteria in the lesion.
Acknowledgments
The authors deeply thank Mr. Izumi Kurita, M.T., Clinical Laboratory Medicine, Shimada Municipal Hospital, Shimada, for identifying M. chelonae.
Consent
The patient gave written informed consent to publication of the case report.
Disclosure
The present address of Kentaro Odani is the Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto. The present address of Hideo Hashizume is the Department of Dermatology, Iwata City Hospital, Iwata, Shizuoka.
Conflicts of Interest
The authors do not have any conflict of interest in the present report.
Authors' Contributions
We declare that all the authors (1) made a substantial contribution to the concept of the case report or interpretation of data and (2) approved the version to be submitted. (3) Each author has participated sufficiently in the work to take public responsibility for appropriate portions of the content.
Figure 1 Pyoderma gangrenosum ((a) gross appearance of left lower thigh, (b) H&E). A demarcated deep ulcer, 4 cm in size, is observed. Fibrinous exudation is seen at the ulcer base, and erythematous change is associated around the ulcer (a). Microscopic features of the first biopsy specimen are nonspecific. Ulcer base is composed of fibrinous exudation and granulation tissue (b). Neither granulomatous reactions nor infectious agents are identified.
Figure 2 A subcutaneous nodule without ulceration ((a) gross appearance; (b) H&E, low-powered view; (c) H&E, high-powered view of the subcutaneous tissue, inset: immunostaining for CMV antigens). Subcutaneous nodularity with mild reddening is observed on the lower thigh near the original ulcer by pyoderma gangrenosum (arrow, (a)). A low-powered view of the second biopsy specimen demonstrates subcutaneous septolobular panniculitis (b). Endothelial cells and perivascular stromal cells with enlarged nuclei reveal intranuclear and cytoplasmic inclusions (c). Immunostaining for CMV antigens is clearly positive (inset).
Figure 3 A large nodular and indurated skin lesion with multiple ulcers ((a) gross appearance, (b) H&E, low-powered view, and (c) H&E, high-powered view of the dermis). Multiple ulcers, 2–3 cm in size, are formed in the irregular-shaped reddish induration (a). The third biopsy specimen reveals diffuse inflammatory infiltration in the dermis through subcutaneous tissue (b). Suppurative granuloma (abscess surrounded by epithelioid granuloma) is scattered in the lesion (c). No CMV inclusions are observed any longer.
Figure 4 Gram-positive acid-fast bacilli in the second (a–c) and third (d–f) biopsy specimens ((a, d) H&E, (b, e) Ziehl-Neelsen stain, and (c, f) Gram stain). Gram-positive acid-fast bacilli are multifocally clustered in microabscess (a–c) and also in fat droplets located in the center of suppurative granuloma (d–f). The bacteria are visible in the fat droplets even in H&E preparations (d). Such patterns of bacterial colonization are seen in both the second and third biopsy specimens.
Figure 5 Colonies of Mycobacterium chelonae on 2% Ogawa medium ((a) gross appearance, (b) Ziehl-Neelsen stain, (c) Gram stain, and (d) MALDI Biotyper analysis). Smooth-surfaced white (nonchromogenic) colonies are formed seven days after inoculation. The formalin-fixed, paraffin-embedded colonies display acid-fastness and Gram reactivity of the rods. By the MALDI biotyping analysis, the spectrum pattern indicates M. chelonae with the log score value of 2.208.
Figure 6 Immunohistochemical demonstration of varied bacterial antigens ((a) BCG, (b) Bacillus cereus, (c) Treponema pallidum, (d) MPT64, (e) LAM, and (f) PAB). The cytoplasm of macrophages infiltrating around the fat droplet exhibits clear cross-reactivity with varied bacterial antigens. Immunoreactivity of T. pallidum antigens is relatively weak.
Table 1 Antibodies used in the present study.
Target antigen Animal/clone Dilution Antigen retrieval Source
Bacillus Calmette-Guérin (BCG) Rabbit antiserum 1 : 10,000 None Agilent
MPT64 (RV1980C, 24 kDa protein) Rabbit antiserum 1 : 800 HIER in 10 mM CB (pH 6) Abcam
LAM (lipoarabinomannan) Mouse TMDU3 1 : 1,000 HIER in 10 mM CB (pH 6) MBL
PAB (Propionibacterium acnes-specific lipoteichoic acid) Mouse TMDU2 1 : 4,000 HIER in 10 mM CB (pH 6) MBL
Bacillus cereus Rabbit antiserum 1 : 500 HIER in 10 mM CB (pH 6) Abcam
Treponema pallidum Rabbit antiserum 1 : 1,000 HIER in 1 mM EDTA (pH 8) BM
Escherichia coli Rabbit antiserum 1 : 20,000 Proteinase K digestion Agilent
MPT: mycobacterial protein tuberculosis; HIER: heat-induced epitope retrieval; CB: citrate buffer; EDTA: ethylenediamine tetraacetic acid; Agilent: Agilent Technologies (Santa Clara, CA, USA); MBL: Medical and Biological Laboratories (Nagoya, Japan); Abcam: Abcam plc (Cambridge, UK); BM: Biocare Medical LLC (Pacheco, Philippines). | CYCLOSPORINE, METFORMIN HYDROCHLORIDE, MITIGLINIDE CALCIUM ANHYDROUS, PREDNISOLONE, SITAGLIPTIN PHOSPHATE | DrugsGivenReaction | CC BY | 33564484 | 19,706,871 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Cutaneous Coinfection of Cytomegalovirus and Mycobacterium chelonae Accelerated by Immunosuppression.
A mildly diabetic 58-year-old male had traumatic ulceration on the left popliteal fossa, and the lesion progressed to a painful 6 cm deep ulcer. After surgical debridement and skin grafting, ulceration recurred. Pyoderma gangrenosum was clinically diagnosed after the first biopsy, indicating a noninfective ulcer. Immunosuppressive therapy (prednisolone and cyclosporine A) induced complete epithelialization in three months. Four months later, subcutaneous nonulcerated nodules appeared on the anterior area of the left lower leg. Subcutaneous induration progressed and ulceration recurred, so that immunosuppressive therapy continued for one year. Cytomegalovirus (CMV) viremia was detected, and the second biopsy demonstrated CMV inclusions of endothelial and perivascular cells in fibrosing septolobular panniculitis. Cyclosporine A was cancelled, prednisolone was tapered, and ganciclovir started. Viremia soon disappeared, but the lesion progressed to large induration with multiple ulcers measuring up to 3 cm. The third biopsy disclosed infection of Gram-positive mycobacteria, accompanying fat droplet-centered suppurative granulomas without CMV infection. Microbial culture identified Mycobacterium chelonae. Clarithromycin with thermotherapy was effective. A review of the second biopsy confirmed coinfection of CMV and Gram-positive mycobacteria. Immunostaining using a panel of anti-bacterial antibodies visualized the mycobacteria in the lesion. Positive findings were obtained with antibodies to Bacillus Calmette-Guérin, Bacillus cereus, MPT64 (Mycobacterium tuberculosis-specific 24 kDa secretory antigen), LAM (Mycobacterium tuberculosis-related lipoarabinomannan), and PAB (Propionibacterium acnes-specific lipoteichoic acid).
1. Introduction
Immunosuppressive conditions may provoke opportunistic skin infection of a variety of bacteria, fungi, and viruses [1, 2]. The present article describes a case of pyoderma gangrenosum on the left popliteal fossa, followed by immunosuppressive therapy-induced opportunistic dual skin infection of cytomegalovirus (CMV) and Mycobacterium chelonae on the left lower leg. Histopathological and immunohistochemical features of this rare combination of pathogens are detailed.
2. Case Report
A 58-year-old Japanese man slipped and fell on the road to have his left knee contused, resulting in a 1.5 cm sized shallow ulceration. The patient had suffered from hypertension and mild type 2 diabetes mellitus for two years, but no history of autoimmune disorders. Serum antibodies against insulin and glutamic acid decarboxylase were negative, excluding the possibility of type 1 diabetes mellitus. He had smoked 15 cigarettes per day for more than 40 years. Five months later, a painful skin ulcer, 6 cm in size, occurred on the inner side of the left popliteal fossa (at the same site of contusion). No pathogens were identified in the biopsy specimen, and microbial culture was negative. Surgical debridement and full-thickness grafting from the abdominal skin were performed by a plastic surgeon, but half of the skin flap was eventually impaired, leaving a 3 cm sized deep ulcer with severe pain. The patient was then consulted to dermatologists. Clinical findings, as well as the first biopsy features displaying nonspecific and noninfective ulcer, were consistent with pyoderma gangrenosum (Figure 1). The serum level of granulocyte colony-stimulating factor, a biomarker of pyoderma gangrenosum [3], was elevated to 48.1 pg/mL (reference value < 30 pg/mL). Administration of prednisolone (PSL) (20 mg/day) and cyclosporine A (CyA: 100 mg/day) started. In order to control exacerbation of the skin lesion, medication of PSL plus CyA was maintained, while PSL was gradually tapered to 10 mg/day. Complete epithelialization was achieved three months later.
Four months later, subcutaneous nonulcerated, painful nodules appeared on the anterior area of the left lower leg, 20 cm distal from the primary ulcer caused by pyoderma gangrenosum. Ulceration recurred, and subcutaneous induration soon progressed toward both the distal and proximal directions. Immunosuppressive therapy restarted, but the painful ulcer persisted for one year. At this point of time, CMV viremia was identified, and the second skin biopsy from one of the subcutaneous nodules identified CMV inclusions in the subcutaneous tissue with fibrosing septolobular panniculitis. The CMV antigens were immunohistochemically visualized in the viral inclusions with 1 : 200 diluted cocktail monoclonal antibodies, CCH2+DDG9, available from Agilent Technologies (Figure 2). Both endothelial cells and perivascular stromal cells were infected. The dermis was free of inflammation. CyA was cancelled, PSL was reduced to 5 mg/day, and instead, ganciclovir (900 mg/day) was administered. Viremia soon disappeared, but the lower leg lesion progressed to form multiple ulcers. The third skin biopsy disclosed that infection involved both the dermis and the subcutaneous fat tissue. Suppurative granulomas (small abscesses surrounded by epithelioid granulomas) were dispersed (Figure 3). Gram-positive acid-fast bacilli were identified in microabscesses and also in fat droplets surrounded by suppurative granulomas (Figure 4). Caseous necrosis was focally associated. Grocott stain gave negative results. CMV infection was no longer identified. The second skin biopsy was retrospectively reevaluated, and Gram-positive acid-fast bacilli were identified mainly in microabscesses and in fat droplets surrounded by suppurative granulomas, multifocally distributed in the inflamed subcutaneous tissue. The final diagnosis of the second biopsy was thus subcutaneous coinfection of CMV and nontuberculous mycobacteria.
Microbial culture on 2% Ogawa medium at 37°C identified rapidly growing nontuberculous mycobacteria. The bacteria were acid-fast and Gram-positive. Mycobacterium chelonae was identified by analyzing with Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS) by using the MALDI Biotyper (Bruker Japan Daltonics division, Yokohama) (Figure 5) [4]. The log score value for M. chelonae was more than 2.0 (2.208).
Clarithromycin administration (800 mg/day), combined with thermotherapy using disposal pocket body warmers for one hour twice a day, resulted in marked regression of the ulcers. PSL tapering induced subcutaneous nodularity with ulceration, and thus, clarithromycin treatment was kept to date. After chemotherapy for 15 months, epithelialization was almost achieved. Valganciclovir was administered when CMV viremia reappeared.
Metformin (an oral antidiabetic) and sitagliptin phosphate hydrate (a selective inhibitor of dipeptidyl peptidase-4) continued for controlling type 2 diabetes mellitus. Mitiglinide calcium hydrate (a stimulator of insulin secretion) was added after the appearance of the skin ulceration for one year. During the clinical course, the patient's blood glucose levels were persistently hyperglycemic, ranging from 106 to 186 mg/dL but without glycosuria. Mild proteinuria ranging from 15 to 100 mg/dL was noted, indicating the complication of stage 2 (early) diabetic nephropathy. His HbA1c levels ranged from 6.4 to 7.3% (standard levels: 4.1–6.2%). The patient thus suffered from mild and controlled diabetes mellitus.
For characterizing the mycobacteria colonizing the skin lesion in the second and third skin biopsy specimens, immunostaining using selected antibodies was performed, as indicated in Table 1. An amino acid polymer method (Simple Stain Max-PO, Nichirei Biosciences, Tokyo) was employed. As reported in the previous article describing a low-specificity and high-sensitivity immunostaining with widely cross-reactive antibacterial antisera [5], the mycobacteria were visualized in formalin-fixed, paraffin-embedded sections. The antibodies gave clearly positive signals in the cytoplasm of macrophages infiltrating in the lesion, in addition to long rods labeled with Gram and Ziehl-Neelsen stains. Figure 6 illustrates positive findings with rabbit antisera to Bacillus Calmette-Guérin (BCG) [6], Bacillus cereus [5], MPT64 (also called as protein Rv1980c, M. tuberculosis-specific 24 kDa secretory antigen) [7], and monoclonal antibodies to LAM (M. tuberculosis-related lipoarabinomannan) [8] and PAB (Propionibacterium acnes-specific lipoteichoic acid) [9]. Antiserum to Treponema pallidum gave weak immunoreactivity. Escherichia coli antigens were scarcely observed. The background staining was minimal.
3. Discussion
Opportunistic infection caused by a variety of bacteria, fungi, or viruses occurs in the skin under the immunosuppressive state such as acquired immunodeficiency syndrome (AIDS) and after the use of immunosuppressive agents [1, 2]. One of the authors (YT) described histopathological features of such conditions in a textbook entitled Pathology of Skin Infections published in 2013 [10]. We describe herein a case of cutaneous coinfection of CMV and M. chelonae, provoked by immunosuppressive therapy against pyoderma gangrenosum. The patient suffered from mild and controlled type 2 diabetes mellitus. Pyoderma gangrenosum is characterized by noninfectious autoimmune-type progressive skin ulceration [11], successfully treated with immunosuppressive agents [12].
Opportunistic skin infection of CMV is rare. CMV mainly affects vascular endothelial cells and perivascular stromal cells, and multifocal anogenital ulcerations are most frequently encountered in AIDS patients [13]. Cutaneous lesions with verrucous elevations [14] and septal panniculitis [15] have also been described in non-AIDS immunosuppressed patients. Since the skin ulcer remained unchanged after ganciclovir treatment, Grushchak et al. regarded CMV infection as a bystander phenomenon [16]. The skin lesion in the present case demonstrated features of septolobular panniculitis with CMV inclusions in endothelial and perivascular stromal cells, but the lesion progressed to form large induration with multiple ulcers after gancyclovir treatment. It is reasonable to consider the CMV infection as bystander incidence associated with nontuberculous mycobacteriosis. In other words, when CMV inclusions are noted in nodular or ulcerated skin lesions, primary causative microbes other than CMV should be searched under the microscope, as was so in the present case.
Varied nontuberculous mycobacteria affect the skin, including M. avium-intracellulare complex, M. marinum, M. ulcerans, M. fortuitum, and M. chelonae-abscessus complex [17, 18]. Reportedly, rapidly growing mycobacteria (RGM) form colonies on a common chocolate agar medium when the culture period is prolonged to two weeks or more [19].
M. chelonae was first isolated from the tortoise by Friedmann in 1902 [20]. M. chelonae belongs to nonchromogenic RGM (Runyon group IV), widely distributed in environmental water [21]. This zoonotic mycobacterium, categorized in M. chelonae-abscessus complex, causes opportunistic infection in the human skin, as well as infection in aquatic animals such as the reptiles and fish [22]. Of notice is that not only traumatic injuries but also surgical procedures make risk factors of human infection [23]. It is plausible that in the present case, medical disposals caused iatrogenic infection of the environmental pathogen. Immunosuppression and diabetic conditions accelerated opportunistic infection, as reported previously [17, 18, 22]. Microscopically, infection of RGM, including M. chelonae, provokes abscess-forming granulomas (suppurative granulomas): some lesions are recognized as abscess surrounded by abortive granuloma formation, while the others predominantly reveal epithelioid granulomas [24, 25]. Acid-fast bacilli are characteristically identified in the lipid droplets (vacuoles) often located in the center of suppurative granulomas. It is noteworthy that the bacilli are positively labeled with Gram stain: namely, Gram positivity is a feature of RGM [26].
The cell wall of mycobacteria contains voluminous mycolic acids, extremely long fatty acids, as molecular forms of mycolic acid-containing glycolipid such as trehalose dimycolate and trehalose monomycolate, giving lipophilic nature of mycobacteria [27]. RGM are characterized by the presence of an additional mycolate, glucose mycolate, on the cell wall [28]. Such biological features may be related to the lipid droplet-centered pattern of infection by RGM.
Lipid droplet-centered suppurative granulomas are commonly observed in granulomatous mastitis caused by a lipophilic bacterium, Corynebacterium kroppenstedtii [29]. The Gram-positive rods are uniquely clustered in the lipid droplets surrounded by suppurative granulomas. The histological features are quite similar to those of RGM infection. Unlike other corynebacteria, C. kroppenstedtii lacks mycolic acid but instead contains tuberculostearic acid in the cell wall [30]. It is understandable from both the microscopic appearance and the pharmacodynamic properties of antibiotics [31] that administration of lipophilic antibiotics is essential for treating not only granulomatous mastitis but also RGM infection. The treatment regimen for tuberculosis using hydrophilic antibiotics such as isoniazid, ethambuthol, pyrazinamide, and streptomycin is consistently ineffective for infection of RGM, which are usually resistant to lipophilic rifampicin [18]. In the present case, clarithromycin, a type of lipophilic macrolides, was effective, as has been reported so far [32, 33]. Thermotherapy was also useful [34], based on the biological features of the bacteria showing low optimal temperature (25–37°C) for growth [17, 18].
Immunohistochemical cross-reactivity of rabbit antisera against BCG and B. cereus was observed in the infected lesion. T. pallidum antiserum also showed weak cross-reactivity. Positive signals with low background staining were observed not only on the mycobacteria in the lipid droplets but also in the cytoplasm of macrophages, so that the detection sensitivity was very high [5]. Similar results were observed in granulomatous mastitis [29]. The visualization of microbes within the lesion is essentially important for making a histopathological diagnosis of infection [5]. Another important point of our findings includes the cross-reactivity of antibodies against MPT64, LAM, and PAB to M. chelonae. It has been reported that MPT64 and LAM are specific to M. tuberculosis, and PAB is solely expressed on Propionibacterium (Cutibacterium) acnes [7–9]. The P. acnes antigens were detected in granulomas of sarcoidosis [35]. The lipophilic bacteria in granulomatous mastitis also expressed LAM and PAB (Tsutsumi, unpublished observation). Such unexpected cross-reactivity should be cautious about applying the antibacterial antibodies as immunohistochemical probes, as has been described previously [5].
4. Conclusion
We reported here rare opportunistic skin coinfection of CMV and M. chelonae, a rapidly growing nontuberculous mycobacterium, after immunosuppressive therapy against pyoderma gangrenosum. It is of note that M. chelonae provoked suppurative granulomas with lipid droplet-centered colonization of Gram-positive and acid-fast rods. Unique immunohistochemical reactivities with a variety of antibacterial antibodies were applicable to visualizing the causative mycobacteria in the lesion.
Acknowledgments
The authors deeply thank Mr. Izumi Kurita, M.T., Clinical Laboratory Medicine, Shimada Municipal Hospital, Shimada, for identifying M. chelonae.
Consent
The patient gave written informed consent to publication of the case report.
Disclosure
The present address of Kentaro Odani is the Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto. The present address of Hideo Hashizume is the Department of Dermatology, Iwata City Hospital, Iwata, Shizuoka.
Conflicts of Interest
The authors do not have any conflict of interest in the present report.
Authors' Contributions
We declare that all the authors (1) made a substantial contribution to the concept of the case report or interpretation of data and (2) approved the version to be submitted. (3) Each author has participated sufficiently in the work to take public responsibility for appropriate portions of the content.
Figure 1 Pyoderma gangrenosum ((a) gross appearance of left lower thigh, (b) H&E). A demarcated deep ulcer, 4 cm in size, is observed. Fibrinous exudation is seen at the ulcer base, and erythematous change is associated around the ulcer (a). Microscopic features of the first biopsy specimen are nonspecific. Ulcer base is composed of fibrinous exudation and granulation tissue (b). Neither granulomatous reactions nor infectious agents are identified.
Figure 2 A subcutaneous nodule without ulceration ((a) gross appearance; (b) H&E, low-powered view; (c) H&E, high-powered view of the subcutaneous tissue, inset: immunostaining for CMV antigens). Subcutaneous nodularity with mild reddening is observed on the lower thigh near the original ulcer by pyoderma gangrenosum (arrow, (a)). A low-powered view of the second biopsy specimen demonstrates subcutaneous septolobular panniculitis (b). Endothelial cells and perivascular stromal cells with enlarged nuclei reveal intranuclear and cytoplasmic inclusions (c). Immunostaining for CMV antigens is clearly positive (inset).
Figure 3 A large nodular and indurated skin lesion with multiple ulcers ((a) gross appearance, (b) H&E, low-powered view, and (c) H&E, high-powered view of the dermis). Multiple ulcers, 2–3 cm in size, are formed in the irregular-shaped reddish induration (a). The third biopsy specimen reveals diffuse inflammatory infiltration in the dermis through subcutaneous tissue (b). Suppurative granuloma (abscess surrounded by epithelioid granuloma) is scattered in the lesion (c). No CMV inclusions are observed any longer.
Figure 4 Gram-positive acid-fast bacilli in the second (a–c) and third (d–f) biopsy specimens ((a, d) H&E, (b, e) Ziehl-Neelsen stain, and (c, f) Gram stain). Gram-positive acid-fast bacilli are multifocally clustered in microabscess (a–c) and also in fat droplets located in the center of suppurative granuloma (d–f). The bacteria are visible in the fat droplets even in H&E preparations (d). Such patterns of bacterial colonization are seen in both the second and third biopsy specimens.
Figure 5 Colonies of Mycobacterium chelonae on 2% Ogawa medium ((a) gross appearance, (b) Ziehl-Neelsen stain, (c) Gram stain, and (d) MALDI Biotyper analysis). Smooth-surfaced white (nonchromogenic) colonies are formed seven days after inoculation. The formalin-fixed, paraffin-embedded colonies display acid-fastness and Gram reactivity of the rods. By the MALDI biotyping analysis, the spectrum pattern indicates M. chelonae with the log score value of 2.208.
Figure 6 Immunohistochemical demonstration of varied bacterial antigens ((a) BCG, (b) Bacillus cereus, (c) Treponema pallidum, (d) MPT64, (e) LAM, and (f) PAB). The cytoplasm of macrophages infiltrating around the fat droplet exhibits clear cross-reactivity with varied bacterial antigens. Immunoreactivity of T. pallidum antigens is relatively weak.
Table 1 Antibodies used in the present study.
Target antigen Animal/clone Dilution Antigen retrieval Source
Bacillus Calmette-Guérin (BCG) Rabbit antiserum 1 : 10,000 None Agilent
MPT64 (RV1980C, 24 kDa protein) Rabbit antiserum 1 : 800 HIER in 10 mM CB (pH 6) Abcam
LAM (lipoarabinomannan) Mouse TMDU3 1 : 1,000 HIER in 10 mM CB (pH 6) MBL
PAB (Propionibacterium acnes-specific lipoteichoic acid) Mouse TMDU2 1 : 4,000 HIER in 10 mM CB (pH 6) MBL
Bacillus cereus Rabbit antiserum 1 : 500 HIER in 10 mM CB (pH 6) Abcam
Treponema pallidum Rabbit antiserum 1 : 1,000 HIER in 1 mM EDTA (pH 8) BM
Escherichia coli Rabbit antiserum 1 : 20,000 Proteinase K digestion Agilent
MPT: mycobacterial protein tuberculosis; HIER: heat-induced epitope retrieval; CB: citrate buffer; EDTA: ethylenediamine tetraacetic acid; Agilent: Agilent Technologies (Santa Clara, CA, USA); MBL: Medical and Biological Laboratories (Nagoya, Japan); Abcam: Abcam plc (Cambridge, UK); BM: Biocare Medical LLC (Pacheco, Philippines). | CYCLOSPORINE, METFORMIN HYDROCHLORIDE, MITIGLINIDE CALCIUM ANHYDROUS, PREDNISOLONE, SITAGLIPTIN PHOSPHATE | DrugsGivenReaction | CC BY | 33564484 | 19,706,871 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Panniculitis'. | Cutaneous Coinfection of Cytomegalovirus and Mycobacterium chelonae Accelerated by Immunosuppression.
A mildly diabetic 58-year-old male had traumatic ulceration on the left popliteal fossa, and the lesion progressed to a painful 6 cm deep ulcer. After surgical debridement and skin grafting, ulceration recurred. Pyoderma gangrenosum was clinically diagnosed after the first biopsy, indicating a noninfective ulcer. Immunosuppressive therapy (prednisolone and cyclosporine A) induced complete epithelialization in three months. Four months later, subcutaneous nonulcerated nodules appeared on the anterior area of the left lower leg. Subcutaneous induration progressed and ulceration recurred, so that immunosuppressive therapy continued for one year. Cytomegalovirus (CMV) viremia was detected, and the second biopsy demonstrated CMV inclusions of endothelial and perivascular cells in fibrosing septolobular panniculitis. Cyclosporine A was cancelled, prednisolone was tapered, and ganciclovir started. Viremia soon disappeared, but the lesion progressed to large induration with multiple ulcers measuring up to 3 cm. The third biopsy disclosed infection of Gram-positive mycobacteria, accompanying fat droplet-centered suppurative granulomas without CMV infection. Microbial culture identified Mycobacterium chelonae. Clarithromycin with thermotherapy was effective. A review of the second biopsy confirmed coinfection of CMV and Gram-positive mycobacteria. Immunostaining using a panel of anti-bacterial antibodies visualized the mycobacteria in the lesion. Positive findings were obtained with antibodies to Bacillus Calmette-Guérin, Bacillus cereus, MPT64 (Mycobacterium tuberculosis-specific 24 kDa secretory antigen), LAM (Mycobacterium tuberculosis-related lipoarabinomannan), and PAB (Propionibacterium acnes-specific lipoteichoic acid).
1. Introduction
Immunosuppressive conditions may provoke opportunistic skin infection of a variety of bacteria, fungi, and viruses [1, 2]. The present article describes a case of pyoderma gangrenosum on the left popliteal fossa, followed by immunosuppressive therapy-induced opportunistic dual skin infection of cytomegalovirus (CMV) and Mycobacterium chelonae on the left lower leg. Histopathological and immunohistochemical features of this rare combination of pathogens are detailed.
2. Case Report
A 58-year-old Japanese man slipped and fell on the road to have his left knee contused, resulting in a 1.5 cm sized shallow ulceration. The patient had suffered from hypertension and mild type 2 diabetes mellitus for two years, but no history of autoimmune disorders. Serum antibodies against insulin and glutamic acid decarboxylase were negative, excluding the possibility of type 1 diabetes mellitus. He had smoked 15 cigarettes per day for more than 40 years. Five months later, a painful skin ulcer, 6 cm in size, occurred on the inner side of the left popliteal fossa (at the same site of contusion). No pathogens were identified in the biopsy specimen, and microbial culture was negative. Surgical debridement and full-thickness grafting from the abdominal skin were performed by a plastic surgeon, but half of the skin flap was eventually impaired, leaving a 3 cm sized deep ulcer with severe pain. The patient was then consulted to dermatologists. Clinical findings, as well as the first biopsy features displaying nonspecific and noninfective ulcer, were consistent with pyoderma gangrenosum (Figure 1). The serum level of granulocyte colony-stimulating factor, a biomarker of pyoderma gangrenosum [3], was elevated to 48.1 pg/mL (reference value < 30 pg/mL). Administration of prednisolone (PSL) (20 mg/day) and cyclosporine A (CyA: 100 mg/day) started. In order to control exacerbation of the skin lesion, medication of PSL plus CyA was maintained, while PSL was gradually tapered to 10 mg/day. Complete epithelialization was achieved three months later.
Four months later, subcutaneous nonulcerated, painful nodules appeared on the anterior area of the left lower leg, 20 cm distal from the primary ulcer caused by pyoderma gangrenosum. Ulceration recurred, and subcutaneous induration soon progressed toward both the distal and proximal directions. Immunosuppressive therapy restarted, but the painful ulcer persisted for one year. At this point of time, CMV viremia was identified, and the second skin biopsy from one of the subcutaneous nodules identified CMV inclusions in the subcutaneous tissue with fibrosing septolobular panniculitis. The CMV antigens were immunohistochemically visualized in the viral inclusions with 1 : 200 diluted cocktail monoclonal antibodies, CCH2+DDG9, available from Agilent Technologies (Figure 2). Both endothelial cells and perivascular stromal cells were infected. The dermis was free of inflammation. CyA was cancelled, PSL was reduced to 5 mg/day, and instead, ganciclovir (900 mg/day) was administered. Viremia soon disappeared, but the lower leg lesion progressed to form multiple ulcers. The third skin biopsy disclosed that infection involved both the dermis and the subcutaneous fat tissue. Suppurative granulomas (small abscesses surrounded by epithelioid granulomas) were dispersed (Figure 3). Gram-positive acid-fast bacilli were identified in microabscesses and also in fat droplets surrounded by suppurative granulomas (Figure 4). Caseous necrosis was focally associated. Grocott stain gave negative results. CMV infection was no longer identified. The second skin biopsy was retrospectively reevaluated, and Gram-positive acid-fast bacilli were identified mainly in microabscesses and in fat droplets surrounded by suppurative granulomas, multifocally distributed in the inflamed subcutaneous tissue. The final diagnosis of the second biopsy was thus subcutaneous coinfection of CMV and nontuberculous mycobacteria.
Microbial culture on 2% Ogawa medium at 37°C identified rapidly growing nontuberculous mycobacteria. The bacteria were acid-fast and Gram-positive. Mycobacterium chelonae was identified by analyzing with Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS) by using the MALDI Biotyper (Bruker Japan Daltonics division, Yokohama) (Figure 5) [4]. The log score value for M. chelonae was more than 2.0 (2.208).
Clarithromycin administration (800 mg/day), combined with thermotherapy using disposal pocket body warmers for one hour twice a day, resulted in marked regression of the ulcers. PSL tapering induced subcutaneous nodularity with ulceration, and thus, clarithromycin treatment was kept to date. After chemotherapy for 15 months, epithelialization was almost achieved. Valganciclovir was administered when CMV viremia reappeared.
Metformin (an oral antidiabetic) and sitagliptin phosphate hydrate (a selective inhibitor of dipeptidyl peptidase-4) continued for controlling type 2 diabetes mellitus. Mitiglinide calcium hydrate (a stimulator of insulin secretion) was added after the appearance of the skin ulceration for one year. During the clinical course, the patient's blood glucose levels were persistently hyperglycemic, ranging from 106 to 186 mg/dL but without glycosuria. Mild proteinuria ranging from 15 to 100 mg/dL was noted, indicating the complication of stage 2 (early) diabetic nephropathy. His HbA1c levels ranged from 6.4 to 7.3% (standard levels: 4.1–6.2%). The patient thus suffered from mild and controlled diabetes mellitus.
For characterizing the mycobacteria colonizing the skin lesion in the second and third skin biopsy specimens, immunostaining using selected antibodies was performed, as indicated in Table 1. An amino acid polymer method (Simple Stain Max-PO, Nichirei Biosciences, Tokyo) was employed. As reported in the previous article describing a low-specificity and high-sensitivity immunostaining with widely cross-reactive antibacterial antisera [5], the mycobacteria were visualized in formalin-fixed, paraffin-embedded sections. The antibodies gave clearly positive signals in the cytoplasm of macrophages infiltrating in the lesion, in addition to long rods labeled with Gram and Ziehl-Neelsen stains. Figure 6 illustrates positive findings with rabbit antisera to Bacillus Calmette-Guérin (BCG) [6], Bacillus cereus [5], MPT64 (also called as protein Rv1980c, M. tuberculosis-specific 24 kDa secretory antigen) [7], and monoclonal antibodies to LAM (M. tuberculosis-related lipoarabinomannan) [8] and PAB (Propionibacterium acnes-specific lipoteichoic acid) [9]. Antiserum to Treponema pallidum gave weak immunoreactivity. Escherichia coli antigens were scarcely observed. The background staining was minimal.
3. Discussion
Opportunistic infection caused by a variety of bacteria, fungi, or viruses occurs in the skin under the immunosuppressive state such as acquired immunodeficiency syndrome (AIDS) and after the use of immunosuppressive agents [1, 2]. One of the authors (YT) described histopathological features of such conditions in a textbook entitled Pathology of Skin Infections published in 2013 [10]. We describe herein a case of cutaneous coinfection of CMV and M. chelonae, provoked by immunosuppressive therapy against pyoderma gangrenosum. The patient suffered from mild and controlled type 2 diabetes mellitus. Pyoderma gangrenosum is characterized by noninfectious autoimmune-type progressive skin ulceration [11], successfully treated with immunosuppressive agents [12].
Opportunistic skin infection of CMV is rare. CMV mainly affects vascular endothelial cells and perivascular stromal cells, and multifocal anogenital ulcerations are most frequently encountered in AIDS patients [13]. Cutaneous lesions with verrucous elevations [14] and septal panniculitis [15] have also been described in non-AIDS immunosuppressed patients. Since the skin ulcer remained unchanged after ganciclovir treatment, Grushchak et al. regarded CMV infection as a bystander phenomenon [16]. The skin lesion in the present case demonstrated features of septolobular panniculitis with CMV inclusions in endothelial and perivascular stromal cells, but the lesion progressed to form large induration with multiple ulcers after gancyclovir treatment. It is reasonable to consider the CMV infection as bystander incidence associated with nontuberculous mycobacteriosis. In other words, when CMV inclusions are noted in nodular or ulcerated skin lesions, primary causative microbes other than CMV should be searched under the microscope, as was so in the present case.
Varied nontuberculous mycobacteria affect the skin, including M. avium-intracellulare complex, M. marinum, M. ulcerans, M. fortuitum, and M. chelonae-abscessus complex [17, 18]. Reportedly, rapidly growing mycobacteria (RGM) form colonies on a common chocolate agar medium when the culture period is prolonged to two weeks or more [19].
M. chelonae was first isolated from the tortoise by Friedmann in 1902 [20]. M. chelonae belongs to nonchromogenic RGM (Runyon group IV), widely distributed in environmental water [21]. This zoonotic mycobacterium, categorized in M. chelonae-abscessus complex, causes opportunistic infection in the human skin, as well as infection in aquatic animals such as the reptiles and fish [22]. Of notice is that not only traumatic injuries but also surgical procedures make risk factors of human infection [23]. It is plausible that in the present case, medical disposals caused iatrogenic infection of the environmental pathogen. Immunosuppression and diabetic conditions accelerated opportunistic infection, as reported previously [17, 18, 22]. Microscopically, infection of RGM, including M. chelonae, provokes abscess-forming granulomas (suppurative granulomas): some lesions are recognized as abscess surrounded by abortive granuloma formation, while the others predominantly reveal epithelioid granulomas [24, 25]. Acid-fast bacilli are characteristically identified in the lipid droplets (vacuoles) often located in the center of suppurative granulomas. It is noteworthy that the bacilli are positively labeled with Gram stain: namely, Gram positivity is a feature of RGM [26].
The cell wall of mycobacteria contains voluminous mycolic acids, extremely long fatty acids, as molecular forms of mycolic acid-containing glycolipid such as trehalose dimycolate and trehalose monomycolate, giving lipophilic nature of mycobacteria [27]. RGM are characterized by the presence of an additional mycolate, glucose mycolate, on the cell wall [28]. Such biological features may be related to the lipid droplet-centered pattern of infection by RGM.
Lipid droplet-centered suppurative granulomas are commonly observed in granulomatous mastitis caused by a lipophilic bacterium, Corynebacterium kroppenstedtii [29]. The Gram-positive rods are uniquely clustered in the lipid droplets surrounded by suppurative granulomas. The histological features are quite similar to those of RGM infection. Unlike other corynebacteria, C. kroppenstedtii lacks mycolic acid but instead contains tuberculostearic acid in the cell wall [30]. It is understandable from both the microscopic appearance and the pharmacodynamic properties of antibiotics [31] that administration of lipophilic antibiotics is essential for treating not only granulomatous mastitis but also RGM infection. The treatment regimen for tuberculosis using hydrophilic antibiotics such as isoniazid, ethambuthol, pyrazinamide, and streptomycin is consistently ineffective for infection of RGM, which are usually resistant to lipophilic rifampicin [18]. In the present case, clarithromycin, a type of lipophilic macrolides, was effective, as has been reported so far [32, 33]. Thermotherapy was also useful [34], based on the biological features of the bacteria showing low optimal temperature (25–37°C) for growth [17, 18].
Immunohistochemical cross-reactivity of rabbit antisera against BCG and B. cereus was observed in the infected lesion. T. pallidum antiserum also showed weak cross-reactivity. Positive signals with low background staining were observed not only on the mycobacteria in the lipid droplets but also in the cytoplasm of macrophages, so that the detection sensitivity was very high [5]. Similar results were observed in granulomatous mastitis [29]. The visualization of microbes within the lesion is essentially important for making a histopathological diagnosis of infection [5]. Another important point of our findings includes the cross-reactivity of antibodies against MPT64, LAM, and PAB to M. chelonae. It has been reported that MPT64 and LAM are specific to M. tuberculosis, and PAB is solely expressed on Propionibacterium (Cutibacterium) acnes [7–9]. The P. acnes antigens were detected in granulomas of sarcoidosis [35]. The lipophilic bacteria in granulomatous mastitis also expressed LAM and PAB (Tsutsumi, unpublished observation). Such unexpected cross-reactivity should be cautious about applying the antibacterial antibodies as immunohistochemical probes, as has been described previously [5].
4. Conclusion
We reported here rare opportunistic skin coinfection of CMV and M. chelonae, a rapidly growing nontuberculous mycobacterium, after immunosuppressive therapy against pyoderma gangrenosum. It is of note that M. chelonae provoked suppurative granulomas with lipid droplet-centered colonization of Gram-positive and acid-fast rods. Unique immunohistochemical reactivities with a variety of antibacterial antibodies were applicable to visualizing the causative mycobacteria in the lesion.
Acknowledgments
The authors deeply thank Mr. Izumi Kurita, M.T., Clinical Laboratory Medicine, Shimada Municipal Hospital, Shimada, for identifying M. chelonae.
Consent
The patient gave written informed consent to publication of the case report.
Disclosure
The present address of Kentaro Odani is the Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto. The present address of Hideo Hashizume is the Department of Dermatology, Iwata City Hospital, Iwata, Shizuoka.
Conflicts of Interest
The authors do not have any conflict of interest in the present report.
Authors' Contributions
We declare that all the authors (1) made a substantial contribution to the concept of the case report or interpretation of data and (2) approved the version to be submitted. (3) Each author has participated sufficiently in the work to take public responsibility for appropriate portions of the content.
Figure 1 Pyoderma gangrenosum ((a) gross appearance of left lower thigh, (b) H&E). A demarcated deep ulcer, 4 cm in size, is observed. Fibrinous exudation is seen at the ulcer base, and erythematous change is associated around the ulcer (a). Microscopic features of the first biopsy specimen are nonspecific. Ulcer base is composed of fibrinous exudation and granulation tissue (b). Neither granulomatous reactions nor infectious agents are identified.
Figure 2 A subcutaneous nodule without ulceration ((a) gross appearance; (b) H&E, low-powered view; (c) H&E, high-powered view of the subcutaneous tissue, inset: immunostaining for CMV antigens). Subcutaneous nodularity with mild reddening is observed on the lower thigh near the original ulcer by pyoderma gangrenosum (arrow, (a)). A low-powered view of the second biopsy specimen demonstrates subcutaneous septolobular panniculitis (b). Endothelial cells and perivascular stromal cells with enlarged nuclei reveal intranuclear and cytoplasmic inclusions (c). Immunostaining for CMV antigens is clearly positive (inset).
Figure 3 A large nodular and indurated skin lesion with multiple ulcers ((a) gross appearance, (b) H&E, low-powered view, and (c) H&E, high-powered view of the dermis). Multiple ulcers, 2–3 cm in size, are formed in the irregular-shaped reddish induration (a). The third biopsy specimen reveals diffuse inflammatory infiltration in the dermis through subcutaneous tissue (b). Suppurative granuloma (abscess surrounded by epithelioid granuloma) is scattered in the lesion (c). No CMV inclusions are observed any longer.
Figure 4 Gram-positive acid-fast bacilli in the second (a–c) and third (d–f) biopsy specimens ((a, d) H&E, (b, e) Ziehl-Neelsen stain, and (c, f) Gram stain). Gram-positive acid-fast bacilli are multifocally clustered in microabscess (a–c) and also in fat droplets located in the center of suppurative granuloma (d–f). The bacteria are visible in the fat droplets even in H&E preparations (d). Such patterns of bacterial colonization are seen in both the second and third biopsy specimens.
Figure 5 Colonies of Mycobacterium chelonae on 2% Ogawa medium ((a) gross appearance, (b) Ziehl-Neelsen stain, (c) Gram stain, and (d) MALDI Biotyper analysis). Smooth-surfaced white (nonchromogenic) colonies are formed seven days after inoculation. The formalin-fixed, paraffin-embedded colonies display acid-fastness and Gram reactivity of the rods. By the MALDI biotyping analysis, the spectrum pattern indicates M. chelonae with the log score value of 2.208.
Figure 6 Immunohistochemical demonstration of varied bacterial antigens ((a) BCG, (b) Bacillus cereus, (c) Treponema pallidum, (d) MPT64, (e) LAM, and (f) PAB). The cytoplasm of macrophages infiltrating around the fat droplet exhibits clear cross-reactivity with varied bacterial antigens. Immunoreactivity of T. pallidum antigens is relatively weak.
Table 1 Antibodies used in the present study.
Target antigen Animal/clone Dilution Antigen retrieval Source
Bacillus Calmette-Guérin (BCG) Rabbit antiserum 1 : 10,000 None Agilent
MPT64 (RV1980C, 24 kDa protein) Rabbit antiserum 1 : 800 HIER in 10 mM CB (pH 6) Abcam
LAM (lipoarabinomannan) Mouse TMDU3 1 : 1,000 HIER in 10 mM CB (pH 6) MBL
PAB (Propionibacterium acnes-specific lipoteichoic acid) Mouse TMDU2 1 : 4,000 HIER in 10 mM CB (pH 6) MBL
Bacillus cereus Rabbit antiserum 1 : 500 HIER in 10 mM CB (pH 6) Abcam
Treponema pallidum Rabbit antiserum 1 : 1,000 HIER in 1 mM EDTA (pH 8) BM
Escherichia coli Rabbit antiserum 1 : 20,000 Proteinase K digestion Agilent
MPT: mycobacterial protein tuberculosis; HIER: heat-induced epitope retrieval; CB: citrate buffer; EDTA: ethylenediamine tetraacetic acid; Agilent: Agilent Technologies (Santa Clara, CA, USA); MBL: Medical and Biological Laboratories (Nagoya, Japan); Abcam: Abcam plc (Cambridge, UK); BM: Biocare Medical LLC (Pacheco, Philippines). | CYCLOSPORINE, METFORMIN HYDROCHLORIDE, MITIGLINIDE CALCIUM ANHYDROUS, PREDNISOLONE, SITAGLIPTIN PHOSPHATE | DrugsGivenReaction | CC BY | 33564484 | 19,706,871 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ulcer'. | Cutaneous Coinfection of Cytomegalovirus and Mycobacterium chelonae Accelerated by Immunosuppression.
A mildly diabetic 58-year-old male had traumatic ulceration on the left popliteal fossa, and the lesion progressed to a painful 6 cm deep ulcer. After surgical debridement and skin grafting, ulceration recurred. Pyoderma gangrenosum was clinically diagnosed after the first biopsy, indicating a noninfective ulcer. Immunosuppressive therapy (prednisolone and cyclosporine A) induced complete epithelialization in three months. Four months later, subcutaneous nonulcerated nodules appeared on the anterior area of the left lower leg. Subcutaneous induration progressed and ulceration recurred, so that immunosuppressive therapy continued for one year. Cytomegalovirus (CMV) viremia was detected, and the second biopsy demonstrated CMV inclusions of endothelial and perivascular cells in fibrosing septolobular panniculitis. Cyclosporine A was cancelled, prednisolone was tapered, and ganciclovir started. Viremia soon disappeared, but the lesion progressed to large induration with multiple ulcers measuring up to 3 cm. The third biopsy disclosed infection of Gram-positive mycobacteria, accompanying fat droplet-centered suppurative granulomas without CMV infection. Microbial culture identified Mycobacterium chelonae. Clarithromycin with thermotherapy was effective. A review of the second biopsy confirmed coinfection of CMV and Gram-positive mycobacteria. Immunostaining using a panel of anti-bacterial antibodies visualized the mycobacteria in the lesion. Positive findings were obtained with antibodies to Bacillus Calmette-Guérin, Bacillus cereus, MPT64 (Mycobacterium tuberculosis-specific 24 kDa secretory antigen), LAM (Mycobacterium tuberculosis-related lipoarabinomannan), and PAB (Propionibacterium acnes-specific lipoteichoic acid).
1. Introduction
Immunosuppressive conditions may provoke opportunistic skin infection of a variety of bacteria, fungi, and viruses [1, 2]. The present article describes a case of pyoderma gangrenosum on the left popliteal fossa, followed by immunosuppressive therapy-induced opportunistic dual skin infection of cytomegalovirus (CMV) and Mycobacterium chelonae on the left lower leg. Histopathological and immunohistochemical features of this rare combination of pathogens are detailed.
2. Case Report
A 58-year-old Japanese man slipped and fell on the road to have his left knee contused, resulting in a 1.5 cm sized shallow ulceration. The patient had suffered from hypertension and mild type 2 diabetes mellitus for two years, but no history of autoimmune disorders. Serum antibodies against insulin and glutamic acid decarboxylase were negative, excluding the possibility of type 1 diabetes mellitus. He had smoked 15 cigarettes per day for more than 40 years. Five months later, a painful skin ulcer, 6 cm in size, occurred on the inner side of the left popliteal fossa (at the same site of contusion). No pathogens were identified in the biopsy specimen, and microbial culture was negative. Surgical debridement and full-thickness grafting from the abdominal skin were performed by a plastic surgeon, but half of the skin flap was eventually impaired, leaving a 3 cm sized deep ulcer with severe pain. The patient was then consulted to dermatologists. Clinical findings, as well as the first biopsy features displaying nonspecific and noninfective ulcer, were consistent with pyoderma gangrenosum (Figure 1). The serum level of granulocyte colony-stimulating factor, a biomarker of pyoderma gangrenosum [3], was elevated to 48.1 pg/mL (reference value < 30 pg/mL). Administration of prednisolone (PSL) (20 mg/day) and cyclosporine A (CyA: 100 mg/day) started. In order to control exacerbation of the skin lesion, medication of PSL plus CyA was maintained, while PSL was gradually tapered to 10 mg/day. Complete epithelialization was achieved three months later.
Four months later, subcutaneous nonulcerated, painful nodules appeared on the anterior area of the left lower leg, 20 cm distal from the primary ulcer caused by pyoderma gangrenosum. Ulceration recurred, and subcutaneous induration soon progressed toward both the distal and proximal directions. Immunosuppressive therapy restarted, but the painful ulcer persisted for one year. At this point of time, CMV viremia was identified, and the second skin biopsy from one of the subcutaneous nodules identified CMV inclusions in the subcutaneous tissue with fibrosing septolobular panniculitis. The CMV antigens were immunohistochemically visualized in the viral inclusions with 1 : 200 diluted cocktail monoclonal antibodies, CCH2+DDG9, available from Agilent Technologies (Figure 2). Both endothelial cells and perivascular stromal cells were infected. The dermis was free of inflammation. CyA was cancelled, PSL was reduced to 5 mg/day, and instead, ganciclovir (900 mg/day) was administered. Viremia soon disappeared, but the lower leg lesion progressed to form multiple ulcers. The third skin biopsy disclosed that infection involved both the dermis and the subcutaneous fat tissue. Suppurative granulomas (small abscesses surrounded by epithelioid granulomas) were dispersed (Figure 3). Gram-positive acid-fast bacilli were identified in microabscesses and also in fat droplets surrounded by suppurative granulomas (Figure 4). Caseous necrosis was focally associated. Grocott stain gave negative results. CMV infection was no longer identified. The second skin biopsy was retrospectively reevaluated, and Gram-positive acid-fast bacilli were identified mainly in microabscesses and in fat droplets surrounded by suppurative granulomas, multifocally distributed in the inflamed subcutaneous tissue. The final diagnosis of the second biopsy was thus subcutaneous coinfection of CMV and nontuberculous mycobacteria.
Microbial culture on 2% Ogawa medium at 37°C identified rapidly growing nontuberculous mycobacteria. The bacteria were acid-fast and Gram-positive. Mycobacterium chelonae was identified by analyzing with Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS) by using the MALDI Biotyper (Bruker Japan Daltonics division, Yokohama) (Figure 5) [4]. The log score value for M. chelonae was more than 2.0 (2.208).
Clarithromycin administration (800 mg/day), combined with thermotherapy using disposal pocket body warmers for one hour twice a day, resulted in marked regression of the ulcers. PSL tapering induced subcutaneous nodularity with ulceration, and thus, clarithromycin treatment was kept to date. After chemotherapy for 15 months, epithelialization was almost achieved. Valganciclovir was administered when CMV viremia reappeared.
Metformin (an oral antidiabetic) and sitagliptin phosphate hydrate (a selective inhibitor of dipeptidyl peptidase-4) continued for controlling type 2 diabetes mellitus. Mitiglinide calcium hydrate (a stimulator of insulin secretion) was added after the appearance of the skin ulceration for one year. During the clinical course, the patient's blood glucose levels were persistently hyperglycemic, ranging from 106 to 186 mg/dL but without glycosuria. Mild proteinuria ranging from 15 to 100 mg/dL was noted, indicating the complication of stage 2 (early) diabetic nephropathy. His HbA1c levels ranged from 6.4 to 7.3% (standard levels: 4.1–6.2%). The patient thus suffered from mild and controlled diabetes mellitus.
For characterizing the mycobacteria colonizing the skin lesion in the second and third skin biopsy specimens, immunostaining using selected antibodies was performed, as indicated in Table 1. An amino acid polymer method (Simple Stain Max-PO, Nichirei Biosciences, Tokyo) was employed. As reported in the previous article describing a low-specificity and high-sensitivity immunostaining with widely cross-reactive antibacterial antisera [5], the mycobacteria were visualized in formalin-fixed, paraffin-embedded sections. The antibodies gave clearly positive signals in the cytoplasm of macrophages infiltrating in the lesion, in addition to long rods labeled with Gram and Ziehl-Neelsen stains. Figure 6 illustrates positive findings with rabbit antisera to Bacillus Calmette-Guérin (BCG) [6], Bacillus cereus [5], MPT64 (also called as protein Rv1980c, M. tuberculosis-specific 24 kDa secretory antigen) [7], and monoclonal antibodies to LAM (M. tuberculosis-related lipoarabinomannan) [8] and PAB (Propionibacterium acnes-specific lipoteichoic acid) [9]. Antiserum to Treponema pallidum gave weak immunoreactivity. Escherichia coli antigens were scarcely observed. The background staining was minimal.
3. Discussion
Opportunistic infection caused by a variety of bacteria, fungi, or viruses occurs in the skin under the immunosuppressive state such as acquired immunodeficiency syndrome (AIDS) and after the use of immunosuppressive agents [1, 2]. One of the authors (YT) described histopathological features of such conditions in a textbook entitled Pathology of Skin Infections published in 2013 [10]. We describe herein a case of cutaneous coinfection of CMV and M. chelonae, provoked by immunosuppressive therapy against pyoderma gangrenosum. The patient suffered from mild and controlled type 2 diabetes mellitus. Pyoderma gangrenosum is characterized by noninfectious autoimmune-type progressive skin ulceration [11], successfully treated with immunosuppressive agents [12].
Opportunistic skin infection of CMV is rare. CMV mainly affects vascular endothelial cells and perivascular stromal cells, and multifocal anogenital ulcerations are most frequently encountered in AIDS patients [13]. Cutaneous lesions with verrucous elevations [14] and septal panniculitis [15] have also been described in non-AIDS immunosuppressed patients. Since the skin ulcer remained unchanged after ganciclovir treatment, Grushchak et al. regarded CMV infection as a bystander phenomenon [16]. The skin lesion in the present case demonstrated features of septolobular panniculitis with CMV inclusions in endothelial and perivascular stromal cells, but the lesion progressed to form large induration with multiple ulcers after gancyclovir treatment. It is reasonable to consider the CMV infection as bystander incidence associated with nontuberculous mycobacteriosis. In other words, when CMV inclusions are noted in nodular or ulcerated skin lesions, primary causative microbes other than CMV should be searched under the microscope, as was so in the present case.
Varied nontuberculous mycobacteria affect the skin, including M. avium-intracellulare complex, M. marinum, M. ulcerans, M. fortuitum, and M. chelonae-abscessus complex [17, 18]. Reportedly, rapidly growing mycobacteria (RGM) form colonies on a common chocolate agar medium when the culture period is prolonged to two weeks or more [19].
M. chelonae was first isolated from the tortoise by Friedmann in 1902 [20]. M. chelonae belongs to nonchromogenic RGM (Runyon group IV), widely distributed in environmental water [21]. This zoonotic mycobacterium, categorized in M. chelonae-abscessus complex, causes opportunistic infection in the human skin, as well as infection in aquatic animals such as the reptiles and fish [22]. Of notice is that not only traumatic injuries but also surgical procedures make risk factors of human infection [23]. It is plausible that in the present case, medical disposals caused iatrogenic infection of the environmental pathogen. Immunosuppression and diabetic conditions accelerated opportunistic infection, as reported previously [17, 18, 22]. Microscopically, infection of RGM, including M. chelonae, provokes abscess-forming granulomas (suppurative granulomas): some lesions are recognized as abscess surrounded by abortive granuloma formation, while the others predominantly reveal epithelioid granulomas [24, 25]. Acid-fast bacilli are characteristically identified in the lipid droplets (vacuoles) often located in the center of suppurative granulomas. It is noteworthy that the bacilli are positively labeled with Gram stain: namely, Gram positivity is a feature of RGM [26].
The cell wall of mycobacteria contains voluminous mycolic acids, extremely long fatty acids, as molecular forms of mycolic acid-containing glycolipid such as trehalose dimycolate and trehalose monomycolate, giving lipophilic nature of mycobacteria [27]. RGM are characterized by the presence of an additional mycolate, glucose mycolate, on the cell wall [28]. Such biological features may be related to the lipid droplet-centered pattern of infection by RGM.
Lipid droplet-centered suppurative granulomas are commonly observed in granulomatous mastitis caused by a lipophilic bacterium, Corynebacterium kroppenstedtii [29]. The Gram-positive rods are uniquely clustered in the lipid droplets surrounded by suppurative granulomas. The histological features are quite similar to those of RGM infection. Unlike other corynebacteria, C. kroppenstedtii lacks mycolic acid but instead contains tuberculostearic acid in the cell wall [30]. It is understandable from both the microscopic appearance and the pharmacodynamic properties of antibiotics [31] that administration of lipophilic antibiotics is essential for treating not only granulomatous mastitis but also RGM infection. The treatment regimen for tuberculosis using hydrophilic antibiotics such as isoniazid, ethambuthol, pyrazinamide, and streptomycin is consistently ineffective for infection of RGM, which are usually resistant to lipophilic rifampicin [18]. In the present case, clarithromycin, a type of lipophilic macrolides, was effective, as has been reported so far [32, 33]. Thermotherapy was also useful [34], based on the biological features of the bacteria showing low optimal temperature (25–37°C) for growth [17, 18].
Immunohistochemical cross-reactivity of rabbit antisera against BCG and B. cereus was observed in the infected lesion. T. pallidum antiserum also showed weak cross-reactivity. Positive signals with low background staining were observed not only on the mycobacteria in the lipid droplets but also in the cytoplasm of macrophages, so that the detection sensitivity was very high [5]. Similar results were observed in granulomatous mastitis [29]. The visualization of microbes within the lesion is essentially important for making a histopathological diagnosis of infection [5]. Another important point of our findings includes the cross-reactivity of antibodies against MPT64, LAM, and PAB to M. chelonae. It has been reported that MPT64 and LAM are specific to M. tuberculosis, and PAB is solely expressed on Propionibacterium (Cutibacterium) acnes [7–9]. The P. acnes antigens were detected in granulomas of sarcoidosis [35]. The lipophilic bacteria in granulomatous mastitis also expressed LAM and PAB (Tsutsumi, unpublished observation). Such unexpected cross-reactivity should be cautious about applying the antibacterial antibodies as immunohistochemical probes, as has been described previously [5].
4. Conclusion
We reported here rare opportunistic skin coinfection of CMV and M. chelonae, a rapidly growing nontuberculous mycobacterium, after immunosuppressive therapy against pyoderma gangrenosum. It is of note that M. chelonae provoked suppurative granulomas with lipid droplet-centered colonization of Gram-positive and acid-fast rods. Unique immunohistochemical reactivities with a variety of antibacterial antibodies were applicable to visualizing the causative mycobacteria in the lesion.
Acknowledgments
The authors deeply thank Mr. Izumi Kurita, M.T., Clinical Laboratory Medicine, Shimada Municipal Hospital, Shimada, for identifying M. chelonae.
Consent
The patient gave written informed consent to publication of the case report.
Disclosure
The present address of Kentaro Odani is the Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto. The present address of Hideo Hashizume is the Department of Dermatology, Iwata City Hospital, Iwata, Shizuoka.
Conflicts of Interest
The authors do not have any conflict of interest in the present report.
Authors' Contributions
We declare that all the authors (1) made a substantial contribution to the concept of the case report or interpretation of data and (2) approved the version to be submitted. (3) Each author has participated sufficiently in the work to take public responsibility for appropriate portions of the content.
Figure 1 Pyoderma gangrenosum ((a) gross appearance of left lower thigh, (b) H&E). A demarcated deep ulcer, 4 cm in size, is observed. Fibrinous exudation is seen at the ulcer base, and erythematous change is associated around the ulcer (a). Microscopic features of the first biopsy specimen are nonspecific. Ulcer base is composed of fibrinous exudation and granulation tissue (b). Neither granulomatous reactions nor infectious agents are identified.
Figure 2 A subcutaneous nodule without ulceration ((a) gross appearance; (b) H&E, low-powered view; (c) H&E, high-powered view of the subcutaneous tissue, inset: immunostaining for CMV antigens). Subcutaneous nodularity with mild reddening is observed on the lower thigh near the original ulcer by pyoderma gangrenosum (arrow, (a)). A low-powered view of the second biopsy specimen demonstrates subcutaneous septolobular panniculitis (b). Endothelial cells and perivascular stromal cells with enlarged nuclei reveal intranuclear and cytoplasmic inclusions (c). Immunostaining for CMV antigens is clearly positive (inset).
Figure 3 A large nodular and indurated skin lesion with multiple ulcers ((a) gross appearance, (b) H&E, low-powered view, and (c) H&E, high-powered view of the dermis). Multiple ulcers, 2–3 cm in size, are formed in the irregular-shaped reddish induration (a). The third biopsy specimen reveals diffuse inflammatory infiltration in the dermis through subcutaneous tissue (b). Suppurative granuloma (abscess surrounded by epithelioid granuloma) is scattered in the lesion (c). No CMV inclusions are observed any longer.
Figure 4 Gram-positive acid-fast bacilli in the second (a–c) and third (d–f) biopsy specimens ((a, d) H&E, (b, e) Ziehl-Neelsen stain, and (c, f) Gram stain). Gram-positive acid-fast bacilli are multifocally clustered in microabscess (a–c) and also in fat droplets located in the center of suppurative granuloma (d–f). The bacteria are visible in the fat droplets even in H&E preparations (d). Such patterns of bacterial colonization are seen in both the second and third biopsy specimens.
Figure 5 Colonies of Mycobacterium chelonae on 2% Ogawa medium ((a) gross appearance, (b) Ziehl-Neelsen stain, (c) Gram stain, and (d) MALDI Biotyper analysis). Smooth-surfaced white (nonchromogenic) colonies are formed seven days after inoculation. The formalin-fixed, paraffin-embedded colonies display acid-fastness and Gram reactivity of the rods. By the MALDI biotyping analysis, the spectrum pattern indicates M. chelonae with the log score value of 2.208.
Figure 6 Immunohistochemical demonstration of varied bacterial antigens ((a) BCG, (b) Bacillus cereus, (c) Treponema pallidum, (d) MPT64, (e) LAM, and (f) PAB). The cytoplasm of macrophages infiltrating around the fat droplet exhibits clear cross-reactivity with varied bacterial antigens. Immunoreactivity of T. pallidum antigens is relatively weak.
Table 1 Antibodies used in the present study.
Target antigen Animal/clone Dilution Antigen retrieval Source
Bacillus Calmette-Guérin (BCG) Rabbit antiserum 1 : 10,000 None Agilent
MPT64 (RV1980C, 24 kDa protein) Rabbit antiserum 1 : 800 HIER in 10 mM CB (pH 6) Abcam
LAM (lipoarabinomannan) Mouse TMDU3 1 : 1,000 HIER in 10 mM CB (pH 6) MBL
PAB (Propionibacterium acnes-specific lipoteichoic acid) Mouse TMDU2 1 : 4,000 HIER in 10 mM CB (pH 6) MBL
Bacillus cereus Rabbit antiserum 1 : 500 HIER in 10 mM CB (pH 6) Abcam
Treponema pallidum Rabbit antiserum 1 : 1,000 HIER in 1 mM EDTA (pH 8) BM
Escherichia coli Rabbit antiserum 1 : 20,000 Proteinase K digestion Agilent
MPT: mycobacterial protein tuberculosis; HIER: heat-induced epitope retrieval; CB: citrate buffer; EDTA: ethylenediamine tetraacetic acid; Agilent: Agilent Technologies (Santa Clara, CA, USA); MBL: Medical and Biological Laboratories (Nagoya, Japan); Abcam: Abcam plc (Cambridge, UK); BM: Biocare Medical LLC (Pacheco, Philippines). | CYCLOSPORINE, METFORMIN HYDROCHLORIDE, MITIGLINIDE CALCIUM ANHYDROUS, PREDNISOLONE, SITAGLIPTIN PHOSPHATE | DrugsGivenReaction | CC BY | 33564484 | 19,706,871 | 2021 |
What was the administration route of drug 'METFORMIN HYDROCHLORIDE'? | Cutaneous Coinfection of Cytomegalovirus and Mycobacterium chelonae Accelerated by Immunosuppression.
A mildly diabetic 58-year-old male had traumatic ulceration on the left popliteal fossa, and the lesion progressed to a painful 6 cm deep ulcer. After surgical debridement and skin grafting, ulceration recurred. Pyoderma gangrenosum was clinically diagnosed after the first biopsy, indicating a noninfective ulcer. Immunosuppressive therapy (prednisolone and cyclosporine A) induced complete epithelialization in three months. Four months later, subcutaneous nonulcerated nodules appeared on the anterior area of the left lower leg. Subcutaneous induration progressed and ulceration recurred, so that immunosuppressive therapy continued for one year. Cytomegalovirus (CMV) viremia was detected, and the second biopsy demonstrated CMV inclusions of endothelial and perivascular cells in fibrosing septolobular panniculitis. Cyclosporine A was cancelled, prednisolone was tapered, and ganciclovir started. Viremia soon disappeared, but the lesion progressed to large induration with multiple ulcers measuring up to 3 cm. The third biopsy disclosed infection of Gram-positive mycobacteria, accompanying fat droplet-centered suppurative granulomas without CMV infection. Microbial culture identified Mycobacterium chelonae. Clarithromycin with thermotherapy was effective. A review of the second biopsy confirmed coinfection of CMV and Gram-positive mycobacteria. Immunostaining using a panel of anti-bacterial antibodies visualized the mycobacteria in the lesion. Positive findings were obtained with antibodies to Bacillus Calmette-Guérin, Bacillus cereus, MPT64 (Mycobacterium tuberculosis-specific 24 kDa secretory antigen), LAM (Mycobacterium tuberculosis-related lipoarabinomannan), and PAB (Propionibacterium acnes-specific lipoteichoic acid).
1. Introduction
Immunosuppressive conditions may provoke opportunistic skin infection of a variety of bacteria, fungi, and viruses [1, 2]. The present article describes a case of pyoderma gangrenosum on the left popliteal fossa, followed by immunosuppressive therapy-induced opportunistic dual skin infection of cytomegalovirus (CMV) and Mycobacterium chelonae on the left lower leg. Histopathological and immunohistochemical features of this rare combination of pathogens are detailed.
2. Case Report
A 58-year-old Japanese man slipped and fell on the road to have his left knee contused, resulting in a 1.5 cm sized shallow ulceration. The patient had suffered from hypertension and mild type 2 diabetes mellitus for two years, but no history of autoimmune disorders. Serum antibodies against insulin and glutamic acid decarboxylase were negative, excluding the possibility of type 1 diabetes mellitus. He had smoked 15 cigarettes per day for more than 40 years. Five months later, a painful skin ulcer, 6 cm in size, occurred on the inner side of the left popliteal fossa (at the same site of contusion). No pathogens were identified in the biopsy specimen, and microbial culture was negative. Surgical debridement and full-thickness grafting from the abdominal skin were performed by a plastic surgeon, but half of the skin flap was eventually impaired, leaving a 3 cm sized deep ulcer with severe pain. The patient was then consulted to dermatologists. Clinical findings, as well as the first biopsy features displaying nonspecific and noninfective ulcer, were consistent with pyoderma gangrenosum (Figure 1). The serum level of granulocyte colony-stimulating factor, a biomarker of pyoderma gangrenosum [3], was elevated to 48.1 pg/mL (reference value < 30 pg/mL). Administration of prednisolone (PSL) (20 mg/day) and cyclosporine A (CyA: 100 mg/day) started. In order to control exacerbation of the skin lesion, medication of PSL plus CyA was maintained, while PSL was gradually tapered to 10 mg/day. Complete epithelialization was achieved three months later.
Four months later, subcutaneous nonulcerated, painful nodules appeared on the anterior area of the left lower leg, 20 cm distal from the primary ulcer caused by pyoderma gangrenosum. Ulceration recurred, and subcutaneous induration soon progressed toward both the distal and proximal directions. Immunosuppressive therapy restarted, but the painful ulcer persisted for one year. At this point of time, CMV viremia was identified, and the second skin biopsy from one of the subcutaneous nodules identified CMV inclusions in the subcutaneous tissue with fibrosing septolobular panniculitis. The CMV antigens were immunohistochemically visualized in the viral inclusions with 1 : 200 diluted cocktail monoclonal antibodies, CCH2+DDG9, available from Agilent Technologies (Figure 2). Both endothelial cells and perivascular stromal cells were infected. The dermis was free of inflammation. CyA was cancelled, PSL was reduced to 5 mg/day, and instead, ganciclovir (900 mg/day) was administered. Viremia soon disappeared, but the lower leg lesion progressed to form multiple ulcers. The third skin biopsy disclosed that infection involved both the dermis and the subcutaneous fat tissue. Suppurative granulomas (small abscesses surrounded by epithelioid granulomas) were dispersed (Figure 3). Gram-positive acid-fast bacilli were identified in microabscesses and also in fat droplets surrounded by suppurative granulomas (Figure 4). Caseous necrosis was focally associated. Grocott stain gave negative results. CMV infection was no longer identified. The second skin biopsy was retrospectively reevaluated, and Gram-positive acid-fast bacilli were identified mainly in microabscesses and in fat droplets surrounded by suppurative granulomas, multifocally distributed in the inflamed subcutaneous tissue. The final diagnosis of the second biopsy was thus subcutaneous coinfection of CMV and nontuberculous mycobacteria.
Microbial culture on 2% Ogawa medium at 37°C identified rapidly growing nontuberculous mycobacteria. The bacteria were acid-fast and Gram-positive. Mycobacterium chelonae was identified by analyzing with Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS) by using the MALDI Biotyper (Bruker Japan Daltonics division, Yokohama) (Figure 5) [4]. The log score value for M. chelonae was more than 2.0 (2.208).
Clarithromycin administration (800 mg/day), combined with thermotherapy using disposal pocket body warmers for one hour twice a day, resulted in marked regression of the ulcers. PSL tapering induced subcutaneous nodularity with ulceration, and thus, clarithromycin treatment was kept to date. After chemotherapy for 15 months, epithelialization was almost achieved. Valganciclovir was administered when CMV viremia reappeared.
Metformin (an oral antidiabetic) and sitagliptin phosphate hydrate (a selective inhibitor of dipeptidyl peptidase-4) continued for controlling type 2 diabetes mellitus. Mitiglinide calcium hydrate (a stimulator of insulin secretion) was added after the appearance of the skin ulceration for one year. During the clinical course, the patient's blood glucose levels were persistently hyperglycemic, ranging from 106 to 186 mg/dL but without glycosuria. Mild proteinuria ranging from 15 to 100 mg/dL was noted, indicating the complication of stage 2 (early) diabetic nephropathy. His HbA1c levels ranged from 6.4 to 7.3% (standard levels: 4.1–6.2%). The patient thus suffered from mild and controlled diabetes mellitus.
For characterizing the mycobacteria colonizing the skin lesion in the second and third skin biopsy specimens, immunostaining using selected antibodies was performed, as indicated in Table 1. An amino acid polymer method (Simple Stain Max-PO, Nichirei Biosciences, Tokyo) was employed. As reported in the previous article describing a low-specificity and high-sensitivity immunostaining with widely cross-reactive antibacterial antisera [5], the mycobacteria were visualized in formalin-fixed, paraffin-embedded sections. The antibodies gave clearly positive signals in the cytoplasm of macrophages infiltrating in the lesion, in addition to long rods labeled with Gram and Ziehl-Neelsen stains. Figure 6 illustrates positive findings with rabbit antisera to Bacillus Calmette-Guérin (BCG) [6], Bacillus cereus [5], MPT64 (also called as protein Rv1980c, M. tuberculosis-specific 24 kDa secretory antigen) [7], and monoclonal antibodies to LAM (M. tuberculosis-related lipoarabinomannan) [8] and PAB (Propionibacterium acnes-specific lipoteichoic acid) [9]. Antiserum to Treponema pallidum gave weak immunoreactivity. Escherichia coli antigens were scarcely observed. The background staining was minimal.
3. Discussion
Opportunistic infection caused by a variety of bacteria, fungi, or viruses occurs in the skin under the immunosuppressive state such as acquired immunodeficiency syndrome (AIDS) and after the use of immunosuppressive agents [1, 2]. One of the authors (YT) described histopathological features of such conditions in a textbook entitled Pathology of Skin Infections published in 2013 [10]. We describe herein a case of cutaneous coinfection of CMV and M. chelonae, provoked by immunosuppressive therapy against pyoderma gangrenosum. The patient suffered from mild and controlled type 2 diabetes mellitus. Pyoderma gangrenosum is characterized by noninfectious autoimmune-type progressive skin ulceration [11], successfully treated with immunosuppressive agents [12].
Opportunistic skin infection of CMV is rare. CMV mainly affects vascular endothelial cells and perivascular stromal cells, and multifocal anogenital ulcerations are most frequently encountered in AIDS patients [13]. Cutaneous lesions with verrucous elevations [14] and septal panniculitis [15] have also been described in non-AIDS immunosuppressed patients. Since the skin ulcer remained unchanged after ganciclovir treatment, Grushchak et al. regarded CMV infection as a bystander phenomenon [16]. The skin lesion in the present case demonstrated features of septolobular panniculitis with CMV inclusions in endothelial and perivascular stromal cells, but the lesion progressed to form large induration with multiple ulcers after gancyclovir treatment. It is reasonable to consider the CMV infection as bystander incidence associated with nontuberculous mycobacteriosis. In other words, when CMV inclusions are noted in nodular or ulcerated skin lesions, primary causative microbes other than CMV should be searched under the microscope, as was so in the present case.
Varied nontuberculous mycobacteria affect the skin, including M. avium-intracellulare complex, M. marinum, M. ulcerans, M. fortuitum, and M. chelonae-abscessus complex [17, 18]. Reportedly, rapidly growing mycobacteria (RGM) form colonies on a common chocolate agar medium when the culture period is prolonged to two weeks or more [19].
M. chelonae was first isolated from the tortoise by Friedmann in 1902 [20]. M. chelonae belongs to nonchromogenic RGM (Runyon group IV), widely distributed in environmental water [21]. This zoonotic mycobacterium, categorized in M. chelonae-abscessus complex, causes opportunistic infection in the human skin, as well as infection in aquatic animals such as the reptiles and fish [22]. Of notice is that not only traumatic injuries but also surgical procedures make risk factors of human infection [23]. It is plausible that in the present case, medical disposals caused iatrogenic infection of the environmental pathogen. Immunosuppression and diabetic conditions accelerated opportunistic infection, as reported previously [17, 18, 22]. Microscopically, infection of RGM, including M. chelonae, provokes abscess-forming granulomas (suppurative granulomas): some lesions are recognized as abscess surrounded by abortive granuloma formation, while the others predominantly reveal epithelioid granulomas [24, 25]. Acid-fast bacilli are characteristically identified in the lipid droplets (vacuoles) often located in the center of suppurative granulomas. It is noteworthy that the bacilli are positively labeled with Gram stain: namely, Gram positivity is a feature of RGM [26].
The cell wall of mycobacteria contains voluminous mycolic acids, extremely long fatty acids, as molecular forms of mycolic acid-containing glycolipid such as trehalose dimycolate and trehalose monomycolate, giving lipophilic nature of mycobacteria [27]. RGM are characterized by the presence of an additional mycolate, glucose mycolate, on the cell wall [28]. Such biological features may be related to the lipid droplet-centered pattern of infection by RGM.
Lipid droplet-centered suppurative granulomas are commonly observed in granulomatous mastitis caused by a lipophilic bacterium, Corynebacterium kroppenstedtii [29]. The Gram-positive rods are uniquely clustered in the lipid droplets surrounded by suppurative granulomas. The histological features are quite similar to those of RGM infection. Unlike other corynebacteria, C. kroppenstedtii lacks mycolic acid but instead contains tuberculostearic acid in the cell wall [30]. It is understandable from both the microscopic appearance and the pharmacodynamic properties of antibiotics [31] that administration of lipophilic antibiotics is essential for treating not only granulomatous mastitis but also RGM infection. The treatment regimen for tuberculosis using hydrophilic antibiotics such as isoniazid, ethambuthol, pyrazinamide, and streptomycin is consistently ineffective for infection of RGM, which are usually resistant to lipophilic rifampicin [18]. In the present case, clarithromycin, a type of lipophilic macrolides, was effective, as has been reported so far [32, 33]. Thermotherapy was also useful [34], based on the biological features of the bacteria showing low optimal temperature (25–37°C) for growth [17, 18].
Immunohistochemical cross-reactivity of rabbit antisera against BCG and B. cereus was observed in the infected lesion. T. pallidum antiserum also showed weak cross-reactivity. Positive signals with low background staining were observed not only on the mycobacteria in the lipid droplets but also in the cytoplasm of macrophages, so that the detection sensitivity was very high [5]. Similar results were observed in granulomatous mastitis [29]. The visualization of microbes within the lesion is essentially important for making a histopathological diagnosis of infection [5]. Another important point of our findings includes the cross-reactivity of antibodies against MPT64, LAM, and PAB to M. chelonae. It has been reported that MPT64 and LAM are specific to M. tuberculosis, and PAB is solely expressed on Propionibacterium (Cutibacterium) acnes [7–9]. The P. acnes antigens were detected in granulomas of sarcoidosis [35]. The lipophilic bacteria in granulomatous mastitis also expressed LAM and PAB (Tsutsumi, unpublished observation). Such unexpected cross-reactivity should be cautious about applying the antibacterial antibodies as immunohistochemical probes, as has been described previously [5].
4. Conclusion
We reported here rare opportunistic skin coinfection of CMV and M. chelonae, a rapidly growing nontuberculous mycobacterium, after immunosuppressive therapy against pyoderma gangrenosum. It is of note that M. chelonae provoked suppurative granulomas with lipid droplet-centered colonization of Gram-positive and acid-fast rods. Unique immunohistochemical reactivities with a variety of antibacterial antibodies were applicable to visualizing the causative mycobacteria in the lesion.
Acknowledgments
The authors deeply thank Mr. Izumi Kurita, M.T., Clinical Laboratory Medicine, Shimada Municipal Hospital, Shimada, for identifying M. chelonae.
Consent
The patient gave written informed consent to publication of the case report.
Disclosure
The present address of Kentaro Odani is the Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto. The present address of Hideo Hashizume is the Department of Dermatology, Iwata City Hospital, Iwata, Shizuoka.
Conflicts of Interest
The authors do not have any conflict of interest in the present report.
Authors' Contributions
We declare that all the authors (1) made a substantial contribution to the concept of the case report or interpretation of data and (2) approved the version to be submitted. (3) Each author has participated sufficiently in the work to take public responsibility for appropriate portions of the content.
Figure 1 Pyoderma gangrenosum ((a) gross appearance of left lower thigh, (b) H&E). A demarcated deep ulcer, 4 cm in size, is observed. Fibrinous exudation is seen at the ulcer base, and erythematous change is associated around the ulcer (a). Microscopic features of the first biopsy specimen are nonspecific. Ulcer base is composed of fibrinous exudation and granulation tissue (b). Neither granulomatous reactions nor infectious agents are identified.
Figure 2 A subcutaneous nodule without ulceration ((a) gross appearance; (b) H&E, low-powered view; (c) H&E, high-powered view of the subcutaneous tissue, inset: immunostaining for CMV antigens). Subcutaneous nodularity with mild reddening is observed on the lower thigh near the original ulcer by pyoderma gangrenosum (arrow, (a)). A low-powered view of the second biopsy specimen demonstrates subcutaneous septolobular panniculitis (b). Endothelial cells and perivascular stromal cells with enlarged nuclei reveal intranuclear and cytoplasmic inclusions (c). Immunostaining for CMV antigens is clearly positive (inset).
Figure 3 A large nodular and indurated skin lesion with multiple ulcers ((a) gross appearance, (b) H&E, low-powered view, and (c) H&E, high-powered view of the dermis). Multiple ulcers, 2–3 cm in size, are formed in the irregular-shaped reddish induration (a). The third biopsy specimen reveals diffuse inflammatory infiltration in the dermis through subcutaneous tissue (b). Suppurative granuloma (abscess surrounded by epithelioid granuloma) is scattered in the lesion (c). No CMV inclusions are observed any longer.
Figure 4 Gram-positive acid-fast bacilli in the second (a–c) and third (d–f) biopsy specimens ((a, d) H&E, (b, e) Ziehl-Neelsen stain, and (c, f) Gram stain). Gram-positive acid-fast bacilli are multifocally clustered in microabscess (a–c) and also in fat droplets located in the center of suppurative granuloma (d–f). The bacteria are visible in the fat droplets even in H&E preparations (d). Such patterns of bacterial colonization are seen in both the second and third biopsy specimens.
Figure 5 Colonies of Mycobacterium chelonae on 2% Ogawa medium ((a) gross appearance, (b) Ziehl-Neelsen stain, (c) Gram stain, and (d) MALDI Biotyper analysis). Smooth-surfaced white (nonchromogenic) colonies are formed seven days after inoculation. The formalin-fixed, paraffin-embedded colonies display acid-fastness and Gram reactivity of the rods. By the MALDI biotyping analysis, the spectrum pattern indicates M. chelonae with the log score value of 2.208.
Figure 6 Immunohistochemical demonstration of varied bacterial antigens ((a) BCG, (b) Bacillus cereus, (c) Treponema pallidum, (d) MPT64, (e) LAM, and (f) PAB). The cytoplasm of macrophages infiltrating around the fat droplet exhibits clear cross-reactivity with varied bacterial antigens. Immunoreactivity of T. pallidum antigens is relatively weak.
Table 1 Antibodies used in the present study.
Target antigen Animal/clone Dilution Antigen retrieval Source
Bacillus Calmette-Guérin (BCG) Rabbit antiserum 1 : 10,000 None Agilent
MPT64 (RV1980C, 24 kDa protein) Rabbit antiserum 1 : 800 HIER in 10 mM CB (pH 6) Abcam
LAM (lipoarabinomannan) Mouse TMDU3 1 : 1,000 HIER in 10 mM CB (pH 6) MBL
PAB (Propionibacterium acnes-specific lipoteichoic acid) Mouse TMDU2 1 : 4,000 HIER in 10 mM CB (pH 6) MBL
Bacillus cereus Rabbit antiserum 1 : 500 HIER in 10 mM CB (pH 6) Abcam
Treponema pallidum Rabbit antiserum 1 : 1,000 HIER in 1 mM EDTA (pH 8) BM
Escherichia coli Rabbit antiserum 1 : 20,000 Proteinase K digestion Agilent
MPT: mycobacterial protein tuberculosis; HIER: heat-induced epitope retrieval; CB: citrate buffer; EDTA: ethylenediamine tetraacetic acid; Agilent: Agilent Technologies (Santa Clara, CA, USA); MBL: Medical and Biological Laboratories (Nagoya, Japan); Abcam: Abcam plc (Cambridge, UK); BM: Biocare Medical LLC (Pacheco, Philippines). | Oral | DrugAdministrationRoute | CC BY | 33564484 | 19,706,871 | 2021 |
What was the outcome of reaction 'Condition aggravated'? | Cutaneous Coinfection of Cytomegalovirus and Mycobacterium chelonae Accelerated by Immunosuppression.
A mildly diabetic 58-year-old male had traumatic ulceration on the left popliteal fossa, and the lesion progressed to a painful 6 cm deep ulcer. After surgical debridement and skin grafting, ulceration recurred. Pyoderma gangrenosum was clinically diagnosed after the first biopsy, indicating a noninfective ulcer. Immunosuppressive therapy (prednisolone and cyclosporine A) induced complete epithelialization in three months. Four months later, subcutaneous nonulcerated nodules appeared on the anterior area of the left lower leg. Subcutaneous induration progressed and ulceration recurred, so that immunosuppressive therapy continued for one year. Cytomegalovirus (CMV) viremia was detected, and the second biopsy demonstrated CMV inclusions of endothelial and perivascular cells in fibrosing septolobular panniculitis. Cyclosporine A was cancelled, prednisolone was tapered, and ganciclovir started. Viremia soon disappeared, but the lesion progressed to large induration with multiple ulcers measuring up to 3 cm. The third biopsy disclosed infection of Gram-positive mycobacteria, accompanying fat droplet-centered suppurative granulomas without CMV infection. Microbial culture identified Mycobacterium chelonae. Clarithromycin with thermotherapy was effective. A review of the second biopsy confirmed coinfection of CMV and Gram-positive mycobacteria. Immunostaining using a panel of anti-bacterial antibodies visualized the mycobacteria in the lesion. Positive findings were obtained with antibodies to Bacillus Calmette-Guérin, Bacillus cereus, MPT64 (Mycobacterium tuberculosis-specific 24 kDa secretory antigen), LAM (Mycobacterium tuberculosis-related lipoarabinomannan), and PAB (Propionibacterium acnes-specific lipoteichoic acid).
1. Introduction
Immunosuppressive conditions may provoke opportunistic skin infection of a variety of bacteria, fungi, and viruses [1, 2]. The present article describes a case of pyoderma gangrenosum on the left popliteal fossa, followed by immunosuppressive therapy-induced opportunistic dual skin infection of cytomegalovirus (CMV) and Mycobacterium chelonae on the left lower leg. Histopathological and immunohistochemical features of this rare combination of pathogens are detailed.
2. Case Report
A 58-year-old Japanese man slipped and fell on the road to have his left knee contused, resulting in a 1.5 cm sized shallow ulceration. The patient had suffered from hypertension and mild type 2 diabetes mellitus for two years, but no history of autoimmune disorders. Serum antibodies against insulin and glutamic acid decarboxylase were negative, excluding the possibility of type 1 diabetes mellitus. He had smoked 15 cigarettes per day for more than 40 years. Five months later, a painful skin ulcer, 6 cm in size, occurred on the inner side of the left popliteal fossa (at the same site of contusion). No pathogens were identified in the biopsy specimen, and microbial culture was negative. Surgical debridement and full-thickness grafting from the abdominal skin were performed by a plastic surgeon, but half of the skin flap was eventually impaired, leaving a 3 cm sized deep ulcer with severe pain. The patient was then consulted to dermatologists. Clinical findings, as well as the first biopsy features displaying nonspecific and noninfective ulcer, were consistent with pyoderma gangrenosum (Figure 1). The serum level of granulocyte colony-stimulating factor, a biomarker of pyoderma gangrenosum [3], was elevated to 48.1 pg/mL (reference value < 30 pg/mL). Administration of prednisolone (PSL) (20 mg/day) and cyclosporine A (CyA: 100 mg/day) started. In order to control exacerbation of the skin lesion, medication of PSL plus CyA was maintained, while PSL was gradually tapered to 10 mg/day. Complete epithelialization was achieved three months later.
Four months later, subcutaneous nonulcerated, painful nodules appeared on the anterior area of the left lower leg, 20 cm distal from the primary ulcer caused by pyoderma gangrenosum. Ulceration recurred, and subcutaneous induration soon progressed toward both the distal and proximal directions. Immunosuppressive therapy restarted, but the painful ulcer persisted for one year. At this point of time, CMV viremia was identified, and the second skin biopsy from one of the subcutaneous nodules identified CMV inclusions in the subcutaneous tissue with fibrosing septolobular panniculitis. The CMV antigens were immunohistochemically visualized in the viral inclusions with 1 : 200 diluted cocktail monoclonal antibodies, CCH2+DDG9, available from Agilent Technologies (Figure 2). Both endothelial cells and perivascular stromal cells were infected. The dermis was free of inflammation. CyA was cancelled, PSL was reduced to 5 mg/day, and instead, ganciclovir (900 mg/day) was administered. Viremia soon disappeared, but the lower leg lesion progressed to form multiple ulcers. The third skin biopsy disclosed that infection involved both the dermis and the subcutaneous fat tissue. Suppurative granulomas (small abscesses surrounded by epithelioid granulomas) were dispersed (Figure 3). Gram-positive acid-fast bacilli were identified in microabscesses and also in fat droplets surrounded by suppurative granulomas (Figure 4). Caseous necrosis was focally associated. Grocott stain gave negative results. CMV infection was no longer identified. The second skin biopsy was retrospectively reevaluated, and Gram-positive acid-fast bacilli were identified mainly in microabscesses and in fat droplets surrounded by suppurative granulomas, multifocally distributed in the inflamed subcutaneous tissue. The final diagnosis of the second biopsy was thus subcutaneous coinfection of CMV and nontuberculous mycobacteria.
Microbial culture on 2% Ogawa medium at 37°C identified rapidly growing nontuberculous mycobacteria. The bacteria were acid-fast and Gram-positive. Mycobacterium chelonae was identified by analyzing with Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS) by using the MALDI Biotyper (Bruker Japan Daltonics division, Yokohama) (Figure 5) [4]. The log score value for M. chelonae was more than 2.0 (2.208).
Clarithromycin administration (800 mg/day), combined with thermotherapy using disposal pocket body warmers for one hour twice a day, resulted in marked regression of the ulcers. PSL tapering induced subcutaneous nodularity with ulceration, and thus, clarithromycin treatment was kept to date. After chemotherapy for 15 months, epithelialization was almost achieved. Valganciclovir was administered when CMV viremia reappeared.
Metformin (an oral antidiabetic) and sitagliptin phosphate hydrate (a selective inhibitor of dipeptidyl peptidase-4) continued for controlling type 2 diabetes mellitus. Mitiglinide calcium hydrate (a stimulator of insulin secretion) was added after the appearance of the skin ulceration for one year. During the clinical course, the patient's blood glucose levels were persistently hyperglycemic, ranging from 106 to 186 mg/dL but without glycosuria. Mild proteinuria ranging from 15 to 100 mg/dL was noted, indicating the complication of stage 2 (early) diabetic nephropathy. His HbA1c levels ranged from 6.4 to 7.3% (standard levels: 4.1–6.2%). The patient thus suffered from mild and controlled diabetes mellitus.
For characterizing the mycobacteria colonizing the skin lesion in the second and third skin biopsy specimens, immunostaining using selected antibodies was performed, as indicated in Table 1. An amino acid polymer method (Simple Stain Max-PO, Nichirei Biosciences, Tokyo) was employed. As reported in the previous article describing a low-specificity and high-sensitivity immunostaining with widely cross-reactive antibacterial antisera [5], the mycobacteria were visualized in formalin-fixed, paraffin-embedded sections. The antibodies gave clearly positive signals in the cytoplasm of macrophages infiltrating in the lesion, in addition to long rods labeled with Gram and Ziehl-Neelsen stains. Figure 6 illustrates positive findings with rabbit antisera to Bacillus Calmette-Guérin (BCG) [6], Bacillus cereus [5], MPT64 (also called as protein Rv1980c, M. tuberculosis-specific 24 kDa secretory antigen) [7], and monoclonal antibodies to LAM (M. tuberculosis-related lipoarabinomannan) [8] and PAB (Propionibacterium acnes-specific lipoteichoic acid) [9]. Antiserum to Treponema pallidum gave weak immunoreactivity. Escherichia coli antigens were scarcely observed. The background staining was minimal.
3. Discussion
Opportunistic infection caused by a variety of bacteria, fungi, or viruses occurs in the skin under the immunosuppressive state such as acquired immunodeficiency syndrome (AIDS) and after the use of immunosuppressive agents [1, 2]. One of the authors (YT) described histopathological features of such conditions in a textbook entitled Pathology of Skin Infections published in 2013 [10]. We describe herein a case of cutaneous coinfection of CMV and M. chelonae, provoked by immunosuppressive therapy against pyoderma gangrenosum. The patient suffered from mild and controlled type 2 diabetes mellitus. Pyoderma gangrenosum is characterized by noninfectious autoimmune-type progressive skin ulceration [11], successfully treated with immunosuppressive agents [12].
Opportunistic skin infection of CMV is rare. CMV mainly affects vascular endothelial cells and perivascular stromal cells, and multifocal anogenital ulcerations are most frequently encountered in AIDS patients [13]. Cutaneous lesions with verrucous elevations [14] and septal panniculitis [15] have also been described in non-AIDS immunosuppressed patients. Since the skin ulcer remained unchanged after ganciclovir treatment, Grushchak et al. regarded CMV infection as a bystander phenomenon [16]. The skin lesion in the present case demonstrated features of septolobular panniculitis with CMV inclusions in endothelial and perivascular stromal cells, but the lesion progressed to form large induration with multiple ulcers after gancyclovir treatment. It is reasonable to consider the CMV infection as bystander incidence associated with nontuberculous mycobacteriosis. In other words, when CMV inclusions are noted in nodular or ulcerated skin lesions, primary causative microbes other than CMV should be searched under the microscope, as was so in the present case.
Varied nontuberculous mycobacteria affect the skin, including M. avium-intracellulare complex, M. marinum, M. ulcerans, M. fortuitum, and M. chelonae-abscessus complex [17, 18]. Reportedly, rapidly growing mycobacteria (RGM) form colonies on a common chocolate agar medium when the culture period is prolonged to two weeks or more [19].
M. chelonae was first isolated from the tortoise by Friedmann in 1902 [20]. M. chelonae belongs to nonchromogenic RGM (Runyon group IV), widely distributed in environmental water [21]. This zoonotic mycobacterium, categorized in M. chelonae-abscessus complex, causes opportunistic infection in the human skin, as well as infection in aquatic animals such as the reptiles and fish [22]. Of notice is that not only traumatic injuries but also surgical procedures make risk factors of human infection [23]. It is plausible that in the present case, medical disposals caused iatrogenic infection of the environmental pathogen. Immunosuppression and diabetic conditions accelerated opportunistic infection, as reported previously [17, 18, 22]. Microscopically, infection of RGM, including M. chelonae, provokes abscess-forming granulomas (suppurative granulomas): some lesions are recognized as abscess surrounded by abortive granuloma formation, while the others predominantly reveal epithelioid granulomas [24, 25]. Acid-fast bacilli are characteristically identified in the lipid droplets (vacuoles) often located in the center of suppurative granulomas. It is noteworthy that the bacilli are positively labeled with Gram stain: namely, Gram positivity is a feature of RGM [26].
The cell wall of mycobacteria contains voluminous mycolic acids, extremely long fatty acids, as molecular forms of mycolic acid-containing glycolipid such as trehalose dimycolate and trehalose monomycolate, giving lipophilic nature of mycobacteria [27]. RGM are characterized by the presence of an additional mycolate, glucose mycolate, on the cell wall [28]. Such biological features may be related to the lipid droplet-centered pattern of infection by RGM.
Lipid droplet-centered suppurative granulomas are commonly observed in granulomatous mastitis caused by a lipophilic bacterium, Corynebacterium kroppenstedtii [29]. The Gram-positive rods are uniquely clustered in the lipid droplets surrounded by suppurative granulomas. The histological features are quite similar to those of RGM infection. Unlike other corynebacteria, C. kroppenstedtii lacks mycolic acid but instead contains tuberculostearic acid in the cell wall [30]. It is understandable from both the microscopic appearance and the pharmacodynamic properties of antibiotics [31] that administration of lipophilic antibiotics is essential for treating not only granulomatous mastitis but also RGM infection. The treatment regimen for tuberculosis using hydrophilic antibiotics such as isoniazid, ethambuthol, pyrazinamide, and streptomycin is consistently ineffective for infection of RGM, which are usually resistant to lipophilic rifampicin [18]. In the present case, clarithromycin, a type of lipophilic macrolides, was effective, as has been reported so far [32, 33]. Thermotherapy was also useful [34], based on the biological features of the bacteria showing low optimal temperature (25–37°C) for growth [17, 18].
Immunohistochemical cross-reactivity of rabbit antisera against BCG and B. cereus was observed in the infected lesion. T. pallidum antiserum also showed weak cross-reactivity. Positive signals with low background staining were observed not only on the mycobacteria in the lipid droplets but also in the cytoplasm of macrophages, so that the detection sensitivity was very high [5]. Similar results were observed in granulomatous mastitis [29]. The visualization of microbes within the lesion is essentially important for making a histopathological diagnosis of infection [5]. Another important point of our findings includes the cross-reactivity of antibodies against MPT64, LAM, and PAB to M. chelonae. It has been reported that MPT64 and LAM are specific to M. tuberculosis, and PAB is solely expressed on Propionibacterium (Cutibacterium) acnes [7–9]. The P. acnes antigens were detected in granulomas of sarcoidosis [35]. The lipophilic bacteria in granulomatous mastitis also expressed LAM and PAB (Tsutsumi, unpublished observation). Such unexpected cross-reactivity should be cautious about applying the antibacterial antibodies as immunohistochemical probes, as has been described previously [5].
4. Conclusion
We reported here rare opportunistic skin coinfection of CMV and M. chelonae, a rapidly growing nontuberculous mycobacterium, after immunosuppressive therapy against pyoderma gangrenosum. It is of note that M. chelonae provoked suppurative granulomas with lipid droplet-centered colonization of Gram-positive and acid-fast rods. Unique immunohistochemical reactivities with a variety of antibacterial antibodies were applicable to visualizing the causative mycobacteria in the lesion.
Acknowledgments
The authors deeply thank Mr. Izumi Kurita, M.T., Clinical Laboratory Medicine, Shimada Municipal Hospital, Shimada, for identifying M. chelonae.
Consent
The patient gave written informed consent to publication of the case report.
Disclosure
The present address of Kentaro Odani is the Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto. The present address of Hideo Hashizume is the Department of Dermatology, Iwata City Hospital, Iwata, Shizuoka.
Conflicts of Interest
The authors do not have any conflict of interest in the present report.
Authors' Contributions
We declare that all the authors (1) made a substantial contribution to the concept of the case report or interpretation of data and (2) approved the version to be submitted. (3) Each author has participated sufficiently in the work to take public responsibility for appropriate portions of the content.
Figure 1 Pyoderma gangrenosum ((a) gross appearance of left lower thigh, (b) H&E). A demarcated deep ulcer, 4 cm in size, is observed. Fibrinous exudation is seen at the ulcer base, and erythematous change is associated around the ulcer (a). Microscopic features of the first biopsy specimen are nonspecific. Ulcer base is composed of fibrinous exudation and granulation tissue (b). Neither granulomatous reactions nor infectious agents are identified.
Figure 2 A subcutaneous nodule without ulceration ((a) gross appearance; (b) H&E, low-powered view; (c) H&E, high-powered view of the subcutaneous tissue, inset: immunostaining for CMV antigens). Subcutaneous nodularity with mild reddening is observed on the lower thigh near the original ulcer by pyoderma gangrenosum (arrow, (a)). A low-powered view of the second biopsy specimen demonstrates subcutaneous septolobular panniculitis (b). Endothelial cells and perivascular stromal cells with enlarged nuclei reveal intranuclear and cytoplasmic inclusions (c). Immunostaining for CMV antigens is clearly positive (inset).
Figure 3 A large nodular and indurated skin lesion with multiple ulcers ((a) gross appearance, (b) H&E, low-powered view, and (c) H&E, high-powered view of the dermis). Multiple ulcers, 2–3 cm in size, are formed in the irregular-shaped reddish induration (a). The third biopsy specimen reveals diffuse inflammatory infiltration in the dermis through subcutaneous tissue (b). Suppurative granuloma (abscess surrounded by epithelioid granuloma) is scattered in the lesion (c). No CMV inclusions are observed any longer.
Figure 4 Gram-positive acid-fast bacilli in the second (a–c) and third (d–f) biopsy specimens ((a, d) H&E, (b, e) Ziehl-Neelsen stain, and (c, f) Gram stain). Gram-positive acid-fast bacilli are multifocally clustered in microabscess (a–c) and also in fat droplets located in the center of suppurative granuloma (d–f). The bacteria are visible in the fat droplets even in H&E preparations (d). Such patterns of bacterial colonization are seen in both the second and third biopsy specimens.
Figure 5 Colonies of Mycobacterium chelonae on 2% Ogawa medium ((a) gross appearance, (b) Ziehl-Neelsen stain, (c) Gram stain, and (d) MALDI Biotyper analysis). Smooth-surfaced white (nonchromogenic) colonies are formed seven days after inoculation. The formalin-fixed, paraffin-embedded colonies display acid-fastness and Gram reactivity of the rods. By the MALDI biotyping analysis, the spectrum pattern indicates M. chelonae with the log score value of 2.208.
Figure 6 Immunohistochemical demonstration of varied bacterial antigens ((a) BCG, (b) Bacillus cereus, (c) Treponema pallidum, (d) MPT64, (e) LAM, and (f) PAB). The cytoplasm of macrophages infiltrating around the fat droplet exhibits clear cross-reactivity with varied bacterial antigens. Immunoreactivity of T. pallidum antigens is relatively weak.
Table 1 Antibodies used in the present study.
Target antigen Animal/clone Dilution Antigen retrieval Source
Bacillus Calmette-Guérin (BCG) Rabbit antiserum 1 : 10,000 None Agilent
MPT64 (RV1980C, 24 kDa protein) Rabbit antiserum 1 : 800 HIER in 10 mM CB (pH 6) Abcam
LAM (lipoarabinomannan) Mouse TMDU3 1 : 1,000 HIER in 10 mM CB (pH 6) MBL
PAB (Propionibacterium acnes-specific lipoteichoic acid) Mouse TMDU2 1 : 4,000 HIER in 10 mM CB (pH 6) MBL
Bacillus cereus Rabbit antiserum 1 : 500 HIER in 10 mM CB (pH 6) Abcam
Treponema pallidum Rabbit antiserum 1 : 1,000 HIER in 1 mM EDTA (pH 8) BM
Escherichia coli Rabbit antiserum 1 : 20,000 Proteinase K digestion Agilent
MPT: mycobacterial protein tuberculosis; HIER: heat-induced epitope retrieval; CB: citrate buffer; EDTA: ethylenediamine tetraacetic acid; Agilent: Agilent Technologies (Santa Clara, CA, USA); MBL: Medical and Biological Laboratories (Nagoya, Japan); Abcam: Abcam plc (Cambridge, UK); BM: Biocare Medical LLC (Pacheco, Philippines). | Recovered | ReactionOutcome | CC BY | 33564484 | 19,706,871 | 2021 |
What was the outcome of reaction 'Cytomegalovirus infection'? | Cutaneous Coinfection of Cytomegalovirus and Mycobacterium chelonae Accelerated by Immunosuppression.
A mildly diabetic 58-year-old male had traumatic ulceration on the left popliteal fossa, and the lesion progressed to a painful 6 cm deep ulcer. After surgical debridement and skin grafting, ulceration recurred. Pyoderma gangrenosum was clinically diagnosed after the first biopsy, indicating a noninfective ulcer. Immunosuppressive therapy (prednisolone and cyclosporine A) induced complete epithelialization in three months. Four months later, subcutaneous nonulcerated nodules appeared on the anterior area of the left lower leg. Subcutaneous induration progressed and ulceration recurred, so that immunosuppressive therapy continued for one year. Cytomegalovirus (CMV) viremia was detected, and the second biopsy demonstrated CMV inclusions of endothelial and perivascular cells in fibrosing septolobular panniculitis. Cyclosporine A was cancelled, prednisolone was tapered, and ganciclovir started. Viremia soon disappeared, but the lesion progressed to large induration with multiple ulcers measuring up to 3 cm. The third biopsy disclosed infection of Gram-positive mycobacteria, accompanying fat droplet-centered suppurative granulomas without CMV infection. Microbial culture identified Mycobacterium chelonae. Clarithromycin with thermotherapy was effective. A review of the second biopsy confirmed coinfection of CMV and Gram-positive mycobacteria. Immunostaining using a panel of anti-bacterial antibodies visualized the mycobacteria in the lesion. Positive findings were obtained with antibodies to Bacillus Calmette-Guérin, Bacillus cereus, MPT64 (Mycobacterium tuberculosis-specific 24 kDa secretory antigen), LAM (Mycobacterium tuberculosis-related lipoarabinomannan), and PAB (Propionibacterium acnes-specific lipoteichoic acid).
1. Introduction
Immunosuppressive conditions may provoke opportunistic skin infection of a variety of bacteria, fungi, and viruses [1, 2]. The present article describes a case of pyoderma gangrenosum on the left popliteal fossa, followed by immunosuppressive therapy-induced opportunistic dual skin infection of cytomegalovirus (CMV) and Mycobacterium chelonae on the left lower leg. Histopathological and immunohistochemical features of this rare combination of pathogens are detailed.
2. Case Report
A 58-year-old Japanese man slipped and fell on the road to have his left knee contused, resulting in a 1.5 cm sized shallow ulceration. The patient had suffered from hypertension and mild type 2 diabetes mellitus for two years, but no history of autoimmune disorders. Serum antibodies against insulin and glutamic acid decarboxylase were negative, excluding the possibility of type 1 diabetes mellitus. He had smoked 15 cigarettes per day for more than 40 years. Five months later, a painful skin ulcer, 6 cm in size, occurred on the inner side of the left popliteal fossa (at the same site of contusion). No pathogens were identified in the biopsy specimen, and microbial culture was negative. Surgical debridement and full-thickness grafting from the abdominal skin were performed by a plastic surgeon, but half of the skin flap was eventually impaired, leaving a 3 cm sized deep ulcer with severe pain. The patient was then consulted to dermatologists. Clinical findings, as well as the first biopsy features displaying nonspecific and noninfective ulcer, were consistent with pyoderma gangrenosum (Figure 1). The serum level of granulocyte colony-stimulating factor, a biomarker of pyoderma gangrenosum [3], was elevated to 48.1 pg/mL (reference value < 30 pg/mL). Administration of prednisolone (PSL) (20 mg/day) and cyclosporine A (CyA: 100 mg/day) started. In order to control exacerbation of the skin lesion, medication of PSL plus CyA was maintained, while PSL was gradually tapered to 10 mg/day. Complete epithelialization was achieved three months later.
Four months later, subcutaneous nonulcerated, painful nodules appeared on the anterior area of the left lower leg, 20 cm distal from the primary ulcer caused by pyoderma gangrenosum. Ulceration recurred, and subcutaneous induration soon progressed toward both the distal and proximal directions. Immunosuppressive therapy restarted, but the painful ulcer persisted for one year. At this point of time, CMV viremia was identified, and the second skin biopsy from one of the subcutaneous nodules identified CMV inclusions in the subcutaneous tissue with fibrosing septolobular panniculitis. The CMV antigens were immunohistochemically visualized in the viral inclusions with 1 : 200 diluted cocktail monoclonal antibodies, CCH2+DDG9, available from Agilent Technologies (Figure 2). Both endothelial cells and perivascular stromal cells were infected. The dermis was free of inflammation. CyA was cancelled, PSL was reduced to 5 mg/day, and instead, ganciclovir (900 mg/day) was administered. Viremia soon disappeared, but the lower leg lesion progressed to form multiple ulcers. The third skin biopsy disclosed that infection involved both the dermis and the subcutaneous fat tissue. Suppurative granulomas (small abscesses surrounded by epithelioid granulomas) were dispersed (Figure 3). Gram-positive acid-fast bacilli were identified in microabscesses and also in fat droplets surrounded by suppurative granulomas (Figure 4). Caseous necrosis was focally associated. Grocott stain gave negative results. CMV infection was no longer identified. The second skin biopsy was retrospectively reevaluated, and Gram-positive acid-fast bacilli were identified mainly in microabscesses and in fat droplets surrounded by suppurative granulomas, multifocally distributed in the inflamed subcutaneous tissue. The final diagnosis of the second biopsy was thus subcutaneous coinfection of CMV and nontuberculous mycobacteria.
Microbial culture on 2% Ogawa medium at 37°C identified rapidly growing nontuberculous mycobacteria. The bacteria were acid-fast and Gram-positive. Mycobacterium chelonae was identified by analyzing with Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS) by using the MALDI Biotyper (Bruker Japan Daltonics division, Yokohama) (Figure 5) [4]. The log score value for M. chelonae was more than 2.0 (2.208).
Clarithromycin administration (800 mg/day), combined with thermotherapy using disposal pocket body warmers for one hour twice a day, resulted in marked regression of the ulcers. PSL tapering induced subcutaneous nodularity with ulceration, and thus, clarithromycin treatment was kept to date. After chemotherapy for 15 months, epithelialization was almost achieved. Valganciclovir was administered when CMV viremia reappeared.
Metformin (an oral antidiabetic) and sitagliptin phosphate hydrate (a selective inhibitor of dipeptidyl peptidase-4) continued for controlling type 2 diabetes mellitus. Mitiglinide calcium hydrate (a stimulator of insulin secretion) was added after the appearance of the skin ulceration for one year. During the clinical course, the patient's blood glucose levels were persistently hyperglycemic, ranging from 106 to 186 mg/dL but without glycosuria. Mild proteinuria ranging from 15 to 100 mg/dL was noted, indicating the complication of stage 2 (early) diabetic nephropathy. His HbA1c levels ranged from 6.4 to 7.3% (standard levels: 4.1–6.2%). The patient thus suffered from mild and controlled diabetes mellitus.
For characterizing the mycobacteria colonizing the skin lesion in the second and third skin biopsy specimens, immunostaining using selected antibodies was performed, as indicated in Table 1. An amino acid polymer method (Simple Stain Max-PO, Nichirei Biosciences, Tokyo) was employed. As reported in the previous article describing a low-specificity and high-sensitivity immunostaining with widely cross-reactive antibacterial antisera [5], the mycobacteria were visualized in formalin-fixed, paraffin-embedded sections. The antibodies gave clearly positive signals in the cytoplasm of macrophages infiltrating in the lesion, in addition to long rods labeled with Gram and Ziehl-Neelsen stains. Figure 6 illustrates positive findings with rabbit antisera to Bacillus Calmette-Guérin (BCG) [6], Bacillus cereus [5], MPT64 (also called as protein Rv1980c, M. tuberculosis-specific 24 kDa secretory antigen) [7], and monoclonal antibodies to LAM (M. tuberculosis-related lipoarabinomannan) [8] and PAB (Propionibacterium acnes-specific lipoteichoic acid) [9]. Antiserum to Treponema pallidum gave weak immunoreactivity. Escherichia coli antigens were scarcely observed. The background staining was minimal.
3. Discussion
Opportunistic infection caused by a variety of bacteria, fungi, or viruses occurs in the skin under the immunosuppressive state such as acquired immunodeficiency syndrome (AIDS) and after the use of immunosuppressive agents [1, 2]. One of the authors (YT) described histopathological features of such conditions in a textbook entitled Pathology of Skin Infections published in 2013 [10]. We describe herein a case of cutaneous coinfection of CMV and M. chelonae, provoked by immunosuppressive therapy against pyoderma gangrenosum. The patient suffered from mild and controlled type 2 diabetes mellitus. Pyoderma gangrenosum is characterized by noninfectious autoimmune-type progressive skin ulceration [11], successfully treated with immunosuppressive agents [12].
Opportunistic skin infection of CMV is rare. CMV mainly affects vascular endothelial cells and perivascular stromal cells, and multifocal anogenital ulcerations are most frequently encountered in AIDS patients [13]. Cutaneous lesions with verrucous elevations [14] and septal panniculitis [15] have also been described in non-AIDS immunosuppressed patients. Since the skin ulcer remained unchanged after ganciclovir treatment, Grushchak et al. regarded CMV infection as a bystander phenomenon [16]. The skin lesion in the present case demonstrated features of septolobular panniculitis with CMV inclusions in endothelial and perivascular stromal cells, but the lesion progressed to form large induration with multiple ulcers after gancyclovir treatment. It is reasonable to consider the CMV infection as bystander incidence associated with nontuberculous mycobacteriosis. In other words, when CMV inclusions are noted in nodular or ulcerated skin lesions, primary causative microbes other than CMV should be searched under the microscope, as was so in the present case.
Varied nontuberculous mycobacteria affect the skin, including M. avium-intracellulare complex, M. marinum, M. ulcerans, M. fortuitum, and M. chelonae-abscessus complex [17, 18]. Reportedly, rapidly growing mycobacteria (RGM) form colonies on a common chocolate agar medium when the culture period is prolonged to two weeks or more [19].
M. chelonae was first isolated from the tortoise by Friedmann in 1902 [20]. M. chelonae belongs to nonchromogenic RGM (Runyon group IV), widely distributed in environmental water [21]. This zoonotic mycobacterium, categorized in M. chelonae-abscessus complex, causes opportunistic infection in the human skin, as well as infection in aquatic animals such as the reptiles and fish [22]. Of notice is that not only traumatic injuries but also surgical procedures make risk factors of human infection [23]. It is plausible that in the present case, medical disposals caused iatrogenic infection of the environmental pathogen. Immunosuppression and diabetic conditions accelerated opportunistic infection, as reported previously [17, 18, 22]. Microscopically, infection of RGM, including M. chelonae, provokes abscess-forming granulomas (suppurative granulomas): some lesions are recognized as abscess surrounded by abortive granuloma formation, while the others predominantly reveal epithelioid granulomas [24, 25]. Acid-fast bacilli are characteristically identified in the lipid droplets (vacuoles) often located in the center of suppurative granulomas. It is noteworthy that the bacilli are positively labeled with Gram stain: namely, Gram positivity is a feature of RGM [26].
The cell wall of mycobacteria contains voluminous mycolic acids, extremely long fatty acids, as molecular forms of mycolic acid-containing glycolipid such as trehalose dimycolate and trehalose monomycolate, giving lipophilic nature of mycobacteria [27]. RGM are characterized by the presence of an additional mycolate, glucose mycolate, on the cell wall [28]. Such biological features may be related to the lipid droplet-centered pattern of infection by RGM.
Lipid droplet-centered suppurative granulomas are commonly observed in granulomatous mastitis caused by a lipophilic bacterium, Corynebacterium kroppenstedtii [29]. The Gram-positive rods are uniquely clustered in the lipid droplets surrounded by suppurative granulomas. The histological features are quite similar to those of RGM infection. Unlike other corynebacteria, C. kroppenstedtii lacks mycolic acid but instead contains tuberculostearic acid in the cell wall [30]. It is understandable from both the microscopic appearance and the pharmacodynamic properties of antibiotics [31] that administration of lipophilic antibiotics is essential for treating not only granulomatous mastitis but also RGM infection. The treatment regimen for tuberculosis using hydrophilic antibiotics such as isoniazid, ethambuthol, pyrazinamide, and streptomycin is consistently ineffective for infection of RGM, which are usually resistant to lipophilic rifampicin [18]. In the present case, clarithromycin, a type of lipophilic macrolides, was effective, as has been reported so far [32, 33]. Thermotherapy was also useful [34], based on the biological features of the bacteria showing low optimal temperature (25–37°C) for growth [17, 18].
Immunohistochemical cross-reactivity of rabbit antisera against BCG and B. cereus was observed in the infected lesion. T. pallidum antiserum also showed weak cross-reactivity. Positive signals with low background staining were observed not only on the mycobacteria in the lipid droplets but also in the cytoplasm of macrophages, so that the detection sensitivity was very high [5]. Similar results were observed in granulomatous mastitis [29]. The visualization of microbes within the lesion is essentially important for making a histopathological diagnosis of infection [5]. Another important point of our findings includes the cross-reactivity of antibodies against MPT64, LAM, and PAB to M. chelonae. It has been reported that MPT64 and LAM are specific to M. tuberculosis, and PAB is solely expressed on Propionibacterium (Cutibacterium) acnes [7–9]. The P. acnes antigens were detected in granulomas of sarcoidosis [35]. The lipophilic bacteria in granulomatous mastitis also expressed LAM and PAB (Tsutsumi, unpublished observation). Such unexpected cross-reactivity should be cautious about applying the antibacterial antibodies as immunohistochemical probes, as has been described previously [5].
4. Conclusion
We reported here rare opportunistic skin coinfection of CMV and M. chelonae, a rapidly growing nontuberculous mycobacterium, after immunosuppressive therapy against pyoderma gangrenosum. It is of note that M. chelonae provoked suppurative granulomas with lipid droplet-centered colonization of Gram-positive and acid-fast rods. Unique immunohistochemical reactivities with a variety of antibacterial antibodies were applicable to visualizing the causative mycobacteria in the lesion.
Acknowledgments
The authors deeply thank Mr. Izumi Kurita, M.T., Clinical Laboratory Medicine, Shimada Municipal Hospital, Shimada, for identifying M. chelonae.
Consent
The patient gave written informed consent to publication of the case report.
Disclosure
The present address of Kentaro Odani is the Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto. The present address of Hideo Hashizume is the Department of Dermatology, Iwata City Hospital, Iwata, Shizuoka.
Conflicts of Interest
The authors do not have any conflict of interest in the present report.
Authors' Contributions
We declare that all the authors (1) made a substantial contribution to the concept of the case report or interpretation of data and (2) approved the version to be submitted. (3) Each author has participated sufficiently in the work to take public responsibility for appropriate portions of the content.
Figure 1 Pyoderma gangrenosum ((a) gross appearance of left lower thigh, (b) H&E). A demarcated deep ulcer, 4 cm in size, is observed. Fibrinous exudation is seen at the ulcer base, and erythematous change is associated around the ulcer (a). Microscopic features of the first biopsy specimen are nonspecific. Ulcer base is composed of fibrinous exudation and granulation tissue (b). Neither granulomatous reactions nor infectious agents are identified.
Figure 2 A subcutaneous nodule without ulceration ((a) gross appearance; (b) H&E, low-powered view; (c) H&E, high-powered view of the subcutaneous tissue, inset: immunostaining for CMV antigens). Subcutaneous nodularity with mild reddening is observed on the lower thigh near the original ulcer by pyoderma gangrenosum (arrow, (a)). A low-powered view of the second biopsy specimen demonstrates subcutaneous septolobular panniculitis (b). Endothelial cells and perivascular stromal cells with enlarged nuclei reveal intranuclear and cytoplasmic inclusions (c). Immunostaining for CMV antigens is clearly positive (inset).
Figure 3 A large nodular and indurated skin lesion with multiple ulcers ((a) gross appearance, (b) H&E, low-powered view, and (c) H&E, high-powered view of the dermis). Multiple ulcers, 2–3 cm in size, are formed in the irregular-shaped reddish induration (a). The third biopsy specimen reveals diffuse inflammatory infiltration in the dermis through subcutaneous tissue (b). Suppurative granuloma (abscess surrounded by epithelioid granuloma) is scattered in the lesion (c). No CMV inclusions are observed any longer.
Figure 4 Gram-positive acid-fast bacilli in the second (a–c) and third (d–f) biopsy specimens ((a, d) H&E, (b, e) Ziehl-Neelsen stain, and (c, f) Gram stain). Gram-positive acid-fast bacilli are multifocally clustered in microabscess (a–c) and also in fat droplets located in the center of suppurative granuloma (d–f). The bacteria are visible in the fat droplets even in H&E preparations (d). Such patterns of bacterial colonization are seen in both the second and third biopsy specimens.
Figure 5 Colonies of Mycobacterium chelonae on 2% Ogawa medium ((a) gross appearance, (b) Ziehl-Neelsen stain, (c) Gram stain, and (d) MALDI Biotyper analysis). Smooth-surfaced white (nonchromogenic) colonies are formed seven days after inoculation. The formalin-fixed, paraffin-embedded colonies display acid-fastness and Gram reactivity of the rods. By the MALDI biotyping analysis, the spectrum pattern indicates M. chelonae with the log score value of 2.208.
Figure 6 Immunohistochemical demonstration of varied bacterial antigens ((a) BCG, (b) Bacillus cereus, (c) Treponema pallidum, (d) MPT64, (e) LAM, and (f) PAB). The cytoplasm of macrophages infiltrating around the fat droplet exhibits clear cross-reactivity with varied bacterial antigens. Immunoreactivity of T. pallidum antigens is relatively weak.
Table 1 Antibodies used in the present study.
Target antigen Animal/clone Dilution Antigen retrieval Source
Bacillus Calmette-Guérin (BCG) Rabbit antiserum 1 : 10,000 None Agilent
MPT64 (RV1980C, 24 kDa protein) Rabbit antiserum 1 : 800 HIER in 10 mM CB (pH 6) Abcam
LAM (lipoarabinomannan) Mouse TMDU3 1 : 1,000 HIER in 10 mM CB (pH 6) MBL
PAB (Propionibacterium acnes-specific lipoteichoic acid) Mouse TMDU2 1 : 4,000 HIER in 10 mM CB (pH 6) MBL
Bacillus cereus Rabbit antiserum 1 : 500 HIER in 10 mM CB (pH 6) Abcam
Treponema pallidum Rabbit antiserum 1 : 1,000 HIER in 1 mM EDTA (pH 8) BM
Escherichia coli Rabbit antiserum 1 : 20,000 Proteinase K digestion Agilent
MPT: mycobacterial protein tuberculosis; HIER: heat-induced epitope retrieval; CB: citrate buffer; EDTA: ethylenediamine tetraacetic acid; Agilent: Agilent Technologies (Santa Clara, CA, USA); MBL: Medical and Biological Laboratories (Nagoya, Japan); Abcam: Abcam plc (Cambridge, UK); BM: Biocare Medical LLC (Pacheco, Philippines). | Not recovered | ReactionOutcome | CC BY | 33564484 | 19,706,871 | 2021 |
What was the outcome of reaction 'Ulcer'? | Cutaneous Coinfection of Cytomegalovirus and Mycobacterium chelonae Accelerated by Immunosuppression.
A mildly diabetic 58-year-old male had traumatic ulceration on the left popliteal fossa, and the lesion progressed to a painful 6 cm deep ulcer. After surgical debridement and skin grafting, ulceration recurred. Pyoderma gangrenosum was clinically diagnosed after the first biopsy, indicating a noninfective ulcer. Immunosuppressive therapy (prednisolone and cyclosporine A) induced complete epithelialization in three months. Four months later, subcutaneous nonulcerated nodules appeared on the anterior area of the left lower leg. Subcutaneous induration progressed and ulceration recurred, so that immunosuppressive therapy continued for one year. Cytomegalovirus (CMV) viremia was detected, and the second biopsy demonstrated CMV inclusions of endothelial and perivascular cells in fibrosing septolobular panniculitis. Cyclosporine A was cancelled, prednisolone was tapered, and ganciclovir started. Viremia soon disappeared, but the lesion progressed to large induration with multiple ulcers measuring up to 3 cm. The third biopsy disclosed infection of Gram-positive mycobacteria, accompanying fat droplet-centered suppurative granulomas without CMV infection. Microbial culture identified Mycobacterium chelonae. Clarithromycin with thermotherapy was effective. A review of the second biopsy confirmed coinfection of CMV and Gram-positive mycobacteria. Immunostaining using a panel of anti-bacterial antibodies visualized the mycobacteria in the lesion. Positive findings were obtained with antibodies to Bacillus Calmette-Guérin, Bacillus cereus, MPT64 (Mycobacterium tuberculosis-specific 24 kDa secretory antigen), LAM (Mycobacterium tuberculosis-related lipoarabinomannan), and PAB (Propionibacterium acnes-specific lipoteichoic acid).
1. Introduction
Immunosuppressive conditions may provoke opportunistic skin infection of a variety of bacteria, fungi, and viruses [1, 2]. The present article describes a case of pyoderma gangrenosum on the left popliteal fossa, followed by immunosuppressive therapy-induced opportunistic dual skin infection of cytomegalovirus (CMV) and Mycobacterium chelonae on the left lower leg. Histopathological and immunohistochemical features of this rare combination of pathogens are detailed.
2. Case Report
A 58-year-old Japanese man slipped and fell on the road to have his left knee contused, resulting in a 1.5 cm sized shallow ulceration. The patient had suffered from hypertension and mild type 2 diabetes mellitus for two years, but no history of autoimmune disorders. Serum antibodies against insulin and glutamic acid decarboxylase were negative, excluding the possibility of type 1 diabetes mellitus. He had smoked 15 cigarettes per day for more than 40 years. Five months later, a painful skin ulcer, 6 cm in size, occurred on the inner side of the left popliteal fossa (at the same site of contusion). No pathogens were identified in the biopsy specimen, and microbial culture was negative. Surgical debridement and full-thickness grafting from the abdominal skin were performed by a plastic surgeon, but half of the skin flap was eventually impaired, leaving a 3 cm sized deep ulcer with severe pain. The patient was then consulted to dermatologists. Clinical findings, as well as the first biopsy features displaying nonspecific and noninfective ulcer, were consistent with pyoderma gangrenosum (Figure 1). The serum level of granulocyte colony-stimulating factor, a biomarker of pyoderma gangrenosum [3], was elevated to 48.1 pg/mL (reference value < 30 pg/mL). Administration of prednisolone (PSL) (20 mg/day) and cyclosporine A (CyA: 100 mg/day) started. In order to control exacerbation of the skin lesion, medication of PSL plus CyA was maintained, while PSL was gradually tapered to 10 mg/day. Complete epithelialization was achieved three months later.
Four months later, subcutaneous nonulcerated, painful nodules appeared on the anterior area of the left lower leg, 20 cm distal from the primary ulcer caused by pyoderma gangrenosum. Ulceration recurred, and subcutaneous induration soon progressed toward both the distal and proximal directions. Immunosuppressive therapy restarted, but the painful ulcer persisted for one year. At this point of time, CMV viremia was identified, and the second skin biopsy from one of the subcutaneous nodules identified CMV inclusions in the subcutaneous tissue with fibrosing septolobular panniculitis. The CMV antigens were immunohistochemically visualized in the viral inclusions with 1 : 200 diluted cocktail monoclonal antibodies, CCH2+DDG9, available from Agilent Technologies (Figure 2). Both endothelial cells and perivascular stromal cells were infected. The dermis was free of inflammation. CyA was cancelled, PSL was reduced to 5 mg/day, and instead, ganciclovir (900 mg/day) was administered. Viremia soon disappeared, but the lower leg lesion progressed to form multiple ulcers. The third skin biopsy disclosed that infection involved both the dermis and the subcutaneous fat tissue. Suppurative granulomas (small abscesses surrounded by epithelioid granulomas) were dispersed (Figure 3). Gram-positive acid-fast bacilli were identified in microabscesses and also in fat droplets surrounded by suppurative granulomas (Figure 4). Caseous necrosis was focally associated. Grocott stain gave negative results. CMV infection was no longer identified. The second skin biopsy was retrospectively reevaluated, and Gram-positive acid-fast bacilli were identified mainly in microabscesses and in fat droplets surrounded by suppurative granulomas, multifocally distributed in the inflamed subcutaneous tissue. The final diagnosis of the second biopsy was thus subcutaneous coinfection of CMV and nontuberculous mycobacteria.
Microbial culture on 2% Ogawa medium at 37°C identified rapidly growing nontuberculous mycobacteria. The bacteria were acid-fast and Gram-positive. Mycobacterium chelonae was identified by analyzing with Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS) by using the MALDI Biotyper (Bruker Japan Daltonics division, Yokohama) (Figure 5) [4]. The log score value for M. chelonae was more than 2.0 (2.208).
Clarithromycin administration (800 mg/day), combined with thermotherapy using disposal pocket body warmers for one hour twice a day, resulted in marked regression of the ulcers. PSL tapering induced subcutaneous nodularity with ulceration, and thus, clarithromycin treatment was kept to date. After chemotherapy for 15 months, epithelialization was almost achieved. Valganciclovir was administered when CMV viremia reappeared.
Metformin (an oral antidiabetic) and sitagliptin phosphate hydrate (a selective inhibitor of dipeptidyl peptidase-4) continued for controlling type 2 diabetes mellitus. Mitiglinide calcium hydrate (a stimulator of insulin secretion) was added after the appearance of the skin ulceration for one year. During the clinical course, the patient's blood glucose levels were persistently hyperglycemic, ranging from 106 to 186 mg/dL but without glycosuria. Mild proteinuria ranging from 15 to 100 mg/dL was noted, indicating the complication of stage 2 (early) diabetic nephropathy. His HbA1c levels ranged from 6.4 to 7.3% (standard levels: 4.1–6.2%). The patient thus suffered from mild and controlled diabetes mellitus.
For characterizing the mycobacteria colonizing the skin lesion in the second and third skin biopsy specimens, immunostaining using selected antibodies was performed, as indicated in Table 1. An amino acid polymer method (Simple Stain Max-PO, Nichirei Biosciences, Tokyo) was employed. As reported in the previous article describing a low-specificity and high-sensitivity immunostaining with widely cross-reactive antibacterial antisera [5], the mycobacteria were visualized in formalin-fixed, paraffin-embedded sections. The antibodies gave clearly positive signals in the cytoplasm of macrophages infiltrating in the lesion, in addition to long rods labeled with Gram and Ziehl-Neelsen stains. Figure 6 illustrates positive findings with rabbit antisera to Bacillus Calmette-Guérin (BCG) [6], Bacillus cereus [5], MPT64 (also called as protein Rv1980c, M. tuberculosis-specific 24 kDa secretory antigen) [7], and monoclonal antibodies to LAM (M. tuberculosis-related lipoarabinomannan) [8] and PAB (Propionibacterium acnes-specific lipoteichoic acid) [9]. Antiserum to Treponema pallidum gave weak immunoreactivity. Escherichia coli antigens were scarcely observed. The background staining was minimal.
3. Discussion
Opportunistic infection caused by a variety of bacteria, fungi, or viruses occurs in the skin under the immunosuppressive state such as acquired immunodeficiency syndrome (AIDS) and after the use of immunosuppressive agents [1, 2]. One of the authors (YT) described histopathological features of such conditions in a textbook entitled Pathology of Skin Infections published in 2013 [10]. We describe herein a case of cutaneous coinfection of CMV and M. chelonae, provoked by immunosuppressive therapy against pyoderma gangrenosum. The patient suffered from mild and controlled type 2 diabetes mellitus. Pyoderma gangrenosum is characterized by noninfectious autoimmune-type progressive skin ulceration [11], successfully treated with immunosuppressive agents [12].
Opportunistic skin infection of CMV is rare. CMV mainly affects vascular endothelial cells and perivascular stromal cells, and multifocal anogenital ulcerations are most frequently encountered in AIDS patients [13]. Cutaneous lesions with verrucous elevations [14] and septal panniculitis [15] have also been described in non-AIDS immunosuppressed patients. Since the skin ulcer remained unchanged after ganciclovir treatment, Grushchak et al. regarded CMV infection as a bystander phenomenon [16]. The skin lesion in the present case demonstrated features of septolobular panniculitis with CMV inclusions in endothelial and perivascular stromal cells, but the lesion progressed to form large induration with multiple ulcers after gancyclovir treatment. It is reasonable to consider the CMV infection as bystander incidence associated with nontuberculous mycobacteriosis. In other words, when CMV inclusions are noted in nodular or ulcerated skin lesions, primary causative microbes other than CMV should be searched under the microscope, as was so in the present case.
Varied nontuberculous mycobacteria affect the skin, including M. avium-intracellulare complex, M. marinum, M. ulcerans, M. fortuitum, and M. chelonae-abscessus complex [17, 18]. Reportedly, rapidly growing mycobacteria (RGM) form colonies on a common chocolate agar medium when the culture period is prolonged to two weeks or more [19].
M. chelonae was first isolated from the tortoise by Friedmann in 1902 [20]. M. chelonae belongs to nonchromogenic RGM (Runyon group IV), widely distributed in environmental water [21]. This zoonotic mycobacterium, categorized in M. chelonae-abscessus complex, causes opportunistic infection in the human skin, as well as infection in aquatic animals such as the reptiles and fish [22]. Of notice is that not only traumatic injuries but also surgical procedures make risk factors of human infection [23]. It is plausible that in the present case, medical disposals caused iatrogenic infection of the environmental pathogen. Immunosuppression and diabetic conditions accelerated opportunistic infection, as reported previously [17, 18, 22]. Microscopically, infection of RGM, including M. chelonae, provokes abscess-forming granulomas (suppurative granulomas): some lesions are recognized as abscess surrounded by abortive granuloma formation, while the others predominantly reveal epithelioid granulomas [24, 25]. Acid-fast bacilli are characteristically identified in the lipid droplets (vacuoles) often located in the center of suppurative granulomas. It is noteworthy that the bacilli are positively labeled with Gram stain: namely, Gram positivity is a feature of RGM [26].
The cell wall of mycobacteria contains voluminous mycolic acids, extremely long fatty acids, as molecular forms of mycolic acid-containing glycolipid such as trehalose dimycolate and trehalose monomycolate, giving lipophilic nature of mycobacteria [27]. RGM are characterized by the presence of an additional mycolate, glucose mycolate, on the cell wall [28]. Such biological features may be related to the lipid droplet-centered pattern of infection by RGM.
Lipid droplet-centered suppurative granulomas are commonly observed in granulomatous mastitis caused by a lipophilic bacterium, Corynebacterium kroppenstedtii [29]. The Gram-positive rods are uniquely clustered in the lipid droplets surrounded by suppurative granulomas. The histological features are quite similar to those of RGM infection. Unlike other corynebacteria, C. kroppenstedtii lacks mycolic acid but instead contains tuberculostearic acid in the cell wall [30]. It is understandable from both the microscopic appearance and the pharmacodynamic properties of antibiotics [31] that administration of lipophilic antibiotics is essential for treating not only granulomatous mastitis but also RGM infection. The treatment regimen for tuberculosis using hydrophilic antibiotics such as isoniazid, ethambuthol, pyrazinamide, and streptomycin is consistently ineffective for infection of RGM, which are usually resistant to lipophilic rifampicin [18]. In the present case, clarithromycin, a type of lipophilic macrolides, was effective, as has been reported so far [32, 33]. Thermotherapy was also useful [34], based on the biological features of the bacteria showing low optimal temperature (25–37°C) for growth [17, 18].
Immunohistochemical cross-reactivity of rabbit antisera against BCG and B. cereus was observed in the infected lesion. T. pallidum antiserum also showed weak cross-reactivity. Positive signals with low background staining were observed not only on the mycobacteria in the lipid droplets but also in the cytoplasm of macrophages, so that the detection sensitivity was very high [5]. Similar results were observed in granulomatous mastitis [29]. The visualization of microbes within the lesion is essentially important for making a histopathological diagnosis of infection [5]. Another important point of our findings includes the cross-reactivity of antibodies against MPT64, LAM, and PAB to M. chelonae. It has been reported that MPT64 and LAM are specific to M. tuberculosis, and PAB is solely expressed on Propionibacterium (Cutibacterium) acnes [7–9]. The P. acnes antigens were detected in granulomas of sarcoidosis [35]. The lipophilic bacteria in granulomatous mastitis also expressed LAM and PAB (Tsutsumi, unpublished observation). Such unexpected cross-reactivity should be cautious about applying the antibacterial antibodies as immunohistochemical probes, as has been described previously [5].
4. Conclusion
We reported here rare opportunistic skin coinfection of CMV and M. chelonae, a rapidly growing nontuberculous mycobacterium, after immunosuppressive therapy against pyoderma gangrenosum. It is of note that M. chelonae provoked suppurative granulomas with lipid droplet-centered colonization of Gram-positive and acid-fast rods. Unique immunohistochemical reactivities with a variety of antibacterial antibodies were applicable to visualizing the causative mycobacteria in the lesion.
Acknowledgments
The authors deeply thank Mr. Izumi Kurita, M.T., Clinical Laboratory Medicine, Shimada Municipal Hospital, Shimada, for identifying M. chelonae.
Consent
The patient gave written informed consent to publication of the case report.
Disclosure
The present address of Kentaro Odani is the Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto. The present address of Hideo Hashizume is the Department of Dermatology, Iwata City Hospital, Iwata, Shizuoka.
Conflicts of Interest
The authors do not have any conflict of interest in the present report.
Authors' Contributions
We declare that all the authors (1) made a substantial contribution to the concept of the case report or interpretation of data and (2) approved the version to be submitted. (3) Each author has participated sufficiently in the work to take public responsibility for appropriate portions of the content.
Figure 1 Pyoderma gangrenosum ((a) gross appearance of left lower thigh, (b) H&E). A demarcated deep ulcer, 4 cm in size, is observed. Fibrinous exudation is seen at the ulcer base, and erythematous change is associated around the ulcer (a). Microscopic features of the first biopsy specimen are nonspecific. Ulcer base is composed of fibrinous exudation and granulation tissue (b). Neither granulomatous reactions nor infectious agents are identified.
Figure 2 A subcutaneous nodule without ulceration ((a) gross appearance; (b) H&E, low-powered view; (c) H&E, high-powered view of the subcutaneous tissue, inset: immunostaining for CMV antigens). Subcutaneous nodularity with mild reddening is observed on the lower thigh near the original ulcer by pyoderma gangrenosum (arrow, (a)). A low-powered view of the second biopsy specimen demonstrates subcutaneous septolobular panniculitis (b). Endothelial cells and perivascular stromal cells with enlarged nuclei reveal intranuclear and cytoplasmic inclusions (c). Immunostaining for CMV antigens is clearly positive (inset).
Figure 3 A large nodular and indurated skin lesion with multiple ulcers ((a) gross appearance, (b) H&E, low-powered view, and (c) H&E, high-powered view of the dermis). Multiple ulcers, 2–3 cm in size, are formed in the irregular-shaped reddish induration (a). The third biopsy specimen reveals diffuse inflammatory infiltration in the dermis through subcutaneous tissue (b). Suppurative granuloma (abscess surrounded by epithelioid granuloma) is scattered in the lesion (c). No CMV inclusions are observed any longer.
Figure 4 Gram-positive acid-fast bacilli in the second (a–c) and third (d–f) biopsy specimens ((a, d) H&E, (b, e) Ziehl-Neelsen stain, and (c, f) Gram stain). Gram-positive acid-fast bacilli are multifocally clustered in microabscess (a–c) and also in fat droplets located in the center of suppurative granuloma (d–f). The bacteria are visible in the fat droplets even in H&E preparations (d). Such patterns of bacterial colonization are seen in both the second and third biopsy specimens.
Figure 5 Colonies of Mycobacterium chelonae on 2% Ogawa medium ((a) gross appearance, (b) Ziehl-Neelsen stain, (c) Gram stain, and (d) MALDI Biotyper analysis). Smooth-surfaced white (nonchromogenic) colonies are formed seven days after inoculation. The formalin-fixed, paraffin-embedded colonies display acid-fastness and Gram reactivity of the rods. By the MALDI biotyping analysis, the spectrum pattern indicates M. chelonae with the log score value of 2.208.
Figure 6 Immunohistochemical demonstration of varied bacterial antigens ((a) BCG, (b) Bacillus cereus, (c) Treponema pallidum, (d) MPT64, (e) LAM, and (f) PAB). The cytoplasm of macrophages infiltrating around the fat droplet exhibits clear cross-reactivity with varied bacterial antigens. Immunoreactivity of T. pallidum antigens is relatively weak.
Table 1 Antibodies used in the present study.
Target antigen Animal/clone Dilution Antigen retrieval Source
Bacillus Calmette-Guérin (BCG) Rabbit antiserum 1 : 10,000 None Agilent
MPT64 (RV1980C, 24 kDa protein) Rabbit antiserum 1 : 800 HIER in 10 mM CB (pH 6) Abcam
LAM (lipoarabinomannan) Mouse TMDU3 1 : 1,000 HIER in 10 mM CB (pH 6) MBL
PAB (Propionibacterium acnes-specific lipoteichoic acid) Mouse TMDU2 1 : 4,000 HIER in 10 mM CB (pH 6) MBL
Bacillus cereus Rabbit antiserum 1 : 500 HIER in 10 mM CB (pH 6) Abcam
Treponema pallidum Rabbit antiserum 1 : 1,000 HIER in 1 mM EDTA (pH 8) BM
Escherichia coli Rabbit antiserum 1 : 20,000 Proteinase K digestion Agilent
MPT: mycobacterial protein tuberculosis; HIER: heat-induced epitope retrieval; CB: citrate buffer; EDTA: ethylenediamine tetraacetic acid; Agilent: Agilent Technologies (Santa Clara, CA, USA); MBL: Medical and Biological Laboratories (Nagoya, Japan); Abcam: Abcam plc (Cambridge, UK); BM: Biocare Medical LLC (Pacheco, Philippines). | Recovered | ReactionOutcome | CC BY | 33564484 | 19,706,871 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Confusional state'. | Amitriptyline Dependence and Its Associations: A Case Report and Literature Review.
Amitriptyline, the second antidepressant invented next to imipramine, is indicated in many psychiatric conditions as well as for some organic disorders. The drug acts by increasing the availability of monoamines in the central nervous system postsynaptic clefts. Amitriptyline has long been suspected for abusive potential based on a few case reports, and the reports add evidence in favor of the hypothesis. This case report brings such material to the arena of evidence and discusses the probable mechanisms by which patients turn to abusing and be addicted to the drug. The article also argues matters associated with drug dispensing that might raise the risk of misuse of the drug, especially in countries where strict legislation for accessibility of prescribed drugs is not in practice.
1. Introduction
Amitriptyline is a tricyclic antidepressant and is used to treat depression, anxiety disorders, posttraumatic stress disorder (PTSD), insomnia, somatoform disorders, premenstrual dysphoric disorder, nocturnal enuresis, migraine, and neuropathic pain [1–3]. It blocks the reuptake of norepinephrine and serotonin and thus increases the availability of these neurotransmitters in the central nervous system (CNS) [1]. The maximum dose per day of amitriptyline is 300 mg, and this is given in divided doses to prevent/minimize adverse effects [2, 3]. The drug has antagonistic action at histaminic-1, alpha-1-adrenergic, and muscarinic cholinergic receptors. Those antiadrenergic and antimuscarinic properties bring about the troublesome adverse effects (hypotension, tachycardia, blurring of vision, urinary retention, constipation, dry mouth, sexual dysfunction) of the drug [1–3]. Amitriptyline also blocks voltage sensitive sodium channels in the heart and brain. In overdose, this action leads to arrhythmia, seizures, coma, and death [1].
The side effects, toxicity, and lethality in overdose, the risk of switch to manic state in predisposed individuals and the invention of selective serotonin reuptake inhibitors (SSRIs), another class of antidepressants with a better safety profile, made amitriptyline a less preferable medication [2]. However, the drug still has its role as a second line treatment for depression and nonpsychiatric conditions [1–3]. Amitriptyline also lowers the seizure threshold, and as such, in higher doses or intoxication, amitriptyline causes seizures [1, 4, 5]. Though it is generally considered that the drug does not possess abusive or addictive properties, there are a few case reports which suggest amitriptyline may exert such effects in susceptible individuals, i.e., patients with a history of another psychoactive substance abuse [6–10].
2. Case History
A 39-year-old married father of two videographer by profession, and who getting treatment for type II diabetes mellitus (DM), was admitted to a divisional hospital (Chankanai, Jaffna) in northern Sri Lanka, as he was found unconscious and suffering from seizure attacks. The patient was then transferred to Teaching Hospital Jaffna, as his seizure attacks could not be controlled with the treatment given at the divisional hospital. The patient was immediately admitted to the intensive care unit (ICU), a diagnosis of status epilepticus was made, and he was anesthetized in view of controlling his seizures. Within the next seven hours, the patient had 12 episodes of seizures. His electroencephalogram (EEG) and noncontrast computerized tomography (CT) scan of the brain, cerebrospinal fluid, liver enzymes, serum electrolytes, random blood sugar, and other routine biochemicals were well within normal limits. His electrocardiogram (ECG) showed sinus tachycardia. Opinion from a neurology team was sought, and it was favored against the diagnosis of epilepsy. The patient's wife gave a history that further enlightened the clinical picture.
Accordingly, the patient was regularly using alcohol for many years. One day, he consulted a surgeon in the private sector as he developed a single episode of haematemesis. The surgeon pointed out the reason behind the problem and advised him to go for total abstinence from alcohol. The surgeon also prescribed a low dose of alprazolam (0.5 mg nocte) to support his sleep without alcohol. In about a year's time, the patient was again presented to the surgeon by his family with a different complaint—“uncontrolled use of alprazolam”. At that point, the surgeon referred the patient to a psychiatrist. The psychiatrist advised the patient to tail off alprazolam and started treating him with 25 mg of amitriptyline, to be taken at night, in view of supporting his sleep problems. In the subsequent visit, the patient was complaining of poor sleep, and the dose of amitriptyline was gradually increased to 75 mg nocte. The patient felt better with that dose and stopped visiting the psychiatrist.
Since then, the patient started a kind of self-medication. He gradually increased the dose of amitriptyline to 250-300 mg at night as he needed more tablets to have good quality sleep and used 100–250 mg in daytimes to prevent dysphoria and restlessness, which were experienced by him in the absence of amitriptyline. He could not control taking amitriptyline in excess doses despite its regular side effects, which include constipation. In addition, from time to time, he engaged in binge ingestion of amitriptyline when he wanted to experience a “high” in his mood. In such circumstances, the number of tablets even reached to 25-30 per occasion (625–750 mg). These binges were associated with one or two seizure attacks, for which he or his family did not seek medical attention. For the past one year, the patient developed a progressive decline in his functionality, and he became dependent on amitriptyline. On the day of admission, the patient ingested about 30 tablets around 3 pm. Soon, the patient developed loss of consciousness and seizures.
After two days, anesthesia was withdrawn, and the patient was observed for the possibility of reappearance of seizure attacks for the next few hours. No more seizures were observed; however, he was continuously found to be confused. The patient was then transferred to an inpatient medical facility. In the medical ward, the patient soon became agitated, overtalkative, euphoric, disinhibited, and slept poorly. The diagnosis of delirious mania or hyperactive delirium as a result of the late effect of amitriptyline intoxication was made, and then he was started on effective doses of haloperidol and quetiapine. His symptoms responded well to haloperidol 6 mg tds and quetiapine 100 mg nocte. After recovery, the patient was assessed for the possibility of underlying depression, anxiety states, suicidal behavior, and any other psychiatric morbidities, and all were negative. However, he fulfilled the dependence criteria for amitriptyline. As per request, the family brought the drug pack for inspection, and it was found to contain about 500 tablets of 25 mg strength amitriptyline.
He was discharged from the hospital after two weeks on quetiapine 200 mg nocte, enrolled in an abstinence programme for amitriptyline dependence, taught sleep hygiene measures and interpersonal social rhythm therapy with the aim of assisting his routine sleep and other day-to-day activities, supported to reengage in his profession and to practice regular physical exercise, and was placed on assertive follow up care to monitor for and to prevent relapse.
3. Discussion
Patients who are treated with amitriptyline for long-term may show discontinuation syndrome upon withdrawal of the drug. This commonly manifests as flu-like symptoms (chills, myalgia, headache, nausea, excessive sweating), insomnia, excessive dreaming, and occasionally, movement disorders, mania, and cardiac arrhythmia [2].However, this patient's symptoms did not fit into this cluster of symptoms. Therefore, the possibility of discontinuation syndrome is least likely.
The diagnosis of amitriptyline dependence was made as the patient showed dependence features to the drug (tolerance, withdrawal symptoms, craving, continuation, and negligence of duty), and they were present for a period of more than one year [11].Features of dependence are broadly categorized into two classes: psychological and physiological [2] .Though the patient displayed both these types of symptoms, the psychological symptoms outweighed the physiological ones.
This case shines light on the long-lasting question of scientists whether amitriptyline holds abusive and dependency potential. Amitriptyline's abusive and addictive properties may result from its euphoric and sedative effects, similar to alcohol [1], and its (psycho) stimulant effect, as evident from this patient's urge to have “highs” that was “satisfied” with binging (overdose) of the drug [10]. Richelson [12] argues that anticholinergic and antihistaminic effects of tertiary tricyclics may underlie their abusive liability. Therefore, it could be argued that the antihistaminic and anticholinergic properties of amitriptyline act synergistically, resulting in its abusive tendency. However, there are case studies which divulge that the antihistaminic and anticholinergic properties of drugs may result in stimulant, euphoric, and/or psychedelic effects that might lead users to abuse these drugs [13–17]. These articles suggest that the stimulant and euphoric properties of amitriptyline may underlie the probable mechanism by which the drug causes addiction and dependence.
The other important concern the case highlights is that individuals with substance use disorders might carry a higher risk for amitriptyline dependence. Psychiatrists and other physicians who use amitriptyline in their practice should be prudent and keep a watchful eye on this long-term risk of the drug. In addition, this case discloses a deficient area of drug prescription and free accessibility of medications which is highly prevalent in Sri Lanka and may be in other countries as well, where no strict legislations govern the purchase of prescribed medications. The patient purchased the medication with an old prescription which was written about one and a half years ago by his psychiatrist. The case supports the argument that there should be a strict protocol to be adhered in accessing prescribed medications.
4. Conclusions
Amitriptyline shows the potential to cause dependence syndrome in vulnerable individuals
A clear protocol should be implemented when dispensing medications from pharmacy to patients
Acknowledgments
The authors acknowledge the support of Dr. Kumanan Thirunavukkarasu (Professor in Internal Medicine, Faculty of Medicine, University of Jaffna, Sri Lanka) who gave valuable inputs and edited the manuscript.
Conflicts of Interest
The authors declare that they do not have any conflict of interest or get any funding from any pharmaceutical company. | ALPRAZOLAM, AMITRIPTYLINE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33564485 | 19,071,921 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Constipation'. | Amitriptyline Dependence and Its Associations: A Case Report and Literature Review.
Amitriptyline, the second antidepressant invented next to imipramine, is indicated in many psychiatric conditions as well as for some organic disorders. The drug acts by increasing the availability of monoamines in the central nervous system postsynaptic clefts. Amitriptyline has long been suspected for abusive potential based on a few case reports, and the reports add evidence in favor of the hypothesis. This case report brings such material to the arena of evidence and discusses the probable mechanisms by which patients turn to abusing and be addicted to the drug. The article also argues matters associated with drug dispensing that might raise the risk of misuse of the drug, especially in countries where strict legislation for accessibility of prescribed drugs is not in practice.
1. Introduction
Amitriptyline is a tricyclic antidepressant and is used to treat depression, anxiety disorders, posttraumatic stress disorder (PTSD), insomnia, somatoform disorders, premenstrual dysphoric disorder, nocturnal enuresis, migraine, and neuropathic pain [1–3]. It blocks the reuptake of norepinephrine and serotonin and thus increases the availability of these neurotransmitters in the central nervous system (CNS) [1]. The maximum dose per day of amitriptyline is 300 mg, and this is given in divided doses to prevent/minimize adverse effects [2, 3]. The drug has antagonistic action at histaminic-1, alpha-1-adrenergic, and muscarinic cholinergic receptors. Those antiadrenergic and antimuscarinic properties bring about the troublesome adverse effects (hypotension, tachycardia, blurring of vision, urinary retention, constipation, dry mouth, sexual dysfunction) of the drug [1–3]. Amitriptyline also blocks voltage sensitive sodium channels in the heart and brain. In overdose, this action leads to arrhythmia, seizures, coma, and death [1].
The side effects, toxicity, and lethality in overdose, the risk of switch to manic state in predisposed individuals and the invention of selective serotonin reuptake inhibitors (SSRIs), another class of antidepressants with a better safety profile, made amitriptyline a less preferable medication [2]. However, the drug still has its role as a second line treatment for depression and nonpsychiatric conditions [1–3]. Amitriptyline also lowers the seizure threshold, and as such, in higher doses or intoxication, amitriptyline causes seizures [1, 4, 5]. Though it is generally considered that the drug does not possess abusive or addictive properties, there are a few case reports which suggest amitriptyline may exert such effects in susceptible individuals, i.e., patients with a history of another psychoactive substance abuse [6–10].
2. Case History
A 39-year-old married father of two videographer by profession, and who getting treatment for type II diabetes mellitus (DM), was admitted to a divisional hospital (Chankanai, Jaffna) in northern Sri Lanka, as he was found unconscious and suffering from seizure attacks. The patient was then transferred to Teaching Hospital Jaffna, as his seizure attacks could not be controlled with the treatment given at the divisional hospital. The patient was immediately admitted to the intensive care unit (ICU), a diagnosis of status epilepticus was made, and he was anesthetized in view of controlling his seizures. Within the next seven hours, the patient had 12 episodes of seizures. His electroencephalogram (EEG) and noncontrast computerized tomography (CT) scan of the brain, cerebrospinal fluid, liver enzymes, serum electrolytes, random blood sugar, and other routine biochemicals were well within normal limits. His electrocardiogram (ECG) showed sinus tachycardia. Opinion from a neurology team was sought, and it was favored against the diagnosis of epilepsy. The patient's wife gave a history that further enlightened the clinical picture.
Accordingly, the patient was regularly using alcohol for many years. One day, he consulted a surgeon in the private sector as he developed a single episode of haematemesis. The surgeon pointed out the reason behind the problem and advised him to go for total abstinence from alcohol. The surgeon also prescribed a low dose of alprazolam (0.5 mg nocte) to support his sleep without alcohol. In about a year's time, the patient was again presented to the surgeon by his family with a different complaint—“uncontrolled use of alprazolam”. At that point, the surgeon referred the patient to a psychiatrist. The psychiatrist advised the patient to tail off alprazolam and started treating him with 25 mg of amitriptyline, to be taken at night, in view of supporting his sleep problems. In the subsequent visit, the patient was complaining of poor sleep, and the dose of amitriptyline was gradually increased to 75 mg nocte. The patient felt better with that dose and stopped visiting the psychiatrist.
Since then, the patient started a kind of self-medication. He gradually increased the dose of amitriptyline to 250-300 mg at night as he needed more tablets to have good quality sleep and used 100–250 mg in daytimes to prevent dysphoria and restlessness, which were experienced by him in the absence of amitriptyline. He could not control taking amitriptyline in excess doses despite its regular side effects, which include constipation. In addition, from time to time, he engaged in binge ingestion of amitriptyline when he wanted to experience a “high” in his mood. In such circumstances, the number of tablets even reached to 25-30 per occasion (625–750 mg). These binges were associated with one or two seizure attacks, for which he or his family did not seek medical attention. For the past one year, the patient developed a progressive decline in his functionality, and he became dependent on amitriptyline. On the day of admission, the patient ingested about 30 tablets around 3 pm. Soon, the patient developed loss of consciousness and seizures.
After two days, anesthesia was withdrawn, and the patient was observed for the possibility of reappearance of seizure attacks for the next few hours. No more seizures were observed; however, he was continuously found to be confused. The patient was then transferred to an inpatient medical facility. In the medical ward, the patient soon became agitated, overtalkative, euphoric, disinhibited, and slept poorly. The diagnosis of delirious mania or hyperactive delirium as a result of the late effect of amitriptyline intoxication was made, and then he was started on effective doses of haloperidol and quetiapine. His symptoms responded well to haloperidol 6 mg tds and quetiapine 100 mg nocte. After recovery, the patient was assessed for the possibility of underlying depression, anxiety states, suicidal behavior, and any other psychiatric morbidities, and all were negative. However, he fulfilled the dependence criteria for amitriptyline. As per request, the family brought the drug pack for inspection, and it was found to contain about 500 tablets of 25 mg strength amitriptyline.
He was discharged from the hospital after two weeks on quetiapine 200 mg nocte, enrolled in an abstinence programme for amitriptyline dependence, taught sleep hygiene measures and interpersonal social rhythm therapy with the aim of assisting his routine sleep and other day-to-day activities, supported to reengage in his profession and to practice regular physical exercise, and was placed on assertive follow up care to monitor for and to prevent relapse.
3. Discussion
Patients who are treated with amitriptyline for long-term may show discontinuation syndrome upon withdrawal of the drug. This commonly manifests as flu-like symptoms (chills, myalgia, headache, nausea, excessive sweating), insomnia, excessive dreaming, and occasionally, movement disorders, mania, and cardiac arrhythmia [2].However, this patient's symptoms did not fit into this cluster of symptoms. Therefore, the possibility of discontinuation syndrome is least likely.
The diagnosis of amitriptyline dependence was made as the patient showed dependence features to the drug (tolerance, withdrawal symptoms, craving, continuation, and negligence of duty), and they were present for a period of more than one year [11].Features of dependence are broadly categorized into two classes: psychological and physiological [2] .Though the patient displayed both these types of symptoms, the psychological symptoms outweighed the physiological ones.
This case shines light on the long-lasting question of scientists whether amitriptyline holds abusive and dependency potential. Amitriptyline's abusive and addictive properties may result from its euphoric and sedative effects, similar to alcohol [1], and its (psycho) stimulant effect, as evident from this patient's urge to have “highs” that was “satisfied” with binging (overdose) of the drug [10]. Richelson [12] argues that anticholinergic and antihistaminic effects of tertiary tricyclics may underlie their abusive liability. Therefore, it could be argued that the antihistaminic and anticholinergic properties of amitriptyline act synergistically, resulting in its abusive tendency. However, there are case studies which divulge that the antihistaminic and anticholinergic properties of drugs may result in stimulant, euphoric, and/or psychedelic effects that might lead users to abuse these drugs [13–17]. These articles suggest that the stimulant and euphoric properties of amitriptyline may underlie the probable mechanism by which the drug causes addiction and dependence.
The other important concern the case highlights is that individuals with substance use disorders might carry a higher risk for amitriptyline dependence. Psychiatrists and other physicians who use amitriptyline in their practice should be prudent and keep a watchful eye on this long-term risk of the drug. In addition, this case discloses a deficient area of drug prescription and free accessibility of medications which is highly prevalent in Sri Lanka and may be in other countries as well, where no strict legislations govern the purchase of prescribed medications. The patient purchased the medication with an old prescription which was written about one and a half years ago by his psychiatrist. The case supports the argument that there should be a strict protocol to be adhered in accessing prescribed medications.
4. Conclusions
Amitriptyline shows the potential to cause dependence syndrome in vulnerable individuals
A clear protocol should be implemented when dispensing medications from pharmacy to patients
Acknowledgments
The authors acknowledge the support of Dr. Kumanan Thirunavukkarasu (Professor in Internal Medicine, Faculty of Medicine, University of Jaffna, Sri Lanka) who gave valuable inputs and edited the manuscript.
Conflicts of Interest
The authors declare that they do not have any conflict of interest or get any funding from any pharmaceutical company. | ALPRAZOLAM, AMITRIPTYLINE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33564485 | 19,071,921 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Delirium'. | Amitriptyline Dependence and Its Associations: A Case Report and Literature Review.
Amitriptyline, the second antidepressant invented next to imipramine, is indicated in many psychiatric conditions as well as for some organic disorders. The drug acts by increasing the availability of monoamines in the central nervous system postsynaptic clefts. Amitriptyline has long been suspected for abusive potential based on a few case reports, and the reports add evidence in favor of the hypothesis. This case report brings such material to the arena of evidence and discusses the probable mechanisms by which patients turn to abusing and be addicted to the drug. The article also argues matters associated with drug dispensing that might raise the risk of misuse of the drug, especially in countries where strict legislation for accessibility of prescribed drugs is not in practice.
1. Introduction
Amitriptyline is a tricyclic antidepressant and is used to treat depression, anxiety disorders, posttraumatic stress disorder (PTSD), insomnia, somatoform disorders, premenstrual dysphoric disorder, nocturnal enuresis, migraine, and neuropathic pain [1–3]. It blocks the reuptake of norepinephrine and serotonin and thus increases the availability of these neurotransmitters in the central nervous system (CNS) [1]. The maximum dose per day of amitriptyline is 300 mg, and this is given in divided doses to prevent/minimize adverse effects [2, 3]. The drug has antagonistic action at histaminic-1, alpha-1-adrenergic, and muscarinic cholinergic receptors. Those antiadrenergic and antimuscarinic properties bring about the troublesome adverse effects (hypotension, tachycardia, blurring of vision, urinary retention, constipation, dry mouth, sexual dysfunction) of the drug [1–3]. Amitriptyline also blocks voltage sensitive sodium channels in the heart and brain. In overdose, this action leads to arrhythmia, seizures, coma, and death [1].
The side effects, toxicity, and lethality in overdose, the risk of switch to manic state in predisposed individuals and the invention of selective serotonin reuptake inhibitors (SSRIs), another class of antidepressants with a better safety profile, made amitriptyline a less preferable medication [2]. However, the drug still has its role as a second line treatment for depression and nonpsychiatric conditions [1–3]. Amitriptyline also lowers the seizure threshold, and as such, in higher doses or intoxication, amitriptyline causes seizures [1, 4, 5]. Though it is generally considered that the drug does not possess abusive or addictive properties, there are a few case reports which suggest amitriptyline may exert such effects in susceptible individuals, i.e., patients with a history of another psychoactive substance abuse [6–10].
2. Case History
A 39-year-old married father of two videographer by profession, and who getting treatment for type II diabetes mellitus (DM), was admitted to a divisional hospital (Chankanai, Jaffna) in northern Sri Lanka, as he was found unconscious and suffering from seizure attacks. The patient was then transferred to Teaching Hospital Jaffna, as his seizure attacks could not be controlled with the treatment given at the divisional hospital. The patient was immediately admitted to the intensive care unit (ICU), a diagnosis of status epilepticus was made, and he was anesthetized in view of controlling his seizures. Within the next seven hours, the patient had 12 episodes of seizures. His electroencephalogram (EEG) and noncontrast computerized tomography (CT) scan of the brain, cerebrospinal fluid, liver enzymes, serum electrolytes, random blood sugar, and other routine biochemicals were well within normal limits. His electrocardiogram (ECG) showed sinus tachycardia. Opinion from a neurology team was sought, and it was favored against the diagnosis of epilepsy. The patient's wife gave a history that further enlightened the clinical picture.
Accordingly, the patient was regularly using alcohol for many years. One day, he consulted a surgeon in the private sector as he developed a single episode of haematemesis. The surgeon pointed out the reason behind the problem and advised him to go for total abstinence from alcohol. The surgeon also prescribed a low dose of alprazolam (0.5 mg nocte) to support his sleep without alcohol. In about a year's time, the patient was again presented to the surgeon by his family with a different complaint—“uncontrolled use of alprazolam”. At that point, the surgeon referred the patient to a psychiatrist. The psychiatrist advised the patient to tail off alprazolam and started treating him with 25 mg of amitriptyline, to be taken at night, in view of supporting his sleep problems. In the subsequent visit, the patient was complaining of poor sleep, and the dose of amitriptyline was gradually increased to 75 mg nocte. The patient felt better with that dose and stopped visiting the psychiatrist.
Since then, the patient started a kind of self-medication. He gradually increased the dose of amitriptyline to 250-300 mg at night as he needed more tablets to have good quality sleep and used 100–250 mg in daytimes to prevent dysphoria and restlessness, which were experienced by him in the absence of amitriptyline. He could not control taking amitriptyline in excess doses despite its regular side effects, which include constipation. In addition, from time to time, he engaged in binge ingestion of amitriptyline when he wanted to experience a “high” in his mood. In such circumstances, the number of tablets even reached to 25-30 per occasion (625–750 mg). These binges were associated with one or two seizure attacks, for which he or his family did not seek medical attention. For the past one year, the patient developed a progressive decline in his functionality, and he became dependent on amitriptyline. On the day of admission, the patient ingested about 30 tablets around 3 pm. Soon, the patient developed loss of consciousness and seizures.
After two days, anesthesia was withdrawn, and the patient was observed for the possibility of reappearance of seizure attacks for the next few hours. No more seizures were observed; however, he was continuously found to be confused. The patient was then transferred to an inpatient medical facility. In the medical ward, the patient soon became agitated, overtalkative, euphoric, disinhibited, and slept poorly. The diagnosis of delirious mania or hyperactive delirium as a result of the late effect of amitriptyline intoxication was made, and then he was started on effective doses of haloperidol and quetiapine. His symptoms responded well to haloperidol 6 mg tds and quetiapine 100 mg nocte. After recovery, the patient was assessed for the possibility of underlying depression, anxiety states, suicidal behavior, and any other psychiatric morbidities, and all were negative. However, he fulfilled the dependence criteria for amitriptyline. As per request, the family brought the drug pack for inspection, and it was found to contain about 500 tablets of 25 mg strength amitriptyline.
He was discharged from the hospital after two weeks on quetiapine 200 mg nocte, enrolled in an abstinence programme for amitriptyline dependence, taught sleep hygiene measures and interpersonal social rhythm therapy with the aim of assisting his routine sleep and other day-to-day activities, supported to reengage in his profession and to practice regular physical exercise, and was placed on assertive follow up care to monitor for and to prevent relapse.
3. Discussion
Patients who are treated with amitriptyline for long-term may show discontinuation syndrome upon withdrawal of the drug. This commonly manifests as flu-like symptoms (chills, myalgia, headache, nausea, excessive sweating), insomnia, excessive dreaming, and occasionally, movement disorders, mania, and cardiac arrhythmia [2].However, this patient's symptoms did not fit into this cluster of symptoms. Therefore, the possibility of discontinuation syndrome is least likely.
The diagnosis of amitriptyline dependence was made as the patient showed dependence features to the drug (tolerance, withdrawal symptoms, craving, continuation, and negligence of duty), and they were present for a period of more than one year [11].Features of dependence are broadly categorized into two classes: psychological and physiological [2] .Though the patient displayed both these types of symptoms, the psychological symptoms outweighed the physiological ones.
This case shines light on the long-lasting question of scientists whether amitriptyline holds abusive and dependency potential. Amitriptyline's abusive and addictive properties may result from its euphoric and sedative effects, similar to alcohol [1], and its (psycho) stimulant effect, as evident from this patient's urge to have “highs” that was “satisfied” with binging (overdose) of the drug [10]. Richelson [12] argues that anticholinergic and antihistaminic effects of tertiary tricyclics may underlie their abusive liability. Therefore, it could be argued that the antihistaminic and anticholinergic properties of amitriptyline act synergistically, resulting in its abusive tendency. However, there are case studies which divulge that the antihistaminic and anticholinergic properties of drugs may result in stimulant, euphoric, and/or psychedelic effects that might lead users to abuse these drugs [13–17]. These articles suggest that the stimulant and euphoric properties of amitriptyline may underlie the probable mechanism by which the drug causes addiction and dependence.
The other important concern the case highlights is that individuals with substance use disorders might carry a higher risk for amitriptyline dependence. Psychiatrists and other physicians who use amitriptyline in their practice should be prudent and keep a watchful eye on this long-term risk of the drug. In addition, this case discloses a deficient area of drug prescription and free accessibility of medications which is highly prevalent in Sri Lanka and may be in other countries as well, where no strict legislations govern the purchase of prescribed medications. The patient purchased the medication with an old prescription which was written about one and a half years ago by his psychiatrist. The case supports the argument that there should be a strict protocol to be adhered in accessing prescribed medications.
4. Conclusions
Amitriptyline shows the potential to cause dependence syndrome in vulnerable individuals
A clear protocol should be implemented when dispensing medications from pharmacy to patients
Acknowledgments
The authors acknowledge the support of Dr. Kumanan Thirunavukkarasu (Professor in Internal Medicine, Faculty of Medicine, University of Jaffna, Sri Lanka) who gave valuable inputs and edited the manuscript.
Conflicts of Interest
The authors declare that they do not have any conflict of interest or get any funding from any pharmaceutical company. | ALPRAZOLAM, AMITRIPTYLINE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33564485 | 19,071,921 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug abuse'. | Amitriptyline Dependence and Its Associations: A Case Report and Literature Review.
Amitriptyline, the second antidepressant invented next to imipramine, is indicated in many psychiatric conditions as well as for some organic disorders. The drug acts by increasing the availability of monoamines in the central nervous system postsynaptic clefts. Amitriptyline has long been suspected for abusive potential based on a few case reports, and the reports add evidence in favor of the hypothesis. This case report brings such material to the arena of evidence and discusses the probable mechanisms by which patients turn to abusing and be addicted to the drug. The article also argues matters associated with drug dispensing that might raise the risk of misuse of the drug, especially in countries where strict legislation for accessibility of prescribed drugs is not in practice.
1. Introduction
Amitriptyline is a tricyclic antidepressant and is used to treat depression, anxiety disorders, posttraumatic stress disorder (PTSD), insomnia, somatoform disorders, premenstrual dysphoric disorder, nocturnal enuresis, migraine, and neuropathic pain [1–3]. It blocks the reuptake of norepinephrine and serotonin and thus increases the availability of these neurotransmitters in the central nervous system (CNS) [1]. The maximum dose per day of amitriptyline is 300 mg, and this is given in divided doses to prevent/minimize adverse effects [2, 3]. The drug has antagonistic action at histaminic-1, alpha-1-adrenergic, and muscarinic cholinergic receptors. Those antiadrenergic and antimuscarinic properties bring about the troublesome adverse effects (hypotension, tachycardia, blurring of vision, urinary retention, constipation, dry mouth, sexual dysfunction) of the drug [1–3]. Amitriptyline also blocks voltage sensitive sodium channels in the heart and brain. In overdose, this action leads to arrhythmia, seizures, coma, and death [1].
The side effects, toxicity, and lethality in overdose, the risk of switch to manic state in predisposed individuals and the invention of selective serotonin reuptake inhibitors (SSRIs), another class of antidepressants with a better safety profile, made amitriptyline a less preferable medication [2]. However, the drug still has its role as a second line treatment for depression and nonpsychiatric conditions [1–3]. Amitriptyline also lowers the seizure threshold, and as such, in higher doses or intoxication, amitriptyline causes seizures [1, 4, 5]. Though it is generally considered that the drug does not possess abusive or addictive properties, there are a few case reports which suggest amitriptyline may exert such effects in susceptible individuals, i.e., patients with a history of another psychoactive substance abuse [6–10].
2. Case History
A 39-year-old married father of two videographer by profession, and who getting treatment for type II diabetes mellitus (DM), was admitted to a divisional hospital (Chankanai, Jaffna) in northern Sri Lanka, as he was found unconscious and suffering from seizure attacks. The patient was then transferred to Teaching Hospital Jaffna, as his seizure attacks could not be controlled with the treatment given at the divisional hospital. The patient was immediately admitted to the intensive care unit (ICU), a diagnosis of status epilepticus was made, and he was anesthetized in view of controlling his seizures. Within the next seven hours, the patient had 12 episodes of seizures. His electroencephalogram (EEG) and noncontrast computerized tomography (CT) scan of the brain, cerebrospinal fluid, liver enzymes, serum electrolytes, random blood sugar, and other routine biochemicals were well within normal limits. His electrocardiogram (ECG) showed sinus tachycardia. Opinion from a neurology team was sought, and it was favored against the diagnosis of epilepsy. The patient's wife gave a history that further enlightened the clinical picture.
Accordingly, the patient was regularly using alcohol for many years. One day, he consulted a surgeon in the private sector as he developed a single episode of haematemesis. The surgeon pointed out the reason behind the problem and advised him to go for total abstinence from alcohol. The surgeon also prescribed a low dose of alprazolam (0.5 mg nocte) to support his sleep without alcohol. In about a year's time, the patient was again presented to the surgeon by his family with a different complaint—“uncontrolled use of alprazolam”. At that point, the surgeon referred the patient to a psychiatrist. The psychiatrist advised the patient to tail off alprazolam and started treating him with 25 mg of amitriptyline, to be taken at night, in view of supporting his sleep problems. In the subsequent visit, the patient was complaining of poor sleep, and the dose of amitriptyline was gradually increased to 75 mg nocte. The patient felt better with that dose and stopped visiting the psychiatrist.
Since then, the patient started a kind of self-medication. He gradually increased the dose of amitriptyline to 250-300 mg at night as he needed more tablets to have good quality sleep and used 100–250 mg in daytimes to prevent dysphoria and restlessness, which were experienced by him in the absence of amitriptyline. He could not control taking amitriptyline in excess doses despite its regular side effects, which include constipation. In addition, from time to time, he engaged in binge ingestion of amitriptyline when he wanted to experience a “high” in his mood. In such circumstances, the number of tablets even reached to 25-30 per occasion (625–750 mg). These binges were associated with one or two seizure attacks, for which he or his family did not seek medical attention. For the past one year, the patient developed a progressive decline in his functionality, and he became dependent on amitriptyline. On the day of admission, the patient ingested about 30 tablets around 3 pm. Soon, the patient developed loss of consciousness and seizures.
After two days, anesthesia was withdrawn, and the patient was observed for the possibility of reappearance of seizure attacks for the next few hours. No more seizures were observed; however, he was continuously found to be confused. The patient was then transferred to an inpatient medical facility. In the medical ward, the patient soon became agitated, overtalkative, euphoric, disinhibited, and slept poorly. The diagnosis of delirious mania or hyperactive delirium as a result of the late effect of amitriptyline intoxication was made, and then he was started on effective doses of haloperidol and quetiapine. His symptoms responded well to haloperidol 6 mg tds and quetiapine 100 mg nocte. After recovery, the patient was assessed for the possibility of underlying depression, anxiety states, suicidal behavior, and any other psychiatric morbidities, and all were negative. However, he fulfilled the dependence criteria for amitriptyline. As per request, the family brought the drug pack for inspection, and it was found to contain about 500 tablets of 25 mg strength amitriptyline.
He was discharged from the hospital after two weeks on quetiapine 200 mg nocte, enrolled in an abstinence programme for amitriptyline dependence, taught sleep hygiene measures and interpersonal social rhythm therapy with the aim of assisting his routine sleep and other day-to-day activities, supported to reengage in his profession and to practice regular physical exercise, and was placed on assertive follow up care to monitor for and to prevent relapse.
3. Discussion
Patients who are treated with amitriptyline for long-term may show discontinuation syndrome upon withdrawal of the drug. This commonly manifests as flu-like symptoms (chills, myalgia, headache, nausea, excessive sweating), insomnia, excessive dreaming, and occasionally, movement disorders, mania, and cardiac arrhythmia [2].However, this patient's symptoms did not fit into this cluster of symptoms. Therefore, the possibility of discontinuation syndrome is least likely.
The diagnosis of amitriptyline dependence was made as the patient showed dependence features to the drug (tolerance, withdrawal symptoms, craving, continuation, and negligence of duty), and they were present for a period of more than one year [11].Features of dependence are broadly categorized into two classes: psychological and physiological [2] .Though the patient displayed both these types of symptoms, the psychological symptoms outweighed the physiological ones.
This case shines light on the long-lasting question of scientists whether amitriptyline holds abusive and dependency potential. Amitriptyline's abusive and addictive properties may result from its euphoric and sedative effects, similar to alcohol [1], and its (psycho) stimulant effect, as evident from this patient's urge to have “highs” that was “satisfied” with binging (overdose) of the drug [10]. Richelson [12] argues that anticholinergic and antihistaminic effects of tertiary tricyclics may underlie their abusive liability. Therefore, it could be argued that the antihistaminic and anticholinergic properties of amitriptyline act synergistically, resulting in its abusive tendency. However, there are case studies which divulge that the antihistaminic and anticholinergic properties of drugs may result in stimulant, euphoric, and/or psychedelic effects that might lead users to abuse these drugs [13–17]. These articles suggest that the stimulant and euphoric properties of amitriptyline may underlie the probable mechanism by which the drug causes addiction and dependence.
The other important concern the case highlights is that individuals with substance use disorders might carry a higher risk for amitriptyline dependence. Psychiatrists and other physicians who use amitriptyline in their practice should be prudent and keep a watchful eye on this long-term risk of the drug. In addition, this case discloses a deficient area of drug prescription and free accessibility of medications which is highly prevalent in Sri Lanka and may be in other countries as well, where no strict legislations govern the purchase of prescribed medications. The patient purchased the medication with an old prescription which was written about one and a half years ago by his psychiatrist. The case supports the argument that there should be a strict protocol to be adhered in accessing prescribed medications.
4. Conclusions
Amitriptyline shows the potential to cause dependence syndrome in vulnerable individuals
A clear protocol should be implemented when dispensing medications from pharmacy to patients
Acknowledgments
The authors acknowledge the support of Dr. Kumanan Thirunavukkarasu (Professor in Internal Medicine, Faculty of Medicine, University of Jaffna, Sri Lanka) who gave valuable inputs and edited the manuscript.
Conflicts of Interest
The authors declare that they do not have any conflict of interest or get any funding from any pharmaceutical company. | ALPRAZOLAM, AMITRIPTYLINE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33564485 | 19,071,921 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug dependence'. | Amitriptyline Dependence and Its Associations: A Case Report and Literature Review.
Amitriptyline, the second antidepressant invented next to imipramine, is indicated in many psychiatric conditions as well as for some organic disorders. The drug acts by increasing the availability of monoamines in the central nervous system postsynaptic clefts. Amitriptyline has long been suspected for abusive potential based on a few case reports, and the reports add evidence in favor of the hypothesis. This case report brings such material to the arena of evidence and discusses the probable mechanisms by which patients turn to abusing and be addicted to the drug. The article also argues matters associated with drug dispensing that might raise the risk of misuse of the drug, especially in countries where strict legislation for accessibility of prescribed drugs is not in practice.
1. Introduction
Amitriptyline is a tricyclic antidepressant and is used to treat depression, anxiety disorders, posttraumatic stress disorder (PTSD), insomnia, somatoform disorders, premenstrual dysphoric disorder, nocturnal enuresis, migraine, and neuropathic pain [1–3]. It blocks the reuptake of norepinephrine and serotonin and thus increases the availability of these neurotransmitters in the central nervous system (CNS) [1]. The maximum dose per day of amitriptyline is 300 mg, and this is given in divided doses to prevent/minimize adverse effects [2, 3]. The drug has antagonistic action at histaminic-1, alpha-1-adrenergic, and muscarinic cholinergic receptors. Those antiadrenergic and antimuscarinic properties bring about the troublesome adverse effects (hypotension, tachycardia, blurring of vision, urinary retention, constipation, dry mouth, sexual dysfunction) of the drug [1–3]. Amitriptyline also blocks voltage sensitive sodium channels in the heart and brain. In overdose, this action leads to arrhythmia, seizures, coma, and death [1].
The side effects, toxicity, and lethality in overdose, the risk of switch to manic state in predisposed individuals and the invention of selective serotonin reuptake inhibitors (SSRIs), another class of antidepressants with a better safety profile, made amitriptyline a less preferable medication [2]. However, the drug still has its role as a second line treatment for depression and nonpsychiatric conditions [1–3]. Amitriptyline also lowers the seizure threshold, and as such, in higher doses or intoxication, amitriptyline causes seizures [1, 4, 5]. Though it is generally considered that the drug does not possess abusive or addictive properties, there are a few case reports which suggest amitriptyline may exert such effects in susceptible individuals, i.e., patients with a history of another psychoactive substance abuse [6–10].
2. Case History
A 39-year-old married father of two videographer by profession, and who getting treatment for type II diabetes mellitus (DM), was admitted to a divisional hospital (Chankanai, Jaffna) in northern Sri Lanka, as he was found unconscious and suffering from seizure attacks. The patient was then transferred to Teaching Hospital Jaffna, as his seizure attacks could not be controlled with the treatment given at the divisional hospital. The patient was immediately admitted to the intensive care unit (ICU), a diagnosis of status epilepticus was made, and he was anesthetized in view of controlling his seizures. Within the next seven hours, the patient had 12 episodes of seizures. His electroencephalogram (EEG) and noncontrast computerized tomography (CT) scan of the brain, cerebrospinal fluid, liver enzymes, serum electrolytes, random blood sugar, and other routine biochemicals were well within normal limits. His electrocardiogram (ECG) showed sinus tachycardia. Opinion from a neurology team was sought, and it was favored against the diagnosis of epilepsy. The patient's wife gave a history that further enlightened the clinical picture.
Accordingly, the patient was regularly using alcohol for many years. One day, he consulted a surgeon in the private sector as he developed a single episode of haematemesis. The surgeon pointed out the reason behind the problem and advised him to go for total abstinence from alcohol. The surgeon also prescribed a low dose of alprazolam (0.5 mg nocte) to support his sleep without alcohol. In about a year's time, the patient was again presented to the surgeon by his family with a different complaint—“uncontrolled use of alprazolam”. At that point, the surgeon referred the patient to a psychiatrist. The psychiatrist advised the patient to tail off alprazolam and started treating him with 25 mg of amitriptyline, to be taken at night, in view of supporting his sleep problems. In the subsequent visit, the patient was complaining of poor sleep, and the dose of amitriptyline was gradually increased to 75 mg nocte. The patient felt better with that dose and stopped visiting the psychiatrist.
Since then, the patient started a kind of self-medication. He gradually increased the dose of amitriptyline to 250-300 mg at night as he needed more tablets to have good quality sleep and used 100–250 mg in daytimes to prevent dysphoria and restlessness, which were experienced by him in the absence of amitriptyline. He could not control taking amitriptyline in excess doses despite its regular side effects, which include constipation. In addition, from time to time, he engaged in binge ingestion of amitriptyline when he wanted to experience a “high” in his mood. In such circumstances, the number of tablets even reached to 25-30 per occasion (625–750 mg). These binges were associated with one or two seizure attacks, for which he or his family did not seek medical attention. For the past one year, the patient developed a progressive decline in his functionality, and he became dependent on amitriptyline. On the day of admission, the patient ingested about 30 tablets around 3 pm. Soon, the patient developed loss of consciousness and seizures.
After two days, anesthesia was withdrawn, and the patient was observed for the possibility of reappearance of seizure attacks for the next few hours. No more seizures were observed; however, he was continuously found to be confused. The patient was then transferred to an inpatient medical facility. In the medical ward, the patient soon became agitated, overtalkative, euphoric, disinhibited, and slept poorly. The diagnosis of delirious mania or hyperactive delirium as a result of the late effect of amitriptyline intoxication was made, and then he was started on effective doses of haloperidol and quetiapine. His symptoms responded well to haloperidol 6 mg tds and quetiapine 100 mg nocte. After recovery, the patient was assessed for the possibility of underlying depression, anxiety states, suicidal behavior, and any other psychiatric morbidities, and all were negative. However, he fulfilled the dependence criteria for amitriptyline. As per request, the family brought the drug pack for inspection, and it was found to contain about 500 tablets of 25 mg strength amitriptyline.
He was discharged from the hospital after two weeks on quetiapine 200 mg nocte, enrolled in an abstinence programme for amitriptyline dependence, taught sleep hygiene measures and interpersonal social rhythm therapy with the aim of assisting his routine sleep and other day-to-day activities, supported to reengage in his profession and to practice regular physical exercise, and was placed on assertive follow up care to monitor for and to prevent relapse.
3. Discussion
Patients who are treated with amitriptyline for long-term may show discontinuation syndrome upon withdrawal of the drug. This commonly manifests as flu-like symptoms (chills, myalgia, headache, nausea, excessive sweating), insomnia, excessive dreaming, and occasionally, movement disorders, mania, and cardiac arrhythmia [2].However, this patient's symptoms did not fit into this cluster of symptoms. Therefore, the possibility of discontinuation syndrome is least likely.
The diagnosis of amitriptyline dependence was made as the patient showed dependence features to the drug (tolerance, withdrawal symptoms, craving, continuation, and negligence of duty), and they were present for a period of more than one year [11].Features of dependence are broadly categorized into two classes: psychological and physiological [2] .Though the patient displayed both these types of symptoms, the psychological symptoms outweighed the physiological ones.
This case shines light on the long-lasting question of scientists whether amitriptyline holds abusive and dependency potential. Amitriptyline's abusive and addictive properties may result from its euphoric and sedative effects, similar to alcohol [1], and its (psycho) stimulant effect, as evident from this patient's urge to have “highs” that was “satisfied” with binging (overdose) of the drug [10]. Richelson [12] argues that anticholinergic and antihistaminic effects of tertiary tricyclics may underlie their abusive liability. Therefore, it could be argued that the antihistaminic and anticholinergic properties of amitriptyline act synergistically, resulting in its abusive tendency. However, there are case studies which divulge that the antihistaminic and anticholinergic properties of drugs may result in stimulant, euphoric, and/or psychedelic effects that might lead users to abuse these drugs [13–17]. These articles suggest that the stimulant and euphoric properties of amitriptyline may underlie the probable mechanism by which the drug causes addiction and dependence.
The other important concern the case highlights is that individuals with substance use disorders might carry a higher risk for amitriptyline dependence. Psychiatrists and other physicians who use amitriptyline in their practice should be prudent and keep a watchful eye on this long-term risk of the drug. In addition, this case discloses a deficient area of drug prescription and free accessibility of medications which is highly prevalent in Sri Lanka and may be in other countries as well, where no strict legislations govern the purchase of prescribed medications. The patient purchased the medication with an old prescription which was written about one and a half years ago by his psychiatrist. The case supports the argument that there should be a strict protocol to be adhered in accessing prescribed medications.
4. Conclusions
Amitriptyline shows the potential to cause dependence syndrome in vulnerable individuals
A clear protocol should be implemented when dispensing medications from pharmacy to patients
Acknowledgments
The authors acknowledge the support of Dr. Kumanan Thirunavukkarasu (Professor in Internal Medicine, Faculty of Medicine, University of Jaffna, Sri Lanka) who gave valuable inputs and edited the manuscript.
Conflicts of Interest
The authors declare that they do not have any conflict of interest or get any funding from any pharmaceutical company. | ALPRAZOLAM, AMITRIPTYLINE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33564485 | 19,071,921 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ill-defined disorder'. | Amitriptyline Dependence and Its Associations: A Case Report and Literature Review.
Amitriptyline, the second antidepressant invented next to imipramine, is indicated in many psychiatric conditions as well as for some organic disorders. The drug acts by increasing the availability of monoamines in the central nervous system postsynaptic clefts. Amitriptyline has long been suspected for abusive potential based on a few case reports, and the reports add evidence in favor of the hypothesis. This case report brings such material to the arena of evidence and discusses the probable mechanisms by which patients turn to abusing and be addicted to the drug. The article also argues matters associated with drug dispensing that might raise the risk of misuse of the drug, especially in countries where strict legislation for accessibility of prescribed drugs is not in practice.
1. Introduction
Amitriptyline is a tricyclic antidepressant and is used to treat depression, anxiety disorders, posttraumatic stress disorder (PTSD), insomnia, somatoform disorders, premenstrual dysphoric disorder, nocturnal enuresis, migraine, and neuropathic pain [1–3]. It blocks the reuptake of norepinephrine and serotonin and thus increases the availability of these neurotransmitters in the central nervous system (CNS) [1]. The maximum dose per day of amitriptyline is 300 mg, and this is given in divided doses to prevent/minimize adverse effects [2, 3]. The drug has antagonistic action at histaminic-1, alpha-1-adrenergic, and muscarinic cholinergic receptors. Those antiadrenergic and antimuscarinic properties bring about the troublesome adverse effects (hypotension, tachycardia, blurring of vision, urinary retention, constipation, dry mouth, sexual dysfunction) of the drug [1–3]. Amitriptyline also blocks voltage sensitive sodium channels in the heart and brain. In overdose, this action leads to arrhythmia, seizures, coma, and death [1].
The side effects, toxicity, and lethality in overdose, the risk of switch to manic state in predisposed individuals and the invention of selective serotonin reuptake inhibitors (SSRIs), another class of antidepressants with a better safety profile, made amitriptyline a less preferable medication [2]. However, the drug still has its role as a second line treatment for depression and nonpsychiatric conditions [1–3]. Amitriptyline also lowers the seizure threshold, and as such, in higher doses or intoxication, amitriptyline causes seizures [1, 4, 5]. Though it is generally considered that the drug does not possess abusive or addictive properties, there are a few case reports which suggest amitriptyline may exert such effects in susceptible individuals, i.e., patients with a history of another psychoactive substance abuse [6–10].
2. Case History
A 39-year-old married father of two videographer by profession, and who getting treatment for type II diabetes mellitus (DM), was admitted to a divisional hospital (Chankanai, Jaffna) in northern Sri Lanka, as he was found unconscious and suffering from seizure attacks. The patient was then transferred to Teaching Hospital Jaffna, as his seizure attacks could not be controlled with the treatment given at the divisional hospital. The patient was immediately admitted to the intensive care unit (ICU), a diagnosis of status epilepticus was made, and he was anesthetized in view of controlling his seizures. Within the next seven hours, the patient had 12 episodes of seizures. His electroencephalogram (EEG) and noncontrast computerized tomography (CT) scan of the brain, cerebrospinal fluid, liver enzymes, serum electrolytes, random blood sugar, and other routine biochemicals were well within normal limits. His electrocardiogram (ECG) showed sinus tachycardia. Opinion from a neurology team was sought, and it was favored against the diagnosis of epilepsy. The patient's wife gave a history that further enlightened the clinical picture.
Accordingly, the patient was regularly using alcohol for many years. One day, he consulted a surgeon in the private sector as he developed a single episode of haematemesis. The surgeon pointed out the reason behind the problem and advised him to go for total abstinence from alcohol. The surgeon also prescribed a low dose of alprazolam (0.5 mg nocte) to support his sleep without alcohol. In about a year's time, the patient was again presented to the surgeon by his family with a different complaint—“uncontrolled use of alprazolam”. At that point, the surgeon referred the patient to a psychiatrist. The psychiatrist advised the patient to tail off alprazolam and started treating him with 25 mg of amitriptyline, to be taken at night, in view of supporting his sleep problems. In the subsequent visit, the patient was complaining of poor sleep, and the dose of amitriptyline was gradually increased to 75 mg nocte. The patient felt better with that dose and stopped visiting the psychiatrist.
Since then, the patient started a kind of self-medication. He gradually increased the dose of amitriptyline to 250-300 mg at night as he needed more tablets to have good quality sleep and used 100–250 mg in daytimes to prevent dysphoria and restlessness, which were experienced by him in the absence of amitriptyline. He could not control taking amitriptyline in excess doses despite its regular side effects, which include constipation. In addition, from time to time, he engaged in binge ingestion of amitriptyline when he wanted to experience a “high” in his mood. In such circumstances, the number of tablets even reached to 25-30 per occasion (625–750 mg). These binges were associated with one or two seizure attacks, for which he or his family did not seek medical attention. For the past one year, the patient developed a progressive decline in his functionality, and he became dependent on amitriptyline. On the day of admission, the patient ingested about 30 tablets around 3 pm. Soon, the patient developed loss of consciousness and seizures.
After two days, anesthesia was withdrawn, and the patient was observed for the possibility of reappearance of seizure attacks for the next few hours. No more seizures were observed; however, he was continuously found to be confused. The patient was then transferred to an inpatient medical facility. In the medical ward, the patient soon became agitated, overtalkative, euphoric, disinhibited, and slept poorly. The diagnosis of delirious mania or hyperactive delirium as a result of the late effect of amitriptyline intoxication was made, and then he was started on effective doses of haloperidol and quetiapine. His symptoms responded well to haloperidol 6 mg tds and quetiapine 100 mg nocte. After recovery, the patient was assessed for the possibility of underlying depression, anxiety states, suicidal behavior, and any other psychiatric morbidities, and all were negative. However, he fulfilled the dependence criteria for amitriptyline. As per request, the family brought the drug pack for inspection, and it was found to contain about 500 tablets of 25 mg strength amitriptyline.
He was discharged from the hospital after two weeks on quetiapine 200 mg nocte, enrolled in an abstinence programme for amitriptyline dependence, taught sleep hygiene measures and interpersonal social rhythm therapy with the aim of assisting his routine sleep and other day-to-day activities, supported to reengage in his profession and to practice regular physical exercise, and was placed on assertive follow up care to monitor for and to prevent relapse.
3. Discussion
Patients who are treated with amitriptyline for long-term may show discontinuation syndrome upon withdrawal of the drug. This commonly manifests as flu-like symptoms (chills, myalgia, headache, nausea, excessive sweating), insomnia, excessive dreaming, and occasionally, movement disorders, mania, and cardiac arrhythmia [2].However, this patient's symptoms did not fit into this cluster of symptoms. Therefore, the possibility of discontinuation syndrome is least likely.
The diagnosis of amitriptyline dependence was made as the patient showed dependence features to the drug (tolerance, withdrawal symptoms, craving, continuation, and negligence of duty), and they were present for a period of more than one year [11].Features of dependence are broadly categorized into two classes: psychological and physiological [2] .Though the patient displayed both these types of symptoms, the psychological symptoms outweighed the physiological ones.
This case shines light on the long-lasting question of scientists whether amitriptyline holds abusive and dependency potential. Amitriptyline's abusive and addictive properties may result from its euphoric and sedative effects, similar to alcohol [1], and its (psycho) stimulant effect, as evident from this patient's urge to have “highs” that was “satisfied” with binging (overdose) of the drug [10]. Richelson [12] argues that anticholinergic and antihistaminic effects of tertiary tricyclics may underlie their abusive liability. Therefore, it could be argued that the antihistaminic and anticholinergic properties of amitriptyline act synergistically, resulting in its abusive tendency. However, there are case studies which divulge that the antihistaminic and anticholinergic properties of drugs may result in stimulant, euphoric, and/or psychedelic effects that might lead users to abuse these drugs [13–17]. These articles suggest that the stimulant and euphoric properties of amitriptyline may underlie the probable mechanism by which the drug causes addiction and dependence.
The other important concern the case highlights is that individuals with substance use disorders might carry a higher risk for amitriptyline dependence. Psychiatrists and other physicians who use amitriptyline in their practice should be prudent and keep a watchful eye on this long-term risk of the drug. In addition, this case discloses a deficient area of drug prescription and free accessibility of medications which is highly prevalent in Sri Lanka and may be in other countries as well, where no strict legislations govern the purchase of prescribed medications. The patient purchased the medication with an old prescription which was written about one and a half years ago by his psychiatrist. The case supports the argument that there should be a strict protocol to be adhered in accessing prescribed medications.
4. Conclusions
Amitriptyline shows the potential to cause dependence syndrome in vulnerable individuals
A clear protocol should be implemented when dispensing medications from pharmacy to patients
Acknowledgments
The authors acknowledge the support of Dr. Kumanan Thirunavukkarasu (Professor in Internal Medicine, Faculty of Medicine, University of Jaffna, Sri Lanka) who gave valuable inputs and edited the manuscript.
Conflicts of Interest
The authors declare that they do not have any conflict of interest or get any funding from any pharmaceutical company. | ALPRAZOLAM, AMITRIPTYLINE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33564485 | 19,071,921 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Amitriptyline Dependence and Its Associations: A Case Report and Literature Review.
Amitriptyline, the second antidepressant invented next to imipramine, is indicated in many psychiatric conditions as well as for some organic disorders. The drug acts by increasing the availability of monoamines in the central nervous system postsynaptic clefts. Amitriptyline has long been suspected for abusive potential based on a few case reports, and the reports add evidence in favor of the hypothesis. This case report brings such material to the arena of evidence and discusses the probable mechanisms by which patients turn to abusing and be addicted to the drug. The article also argues matters associated with drug dispensing that might raise the risk of misuse of the drug, especially in countries where strict legislation for accessibility of prescribed drugs is not in practice.
1. Introduction
Amitriptyline is a tricyclic antidepressant and is used to treat depression, anxiety disorders, posttraumatic stress disorder (PTSD), insomnia, somatoform disorders, premenstrual dysphoric disorder, nocturnal enuresis, migraine, and neuropathic pain [1–3]. It blocks the reuptake of norepinephrine and serotonin and thus increases the availability of these neurotransmitters in the central nervous system (CNS) [1]. The maximum dose per day of amitriptyline is 300 mg, and this is given in divided doses to prevent/minimize adverse effects [2, 3]. The drug has antagonistic action at histaminic-1, alpha-1-adrenergic, and muscarinic cholinergic receptors. Those antiadrenergic and antimuscarinic properties bring about the troublesome adverse effects (hypotension, tachycardia, blurring of vision, urinary retention, constipation, dry mouth, sexual dysfunction) of the drug [1–3]. Amitriptyline also blocks voltage sensitive sodium channels in the heart and brain. In overdose, this action leads to arrhythmia, seizures, coma, and death [1].
The side effects, toxicity, and lethality in overdose, the risk of switch to manic state in predisposed individuals and the invention of selective serotonin reuptake inhibitors (SSRIs), another class of antidepressants with a better safety profile, made amitriptyline a less preferable medication [2]. However, the drug still has its role as a second line treatment for depression and nonpsychiatric conditions [1–3]. Amitriptyline also lowers the seizure threshold, and as such, in higher doses or intoxication, amitriptyline causes seizures [1, 4, 5]. Though it is generally considered that the drug does not possess abusive or addictive properties, there are a few case reports which suggest amitriptyline may exert such effects in susceptible individuals, i.e., patients with a history of another psychoactive substance abuse [6–10].
2. Case History
A 39-year-old married father of two videographer by profession, and who getting treatment for type II diabetes mellitus (DM), was admitted to a divisional hospital (Chankanai, Jaffna) in northern Sri Lanka, as he was found unconscious and suffering from seizure attacks. The patient was then transferred to Teaching Hospital Jaffna, as his seizure attacks could not be controlled with the treatment given at the divisional hospital. The patient was immediately admitted to the intensive care unit (ICU), a diagnosis of status epilepticus was made, and he was anesthetized in view of controlling his seizures. Within the next seven hours, the patient had 12 episodes of seizures. His electroencephalogram (EEG) and noncontrast computerized tomography (CT) scan of the brain, cerebrospinal fluid, liver enzymes, serum electrolytes, random blood sugar, and other routine biochemicals were well within normal limits. His electrocardiogram (ECG) showed sinus tachycardia. Opinion from a neurology team was sought, and it was favored against the diagnosis of epilepsy. The patient's wife gave a history that further enlightened the clinical picture.
Accordingly, the patient was regularly using alcohol for many years. One day, he consulted a surgeon in the private sector as he developed a single episode of haematemesis. The surgeon pointed out the reason behind the problem and advised him to go for total abstinence from alcohol. The surgeon also prescribed a low dose of alprazolam (0.5 mg nocte) to support his sleep without alcohol. In about a year's time, the patient was again presented to the surgeon by his family with a different complaint—“uncontrolled use of alprazolam”. At that point, the surgeon referred the patient to a psychiatrist. The psychiatrist advised the patient to tail off alprazolam and started treating him with 25 mg of amitriptyline, to be taken at night, in view of supporting his sleep problems. In the subsequent visit, the patient was complaining of poor sleep, and the dose of amitriptyline was gradually increased to 75 mg nocte. The patient felt better with that dose and stopped visiting the psychiatrist.
Since then, the patient started a kind of self-medication. He gradually increased the dose of amitriptyline to 250-300 mg at night as he needed more tablets to have good quality sleep and used 100–250 mg in daytimes to prevent dysphoria and restlessness, which were experienced by him in the absence of amitriptyline. He could not control taking amitriptyline in excess doses despite its regular side effects, which include constipation. In addition, from time to time, he engaged in binge ingestion of amitriptyline when he wanted to experience a “high” in his mood. In such circumstances, the number of tablets even reached to 25-30 per occasion (625–750 mg). These binges were associated with one or two seizure attacks, for which he or his family did not seek medical attention. For the past one year, the patient developed a progressive decline in his functionality, and he became dependent on amitriptyline. On the day of admission, the patient ingested about 30 tablets around 3 pm. Soon, the patient developed loss of consciousness and seizures.
After two days, anesthesia was withdrawn, and the patient was observed for the possibility of reappearance of seizure attacks for the next few hours. No more seizures were observed; however, he was continuously found to be confused. The patient was then transferred to an inpatient medical facility. In the medical ward, the patient soon became agitated, overtalkative, euphoric, disinhibited, and slept poorly. The diagnosis of delirious mania or hyperactive delirium as a result of the late effect of amitriptyline intoxication was made, and then he was started on effective doses of haloperidol and quetiapine. His symptoms responded well to haloperidol 6 mg tds and quetiapine 100 mg nocte. After recovery, the patient was assessed for the possibility of underlying depression, anxiety states, suicidal behavior, and any other psychiatric morbidities, and all were negative. However, he fulfilled the dependence criteria for amitriptyline. As per request, the family brought the drug pack for inspection, and it was found to contain about 500 tablets of 25 mg strength amitriptyline.
He was discharged from the hospital after two weeks on quetiapine 200 mg nocte, enrolled in an abstinence programme for amitriptyline dependence, taught sleep hygiene measures and interpersonal social rhythm therapy with the aim of assisting his routine sleep and other day-to-day activities, supported to reengage in his profession and to practice regular physical exercise, and was placed on assertive follow up care to monitor for and to prevent relapse.
3. Discussion
Patients who are treated with amitriptyline for long-term may show discontinuation syndrome upon withdrawal of the drug. This commonly manifests as flu-like symptoms (chills, myalgia, headache, nausea, excessive sweating), insomnia, excessive dreaming, and occasionally, movement disorders, mania, and cardiac arrhythmia [2].However, this patient's symptoms did not fit into this cluster of symptoms. Therefore, the possibility of discontinuation syndrome is least likely.
The diagnosis of amitriptyline dependence was made as the patient showed dependence features to the drug (tolerance, withdrawal symptoms, craving, continuation, and negligence of duty), and they were present for a period of more than one year [11].Features of dependence are broadly categorized into two classes: psychological and physiological [2] .Though the patient displayed both these types of symptoms, the psychological symptoms outweighed the physiological ones.
This case shines light on the long-lasting question of scientists whether amitriptyline holds abusive and dependency potential. Amitriptyline's abusive and addictive properties may result from its euphoric and sedative effects, similar to alcohol [1], and its (psycho) stimulant effect, as evident from this patient's urge to have “highs” that was “satisfied” with binging (overdose) of the drug [10]. Richelson [12] argues that anticholinergic and antihistaminic effects of tertiary tricyclics may underlie their abusive liability. Therefore, it could be argued that the antihistaminic and anticholinergic properties of amitriptyline act synergistically, resulting in its abusive tendency. However, there are case studies which divulge that the antihistaminic and anticholinergic properties of drugs may result in stimulant, euphoric, and/or psychedelic effects that might lead users to abuse these drugs [13–17]. These articles suggest that the stimulant and euphoric properties of amitriptyline may underlie the probable mechanism by which the drug causes addiction and dependence.
The other important concern the case highlights is that individuals with substance use disorders might carry a higher risk for amitriptyline dependence. Psychiatrists and other physicians who use amitriptyline in their practice should be prudent and keep a watchful eye on this long-term risk of the drug. In addition, this case discloses a deficient area of drug prescription and free accessibility of medications which is highly prevalent in Sri Lanka and may be in other countries as well, where no strict legislations govern the purchase of prescribed medications. The patient purchased the medication with an old prescription which was written about one and a half years ago by his psychiatrist. The case supports the argument that there should be a strict protocol to be adhered in accessing prescribed medications.
4. Conclusions
Amitriptyline shows the potential to cause dependence syndrome in vulnerable individuals
A clear protocol should be implemented when dispensing medications from pharmacy to patients
Acknowledgments
The authors acknowledge the support of Dr. Kumanan Thirunavukkarasu (Professor in Internal Medicine, Faculty of Medicine, University of Jaffna, Sri Lanka) who gave valuable inputs and edited the manuscript.
Conflicts of Interest
The authors declare that they do not have any conflict of interest or get any funding from any pharmaceutical company. | ALPRAZOLAM, AMITRIPTYLINE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33564485 | 19,071,921 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Status epilepticus'. | Amitriptyline Dependence and Its Associations: A Case Report and Literature Review.
Amitriptyline, the second antidepressant invented next to imipramine, is indicated in many psychiatric conditions as well as for some organic disorders. The drug acts by increasing the availability of monoamines in the central nervous system postsynaptic clefts. Amitriptyline has long been suspected for abusive potential based on a few case reports, and the reports add evidence in favor of the hypothesis. This case report brings such material to the arena of evidence and discusses the probable mechanisms by which patients turn to abusing and be addicted to the drug. The article also argues matters associated with drug dispensing that might raise the risk of misuse of the drug, especially in countries where strict legislation for accessibility of prescribed drugs is not in practice.
1. Introduction
Amitriptyline is a tricyclic antidepressant and is used to treat depression, anxiety disorders, posttraumatic stress disorder (PTSD), insomnia, somatoform disorders, premenstrual dysphoric disorder, nocturnal enuresis, migraine, and neuropathic pain [1–3]. It blocks the reuptake of norepinephrine and serotonin and thus increases the availability of these neurotransmitters in the central nervous system (CNS) [1]. The maximum dose per day of amitriptyline is 300 mg, and this is given in divided doses to prevent/minimize adverse effects [2, 3]. The drug has antagonistic action at histaminic-1, alpha-1-adrenergic, and muscarinic cholinergic receptors. Those antiadrenergic and antimuscarinic properties bring about the troublesome adverse effects (hypotension, tachycardia, blurring of vision, urinary retention, constipation, dry mouth, sexual dysfunction) of the drug [1–3]. Amitriptyline also blocks voltage sensitive sodium channels in the heart and brain. In overdose, this action leads to arrhythmia, seizures, coma, and death [1].
The side effects, toxicity, and lethality in overdose, the risk of switch to manic state in predisposed individuals and the invention of selective serotonin reuptake inhibitors (SSRIs), another class of antidepressants with a better safety profile, made amitriptyline a less preferable medication [2]. However, the drug still has its role as a second line treatment for depression and nonpsychiatric conditions [1–3]. Amitriptyline also lowers the seizure threshold, and as such, in higher doses or intoxication, amitriptyline causes seizures [1, 4, 5]. Though it is generally considered that the drug does not possess abusive or addictive properties, there are a few case reports which suggest amitriptyline may exert such effects in susceptible individuals, i.e., patients with a history of another psychoactive substance abuse [6–10].
2. Case History
A 39-year-old married father of two videographer by profession, and who getting treatment for type II diabetes mellitus (DM), was admitted to a divisional hospital (Chankanai, Jaffna) in northern Sri Lanka, as he was found unconscious and suffering from seizure attacks. The patient was then transferred to Teaching Hospital Jaffna, as his seizure attacks could not be controlled with the treatment given at the divisional hospital. The patient was immediately admitted to the intensive care unit (ICU), a diagnosis of status epilepticus was made, and he was anesthetized in view of controlling his seizures. Within the next seven hours, the patient had 12 episodes of seizures. His electroencephalogram (EEG) and noncontrast computerized tomography (CT) scan of the brain, cerebrospinal fluid, liver enzymes, serum electrolytes, random blood sugar, and other routine biochemicals were well within normal limits. His electrocardiogram (ECG) showed sinus tachycardia. Opinion from a neurology team was sought, and it was favored against the diagnosis of epilepsy. The patient's wife gave a history that further enlightened the clinical picture.
Accordingly, the patient was regularly using alcohol for many years. One day, he consulted a surgeon in the private sector as he developed a single episode of haematemesis. The surgeon pointed out the reason behind the problem and advised him to go for total abstinence from alcohol. The surgeon also prescribed a low dose of alprazolam (0.5 mg nocte) to support his sleep without alcohol. In about a year's time, the patient was again presented to the surgeon by his family with a different complaint—“uncontrolled use of alprazolam”. At that point, the surgeon referred the patient to a psychiatrist. The psychiatrist advised the patient to tail off alprazolam and started treating him with 25 mg of amitriptyline, to be taken at night, in view of supporting his sleep problems. In the subsequent visit, the patient was complaining of poor sleep, and the dose of amitriptyline was gradually increased to 75 mg nocte. The patient felt better with that dose and stopped visiting the psychiatrist.
Since then, the patient started a kind of self-medication. He gradually increased the dose of amitriptyline to 250-300 mg at night as he needed more tablets to have good quality sleep and used 100–250 mg in daytimes to prevent dysphoria and restlessness, which were experienced by him in the absence of amitriptyline. He could not control taking amitriptyline in excess doses despite its regular side effects, which include constipation. In addition, from time to time, he engaged in binge ingestion of amitriptyline when he wanted to experience a “high” in his mood. In such circumstances, the number of tablets even reached to 25-30 per occasion (625–750 mg). These binges were associated with one or two seizure attacks, for which he or his family did not seek medical attention. For the past one year, the patient developed a progressive decline in his functionality, and he became dependent on amitriptyline. On the day of admission, the patient ingested about 30 tablets around 3 pm. Soon, the patient developed loss of consciousness and seizures.
After two days, anesthesia was withdrawn, and the patient was observed for the possibility of reappearance of seizure attacks for the next few hours. No more seizures were observed; however, he was continuously found to be confused. The patient was then transferred to an inpatient medical facility. In the medical ward, the patient soon became agitated, overtalkative, euphoric, disinhibited, and slept poorly. The diagnosis of delirious mania or hyperactive delirium as a result of the late effect of amitriptyline intoxication was made, and then he was started on effective doses of haloperidol and quetiapine. His symptoms responded well to haloperidol 6 mg tds and quetiapine 100 mg nocte. After recovery, the patient was assessed for the possibility of underlying depression, anxiety states, suicidal behavior, and any other psychiatric morbidities, and all were negative. However, he fulfilled the dependence criteria for amitriptyline. As per request, the family brought the drug pack for inspection, and it was found to contain about 500 tablets of 25 mg strength amitriptyline.
He was discharged from the hospital after two weeks on quetiapine 200 mg nocte, enrolled in an abstinence programme for amitriptyline dependence, taught sleep hygiene measures and interpersonal social rhythm therapy with the aim of assisting his routine sleep and other day-to-day activities, supported to reengage in his profession and to practice regular physical exercise, and was placed on assertive follow up care to monitor for and to prevent relapse.
3. Discussion
Patients who are treated with amitriptyline for long-term may show discontinuation syndrome upon withdrawal of the drug. This commonly manifests as flu-like symptoms (chills, myalgia, headache, nausea, excessive sweating), insomnia, excessive dreaming, and occasionally, movement disorders, mania, and cardiac arrhythmia [2].However, this patient's symptoms did not fit into this cluster of symptoms. Therefore, the possibility of discontinuation syndrome is least likely.
The diagnosis of amitriptyline dependence was made as the patient showed dependence features to the drug (tolerance, withdrawal symptoms, craving, continuation, and negligence of duty), and they were present for a period of more than one year [11].Features of dependence are broadly categorized into two classes: psychological and physiological [2] .Though the patient displayed both these types of symptoms, the psychological symptoms outweighed the physiological ones.
This case shines light on the long-lasting question of scientists whether amitriptyline holds abusive and dependency potential. Amitriptyline's abusive and addictive properties may result from its euphoric and sedative effects, similar to alcohol [1], and its (psycho) stimulant effect, as evident from this patient's urge to have “highs” that was “satisfied” with binging (overdose) of the drug [10]. Richelson [12] argues that anticholinergic and antihistaminic effects of tertiary tricyclics may underlie their abusive liability. Therefore, it could be argued that the antihistaminic and anticholinergic properties of amitriptyline act synergistically, resulting in its abusive tendency. However, there are case studies which divulge that the antihistaminic and anticholinergic properties of drugs may result in stimulant, euphoric, and/or psychedelic effects that might lead users to abuse these drugs [13–17]. These articles suggest that the stimulant and euphoric properties of amitriptyline may underlie the probable mechanism by which the drug causes addiction and dependence.
The other important concern the case highlights is that individuals with substance use disorders might carry a higher risk for amitriptyline dependence. Psychiatrists and other physicians who use amitriptyline in their practice should be prudent and keep a watchful eye on this long-term risk of the drug. In addition, this case discloses a deficient area of drug prescription and free accessibility of medications which is highly prevalent in Sri Lanka and may be in other countries as well, where no strict legislations govern the purchase of prescribed medications. The patient purchased the medication with an old prescription which was written about one and a half years ago by his psychiatrist. The case supports the argument that there should be a strict protocol to be adhered in accessing prescribed medications.
4. Conclusions
Amitriptyline shows the potential to cause dependence syndrome in vulnerable individuals
A clear protocol should be implemented when dispensing medications from pharmacy to patients
Acknowledgments
The authors acknowledge the support of Dr. Kumanan Thirunavukkarasu (Professor in Internal Medicine, Faculty of Medicine, University of Jaffna, Sri Lanka) who gave valuable inputs and edited the manuscript.
Conflicts of Interest
The authors declare that they do not have any conflict of interest or get any funding from any pharmaceutical company. | ALPRAZOLAM, AMITRIPTYLINE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33564485 | 19,071,921 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Toxicity to various agents'. | Amitriptyline Dependence and Its Associations: A Case Report and Literature Review.
Amitriptyline, the second antidepressant invented next to imipramine, is indicated in many psychiatric conditions as well as for some organic disorders. The drug acts by increasing the availability of monoamines in the central nervous system postsynaptic clefts. Amitriptyline has long been suspected for abusive potential based on a few case reports, and the reports add evidence in favor of the hypothesis. This case report brings such material to the arena of evidence and discusses the probable mechanisms by which patients turn to abusing and be addicted to the drug. The article also argues matters associated with drug dispensing that might raise the risk of misuse of the drug, especially in countries where strict legislation for accessibility of prescribed drugs is not in practice.
1. Introduction
Amitriptyline is a tricyclic antidepressant and is used to treat depression, anxiety disorders, posttraumatic stress disorder (PTSD), insomnia, somatoform disorders, premenstrual dysphoric disorder, nocturnal enuresis, migraine, and neuropathic pain [1–3]. It blocks the reuptake of norepinephrine and serotonin and thus increases the availability of these neurotransmitters in the central nervous system (CNS) [1]. The maximum dose per day of amitriptyline is 300 mg, and this is given in divided doses to prevent/minimize adverse effects [2, 3]. The drug has antagonistic action at histaminic-1, alpha-1-adrenergic, and muscarinic cholinergic receptors. Those antiadrenergic and antimuscarinic properties bring about the troublesome adverse effects (hypotension, tachycardia, blurring of vision, urinary retention, constipation, dry mouth, sexual dysfunction) of the drug [1–3]. Amitriptyline also blocks voltage sensitive sodium channels in the heart and brain. In overdose, this action leads to arrhythmia, seizures, coma, and death [1].
The side effects, toxicity, and lethality in overdose, the risk of switch to manic state in predisposed individuals and the invention of selective serotonin reuptake inhibitors (SSRIs), another class of antidepressants with a better safety profile, made amitriptyline a less preferable medication [2]. However, the drug still has its role as a second line treatment for depression and nonpsychiatric conditions [1–3]. Amitriptyline also lowers the seizure threshold, and as such, in higher doses or intoxication, amitriptyline causes seizures [1, 4, 5]. Though it is generally considered that the drug does not possess abusive or addictive properties, there are a few case reports which suggest amitriptyline may exert such effects in susceptible individuals, i.e., patients with a history of another psychoactive substance abuse [6–10].
2. Case History
A 39-year-old married father of two videographer by profession, and who getting treatment for type II diabetes mellitus (DM), was admitted to a divisional hospital (Chankanai, Jaffna) in northern Sri Lanka, as he was found unconscious and suffering from seizure attacks. The patient was then transferred to Teaching Hospital Jaffna, as his seizure attacks could not be controlled with the treatment given at the divisional hospital. The patient was immediately admitted to the intensive care unit (ICU), a diagnosis of status epilepticus was made, and he was anesthetized in view of controlling his seizures. Within the next seven hours, the patient had 12 episodes of seizures. His electroencephalogram (EEG) and noncontrast computerized tomography (CT) scan of the brain, cerebrospinal fluid, liver enzymes, serum electrolytes, random blood sugar, and other routine biochemicals were well within normal limits. His electrocardiogram (ECG) showed sinus tachycardia. Opinion from a neurology team was sought, and it was favored against the diagnosis of epilepsy. The patient's wife gave a history that further enlightened the clinical picture.
Accordingly, the patient was regularly using alcohol for many years. One day, he consulted a surgeon in the private sector as he developed a single episode of haematemesis. The surgeon pointed out the reason behind the problem and advised him to go for total abstinence from alcohol. The surgeon also prescribed a low dose of alprazolam (0.5 mg nocte) to support his sleep without alcohol. In about a year's time, the patient was again presented to the surgeon by his family with a different complaint—“uncontrolled use of alprazolam”. At that point, the surgeon referred the patient to a psychiatrist. The psychiatrist advised the patient to tail off alprazolam and started treating him with 25 mg of amitriptyline, to be taken at night, in view of supporting his sleep problems. In the subsequent visit, the patient was complaining of poor sleep, and the dose of amitriptyline was gradually increased to 75 mg nocte. The patient felt better with that dose and stopped visiting the psychiatrist.
Since then, the patient started a kind of self-medication. He gradually increased the dose of amitriptyline to 250-300 mg at night as he needed more tablets to have good quality sleep and used 100–250 mg in daytimes to prevent dysphoria and restlessness, which were experienced by him in the absence of amitriptyline. He could not control taking amitriptyline in excess doses despite its regular side effects, which include constipation. In addition, from time to time, he engaged in binge ingestion of amitriptyline when he wanted to experience a “high” in his mood. In such circumstances, the number of tablets even reached to 25-30 per occasion (625–750 mg). These binges were associated with one or two seizure attacks, for which he or his family did not seek medical attention. For the past one year, the patient developed a progressive decline in his functionality, and he became dependent on amitriptyline. On the day of admission, the patient ingested about 30 tablets around 3 pm. Soon, the patient developed loss of consciousness and seizures.
After two days, anesthesia was withdrawn, and the patient was observed for the possibility of reappearance of seizure attacks for the next few hours. No more seizures were observed; however, he was continuously found to be confused. The patient was then transferred to an inpatient medical facility. In the medical ward, the patient soon became agitated, overtalkative, euphoric, disinhibited, and slept poorly. The diagnosis of delirious mania or hyperactive delirium as a result of the late effect of amitriptyline intoxication was made, and then he was started on effective doses of haloperidol and quetiapine. His symptoms responded well to haloperidol 6 mg tds and quetiapine 100 mg nocte. After recovery, the patient was assessed for the possibility of underlying depression, anxiety states, suicidal behavior, and any other psychiatric morbidities, and all were negative. However, he fulfilled the dependence criteria for amitriptyline. As per request, the family brought the drug pack for inspection, and it was found to contain about 500 tablets of 25 mg strength amitriptyline.
He was discharged from the hospital after two weeks on quetiapine 200 mg nocte, enrolled in an abstinence programme for amitriptyline dependence, taught sleep hygiene measures and interpersonal social rhythm therapy with the aim of assisting his routine sleep and other day-to-day activities, supported to reengage in his profession and to practice regular physical exercise, and was placed on assertive follow up care to monitor for and to prevent relapse.
3. Discussion
Patients who are treated with amitriptyline for long-term may show discontinuation syndrome upon withdrawal of the drug. This commonly manifests as flu-like symptoms (chills, myalgia, headache, nausea, excessive sweating), insomnia, excessive dreaming, and occasionally, movement disorders, mania, and cardiac arrhythmia [2].However, this patient's symptoms did not fit into this cluster of symptoms. Therefore, the possibility of discontinuation syndrome is least likely.
The diagnosis of amitriptyline dependence was made as the patient showed dependence features to the drug (tolerance, withdrawal symptoms, craving, continuation, and negligence of duty), and they were present for a period of more than one year [11].Features of dependence are broadly categorized into two classes: psychological and physiological [2] .Though the patient displayed both these types of symptoms, the psychological symptoms outweighed the physiological ones.
This case shines light on the long-lasting question of scientists whether amitriptyline holds abusive and dependency potential. Amitriptyline's abusive and addictive properties may result from its euphoric and sedative effects, similar to alcohol [1], and its (psycho) stimulant effect, as evident from this patient's urge to have “highs” that was “satisfied” with binging (overdose) of the drug [10]. Richelson [12] argues that anticholinergic and antihistaminic effects of tertiary tricyclics may underlie their abusive liability. Therefore, it could be argued that the antihistaminic and anticholinergic properties of amitriptyline act synergistically, resulting in its abusive tendency. However, there are case studies which divulge that the antihistaminic and anticholinergic properties of drugs may result in stimulant, euphoric, and/or psychedelic effects that might lead users to abuse these drugs [13–17]. These articles suggest that the stimulant and euphoric properties of amitriptyline may underlie the probable mechanism by which the drug causes addiction and dependence.
The other important concern the case highlights is that individuals with substance use disorders might carry a higher risk for amitriptyline dependence. Psychiatrists and other physicians who use amitriptyline in their practice should be prudent and keep a watchful eye on this long-term risk of the drug. In addition, this case discloses a deficient area of drug prescription and free accessibility of medications which is highly prevalent in Sri Lanka and may be in other countries as well, where no strict legislations govern the purchase of prescribed medications. The patient purchased the medication with an old prescription which was written about one and a half years ago by his psychiatrist. The case supports the argument that there should be a strict protocol to be adhered in accessing prescribed medications.
4. Conclusions
Amitriptyline shows the potential to cause dependence syndrome in vulnerable individuals
A clear protocol should be implemented when dispensing medications from pharmacy to patients
Acknowledgments
The authors acknowledge the support of Dr. Kumanan Thirunavukkarasu (Professor in Internal Medicine, Faculty of Medicine, University of Jaffna, Sri Lanka) who gave valuable inputs and edited the manuscript.
Conflicts of Interest
The authors declare that they do not have any conflict of interest or get any funding from any pharmaceutical company. | ALPRAZOLAM, AMITRIPTYLINE HYDROCHLORIDE | DrugsGivenReaction | CC BY | 33564485 | 19,071,921 | 2021 |
What was the administration route of drug 'AMITRIPTYLINE HYDROCHLORIDE'? | Amitriptyline Dependence and Its Associations: A Case Report and Literature Review.
Amitriptyline, the second antidepressant invented next to imipramine, is indicated in many psychiatric conditions as well as for some organic disorders. The drug acts by increasing the availability of monoamines in the central nervous system postsynaptic clefts. Amitriptyline has long been suspected for abusive potential based on a few case reports, and the reports add evidence in favor of the hypothesis. This case report brings such material to the arena of evidence and discusses the probable mechanisms by which patients turn to abusing and be addicted to the drug. The article also argues matters associated with drug dispensing that might raise the risk of misuse of the drug, especially in countries where strict legislation for accessibility of prescribed drugs is not in practice.
1. Introduction
Amitriptyline is a tricyclic antidepressant and is used to treat depression, anxiety disorders, posttraumatic stress disorder (PTSD), insomnia, somatoform disorders, premenstrual dysphoric disorder, nocturnal enuresis, migraine, and neuropathic pain [1–3]. It blocks the reuptake of norepinephrine and serotonin and thus increases the availability of these neurotransmitters in the central nervous system (CNS) [1]. The maximum dose per day of amitriptyline is 300 mg, and this is given in divided doses to prevent/minimize adverse effects [2, 3]. The drug has antagonistic action at histaminic-1, alpha-1-adrenergic, and muscarinic cholinergic receptors. Those antiadrenergic and antimuscarinic properties bring about the troublesome adverse effects (hypotension, tachycardia, blurring of vision, urinary retention, constipation, dry mouth, sexual dysfunction) of the drug [1–3]. Amitriptyline also blocks voltage sensitive sodium channels in the heart and brain. In overdose, this action leads to arrhythmia, seizures, coma, and death [1].
The side effects, toxicity, and lethality in overdose, the risk of switch to manic state in predisposed individuals and the invention of selective serotonin reuptake inhibitors (SSRIs), another class of antidepressants with a better safety profile, made amitriptyline a less preferable medication [2]. However, the drug still has its role as a second line treatment for depression and nonpsychiatric conditions [1–3]. Amitriptyline also lowers the seizure threshold, and as such, in higher doses or intoxication, amitriptyline causes seizures [1, 4, 5]. Though it is generally considered that the drug does not possess abusive or addictive properties, there are a few case reports which suggest amitriptyline may exert such effects in susceptible individuals, i.e., patients with a history of another psychoactive substance abuse [6–10].
2. Case History
A 39-year-old married father of two videographer by profession, and who getting treatment for type II diabetes mellitus (DM), was admitted to a divisional hospital (Chankanai, Jaffna) in northern Sri Lanka, as he was found unconscious and suffering from seizure attacks. The patient was then transferred to Teaching Hospital Jaffna, as his seizure attacks could not be controlled with the treatment given at the divisional hospital. The patient was immediately admitted to the intensive care unit (ICU), a diagnosis of status epilepticus was made, and he was anesthetized in view of controlling his seizures. Within the next seven hours, the patient had 12 episodes of seizures. His electroencephalogram (EEG) and noncontrast computerized tomography (CT) scan of the brain, cerebrospinal fluid, liver enzymes, serum electrolytes, random blood sugar, and other routine biochemicals were well within normal limits. His electrocardiogram (ECG) showed sinus tachycardia. Opinion from a neurology team was sought, and it was favored against the diagnosis of epilepsy. The patient's wife gave a history that further enlightened the clinical picture.
Accordingly, the patient was regularly using alcohol for many years. One day, he consulted a surgeon in the private sector as he developed a single episode of haematemesis. The surgeon pointed out the reason behind the problem and advised him to go for total abstinence from alcohol. The surgeon also prescribed a low dose of alprazolam (0.5 mg nocte) to support his sleep without alcohol. In about a year's time, the patient was again presented to the surgeon by his family with a different complaint—“uncontrolled use of alprazolam”. At that point, the surgeon referred the patient to a psychiatrist. The psychiatrist advised the patient to tail off alprazolam and started treating him with 25 mg of amitriptyline, to be taken at night, in view of supporting his sleep problems. In the subsequent visit, the patient was complaining of poor sleep, and the dose of amitriptyline was gradually increased to 75 mg nocte. The patient felt better with that dose and stopped visiting the psychiatrist.
Since then, the patient started a kind of self-medication. He gradually increased the dose of amitriptyline to 250-300 mg at night as he needed more tablets to have good quality sleep and used 100–250 mg in daytimes to prevent dysphoria and restlessness, which were experienced by him in the absence of amitriptyline. He could not control taking amitriptyline in excess doses despite its regular side effects, which include constipation. In addition, from time to time, he engaged in binge ingestion of amitriptyline when he wanted to experience a “high” in his mood. In such circumstances, the number of tablets even reached to 25-30 per occasion (625–750 mg). These binges were associated with one or two seizure attacks, for which he or his family did not seek medical attention. For the past one year, the patient developed a progressive decline in his functionality, and he became dependent on amitriptyline. On the day of admission, the patient ingested about 30 tablets around 3 pm. Soon, the patient developed loss of consciousness and seizures.
After two days, anesthesia was withdrawn, and the patient was observed for the possibility of reappearance of seizure attacks for the next few hours. No more seizures were observed; however, he was continuously found to be confused. The patient was then transferred to an inpatient medical facility. In the medical ward, the patient soon became agitated, overtalkative, euphoric, disinhibited, and slept poorly. The diagnosis of delirious mania or hyperactive delirium as a result of the late effect of amitriptyline intoxication was made, and then he was started on effective doses of haloperidol and quetiapine. His symptoms responded well to haloperidol 6 mg tds and quetiapine 100 mg nocte. After recovery, the patient was assessed for the possibility of underlying depression, anxiety states, suicidal behavior, and any other psychiatric morbidities, and all were negative. However, he fulfilled the dependence criteria for amitriptyline. As per request, the family brought the drug pack for inspection, and it was found to contain about 500 tablets of 25 mg strength amitriptyline.
He was discharged from the hospital after two weeks on quetiapine 200 mg nocte, enrolled in an abstinence programme for amitriptyline dependence, taught sleep hygiene measures and interpersonal social rhythm therapy with the aim of assisting his routine sleep and other day-to-day activities, supported to reengage in his profession and to practice regular physical exercise, and was placed on assertive follow up care to monitor for and to prevent relapse.
3. Discussion
Patients who are treated with amitriptyline for long-term may show discontinuation syndrome upon withdrawal of the drug. This commonly manifests as flu-like symptoms (chills, myalgia, headache, nausea, excessive sweating), insomnia, excessive dreaming, and occasionally, movement disorders, mania, and cardiac arrhythmia [2].However, this patient's symptoms did not fit into this cluster of symptoms. Therefore, the possibility of discontinuation syndrome is least likely.
The diagnosis of amitriptyline dependence was made as the patient showed dependence features to the drug (tolerance, withdrawal symptoms, craving, continuation, and negligence of duty), and they were present for a period of more than one year [11].Features of dependence are broadly categorized into two classes: psychological and physiological [2] .Though the patient displayed both these types of symptoms, the psychological symptoms outweighed the physiological ones.
This case shines light on the long-lasting question of scientists whether amitriptyline holds abusive and dependency potential. Amitriptyline's abusive and addictive properties may result from its euphoric and sedative effects, similar to alcohol [1], and its (psycho) stimulant effect, as evident from this patient's urge to have “highs” that was “satisfied” with binging (overdose) of the drug [10]. Richelson [12] argues that anticholinergic and antihistaminic effects of tertiary tricyclics may underlie their abusive liability. Therefore, it could be argued that the antihistaminic and anticholinergic properties of amitriptyline act synergistically, resulting in its abusive tendency. However, there are case studies which divulge that the antihistaminic and anticholinergic properties of drugs may result in stimulant, euphoric, and/or psychedelic effects that might lead users to abuse these drugs [13–17]. These articles suggest that the stimulant and euphoric properties of amitriptyline may underlie the probable mechanism by which the drug causes addiction and dependence.
The other important concern the case highlights is that individuals with substance use disorders might carry a higher risk for amitriptyline dependence. Psychiatrists and other physicians who use amitriptyline in their practice should be prudent and keep a watchful eye on this long-term risk of the drug. In addition, this case discloses a deficient area of drug prescription and free accessibility of medications which is highly prevalent in Sri Lanka and may be in other countries as well, where no strict legislations govern the purchase of prescribed medications. The patient purchased the medication with an old prescription which was written about one and a half years ago by his psychiatrist. The case supports the argument that there should be a strict protocol to be adhered in accessing prescribed medications.
4. Conclusions
Amitriptyline shows the potential to cause dependence syndrome in vulnerable individuals
A clear protocol should be implemented when dispensing medications from pharmacy to patients
Acknowledgments
The authors acknowledge the support of Dr. Kumanan Thirunavukkarasu (Professor in Internal Medicine, Faculty of Medicine, University of Jaffna, Sri Lanka) who gave valuable inputs and edited the manuscript.
Conflicts of Interest
The authors declare that they do not have any conflict of interest or get any funding from any pharmaceutical company. | Oral | DrugAdministrationRoute | CC BY | 33564485 | 19,071,921 | 2021 |
What was the outcome of reaction 'Confusional state'? | Amitriptyline Dependence and Its Associations: A Case Report and Literature Review.
Amitriptyline, the second antidepressant invented next to imipramine, is indicated in many psychiatric conditions as well as for some organic disorders. The drug acts by increasing the availability of monoamines in the central nervous system postsynaptic clefts. Amitriptyline has long been suspected for abusive potential based on a few case reports, and the reports add evidence in favor of the hypothesis. This case report brings such material to the arena of evidence and discusses the probable mechanisms by which patients turn to abusing and be addicted to the drug. The article also argues matters associated with drug dispensing that might raise the risk of misuse of the drug, especially in countries where strict legislation for accessibility of prescribed drugs is not in practice.
1. Introduction
Amitriptyline is a tricyclic antidepressant and is used to treat depression, anxiety disorders, posttraumatic stress disorder (PTSD), insomnia, somatoform disorders, premenstrual dysphoric disorder, nocturnal enuresis, migraine, and neuropathic pain [1–3]. It blocks the reuptake of norepinephrine and serotonin and thus increases the availability of these neurotransmitters in the central nervous system (CNS) [1]. The maximum dose per day of amitriptyline is 300 mg, and this is given in divided doses to prevent/minimize adverse effects [2, 3]. The drug has antagonistic action at histaminic-1, alpha-1-adrenergic, and muscarinic cholinergic receptors. Those antiadrenergic and antimuscarinic properties bring about the troublesome adverse effects (hypotension, tachycardia, blurring of vision, urinary retention, constipation, dry mouth, sexual dysfunction) of the drug [1–3]. Amitriptyline also blocks voltage sensitive sodium channels in the heart and brain. In overdose, this action leads to arrhythmia, seizures, coma, and death [1].
The side effects, toxicity, and lethality in overdose, the risk of switch to manic state in predisposed individuals and the invention of selective serotonin reuptake inhibitors (SSRIs), another class of antidepressants with a better safety profile, made amitriptyline a less preferable medication [2]. However, the drug still has its role as a second line treatment for depression and nonpsychiatric conditions [1–3]. Amitriptyline also lowers the seizure threshold, and as such, in higher doses or intoxication, amitriptyline causes seizures [1, 4, 5]. Though it is generally considered that the drug does not possess abusive or addictive properties, there are a few case reports which suggest amitriptyline may exert such effects in susceptible individuals, i.e., patients with a history of another psychoactive substance abuse [6–10].
2. Case History
A 39-year-old married father of two videographer by profession, and who getting treatment for type II diabetes mellitus (DM), was admitted to a divisional hospital (Chankanai, Jaffna) in northern Sri Lanka, as he was found unconscious and suffering from seizure attacks. The patient was then transferred to Teaching Hospital Jaffna, as his seizure attacks could not be controlled with the treatment given at the divisional hospital. The patient was immediately admitted to the intensive care unit (ICU), a diagnosis of status epilepticus was made, and he was anesthetized in view of controlling his seizures. Within the next seven hours, the patient had 12 episodes of seizures. His electroencephalogram (EEG) and noncontrast computerized tomography (CT) scan of the brain, cerebrospinal fluid, liver enzymes, serum electrolytes, random blood sugar, and other routine biochemicals were well within normal limits. His electrocardiogram (ECG) showed sinus tachycardia. Opinion from a neurology team was sought, and it was favored against the diagnosis of epilepsy. The patient's wife gave a history that further enlightened the clinical picture.
Accordingly, the patient was regularly using alcohol for many years. One day, he consulted a surgeon in the private sector as he developed a single episode of haematemesis. The surgeon pointed out the reason behind the problem and advised him to go for total abstinence from alcohol. The surgeon also prescribed a low dose of alprazolam (0.5 mg nocte) to support his sleep without alcohol. In about a year's time, the patient was again presented to the surgeon by his family with a different complaint—“uncontrolled use of alprazolam”. At that point, the surgeon referred the patient to a psychiatrist. The psychiatrist advised the patient to tail off alprazolam and started treating him with 25 mg of amitriptyline, to be taken at night, in view of supporting his sleep problems. In the subsequent visit, the patient was complaining of poor sleep, and the dose of amitriptyline was gradually increased to 75 mg nocte. The patient felt better with that dose and stopped visiting the psychiatrist.
Since then, the patient started a kind of self-medication. He gradually increased the dose of amitriptyline to 250-300 mg at night as he needed more tablets to have good quality sleep and used 100–250 mg in daytimes to prevent dysphoria and restlessness, which were experienced by him in the absence of amitriptyline. He could not control taking amitriptyline in excess doses despite its regular side effects, which include constipation. In addition, from time to time, he engaged in binge ingestion of amitriptyline when he wanted to experience a “high” in his mood. In such circumstances, the number of tablets even reached to 25-30 per occasion (625–750 mg). These binges were associated with one or two seizure attacks, for which he or his family did not seek medical attention. For the past one year, the patient developed a progressive decline in his functionality, and he became dependent on amitriptyline. On the day of admission, the patient ingested about 30 tablets around 3 pm. Soon, the patient developed loss of consciousness and seizures.
After two days, anesthesia was withdrawn, and the patient was observed for the possibility of reappearance of seizure attacks for the next few hours. No more seizures were observed; however, he was continuously found to be confused. The patient was then transferred to an inpatient medical facility. In the medical ward, the patient soon became agitated, overtalkative, euphoric, disinhibited, and slept poorly. The diagnosis of delirious mania or hyperactive delirium as a result of the late effect of amitriptyline intoxication was made, and then he was started on effective doses of haloperidol and quetiapine. His symptoms responded well to haloperidol 6 mg tds and quetiapine 100 mg nocte. After recovery, the patient was assessed for the possibility of underlying depression, anxiety states, suicidal behavior, and any other psychiatric morbidities, and all were negative. However, he fulfilled the dependence criteria for amitriptyline. As per request, the family brought the drug pack for inspection, and it was found to contain about 500 tablets of 25 mg strength amitriptyline.
He was discharged from the hospital after two weeks on quetiapine 200 mg nocte, enrolled in an abstinence programme for amitriptyline dependence, taught sleep hygiene measures and interpersonal social rhythm therapy with the aim of assisting his routine sleep and other day-to-day activities, supported to reengage in his profession and to practice regular physical exercise, and was placed on assertive follow up care to monitor for and to prevent relapse.
3. Discussion
Patients who are treated with amitriptyline for long-term may show discontinuation syndrome upon withdrawal of the drug. This commonly manifests as flu-like symptoms (chills, myalgia, headache, nausea, excessive sweating), insomnia, excessive dreaming, and occasionally, movement disorders, mania, and cardiac arrhythmia [2].However, this patient's symptoms did not fit into this cluster of symptoms. Therefore, the possibility of discontinuation syndrome is least likely.
The diagnosis of amitriptyline dependence was made as the patient showed dependence features to the drug (tolerance, withdrawal symptoms, craving, continuation, and negligence of duty), and they were present for a period of more than one year [11].Features of dependence are broadly categorized into two classes: psychological and physiological [2] .Though the patient displayed both these types of symptoms, the psychological symptoms outweighed the physiological ones.
This case shines light on the long-lasting question of scientists whether amitriptyline holds abusive and dependency potential. Amitriptyline's abusive and addictive properties may result from its euphoric and sedative effects, similar to alcohol [1], and its (psycho) stimulant effect, as evident from this patient's urge to have “highs” that was “satisfied” with binging (overdose) of the drug [10]. Richelson [12] argues that anticholinergic and antihistaminic effects of tertiary tricyclics may underlie their abusive liability. Therefore, it could be argued that the antihistaminic and anticholinergic properties of amitriptyline act synergistically, resulting in its abusive tendency. However, there are case studies which divulge that the antihistaminic and anticholinergic properties of drugs may result in stimulant, euphoric, and/or psychedelic effects that might lead users to abuse these drugs [13–17]. These articles suggest that the stimulant and euphoric properties of amitriptyline may underlie the probable mechanism by which the drug causes addiction and dependence.
The other important concern the case highlights is that individuals with substance use disorders might carry a higher risk for amitriptyline dependence. Psychiatrists and other physicians who use amitriptyline in their practice should be prudent and keep a watchful eye on this long-term risk of the drug. In addition, this case discloses a deficient area of drug prescription and free accessibility of medications which is highly prevalent in Sri Lanka and may be in other countries as well, where no strict legislations govern the purchase of prescribed medications. The patient purchased the medication with an old prescription which was written about one and a half years ago by his psychiatrist. The case supports the argument that there should be a strict protocol to be adhered in accessing prescribed medications.
4. Conclusions
Amitriptyline shows the potential to cause dependence syndrome in vulnerable individuals
A clear protocol should be implemented when dispensing medications from pharmacy to patients
Acknowledgments
The authors acknowledge the support of Dr. Kumanan Thirunavukkarasu (Professor in Internal Medicine, Faculty of Medicine, University of Jaffna, Sri Lanka) who gave valuable inputs and edited the manuscript.
Conflicts of Interest
The authors declare that they do not have any conflict of interest or get any funding from any pharmaceutical company. | Recovered | ReactionOutcome | CC BY | 33564485 | 19,071,921 | 2021 |
What was the outcome of reaction 'Delirium'? | Amitriptyline Dependence and Its Associations: A Case Report and Literature Review.
Amitriptyline, the second antidepressant invented next to imipramine, is indicated in many psychiatric conditions as well as for some organic disorders. The drug acts by increasing the availability of monoamines in the central nervous system postsynaptic clefts. Amitriptyline has long been suspected for abusive potential based on a few case reports, and the reports add evidence in favor of the hypothesis. This case report brings such material to the arena of evidence and discusses the probable mechanisms by which patients turn to abusing and be addicted to the drug. The article also argues matters associated with drug dispensing that might raise the risk of misuse of the drug, especially in countries where strict legislation for accessibility of prescribed drugs is not in practice.
1. Introduction
Amitriptyline is a tricyclic antidepressant and is used to treat depression, anxiety disorders, posttraumatic stress disorder (PTSD), insomnia, somatoform disorders, premenstrual dysphoric disorder, nocturnal enuresis, migraine, and neuropathic pain [1–3]. It blocks the reuptake of norepinephrine and serotonin and thus increases the availability of these neurotransmitters in the central nervous system (CNS) [1]. The maximum dose per day of amitriptyline is 300 mg, and this is given in divided doses to prevent/minimize adverse effects [2, 3]. The drug has antagonistic action at histaminic-1, alpha-1-adrenergic, and muscarinic cholinergic receptors. Those antiadrenergic and antimuscarinic properties bring about the troublesome adverse effects (hypotension, tachycardia, blurring of vision, urinary retention, constipation, dry mouth, sexual dysfunction) of the drug [1–3]. Amitriptyline also blocks voltage sensitive sodium channels in the heart and brain. In overdose, this action leads to arrhythmia, seizures, coma, and death [1].
The side effects, toxicity, and lethality in overdose, the risk of switch to manic state in predisposed individuals and the invention of selective serotonin reuptake inhibitors (SSRIs), another class of antidepressants with a better safety profile, made amitriptyline a less preferable medication [2]. However, the drug still has its role as a second line treatment for depression and nonpsychiatric conditions [1–3]. Amitriptyline also lowers the seizure threshold, and as such, in higher doses or intoxication, amitriptyline causes seizures [1, 4, 5]. Though it is generally considered that the drug does not possess abusive or addictive properties, there are a few case reports which suggest amitriptyline may exert such effects in susceptible individuals, i.e., patients with a history of another psychoactive substance abuse [6–10].
2. Case History
A 39-year-old married father of two videographer by profession, and who getting treatment for type II diabetes mellitus (DM), was admitted to a divisional hospital (Chankanai, Jaffna) in northern Sri Lanka, as he was found unconscious and suffering from seizure attacks. The patient was then transferred to Teaching Hospital Jaffna, as his seizure attacks could not be controlled with the treatment given at the divisional hospital. The patient was immediately admitted to the intensive care unit (ICU), a diagnosis of status epilepticus was made, and he was anesthetized in view of controlling his seizures. Within the next seven hours, the patient had 12 episodes of seizures. His electroencephalogram (EEG) and noncontrast computerized tomography (CT) scan of the brain, cerebrospinal fluid, liver enzymes, serum electrolytes, random blood sugar, and other routine biochemicals were well within normal limits. His electrocardiogram (ECG) showed sinus tachycardia. Opinion from a neurology team was sought, and it was favored against the diagnosis of epilepsy. The patient's wife gave a history that further enlightened the clinical picture.
Accordingly, the patient was regularly using alcohol for many years. One day, he consulted a surgeon in the private sector as he developed a single episode of haematemesis. The surgeon pointed out the reason behind the problem and advised him to go for total abstinence from alcohol. The surgeon also prescribed a low dose of alprazolam (0.5 mg nocte) to support his sleep without alcohol. In about a year's time, the patient was again presented to the surgeon by his family with a different complaint—“uncontrolled use of alprazolam”. At that point, the surgeon referred the patient to a psychiatrist. The psychiatrist advised the patient to tail off alprazolam and started treating him with 25 mg of amitriptyline, to be taken at night, in view of supporting his sleep problems. In the subsequent visit, the patient was complaining of poor sleep, and the dose of amitriptyline was gradually increased to 75 mg nocte. The patient felt better with that dose and stopped visiting the psychiatrist.
Since then, the patient started a kind of self-medication. He gradually increased the dose of amitriptyline to 250-300 mg at night as he needed more tablets to have good quality sleep and used 100–250 mg in daytimes to prevent dysphoria and restlessness, which were experienced by him in the absence of amitriptyline. He could not control taking amitriptyline in excess doses despite its regular side effects, which include constipation. In addition, from time to time, he engaged in binge ingestion of amitriptyline when he wanted to experience a “high” in his mood. In such circumstances, the number of tablets even reached to 25-30 per occasion (625–750 mg). These binges were associated with one or two seizure attacks, for which he or his family did not seek medical attention. For the past one year, the patient developed a progressive decline in his functionality, and he became dependent on amitriptyline. On the day of admission, the patient ingested about 30 tablets around 3 pm. Soon, the patient developed loss of consciousness and seizures.
After two days, anesthesia was withdrawn, and the patient was observed for the possibility of reappearance of seizure attacks for the next few hours. No more seizures were observed; however, he was continuously found to be confused. The patient was then transferred to an inpatient medical facility. In the medical ward, the patient soon became agitated, overtalkative, euphoric, disinhibited, and slept poorly. The diagnosis of delirious mania or hyperactive delirium as a result of the late effect of amitriptyline intoxication was made, and then he was started on effective doses of haloperidol and quetiapine. His symptoms responded well to haloperidol 6 mg tds and quetiapine 100 mg nocte. After recovery, the patient was assessed for the possibility of underlying depression, anxiety states, suicidal behavior, and any other psychiatric morbidities, and all were negative. However, he fulfilled the dependence criteria for amitriptyline. As per request, the family brought the drug pack for inspection, and it was found to contain about 500 tablets of 25 mg strength amitriptyline.
He was discharged from the hospital after two weeks on quetiapine 200 mg nocte, enrolled in an abstinence programme for amitriptyline dependence, taught sleep hygiene measures and interpersonal social rhythm therapy with the aim of assisting his routine sleep and other day-to-day activities, supported to reengage in his profession and to practice regular physical exercise, and was placed on assertive follow up care to monitor for and to prevent relapse.
3. Discussion
Patients who are treated with amitriptyline for long-term may show discontinuation syndrome upon withdrawal of the drug. This commonly manifests as flu-like symptoms (chills, myalgia, headache, nausea, excessive sweating), insomnia, excessive dreaming, and occasionally, movement disorders, mania, and cardiac arrhythmia [2].However, this patient's symptoms did not fit into this cluster of symptoms. Therefore, the possibility of discontinuation syndrome is least likely.
The diagnosis of amitriptyline dependence was made as the patient showed dependence features to the drug (tolerance, withdrawal symptoms, craving, continuation, and negligence of duty), and they were present for a period of more than one year [11].Features of dependence are broadly categorized into two classes: psychological and physiological [2] .Though the patient displayed both these types of symptoms, the psychological symptoms outweighed the physiological ones.
This case shines light on the long-lasting question of scientists whether amitriptyline holds abusive and dependency potential. Amitriptyline's abusive and addictive properties may result from its euphoric and sedative effects, similar to alcohol [1], and its (psycho) stimulant effect, as evident from this patient's urge to have “highs” that was “satisfied” with binging (overdose) of the drug [10]. Richelson [12] argues that anticholinergic and antihistaminic effects of tertiary tricyclics may underlie their abusive liability. Therefore, it could be argued that the antihistaminic and anticholinergic properties of amitriptyline act synergistically, resulting in its abusive tendency. However, there are case studies which divulge that the antihistaminic and anticholinergic properties of drugs may result in stimulant, euphoric, and/or psychedelic effects that might lead users to abuse these drugs [13–17]. These articles suggest that the stimulant and euphoric properties of amitriptyline may underlie the probable mechanism by which the drug causes addiction and dependence.
The other important concern the case highlights is that individuals with substance use disorders might carry a higher risk for amitriptyline dependence. Psychiatrists and other physicians who use amitriptyline in their practice should be prudent and keep a watchful eye on this long-term risk of the drug. In addition, this case discloses a deficient area of drug prescription and free accessibility of medications which is highly prevalent in Sri Lanka and may be in other countries as well, where no strict legislations govern the purchase of prescribed medications. The patient purchased the medication with an old prescription which was written about one and a half years ago by his psychiatrist. The case supports the argument that there should be a strict protocol to be adhered in accessing prescribed medications.
4. Conclusions
Amitriptyline shows the potential to cause dependence syndrome in vulnerable individuals
A clear protocol should be implemented when dispensing medications from pharmacy to patients
Acknowledgments
The authors acknowledge the support of Dr. Kumanan Thirunavukkarasu (Professor in Internal Medicine, Faculty of Medicine, University of Jaffna, Sri Lanka) who gave valuable inputs and edited the manuscript.
Conflicts of Interest
The authors declare that they do not have any conflict of interest or get any funding from any pharmaceutical company. | Recovered | ReactionOutcome | CC BY | 33564485 | 19,071,921 | 2021 |
What was the outcome of reaction 'Off label use'? | Amitriptyline Dependence and Its Associations: A Case Report and Literature Review.
Amitriptyline, the second antidepressant invented next to imipramine, is indicated in many psychiatric conditions as well as for some organic disorders. The drug acts by increasing the availability of monoamines in the central nervous system postsynaptic clefts. Amitriptyline has long been suspected for abusive potential based on a few case reports, and the reports add evidence in favor of the hypothesis. This case report brings such material to the arena of evidence and discusses the probable mechanisms by which patients turn to abusing and be addicted to the drug. The article also argues matters associated with drug dispensing that might raise the risk of misuse of the drug, especially in countries where strict legislation for accessibility of prescribed drugs is not in practice.
1. Introduction
Amitriptyline is a tricyclic antidepressant and is used to treat depression, anxiety disorders, posttraumatic stress disorder (PTSD), insomnia, somatoform disorders, premenstrual dysphoric disorder, nocturnal enuresis, migraine, and neuropathic pain [1–3]. It blocks the reuptake of norepinephrine and serotonin and thus increases the availability of these neurotransmitters in the central nervous system (CNS) [1]. The maximum dose per day of amitriptyline is 300 mg, and this is given in divided doses to prevent/minimize adverse effects [2, 3]. The drug has antagonistic action at histaminic-1, alpha-1-adrenergic, and muscarinic cholinergic receptors. Those antiadrenergic and antimuscarinic properties bring about the troublesome adverse effects (hypotension, tachycardia, blurring of vision, urinary retention, constipation, dry mouth, sexual dysfunction) of the drug [1–3]. Amitriptyline also blocks voltage sensitive sodium channels in the heart and brain. In overdose, this action leads to arrhythmia, seizures, coma, and death [1].
The side effects, toxicity, and lethality in overdose, the risk of switch to manic state in predisposed individuals and the invention of selective serotonin reuptake inhibitors (SSRIs), another class of antidepressants with a better safety profile, made amitriptyline a less preferable medication [2]. However, the drug still has its role as a second line treatment for depression and nonpsychiatric conditions [1–3]. Amitriptyline also lowers the seizure threshold, and as such, in higher doses or intoxication, amitriptyline causes seizures [1, 4, 5]. Though it is generally considered that the drug does not possess abusive or addictive properties, there are a few case reports which suggest amitriptyline may exert such effects in susceptible individuals, i.e., patients with a history of another psychoactive substance abuse [6–10].
2. Case History
A 39-year-old married father of two videographer by profession, and who getting treatment for type II diabetes mellitus (DM), was admitted to a divisional hospital (Chankanai, Jaffna) in northern Sri Lanka, as he was found unconscious and suffering from seizure attacks. The patient was then transferred to Teaching Hospital Jaffna, as his seizure attacks could not be controlled with the treatment given at the divisional hospital. The patient was immediately admitted to the intensive care unit (ICU), a diagnosis of status epilepticus was made, and he was anesthetized in view of controlling his seizures. Within the next seven hours, the patient had 12 episodes of seizures. His electroencephalogram (EEG) and noncontrast computerized tomography (CT) scan of the brain, cerebrospinal fluid, liver enzymes, serum electrolytes, random blood sugar, and other routine biochemicals were well within normal limits. His electrocardiogram (ECG) showed sinus tachycardia. Opinion from a neurology team was sought, and it was favored against the diagnosis of epilepsy. The patient's wife gave a history that further enlightened the clinical picture.
Accordingly, the patient was regularly using alcohol for many years. One day, he consulted a surgeon in the private sector as he developed a single episode of haematemesis. The surgeon pointed out the reason behind the problem and advised him to go for total abstinence from alcohol. The surgeon also prescribed a low dose of alprazolam (0.5 mg nocte) to support his sleep without alcohol. In about a year's time, the patient was again presented to the surgeon by his family with a different complaint—“uncontrolled use of alprazolam”. At that point, the surgeon referred the patient to a psychiatrist. The psychiatrist advised the patient to tail off alprazolam and started treating him with 25 mg of amitriptyline, to be taken at night, in view of supporting his sleep problems. In the subsequent visit, the patient was complaining of poor sleep, and the dose of amitriptyline was gradually increased to 75 mg nocte. The patient felt better with that dose and stopped visiting the psychiatrist.
Since then, the patient started a kind of self-medication. He gradually increased the dose of amitriptyline to 250-300 mg at night as he needed more tablets to have good quality sleep and used 100–250 mg in daytimes to prevent dysphoria and restlessness, which were experienced by him in the absence of amitriptyline. He could not control taking amitriptyline in excess doses despite its regular side effects, which include constipation. In addition, from time to time, he engaged in binge ingestion of amitriptyline when he wanted to experience a “high” in his mood. In such circumstances, the number of tablets even reached to 25-30 per occasion (625–750 mg). These binges were associated with one or two seizure attacks, for which he or his family did not seek medical attention. For the past one year, the patient developed a progressive decline in his functionality, and he became dependent on amitriptyline. On the day of admission, the patient ingested about 30 tablets around 3 pm. Soon, the patient developed loss of consciousness and seizures.
After two days, anesthesia was withdrawn, and the patient was observed for the possibility of reappearance of seizure attacks for the next few hours. No more seizures were observed; however, he was continuously found to be confused. The patient was then transferred to an inpatient medical facility. In the medical ward, the patient soon became agitated, overtalkative, euphoric, disinhibited, and slept poorly. The diagnosis of delirious mania or hyperactive delirium as a result of the late effect of amitriptyline intoxication was made, and then he was started on effective doses of haloperidol and quetiapine. His symptoms responded well to haloperidol 6 mg tds and quetiapine 100 mg nocte. After recovery, the patient was assessed for the possibility of underlying depression, anxiety states, suicidal behavior, and any other psychiatric morbidities, and all were negative. However, he fulfilled the dependence criteria for amitriptyline. As per request, the family brought the drug pack for inspection, and it was found to contain about 500 tablets of 25 mg strength amitriptyline.
He was discharged from the hospital after two weeks on quetiapine 200 mg nocte, enrolled in an abstinence programme for amitriptyline dependence, taught sleep hygiene measures and interpersonal social rhythm therapy with the aim of assisting his routine sleep and other day-to-day activities, supported to reengage in his profession and to practice regular physical exercise, and was placed on assertive follow up care to monitor for and to prevent relapse.
3. Discussion
Patients who are treated with amitriptyline for long-term may show discontinuation syndrome upon withdrawal of the drug. This commonly manifests as flu-like symptoms (chills, myalgia, headache, nausea, excessive sweating), insomnia, excessive dreaming, and occasionally, movement disorders, mania, and cardiac arrhythmia [2].However, this patient's symptoms did not fit into this cluster of symptoms. Therefore, the possibility of discontinuation syndrome is least likely.
The diagnosis of amitriptyline dependence was made as the patient showed dependence features to the drug (tolerance, withdrawal symptoms, craving, continuation, and negligence of duty), and they were present for a period of more than one year [11].Features of dependence are broadly categorized into two classes: psychological and physiological [2] .Though the patient displayed both these types of symptoms, the psychological symptoms outweighed the physiological ones.
This case shines light on the long-lasting question of scientists whether amitriptyline holds abusive and dependency potential. Amitriptyline's abusive and addictive properties may result from its euphoric and sedative effects, similar to alcohol [1], and its (psycho) stimulant effect, as evident from this patient's urge to have “highs” that was “satisfied” with binging (overdose) of the drug [10]. Richelson [12] argues that anticholinergic and antihistaminic effects of tertiary tricyclics may underlie their abusive liability. Therefore, it could be argued that the antihistaminic and anticholinergic properties of amitriptyline act synergistically, resulting in its abusive tendency. However, there are case studies which divulge that the antihistaminic and anticholinergic properties of drugs may result in stimulant, euphoric, and/or psychedelic effects that might lead users to abuse these drugs [13–17]. These articles suggest that the stimulant and euphoric properties of amitriptyline may underlie the probable mechanism by which the drug causes addiction and dependence.
The other important concern the case highlights is that individuals with substance use disorders might carry a higher risk for amitriptyline dependence. Psychiatrists and other physicians who use amitriptyline in their practice should be prudent and keep a watchful eye on this long-term risk of the drug. In addition, this case discloses a deficient area of drug prescription and free accessibility of medications which is highly prevalent in Sri Lanka and may be in other countries as well, where no strict legislations govern the purchase of prescribed medications. The patient purchased the medication with an old prescription which was written about one and a half years ago by his psychiatrist. The case supports the argument that there should be a strict protocol to be adhered in accessing prescribed medications.
4. Conclusions
Amitriptyline shows the potential to cause dependence syndrome in vulnerable individuals
A clear protocol should be implemented when dispensing medications from pharmacy to patients
Acknowledgments
The authors acknowledge the support of Dr. Kumanan Thirunavukkarasu (Professor in Internal Medicine, Faculty of Medicine, University of Jaffna, Sri Lanka) who gave valuable inputs and edited the manuscript.
Conflicts of Interest
The authors declare that they do not have any conflict of interest or get any funding from any pharmaceutical company. | Recovered | ReactionOutcome | CC BY | 33564485 | 19,071,921 | 2021 |
What was the outcome of reaction 'Status epilepticus'? | Amitriptyline Dependence and Its Associations: A Case Report and Literature Review.
Amitriptyline, the second antidepressant invented next to imipramine, is indicated in many psychiatric conditions as well as for some organic disorders. The drug acts by increasing the availability of monoamines in the central nervous system postsynaptic clefts. Amitriptyline has long been suspected for abusive potential based on a few case reports, and the reports add evidence in favor of the hypothesis. This case report brings such material to the arena of evidence and discusses the probable mechanisms by which patients turn to abusing and be addicted to the drug. The article also argues matters associated with drug dispensing that might raise the risk of misuse of the drug, especially in countries where strict legislation for accessibility of prescribed drugs is not in practice.
1. Introduction
Amitriptyline is a tricyclic antidepressant and is used to treat depression, anxiety disorders, posttraumatic stress disorder (PTSD), insomnia, somatoform disorders, premenstrual dysphoric disorder, nocturnal enuresis, migraine, and neuropathic pain [1–3]. It blocks the reuptake of norepinephrine and serotonin and thus increases the availability of these neurotransmitters in the central nervous system (CNS) [1]. The maximum dose per day of amitriptyline is 300 mg, and this is given in divided doses to prevent/minimize adverse effects [2, 3]. The drug has antagonistic action at histaminic-1, alpha-1-adrenergic, and muscarinic cholinergic receptors. Those antiadrenergic and antimuscarinic properties bring about the troublesome adverse effects (hypotension, tachycardia, blurring of vision, urinary retention, constipation, dry mouth, sexual dysfunction) of the drug [1–3]. Amitriptyline also blocks voltage sensitive sodium channels in the heart and brain. In overdose, this action leads to arrhythmia, seizures, coma, and death [1].
The side effects, toxicity, and lethality in overdose, the risk of switch to manic state in predisposed individuals and the invention of selective serotonin reuptake inhibitors (SSRIs), another class of antidepressants with a better safety profile, made amitriptyline a less preferable medication [2]. However, the drug still has its role as a second line treatment for depression and nonpsychiatric conditions [1–3]. Amitriptyline also lowers the seizure threshold, and as such, in higher doses or intoxication, amitriptyline causes seizures [1, 4, 5]. Though it is generally considered that the drug does not possess abusive or addictive properties, there are a few case reports which suggest amitriptyline may exert such effects in susceptible individuals, i.e., patients with a history of another psychoactive substance abuse [6–10].
2. Case History
A 39-year-old married father of two videographer by profession, and who getting treatment for type II diabetes mellitus (DM), was admitted to a divisional hospital (Chankanai, Jaffna) in northern Sri Lanka, as he was found unconscious and suffering from seizure attacks. The patient was then transferred to Teaching Hospital Jaffna, as his seizure attacks could not be controlled with the treatment given at the divisional hospital. The patient was immediately admitted to the intensive care unit (ICU), a diagnosis of status epilepticus was made, and he was anesthetized in view of controlling his seizures. Within the next seven hours, the patient had 12 episodes of seizures. His electroencephalogram (EEG) and noncontrast computerized tomography (CT) scan of the brain, cerebrospinal fluid, liver enzymes, serum electrolytes, random blood sugar, and other routine biochemicals were well within normal limits. His electrocardiogram (ECG) showed sinus tachycardia. Opinion from a neurology team was sought, and it was favored against the diagnosis of epilepsy. The patient's wife gave a history that further enlightened the clinical picture.
Accordingly, the patient was regularly using alcohol for many years. One day, he consulted a surgeon in the private sector as he developed a single episode of haematemesis. The surgeon pointed out the reason behind the problem and advised him to go for total abstinence from alcohol. The surgeon also prescribed a low dose of alprazolam (0.5 mg nocte) to support his sleep without alcohol. In about a year's time, the patient was again presented to the surgeon by his family with a different complaint—“uncontrolled use of alprazolam”. At that point, the surgeon referred the patient to a psychiatrist. The psychiatrist advised the patient to tail off alprazolam and started treating him with 25 mg of amitriptyline, to be taken at night, in view of supporting his sleep problems. In the subsequent visit, the patient was complaining of poor sleep, and the dose of amitriptyline was gradually increased to 75 mg nocte. The patient felt better with that dose and stopped visiting the psychiatrist.
Since then, the patient started a kind of self-medication. He gradually increased the dose of amitriptyline to 250-300 mg at night as he needed more tablets to have good quality sleep and used 100–250 mg in daytimes to prevent dysphoria and restlessness, which were experienced by him in the absence of amitriptyline. He could not control taking amitriptyline in excess doses despite its regular side effects, which include constipation. In addition, from time to time, he engaged in binge ingestion of amitriptyline when he wanted to experience a “high” in his mood. In such circumstances, the number of tablets even reached to 25-30 per occasion (625–750 mg). These binges were associated with one or two seizure attacks, for which he or his family did not seek medical attention. For the past one year, the patient developed a progressive decline in his functionality, and he became dependent on amitriptyline. On the day of admission, the patient ingested about 30 tablets around 3 pm. Soon, the patient developed loss of consciousness and seizures.
After two days, anesthesia was withdrawn, and the patient was observed for the possibility of reappearance of seizure attacks for the next few hours. No more seizures were observed; however, he was continuously found to be confused. The patient was then transferred to an inpatient medical facility. In the medical ward, the patient soon became agitated, overtalkative, euphoric, disinhibited, and slept poorly. The diagnosis of delirious mania or hyperactive delirium as a result of the late effect of amitriptyline intoxication was made, and then he was started on effective doses of haloperidol and quetiapine. His symptoms responded well to haloperidol 6 mg tds and quetiapine 100 mg nocte. After recovery, the patient was assessed for the possibility of underlying depression, anxiety states, suicidal behavior, and any other psychiatric morbidities, and all were negative. However, he fulfilled the dependence criteria for amitriptyline. As per request, the family brought the drug pack for inspection, and it was found to contain about 500 tablets of 25 mg strength amitriptyline.
He was discharged from the hospital after two weeks on quetiapine 200 mg nocte, enrolled in an abstinence programme for amitriptyline dependence, taught sleep hygiene measures and interpersonal social rhythm therapy with the aim of assisting his routine sleep and other day-to-day activities, supported to reengage in his profession and to practice regular physical exercise, and was placed on assertive follow up care to monitor for and to prevent relapse.
3. Discussion
Patients who are treated with amitriptyline for long-term may show discontinuation syndrome upon withdrawal of the drug. This commonly manifests as flu-like symptoms (chills, myalgia, headache, nausea, excessive sweating), insomnia, excessive dreaming, and occasionally, movement disorders, mania, and cardiac arrhythmia [2].However, this patient's symptoms did not fit into this cluster of symptoms. Therefore, the possibility of discontinuation syndrome is least likely.
The diagnosis of amitriptyline dependence was made as the patient showed dependence features to the drug (tolerance, withdrawal symptoms, craving, continuation, and negligence of duty), and they were present for a period of more than one year [11].Features of dependence are broadly categorized into two classes: psychological and physiological [2] .Though the patient displayed both these types of symptoms, the psychological symptoms outweighed the physiological ones.
This case shines light on the long-lasting question of scientists whether amitriptyline holds abusive and dependency potential. Amitriptyline's abusive and addictive properties may result from its euphoric and sedative effects, similar to alcohol [1], and its (psycho) stimulant effect, as evident from this patient's urge to have “highs” that was “satisfied” with binging (overdose) of the drug [10]. Richelson [12] argues that anticholinergic and antihistaminic effects of tertiary tricyclics may underlie their abusive liability. Therefore, it could be argued that the antihistaminic and anticholinergic properties of amitriptyline act synergistically, resulting in its abusive tendency. However, there are case studies which divulge that the antihistaminic and anticholinergic properties of drugs may result in stimulant, euphoric, and/or psychedelic effects that might lead users to abuse these drugs [13–17]. These articles suggest that the stimulant and euphoric properties of amitriptyline may underlie the probable mechanism by which the drug causes addiction and dependence.
The other important concern the case highlights is that individuals with substance use disorders might carry a higher risk for amitriptyline dependence. Psychiatrists and other physicians who use amitriptyline in their practice should be prudent and keep a watchful eye on this long-term risk of the drug. In addition, this case discloses a deficient area of drug prescription and free accessibility of medications which is highly prevalent in Sri Lanka and may be in other countries as well, where no strict legislations govern the purchase of prescribed medications. The patient purchased the medication with an old prescription which was written about one and a half years ago by his psychiatrist. The case supports the argument that there should be a strict protocol to be adhered in accessing prescribed medications.
4. Conclusions
Amitriptyline shows the potential to cause dependence syndrome in vulnerable individuals
A clear protocol should be implemented when dispensing medications from pharmacy to patients
Acknowledgments
The authors acknowledge the support of Dr. Kumanan Thirunavukkarasu (Professor in Internal Medicine, Faculty of Medicine, University of Jaffna, Sri Lanka) who gave valuable inputs and edited the manuscript.
Conflicts of Interest
The authors declare that they do not have any conflict of interest or get any funding from any pharmaceutical company. | Recovered | ReactionOutcome | CC BY | 33564485 | 19,071,921 | 2021 |
What was the outcome of reaction 'Toxicity to various agents'? | Amitriptyline Dependence and Its Associations: A Case Report and Literature Review.
Amitriptyline, the second antidepressant invented next to imipramine, is indicated in many psychiatric conditions as well as for some organic disorders. The drug acts by increasing the availability of monoamines in the central nervous system postsynaptic clefts. Amitriptyline has long been suspected for abusive potential based on a few case reports, and the reports add evidence in favor of the hypothesis. This case report brings such material to the arena of evidence and discusses the probable mechanisms by which patients turn to abusing and be addicted to the drug. The article also argues matters associated with drug dispensing that might raise the risk of misuse of the drug, especially in countries where strict legislation for accessibility of prescribed drugs is not in practice.
1. Introduction
Amitriptyline is a tricyclic antidepressant and is used to treat depression, anxiety disorders, posttraumatic stress disorder (PTSD), insomnia, somatoform disorders, premenstrual dysphoric disorder, nocturnal enuresis, migraine, and neuropathic pain [1–3]. It blocks the reuptake of norepinephrine and serotonin and thus increases the availability of these neurotransmitters in the central nervous system (CNS) [1]. The maximum dose per day of amitriptyline is 300 mg, and this is given in divided doses to prevent/minimize adverse effects [2, 3]. The drug has antagonistic action at histaminic-1, alpha-1-adrenergic, and muscarinic cholinergic receptors. Those antiadrenergic and antimuscarinic properties bring about the troublesome adverse effects (hypotension, tachycardia, blurring of vision, urinary retention, constipation, dry mouth, sexual dysfunction) of the drug [1–3]. Amitriptyline also blocks voltage sensitive sodium channels in the heart and brain. In overdose, this action leads to arrhythmia, seizures, coma, and death [1].
The side effects, toxicity, and lethality in overdose, the risk of switch to manic state in predisposed individuals and the invention of selective serotonin reuptake inhibitors (SSRIs), another class of antidepressants with a better safety profile, made amitriptyline a less preferable medication [2]. However, the drug still has its role as a second line treatment for depression and nonpsychiatric conditions [1–3]. Amitriptyline also lowers the seizure threshold, and as such, in higher doses or intoxication, amitriptyline causes seizures [1, 4, 5]. Though it is generally considered that the drug does not possess abusive or addictive properties, there are a few case reports which suggest amitriptyline may exert such effects in susceptible individuals, i.e., patients with a history of another psychoactive substance abuse [6–10].
2. Case History
A 39-year-old married father of two videographer by profession, and who getting treatment for type II diabetes mellitus (DM), was admitted to a divisional hospital (Chankanai, Jaffna) in northern Sri Lanka, as he was found unconscious and suffering from seizure attacks. The patient was then transferred to Teaching Hospital Jaffna, as his seizure attacks could not be controlled with the treatment given at the divisional hospital. The patient was immediately admitted to the intensive care unit (ICU), a diagnosis of status epilepticus was made, and he was anesthetized in view of controlling his seizures. Within the next seven hours, the patient had 12 episodes of seizures. His electroencephalogram (EEG) and noncontrast computerized tomography (CT) scan of the brain, cerebrospinal fluid, liver enzymes, serum electrolytes, random blood sugar, and other routine biochemicals were well within normal limits. His electrocardiogram (ECG) showed sinus tachycardia. Opinion from a neurology team was sought, and it was favored against the diagnosis of epilepsy. The patient's wife gave a history that further enlightened the clinical picture.
Accordingly, the patient was regularly using alcohol for many years. One day, he consulted a surgeon in the private sector as he developed a single episode of haematemesis. The surgeon pointed out the reason behind the problem and advised him to go for total abstinence from alcohol. The surgeon also prescribed a low dose of alprazolam (0.5 mg nocte) to support his sleep without alcohol. In about a year's time, the patient was again presented to the surgeon by his family with a different complaint—“uncontrolled use of alprazolam”. At that point, the surgeon referred the patient to a psychiatrist. The psychiatrist advised the patient to tail off alprazolam and started treating him with 25 mg of amitriptyline, to be taken at night, in view of supporting his sleep problems. In the subsequent visit, the patient was complaining of poor sleep, and the dose of amitriptyline was gradually increased to 75 mg nocte. The patient felt better with that dose and stopped visiting the psychiatrist.
Since then, the patient started a kind of self-medication. He gradually increased the dose of amitriptyline to 250-300 mg at night as he needed more tablets to have good quality sleep and used 100–250 mg in daytimes to prevent dysphoria and restlessness, which were experienced by him in the absence of amitriptyline. He could not control taking amitriptyline in excess doses despite its regular side effects, which include constipation. In addition, from time to time, he engaged in binge ingestion of amitriptyline when he wanted to experience a “high” in his mood. In such circumstances, the number of tablets even reached to 25-30 per occasion (625–750 mg). These binges were associated with one or two seizure attacks, for which he or his family did not seek medical attention. For the past one year, the patient developed a progressive decline in his functionality, and he became dependent on amitriptyline. On the day of admission, the patient ingested about 30 tablets around 3 pm. Soon, the patient developed loss of consciousness and seizures.
After two days, anesthesia was withdrawn, and the patient was observed for the possibility of reappearance of seizure attacks for the next few hours. No more seizures were observed; however, he was continuously found to be confused. The patient was then transferred to an inpatient medical facility. In the medical ward, the patient soon became agitated, overtalkative, euphoric, disinhibited, and slept poorly. The diagnosis of delirious mania or hyperactive delirium as a result of the late effect of amitriptyline intoxication was made, and then he was started on effective doses of haloperidol and quetiapine. His symptoms responded well to haloperidol 6 mg tds and quetiapine 100 mg nocte. After recovery, the patient was assessed for the possibility of underlying depression, anxiety states, suicidal behavior, and any other psychiatric morbidities, and all were negative. However, he fulfilled the dependence criteria for amitriptyline. As per request, the family brought the drug pack for inspection, and it was found to contain about 500 tablets of 25 mg strength amitriptyline.
He was discharged from the hospital after two weeks on quetiapine 200 mg nocte, enrolled in an abstinence programme for amitriptyline dependence, taught sleep hygiene measures and interpersonal social rhythm therapy with the aim of assisting his routine sleep and other day-to-day activities, supported to reengage in his profession and to practice regular physical exercise, and was placed on assertive follow up care to monitor for and to prevent relapse.
3. Discussion
Patients who are treated with amitriptyline for long-term may show discontinuation syndrome upon withdrawal of the drug. This commonly manifests as flu-like symptoms (chills, myalgia, headache, nausea, excessive sweating), insomnia, excessive dreaming, and occasionally, movement disorders, mania, and cardiac arrhythmia [2].However, this patient's symptoms did not fit into this cluster of symptoms. Therefore, the possibility of discontinuation syndrome is least likely.
The diagnosis of amitriptyline dependence was made as the patient showed dependence features to the drug (tolerance, withdrawal symptoms, craving, continuation, and negligence of duty), and they were present for a period of more than one year [11].Features of dependence are broadly categorized into two classes: psychological and physiological [2] .Though the patient displayed both these types of symptoms, the psychological symptoms outweighed the physiological ones.
This case shines light on the long-lasting question of scientists whether amitriptyline holds abusive and dependency potential. Amitriptyline's abusive and addictive properties may result from its euphoric and sedative effects, similar to alcohol [1], and its (psycho) stimulant effect, as evident from this patient's urge to have “highs” that was “satisfied” with binging (overdose) of the drug [10]. Richelson [12] argues that anticholinergic and antihistaminic effects of tertiary tricyclics may underlie their abusive liability. Therefore, it could be argued that the antihistaminic and anticholinergic properties of amitriptyline act synergistically, resulting in its abusive tendency. However, there are case studies which divulge that the antihistaminic and anticholinergic properties of drugs may result in stimulant, euphoric, and/or psychedelic effects that might lead users to abuse these drugs [13–17]. These articles suggest that the stimulant and euphoric properties of amitriptyline may underlie the probable mechanism by which the drug causes addiction and dependence.
The other important concern the case highlights is that individuals with substance use disorders might carry a higher risk for amitriptyline dependence. Psychiatrists and other physicians who use amitriptyline in their practice should be prudent and keep a watchful eye on this long-term risk of the drug. In addition, this case discloses a deficient area of drug prescription and free accessibility of medications which is highly prevalent in Sri Lanka and may be in other countries as well, where no strict legislations govern the purchase of prescribed medications. The patient purchased the medication with an old prescription which was written about one and a half years ago by his psychiatrist. The case supports the argument that there should be a strict protocol to be adhered in accessing prescribed medications.
4. Conclusions
Amitriptyline shows the potential to cause dependence syndrome in vulnerable individuals
A clear protocol should be implemented when dispensing medications from pharmacy to patients
Acknowledgments
The authors acknowledge the support of Dr. Kumanan Thirunavukkarasu (Professor in Internal Medicine, Faculty of Medicine, University of Jaffna, Sri Lanka) who gave valuable inputs and edited the manuscript.
Conflicts of Interest
The authors declare that they do not have any conflict of interest or get any funding from any pharmaceutical company. | Recovered | ReactionOutcome | CC BY | 33564485 | 19,071,921 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cutaneous nocardiosis'. | Disseminated Nocardiosis in a Renal Transplant Recipient.
Nocardiosis is an uncommon opportunistic Gram-positive bacterial infection caused by aerobic actinomycetes in the genus Nocardia. Nocardia can cause localized or systemic suppurative diseases involving eyes, kidneys, skin, lungs, bone, and central nervous system. Disseminated nocardiosis is a rare condition, seen among immunocompromised patients. We report the case of a 55-year-old African American, kidney transplant male recipient on maintenance immunosuppression, who was diagnosed with cutaneous and pulmonary nocardiosis. Presenting symptoms were shortness of breath, and bilateral lower extremities pain and swelling. Tissue culture grew Gram-positive bacilli specified as Nocardia farcinica from thigh and gluteal abscesses. CT thorax showed bilateral reticulonodular opacities. The patient was managed with immunosuppression reduction and specific treatment with high-dose trimethoprim-sulfamethoxazole (TMP-SMX) in conjunction with linezolid. Combination antibiotics were continued for four weeks, and thereafter, TMP-SMX alone was continued for 12 months, at which point all lesions had healed. Nocardiosis with systemic involvement carries a poor prognosis. However, early diagnosis and appropriate antibiotic coverage had a favorable outcome in a renal transplant recipient. Recommended treatment duration is 6 to 12 months.
Introduction
Nocardiosis is an uncommon opportunistic Gram-positive bacterial infection caused by aerobic actinomycetes in the genus Nocardia. It can cause localized or systemic suppurative diseases in humans, involving eyes, kidneys, skin, pulmonary, brain as well as disseminated infection. Inhalation of the organism is the most common mode of entry; that is why the majority of infections involve lungs. Herein, we report a case of a renal transplant recipient who presented with disseminated nocardiosis with pulmonary and cutaneous involvement and was successfully treated with combined antibiotic therapy and surgical drainage.
Case presentation
We report the case of a 55-year-old male with a past medical history of end-stage kidney disease secondary to medical renal disease of hypertension. After a dialysis vintage of six years, he received a deceased donor renal transplant in 2018. Post-transplant, his allograft function remained stable with a baseline serum creatinine level at 1.6-1.8 mg/dL. After induction with basiliximab, the patient was maintained on triple immunosuppressive therapy consisting of mycophenolic acid 720 mg twice daily per oral (PO), tacrolimus 2 mg twice daily PO, and prednisone 5 mg daily PO.
Six months following the renal transplant, the patient presented to the hospital with a chief complaint of progressive bilateral lower extremities pain with swelling, which started 10 days before presentation. Associated symptoms included shortness of breath. Workup included an ultrasound of the right lower leg, which showed a heterogeneous mass in the right posterior thigh; nevertheless, the patient received hydrocodone/acetaminophen and was instructed to follow up with his primary care physician in a week. However, one week later, the patient presented again due to the worsening of symptoms; physical exam revealed a palpable, fluctuant, and tender fullness involving the left gluteal and the right posterior thigh region with associated left knee swelling.
Laboratory workup revealed the following: C-reactive protein 149 mg/L, creatinine 1.65 mg/dL (baseline creatinine 1.6-1.8 mg/dL), and white blood cell count 9,500/mm3. CT pelvis and bilateral lower extremities without contrast showed a 3.5-cm fluid collection in the right posterior thigh and the left buttock (Figure 1). Chest CT showed multi-focal irregular airspace opacities with new scattered sub-centimeter pulmonary nodules (Figure 2). The two-dimensional echo was negative for valve vegetations. MRI brain was negative for masses or abscesses; blood cultures were negative and tissue culture grew Gram-positive bacilli identified as Nocardia farcinica. The patient underwent incision and drainage of the thigh and gluteal abscesses with the placement of Penrose drain and surgical site cultures obtained. Tacrolimus and myfortic acid were held for two weeks due to the presumed infectious process; prednisone 20 mg daily PO was initiated along with high-dose trimethoprim-sulfamethoxazole (TMP-SMX) in conjunction with linezolid. The patient’s condition subsequently improved and he was discharged on oral linezolid and TMP-SMX. He was treated with the combination for four weeks, and then continued with TMP-SMX alone for a total of 12 months at which point all lesions had resolved without allograft dysfunction.
Figure 1 CT pelvis and bilateral lower extremities without contrast showed a 3.5-cm fluid collection (arrow) in the right posterior thigh
Figure 2 CT thorax showing pulmonary nodule (arrow)
Discussion
Renal transplant patients are at an increased risk of certain infections, particularly following the initiation of immunosuppressive drugs after the transplant [1]. Nocardia infection is commonly seen among patients with T-cell and macrophage function disorders, such as patients who are taking immunosuppressive agents [2]. The risk of nocardiosis is increased in the first year following renal transplantation, presumably due to using immunosuppression to prevent rejection [3]. Patients treated with steroid-sparing regimens, such as cyclosporine, have found significantly reduced rates of nocardial infections, to 0.7%, in renal transplant recipients [4]. The patient was diagnosed with nocardiosis six months following the renal transplant.
Nocardia species are not ordinarily seen in the respiratory tract, yet pulmonary involvement is the primary site of nocardial infection in more than two-thirds of cases [3,5]. Therefore, a sputum culture is mostly indicative of Nocardia infection. Rarely, respiratory nocardial isolate has been considered a non-pathogen (i.e., colonizer) [6]. Most pulmonary infections are primary, but Nocardia can spread to the lung from other sites, such as the skin [7]. On the other hand, cutaneous lesions are reported in kidney transplant recipients with a Nocardia infection [2]. Manifestations of primary cutaneous nocardiosis include ulcerations, pyoderma, cellulitis, nodules, and subcutaneous abscesses [8,9]. The reported patient had disseminated nocardiosis involving lungs and skin, though lungs were thought to be the primary source of infection. Also, imaging findings in pulmonary nocardiosis are different, including lung nodules, lung masses (with or without cavitation), reticulonodular infiltrates, interstitial infiltrates, lobar consolidation, subpleural plaques, and pleural effusions [10]. Our patient’s CT thorax showed irregular airspace opacities in the left upper lobe.
TMP-SMX is considered first-line therapy for nocardiosis. However, some Nocardia species are resistant to TMP-SMX, including N. farcinica, while Nocardia asteroides and Nocardia nova remain sensitive primarily to TMP-SMX, with susceptibility rates of >95% and 89%, respectively [11,12]. Moreover, there is no consensus for the role of TMP-SMX as prophylaxis for Nocardia. Although one study proposed that TMP-SMX prophylaxis is effective in heart transplant recipients, nocardiosis has been documented in one-third of the renal transplant recipients who received TMP-SMX as Pneumocystis carinii prophylaxis [13]. Deaths related to Nocardia infection in transplant recipients have been rare. In one study, the nocardial infection has been neither found to be associated with mortality nor overall survival. Also, in the same study, early diagnosis suggests a favorable therapeutic outcome [14].
Conclusions
Overall, disseminated nocardiosis with systemic involvement carries a grave prognosis. However, early diagnosis of the case, with proper antibiotic coverage, leads to a favorable outcome, even in a post-renal transplant patient.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained by all participants in this study | LINEZOLID, MYCOPHENOLIC ACID, PREDNISONE, SULFAMETHOXAZOLE\TRIMETHOPRIM, TACROLIMUS | DrugsGivenReaction | CC BY | 33564506 | 18,949,258 | 2021-01-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug effective for unapproved indication'. | Disseminated Nocardiosis in a Renal Transplant Recipient.
Nocardiosis is an uncommon opportunistic Gram-positive bacterial infection caused by aerobic actinomycetes in the genus Nocardia. Nocardia can cause localized or systemic suppurative diseases involving eyes, kidneys, skin, lungs, bone, and central nervous system. Disseminated nocardiosis is a rare condition, seen among immunocompromised patients. We report the case of a 55-year-old African American, kidney transplant male recipient on maintenance immunosuppression, who was diagnosed with cutaneous and pulmonary nocardiosis. Presenting symptoms were shortness of breath, and bilateral lower extremities pain and swelling. Tissue culture grew Gram-positive bacilli specified as Nocardia farcinica from thigh and gluteal abscesses. CT thorax showed bilateral reticulonodular opacities. The patient was managed with immunosuppression reduction and specific treatment with high-dose trimethoprim-sulfamethoxazole (TMP-SMX) in conjunction with linezolid. Combination antibiotics were continued for four weeks, and thereafter, TMP-SMX alone was continued for 12 months, at which point all lesions had healed. Nocardiosis with systemic involvement carries a poor prognosis. However, early diagnosis and appropriate antibiotic coverage had a favorable outcome in a renal transplant recipient. Recommended treatment duration is 6 to 12 months.
Introduction
Nocardiosis is an uncommon opportunistic Gram-positive bacterial infection caused by aerobic actinomycetes in the genus Nocardia. It can cause localized or systemic suppurative diseases in humans, involving eyes, kidneys, skin, pulmonary, brain as well as disseminated infection. Inhalation of the organism is the most common mode of entry; that is why the majority of infections involve lungs. Herein, we report a case of a renal transplant recipient who presented with disseminated nocardiosis with pulmonary and cutaneous involvement and was successfully treated with combined antibiotic therapy and surgical drainage.
Case presentation
We report the case of a 55-year-old male with a past medical history of end-stage kidney disease secondary to medical renal disease of hypertension. After a dialysis vintage of six years, he received a deceased donor renal transplant in 2018. Post-transplant, his allograft function remained stable with a baseline serum creatinine level at 1.6-1.8 mg/dL. After induction with basiliximab, the patient was maintained on triple immunosuppressive therapy consisting of mycophenolic acid 720 mg twice daily per oral (PO), tacrolimus 2 mg twice daily PO, and prednisone 5 mg daily PO.
Six months following the renal transplant, the patient presented to the hospital with a chief complaint of progressive bilateral lower extremities pain with swelling, which started 10 days before presentation. Associated symptoms included shortness of breath. Workup included an ultrasound of the right lower leg, which showed a heterogeneous mass in the right posterior thigh; nevertheless, the patient received hydrocodone/acetaminophen and was instructed to follow up with his primary care physician in a week. However, one week later, the patient presented again due to the worsening of symptoms; physical exam revealed a palpable, fluctuant, and tender fullness involving the left gluteal and the right posterior thigh region with associated left knee swelling.
Laboratory workup revealed the following: C-reactive protein 149 mg/L, creatinine 1.65 mg/dL (baseline creatinine 1.6-1.8 mg/dL), and white blood cell count 9,500/mm3. CT pelvis and bilateral lower extremities without contrast showed a 3.5-cm fluid collection in the right posterior thigh and the left buttock (Figure 1). Chest CT showed multi-focal irregular airspace opacities with new scattered sub-centimeter pulmonary nodules (Figure 2). The two-dimensional echo was negative for valve vegetations. MRI brain was negative for masses or abscesses; blood cultures were negative and tissue culture grew Gram-positive bacilli identified as Nocardia farcinica. The patient underwent incision and drainage of the thigh and gluteal abscesses with the placement of Penrose drain and surgical site cultures obtained. Tacrolimus and myfortic acid were held for two weeks due to the presumed infectious process; prednisone 20 mg daily PO was initiated along with high-dose trimethoprim-sulfamethoxazole (TMP-SMX) in conjunction with linezolid. The patient’s condition subsequently improved and he was discharged on oral linezolid and TMP-SMX. He was treated with the combination for four weeks, and then continued with TMP-SMX alone for a total of 12 months at which point all lesions had resolved without allograft dysfunction.
Figure 1 CT pelvis and bilateral lower extremities without contrast showed a 3.5-cm fluid collection (arrow) in the right posterior thigh
Figure 2 CT thorax showing pulmonary nodule (arrow)
Discussion
Renal transplant patients are at an increased risk of certain infections, particularly following the initiation of immunosuppressive drugs after the transplant [1]. Nocardia infection is commonly seen among patients with T-cell and macrophage function disorders, such as patients who are taking immunosuppressive agents [2]. The risk of nocardiosis is increased in the first year following renal transplantation, presumably due to using immunosuppression to prevent rejection [3]. Patients treated with steroid-sparing regimens, such as cyclosporine, have found significantly reduced rates of nocardial infections, to 0.7%, in renal transplant recipients [4]. The patient was diagnosed with nocardiosis six months following the renal transplant.
Nocardia species are not ordinarily seen in the respiratory tract, yet pulmonary involvement is the primary site of nocardial infection in more than two-thirds of cases [3,5]. Therefore, a sputum culture is mostly indicative of Nocardia infection. Rarely, respiratory nocardial isolate has been considered a non-pathogen (i.e., colonizer) [6]. Most pulmonary infections are primary, but Nocardia can spread to the lung from other sites, such as the skin [7]. On the other hand, cutaneous lesions are reported in kidney transplant recipients with a Nocardia infection [2]. Manifestations of primary cutaneous nocardiosis include ulcerations, pyoderma, cellulitis, nodules, and subcutaneous abscesses [8,9]. The reported patient had disseminated nocardiosis involving lungs and skin, though lungs were thought to be the primary source of infection. Also, imaging findings in pulmonary nocardiosis are different, including lung nodules, lung masses (with or without cavitation), reticulonodular infiltrates, interstitial infiltrates, lobar consolidation, subpleural plaques, and pleural effusions [10]. Our patient’s CT thorax showed irregular airspace opacities in the left upper lobe.
TMP-SMX is considered first-line therapy for nocardiosis. However, some Nocardia species are resistant to TMP-SMX, including N. farcinica, while Nocardia asteroides and Nocardia nova remain sensitive primarily to TMP-SMX, with susceptibility rates of >95% and 89%, respectively [11,12]. Moreover, there is no consensus for the role of TMP-SMX as prophylaxis for Nocardia. Although one study proposed that TMP-SMX prophylaxis is effective in heart transplant recipients, nocardiosis has been documented in one-third of the renal transplant recipients who received TMP-SMX as Pneumocystis carinii prophylaxis [13]. Deaths related to Nocardia infection in transplant recipients have been rare. In one study, the nocardial infection has been neither found to be associated with mortality nor overall survival. Also, in the same study, early diagnosis suggests a favorable therapeutic outcome [14].
Conclusions
Overall, disseminated nocardiosis with systemic involvement carries a grave prognosis. However, early diagnosis of the case, with proper antibiotic coverage, leads to a favorable outcome, even in a post-renal transplant patient.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained by all participants in this study | LINEZOLID, MYCOPHENOLIC ACID, PREDNISONE, SULFAMETHOXAZOLE\TRIMETHOPRIM, TACROLIMUS | DrugsGivenReaction | CC BY | 33564506 | 18,949,258 | 2021-01-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pulmonary nocardiosis'. | Disseminated Nocardiosis in a Renal Transplant Recipient.
Nocardiosis is an uncommon opportunistic Gram-positive bacterial infection caused by aerobic actinomycetes in the genus Nocardia. Nocardia can cause localized or systemic suppurative diseases involving eyes, kidneys, skin, lungs, bone, and central nervous system. Disseminated nocardiosis is a rare condition, seen among immunocompromised patients. We report the case of a 55-year-old African American, kidney transplant male recipient on maintenance immunosuppression, who was diagnosed with cutaneous and pulmonary nocardiosis. Presenting symptoms were shortness of breath, and bilateral lower extremities pain and swelling. Tissue culture grew Gram-positive bacilli specified as Nocardia farcinica from thigh and gluteal abscesses. CT thorax showed bilateral reticulonodular opacities. The patient was managed with immunosuppression reduction and specific treatment with high-dose trimethoprim-sulfamethoxazole (TMP-SMX) in conjunction with linezolid. Combination antibiotics were continued for four weeks, and thereafter, TMP-SMX alone was continued for 12 months, at which point all lesions had healed. Nocardiosis with systemic involvement carries a poor prognosis. However, early diagnosis and appropriate antibiotic coverage had a favorable outcome in a renal transplant recipient. Recommended treatment duration is 6 to 12 months.
Introduction
Nocardiosis is an uncommon opportunistic Gram-positive bacterial infection caused by aerobic actinomycetes in the genus Nocardia. It can cause localized or systemic suppurative diseases in humans, involving eyes, kidneys, skin, pulmonary, brain as well as disseminated infection. Inhalation of the organism is the most common mode of entry; that is why the majority of infections involve lungs. Herein, we report a case of a renal transplant recipient who presented with disseminated nocardiosis with pulmonary and cutaneous involvement and was successfully treated with combined antibiotic therapy and surgical drainage.
Case presentation
We report the case of a 55-year-old male with a past medical history of end-stage kidney disease secondary to medical renal disease of hypertension. After a dialysis vintage of six years, he received a deceased donor renal transplant in 2018. Post-transplant, his allograft function remained stable with a baseline serum creatinine level at 1.6-1.8 mg/dL. After induction with basiliximab, the patient was maintained on triple immunosuppressive therapy consisting of mycophenolic acid 720 mg twice daily per oral (PO), tacrolimus 2 mg twice daily PO, and prednisone 5 mg daily PO.
Six months following the renal transplant, the patient presented to the hospital with a chief complaint of progressive bilateral lower extremities pain with swelling, which started 10 days before presentation. Associated symptoms included shortness of breath. Workup included an ultrasound of the right lower leg, which showed a heterogeneous mass in the right posterior thigh; nevertheless, the patient received hydrocodone/acetaminophen and was instructed to follow up with his primary care physician in a week. However, one week later, the patient presented again due to the worsening of symptoms; physical exam revealed a palpable, fluctuant, and tender fullness involving the left gluteal and the right posterior thigh region with associated left knee swelling.
Laboratory workup revealed the following: C-reactive protein 149 mg/L, creatinine 1.65 mg/dL (baseline creatinine 1.6-1.8 mg/dL), and white blood cell count 9,500/mm3. CT pelvis and bilateral lower extremities without contrast showed a 3.5-cm fluid collection in the right posterior thigh and the left buttock (Figure 1). Chest CT showed multi-focal irregular airspace opacities with new scattered sub-centimeter pulmonary nodules (Figure 2). The two-dimensional echo was negative for valve vegetations. MRI brain was negative for masses or abscesses; blood cultures were negative and tissue culture grew Gram-positive bacilli identified as Nocardia farcinica. The patient underwent incision and drainage of the thigh and gluteal abscesses with the placement of Penrose drain and surgical site cultures obtained. Tacrolimus and myfortic acid were held for two weeks due to the presumed infectious process; prednisone 20 mg daily PO was initiated along with high-dose trimethoprim-sulfamethoxazole (TMP-SMX) in conjunction with linezolid. The patient’s condition subsequently improved and he was discharged on oral linezolid and TMP-SMX. He was treated with the combination for four weeks, and then continued with TMP-SMX alone for a total of 12 months at which point all lesions had resolved without allograft dysfunction.
Figure 1 CT pelvis and bilateral lower extremities without contrast showed a 3.5-cm fluid collection (arrow) in the right posterior thigh
Figure 2 CT thorax showing pulmonary nodule (arrow)
Discussion
Renal transplant patients are at an increased risk of certain infections, particularly following the initiation of immunosuppressive drugs after the transplant [1]. Nocardia infection is commonly seen among patients with T-cell and macrophage function disorders, such as patients who are taking immunosuppressive agents [2]. The risk of nocardiosis is increased in the first year following renal transplantation, presumably due to using immunosuppression to prevent rejection [3]. Patients treated with steroid-sparing regimens, such as cyclosporine, have found significantly reduced rates of nocardial infections, to 0.7%, in renal transplant recipients [4]. The patient was diagnosed with nocardiosis six months following the renal transplant.
Nocardia species are not ordinarily seen in the respiratory tract, yet pulmonary involvement is the primary site of nocardial infection in more than two-thirds of cases [3,5]. Therefore, a sputum culture is mostly indicative of Nocardia infection. Rarely, respiratory nocardial isolate has been considered a non-pathogen (i.e., colonizer) [6]. Most pulmonary infections are primary, but Nocardia can spread to the lung from other sites, such as the skin [7]. On the other hand, cutaneous lesions are reported in kidney transplant recipients with a Nocardia infection [2]. Manifestations of primary cutaneous nocardiosis include ulcerations, pyoderma, cellulitis, nodules, and subcutaneous abscesses [8,9]. The reported patient had disseminated nocardiosis involving lungs and skin, though lungs were thought to be the primary source of infection. Also, imaging findings in pulmonary nocardiosis are different, including lung nodules, lung masses (with or without cavitation), reticulonodular infiltrates, interstitial infiltrates, lobar consolidation, subpleural plaques, and pleural effusions [10]. Our patient’s CT thorax showed irregular airspace opacities in the left upper lobe.
TMP-SMX is considered first-line therapy for nocardiosis. However, some Nocardia species are resistant to TMP-SMX, including N. farcinica, while Nocardia asteroides and Nocardia nova remain sensitive primarily to TMP-SMX, with susceptibility rates of >95% and 89%, respectively [11,12]. Moreover, there is no consensus for the role of TMP-SMX as prophylaxis for Nocardia. Although one study proposed that TMP-SMX prophylaxis is effective in heart transplant recipients, nocardiosis has been documented in one-third of the renal transplant recipients who received TMP-SMX as Pneumocystis carinii prophylaxis [13]. Deaths related to Nocardia infection in transplant recipients have been rare. In one study, the nocardial infection has been neither found to be associated with mortality nor overall survival. Also, in the same study, early diagnosis suggests a favorable therapeutic outcome [14].
Conclusions
Overall, disseminated nocardiosis with systemic involvement carries a grave prognosis. However, early diagnosis of the case, with proper antibiotic coverage, leads to a favorable outcome, even in a post-renal transplant patient.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained by all participants in this study | LINEZOLID, MYCOPHENOLIC ACID, PREDNISONE, SULFAMETHOXAZOLE\TRIMETHOPRIM, TACROLIMUS | DrugsGivenReaction | CC BY | 33564506 | 18,949,258 | 2021-01-05 |
What was the administration route of drug 'LINEZOLID'? | Disseminated Nocardiosis in a Renal Transplant Recipient.
Nocardiosis is an uncommon opportunistic Gram-positive bacterial infection caused by aerobic actinomycetes in the genus Nocardia. Nocardia can cause localized or systemic suppurative diseases involving eyes, kidneys, skin, lungs, bone, and central nervous system. Disseminated nocardiosis is a rare condition, seen among immunocompromised patients. We report the case of a 55-year-old African American, kidney transplant male recipient on maintenance immunosuppression, who was diagnosed with cutaneous and pulmonary nocardiosis. Presenting symptoms were shortness of breath, and bilateral lower extremities pain and swelling. Tissue culture grew Gram-positive bacilli specified as Nocardia farcinica from thigh and gluteal abscesses. CT thorax showed bilateral reticulonodular opacities. The patient was managed with immunosuppression reduction and specific treatment with high-dose trimethoprim-sulfamethoxazole (TMP-SMX) in conjunction with linezolid. Combination antibiotics were continued for four weeks, and thereafter, TMP-SMX alone was continued for 12 months, at which point all lesions had healed. Nocardiosis with systemic involvement carries a poor prognosis. However, early diagnosis and appropriate antibiotic coverage had a favorable outcome in a renal transplant recipient. Recommended treatment duration is 6 to 12 months.
Introduction
Nocardiosis is an uncommon opportunistic Gram-positive bacterial infection caused by aerobic actinomycetes in the genus Nocardia. It can cause localized or systemic suppurative diseases in humans, involving eyes, kidneys, skin, pulmonary, brain as well as disseminated infection. Inhalation of the organism is the most common mode of entry; that is why the majority of infections involve lungs. Herein, we report a case of a renal transplant recipient who presented with disseminated nocardiosis with pulmonary and cutaneous involvement and was successfully treated with combined antibiotic therapy and surgical drainage.
Case presentation
We report the case of a 55-year-old male with a past medical history of end-stage kidney disease secondary to medical renal disease of hypertension. After a dialysis vintage of six years, he received a deceased donor renal transplant in 2018. Post-transplant, his allograft function remained stable with a baseline serum creatinine level at 1.6-1.8 mg/dL. After induction with basiliximab, the patient was maintained on triple immunosuppressive therapy consisting of mycophenolic acid 720 mg twice daily per oral (PO), tacrolimus 2 mg twice daily PO, and prednisone 5 mg daily PO.
Six months following the renal transplant, the patient presented to the hospital with a chief complaint of progressive bilateral lower extremities pain with swelling, which started 10 days before presentation. Associated symptoms included shortness of breath. Workup included an ultrasound of the right lower leg, which showed a heterogeneous mass in the right posterior thigh; nevertheless, the patient received hydrocodone/acetaminophen and was instructed to follow up with his primary care physician in a week. However, one week later, the patient presented again due to the worsening of symptoms; physical exam revealed a palpable, fluctuant, and tender fullness involving the left gluteal and the right posterior thigh region with associated left knee swelling.
Laboratory workup revealed the following: C-reactive protein 149 mg/L, creatinine 1.65 mg/dL (baseline creatinine 1.6-1.8 mg/dL), and white blood cell count 9,500/mm3. CT pelvis and bilateral lower extremities without contrast showed a 3.5-cm fluid collection in the right posterior thigh and the left buttock (Figure 1). Chest CT showed multi-focal irregular airspace opacities with new scattered sub-centimeter pulmonary nodules (Figure 2). The two-dimensional echo was negative for valve vegetations. MRI brain was negative for masses or abscesses; blood cultures were negative and tissue culture grew Gram-positive bacilli identified as Nocardia farcinica. The patient underwent incision and drainage of the thigh and gluteal abscesses with the placement of Penrose drain and surgical site cultures obtained. Tacrolimus and myfortic acid were held for two weeks due to the presumed infectious process; prednisone 20 mg daily PO was initiated along with high-dose trimethoprim-sulfamethoxazole (TMP-SMX) in conjunction with linezolid. The patient’s condition subsequently improved and he was discharged on oral linezolid and TMP-SMX. He was treated with the combination for four weeks, and then continued with TMP-SMX alone for a total of 12 months at which point all lesions had resolved without allograft dysfunction.
Figure 1 CT pelvis and bilateral lower extremities without contrast showed a 3.5-cm fluid collection (arrow) in the right posterior thigh
Figure 2 CT thorax showing pulmonary nodule (arrow)
Discussion
Renal transplant patients are at an increased risk of certain infections, particularly following the initiation of immunosuppressive drugs after the transplant [1]. Nocardia infection is commonly seen among patients with T-cell and macrophage function disorders, such as patients who are taking immunosuppressive agents [2]. The risk of nocardiosis is increased in the first year following renal transplantation, presumably due to using immunosuppression to prevent rejection [3]. Patients treated with steroid-sparing regimens, such as cyclosporine, have found significantly reduced rates of nocardial infections, to 0.7%, in renal transplant recipients [4]. The patient was diagnosed with nocardiosis six months following the renal transplant.
Nocardia species are not ordinarily seen in the respiratory tract, yet pulmonary involvement is the primary site of nocardial infection in more than two-thirds of cases [3,5]. Therefore, a sputum culture is mostly indicative of Nocardia infection. Rarely, respiratory nocardial isolate has been considered a non-pathogen (i.e., colonizer) [6]. Most pulmonary infections are primary, but Nocardia can spread to the lung from other sites, such as the skin [7]. On the other hand, cutaneous lesions are reported in kidney transplant recipients with a Nocardia infection [2]. Manifestations of primary cutaneous nocardiosis include ulcerations, pyoderma, cellulitis, nodules, and subcutaneous abscesses [8,9]. The reported patient had disseminated nocardiosis involving lungs and skin, though lungs were thought to be the primary source of infection. Also, imaging findings in pulmonary nocardiosis are different, including lung nodules, lung masses (with or without cavitation), reticulonodular infiltrates, interstitial infiltrates, lobar consolidation, subpleural plaques, and pleural effusions [10]. Our patient’s CT thorax showed irregular airspace opacities in the left upper lobe.
TMP-SMX is considered first-line therapy for nocardiosis. However, some Nocardia species are resistant to TMP-SMX, including N. farcinica, while Nocardia asteroides and Nocardia nova remain sensitive primarily to TMP-SMX, with susceptibility rates of >95% and 89%, respectively [11,12]. Moreover, there is no consensus for the role of TMP-SMX as prophylaxis for Nocardia. Although one study proposed that TMP-SMX prophylaxis is effective in heart transplant recipients, nocardiosis has been documented in one-third of the renal transplant recipients who received TMP-SMX as Pneumocystis carinii prophylaxis [13]. Deaths related to Nocardia infection in transplant recipients have been rare. In one study, the nocardial infection has been neither found to be associated with mortality nor overall survival. Also, in the same study, early diagnosis suggests a favorable therapeutic outcome [14].
Conclusions
Overall, disseminated nocardiosis with systemic involvement carries a grave prognosis. However, early diagnosis of the case, with proper antibiotic coverage, leads to a favorable outcome, even in a post-renal transplant patient.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained by all participants in this study | Oral | DrugAdministrationRoute | CC BY | 33564506 | 18,949,258 | 2021-01-05 |
What was the administration route of drug 'MYCOPHENOLIC ACID'? | Disseminated Nocardiosis in a Renal Transplant Recipient.
Nocardiosis is an uncommon opportunistic Gram-positive bacterial infection caused by aerobic actinomycetes in the genus Nocardia. Nocardia can cause localized or systemic suppurative diseases involving eyes, kidneys, skin, lungs, bone, and central nervous system. Disseminated nocardiosis is a rare condition, seen among immunocompromised patients. We report the case of a 55-year-old African American, kidney transplant male recipient on maintenance immunosuppression, who was diagnosed with cutaneous and pulmonary nocardiosis. Presenting symptoms were shortness of breath, and bilateral lower extremities pain and swelling. Tissue culture grew Gram-positive bacilli specified as Nocardia farcinica from thigh and gluteal abscesses. CT thorax showed bilateral reticulonodular opacities. The patient was managed with immunosuppression reduction and specific treatment with high-dose trimethoprim-sulfamethoxazole (TMP-SMX) in conjunction with linezolid. Combination antibiotics were continued for four weeks, and thereafter, TMP-SMX alone was continued for 12 months, at which point all lesions had healed. Nocardiosis with systemic involvement carries a poor prognosis. However, early diagnosis and appropriate antibiotic coverage had a favorable outcome in a renal transplant recipient. Recommended treatment duration is 6 to 12 months.
Introduction
Nocardiosis is an uncommon opportunistic Gram-positive bacterial infection caused by aerobic actinomycetes in the genus Nocardia. It can cause localized or systemic suppurative diseases in humans, involving eyes, kidneys, skin, pulmonary, brain as well as disseminated infection. Inhalation of the organism is the most common mode of entry; that is why the majority of infections involve lungs. Herein, we report a case of a renal transplant recipient who presented with disseminated nocardiosis with pulmonary and cutaneous involvement and was successfully treated with combined antibiotic therapy and surgical drainage.
Case presentation
We report the case of a 55-year-old male with a past medical history of end-stage kidney disease secondary to medical renal disease of hypertension. After a dialysis vintage of six years, he received a deceased donor renal transplant in 2018. Post-transplant, his allograft function remained stable with a baseline serum creatinine level at 1.6-1.8 mg/dL. After induction with basiliximab, the patient was maintained on triple immunosuppressive therapy consisting of mycophenolic acid 720 mg twice daily per oral (PO), tacrolimus 2 mg twice daily PO, and prednisone 5 mg daily PO.
Six months following the renal transplant, the patient presented to the hospital with a chief complaint of progressive bilateral lower extremities pain with swelling, which started 10 days before presentation. Associated symptoms included shortness of breath. Workup included an ultrasound of the right lower leg, which showed a heterogeneous mass in the right posterior thigh; nevertheless, the patient received hydrocodone/acetaminophen and was instructed to follow up with his primary care physician in a week. However, one week later, the patient presented again due to the worsening of symptoms; physical exam revealed a palpable, fluctuant, and tender fullness involving the left gluteal and the right posterior thigh region with associated left knee swelling.
Laboratory workup revealed the following: C-reactive protein 149 mg/L, creatinine 1.65 mg/dL (baseline creatinine 1.6-1.8 mg/dL), and white blood cell count 9,500/mm3. CT pelvis and bilateral lower extremities without contrast showed a 3.5-cm fluid collection in the right posterior thigh and the left buttock (Figure 1). Chest CT showed multi-focal irregular airspace opacities with new scattered sub-centimeter pulmonary nodules (Figure 2). The two-dimensional echo was negative for valve vegetations. MRI brain was negative for masses or abscesses; blood cultures were negative and tissue culture grew Gram-positive bacilli identified as Nocardia farcinica. The patient underwent incision and drainage of the thigh and gluteal abscesses with the placement of Penrose drain and surgical site cultures obtained. Tacrolimus and myfortic acid were held for two weeks due to the presumed infectious process; prednisone 20 mg daily PO was initiated along with high-dose trimethoprim-sulfamethoxazole (TMP-SMX) in conjunction with linezolid. The patient’s condition subsequently improved and he was discharged on oral linezolid and TMP-SMX. He was treated with the combination for four weeks, and then continued with TMP-SMX alone for a total of 12 months at which point all lesions had resolved without allograft dysfunction.
Figure 1 CT pelvis and bilateral lower extremities without contrast showed a 3.5-cm fluid collection (arrow) in the right posterior thigh
Figure 2 CT thorax showing pulmonary nodule (arrow)
Discussion
Renal transplant patients are at an increased risk of certain infections, particularly following the initiation of immunosuppressive drugs after the transplant [1]. Nocardia infection is commonly seen among patients with T-cell and macrophage function disorders, such as patients who are taking immunosuppressive agents [2]. The risk of nocardiosis is increased in the first year following renal transplantation, presumably due to using immunosuppression to prevent rejection [3]. Patients treated with steroid-sparing regimens, such as cyclosporine, have found significantly reduced rates of nocardial infections, to 0.7%, in renal transplant recipients [4]. The patient was diagnosed with nocardiosis six months following the renal transplant.
Nocardia species are not ordinarily seen in the respiratory tract, yet pulmonary involvement is the primary site of nocardial infection in more than two-thirds of cases [3,5]. Therefore, a sputum culture is mostly indicative of Nocardia infection. Rarely, respiratory nocardial isolate has been considered a non-pathogen (i.e., colonizer) [6]. Most pulmonary infections are primary, but Nocardia can spread to the lung from other sites, such as the skin [7]. On the other hand, cutaneous lesions are reported in kidney transplant recipients with a Nocardia infection [2]. Manifestations of primary cutaneous nocardiosis include ulcerations, pyoderma, cellulitis, nodules, and subcutaneous abscesses [8,9]. The reported patient had disseminated nocardiosis involving lungs and skin, though lungs were thought to be the primary source of infection. Also, imaging findings in pulmonary nocardiosis are different, including lung nodules, lung masses (with or without cavitation), reticulonodular infiltrates, interstitial infiltrates, lobar consolidation, subpleural plaques, and pleural effusions [10]. Our patient’s CT thorax showed irregular airspace opacities in the left upper lobe.
TMP-SMX is considered first-line therapy for nocardiosis. However, some Nocardia species are resistant to TMP-SMX, including N. farcinica, while Nocardia asteroides and Nocardia nova remain sensitive primarily to TMP-SMX, with susceptibility rates of >95% and 89%, respectively [11,12]. Moreover, there is no consensus for the role of TMP-SMX as prophylaxis for Nocardia. Although one study proposed that TMP-SMX prophylaxis is effective in heart transplant recipients, nocardiosis has been documented in one-third of the renal transplant recipients who received TMP-SMX as Pneumocystis carinii prophylaxis [13]. Deaths related to Nocardia infection in transplant recipients have been rare. In one study, the nocardial infection has been neither found to be associated with mortality nor overall survival. Also, in the same study, early diagnosis suggests a favorable therapeutic outcome [14].
Conclusions
Overall, disseminated nocardiosis with systemic involvement carries a grave prognosis. However, early diagnosis of the case, with proper antibiotic coverage, leads to a favorable outcome, even in a post-renal transplant patient.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained by all participants in this study | Oral | DrugAdministrationRoute | CC BY | 33564506 | 18,949,258 | 2021-01-05 |
What was the administration route of drug 'PREDNISONE'? | Disseminated Nocardiosis in a Renal Transplant Recipient.
Nocardiosis is an uncommon opportunistic Gram-positive bacterial infection caused by aerobic actinomycetes in the genus Nocardia. Nocardia can cause localized or systemic suppurative diseases involving eyes, kidneys, skin, lungs, bone, and central nervous system. Disseminated nocardiosis is a rare condition, seen among immunocompromised patients. We report the case of a 55-year-old African American, kidney transplant male recipient on maintenance immunosuppression, who was diagnosed with cutaneous and pulmonary nocardiosis. Presenting symptoms were shortness of breath, and bilateral lower extremities pain and swelling. Tissue culture grew Gram-positive bacilli specified as Nocardia farcinica from thigh and gluteal abscesses. CT thorax showed bilateral reticulonodular opacities. The patient was managed with immunosuppression reduction and specific treatment with high-dose trimethoprim-sulfamethoxazole (TMP-SMX) in conjunction with linezolid. Combination antibiotics were continued for four weeks, and thereafter, TMP-SMX alone was continued for 12 months, at which point all lesions had healed. Nocardiosis with systemic involvement carries a poor prognosis. However, early diagnosis and appropriate antibiotic coverage had a favorable outcome in a renal transplant recipient. Recommended treatment duration is 6 to 12 months.
Introduction
Nocardiosis is an uncommon opportunistic Gram-positive bacterial infection caused by aerobic actinomycetes in the genus Nocardia. It can cause localized or systemic suppurative diseases in humans, involving eyes, kidneys, skin, pulmonary, brain as well as disseminated infection. Inhalation of the organism is the most common mode of entry; that is why the majority of infections involve lungs. Herein, we report a case of a renal transplant recipient who presented with disseminated nocardiosis with pulmonary and cutaneous involvement and was successfully treated with combined antibiotic therapy and surgical drainage.
Case presentation
We report the case of a 55-year-old male with a past medical history of end-stage kidney disease secondary to medical renal disease of hypertension. After a dialysis vintage of six years, he received a deceased donor renal transplant in 2018. Post-transplant, his allograft function remained stable with a baseline serum creatinine level at 1.6-1.8 mg/dL. After induction with basiliximab, the patient was maintained on triple immunosuppressive therapy consisting of mycophenolic acid 720 mg twice daily per oral (PO), tacrolimus 2 mg twice daily PO, and prednisone 5 mg daily PO.
Six months following the renal transplant, the patient presented to the hospital with a chief complaint of progressive bilateral lower extremities pain with swelling, which started 10 days before presentation. Associated symptoms included shortness of breath. Workup included an ultrasound of the right lower leg, which showed a heterogeneous mass in the right posterior thigh; nevertheless, the patient received hydrocodone/acetaminophen and was instructed to follow up with his primary care physician in a week. However, one week later, the patient presented again due to the worsening of symptoms; physical exam revealed a palpable, fluctuant, and tender fullness involving the left gluteal and the right posterior thigh region with associated left knee swelling.
Laboratory workup revealed the following: C-reactive protein 149 mg/L, creatinine 1.65 mg/dL (baseline creatinine 1.6-1.8 mg/dL), and white blood cell count 9,500/mm3. CT pelvis and bilateral lower extremities without contrast showed a 3.5-cm fluid collection in the right posterior thigh and the left buttock (Figure 1). Chest CT showed multi-focal irregular airspace opacities with new scattered sub-centimeter pulmonary nodules (Figure 2). The two-dimensional echo was negative for valve vegetations. MRI brain was negative for masses or abscesses; blood cultures were negative and tissue culture grew Gram-positive bacilli identified as Nocardia farcinica. The patient underwent incision and drainage of the thigh and gluteal abscesses with the placement of Penrose drain and surgical site cultures obtained. Tacrolimus and myfortic acid were held for two weeks due to the presumed infectious process; prednisone 20 mg daily PO was initiated along with high-dose trimethoprim-sulfamethoxazole (TMP-SMX) in conjunction with linezolid. The patient’s condition subsequently improved and he was discharged on oral linezolid and TMP-SMX. He was treated with the combination for four weeks, and then continued with TMP-SMX alone for a total of 12 months at which point all lesions had resolved without allograft dysfunction.
Figure 1 CT pelvis and bilateral lower extremities without contrast showed a 3.5-cm fluid collection (arrow) in the right posterior thigh
Figure 2 CT thorax showing pulmonary nodule (arrow)
Discussion
Renal transplant patients are at an increased risk of certain infections, particularly following the initiation of immunosuppressive drugs after the transplant [1]. Nocardia infection is commonly seen among patients with T-cell and macrophage function disorders, such as patients who are taking immunosuppressive agents [2]. The risk of nocardiosis is increased in the first year following renal transplantation, presumably due to using immunosuppression to prevent rejection [3]. Patients treated with steroid-sparing regimens, such as cyclosporine, have found significantly reduced rates of nocardial infections, to 0.7%, in renal transplant recipients [4]. The patient was diagnosed with nocardiosis six months following the renal transplant.
Nocardia species are not ordinarily seen in the respiratory tract, yet pulmonary involvement is the primary site of nocardial infection in more than two-thirds of cases [3,5]. Therefore, a sputum culture is mostly indicative of Nocardia infection. Rarely, respiratory nocardial isolate has been considered a non-pathogen (i.e., colonizer) [6]. Most pulmonary infections are primary, but Nocardia can spread to the lung from other sites, such as the skin [7]. On the other hand, cutaneous lesions are reported in kidney transplant recipients with a Nocardia infection [2]. Manifestations of primary cutaneous nocardiosis include ulcerations, pyoderma, cellulitis, nodules, and subcutaneous abscesses [8,9]. The reported patient had disseminated nocardiosis involving lungs and skin, though lungs were thought to be the primary source of infection. Also, imaging findings in pulmonary nocardiosis are different, including lung nodules, lung masses (with or without cavitation), reticulonodular infiltrates, interstitial infiltrates, lobar consolidation, subpleural plaques, and pleural effusions [10]. Our patient’s CT thorax showed irregular airspace opacities in the left upper lobe.
TMP-SMX is considered first-line therapy for nocardiosis. However, some Nocardia species are resistant to TMP-SMX, including N. farcinica, while Nocardia asteroides and Nocardia nova remain sensitive primarily to TMP-SMX, with susceptibility rates of >95% and 89%, respectively [11,12]. Moreover, there is no consensus for the role of TMP-SMX as prophylaxis for Nocardia. Although one study proposed that TMP-SMX prophylaxis is effective in heart transplant recipients, nocardiosis has been documented in one-third of the renal transplant recipients who received TMP-SMX as Pneumocystis carinii prophylaxis [13]. Deaths related to Nocardia infection in transplant recipients have been rare. In one study, the nocardial infection has been neither found to be associated with mortality nor overall survival. Also, in the same study, early diagnosis suggests a favorable therapeutic outcome [14].
Conclusions
Overall, disseminated nocardiosis with systemic involvement carries a grave prognosis. However, early diagnosis of the case, with proper antibiotic coverage, leads to a favorable outcome, even in a post-renal transplant patient.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained by all participants in this study | Oral | DrugAdministrationRoute | CC BY | 33564506 | 18,949,258 | 2021-01-05 |
What was the administration route of drug 'TACROLIMUS'? | Disseminated Nocardiosis in a Renal Transplant Recipient.
Nocardiosis is an uncommon opportunistic Gram-positive bacterial infection caused by aerobic actinomycetes in the genus Nocardia. Nocardia can cause localized or systemic suppurative diseases involving eyes, kidneys, skin, lungs, bone, and central nervous system. Disseminated nocardiosis is a rare condition, seen among immunocompromised patients. We report the case of a 55-year-old African American, kidney transplant male recipient on maintenance immunosuppression, who was diagnosed with cutaneous and pulmonary nocardiosis. Presenting symptoms were shortness of breath, and bilateral lower extremities pain and swelling. Tissue culture grew Gram-positive bacilli specified as Nocardia farcinica from thigh and gluteal abscesses. CT thorax showed bilateral reticulonodular opacities. The patient was managed with immunosuppression reduction and specific treatment with high-dose trimethoprim-sulfamethoxazole (TMP-SMX) in conjunction with linezolid. Combination antibiotics were continued for four weeks, and thereafter, TMP-SMX alone was continued for 12 months, at which point all lesions had healed. Nocardiosis with systemic involvement carries a poor prognosis. However, early diagnosis and appropriate antibiotic coverage had a favorable outcome in a renal transplant recipient. Recommended treatment duration is 6 to 12 months.
Introduction
Nocardiosis is an uncommon opportunistic Gram-positive bacterial infection caused by aerobic actinomycetes in the genus Nocardia. It can cause localized or systemic suppurative diseases in humans, involving eyes, kidneys, skin, pulmonary, brain as well as disseminated infection. Inhalation of the organism is the most common mode of entry; that is why the majority of infections involve lungs. Herein, we report a case of a renal transplant recipient who presented with disseminated nocardiosis with pulmonary and cutaneous involvement and was successfully treated with combined antibiotic therapy and surgical drainage.
Case presentation
We report the case of a 55-year-old male with a past medical history of end-stage kidney disease secondary to medical renal disease of hypertension. After a dialysis vintage of six years, he received a deceased donor renal transplant in 2018. Post-transplant, his allograft function remained stable with a baseline serum creatinine level at 1.6-1.8 mg/dL. After induction with basiliximab, the patient was maintained on triple immunosuppressive therapy consisting of mycophenolic acid 720 mg twice daily per oral (PO), tacrolimus 2 mg twice daily PO, and prednisone 5 mg daily PO.
Six months following the renal transplant, the patient presented to the hospital with a chief complaint of progressive bilateral lower extremities pain with swelling, which started 10 days before presentation. Associated symptoms included shortness of breath. Workup included an ultrasound of the right lower leg, which showed a heterogeneous mass in the right posterior thigh; nevertheless, the patient received hydrocodone/acetaminophen and was instructed to follow up with his primary care physician in a week. However, one week later, the patient presented again due to the worsening of symptoms; physical exam revealed a palpable, fluctuant, and tender fullness involving the left gluteal and the right posterior thigh region with associated left knee swelling.
Laboratory workup revealed the following: C-reactive protein 149 mg/L, creatinine 1.65 mg/dL (baseline creatinine 1.6-1.8 mg/dL), and white blood cell count 9,500/mm3. CT pelvis and bilateral lower extremities without contrast showed a 3.5-cm fluid collection in the right posterior thigh and the left buttock (Figure 1). Chest CT showed multi-focal irregular airspace opacities with new scattered sub-centimeter pulmonary nodules (Figure 2). The two-dimensional echo was negative for valve vegetations. MRI brain was negative for masses or abscesses; blood cultures were negative and tissue culture grew Gram-positive bacilli identified as Nocardia farcinica. The patient underwent incision and drainage of the thigh and gluteal abscesses with the placement of Penrose drain and surgical site cultures obtained. Tacrolimus and myfortic acid were held for two weeks due to the presumed infectious process; prednisone 20 mg daily PO was initiated along with high-dose trimethoprim-sulfamethoxazole (TMP-SMX) in conjunction with linezolid. The patient’s condition subsequently improved and he was discharged on oral linezolid and TMP-SMX. He was treated with the combination for four weeks, and then continued with TMP-SMX alone for a total of 12 months at which point all lesions had resolved without allograft dysfunction.
Figure 1 CT pelvis and bilateral lower extremities without contrast showed a 3.5-cm fluid collection (arrow) in the right posterior thigh
Figure 2 CT thorax showing pulmonary nodule (arrow)
Discussion
Renal transplant patients are at an increased risk of certain infections, particularly following the initiation of immunosuppressive drugs after the transplant [1]. Nocardia infection is commonly seen among patients with T-cell and macrophage function disorders, such as patients who are taking immunosuppressive agents [2]. The risk of nocardiosis is increased in the first year following renal transplantation, presumably due to using immunosuppression to prevent rejection [3]. Patients treated with steroid-sparing regimens, such as cyclosporine, have found significantly reduced rates of nocardial infections, to 0.7%, in renal transplant recipients [4]. The patient was diagnosed with nocardiosis six months following the renal transplant.
Nocardia species are not ordinarily seen in the respiratory tract, yet pulmonary involvement is the primary site of nocardial infection in more than two-thirds of cases [3,5]. Therefore, a sputum culture is mostly indicative of Nocardia infection. Rarely, respiratory nocardial isolate has been considered a non-pathogen (i.e., colonizer) [6]. Most pulmonary infections are primary, but Nocardia can spread to the lung from other sites, such as the skin [7]. On the other hand, cutaneous lesions are reported in kidney transplant recipients with a Nocardia infection [2]. Manifestations of primary cutaneous nocardiosis include ulcerations, pyoderma, cellulitis, nodules, and subcutaneous abscesses [8,9]. The reported patient had disseminated nocardiosis involving lungs and skin, though lungs were thought to be the primary source of infection. Also, imaging findings in pulmonary nocardiosis are different, including lung nodules, lung masses (with or without cavitation), reticulonodular infiltrates, interstitial infiltrates, lobar consolidation, subpleural plaques, and pleural effusions [10]. Our patient’s CT thorax showed irregular airspace opacities in the left upper lobe.
TMP-SMX is considered first-line therapy for nocardiosis. However, some Nocardia species are resistant to TMP-SMX, including N. farcinica, while Nocardia asteroides and Nocardia nova remain sensitive primarily to TMP-SMX, with susceptibility rates of >95% and 89%, respectively [11,12]. Moreover, there is no consensus for the role of TMP-SMX as prophylaxis for Nocardia. Although one study proposed that TMP-SMX prophylaxis is effective in heart transplant recipients, nocardiosis has been documented in one-third of the renal transplant recipients who received TMP-SMX as Pneumocystis carinii prophylaxis [13]. Deaths related to Nocardia infection in transplant recipients have been rare. In one study, the nocardial infection has been neither found to be associated with mortality nor overall survival. Also, in the same study, early diagnosis suggests a favorable therapeutic outcome [14].
Conclusions
Overall, disseminated nocardiosis with systemic involvement carries a grave prognosis. However, early diagnosis of the case, with proper antibiotic coverage, leads to a favorable outcome, even in a post-renal transplant patient.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained by all participants in this study | Oral | DrugAdministrationRoute | CC BY | 33564506 | 18,949,258 | 2021-01-05 |
What was the dosage of drug 'SULFAMETHOXAZOLE\TRIMETHOPRIM'? | Disseminated Nocardiosis in a Renal Transplant Recipient.
Nocardiosis is an uncommon opportunistic Gram-positive bacterial infection caused by aerobic actinomycetes in the genus Nocardia. Nocardia can cause localized or systemic suppurative diseases involving eyes, kidneys, skin, lungs, bone, and central nervous system. Disseminated nocardiosis is a rare condition, seen among immunocompromised patients. We report the case of a 55-year-old African American, kidney transplant male recipient on maintenance immunosuppression, who was diagnosed with cutaneous and pulmonary nocardiosis. Presenting symptoms were shortness of breath, and bilateral lower extremities pain and swelling. Tissue culture grew Gram-positive bacilli specified as Nocardia farcinica from thigh and gluteal abscesses. CT thorax showed bilateral reticulonodular opacities. The patient was managed with immunosuppression reduction and specific treatment with high-dose trimethoprim-sulfamethoxazole (TMP-SMX) in conjunction with linezolid. Combination antibiotics were continued for four weeks, and thereafter, TMP-SMX alone was continued for 12 months, at which point all lesions had healed. Nocardiosis with systemic involvement carries a poor prognosis. However, early diagnosis and appropriate antibiotic coverage had a favorable outcome in a renal transplant recipient. Recommended treatment duration is 6 to 12 months.
Introduction
Nocardiosis is an uncommon opportunistic Gram-positive bacterial infection caused by aerobic actinomycetes in the genus Nocardia. It can cause localized or systemic suppurative diseases in humans, involving eyes, kidneys, skin, pulmonary, brain as well as disseminated infection. Inhalation of the organism is the most common mode of entry; that is why the majority of infections involve lungs. Herein, we report a case of a renal transplant recipient who presented with disseminated nocardiosis with pulmonary and cutaneous involvement and was successfully treated with combined antibiotic therapy and surgical drainage.
Case presentation
We report the case of a 55-year-old male with a past medical history of end-stage kidney disease secondary to medical renal disease of hypertension. After a dialysis vintage of six years, he received a deceased donor renal transplant in 2018. Post-transplant, his allograft function remained stable with a baseline serum creatinine level at 1.6-1.8 mg/dL. After induction with basiliximab, the patient was maintained on triple immunosuppressive therapy consisting of mycophenolic acid 720 mg twice daily per oral (PO), tacrolimus 2 mg twice daily PO, and prednisone 5 mg daily PO.
Six months following the renal transplant, the patient presented to the hospital with a chief complaint of progressive bilateral lower extremities pain with swelling, which started 10 days before presentation. Associated symptoms included shortness of breath. Workup included an ultrasound of the right lower leg, which showed a heterogeneous mass in the right posterior thigh; nevertheless, the patient received hydrocodone/acetaminophen and was instructed to follow up with his primary care physician in a week. However, one week later, the patient presented again due to the worsening of symptoms; physical exam revealed a palpable, fluctuant, and tender fullness involving the left gluteal and the right posterior thigh region with associated left knee swelling.
Laboratory workup revealed the following: C-reactive protein 149 mg/L, creatinine 1.65 mg/dL (baseline creatinine 1.6-1.8 mg/dL), and white blood cell count 9,500/mm3. CT pelvis and bilateral lower extremities without contrast showed a 3.5-cm fluid collection in the right posterior thigh and the left buttock (Figure 1). Chest CT showed multi-focal irregular airspace opacities with new scattered sub-centimeter pulmonary nodules (Figure 2). The two-dimensional echo was negative for valve vegetations. MRI brain was negative for masses or abscesses; blood cultures were negative and tissue culture grew Gram-positive bacilli identified as Nocardia farcinica. The patient underwent incision and drainage of the thigh and gluteal abscesses with the placement of Penrose drain and surgical site cultures obtained. Tacrolimus and myfortic acid were held for two weeks due to the presumed infectious process; prednisone 20 mg daily PO was initiated along with high-dose trimethoprim-sulfamethoxazole (TMP-SMX) in conjunction with linezolid. The patient’s condition subsequently improved and he was discharged on oral linezolid and TMP-SMX. He was treated with the combination for four weeks, and then continued with TMP-SMX alone for a total of 12 months at which point all lesions had resolved without allograft dysfunction.
Figure 1 CT pelvis and bilateral lower extremities without contrast showed a 3.5-cm fluid collection (arrow) in the right posterior thigh
Figure 2 CT thorax showing pulmonary nodule (arrow)
Discussion
Renal transplant patients are at an increased risk of certain infections, particularly following the initiation of immunosuppressive drugs after the transplant [1]. Nocardia infection is commonly seen among patients with T-cell and macrophage function disorders, such as patients who are taking immunosuppressive agents [2]. The risk of nocardiosis is increased in the first year following renal transplantation, presumably due to using immunosuppression to prevent rejection [3]. Patients treated with steroid-sparing regimens, such as cyclosporine, have found significantly reduced rates of nocardial infections, to 0.7%, in renal transplant recipients [4]. The patient was diagnosed with nocardiosis six months following the renal transplant.
Nocardia species are not ordinarily seen in the respiratory tract, yet pulmonary involvement is the primary site of nocardial infection in more than two-thirds of cases [3,5]. Therefore, a sputum culture is mostly indicative of Nocardia infection. Rarely, respiratory nocardial isolate has been considered a non-pathogen (i.e., colonizer) [6]. Most pulmonary infections are primary, but Nocardia can spread to the lung from other sites, such as the skin [7]. On the other hand, cutaneous lesions are reported in kidney transplant recipients with a Nocardia infection [2]. Manifestations of primary cutaneous nocardiosis include ulcerations, pyoderma, cellulitis, nodules, and subcutaneous abscesses [8,9]. The reported patient had disseminated nocardiosis involving lungs and skin, though lungs were thought to be the primary source of infection. Also, imaging findings in pulmonary nocardiosis are different, including lung nodules, lung masses (with or without cavitation), reticulonodular infiltrates, interstitial infiltrates, lobar consolidation, subpleural plaques, and pleural effusions [10]. Our patient’s CT thorax showed irregular airspace opacities in the left upper lobe.
TMP-SMX is considered first-line therapy for nocardiosis. However, some Nocardia species are resistant to TMP-SMX, including N. farcinica, while Nocardia asteroides and Nocardia nova remain sensitive primarily to TMP-SMX, with susceptibility rates of >95% and 89%, respectively [11,12]. Moreover, there is no consensus for the role of TMP-SMX as prophylaxis for Nocardia. Although one study proposed that TMP-SMX prophylaxis is effective in heart transplant recipients, nocardiosis has been documented in one-third of the renal transplant recipients who received TMP-SMX as Pneumocystis carinii prophylaxis [13]. Deaths related to Nocardia infection in transplant recipients have been rare. In one study, the nocardial infection has been neither found to be associated with mortality nor overall survival. Also, in the same study, early diagnosis suggests a favorable therapeutic outcome [14].
Conclusions
Overall, disseminated nocardiosis with systemic involvement carries a grave prognosis. However, early diagnosis of the case, with proper antibiotic coverage, leads to a favorable outcome, even in a post-renal transplant patient.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained by all participants in this study | UNK; HIGH DOSE | DrugDosageText | CC BY | 33564506 | 18,949,258 | 2021-01-05 |
What was the outcome of reaction 'Cutaneous nocardiosis'? | Disseminated Nocardiosis in a Renal Transplant Recipient.
Nocardiosis is an uncommon opportunistic Gram-positive bacterial infection caused by aerobic actinomycetes in the genus Nocardia. Nocardia can cause localized or systemic suppurative diseases involving eyes, kidneys, skin, lungs, bone, and central nervous system. Disseminated nocardiosis is a rare condition, seen among immunocompromised patients. We report the case of a 55-year-old African American, kidney transplant male recipient on maintenance immunosuppression, who was diagnosed with cutaneous and pulmonary nocardiosis. Presenting symptoms were shortness of breath, and bilateral lower extremities pain and swelling. Tissue culture grew Gram-positive bacilli specified as Nocardia farcinica from thigh and gluteal abscesses. CT thorax showed bilateral reticulonodular opacities. The patient was managed with immunosuppression reduction and specific treatment with high-dose trimethoprim-sulfamethoxazole (TMP-SMX) in conjunction with linezolid. Combination antibiotics were continued for four weeks, and thereafter, TMP-SMX alone was continued for 12 months, at which point all lesions had healed. Nocardiosis with systemic involvement carries a poor prognosis. However, early diagnosis and appropriate antibiotic coverage had a favorable outcome in a renal transplant recipient. Recommended treatment duration is 6 to 12 months.
Introduction
Nocardiosis is an uncommon opportunistic Gram-positive bacterial infection caused by aerobic actinomycetes in the genus Nocardia. It can cause localized or systemic suppurative diseases in humans, involving eyes, kidneys, skin, pulmonary, brain as well as disseminated infection. Inhalation of the organism is the most common mode of entry; that is why the majority of infections involve lungs. Herein, we report a case of a renal transplant recipient who presented with disseminated nocardiosis with pulmonary and cutaneous involvement and was successfully treated with combined antibiotic therapy and surgical drainage.
Case presentation
We report the case of a 55-year-old male with a past medical history of end-stage kidney disease secondary to medical renal disease of hypertension. After a dialysis vintage of six years, he received a deceased donor renal transplant in 2018. Post-transplant, his allograft function remained stable with a baseline serum creatinine level at 1.6-1.8 mg/dL. After induction with basiliximab, the patient was maintained on triple immunosuppressive therapy consisting of mycophenolic acid 720 mg twice daily per oral (PO), tacrolimus 2 mg twice daily PO, and prednisone 5 mg daily PO.
Six months following the renal transplant, the patient presented to the hospital with a chief complaint of progressive bilateral lower extremities pain with swelling, which started 10 days before presentation. Associated symptoms included shortness of breath. Workup included an ultrasound of the right lower leg, which showed a heterogeneous mass in the right posterior thigh; nevertheless, the patient received hydrocodone/acetaminophen and was instructed to follow up with his primary care physician in a week. However, one week later, the patient presented again due to the worsening of symptoms; physical exam revealed a palpable, fluctuant, and tender fullness involving the left gluteal and the right posterior thigh region with associated left knee swelling.
Laboratory workup revealed the following: C-reactive protein 149 mg/L, creatinine 1.65 mg/dL (baseline creatinine 1.6-1.8 mg/dL), and white blood cell count 9,500/mm3. CT pelvis and bilateral lower extremities without contrast showed a 3.5-cm fluid collection in the right posterior thigh and the left buttock (Figure 1). Chest CT showed multi-focal irregular airspace opacities with new scattered sub-centimeter pulmonary nodules (Figure 2). The two-dimensional echo was negative for valve vegetations. MRI brain was negative for masses or abscesses; blood cultures were negative and tissue culture grew Gram-positive bacilli identified as Nocardia farcinica. The patient underwent incision and drainage of the thigh and gluteal abscesses with the placement of Penrose drain and surgical site cultures obtained. Tacrolimus and myfortic acid were held for two weeks due to the presumed infectious process; prednisone 20 mg daily PO was initiated along with high-dose trimethoprim-sulfamethoxazole (TMP-SMX) in conjunction with linezolid. The patient’s condition subsequently improved and he was discharged on oral linezolid and TMP-SMX. He was treated with the combination for four weeks, and then continued with TMP-SMX alone for a total of 12 months at which point all lesions had resolved without allograft dysfunction.
Figure 1 CT pelvis and bilateral lower extremities without contrast showed a 3.5-cm fluid collection (arrow) in the right posterior thigh
Figure 2 CT thorax showing pulmonary nodule (arrow)
Discussion
Renal transplant patients are at an increased risk of certain infections, particularly following the initiation of immunosuppressive drugs after the transplant [1]. Nocardia infection is commonly seen among patients with T-cell and macrophage function disorders, such as patients who are taking immunosuppressive agents [2]. The risk of nocardiosis is increased in the first year following renal transplantation, presumably due to using immunosuppression to prevent rejection [3]. Patients treated with steroid-sparing regimens, such as cyclosporine, have found significantly reduced rates of nocardial infections, to 0.7%, in renal transplant recipients [4]. The patient was diagnosed with nocardiosis six months following the renal transplant.
Nocardia species are not ordinarily seen in the respiratory tract, yet pulmonary involvement is the primary site of nocardial infection in more than two-thirds of cases [3,5]. Therefore, a sputum culture is mostly indicative of Nocardia infection. Rarely, respiratory nocardial isolate has been considered a non-pathogen (i.e., colonizer) [6]. Most pulmonary infections are primary, but Nocardia can spread to the lung from other sites, such as the skin [7]. On the other hand, cutaneous lesions are reported in kidney transplant recipients with a Nocardia infection [2]. Manifestations of primary cutaneous nocardiosis include ulcerations, pyoderma, cellulitis, nodules, and subcutaneous abscesses [8,9]. The reported patient had disseminated nocardiosis involving lungs and skin, though lungs were thought to be the primary source of infection. Also, imaging findings in pulmonary nocardiosis are different, including lung nodules, lung masses (with or without cavitation), reticulonodular infiltrates, interstitial infiltrates, lobar consolidation, subpleural plaques, and pleural effusions [10]. Our patient’s CT thorax showed irregular airspace opacities in the left upper lobe.
TMP-SMX is considered first-line therapy for nocardiosis. However, some Nocardia species are resistant to TMP-SMX, including N. farcinica, while Nocardia asteroides and Nocardia nova remain sensitive primarily to TMP-SMX, with susceptibility rates of >95% and 89%, respectively [11,12]. Moreover, there is no consensus for the role of TMP-SMX as prophylaxis for Nocardia. Although one study proposed that TMP-SMX prophylaxis is effective in heart transplant recipients, nocardiosis has been documented in one-third of the renal transplant recipients who received TMP-SMX as Pneumocystis carinii prophylaxis [13]. Deaths related to Nocardia infection in transplant recipients have been rare. In one study, the nocardial infection has been neither found to be associated with mortality nor overall survival. Also, in the same study, early diagnosis suggests a favorable therapeutic outcome [14].
Conclusions
Overall, disseminated nocardiosis with systemic involvement carries a grave prognosis. However, early diagnosis of the case, with proper antibiotic coverage, leads to a favorable outcome, even in a post-renal transplant patient.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained by all participants in this study | Recovered | ReactionOutcome | CC BY | 33564506 | 18,949,258 | 2021-01-05 |
What was the outcome of reaction 'Pulmonary nocardiosis'? | Disseminated Nocardiosis in a Renal Transplant Recipient.
Nocardiosis is an uncommon opportunistic Gram-positive bacterial infection caused by aerobic actinomycetes in the genus Nocardia. Nocardia can cause localized or systemic suppurative diseases involving eyes, kidneys, skin, lungs, bone, and central nervous system. Disseminated nocardiosis is a rare condition, seen among immunocompromised patients. We report the case of a 55-year-old African American, kidney transplant male recipient on maintenance immunosuppression, who was diagnosed with cutaneous and pulmonary nocardiosis. Presenting symptoms were shortness of breath, and bilateral lower extremities pain and swelling. Tissue culture grew Gram-positive bacilli specified as Nocardia farcinica from thigh and gluteal abscesses. CT thorax showed bilateral reticulonodular opacities. The patient was managed with immunosuppression reduction and specific treatment with high-dose trimethoprim-sulfamethoxazole (TMP-SMX) in conjunction with linezolid. Combination antibiotics were continued for four weeks, and thereafter, TMP-SMX alone was continued for 12 months, at which point all lesions had healed. Nocardiosis with systemic involvement carries a poor prognosis. However, early diagnosis and appropriate antibiotic coverage had a favorable outcome in a renal transplant recipient. Recommended treatment duration is 6 to 12 months.
Introduction
Nocardiosis is an uncommon opportunistic Gram-positive bacterial infection caused by aerobic actinomycetes in the genus Nocardia. It can cause localized or systemic suppurative diseases in humans, involving eyes, kidneys, skin, pulmonary, brain as well as disseminated infection. Inhalation of the organism is the most common mode of entry; that is why the majority of infections involve lungs. Herein, we report a case of a renal transplant recipient who presented with disseminated nocardiosis with pulmonary and cutaneous involvement and was successfully treated with combined antibiotic therapy and surgical drainage.
Case presentation
We report the case of a 55-year-old male with a past medical history of end-stage kidney disease secondary to medical renal disease of hypertension. After a dialysis vintage of six years, he received a deceased donor renal transplant in 2018. Post-transplant, his allograft function remained stable with a baseline serum creatinine level at 1.6-1.8 mg/dL. After induction with basiliximab, the patient was maintained on triple immunosuppressive therapy consisting of mycophenolic acid 720 mg twice daily per oral (PO), tacrolimus 2 mg twice daily PO, and prednisone 5 mg daily PO.
Six months following the renal transplant, the patient presented to the hospital with a chief complaint of progressive bilateral lower extremities pain with swelling, which started 10 days before presentation. Associated symptoms included shortness of breath. Workup included an ultrasound of the right lower leg, which showed a heterogeneous mass in the right posterior thigh; nevertheless, the patient received hydrocodone/acetaminophen and was instructed to follow up with his primary care physician in a week. However, one week later, the patient presented again due to the worsening of symptoms; physical exam revealed a palpable, fluctuant, and tender fullness involving the left gluteal and the right posterior thigh region with associated left knee swelling.
Laboratory workup revealed the following: C-reactive protein 149 mg/L, creatinine 1.65 mg/dL (baseline creatinine 1.6-1.8 mg/dL), and white blood cell count 9,500/mm3. CT pelvis and bilateral lower extremities without contrast showed a 3.5-cm fluid collection in the right posterior thigh and the left buttock (Figure 1). Chest CT showed multi-focal irregular airspace opacities with new scattered sub-centimeter pulmonary nodules (Figure 2). The two-dimensional echo was negative for valve vegetations. MRI brain was negative for masses or abscesses; blood cultures were negative and tissue culture grew Gram-positive bacilli identified as Nocardia farcinica. The patient underwent incision and drainage of the thigh and gluteal abscesses with the placement of Penrose drain and surgical site cultures obtained. Tacrolimus and myfortic acid were held for two weeks due to the presumed infectious process; prednisone 20 mg daily PO was initiated along with high-dose trimethoprim-sulfamethoxazole (TMP-SMX) in conjunction with linezolid. The patient’s condition subsequently improved and he was discharged on oral linezolid and TMP-SMX. He was treated with the combination for four weeks, and then continued with TMP-SMX alone for a total of 12 months at which point all lesions had resolved without allograft dysfunction.
Figure 1 CT pelvis and bilateral lower extremities without contrast showed a 3.5-cm fluid collection (arrow) in the right posterior thigh
Figure 2 CT thorax showing pulmonary nodule (arrow)
Discussion
Renal transplant patients are at an increased risk of certain infections, particularly following the initiation of immunosuppressive drugs after the transplant [1]. Nocardia infection is commonly seen among patients with T-cell and macrophage function disorders, such as patients who are taking immunosuppressive agents [2]. The risk of nocardiosis is increased in the first year following renal transplantation, presumably due to using immunosuppression to prevent rejection [3]. Patients treated with steroid-sparing regimens, such as cyclosporine, have found significantly reduced rates of nocardial infections, to 0.7%, in renal transplant recipients [4]. The patient was diagnosed with nocardiosis six months following the renal transplant.
Nocardia species are not ordinarily seen in the respiratory tract, yet pulmonary involvement is the primary site of nocardial infection in more than two-thirds of cases [3,5]. Therefore, a sputum culture is mostly indicative of Nocardia infection. Rarely, respiratory nocardial isolate has been considered a non-pathogen (i.e., colonizer) [6]. Most pulmonary infections are primary, but Nocardia can spread to the lung from other sites, such as the skin [7]. On the other hand, cutaneous lesions are reported in kidney transplant recipients with a Nocardia infection [2]. Manifestations of primary cutaneous nocardiosis include ulcerations, pyoderma, cellulitis, nodules, and subcutaneous abscesses [8,9]. The reported patient had disseminated nocardiosis involving lungs and skin, though lungs were thought to be the primary source of infection. Also, imaging findings in pulmonary nocardiosis are different, including lung nodules, lung masses (with or without cavitation), reticulonodular infiltrates, interstitial infiltrates, lobar consolidation, subpleural plaques, and pleural effusions [10]. Our patient’s CT thorax showed irregular airspace opacities in the left upper lobe.
TMP-SMX is considered first-line therapy for nocardiosis. However, some Nocardia species are resistant to TMP-SMX, including N. farcinica, while Nocardia asteroides and Nocardia nova remain sensitive primarily to TMP-SMX, with susceptibility rates of >95% and 89%, respectively [11,12]. Moreover, there is no consensus for the role of TMP-SMX as prophylaxis for Nocardia. Although one study proposed that TMP-SMX prophylaxis is effective in heart transplant recipients, nocardiosis has been documented in one-third of the renal transplant recipients who received TMP-SMX as Pneumocystis carinii prophylaxis [13]. Deaths related to Nocardia infection in transplant recipients have been rare. In one study, the nocardial infection has been neither found to be associated with mortality nor overall survival. Also, in the same study, early diagnosis suggests a favorable therapeutic outcome [14].
Conclusions
Overall, disseminated nocardiosis with systemic involvement carries a grave prognosis. However, early diagnosis of the case, with proper antibiotic coverage, leads to a favorable outcome, even in a post-renal transplant patient.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained by all participants in this study | Recovered | ReactionOutcome | CC BY | 33564506 | 18,949,258 | 2021-01-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Thrombocytopenia'. | Atorvastatin-Induced Refractory Thrombocytopenia.
Drug-induced thrombocytopenia is rarely associated with statin medications. We describe the case of a 69-year-old woman who developed refractory thrombocytopenia following atorvastatin use. To our knowledge, this is the fourth reported case of atorvastatin-induced thrombocytopenia and the first reported case of atorvastatin-induced refractory thrombocytopenia. Additionally, we summarize the cases of statin-induced thrombocytopenia reported in the medical literature.
Introduction
Atorvastatin is used to treat dyslipidemia and the prevention of cardiovascular and cerebrovascular diseases, particularly in people who are unable to meet their lipid-lowering goals through lifestyle modifications [1-3]. It inhibits 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, a key enzyme in cholesterol synthesis. The most common adverse effects of statins are dyspepsia, constipation, abdominal pain, flatulence, headache, and myalgia [4]. Myopathy, rhabdomyolysis, and liver enzyme abnormalities are rare, but major side effects seen with statin use [5,6]. A few case reports of statin-induced thrombocytopenia, specifically with atorvastatin, rosuvastatin, and simvastatin [7-15].
Thrombocytopenia can be either inherited or acquired. Acquired causes include drug-induced thrombocytopenia (DIT), viral or bacterial infections, malignancy, liver failure, and hypersplenism. Several mechanisms are proposed for DIT, but the most recent hypothesis suggests that weakly reactive platelet autoantibodies develop an increased affinity for platelet glycoprotein epitopes in the presence of the sensitizing drug [16]. Patients present with epistaxis, bruising, and petechiae [16]. In this case report, we present a probable temporal relationship between atorvastatin initiation and the onset of refractory thrombocytopenia.
Case presentation
A 69-year-old female with a history of hyperlipidemia presented to the hospital with atraumatic bruising, traumatic right knee hematoma, and multiple painless "blood blisters" on her buccal mucosa which she noticed one day prior. Her history was negative for bleeding disorders, anticoagulant use, and antiplatelet use. She started taking atorvastatin 20 mg daily about 10 weeks before presenting for hyperlipidemia. The patient's baseline low-density lipoprotein was between 125 and 146 mg/dL (reference range: < 100 mg/dL) and high-density lipoprotein was between 66 and 72 mg/dL (reference range: > 40 mg/dL). The patient was found to have profound thrombocytopenia on this admission with a platelet count of 2,000 / μL (reference range: 164,000-446,000/μL), and her other cell lines were within normal limits. Complete blood count from two months prior demonstrated a platelet count of 245,000 / μL. The patient was admitted for further workup.
Our patient's coagulation studies, infectious panel, and autoimmune panel (anti-nuclear antibodies, rheumatoid factor, serum immunofixation test, serum protein electrophoresis including alpha and gamma globulins) were unremarkable. She received an infusion of two units of platelets with minimal increase in her platelet count. Suspecting immune-thrombocytopenic purpura (ITP), we subsequently treated her with two doses of intravenous immunoglobulin (IVIG) over two days and oral dexamethasone 40mg for four days. Her platelet counts improved to 55,000/μL, and she was discharged home with close follow-up. She continued taking atorvastatin 20mg.
Two days after discharge, the patient returned to the hospital, presenting with worsening fatigue and purpura. She was found to have a platelet count of 1,000 / μL and was readmitted. We discontinued her atorvastatin and started her on a regimen of IVIG for two days and prednisone 80mg for five days. Although she responded to this regimen, we added rituximab given our high suspicion for refractory thrombocytopenia, indicated by the lack of response to two or more treatments. Our patient's platelet count improved to 118,000 / μL, and she was discharged home in stable condition with instructions to complete seven days of 60 mg of prednisone and weekly doses of rituximab. The patient was not restarted on atorvastatin or any other statin. At follow-up five months after her hospital discharge and after completing four doses of rituximab, our patient's platelet count returned to baseline, and her purpura had resolved. A timeline of the variations in our patient's platelet count is illustrated in Figure 1. She currently manages her hyperlipidemia with diet and exercise.
Figure 1 Temporal variations in platelet count after initiation of atorvastatin and response to interventions.
IVIG- Intravenous mmunoglobulin
Discussion
DIT presents with rapid symptomatic improvement following the discontinuation of the drug [16]. DIT has been associated with over 100 different mediations [16]. Two major pathologic mechanisms behind drug-induced thrombocytopenia include decreased platelet production via marrow suppression and peripheral platelet clearance [10]. Patients are exposed to the implicated medication for at least a week before developing clinical signs of thrombocytopenia [16]. DIT is suggested by rapid recovery following discontinuation of the implicated medication and the temporal relationship between symptom onset and medication exposure [7]. It is common practice to discontinue the medication and treat with steroid, and IVIG and plasma exchange may be considered for refractory cases [16]. Our patient's case was considered to be refractory given that she failed two or more treatments (steroids and IVIG), and the hematology-oncology consultant on the case agreed with this determination. We recognize that ITP may present similarly and that the resolution of our patient's thrombocytopenia may be attributed to rituximab initiation, rather than atorvastatin discontinuation alone [17].
The Naranjo Algorithm is a validated standardized questionnaire of 10 question items designed to estimate the probability of a drug causing an adverse clinical event. Scores greater than 8 are considered a definite reaction, 5 to 8 considered probable, 1 to 4 considered possible, and less than 1 considered doubtful [18,19]. Our patient’s Naranjo algorithm score of 8 (Table 1) suggests a probable association between initiation of atorvastatin and the onset of thrombocytopenia in this case.
Table 1 The Naranjo Scale for assessing the association between atorvastatin use and the adverse drug reaction (ADR) of thrombocytopenia. Our patient had a probable ADR given a score of “8”. The reaction followed a reasonable temporal sequence after a drug, followed a recognized response to the suspected drug, was confirmed by withdrawal but not by exposure to the drug, and could not be reasonably explained by the known characteristics of the patient’s clinical state [16].
Naranjo Question Item Response Score
1. Are there previous conclusive reports on this reaction? Yes 1
2. Did the adverse event appear after the suspected drug was given? Yes 2
3. Did the adverse reaction improve when the drug was discontinued, or a specific antagonist was given? Yes 1
4. Did the adverse reaction appear when the drug was re-administered? Yes 2
5. Are there alternative causes that could have caused the reaction? No 2
6. Did the reaction reappear when a placebo was given? N/A 0
7. Was the drug detected in any body fluid in toxic concentrations? N/A 0
8. Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? N/A 0
9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? N/A 0
10. Was the adverse event confirmed by any objective evidence? No 0
Score 8
Lovastatin has been found to dose-dependently induce platelet apoptosis via mitochondrial caspase activation. In mouse models, lovastatin impairs platelet function and reduces circulating platelets in vivo, suggesting the possible pathogenesis of thrombocytopenia and hemorrhage in patients treated with statins [20]. Given these findings, it is interesting that lovastatin-induced thrombocytopenia has not yet been reported in the literature.
The reported cases of statin-induced thrombocytopenia are summarized in Table 2. It is difficult to draw conclusions from a small set of case reports; however, statin-induced thrombocytopenia has been associated with atorvastatin, rosuvastatin, and simvastatin in the literature, two of which are lipophilic molecules. Additionally, the lipophilic statin lovastatin has been demonstrated to cause platelet apoptosis in vivo. Atorvastatin-induced thrombocytopenia has been reported three times in the literature, however, our case reports a refractory presentation [9].
Table 2 Table summarizing reported cases of statin-induced thrombocytopenia in the literature.
IVIG- Intravenous immunoglobulin; M- male; F- Female
Case Drug Dose Age / Gender Length of statin treatment Clinical Symptoms Lowest platelet count (/μL) Treatment regimen Time to resolution Alternate hyperlipidemia treatment Tolerated another statin?
Present case Atorvastatin 20mg 69/F 2.5 months Diffuse petechial rash, purpura, oral mucosal bleeding, traumatic knee hematoma 1,000 Platelet transfusion, steroids, IVIG, rituximab 5 months Lifestyle modification No
Moitra et al (2016) [9] Atorvastatin 10mg 65/M 6 days Diffuse petechial rash, gingival bleeding 15,000 Platelet transfusion, steroids, IVIG 10 days Lifestyle modification No
Cvetković et al (2013) [15] Simvastatin 20mg 78/F 1 day Generalized urticaria (immediate hypersensitivity reaction) 85,000 Steroids 12 days Unspecified No
Narayanan et al (2010) [7] Atorvastatin 20mg 44/M 6 months Diffuse petechial rash, gingival bleeding 4,000 Steroids Unspecified Rosuvastatin Yes, rosuvastatin
Vrettos et al (2009) [10] Rosuvastatin Unspecified 65/F 1 year None 31,000 None (statin discontinuation only) 6 months Unspecified No / unknown
Ames et al (2008) [11] Simvastatin 10mg 63/M 2 months None 122,000 None (statin discontinuation only) 1 month Unspecified No / unknown
Groneberg et al (2001) [12] Simvastatin 10mg 77/F 11 months Epistaxis, easy bruising 12,000 None (statin discontinuation only) 3 weeks Unspecified No / unknown
González-Ponte et al (1998) [8] Atorvastatin 10mg 46/M 2 months Widespread purpura 3,000 Platelet transfusion, steroids, IVIG 1 month Unspecified Yes, simvastatin
Yamada et al (1998) [13] Simvastatin 5mg 75/F 3 years Multiple purpura of extremities and trunk 2,000 Platelet transfusion, steroids 2 months Unspecified No / unknown
Possamai et al (1992) [14] Simvastatin 10mg 64/F 1 year Epistaxis, gingival bleeding, diffuse petechiae of trunk and limbs 3,000 Platelet transfusion, steroids, IVIG 3 weeks Lifestyle modification No
Conclusions
To our knowledge, this is the fourth reported case of atorvastatin-induced thrombocytopenia and the first reported case of atorvastatin-induced refractory thrombocytopenia. Clinicians need to be aware of this association and discontinue atorvastatin if thrombocytopenia develops. Future investigations into the relationship between statin medications and thrombocytopenia would prove useful to the medical literature.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained by all participants in this study | ATORVASTATIN CALCIUM | DrugsGivenReaction | CC BY | 33564510 | 18,918,919 | 2021-01-05 |
What was the outcome of reaction 'Thrombocytopenia'? | Atorvastatin-Induced Refractory Thrombocytopenia.
Drug-induced thrombocytopenia is rarely associated with statin medications. We describe the case of a 69-year-old woman who developed refractory thrombocytopenia following atorvastatin use. To our knowledge, this is the fourth reported case of atorvastatin-induced thrombocytopenia and the first reported case of atorvastatin-induced refractory thrombocytopenia. Additionally, we summarize the cases of statin-induced thrombocytopenia reported in the medical literature.
Introduction
Atorvastatin is used to treat dyslipidemia and the prevention of cardiovascular and cerebrovascular diseases, particularly in people who are unable to meet their lipid-lowering goals through lifestyle modifications [1-3]. It inhibits 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, a key enzyme in cholesterol synthesis. The most common adverse effects of statins are dyspepsia, constipation, abdominal pain, flatulence, headache, and myalgia [4]. Myopathy, rhabdomyolysis, and liver enzyme abnormalities are rare, but major side effects seen with statin use [5,6]. A few case reports of statin-induced thrombocytopenia, specifically with atorvastatin, rosuvastatin, and simvastatin [7-15].
Thrombocytopenia can be either inherited or acquired. Acquired causes include drug-induced thrombocytopenia (DIT), viral or bacterial infections, malignancy, liver failure, and hypersplenism. Several mechanisms are proposed for DIT, but the most recent hypothesis suggests that weakly reactive platelet autoantibodies develop an increased affinity for platelet glycoprotein epitopes in the presence of the sensitizing drug [16]. Patients present with epistaxis, bruising, and petechiae [16]. In this case report, we present a probable temporal relationship between atorvastatin initiation and the onset of refractory thrombocytopenia.
Case presentation
A 69-year-old female with a history of hyperlipidemia presented to the hospital with atraumatic bruising, traumatic right knee hematoma, and multiple painless "blood blisters" on her buccal mucosa which she noticed one day prior. Her history was negative for bleeding disorders, anticoagulant use, and antiplatelet use. She started taking atorvastatin 20 mg daily about 10 weeks before presenting for hyperlipidemia. The patient's baseline low-density lipoprotein was between 125 and 146 mg/dL (reference range: < 100 mg/dL) and high-density lipoprotein was between 66 and 72 mg/dL (reference range: > 40 mg/dL). The patient was found to have profound thrombocytopenia on this admission with a platelet count of 2,000 / μL (reference range: 164,000-446,000/μL), and her other cell lines were within normal limits. Complete blood count from two months prior demonstrated a platelet count of 245,000 / μL. The patient was admitted for further workup.
Our patient's coagulation studies, infectious panel, and autoimmune panel (anti-nuclear antibodies, rheumatoid factor, serum immunofixation test, serum protein electrophoresis including alpha and gamma globulins) were unremarkable. She received an infusion of two units of platelets with minimal increase in her platelet count. Suspecting immune-thrombocytopenic purpura (ITP), we subsequently treated her with two doses of intravenous immunoglobulin (IVIG) over two days and oral dexamethasone 40mg for four days. Her platelet counts improved to 55,000/μL, and she was discharged home with close follow-up. She continued taking atorvastatin 20mg.
Two days after discharge, the patient returned to the hospital, presenting with worsening fatigue and purpura. She was found to have a platelet count of 1,000 / μL and was readmitted. We discontinued her atorvastatin and started her on a regimen of IVIG for two days and prednisone 80mg for five days. Although she responded to this regimen, we added rituximab given our high suspicion for refractory thrombocytopenia, indicated by the lack of response to two or more treatments. Our patient's platelet count improved to 118,000 / μL, and she was discharged home in stable condition with instructions to complete seven days of 60 mg of prednisone and weekly doses of rituximab. The patient was not restarted on atorvastatin or any other statin. At follow-up five months after her hospital discharge and after completing four doses of rituximab, our patient's platelet count returned to baseline, and her purpura had resolved. A timeline of the variations in our patient's platelet count is illustrated in Figure 1. She currently manages her hyperlipidemia with diet and exercise.
Figure 1 Temporal variations in platelet count after initiation of atorvastatin and response to interventions.
IVIG- Intravenous mmunoglobulin
Discussion
DIT presents with rapid symptomatic improvement following the discontinuation of the drug [16]. DIT has been associated with over 100 different mediations [16]. Two major pathologic mechanisms behind drug-induced thrombocytopenia include decreased platelet production via marrow suppression and peripheral platelet clearance [10]. Patients are exposed to the implicated medication for at least a week before developing clinical signs of thrombocytopenia [16]. DIT is suggested by rapid recovery following discontinuation of the implicated medication and the temporal relationship between symptom onset and medication exposure [7]. It is common practice to discontinue the medication and treat with steroid, and IVIG and plasma exchange may be considered for refractory cases [16]. Our patient's case was considered to be refractory given that she failed two or more treatments (steroids and IVIG), and the hematology-oncology consultant on the case agreed with this determination. We recognize that ITP may present similarly and that the resolution of our patient's thrombocytopenia may be attributed to rituximab initiation, rather than atorvastatin discontinuation alone [17].
The Naranjo Algorithm is a validated standardized questionnaire of 10 question items designed to estimate the probability of a drug causing an adverse clinical event. Scores greater than 8 are considered a definite reaction, 5 to 8 considered probable, 1 to 4 considered possible, and less than 1 considered doubtful [18,19]. Our patient’s Naranjo algorithm score of 8 (Table 1) suggests a probable association between initiation of atorvastatin and the onset of thrombocytopenia in this case.
Table 1 The Naranjo Scale for assessing the association between atorvastatin use and the adverse drug reaction (ADR) of thrombocytopenia. Our patient had a probable ADR given a score of “8”. The reaction followed a reasonable temporal sequence after a drug, followed a recognized response to the suspected drug, was confirmed by withdrawal but not by exposure to the drug, and could not be reasonably explained by the known characteristics of the patient’s clinical state [16].
Naranjo Question Item Response Score
1. Are there previous conclusive reports on this reaction? Yes 1
2. Did the adverse event appear after the suspected drug was given? Yes 2
3. Did the adverse reaction improve when the drug was discontinued, or a specific antagonist was given? Yes 1
4. Did the adverse reaction appear when the drug was re-administered? Yes 2
5. Are there alternative causes that could have caused the reaction? No 2
6. Did the reaction reappear when a placebo was given? N/A 0
7. Was the drug detected in any body fluid in toxic concentrations? N/A 0
8. Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? N/A 0
9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? N/A 0
10. Was the adverse event confirmed by any objective evidence? No 0
Score 8
Lovastatin has been found to dose-dependently induce platelet apoptosis via mitochondrial caspase activation. In mouse models, lovastatin impairs platelet function and reduces circulating platelets in vivo, suggesting the possible pathogenesis of thrombocytopenia and hemorrhage in patients treated with statins [20]. Given these findings, it is interesting that lovastatin-induced thrombocytopenia has not yet been reported in the literature.
The reported cases of statin-induced thrombocytopenia are summarized in Table 2. It is difficult to draw conclusions from a small set of case reports; however, statin-induced thrombocytopenia has been associated with atorvastatin, rosuvastatin, and simvastatin in the literature, two of which are lipophilic molecules. Additionally, the lipophilic statin lovastatin has been demonstrated to cause platelet apoptosis in vivo. Atorvastatin-induced thrombocytopenia has been reported three times in the literature, however, our case reports a refractory presentation [9].
Table 2 Table summarizing reported cases of statin-induced thrombocytopenia in the literature.
IVIG- Intravenous immunoglobulin; M- male; F- Female
Case Drug Dose Age / Gender Length of statin treatment Clinical Symptoms Lowest platelet count (/μL) Treatment regimen Time to resolution Alternate hyperlipidemia treatment Tolerated another statin?
Present case Atorvastatin 20mg 69/F 2.5 months Diffuse petechial rash, purpura, oral mucosal bleeding, traumatic knee hematoma 1,000 Platelet transfusion, steroids, IVIG, rituximab 5 months Lifestyle modification No
Moitra et al (2016) [9] Atorvastatin 10mg 65/M 6 days Diffuse petechial rash, gingival bleeding 15,000 Platelet transfusion, steroids, IVIG 10 days Lifestyle modification No
Cvetković et al (2013) [15] Simvastatin 20mg 78/F 1 day Generalized urticaria (immediate hypersensitivity reaction) 85,000 Steroids 12 days Unspecified No
Narayanan et al (2010) [7] Atorvastatin 20mg 44/M 6 months Diffuse petechial rash, gingival bleeding 4,000 Steroids Unspecified Rosuvastatin Yes, rosuvastatin
Vrettos et al (2009) [10] Rosuvastatin Unspecified 65/F 1 year None 31,000 None (statin discontinuation only) 6 months Unspecified No / unknown
Ames et al (2008) [11] Simvastatin 10mg 63/M 2 months None 122,000 None (statin discontinuation only) 1 month Unspecified No / unknown
Groneberg et al (2001) [12] Simvastatin 10mg 77/F 11 months Epistaxis, easy bruising 12,000 None (statin discontinuation only) 3 weeks Unspecified No / unknown
González-Ponte et al (1998) [8] Atorvastatin 10mg 46/M 2 months Widespread purpura 3,000 Platelet transfusion, steroids, IVIG 1 month Unspecified Yes, simvastatin
Yamada et al (1998) [13] Simvastatin 5mg 75/F 3 years Multiple purpura of extremities and trunk 2,000 Platelet transfusion, steroids 2 months Unspecified No / unknown
Possamai et al (1992) [14] Simvastatin 10mg 64/F 1 year Epistaxis, gingival bleeding, diffuse petechiae of trunk and limbs 3,000 Platelet transfusion, steroids, IVIG 3 weeks Lifestyle modification No
Conclusions
To our knowledge, this is the fourth reported case of atorvastatin-induced thrombocytopenia and the first reported case of atorvastatin-induced refractory thrombocytopenia. Clinicians need to be aware of this association and discontinue atorvastatin if thrombocytopenia develops. Future investigations into the relationship between statin medications and thrombocytopenia would prove useful to the medical literature.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained by all participants in this study | Recovered | ReactionOutcome | CC BY | 33564510 | 18,918,919 | 2021-01-05 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Aspiration'. | Clinical and Radiological Dissociation in Massive Barium Aspiration.
Barium studies are commonly used to rule out gastrointestinal (GI) pathologies and sometimes they are associated with complications such as barium aspiration with heterogeneity in clinical features ranging from mild to severe symptoms. We present a case of large volume barium aspiration in a 73-year-old male with past medical history of dysphagia diagnosed with diffuse esophageal spasm. Barium is an inert material commonly used for GI tract study. Although complications associated with barium studies are rare, aspiration of barium can have dramatic findings resulting in mild to severe symptoms. Clinically patient had very minimal symptoms but radiographic studies appeared dramatic. Therefore, a clinical and radiographic paradox must be kept in mind when evaluating patients and reviewing large volume barium aspiration imaging. Our case remained asymptomatic and had no respiratory complaints, nor did he develop any respiratory distress post barium aspiration.
Introduction
Barium is an inert material commonly used for gastrointestinal (GI) tract study. We present a case of large volume barium aspiration in a 73-year-old male with past medical history of dysphagia diagnosed with diffuse esophageal spasm. Although complications associated with barium studies are rare, aspiration of barium can have dramatic findings resulting in mild to severe symptoms. Clinically patient had very minimal symptoms but radiographic studies appeared dramatic.
Case presentation
A 73-year-old male presented to emergency department due to presyncope with an episode of loss of consciousness for three minutes. He also complained of productive cough with whitish sputum. Vital signs were normal and physical examination was benign. Chest X-ray (CXR) showed evidence of consolidation, which was followed by a computed tomography (CT) chest that revealed a dilated esophagus (Figure 1). Barium swallow was done for optimal evaluation of dilated esophagus (Figure 2). Post-procedure CXR revealed interval development of complete opacification of left hemithorax and retained barium in the left upper chest (Figure 3). CT chest was followed, which revealed retained barium within the upper to the mid-thoracic esophagus. Complete left lung atelectasis was noted, likely related to the obstructing filling defect within the left main bronchus (Figure 4). Subsequently, the CXR showed persistently retained contrast within the esophagus and improved left lobar airspace disease with moderate to large pleural effusion (Figure 5). However, bedside sonogram showed predominantly consolidation. The patient had no symptoms and was clinically stable to be discharged. He was advised to follow up as an outpatient at the chest clinic in six weeks.
Figure 1 CT chest without contrast revealed fluid-filled dilated esophagus, which was suboptimally evaluated due to lack of contrast. The patient also had left lower lobe consolidation consistent with pneumonia.
Figure 2 A barium study was done, which revealed diffuse esophageal spasm and akinesis of the mid-thoracic esophagus.
Figure 3 Chest X-ray revealed interval development of complete opacification of left hemithorax and retained barium in the left upper chest.
Figure 4 CT chest revealed retained barium within the upper to the mid-thoracic esophagus. Complete left lung atelectasis was noted, likely related to the obstructing filling defect within the left main bronchus.
Figure 5 Subsequently, a chest x-ray showed persistently retained contrast within the esophagus and improved left lobar airspace disease with moderate to large pleural effusion.
Discussion
Barium studies are regularly performed to rule out GI lumen pathologies. Despite the risk of barium aspiration, which is present, the complications are rare [1,2]. We present a case of large volume barium aspiration which was clinically asymptomatic with dramatic radiographic findings. In most cases, patients remain largely asymptomatic despite the paradoxical radiographic findings [3]. However, mechanical obstruction leading to atelectasis as well as uncommon acute inflammatory reactions have been reported [3-5].
There are few articles published reporting mild cases of large volume barium aspiration [1]. Most patients do not develop severe symptoms as seen on the imaging, which is alarming. Our case remained asymptomatic and neither had any respiratory complaints nor did he develop any respiratory distress post barium aspiration. CT chest revealed complete left lung atelectasis, which subsequently improved within days, revealing moderate pleural effusion. Although there was a pleural effusion on the CXR, a bedside sonogram of the lung revealed a predominant consolidation pattern. The patient was kept under observation. A 6-minute walk test was carried out and no desaturation or symptoms were noted. Steroids or antibiotics were not used and bronchoscopy was not performed due to the risk of spreading the contrast to unaffected areas [4]. The patient was asked to follow up in the pulmonary clinic six weeks post-discharge.
We prefer to classify patients based on radiographic, physiologic, and clinical parameters: positive radiographic findings and no change in physiological findings; positive radiographic findings and altered ventilation/perfusion (V/Q) ratio [6]; positive radiographic findings with shunt effect [7]; and positive radiographic findings with inflammatory response [8]. Most patients are completely asymptomatic after aspiration and treatment remains observation [2]. Aspiration pneumonia should be suspected whenever a patient complains of dysphagia and radiographic evidence of consolidation. Nevertheless, the risk of aspirations and complications remains high in patients with dysphagia or the elderly [1,9]. Treatment strategies vary depending on the underlying baseline comorbidities in patients with severe respiratory complications, although bronchoscopy and suctioning have been tried [10]. Furthermore, if gastric contents are aspirated along with barium, antibiotics have been used [11].
Most patients appear to recover completely one-year post aspiration. High-resolution CT has reported subtle evidence of early fibrosis even one-year post aspiration, although limited data is available on patient outcome years after aspiration [3]. The clinical significance of such findings remains unknown.
Conclusions
Although barium aspiration has dramatic radiographic findings, most patients are asymptomatic. Therefore, a clinical and radiographic paradox must be kept in mind when evaluating the patients and reviewing large volume barium aspiration imaging. We recommend longer follow-ups to check for delayed developments post barium aspiration.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained by all participants in this study | BARIUM SULFATE | DrugsGivenReaction | CC BY | 33564548 | 18,927,940 | 2021-01-07 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Atelectasis'. | Clinical and Radiological Dissociation in Massive Barium Aspiration.
Barium studies are commonly used to rule out gastrointestinal (GI) pathologies and sometimes they are associated with complications such as barium aspiration with heterogeneity in clinical features ranging from mild to severe symptoms. We present a case of large volume barium aspiration in a 73-year-old male with past medical history of dysphagia diagnosed with diffuse esophageal spasm. Barium is an inert material commonly used for GI tract study. Although complications associated with barium studies are rare, aspiration of barium can have dramatic findings resulting in mild to severe symptoms. Clinically patient had very minimal symptoms but radiographic studies appeared dramatic. Therefore, a clinical and radiographic paradox must be kept in mind when evaluating patients and reviewing large volume barium aspiration imaging. Our case remained asymptomatic and had no respiratory complaints, nor did he develop any respiratory distress post barium aspiration.
Introduction
Barium is an inert material commonly used for gastrointestinal (GI) tract study. We present a case of large volume barium aspiration in a 73-year-old male with past medical history of dysphagia diagnosed with diffuse esophageal spasm. Although complications associated with barium studies are rare, aspiration of barium can have dramatic findings resulting in mild to severe symptoms. Clinically patient had very minimal symptoms but radiographic studies appeared dramatic.
Case presentation
A 73-year-old male presented to emergency department due to presyncope with an episode of loss of consciousness for three minutes. He also complained of productive cough with whitish sputum. Vital signs were normal and physical examination was benign. Chest X-ray (CXR) showed evidence of consolidation, which was followed by a computed tomography (CT) chest that revealed a dilated esophagus (Figure 1). Barium swallow was done for optimal evaluation of dilated esophagus (Figure 2). Post-procedure CXR revealed interval development of complete opacification of left hemithorax and retained barium in the left upper chest (Figure 3). CT chest was followed, which revealed retained barium within the upper to the mid-thoracic esophagus. Complete left lung atelectasis was noted, likely related to the obstructing filling defect within the left main bronchus (Figure 4). Subsequently, the CXR showed persistently retained contrast within the esophagus and improved left lobar airspace disease with moderate to large pleural effusion (Figure 5). However, bedside sonogram showed predominantly consolidation. The patient had no symptoms and was clinically stable to be discharged. He was advised to follow up as an outpatient at the chest clinic in six weeks.
Figure 1 CT chest without contrast revealed fluid-filled dilated esophagus, which was suboptimally evaluated due to lack of contrast. The patient also had left lower lobe consolidation consistent with pneumonia.
Figure 2 A barium study was done, which revealed diffuse esophageal spasm and akinesis of the mid-thoracic esophagus.
Figure 3 Chest X-ray revealed interval development of complete opacification of left hemithorax and retained barium in the left upper chest.
Figure 4 CT chest revealed retained barium within the upper to the mid-thoracic esophagus. Complete left lung atelectasis was noted, likely related to the obstructing filling defect within the left main bronchus.
Figure 5 Subsequently, a chest x-ray showed persistently retained contrast within the esophagus and improved left lobar airspace disease with moderate to large pleural effusion.
Discussion
Barium studies are regularly performed to rule out GI lumen pathologies. Despite the risk of barium aspiration, which is present, the complications are rare [1,2]. We present a case of large volume barium aspiration which was clinically asymptomatic with dramatic radiographic findings. In most cases, patients remain largely asymptomatic despite the paradoxical radiographic findings [3]. However, mechanical obstruction leading to atelectasis as well as uncommon acute inflammatory reactions have been reported [3-5].
There are few articles published reporting mild cases of large volume barium aspiration [1]. Most patients do not develop severe symptoms as seen on the imaging, which is alarming. Our case remained asymptomatic and neither had any respiratory complaints nor did he develop any respiratory distress post barium aspiration. CT chest revealed complete left lung atelectasis, which subsequently improved within days, revealing moderate pleural effusion. Although there was a pleural effusion on the CXR, a bedside sonogram of the lung revealed a predominant consolidation pattern. The patient was kept under observation. A 6-minute walk test was carried out and no desaturation or symptoms were noted. Steroids or antibiotics were not used and bronchoscopy was not performed due to the risk of spreading the contrast to unaffected areas [4]. The patient was asked to follow up in the pulmonary clinic six weeks post-discharge.
We prefer to classify patients based on radiographic, physiologic, and clinical parameters: positive radiographic findings and no change in physiological findings; positive radiographic findings and altered ventilation/perfusion (V/Q) ratio [6]; positive radiographic findings with shunt effect [7]; and positive radiographic findings with inflammatory response [8]. Most patients are completely asymptomatic after aspiration and treatment remains observation [2]. Aspiration pneumonia should be suspected whenever a patient complains of dysphagia and radiographic evidence of consolidation. Nevertheless, the risk of aspirations and complications remains high in patients with dysphagia or the elderly [1,9]. Treatment strategies vary depending on the underlying baseline comorbidities in patients with severe respiratory complications, although bronchoscopy and suctioning have been tried [10]. Furthermore, if gastric contents are aspirated along with barium, antibiotics have been used [11].
Most patients appear to recover completely one-year post aspiration. High-resolution CT has reported subtle evidence of early fibrosis even one-year post aspiration, although limited data is available on patient outcome years after aspiration [3]. The clinical significance of such findings remains unknown.
Conclusions
Although barium aspiration has dramatic radiographic findings, most patients are asymptomatic. Therefore, a clinical and radiographic paradox must be kept in mind when evaluating the patients and reviewing large volume barium aspiration imaging. We recommend longer follow-ups to check for delayed developments post barium aspiration.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained by all participants in this study | BARIUM SULFATE | DrugsGivenReaction | CC BY | 33564548 | 18,927,940 | 2021-01-07 |
What was the administration route of drug 'BARIUM SULFATE'? | Clinical and Radiological Dissociation in Massive Barium Aspiration.
Barium studies are commonly used to rule out gastrointestinal (GI) pathologies and sometimes they are associated with complications such as barium aspiration with heterogeneity in clinical features ranging from mild to severe symptoms. We present a case of large volume barium aspiration in a 73-year-old male with past medical history of dysphagia diagnosed with diffuse esophageal spasm. Barium is an inert material commonly used for GI tract study. Although complications associated with barium studies are rare, aspiration of barium can have dramatic findings resulting in mild to severe symptoms. Clinically patient had very minimal symptoms but radiographic studies appeared dramatic. Therefore, a clinical and radiographic paradox must be kept in mind when evaluating patients and reviewing large volume barium aspiration imaging. Our case remained asymptomatic and had no respiratory complaints, nor did he develop any respiratory distress post barium aspiration.
Introduction
Barium is an inert material commonly used for gastrointestinal (GI) tract study. We present a case of large volume barium aspiration in a 73-year-old male with past medical history of dysphagia diagnosed with diffuse esophageal spasm. Although complications associated with barium studies are rare, aspiration of barium can have dramatic findings resulting in mild to severe symptoms. Clinically patient had very minimal symptoms but radiographic studies appeared dramatic.
Case presentation
A 73-year-old male presented to emergency department due to presyncope with an episode of loss of consciousness for three minutes. He also complained of productive cough with whitish sputum. Vital signs were normal and physical examination was benign. Chest X-ray (CXR) showed evidence of consolidation, which was followed by a computed tomography (CT) chest that revealed a dilated esophagus (Figure 1). Barium swallow was done for optimal evaluation of dilated esophagus (Figure 2). Post-procedure CXR revealed interval development of complete opacification of left hemithorax and retained barium in the left upper chest (Figure 3). CT chest was followed, which revealed retained barium within the upper to the mid-thoracic esophagus. Complete left lung atelectasis was noted, likely related to the obstructing filling defect within the left main bronchus (Figure 4). Subsequently, the CXR showed persistently retained contrast within the esophagus and improved left lobar airspace disease with moderate to large pleural effusion (Figure 5). However, bedside sonogram showed predominantly consolidation. The patient had no symptoms and was clinically stable to be discharged. He was advised to follow up as an outpatient at the chest clinic in six weeks.
Figure 1 CT chest without contrast revealed fluid-filled dilated esophagus, which was suboptimally evaluated due to lack of contrast. The patient also had left lower lobe consolidation consistent with pneumonia.
Figure 2 A barium study was done, which revealed diffuse esophageal spasm and akinesis of the mid-thoracic esophagus.
Figure 3 Chest X-ray revealed interval development of complete opacification of left hemithorax and retained barium in the left upper chest.
Figure 4 CT chest revealed retained barium within the upper to the mid-thoracic esophagus. Complete left lung atelectasis was noted, likely related to the obstructing filling defect within the left main bronchus.
Figure 5 Subsequently, a chest x-ray showed persistently retained contrast within the esophagus and improved left lobar airspace disease with moderate to large pleural effusion.
Discussion
Barium studies are regularly performed to rule out GI lumen pathologies. Despite the risk of barium aspiration, which is present, the complications are rare [1,2]. We present a case of large volume barium aspiration which was clinically asymptomatic with dramatic radiographic findings. In most cases, patients remain largely asymptomatic despite the paradoxical radiographic findings [3]. However, mechanical obstruction leading to atelectasis as well as uncommon acute inflammatory reactions have been reported [3-5].
There are few articles published reporting mild cases of large volume barium aspiration [1]. Most patients do not develop severe symptoms as seen on the imaging, which is alarming. Our case remained asymptomatic and neither had any respiratory complaints nor did he develop any respiratory distress post barium aspiration. CT chest revealed complete left lung atelectasis, which subsequently improved within days, revealing moderate pleural effusion. Although there was a pleural effusion on the CXR, a bedside sonogram of the lung revealed a predominant consolidation pattern. The patient was kept under observation. A 6-minute walk test was carried out and no desaturation or symptoms were noted. Steroids or antibiotics were not used and bronchoscopy was not performed due to the risk of spreading the contrast to unaffected areas [4]. The patient was asked to follow up in the pulmonary clinic six weeks post-discharge.
We prefer to classify patients based on radiographic, physiologic, and clinical parameters: positive radiographic findings and no change in physiological findings; positive radiographic findings and altered ventilation/perfusion (V/Q) ratio [6]; positive radiographic findings with shunt effect [7]; and positive radiographic findings with inflammatory response [8]. Most patients are completely asymptomatic after aspiration and treatment remains observation [2]. Aspiration pneumonia should be suspected whenever a patient complains of dysphagia and radiographic evidence of consolidation. Nevertheless, the risk of aspirations and complications remains high in patients with dysphagia or the elderly [1,9]. Treatment strategies vary depending on the underlying baseline comorbidities in patients with severe respiratory complications, although bronchoscopy and suctioning have been tried [10]. Furthermore, if gastric contents are aspirated along with barium, antibiotics have been used [11].
Most patients appear to recover completely one-year post aspiration. High-resolution CT has reported subtle evidence of early fibrosis even one-year post aspiration, although limited data is available on patient outcome years after aspiration [3]. The clinical significance of such findings remains unknown.
Conclusions
Although barium aspiration has dramatic radiographic findings, most patients are asymptomatic. Therefore, a clinical and radiographic paradox must be kept in mind when evaluating the patients and reviewing large volume barium aspiration imaging. We recommend longer follow-ups to check for delayed developments post barium aspiration.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained by all participants in this study | Oral | DrugAdministrationRoute | CC BY | 33564548 | 18,927,940 | 2021-01-07 |
What was the dosage of drug 'BARIUM SULFATE'? | Clinical and Radiological Dissociation in Massive Barium Aspiration.
Barium studies are commonly used to rule out gastrointestinal (GI) pathologies and sometimes they are associated with complications such as barium aspiration with heterogeneity in clinical features ranging from mild to severe symptoms. We present a case of large volume barium aspiration in a 73-year-old male with past medical history of dysphagia diagnosed with diffuse esophageal spasm. Barium is an inert material commonly used for GI tract study. Although complications associated with barium studies are rare, aspiration of barium can have dramatic findings resulting in mild to severe symptoms. Clinically patient had very minimal symptoms but radiographic studies appeared dramatic. Therefore, a clinical and radiographic paradox must be kept in mind when evaluating patients and reviewing large volume barium aspiration imaging. Our case remained asymptomatic and had no respiratory complaints, nor did he develop any respiratory distress post barium aspiration.
Introduction
Barium is an inert material commonly used for gastrointestinal (GI) tract study. We present a case of large volume barium aspiration in a 73-year-old male with past medical history of dysphagia diagnosed with diffuse esophageal spasm. Although complications associated with barium studies are rare, aspiration of barium can have dramatic findings resulting in mild to severe symptoms. Clinically patient had very minimal symptoms but radiographic studies appeared dramatic.
Case presentation
A 73-year-old male presented to emergency department due to presyncope with an episode of loss of consciousness for three minutes. He also complained of productive cough with whitish sputum. Vital signs were normal and physical examination was benign. Chest X-ray (CXR) showed evidence of consolidation, which was followed by a computed tomography (CT) chest that revealed a dilated esophagus (Figure 1). Barium swallow was done for optimal evaluation of dilated esophagus (Figure 2). Post-procedure CXR revealed interval development of complete opacification of left hemithorax and retained barium in the left upper chest (Figure 3). CT chest was followed, which revealed retained barium within the upper to the mid-thoracic esophagus. Complete left lung atelectasis was noted, likely related to the obstructing filling defect within the left main bronchus (Figure 4). Subsequently, the CXR showed persistently retained contrast within the esophagus and improved left lobar airspace disease with moderate to large pleural effusion (Figure 5). However, bedside sonogram showed predominantly consolidation. The patient had no symptoms and was clinically stable to be discharged. He was advised to follow up as an outpatient at the chest clinic in six weeks.
Figure 1 CT chest without contrast revealed fluid-filled dilated esophagus, which was suboptimally evaluated due to lack of contrast. The patient also had left lower lobe consolidation consistent with pneumonia.
Figure 2 A barium study was done, which revealed diffuse esophageal spasm and akinesis of the mid-thoracic esophagus.
Figure 3 Chest X-ray revealed interval development of complete opacification of left hemithorax and retained barium in the left upper chest.
Figure 4 CT chest revealed retained barium within the upper to the mid-thoracic esophagus. Complete left lung atelectasis was noted, likely related to the obstructing filling defect within the left main bronchus.
Figure 5 Subsequently, a chest x-ray showed persistently retained contrast within the esophagus and improved left lobar airspace disease with moderate to large pleural effusion.
Discussion
Barium studies are regularly performed to rule out GI lumen pathologies. Despite the risk of barium aspiration, which is present, the complications are rare [1,2]. We present a case of large volume barium aspiration which was clinically asymptomatic with dramatic radiographic findings. In most cases, patients remain largely asymptomatic despite the paradoxical radiographic findings [3]. However, mechanical obstruction leading to atelectasis as well as uncommon acute inflammatory reactions have been reported [3-5].
There are few articles published reporting mild cases of large volume barium aspiration [1]. Most patients do not develop severe symptoms as seen on the imaging, which is alarming. Our case remained asymptomatic and neither had any respiratory complaints nor did he develop any respiratory distress post barium aspiration. CT chest revealed complete left lung atelectasis, which subsequently improved within days, revealing moderate pleural effusion. Although there was a pleural effusion on the CXR, a bedside sonogram of the lung revealed a predominant consolidation pattern. The patient was kept under observation. A 6-minute walk test was carried out and no desaturation or symptoms were noted. Steroids or antibiotics were not used and bronchoscopy was not performed due to the risk of spreading the contrast to unaffected areas [4]. The patient was asked to follow up in the pulmonary clinic six weeks post-discharge.
We prefer to classify patients based on radiographic, physiologic, and clinical parameters: positive radiographic findings and no change in physiological findings; positive radiographic findings and altered ventilation/perfusion (V/Q) ratio [6]; positive radiographic findings with shunt effect [7]; and positive radiographic findings with inflammatory response [8]. Most patients are completely asymptomatic after aspiration and treatment remains observation [2]. Aspiration pneumonia should be suspected whenever a patient complains of dysphagia and radiographic evidence of consolidation. Nevertheless, the risk of aspirations and complications remains high in patients with dysphagia or the elderly [1,9]. Treatment strategies vary depending on the underlying baseline comorbidities in patients with severe respiratory complications, although bronchoscopy and suctioning have been tried [10]. Furthermore, if gastric contents are aspirated along with barium, antibiotics have been used [11].
Most patients appear to recover completely one-year post aspiration. High-resolution CT has reported subtle evidence of early fibrosis even one-year post aspiration, although limited data is available on patient outcome years after aspiration [3]. The clinical significance of such findings remains unknown.
Conclusions
Although barium aspiration has dramatic radiographic findings, most patients are asymptomatic. Therefore, a clinical and radiographic paradox must be kept in mind when evaluating the patients and reviewing large volume barium aspiration imaging. We recommend longer follow-ups to check for delayed developments post barium aspiration.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained by all participants in this study | UNK UNK, SINGLE | DrugDosageText | CC BY | 33564548 | 18,927,940 | 2021-01-07 |
What was the outcome of reaction 'Atelectasis'? | Clinical and Radiological Dissociation in Massive Barium Aspiration.
Barium studies are commonly used to rule out gastrointestinal (GI) pathologies and sometimes they are associated with complications such as barium aspiration with heterogeneity in clinical features ranging from mild to severe symptoms. We present a case of large volume barium aspiration in a 73-year-old male with past medical history of dysphagia diagnosed with diffuse esophageal spasm. Barium is an inert material commonly used for GI tract study. Although complications associated with barium studies are rare, aspiration of barium can have dramatic findings resulting in mild to severe symptoms. Clinically patient had very minimal symptoms but radiographic studies appeared dramatic. Therefore, a clinical and radiographic paradox must be kept in mind when evaluating patients and reviewing large volume barium aspiration imaging. Our case remained asymptomatic and had no respiratory complaints, nor did he develop any respiratory distress post barium aspiration.
Introduction
Barium is an inert material commonly used for gastrointestinal (GI) tract study. We present a case of large volume barium aspiration in a 73-year-old male with past medical history of dysphagia diagnosed with diffuse esophageal spasm. Although complications associated with barium studies are rare, aspiration of barium can have dramatic findings resulting in mild to severe symptoms. Clinically patient had very minimal symptoms but radiographic studies appeared dramatic.
Case presentation
A 73-year-old male presented to emergency department due to presyncope with an episode of loss of consciousness for three minutes. He also complained of productive cough with whitish sputum. Vital signs were normal and physical examination was benign. Chest X-ray (CXR) showed evidence of consolidation, which was followed by a computed tomography (CT) chest that revealed a dilated esophagus (Figure 1). Barium swallow was done for optimal evaluation of dilated esophagus (Figure 2). Post-procedure CXR revealed interval development of complete opacification of left hemithorax and retained barium in the left upper chest (Figure 3). CT chest was followed, which revealed retained barium within the upper to the mid-thoracic esophagus. Complete left lung atelectasis was noted, likely related to the obstructing filling defect within the left main bronchus (Figure 4). Subsequently, the CXR showed persistently retained contrast within the esophagus and improved left lobar airspace disease with moderate to large pleural effusion (Figure 5). However, bedside sonogram showed predominantly consolidation. The patient had no symptoms and was clinically stable to be discharged. He was advised to follow up as an outpatient at the chest clinic in six weeks.
Figure 1 CT chest without contrast revealed fluid-filled dilated esophagus, which was suboptimally evaluated due to lack of contrast. The patient also had left lower lobe consolidation consistent with pneumonia.
Figure 2 A barium study was done, which revealed diffuse esophageal spasm and akinesis of the mid-thoracic esophagus.
Figure 3 Chest X-ray revealed interval development of complete opacification of left hemithorax and retained barium in the left upper chest.
Figure 4 CT chest revealed retained barium within the upper to the mid-thoracic esophagus. Complete left lung atelectasis was noted, likely related to the obstructing filling defect within the left main bronchus.
Figure 5 Subsequently, a chest x-ray showed persistently retained contrast within the esophagus and improved left lobar airspace disease with moderate to large pleural effusion.
Discussion
Barium studies are regularly performed to rule out GI lumen pathologies. Despite the risk of barium aspiration, which is present, the complications are rare [1,2]. We present a case of large volume barium aspiration which was clinically asymptomatic with dramatic radiographic findings. In most cases, patients remain largely asymptomatic despite the paradoxical radiographic findings [3]. However, mechanical obstruction leading to atelectasis as well as uncommon acute inflammatory reactions have been reported [3-5].
There are few articles published reporting mild cases of large volume barium aspiration [1]. Most patients do not develop severe symptoms as seen on the imaging, which is alarming. Our case remained asymptomatic and neither had any respiratory complaints nor did he develop any respiratory distress post barium aspiration. CT chest revealed complete left lung atelectasis, which subsequently improved within days, revealing moderate pleural effusion. Although there was a pleural effusion on the CXR, a bedside sonogram of the lung revealed a predominant consolidation pattern. The patient was kept under observation. A 6-minute walk test was carried out and no desaturation or symptoms were noted. Steroids or antibiotics were not used and bronchoscopy was not performed due to the risk of spreading the contrast to unaffected areas [4]. The patient was asked to follow up in the pulmonary clinic six weeks post-discharge.
We prefer to classify patients based on radiographic, physiologic, and clinical parameters: positive radiographic findings and no change in physiological findings; positive radiographic findings and altered ventilation/perfusion (V/Q) ratio [6]; positive radiographic findings with shunt effect [7]; and positive radiographic findings with inflammatory response [8]. Most patients are completely asymptomatic after aspiration and treatment remains observation [2]. Aspiration pneumonia should be suspected whenever a patient complains of dysphagia and radiographic evidence of consolidation. Nevertheless, the risk of aspirations and complications remains high in patients with dysphagia or the elderly [1,9]. Treatment strategies vary depending on the underlying baseline comorbidities in patients with severe respiratory complications, although bronchoscopy and suctioning have been tried [10]. Furthermore, if gastric contents are aspirated along with barium, antibiotics have been used [11].
Most patients appear to recover completely one-year post aspiration. High-resolution CT has reported subtle evidence of early fibrosis even one-year post aspiration, although limited data is available on patient outcome years after aspiration [3]. The clinical significance of such findings remains unknown.
Conclusions
Although barium aspiration has dramatic radiographic findings, most patients are asymptomatic. Therefore, a clinical and radiographic paradox must be kept in mind when evaluating the patients and reviewing large volume barium aspiration imaging. We recommend longer follow-ups to check for delayed developments post barium aspiration.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained by all participants in this study | Recovering | ReactionOutcome | CC BY | 33564548 | 18,927,940 | 2021-01-07 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Kidney transplant rejection'. | Autologous bone marrow-derived mesenchymal stromal cell therapy with early tacrolimus withdrawal: The randomized prospective, single-center, open-label TRITON study.
After renal transplantation, there is a need for immunosuppressive regimens which effectively prevent allograft rejection, while preserving renal function and minimizing side effects. From this perspective, mesenchymal stromal cell (MSC) therapy is of interest. In this randomized prospective, single-center, open-label trial, we compared MSCs infused 6 and 7 weeks after renal transplantation and early tacrolimus withdrawal with a control tacrolimus group. Primary end point was quantitative evaluation of interstitial fibrosis in protocol biopsies at 4 and 24 weeks posttransplant. Secondary end points included acute rejection, graft loss, death, renal function, adverse events, and immunological responses. Seventy patients were randomly assigned of which 57 patients were included in the final analysis (29 MSC; 28 controls). Quantitative progression of fibrosis failed to show benefit in the MSC group and GFR remained stable in both groups. One acute rejection was documented (MSC group), while subclinical rejection in week 24 protocol biopsies occurred in seven patients (four MSC; three controls). In the MSC group, regulatory T cell numbers were significantly higher compared to controls (p = .014, week 24). In conclusion, early tacrolimus withdrawal with MSC therapy was safe and feasible without increased rejection and with preserved renal function. MSC therapy is a potentially useful approach after renal transplantation.
pmcAbbreviations
ABMR antibody‐mediated rejection
AE adverse event
BM bone marrow
BPAR biopsy‐proven acute rejection
CCMO Dutch Central Committee on Research involving Human Subjects
CNI calcineurin inhibitor
dnDSA de novo donor‐specific antibodies
DSMB data safety monitoring board
EVL everolimus
GFR glomerular filtration rate
GMP Good Manufacturing Practice
HLA human leukocyte antigen
I/R ischemia reperfusion
IFTA interstitial fibrosis and tubular atrophy
LUMC Leiden University Medical Center
MSC mesenchymal stromal cells
SAB single antigen bead
SAE serious adverse event
SCAR subclinical acute rejection
SD standard deviation
SR Sirius Red
TCMR T cell‐mediated rejection
Treg regulatory T cell
UMCG University Medical Center Groningen
1 INTRODUCTION
Over the last two decades significant progress has been achieved in short‐term survival of kidney transplants. 1 , 2 Unfortunately, these advancements have not led to a similar improvement in long‐term kidney transplant survival rates. Various factors, including donor graft quality, ischemia/reperfusion (I/R) injury, alloreactivity, viral infections, and drug therapy, may adversely affect renal structure causing graft scarring and compromising long‐term function. 3 The intensity of current immunosuppressive drugs, albeit efficacious in preventing rejection, is associated with increased risk for (viral) infections and malignancies. Calcineurin inhibitors (CNIs) are the cornerstone of current immunosuppressive therapy, but they have direct nephrotoxic effects. It has been demonstrated that CNI withdrawal should be undertaken before month 6 to prevent the occurrence of irreversible tubulointerstitial damage. 4 , 5 So far, early CNI withdrawal studies have proven to be risky and invariably lead to increased rejection and even loss of grafts. 6 Consequently, there is a need for immunosuppressive regimens that can prevent allograft rejection, while preserving renal function and promoting patient and graft survival in the long term. MSCs have immunosuppressive properties and roles in tissue repair, and various (mainly experimental) studies have demonstrated that MSCs may increase regulatory T cell (Treg) levels and polarize the immune system toward tolerance. 7 , 8 In renal transplantation, early studies using MSCs focused on safety and feasibility. 9 , 10 , 11 , 12 Although most of these studies were not designed as efficacy trials, there were indications that MSCs possess immunosuppressive properties, as evidenced by an increase in Tregs and downregulation of cytotoxic CD8T+ cells in a small number of patients. We performed a randomized, prospective, single‐center, open‐label study in living‐donor kidney transplant recipients in which we compared autologous bone marrow (BM)‐derived MSC therapy (infused at weeks 6 and 7) with concomitant early tacrolimus withdrawal (at week 8) to standard tacrolimus dose. Primary end point was quantitative evaluation of interstitial fibrosis and secondary end points included biopsy‐proven acute rejection, graft loss, death, renal function, adverse events, and immunological responses at week 24. We chose to perform the study on a background of alemtuzumab‐based induction to minimize the risk for acute rejection 13 and mTOR inhibition, since experimental studies demonstrated tolerogenic properties in combination with MSCs. 14 In a post hoc long‐term analysis, peripheral blood immune cell composition was also obtained at week 52 in patients with sufficient follow‐up. In addition, the efficacy end point (biopsy‐proven acute rejection (BPAR), graft loss, or death) was obtained up to 5 years in patients who had a longer follow‐up.
2 MATERIAL AND METHODS
2.1 Study design and patients
The TRITON study is a 24‐weeks investigator‐initiated, randomized, prospective, open‐label, single‐center, clinical study, performed at the Leiden University Medical Center (LUMC), the Netherlands. The trial design has been published previously. 15 The trial protocol, available at the Appendix S1 and S2 section, was approved by the local ethics committee at the LUMC, Leiden, and by the Central Committee on Research involving Human Subjects (CCMO) in the Netherlands. The trial was performed in accordance with the principles of the Declaration of Helsinki. In total, 70 de novo renal recipients of a kidney from a living donor, 18–75 years of age, were recruited from the transplant clinics of the LUMC. The inclusion/exclusion criteria were described previously. 15 Written informed consent was obtained from all participants.
2.2 Randomization and masking
Patients were randomly assigned before transplantation to either the MSC or control group in a ratio 1:1 (Figure S1). A patient was randomized only after verification of eligibility and informed consent. The randomization procedure was designed and implemented by the IMO (Informatie Management Onderzoek) department of the University Medical Center Groningen (UMCG), the Netherlands, using a web‐based system (ALEA). Investigator or authorized delegate from the study staff received an individual login code with which they could randomize their patients. The web application returned the allocated treatment. As a confirmation, the web application also sent an e‐mail with the randomization information to selected users. Patients maintained this randomization number throughout the study. Because of the nature of the intervention (BM biopsy and MSC infusions), participants and physicians were not masked to treatment assignment.
2.3 Procedures
All patients in the study received alemtuzumab (anti‐CD52),15 mg subcutaneously, at days 0 and 1 as well as tacrolimus (Prograft®), everolimus (EVL; Certican®), and low‐dose prednisone, as maintenance therapy (Figure S1). 15 Patients in the MSC group received two doses of autologous BM MSCs, intravenously at weeks 6 and 7 after transplantation. Autologous MSCs were chosen instead of third‐party MSCs to prevent alloimmunization. The dose of tacrolimus was reduced to 50% at the time of the second MSC infusion and completely withdrawn 1 week later. Patients received a higher dose of prednisolone (15 mg instead of 10 mg) for 14 days after the second infusion to diminish risks of tacrolimus withdrawal. In patients in the control group, the trough level of tacrolimus was lowered to a target of 6–8 ng/ml 8 weeks after transplantation. BM was aspirated from the posterior iliac crest of all patients in the MSC group under general anesthesia during the renal transplantation, as described previously. 15 This protocol was approved by the local ethics committee (P13.283) and by the CCMO (NL4371200013). Processing of the MSCs took place at the Interdivisional Good Manufacturing Practice (GMP) Facility of the LUMC (Table S1). 15 The MSC product was infused via peripheral infusion within 30 min with a target dose of 1.5 × 106 per/kg body weight IV (range 1–2 × 106), according to our previous study. 15 Monitoring of the patients occurred according to the assessment schedule, as described in the protocol (page 28).
2.4 Outcomes
The primary end point was the quantitative progression of interstitial fibrosis between the 4‐ and 24‐week protocol biopsies as measured by morphometric analysis of collagen deposition. Interstitial collagen fibers in protocol biopsies were visualized by Sirius Red (SR) staining and quantified as a percentage of total tubulointerstitial tissue (glomeruli and large vessels excluded) by quantifying positive pixels in five representative locations at 40× magnification with a macro created in ImageJ version 1.50i. 16 Included secondary end points were composite end point efficacy failure (BPAR, graft loss, or death); proteinuria, Banff scores at the protocol biopsies, renal function as measured by estimated (e)glomerular filtration rate (GFR), (serious) adverse events ((S)AE), including (viral) infections, the presence of de novo donor‐specific antibodies (dnDSA), and peripheral blood immune cell composition. Scoring of renal biopsies was performed in a blinded fashion by a renal pathologist from our center after completion of the study, using the most recent Banff classification. 17 Findings in a protocol biopsy with evidence of rejection were reported as subclinical acute rejection (SCAR). Renal function was calculated by the eGFR (ml/min/1.73 m2) using the CKD‐EPI formula. 15 AEs and SAEs were documented according to Medical Dictionary for Regulatory Activities (MedDRA®); the international medical terminology developed under the auspices of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use. Tacrolimus and EVL quantification was assessed using a previously validated LC–MS/MS assay. 18
2.5 Immunological monitoring
For human leukocyte antigen (HLA) antibody analysis, serum samples were screened using Luminex screen assay (Lifecodes, Immucor) and analyzed with a Luminex 200 reader. Definitions of the negative/positive discriminations were used as suggested by the provider. When positive, a single antigen bead (SAB) assay (Lifecodes, Immucor) was performed as standard‐of‐care. Assignment of positivity was assessed according to the manufacturer's instructions. Since MSCs are suggested to have immunomodulatory properties, we performed phenotypical analysis of leukocyte subpopulations on fresh whole blood. Staining, acquisition, and data analysis were performed strictly adhering to “The One” study protocol. 19 Absolute cell counts were obtained using the BD Multitest kit (BD Biosciences).
2.6 Post hoc analysis
Phenotypical analysis of leukocyte subpopulations was, in addition to the 24‐week time point, also performed 52 weeks after renal transplantation. Assessment of composite end point efficacy failure (BPAR, graft loss, or death) and renal function by eGFR was also obtained in patients with a follow‐up up to 5 years in a post hoc analysis (n = 52 at 1 year, n = 40 at 2 years, n = 24 at 3 years, n = 17 at 4 years, and n = 13 at 5 years, Table 4).
2.7 Statistical analysis
The study was designed to have a sample size of 25 in each group, or 50 in total, to have a power to detect a relative difference in mean percentages of fibrosis of at least 25% using an independent sample t test with a 0.05 two‐sided significance level (α), as described previously. 15 We anticipated that 70% of the included patients would have valid measurements (withdrawal included) and therefore included 70 patients. Data analysis was performed using SPSS version 25.0 (SPSS, Inc.) and all graphs were created using GraphPad Prism version 8.0 (GraphPad Prism Software, Inc.). Parametric data were described as mean ± SD, nonparametric data as median and interquartile range (IQR), and categorical data as numbers and percentages. p < .05 were considered statistically significant. The slopes of eGFR data were calculated and analyzed using a linear regression analysis. Immune monitoring data were analyzed using the Mann–Whitney test with Bonferroni correction for multiple testing. A data safety monitoring board (DSMB) monitored the safety of subjects. The trial is registered with ClinicalTrials.gov, NCT02057965.
3 RESULTS
3.1 Patients
Between March 3, 2014 and January 17, 2020, 70 patients, aged 19 to 74 years, were enrolled in the study: 36 patients were randomly assigned to the MSC group and 34 to the control group (Figure 1). Thirteen patients did not receive allocated treatment, because of abnormal MSC growth (defined as karyotypic abnormalities in the final product; n = 4), contra indication for MSC infusion due to the COVID‐19 pandemic (n = 1), impossibility of obtaining a baseline renal biopsy (n = 2 in MSC and n = 1 in control group), withdrawn informed consent (n = 4 in control group) and (relative) contra indication for prednisone usage (n = 1 control group). In total, 29 patients were assigned to the MSC and 28 to the control group (Figure 1). Patient baseline characteristics were similar in both groups (Table 1). Of the 29 patients in the MSC group, 28 patients received two infusions of MSCs, all within the proposed range. One patient received one dose of MSCs within the proposed range. The second dose was not given because of the COVID‐19 pandemic. This patient gave informed consent to continue the study. All patients had stable vital signs before and after MSC infusion monitored using MEWS (Table S1). In 28 patients in the MSC group and 23 patients in the control group, two renal biopsies could be obtained (Figure 1), in order to assess the quantitative progression of interstitial fibrosis.
FIGURE 1 Trial profile. MSC, mesenchymal stromal cell
TABLE 1 Baseline characteristics
Characteristic MSC (n = 29) Control (n = 28)
Recipient
Age, mean (SD), years 50 (14) 50 (15)
Male sex, no. (%) 26 (90) 20 (71)
Body weight, mean (SD), kg 81 (14) 82 (14)
Primary diagnosis, no. (%)
IgA nephropathy 7 (24) 3 (11)
Hypertension 3 (10) 9 (32)
Polycystic kidney disease 9 (31) 3 (11)
Diabetes 5 (17) 0
Reflux nephropathy 0 2 (7)
Membranous nephropathy 1 (3) 1 (4)
Lupus nephritis 1 (3) 0
Other 2 (7) 3 (11)
Unknown 1 (3) 7 (25)
Donor
Age, mean (SD), years 55 (13) 51 (11)
Male sex, no. (%) 14 (48) 10 (36)
eGFR (pre‐donation), mean (SD) 109.7 (12.0) 109.3 (12.7)
Transplant
Type, related, no. (%) 13 (45) 15 (54)
HLA A/B mismatch, mean (SD) 2.3 (1.3) 2.4 (0.9)
HLA DQ/DR mismatch, mean (SD) 1.2 (0.6) 1.3 (0.5)
Cold‐ischemia time, mean (SD), h 3.1 (0.6) 3.0 (0.5)
First warm ischemia time, mean (SD), min 3.7 (2.1) 5.2 (4.3)
Second warm ischemia time, mean (SD), min 27.0 (3.7) 31.1 (14.4)
Cytomegalovirus IgG status, no. (%)
D+/R+ 9 (31) 6 (21)
D+/R− 7 (24) 9 (32)
D−/R+ 1 (3) 2 (7)
D−/R− 12 (41) 11 (39)
Epstein‐Barr virus IgG D+/R, no. (%) 1 (3) 1 (4)
Note
Data are described as mean standard deviation (SD). Categorical data are described as number (%) (mentioned in every specific variable row).
Abbreviations: GFR, glomerular filtration rate; HLA, human leukocyte antigen.
John Wiley & Sons, Ltd
3.2 Quantitative progression of fibrosis score
The quantitative progression of fibrosis score in the biopsies was similar in both groups (MSC group 1.0 ± 7.9; control group 0.3 ± 7.8, p = .755). The fibrosis score remained stable both within the MSC (week 4, 15.2 ± 6.6 and week 24, 16.2 ± 5.3, p = .526) and control group (week 4, 17.0 ± 4.6 and week 24 17.3 ± 5.7, p = .870) (Figure 2; Figure S2). Delta Banff scores from 4 to 24 weeks were similar in the two groups, in particular the delta ti‐score (p = .8), the delta interstitial fibrosis/tubular atrophy (IFTA) score (p = .4), and the delta ah‐score (p = .4) (Figure S3).
FIGURE 2 Interstitial fibrosis scores. Quantitative progression of interstitial fibrosis (delta Sirius Red) between the 4‐ and 24‐week renal biopsy (percentage). MSC, mesenchymal stromal cell
3.3 Patient survival, renal function, and biopsy scores
Patient survival during the study follow‐up was 100% in both groups. All patients had a functioning kidney graft at the end of the 24‐week study period (Table 2). eGFR was 56 ± 16 ml/min/1.73 m2 in the MSC (n = 29) and 42 ± 9 ml/min/1.73 m2 in the control group (n = 28) at the time of MSC infusion (Figure 3A). Mean eGFR and 24‐h proteinuria (Table S2) in the MSC group were similar as compared with the control group, with a mean of 56 ± 15 ml/min/1.73 m2 and 47 ± 16 ml/min/1.73 m2, respectively, at week 24 (Figure 3A). The slope from 4 to 24 weeks in the MSC group (slope = −0.22; intercept = 58.15) was not significantly different from the control group (slope = 0.09; intercept = 43.33) (p = .08, Figure 3B). Only one acute rejection episode (combination of T cell [TCMR] and antibody‐mediated rejection [ABMR]), documented by for‐cause biopsy, was found during the study period in the MSC group (1/29 or 3.4%) (Table 2). In this patient, immune suppression had been further reduced due to persistent BK viremia/nephropathy. In the control group, four patients had an indication for a for‐cause renal biopsy, without evidence of rejection (Table 2). The 24‐week protocol biopsies showed SCAR in 14.3% and 13.0% of patients in the MSC (4/28) and control group (3/23), respectively. Protocol biopsies in the MSC group showed a chronic active TCMR Banff IA (n = 1 patient), active ABMR (n = 2, of which one also had active ABMR in the 4‐week protocol biopsy; both having class I and II DSAs, C4d positive only at 6 months), and one mixed active ABMR and acute TCMR IA. Biopsies in the control group demonstrated acute TCMR Banff IA (n = 2 patients) and a mixed active ABMR and acute TCMR IA (n = 1 patient) (Table 2). All patients had a negative HLA antibody screening before and 4 weeks after transplantation. In the MSC group, seven patients developed dnDSA at week 24 (24%) (Table 3). Their protocol renal biopsies demonstrated no rejection (n = 3), borderline suspicious for acute TCMR (n = 1), ABMR (n = 2, both C4d negative), and ABMR/TCMR IA (n = 1, C4d+). In the control group, two patients developed HLA class‐II dnDSA without signs of rejection in their protocol biopsies.
TABLE 2 Secondary end points (graft loss, renal function, and biopsy scores) during the study period of 24 weeks
End point study period of 24 weeks MSC group (n = 29) Control group (n = 28)
Graft loss, no. (%) 0 0
eGFR < 30 ml/min/1.73 m2, no. (%) 0 3 (12)
Patients with for‐cause biopsies, no. (%) 1 (3) 4 (14)
ABMR, TCMR II and BK nephropathy 1
BK nephropathy 1
Acute tubular necrosis 1
Hyaline thickening 1
No abnormalities 1
Patient's protocol biopsies, no. (%)
4 weeks 29 (100) 28 (100)
ABMR 1 0
No rejection 28 28
24 weeks 28 (97) 23 (82)
TCMR IA 1 2
ABMR 2 a 0
ABMR and TCMR IA 1 1
No rejection 24 20
Note
Data are described as number (%) (also mentioned in every specific variable row).
Abbreviations: ABMR, antibody‐mediated rejection; eGFR, estimated glomerular filtration rate; IFTA, interstitial fibrosis and tubular atrophy; MSC, mesenchymal stromal cell; TCMR, T cell‐mediated rejection; TIN, tubulointerstitial nephritis.
a One patient demonstrated ABMR at 4 and 24 weeks.
John Wiley & Sons, Ltd
FIGURE 3 eGFR during the study period of 24 weeks. (A) eGFR (ml/min/1.73 m2), calculated by the CKD‐EPI formula and depicted per time point as mean ± SD, of patients in the MSC and control groups. (B) Slopes of the eGFR in the MSC group were not significantly different from the control group (p = .08). Slope and intercept data per group are described, including 95% confidence intervals [Color figure can be viewed at wileyonlinelibrary.com]
TABLE 3 Secondary end points (SAE, AE, viral infections, and dnDSA) during the study period of 24 weeks
End point study period of 24 weeks MSC group (n = 29) Control group (n = 28)
Serious adverse events, total, no. 19 25
Injury, poisoning, and procedural complications 6 7
Infections and infestations 2 7
Gastrointestinal disorders 2 3
Renal and urinary disorders 2 2
Metabolism and nutrition disorders 2 2
Therapeutic and nontherapeutic responses 2 1
Investigations 1 1
Vascular disorders 0 1
Musculoskeletal and connective tissue disorders 0 1
Immune system disorders 1 0
Psychiatric disorders 1 0
Adverse events, total, no. 272 301
Investigations 51 46
Blood and lymphatic system disorders 39 36
Infections and infestations 32 38
Vascular disorders 35 31
Metabolism and nutrition disorders 26 30
Gastrointestinal disorders 21 32
Renal and urinary disorders 5 17
Injury, poisoning and procedural complications 9 15
General disorders and administration site conditions 10 12
Nervous system disorders 6 10
Musculoskeletal and connective tissue disorders 9 7
Cardiac disorders 10 5
Respiratory, thoracic and mediastinal disorders 5 7
Skin and subcutaneous tissue disorders 8 4
Psychiatric disorders 2 4
Reproductive system and breast disorders 1 2
Neoplasm benign, malignant and unspecified 1 2
Eye disorders 1 2
Immune system disorders 0 1
Ear and labyrinth disorders 1 0
Viral infections, no. (%)
EBV virus infection a 1 (3) 2 (7)
CMV virus infection a 2 (7) 3 (11)
BK virus infection b 11 (38) 10 (36)
BK nephropathy 1 (3) 3 (11)
dnDSA, no. (%)
Yes c 7 (24) 2 (7)
Anti‐class I 0 0
Anti‐class II 4 (14) 2 (7)
Anti‐class I and II 3 (10) 0
No 22 (76) 26 (89)
Note
(Serious) adverse events are reported using the MedDRA classification with standardized categories. All data are described as the total count. Numbers in parentheses are percentages.
Abbreviations: CMV, cytomegalovirus; dnDSA, de novo donor‐specific antibodies measured at week 24; EBV, Epstein‐Barr virus; MSC, mesenchymal stromal cells.
a Peak serum levels (logarithmic) of EBV and CMV range from 2.5 to 3.2 and from 2.7 to 4, respectively.
b Peak serum levels of BK range from 5.1 to 6.9 in patients with BK nephropathy and from 2.6 to 6.9 in patients without signs of BK nephropathy.
c dnDSA is considered positive in case of an MFI ≥ 500.
John Wiley & Sons, Ltd
3.4 Immunosuppressive drug levels and change of regime
Immunosuppressive drug levels were within or only slightly out of prespecified target ranges. EVL levels, however, were significantly lower at three time points in the control group (Table S3). All patients in the MSC group were on EVL at the end of the 24‐week study period. In the MSC group, tacrolimus was reintroduced in one patient, because of acute rejection. In the control group, tacrolimus was discontinued in two patients because of BK nephropathy. EVL was switched to mycophenolate mofetil in four patients after a thrombovascular event and discontinued in two patients (CMV infection and infected lymphocele, respectively).
3.5 (Serious) adverse events
Forty‐four SAEs were reported, of which 19 in the MSC and 25 in the control group. In total, 272 AEs were reported in the MSC and 301 in the control group (Table 3). There were no AEs directly related to the MSC infusions. In the control group, 15 viral infections (EBV, CMV, and BK viremia) developed and 14 in the MSC group (Table 3). BK nephropathy occurred in one patient in the MSC (3%) and in three patients in the control group (11%).
3.6 Immune monitoring
Immune monitoring studies demonstrated that absolute numbers of peripheral blood CD45+ leukocytes and CD14+ monocytes remain stable after transplantation between weeks 6 and 52 in the MSC and control groups (Figure 4A,B). CD19+ B cells and CD56+ NK cells decreased after alemtuzumab‐based induction in both groups and re‐appeared from week 12 onwards; however, no statistically significant change was measured between the groups (Figure 4C,D). CD3+CD8+ T cells, CD3+CD4+ T cells, as well as CD4+CD25hiCD127lo Tregs showed a decrease after alemtuzumab‐based induction in both groups while still being suppressed at week 52 (Figure 4E,G). Total Treg numbers were significantly higher in the MSC group with tacrolimus withdrawal as compared to the control group at 24 and 52 weeks after transplantation (p = .014 and p = .047, respectively), due to the increase in absolute number of CD4+CD25hiCD127loCD45RA− memory Tregs (p = .040 and p = .047) (Figure 4G,H). Absolute numbers of naïve Tregs (CD4+CD25hiCD127loCD45RA+) were similar in both groups (Figure S4). Percentages of total and naïve Tregs were not different between the two groups at any time points, whereas percentages of memory Tregs within the total CD4 population were elevated in the control group only at week 12, which normalized the weeks thereafter (Figure S5).
FIGURE 4 Peripheral blood immune cell composition before and after MSC infusion. Absolute numbers of (A) CD45+ leucocytes, (B) CD14+ monocytes, (C) CD19+ B cells, (D) CD56+ NK cells, (E) CD8+ T cells, (F) CD4+ T cells, (G) CD4+CD25hiCD127lo Tregs, and (H) CD4+CD25hiCD127loCD45RA‐ memory Tregs per mL of blood are shown at baseline before transplantation, before the first MSC infusion (week 6), and time points after both infusions (weeks 12, 24, and 52). Violin plots are given for every time point with the number of individuals studied at each time point below the x‐axis. p values are given for the differences between MSC and control groups when <.05 after Bonferroni correction for multiple testing. MSC, mesenchymal stromal cell; NK, natural killer; Treg, regulatory T cell
3.7 Post hoc analysis
In the post hoc longer (intermediate)‐term follow‐up analysis (up to 5 years), graft loss was observed in two patients in the control group (Table 4). Renal function in the MSC group was preserved with an eGFR between 47 and 57 ml/min/1.73 m2 (Table 4). In the patients in the control group, eGFR gradually declined with a mean of 42 ml/min/1.73 m2 at year 1 and 37 ml/min/1.73 m2 at year 5, while seven patients dropped with their eGFR < 30 ml/min/1.73 m2. For‐cause biopsies were indicated in one patient in the MSC and eight patients in the control group. In the for‐cause biopsy in the MSC group, recurrence of IgA nephropathy was found (n = 1). In the control group, acute TCMR IB (n = 1), acute TCMR II (n = 1), mixed active ABMR and acute TCMR IB (n = 1), BK nephropathy (n = 2), tubulointerstitial nephritis/pyelonephritis (n‐1), IFTA grade III (n = 1), and medullary inflammation NOS (sv negative) (n = 1) were observed. In the post hoc analyses, none of the seven patients with de novo DSA needed a for‐cause biopsy renal biopsy or developed an eGFR < 30 ml/min/1.73 m2. However, it is of importance to note that in three of these seven patients CNI was restarted by their treating nephrologist after the 24‐week study period (Table S4).
TABLE 4 Post hoc analysis (1–5 years) of end points (graft loss, renal function, and biopsy scores)
End point post hoc analysis MSC group Control group
1 year n = 26 n = 26
2 years n = 20 n = 20
3 years n = 10 n = 14
4 years n = 7 n = 10
5 years n = 6 n = 7
Graft loss, no. 0 2 a
Time after Tx, years 3.8 and 4.5
eGFR, mean (SD) [n], ml/min/1.73 m2
1 year 57 (15) [26] 42 (11) [26]
2 years 55 (15) [20] 39 (12) [20]
3 years 53 (14) [10] 34 (14) [14]
4 years 47 (10) [7] 36 (12) [9]
5 years 50 (20) [6] 37 (15) [5]
eGFR < 30 ml/min/1.73 m2, no. 0 7
Time after Tx, median (IQR), years 3 (1–3)
Patients with for‐cause biopsies, no. (%) 1 (3) 8 (29)
Recurrence IgA nephropathy 1
TCMR IB 1
TCMR II 1
ABMR and TCMR IB 1
BK nephropathy 2
TIN/pyelonephritis 1
IFTA grade III 1
Medullary inflammation 1
Note
All data are described as the total count. Numbers in parentheses are percentages (also mentioned in the specific variable row).
Abbreviations: ABMR, antibody‐mediated rejection; eGFR, estimated glomerular filtration rate; IFTA, interstitial fibrosis and tubular atrophy; MSC, mesenchymal stromal cell; TCMR, T cell‐mediated rejection; TIN, tubulointerstitial nephritis.
a One patient TCMR and recurrence membranous nephropathy; one patient chronic transplant dysfunction.
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4 DISCUSSION
In this randomized clinical study, we found that quantitative fibrosis scores and renal function remained stable in patients with MSC therapy and concomitant early tacrolimus withdrawal within the study period of 24 weeks. Only one acute rejection episode was documented in the MSC group after further reduction of clinical immunosuppression in the context of persistent BK viremia/nephropathy. Of interest, there were significantly higher numbers of Tregs in the MSC group with tacrolimus withdrawal compared to the controls. In addition, post hoc analyses demonstrated preserved renal function in the MSC group without evidence of late rejection. Clinical studies with MSCs in kidney transplantation, mainly phase 1 trials with still limited numbers of patients, have demonstrated that MSC treatment after kidney transplantation is safe and feasible. 9 , 10 , 11 , 12 , 20 , 21 In most studies, MSCs were administered at an early time point against the background of regular immune suppression with the aim to induce immunologic tolerance. The current strategy with MSCs and complete withdrawal of CNI have not been studied before in a randomized trial. Minimization of CNIs is a well‐established strategy to limit structural long‐term damage to the graft and minimize the side effects associated with clinical immunosuppression. 5 , 22 A number of trials have demonstrated the efficacy of EVL in conjunction with reduced exposure to CNIs in preventing organ loss or dysfunction in kidney transplant recipients. 23 Of importance, complete avoidance and replacement of a CNI by EVL in de novo transplant recipients are not justified, since unacceptable high acute rejection rates were observed with this strategy. 24 The capability of MSCs to allow reduction of 50% CNI was demonstrated in a previous study with third‐party MSCs in 16 living kidney transplant recipients. 21 The combination of an mTOR inhibitor and MSCs was chosen in the current study since experimental evidence demonstrated tolerogenic properties and an increase in regulatory immune cell subsets. 14 In our study, fibrosis scores were similar in both the MSC group and the controls, thereby failing to meet the primary end point, and the incidence of acute rejection 24 weeks after implantation was low. One explanation might be the use of alemtuzumab, 13 which was chosen as we anticipated a higher immunological risk due to the early CNI withdrawal. Indeed, given the potency of the immunosuppression regimen used in our study, seeing differences in fibrosis scores and rejection with the short study duration is unlikely. Of interest, however, the post hoc analysis with follow‐up up to 5 years showed a higher incidence of for‐cause biopsies in the control group, with findings of both BPAR and BK nephropathy, suggesting that the effect of MSC infusion in combination with CNI withdrawal carried through way beyond the period that alemtuzumab is effective. Future studies with a sufficient number of patients and duration of follow‐up are needed to be able to draw more definite conclusions. Several studies have reported an increased incidence of dnDSA in renal transplant recipients receiving EVL, especially when converted early after transplantation, and it was also suggested that the use of alemtuzumab‐based induction could aggravate this. 25 , 26 In general, dnDSA has been shown to be associated with poor graft survival and increased acute rejection in kidney transplant recipients. 27 In the large ELEVATE Trial, however, conversion to EVL at 10–14 weeks posttransplant was associated with renal function parameters similar to that observed with standard therapy. In this study, the dnDSA data, available in a subset of patients, suggested more frequent anti‐HLA Class‐I DSA under EVL. Differences in propensity to develop dnDSA, however, did not appear to have resulted in ABMR within the 2‐year observation frame of the study. 28 In our study, we also found an increased incidence of dnDSA in patients where tacrolimus was withdrawn. This was associated with (asymptomatic) signs of ABMR in the protocol biopsies of three of these patients of which one, in retrospect, already had subclinical ABMR in the 4‐week biopsy. There were no signs of deteriorating graft function in these patients. Furthermore, the post hoc analyses showed no graft losses, no need for additional for‐cause biopsies, and stable renal function in these patients as well as the MSC group as a whole. Nevertheless, given the epidemiological association with graft loss (which is, however, based on for‐cause DSA measurements), the nephrologists taking care of these patients restarted the CNI in three patients after the study period. Longer follow‐up in all patients is warranted to draw more definite conclusions here. Variable outcomes on renal function after MSC therapy have been described and it has been suggested that timing of MSC administration is of major importance. Indeed, early clinical trials have demonstrated an engraftment syndrome with infiltration of immune cells and C3 deposits when MSCs were administered 7 days after renal transplantation, which was not observed when MSCs were given before implantation. 29 In the study by Erpicum et al., eGFR values at day 7 were higher in the MSC‐treated patients. 12 In our study, patients in the MSC group started with a higher eGFR, as compared to controls, which was preserved throughout the study period and the post hoc follow‐up period. This unequal randomization was, to the best of our knowledge, found by chance and could have influenced our results. In the control group, there was increased graft loss as well as a higher number of patients with inferior renal function (i.e., eGFR < 30 ml/min/1.73 m2), possibly due to an increase in BPAR and BK nephropathy in these patients.
So far, hardly any safety issues have been reported after systemic infusion of MSCs in humans, except for a transient fever and one cardiac event with an unclear causal relationship to the intervention. 12 In our study, there were no side effects directly related to the MSC infusion. We found that (S)AEs (including viral infections) were similar in the two groups. This is in contrast to our previous study where an increased incidence of viral infections was observed after MSC therapy. 10 Possibly this is due to the fact that MSCs were given on top of regular immune suppression in our previous study. This observation is of particular relevance with the ongoing COVID‐19 pandemic. Recent observational studies have shown that kidney transplant recipients are at increased risk for severe morbidity due to their systemic immune suppression and often reduced renal function. 30
MSCs have shown to condition the immune system, by releasing extracellular vesicles or membrane particles or by undergoing apoptosis. This may actively engage recipient monocytes/phagocytes and eventually Tregs, enabling long‐term tolerogenic activity that becomes self‐sustained even after disappearance of the infused MSCs themselves. 8 , 31 Of interest, in our current study, we found an increase in the absolute number of Tregs in the MSC group with tacrolimus withdrawal versus control, which has not been reported before in a randomized clinical trial with MSCs in transplant recipients. However, since there was a difference in tacrolimus use between both groups and a difference in total CD4+ T cell counts at week 12, it is not possible to deduce the results solely to the MSC treatment. Concomitantly, the percentage of memory Tregs within total CD4 T cells showed an increase in the control group compared to the MSC group at 12 weeks (Figure S5), after which the percentages in total and Treg subsets remained similar, indicating that the increase in absolute Treg numbers in the MSC group is at least partially due to changes in the total CD4+ T cell number.
At present, randomized trials with MSCs are still very limited and the field is only slowly advancing also due to stringent regulatory requirements, the need for clinical grade cell production facilities, and the associated costs. However, we recently also reported the feasibility of administration of third‐party “off‐the‐shelf” MSCs in kidney transplant recipients. 11 This option makes manufacturing and regulation easier and the use of MSC suitable for a wider spectrum of clinical application and much more feasible. We believe that the results of our current trial set the stage for the next steps and use of MSCs in the field of kidney transplantation to reduce the need for excessive use of clinical immunosuppressants.
DISCLOSURE
The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.
Supporting information
Appendix S1
Click here for additional data file.
Appendix S2
Click here for additional data file.
ACKNOWLEDGMENTS
We thank the research department of internal medicine of the Leiden University Medical Center for their help with the study visits. We thank the research technicians from the Transplant Immunology lab for technical assistance with the immune monitoring. This investigator‐initiated study was partially funded by unrestricted research grants from Astellas and Novartis. The funders had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. Part of this work was supported by a grant from ZonMW‐TAS program nr 116004104. | ALEMTUZUMAB, EVEROLIMUS, PREDNISONE, TACROLIMUS | DrugsGivenReaction | CC BY-NC | 33565206 | 19,393,094 | 2021-09 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nephropathy'. | Autologous bone marrow-derived mesenchymal stromal cell therapy with early tacrolimus withdrawal: The randomized prospective, single-center, open-label TRITON study.
After renal transplantation, there is a need for immunosuppressive regimens which effectively prevent allograft rejection, while preserving renal function and minimizing side effects. From this perspective, mesenchymal stromal cell (MSC) therapy is of interest. In this randomized prospective, single-center, open-label trial, we compared MSCs infused 6 and 7 weeks after renal transplantation and early tacrolimus withdrawal with a control tacrolimus group. Primary end point was quantitative evaluation of interstitial fibrosis in protocol biopsies at 4 and 24 weeks posttransplant. Secondary end points included acute rejection, graft loss, death, renal function, adverse events, and immunological responses. Seventy patients were randomly assigned of which 57 patients were included in the final analysis (29 MSC; 28 controls). Quantitative progression of fibrosis failed to show benefit in the MSC group and GFR remained stable in both groups. One acute rejection was documented (MSC group), while subclinical rejection in week 24 protocol biopsies occurred in seven patients (four MSC; three controls). In the MSC group, regulatory T cell numbers were significantly higher compared to controls (p = .014, week 24). In conclusion, early tacrolimus withdrawal with MSC therapy was safe and feasible without increased rejection and with preserved renal function. MSC therapy is a potentially useful approach after renal transplantation.
pmcAbbreviations
ABMR antibody‐mediated rejection
AE adverse event
BM bone marrow
BPAR biopsy‐proven acute rejection
CCMO Dutch Central Committee on Research involving Human Subjects
CNI calcineurin inhibitor
dnDSA de novo donor‐specific antibodies
DSMB data safety monitoring board
EVL everolimus
GFR glomerular filtration rate
GMP Good Manufacturing Practice
HLA human leukocyte antigen
I/R ischemia reperfusion
IFTA interstitial fibrosis and tubular atrophy
LUMC Leiden University Medical Center
MSC mesenchymal stromal cells
SAB single antigen bead
SAE serious adverse event
SCAR subclinical acute rejection
SD standard deviation
SR Sirius Red
TCMR T cell‐mediated rejection
Treg regulatory T cell
UMCG University Medical Center Groningen
1 INTRODUCTION
Over the last two decades significant progress has been achieved in short‐term survival of kidney transplants. 1 , 2 Unfortunately, these advancements have not led to a similar improvement in long‐term kidney transplant survival rates. Various factors, including donor graft quality, ischemia/reperfusion (I/R) injury, alloreactivity, viral infections, and drug therapy, may adversely affect renal structure causing graft scarring and compromising long‐term function. 3 The intensity of current immunosuppressive drugs, albeit efficacious in preventing rejection, is associated with increased risk for (viral) infections and malignancies. Calcineurin inhibitors (CNIs) are the cornerstone of current immunosuppressive therapy, but they have direct nephrotoxic effects. It has been demonstrated that CNI withdrawal should be undertaken before month 6 to prevent the occurrence of irreversible tubulointerstitial damage. 4 , 5 So far, early CNI withdrawal studies have proven to be risky and invariably lead to increased rejection and even loss of grafts. 6 Consequently, there is a need for immunosuppressive regimens that can prevent allograft rejection, while preserving renal function and promoting patient and graft survival in the long term. MSCs have immunosuppressive properties and roles in tissue repair, and various (mainly experimental) studies have demonstrated that MSCs may increase regulatory T cell (Treg) levels and polarize the immune system toward tolerance. 7 , 8 In renal transplantation, early studies using MSCs focused on safety and feasibility. 9 , 10 , 11 , 12 Although most of these studies were not designed as efficacy trials, there were indications that MSCs possess immunosuppressive properties, as evidenced by an increase in Tregs and downregulation of cytotoxic CD8T+ cells in a small number of patients. We performed a randomized, prospective, single‐center, open‐label study in living‐donor kidney transplant recipients in which we compared autologous bone marrow (BM)‐derived MSC therapy (infused at weeks 6 and 7) with concomitant early tacrolimus withdrawal (at week 8) to standard tacrolimus dose. Primary end point was quantitative evaluation of interstitial fibrosis and secondary end points included biopsy‐proven acute rejection, graft loss, death, renal function, adverse events, and immunological responses at week 24. We chose to perform the study on a background of alemtuzumab‐based induction to minimize the risk for acute rejection 13 and mTOR inhibition, since experimental studies demonstrated tolerogenic properties in combination with MSCs. 14 In a post hoc long‐term analysis, peripheral blood immune cell composition was also obtained at week 52 in patients with sufficient follow‐up. In addition, the efficacy end point (biopsy‐proven acute rejection (BPAR), graft loss, or death) was obtained up to 5 years in patients who had a longer follow‐up.
2 MATERIAL AND METHODS
2.1 Study design and patients
The TRITON study is a 24‐weeks investigator‐initiated, randomized, prospective, open‐label, single‐center, clinical study, performed at the Leiden University Medical Center (LUMC), the Netherlands. The trial design has been published previously. 15 The trial protocol, available at the Appendix S1 and S2 section, was approved by the local ethics committee at the LUMC, Leiden, and by the Central Committee on Research involving Human Subjects (CCMO) in the Netherlands. The trial was performed in accordance with the principles of the Declaration of Helsinki. In total, 70 de novo renal recipients of a kidney from a living donor, 18–75 years of age, were recruited from the transplant clinics of the LUMC. The inclusion/exclusion criteria were described previously. 15 Written informed consent was obtained from all participants.
2.2 Randomization and masking
Patients were randomly assigned before transplantation to either the MSC or control group in a ratio 1:1 (Figure S1). A patient was randomized only after verification of eligibility and informed consent. The randomization procedure was designed and implemented by the IMO (Informatie Management Onderzoek) department of the University Medical Center Groningen (UMCG), the Netherlands, using a web‐based system (ALEA). Investigator or authorized delegate from the study staff received an individual login code with which they could randomize their patients. The web application returned the allocated treatment. As a confirmation, the web application also sent an e‐mail with the randomization information to selected users. Patients maintained this randomization number throughout the study. Because of the nature of the intervention (BM biopsy and MSC infusions), participants and physicians were not masked to treatment assignment.
2.3 Procedures
All patients in the study received alemtuzumab (anti‐CD52),15 mg subcutaneously, at days 0 and 1 as well as tacrolimus (Prograft®), everolimus (EVL; Certican®), and low‐dose prednisone, as maintenance therapy (Figure S1). 15 Patients in the MSC group received two doses of autologous BM MSCs, intravenously at weeks 6 and 7 after transplantation. Autologous MSCs were chosen instead of third‐party MSCs to prevent alloimmunization. The dose of tacrolimus was reduced to 50% at the time of the second MSC infusion and completely withdrawn 1 week later. Patients received a higher dose of prednisolone (15 mg instead of 10 mg) for 14 days after the second infusion to diminish risks of tacrolimus withdrawal. In patients in the control group, the trough level of tacrolimus was lowered to a target of 6–8 ng/ml 8 weeks after transplantation. BM was aspirated from the posterior iliac crest of all patients in the MSC group under general anesthesia during the renal transplantation, as described previously. 15 This protocol was approved by the local ethics committee (P13.283) and by the CCMO (NL4371200013). Processing of the MSCs took place at the Interdivisional Good Manufacturing Practice (GMP) Facility of the LUMC (Table S1). 15 The MSC product was infused via peripheral infusion within 30 min with a target dose of 1.5 × 106 per/kg body weight IV (range 1–2 × 106), according to our previous study. 15 Monitoring of the patients occurred according to the assessment schedule, as described in the protocol (page 28).
2.4 Outcomes
The primary end point was the quantitative progression of interstitial fibrosis between the 4‐ and 24‐week protocol biopsies as measured by morphometric analysis of collagen deposition. Interstitial collagen fibers in protocol biopsies were visualized by Sirius Red (SR) staining and quantified as a percentage of total tubulointerstitial tissue (glomeruli and large vessels excluded) by quantifying positive pixels in five representative locations at 40× magnification with a macro created in ImageJ version 1.50i. 16 Included secondary end points were composite end point efficacy failure (BPAR, graft loss, or death); proteinuria, Banff scores at the protocol biopsies, renal function as measured by estimated (e)glomerular filtration rate (GFR), (serious) adverse events ((S)AE), including (viral) infections, the presence of de novo donor‐specific antibodies (dnDSA), and peripheral blood immune cell composition. Scoring of renal biopsies was performed in a blinded fashion by a renal pathologist from our center after completion of the study, using the most recent Banff classification. 17 Findings in a protocol biopsy with evidence of rejection were reported as subclinical acute rejection (SCAR). Renal function was calculated by the eGFR (ml/min/1.73 m2) using the CKD‐EPI formula. 15 AEs and SAEs were documented according to Medical Dictionary for Regulatory Activities (MedDRA®); the international medical terminology developed under the auspices of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use. Tacrolimus and EVL quantification was assessed using a previously validated LC–MS/MS assay. 18
2.5 Immunological monitoring
For human leukocyte antigen (HLA) antibody analysis, serum samples were screened using Luminex screen assay (Lifecodes, Immucor) and analyzed with a Luminex 200 reader. Definitions of the negative/positive discriminations were used as suggested by the provider. When positive, a single antigen bead (SAB) assay (Lifecodes, Immucor) was performed as standard‐of‐care. Assignment of positivity was assessed according to the manufacturer's instructions. Since MSCs are suggested to have immunomodulatory properties, we performed phenotypical analysis of leukocyte subpopulations on fresh whole blood. Staining, acquisition, and data analysis were performed strictly adhering to “The One” study protocol. 19 Absolute cell counts were obtained using the BD Multitest kit (BD Biosciences).
2.6 Post hoc analysis
Phenotypical analysis of leukocyte subpopulations was, in addition to the 24‐week time point, also performed 52 weeks after renal transplantation. Assessment of composite end point efficacy failure (BPAR, graft loss, or death) and renal function by eGFR was also obtained in patients with a follow‐up up to 5 years in a post hoc analysis (n = 52 at 1 year, n = 40 at 2 years, n = 24 at 3 years, n = 17 at 4 years, and n = 13 at 5 years, Table 4).
2.7 Statistical analysis
The study was designed to have a sample size of 25 in each group, or 50 in total, to have a power to detect a relative difference in mean percentages of fibrosis of at least 25% using an independent sample t test with a 0.05 two‐sided significance level (α), as described previously. 15 We anticipated that 70% of the included patients would have valid measurements (withdrawal included) and therefore included 70 patients. Data analysis was performed using SPSS version 25.0 (SPSS, Inc.) and all graphs were created using GraphPad Prism version 8.0 (GraphPad Prism Software, Inc.). Parametric data were described as mean ± SD, nonparametric data as median and interquartile range (IQR), and categorical data as numbers and percentages. p < .05 were considered statistically significant. The slopes of eGFR data were calculated and analyzed using a linear regression analysis. Immune monitoring data were analyzed using the Mann–Whitney test with Bonferroni correction for multiple testing. A data safety monitoring board (DSMB) monitored the safety of subjects. The trial is registered with ClinicalTrials.gov, NCT02057965.
3 RESULTS
3.1 Patients
Between March 3, 2014 and January 17, 2020, 70 patients, aged 19 to 74 years, were enrolled in the study: 36 patients were randomly assigned to the MSC group and 34 to the control group (Figure 1). Thirteen patients did not receive allocated treatment, because of abnormal MSC growth (defined as karyotypic abnormalities in the final product; n = 4), contra indication for MSC infusion due to the COVID‐19 pandemic (n = 1), impossibility of obtaining a baseline renal biopsy (n = 2 in MSC and n = 1 in control group), withdrawn informed consent (n = 4 in control group) and (relative) contra indication for prednisone usage (n = 1 control group). In total, 29 patients were assigned to the MSC and 28 to the control group (Figure 1). Patient baseline characteristics were similar in both groups (Table 1). Of the 29 patients in the MSC group, 28 patients received two infusions of MSCs, all within the proposed range. One patient received one dose of MSCs within the proposed range. The second dose was not given because of the COVID‐19 pandemic. This patient gave informed consent to continue the study. All patients had stable vital signs before and after MSC infusion monitored using MEWS (Table S1). In 28 patients in the MSC group and 23 patients in the control group, two renal biopsies could be obtained (Figure 1), in order to assess the quantitative progression of interstitial fibrosis.
FIGURE 1 Trial profile. MSC, mesenchymal stromal cell
TABLE 1 Baseline characteristics
Characteristic MSC (n = 29) Control (n = 28)
Recipient
Age, mean (SD), years 50 (14) 50 (15)
Male sex, no. (%) 26 (90) 20 (71)
Body weight, mean (SD), kg 81 (14) 82 (14)
Primary diagnosis, no. (%)
IgA nephropathy 7 (24) 3 (11)
Hypertension 3 (10) 9 (32)
Polycystic kidney disease 9 (31) 3 (11)
Diabetes 5 (17) 0
Reflux nephropathy 0 2 (7)
Membranous nephropathy 1 (3) 1 (4)
Lupus nephritis 1 (3) 0
Other 2 (7) 3 (11)
Unknown 1 (3) 7 (25)
Donor
Age, mean (SD), years 55 (13) 51 (11)
Male sex, no. (%) 14 (48) 10 (36)
eGFR (pre‐donation), mean (SD) 109.7 (12.0) 109.3 (12.7)
Transplant
Type, related, no. (%) 13 (45) 15 (54)
HLA A/B mismatch, mean (SD) 2.3 (1.3) 2.4 (0.9)
HLA DQ/DR mismatch, mean (SD) 1.2 (0.6) 1.3 (0.5)
Cold‐ischemia time, mean (SD), h 3.1 (0.6) 3.0 (0.5)
First warm ischemia time, mean (SD), min 3.7 (2.1) 5.2 (4.3)
Second warm ischemia time, mean (SD), min 27.0 (3.7) 31.1 (14.4)
Cytomegalovirus IgG status, no. (%)
D+/R+ 9 (31) 6 (21)
D+/R− 7 (24) 9 (32)
D−/R+ 1 (3) 2 (7)
D−/R− 12 (41) 11 (39)
Epstein‐Barr virus IgG D+/R, no. (%) 1 (3) 1 (4)
Note
Data are described as mean standard deviation (SD). Categorical data are described as number (%) (mentioned in every specific variable row).
Abbreviations: GFR, glomerular filtration rate; HLA, human leukocyte antigen.
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3.2 Quantitative progression of fibrosis score
The quantitative progression of fibrosis score in the biopsies was similar in both groups (MSC group 1.0 ± 7.9; control group 0.3 ± 7.8, p = .755). The fibrosis score remained stable both within the MSC (week 4, 15.2 ± 6.6 and week 24, 16.2 ± 5.3, p = .526) and control group (week 4, 17.0 ± 4.6 and week 24 17.3 ± 5.7, p = .870) (Figure 2; Figure S2). Delta Banff scores from 4 to 24 weeks were similar in the two groups, in particular the delta ti‐score (p = .8), the delta interstitial fibrosis/tubular atrophy (IFTA) score (p = .4), and the delta ah‐score (p = .4) (Figure S3).
FIGURE 2 Interstitial fibrosis scores. Quantitative progression of interstitial fibrosis (delta Sirius Red) between the 4‐ and 24‐week renal biopsy (percentage). MSC, mesenchymal stromal cell
3.3 Patient survival, renal function, and biopsy scores
Patient survival during the study follow‐up was 100% in both groups. All patients had a functioning kidney graft at the end of the 24‐week study period (Table 2). eGFR was 56 ± 16 ml/min/1.73 m2 in the MSC (n = 29) and 42 ± 9 ml/min/1.73 m2 in the control group (n = 28) at the time of MSC infusion (Figure 3A). Mean eGFR and 24‐h proteinuria (Table S2) in the MSC group were similar as compared with the control group, with a mean of 56 ± 15 ml/min/1.73 m2 and 47 ± 16 ml/min/1.73 m2, respectively, at week 24 (Figure 3A). The slope from 4 to 24 weeks in the MSC group (slope = −0.22; intercept = 58.15) was not significantly different from the control group (slope = 0.09; intercept = 43.33) (p = .08, Figure 3B). Only one acute rejection episode (combination of T cell [TCMR] and antibody‐mediated rejection [ABMR]), documented by for‐cause biopsy, was found during the study period in the MSC group (1/29 or 3.4%) (Table 2). In this patient, immune suppression had been further reduced due to persistent BK viremia/nephropathy. In the control group, four patients had an indication for a for‐cause renal biopsy, without evidence of rejection (Table 2). The 24‐week protocol biopsies showed SCAR in 14.3% and 13.0% of patients in the MSC (4/28) and control group (3/23), respectively. Protocol biopsies in the MSC group showed a chronic active TCMR Banff IA (n = 1 patient), active ABMR (n = 2, of which one also had active ABMR in the 4‐week protocol biopsy; both having class I and II DSAs, C4d positive only at 6 months), and one mixed active ABMR and acute TCMR IA. Biopsies in the control group demonstrated acute TCMR Banff IA (n = 2 patients) and a mixed active ABMR and acute TCMR IA (n = 1 patient) (Table 2). All patients had a negative HLA antibody screening before and 4 weeks after transplantation. In the MSC group, seven patients developed dnDSA at week 24 (24%) (Table 3). Their protocol renal biopsies demonstrated no rejection (n = 3), borderline suspicious for acute TCMR (n = 1), ABMR (n = 2, both C4d negative), and ABMR/TCMR IA (n = 1, C4d+). In the control group, two patients developed HLA class‐II dnDSA without signs of rejection in their protocol biopsies.
TABLE 2 Secondary end points (graft loss, renal function, and biopsy scores) during the study period of 24 weeks
End point study period of 24 weeks MSC group (n = 29) Control group (n = 28)
Graft loss, no. (%) 0 0
eGFR < 30 ml/min/1.73 m2, no. (%) 0 3 (12)
Patients with for‐cause biopsies, no. (%) 1 (3) 4 (14)
ABMR, TCMR II and BK nephropathy 1
BK nephropathy 1
Acute tubular necrosis 1
Hyaline thickening 1
No abnormalities 1
Patient's protocol biopsies, no. (%)
4 weeks 29 (100) 28 (100)
ABMR 1 0
No rejection 28 28
24 weeks 28 (97) 23 (82)
TCMR IA 1 2
ABMR 2 a 0
ABMR and TCMR IA 1 1
No rejection 24 20
Note
Data are described as number (%) (also mentioned in every specific variable row).
Abbreviations: ABMR, antibody‐mediated rejection; eGFR, estimated glomerular filtration rate; IFTA, interstitial fibrosis and tubular atrophy; MSC, mesenchymal stromal cell; TCMR, T cell‐mediated rejection; TIN, tubulointerstitial nephritis.
a One patient demonstrated ABMR at 4 and 24 weeks.
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FIGURE 3 eGFR during the study period of 24 weeks. (A) eGFR (ml/min/1.73 m2), calculated by the CKD‐EPI formula and depicted per time point as mean ± SD, of patients in the MSC and control groups. (B) Slopes of the eGFR in the MSC group were not significantly different from the control group (p = .08). Slope and intercept data per group are described, including 95% confidence intervals [Color figure can be viewed at wileyonlinelibrary.com]
TABLE 3 Secondary end points (SAE, AE, viral infections, and dnDSA) during the study period of 24 weeks
End point study period of 24 weeks MSC group (n = 29) Control group (n = 28)
Serious adverse events, total, no. 19 25
Injury, poisoning, and procedural complications 6 7
Infections and infestations 2 7
Gastrointestinal disorders 2 3
Renal and urinary disorders 2 2
Metabolism and nutrition disorders 2 2
Therapeutic and nontherapeutic responses 2 1
Investigations 1 1
Vascular disorders 0 1
Musculoskeletal and connective tissue disorders 0 1
Immune system disorders 1 0
Psychiatric disorders 1 0
Adverse events, total, no. 272 301
Investigations 51 46
Blood and lymphatic system disorders 39 36
Infections and infestations 32 38
Vascular disorders 35 31
Metabolism and nutrition disorders 26 30
Gastrointestinal disorders 21 32
Renal and urinary disorders 5 17
Injury, poisoning and procedural complications 9 15
General disorders and administration site conditions 10 12
Nervous system disorders 6 10
Musculoskeletal and connective tissue disorders 9 7
Cardiac disorders 10 5
Respiratory, thoracic and mediastinal disorders 5 7
Skin and subcutaneous tissue disorders 8 4
Psychiatric disorders 2 4
Reproductive system and breast disorders 1 2
Neoplasm benign, malignant and unspecified 1 2
Eye disorders 1 2
Immune system disorders 0 1
Ear and labyrinth disorders 1 0
Viral infections, no. (%)
EBV virus infection a 1 (3) 2 (7)
CMV virus infection a 2 (7) 3 (11)
BK virus infection b 11 (38) 10 (36)
BK nephropathy 1 (3) 3 (11)
dnDSA, no. (%)
Yes c 7 (24) 2 (7)
Anti‐class I 0 0
Anti‐class II 4 (14) 2 (7)
Anti‐class I and II 3 (10) 0
No 22 (76) 26 (89)
Note
(Serious) adverse events are reported using the MedDRA classification with standardized categories. All data are described as the total count. Numbers in parentheses are percentages.
Abbreviations: CMV, cytomegalovirus; dnDSA, de novo donor‐specific antibodies measured at week 24; EBV, Epstein‐Barr virus; MSC, mesenchymal stromal cells.
a Peak serum levels (logarithmic) of EBV and CMV range from 2.5 to 3.2 and from 2.7 to 4, respectively.
b Peak serum levels of BK range from 5.1 to 6.9 in patients with BK nephropathy and from 2.6 to 6.9 in patients without signs of BK nephropathy.
c dnDSA is considered positive in case of an MFI ≥ 500.
John Wiley & Sons, Ltd
3.4 Immunosuppressive drug levels and change of regime
Immunosuppressive drug levels were within or only slightly out of prespecified target ranges. EVL levels, however, were significantly lower at three time points in the control group (Table S3). All patients in the MSC group were on EVL at the end of the 24‐week study period. In the MSC group, tacrolimus was reintroduced in one patient, because of acute rejection. In the control group, tacrolimus was discontinued in two patients because of BK nephropathy. EVL was switched to mycophenolate mofetil in four patients after a thrombovascular event and discontinued in two patients (CMV infection and infected lymphocele, respectively).
3.5 (Serious) adverse events
Forty‐four SAEs were reported, of which 19 in the MSC and 25 in the control group. In total, 272 AEs were reported in the MSC and 301 in the control group (Table 3). There were no AEs directly related to the MSC infusions. In the control group, 15 viral infections (EBV, CMV, and BK viremia) developed and 14 in the MSC group (Table 3). BK nephropathy occurred in one patient in the MSC (3%) and in three patients in the control group (11%).
3.6 Immune monitoring
Immune monitoring studies demonstrated that absolute numbers of peripheral blood CD45+ leukocytes and CD14+ monocytes remain stable after transplantation between weeks 6 and 52 in the MSC and control groups (Figure 4A,B). CD19+ B cells and CD56+ NK cells decreased after alemtuzumab‐based induction in both groups and re‐appeared from week 12 onwards; however, no statistically significant change was measured between the groups (Figure 4C,D). CD3+CD8+ T cells, CD3+CD4+ T cells, as well as CD4+CD25hiCD127lo Tregs showed a decrease after alemtuzumab‐based induction in both groups while still being suppressed at week 52 (Figure 4E,G). Total Treg numbers were significantly higher in the MSC group with tacrolimus withdrawal as compared to the control group at 24 and 52 weeks after transplantation (p = .014 and p = .047, respectively), due to the increase in absolute number of CD4+CD25hiCD127loCD45RA− memory Tregs (p = .040 and p = .047) (Figure 4G,H). Absolute numbers of naïve Tregs (CD4+CD25hiCD127loCD45RA+) were similar in both groups (Figure S4). Percentages of total and naïve Tregs were not different between the two groups at any time points, whereas percentages of memory Tregs within the total CD4 population were elevated in the control group only at week 12, which normalized the weeks thereafter (Figure S5).
FIGURE 4 Peripheral blood immune cell composition before and after MSC infusion. Absolute numbers of (A) CD45+ leucocytes, (B) CD14+ monocytes, (C) CD19+ B cells, (D) CD56+ NK cells, (E) CD8+ T cells, (F) CD4+ T cells, (G) CD4+CD25hiCD127lo Tregs, and (H) CD4+CD25hiCD127loCD45RA‐ memory Tregs per mL of blood are shown at baseline before transplantation, before the first MSC infusion (week 6), and time points after both infusions (weeks 12, 24, and 52). Violin plots are given for every time point with the number of individuals studied at each time point below the x‐axis. p values are given for the differences between MSC and control groups when <.05 after Bonferroni correction for multiple testing. MSC, mesenchymal stromal cell; NK, natural killer; Treg, regulatory T cell
3.7 Post hoc analysis
In the post hoc longer (intermediate)‐term follow‐up analysis (up to 5 years), graft loss was observed in two patients in the control group (Table 4). Renal function in the MSC group was preserved with an eGFR between 47 and 57 ml/min/1.73 m2 (Table 4). In the patients in the control group, eGFR gradually declined with a mean of 42 ml/min/1.73 m2 at year 1 and 37 ml/min/1.73 m2 at year 5, while seven patients dropped with their eGFR < 30 ml/min/1.73 m2. For‐cause biopsies were indicated in one patient in the MSC and eight patients in the control group. In the for‐cause biopsy in the MSC group, recurrence of IgA nephropathy was found (n = 1). In the control group, acute TCMR IB (n = 1), acute TCMR II (n = 1), mixed active ABMR and acute TCMR IB (n = 1), BK nephropathy (n = 2), tubulointerstitial nephritis/pyelonephritis (n‐1), IFTA grade III (n = 1), and medullary inflammation NOS (sv negative) (n = 1) were observed. In the post hoc analyses, none of the seven patients with de novo DSA needed a for‐cause biopsy renal biopsy or developed an eGFR < 30 ml/min/1.73 m2. However, it is of importance to note that in three of these seven patients CNI was restarted by their treating nephrologist after the 24‐week study period (Table S4).
TABLE 4 Post hoc analysis (1–5 years) of end points (graft loss, renal function, and biopsy scores)
End point post hoc analysis MSC group Control group
1 year n = 26 n = 26
2 years n = 20 n = 20
3 years n = 10 n = 14
4 years n = 7 n = 10
5 years n = 6 n = 7
Graft loss, no. 0 2 a
Time after Tx, years 3.8 and 4.5
eGFR, mean (SD) [n], ml/min/1.73 m2
1 year 57 (15) [26] 42 (11) [26]
2 years 55 (15) [20] 39 (12) [20]
3 years 53 (14) [10] 34 (14) [14]
4 years 47 (10) [7] 36 (12) [9]
5 years 50 (20) [6] 37 (15) [5]
eGFR < 30 ml/min/1.73 m2, no. 0 7
Time after Tx, median (IQR), years 3 (1–3)
Patients with for‐cause biopsies, no. (%) 1 (3) 8 (29)
Recurrence IgA nephropathy 1
TCMR IB 1
TCMR II 1
ABMR and TCMR IB 1
BK nephropathy 2
TIN/pyelonephritis 1
IFTA grade III 1
Medullary inflammation 1
Note
All data are described as the total count. Numbers in parentheses are percentages (also mentioned in the specific variable row).
Abbreviations: ABMR, antibody‐mediated rejection; eGFR, estimated glomerular filtration rate; IFTA, interstitial fibrosis and tubular atrophy; MSC, mesenchymal stromal cell; TCMR, T cell‐mediated rejection; TIN, tubulointerstitial nephritis.
a One patient TCMR and recurrence membranous nephropathy; one patient chronic transplant dysfunction.
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4 DISCUSSION
In this randomized clinical study, we found that quantitative fibrosis scores and renal function remained stable in patients with MSC therapy and concomitant early tacrolimus withdrawal within the study period of 24 weeks. Only one acute rejection episode was documented in the MSC group after further reduction of clinical immunosuppression in the context of persistent BK viremia/nephropathy. Of interest, there were significantly higher numbers of Tregs in the MSC group with tacrolimus withdrawal compared to the controls. In addition, post hoc analyses demonstrated preserved renal function in the MSC group without evidence of late rejection. Clinical studies with MSCs in kidney transplantation, mainly phase 1 trials with still limited numbers of patients, have demonstrated that MSC treatment after kidney transplantation is safe and feasible. 9 , 10 , 11 , 12 , 20 , 21 In most studies, MSCs were administered at an early time point against the background of regular immune suppression with the aim to induce immunologic tolerance. The current strategy with MSCs and complete withdrawal of CNI have not been studied before in a randomized trial. Minimization of CNIs is a well‐established strategy to limit structural long‐term damage to the graft and minimize the side effects associated with clinical immunosuppression. 5 , 22 A number of trials have demonstrated the efficacy of EVL in conjunction with reduced exposure to CNIs in preventing organ loss or dysfunction in kidney transplant recipients. 23 Of importance, complete avoidance and replacement of a CNI by EVL in de novo transplant recipients are not justified, since unacceptable high acute rejection rates were observed with this strategy. 24 The capability of MSCs to allow reduction of 50% CNI was demonstrated in a previous study with third‐party MSCs in 16 living kidney transplant recipients. 21 The combination of an mTOR inhibitor and MSCs was chosen in the current study since experimental evidence demonstrated tolerogenic properties and an increase in regulatory immune cell subsets. 14 In our study, fibrosis scores were similar in both the MSC group and the controls, thereby failing to meet the primary end point, and the incidence of acute rejection 24 weeks after implantation was low. One explanation might be the use of alemtuzumab, 13 which was chosen as we anticipated a higher immunological risk due to the early CNI withdrawal. Indeed, given the potency of the immunosuppression regimen used in our study, seeing differences in fibrosis scores and rejection with the short study duration is unlikely. Of interest, however, the post hoc analysis with follow‐up up to 5 years showed a higher incidence of for‐cause biopsies in the control group, with findings of both BPAR and BK nephropathy, suggesting that the effect of MSC infusion in combination with CNI withdrawal carried through way beyond the period that alemtuzumab is effective. Future studies with a sufficient number of patients and duration of follow‐up are needed to be able to draw more definite conclusions. Several studies have reported an increased incidence of dnDSA in renal transplant recipients receiving EVL, especially when converted early after transplantation, and it was also suggested that the use of alemtuzumab‐based induction could aggravate this. 25 , 26 In general, dnDSA has been shown to be associated with poor graft survival and increased acute rejection in kidney transplant recipients. 27 In the large ELEVATE Trial, however, conversion to EVL at 10–14 weeks posttransplant was associated with renal function parameters similar to that observed with standard therapy. In this study, the dnDSA data, available in a subset of patients, suggested more frequent anti‐HLA Class‐I DSA under EVL. Differences in propensity to develop dnDSA, however, did not appear to have resulted in ABMR within the 2‐year observation frame of the study. 28 In our study, we also found an increased incidence of dnDSA in patients where tacrolimus was withdrawn. This was associated with (asymptomatic) signs of ABMR in the protocol biopsies of three of these patients of which one, in retrospect, already had subclinical ABMR in the 4‐week biopsy. There were no signs of deteriorating graft function in these patients. Furthermore, the post hoc analyses showed no graft losses, no need for additional for‐cause biopsies, and stable renal function in these patients as well as the MSC group as a whole. Nevertheless, given the epidemiological association with graft loss (which is, however, based on for‐cause DSA measurements), the nephrologists taking care of these patients restarted the CNI in three patients after the study period. Longer follow‐up in all patients is warranted to draw more definite conclusions here. Variable outcomes on renal function after MSC therapy have been described and it has been suggested that timing of MSC administration is of major importance. Indeed, early clinical trials have demonstrated an engraftment syndrome with infiltration of immune cells and C3 deposits when MSCs were administered 7 days after renal transplantation, which was not observed when MSCs were given before implantation. 29 In the study by Erpicum et al., eGFR values at day 7 were higher in the MSC‐treated patients. 12 In our study, patients in the MSC group started with a higher eGFR, as compared to controls, which was preserved throughout the study period and the post hoc follow‐up period. This unequal randomization was, to the best of our knowledge, found by chance and could have influenced our results. In the control group, there was increased graft loss as well as a higher number of patients with inferior renal function (i.e., eGFR < 30 ml/min/1.73 m2), possibly due to an increase in BPAR and BK nephropathy in these patients.
So far, hardly any safety issues have been reported after systemic infusion of MSCs in humans, except for a transient fever and one cardiac event with an unclear causal relationship to the intervention. 12 In our study, there were no side effects directly related to the MSC infusion. We found that (S)AEs (including viral infections) were similar in the two groups. This is in contrast to our previous study where an increased incidence of viral infections was observed after MSC therapy. 10 Possibly this is due to the fact that MSCs were given on top of regular immune suppression in our previous study. This observation is of particular relevance with the ongoing COVID‐19 pandemic. Recent observational studies have shown that kidney transplant recipients are at increased risk for severe morbidity due to their systemic immune suppression and often reduced renal function. 30
MSCs have shown to condition the immune system, by releasing extracellular vesicles or membrane particles or by undergoing apoptosis. This may actively engage recipient monocytes/phagocytes and eventually Tregs, enabling long‐term tolerogenic activity that becomes self‐sustained even after disappearance of the infused MSCs themselves. 8 , 31 Of interest, in our current study, we found an increase in the absolute number of Tregs in the MSC group with tacrolimus withdrawal versus control, which has not been reported before in a randomized clinical trial with MSCs in transplant recipients. However, since there was a difference in tacrolimus use between both groups and a difference in total CD4+ T cell counts at week 12, it is not possible to deduce the results solely to the MSC treatment. Concomitantly, the percentage of memory Tregs within total CD4 T cells showed an increase in the control group compared to the MSC group at 12 weeks (Figure S5), after which the percentages in total and Treg subsets remained similar, indicating that the increase in absolute Treg numbers in the MSC group is at least partially due to changes in the total CD4+ T cell number.
At present, randomized trials with MSCs are still very limited and the field is only slowly advancing also due to stringent regulatory requirements, the need for clinical grade cell production facilities, and the associated costs. However, we recently also reported the feasibility of administration of third‐party “off‐the‐shelf” MSCs in kidney transplant recipients. 11 This option makes manufacturing and regulation easier and the use of MSC suitable for a wider spectrum of clinical application and much more feasible. We believe that the results of our current trial set the stage for the next steps and use of MSCs in the field of kidney transplantation to reduce the need for excessive use of clinical immunosuppressants.
DISCLOSURE
The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.
Supporting information
Appendix S1
Click here for additional data file.
Appendix S2
Click here for additional data file.
ACKNOWLEDGMENTS
We thank the research department of internal medicine of the Leiden University Medical Center for their help with the study visits. We thank the research technicians from the Transplant Immunology lab for technical assistance with the immune monitoring. This investigator‐initiated study was partially funded by unrestricted research grants from Astellas and Novartis. The funders had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. Part of this work was supported by a grant from ZonMW‐TAS program nr 116004104. | ALEMTUZUMAB, EVEROLIMUS, PREDNISONE, TACROLIMUS | DrugsGivenReaction | CC BY-NC | 33565206 | 19,393,098 | 2021-09 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Polyomavirus viraemia'. | Autologous bone marrow-derived mesenchymal stromal cell therapy with early tacrolimus withdrawal: The randomized prospective, single-center, open-label TRITON study.
After renal transplantation, there is a need for immunosuppressive regimens which effectively prevent allograft rejection, while preserving renal function and minimizing side effects. From this perspective, mesenchymal stromal cell (MSC) therapy is of interest. In this randomized prospective, single-center, open-label trial, we compared MSCs infused 6 and 7 weeks after renal transplantation and early tacrolimus withdrawal with a control tacrolimus group. Primary end point was quantitative evaluation of interstitial fibrosis in protocol biopsies at 4 and 24 weeks posttransplant. Secondary end points included acute rejection, graft loss, death, renal function, adverse events, and immunological responses. Seventy patients were randomly assigned of which 57 patients were included in the final analysis (29 MSC; 28 controls). Quantitative progression of fibrosis failed to show benefit in the MSC group and GFR remained stable in both groups. One acute rejection was documented (MSC group), while subclinical rejection in week 24 protocol biopsies occurred in seven patients (four MSC; three controls). In the MSC group, regulatory T cell numbers were significantly higher compared to controls (p = .014, week 24). In conclusion, early tacrolimus withdrawal with MSC therapy was safe and feasible without increased rejection and with preserved renal function. MSC therapy is a potentially useful approach after renal transplantation.
pmcAbbreviations
ABMR antibody‐mediated rejection
AE adverse event
BM bone marrow
BPAR biopsy‐proven acute rejection
CCMO Dutch Central Committee on Research involving Human Subjects
CNI calcineurin inhibitor
dnDSA de novo donor‐specific antibodies
DSMB data safety monitoring board
EVL everolimus
GFR glomerular filtration rate
GMP Good Manufacturing Practice
HLA human leukocyte antigen
I/R ischemia reperfusion
IFTA interstitial fibrosis and tubular atrophy
LUMC Leiden University Medical Center
MSC mesenchymal stromal cells
SAB single antigen bead
SAE serious adverse event
SCAR subclinical acute rejection
SD standard deviation
SR Sirius Red
TCMR T cell‐mediated rejection
Treg regulatory T cell
UMCG University Medical Center Groningen
1 INTRODUCTION
Over the last two decades significant progress has been achieved in short‐term survival of kidney transplants. 1 , 2 Unfortunately, these advancements have not led to a similar improvement in long‐term kidney transplant survival rates. Various factors, including donor graft quality, ischemia/reperfusion (I/R) injury, alloreactivity, viral infections, and drug therapy, may adversely affect renal structure causing graft scarring and compromising long‐term function. 3 The intensity of current immunosuppressive drugs, albeit efficacious in preventing rejection, is associated with increased risk for (viral) infections and malignancies. Calcineurin inhibitors (CNIs) are the cornerstone of current immunosuppressive therapy, but they have direct nephrotoxic effects. It has been demonstrated that CNI withdrawal should be undertaken before month 6 to prevent the occurrence of irreversible tubulointerstitial damage. 4 , 5 So far, early CNI withdrawal studies have proven to be risky and invariably lead to increased rejection and even loss of grafts. 6 Consequently, there is a need for immunosuppressive regimens that can prevent allograft rejection, while preserving renal function and promoting patient and graft survival in the long term. MSCs have immunosuppressive properties and roles in tissue repair, and various (mainly experimental) studies have demonstrated that MSCs may increase regulatory T cell (Treg) levels and polarize the immune system toward tolerance. 7 , 8 In renal transplantation, early studies using MSCs focused on safety and feasibility. 9 , 10 , 11 , 12 Although most of these studies were not designed as efficacy trials, there were indications that MSCs possess immunosuppressive properties, as evidenced by an increase in Tregs and downregulation of cytotoxic CD8T+ cells in a small number of patients. We performed a randomized, prospective, single‐center, open‐label study in living‐donor kidney transplant recipients in which we compared autologous bone marrow (BM)‐derived MSC therapy (infused at weeks 6 and 7) with concomitant early tacrolimus withdrawal (at week 8) to standard tacrolimus dose. Primary end point was quantitative evaluation of interstitial fibrosis and secondary end points included biopsy‐proven acute rejection, graft loss, death, renal function, adverse events, and immunological responses at week 24. We chose to perform the study on a background of alemtuzumab‐based induction to minimize the risk for acute rejection 13 and mTOR inhibition, since experimental studies demonstrated tolerogenic properties in combination with MSCs. 14 In a post hoc long‐term analysis, peripheral blood immune cell composition was also obtained at week 52 in patients with sufficient follow‐up. In addition, the efficacy end point (biopsy‐proven acute rejection (BPAR), graft loss, or death) was obtained up to 5 years in patients who had a longer follow‐up.
2 MATERIAL AND METHODS
2.1 Study design and patients
The TRITON study is a 24‐weeks investigator‐initiated, randomized, prospective, open‐label, single‐center, clinical study, performed at the Leiden University Medical Center (LUMC), the Netherlands. The trial design has been published previously. 15 The trial protocol, available at the Appendix S1 and S2 section, was approved by the local ethics committee at the LUMC, Leiden, and by the Central Committee on Research involving Human Subjects (CCMO) in the Netherlands. The trial was performed in accordance with the principles of the Declaration of Helsinki. In total, 70 de novo renal recipients of a kidney from a living donor, 18–75 years of age, were recruited from the transplant clinics of the LUMC. The inclusion/exclusion criteria were described previously. 15 Written informed consent was obtained from all participants.
2.2 Randomization and masking
Patients were randomly assigned before transplantation to either the MSC or control group in a ratio 1:1 (Figure S1). A patient was randomized only after verification of eligibility and informed consent. The randomization procedure was designed and implemented by the IMO (Informatie Management Onderzoek) department of the University Medical Center Groningen (UMCG), the Netherlands, using a web‐based system (ALEA). Investigator or authorized delegate from the study staff received an individual login code with which they could randomize their patients. The web application returned the allocated treatment. As a confirmation, the web application also sent an e‐mail with the randomization information to selected users. Patients maintained this randomization number throughout the study. Because of the nature of the intervention (BM biopsy and MSC infusions), participants and physicians were not masked to treatment assignment.
2.3 Procedures
All patients in the study received alemtuzumab (anti‐CD52),15 mg subcutaneously, at days 0 and 1 as well as tacrolimus (Prograft®), everolimus (EVL; Certican®), and low‐dose prednisone, as maintenance therapy (Figure S1). 15 Patients in the MSC group received two doses of autologous BM MSCs, intravenously at weeks 6 and 7 after transplantation. Autologous MSCs were chosen instead of third‐party MSCs to prevent alloimmunization. The dose of tacrolimus was reduced to 50% at the time of the second MSC infusion and completely withdrawn 1 week later. Patients received a higher dose of prednisolone (15 mg instead of 10 mg) for 14 days after the second infusion to diminish risks of tacrolimus withdrawal. In patients in the control group, the trough level of tacrolimus was lowered to a target of 6–8 ng/ml 8 weeks after transplantation. BM was aspirated from the posterior iliac crest of all patients in the MSC group under general anesthesia during the renal transplantation, as described previously. 15 This protocol was approved by the local ethics committee (P13.283) and by the CCMO (NL4371200013). Processing of the MSCs took place at the Interdivisional Good Manufacturing Practice (GMP) Facility of the LUMC (Table S1). 15 The MSC product was infused via peripheral infusion within 30 min with a target dose of 1.5 × 106 per/kg body weight IV (range 1–2 × 106), according to our previous study. 15 Monitoring of the patients occurred according to the assessment schedule, as described in the protocol (page 28).
2.4 Outcomes
The primary end point was the quantitative progression of interstitial fibrosis between the 4‐ and 24‐week protocol biopsies as measured by morphometric analysis of collagen deposition. Interstitial collagen fibers in protocol biopsies were visualized by Sirius Red (SR) staining and quantified as a percentage of total tubulointerstitial tissue (glomeruli and large vessels excluded) by quantifying positive pixels in five representative locations at 40× magnification with a macro created in ImageJ version 1.50i. 16 Included secondary end points were composite end point efficacy failure (BPAR, graft loss, or death); proteinuria, Banff scores at the protocol biopsies, renal function as measured by estimated (e)glomerular filtration rate (GFR), (serious) adverse events ((S)AE), including (viral) infections, the presence of de novo donor‐specific antibodies (dnDSA), and peripheral blood immune cell composition. Scoring of renal biopsies was performed in a blinded fashion by a renal pathologist from our center after completion of the study, using the most recent Banff classification. 17 Findings in a protocol biopsy with evidence of rejection were reported as subclinical acute rejection (SCAR). Renal function was calculated by the eGFR (ml/min/1.73 m2) using the CKD‐EPI formula. 15 AEs and SAEs were documented according to Medical Dictionary for Regulatory Activities (MedDRA®); the international medical terminology developed under the auspices of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use. Tacrolimus and EVL quantification was assessed using a previously validated LC–MS/MS assay. 18
2.5 Immunological monitoring
For human leukocyte antigen (HLA) antibody analysis, serum samples were screened using Luminex screen assay (Lifecodes, Immucor) and analyzed with a Luminex 200 reader. Definitions of the negative/positive discriminations were used as suggested by the provider. When positive, a single antigen bead (SAB) assay (Lifecodes, Immucor) was performed as standard‐of‐care. Assignment of positivity was assessed according to the manufacturer's instructions. Since MSCs are suggested to have immunomodulatory properties, we performed phenotypical analysis of leukocyte subpopulations on fresh whole blood. Staining, acquisition, and data analysis were performed strictly adhering to “The One” study protocol. 19 Absolute cell counts were obtained using the BD Multitest kit (BD Biosciences).
2.6 Post hoc analysis
Phenotypical analysis of leukocyte subpopulations was, in addition to the 24‐week time point, also performed 52 weeks after renal transplantation. Assessment of composite end point efficacy failure (BPAR, graft loss, or death) and renal function by eGFR was also obtained in patients with a follow‐up up to 5 years in a post hoc analysis (n = 52 at 1 year, n = 40 at 2 years, n = 24 at 3 years, n = 17 at 4 years, and n = 13 at 5 years, Table 4).
2.7 Statistical analysis
The study was designed to have a sample size of 25 in each group, or 50 in total, to have a power to detect a relative difference in mean percentages of fibrosis of at least 25% using an independent sample t test with a 0.05 two‐sided significance level (α), as described previously. 15 We anticipated that 70% of the included patients would have valid measurements (withdrawal included) and therefore included 70 patients. Data analysis was performed using SPSS version 25.0 (SPSS, Inc.) and all graphs were created using GraphPad Prism version 8.0 (GraphPad Prism Software, Inc.). Parametric data were described as mean ± SD, nonparametric data as median and interquartile range (IQR), and categorical data as numbers and percentages. p < .05 were considered statistically significant. The slopes of eGFR data were calculated and analyzed using a linear regression analysis. Immune monitoring data were analyzed using the Mann–Whitney test with Bonferroni correction for multiple testing. A data safety monitoring board (DSMB) monitored the safety of subjects. The trial is registered with ClinicalTrials.gov, NCT02057965.
3 RESULTS
3.1 Patients
Between March 3, 2014 and January 17, 2020, 70 patients, aged 19 to 74 years, were enrolled in the study: 36 patients were randomly assigned to the MSC group and 34 to the control group (Figure 1). Thirteen patients did not receive allocated treatment, because of abnormal MSC growth (defined as karyotypic abnormalities in the final product; n = 4), contra indication for MSC infusion due to the COVID‐19 pandemic (n = 1), impossibility of obtaining a baseline renal biopsy (n = 2 in MSC and n = 1 in control group), withdrawn informed consent (n = 4 in control group) and (relative) contra indication for prednisone usage (n = 1 control group). In total, 29 patients were assigned to the MSC and 28 to the control group (Figure 1). Patient baseline characteristics were similar in both groups (Table 1). Of the 29 patients in the MSC group, 28 patients received two infusions of MSCs, all within the proposed range. One patient received one dose of MSCs within the proposed range. The second dose was not given because of the COVID‐19 pandemic. This patient gave informed consent to continue the study. All patients had stable vital signs before and after MSC infusion monitored using MEWS (Table S1). In 28 patients in the MSC group and 23 patients in the control group, two renal biopsies could be obtained (Figure 1), in order to assess the quantitative progression of interstitial fibrosis.
FIGURE 1 Trial profile. MSC, mesenchymal stromal cell
TABLE 1 Baseline characteristics
Characteristic MSC (n = 29) Control (n = 28)
Recipient
Age, mean (SD), years 50 (14) 50 (15)
Male sex, no. (%) 26 (90) 20 (71)
Body weight, mean (SD), kg 81 (14) 82 (14)
Primary diagnosis, no. (%)
IgA nephropathy 7 (24) 3 (11)
Hypertension 3 (10) 9 (32)
Polycystic kidney disease 9 (31) 3 (11)
Diabetes 5 (17) 0
Reflux nephropathy 0 2 (7)
Membranous nephropathy 1 (3) 1 (4)
Lupus nephritis 1 (3) 0
Other 2 (7) 3 (11)
Unknown 1 (3) 7 (25)
Donor
Age, mean (SD), years 55 (13) 51 (11)
Male sex, no. (%) 14 (48) 10 (36)
eGFR (pre‐donation), mean (SD) 109.7 (12.0) 109.3 (12.7)
Transplant
Type, related, no. (%) 13 (45) 15 (54)
HLA A/B mismatch, mean (SD) 2.3 (1.3) 2.4 (0.9)
HLA DQ/DR mismatch, mean (SD) 1.2 (0.6) 1.3 (0.5)
Cold‐ischemia time, mean (SD), h 3.1 (0.6) 3.0 (0.5)
First warm ischemia time, mean (SD), min 3.7 (2.1) 5.2 (4.3)
Second warm ischemia time, mean (SD), min 27.0 (3.7) 31.1 (14.4)
Cytomegalovirus IgG status, no. (%)
D+/R+ 9 (31) 6 (21)
D+/R− 7 (24) 9 (32)
D−/R+ 1 (3) 2 (7)
D−/R− 12 (41) 11 (39)
Epstein‐Barr virus IgG D+/R, no. (%) 1 (3) 1 (4)
Note
Data are described as mean standard deviation (SD). Categorical data are described as number (%) (mentioned in every specific variable row).
Abbreviations: GFR, glomerular filtration rate; HLA, human leukocyte antigen.
John Wiley & Sons, Ltd
3.2 Quantitative progression of fibrosis score
The quantitative progression of fibrosis score in the biopsies was similar in both groups (MSC group 1.0 ± 7.9; control group 0.3 ± 7.8, p = .755). The fibrosis score remained stable both within the MSC (week 4, 15.2 ± 6.6 and week 24, 16.2 ± 5.3, p = .526) and control group (week 4, 17.0 ± 4.6 and week 24 17.3 ± 5.7, p = .870) (Figure 2; Figure S2). Delta Banff scores from 4 to 24 weeks were similar in the two groups, in particular the delta ti‐score (p = .8), the delta interstitial fibrosis/tubular atrophy (IFTA) score (p = .4), and the delta ah‐score (p = .4) (Figure S3).
FIGURE 2 Interstitial fibrosis scores. Quantitative progression of interstitial fibrosis (delta Sirius Red) between the 4‐ and 24‐week renal biopsy (percentage). MSC, mesenchymal stromal cell
3.3 Patient survival, renal function, and biopsy scores
Patient survival during the study follow‐up was 100% in both groups. All patients had a functioning kidney graft at the end of the 24‐week study period (Table 2). eGFR was 56 ± 16 ml/min/1.73 m2 in the MSC (n = 29) and 42 ± 9 ml/min/1.73 m2 in the control group (n = 28) at the time of MSC infusion (Figure 3A). Mean eGFR and 24‐h proteinuria (Table S2) in the MSC group were similar as compared with the control group, with a mean of 56 ± 15 ml/min/1.73 m2 and 47 ± 16 ml/min/1.73 m2, respectively, at week 24 (Figure 3A). The slope from 4 to 24 weeks in the MSC group (slope = −0.22; intercept = 58.15) was not significantly different from the control group (slope = 0.09; intercept = 43.33) (p = .08, Figure 3B). Only one acute rejection episode (combination of T cell [TCMR] and antibody‐mediated rejection [ABMR]), documented by for‐cause biopsy, was found during the study period in the MSC group (1/29 or 3.4%) (Table 2). In this patient, immune suppression had been further reduced due to persistent BK viremia/nephropathy. In the control group, four patients had an indication for a for‐cause renal biopsy, without evidence of rejection (Table 2). The 24‐week protocol biopsies showed SCAR in 14.3% and 13.0% of patients in the MSC (4/28) and control group (3/23), respectively. Protocol biopsies in the MSC group showed a chronic active TCMR Banff IA (n = 1 patient), active ABMR (n = 2, of which one also had active ABMR in the 4‐week protocol biopsy; both having class I and II DSAs, C4d positive only at 6 months), and one mixed active ABMR and acute TCMR IA. Biopsies in the control group demonstrated acute TCMR Banff IA (n = 2 patients) and a mixed active ABMR and acute TCMR IA (n = 1 patient) (Table 2). All patients had a negative HLA antibody screening before and 4 weeks after transplantation. In the MSC group, seven patients developed dnDSA at week 24 (24%) (Table 3). Their protocol renal biopsies demonstrated no rejection (n = 3), borderline suspicious for acute TCMR (n = 1), ABMR (n = 2, both C4d negative), and ABMR/TCMR IA (n = 1, C4d+). In the control group, two patients developed HLA class‐II dnDSA without signs of rejection in their protocol biopsies.
TABLE 2 Secondary end points (graft loss, renal function, and biopsy scores) during the study period of 24 weeks
End point study period of 24 weeks MSC group (n = 29) Control group (n = 28)
Graft loss, no. (%) 0 0
eGFR < 30 ml/min/1.73 m2, no. (%) 0 3 (12)
Patients with for‐cause biopsies, no. (%) 1 (3) 4 (14)
ABMR, TCMR II and BK nephropathy 1
BK nephropathy 1
Acute tubular necrosis 1
Hyaline thickening 1
No abnormalities 1
Patient's protocol biopsies, no. (%)
4 weeks 29 (100) 28 (100)
ABMR 1 0
No rejection 28 28
24 weeks 28 (97) 23 (82)
TCMR IA 1 2
ABMR 2 a 0
ABMR and TCMR IA 1 1
No rejection 24 20
Note
Data are described as number (%) (also mentioned in every specific variable row).
Abbreviations: ABMR, antibody‐mediated rejection; eGFR, estimated glomerular filtration rate; IFTA, interstitial fibrosis and tubular atrophy; MSC, mesenchymal stromal cell; TCMR, T cell‐mediated rejection; TIN, tubulointerstitial nephritis.
a One patient demonstrated ABMR at 4 and 24 weeks.
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FIGURE 3 eGFR during the study period of 24 weeks. (A) eGFR (ml/min/1.73 m2), calculated by the CKD‐EPI formula and depicted per time point as mean ± SD, of patients in the MSC and control groups. (B) Slopes of the eGFR in the MSC group were not significantly different from the control group (p = .08). Slope and intercept data per group are described, including 95% confidence intervals [Color figure can be viewed at wileyonlinelibrary.com]
TABLE 3 Secondary end points (SAE, AE, viral infections, and dnDSA) during the study period of 24 weeks
End point study period of 24 weeks MSC group (n = 29) Control group (n = 28)
Serious adverse events, total, no. 19 25
Injury, poisoning, and procedural complications 6 7
Infections and infestations 2 7
Gastrointestinal disorders 2 3
Renal and urinary disorders 2 2
Metabolism and nutrition disorders 2 2
Therapeutic and nontherapeutic responses 2 1
Investigations 1 1
Vascular disorders 0 1
Musculoskeletal and connective tissue disorders 0 1
Immune system disorders 1 0
Psychiatric disorders 1 0
Adverse events, total, no. 272 301
Investigations 51 46
Blood and lymphatic system disorders 39 36
Infections and infestations 32 38
Vascular disorders 35 31
Metabolism and nutrition disorders 26 30
Gastrointestinal disorders 21 32
Renal and urinary disorders 5 17
Injury, poisoning and procedural complications 9 15
General disorders and administration site conditions 10 12
Nervous system disorders 6 10
Musculoskeletal and connective tissue disorders 9 7
Cardiac disorders 10 5
Respiratory, thoracic and mediastinal disorders 5 7
Skin and subcutaneous tissue disorders 8 4
Psychiatric disorders 2 4
Reproductive system and breast disorders 1 2
Neoplasm benign, malignant and unspecified 1 2
Eye disorders 1 2
Immune system disorders 0 1
Ear and labyrinth disorders 1 0
Viral infections, no. (%)
EBV virus infection a 1 (3) 2 (7)
CMV virus infection a 2 (7) 3 (11)
BK virus infection b 11 (38) 10 (36)
BK nephropathy 1 (3) 3 (11)
dnDSA, no. (%)
Yes c 7 (24) 2 (7)
Anti‐class I 0 0
Anti‐class II 4 (14) 2 (7)
Anti‐class I and II 3 (10) 0
No 22 (76) 26 (89)
Note
(Serious) adverse events are reported using the MedDRA classification with standardized categories. All data are described as the total count. Numbers in parentheses are percentages.
Abbreviations: CMV, cytomegalovirus; dnDSA, de novo donor‐specific antibodies measured at week 24; EBV, Epstein‐Barr virus; MSC, mesenchymal stromal cells.
a Peak serum levels (logarithmic) of EBV and CMV range from 2.5 to 3.2 and from 2.7 to 4, respectively.
b Peak serum levels of BK range from 5.1 to 6.9 in patients with BK nephropathy and from 2.6 to 6.9 in patients without signs of BK nephropathy.
c dnDSA is considered positive in case of an MFI ≥ 500.
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3.4 Immunosuppressive drug levels and change of regime
Immunosuppressive drug levels were within or only slightly out of prespecified target ranges. EVL levels, however, were significantly lower at three time points in the control group (Table S3). All patients in the MSC group were on EVL at the end of the 24‐week study period. In the MSC group, tacrolimus was reintroduced in one patient, because of acute rejection. In the control group, tacrolimus was discontinued in two patients because of BK nephropathy. EVL was switched to mycophenolate mofetil in four patients after a thrombovascular event and discontinued in two patients (CMV infection and infected lymphocele, respectively).
3.5 (Serious) adverse events
Forty‐four SAEs were reported, of which 19 in the MSC and 25 in the control group. In total, 272 AEs were reported in the MSC and 301 in the control group (Table 3). There were no AEs directly related to the MSC infusions. In the control group, 15 viral infections (EBV, CMV, and BK viremia) developed and 14 in the MSC group (Table 3). BK nephropathy occurred in one patient in the MSC (3%) and in three patients in the control group (11%).
3.6 Immune monitoring
Immune monitoring studies demonstrated that absolute numbers of peripheral blood CD45+ leukocytes and CD14+ monocytes remain stable after transplantation between weeks 6 and 52 in the MSC and control groups (Figure 4A,B). CD19+ B cells and CD56+ NK cells decreased after alemtuzumab‐based induction in both groups and re‐appeared from week 12 onwards; however, no statistically significant change was measured between the groups (Figure 4C,D). CD3+CD8+ T cells, CD3+CD4+ T cells, as well as CD4+CD25hiCD127lo Tregs showed a decrease after alemtuzumab‐based induction in both groups while still being suppressed at week 52 (Figure 4E,G). Total Treg numbers were significantly higher in the MSC group with tacrolimus withdrawal as compared to the control group at 24 and 52 weeks after transplantation (p = .014 and p = .047, respectively), due to the increase in absolute number of CD4+CD25hiCD127loCD45RA− memory Tregs (p = .040 and p = .047) (Figure 4G,H). Absolute numbers of naïve Tregs (CD4+CD25hiCD127loCD45RA+) were similar in both groups (Figure S4). Percentages of total and naïve Tregs were not different between the two groups at any time points, whereas percentages of memory Tregs within the total CD4 population were elevated in the control group only at week 12, which normalized the weeks thereafter (Figure S5).
FIGURE 4 Peripheral blood immune cell composition before and after MSC infusion. Absolute numbers of (A) CD45+ leucocytes, (B) CD14+ monocytes, (C) CD19+ B cells, (D) CD56+ NK cells, (E) CD8+ T cells, (F) CD4+ T cells, (G) CD4+CD25hiCD127lo Tregs, and (H) CD4+CD25hiCD127loCD45RA‐ memory Tregs per mL of blood are shown at baseline before transplantation, before the first MSC infusion (week 6), and time points after both infusions (weeks 12, 24, and 52). Violin plots are given for every time point with the number of individuals studied at each time point below the x‐axis. p values are given for the differences between MSC and control groups when <.05 after Bonferroni correction for multiple testing. MSC, mesenchymal stromal cell; NK, natural killer; Treg, regulatory T cell
3.7 Post hoc analysis
In the post hoc longer (intermediate)‐term follow‐up analysis (up to 5 years), graft loss was observed in two patients in the control group (Table 4). Renal function in the MSC group was preserved with an eGFR between 47 and 57 ml/min/1.73 m2 (Table 4). In the patients in the control group, eGFR gradually declined with a mean of 42 ml/min/1.73 m2 at year 1 and 37 ml/min/1.73 m2 at year 5, while seven patients dropped with their eGFR < 30 ml/min/1.73 m2. For‐cause biopsies were indicated in one patient in the MSC and eight patients in the control group. In the for‐cause biopsy in the MSC group, recurrence of IgA nephropathy was found (n = 1). In the control group, acute TCMR IB (n = 1), acute TCMR II (n = 1), mixed active ABMR and acute TCMR IB (n = 1), BK nephropathy (n = 2), tubulointerstitial nephritis/pyelonephritis (n‐1), IFTA grade III (n = 1), and medullary inflammation NOS (sv negative) (n = 1) were observed. In the post hoc analyses, none of the seven patients with de novo DSA needed a for‐cause biopsy renal biopsy or developed an eGFR < 30 ml/min/1.73 m2. However, it is of importance to note that in three of these seven patients CNI was restarted by their treating nephrologist after the 24‐week study period (Table S4).
TABLE 4 Post hoc analysis (1–5 years) of end points (graft loss, renal function, and biopsy scores)
End point post hoc analysis MSC group Control group
1 year n = 26 n = 26
2 years n = 20 n = 20
3 years n = 10 n = 14
4 years n = 7 n = 10
5 years n = 6 n = 7
Graft loss, no. 0 2 a
Time after Tx, years 3.8 and 4.5
eGFR, mean (SD) [n], ml/min/1.73 m2
1 year 57 (15) [26] 42 (11) [26]
2 years 55 (15) [20] 39 (12) [20]
3 years 53 (14) [10] 34 (14) [14]
4 years 47 (10) [7] 36 (12) [9]
5 years 50 (20) [6] 37 (15) [5]
eGFR < 30 ml/min/1.73 m2, no. 0 7
Time after Tx, median (IQR), years 3 (1–3)
Patients with for‐cause biopsies, no. (%) 1 (3) 8 (29)
Recurrence IgA nephropathy 1
TCMR IB 1
TCMR II 1
ABMR and TCMR IB 1
BK nephropathy 2
TIN/pyelonephritis 1
IFTA grade III 1
Medullary inflammation 1
Note
All data are described as the total count. Numbers in parentheses are percentages (also mentioned in the specific variable row).
Abbreviations: ABMR, antibody‐mediated rejection; eGFR, estimated glomerular filtration rate; IFTA, interstitial fibrosis and tubular atrophy; MSC, mesenchymal stromal cell; TCMR, T cell‐mediated rejection; TIN, tubulointerstitial nephritis.
a One patient TCMR and recurrence membranous nephropathy; one patient chronic transplant dysfunction.
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4 DISCUSSION
In this randomized clinical study, we found that quantitative fibrosis scores and renal function remained stable in patients with MSC therapy and concomitant early tacrolimus withdrawal within the study period of 24 weeks. Only one acute rejection episode was documented in the MSC group after further reduction of clinical immunosuppression in the context of persistent BK viremia/nephropathy. Of interest, there were significantly higher numbers of Tregs in the MSC group with tacrolimus withdrawal compared to the controls. In addition, post hoc analyses demonstrated preserved renal function in the MSC group without evidence of late rejection. Clinical studies with MSCs in kidney transplantation, mainly phase 1 trials with still limited numbers of patients, have demonstrated that MSC treatment after kidney transplantation is safe and feasible. 9 , 10 , 11 , 12 , 20 , 21 In most studies, MSCs were administered at an early time point against the background of regular immune suppression with the aim to induce immunologic tolerance. The current strategy with MSCs and complete withdrawal of CNI have not been studied before in a randomized trial. Minimization of CNIs is a well‐established strategy to limit structural long‐term damage to the graft and minimize the side effects associated with clinical immunosuppression. 5 , 22 A number of trials have demonstrated the efficacy of EVL in conjunction with reduced exposure to CNIs in preventing organ loss or dysfunction in kidney transplant recipients. 23 Of importance, complete avoidance and replacement of a CNI by EVL in de novo transplant recipients are not justified, since unacceptable high acute rejection rates were observed with this strategy. 24 The capability of MSCs to allow reduction of 50% CNI was demonstrated in a previous study with third‐party MSCs in 16 living kidney transplant recipients. 21 The combination of an mTOR inhibitor and MSCs was chosen in the current study since experimental evidence demonstrated tolerogenic properties and an increase in regulatory immune cell subsets. 14 In our study, fibrosis scores were similar in both the MSC group and the controls, thereby failing to meet the primary end point, and the incidence of acute rejection 24 weeks after implantation was low. One explanation might be the use of alemtuzumab, 13 which was chosen as we anticipated a higher immunological risk due to the early CNI withdrawal. Indeed, given the potency of the immunosuppression regimen used in our study, seeing differences in fibrosis scores and rejection with the short study duration is unlikely. Of interest, however, the post hoc analysis with follow‐up up to 5 years showed a higher incidence of for‐cause biopsies in the control group, with findings of both BPAR and BK nephropathy, suggesting that the effect of MSC infusion in combination with CNI withdrawal carried through way beyond the period that alemtuzumab is effective. Future studies with a sufficient number of patients and duration of follow‐up are needed to be able to draw more definite conclusions. Several studies have reported an increased incidence of dnDSA in renal transplant recipients receiving EVL, especially when converted early after transplantation, and it was also suggested that the use of alemtuzumab‐based induction could aggravate this. 25 , 26 In general, dnDSA has been shown to be associated with poor graft survival and increased acute rejection in kidney transplant recipients. 27 In the large ELEVATE Trial, however, conversion to EVL at 10–14 weeks posttransplant was associated with renal function parameters similar to that observed with standard therapy. In this study, the dnDSA data, available in a subset of patients, suggested more frequent anti‐HLA Class‐I DSA under EVL. Differences in propensity to develop dnDSA, however, did not appear to have resulted in ABMR within the 2‐year observation frame of the study. 28 In our study, we also found an increased incidence of dnDSA in patients where tacrolimus was withdrawn. This was associated with (asymptomatic) signs of ABMR in the protocol biopsies of three of these patients of which one, in retrospect, already had subclinical ABMR in the 4‐week biopsy. There were no signs of deteriorating graft function in these patients. Furthermore, the post hoc analyses showed no graft losses, no need for additional for‐cause biopsies, and stable renal function in these patients as well as the MSC group as a whole. Nevertheless, given the epidemiological association with graft loss (which is, however, based on for‐cause DSA measurements), the nephrologists taking care of these patients restarted the CNI in three patients after the study period. Longer follow‐up in all patients is warranted to draw more definite conclusions here. Variable outcomes on renal function after MSC therapy have been described and it has been suggested that timing of MSC administration is of major importance. Indeed, early clinical trials have demonstrated an engraftment syndrome with infiltration of immune cells and C3 deposits when MSCs were administered 7 days after renal transplantation, which was not observed when MSCs were given before implantation. 29 In the study by Erpicum et al., eGFR values at day 7 were higher in the MSC‐treated patients. 12 In our study, patients in the MSC group started with a higher eGFR, as compared to controls, which was preserved throughout the study period and the post hoc follow‐up period. This unequal randomization was, to the best of our knowledge, found by chance and could have influenced our results. In the control group, there was increased graft loss as well as a higher number of patients with inferior renal function (i.e., eGFR < 30 ml/min/1.73 m2), possibly due to an increase in BPAR and BK nephropathy in these patients.
So far, hardly any safety issues have been reported after systemic infusion of MSCs in humans, except for a transient fever and one cardiac event with an unclear causal relationship to the intervention. 12 In our study, there were no side effects directly related to the MSC infusion. We found that (S)AEs (including viral infections) were similar in the two groups. This is in contrast to our previous study where an increased incidence of viral infections was observed after MSC therapy. 10 Possibly this is due to the fact that MSCs were given on top of regular immune suppression in our previous study. This observation is of particular relevance with the ongoing COVID‐19 pandemic. Recent observational studies have shown that kidney transplant recipients are at increased risk for severe morbidity due to their systemic immune suppression and often reduced renal function. 30
MSCs have shown to condition the immune system, by releasing extracellular vesicles or membrane particles or by undergoing apoptosis. This may actively engage recipient monocytes/phagocytes and eventually Tregs, enabling long‐term tolerogenic activity that becomes self‐sustained even after disappearance of the infused MSCs themselves. 8 , 31 Of interest, in our current study, we found an increase in the absolute number of Tregs in the MSC group with tacrolimus withdrawal versus control, which has not been reported before in a randomized clinical trial with MSCs in transplant recipients. However, since there was a difference in tacrolimus use between both groups and a difference in total CD4+ T cell counts at week 12, it is not possible to deduce the results solely to the MSC treatment. Concomitantly, the percentage of memory Tregs within total CD4 T cells showed an increase in the control group compared to the MSC group at 12 weeks (Figure S5), after which the percentages in total and Treg subsets remained similar, indicating that the increase in absolute Treg numbers in the MSC group is at least partially due to changes in the total CD4+ T cell number.
At present, randomized trials with MSCs are still very limited and the field is only slowly advancing also due to stringent regulatory requirements, the need for clinical grade cell production facilities, and the associated costs. However, we recently also reported the feasibility of administration of third‐party “off‐the‐shelf” MSCs in kidney transplant recipients. 11 This option makes manufacturing and regulation easier and the use of MSC suitable for a wider spectrum of clinical application and much more feasible. We believe that the results of our current trial set the stage for the next steps and use of MSCs in the field of kidney transplantation to reduce the need for excessive use of clinical immunosuppressants.
DISCLOSURE
The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.
Supporting information
Appendix S1
Click here for additional data file.
Appendix S2
Click here for additional data file.
ACKNOWLEDGMENTS
We thank the research department of internal medicine of the Leiden University Medical Center for their help with the study visits. We thank the research technicians from the Transplant Immunology lab for technical assistance with the immune monitoring. This investigator‐initiated study was partially funded by unrestricted research grants from Astellas and Novartis. The funders had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. Part of this work was supported by a grant from ZonMW‐TAS program nr 116004104. | ALEMTUZUMAB, EVEROLIMUS, PREDNISONE, TACROLIMUS | DrugsGivenReaction | CC BY-NC | 33565206 | 19,393,098 | 2021-09 |
What was the administration route of drug 'ALEMTUZUMAB'? | Autologous bone marrow-derived mesenchymal stromal cell therapy with early tacrolimus withdrawal: The randomized prospective, single-center, open-label TRITON study.
After renal transplantation, there is a need for immunosuppressive regimens which effectively prevent allograft rejection, while preserving renal function and minimizing side effects. From this perspective, mesenchymal stromal cell (MSC) therapy is of interest. In this randomized prospective, single-center, open-label trial, we compared MSCs infused 6 and 7 weeks after renal transplantation and early tacrolimus withdrawal with a control tacrolimus group. Primary end point was quantitative evaluation of interstitial fibrosis in protocol biopsies at 4 and 24 weeks posttransplant. Secondary end points included acute rejection, graft loss, death, renal function, adverse events, and immunological responses. Seventy patients were randomly assigned of which 57 patients were included in the final analysis (29 MSC; 28 controls). Quantitative progression of fibrosis failed to show benefit in the MSC group and GFR remained stable in both groups. One acute rejection was documented (MSC group), while subclinical rejection in week 24 protocol biopsies occurred in seven patients (four MSC; three controls). In the MSC group, regulatory T cell numbers were significantly higher compared to controls (p = .014, week 24). In conclusion, early tacrolimus withdrawal with MSC therapy was safe and feasible without increased rejection and with preserved renal function. MSC therapy is a potentially useful approach after renal transplantation.
pmcAbbreviations
ABMR antibody‐mediated rejection
AE adverse event
BM bone marrow
BPAR biopsy‐proven acute rejection
CCMO Dutch Central Committee on Research involving Human Subjects
CNI calcineurin inhibitor
dnDSA de novo donor‐specific antibodies
DSMB data safety monitoring board
EVL everolimus
GFR glomerular filtration rate
GMP Good Manufacturing Practice
HLA human leukocyte antigen
I/R ischemia reperfusion
IFTA interstitial fibrosis and tubular atrophy
LUMC Leiden University Medical Center
MSC mesenchymal stromal cells
SAB single antigen bead
SAE serious adverse event
SCAR subclinical acute rejection
SD standard deviation
SR Sirius Red
TCMR T cell‐mediated rejection
Treg regulatory T cell
UMCG University Medical Center Groningen
1 INTRODUCTION
Over the last two decades significant progress has been achieved in short‐term survival of kidney transplants. 1 , 2 Unfortunately, these advancements have not led to a similar improvement in long‐term kidney transplant survival rates. Various factors, including donor graft quality, ischemia/reperfusion (I/R) injury, alloreactivity, viral infections, and drug therapy, may adversely affect renal structure causing graft scarring and compromising long‐term function. 3 The intensity of current immunosuppressive drugs, albeit efficacious in preventing rejection, is associated with increased risk for (viral) infections and malignancies. Calcineurin inhibitors (CNIs) are the cornerstone of current immunosuppressive therapy, but they have direct nephrotoxic effects. It has been demonstrated that CNI withdrawal should be undertaken before month 6 to prevent the occurrence of irreversible tubulointerstitial damage. 4 , 5 So far, early CNI withdrawal studies have proven to be risky and invariably lead to increased rejection and even loss of grafts. 6 Consequently, there is a need for immunosuppressive regimens that can prevent allograft rejection, while preserving renal function and promoting patient and graft survival in the long term. MSCs have immunosuppressive properties and roles in tissue repair, and various (mainly experimental) studies have demonstrated that MSCs may increase regulatory T cell (Treg) levels and polarize the immune system toward tolerance. 7 , 8 In renal transplantation, early studies using MSCs focused on safety and feasibility. 9 , 10 , 11 , 12 Although most of these studies were not designed as efficacy trials, there were indications that MSCs possess immunosuppressive properties, as evidenced by an increase in Tregs and downregulation of cytotoxic CD8T+ cells in a small number of patients. We performed a randomized, prospective, single‐center, open‐label study in living‐donor kidney transplant recipients in which we compared autologous bone marrow (BM)‐derived MSC therapy (infused at weeks 6 and 7) with concomitant early tacrolimus withdrawal (at week 8) to standard tacrolimus dose. Primary end point was quantitative evaluation of interstitial fibrosis and secondary end points included biopsy‐proven acute rejection, graft loss, death, renal function, adverse events, and immunological responses at week 24. We chose to perform the study on a background of alemtuzumab‐based induction to minimize the risk for acute rejection 13 and mTOR inhibition, since experimental studies demonstrated tolerogenic properties in combination with MSCs. 14 In a post hoc long‐term analysis, peripheral blood immune cell composition was also obtained at week 52 in patients with sufficient follow‐up. In addition, the efficacy end point (biopsy‐proven acute rejection (BPAR), graft loss, or death) was obtained up to 5 years in patients who had a longer follow‐up.
2 MATERIAL AND METHODS
2.1 Study design and patients
The TRITON study is a 24‐weeks investigator‐initiated, randomized, prospective, open‐label, single‐center, clinical study, performed at the Leiden University Medical Center (LUMC), the Netherlands. The trial design has been published previously. 15 The trial protocol, available at the Appendix S1 and S2 section, was approved by the local ethics committee at the LUMC, Leiden, and by the Central Committee on Research involving Human Subjects (CCMO) in the Netherlands. The trial was performed in accordance with the principles of the Declaration of Helsinki. In total, 70 de novo renal recipients of a kidney from a living donor, 18–75 years of age, were recruited from the transplant clinics of the LUMC. The inclusion/exclusion criteria were described previously. 15 Written informed consent was obtained from all participants.
2.2 Randomization and masking
Patients were randomly assigned before transplantation to either the MSC or control group in a ratio 1:1 (Figure S1). A patient was randomized only after verification of eligibility and informed consent. The randomization procedure was designed and implemented by the IMO (Informatie Management Onderzoek) department of the University Medical Center Groningen (UMCG), the Netherlands, using a web‐based system (ALEA). Investigator or authorized delegate from the study staff received an individual login code with which they could randomize their patients. The web application returned the allocated treatment. As a confirmation, the web application also sent an e‐mail with the randomization information to selected users. Patients maintained this randomization number throughout the study. Because of the nature of the intervention (BM biopsy and MSC infusions), participants and physicians were not masked to treatment assignment.
2.3 Procedures
All patients in the study received alemtuzumab (anti‐CD52),15 mg subcutaneously, at days 0 and 1 as well as tacrolimus (Prograft®), everolimus (EVL; Certican®), and low‐dose prednisone, as maintenance therapy (Figure S1). 15 Patients in the MSC group received two doses of autologous BM MSCs, intravenously at weeks 6 and 7 after transplantation. Autologous MSCs were chosen instead of third‐party MSCs to prevent alloimmunization. The dose of tacrolimus was reduced to 50% at the time of the second MSC infusion and completely withdrawn 1 week later. Patients received a higher dose of prednisolone (15 mg instead of 10 mg) for 14 days after the second infusion to diminish risks of tacrolimus withdrawal. In patients in the control group, the trough level of tacrolimus was lowered to a target of 6–8 ng/ml 8 weeks after transplantation. BM was aspirated from the posterior iliac crest of all patients in the MSC group under general anesthesia during the renal transplantation, as described previously. 15 This protocol was approved by the local ethics committee (P13.283) and by the CCMO (NL4371200013). Processing of the MSCs took place at the Interdivisional Good Manufacturing Practice (GMP) Facility of the LUMC (Table S1). 15 The MSC product was infused via peripheral infusion within 30 min with a target dose of 1.5 × 106 per/kg body weight IV (range 1–2 × 106), according to our previous study. 15 Monitoring of the patients occurred according to the assessment schedule, as described in the protocol (page 28).
2.4 Outcomes
The primary end point was the quantitative progression of interstitial fibrosis between the 4‐ and 24‐week protocol biopsies as measured by morphometric analysis of collagen deposition. Interstitial collagen fibers in protocol biopsies were visualized by Sirius Red (SR) staining and quantified as a percentage of total tubulointerstitial tissue (glomeruli and large vessels excluded) by quantifying positive pixels in five representative locations at 40× magnification with a macro created in ImageJ version 1.50i. 16 Included secondary end points were composite end point efficacy failure (BPAR, graft loss, or death); proteinuria, Banff scores at the protocol biopsies, renal function as measured by estimated (e)glomerular filtration rate (GFR), (serious) adverse events ((S)AE), including (viral) infections, the presence of de novo donor‐specific antibodies (dnDSA), and peripheral blood immune cell composition. Scoring of renal biopsies was performed in a blinded fashion by a renal pathologist from our center after completion of the study, using the most recent Banff classification. 17 Findings in a protocol biopsy with evidence of rejection were reported as subclinical acute rejection (SCAR). Renal function was calculated by the eGFR (ml/min/1.73 m2) using the CKD‐EPI formula. 15 AEs and SAEs were documented according to Medical Dictionary for Regulatory Activities (MedDRA®); the international medical terminology developed under the auspices of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use. Tacrolimus and EVL quantification was assessed using a previously validated LC–MS/MS assay. 18
2.5 Immunological monitoring
For human leukocyte antigen (HLA) antibody analysis, serum samples were screened using Luminex screen assay (Lifecodes, Immucor) and analyzed with a Luminex 200 reader. Definitions of the negative/positive discriminations were used as suggested by the provider. When positive, a single antigen bead (SAB) assay (Lifecodes, Immucor) was performed as standard‐of‐care. Assignment of positivity was assessed according to the manufacturer's instructions. Since MSCs are suggested to have immunomodulatory properties, we performed phenotypical analysis of leukocyte subpopulations on fresh whole blood. Staining, acquisition, and data analysis were performed strictly adhering to “The One” study protocol. 19 Absolute cell counts were obtained using the BD Multitest kit (BD Biosciences).
2.6 Post hoc analysis
Phenotypical analysis of leukocyte subpopulations was, in addition to the 24‐week time point, also performed 52 weeks after renal transplantation. Assessment of composite end point efficacy failure (BPAR, graft loss, or death) and renal function by eGFR was also obtained in patients with a follow‐up up to 5 years in a post hoc analysis (n = 52 at 1 year, n = 40 at 2 years, n = 24 at 3 years, n = 17 at 4 years, and n = 13 at 5 years, Table 4).
2.7 Statistical analysis
The study was designed to have a sample size of 25 in each group, or 50 in total, to have a power to detect a relative difference in mean percentages of fibrosis of at least 25% using an independent sample t test with a 0.05 two‐sided significance level (α), as described previously. 15 We anticipated that 70% of the included patients would have valid measurements (withdrawal included) and therefore included 70 patients. Data analysis was performed using SPSS version 25.0 (SPSS, Inc.) and all graphs were created using GraphPad Prism version 8.0 (GraphPad Prism Software, Inc.). Parametric data were described as mean ± SD, nonparametric data as median and interquartile range (IQR), and categorical data as numbers and percentages. p < .05 were considered statistically significant. The slopes of eGFR data were calculated and analyzed using a linear regression analysis. Immune monitoring data were analyzed using the Mann–Whitney test with Bonferroni correction for multiple testing. A data safety monitoring board (DSMB) monitored the safety of subjects. The trial is registered with ClinicalTrials.gov, NCT02057965.
3 RESULTS
3.1 Patients
Between March 3, 2014 and January 17, 2020, 70 patients, aged 19 to 74 years, were enrolled in the study: 36 patients were randomly assigned to the MSC group and 34 to the control group (Figure 1). Thirteen patients did not receive allocated treatment, because of abnormal MSC growth (defined as karyotypic abnormalities in the final product; n = 4), contra indication for MSC infusion due to the COVID‐19 pandemic (n = 1), impossibility of obtaining a baseline renal biopsy (n = 2 in MSC and n = 1 in control group), withdrawn informed consent (n = 4 in control group) and (relative) contra indication for prednisone usage (n = 1 control group). In total, 29 patients were assigned to the MSC and 28 to the control group (Figure 1). Patient baseline characteristics were similar in both groups (Table 1). Of the 29 patients in the MSC group, 28 patients received two infusions of MSCs, all within the proposed range. One patient received one dose of MSCs within the proposed range. The second dose was not given because of the COVID‐19 pandemic. This patient gave informed consent to continue the study. All patients had stable vital signs before and after MSC infusion monitored using MEWS (Table S1). In 28 patients in the MSC group and 23 patients in the control group, two renal biopsies could be obtained (Figure 1), in order to assess the quantitative progression of interstitial fibrosis.
FIGURE 1 Trial profile. MSC, mesenchymal stromal cell
TABLE 1 Baseline characteristics
Characteristic MSC (n = 29) Control (n = 28)
Recipient
Age, mean (SD), years 50 (14) 50 (15)
Male sex, no. (%) 26 (90) 20 (71)
Body weight, mean (SD), kg 81 (14) 82 (14)
Primary diagnosis, no. (%)
IgA nephropathy 7 (24) 3 (11)
Hypertension 3 (10) 9 (32)
Polycystic kidney disease 9 (31) 3 (11)
Diabetes 5 (17) 0
Reflux nephropathy 0 2 (7)
Membranous nephropathy 1 (3) 1 (4)
Lupus nephritis 1 (3) 0
Other 2 (7) 3 (11)
Unknown 1 (3) 7 (25)
Donor
Age, mean (SD), years 55 (13) 51 (11)
Male sex, no. (%) 14 (48) 10 (36)
eGFR (pre‐donation), mean (SD) 109.7 (12.0) 109.3 (12.7)
Transplant
Type, related, no. (%) 13 (45) 15 (54)
HLA A/B mismatch, mean (SD) 2.3 (1.3) 2.4 (0.9)
HLA DQ/DR mismatch, mean (SD) 1.2 (0.6) 1.3 (0.5)
Cold‐ischemia time, mean (SD), h 3.1 (0.6) 3.0 (0.5)
First warm ischemia time, mean (SD), min 3.7 (2.1) 5.2 (4.3)
Second warm ischemia time, mean (SD), min 27.0 (3.7) 31.1 (14.4)
Cytomegalovirus IgG status, no. (%)
D+/R+ 9 (31) 6 (21)
D+/R− 7 (24) 9 (32)
D−/R+ 1 (3) 2 (7)
D−/R− 12 (41) 11 (39)
Epstein‐Barr virus IgG D+/R, no. (%) 1 (3) 1 (4)
Note
Data are described as mean standard deviation (SD). Categorical data are described as number (%) (mentioned in every specific variable row).
Abbreviations: GFR, glomerular filtration rate; HLA, human leukocyte antigen.
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3.2 Quantitative progression of fibrosis score
The quantitative progression of fibrosis score in the biopsies was similar in both groups (MSC group 1.0 ± 7.9; control group 0.3 ± 7.8, p = .755). The fibrosis score remained stable both within the MSC (week 4, 15.2 ± 6.6 and week 24, 16.2 ± 5.3, p = .526) and control group (week 4, 17.0 ± 4.6 and week 24 17.3 ± 5.7, p = .870) (Figure 2; Figure S2). Delta Banff scores from 4 to 24 weeks were similar in the two groups, in particular the delta ti‐score (p = .8), the delta interstitial fibrosis/tubular atrophy (IFTA) score (p = .4), and the delta ah‐score (p = .4) (Figure S3).
FIGURE 2 Interstitial fibrosis scores. Quantitative progression of interstitial fibrosis (delta Sirius Red) between the 4‐ and 24‐week renal biopsy (percentage). MSC, mesenchymal stromal cell
3.3 Patient survival, renal function, and biopsy scores
Patient survival during the study follow‐up was 100% in both groups. All patients had a functioning kidney graft at the end of the 24‐week study period (Table 2). eGFR was 56 ± 16 ml/min/1.73 m2 in the MSC (n = 29) and 42 ± 9 ml/min/1.73 m2 in the control group (n = 28) at the time of MSC infusion (Figure 3A). Mean eGFR and 24‐h proteinuria (Table S2) in the MSC group were similar as compared with the control group, with a mean of 56 ± 15 ml/min/1.73 m2 and 47 ± 16 ml/min/1.73 m2, respectively, at week 24 (Figure 3A). The slope from 4 to 24 weeks in the MSC group (slope = −0.22; intercept = 58.15) was not significantly different from the control group (slope = 0.09; intercept = 43.33) (p = .08, Figure 3B). Only one acute rejection episode (combination of T cell [TCMR] and antibody‐mediated rejection [ABMR]), documented by for‐cause biopsy, was found during the study period in the MSC group (1/29 or 3.4%) (Table 2). In this patient, immune suppression had been further reduced due to persistent BK viremia/nephropathy. In the control group, four patients had an indication for a for‐cause renal biopsy, without evidence of rejection (Table 2). The 24‐week protocol biopsies showed SCAR in 14.3% and 13.0% of patients in the MSC (4/28) and control group (3/23), respectively. Protocol biopsies in the MSC group showed a chronic active TCMR Banff IA (n = 1 patient), active ABMR (n = 2, of which one also had active ABMR in the 4‐week protocol biopsy; both having class I and II DSAs, C4d positive only at 6 months), and one mixed active ABMR and acute TCMR IA. Biopsies in the control group demonstrated acute TCMR Banff IA (n = 2 patients) and a mixed active ABMR and acute TCMR IA (n = 1 patient) (Table 2). All patients had a negative HLA antibody screening before and 4 weeks after transplantation. In the MSC group, seven patients developed dnDSA at week 24 (24%) (Table 3). Their protocol renal biopsies demonstrated no rejection (n = 3), borderline suspicious for acute TCMR (n = 1), ABMR (n = 2, both C4d negative), and ABMR/TCMR IA (n = 1, C4d+). In the control group, two patients developed HLA class‐II dnDSA without signs of rejection in their protocol biopsies.
TABLE 2 Secondary end points (graft loss, renal function, and biopsy scores) during the study period of 24 weeks
End point study period of 24 weeks MSC group (n = 29) Control group (n = 28)
Graft loss, no. (%) 0 0
eGFR < 30 ml/min/1.73 m2, no. (%) 0 3 (12)
Patients with for‐cause biopsies, no. (%) 1 (3) 4 (14)
ABMR, TCMR II and BK nephropathy 1
BK nephropathy 1
Acute tubular necrosis 1
Hyaline thickening 1
No abnormalities 1
Patient's protocol biopsies, no. (%)
4 weeks 29 (100) 28 (100)
ABMR 1 0
No rejection 28 28
24 weeks 28 (97) 23 (82)
TCMR IA 1 2
ABMR 2 a 0
ABMR and TCMR IA 1 1
No rejection 24 20
Note
Data are described as number (%) (also mentioned in every specific variable row).
Abbreviations: ABMR, antibody‐mediated rejection; eGFR, estimated glomerular filtration rate; IFTA, interstitial fibrosis and tubular atrophy; MSC, mesenchymal stromal cell; TCMR, T cell‐mediated rejection; TIN, tubulointerstitial nephritis.
a One patient demonstrated ABMR at 4 and 24 weeks.
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FIGURE 3 eGFR during the study period of 24 weeks. (A) eGFR (ml/min/1.73 m2), calculated by the CKD‐EPI formula and depicted per time point as mean ± SD, of patients in the MSC and control groups. (B) Slopes of the eGFR in the MSC group were not significantly different from the control group (p = .08). Slope and intercept data per group are described, including 95% confidence intervals [Color figure can be viewed at wileyonlinelibrary.com]
TABLE 3 Secondary end points (SAE, AE, viral infections, and dnDSA) during the study period of 24 weeks
End point study period of 24 weeks MSC group (n = 29) Control group (n = 28)
Serious adverse events, total, no. 19 25
Injury, poisoning, and procedural complications 6 7
Infections and infestations 2 7
Gastrointestinal disorders 2 3
Renal and urinary disorders 2 2
Metabolism and nutrition disorders 2 2
Therapeutic and nontherapeutic responses 2 1
Investigations 1 1
Vascular disorders 0 1
Musculoskeletal and connective tissue disorders 0 1
Immune system disorders 1 0
Psychiatric disorders 1 0
Adverse events, total, no. 272 301
Investigations 51 46
Blood and lymphatic system disorders 39 36
Infections and infestations 32 38
Vascular disorders 35 31
Metabolism and nutrition disorders 26 30
Gastrointestinal disorders 21 32
Renal and urinary disorders 5 17
Injury, poisoning and procedural complications 9 15
General disorders and administration site conditions 10 12
Nervous system disorders 6 10
Musculoskeletal and connective tissue disorders 9 7
Cardiac disorders 10 5
Respiratory, thoracic and mediastinal disorders 5 7
Skin and subcutaneous tissue disorders 8 4
Psychiatric disorders 2 4
Reproductive system and breast disorders 1 2
Neoplasm benign, malignant and unspecified 1 2
Eye disorders 1 2
Immune system disorders 0 1
Ear and labyrinth disorders 1 0
Viral infections, no. (%)
EBV virus infection a 1 (3) 2 (7)
CMV virus infection a 2 (7) 3 (11)
BK virus infection b 11 (38) 10 (36)
BK nephropathy 1 (3) 3 (11)
dnDSA, no. (%)
Yes c 7 (24) 2 (7)
Anti‐class I 0 0
Anti‐class II 4 (14) 2 (7)
Anti‐class I and II 3 (10) 0
No 22 (76) 26 (89)
Note
(Serious) adverse events are reported using the MedDRA classification with standardized categories. All data are described as the total count. Numbers in parentheses are percentages.
Abbreviations: CMV, cytomegalovirus; dnDSA, de novo donor‐specific antibodies measured at week 24; EBV, Epstein‐Barr virus; MSC, mesenchymal stromal cells.
a Peak serum levels (logarithmic) of EBV and CMV range from 2.5 to 3.2 and from 2.7 to 4, respectively.
b Peak serum levels of BK range from 5.1 to 6.9 in patients with BK nephropathy and from 2.6 to 6.9 in patients without signs of BK nephropathy.
c dnDSA is considered positive in case of an MFI ≥ 500.
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3.4 Immunosuppressive drug levels and change of regime
Immunosuppressive drug levels were within or only slightly out of prespecified target ranges. EVL levels, however, were significantly lower at three time points in the control group (Table S3). All patients in the MSC group were on EVL at the end of the 24‐week study period. In the MSC group, tacrolimus was reintroduced in one patient, because of acute rejection. In the control group, tacrolimus was discontinued in two patients because of BK nephropathy. EVL was switched to mycophenolate mofetil in four patients after a thrombovascular event and discontinued in two patients (CMV infection and infected lymphocele, respectively).
3.5 (Serious) adverse events
Forty‐four SAEs were reported, of which 19 in the MSC and 25 in the control group. In total, 272 AEs were reported in the MSC and 301 in the control group (Table 3). There were no AEs directly related to the MSC infusions. In the control group, 15 viral infections (EBV, CMV, and BK viremia) developed and 14 in the MSC group (Table 3). BK nephropathy occurred in one patient in the MSC (3%) and in three patients in the control group (11%).
3.6 Immune monitoring
Immune monitoring studies demonstrated that absolute numbers of peripheral blood CD45+ leukocytes and CD14+ monocytes remain stable after transplantation between weeks 6 and 52 in the MSC and control groups (Figure 4A,B). CD19+ B cells and CD56+ NK cells decreased after alemtuzumab‐based induction in both groups and re‐appeared from week 12 onwards; however, no statistically significant change was measured between the groups (Figure 4C,D). CD3+CD8+ T cells, CD3+CD4+ T cells, as well as CD4+CD25hiCD127lo Tregs showed a decrease after alemtuzumab‐based induction in both groups while still being suppressed at week 52 (Figure 4E,G). Total Treg numbers were significantly higher in the MSC group with tacrolimus withdrawal as compared to the control group at 24 and 52 weeks after transplantation (p = .014 and p = .047, respectively), due to the increase in absolute number of CD4+CD25hiCD127loCD45RA− memory Tregs (p = .040 and p = .047) (Figure 4G,H). Absolute numbers of naïve Tregs (CD4+CD25hiCD127loCD45RA+) were similar in both groups (Figure S4). Percentages of total and naïve Tregs were not different between the two groups at any time points, whereas percentages of memory Tregs within the total CD4 population were elevated in the control group only at week 12, which normalized the weeks thereafter (Figure S5).
FIGURE 4 Peripheral blood immune cell composition before and after MSC infusion. Absolute numbers of (A) CD45+ leucocytes, (B) CD14+ monocytes, (C) CD19+ B cells, (D) CD56+ NK cells, (E) CD8+ T cells, (F) CD4+ T cells, (G) CD4+CD25hiCD127lo Tregs, and (H) CD4+CD25hiCD127loCD45RA‐ memory Tregs per mL of blood are shown at baseline before transplantation, before the first MSC infusion (week 6), and time points after both infusions (weeks 12, 24, and 52). Violin plots are given for every time point with the number of individuals studied at each time point below the x‐axis. p values are given for the differences between MSC and control groups when <.05 after Bonferroni correction for multiple testing. MSC, mesenchymal stromal cell; NK, natural killer; Treg, regulatory T cell
3.7 Post hoc analysis
In the post hoc longer (intermediate)‐term follow‐up analysis (up to 5 years), graft loss was observed in two patients in the control group (Table 4). Renal function in the MSC group was preserved with an eGFR between 47 and 57 ml/min/1.73 m2 (Table 4). In the patients in the control group, eGFR gradually declined with a mean of 42 ml/min/1.73 m2 at year 1 and 37 ml/min/1.73 m2 at year 5, while seven patients dropped with their eGFR < 30 ml/min/1.73 m2. For‐cause biopsies were indicated in one patient in the MSC and eight patients in the control group. In the for‐cause biopsy in the MSC group, recurrence of IgA nephropathy was found (n = 1). In the control group, acute TCMR IB (n = 1), acute TCMR II (n = 1), mixed active ABMR and acute TCMR IB (n = 1), BK nephropathy (n = 2), tubulointerstitial nephritis/pyelonephritis (n‐1), IFTA grade III (n = 1), and medullary inflammation NOS (sv negative) (n = 1) were observed. In the post hoc analyses, none of the seven patients with de novo DSA needed a for‐cause biopsy renal biopsy or developed an eGFR < 30 ml/min/1.73 m2. However, it is of importance to note that in three of these seven patients CNI was restarted by their treating nephrologist after the 24‐week study period (Table S4).
TABLE 4 Post hoc analysis (1–5 years) of end points (graft loss, renal function, and biopsy scores)
End point post hoc analysis MSC group Control group
1 year n = 26 n = 26
2 years n = 20 n = 20
3 years n = 10 n = 14
4 years n = 7 n = 10
5 years n = 6 n = 7
Graft loss, no. 0 2 a
Time after Tx, years 3.8 and 4.5
eGFR, mean (SD) [n], ml/min/1.73 m2
1 year 57 (15) [26] 42 (11) [26]
2 years 55 (15) [20] 39 (12) [20]
3 years 53 (14) [10] 34 (14) [14]
4 years 47 (10) [7] 36 (12) [9]
5 years 50 (20) [6] 37 (15) [5]
eGFR < 30 ml/min/1.73 m2, no. 0 7
Time after Tx, median (IQR), years 3 (1–3)
Patients with for‐cause biopsies, no. (%) 1 (3) 8 (29)
Recurrence IgA nephropathy 1
TCMR IB 1
TCMR II 1
ABMR and TCMR IB 1
BK nephropathy 2
TIN/pyelonephritis 1
IFTA grade III 1
Medullary inflammation 1
Note
All data are described as the total count. Numbers in parentheses are percentages (also mentioned in the specific variable row).
Abbreviations: ABMR, antibody‐mediated rejection; eGFR, estimated glomerular filtration rate; IFTA, interstitial fibrosis and tubular atrophy; MSC, mesenchymal stromal cell; TCMR, T cell‐mediated rejection; TIN, tubulointerstitial nephritis.
a One patient TCMR and recurrence membranous nephropathy; one patient chronic transplant dysfunction.
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4 DISCUSSION
In this randomized clinical study, we found that quantitative fibrosis scores and renal function remained stable in patients with MSC therapy and concomitant early tacrolimus withdrawal within the study period of 24 weeks. Only one acute rejection episode was documented in the MSC group after further reduction of clinical immunosuppression in the context of persistent BK viremia/nephropathy. Of interest, there were significantly higher numbers of Tregs in the MSC group with tacrolimus withdrawal compared to the controls. In addition, post hoc analyses demonstrated preserved renal function in the MSC group without evidence of late rejection. Clinical studies with MSCs in kidney transplantation, mainly phase 1 trials with still limited numbers of patients, have demonstrated that MSC treatment after kidney transplantation is safe and feasible. 9 , 10 , 11 , 12 , 20 , 21 In most studies, MSCs were administered at an early time point against the background of regular immune suppression with the aim to induce immunologic tolerance. The current strategy with MSCs and complete withdrawal of CNI have not been studied before in a randomized trial. Minimization of CNIs is a well‐established strategy to limit structural long‐term damage to the graft and minimize the side effects associated with clinical immunosuppression. 5 , 22 A number of trials have demonstrated the efficacy of EVL in conjunction with reduced exposure to CNIs in preventing organ loss or dysfunction in kidney transplant recipients. 23 Of importance, complete avoidance and replacement of a CNI by EVL in de novo transplant recipients are not justified, since unacceptable high acute rejection rates were observed with this strategy. 24 The capability of MSCs to allow reduction of 50% CNI was demonstrated in a previous study with third‐party MSCs in 16 living kidney transplant recipients. 21 The combination of an mTOR inhibitor and MSCs was chosen in the current study since experimental evidence demonstrated tolerogenic properties and an increase in regulatory immune cell subsets. 14 In our study, fibrosis scores were similar in both the MSC group and the controls, thereby failing to meet the primary end point, and the incidence of acute rejection 24 weeks after implantation was low. One explanation might be the use of alemtuzumab, 13 which was chosen as we anticipated a higher immunological risk due to the early CNI withdrawal. Indeed, given the potency of the immunosuppression regimen used in our study, seeing differences in fibrosis scores and rejection with the short study duration is unlikely. Of interest, however, the post hoc analysis with follow‐up up to 5 years showed a higher incidence of for‐cause biopsies in the control group, with findings of both BPAR and BK nephropathy, suggesting that the effect of MSC infusion in combination with CNI withdrawal carried through way beyond the period that alemtuzumab is effective. Future studies with a sufficient number of patients and duration of follow‐up are needed to be able to draw more definite conclusions. Several studies have reported an increased incidence of dnDSA in renal transplant recipients receiving EVL, especially when converted early after transplantation, and it was also suggested that the use of alemtuzumab‐based induction could aggravate this. 25 , 26 In general, dnDSA has been shown to be associated with poor graft survival and increased acute rejection in kidney transplant recipients. 27 In the large ELEVATE Trial, however, conversion to EVL at 10–14 weeks posttransplant was associated with renal function parameters similar to that observed with standard therapy. In this study, the dnDSA data, available in a subset of patients, suggested more frequent anti‐HLA Class‐I DSA under EVL. Differences in propensity to develop dnDSA, however, did not appear to have resulted in ABMR within the 2‐year observation frame of the study. 28 In our study, we also found an increased incidence of dnDSA in patients where tacrolimus was withdrawn. This was associated with (asymptomatic) signs of ABMR in the protocol biopsies of three of these patients of which one, in retrospect, already had subclinical ABMR in the 4‐week biopsy. There were no signs of deteriorating graft function in these patients. Furthermore, the post hoc analyses showed no graft losses, no need for additional for‐cause biopsies, and stable renal function in these patients as well as the MSC group as a whole. Nevertheless, given the epidemiological association with graft loss (which is, however, based on for‐cause DSA measurements), the nephrologists taking care of these patients restarted the CNI in three patients after the study period. Longer follow‐up in all patients is warranted to draw more definite conclusions here. Variable outcomes on renal function after MSC therapy have been described and it has been suggested that timing of MSC administration is of major importance. Indeed, early clinical trials have demonstrated an engraftment syndrome with infiltration of immune cells and C3 deposits when MSCs were administered 7 days after renal transplantation, which was not observed when MSCs were given before implantation. 29 In the study by Erpicum et al., eGFR values at day 7 were higher in the MSC‐treated patients. 12 In our study, patients in the MSC group started with a higher eGFR, as compared to controls, which was preserved throughout the study period and the post hoc follow‐up period. This unequal randomization was, to the best of our knowledge, found by chance and could have influenced our results. In the control group, there was increased graft loss as well as a higher number of patients with inferior renal function (i.e., eGFR < 30 ml/min/1.73 m2), possibly due to an increase in BPAR and BK nephropathy in these patients.
So far, hardly any safety issues have been reported after systemic infusion of MSCs in humans, except for a transient fever and one cardiac event with an unclear causal relationship to the intervention. 12 In our study, there were no side effects directly related to the MSC infusion. We found that (S)AEs (including viral infections) were similar in the two groups. This is in contrast to our previous study where an increased incidence of viral infections was observed after MSC therapy. 10 Possibly this is due to the fact that MSCs were given on top of regular immune suppression in our previous study. This observation is of particular relevance with the ongoing COVID‐19 pandemic. Recent observational studies have shown that kidney transplant recipients are at increased risk for severe morbidity due to their systemic immune suppression and often reduced renal function. 30
MSCs have shown to condition the immune system, by releasing extracellular vesicles or membrane particles or by undergoing apoptosis. This may actively engage recipient monocytes/phagocytes and eventually Tregs, enabling long‐term tolerogenic activity that becomes self‐sustained even after disappearance of the infused MSCs themselves. 8 , 31 Of interest, in our current study, we found an increase in the absolute number of Tregs in the MSC group with tacrolimus withdrawal versus control, which has not been reported before in a randomized clinical trial with MSCs in transplant recipients. However, since there was a difference in tacrolimus use between both groups and a difference in total CD4+ T cell counts at week 12, it is not possible to deduce the results solely to the MSC treatment. Concomitantly, the percentage of memory Tregs within total CD4 T cells showed an increase in the control group compared to the MSC group at 12 weeks (Figure S5), after which the percentages in total and Treg subsets remained similar, indicating that the increase in absolute Treg numbers in the MSC group is at least partially due to changes in the total CD4+ T cell number.
At present, randomized trials with MSCs are still very limited and the field is only slowly advancing also due to stringent regulatory requirements, the need for clinical grade cell production facilities, and the associated costs. However, we recently also reported the feasibility of administration of third‐party “off‐the‐shelf” MSCs in kidney transplant recipients. 11 This option makes manufacturing and regulation easier and the use of MSC suitable for a wider spectrum of clinical application and much more feasible. We believe that the results of our current trial set the stage for the next steps and use of MSCs in the field of kidney transplantation to reduce the need for excessive use of clinical immunosuppressants.
DISCLOSURE
The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.
Supporting information
Appendix S1
Click here for additional data file.
Appendix S2
Click here for additional data file.
ACKNOWLEDGMENTS
We thank the research department of internal medicine of the Leiden University Medical Center for their help with the study visits. We thank the research technicians from the Transplant Immunology lab for technical assistance with the immune monitoring. This investigator‐initiated study was partially funded by unrestricted research grants from Astellas and Novartis. The funders had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. Part of this work was supported by a grant from ZonMW‐TAS program nr 116004104. | Subcutaneous | DrugAdministrationRoute | CC BY-NC | 33565206 | 19,393,098 | 2021-09 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug interaction'. | Prolonged SARS-CoV-2-RNA Detection from Nasopharyngeal Swabs in an Oncologic Patient: What Impact on Cancer Treatment?
The pandemic of SARS-CoV-2 is a serious global challenge affecting millions of people worldwide. Cancer patients are at risk for infection exposure and serious complications. A prompt diagnosis of SARS-CoV-2 infection is crucial for the timely adoption of isolation measures and the appropriate management of cancer treatments. In lung cancer patients the symptoms of infection 19 may resemble those exhibited by the underlying oncologic condition, possibly leading to diagnostic overlap and delays. Moreover, cancer patients might display a prolonged positivity of nasopharyngeal RT-PCR assays for SARS-CoV-2, causing long interruptions or delay of cancer treatments. However, the association between the positivity of RT-PCR assays and the patient's infectivity remains uncertain. We describe the case of a patient with non-small cell lung cancer, and a severe ab extrinseco compression of the trachea, whose palliative radiotherapy was delayed because of the prolonged positivity of nasopharyngeal swabs for SARS-CoV-2. The patient did not show clinical symptoms suggestive of active infection, but the persistent positivity of RT-PCR assays imposed the continuation of isolation measures and the delay of radiotherapy for over two months. Finally, the negative result of SARS-CoV-2 viral culture allowed us to verify the absence of viral activity and to rule out the infectivity of the patient, who could finally continue her cancer treatment.
1. Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is a complex global challenge affecting millions of people worldwide [1]. Cancer patients are at high risk for serious complications and the infection itself may compromise the continuation of cancer therapies and supportive care [2,3,4]. Moreover, the frequent visits to the hospital for treatment and monitoring represent for cancer patients a major risk factor for exposure to SARS-CoV-2 [5]. In order to optimize the cancer care pathway and improve the clinical outcomes during the pandemic, a large, international and multidisciplinary consortium reviewed and discussed the clinical evidence in cancer management. In this current situation, the risk of infection must be individualized taking into consideration the primary tumor type, stage, age, and sex. In addition, cancer treatment must be patient tailored [6]. Thus far, the gold standard test for the diagnosis of COVID-19 has been the RT-PCR test performed on nasopharyngeal swabs or other upper respiratory tract specimens. However, a “positive” PCR result reflects the detection of viral RNA and does not necessarily prove the presence of active viral replication. To ascertain the infectivity of RT-PCR positive patients, several diagnostic methods such as the viral culture, the viral RNA measured by the cycle threshold (Ct), the antigen rapid test, and the detection of sub-genomic RNAs (sg-RNAs) have been recently introduced in clinical care. All these tests, when correlated with the time course of disease, may help define the contagiousness of patients diagnosed with SARS-CoV-2 infection [7,8,9,10]. We describe the case of a cancer patient whose palliative radiotherapy treatment was delayed because of the prolonged positivity of RT-PCR assays for SARS-CoV-2 on nasopharyngeal swabs, despite the absence of acute signs of infection. Eventually, the negative viral culture result allowed the physicians to continue the treatment.
2. Case Report
On 1 April 2020, a 72-year-old Caucasian woman affected by non-small cell lung cancer of the upper right lobe, was referred to the Istituto Oncologico Veneto (IOV) of Padua, Italy, for the acute onset of progressive shortness of breath and dry cough. Her past medical history was relevant for glaucoma, depression, and Parkinson disease. The patient had undergone a right upper lobe lung resection with ilo-mediastinic lymph node dissection in 2015; the histo-pathological examination revealed an EGFR exon19 deletion mutated adenocarcinoma. After four courses of adjuvant chemotherapy (cisplatin plus gemticitabine), due to disease progression, in 2018 targeted therapy with osimertinib was started with partial response according to RECIST (response evaluation criteria in solid tumors version 1.1).
At hospital admission, the physical examination revealed moderate inspiratory retraction and diffuse inspiratory wheezing; the body temperature was 36.8 °C; heart rate 68 bpm; blood pressure 125/80 mm Hg; respiratory rates 25 per minute; oxygen saturation 98% with 3 L/min oxygen supplement. Her ECOG PS (Eastern Cooperative Oncology Group performance status) was 2.
Laboratory investigations were all within the normal range, including lactate dehydrogenase (LDH), C-reactive protein (CRP), and procalcitonin. The nasopharyngeal swab for the detection of SARS-CoV-2 RNA by RT-PCR [11] was negative. A computed tomography (CT) scan of the thorax showed progressive disease in the superior mediastinum with significant reduction of the tracheal lumen (Figure 1). Palliative mediastinal radiotherapy was planned in order to reduce the tracheal compression, and methylprednisolone 40 mg bid was initiated obtaining a slight reduction of dyspnea.
During the hospital stay, the patient was exposed to an asymptomatic SARS-CoV-2 virus carrier. On 6 April 2020, she underwent screening nasopharyngeal swab for detection of SARS-CoV-2, which was positive. The scheduled radiotherapy was postponed and the patient was transferred to the infectious diseases unit. At admission she presented with mild inspiratory retraction but all the vital signs were normal. Blood examinations showed a moderate elevation of CRP (91 mg/L, normal value 0–6). Because of the high-risk condition, she was treated with the therapy currently recommended: hydroxychloroquine (HCQ) (400 mg bid for 24 h, then 200 mg bid) and azithromycin (AZI) (500 mg qd) [12]. Both drugs were stopped after two days because of QTc prolongation. Tapered steroidal therapy, osimertinib, and subcutaneous enoxaparin were continued.
The patient did not develop any coronavirus disease 2019 (COVID-19)-related symptoms, but nasopharyngeal swabs were persistently positive for SARS-CoV-2 for over one month. On 13 May after two consecutive negative swabs, she was transferred to the oncology ward to start radiotherapy treatment. Her ECOG PS was 3. Unfortunately, on May 19, the nasopharyngeal swab for SARS-CoV-2 RNA was positive. Once again the radiotherapy was postponed and the patient was isolated in the infectious diseases ward. The clinical conditions remained stable and the nasopharyngeal swabs were repeated at regular intervals with alternating results (Figure 2). On 30 May, a viral culture with Vero cells [13] was performed and resulted negative. The same result was achieved also 15 days later, despite the occurrence of new positive swabs.
Interestingly, serological tests showed the presence of high levels of anti-SARS-CoV-2 IgG [75,400 kAU/L (Positive: >1100 kAU/L)] and high titers persisted during the whole observation period; IgM title was persistently negative (Figure 2).
On the basis of these results, a single-fraction radiotherapy was performed on 4 June and the patient continued her regular follow-up with no need of oxygen supplementation. The last total body CT scan performed in July 2020 confirmed stable disease.
3. Discussion
SARS-CoV-2 pandemic caught clinicians and health authorities unprepared to manage cancer patients. Diagnostic and treatment guidelines were lacking at the beginning of the outbreak. Clinicians were challenged to manage COVID-19 disease with clinical characteristics which might be partly masked or confounded by coexisting cancer conditions. Moreover, the risk of nosocomial transmission of SARS-CoV-2 and the need for isolation contributed to the risk of progression of the malignant disease because of cancer treatments’ delays [14,15,16].
After the detection of SARS-CoV-2 our patient did not show any acute signs of infection and her symptoms could be attributed to her lung cancer. However SARS-CoV-2 swabs remained positive for more than 90 days, showing alternating results: in five occasions they turned out positive after one or two consecutive negative tests. It has been described that, after clinical resolution, some COVID-19 patients may experience a prolonged nucleic acid conversion [17,18]. Xiao and colleagues, from Wuhan, reported 21.4% of patients experiencing a “turn positive” of nucleic acid detection by RT-PCR test after two consecutive negative results [18]. In addition, it is still to be determined whether these patients are able to transmit the infection. However, relevant recent studies have shown that COVID-19 patients with mild-to-moderate illness are highly unlikely to be infectious longer than 10 days after symptom onset [19]. The molecular detection of SARS-CoV-2 by RT-PCR is a rapid and highly sensitive diagnostic method, but its ability to determine the duration of infectivity of patients is quite limited [20]. Viral culture is a more accurate tool to demonstrate the “in vitro” infectivity, giving surrogate information on viral transmission [9]. It is a complex diagnostic tool that needs expertise and biosafety level 3 laboratories, but it could be of crucial importance to define viral transmission and the infectivity of patients in particular conditions, such as the oncological setting [21]. Aside from viral culture, other diagnostic methods such as the threshold cycle (Ct) of RT-PCR and antigen-tests have been reported to be able to determine patients’ contagiousness. It has been demonstrated that infectivity is significantly reduced when Ct values are >24; for every unit increase in Ct, the odds ratio for infectivity decreases by 32%, suggesting that Ct values >24, along with the duration of symptoms >8 days may be used in combination to rule out patients’ contagiousness. Similar results are reported by La Scola et al. who showed a strong correlation between Ct value and sample infectivity in a cell culture model. Based on their data, they inferred that patients with Ct values equal or above 34 do not excrete infectious viral particles [22]. Rapid antigen tests may also have a role in this setting. They have a lower sensitivity compared to the standard RT-PCR test, but may be sensitive enough to detect cases with a high viral load (i.e., low RT-PCR cycle threshold (Ct) value <25), which likely account for a significant proportion of transmissions [8,23]. In addition, as reported in 68 respiratory specimens from 35 COVID patients in Hong Kong, the detection of subgenomic viral RNA (sgRNA) strongly correlated with the presence of active virus replication, with sgRNA being rarely detectable 8 days after the onset of the illness [7]. On the contrary, there is no consensus yet on the significance of the dynamic profile of SARS-CoV-2-specific antibody response. In our case the persistent positivity of RT-PCR assays coexisted with a strong serologic response, and none of the diagnostic procedures could prove or rule out the infectivity of the patient [24]. Unfortunately, in the first half of 2020, when our patient was hospitalized, viral load estimation by threshold cycle of RT-PCR and antigen-based tests were still under investigation, and the detection of sub-genomic RNAs was not available. Furthermore, the World Health Organization guidelines for releasing COVID-19 patients from isolation (i.e., ten days after symptom onset and at least three additional days without symptoms) were not yet amended. Nevertheless these guidelines do not specifically address immunocompromised individuals [25].
An Italian group has recently proposed an algorithm for the management of oncologic patients who need radiation therapy. Their recommendation is to delay or discontinue the radiation treatment in symptomatic and asymptomatic patients diagnosed with COVID-19 and to carefully start the treatment only when the patients are declared no longer exhibiting infection by the infectious diseases specialist [26].
In line with this recommendation we could discontinue hospital isolation owing to the repeatedly negative cell culture results, which allowed us to verify the absence of viral activity despite the persistent positivity of nasopharyngeal swabs. In this way the patient could finally undergo palliative radiotherapy for airway obstruction with a delay of eight weeks from the initial scheduled time. Although it is unlikely that the delayed palliative radiotherapy affected the short-term poor prognosis, it surely prolonged the length of hospitalization and negatively affected the patient’s quality of life.
4. Conclusions
This clinical case emphasizes the multifaceted and challenging approach to SARS-CoV-2 infection in the oncological setting. Clinicians must protect the vulnerable cancer population from a potentially severe infection without jeopardizing cancer care and support. The development of diagnostic tests able to determine the activity of the disease and patients’ infectivity may contribute to the fight against SARS-CoV-2, limiting the number of COVID-19-related deaths and the excess indirect mortality and morbidity in patients suffering from cancer.
Author Contributions
A.F.—Conceptualization, writing original draft. M.T.—Writing review & editing, supervision. L.S.—Writing review & editing. E.D.L.—Writing original draft. T.T.—Data curation. L.R.—Case analysis. E.D.M.—Writing review & editing. A.M.C.—Conceptualization, writing review and editing. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Informed Consent Statement
Verbal informed consent for this report was obtained from the patient involved in the study.
Conflicts of Interest
We have read and understood Current Oncology’s policy on conflicts of interest disclosure and declare that we have none.
Figure 1 Chest computed tomography (CT) scan: axial lung image showing huge reduction (arrow) of the trachea lumen (2 mm) due to mediastinal pathological tissue.
Figure 2 Timeline of SARS-CoV-2 nucleic acid testing results from nasopharyngeal swabs along with the anti-SARS-CoV-2 serology and viral culture testing.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | AZITHROMYCIN DIHYDRATE, ENOXAPARIN, HYDROXYCHLOROQUINE SULFATE, METHYLPREDNISOLONE, OSIMERTINIB, OXYGEN | DrugsGivenReaction | CC BY | 33567626 | 20,166,650 | 2021-02-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Electrocardiogram QT interval'. | Prolonged SARS-CoV-2-RNA Detection from Nasopharyngeal Swabs in an Oncologic Patient: What Impact on Cancer Treatment?
The pandemic of SARS-CoV-2 is a serious global challenge affecting millions of people worldwide. Cancer patients are at risk for infection exposure and serious complications. A prompt diagnosis of SARS-CoV-2 infection is crucial for the timely adoption of isolation measures and the appropriate management of cancer treatments. In lung cancer patients the symptoms of infection 19 may resemble those exhibited by the underlying oncologic condition, possibly leading to diagnostic overlap and delays. Moreover, cancer patients might display a prolonged positivity of nasopharyngeal RT-PCR assays for SARS-CoV-2, causing long interruptions or delay of cancer treatments. However, the association between the positivity of RT-PCR assays and the patient's infectivity remains uncertain. We describe the case of a patient with non-small cell lung cancer, and a severe ab extrinseco compression of the trachea, whose palliative radiotherapy was delayed because of the prolonged positivity of nasopharyngeal swabs for SARS-CoV-2. The patient did not show clinical symptoms suggestive of active infection, but the persistent positivity of RT-PCR assays imposed the continuation of isolation measures and the delay of radiotherapy for over two months. Finally, the negative result of SARS-CoV-2 viral culture allowed us to verify the absence of viral activity and to rule out the infectivity of the patient, who could finally continue her cancer treatment.
1. Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is a complex global challenge affecting millions of people worldwide [1]. Cancer patients are at high risk for serious complications and the infection itself may compromise the continuation of cancer therapies and supportive care [2,3,4]. Moreover, the frequent visits to the hospital for treatment and monitoring represent for cancer patients a major risk factor for exposure to SARS-CoV-2 [5]. In order to optimize the cancer care pathway and improve the clinical outcomes during the pandemic, a large, international and multidisciplinary consortium reviewed and discussed the clinical evidence in cancer management. In this current situation, the risk of infection must be individualized taking into consideration the primary tumor type, stage, age, and sex. In addition, cancer treatment must be patient tailored [6]. Thus far, the gold standard test for the diagnosis of COVID-19 has been the RT-PCR test performed on nasopharyngeal swabs or other upper respiratory tract specimens. However, a “positive” PCR result reflects the detection of viral RNA and does not necessarily prove the presence of active viral replication. To ascertain the infectivity of RT-PCR positive patients, several diagnostic methods such as the viral culture, the viral RNA measured by the cycle threshold (Ct), the antigen rapid test, and the detection of sub-genomic RNAs (sg-RNAs) have been recently introduced in clinical care. All these tests, when correlated with the time course of disease, may help define the contagiousness of patients diagnosed with SARS-CoV-2 infection [7,8,9,10]. We describe the case of a cancer patient whose palliative radiotherapy treatment was delayed because of the prolonged positivity of RT-PCR assays for SARS-CoV-2 on nasopharyngeal swabs, despite the absence of acute signs of infection. Eventually, the negative viral culture result allowed the physicians to continue the treatment.
2. Case Report
On 1 April 2020, a 72-year-old Caucasian woman affected by non-small cell lung cancer of the upper right lobe, was referred to the Istituto Oncologico Veneto (IOV) of Padua, Italy, for the acute onset of progressive shortness of breath and dry cough. Her past medical history was relevant for glaucoma, depression, and Parkinson disease. The patient had undergone a right upper lobe lung resection with ilo-mediastinic lymph node dissection in 2015; the histo-pathological examination revealed an EGFR exon19 deletion mutated adenocarcinoma. After four courses of adjuvant chemotherapy (cisplatin plus gemticitabine), due to disease progression, in 2018 targeted therapy with osimertinib was started with partial response according to RECIST (response evaluation criteria in solid tumors version 1.1).
At hospital admission, the physical examination revealed moderate inspiratory retraction and diffuse inspiratory wheezing; the body temperature was 36.8 °C; heart rate 68 bpm; blood pressure 125/80 mm Hg; respiratory rates 25 per minute; oxygen saturation 98% with 3 L/min oxygen supplement. Her ECOG PS (Eastern Cooperative Oncology Group performance status) was 2.
Laboratory investigations were all within the normal range, including lactate dehydrogenase (LDH), C-reactive protein (CRP), and procalcitonin. The nasopharyngeal swab for the detection of SARS-CoV-2 RNA by RT-PCR [11] was negative. A computed tomography (CT) scan of the thorax showed progressive disease in the superior mediastinum with significant reduction of the tracheal lumen (Figure 1). Palliative mediastinal radiotherapy was planned in order to reduce the tracheal compression, and methylprednisolone 40 mg bid was initiated obtaining a slight reduction of dyspnea.
During the hospital stay, the patient was exposed to an asymptomatic SARS-CoV-2 virus carrier. On 6 April 2020, she underwent screening nasopharyngeal swab for detection of SARS-CoV-2, which was positive. The scheduled radiotherapy was postponed and the patient was transferred to the infectious diseases unit. At admission she presented with mild inspiratory retraction but all the vital signs were normal. Blood examinations showed a moderate elevation of CRP (91 mg/L, normal value 0–6). Because of the high-risk condition, she was treated with the therapy currently recommended: hydroxychloroquine (HCQ) (400 mg bid for 24 h, then 200 mg bid) and azithromycin (AZI) (500 mg qd) [12]. Both drugs were stopped after two days because of QTc prolongation. Tapered steroidal therapy, osimertinib, and subcutaneous enoxaparin were continued.
The patient did not develop any coronavirus disease 2019 (COVID-19)-related symptoms, but nasopharyngeal swabs were persistently positive for SARS-CoV-2 for over one month. On 13 May after two consecutive negative swabs, she was transferred to the oncology ward to start radiotherapy treatment. Her ECOG PS was 3. Unfortunately, on May 19, the nasopharyngeal swab for SARS-CoV-2 RNA was positive. Once again the radiotherapy was postponed and the patient was isolated in the infectious diseases ward. The clinical conditions remained stable and the nasopharyngeal swabs were repeated at regular intervals with alternating results (Figure 2). On 30 May, a viral culture with Vero cells [13] was performed and resulted negative. The same result was achieved also 15 days later, despite the occurrence of new positive swabs.
Interestingly, serological tests showed the presence of high levels of anti-SARS-CoV-2 IgG [75,400 kAU/L (Positive: >1100 kAU/L)] and high titers persisted during the whole observation period; IgM title was persistently negative (Figure 2).
On the basis of these results, a single-fraction radiotherapy was performed on 4 June and the patient continued her regular follow-up with no need of oxygen supplementation. The last total body CT scan performed in July 2020 confirmed stable disease.
3. Discussion
SARS-CoV-2 pandemic caught clinicians and health authorities unprepared to manage cancer patients. Diagnostic and treatment guidelines were lacking at the beginning of the outbreak. Clinicians were challenged to manage COVID-19 disease with clinical characteristics which might be partly masked or confounded by coexisting cancer conditions. Moreover, the risk of nosocomial transmission of SARS-CoV-2 and the need for isolation contributed to the risk of progression of the malignant disease because of cancer treatments’ delays [14,15,16].
After the detection of SARS-CoV-2 our patient did not show any acute signs of infection and her symptoms could be attributed to her lung cancer. However SARS-CoV-2 swabs remained positive for more than 90 days, showing alternating results: in five occasions they turned out positive after one or two consecutive negative tests. It has been described that, after clinical resolution, some COVID-19 patients may experience a prolonged nucleic acid conversion [17,18]. Xiao and colleagues, from Wuhan, reported 21.4% of patients experiencing a “turn positive” of nucleic acid detection by RT-PCR test after two consecutive negative results [18]. In addition, it is still to be determined whether these patients are able to transmit the infection. However, relevant recent studies have shown that COVID-19 patients with mild-to-moderate illness are highly unlikely to be infectious longer than 10 days after symptom onset [19]. The molecular detection of SARS-CoV-2 by RT-PCR is a rapid and highly sensitive diagnostic method, but its ability to determine the duration of infectivity of patients is quite limited [20]. Viral culture is a more accurate tool to demonstrate the “in vitro” infectivity, giving surrogate information on viral transmission [9]. It is a complex diagnostic tool that needs expertise and biosafety level 3 laboratories, but it could be of crucial importance to define viral transmission and the infectivity of patients in particular conditions, such as the oncological setting [21]. Aside from viral culture, other diagnostic methods such as the threshold cycle (Ct) of RT-PCR and antigen-tests have been reported to be able to determine patients’ contagiousness. It has been demonstrated that infectivity is significantly reduced when Ct values are >24; for every unit increase in Ct, the odds ratio for infectivity decreases by 32%, suggesting that Ct values >24, along with the duration of symptoms >8 days may be used in combination to rule out patients’ contagiousness. Similar results are reported by La Scola et al. who showed a strong correlation between Ct value and sample infectivity in a cell culture model. Based on their data, they inferred that patients with Ct values equal or above 34 do not excrete infectious viral particles [22]. Rapid antigen tests may also have a role in this setting. They have a lower sensitivity compared to the standard RT-PCR test, but may be sensitive enough to detect cases with a high viral load (i.e., low RT-PCR cycle threshold (Ct) value <25), which likely account for a significant proportion of transmissions [8,23]. In addition, as reported in 68 respiratory specimens from 35 COVID patients in Hong Kong, the detection of subgenomic viral RNA (sgRNA) strongly correlated with the presence of active virus replication, with sgRNA being rarely detectable 8 days after the onset of the illness [7]. On the contrary, there is no consensus yet on the significance of the dynamic profile of SARS-CoV-2-specific antibody response. In our case the persistent positivity of RT-PCR assays coexisted with a strong serologic response, and none of the diagnostic procedures could prove or rule out the infectivity of the patient [24]. Unfortunately, in the first half of 2020, when our patient was hospitalized, viral load estimation by threshold cycle of RT-PCR and antigen-based tests were still under investigation, and the detection of sub-genomic RNAs was not available. Furthermore, the World Health Organization guidelines for releasing COVID-19 patients from isolation (i.e., ten days after symptom onset and at least three additional days without symptoms) were not yet amended. Nevertheless these guidelines do not specifically address immunocompromised individuals [25].
An Italian group has recently proposed an algorithm for the management of oncologic patients who need radiation therapy. Their recommendation is to delay or discontinue the radiation treatment in symptomatic and asymptomatic patients diagnosed with COVID-19 and to carefully start the treatment only when the patients are declared no longer exhibiting infection by the infectious diseases specialist [26].
In line with this recommendation we could discontinue hospital isolation owing to the repeatedly negative cell culture results, which allowed us to verify the absence of viral activity despite the persistent positivity of nasopharyngeal swabs. In this way the patient could finally undergo palliative radiotherapy for airway obstruction with a delay of eight weeks from the initial scheduled time. Although it is unlikely that the delayed palliative radiotherapy affected the short-term poor prognosis, it surely prolonged the length of hospitalization and negatively affected the patient’s quality of life.
4. Conclusions
This clinical case emphasizes the multifaceted and challenging approach to SARS-CoV-2 infection in the oncological setting. Clinicians must protect the vulnerable cancer population from a potentially severe infection without jeopardizing cancer care and support. The development of diagnostic tests able to determine the activity of the disease and patients’ infectivity may contribute to the fight against SARS-CoV-2, limiting the number of COVID-19-related deaths and the excess indirect mortality and morbidity in patients suffering from cancer.
Author Contributions
A.F.—Conceptualization, writing original draft. M.T.—Writing review & editing, supervision. L.S.—Writing review & editing. E.D.L.—Writing original draft. T.T.—Data curation. L.R.—Case analysis. E.D.M.—Writing review & editing. A.M.C.—Conceptualization, writing review and editing. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Informed Consent Statement
Verbal informed consent for this report was obtained from the patient involved in the study.
Conflicts of Interest
We have read and understood Current Oncology’s policy on conflicts of interest disclosure and declare that we have none.
Figure 1 Chest computed tomography (CT) scan: axial lung image showing huge reduction (arrow) of the trachea lumen (2 mm) due to mediastinal pathological tissue.
Figure 2 Timeline of SARS-CoV-2 nucleic acid testing results from nasopharyngeal swabs along with the anti-SARS-CoV-2 serology and viral culture testing.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | AZITHROMYCIN, ENOXAPARIN SODIUM, HYDROXYCHLOROQUINE, OSIMERTINIB | DrugsGivenReaction | CC BY | 33567626 | 19,099,889 | 2021-02-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Electrocardiogram QT prolonged'. | Prolonged SARS-CoV-2-RNA Detection from Nasopharyngeal Swabs in an Oncologic Patient: What Impact on Cancer Treatment?
The pandemic of SARS-CoV-2 is a serious global challenge affecting millions of people worldwide. Cancer patients are at risk for infection exposure and serious complications. A prompt diagnosis of SARS-CoV-2 infection is crucial for the timely adoption of isolation measures and the appropriate management of cancer treatments. In lung cancer patients the symptoms of infection 19 may resemble those exhibited by the underlying oncologic condition, possibly leading to diagnostic overlap and delays. Moreover, cancer patients might display a prolonged positivity of nasopharyngeal RT-PCR assays for SARS-CoV-2, causing long interruptions or delay of cancer treatments. However, the association between the positivity of RT-PCR assays and the patient's infectivity remains uncertain. We describe the case of a patient with non-small cell lung cancer, and a severe ab extrinseco compression of the trachea, whose palliative radiotherapy was delayed because of the prolonged positivity of nasopharyngeal swabs for SARS-CoV-2. The patient did not show clinical symptoms suggestive of active infection, but the persistent positivity of RT-PCR assays imposed the continuation of isolation measures and the delay of radiotherapy for over two months. Finally, the negative result of SARS-CoV-2 viral culture allowed us to verify the absence of viral activity and to rule out the infectivity of the patient, who could finally continue her cancer treatment.
1. Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is a complex global challenge affecting millions of people worldwide [1]. Cancer patients are at high risk for serious complications and the infection itself may compromise the continuation of cancer therapies and supportive care [2,3,4]. Moreover, the frequent visits to the hospital for treatment and monitoring represent for cancer patients a major risk factor for exposure to SARS-CoV-2 [5]. In order to optimize the cancer care pathway and improve the clinical outcomes during the pandemic, a large, international and multidisciplinary consortium reviewed and discussed the clinical evidence in cancer management. In this current situation, the risk of infection must be individualized taking into consideration the primary tumor type, stage, age, and sex. In addition, cancer treatment must be patient tailored [6]. Thus far, the gold standard test for the diagnosis of COVID-19 has been the RT-PCR test performed on nasopharyngeal swabs or other upper respiratory tract specimens. However, a “positive” PCR result reflects the detection of viral RNA and does not necessarily prove the presence of active viral replication. To ascertain the infectivity of RT-PCR positive patients, several diagnostic methods such as the viral culture, the viral RNA measured by the cycle threshold (Ct), the antigen rapid test, and the detection of sub-genomic RNAs (sg-RNAs) have been recently introduced in clinical care. All these tests, when correlated with the time course of disease, may help define the contagiousness of patients diagnosed with SARS-CoV-2 infection [7,8,9,10]. We describe the case of a cancer patient whose palliative radiotherapy treatment was delayed because of the prolonged positivity of RT-PCR assays for SARS-CoV-2 on nasopharyngeal swabs, despite the absence of acute signs of infection. Eventually, the negative viral culture result allowed the physicians to continue the treatment.
2. Case Report
On 1 April 2020, a 72-year-old Caucasian woman affected by non-small cell lung cancer of the upper right lobe, was referred to the Istituto Oncologico Veneto (IOV) of Padua, Italy, for the acute onset of progressive shortness of breath and dry cough. Her past medical history was relevant for glaucoma, depression, and Parkinson disease. The patient had undergone a right upper lobe lung resection with ilo-mediastinic lymph node dissection in 2015; the histo-pathological examination revealed an EGFR exon19 deletion mutated adenocarcinoma. After four courses of adjuvant chemotherapy (cisplatin plus gemticitabine), due to disease progression, in 2018 targeted therapy with osimertinib was started with partial response according to RECIST (response evaluation criteria in solid tumors version 1.1).
At hospital admission, the physical examination revealed moderate inspiratory retraction and diffuse inspiratory wheezing; the body temperature was 36.8 °C; heart rate 68 bpm; blood pressure 125/80 mm Hg; respiratory rates 25 per minute; oxygen saturation 98% with 3 L/min oxygen supplement. Her ECOG PS (Eastern Cooperative Oncology Group performance status) was 2.
Laboratory investigations were all within the normal range, including lactate dehydrogenase (LDH), C-reactive protein (CRP), and procalcitonin. The nasopharyngeal swab for the detection of SARS-CoV-2 RNA by RT-PCR [11] was negative. A computed tomography (CT) scan of the thorax showed progressive disease in the superior mediastinum with significant reduction of the tracheal lumen (Figure 1). Palliative mediastinal radiotherapy was planned in order to reduce the tracheal compression, and methylprednisolone 40 mg bid was initiated obtaining a slight reduction of dyspnea.
During the hospital stay, the patient was exposed to an asymptomatic SARS-CoV-2 virus carrier. On 6 April 2020, she underwent screening nasopharyngeal swab for detection of SARS-CoV-2, which was positive. The scheduled radiotherapy was postponed and the patient was transferred to the infectious diseases unit. At admission she presented with mild inspiratory retraction but all the vital signs were normal. Blood examinations showed a moderate elevation of CRP (91 mg/L, normal value 0–6). Because of the high-risk condition, she was treated with the therapy currently recommended: hydroxychloroquine (HCQ) (400 mg bid for 24 h, then 200 mg bid) and azithromycin (AZI) (500 mg qd) [12]. Both drugs were stopped after two days because of QTc prolongation. Tapered steroidal therapy, osimertinib, and subcutaneous enoxaparin were continued.
The patient did not develop any coronavirus disease 2019 (COVID-19)-related symptoms, but nasopharyngeal swabs were persistently positive for SARS-CoV-2 for over one month. On 13 May after two consecutive negative swabs, she was transferred to the oncology ward to start radiotherapy treatment. Her ECOG PS was 3. Unfortunately, on May 19, the nasopharyngeal swab for SARS-CoV-2 RNA was positive. Once again the radiotherapy was postponed and the patient was isolated in the infectious diseases ward. The clinical conditions remained stable and the nasopharyngeal swabs were repeated at regular intervals with alternating results (Figure 2). On 30 May, a viral culture with Vero cells [13] was performed and resulted negative. The same result was achieved also 15 days later, despite the occurrence of new positive swabs.
Interestingly, serological tests showed the presence of high levels of anti-SARS-CoV-2 IgG [75,400 kAU/L (Positive: >1100 kAU/L)] and high titers persisted during the whole observation period; IgM title was persistently negative (Figure 2).
On the basis of these results, a single-fraction radiotherapy was performed on 4 June and the patient continued her regular follow-up with no need of oxygen supplementation. The last total body CT scan performed in July 2020 confirmed stable disease.
3. Discussion
SARS-CoV-2 pandemic caught clinicians and health authorities unprepared to manage cancer patients. Diagnostic and treatment guidelines were lacking at the beginning of the outbreak. Clinicians were challenged to manage COVID-19 disease with clinical characteristics which might be partly masked or confounded by coexisting cancer conditions. Moreover, the risk of nosocomial transmission of SARS-CoV-2 and the need for isolation contributed to the risk of progression of the malignant disease because of cancer treatments’ delays [14,15,16].
After the detection of SARS-CoV-2 our patient did not show any acute signs of infection and her symptoms could be attributed to her lung cancer. However SARS-CoV-2 swabs remained positive for more than 90 days, showing alternating results: in five occasions they turned out positive after one or two consecutive negative tests. It has been described that, after clinical resolution, some COVID-19 patients may experience a prolonged nucleic acid conversion [17,18]. Xiao and colleagues, from Wuhan, reported 21.4% of patients experiencing a “turn positive” of nucleic acid detection by RT-PCR test after two consecutive negative results [18]. In addition, it is still to be determined whether these patients are able to transmit the infection. However, relevant recent studies have shown that COVID-19 patients with mild-to-moderate illness are highly unlikely to be infectious longer than 10 days after symptom onset [19]. The molecular detection of SARS-CoV-2 by RT-PCR is a rapid and highly sensitive diagnostic method, but its ability to determine the duration of infectivity of patients is quite limited [20]. Viral culture is a more accurate tool to demonstrate the “in vitro” infectivity, giving surrogate information on viral transmission [9]. It is a complex diagnostic tool that needs expertise and biosafety level 3 laboratories, but it could be of crucial importance to define viral transmission and the infectivity of patients in particular conditions, such as the oncological setting [21]. Aside from viral culture, other diagnostic methods such as the threshold cycle (Ct) of RT-PCR and antigen-tests have been reported to be able to determine patients’ contagiousness. It has been demonstrated that infectivity is significantly reduced when Ct values are >24; for every unit increase in Ct, the odds ratio for infectivity decreases by 32%, suggesting that Ct values >24, along with the duration of symptoms >8 days may be used in combination to rule out patients’ contagiousness. Similar results are reported by La Scola et al. who showed a strong correlation between Ct value and sample infectivity in a cell culture model. Based on their data, they inferred that patients with Ct values equal or above 34 do not excrete infectious viral particles [22]. Rapid antigen tests may also have a role in this setting. They have a lower sensitivity compared to the standard RT-PCR test, but may be sensitive enough to detect cases with a high viral load (i.e., low RT-PCR cycle threshold (Ct) value <25), which likely account for a significant proportion of transmissions [8,23]. In addition, as reported in 68 respiratory specimens from 35 COVID patients in Hong Kong, the detection of subgenomic viral RNA (sgRNA) strongly correlated with the presence of active virus replication, with sgRNA being rarely detectable 8 days after the onset of the illness [7]. On the contrary, there is no consensus yet on the significance of the dynamic profile of SARS-CoV-2-specific antibody response. In our case the persistent positivity of RT-PCR assays coexisted with a strong serologic response, and none of the diagnostic procedures could prove or rule out the infectivity of the patient [24]. Unfortunately, in the first half of 2020, when our patient was hospitalized, viral load estimation by threshold cycle of RT-PCR and antigen-based tests were still under investigation, and the detection of sub-genomic RNAs was not available. Furthermore, the World Health Organization guidelines for releasing COVID-19 patients from isolation (i.e., ten days after symptom onset and at least three additional days without symptoms) were not yet amended. Nevertheless these guidelines do not specifically address immunocompromised individuals [25].
An Italian group has recently proposed an algorithm for the management of oncologic patients who need radiation therapy. Their recommendation is to delay or discontinue the radiation treatment in symptomatic and asymptomatic patients diagnosed with COVID-19 and to carefully start the treatment only when the patients are declared no longer exhibiting infection by the infectious diseases specialist [26].
In line with this recommendation we could discontinue hospital isolation owing to the repeatedly negative cell culture results, which allowed us to verify the absence of viral activity despite the persistent positivity of nasopharyngeal swabs. In this way the patient could finally undergo palliative radiotherapy for airway obstruction with a delay of eight weeks from the initial scheduled time. Although it is unlikely that the delayed palliative radiotherapy affected the short-term poor prognosis, it surely prolonged the length of hospitalization and negatively affected the patient’s quality of life.
4. Conclusions
This clinical case emphasizes the multifaceted and challenging approach to SARS-CoV-2 infection in the oncological setting. Clinicians must protect the vulnerable cancer population from a potentially severe infection without jeopardizing cancer care and support. The development of diagnostic tests able to determine the activity of the disease and patients’ infectivity may contribute to the fight against SARS-CoV-2, limiting the number of COVID-19-related deaths and the excess indirect mortality and morbidity in patients suffering from cancer.
Author Contributions
A.F.—Conceptualization, writing original draft. M.T.—Writing review & editing, supervision. L.S.—Writing review & editing. E.D.L.—Writing original draft. T.T.—Data curation. L.R.—Case analysis. E.D.M.—Writing review & editing. A.M.C.—Conceptualization, writing review and editing. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Informed Consent Statement
Verbal informed consent for this report was obtained from the patient involved in the study.
Conflicts of Interest
We have read and understood Current Oncology’s policy on conflicts of interest disclosure and declare that we have none.
Figure 1 Chest computed tomography (CT) scan: axial lung image showing huge reduction (arrow) of the trachea lumen (2 mm) due to mediastinal pathological tissue.
Figure 2 Timeline of SARS-CoV-2 nucleic acid testing results from nasopharyngeal swabs along with the anti-SARS-CoV-2 serology and viral culture testing.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | AZITHROMYCIN DIHYDRATE, ENOXAPARIN, HYDROXYCHLOROQUINE SULFATE, METHYLPREDNISOLONE, OSIMERTINIB, OXYGEN | DrugsGivenReaction | CC BY | 33567626 | 20,166,650 | 2021-02-08 |
What was the administration route of drug 'ENOXAPARIN SODIUM'? | Prolonged SARS-CoV-2-RNA Detection from Nasopharyngeal Swabs in an Oncologic Patient: What Impact on Cancer Treatment?
The pandemic of SARS-CoV-2 is a serious global challenge affecting millions of people worldwide. Cancer patients are at risk for infection exposure and serious complications. A prompt diagnosis of SARS-CoV-2 infection is crucial for the timely adoption of isolation measures and the appropriate management of cancer treatments. In lung cancer patients the symptoms of infection 19 may resemble those exhibited by the underlying oncologic condition, possibly leading to diagnostic overlap and delays. Moreover, cancer patients might display a prolonged positivity of nasopharyngeal RT-PCR assays for SARS-CoV-2, causing long interruptions or delay of cancer treatments. However, the association between the positivity of RT-PCR assays and the patient's infectivity remains uncertain. We describe the case of a patient with non-small cell lung cancer, and a severe ab extrinseco compression of the trachea, whose palliative radiotherapy was delayed because of the prolonged positivity of nasopharyngeal swabs for SARS-CoV-2. The patient did not show clinical symptoms suggestive of active infection, but the persistent positivity of RT-PCR assays imposed the continuation of isolation measures and the delay of radiotherapy for over two months. Finally, the negative result of SARS-CoV-2 viral culture allowed us to verify the absence of viral activity and to rule out the infectivity of the patient, who could finally continue her cancer treatment.
1. Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is a complex global challenge affecting millions of people worldwide [1]. Cancer patients are at high risk for serious complications and the infection itself may compromise the continuation of cancer therapies and supportive care [2,3,4]. Moreover, the frequent visits to the hospital for treatment and monitoring represent for cancer patients a major risk factor for exposure to SARS-CoV-2 [5]. In order to optimize the cancer care pathway and improve the clinical outcomes during the pandemic, a large, international and multidisciplinary consortium reviewed and discussed the clinical evidence in cancer management. In this current situation, the risk of infection must be individualized taking into consideration the primary tumor type, stage, age, and sex. In addition, cancer treatment must be patient tailored [6]. Thus far, the gold standard test for the diagnosis of COVID-19 has been the RT-PCR test performed on nasopharyngeal swabs or other upper respiratory tract specimens. However, a “positive” PCR result reflects the detection of viral RNA and does not necessarily prove the presence of active viral replication. To ascertain the infectivity of RT-PCR positive patients, several diagnostic methods such as the viral culture, the viral RNA measured by the cycle threshold (Ct), the antigen rapid test, and the detection of sub-genomic RNAs (sg-RNAs) have been recently introduced in clinical care. All these tests, when correlated with the time course of disease, may help define the contagiousness of patients diagnosed with SARS-CoV-2 infection [7,8,9,10]. We describe the case of a cancer patient whose palliative radiotherapy treatment was delayed because of the prolonged positivity of RT-PCR assays for SARS-CoV-2 on nasopharyngeal swabs, despite the absence of acute signs of infection. Eventually, the negative viral culture result allowed the physicians to continue the treatment.
2. Case Report
On 1 April 2020, a 72-year-old Caucasian woman affected by non-small cell lung cancer of the upper right lobe, was referred to the Istituto Oncologico Veneto (IOV) of Padua, Italy, for the acute onset of progressive shortness of breath and dry cough. Her past medical history was relevant for glaucoma, depression, and Parkinson disease. The patient had undergone a right upper lobe lung resection with ilo-mediastinic lymph node dissection in 2015; the histo-pathological examination revealed an EGFR exon19 deletion mutated adenocarcinoma. After four courses of adjuvant chemotherapy (cisplatin plus gemticitabine), due to disease progression, in 2018 targeted therapy with osimertinib was started with partial response according to RECIST (response evaluation criteria in solid tumors version 1.1).
At hospital admission, the physical examination revealed moderate inspiratory retraction and diffuse inspiratory wheezing; the body temperature was 36.8 °C; heart rate 68 bpm; blood pressure 125/80 mm Hg; respiratory rates 25 per minute; oxygen saturation 98% with 3 L/min oxygen supplement. Her ECOG PS (Eastern Cooperative Oncology Group performance status) was 2.
Laboratory investigations were all within the normal range, including lactate dehydrogenase (LDH), C-reactive protein (CRP), and procalcitonin. The nasopharyngeal swab for the detection of SARS-CoV-2 RNA by RT-PCR [11] was negative. A computed tomography (CT) scan of the thorax showed progressive disease in the superior mediastinum with significant reduction of the tracheal lumen (Figure 1). Palliative mediastinal radiotherapy was planned in order to reduce the tracheal compression, and methylprednisolone 40 mg bid was initiated obtaining a slight reduction of dyspnea.
During the hospital stay, the patient was exposed to an asymptomatic SARS-CoV-2 virus carrier. On 6 April 2020, she underwent screening nasopharyngeal swab for detection of SARS-CoV-2, which was positive. The scheduled radiotherapy was postponed and the patient was transferred to the infectious diseases unit. At admission she presented with mild inspiratory retraction but all the vital signs were normal. Blood examinations showed a moderate elevation of CRP (91 mg/L, normal value 0–6). Because of the high-risk condition, she was treated with the therapy currently recommended: hydroxychloroquine (HCQ) (400 mg bid for 24 h, then 200 mg bid) and azithromycin (AZI) (500 mg qd) [12]. Both drugs were stopped after two days because of QTc prolongation. Tapered steroidal therapy, osimertinib, and subcutaneous enoxaparin were continued.
The patient did not develop any coronavirus disease 2019 (COVID-19)-related symptoms, but nasopharyngeal swabs were persistently positive for SARS-CoV-2 for over one month. On 13 May after two consecutive negative swabs, she was transferred to the oncology ward to start radiotherapy treatment. Her ECOG PS was 3. Unfortunately, on May 19, the nasopharyngeal swab for SARS-CoV-2 RNA was positive. Once again the radiotherapy was postponed and the patient was isolated in the infectious diseases ward. The clinical conditions remained stable and the nasopharyngeal swabs were repeated at regular intervals with alternating results (Figure 2). On 30 May, a viral culture with Vero cells [13] was performed and resulted negative. The same result was achieved also 15 days later, despite the occurrence of new positive swabs.
Interestingly, serological tests showed the presence of high levels of anti-SARS-CoV-2 IgG [75,400 kAU/L (Positive: >1100 kAU/L)] and high titers persisted during the whole observation period; IgM title was persistently negative (Figure 2).
On the basis of these results, a single-fraction radiotherapy was performed on 4 June and the patient continued her regular follow-up with no need of oxygen supplementation. The last total body CT scan performed in July 2020 confirmed stable disease.
3. Discussion
SARS-CoV-2 pandemic caught clinicians and health authorities unprepared to manage cancer patients. Diagnostic and treatment guidelines were lacking at the beginning of the outbreak. Clinicians were challenged to manage COVID-19 disease with clinical characteristics which might be partly masked or confounded by coexisting cancer conditions. Moreover, the risk of nosocomial transmission of SARS-CoV-2 and the need for isolation contributed to the risk of progression of the malignant disease because of cancer treatments’ delays [14,15,16].
After the detection of SARS-CoV-2 our patient did not show any acute signs of infection and her symptoms could be attributed to her lung cancer. However SARS-CoV-2 swabs remained positive for more than 90 days, showing alternating results: in five occasions they turned out positive after one or two consecutive negative tests. It has been described that, after clinical resolution, some COVID-19 patients may experience a prolonged nucleic acid conversion [17,18]. Xiao and colleagues, from Wuhan, reported 21.4% of patients experiencing a “turn positive” of nucleic acid detection by RT-PCR test after two consecutive negative results [18]. In addition, it is still to be determined whether these patients are able to transmit the infection. However, relevant recent studies have shown that COVID-19 patients with mild-to-moderate illness are highly unlikely to be infectious longer than 10 days after symptom onset [19]. The molecular detection of SARS-CoV-2 by RT-PCR is a rapid and highly sensitive diagnostic method, but its ability to determine the duration of infectivity of patients is quite limited [20]. Viral culture is a more accurate tool to demonstrate the “in vitro” infectivity, giving surrogate information on viral transmission [9]. It is a complex diagnostic tool that needs expertise and biosafety level 3 laboratories, but it could be of crucial importance to define viral transmission and the infectivity of patients in particular conditions, such as the oncological setting [21]. Aside from viral culture, other diagnostic methods such as the threshold cycle (Ct) of RT-PCR and antigen-tests have been reported to be able to determine patients’ contagiousness. It has been demonstrated that infectivity is significantly reduced when Ct values are >24; for every unit increase in Ct, the odds ratio for infectivity decreases by 32%, suggesting that Ct values >24, along with the duration of symptoms >8 days may be used in combination to rule out patients’ contagiousness. Similar results are reported by La Scola et al. who showed a strong correlation between Ct value and sample infectivity in a cell culture model. Based on their data, they inferred that patients with Ct values equal or above 34 do not excrete infectious viral particles [22]. Rapid antigen tests may also have a role in this setting. They have a lower sensitivity compared to the standard RT-PCR test, but may be sensitive enough to detect cases with a high viral load (i.e., low RT-PCR cycle threshold (Ct) value <25), which likely account for a significant proportion of transmissions [8,23]. In addition, as reported in 68 respiratory specimens from 35 COVID patients in Hong Kong, the detection of subgenomic viral RNA (sgRNA) strongly correlated with the presence of active virus replication, with sgRNA being rarely detectable 8 days after the onset of the illness [7]. On the contrary, there is no consensus yet on the significance of the dynamic profile of SARS-CoV-2-specific antibody response. In our case the persistent positivity of RT-PCR assays coexisted with a strong serologic response, and none of the diagnostic procedures could prove or rule out the infectivity of the patient [24]. Unfortunately, in the first half of 2020, when our patient was hospitalized, viral load estimation by threshold cycle of RT-PCR and antigen-based tests were still under investigation, and the detection of sub-genomic RNAs was not available. Furthermore, the World Health Organization guidelines for releasing COVID-19 patients from isolation (i.e., ten days after symptom onset and at least three additional days without symptoms) were not yet amended. Nevertheless these guidelines do not specifically address immunocompromised individuals [25].
An Italian group has recently proposed an algorithm for the management of oncologic patients who need radiation therapy. Their recommendation is to delay or discontinue the radiation treatment in symptomatic and asymptomatic patients diagnosed with COVID-19 and to carefully start the treatment only when the patients are declared no longer exhibiting infection by the infectious diseases specialist [26].
In line with this recommendation we could discontinue hospital isolation owing to the repeatedly negative cell culture results, which allowed us to verify the absence of viral activity despite the persistent positivity of nasopharyngeal swabs. In this way the patient could finally undergo palliative radiotherapy for airway obstruction with a delay of eight weeks from the initial scheduled time. Although it is unlikely that the delayed palliative radiotherapy affected the short-term poor prognosis, it surely prolonged the length of hospitalization and negatively affected the patient’s quality of life.
4. Conclusions
This clinical case emphasizes the multifaceted and challenging approach to SARS-CoV-2 infection in the oncological setting. Clinicians must protect the vulnerable cancer population from a potentially severe infection without jeopardizing cancer care and support. The development of diagnostic tests able to determine the activity of the disease and patients’ infectivity may contribute to the fight against SARS-CoV-2, limiting the number of COVID-19-related deaths and the excess indirect mortality and morbidity in patients suffering from cancer.
Author Contributions
A.F.—Conceptualization, writing original draft. M.T.—Writing review & editing, supervision. L.S.—Writing review & editing. E.D.L.—Writing original draft. T.T.—Data curation. L.R.—Case analysis. E.D.M.—Writing review & editing. A.M.C.—Conceptualization, writing review and editing. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Informed Consent Statement
Verbal informed consent for this report was obtained from the patient involved in the study.
Conflicts of Interest
We have read and understood Current Oncology’s policy on conflicts of interest disclosure and declare that we have none.
Figure 1 Chest computed tomography (CT) scan: axial lung image showing huge reduction (arrow) of the trachea lumen (2 mm) due to mediastinal pathological tissue.
Figure 2 Timeline of SARS-CoV-2 nucleic acid testing results from nasopharyngeal swabs along with the anti-SARS-CoV-2 serology and viral culture testing.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Subcutaneous | DrugAdministrationRoute | CC BY | 33567626 | 19,099,889 | 2021-02-08 |
What was the administration route of drug 'ENOXAPARIN'? | Prolonged SARS-CoV-2-RNA Detection from Nasopharyngeal Swabs in an Oncologic Patient: What Impact on Cancer Treatment?
The pandemic of SARS-CoV-2 is a serious global challenge affecting millions of people worldwide. Cancer patients are at risk for infection exposure and serious complications. A prompt diagnosis of SARS-CoV-2 infection is crucial for the timely adoption of isolation measures and the appropriate management of cancer treatments. In lung cancer patients the symptoms of infection 19 may resemble those exhibited by the underlying oncologic condition, possibly leading to diagnostic overlap and delays. Moreover, cancer patients might display a prolonged positivity of nasopharyngeal RT-PCR assays for SARS-CoV-2, causing long interruptions or delay of cancer treatments. However, the association between the positivity of RT-PCR assays and the patient's infectivity remains uncertain. We describe the case of a patient with non-small cell lung cancer, and a severe ab extrinseco compression of the trachea, whose palliative radiotherapy was delayed because of the prolonged positivity of nasopharyngeal swabs for SARS-CoV-2. The patient did not show clinical symptoms suggestive of active infection, but the persistent positivity of RT-PCR assays imposed the continuation of isolation measures and the delay of radiotherapy for over two months. Finally, the negative result of SARS-CoV-2 viral culture allowed us to verify the absence of viral activity and to rule out the infectivity of the patient, who could finally continue her cancer treatment.
1. Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is a complex global challenge affecting millions of people worldwide [1]. Cancer patients are at high risk for serious complications and the infection itself may compromise the continuation of cancer therapies and supportive care [2,3,4]. Moreover, the frequent visits to the hospital for treatment and monitoring represent for cancer patients a major risk factor for exposure to SARS-CoV-2 [5]. In order to optimize the cancer care pathway and improve the clinical outcomes during the pandemic, a large, international and multidisciplinary consortium reviewed and discussed the clinical evidence in cancer management. In this current situation, the risk of infection must be individualized taking into consideration the primary tumor type, stage, age, and sex. In addition, cancer treatment must be patient tailored [6]. Thus far, the gold standard test for the diagnosis of COVID-19 has been the RT-PCR test performed on nasopharyngeal swabs or other upper respiratory tract specimens. However, a “positive” PCR result reflects the detection of viral RNA and does not necessarily prove the presence of active viral replication. To ascertain the infectivity of RT-PCR positive patients, several diagnostic methods such as the viral culture, the viral RNA measured by the cycle threshold (Ct), the antigen rapid test, and the detection of sub-genomic RNAs (sg-RNAs) have been recently introduced in clinical care. All these tests, when correlated with the time course of disease, may help define the contagiousness of patients diagnosed with SARS-CoV-2 infection [7,8,9,10]. We describe the case of a cancer patient whose palliative radiotherapy treatment was delayed because of the prolonged positivity of RT-PCR assays for SARS-CoV-2 on nasopharyngeal swabs, despite the absence of acute signs of infection. Eventually, the negative viral culture result allowed the physicians to continue the treatment.
2. Case Report
On 1 April 2020, a 72-year-old Caucasian woman affected by non-small cell lung cancer of the upper right lobe, was referred to the Istituto Oncologico Veneto (IOV) of Padua, Italy, for the acute onset of progressive shortness of breath and dry cough. Her past medical history was relevant for glaucoma, depression, and Parkinson disease. The patient had undergone a right upper lobe lung resection with ilo-mediastinic lymph node dissection in 2015; the histo-pathological examination revealed an EGFR exon19 deletion mutated adenocarcinoma. After four courses of adjuvant chemotherapy (cisplatin plus gemticitabine), due to disease progression, in 2018 targeted therapy with osimertinib was started with partial response according to RECIST (response evaluation criteria in solid tumors version 1.1).
At hospital admission, the physical examination revealed moderate inspiratory retraction and diffuse inspiratory wheezing; the body temperature was 36.8 °C; heart rate 68 bpm; blood pressure 125/80 mm Hg; respiratory rates 25 per minute; oxygen saturation 98% with 3 L/min oxygen supplement. Her ECOG PS (Eastern Cooperative Oncology Group performance status) was 2.
Laboratory investigations were all within the normal range, including lactate dehydrogenase (LDH), C-reactive protein (CRP), and procalcitonin. The nasopharyngeal swab for the detection of SARS-CoV-2 RNA by RT-PCR [11] was negative. A computed tomography (CT) scan of the thorax showed progressive disease in the superior mediastinum with significant reduction of the tracheal lumen (Figure 1). Palliative mediastinal radiotherapy was planned in order to reduce the tracheal compression, and methylprednisolone 40 mg bid was initiated obtaining a slight reduction of dyspnea.
During the hospital stay, the patient was exposed to an asymptomatic SARS-CoV-2 virus carrier. On 6 April 2020, she underwent screening nasopharyngeal swab for detection of SARS-CoV-2, which was positive. The scheduled radiotherapy was postponed and the patient was transferred to the infectious diseases unit. At admission she presented with mild inspiratory retraction but all the vital signs were normal. Blood examinations showed a moderate elevation of CRP (91 mg/L, normal value 0–6). Because of the high-risk condition, she was treated with the therapy currently recommended: hydroxychloroquine (HCQ) (400 mg bid for 24 h, then 200 mg bid) and azithromycin (AZI) (500 mg qd) [12]. Both drugs were stopped after two days because of QTc prolongation. Tapered steroidal therapy, osimertinib, and subcutaneous enoxaparin were continued.
The patient did not develop any coronavirus disease 2019 (COVID-19)-related symptoms, but nasopharyngeal swabs were persistently positive for SARS-CoV-2 for over one month. On 13 May after two consecutive negative swabs, she was transferred to the oncology ward to start radiotherapy treatment. Her ECOG PS was 3. Unfortunately, on May 19, the nasopharyngeal swab for SARS-CoV-2 RNA was positive. Once again the radiotherapy was postponed and the patient was isolated in the infectious diseases ward. The clinical conditions remained stable and the nasopharyngeal swabs were repeated at regular intervals with alternating results (Figure 2). On 30 May, a viral culture with Vero cells [13] was performed and resulted negative. The same result was achieved also 15 days later, despite the occurrence of new positive swabs.
Interestingly, serological tests showed the presence of high levels of anti-SARS-CoV-2 IgG [75,400 kAU/L (Positive: >1100 kAU/L)] and high titers persisted during the whole observation period; IgM title was persistently negative (Figure 2).
On the basis of these results, a single-fraction radiotherapy was performed on 4 June and the patient continued her regular follow-up with no need of oxygen supplementation. The last total body CT scan performed in July 2020 confirmed stable disease.
3. Discussion
SARS-CoV-2 pandemic caught clinicians and health authorities unprepared to manage cancer patients. Diagnostic and treatment guidelines were lacking at the beginning of the outbreak. Clinicians were challenged to manage COVID-19 disease with clinical characteristics which might be partly masked or confounded by coexisting cancer conditions. Moreover, the risk of nosocomial transmission of SARS-CoV-2 and the need for isolation contributed to the risk of progression of the malignant disease because of cancer treatments’ delays [14,15,16].
After the detection of SARS-CoV-2 our patient did not show any acute signs of infection and her symptoms could be attributed to her lung cancer. However SARS-CoV-2 swabs remained positive for more than 90 days, showing alternating results: in five occasions they turned out positive after one or two consecutive negative tests. It has been described that, after clinical resolution, some COVID-19 patients may experience a prolonged nucleic acid conversion [17,18]. Xiao and colleagues, from Wuhan, reported 21.4% of patients experiencing a “turn positive” of nucleic acid detection by RT-PCR test after two consecutive negative results [18]. In addition, it is still to be determined whether these patients are able to transmit the infection. However, relevant recent studies have shown that COVID-19 patients with mild-to-moderate illness are highly unlikely to be infectious longer than 10 days after symptom onset [19]. The molecular detection of SARS-CoV-2 by RT-PCR is a rapid and highly sensitive diagnostic method, but its ability to determine the duration of infectivity of patients is quite limited [20]. Viral culture is a more accurate tool to demonstrate the “in vitro” infectivity, giving surrogate information on viral transmission [9]. It is a complex diagnostic tool that needs expertise and biosafety level 3 laboratories, but it could be of crucial importance to define viral transmission and the infectivity of patients in particular conditions, such as the oncological setting [21]. Aside from viral culture, other diagnostic methods such as the threshold cycle (Ct) of RT-PCR and antigen-tests have been reported to be able to determine patients’ contagiousness. It has been demonstrated that infectivity is significantly reduced when Ct values are >24; for every unit increase in Ct, the odds ratio for infectivity decreases by 32%, suggesting that Ct values >24, along with the duration of symptoms >8 days may be used in combination to rule out patients’ contagiousness. Similar results are reported by La Scola et al. who showed a strong correlation between Ct value and sample infectivity in a cell culture model. Based on their data, they inferred that patients with Ct values equal or above 34 do not excrete infectious viral particles [22]. Rapid antigen tests may also have a role in this setting. They have a lower sensitivity compared to the standard RT-PCR test, but may be sensitive enough to detect cases with a high viral load (i.e., low RT-PCR cycle threshold (Ct) value <25), which likely account for a significant proportion of transmissions [8,23]. In addition, as reported in 68 respiratory specimens from 35 COVID patients in Hong Kong, the detection of subgenomic viral RNA (sgRNA) strongly correlated with the presence of active virus replication, with sgRNA being rarely detectable 8 days after the onset of the illness [7]. On the contrary, there is no consensus yet on the significance of the dynamic profile of SARS-CoV-2-specific antibody response. In our case the persistent positivity of RT-PCR assays coexisted with a strong serologic response, and none of the diagnostic procedures could prove or rule out the infectivity of the patient [24]. Unfortunately, in the first half of 2020, when our patient was hospitalized, viral load estimation by threshold cycle of RT-PCR and antigen-based tests were still under investigation, and the detection of sub-genomic RNAs was not available. Furthermore, the World Health Organization guidelines for releasing COVID-19 patients from isolation (i.e., ten days after symptom onset and at least three additional days without symptoms) were not yet amended. Nevertheless these guidelines do not specifically address immunocompromised individuals [25].
An Italian group has recently proposed an algorithm for the management of oncologic patients who need radiation therapy. Their recommendation is to delay or discontinue the radiation treatment in symptomatic and asymptomatic patients diagnosed with COVID-19 and to carefully start the treatment only when the patients are declared no longer exhibiting infection by the infectious diseases specialist [26].
In line with this recommendation we could discontinue hospital isolation owing to the repeatedly negative cell culture results, which allowed us to verify the absence of viral activity despite the persistent positivity of nasopharyngeal swabs. In this way the patient could finally undergo palliative radiotherapy for airway obstruction with a delay of eight weeks from the initial scheduled time. Although it is unlikely that the delayed palliative radiotherapy affected the short-term poor prognosis, it surely prolonged the length of hospitalization and negatively affected the patient’s quality of life.
4. Conclusions
This clinical case emphasizes the multifaceted and challenging approach to SARS-CoV-2 infection in the oncological setting. Clinicians must protect the vulnerable cancer population from a potentially severe infection without jeopardizing cancer care and support. The development of diagnostic tests able to determine the activity of the disease and patients’ infectivity may contribute to the fight against SARS-CoV-2, limiting the number of COVID-19-related deaths and the excess indirect mortality and morbidity in patients suffering from cancer.
Author Contributions
A.F.—Conceptualization, writing original draft. M.T.—Writing review & editing, supervision. L.S.—Writing review & editing. E.D.L.—Writing original draft. T.T.—Data curation. L.R.—Case analysis. E.D.M.—Writing review & editing. A.M.C.—Conceptualization, writing review and editing. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Informed Consent Statement
Verbal informed consent for this report was obtained from the patient involved in the study.
Conflicts of Interest
We have read and understood Current Oncology’s policy on conflicts of interest disclosure and declare that we have none.
Figure 1 Chest computed tomography (CT) scan: axial lung image showing huge reduction (arrow) of the trachea lumen (2 mm) due to mediastinal pathological tissue.
Figure 2 Timeline of SARS-CoV-2 nucleic acid testing results from nasopharyngeal swabs along with the anti-SARS-CoV-2 serology and viral culture testing.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | Subcutaneous | DrugAdministrationRoute | CC BY | 33567626 | 20,166,650 | 2021-02-08 |
What was the dosage of drug 'AZITHROMYCIN DIHYDRATE'? | Prolonged SARS-CoV-2-RNA Detection from Nasopharyngeal Swabs in an Oncologic Patient: What Impact on Cancer Treatment?
The pandemic of SARS-CoV-2 is a serious global challenge affecting millions of people worldwide. Cancer patients are at risk for infection exposure and serious complications. A prompt diagnosis of SARS-CoV-2 infection is crucial for the timely adoption of isolation measures and the appropriate management of cancer treatments. In lung cancer patients the symptoms of infection 19 may resemble those exhibited by the underlying oncologic condition, possibly leading to diagnostic overlap and delays. Moreover, cancer patients might display a prolonged positivity of nasopharyngeal RT-PCR assays for SARS-CoV-2, causing long interruptions or delay of cancer treatments. However, the association between the positivity of RT-PCR assays and the patient's infectivity remains uncertain. We describe the case of a patient with non-small cell lung cancer, and a severe ab extrinseco compression of the trachea, whose palliative radiotherapy was delayed because of the prolonged positivity of nasopharyngeal swabs for SARS-CoV-2. The patient did not show clinical symptoms suggestive of active infection, but the persistent positivity of RT-PCR assays imposed the continuation of isolation measures and the delay of radiotherapy for over two months. Finally, the negative result of SARS-CoV-2 viral culture allowed us to verify the absence of viral activity and to rule out the infectivity of the patient, who could finally continue her cancer treatment.
1. Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is a complex global challenge affecting millions of people worldwide [1]. Cancer patients are at high risk for serious complications and the infection itself may compromise the continuation of cancer therapies and supportive care [2,3,4]. Moreover, the frequent visits to the hospital for treatment and monitoring represent for cancer patients a major risk factor for exposure to SARS-CoV-2 [5]. In order to optimize the cancer care pathway and improve the clinical outcomes during the pandemic, a large, international and multidisciplinary consortium reviewed and discussed the clinical evidence in cancer management. In this current situation, the risk of infection must be individualized taking into consideration the primary tumor type, stage, age, and sex. In addition, cancer treatment must be patient tailored [6]. Thus far, the gold standard test for the diagnosis of COVID-19 has been the RT-PCR test performed on nasopharyngeal swabs or other upper respiratory tract specimens. However, a “positive” PCR result reflects the detection of viral RNA and does not necessarily prove the presence of active viral replication. To ascertain the infectivity of RT-PCR positive patients, several diagnostic methods such as the viral culture, the viral RNA measured by the cycle threshold (Ct), the antigen rapid test, and the detection of sub-genomic RNAs (sg-RNAs) have been recently introduced in clinical care. All these tests, when correlated with the time course of disease, may help define the contagiousness of patients diagnosed with SARS-CoV-2 infection [7,8,9,10]. We describe the case of a cancer patient whose palliative radiotherapy treatment was delayed because of the prolonged positivity of RT-PCR assays for SARS-CoV-2 on nasopharyngeal swabs, despite the absence of acute signs of infection. Eventually, the negative viral culture result allowed the physicians to continue the treatment.
2. Case Report
On 1 April 2020, a 72-year-old Caucasian woman affected by non-small cell lung cancer of the upper right lobe, was referred to the Istituto Oncologico Veneto (IOV) of Padua, Italy, for the acute onset of progressive shortness of breath and dry cough. Her past medical history was relevant for glaucoma, depression, and Parkinson disease. The patient had undergone a right upper lobe lung resection with ilo-mediastinic lymph node dissection in 2015; the histo-pathological examination revealed an EGFR exon19 deletion mutated adenocarcinoma. After four courses of adjuvant chemotherapy (cisplatin plus gemticitabine), due to disease progression, in 2018 targeted therapy with osimertinib was started with partial response according to RECIST (response evaluation criteria in solid tumors version 1.1).
At hospital admission, the physical examination revealed moderate inspiratory retraction and diffuse inspiratory wheezing; the body temperature was 36.8 °C; heart rate 68 bpm; blood pressure 125/80 mm Hg; respiratory rates 25 per minute; oxygen saturation 98% with 3 L/min oxygen supplement. Her ECOG PS (Eastern Cooperative Oncology Group performance status) was 2.
Laboratory investigations were all within the normal range, including lactate dehydrogenase (LDH), C-reactive protein (CRP), and procalcitonin. The nasopharyngeal swab for the detection of SARS-CoV-2 RNA by RT-PCR [11] was negative. A computed tomography (CT) scan of the thorax showed progressive disease in the superior mediastinum with significant reduction of the tracheal lumen (Figure 1). Palliative mediastinal radiotherapy was planned in order to reduce the tracheal compression, and methylprednisolone 40 mg bid was initiated obtaining a slight reduction of dyspnea.
During the hospital stay, the patient was exposed to an asymptomatic SARS-CoV-2 virus carrier. On 6 April 2020, she underwent screening nasopharyngeal swab for detection of SARS-CoV-2, which was positive. The scheduled radiotherapy was postponed and the patient was transferred to the infectious diseases unit. At admission she presented with mild inspiratory retraction but all the vital signs were normal. Blood examinations showed a moderate elevation of CRP (91 mg/L, normal value 0–6). Because of the high-risk condition, she was treated with the therapy currently recommended: hydroxychloroquine (HCQ) (400 mg bid for 24 h, then 200 mg bid) and azithromycin (AZI) (500 mg qd) [12]. Both drugs were stopped after two days because of QTc prolongation. Tapered steroidal therapy, osimertinib, and subcutaneous enoxaparin were continued.
The patient did not develop any coronavirus disease 2019 (COVID-19)-related symptoms, but nasopharyngeal swabs were persistently positive for SARS-CoV-2 for over one month. On 13 May after two consecutive negative swabs, she was transferred to the oncology ward to start radiotherapy treatment. Her ECOG PS was 3. Unfortunately, on May 19, the nasopharyngeal swab for SARS-CoV-2 RNA was positive. Once again the radiotherapy was postponed and the patient was isolated in the infectious diseases ward. The clinical conditions remained stable and the nasopharyngeal swabs were repeated at regular intervals with alternating results (Figure 2). On 30 May, a viral culture with Vero cells [13] was performed and resulted negative. The same result was achieved also 15 days later, despite the occurrence of new positive swabs.
Interestingly, serological tests showed the presence of high levels of anti-SARS-CoV-2 IgG [75,400 kAU/L (Positive: >1100 kAU/L)] and high titers persisted during the whole observation period; IgM title was persistently negative (Figure 2).
On the basis of these results, a single-fraction radiotherapy was performed on 4 June and the patient continued her regular follow-up with no need of oxygen supplementation. The last total body CT scan performed in July 2020 confirmed stable disease.
3. Discussion
SARS-CoV-2 pandemic caught clinicians and health authorities unprepared to manage cancer patients. Diagnostic and treatment guidelines were lacking at the beginning of the outbreak. Clinicians were challenged to manage COVID-19 disease with clinical characteristics which might be partly masked or confounded by coexisting cancer conditions. Moreover, the risk of nosocomial transmission of SARS-CoV-2 and the need for isolation contributed to the risk of progression of the malignant disease because of cancer treatments’ delays [14,15,16].
After the detection of SARS-CoV-2 our patient did not show any acute signs of infection and her symptoms could be attributed to her lung cancer. However SARS-CoV-2 swabs remained positive for more than 90 days, showing alternating results: in five occasions they turned out positive after one or two consecutive negative tests. It has been described that, after clinical resolution, some COVID-19 patients may experience a prolonged nucleic acid conversion [17,18]. Xiao and colleagues, from Wuhan, reported 21.4% of patients experiencing a “turn positive” of nucleic acid detection by RT-PCR test after two consecutive negative results [18]. In addition, it is still to be determined whether these patients are able to transmit the infection. However, relevant recent studies have shown that COVID-19 patients with mild-to-moderate illness are highly unlikely to be infectious longer than 10 days after symptom onset [19]. The molecular detection of SARS-CoV-2 by RT-PCR is a rapid and highly sensitive diagnostic method, but its ability to determine the duration of infectivity of patients is quite limited [20]. Viral culture is a more accurate tool to demonstrate the “in vitro” infectivity, giving surrogate information on viral transmission [9]. It is a complex diagnostic tool that needs expertise and biosafety level 3 laboratories, but it could be of crucial importance to define viral transmission and the infectivity of patients in particular conditions, such as the oncological setting [21]. Aside from viral culture, other diagnostic methods such as the threshold cycle (Ct) of RT-PCR and antigen-tests have been reported to be able to determine patients’ contagiousness. It has been demonstrated that infectivity is significantly reduced when Ct values are >24; for every unit increase in Ct, the odds ratio for infectivity decreases by 32%, suggesting that Ct values >24, along with the duration of symptoms >8 days may be used in combination to rule out patients’ contagiousness. Similar results are reported by La Scola et al. who showed a strong correlation between Ct value and sample infectivity in a cell culture model. Based on their data, they inferred that patients with Ct values equal or above 34 do not excrete infectious viral particles [22]. Rapid antigen tests may also have a role in this setting. They have a lower sensitivity compared to the standard RT-PCR test, but may be sensitive enough to detect cases with a high viral load (i.e., low RT-PCR cycle threshold (Ct) value <25), which likely account for a significant proportion of transmissions [8,23]. In addition, as reported in 68 respiratory specimens from 35 COVID patients in Hong Kong, the detection of subgenomic viral RNA (sgRNA) strongly correlated with the presence of active virus replication, with sgRNA being rarely detectable 8 days after the onset of the illness [7]. On the contrary, there is no consensus yet on the significance of the dynamic profile of SARS-CoV-2-specific antibody response. In our case the persistent positivity of RT-PCR assays coexisted with a strong serologic response, and none of the diagnostic procedures could prove or rule out the infectivity of the patient [24]. Unfortunately, in the first half of 2020, when our patient was hospitalized, viral load estimation by threshold cycle of RT-PCR and antigen-based tests were still under investigation, and the detection of sub-genomic RNAs was not available. Furthermore, the World Health Organization guidelines for releasing COVID-19 patients from isolation (i.e., ten days after symptom onset and at least three additional days without symptoms) were not yet amended. Nevertheless these guidelines do not specifically address immunocompromised individuals [25].
An Italian group has recently proposed an algorithm for the management of oncologic patients who need radiation therapy. Their recommendation is to delay or discontinue the radiation treatment in symptomatic and asymptomatic patients diagnosed with COVID-19 and to carefully start the treatment only when the patients are declared no longer exhibiting infection by the infectious diseases specialist [26].
In line with this recommendation we could discontinue hospital isolation owing to the repeatedly negative cell culture results, which allowed us to verify the absence of viral activity despite the persistent positivity of nasopharyngeal swabs. In this way the patient could finally undergo palliative radiotherapy for airway obstruction with a delay of eight weeks from the initial scheduled time. Although it is unlikely that the delayed palliative radiotherapy affected the short-term poor prognosis, it surely prolonged the length of hospitalization and negatively affected the patient’s quality of life.
4. Conclusions
This clinical case emphasizes the multifaceted and challenging approach to SARS-CoV-2 infection in the oncological setting. Clinicians must protect the vulnerable cancer population from a potentially severe infection without jeopardizing cancer care and support. The development of diagnostic tests able to determine the activity of the disease and patients’ infectivity may contribute to the fight against SARS-CoV-2, limiting the number of COVID-19-related deaths and the excess indirect mortality and morbidity in patients suffering from cancer.
Author Contributions
A.F.—Conceptualization, writing original draft. M.T.—Writing review & editing, supervision. L.S.—Writing review & editing. E.D.L.—Writing original draft. T.T.—Data curation. L.R.—Case analysis. E.D.M.—Writing review & editing. A.M.C.—Conceptualization, writing review and editing. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Informed Consent Statement
Verbal informed consent for this report was obtained from the patient involved in the study.
Conflicts of Interest
We have read and understood Current Oncology’s policy on conflicts of interest disclosure and declare that we have none.
Figure 1 Chest computed tomography (CT) scan: axial lung image showing huge reduction (arrow) of the trachea lumen (2 mm) due to mediastinal pathological tissue.
Figure 2 Timeline of SARS-CoV-2 nucleic acid testing results from nasopharyngeal swabs along with the anti-SARS-CoV-2 serology and viral culture testing.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | 500 MG, QD | DrugDosageText | CC BY | 33567626 | 20,166,650 | 2021-02-08 |
What was the dosage of drug 'METHYLPREDNISOLONE'? | Prolonged SARS-CoV-2-RNA Detection from Nasopharyngeal Swabs in an Oncologic Patient: What Impact on Cancer Treatment?
The pandemic of SARS-CoV-2 is a serious global challenge affecting millions of people worldwide. Cancer patients are at risk for infection exposure and serious complications. A prompt diagnosis of SARS-CoV-2 infection is crucial for the timely adoption of isolation measures and the appropriate management of cancer treatments. In lung cancer patients the symptoms of infection 19 may resemble those exhibited by the underlying oncologic condition, possibly leading to diagnostic overlap and delays. Moreover, cancer patients might display a prolonged positivity of nasopharyngeal RT-PCR assays for SARS-CoV-2, causing long interruptions or delay of cancer treatments. However, the association between the positivity of RT-PCR assays and the patient's infectivity remains uncertain. We describe the case of a patient with non-small cell lung cancer, and a severe ab extrinseco compression of the trachea, whose palliative radiotherapy was delayed because of the prolonged positivity of nasopharyngeal swabs for SARS-CoV-2. The patient did not show clinical symptoms suggestive of active infection, but the persistent positivity of RT-PCR assays imposed the continuation of isolation measures and the delay of radiotherapy for over two months. Finally, the negative result of SARS-CoV-2 viral culture allowed us to verify the absence of viral activity and to rule out the infectivity of the patient, who could finally continue her cancer treatment.
1. Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is a complex global challenge affecting millions of people worldwide [1]. Cancer patients are at high risk for serious complications and the infection itself may compromise the continuation of cancer therapies and supportive care [2,3,4]. Moreover, the frequent visits to the hospital for treatment and monitoring represent for cancer patients a major risk factor for exposure to SARS-CoV-2 [5]. In order to optimize the cancer care pathway and improve the clinical outcomes during the pandemic, a large, international and multidisciplinary consortium reviewed and discussed the clinical evidence in cancer management. In this current situation, the risk of infection must be individualized taking into consideration the primary tumor type, stage, age, and sex. In addition, cancer treatment must be patient tailored [6]. Thus far, the gold standard test for the diagnosis of COVID-19 has been the RT-PCR test performed on nasopharyngeal swabs or other upper respiratory tract specimens. However, a “positive” PCR result reflects the detection of viral RNA and does not necessarily prove the presence of active viral replication. To ascertain the infectivity of RT-PCR positive patients, several diagnostic methods such as the viral culture, the viral RNA measured by the cycle threshold (Ct), the antigen rapid test, and the detection of sub-genomic RNAs (sg-RNAs) have been recently introduced in clinical care. All these tests, when correlated with the time course of disease, may help define the contagiousness of patients diagnosed with SARS-CoV-2 infection [7,8,9,10]. We describe the case of a cancer patient whose palliative radiotherapy treatment was delayed because of the prolonged positivity of RT-PCR assays for SARS-CoV-2 on nasopharyngeal swabs, despite the absence of acute signs of infection. Eventually, the negative viral culture result allowed the physicians to continue the treatment.
2. Case Report
On 1 April 2020, a 72-year-old Caucasian woman affected by non-small cell lung cancer of the upper right lobe, was referred to the Istituto Oncologico Veneto (IOV) of Padua, Italy, for the acute onset of progressive shortness of breath and dry cough. Her past medical history was relevant for glaucoma, depression, and Parkinson disease. The patient had undergone a right upper lobe lung resection with ilo-mediastinic lymph node dissection in 2015; the histo-pathological examination revealed an EGFR exon19 deletion mutated adenocarcinoma. After four courses of adjuvant chemotherapy (cisplatin plus gemticitabine), due to disease progression, in 2018 targeted therapy with osimertinib was started with partial response according to RECIST (response evaluation criteria in solid tumors version 1.1).
At hospital admission, the physical examination revealed moderate inspiratory retraction and diffuse inspiratory wheezing; the body temperature was 36.8 °C; heart rate 68 bpm; blood pressure 125/80 mm Hg; respiratory rates 25 per minute; oxygen saturation 98% with 3 L/min oxygen supplement. Her ECOG PS (Eastern Cooperative Oncology Group performance status) was 2.
Laboratory investigations were all within the normal range, including lactate dehydrogenase (LDH), C-reactive protein (CRP), and procalcitonin. The nasopharyngeal swab for the detection of SARS-CoV-2 RNA by RT-PCR [11] was negative. A computed tomography (CT) scan of the thorax showed progressive disease in the superior mediastinum with significant reduction of the tracheal lumen (Figure 1). Palliative mediastinal radiotherapy was planned in order to reduce the tracheal compression, and methylprednisolone 40 mg bid was initiated obtaining a slight reduction of dyspnea.
During the hospital stay, the patient was exposed to an asymptomatic SARS-CoV-2 virus carrier. On 6 April 2020, she underwent screening nasopharyngeal swab for detection of SARS-CoV-2, which was positive. The scheduled radiotherapy was postponed and the patient was transferred to the infectious diseases unit. At admission she presented with mild inspiratory retraction but all the vital signs were normal. Blood examinations showed a moderate elevation of CRP (91 mg/L, normal value 0–6). Because of the high-risk condition, she was treated with the therapy currently recommended: hydroxychloroquine (HCQ) (400 mg bid for 24 h, then 200 mg bid) and azithromycin (AZI) (500 mg qd) [12]. Both drugs were stopped after two days because of QTc prolongation. Tapered steroidal therapy, osimertinib, and subcutaneous enoxaparin were continued.
The patient did not develop any coronavirus disease 2019 (COVID-19)-related symptoms, but nasopharyngeal swabs were persistently positive for SARS-CoV-2 for over one month. On 13 May after two consecutive negative swabs, she was transferred to the oncology ward to start radiotherapy treatment. Her ECOG PS was 3. Unfortunately, on May 19, the nasopharyngeal swab for SARS-CoV-2 RNA was positive. Once again the radiotherapy was postponed and the patient was isolated in the infectious diseases ward. The clinical conditions remained stable and the nasopharyngeal swabs were repeated at regular intervals with alternating results (Figure 2). On 30 May, a viral culture with Vero cells [13] was performed and resulted negative. The same result was achieved also 15 days later, despite the occurrence of new positive swabs.
Interestingly, serological tests showed the presence of high levels of anti-SARS-CoV-2 IgG [75,400 kAU/L (Positive: >1100 kAU/L)] and high titers persisted during the whole observation period; IgM title was persistently negative (Figure 2).
On the basis of these results, a single-fraction radiotherapy was performed on 4 June and the patient continued her regular follow-up with no need of oxygen supplementation. The last total body CT scan performed in July 2020 confirmed stable disease.
3. Discussion
SARS-CoV-2 pandemic caught clinicians and health authorities unprepared to manage cancer patients. Diagnostic and treatment guidelines were lacking at the beginning of the outbreak. Clinicians were challenged to manage COVID-19 disease with clinical characteristics which might be partly masked or confounded by coexisting cancer conditions. Moreover, the risk of nosocomial transmission of SARS-CoV-2 and the need for isolation contributed to the risk of progression of the malignant disease because of cancer treatments’ delays [14,15,16].
After the detection of SARS-CoV-2 our patient did not show any acute signs of infection and her symptoms could be attributed to her lung cancer. However SARS-CoV-2 swabs remained positive for more than 90 days, showing alternating results: in five occasions they turned out positive after one or two consecutive negative tests. It has been described that, after clinical resolution, some COVID-19 patients may experience a prolonged nucleic acid conversion [17,18]. Xiao and colleagues, from Wuhan, reported 21.4% of patients experiencing a “turn positive” of nucleic acid detection by RT-PCR test after two consecutive negative results [18]. In addition, it is still to be determined whether these patients are able to transmit the infection. However, relevant recent studies have shown that COVID-19 patients with mild-to-moderate illness are highly unlikely to be infectious longer than 10 days after symptom onset [19]. The molecular detection of SARS-CoV-2 by RT-PCR is a rapid and highly sensitive diagnostic method, but its ability to determine the duration of infectivity of patients is quite limited [20]. Viral culture is a more accurate tool to demonstrate the “in vitro” infectivity, giving surrogate information on viral transmission [9]. It is a complex diagnostic tool that needs expertise and biosafety level 3 laboratories, but it could be of crucial importance to define viral transmission and the infectivity of patients in particular conditions, such as the oncological setting [21]. Aside from viral culture, other diagnostic methods such as the threshold cycle (Ct) of RT-PCR and antigen-tests have been reported to be able to determine patients’ contagiousness. It has been demonstrated that infectivity is significantly reduced when Ct values are >24; for every unit increase in Ct, the odds ratio for infectivity decreases by 32%, suggesting that Ct values >24, along with the duration of symptoms >8 days may be used in combination to rule out patients’ contagiousness. Similar results are reported by La Scola et al. who showed a strong correlation between Ct value and sample infectivity in a cell culture model. Based on their data, they inferred that patients with Ct values equal or above 34 do not excrete infectious viral particles [22]. Rapid antigen tests may also have a role in this setting. They have a lower sensitivity compared to the standard RT-PCR test, but may be sensitive enough to detect cases with a high viral load (i.e., low RT-PCR cycle threshold (Ct) value <25), which likely account for a significant proportion of transmissions [8,23]. In addition, as reported in 68 respiratory specimens from 35 COVID patients in Hong Kong, the detection of subgenomic viral RNA (sgRNA) strongly correlated with the presence of active virus replication, with sgRNA being rarely detectable 8 days after the onset of the illness [7]. On the contrary, there is no consensus yet on the significance of the dynamic profile of SARS-CoV-2-specific antibody response. In our case the persistent positivity of RT-PCR assays coexisted with a strong serologic response, and none of the diagnostic procedures could prove or rule out the infectivity of the patient [24]. Unfortunately, in the first half of 2020, when our patient was hospitalized, viral load estimation by threshold cycle of RT-PCR and antigen-based tests were still under investigation, and the detection of sub-genomic RNAs was not available. Furthermore, the World Health Organization guidelines for releasing COVID-19 patients from isolation (i.e., ten days after symptom onset and at least three additional days without symptoms) were not yet amended. Nevertheless these guidelines do not specifically address immunocompromised individuals [25].
An Italian group has recently proposed an algorithm for the management of oncologic patients who need radiation therapy. Their recommendation is to delay or discontinue the radiation treatment in symptomatic and asymptomatic patients diagnosed with COVID-19 and to carefully start the treatment only when the patients are declared no longer exhibiting infection by the infectious diseases specialist [26].
In line with this recommendation we could discontinue hospital isolation owing to the repeatedly negative cell culture results, which allowed us to verify the absence of viral activity despite the persistent positivity of nasopharyngeal swabs. In this way the patient could finally undergo palliative radiotherapy for airway obstruction with a delay of eight weeks from the initial scheduled time. Although it is unlikely that the delayed palliative radiotherapy affected the short-term poor prognosis, it surely prolonged the length of hospitalization and negatively affected the patient’s quality of life.
4. Conclusions
This clinical case emphasizes the multifaceted and challenging approach to SARS-CoV-2 infection in the oncological setting. Clinicians must protect the vulnerable cancer population from a potentially severe infection without jeopardizing cancer care and support. The development of diagnostic tests able to determine the activity of the disease and patients’ infectivity may contribute to the fight against SARS-CoV-2, limiting the number of COVID-19-related deaths and the excess indirect mortality and morbidity in patients suffering from cancer.
Author Contributions
A.F.—Conceptualization, writing original draft. M.T.—Writing review & editing, supervision. L.S.—Writing review & editing. E.D.L.—Writing original draft. T.T.—Data curation. L.R.—Case analysis. E.D.M.—Writing review & editing. A.M.C.—Conceptualization, writing review and editing. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Informed Consent Statement
Verbal informed consent for this report was obtained from the patient involved in the study.
Conflicts of Interest
We have read and understood Current Oncology’s policy on conflicts of interest disclosure and declare that we have none.
Figure 1 Chest computed tomography (CT) scan: axial lung image showing huge reduction (arrow) of the trachea lumen (2 mm) due to mediastinal pathological tissue.
Figure 2 Timeline of SARS-CoV-2 nucleic acid testing results from nasopharyngeal swabs along with the anti-SARS-CoV-2 serology and viral culture testing.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | 40 MG, BID (2/DAY) | DrugDosageText | CC BY | 33567626 | 20,166,650 | 2021-02-08 |
What was the dosage of drug 'OXYGEN'? | Prolonged SARS-CoV-2-RNA Detection from Nasopharyngeal Swabs in an Oncologic Patient: What Impact on Cancer Treatment?
The pandemic of SARS-CoV-2 is a serious global challenge affecting millions of people worldwide. Cancer patients are at risk for infection exposure and serious complications. A prompt diagnosis of SARS-CoV-2 infection is crucial for the timely adoption of isolation measures and the appropriate management of cancer treatments. In lung cancer patients the symptoms of infection 19 may resemble those exhibited by the underlying oncologic condition, possibly leading to diagnostic overlap and delays. Moreover, cancer patients might display a prolonged positivity of nasopharyngeal RT-PCR assays for SARS-CoV-2, causing long interruptions or delay of cancer treatments. However, the association between the positivity of RT-PCR assays and the patient's infectivity remains uncertain. We describe the case of a patient with non-small cell lung cancer, and a severe ab extrinseco compression of the trachea, whose palliative radiotherapy was delayed because of the prolonged positivity of nasopharyngeal swabs for SARS-CoV-2. The patient did not show clinical symptoms suggestive of active infection, but the persistent positivity of RT-PCR assays imposed the continuation of isolation measures and the delay of radiotherapy for over two months. Finally, the negative result of SARS-CoV-2 viral culture allowed us to verify the absence of viral activity and to rule out the infectivity of the patient, who could finally continue her cancer treatment.
1. Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is a complex global challenge affecting millions of people worldwide [1]. Cancer patients are at high risk for serious complications and the infection itself may compromise the continuation of cancer therapies and supportive care [2,3,4]. Moreover, the frequent visits to the hospital for treatment and monitoring represent for cancer patients a major risk factor for exposure to SARS-CoV-2 [5]. In order to optimize the cancer care pathway and improve the clinical outcomes during the pandemic, a large, international and multidisciplinary consortium reviewed and discussed the clinical evidence in cancer management. In this current situation, the risk of infection must be individualized taking into consideration the primary tumor type, stage, age, and sex. In addition, cancer treatment must be patient tailored [6]. Thus far, the gold standard test for the diagnosis of COVID-19 has been the RT-PCR test performed on nasopharyngeal swabs or other upper respiratory tract specimens. However, a “positive” PCR result reflects the detection of viral RNA and does not necessarily prove the presence of active viral replication. To ascertain the infectivity of RT-PCR positive patients, several diagnostic methods such as the viral culture, the viral RNA measured by the cycle threshold (Ct), the antigen rapid test, and the detection of sub-genomic RNAs (sg-RNAs) have been recently introduced in clinical care. All these tests, when correlated with the time course of disease, may help define the contagiousness of patients diagnosed with SARS-CoV-2 infection [7,8,9,10]. We describe the case of a cancer patient whose palliative radiotherapy treatment was delayed because of the prolonged positivity of RT-PCR assays for SARS-CoV-2 on nasopharyngeal swabs, despite the absence of acute signs of infection. Eventually, the negative viral culture result allowed the physicians to continue the treatment.
2. Case Report
On 1 April 2020, a 72-year-old Caucasian woman affected by non-small cell lung cancer of the upper right lobe, was referred to the Istituto Oncologico Veneto (IOV) of Padua, Italy, for the acute onset of progressive shortness of breath and dry cough. Her past medical history was relevant for glaucoma, depression, and Parkinson disease. The patient had undergone a right upper lobe lung resection with ilo-mediastinic lymph node dissection in 2015; the histo-pathological examination revealed an EGFR exon19 deletion mutated adenocarcinoma. After four courses of adjuvant chemotherapy (cisplatin plus gemticitabine), due to disease progression, in 2018 targeted therapy with osimertinib was started with partial response according to RECIST (response evaluation criteria in solid tumors version 1.1).
At hospital admission, the physical examination revealed moderate inspiratory retraction and diffuse inspiratory wheezing; the body temperature was 36.8 °C; heart rate 68 bpm; blood pressure 125/80 mm Hg; respiratory rates 25 per minute; oxygen saturation 98% with 3 L/min oxygen supplement. Her ECOG PS (Eastern Cooperative Oncology Group performance status) was 2.
Laboratory investigations were all within the normal range, including lactate dehydrogenase (LDH), C-reactive protein (CRP), and procalcitonin. The nasopharyngeal swab for the detection of SARS-CoV-2 RNA by RT-PCR [11] was negative. A computed tomography (CT) scan of the thorax showed progressive disease in the superior mediastinum with significant reduction of the tracheal lumen (Figure 1). Palliative mediastinal radiotherapy was planned in order to reduce the tracheal compression, and methylprednisolone 40 mg bid was initiated obtaining a slight reduction of dyspnea.
During the hospital stay, the patient was exposed to an asymptomatic SARS-CoV-2 virus carrier. On 6 April 2020, she underwent screening nasopharyngeal swab for detection of SARS-CoV-2, which was positive. The scheduled radiotherapy was postponed and the patient was transferred to the infectious diseases unit. At admission she presented with mild inspiratory retraction but all the vital signs were normal. Blood examinations showed a moderate elevation of CRP (91 mg/L, normal value 0–6). Because of the high-risk condition, she was treated with the therapy currently recommended: hydroxychloroquine (HCQ) (400 mg bid for 24 h, then 200 mg bid) and azithromycin (AZI) (500 mg qd) [12]. Both drugs were stopped after two days because of QTc prolongation. Tapered steroidal therapy, osimertinib, and subcutaneous enoxaparin were continued.
The patient did not develop any coronavirus disease 2019 (COVID-19)-related symptoms, but nasopharyngeal swabs were persistently positive for SARS-CoV-2 for over one month. On 13 May after two consecutive negative swabs, she was transferred to the oncology ward to start radiotherapy treatment. Her ECOG PS was 3. Unfortunately, on May 19, the nasopharyngeal swab for SARS-CoV-2 RNA was positive. Once again the radiotherapy was postponed and the patient was isolated in the infectious diseases ward. The clinical conditions remained stable and the nasopharyngeal swabs were repeated at regular intervals with alternating results (Figure 2). On 30 May, a viral culture with Vero cells [13] was performed and resulted negative. The same result was achieved also 15 days later, despite the occurrence of new positive swabs.
Interestingly, serological tests showed the presence of high levels of anti-SARS-CoV-2 IgG [75,400 kAU/L (Positive: >1100 kAU/L)] and high titers persisted during the whole observation period; IgM title was persistently negative (Figure 2).
On the basis of these results, a single-fraction radiotherapy was performed on 4 June and the patient continued her regular follow-up with no need of oxygen supplementation. The last total body CT scan performed in July 2020 confirmed stable disease.
3. Discussion
SARS-CoV-2 pandemic caught clinicians and health authorities unprepared to manage cancer patients. Diagnostic and treatment guidelines were lacking at the beginning of the outbreak. Clinicians were challenged to manage COVID-19 disease with clinical characteristics which might be partly masked or confounded by coexisting cancer conditions. Moreover, the risk of nosocomial transmission of SARS-CoV-2 and the need for isolation contributed to the risk of progression of the malignant disease because of cancer treatments’ delays [14,15,16].
After the detection of SARS-CoV-2 our patient did not show any acute signs of infection and her symptoms could be attributed to her lung cancer. However SARS-CoV-2 swabs remained positive for more than 90 days, showing alternating results: in five occasions they turned out positive after one or two consecutive negative tests. It has been described that, after clinical resolution, some COVID-19 patients may experience a prolonged nucleic acid conversion [17,18]. Xiao and colleagues, from Wuhan, reported 21.4% of patients experiencing a “turn positive” of nucleic acid detection by RT-PCR test after two consecutive negative results [18]. In addition, it is still to be determined whether these patients are able to transmit the infection. However, relevant recent studies have shown that COVID-19 patients with mild-to-moderate illness are highly unlikely to be infectious longer than 10 days after symptom onset [19]. The molecular detection of SARS-CoV-2 by RT-PCR is a rapid and highly sensitive diagnostic method, but its ability to determine the duration of infectivity of patients is quite limited [20]. Viral culture is a more accurate tool to demonstrate the “in vitro” infectivity, giving surrogate information on viral transmission [9]. It is a complex diagnostic tool that needs expertise and biosafety level 3 laboratories, but it could be of crucial importance to define viral transmission and the infectivity of patients in particular conditions, such as the oncological setting [21]. Aside from viral culture, other diagnostic methods such as the threshold cycle (Ct) of RT-PCR and antigen-tests have been reported to be able to determine patients’ contagiousness. It has been demonstrated that infectivity is significantly reduced when Ct values are >24; for every unit increase in Ct, the odds ratio for infectivity decreases by 32%, suggesting that Ct values >24, along with the duration of symptoms >8 days may be used in combination to rule out patients’ contagiousness. Similar results are reported by La Scola et al. who showed a strong correlation between Ct value and sample infectivity in a cell culture model. Based on their data, they inferred that patients with Ct values equal or above 34 do not excrete infectious viral particles [22]. Rapid antigen tests may also have a role in this setting. They have a lower sensitivity compared to the standard RT-PCR test, but may be sensitive enough to detect cases with a high viral load (i.e., low RT-PCR cycle threshold (Ct) value <25), which likely account for a significant proportion of transmissions [8,23]. In addition, as reported in 68 respiratory specimens from 35 COVID patients in Hong Kong, the detection of subgenomic viral RNA (sgRNA) strongly correlated with the presence of active virus replication, with sgRNA being rarely detectable 8 days after the onset of the illness [7]. On the contrary, there is no consensus yet on the significance of the dynamic profile of SARS-CoV-2-specific antibody response. In our case the persistent positivity of RT-PCR assays coexisted with a strong serologic response, and none of the diagnostic procedures could prove or rule out the infectivity of the patient [24]. Unfortunately, in the first half of 2020, when our patient was hospitalized, viral load estimation by threshold cycle of RT-PCR and antigen-based tests were still under investigation, and the detection of sub-genomic RNAs was not available. Furthermore, the World Health Organization guidelines for releasing COVID-19 patients from isolation (i.e., ten days after symptom onset and at least three additional days without symptoms) were not yet amended. Nevertheless these guidelines do not specifically address immunocompromised individuals [25].
An Italian group has recently proposed an algorithm for the management of oncologic patients who need radiation therapy. Their recommendation is to delay or discontinue the radiation treatment in symptomatic and asymptomatic patients diagnosed with COVID-19 and to carefully start the treatment only when the patients are declared no longer exhibiting infection by the infectious diseases specialist [26].
In line with this recommendation we could discontinue hospital isolation owing to the repeatedly negative cell culture results, which allowed us to verify the absence of viral activity despite the persistent positivity of nasopharyngeal swabs. In this way the patient could finally undergo palliative radiotherapy for airway obstruction with a delay of eight weeks from the initial scheduled time. Although it is unlikely that the delayed palliative radiotherapy affected the short-term poor prognosis, it surely prolonged the length of hospitalization and negatively affected the patient’s quality of life.
4. Conclusions
This clinical case emphasizes the multifaceted and challenging approach to SARS-CoV-2 infection in the oncological setting. Clinicians must protect the vulnerable cancer population from a potentially severe infection without jeopardizing cancer care and support. The development of diagnostic tests able to determine the activity of the disease and patients’ infectivity may contribute to the fight against SARS-CoV-2, limiting the number of COVID-19-related deaths and the excess indirect mortality and morbidity in patients suffering from cancer.
Author Contributions
A.F.—Conceptualization, writing original draft. M.T.—Writing review & editing, supervision. L.S.—Writing review & editing. E.D.L.—Writing original draft. T.T.—Data curation. L.R.—Case analysis. E.D.M.—Writing review & editing. A.M.C.—Conceptualization, writing review and editing. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Informed Consent Statement
Verbal informed consent for this report was obtained from the patient involved in the study.
Conflicts of Interest
We have read and understood Current Oncology’s policy on conflicts of interest disclosure and declare that we have none.
Figure 1 Chest computed tomography (CT) scan: axial lung image showing huge reduction (arrow) of the trachea lumen (2 mm) due to mediastinal pathological tissue.
Figure 2 Timeline of SARS-CoV-2 nucleic acid testing results from nasopharyngeal swabs along with the anti-SARS-CoV-2 serology and viral culture testing.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. | 3 L PER MINUTE | DrugDosageText | CC BY | 33567626 | 20,166,650 | 2021-02-08 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Glomerular filtration rate decreased'. | More than myalgia: An unusual presentation of exertional rhabdomyolysis.
Exertional or exercise-induced rhabdomyolysis (ER) is a condition in which excessive and unaccustomed physical activity results in skeletal muscle damage. The ER is a relatively uncommon condition but can have very serious consequences such as acute renal failure, severe electrolyte abnormalities, acid base disturbances and death if not recognised and managed appropriately. The risk factors for rhabdomyolysis exist in our local setting, hence, it is paramount that healthcare practitioners (GPs) in our settings be made aware of ER, its prevention and symptoms. Cases of ER are often reported in sports men or women. Here, we report a case of a 33-year-old healthy female, with clinical and serological presentation, which is typical of ER following the commencement of a regimen of exercise to lose weight.
Background
Rhabdomyolysis is a clinical syndrome resulting from significant skeletal muscle injury and breakdown.1 Many cases of rhabdomyolysis are often undetected and its occurrence has been reported only in subgroups of populations at risk.2 Exertional rhabdomyolysis (ER) is a potentially life-threatening clinical condition that is characterised by the breakdown and necrosis of skeletal muscle induced by physical activity.3 Exertional or exercise-induced rhabdomyolysis is a relatively uncommon condition with an incidence of approximately 29.9 per 100 000 patient-years but can have very serious consequences such as acute renal failure, severe electrolyte abnormalities, acid-base disturbances and death if not recognised and managed appropriately.4 Exertional or exercise-induced rhabdomyolysis is not always evident, but early recognition of this entity and prompt intervention may prevent a serious injury or even death. Hence, healthcare professionals should be able to recognise the basic signs of ER in order to administer prompt treatment.1 Distinguishing features of ER include the history of intense, repetitive exercise or a sudden increase in exercise in an untrained person,5 associated with biochemical changes such as elevated serum creatine kinase (CK) levels five times the upper limit of normal (> 1000 IU/L) and myoglobinuria (> 1000 μg/mL), which present clinically as rust-coloured urine.6 To make a definitive diagnosis of ER, a practitioner must combine findings from history, physical examination and serological assay.4 Treatment modalities include rest and hydration with intravenous (IV) fluids. Cases of ER are often reported in sports men or women.7,8,9 Herein, we present an unusual case of ER that occurred in a healthy individual following the commencement of a regimen of exercise to lose weight.
Case presentation
Ms JR is a 33-year-old female who presented at the emergency department (ED) of a district hospital in the Free State province, South Africa, with 5 days’ history of generalised muscle pain. There was no history of trauma. She has been healthy, with no previous medical history of significance. No fever or any further symptom suggestive of viral or bacterial infection was observed. On her doctor’s advice, she recently commenced a regimen of exercise, because she was slightly overweight (body mass index [BMI] 27.3). Few days into her workouts, she developed muscle pains, which she was treated with ‘Mypaid’ (an analgesic containing Ibuprofen and Paracetamol), purchased over-the-counter. A few days later, she consulted her general practitioner (GP) who, according to patient report, made a diagnosis of myalgia. She was given Voltaren (Diclofenac) injection intramuscularly and was requested to continue her analgesic, take some days off work to rest and to ‘go slow’ with her workouts. There was no other history of relevance.
General examination done at the ED, revealed a young healthy looking female, not in painful distress, comfortable, although a little anxious. Her vital signs were all within normal ranges and no other significant findings were noted. Examination of the musculoskeletal system revealed mild tenderness in her quadriceps femoris and latissimus dorsi muscles with no sign of inflammation or trauma. Other systems were normal.
Urinalysis was performed. Macroscopically, the urine was turbid and dark brown in colour, which was unusual according to the patient. She, however, thought that it was because of the analgesic she was taking. Microscopic findings include 1–5 red blood cells per microliter (reference range ≤ 5 cells/µL), no pus cells, moderate squamous epithelial cells and granular casts. Crystals, parasites and yeast cells were absent. Urine chemistry (dipstick) showed blood3+, protein3+ and bilirubin+ (Figure 1). Other parameters were negative or normal. At this stage, a diagnosis of ER became high on the list of differential diagnoses.
FIGURE 1 Urinalysis of the random urine sample collected at presentation at the emergency department.
Full blood count, electrolyte and urea and creatinine kinase were determined from the patient blood sample. CK was significantly elevated at 119,800 IU/L (reference range 26 IU/L–192 IU/L). Potassium level was normal (3.9 mmol/L) along with other electrolytes and urea. The full blood count was normal as well (Table 1). Based on these findings, a diagnosis of ER was made.
TABLE 1 Relevant investigations during admission.
Test Reference ranges Days on admission
05 October 2019 (Day 1) 06 October 2019 (Day 2) 07 October 2019 (Day 3) 08 October 2019 (Day 4)
Haemoglobin 12.1–16.3 g/dL 14.0 – – –
White cell 3.92–9.88 5.6 – – –
Sodium 136–145 mmol/L 139 137 137 –
Potassium 3.5–5.1 mmol/L 3.9 3.6 4.1 –
Chloride 98–107 mmol/L 103 104 103 –
Bicarbonate 22–29 mmol/L 23 24 24 –
Anion gap 8–20 mmol/L 17 13 14 –
Urea < 8.4 mmol/L 3.4 3.9 3.8 –
Creatinine 49–90 μmol/L 84 71 60 –
eGFR > 90 mL/min 79 97 115 –
CK 26–192 U/L 119 800 88 787 83 142 68 948
Note: Data in bold highlight the daily creatine kinase levels which are plotted on Figure 2.
eGFR, estimated glomerular filtration rate; CK, creatine kinase.
IV fluid (0.9% NaCl) treatment was commenced at an initial rate of 300 mL/h and the patient was admitted to a high care unit. IVfluid treatment with 0.9% NaCl was later reviewed to 500 mL/h, reaching a urinary output > 200 mL/h. During her clinical course, no complication was noted. Day 2 CK concentration was 88 787 U/L, day 3 concentration was 83 142 U/L and day 4 concentration was 68 948 U/L (Figure 2). The urea and creatinine levels remained normal and after 4 days of IV fluids, the urine was completely clear.
FIGURE 2 Trend in creatine kinase concentration during intravenous fluid treatment.
The patient was discharged on day 5 completely asymptomatic. No further repeats of blood tests were performed. She was subsequently booked for outpatient monitoring of her CK and renal function. The patient did not attend the follow-up clinic, however, a telephonic consultation was performed with the patient during which she indicated that she was doing well with no further complaints post discharge.
Discussion
The causes of rhabdomyolysis are numerous and can include direct muscle injury, unaccustomed exercise, ischaemia, extreme temperatures, electrolyte abnormalities, endocrinologic conditions, genetic disorders, autoimmune disorders, infections, drugs, toxins and venoms.10,11 The patient in this case study was overweight, thus, fall within the population at risk of developing rhabdomyolysis was observed as described in the literature.2 These groups of individuals (overweight or obese) are likely to be on statins, which has been implicated in rhabdomyolysis,12 and are often advised to exercise more to lose weight or placed on some sort of weight-losing exercise schedule.13 Progressive increase in the prevalence of obesity in Africa and indeed South Africa, particularly amongst women has been reported.14,15 Also, trauma from inter-personal or community assault is common in our communities.16 Hence, there is a need for a high index of suspicion for rhabdomyolysis in our setting. In this study, the patient’s GP should have considered ER as against ‘Myalgia’ considering the recent history of unaccustomed exercise. The change in urine colour could have prompted the GP to re-consider his diagnosis, but this history was missed. It is a common practice for GPs to prescribe non-steroidal anti-inflammatory drugs (NSAIDs) for the treatment of myalgia. However, the use of NSAIDs in this scenario could ‘potentiate’ acute kidney injury and other complications. Analgesics, particularly NSAIDs, can reduce renal perfusion, leading to a depressed glomerular filtration rate.17
The diagnosis could have been easily missed at the ED if the attending doctor did not check the urine. The dark-brown urine was an important clue to the diagnosis, which was confirmed by the elevated CK. It is, therefore, important that in the presence of these risk factors, and an appropriate clinical setting, the urine of the patient should be properly examined and CK levels checked when history and findings on examination are suggestive of rhabdomyolysis or ER. Studies have shown several cases of non-complicated rhabdomyolysis despite CK levels over 100 000.18 Similarly, the patient presented herein made a complete recovery following IV hydration, despite overtly elevated CK levels. It has been reported that the outcome or prognosis in cases of rhabdomyolysis is dependent on cofactors such as the aetiology and the presence of comorbidities, and not just based on the CK levels alone.19 Along with IV hydration, the tracking of CK levels, kidney function and electrolyte should be monitored daily.4 If levels of CK continue to rise post 48 to 72 h after the presentation and depending on the severity of kidney disease or presence of compartment syndrome, consultation of a nephrologist or surgeon should be considered.4 The ability of medical response teams to provide aggressive hydration and dialysis services enhances survival. If treatment modalities are implemented early, patients should recover completely.19
The decision to discharge the patient with a CK level > 60 000 was made because the CK level was on the downward trend, urine became clear, the patient was clinically asymptomatic and other laboratory tests were normal. The acceptable discharge CK level following the treatment of rhabdomyolysis is presently debatable. Some experts have argued that discharge at higher CK thresholds of 20 000 to 50 000 U/L can be safely achieved in the ED, whilst others have recommended hospitalisation for rhabdomyolysis until CK level drops to less than 1000 U/L.20 Outpatient management with oral hydration may suffice for a stable patient with a CK level of 20 000 U/L to 50 000 U/L (and possibly higher), normal creatinine level and good urine flow.21 In a study carried out on 41 patients presenting with ER, the median discharged CK was 5287 (range, 10–61 617) U/L with a mean length of stay of approximately 3 days.20
Conclusion
Patients presenting with myalgia, obese patients, patients on statins and patients taking NSAIDs are very common in our setting. Also, GPs are encouraging patients to exercise more. This suggests that the risk factors for rhabdomyolysis exist in our local setting. It is, therefore, paramount that healthcare practitioners (GPs) in our settings should be made aware of ER, its prevention and symptoms. Exertional or exercise-induced rhabdomyolysis is a relatively uncommon condition but can have severe consequences if not recognised and managed appropriately. Most resource-poor primary healthcare facilities in Africa do not have 24-h laboratory services.22 A high index of suspicion is, therefore, pertinent; the presence of symptoms (pain, tenderness, weakness and swelling in the muscles affected after engaging in physical activity) and typical urine discolouration are enough to prompt commencement of IV normal saline, whilst awaiting serological report on CK level.
Acknowledgements
Competing interests
The authors have declared that no competing interests exist.
Authors’ contributions
All authors contributed equally to this work.
Ethical consideration
Written consent was obtained from the patient.
Funding information
This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.
Data availability statement
Data sharing is not applicable to this study as no new data were created or analysed in this study.
Disclaimer
The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors.
How to cite this article: Benedict MOA, Adefuye AO. More than myalgia: An unusual presentation of exertional rhabdomyolysis. S Afr Fam Pract. 2021;63(1), a5194. https://doi.org/10.4102/safp.v63i1.5194 | ACETAMINOPHEN\IBUPROFEN, DICLOFENAC | DrugsGivenReaction | CC BY | 33567839 | 18,941,160 | 2021-01-13 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Rhabdomyolysis'. | More than myalgia: An unusual presentation of exertional rhabdomyolysis.
Exertional or exercise-induced rhabdomyolysis (ER) is a condition in which excessive and unaccustomed physical activity results in skeletal muscle damage. The ER is a relatively uncommon condition but can have very serious consequences such as acute renal failure, severe electrolyte abnormalities, acid base disturbances and death if not recognised and managed appropriately. The risk factors for rhabdomyolysis exist in our local setting, hence, it is paramount that healthcare practitioners (GPs) in our settings be made aware of ER, its prevention and symptoms. Cases of ER are often reported in sports men or women. Here, we report a case of a 33-year-old healthy female, with clinical and serological presentation, which is typical of ER following the commencement of a regimen of exercise to lose weight.
Background
Rhabdomyolysis is a clinical syndrome resulting from significant skeletal muscle injury and breakdown.1 Many cases of rhabdomyolysis are often undetected and its occurrence has been reported only in subgroups of populations at risk.2 Exertional rhabdomyolysis (ER) is a potentially life-threatening clinical condition that is characterised by the breakdown and necrosis of skeletal muscle induced by physical activity.3 Exertional or exercise-induced rhabdomyolysis is a relatively uncommon condition with an incidence of approximately 29.9 per 100 000 patient-years but can have very serious consequences such as acute renal failure, severe electrolyte abnormalities, acid-base disturbances and death if not recognised and managed appropriately.4 Exertional or exercise-induced rhabdomyolysis is not always evident, but early recognition of this entity and prompt intervention may prevent a serious injury or even death. Hence, healthcare professionals should be able to recognise the basic signs of ER in order to administer prompt treatment.1 Distinguishing features of ER include the history of intense, repetitive exercise or a sudden increase in exercise in an untrained person,5 associated with biochemical changes such as elevated serum creatine kinase (CK) levels five times the upper limit of normal (> 1000 IU/L) and myoglobinuria (> 1000 μg/mL), which present clinically as rust-coloured urine.6 To make a definitive diagnosis of ER, a practitioner must combine findings from history, physical examination and serological assay.4 Treatment modalities include rest and hydration with intravenous (IV) fluids. Cases of ER are often reported in sports men or women.7,8,9 Herein, we present an unusual case of ER that occurred in a healthy individual following the commencement of a regimen of exercise to lose weight.
Case presentation
Ms JR is a 33-year-old female who presented at the emergency department (ED) of a district hospital in the Free State province, South Africa, with 5 days’ history of generalised muscle pain. There was no history of trauma. She has been healthy, with no previous medical history of significance. No fever or any further symptom suggestive of viral or bacterial infection was observed. On her doctor’s advice, she recently commenced a regimen of exercise, because she was slightly overweight (body mass index [BMI] 27.3). Few days into her workouts, she developed muscle pains, which she was treated with ‘Mypaid’ (an analgesic containing Ibuprofen and Paracetamol), purchased over-the-counter. A few days later, she consulted her general practitioner (GP) who, according to patient report, made a diagnosis of myalgia. She was given Voltaren (Diclofenac) injection intramuscularly and was requested to continue her analgesic, take some days off work to rest and to ‘go slow’ with her workouts. There was no other history of relevance.
General examination done at the ED, revealed a young healthy looking female, not in painful distress, comfortable, although a little anxious. Her vital signs were all within normal ranges and no other significant findings were noted. Examination of the musculoskeletal system revealed mild tenderness in her quadriceps femoris and latissimus dorsi muscles with no sign of inflammation or trauma. Other systems were normal.
Urinalysis was performed. Macroscopically, the urine was turbid and dark brown in colour, which was unusual according to the patient. She, however, thought that it was because of the analgesic she was taking. Microscopic findings include 1–5 red blood cells per microliter (reference range ≤ 5 cells/µL), no pus cells, moderate squamous epithelial cells and granular casts. Crystals, parasites and yeast cells were absent. Urine chemistry (dipstick) showed blood3+, protein3+ and bilirubin+ (Figure 1). Other parameters were negative or normal. At this stage, a diagnosis of ER became high on the list of differential diagnoses.
FIGURE 1 Urinalysis of the random urine sample collected at presentation at the emergency department.
Full blood count, electrolyte and urea and creatinine kinase were determined from the patient blood sample. CK was significantly elevated at 119,800 IU/L (reference range 26 IU/L–192 IU/L). Potassium level was normal (3.9 mmol/L) along with other electrolytes and urea. The full blood count was normal as well (Table 1). Based on these findings, a diagnosis of ER was made.
TABLE 1 Relevant investigations during admission.
Test Reference ranges Days on admission
05 October 2019 (Day 1) 06 October 2019 (Day 2) 07 October 2019 (Day 3) 08 October 2019 (Day 4)
Haemoglobin 12.1–16.3 g/dL 14.0 – – –
White cell 3.92–9.88 5.6 – – –
Sodium 136–145 mmol/L 139 137 137 –
Potassium 3.5–5.1 mmol/L 3.9 3.6 4.1 –
Chloride 98–107 mmol/L 103 104 103 –
Bicarbonate 22–29 mmol/L 23 24 24 –
Anion gap 8–20 mmol/L 17 13 14 –
Urea < 8.4 mmol/L 3.4 3.9 3.8 –
Creatinine 49–90 μmol/L 84 71 60 –
eGFR > 90 mL/min 79 97 115 –
CK 26–192 U/L 119 800 88 787 83 142 68 948
Note: Data in bold highlight the daily creatine kinase levels which are plotted on Figure 2.
eGFR, estimated glomerular filtration rate; CK, creatine kinase.
IV fluid (0.9% NaCl) treatment was commenced at an initial rate of 300 mL/h and the patient was admitted to a high care unit. IVfluid treatment with 0.9% NaCl was later reviewed to 500 mL/h, reaching a urinary output > 200 mL/h. During her clinical course, no complication was noted. Day 2 CK concentration was 88 787 U/L, day 3 concentration was 83 142 U/L and day 4 concentration was 68 948 U/L (Figure 2). The urea and creatinine levels remained normal and after 4 days of IV fluids, the urine was completely clear.
FIGURE 2 Trend in creatine kinase concentration during intravenous fluid treatment.
The patient was discharged on day 5 completely asymptomatic. No further repeats of blood tests were performed. She was subsequently booked for outpatient monitoring of her CK and renal function. The patient did not attend the follow-up clinic, however, a telephonic consultation was performed with the patient during which she indicated that she was doing well with no further complaints post discharge.
Discussion
The causes of rhabdomyolysis are numerous and can include direct muscle injury, unaccustomed exercise, ischaemia, extreme temperatures, electrolyte abnormalities, endocrinologic conditions, genetic disorders, autoimmune disorders, infections, drugs, toxins and venoms.10,11 The patient in this case study was overweight, thus, fall within the population at risk of developing rhabdomyolysis was observed as described in the literature.2 These groups of individuals (overweight or obese) are likely to be on statins, which has been implicated in rhabdomyolysis,12 and are often advised to exercise more to lose weight or placed on some sort of weight-losing exercise schedule.13 Progressive increase in the prevalence of obesity in Africa and indeed South Africa, particularly amongst women has been reported.14,15 Also, trauma from inter-personal or community assault is common in our communities.16 Hence, there is a need for a high index of suspicion for rhabdomyolysis in our setting. In this study, the patient’s GP should have considered ER as against ‘Myalgia’ considering the recent history of unaccustomed exercise. The change in urine colour could have prompted the GP to re-consider his diagnosis, but this history was missed. It is a common practice for GPs to prescribe non-steroidal anti-inflammatory drugs (NSAIDs) for the treatment of myalgia. However, the use of NSAIDs in this scenario could ‘potentiate’ acute kidney injury and other complications. Analgesics, particularly NSAIDs, can reduce renal perfusion, leading to a depressed glomerular filtration rate.17
The diagnosis could have been easily missed at the ED if the attending doctor did not check the urine. The dark-brown urine was an important clue to the diagnosis, which was confirmed by the elevated CK. It is, therefore, important that in the presence of these risk factors, and an appropriate clinical setting, the urine of the patient should be properly examined and CK levels checked when history and findings on examination are suggestive of rhabdomyolysis or ER. Studies have shown several cases of non-complicated rhabdomyolysis despite CK levels over 100 000.18 Similarly, the patient presented herein made a complete recovery following IV hydration, despite overtly elevated CK levels. It has been reported that the outcome or prognosis in cases of rhabdomyolysis is dependent on cofactors such as the aetiology and the presence of comorbidities, and not just based on the CK levels alone.19 Along with IV hydration, the tracking of CK levels, kidney function and electrolyte should be monitored daily.4 If levels of CK continue to rise post 48 to 72 h after the presentation and depending on the severity of kidney disease or presence of compartment syndrome, consultation of a nephrologist or surgeon should be considered.4 The ability of medical response teams to provide aggressive hydration and dialysis services enhances survival. If treatment modalities are implemented early, patients should recover completely.19
The decision to discharge the patient with a CK level > 60 000 was made because the CK level was on the downward trend, urine became clear, the patient was clinically asymptomatic and other laboratory tests were normal. The acceptable discharge CK level following the treatment of rhabdomyolysis is presently debatable. Some experts have argued that discharge at higher CK thresholds of 20 000 to 50 000 U/L can be safely achieved in the ED, whilst others have recommended hospitalisation for rhabdomyolysis until CK level drops to less than 1000 U/L.20 Outpatient management with oral hydration may suffice for a stable patient with a CK level of 20 000 U/L to 50 000 U/L (and possibly higher), normal creatinine level and good urine flow.21 In a study carried out on 41 patients presenting with ER, the median discharged CK was 5287 (range, 10–61 617) U/L with a mean length of stay of approximately 3 days.20
Conclusion
Patients presenting with myalgia, obese patients, patients on statins and patients taking NSAIDs are very common in our setting. Also, GPs are encouraging patients to exercise more. This suggests that the risk factors for rhabdomyolysis exist in our local setting. It is, therefore, paramount that healthcare practitioners (GPs) in our settings should be made aware of ER, its prevention and symptoms. Exertional or exercise-induced rhabdomyolysis is a relatively uncommon condition but can have severe consequences if not recognised and managed appropriately. Most resource-poor primary healthcare facilities in Africa do not have 24-h laboratory services.22 A high index of suspicion is, therefore, pertinent; the presence of symptoms (pain, tenderness, weakness and swelling in the muscles affected after engaging in physical activity) and typical urine discolouration are enough to prompt commencement of IV normal saline, whilst awaiting serological report on CK level.
Acknowledgements
Competing interests
The authors have declared that no competing interests exist.
Authors’ contributions
All authors contributed equally to this work.
Ethical consideration
Written consent was obtained from the patient.
Funding information
This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.
Data availability statement
Data sharing is not applicable to this study as no new data were created or analysed in this study.
Disclaimer
The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors.
How to cite this article: Benedict MOA, Adefuye AO. More than myalgia: An unusual presentation of exertional rhabdomyolysis. S Afr Fam Pract. 2021;63(1), a5194. https://doi.org/10.4102/safp.v63i1.5194 | ACETAMINOPHEN\IBUPROFEN, DICLOFENAC | DrugsGivenReaction | CC BY | 33567839 | 18,941,160 | 2021-01-13 |
What was the administration route of drug 'DICLOFENAC'? | More than myalgia: An unusual presentation of exertional rhabdomyolysis.
Exertional or exercise-induced rhabdomyolysis (ER) is a condition in which excessive and unaccustomed physical activity results in skeletal muscle damage. The ER is a relatively uncommon condition but can have very serious consequences such as acute renal failure, severe electrolyte abnormalities, acid base disturbances and death if not recognised and managed appropriately. The risk factors for rhabdomyolysis exist in our local setting, hence, it is paramount that healthcare practitioners (GPs) in our settings be made aware of ER, its prevention and symptoms. Cases of ER are often reported in sports men or women. Here, we report a case of a 33-year-old healthy female, with clinical and serological presentation, which is typical of ER following the commencement of a regimen of exercise to lose weight.
Background
Rhabdomyolysis is a clinical syndrome resulting from significant skeletal muscle injury and breakdown.1 Many cases of rhabdomyolysis are often undetected and its occurrence has been reported only in subgroups of populations at risk.2 Exertional rhabdomyolysis (ER) is a potentially life-threatening clinical condition that is characterised by the breakdown and necrosis of skeletal muscle induced by physical activity.3 Exertional or exercise-induced rhabdomyolysis is a relatively uncommon condition with an incidence of approximately 29.9 per 100 000 patient-years but can have very serious consequences such as acute renal failure, severe electrolyte abnormalities, acid-base disturbances and death if not recognised and managed appropriately.4 Exertional or exercise-induced rhabdomyolysis is not always evident, but early recognition of this entity and prompt intervention may prevent a serious injury or even death. Hence, healthcare professionals should be able to recognise the basic signs of ER in order to administer prompt treatment.1 Distinguishing features of ER include the history of intense, repetitive exercise or a sudden increase in exercise in an untrained person,5 associated with biochemical changes such as elevated serum creatine kinase (CK) levels five times the upper limit of normal (> 1000 IU/L) and myoglobinuria (> 1000 μg/mL), which present clinically as rust-coloured urine.6 To make a definitive diagnosis of ER, a practitioner must combine findings from history, physical examination and serological assay.4 Treatment modalities include rest and hydration with intravenous (IV) fluids. Cases of ER are often reported in sports men or women.7,8,9 Herein, we present an unusual case of ER that occurred in a healthy individual following the commencement of a regimen of exercise to lose weight.
Case presentation
Ms JR is a 33-year-old female who presented at the emergency department (ED) of a district hospital in the Free State province, South Africa, with 5 days’ history of generalised muscle pain. There was no history of trauma. She has been healthy, with no previous medical history of significance. No fever or any further symptom suggestive of viral or bacterial infection was observed. On her doctor’s advice, she recently commenced a regimen of exercise, because she was slightly overweight (body mass index [BMI] 27.3). Few days into her workouts, she developed muscle pains, which she was treated with ‘Mypaid’ (an analgesic containing Ibuprofen and Paracetamol), purchased over-the-counter. A few days later, she consulted her general practitioner (GP) who, according to patient report, made a diagnosis of myalgia. She was given Voltaren (Diclofenac) injection intramuscularly and was requested to continue her analgesic, take some days off work to rest and to ‘go slow’ with her workouts. There was no other history of relevance.
General examination done at the ED, revealed a young healthy looking female, not in painful distress, comfortable, although a little anxious. Her vital signs were all within normal ranges and no other significant findings were noted. Examination of the musculoskeletal system revealed mild tenderness in her quadriceps femoris and latissimus dorsi muscles with no sign of inflammation or trauma. Other systems were normal.
Urinalysis was performed. Macroscopically, the urine was turbid and dark brown in colour, which was unusual according to the patient. She, however, thought that it was because of the analgesic she was taking. Microscopic findings include 1–5 red blood cells per microliter (reference range ≤ 5 cells/µL), no pus cells, moderate squamous epithelial cells and granular casts. Crystals, parasites and yeast cells were absent. Urine chemistry (dipstick) showed blood3+, protein3+ and bilirubin+ (Figure 1). Other parameters were negative or normal. At this stage, a diagnosis of ER became high on the list of differential diagnoses.
FIGURE 1 Urinalysis of the random urine sample collected at presentation at the emergency department.
Full blood count, electrolyte and urea and creatinine kinase were determined from the patient blood sample. CK was significantly elevated at 119,800 IU/L (reference range 26 IU/L–192 IU/L). Potassium level was normal (3.9 mmol/L) along with other electrolytes and urea. The full blood count was normal as well (Table 1). Based on these findings, a diagnosis of ER was made.
TABLE 1 Relevant investigations during admission.
Test Reference ranges Days on admission
05 October 2019 (Day 1) 06 October 2019 (Day 2) 07 October 2019 (Day 3) 08 October 2019 (Day 4)
Haemoglobin 12.1–16.3 g/dL 14.0 – – –
White cell 3.92–9.88 5.6 – – –
Sodium 136–145 mmol/L 139 137 137 –
Potassium 3.5–5.1 mmol/L 3.9 3.6 4.1 –
Chloride 98–107 mmol/L 103 104 103 –
Bicarbonate 22–29 mmol/L 23 24 24 –
Anion gap 8–20 mmol/L 17 13 14 –
Urea < 8.4 mmol/L 3.4 3.9 3.8 –
Creatinine 49–90 μmol/L 84 71 60 –
eGFR > 90 mL/min 79 97 115 –
CK 26–192 U/L 119 800 88 787 83 142 68 948
Note: Data in bold highlight the daily creatine kinase levels which are plotted on Figure 2.
eGFR, estimated glomerular filtration rate; CK, creatine kinase.
IV fluid (0.9% NaCl) treatment was commenced at an initial rate of 300 mL/h and the patient was admitted to a high care unit. IVfluid treatment with 0.9% NaCl was later reviewed to 500 mL/h, reaching a urinary output > 200 mL/h. During her clinical course, no complication was noted. Day 2 CK concentration was 88 787 U/L, day 3 concentration was 83 142 U/L and day 4 concentration was 68 948 U/L (Figure 2). The urea and creatinine levels remained normal and after 4 days of IV fluids, the urine was completely clear.
FIGURE 2 Trend in creatine kinase concentration during intravenous fluid treatment.
The patient was discharged on day 5 completely asymptomatic. No further repeats of blood tests were performed. She was subsequently booked for outpatient monitoring of her CK and renal function. The patient did not attend the follow-up clinic, however, a telephonic consultation was performed with the patient during which she indicated that she was doing well with no further complaints post discharge.
Discussion
The causes of rhabdomyolysis are numerous and can include direct muscle injury, unaccustomed exercise, ischaemia, extreme temperatures, electrolyte abnormalities, endocrinologic conditions, genetic disorders, autoimmune disorders, infections, drugs, toxins and venoms.10,11 The patient in this case study was overweight, thus, fall within the population at risk of developing rhabdomyolysis was observed as described in the literature.2 These groups of individuals (overweight or obese) are likely to be on statins, which has been implicated in rhabdomyolysis,12 and are often advised to exercise more to lose weight or placed on some sort of weight-losing exercise schedule.13 Progressive increase in the prevalence of obesity in Africa and indeed South Africa, particularly amongst women has been reported.14,15 Also, trauma from inter-personal or community assault is common in our communities.16 Hence, there is a need for a high index of suspicion for rhabdomyolysis in our setting. In this study, the patient’s GP should have considered ER as against ‘Myalgia’ considering the recent history of unaccustomed exercise. The change in urine colour could have prompted the GP to re-consider his diagnosis, but this history was missed. It is a common practice for GPs to prescribe non-steroidal anti-inflammatory drugs (NSAIDs) for the treatment of myalgia. However, the use of NSAIDs in this scenario could ‘potentiate’ acute kidney injury and other complications. Analgesics, particularly NSAIDs, can reduce renal perfusion, leading to a depressed glomerular filtration rate.17
The diagnosis could have been easily missed at the ED if the attending doctor did not check the urine. The dark-brown urine was an important clue to the diagnosis, which was confirmed by the elevated CK. It is, therefore, important that in the presence of these risk factors, and an appropriate clinical setting, the urine of the patient should be properly examined and CK levels checked when history and findings on examination are suggestive of rhabdomyolysis or ER. Studies have shown several cases of non-complicated rhabdomyolysis despite CK levels over 100 000.18 Similarly, the patient presented herein made a complete recovery following IV hydration, despite overtly elevated CK levels. It has been reported that the outcome or prognosis in cases of rhabdomyolysis is dependent on cofactors such as the aetiology and the presence of comorbidities, and not just based on the CK levels alone.19 Along with IV hydration, the tracking of CK levels, kidney function and electrolyte should be monitored daily.4 If levels of CK continue to rise post 48 to 72 h after the presentation and depending on the severity of kidney disease or presence of compartment syndrome, consultation of a nephrologist or surgeon should be considered.4 The ability of medical response teams to provide aggressive hydration and dialysis services enhances survival. If treatment modalities are implemented early, patients should recover completely.19
The decision to discharge the patient with a CK level > 60 000 was made because the CK level was on the downward trend, urine became clear, the patient was clinically asymptomatic and other laboratory tests were normal. The acceptable discharge CK level following the treatment of rhabdomyolysis is presently debatable. Some experts have argued that discharge at higher CK thresholds of 20 000 to 50 000 U/L can be safely achieved in the ED, whilst others have recommended hospitalisation for rhabdomyolysis until CK level drops to less than 1000 U/L.20 Outpatient management with oral hydration may suffice for a stable patient with a CK level of 20 000 U/L to 50 000 U/L (and possibly higher), normal creatinine level and good urine flow.21 In a study carried out on 41 patients presenting with ER, the median discharged CK was 5287 (range, 10–61 617) U/L with a mean length of stay of approximately 3 days.20
Conclusion
Patients presenting with myalgia, obese patients, patients on statins and patients taking NSAIDs are very common in our setting. Also, GPs are encouraging patients to exercise more. This suggests that the risk factors for rhabdomyolysis exist in our local setting. It is, therefore, paramount that healthcare practitioners (GPs) in our settings should be made aware of ER, its prevention and symptoms. Exertional or exercise-induced rhabdomyolysis is a relatively uncommon condition but can have severe consequences if not recognised and managed appropriately. Most resource-poor primary healthcare facilities in Africa do not have 24-h laboratory services.22 A high index of suspicion is, therefore, pertinent; the presence of symptoms (pain, tenderness, weakness and swelling in the muscles affected after engaging in physical activity) and typical urine discolouration are enough to prompt commencement of IV normal saline, whilst awaiting serological report on CK level.
Acknowledgements
Competing interests
The authors have declared that no competing interests exist.
Authors’ contributions
All authors contributed equally to this work.
Ethical consideration
Written consent was obtained from the patient.
Funding information
This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.
Data availability statement
Data sharing is not applicable to this study as no new data were created or analysed in this study.
Disclaimer
The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors.
How to cite this article: Benedict MOA, Adefuye AO. More than myalgia: An unusual presentation of exertional rhabdomyolysis. S Afr Fam Pract. 2021;63(1), a5194. https://doi.org/10.4102/safp.v63i1.5194 | Intramuscular | DrugAdministrationRoute | CC BY | 33567839 | 18,941,160 | 2021-01-13 |
What was the outcome of reaction 'Glomerular filtration rate decreased'? | More than myalgia: An unusual presentation of exertional rhabdomyolysis.
Exertional or exercise-induced rhabdomyolysis (ER) is a condition in which excessive and unaccustomed physical activity results in skeletal muscle damage. The ER is a relatively uncommon condition but can have very serious consequences such as acute renal failure, severe electrolyte abnormalities, acid base disturbances and death if not recognised and managed appropriately. The risk factors for rhabdomyolysis exist in our local setting, hence, it is paramount that healthcare practitioners (GPs) in our settings be made aware of ER, its prevention and symptoms. Cases of ER are often reported in sports men or women. Here, we report a case of a 33-year-old healthy female, with clinical and serological presentation, which is typical of ER following the commencement of a regimen of exercise to lose weight.
Background
Rhabdomyolysis is a clinical syndrome resulting from significant skeletal muscle injury and breakdown.1 Many cases of rhabdomyolysis are often undetected and its occurrence has been reported only in subgroups of populations at risk.2 Exertional rhabdomyolysis (ER) is a potentially life-threatening clinical condition that is characterised by the breakdown and necrosis of skeletal muscle induced by physical activity.3 Exertional or exercise-induced rhabdomyolysis is a relatively uncommon condition with an incidence of approximately 29.9 per 100 000 patient-years but can have very serious consequences such as acute renal failure, severe electrolyte abnormalities, acid-base disturbances and death if not recognised and managed appropriately.4 Exertional or exercise-induced rhabdomyolysis is not always evident, but early recognition of this entity and prompt intervention may prevent a serious injury or even death. Hence, healthcare professionals should be able to recognise the basic signs of ER in order to administer prompt treatment.1 Distinguishing features of ER include the history of intense, repetitive exercise or a sudden increase in exercise in an untrained person,5 associated with biochemical changes such as elevated serum creatine kinase (CK) levels five times the upper limit of normal (> 1000 IU/L) and myoglobinuria (> 1000 μg/mL), which present clinically as rust-coloured urine.6 To make a definitive diagnosis of ER, a practitioner must combine findings from history, physical examination and serological assay.4 Treatment modalities include rest and hydration with intravenous (IV) fluids. Cases of ER are often reported in sports men or women.7,8,9 Herein, we present an unusual case of ER that occurred in a healthy individual following the commencement of a regimen of exercise to lose weight.
Case presentation
Ms JR is a 33-year-old female who presented at the emergency department (ED) of a district hospital in the Free State province, South Africa, with 5 days’ history of generalised muscle pain. There was no history of trauma. She has been healthy, with no previous medical history of significance. No fever or any further symptom suggestive of viral or bacterial infection was observed. On her doctor’s advice, she recently commenced a regimen of exercise, because she was slightly overweight (body mass index [BMI] 27.3). Few days into her workouts, she developed muscle pains, which she was treated with ‘Mypaid’ (an analgesic containing Ibuprofen and Paracetamol), purchased over-the-counter. A few days later, she consulted her general practitioner (GP) who, according to patient report, made a diagnosis of myalgia. She was given Voltaren (Diclofenac) injection intramuscularly and was requested to continue her analgesic, take some days off work to rest and to ‘go slow’ with her workouts. There was no other history of relevance.
General examination done at the ED, revealed a young healthy looking female, not in painful distress, comfortable, although a little anxious. Her vital signs were all within normal ranges and no other significant findings were noted. Examination of the musculoskeletal system revealed mild tenderness in her quadriceps femoris and latissimus dorsi muscles with no sign of inflammation or trauma. Other systems were normal.
Urinalysis was performed. Macroscopically, the urine was turbid and dark brown in colour, which was unusual according to the patient. She, however, thought that it was because of the analgesic she was taking. Microscopic findings include 1–5 red blood cells per microliter (reference range ≤ 5 cells/µL), no pus cells, moderate squamous epithelial cells and granular casts. Crystals, parasites and yeast cells were absent. Urine chemistry (dipstick) showed blood3+, protein3+ and bilirubin+ (Figure 1). Other parameters were negative or normal. At this stage, a diagnosis of ER became high on the list of differential diagnoses.
FIGURE 1 Urinalysis of the random urine sample collected at presentation at the emergency department.
Full blood count, electrolyte and urea and creatinine kinase were determined from the patient blood sample. CK was significantly elevated at 119,800 IU/L (reference range 26 IU/L–192 IU/L). Potassium level was normal (3.9 mmol/L) along with other electrolytes and urea. The full blood count was normal as well (Table 1). Based on these findings, a diagnosis of ER was made.
TABLE 1 Relevant investigations during admission.
Test Reference ranges Days on admission
05 October 2019 (Day 1) 06 October 2019 (Day 2) 07 October 2019 (Day 3) 08 October 2019 (Day 4)
Haemoglobin 12.1–16.3 g/dL 14.0 – – –
White cell 3.92–9.88 5.6 – – –
Sodium 136–145 mmol/L 139 137 137 –
Potassium 3.5–5.1 mmol/L 3.9 3.6 4.1 –
Chloride 98–107 mmol/L 103 104 103 –
Bicarbonate 22–29 mmol/L 23 24 24 –
Anion gap 8–20 mmol/L 17 13 14 –
Urea < 8.4 mmol/L 3.4 3.9 3.8 –
Creatinine 49–90 μmol/L 84 71 60 –
eGFR > 90 mL/min 79 97 115 –
CK 26–192 U/L 119 800 88 787 83 142 68 948
Note: Data in bold highlight the daily creatine kinase levels which are plotted on Figure 2.
eGFR, estimated glomerular filtration rate; CK, creatine kinase.
IV fluid (0.9% NaCl) treatment was commenced at an initial rate of 300 mL/h and the patient was admitted to a high care unit. IVfluid treatment with 0.9% NaCl was later reviewed to 500 mL/h, reaching a urinary output > 200 mL/h. During her clinical course, no complication was noted. Day 2 CK concentration was 88 787 U/L, day 3 concentration was 83 142 U/L and day 4 concentration was 68 948 U/L (Figure 2). The urea and creatinine levels remained normal and after 4 days of IV fluids, the urine was completely clear.
FIGURE 2 Trend in creatine kinase concentration during intravenous fluid treatment.
The patient was discharged on day 5 completely asymptomatic. No further repeats of blood tests were performed. She was subsequently booked for outpatient monitoring of her CK and renal function. The patient did not attend the follow-up clinic, however, a telephonic consultation was performed with the patient during which she indicated that she was doing well with no further complaints post discharge.
Discussion
The causes of rhabdomyolysis are numerous and can include direct muscle injury, unaccustomed exercise, ischaemia, extreme temperatures, electrolyte abnormalities, endocrinologic conditions, genetic disorders, autoimmune disorders, infections, drugs, toxins and venoms.10,11 The patient in this case study was overweight, thus, fall within the population at risk of developing rhabdomyolysis was observed as described in the literature.2 These groups of individuals (overweight or obese) are likely to be on statins, which has been implicated in rhabdomyolysis,12 and are often advised to exercise more to lose weight or placed on some sort of weight-losing exercise schedule.13 Progressive increase in the prevalence of obesity in Africa and indeed South Africa, particularly amongst women has been reported.14,15 Also, trauma from inter-personal or community assault is common in our communities.16 Hence, there is a need for a high index of suspicion for rhabdomyolysis in our setting. In this study, the patient’s GP should have considered ER as against ‘Myalgia’ considering the recent history of unaccustomed exercise. The change in urine colour could have prompted the GP to re-consider his diagnosis, but this history was missed. It is a common practice for GPs to prescribe non-steroidal anti-inflammatory drugs (NSAIDs) for the treatment of myalgia. However, the use of NSAIDs in this scenario could ‘potentiate’ acute kidney injury and other complications. Analgesics, particularly NSAIDs, can reduce renal perfusion, leading to a depressed glomerular filtration rate.17
The diagnosis could have been easily missed at the ED if the attending doctor did not check the urine. The dark-brown urine was an important clue to the diagnosis, which was confirmed by the elevated CK. It is, therefore, important that in the presence of these risk factors, and an appropriate clinical setting, the urine of the patient should be properly examined and CK levels checked when history and findings on examination are suggestive of rhabdomyolysis or ER. Studies have shown several cases of non-complicated rhabdomyolysis despite CK levels over 100 000.18 Similarly, the patient presented herein made a complete recovery following IV hydration, despite overtly elevated CK levels. It has been reported that the outcome or prognosis in cases of rhabdomyolysis is dependent on cofactors such as the aetiology and the presence of comorbidities, and not just based on the CK levels alone.19 Along with IV hydration, the tracking of CK levels, kidney function and electrolyte should be monitored daily.4 If levels of CK continue to rise post 48 to 72 h after the presentation and depending on the severity of kidney disease or presence of compartment syndrome, consultation of a nephrologist or surgeon should be considered.4 The ability of medical response teams to provide aggressive hydration and dialysis services enhances survival. If treatment modalities are implemented early, patients should recover completely.19
The decision to discharge the patient with a CK level > 60 000 was made because the CK level was on the downward trend, urine became clear, the patient was clinically asymptomatic and other laboratory tests were normal. The acceptable discharge CK level following the treatment of rhabdomyolysis is presently debatable. Some experts have argued that discharge at higher CK thresholds of 20 000 to 50 000 U/L can be safely achieved in the ED, whilst others have recommended hospitalisation for rhabdomyolysis until CK level drops to less than 1000 U/L.20 Outpatient management with oral hydration may suffice for a stable patient with a CK level of 20 000 U/L to 50 000 U/L (and possibly higher), normal creatinine level and good urine flow.21 In a study carried out on 41 patients presenting with ER, the median discharged CK was 5287 (range, 10–61 617) U/L with a mean length of stay of approximately 3 days.20
Conclusion
Patients presenting with myalgia, obese patients, patients on statins and patients taking NSAIDs are very common in our setting. Also, GPs are encouraging patients to exercise more. This suggests that the risk factors for rhabdomyolysis exist in our local setting. It is, therefore, paramount that healthcare practitioners (GPs) in our settings should be made aware of ER, its prevention and symptoms. Exertional or exercise-induced rhabdomyolysis is a relatively uncommon condition but can have severe consequences if not recognised and managed appropriately. Most resource-poor primary healthcare facilities in Africa do not have 24-h laboratory services.22 A high index of suspicion is, therefore, pertinent; the presence of symptoms (pain, tenderness, weakness and swelling in the muscles affected after engaging in physical activity) and typical urine discolouration are enough to prompt commencement of IV normal saline, whilst awaiting serological report on CK level.
Acknowledgements
Competing interests
The authors have declared that no competing interests exist.
Authors’ contributions
All authors contributed equally to this work.
Ethical consideration
Written consent was obtained from the patient.
Funding information
This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.
Data availability statement
Data sharing is not applicable to this study as no new data were created or analysed in this study.
Disclaimer
The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors.
How to cite this article: Benedict MOA, Adefuye AO. More than myalgia: An unusual presentation of exertional rhabdomyolysis. S Afr Fam Pract. 2021;63(1), a5194. https://doi.org/10.4102/safp.v63i1.5194 | Recovered | ReactionOutcome | CC BY | 33567839 | 18,941,160 | 2021-01-13 |
What was the outcome of reaction 'Rhabdomyolysis'? | More than myalgia: An unusual presentation of exertional rhabdomyolysis.
Exertional or exercise-induced rhabdomyolysis (ER) is a condition in which excessive and unaccustomed physical activity results in skeletal muscle damage. The ER is a relatively uncommon condition but can have very serious consequences such as acute renal failure, severe electrolyte abnormalities, acid base disturbances and death if not recognised and managed appropriately. The risk factors for rhabdomyolysis exist in our local setting, hence, it is paramount that healthcare practitioners (GPs) in our settings be made aware of ER, its prevention and symptoms. Cases of ER are often reported in sports men or women. Here, we report a case of a 33-year-old healthy female, with clinical and serological presentation, which is typical of ER following the commencement of a regimen of exercise to lose weight.
Background
Rhabdomyolysis is a clinical syndrome resulting from significant skeletal muscle injury and breakdown.1 Many cases of rhabdomyolysis are often undetected and its occurrence has been reported only in subgroups of populations at risk.2 Exertional rhabdomyolysis (ER) is a potentially life-threatening clinical condition that is characterised by the breakdown and necrosis of skeletal muscle induced by physical activity.3 Exertional or exercise-induced rhabdomyolysis is a relatively uncommon condition with an incidence of approximately 29.9 per 100 000 patient-years but can have very serious consequences such as acute renal failure, severe electrolyte abnormalities, acid-base disturbances and death if not recognised and managed appropriately.4 Exertional or exercise-induced rhabdomyolysis is not always evident, but early recognition of this entity and prompt intervention may prevent a serious injury or even death. Hence, healthcare professionals should be able to recognise the basic signs of ER in order to administer prompt treatment.1 Distinguishing features of ER include the history of intense, repetitive exercise or a sudden increase in exercise in an untrained person,5 associated with biochemical changes such as elevated serum creatine kinase (CK) levels five times the upper limit of normal (> 1000 IU/L) and myoglobinuria (> 1000 μg/mL), which present clinically as rust-coloured urine.6 To make a definitive diagnosis of ER, a practitioner must combine findings from history, physical examination and serological assay.4 Treatment modalities include rest and hydration with intravenous (IV) fluids. Cases of ER are often reported in sports men or women.7,8,9 Herein, we present an unusual case of ER that occurred in a healthy individual following the commencement of a regimen of exercise to lose weight.
Case presentation
Ms JR is a 33-year-old female who presented at the emergency department (ED) of a district hospital in the Free State province, South Africa, with 5 days’ history of generalised muscle pain. There was no history of trauma. She has been healthy, with no previous medical history of significance. No fever or any further symptom suggestive of viral or bacterial infection was observed. On her doctor’s advice, she recently commenced a regimen of exercise, because she was slightly overweight (body mass index [BMI] 27.3). Few days into her workouts, she developed muscle pains, which she was treated with ‘Mypaid’ (an analgesic containing Ibuprofen and Paracetamol), purchased over-the-counter. A few days later, she consulted her general practitioner (GP) who, according to patient report, made a diagnosis of myalgia. She was given Voltaren (Diclofenac) injection intramuscularly and was requested to continue her analgesic, take some days off work to rest and to ‘go slow’ with her workouts. There was no other history of relevance.
General examination done at the ED, revealed a young healthy looking female, not in painful distress, comfortable, although a little anxious. Her vital signs were all within normal ranges and no other significant findings were noted. Examination of the musculoskeletal system revealed mild tenderness in her quadriceps femoris and latissimus dorsi muscles with no sign of inflammation or trauma. Other systems were normal.
Urinalysis was performed. Macroscopically, the urine was turbid and dark brown in colour, which was unusual according to the patient. She, however, thought that it was because of the analgesic she was taking. Microscopic findings include 1–5 red blood cells per microliter (reference range ≤ 5 cells/µL), no pus cells, moderate squamous epithelial cells and granular casts. Crystals, parasites and yeast cells were absent. Urine chemistry (dipstick) showed blood3+, protein3+ and bilirubin+ (Figure 1). Other parameters were negative or normal. At this stage, a diagnosis of ER became high on the list of differential diagnoses.
FIGURE 1 Urinalysis of the random urine sample collected at presentation at the emergency department.
Full blood count, electrolyte and urea and creatinine kinase were determined from the patient blood sample. CK was significantly elevated at 119,800 IU/L (reference range 26 IU/L–192 IU/L). Potassium level was normal (3.9 mmol/L) along with other electrolytes and urea. The full blood count was normal as well (Table 1). Based on these findings, a diagnosis of ER was made.
TABLE 1 Relevant investigations during admission.
Test Reference ranges Days on admission
05 October 2019 (Day 1) 06 October 2019 (Day 2) 07 October 2019 (Day 3) 08 October 2019 (Day 4)
Haemoglobin 12.1–16.3 g/dL 14.0 – – –
White cell 3.92–9.88 5.6 – – –
Sodium 136–145 mmol/L 139 137 137 –
Potassium 3.5–5.1 mmol/L 3.9 3.6 4.1 –
Chloride 98–107 mmol/L 103 104 103 –
Bicarbonate 22–29 mmol/L 23 24 24 –
Anion gap 8–20 mmol/L 17 13 14 –
Urea < 8.4 mmol/L 3.4 3.9 3.8 –
Creatinine 49–90 μmol/L 84 71 60 –
eGFR > 90 mL/min 79 97 115 –
CK 26–192 U/L 119 800 88 787 83 142 68 948
Note: Data in bold highlight the daily creatine kinase levels which are plotted on Figure 2.
eGFR, estimated glomerular filtration rate; CK, creatine kinase.
IV fluid (0.9% NaCl) treatment was commenced at an initial rate of 300 mL/h and the patient was admitted to a high care unit. IVfluid treatment with 0.9% NaCl was later reviewed to 500 mL/h, reaching a urinary output > 200 mL/h. During her clinical course, no complication was noted. Day 2 CK concentration was 88 787 U/L, day 3 concentration was 83 142 U/L and day 4 concentration was 68 948 U/L (Figure 2). The urea and creatinine levels remained normal and after 4 days of IV fluids, the urine was completely clear.
FIGURE 2 Trend in creatine kinase concentration during intravenous fluid treatment.
The patient was discharged on day 5 completely asymptomatic. No further repeats of blood tests were performed. She was subsequently booked for outpatient monitoring of her CK and renal function. The patient did not attend the follow-up clinic, however, a telephonic consultation was performed with the patient during which she indicated that she was doing well with no further complaints post discharge.
Discussion
The causes of rhabdomyolysis are numerous and can include direct muscle injury, unaccustomed exercise, ischaemia, extreme temperatures, electrolyte abnormalities, endocrinologic conditions, genetic disorders, autoimmune disorders, infections, drugs, toxins and venoms.10,11 The patient in this case study was overweight, thus, fall within the population at risk of developing rhabdomyolysis was observed as described in the literature.2 These groups of individuals (overweight or obese) are likely to be on statins, which has been implicated in rhabdomyolysis,12 and are often advised to exercise more to lose weight or placed on some sort of weight-losing exercise schedule.13 Progressive increase in the prevalence of obesity in Africa and indeed South Africa, particularly amongst women has been reported.14,15 Also, trauma from inter-personal or community assault is common in our communities.16 Hence, there is a need for a high index of suspicion for rhabdomyolysis in our setting. In this study, the patient’s GP should have considered ER as against ‘Myalgia’ considering the recent history of unaccustomed exercise. The change in urine colour could have prompted the GP to re-consider his diagnosis, but this history was missed. It is a common practice for GPs to prescribe non-steroidal anti-inflammatory drugs (NSAIDs) for the treatment of myalgia. However, the use of NSAIDs in this scenario could ‘potentiate’ acute kidney injury and other complications. Analgesics, particularly NSAIDs, can reduce renal perfusion, leading to a depressed glomerular filtration rate.17
The diagnosis could have been easily missed at the ED if the attending doctor did not check the urine. The dark-brown urine was an important clue to the diagnosis, which was confirmed by the elevated CK. It is, therefore, important that in the presence of these risk factors, and an appropriate clinical setting, the urine of the patient should be properly examined and CK levels checked when history and findings on examination are suggestive of rhabdomyolysis or ER. Studies have shown several cases of non-complicated rhabdomyolysis despite CK levels over 100 000.18 Similarly, the patient presented herein made a complete recovery following IV hydration, despite overtly elevated CK levels. It has been reported that the outcome or prognosis in cases of rhabdomyolysis is dependent on cofactors such as the aetiology and the presence of comorbidities, and not just based on the CK levels alone.19 Along with IV hydration, the tracking of CK levels, kidney function and electrolyte should be monitored daily.4 If levels of CK continue to rise post 48 to 72 h after the presentation and depending on the severity of kidney disease or presence of compartment syndrome, consultation of a nephrologist or surgeon should be considered.4 The ability of medical response teams to provide aggressive hydration and dialysis services enhances survival. If treatment modalities are implemented early, patients should recover completely.19
The decision to discharge the patient with a CK level > 60 000 was made because the CK level was on the downward trend, urine became clear, the patient was clinically asymptomatic and other laboratory tests were normal. The acceptable discharge CK level following the treatment of rhabdomyolysis is presently debatable. Some experts have argued that discharge at higher CK thresholds of 20 000 to 50 000 U/L can be safely achieved in the ED, whilst others have recommended hospitalisation for rhabdomyolysis until CK level drops to less than 1000 U/L.20 Outpatient management with oral hydration may suffice for a stable patient with a CK level of 20 000 U/L to 50 000 U/L (and possibly higher), normal creatinine level and good urine flow.21 In a study carried out on 41 patients presenting with ER, the median discharged CK was 5287 (range, 10–61 617) U/L with a mean length of stay of approximately 3 days.20
Conclusion
Patients presenting with myalgia, obese patients, patients on statins and patients taking NSAIDs are very common in our setting. Also, GPs are encouraging patients to exercise more. This suggests that the risk factors for rhabdomyolysis exist in our local setting. It is, therefore, paramount that healthcare practitioners (GPs) in our settings should be made aware of ER, its prevention and symptoms. Exertional or exercise-induced rhabdomyolysis is a relatively uncommon condition but can have severe consequences if not recognised and managed appropriately. Most resource-poor primary healthcare facilities in Africa do not have 24-h laboratory services.22 A high index of suspicion is, therefore, pertinent; the presence of symptoms (pain, tenderness, weakness and swelling in the muscles affected after engaging in physical activity) and typical urine discolouration are enough to prompt commencement of IV normal saline, whilst awaiting serological report on CK level.
Acknowledgements
Competing interests
The authors have declared that no competing interests exist.
Authors’ contributions
All authors contributed equally to this work.
Ethical consideration
Written consent was obtained from the patient.
Funding information
This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.
Data availability statement
Data sharing is not applicable to this study as no new data were created or analysed in this study.
Disclaimer
The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors.
How to cite this article: Benedict MOA, Adefuye AO. More than myalgia: An unusual presentation of exertional rhabdomyolysis. S Afr Fam Pract. 2021;63(1), a5194. https://doi.org/10.4102/safp.v63i1.5194 | Recovered | ReactionOutcome | CC BY | 33567839 | 18,941,160 | 2021-01-13 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neuralgia'. | Ibrutinib-induced acute kidney injury via interstitial nephritis.
The introduction of Bruton's tyrosine kinase inhibitor ibrutinib has made a significant progress in the treatment of chronic lymphocytic leukemia and other B-cell malignancies. Due to the reduction of cytokine release, it is effective in chronic graft-versus-host disease, and its use has also been suggested in autoimmune diseases and in prevention of COVID-19-associated lung damage. Despite this effect on the immune response, we report a severe hypersensitivity reaction in a 76-year-old male patient diagnosed with prolymphocytic leukemia. Four weeks after the ibrutinib start, non-oliguric acute kidney injury with proteinuria and microscopic hematuria developed and that was accompanied by lower limb purpuras and paresthesia. Renal biopsy revealed acute interstitial nephritis. Employing 1 mg/kg methylprednisolone administration, serum creatinine decreased from 365 μmol/L to 125 μmol/L at 11 days and the proteinuria-hematuria as well as the purpura, paresthesia resolved. Three months later at stabile eGFR of 56 ml/min/1.73 m2 methylprednisolone was withdrawn and a rituximab-venetoclax treatment was initiated without side effects. We conclude that despite the beneficial effect on cytokines response in Th1 direction, ibrutinib can cause acute interstitial nephritis. Early detection, discontinuation of ibrutinib, glucocorticoid administration may help to better preserve renal function, thereby lowering the risk of potential subsequent kidney injury.
Introduction
The Bruton's tyrosine kinase (BTK) is an essential B-cell antigen receptor signaling molecule for B-cell development and activation pathway, which is involved in the pathogenesis of several B-cell malignancies. Ibrutinib, the first representative of BTK inhibitors, significantly improved the prognosis in high genetic risk chronic lymphocytic leukemia (CLL) resistant to traditional chemoimmunotherapy [1], in mantle cell lymphoma and in Waldenström’s macroglobulinemia as well.
BTK is required for the normal function of immune cells other than B cells, it controls cytokine production, phagocytosis, and the formation of inflammatory mediators. Ibrutinib treatment improves immune dysfunctions associated with CLL, the nonmalignant B-cell immune repertoire remains stable, T-cell and myeloid cell defects are partially restored [2–4]. Irreversible inhibition of the BTK-homologous interleukin-2-inducible T-cell kinase also contributes to this, stimulation of which is involved in selective Th2 cell activation, directing the immune response to healthy tissues. Therefore, ibrutinib also significantly improved the steroid-resistant/dependent chronic graft-versus-host disease [5]. It may be effective in preventing COVID-19-induced lung injury and may even improve the hypoxic, coronavirus-infected individuals’ lung function [6]. Reduction of cytokine release syndrome has also been observed in CLL patients receiving ibrutinib prior to obinutuzumab infusion [7]. Due to additive effects beyond B-cell depletion, BTK inhibition appears promising also in autoimmune diseases [8,9].
The more widespread use of ibrutinib is due to being a well-tolerated, orally applicable drug. Its most common side effects (diarrhea, skin hemorrhages, hypertension, upper respiratory tract infections) are usually mild; rarely, more severe bleeding complications or atrial fibrillation may occur as grade 3/4 side effects. It very rarely causes tumor lysis syndrome [10] or other kidney injuries in itself, not mentioned in the recent summary of adverse reactions [11], nor has been observed in a 6-year follow-up [12]. The acute kidney injury (AKI) cases reported in a previous trial were due to preceding renal diseases and concomitant pre/postrenal reasons [13]. In two renal biopsy cases degenerative tubular damage was assumed as a consequence of long-term ibrutinib administration [14].
In our patient, 4 weeks after ibrutinib start, acute interstitial nephritis (AIN) was recognized during investigations for lower limb purpura and neuropathic pain. The occurrence of a severe hypersensitivity reaction is unexpected given the ‘beneficial’ effect of ibrutinib on cytokines, no similar case was reported.
Case report
A 76-year-old man with a history of depression, hypertension, previous regular smoking (half pack/day for 20 years) and alcohol consumption (5 unit/day for 30 years) presented with AKI. In January 2018, close hematological monitoring was started due to high white blood cell count (42 G/L, predominantly lymphocytes 32 G/L). By peripheral flow cytometry, 77% of the B cells proved to be abnormal, the immunophenotype raised the possibility of prolymphocytic leukemic transformation. In January 2020 white blood cell count increased to 116 G/L, CT scan showed significant splenomegaly, paraaortic lymph node enlargement, with serum creatinine (sCr) of 59 μmol/L at that time. Because of progression of the underlying disease, with prognostic markers including monosomy 13, TP53 (17p13.1) deletion, and borderline mutation status of immunoglobulin heavy chain variable region, ibrutinib was initiated in March 2020 at a daily dose of 420 mg. Previous medications (tianeptine, enalapril, spironolactone, diosmin) were continued except aspirin. Four weeks later, he was referred to the Emergency Department because of lower limb purpuras, burning pain in both feet and soles. A significant sCr increase (296 μmol/L) was discovered. On the following day, despite preserved urinary output, sCr increased to 365 μmol/L, with significant proteinuria (urine protein to creatinin ratio: 70 mg/mmol), and microscopic hematuria. No other abnormalities than moderate serum uric acid (537 μmol/L), and phosphate (1.8 mmol/L) elevations, a slightly decreasing white blood cell count (98 G/L), and anemia (hemoglobin 113 g/L) were detected. Serum potassium, tCO2, calcium, platelet and eosinophil cell counts, liver and muscle enzymes, immunoglobulin and complement levels were normal. Urgent anti-neutrophil cytoplasmic antibody (ANCA) and anti-glomerular basement membrane antibody test results were also negative. Ultrasonography showed normal-sized kidneys, without urine outflow obstruction. Because of rapidly deteriorating renal function, parenteral methylprednisolone was initiated at a dose of 1 mg/kg body weight, and ibrutinib was omitted. Renal biopsy confirmed acute interstitial nephritis, it showed no crescent formation, interstitial B-cell infiltration or other significant abnormalities on day 4 (Figure 1). Immunofluorescence revealed no immunodeposits in the glomeruli, the blood vessels, interstitium, tubules. Focal intense, interstitial infiltration of mixed inflammatory cells with some eosinophil cells and mastocytes were seen. Methylprednisolone treatment was continued, with which the patient’s skin symptoms, lower limb numbness were completely resolved, on day 11 of treatment, sCr was reduced to 125 μmol/L, when no proteinuria/hematuria was detectable. Apixaban was started due to atrial fibrillation occurring at this time and high stroke risk score. Methylprednisolone therapy was gradually tapered off over 3 months, and eGFR stabilized at 56 mL/min/1.73 m2. Due to further increase in white blood cell count (160 G/L), rituximab—venetoclax treatment was initiated in August 2020. Tumor lysis syndrome did not occur with rasburicase and allopurinol prophylaxis.
Figure 1. Kidney biopsy specimen, monoclonal interstitial infiltration cannot be confirmed. (A) CD68-positive macrophages (100×), (B) CD20-positive B cells (100×), (C) CD3-positive T cells (100×), (D) CD117-positive mastocytes in the interstitium (3 cells on the right side of the FOV), (E) HE (40×) focal, mixed inflammatory cell infiltration in the interstitium
Discussion
Significant progress has been made in the treatment of CLL over the past decade. In our patient, genetic tests clearly indicated a poor prognosis, thus according to the recommendations [1], ibrutinib was initiated at disease progression, after which, 4 weeks later, non-oliguric AKI occurred. Both pre/postrenal etiologies and tumor lysis syndrome were ruled out on the basis of the clinical picture, renal ultrasonography and laboratory tests. Proteinuria and microscopic hematuria raised the possibility of both glomerular and tubulointerstitial damage. Because sCr, urine tests were not performed before starting treatment, it could not be ruled out that renal involvement may be a rare consequence of CLL. Leukemic cell infiltration is usually associated with renal enlargement, while paraneoplastic glomerular diseases are often associated with nephrotic syndrome, which were all absent in our case. However, they can only be ruled out by kidney biopsy, which also enables us to distinguish among the various histological forms of involvement. In the Mayo Clinic’s 10 years of practice, renal biopsy was required in 1.2% of CLL patients due to kidney failure or nephrotic syndrome [15].
The coinciding skin symptoms and neuropathy a month after the initiation of ibrutinib made us think of its provocative role in the development of AKI. The discontinuation of a potentially life-saving treatment warranted a kidney biopsy. Ibrutinib inhibits of collage-induced platelet aggregation by inhibiting platelet BTK and it is generally recommended to hold it 3–7 days before and after and invasive interventions [11]. This resulted in waiting until day 4 to perform a renal biopsy to decrease the risk of bleeding from platelet dysfunction.
Thrombocytopathy may have a role in the formation of small, non-palpable petechias usually developing after 2 months of ibrutinib treatment. In our patient, the prompt presence of skin symptoms within one month of therapy was more suggestive of vasculitis. Such early onset of palpable purpuriform lesions may suggest more severe disease and may require discontinuation of treatment, glucocorticoid therapy, and could recur upon repeated administration of the drug [16]. Peripheral neuropathies due to various pathomechanisms are not uncommon in hematologic malignancies [17]. Ibrutinib may ameliorate anti-myelin-associated glycoprotein mediated form but can also provoke it [11,17] by an unknown mechanism. In our case, its simultaneous appearance with skin and kidney symptoms raised the possibility of vasculitis.
The related clinical picture abovemade drug-induced interstitial nephritis higher on the differential over IgA or ANCA induced vasculitis. The rapid loss in GFR prompted us to start glucocorticoid immediately prior to any histological verification along with holding ibrutinib. Renal biopsy confirmed our suspicions. One prior case showed biopsy-proven ibrutinib induced AIN to date; however, in that case, chronic kidney disease and diarrhea were also implicated in the AKI [18].
In the background of drug-induced AIN, a hypersensitive reaction is suggested, primarily characterized by the Th2 cytokine response. Its occurrence is unusual because ibrutinib can prevent cytokine release in CLL patients [6,7], decreases the elevated cytokine, chemokine levels and polarizes T cells in Th1 direction [3]. Macrophage response shifts from M1 toward M2 based on mouse models and human studies, too [4,6]. In our case, we did not examine cytokine levels. Recently serum and urine levels of several cytokines were found to be higher in AIN patients compared to healthy ones, but cytokine levels characteristic of Th2 response did not differ [19]. Because AIN is mostly restricted to the kidneys, testing urine cytokine levels is more relevant. Th2-specific TNF-alpha urinary level was higher in AIN compared to other AKI, but it can be mast cell origin, as indicated by higher IL-9 levels [20]. Mast cells were present in our case biopsy specimen also.
With glucocorticoid treatment, proteinuria, hematuria resolved within 2 weeks, and renal function improved significantly. Glucocorticoid treatment efficacy is contentious in AIN [19], and many consider it only if no improvement in renal function is observed within 3–5 days despite omitting the responsible drug. This wait would certainly have resulted in lower GFR later. In case of malignant diseases, we consider it important to better preserve kidney function also for the prevention of AKI that may be superimposed due to possible subsequent damages.
With this case report, we would like to draw the attention to careful use of ibrutinib, which certainly will be applied more widely. Publication of our case may also contribute to explore the pathomechanism of AIN.
Acknowledgement
The work was supported by the University of Debrecen Kalman Laki Doctoral School of Biomedical and Clinical Sciences.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Abbreviations
AIN acute interstitial nephritis
AKI acute kidney injury
BTK Bruton's tyrosine kinase
CLL chronic lymphocytic leukemia
sCr serum creatinine
GFR glomerular filtration ratio
ANCA anti-neutrophil cytoplasmic antibody | ALLOPURINOL, APIXABAN, DIOSMIN, ENALAPRIL, IBRUTINIB, RASBURICASE, RITUXIMAB, SPIRONOLACTONE, TIANEPTINE, VENETOCLAX | DrugsGivenReaction | CC BY | 33567947 | 18,954,566 | 2021-12 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Tubulointerstitial nephritis'. | Ibrutinib-induced acute kidney injury via interstitial nephritis.
The introduction of Bruton's tyrosine kinase inhibitor ibrutinib has made a significant progress in the treatment of chronic lymphocytic leukemia and other B-cell malignancies. Due to the reduction of cytokine release, it is effective in chronic graft-versus-host disease, and its use has also been suggested in autoimmune diseases and in prevention of COVID-19-associated lung damage. Despite this effect on the immune response, we report a severe hypersensitivity reaction in a 76-year-old male patient diagnosed with prolymphocytic leukemia. Four weeks after the ibrutinib start, non-oliguric acute kidney injury with proteinuria and microscopic hematuria developed and that was accompanied by lower limb purpuras and paresthesia. Renal biopsy revealed acute interstitial nephritis. Employing 1 mg/kg methylprednisolone administration, serum creatinine decreased from 365 μmol/L to 125 μmol/L at 11 days and the proteinuria-hematuria as well as the purpura, paresthesia resolved. Three months later at stabile eGFR of 56 ml/min/1.73 m2 methylprednisolone was withdrawn and a rituximab-venetoclax treatment was initiated without side effects. We conclude that despite the beneficial effect on cytokines response in Th1 direction, ibrutinib can cause acute interstitial nephritis. Early detection, discontinuation of ibrutinib, glucocorticoid administration may help to better preserve renal function, thereby lowering the risk of potential subsequent kidney injury.
Introduction
The Bruton's tyrosine kinase (BTK) is an essential B-cell antigen receptor signaling molecule for B-cell development and activation pathway, which is involved in the pathogenesis of several B-cell malignancies. Ibrutinib, the first representative of BTK inhibitors, significantly improved the prognosis in high genetic risk chronic lymphocytic leukemia (CLL) resistant to traditional chemoimmunotherapy [1], in mantle cell lymphoma and in Waldenström’s macroglobulinemia as well.
BTK is required for the normal function of immune cells other than B cells, it controls cytokine production, phagocytosis, and the formation of inflammatory mediators. Ibrutinib treatment improves immune dysfunctions associated with CLL, the nonmalignant B-cell immune repertoire remains stable, T-cell and myeloid cell defects are partially restored [2–4]. Irreversible inhibition of the BTK-homologous interleukin-2-inducible T-cell kinase also contributes to this, stimulation of which is involved in selective Th2 cell activation, directing the immune response to healthy tissues. Therefore, ibrutinib also significantly improved the steroid-resistant/dependent chronic graft-versus-host disease [5]. It may be effective in preventing COVID-19-induced lung injury and may even improve the hypoxic, coronavirus-infected individuals’ lung function [6]. Reduction of cytokine release syndrome has also been observed in CLL patients receiving ibrutinib prior to obinutuzumab infusion [7]. Due to additive effects beyond B-cell depletion, BTK inhibition appears promising also in autoimmune diseases [8,9].
The more widespread use of ibrutinib is due to being a well-tolerated, orally applicable drug. Its most common side effects (diarrhea, skin hemorrhages, hypertension, upper respiratory tract infections) are usually mild; rarely, more severe bleeding complications or atrial fibrillation may occur as grade 3/4 side effects. It very rarely causes tumor lysis syndrome [10] or other kidney injuries in itself, not mentioned in the recent summary of adverse reactions [11], nor has been observed in a 6-year follow-up [12]. The acute kidney injury (AKI) cases reported in a previous trial were due to preceding renal diseases and concomitant pre/postrenal reasons [13]. In two renal biopsy cases degenerative tubular damage was assumed as a consequence of long-term ibrutinib administration [14].
In our patient, 4 weeks after ibrutinib start, acute interstitial nephritis (AIN) was recognized during investigations for lower limb purpura and neuropathic pain. The occurrence of a severe hypersensitivity reaction is unexpected given the ‘beneficial’ effect of ibrutinib on cytokines, no similar case was reported.
Case report
A 76-year-old man with a history of depression, hypertension, previous regular smoking (half pack/day for 20 years) and alcohol consumption (5 unit/day for 30 years) presented with AKI. In January 2018, close hematological monitoring was started due to high white blood cell count (42 G/L, predominantly lymphocytes 32 G/L). By peripheral flow cytometry, 77% of the B cells proved to be abnormal, the immunophenotype raised the possibility of prolymphocytic leukemic transformation. In January 2020 white blood cell count increased to 116 G/L, CT scan showed significant splenomegaly, paraaortic lymph node enlargement, with serum creatinine (sCr) of 59 μmol/L at that time. Because of progression of the underlying disease, with prognostic markers including monosomy 13, TP53 (17p13.1) deletion, and borderline mutation status of immunoglobulin heavy chain variable region, ibrutinib was initiated in March 2020 at a daily dose of 420 mg. Previous medications (tianeptine, enalapril, spironolactone, diosmin) were continued except aspirin. Four weeks later, he was referred to the Emergency Department because of lower limb purpuras, burning pain in both feet and soles. A significant sCr increase (296 μmol/L) was discovered. On the following day, despite preserved urinary output, sCr increased to 365 μmol/L, with significant proteinuria (urine protein to creatinin ratio: 70 mg/mmol), and microscopic hematuria. No other abnormalities than moderate serum uric acid (537 μmol/L), and phosphate (1.8 mmol/L) elevations, a slightly decreasing white blood cell count (98 G/L), and anemia (hemoglobin 113 g/L) were detected. Serum potassium, tCO2, calcium, platelet and eosinophil cell counts, liver and muscle enzymes, immunoglobulin and complement levels were normal. Urgent anti-neutrophil cytoplasmic antibody (ANCA) and anti-glomerular basement membrane antibody test results were also negative. Ultrasonography showed normal-sized kidneys, without urine outflow obstruction. Because of rapidly deteriorating renal function, parenteral methylprednisolone was initiated at a dose of 1 mg/kg body weight, and ibrutinib was omitted. Renal biopsy confirmed acute interstitial nephritis, it showed no crescent formation, interstitial B-cell infiltration or other significant abnormalities on day 4 (Figure 1). Immunofluorescence revealed no immunodeposits in the glomeruli, the blood vessels, interstitium, tubules. Focal intense, interstitial infiltration of mixed inflammatory cells with some eosinophil cells and mastocytes were seen. Methylprednisolone treatment was continued, with which the patient’s skin symptoms, lower limb numbness were completely resolved, on day 11 of treatment, sCr was reduced to 125 μmol/L, when no proteinuria/hematuria was detectable. Apixaban was started due to atrial fibrillation occurring at this time and high stroke risk score. Methylprednisolone therapy was gradually tapered off over 3 months, and eGFR stabilized at 56 mL/min/1.73 m2. Due to further increase in white blood cell count (160 G/L), rituximab—venetoclax treatment was initiated in August 2020. Tumor lysis syndrome did not occur with rasburicase and allopurinol prophylaxis.
Figure 1. Kidney biopsy specimen, monoclonal interstitial infiltration cannot be confirmed. (A) CD68-positive macrophages (100×), (B) CD20-positive B cells (100×), (C) CD3-positive T cells (100×), (D) CD117-positive mastocytes in the interstitium (3 cells on the right side of the FOV), (E) HE (40×) focal, mixed inflammatory cell infiltration in the interstitium
Discussion
Significant progress has been made in the treatment of CLL over the past decade. In our patient, genetic tests clearly indicated a poor prognosis, thus according to the recommendations [1], ibrutinib was initiated at disease progression, after which, 4 weeks later, non-oliguric AKI occurred. Both pre/postrenal etiologies and tumor lysis syndrome were ruled out on the basis of the clinical picture, renal ultrasonography and laboratory tests. Proteinuria and microscopic hematuria raised the possibility of both glomerular and tubulointerstitial damage. Because sCr, urine tests were not performed before starting treatment, it could not be ruled out that renal involvement may be a rare consequence of CLL. Leukemic cell infiltration is usually associated with renal enlargement, while paraneoplastic glomerular diseases are often associated with nephrotic syndrome, which were all absent in our case. However, they can only be ruled out by kidney biopsy, which also enables us to distinguish among the various histological forms of involvement. In the Mayo Clinic’s 10 years of practice, renal biopsy was required in 1.2% of CLL patients due to kidney failure or nephrotic syndrome [15].
The coinciding skin symptoms and neuropathy a month after the initiation of ibrutinib made us think of its provocative role in the development of AKI. The discontinuation of a potentially life-saving treatment warranted a kidney biopsy. Ibrutinib inhibits of collage-induced platelet aggregation by inhibiting platelet BTK and it is generally recommended to hold it 3–7 days before and after and invasive interventions [11]. This resulted in waiting until day 4 to perform a renal biopsy to decrease the risk of bleeding from platelet dysfunction.
Thrombocytopathy may have a role in the formation of small, non-palpable petechias usually developing after 2 months of ibrutinib treatment. In our patient, the prompt presence of skin symptoms within one month of therapy was more suggestive of vasculitis. Such early onset of palpable purpuriform lesions may suggest more severe disease and may require discontinuation of treatment, glucocorticoid therapy, and could recur upon repeated administration of the drug [16]. Peripheral neuropathies due to various pathomechanisms are not uncommon in hematologic malignancies [17]. Ibrutinib may ameliorate anti-myelin-associated glycoprotein mediated form but can also provoke it [11,17] by an unknown mechanism. In our case, its simultaneous appearance with skin and kidney symptoms raised the possibility of vasculitis.
The related clinical picture abovemade drug-induced interstitial nephritis higher on the differential over IgA or ANCA induced vasculitis. The rapid loss in GFR prompted us to start glucocorticoid immediately prior to any histological verification along with holding ibrutinib. Renal biopsy confirmed our suspicions. One prior case showed biopsy-proven ibrutinib induced AIN to date; however, in that case, chronic kidney disease and diarrhea were also implicated in the AKI [18].
In the background of drug-induced AIN, a hypersensitive reaction is suggested, primarily characterized by the Th2 cytokine response. Its occurrence is unusual because ibrutinib can prevent cytokine release in CLL patients [6,7], decreases the elevated cytokine, chemokine levels and polarizes T cells in Th1 direction [3]. Macrophage response shifts from M1 toward M2 based on mouse models and human studies, too [4,6]. In our case, we did not examine cytokine levels. Recently serum and urine levels of several cytokines were found to be higher in AIN patients compared to healthy ones, but cytokine levels characteristic of Th2 response did not differ [19]. Because AIN is mostly restricted to the kidneys, testing urine cytokine levels is more relevant. Th2-specific TNF-alpha urinary level was higher in AIN compared to other AKI, but it can be mast cell origin, as indicated by higher IL-9 levels [20]. Mast cells were present in our case biopsy specimen also.
With glucocorticoid treatment, proteinuria, hematuria resolved within 2 weeks, and renal function improved significantly. Glucocorticoid treatment efficacy is contentious in AIN [19], and many consider it only if no improvement in renal function is observed within 3–5 days despite omitting the responsible drug. This wait would certainly have resulted in lower GFR later. In case of malignant diseases, we consider it important to better preserve kidney function also for the prevention of AKI that may be superimposed due to possible subsequent damages.
With this case report, we would like to draw the attention to careful use of ibrutinib, which certainly will be applied more widely. Publication of our case may also contribute to explore the pathomechanism of AIN.
Acknowledgement
The work was supported by the University of Debrecen Kalman Laki Doctoral School of Biomedical and Clinical Sciences.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Abbreviations
AIN acute interstitial nephritis
AKI acute kidney injury
BTK Bruton's tyrosine kinase
CLL chronic lymphocytic leukemia
sCr serum creatinine
GFR glomerular filtration ratio
ANCA anti-neutrophil cytoplasmic antibody | ALLOPURINOL, APIXABAN, DIOSMIN, ENALAPRIL, IBRUTINIB, RASBURICASE, RITUXIMAB, SPIRONOLACTONE, TIANEPTINE, VENETOCLAX | DrugsGivenReaction | CC BY | 33567947 | 18,954,566 | 2021-12 |
What was the administration route of drug 'IBRUTINIB'? | Ibrutinib-induced acute kidney injury via interstitial nephritis.
The introduction of Bruton's tyrosine kinase inhibitor ibrutinib has made a significant progress in the treatment of chronic lymphocytic leukemia and other B-cell malignancies. Due to the reduction of cytokine release, it is effective in chronic graft-versus-host disease, and its use has also been suggested in autoimmune diseases and in prevention of COVID-19-associated lung damage. Despite this effect on the immune response, we report a severe hypersensitivity reaction in a 76-year-old male patient diagnosed with prolymphocytic leukemia. Four weeks after the ibrutinib start, non-oliguric acute kidney injury with proteinuria and microscopic hematuria developed and that was accompanied by lower limb purpuras and paresthesia. Renal biopsy revealed acute interstitial nephritis. Employing 1 mg/kg methylprednisolone administration, serum creatinine decreased from 365 μmol/L to 125 μmol/L at 11 days and the proteinuria-hematuria as well as the purpura, paresthesia resolved. Three months later at stabile eGFR of 56 ml/min/1.73 m2 methylprednisolone was withdrawn and a rituximab-venetoclax treatment was initiated without side effects. We conclude that despite the beneficial effect on cytokines response in Th1 direction, ibrutinib can cause acute interstitial nephritis. Early detection, discontinuation of ibrutinib, glucocorticoid administration may help to better preserve renal function, thereby lowering the risk of potential subsequent kidney injury.
Introduction
The Bruton's tyrosine kinase (BTK) is an essential B-cell antigen receptor signaling molecule for B-cell development and activation pathway, which is involved in the pathogenesis of several B-cell malignancies. Ibrutinib, the first representative of BTK inhibitors, significantly improved the prognosis in high genetic risk chronic lymphocytic leukemia (CLL) resistant to traditional chemoimmunotherapy [1], in mantle cell lymphoma and in Waldenström’s macroglobulinemia as well.
BTK is required for the normal function of immune cells other than B cells, it controls cytokine production, phagocytosis, and the formation of inflammatory mediators. Ibrutinib treatment improves immune dysfunctions associated with CLL, the nonmalignant B-cell immune repertoire remains stable, T-cell and myeloid cell defects are partially restored [2–4]. Irreversible inhibition of the BTK-homologous interleukin-2-inducible T-cell kinase also contributes to this, stimulation of which is involved in selective Th2 cell activation, directing the immune response to healthy tissues. Therefore, ibrutinib also significantly improved the steroid-resistant/dependent chronic graft-versus-host disease [5]. It may be effective in preventing COVID-19-induced lung injury and may even improve the hypoxic, coronavirus-infected individuals’ lung function [6]. Reduction of cytokine release syndrome has also been observed in CLL patients receiving ibrutinib prior to obinutuzumab infusion [7]. Due to additive effects beyond B-cell depletion, BTK inhibition appears promising also in autoimmune diseases [8,9].
The more widespread use of ibrutinib is due to being a well-tolerated, orally applicable drug. Its most common side effects (diarrhea, skin hemorrhages, hypertension, upper respiratory tract infections) are usually mild; rarely, more severe bleeding complications or atrial fibrillation may occur as grade 3/4 side effects. It very rarely causes tumor lysis syndrome [10] or other kidney injuries in itself, not mentioned in the recent summary of adverse reactions [11], nor has been observed in a 6-year follow-up [12]. The acute kidney injury (AKI) cases reported in a previous trial were due to preceding renal diseases and concomitant pre/postrenal reasons [13]. In two renal biopsy cases degenerative tubular damage was assumed as a consequence of long-term ibrutinib administration [14].
In our patient, 4 weeks after ibrutinib start, acute interstitial nephritis (AIN) was recognized during investigations for lower limb purpura and neuropathic pain. The occurrence of a severe hypersensitivity reaction is unexpected given the ‘beneficial’ effect of ibrutinib on cytokines, no similar case was reported.
Case report
A 76-year-old man with a history of depression, hypertension, previous regular smoking (half pack/day for 20 years) and alcohol consumption (5 unit/day for 30 years) presented with AKI. In January 2018, close hematological monitoring was started due to high white blood cell count (42 G/L, predominantly lymphocytes 32 G/L). By peripheral flow cytometry, 77% of the B cells proved to be abnormal, the immunophenotype raised the possibility of prolymphocytic leukemic transformation. In January 2020 white blood cell count increased to 116 G/L, CT scan showed significant splenomegaly, paraaortic lymph node enlargement, with serum creatinine (sCr) of 59 μmol/L at that time. Because of progression of the underlying disease, with prognostic markers including monosomy 13, TP53 (17p13.1) deletion, and borderline mutation status of immunoglobulin heavy chain variable region, ibrutinib was initiated in March 2020 at a daily dose of 420 mg. Previous medications (tianeptine, enalapril, spironolactone, diosmin) were continued except aspirin. Four weeks later, he was referred to the Emergency Department because of lower limb purpuras, burning pain in both feet and soles. A significant sCr increase (296 μmol/L) was discovered. On the following day, despite preserved urinary output, sCr increased to 365 μmol/L, with significant proteinuria (urine protein to creatinin ratio: 70 mg/mmol), and microscopic hematuria. No other abnormalities than moderate serum uric acid (537 μmol/L), and phosphate (1.8 mmol/L) elevations, a slightly decreasing white blood cell count (98 G/L), and anemia (hemoglobin 113 g/L) were detected. Serum potassium, tCO2, calcium, platelet and eosinophil cell counts, liver and muscle enzymes, immunoglobulin and complement levels were normal. Urgent anti-neutrophil cytoplasmic antibody (ANCA) and anti-glomerular basement membrane antibody test results were also negative. Ultrasonography showed normal-sized kidneys, without urine outflow obstruction. Because of rapidly deteriorating renal function, parenteral methylprednisolone was initiated at a dose of 1 mg/kg body weight, and ibrutinib was omitted. Renal biopsy confirmed acute interstitial nephritis, it showed no crescent formation, interstitial B-cell infiltration or other significant abnormalities on day 4 (Figure 1). Immunofluorescence revealed no immunodeposits in the glomeruli, the blood vessels, interstitium, tubules. Focal intense, interstitial infiltration of mixed inflammatory cells with some eosinophil cells and mastocytes were seen. Methylprednisolone treatment was continued, with which the patient’s skin symptoms, lower limb numbness were completely resolved, on day 11 of treatment, sCr was reduced to 125 μmol/L, when no proteinuria/hematuria was detectable. Apixaban was started due to atrial fibrillation occurring at this time and high stroke risk score. Methylprednisolone therapy was gradually tapered off over 3 months, and eGFR stabilized at 56 mL/min/1.73 m2. Due to further increase in white blood cell count (160 G/L), rituximab—venetoclax treatment was initiated in August 2020. Tumor lysis syndrome did not occur with rasburicase and allopurinol prophylaxis.
Figure 1. Kidney biopsy specimen, monoclonal interstitial infiltration cannot be confirmed. (A) CD68-positive macrophages (100×), (B) CD20-positive B cells (100×), (C) CD3-positive T cells (100×), (D) CD117-positive mastocytes in the interstitium (3 cells on the right side of the FOV), (E) HE (40×) focal, mixed inflammatory cell infiltration in the interstitium
Discussion
Significant progress has been made in the treatment of CLL over the past decade. In our patient, genetic tests clearly indicated a poor prognosis, thus according to the recommendations [1], ibrutinib was initiated at disease progression, after which, 4 weeks later, non-oliguric AKI occurred. Both pre/postrenal etiologies and tumor lysis syndrome were ruled out on the basis of the clinical picture, renal ultrasonography and laboratory tests. Proteinuria and microscopic hematuria raised the possibility of both glomerular and tubulointerstitial damage. Because sCr, urine tests were not performed before starting treatment, it could not be ruled out that renal involvement may be a rare consequence of CLL. Leukemic cell infiltration is usually associated with renal enlargement, while paraneoplastic glomerular diseases are often associated with nephrotic syndrome, which were all absent in our case. However, they can only be ruled out by kidney biopsy, which also enables us to distinguish among the various histological forms of involvement. In the Mayo Clinic’s 10 years of practice, renal biopsy was required in 1.2% of CLL patients due to kidney failure or nephrotic syndrome [15].
The coinciding skin symptoms and neuropathy a month after the initiation of ibrutinib made us think of its provocative role in the development of AKI. The discontinuation of a potentially life-saving treatment warranted a kidney biopsy. Ibrutinib inhibits of collage-induced platelet aggregation by inhibiting platelet BTK and it is generally recommended to hold it 3–7 days before and after and invasive interventions [11]. This resulted in waiting until day 4 to perform a renal biopsy to decrease the risk of bleeding from platelet dysfunction.
Thrombocytopathy may have a role in the formation of small, non-palpable petechias usually developing after 2 months of ibrutinib treatment. In our patient, the prompt presence of skin symptoms within one month of therapy was more suggestive of vasculitis. Such early onset of palpable purpuriform lesions may suggest more severe disease and may require discontinuation of treatment, glucocorticoid therapy, and could recur upon repeated administration of the drug [16]. Peripheral neuropathies due to various pathomechanisms are not uncommon in hematologic malignancies [17]. Ibrutinib may ameliorate anti-myelin-associated glycoprotein mediated form but can also provoke it [11,17] by an unknown mechanism. In our case, its simultaneous appearance with skin and kidney symptoms raised the possibility of vasculitis.
The related clinical picture abovemade drug-induced interstitial nephritis higher on the differential over IgA or ANCA induced vasculitis. The rapid loss in GFR prompted us to start glucocorticoid immediately prior to any histological verification along with holding ibrutinib. Renal biopsy confirmed our suspicions. One prior case showed biopsy-proven ibrutinib induced AIN to date; however, in that case, chronic kidney disease and diarrhea were also implicated in the AKI [18].
In the background of drug-induced AIN, a hypersensitive reaction is suggested, primarily characterized by the Th2 cytokine response. Its occurrence is unusual because ibrutinib can prevent cytokine release in CLL patients [6,7], decreases the elevated cytokine, chemokine levels and polarizes T cells in Th1 direction [3]. Macrophage response shifts from M1 toward M2 based on mouse models and human studies, too [4,6]. In our case, we did not examine cytokine levels. Recently serum and urine levels of several cytokines were found to be higher in AIN patients compared to healthy ones, but cytokine levels characteristic of Th2 response did not differ [19]. Because AIN is mostly restricted to the kidneys, testing urine cytokine levels is more relevant. Th2-specific TNF-alpha urinary level was higher in AIN compared to other AKI, but it can be mast cell origin, as indicated by higher IL-9 levels [20]. Mast cells were present in our case biopsy specimen also.
With glucocorticoid treatment, proteinuria, hematuria resolved within 2 weeks, and renal function improved significantly. Glucocorticoid treatment efficacy is contentious in AIN [19], and many consider it only if no improvement in renal function is observed within 3–5 days despite omitting the responsible drug. This wait would certainly have resulted in lower GFR later. In case of malignant diseases, we consider it important to better preserve kidney function also for the prevention of AKI that may be superimposed due to possible subsequent damages.
With this case report, we would like to draw the attention to careful use of ibrutinib, which certainly will be applied more widely. Publication of our case may also contribute to explore the pathomechanism of AIN.
Acknowledgement
The work was supported by the University of Debrecen Kalman Laki Doctoral School of Biomedical and Clinical Sciences.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Abbreviations
AIN acute interstitial nephritis
AKI acute kidney injury
BTK Bruton's tyrosine kinase
CLL chronic lymphocytic leukemia
sCr serum creatinine
GFR glomerular filtration ratio
ANCA anti-neutrophil cytoplasmic antibody | Oral | DrugAdministrationRoute | CC BY | 33567947 | 18,954,566 | 2021-12 |
What was the dosage of drug 'IBRUTINIB'? | Ibrutinib-induced acute kidney injury via interstitial nephritis.
The introduction of Bruton's tyrosine kinase inhibitor ibrutinib has made a significant progress in the treatment of chronic lymphocytic leukemia and other B-cell malignancies. Due to the reduction of cytokine release, it is effective in chronic graft-versus-host disease, and its use has also been suggested in autoimmune diseases and in prevention of COVID-19-associated lung damage. Despite this effect on the immune response, we report a severe hypersensitivity reaction in a 76-year-old male patient diagnosed with prolymphocytic leukemia. Four weeks after the ibrutinib start, non-oliguric acute kidney injury with proteinuria and microscopic hematuria developed and that was accompanied by lower limb purpuras and paresthesia. Renal biopsy revealed acute interstitial nephritis. Employing 1 mg/kg methylprednisolone administration, serum creatinine decreased from 365 μmol/L to 125 μmol/L at 11 days and the proteinuria-hematuria as well as the purpura, paresthesia resolved. Three months later at stabile eGFR of 56 ml/min/1.73 m2 methylprednisolone was withdrawn and a rituximab-venetoclax treatment was initiated without side effects. We conclude that despite the beneficial effect on cytokines response in Th1 direction, ibrutinib can cause acute interstitial nephritis. Early detection, discontinuation of ibrutinib, glucocorticoid administration may help to better preserve renal function, thereby lowering the risk of potential subsequent kidney injury.
Introduction
The Bruton's tyrosine kinase (BTK) is an essential B-cell antigen receptor signaling molecule for B-cell development and activation pathway, which is involved in the pathogenesis of several B-cell malignancies. Ibrutinib, the first representative of BTK inhibitors, significantly improved the prognosis in high genetic risk chronic lymphocytic leukemia (CLL) resistant to traditional chemoimmunotherapy [1], in mantle cell lymphoma and in Waldenström’s macroglobulinemia as well.
BTK is required for the normal function of immune cells other than B cells, it controls cytokine production, phagocytosis, and the formation of inflammatory mediators. Ibrutinib treatment improves immune dysfunctions associated with CLL, the nonmalignant B-cell immune repertoire remains stable, T-cell and myeloid cell defects are partially restored [2–4]. Irreversible inhibition of the BTK-homologous interleukin-2-inducible T-cell kinase also contributes to this, stimulation of which is involved in selective Th2 cell activation, directing the immune response to healthy tissues. Therefore, ibrutinib also significantly improved the steroid-resistant/dependent chronic graft-versus-host disease [5]. It may be effective in preventing COVID-19-induced lung injury and may even improve the hypoxic, coronavirus-infected individuals’ lung function [6]. Reduction of cytokine release syndrome has also been observed in CLL patients receiving ibrutinib prior to obinutuzumab infusion [7]. Due to additive effects beyond B-cell depletion, BTK inhibition appears promising also in autoimmune diseases [8,9].
The more widespread use of ibrutinib is due to being a well-tolerated, orally applicable drug. Its most common side effects (diarrhea, skin hemorrhages, hypertension, upper respiratory tract infections) are usually mild; rarely, more severe bleeding complications or atrial fibrillation may occur as grade 3/4 side effects. It very rarely causes tumor lysis syndrome [10] or other kidney injuries in itself, not mentioned in the recent summary of adverse reactions [11], nor has been observed in a 6-year follow-up [12]. The acute kidney injury (AKI) cases reported in a previous trial were due to preceding renal diseases and concomitant pre/postrenal reasons [13]. In two renal biopsy cases degenerative tubular damage was assumed as a consequence of long-term ibrutinib administration [14].
In our patient, 4 weeks after ibrutinib start, acute interstitial nephritis (AIN) was recognized during investigations for lower limb purpura and neuropathic pain. The occurrence of a severe hypersensitivity reaction is unexpected given the ‘beneficial’ effect of ibrutinib on cytokines, no similar case was reported.
Case report
A 76-year-old man with a history of depression, hypertension, previous regular smoking (half pack/day for 20 years) and alcohol consumption (5 unit/day for 30 years) presented with AKI. In January 2018, close hematological monitoring was started due to high white blood cell count (42 G/L, predominantly lymphocytes 32 G/L). By peripheral flow cytometry, 77% of the B cells proved to be abnormal, the immunophenotype raised the possibility of prolymphocytic leukemic transformation. In January 2020 white blood cell count increased to 116 G/L, CT scan showed significant splenomegaly, paraaortic lymph node enlargement, with serum creatinine (sCr) of 59 μmol/L at that time. Because of progression of the underlying disease, with prognostic markers including monosomy 13, TP53 (17p13.1) deletion, and borderline mutation status of immunoglobulin heavy chain variable region, ibrutinib was initiated in March 2020 at a daily dose of 420 mg. Previous medications (tianeptine, enalapril, spironolactone, diosmin) were continued except aspirin. Four weeks later, he was referred to the Emergency Department because of lower limb purpuras, burning pain in both feet and soles. A significant sCr increase (296 μmol/L) was discovered. On the following day, despite preserved urinary output, sCr increased to 365 μmol/L, with significant proteinuria (urine protein to creatinin ratio: 70 mg/mmol), and microscopic hematuria. No other abnormalities than moderate serum uric acid (537 μmol/L), and phosphate (1.8 mmol/L) elevations, a slightly decreasing white blood cell count (98 G/L), and anemia (hemoglobin 113 g/L) were detected. Serum potassium, tCO2, calcium, platelet and eosinophil cell counts, liver and muscle enzymes, immunoglobulin and complement levels were normal. Urgent anti-neutrophil cytoplasmic antibody (ANCA) and anti-glomerular basement membrane antibody test results were also negative. Ultrasonography showed normal-sized kidneys, without urine outflow obstruction. Because of rapidly deteriorating renal function, parenteral methylprednisolone was initiated at a dose of 1 mg/kg body weight, and ibrutinib was omitted. Renal biopsy confirmed acute interstitial nephritis, it showed no crescent formation, interstitial B-cell infiltration or other significant abnormalities on day 4 (Figure 1). Immunofluorescence revealed no immunodeposits in the glomeruli, the blood vessels, interstitium, tubules. Focal intense, interstitial infiltration of mixed inflammatory cells with some eosinophil cells and mastocytes were seen. Methylprednisolone treatment was continued, with which the patient’s skin symptoms, lower limb numbness were completely resolved, on day 11 of treatment, sCr was reduced to 125 μmol/L, when no proteinuria/hematuria was detectable. Apixaban was started due to atrial fibrillation occurring at this time and high stroke risk score. Methylprednisolone therapy was gradually tapered off over 3 months, and eGFR stabilized at 56 mL/min/1.73 m2. Due to further increase in white blood cell count (160 G/L), rituximab—venetoclax treatment was initiated in August 2020. Tumor lysis syndrome did not occur with rasburicase and allopurinol prophylaxis.
Figure 1. Kidney biopsy specimen, monoclonal interstitial infiltration cannot be confirmed. (A) CD68-positive macrophages (100×), (B) CD20-positive B cells (100×), (C) CD3-positive T cells (100×), (D) CD117-positive mastocytes in the interstitium (3 cells on the right side of the FOV), (E) HE (40×) focal, mixed inflammatory cell infiltration in the interstitium
Discussion
Significant progress has been made in the treatment of CLL over the past decade. In our patient, genetic tests clearly indicated a poor prognosis, thus according to the recommendations [1], ibrutinib was initiated at disease progression, after which, 4 weeks later, non-oliguric AKI occurred. Both pre/postrenal etiologies and tumor lysis syndrome were ruled out on the basis of the clinical picture, renal ultrasonography and laboratory tests. Proteinuria and microscopic hematuria raised the possibility of both glomerular and tubulointerstitial damage. Because sCr, urine tests were not performed before starting treatment, it could not be ruled out that renal involvement may be a rare consequence of CLL. Leukemic cell infiltration is usually associated with renal enlargement, while paraneoplastic glomerular diseases are often associated with nephrotic syndrome, which were all absent in our case. However, they can only be ruled out by kidney biopsy, which also enables us to distinguish among the various histological forms of involvement. In the Mayo Clinic’s 10 years of practice, renal biopsy was required in 1.2% of CLL patients due to kidney failure or nephrotic syndrome [15].
The coinciding skin symptoms and neuropathy a month after the initiation of ibrutinib made us think of its provocative role in the development of AKI. The discontinuation of a potentially life-saving treatment warranted a kidney biopsy. Ibrutinib inhibits of collage-induced platelet aggregation by inhibiting platelet BTK and it is generally recommended to hold it 3–7 days before and after and invasive interventions [11]. This resulted in waiting until day 4 to perform a renal biopsy to decrease the risk of bleeding from platelet dysfunction.
Thrombocytopathy may have a role in the formation of small, non-palpable petechias usually developing after 2 months of ibrutinib treatment. In our patient, the prompt presence of skin symptoms within one month of therapy was more suggestive of vasculitis. Such early onset of palpable purpuriform lesions may suggest more severe disease and may require discontinuation of treatment, glucocorticoid therapy, and could recur upon repeated administration of the drug [16]. Peripheral neuropathies due to various pathomechanisms are not uncommon in hematologic malignancies [17]. Ibrutinib may ameliorate anti-myelin-associated glycoprotein mediated form but can also provoke it [11,17] by an unknown mechanism. In our case, its simultaneous appearance with skin and kidney symptoms raised the possibility of vasculitis.
The related clinical picture abovemade drug-induced interstitial nephritis higher on the differential over IgA or ANCA induced vasculitis. The rapid loss in GFR prompted us to start glucocorticoid immediately prior to any histological verification along with holding ibrutinib. Renal biopsy confirmed our suspicions. One prior case showed biopsy-proven ibrutinib induced AIN to date; however, in that case, chronic kidney disease and diarrhea were also implicated in the AKI [18].
In the background of drug-induced AIN, a hypersensitive reaction is suggested, primarily characterized by the Th2 cytokine response. Its occurrence is unusual because ibrutinib can prevent cytokine release in CLL patients [6,7], decreases the elevated cytokine, chemokine levels and polarizes T cells in Th1 direction [3]. Macrophage response shifts from M1 toward M2 based on mouse models and human studies, too [4,6]. In our case, we did not examine cytokine levels. Recently serum and urine levels of several cytokines were found to be higher in AIN patients compared to healthy ones, but cytokine levels characteristic of Th2 response did not differ [19]. Because AIN is mostly restricted to the kidneys, testing urine cytokine levels is more relevant. Th2-specific TNF-alpha urinary level was higher in AIN compared to other AKI, but it can be mast cell origin, as indicated by higher IL-9 levels [20]. Mast cells were present in our case biopsy specimen also.
With glucocorticoid treatment, proteinuria, hematuria resolved within 2 weeks, and renal function improved significantly. Glucocorticoid treatment efficacy is contentious in AIN [19], and many consider it only if no improvement in renal function is observed within 3–5 days despite omitting the responsible drug. This wait would certainly have resulted in lower GFR later. In case of malignant diseases, we consider it important to better preserve kidney function also for the prevention of AKI that may be superimposed due to possible subsequent damages.
With this case report, we would like to draw the attention to careful use of ibrutinib, which certainly will be applied more widely. Publication of our case may also contribute to explore the pathomechanism of AIN.
Acknowledgement
The work was supported by the University of Debrecen Kalman Laki Doctoral School of Biomedical and Clinical Sciences.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Abbreviations
AIN acute interstitial nephritis
AKI acute kidney injury
BTK Bruton's tyrosine kinase
CLL chronic lymphocytic leukemia
sCr serum creatinine
GFR glomerular filtration ratio
ANCA anti-neutrophil cytoplasmic antibody | 420 mg (milligrams). | DrugDosage | CC BY | 33567947 | 18,954,566 | 2021-12 |
What was the outcome of reaction 'Neuralgia'? | Ibrutinib-induced acute kidney injury via interstitial nephritis.
The introduction of Bruton's tyrosine kinase inhibitor ibrutinib has made a significant progress in the treatment of chronic lymphocytic leukemia and other B-cell malignancies. Due to the reduction of cytokine release, it is effective in chronic graft-versus-host disease, and its use has also been suggested in autoimmune diseases and in prevention of COVID-19-associated lung damage. Despite this effect on the immune response, we report a severe hypersensitivity reaction in a 76-year-old male patient diagnosed with prolymphocytic leukemia. Four weeks after the ibrutinib start, non-oliguric acute kidney injury with proteinuria and microscopic hematuria developed and that was accompanied by lower limb purpuras and paresthesia. Renal biopsy revealed acute interstitial nephritis. Employing 1 mg/kg methylprednisolone administration, serum creatinine decreased from 365 μmol/L to 125 μmol/L at 11 days and the proteinuria-hematuria as well as the purpura, paresthesia resolved. Three months later at stabile eGFR of 56 ml/min/1.73 m2 methylprednisolone was withdrawn and a rituximab-venetoclax treatment was initiated without side effects. We conclude that despite the beneficial effect on cytokines response in Th1 direction, ibrutinib can cause acute interstitial nephritis. Early detection, discontinuation of ibrutinib, glucocorticoid administration may help to better preserve renal function, thereby lowering the risk of potential subsequent kidney injury.
Introduction
The Bruton's tyrosine kinase (BTK) is an essential B-cell antigen receptor signaling molecule for B-cell development and activation pathway, which is involved in the pathogenesis of several B-cell malignancies. Ibrutinib, the first representative of BTK inhibitors, significantly improved the prognosis in high genetic risk chronic lymphocytic leukemia (CLL) resistant to traditional chemoimmunotherapy [1], in mantle cell lymphoma and in Waldenström’s macroglobulinemia as well.
BTK is required for the normal function of immune cells other than B cells, it controls cytokine production, phagocytosis, and the formation of inflammatory mediators. Ibrutinib treatment improves immune dysfunctions associated with CLL, the nonmalignant B-cell immune repertoire remains stable, T-cell and myeloid cell defects are partially restored [2–4]. Irreversible inhibition of the BTK-homologous interleukin-2-inducible T-cell kinase also contributes to this, stimulation of which is involved in selective Th2 cell activation, directing the immune response to healthy tissues. Therefore, ibrutinib also significantly improved the steroid-resistant/dependent chronic graft-versus-host disease [5]. It may be effective in preventing COVID-19-induced lung injury and may even improve the hypoxic, coronavirus-infected individuals’ lung function [6]. Reduction of cytokine release syndrome has also been observed in CLL patients receiving ibrutinib prior to obinutuzumab infusion [7]. Due to additive effects beyond B-cell depletion, BTK inhibition appears promising also in autoimmune diseases [8,9].
The more widespread use of ibrutinib is due to being a well-tolerated, orally applicable drug. Its most common side effects (diarrhea, skin hemorrhages, hypertension, upper respiratory tract infections) are usually mild; rarely, more severe bleeding complications or atrial fibrillation may occur as grade 3/4 side effects. It very rarely causes tumor lysis syndrome [10] or other kidney injuries in itself, not mentioned in the recent summary of adverse reactions [11], nor has been observed in a 6-year follow-up [12]. The acute kidney injury (AKI) cases reported in a previous trial were due to preceding renal diseases and concomitant pre/postrenal reasons [13]. In two renal biopsy cases degenerative tubular damage was assumed as a consequence of long-term ibrutinib administration [14].
In our patient, 4 weeks after ibrutinib start, acute interstitial nephritis (AIN) was recognized during investigations for lower limb purpura and neuropathic pain. The occurrence of a severe hypersensitivity reaction is unexpected given the ‘beneficial’ effect of ibrutinib on cytokines, no similar case was reported.
Case report
A 76-year-old man with a history of depression, hypertension, previous regular smoking (half pack/day for 20 years) and alcohol consumption (5 unit/day for 30 years) presented with AKI. In January 2018, close hematological monitoring was started due to high white blood cell count (42 G/L, predominantly lymphocytes 32 G/L). By peripheral flow cytometry, 77% of the B cells proved to be abnormal, the immunophenotype raised the possibility of prolymphocytic leukemic transformation. In January 2020 white blood cell count increased to 116 G/L, CT scan showed significant splenomegaly, paraaortic lymph node enlargement, with serum creatinine (sCr) of 59 μmol/L at that time. Because of progression of the underlying disease, with prognostic markers including monosomy 13, TP53 (17p13.1) deletion, and borderline mutation status of immunoglobulin heavy chain variable region, ibrutinib was initiated in March 2020 at a daily dose of 420 mg. Previous medications (tianeptine, enalapril, spironolactone, diosmin) were continued except aspirin. Four weeks later, he was referred to the Emergency Department because of lower limb purpuras, burning pain in both feet and soles. A significant sCr increase (296 μmol/L) was discovered. On the following day, despite preserved urinary output, sCr increased to 365 μmol/L, with significant proteinuria (urine protein to creatinin ratio: 70 mg/mmol), and microscopic hematuria. No other abnormalities than moderate serum uric acid (537 μmol/L), and phosphate (1.8 mmol/L) elevations, a slightly decreasing white blood cell count (98 G/L), and anemia (hemoglobin 113 g/L) were detected. Serum potassium, tCO2, calcium, platelet and eosinophil cell counts, liver and muscle enzymes, immunoglobulin and complement levels were normal. Urgent anti-neutrophil cytoplasmic antibody (ANCA) and anti-glomerular basement membrane antibody test results were also negative. Ultrasonography showed normal-sized kidneys, without urine outflow obstruction. Because of rapidly deteriorating renal function, parenteral methylprednisolone was initiated at a dose of 1 mg/kg body weight, and ibrutinib was omitted. Renal biopsy confirmed acute interstitial nephritis, it showed no crescent formation, interstitial B-cell infiltration or other significant abnormalities on day 4 (Figure 1). Immunofluorescence revealed no immunodeposits in the glomeruli, the blood vessels, interstitium, tubules. Focal intense, interstitial infiltration of mixed inflammatory cells with some eosinophil cells and mastocytes were seen. Methylprednisolone treatment was continued, with which the patient’s skin symptoms, lower limb numbness were completely resolved, on day 11 of treatment, sCr was reduced to 125 μmol/L, when no proteinuria/hematuria was detectable. Apixaban was started due to atrial fibrillation occurring at this time and high stroke risk score. Methylprednisolone therapy was gradually tapered off over 3 months, and eGFR stabilized at 56 mL/min/1.73 m2. Due to further increase in white blood cell count (160 G/L), rituximab—venetoclax treatment was initiated in August 2020. Tumor lysis syndrome did not occur with rasburicase and allopurinol prophylaxis.
Figure 1. Kidney biopsy specimen, monoclonal interstitial infiltration cannot be confirmed. (A) CD68-positive macrophages (100×), (B) CD20-positive B cells (100×), (C) CD3-positive T cells (100×), (D) CD117-positive mastocytes in the interstitium (3 cells on the right side of the FOV), (E) HE (40×) focal, mixed inflammatory cell infiltration in the interstitium
Discussion
Significant progress has been made in the treatment of CLL over the past decade. In our patient, genetic tests clearly indicated a poor prognosis, thus according to the recommendations [1], ibrutinib was initiated at disease progression, after which, 4 weeks later, non-oliguric AKI occurred. Both pre/postrenal etiologies and tumor lysis syndrome were ruled out on the basis of the clinical picture, renal ultrasonography and laboratory tests. Proteinuria and microscopic hematuria raised the possibility of both glomerular and tubulointerstitial damage. Because sCr, urine tests were not performed before starting treatment, it could not be ruled out that renal involvement may be a rare consequence of CLL. Leukemic cell infiltration is usually associated with renal enlargement, while paraneoplastic glomerular diseases are often associated with nephrotic syndrome, which were all absent in our case. However, they can only be ruled out by kidney biopsy, which also enables us to distinguish among the various histological forms of involvement. In the Mayo Clinic’s 10 years of practice, renal biopsy was required in 1.2% of CLL patients due to kidney failure or nephrotic syndrome [15].
The coinciding skin symptoms and neuropathy a month after the initiation of ibrutinib made us think of its provocative role in the development of AKI. The discontinuation of a potentially life-saving treatment warranted a kidney biopsy. Ibrutinib inhibits of collage-induced platelet aggregation by inhibiting platelet BTK and it is generally recommended to hold it 3–7 days before and after and invasive interventions [11]. This resulted in waiting until day 4 to perform a renal biopsy to decrease the risk of bleeding from platelet dysfunction.
Thrombocytopathy may have a role in the formation of small, non-palpable petechias usually developing after 2 months of ibrutinib treatment. In our patient, the prompt presence of skin symptoms within one month of therapy was more suggestive of vasculitis. Such early onset of palpable purpuriform lesions may suggest more severe disease and may require discontinuation of treatment, glucocorticoid therapy, and could recur upon repeated administration of the drug [16]. Peripheral neuropathies due to various pathomechanisms are not uncommon in hematologic malignancies [17]. Ibrutinib may ameliorate anti-myelin-associated glycoprotein mediated form but can also provoke it [11,17] by an unknown mechanism. In our case, its simultaneous appearance with skin and kidney symptoms raised the possibility of vasculitis.
The related clinical picture abovemade drug-induced interstitial nephritis higher on the differential over IgA or ANCA induced vasculitis. The rapid loss in GFR prompted us to start glucocorticoid immediately prior to any histological verification along with holding ibrutinib. Renal biopsy confirmed our suspicions. One prior case showed biopsy-proven ibrutinib induced AIN to date; however, in that case, chronic kidney disease and diarrhea were also implicated in the AKI [18].
In the background of drug-induced AIN, a hypersensitive reaction is suggested, primarily characterized by the Th2 cytokine response. Its occurrence is unusual because ibrutinib can prevent cytokine release in CLL patients [6,7], decreases the elevated cytokine, chemokine levels and polarizes T cells in Th1 direction [3]. Macrophage response shifts from M1 toward M2 based on mouse models and human studies, too [4,6]. In our case, we did not examine cytokine levels. Recently serum and urine levels of several cytokines were found to be higher in AIN patients compared to healthy ones, but cytokine levels characteristic of Th2 response did not differ [19]. Because AIN is mostly restricted to the kidneys, testing urine cytokine levels is more relevant. Th2-specific TNF-alpha urinary level was higher in AIN compared to other AKI, but it can be mast cell origin, as indicated by higher IL-9 levels [20]. Mast cells were present in our case biopsy specimen also.
With glucocorticoid treatment, proteinuria, hematuria resolved within 2 weeks, and renal function improved significantly. Glucocorticoid treatment efficacy is contentious in AIN [19], and many consider it only if no improvement in renal function is observed within 3–5 days despite omitting the responsible drug. This wait would certainly have resulted in lower GFR later. In case of malignant diseases, we consider it important to better preserve kidney function also for the prevention of AKI that may be superimposed due to possible subsequent damages.
With this case report, we would like to draw the attention to careful use of ibrutinib, which certainly will be applied more widely. Publication of our case may also contribute to explore the pathomechanism of AIN.
Acknowledgement
The work was supported by the University of Debrecen Kalman Laki Doctoral School of Biomedical and Clinical Sciences.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Abbreviations
AIN acute interstitial nephritis
AKI acute kidney injury
BTK Bruton's tyrosine kinase
CLL chronic lymphocytic leukemia
sCr serum creatinine
GFR glomerular filtration ratio
ANCA anti-neutrophil cytoplasmic antibody | Recovered | ReactionOutcome | CC BY | 33567947 | 18,954,566 | 2021-12 |
What was the outcome of reaction 'Tubulointerstitial nephritis'? | Ibrutinib-induced acute kidney injury via interstitial nephritis.
The introduction of Bruton's tyrosine kinase inhibitor ibrutinib has made a significant progress in the treatment of chronic lymphocytic leukemia and other B-cell malignancies. Due to the reduction of cytokine release, it is effective in chronic graft-versus-host disease, and its use has also been suggested in autoimmune diseases and in prevention of COVID-19-associated lung damage. Despite this effect on the immune response, we report a severe hypersensitivity reaction in a 76-year-old male patient diagnosed with prolymphocytic leukemia. Four weeks after the ibrutinib start, non-oliguric acute kidney injury with proteinuria and microscopic hematuria developed and that was accompanied by lower limb purpuras and paresthesia. Renal biopsy revealed acute interstitial nephritis. Employing 1 mg/kg methylprednisolone administration, serum creatinine decreased from 365 μmol/L to 125 μmol/L at 11 days and the proteinuria-hematuria as well as the purpura, paresthesia resolved. Three months later at stabile eGFR of 56 ml/min/1.73 m2 methylprednisolone was withdrawn and a rituximab-venetoclax treatment was initiated without side effects. We conclude that despite the beneficial effect on cytokines response in Th1 direction, ibrutinib can cause acute interstitial nephritis. Early detection, discontinuation of ibrutinib, glucocorticoid administration may help to better preserve renal function, thereby lowering the risk of potential subsequent kidney injury.
Introduction
The Bruton's tyrosine kinase (BTK) is an essential B-cell antigen receptor signaling molecule for B-cell development and activation pathway, which is involved in the pathogenesis of several B-cell malignancies. Ibrutinib, the first representative of BTK inhibitors, significantly improved the prognosis in high genetic risk chronic lymphocytic leukemia (CLL) resistant to traditional chemoimmunotherapy [1], in mantle cell lymphoma and in Waldenström’s macroglobulinemia as well.
BTK is required for the normal function of immune cells other than B cells, it controls cytokine production, phagocytosis, and the formation of inflammatory mediators. Ibrutinib treatment improves immune dysfunctions associated with CLL, the nonmalignant B-cell immune repertoire remains stable, T-cell and myeloid cell defects are partially restored [2–4]. Irreversible inhibition of the BTK-homologous interleukin-2-inducible T-cell kinase also contributes to this, stimulation of which is involved in selective Th2 cell activation, directing the immune response to healthy tissues. Therefore, ibrutinib also significantly improved the steroid-resistant/dependent chronic graft-versus-host disease [5]. It may be effective in preventing COVID-19-induced lung injury and may even improve the hypoxic, coronavirus-infected individuals’ lung function [6]. Reduction of cytokine release syndrome has also been observed in CLL patients receiving ibrutinib prior to obinutuzumab infusion [7]. Due to additive effects beyond B-cell depletion, BTK inhibition appears promising also in autoimmune diseases [8,9].
The more widespread use of ibrutinib is due to being a well-tolerated, orally applicable drug. Its most common side effects (diarrhea, skin hemorrhages, hypertension, upper respiratory tract infections) are usually mild; rarely, more severe bleeding complications or atrial fibrillation may occur as grade 3/4 side effects. It very rarely causes tumor lysis syndrome [10] or other kidney injuries in itself, not mentioned in the recent summary of adverse reactions [11], nor has been observed in a 6-year follow-up [12]. The acute kidney injury (AKI) cases reported in a previous trial were due to preceding renal diseases and concomitant pre/postrenal reasons [13]. In two renal biopsy cases degenerative tubular damage was assumed as a consequence of long-term ibrutinib administration [14].
In our patient, 4 weeks after ibrutinib start, acute interstitial nephritis (AIN) was recognized during investigations for lower limb purpura and neuropathic pain. The occurrence of a severe hypersensitivity reaction is unexpected given the ‘beneficial’ effect of ibrutinib on cytokines, no similar case was reported.
Case report
A 76-year-old man with a history of depression, hypertension, previous regular smoking (half pack/day for 20 years) and alcohol consumption (5 unit/day for 30 years) presented with AKI. In January 2018, close hematological monitoring was started due to high white blood cell count (42 G/L, predominantly lymphocytes 32 G/L). By peripheral flow cytometry, 77% of the B cells proved to be abnormal, the immunophenotype raised the possibility of prolymphocytic leukemic transformation. In January 2020 white blood cell count increased to 116 G/L, CT scan showed significant splenomegaly, paraaortic lymph node enlargement, with serum creatinine (sCr) of 59 μmol/L at that time. Because of progression of the underlying disease, with prognostic markers including monosomy 13, TP53 (17p13.1) deletion, and borderline mutation status of immunoglobulin heavy chain variable region, ibrutinib was initiated in March 2020 at a daily dose of 420 mg. Previous medications (tianeptine, enalapril, spironolactone, diosmin) were continued except aspirin. Four weeks later, he was referred to the Emergency Department because of lower limb purpuras, burning pain in both feet and soles. A significant sCr increase (296 μmol/L) was discovered. On the following day, despite preserved urinary output, sCr increased to 365 μmol/L, with significant proteinuria (urine protein to creatinin ratio: 70 mg/mmol), and microscopic hematuria. No other abnormalities than moderate serum uric acid (537 μmol/L), and phosphate (1.8 mmol/L) elevations, a slightly decreasing white blood cell count (98 G/L), and anemia (hemoglobin 113 g/L) were detected. Serum potassium, tCO2, calcium, platelet and eosinophil cell counts, liver and muscle enzymes, immunoglobulin and complement levels were normal. Urgent anti-neutrophil cytoplasmic antibody (ANCA) and anti-glomerular basement membrane antibody test results were also negative. Ultrasonography showed normal-sized kidneys, without urine outflow obstruction. Because of rapidly deteriorating renal function, parenteral methylprednisolone was initiated at a dose of 1 mg/kg body weight, and ibrutinib was omitted. Renal biopsy confirmed acute interstitial nephritis, it showed no crescent formation, interstitial B-cell infiltration or other significant abnormalities on day 4 (Figure 1). Immunofluorescence revealed no immunodeposits in the glomeruli, the blood vessels, interstitium, tubules. Focal intense, interstitial infiltration of mixed inflammatory cells with some eosinophil cells and mastocytes were seen. Methylprednisolone treatment was continued, with which the patient’s skin symptoms, lower limb numbness were completely resolved, on day 11 of treatment, sCr was reduced to 125 μmol/L, when no proteinuria/hematuria was detectable. Apixaban was started due to atrial fibrillation occurring at this time and high stroke risk score. Methylprednisolone therapy was gradually tapered off over 3 months, and eGFR stabilized at 56 mL/min/1.73 m2. Due to further increase in white blood cell count (160 G/L), rituximab—venetoclax treatment was initiated in August 2020. Tumor lysis syndrome did not occur with rasburicase and allopurinol prophylaxis.
Figure 1. Kidney biopsy specimen, monoclonal interstitial infiltration cannot be confirmed. (A) CD68-positive macrophages (100×), (B) CD20-positive B cells (100×), (C) CD3-positive T cells (100×), (D) CD117-positive mastocytes in the interstitium (3 cells on the right side of the FOV), (E) HE (40×) focal, mixed inflammatory cell infiltration in the interstitium
Discussion
Significant progress has been made in the treatment of CLL over the past decade. In our patient, genetic tests clearly indicated a poor prognosis, thus according to the recommendations [1], ibrutinib was initiated at disease progression, after which, 4 weeks later, non-oliguric AKI occurred. Both pre/postrenal etiologies and tumor lysis syndrome were ruled out on the basis of the clinical picture, renal ultrasonography and laboratory tests. Proteinuria and microscopic hematuria raised the possibility of both glomerular and tubulointerstitial damage. Because sCr, urine tests were not performed before starting treatment, it could not be ruled out that renal involvement may be a rare consequence of CLL. Leukemic cell infiltration is usually associated with renal enlargement, while paraneoplastic glomerular diseases are often associated with nephrotic syndrome, which were all absent in our case. However, they can only be ruled out by kidney biopsy, which also enables us to distinguish among the various histological forms of involvement. In the Mayo Clinic’s 10 years of practice, renal biopsy was required in 1.2% of CLL patients due to kidney failure or nephrotic syndrome [15].
The coinciding skin symptoms and neuropathy a month after the initiation of ibrutinib made us think of its provocative role in the development of AKI. The discontinuation of a potentially life-saving treatment warranted a kidney biopsy. Ibrutinib inhibits of collage-induced platelet aggregation by inhibiting platelet BTK and it is generally recommended to hold it 3–7 days before and after and invasive interventions [11]. This resulted in waiting until day 4 to perform a renal biopsy to decrease the risk of bleeding from platelet dysfunction.
Thrombocytopathy may have a role in the formation of small, non-palpable petechias usually developing after 2 months of ibrutinib treatment. In our patient, the prompt presence of skin symptoms within one month of therapy was more suggestive of vasculitis. Such early onset of palpable purpuriform lesions may suggest more severe disease and may require discontinuation of treatment, glucocorticoid therapy, and could recur upon repeated administration of the drug [16]. Peripheral neuropathies due to various pathomechanisms are not uncommon in hematologic malignancies [17]. Ibrutinib may ameliorate anti-myelin-associated glycoprotein mediated form but can also provoke it [11,17] by an unknown mechanism. In our case, its simultaneous appearance with skin and kidney symptoms raised the possibility of vasculitis.
The related clinical picture abovemade drug-induced interstitial nephritis higher on the differential over IgA or ANCA induced vasculitis. The rapid loss in GFR prompted us to start glucocorticoid immediately prior to any histological verification along with holding ibrutinib. Renal biopsy confirmed our suspicions. One prior case showed biopsy-proven ibrutinib induced AIN to date; however, in that case, chronic kidney disease and diarrhea were also implicated in the AKI [18].
In the background of drug-induced AIN, a hypersensitive reaction is suggested, primarily characterized by the Th2 cytokine response. Its occurrence is unusual because ibrutinib can prevent cytokine release in CLL patients [6,7], decreases the elevated cytokine, chemokine levels and polarizes T cells in Th1 direction [3]. Macrophage response shifts from M1 toward M2 based on mouse models and human studies, too [4,6]. In our case, we did not examine cytokine levels. Recently serum and urine levels of several cytokines were found to be higher in AIN patients compared to healthy ones, but cytokine levels characteristic of Th2 response did not differ [19]. Because AIN is mostly restricted to the kidneys, testing urine cytokine levels is more relevant. Th2-specific TNF-alpha urinary level was higher in AIN compared to other AKI, but it can be mast cell origin, as indicated by higher IL-9 levels [20]. Mast cells were present in our case biopsy specimen also.
With glucocorticoid treatment, proteinuria, hematuria resolved within 2 weeks, and renal function improved significantly. Glucocorticoid treatment efficacy is contentious in AIN [19], and many consider it only if no improvement in renal function is observed within 3–5 days despite omitting the responsible drug. This wait would certainly have resulted in lower GFR later. In case of malignant diseases, we consider it important to better preserve kidney function also for the prevention of AKI that may be superimposed due to possible subsequent damages.
With this case report, we would like to draw the attention to careful use of ibrutinib, which certainly will be applied more widely. Publication of our case may also contribute to explore the pathomechanism of AIN.
Acknowledgement
The work was supported by the University of Debrecen Kalman Laki Doctoral School of Biomedical and Clinical Sciences.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Abbreviations
AIN acute interstitial nephritis
AKI acute kidney injury
BTK Bruton's tyrosine kinase
CLL chronic lymphocytic leukemia
sCr serum creatinine
GFR glomerular filtration ratio
ANCA anti-neutrophil cytoplasmic antibody | Recovered | ReactionOutcome | CC BY | 33567947 | 18,954,566 | 2021-12 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Bronchitis'. | Rivastigmine improves dual-task gait velocity in patients with Alzheimer's disease.
BACKGROUND
Gait impairments are common in patients with Alzheimer's disease. Cholinesterase inhibitors are used to treat the symptoms of patients with Alzheimer's disease, but they have not been shown to reduce the severity of Alzheimer's disease-related gait disorders.
METHODS
This was a prospective, single-arm, open-label, non-randomized study. The aim of the present study was to determine the effect of the acetylcholinesterase inhibitor rivastigmine on gait in 21 newly diagnosed patients with mild to moderate Alzheimer's disease. The outcome variables were velocity, stride length, and cadence during single-task and dual-task gait trials. The subjects were also assessed with the Mini-Mental State Examination, Alzheimer's Disease Cooperative Study Activities of Daily Living, Functional Assessment Staging, and Geriatric Depression Scale.
RESULTS
After 12 weeks of treatment with rivastigmine, gait velocity was significantly improved in the dual-task gait trials; gait velocity was increased from 40.59 ± 13.59 m/min at baseline to 46.88 ± 12.73 m/min when counting backward from 100 in steps of 7 while walking, and gait velocity was increased from 37.06 ± 15.57 m/min at baseline to 42.03 ± 14.02 m/min when naming animals while walking. In the single-task gait trials, which consisted only of walking at their usual pace or at a fast pace, gait velocity was not increased by rivastigmine administration.
CONCLUSIONS
Our findings indicated that rivastigmine improved gait in subjects with mild to moderate Alzheimer's disease during dual-task trials. The observed enhancement of dual-task gait might be caused by an improvement of cognitive function rather than motor function.
BACKGROUND
UMIN, UMIN000025869. Registered December 16, 2016, https://upload.umin.ac.jp/cgi-open-bin/icdr/ctr_view.cgi?recptno=R000029744.
Background
Alzheimer’s disease (AD) is the most common neurodegenerative disorder and one of the leading causes of death in old age [1]. AD affects a variety of functional areas, including cognitive and motor functions [1]. Recently, the relationship between motor activity and dementia has received increasing research attention [2]. Gait abnormalities are commonly observed in patients with AD and increase in frequency and severity over time [3]. Gait disorders decrease mobility and increase the risk of falling [4]. The consequences of gait disorders and associated falls can be severe, including fractures, worsening of mobility, loss of independence, and increased cardiovascular morbidity and mortality [5]. The presence of gait abnormalities in AD is important for predicting faster cognitive decline, institutionalization, and death [6].
Gait disturbance in patients with AD is particularly evident under dual-task conditions [7, 8], e.g., in simple tasks performed while walking such as counting backward or in more complex tasks such as verbal fluency [2]. As dual-task gait assessments isolate the cognitive cost of maintaining a safe gait while distracted, they have been used to indicate that impairments in cognition lead to deficits in gait control that are independent of the decline in muscle strength and osteoarticular function that accompanies aging [9]. Specifically, higher-level motor control requires cognition to produce the complex motor responses that are adapted to multiple sensory inputs and environmental challenges. Thus, impaired cognitive abilities, especially attention and executive function, compromise postural and gait stability [10]. The dual-task paradigm can be used to study the allocation of attentional resources during a motor task and to separate the cognitive and motor components of executing a movement [2].
Previous studies suggest that cholinesterase inhibitors (ChEIs), a current treatment for the symptoms of AD, may improve gait performance [11–13]. Since, cholinesterase inhibition improves attention and executive function in patients with AD [14], which are both associated with gait quality [15], we hypothesized that the acetylcholinesterase inhibitor (AChEI) rivastigmine would improve gait quality, as quantified by gait velocity, stride length, and cadence, in single- and dual-task gait trials.
Methods
Participant flow
Patient flow in the study is described in Fig. 1.
Fig. 1 CONSORT 2010 Flow Diagram
Participants and procedure
The participants were recruited from December 2016 to June 2018 from the Memory Clinic at Juntendo University Urayasu Hospital. Newly diagnosed older adults with mild to moderate AD who were prescribed a rivastigmine patch were approached for recruitment. The participants were eligible to enter the trial if they met all of the following criteria at baseline: diagnosis of probable AD according to the criteria of the National Institute of Neurologic and Communicative Disorder and Stroke-AD and Related Disorders Association; Mini-Mental State Examination (MMSE) score greater than 14 to be considered mild or moderate AD; had a caregiver who could assist the participant with medication; and had the ability to walk independently, i.e., without a walking aid or without assistance from other people. Participants aged 65 years or older were recruited. Subjects were not included if they had a history of head trauma with loss of consciousness and concomitant medication including benzodiazepines or antipsychotics. We also excluded patients with any neurological disorder with motor residual deficits including parkinsonism, stroke, and polyneuropathy that influenced their ability to carry out a walking task. All participants received magnetic resonance imaging or computed tomography, and an N-isopropyl-p-(123 I)-iodoamphetamine single photon emission computed tomography cerebral blood flow test was performed in all participants. The absence of a large lesion, i.e., infarction, tumor, and inflammation, was confirmed in all participants. We also confirmed the presence of hypoperfusion in the parietal lobe, which is consistent with a diagnosis of AD.
Design
Baseline cognitive and gait assessments were performed on the day before rivastigmine was administered. The participants received 9 mg/day rivastigmine for 4 weeks and 18 mg/day by transdermal patch for the subsequent 8 weeks of follow-up. Gait, cognitive, and psychological functions and AChE activity in plasma were analyzed at baseline, 4 weeks, and 12 weeks.
Cognitive and psychological assessments
We administered the MMSE, Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS-ADL), Functional Assessment Staging (FAST), and Geriatric Depression Scale (GDS) to all participants.
Gait assessment
Quantitative gait variables were assessed using a portable gait rhythmograph (MG-M 1110; LSI Medience Corporation, Tokyo, Japan), which is a small device (8 × 6 × 2 cm; weight, 80 g) with an accelerometer. The portable gait rhythmograph measures the acceleration accompanied by limb and trunk movements and acceleration induced by step-in and kick-off during gait in three dimensions (ax, ay, az). Its accuracy has been verified previously [16].
Gait speed, average step length, acceleration, and cadence, which is the number of steps per minute, were measured in single- and dual-task gait trials. The single-task trials consisted of normal gait at a self-selected usual pace and fast gait. For the dual-task trials, the participants walked while counting backward from 100 in steps of 7 or while naming animals aloud. Ten-meter-walk tests were performed on the level floor of the hospital in the presence of two investigators (SA and HS). The order of gait analysis was normal gait for the first trial, fast gait for the second trial, counting backward by seven for the third trial, and animal naming for the fourth trial. The participants briefly practiced dual-task walking before the first assessment. The participants did not practice dual-task walking during the study period.
Gait analysis
Using the portable gait rhythmograph, gait-induced acceleration was extracted from limb and trunk movements with an automatic gait detection algorithm [16, 17]. The portable gait rhythmograph performs three-dimensional measurements of acceleration associated with voluntary limb and trunk movements, heel strike, and toe-off when walking. Data were collected at a sampling frequency of 100 Hz and stored on a microSD card in the device for subsequent analysis. When recording was complete, the absolute values of the acceleration vectors were calculated and displayed graphically on a PC.
Statistical analysis
A paired Student’s t-test was used to detect group differences before and at 12 weeks after rivastigmine treatment for gait speed, average step length, acceleration, and cadence in single- and dual-task gait trials. Statistical significance was considered for P-values less than 0.05.
Standard protocol approval registration and patient consent
This study was conducted in accordance with the ethical standards set forth in the Declaration of Helsinki (1983). This study was approved by the local ethics committee of Juntendo University Urayasu Hospital. Each participant provided written informed consent. If a participant had impaired decisional capacity, their family provided consent and the participants provided assent.
Results
Subject characteristics and follow-up
Thirty participants with mild to moderate AD were initially enrolled, of which 21 completed the full study and were included in the analyses. The nine subjects who withdrew did so for the following reasons: two did not use rivastigmine properly, two were no longer interested in participating, two suffered a fracture, one did not visit our hospital because their caregiver suffered a fracture, one developed mild pneumonia, and one could not continue using the rivastigmine patch because of dermatitis.
Adverse events
One participant collided with another person while riding a crowded train and fractured his left humerus; he underwent open fusion for the fracture and recovered without sequelae. Another patient suffered a lumbar compression fracture by bumping into another person while walking; she was hospitalized for 1 month and recovered without sequelae. Both of these patients continued to use rivastigmine. One participant was withdrawn due to medication intolerance by dermatitis (as stated in the previous section).
Baseline characteristics and outcomes after intervention
The baseline characteristics of the subjects are presented in Table 1. At baseline, the subjects had a mean single-task gait velocity of 59.21 m/min, which is considered normal gait velocity. Dual-task gait velocity while counting backward by seven was decreased to 40.59 m/min compared to single-task gait, and decreased to 37.06 m/min when naming animals (Table 1).
Table 1 Baseline Characteristics of the Subjects
Age (mean, SD) 79.03 (6.89)
Sex (female; n, %) 13 (61.9%)
Mini-Mental State Examination (mean, SD) 19.62 (4.71)
Geriatric Depression Scale (mean, SD) 2.76 (1.09)
Functional Assessment Staging (mean, SD) 4.24 (0.83)
Alzheimer’s Disease Cooperative Study Activities of Daily Living (mean, SD) 63.14 (8.6)
Single-task gait trials velocity (m/min) stride length (cm) cadence (steps/min)
Normal gait (mean, SD) 59.21 (12.21) 50.11 (7.52) 117.69 (12.26)
Fast gait (mean, SD) 70.33 (16.06) 54.64 (8.58) 127.69 (13.37)
Dual-task gait trials
Counting backward by 7 40.59 (13.59) 46 (9.29) 95.38 (23.88)
Naming animals 37.06 (15.57) 46.25 (9.24) 80.46 (27.15)
SD Standard deviation
Gait assessment
In single-task gait analysis, the gait velocity, stride length, and cadence of the subjects did not significantly change from baseline to after 12 weeks intervention. In dual-task gait analysis, the subjects increased their gait velocity when counting backward by seven from 40.59 ± 13.59 at baseline to 46.88 ± 12.73 m/min at 12 weeks (p = 0.025), and their gait velocity when naming animals increased from 37.06 ± 15.57 at baseline to 42.03 ± 14.02 m/min at 12 weeks (p = 0.036). The subjects also increased their cadence when counting backward by seven from 89.37 ± 24.64 at baseline to 99.35 ± 18.02 at 12 weeks (p = 0.048). Stride length did not significantly change from baseline to after 12 weeks intervention (Table 2).
Table 2 Gait Assessment
Baseline 12 weeks p-value (12 weeks vs. baseline)
Rivastigmine 0 mg 18 mg/day
Single-task gait trials
Normal gait (mean, SD)
velocity (m/min) 59.21 (12.21) 59.82 (11.46) 0.733
stride length (cm) 50.11 (7.52) 51.68 (7.27) 0.111
cadence (steps/min) 117.69 (12.26) 115.55 (13.26) 0.412
Fast gait (mean, SD)
velocity (m/min) 70.33 (16.06) 69.44 (12.62) 0.691
stride length (cm) 54.64 (8.58) 55.5 (7.95) 0.367
cadence (steps/min) 127.69 (13.37) 125.11 (13.17) 0.406
Dual-task gait trials
Counting backward by 7 s
velocity (m/min) 40.59 (13.59) 46.88 (12.73) 0.025*
stride length (cm) 46 (9.29) 46.37 (6.61) 0.716
cadence (steps/min) 89.37 (24.64) 99.35 (18.02) 0.048*
Naming animals
velocity (m/min) 37.06 (15.57) 42.03 (14.02) 0.036*
stride length (cm) 46.25 (9.24) 47.55 (7.46) 0.199
cadence (steps/min) 80.46 (27.15) 88.76 (23.42) 0.076
Paired sample t-test: *p < 0.05
SD Standard deviation
Cognitive and psychological assessments
The subjects showed an improvement in the MMSE score from 19.62 ± 4.71 at baseline to 20.29 ± 4.66 at 12 weeks (p = 0.001). However, there was no significant improvement of the scores for FAST, GDS, and ADCS-ADL (Table 3).
Table 3 Cognitive and Psychological Assessments and Acetylcholinesterase Activity
Baseline 12 weeks p-value (12 weeks vs. baseline)
MMSE 19.62 ± 4.71 20.29 ± 4.66 0.001*
FAST 4.24 ± 0.83 4.14 ± 0.85 0.16
ADCS-ADL 63.14 ± 8.6 63.29 ± 8.17 0.48
GDS 2.76 ± 1.09 2.86 ± 1.11 0.16
AChE activity (IU/L) 276.81 ± 56.28 159.81 ± 60.25 < 0.001*
Paired sample t-test: *p < 0.05
AChE Acetylcholinesterase, ADCS-ADL Alzheimer’s Disease Cooperative Study Activities of Daily Living, FAST Functional Assessment Staging, GDS Geriatric Depression Scale, MMSE Mini-Mental State Examination
AChE activity
AChE activity was significantly decreased from 276.81 ± 56.28 IU/L at baseline to 159.81 ± 60.25 IU/L at 12 weeks (Table 3), indicating that the subjects took rivastigmine as prescribed.
Discussion
The present study showed that rivastigmine improved gait velocity under dual-task conditions in subjects with mild to moderate AD. Conversely, rivastigmine did not improve gait velocity, cadence, and stride length under single-task conditions.
AChEIs stabilize cognitive function and delay functional decrease [18]. Although it is not clear by which mechanism AChEIs have this effect, it is recognized that they improve not only cognitive function but also motor function. Acetylcholine has an important role in cognitive function and in controlling gait and balance [19]. AChEIs are thought to contribute to the initiation and maintenance of gait by improving executive function and attention and the control of step length and gait velocity. A limited number of studies have shown that ChEIs improved gait performance in patients with AD. Donepezil significantly improved gait velocity in subjects with mild AD under single- and dual-task conditions measured using an electronic walkway [20]. Galantamine improved dual-task stride time in a small number of patients with moderate AD [12]. In the present study, rivastigmine significantly improved gait velocity under dual-task conditions in 21 subjects with mild to moderate AD.
Cognitive enhancers could improve gait by a number of mechanisms. Cognitive function and neural control of gait share brain cortical networks and neurotransmitters [2]. The neurotransmitter acetylcholine has an important role in cognitive function and in controlling gait and balance [13]. Specifically, thalamic activity is derived mainly from the brainstem pedunculopontine nucleus, which plays a central role in the generation of movement, gait, and balance control [21]. Cholinergic forebrain projections from the nucleus basalis of Meynert also have a specific role in the control of selective attention, which is an important factor in the cost of dual-tasking while walking in subjects with AD. ChEIs stabilize and improve attention and executive function in patients with AD and other neurodegenerative disorders [22]. There may be cognitive- and non-cognitive-related enhancement mechanisms by which ChEIs improve gait and potentially improve gait performance.
In our study, rivastigmine increased gait velocity in the dual-task trials, but not in the single-task trials. The principle dual-task paradigm involving gait is the creation of an attention-demanding task [23]. A decline in gait performance while performing a dual task when compared to a single task is usually interpreted as interference due to competing demands for attention between both tasks [23]. Thus, gait performance while dual tasking appears to be more dependent on cortical cholinergic levels than while performing a single task [24], suggesting that cognitive enhancement may have affected the increase of gait velocity in our subjects rather than non-cognitive enhancement. The increase in gait velocity during the dual task was mainly due to an increase in cadence, but not stride length, in our study. We speculate that motor function may be more involved in stride length than cognitive function as compared with cadence. Although both the animal naming test and the counting backward by seven test are associated with prefrontal and anterior cortex regions, there was a significant improvement in cadence when counting backward rather than when naming animals. The participants were faster and more accurate when counting backward than when naming animals. Baseline cadence data were better when the participants counted backward than when naming animals, which may be related to the fact that cadence was significantly improved when the participants counted backward. Cadence did improve slightly during the animal naming test, but not significantly so. The reason for this discrepancy between the two dual tasks should be examined in future studies.
Rivastigmine also significantly improved the MMSE score, but this improvement was negligible. Rivastigmine did not significantly improve the scores for FAST, GDS, and ADCS-ADL. The AChE activity of all subjects was decreased. These results indicate that rivastigmine did not greatly improve the cognitive function of the participants in this study.
Some limitations of this study need to be considered. Firstly, we used a single-arm open-label design with no randomization and no placebo group. Future studies will be needed with a placebo group. Second, there is a possibility of a learning effect due to the repetition of the dual tasks and MMSE, which may have affected the results of these tests. Third, the small number of participants from one clinic may be unrepresentative of the general population of patients with AD. Fourth, although we were able to control for changes of gait and treatment, residual confounders (e.g., physical condition or motivation) might still be present.
Two participants suffered a fracture during the study period. The contribution of rivastigmine to fracture cannot be ruled out completely, but we believe that any direct effect is small as both fractures occurred by accidental collision.
Conclusions
In conclusion, we found a rivastigmine-related increase in gait velocity of patients with AD in dual-task trials. This improvement may contribute to gait function in patients with AD. This study had a single arm design with a small number of participants and the statistical strength of the study was not strong. Double blind randomized placebo-controlled parallel trial testing is necessary to confirm the effectiveness of rivastigmine on gait disorders in patients with AD in the future.
Abbreviations
AChEIAcetylcholinesterase inhibitor
ADAlzheimer’s disease
ADCS-ADLAlzheimer’s Disease Cooperative Study Activities of Daily Living
FASTFunctional Assessment Staging
GDSGeriatric Depression Scale
MMSEMini-Mental State Examination
Publisher’s Note
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Acknowledgements
We are grateful to the participants and their families for their cooperation.
Authors’ contributions
HS, SA, and AH participated in designing the study and writing and reviewing the manuscript. NH and TU participated in reviewing the manuscript. All authors read and approved the final manuscript.
Funding
The study was financially supported by the Ono Pharmaceutical company. The sponsors had no role in the design and conduct of the study, in the collection, management, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
This study was approved by the local ethics committee of Juntendo University Urayasu Hospital. Each participant provided written informed consent. The study was prospectively registered with UMIN, UMIN000025869. Registered December 16, 2016, https://upload.umin.ac.jp/cgi-open-bin/icdr/ctr_view.cgi?recptno=R000029744.
Consent for publication
Not applicable.
Competing interests
All authors declare that they have no competing interests. | RIVASTIGMINE | DrugsGivenReaction | CC BY | 33568083 | 15,730,979 | 2021-02-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Fall'. | Rivastigmine improves dual-task gait velocity in patients with Alzheimer's disease.
BACKGROUND
Gait impairments are common in patients with Alzheimer's disease. Cholinesterase inhibitors are used to treat the symptoms of patients with Alzheimer's disease, but they have not been shown to reduce the severity of Alzheimer's disease-related gait disorders.
METHODS
This was a prospective, single-arm, open-label, non-randomized study. The aim of the present study was to determine the effect of the acetylcholinesterase inhibitor rivastigmine on gait in 21 newly diagnosed patients with mild to moderate Alzheimer's disease. The outcome variables were velocity, stride length, and cadence during single-task and dual-task gait trials. The subjects were also assessed with the Mini-Mental State Examination, Alzheimer's Disease Cooperative Study Activities of Daily Living, Functional Assessment Staging, and Geriatric Depression Scale.
RESULTS
After 12 weeks of treatment with rivastigmine, gait velocity was significantly improved in the dual-task gait trials; gait velocity was increased from 40.59 ± 13.59 m/min at baseline to 46.88 ± 12.73 m/min when counting backward from 100 in steps of 7 while walking, and gait velocity was increased from 37.06 ± 15.57 m/min at baseline to 42.03 ± 14.02 m/min when naming animals while walking. In the single-task gait trials, which consisted only of walking at their usual pace or at a fast pace, gait velocity was not increased by rivastigmine administration.
CONCLUSIONS
Our findings indicated that rivastigmine improved gait in subjects with mild to moderate Alzheimer's disease during dual-task trials. The observed enhancement of dual-task gait might be caused by an improvement of cognitive function rather than motor function.
BACKGROUND
UMIN, UMIN000025869. Registered December 16, 2016, https://upload.umin.ac.jp/cgi-open-bin/icdr/ctr_view.cgi?recptno=R000029744.
Background
Alzheimer’s disease (AD) is the most common neurodegenerative disorder and one of the leading causes of death in old age [1]. AD affects a variety of functional areas, including cognitive and motor functions [1]. Recently, the relationship between motor activity and dementia has received increasing research attention [2]. Gait abnormalities are commonly observed in patients with AD and increase in frequency and severity over time [3]. Gait disorders decrease mobility and increase the risk of falling [4]. The consequences of gait disorders and associated falls can be severe, including fractures, worsening of mobility, loss of independence, and increased cardiovascular morbidity and mortality [5]. The presence of gait abnormalities in AD is important for predicting faster cognitive decline, institutionalization, and death [6].
Gait disturbance in patients with AD is particularly evident under dual-task conditions [7, 8], e.g., in simple tasks performed while walking such as counting backward or in more complex tasks such as verbal fluency [2]. As dual-task gait assessments isolate the cognitive cost of maintaining a safe gait while distracted, they have been used to indicate that impairments in cognition lead to deficits in gait control that are independent of the decline in muscle strength and osteoarticular function that accompanies aging [9]. Specifically, higher-level motor control requires cognition to produce the complex motor responses that are adapted to multiple sensory inputs and environmental challenges. Thus, impaired cognitive abilities, especially attention and executive function, compromise postural and gait stability [10]. The dual-task paradigm can be used to study the allocation of attentional resources during a motor task and to separate the cognitive and motor components of executing a movement [2].
Previous studies suggest that cholinesterase inhibitors (ChEIs), a current treatment for the symptoms of AD, may improve gait performance [11–13]. Since, cholinesterase inhibition improves attention and executive function in patients with AD [14], which are both associated with gait quality [15], we hypothesized that the acetylcholinesterase inhibitor (AChEI) rivastigmine would improve gait quality, as quantified by gait velocity, stride length, and cadence, in single- and dual-task gait trials.
Methods
Participant flow
Patient flow in the study is described in Fig. 1.
Fig. 1 CONSORT 2010 Flow Diagram
Participants and procedure
The participants were recruited from December 2016 to June 2018 from the Memory Clinic at Juntendo University Urayasu Hospital. Newly diagnosed older adults with mild to moderate AD who were prescribed a rivastigmine patch were approached for recruitment. The participants were eligible to enter the trial if they met all of the following criteria at baseline: diagnosis of probable AD according to the criteria of the National Institute of Neurologic and Communicative Disorder and Stroke-AD and Related Disorders Association; Mini-Mental State Examination (MMSE) score greater than 14 to be considered mild or moderate AD; had a caregiver who could assist the participant with medication; and had the ability to walk independently, i.e., without a walking aid or without assistance from other people. Participants aged 65 years or older were recruited. Subjects were not included if they had a history of head trauma with loss of consciousness and concomitant medication including benzodiazepines or antipsychotics. We also excluded patients with any neurological disorder with motor residual deficits including parkinsonism, stroke, and polyneuropathy that influenced their ability to carry out a walking task. All participants received magnetic resonance imaging or computed tomography, and an N-isopropyl-p-(123 I)-iodoamphetamine single photon emission computed tomography cerebral blood flow test was performed in all participants. The absence of a large lesion, i.e., infarction, tumor, and inflammation, was confirmed in all participants. We also confirmed the presence of hypoperfusion in the parietal lobe, which is consistent with a diagnosis of AD.
Design
Baseline cognitive and gait assessments were performed on the day before rivastigmine was administered. The participants received 9 mg/day rivastigmine for 4 weeks and 18 mg/day by transdermal patch for the subsequent 8 weeks of follow-up. Gait, cognitive, and psychological functions and AChE activity in plasma were analyzed at baseline, 4 weeks, and 12 weeks.
Cognitive and psychological assessments
We administered the MMSE, Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS-ADL), Functional Assessment Staging (FAST), and Geriatric Depression Scale (GDS) to all participants.
Gait assessment
Quantitative gait variables were assessed using a portable gait rhythmograph (MG-M 1110; LSI Medience Corporation, Tokyo, Japan), which is a small device (8 × 6 × 2 cm; weight, 80 g) with an accelerometer. The portable gait rhythmograph measures the acceleration accompanied by limb and trunk movements and acceleration induced by step-in and kick-off during gait in three dimensions (ax, ay, az). Its accuracy has been verified previously [16].
Gait speed, average step length, acceleration, and cadence, which is the number of steps per minute, were measured in single- and dual-task gait trials. The single-task trials consisted of normal gait at a self-selected usual pace and fast gait. For the dual-task trials, the participants walked while counting backward from 100 in steps of 7 or while naming animals aloud. Ten-meter-walk tests were performed on the level floor of the hospital in the presence of two investigators (SA and HS). The order of gait analysis was normal gait for the first trial, fast gait for the second trial, counting backward by seven for the third trial, and animal naming for the fourth trial. The participants briefly practiced dual-task walking before the first assessment. The participants did not practice dual-task walking during the study period.
Gait analysis
Using the portable gait rhythmograph, gait-induced acceleration was extracted from limb and trunk movements with an automatic gait detection algorithm [16, 17]. The portable gait rhythmograph performs three-dimensional measurements of acceleration associated with voluntary limb and trunk movements, heel strike, and toe-off when walking. Data were collected at a sampling frequency of 100 Hz and stored on a microSD card in the device for subsequent analysis. When recording was complete, the absolute values of the acceleration vectors were calculated and displayed graphically on a PC.
Statistical analysis
A paired Student’s t-test was used to detect group differences before and at 12 weeks after rivastigmine treatment for gait speed, average step length, acceleration, and cadence in single- and dual-task gait trials. Statistical significance was considered for P-values less than 0.05.
Standard protocol approval registration and patient consent
This study was conducted in accordance with the ethical standards set forth in the Declaration of Helsinki (1983). This study was approved by the local ethics committee of Juntendo University Urayasu Hospital. Each participant provided written informed consent. If a participant had impaired decisional capacity, their family provided consent and the participants provided assent.
Results
Subject characteristics and follow-up
Thirty participants with mild to moderate AD were initially enrolled, of which 21 completed the full study and were included in the analyses. The nine subjects who withdrew did so for the following reasons: two did not use rivastigmine properly, two were no longer interested in participating, two suffered a fracture, one did not visit our hospital because their caregiver suffered a fracture, one developed mild pneumonia, and one could not continue using the rivastigmine patch because of dermatitis.
Adverse events
One participant collided with another person while riding a crowded train and fractured his left humerus; he underwent open fusion for the fracture and recovered without sequelae. Another patient suffered a lumbar compression fracture by bumping into another person while walking; she was hospitalized for 1 month and recovered without sequelae. Both of these patients continued to use rivastigmine. One participant was withdrawn due to medication intolerance by dermatitis (as stated in the previous section).
Baseline characteristics and outcomes after intervention
The baseline characteristics of the subjects are presented in Table 1. At baseline, the subjects had a mean single-task gait velocity of 59.21 m/min, which is considered normal gait velocity. Dual-task gait velocity while counting backward by seven was decreased to 40.59 m/min compared to single-task gait, and decreased to 37.06 m/min when naming animals (Table 1).
Table 1 Baseline Characteristics of the Subjects
Age (mean, SD) 79.03 (6.89)
Sex (female; n, %) 13 (61.9%)
Mini-Mental State Examination (mean, SD) 19.62 (4.71)
Geriatric Depression Scale (mean, SD) 2.76 (1.09)
Functional Assessment Staging (mean, SD) 4.24 (0.83)
Alzheimer’s Disease Cooperative Study Activities of Daily Living (mean, SD) 63.14 (8.6)
Single-task gait trials velocity (m/min) stride length (cm) cadence (steps/min)
Normal gait (mean, SD) 59.21 (12.21) 50.11 (7.52) 117.69 (12.26)
Fast gait (mean, SD) 70.33 (16.06) 54.64 (8.58) 127.69 (13.37)
Dual-task gait trials
Counting backward by 7 40.59 (13.59) 46 (9.29) 95.38 (23.88)
Naming animals 37.06 (15.57) 46.25 (9.24) 80.46 (27.15)
SD Standard deviation
Gait assessment
In single-task gait analysis, the gait velocity, stride length, and cadence of the subjects did not significantly change from baseline to after 12 weeks intervention. In dual-task gait analysis, the subjects increased their gait velocity when counting backward by seven from 40.59 ± 13.59 at baseline to 46.88 ± 12.73 m/min at 12 weeks (p = 0.025), and their gait velocity when naming animals increased from 37.06 ± 15.57 at baseline to 42.03 ± 14.02 m/min at 12 weeks (p = 0.036). The subjects also increased their cadence when counting backward by seven from 89.37 ± 24.64 at baseline to 99.35 ± 18.02 at 12 weeks (p = 0.048). Stride length did not significantly change from baseline to after 12 weeks intervention (Table 2).
Table 2 Gait Assessment
Baseline 12 weeks p-value (12 weeks vs. baseline)
Rivastigmine 0 mg 18 mg/day
Single-task gait trials
Normal gait (mean, SD)
velocity (m/min) 59.21 (12.21) 59.82 (11.46) 0.733
stride length (cm) 50.11 (7.52) 51.68 (7.27) 0.111
cadence (steps/min) 117.69 (12.26) 115.55 (13.26) 0.412
Fast gait (mean, SD)
velocity (m/min) 70.33 (16.06) 69.44 (12.62) 0.691
stride length (cm) 54.64 (8.58) 55.5 (7.95) 0.367
cadence (steps/min) 127.69 (13.37) 125.11 (13.17) 0.406
Dual-task gait trials
Counting backward by 7 s
velocity (m/min) 40.59 (13.59) 46.88 (12.73) 0.025*
stride length (cm) 46 (9.29) 46.37 (6.61) 0.716
cadence (steps/min) 89.37 (24.64) 99.35 (18.02) 0.048*
Naming animals
velocity (m/min) 37.06 (15.57) 42.03 (14.02) 0.036*
stride length (cm) 46.25 (9.24) 47.55 (7.46) 0.199
cadence (steps/min) 80.46 (27.15) 88.76 (23.42) 0.076
Paired sample t-test: *p < 0.05
SD Standard deviation
Cognitive and psychological assessments
The subjects showed an improvement in the MMSE score from 19.62 ± 4.71 at baseline to 20.29 ± 4.66 at 12 weeks (p = 0.001). However, there was no significant improvement of the scores for FAST, GDS, and ADCS-ADL (Table 3).
Table 3 Cognitive and Psychological Assessments and Acetylcholinesterase Activity
Baseline 12 weeks p-value (12 weeks vs. baseline)
MMSE 19.62 ± 4.71 20.29 ± 4.66 0.001*
FAST 4.24 ± 0.83 4.14 ± 0.85 0.16
ADCS-ADL 63.14 ± 8.6 63.29 ± 8.17 0.48
GDS 2.76 ± 1.09 2.86 ± 1.11 0.16
AChE activity (IU/L) 276.81 ± 56.28 159.81 ± 60.25 < 0.001*
Paired sample t-test: *p < 0.05
AChE Acetylcholinesterase, ADCS-ADL Alzheimer’s Disease Cooperative Study Activities of Daily Living, FAST Functional Assessment Staging, GDS Geriatric Depression Scale, MMSE Mini-Mental State Examination
AChE activity
AChE activity was significantly decreased from 276.81 ± 56.28 IU/L at baseline to 159.81 ± 60.25 IU/L at 12 weeks (Table 3), indicating that the subjects took rivastigmine as prescribed.
Discussion
The present study showed that rivastigmine improved gait velocity under dual-task conditions in subjects with mild to moderate AD. Conversely, rivastigmine did not improve gait velocity, cadence, and stride length under single-task conditions.
AChEIs stabilize cognitive function and delay functional decrease [18]. Although it is not clear by which mechanism AChEIs have this effect, it is recognized that they improve not only cognitive function but also motor function. Acetylcholine has an important role in cognitive function and in controlling gait and balance [19]. AChEIs are thought to contribute to the initiation and maintenance of gait by improving executive function and attention and the control of step length and gait velocity. A limited number of studies have shown that ChEIs improved gait performance in patients with AD. Donepezil significantly improved gait velocity in subjects with mild AD under single- and dual-task conditions measured using an electronic walkway [20]. Galantamine improved dual-task stride time in a small number of patients with moderate AD [12]. In the present study, rivastigmine significantly improved gait velocity under dual-task conditions in 21 subjects with mild to moderate AD.
Cognitive enhancers could improve gait by a number of mechanisms. Cognitive function and neural control of gait share brain cortical networks and neurotransmitters [2]. The neurotransmitter acetylcholine has an important role in cognitive function and in controlling gait and balance [13]. Specifically, thalamic activity is derived mainly from the brainstem pedunculopontine nucleus, which plays a central role in the generation of movement, gait, and balance control [21]. Cholinergic forebrain projections from the nucleus basalis of Meynert also have a specific role in the control of selective attention, which is an important factor in the cost of dual-tasking while walking in subjects with AD. ChEIs stabilize and improve attention and executive function in patients with AD and other neurodegenerative disorders [22]. There may be cognitive- and non-cognitive-related enhancement mechanisms by which ChEIs improve gait and potentially improve gait performance.
In our study, rivastigmine increased gait velocity in the dual-task trials, but not in the single-task trials. The principle dual-task paradigm involving gait is the creation of an attention-demanding task [23]. A decline in gait performance while performing a dual task when compared to a single task is usually interpreted as interference due to competing demands for attention between both tasks [23]. Thus, gait performance while dual tasking appears to be more dependent on cortical cholinergic levels than while performing a single task [24], suggesting that cognitive enhancement may have affected the increase of gait velocity in our subjects rather than non-cognitive enhancement. The increase in gait velocity during the dual task was mainly due to an increase in cadence, but not stride length, in our study. We speculate that motor function may be more involved in stride length than cognitive function as compared with cadence. Although both the animal naming test and the counting backward by seven test are associated with prefrontal and anterior cortex regions, there was a significant improvement in cadence when counting backward rather than when naming animals. The participants were faster and more accurate when counting backward than when naming animals. Baseline cadence data were better when the participants counted backward than when naming animals, which may be related to the fact that cadence was significantly improved when the participants counted backward. Cadence did improve slightly during the animal naming test, but not significantly so. The reason for this discrepancy between the two dual tasks should be examined in future studies.
Rivastigmine also significantly improved the MMSE score, but this improvement was negligible. Rivastigmine did not significantly improve the scores for FAST, GDS, and ADCS-ADL. The AChE activity of all subjects was decreased. These results indicate that rivastigmine did not greatly improve the cognitive function of the participants in this study.
Some limitations of this study need to be considered. Firstly, we used a single-arm open-label design with no randomization and no placebo group. Future studies will be needed with a placebo group. Second, there is a possibility of a learning effect due to the repetition of the dual tasks and MMSE, which may have affected the results of these tests. Third, the small number of participants from one clinic may be unrepresentative of the general population of patients with AD. Fourth, although we were able to control for changes of gait and treatment, residual confounders (e.g., physical condition or motivation) might still be present.
Two participants suffered a fracture during the study period. The contribution of rivastigmine to fracture cannot be ruled out completely, but we believe that any direct effect is small as both fractures occurred by accidental collision.
Conclusions
In conclusion, we found a rivastigmine-related increase in gait velocity of patients with AD in dual-task trials. This improvement may contribute to gait function in patients with AD. This study had a single arm design with a small number of participants and the statistical strength of the study was not strong. Double blind randomized placebo-controlled parallel trial testing is necessary to confirm the effectiveness of rivastigmine on gait disorders in patients with AD in the future.
Abbreviations
AChEIAcetylcholinesterase inhibitor
ADAlzheimer’s disease
ADCS-ADLAlzheimer’s Disease Cooperative Study Activities of Daily Living
FASTFunctional Assessment Staging
GDSGeriatric Depression Scale
MMSEMini-Mental State Examination
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We are grateful to the participants and their families for their cooperation.
Authors’ contributions
HS, SA, and AH participated in designing the study and writing and reviewing the manuscript. NH and TU participated in reviewing the manuscript. All authors read and approved the final manuscript.
Funding
The study was financially supported by the Ono Pharmaceutical company. The sponsors had no role in the design and conduct of the study, in the collection, management, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
This study was approved by the local ethics committee of Juntendo University Urayasu Hospital. Each participant provided written informed consent. The study was prospectively registered with UMIN, UMIN000025869. Registered December 16, 2016, https://upload.umin.ac.jp/cgi-open-bin/icdr/ctr_view.cgi?recptno=R000029744.
Consent for publication
Not applicable.
Competing interests
All authors declare that they have no competing interests. | RIVASTIGMINE | DrugsGivenReaction | CC BY | 33568083 | 17,267,567 | 2021-02-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Humerus fracture'. | Rivastigmine improves dual-task gait velocity in patients with Alzheimer's disease.
BACKGROUND
Gait impairments are common in patients with Alzheimer's disease. Cholinesterase inhibitors are used to treat the symptoms of patients with Alzheimer's disease, but they have not been shown to reduce the severity of Alzheimer's disease-related gait disorders.
METHODS
This was a prospective, single-arm, open-label, non-randomized study. The aim of the present study was to determine the effect of the acetylcholinesterase inhibitor rivastigmine on gait in 21 newly diagnosed patients with mild to moderate Alzheimer's disease. The outcome variables were velocity, stride length, and cadence during single-task and dual-task gait trials. The subjects were also assessed with the Mini-Mental State Examination, Alzheimer's Disease Cooperative Study Activities of Daily Living, Functional Assessment Staging, and Geriatric Depression Scale.
RESULTS
After 12 weeks of treatment with rivastigmine, gait velocity was significantly improved in the dual-task gait trials; gait velocity was increased from 40.59 ± 13.59 m/min at baseline to 46.88 ± 12.73 m/min when counting backward from 100 in steps of 7 while walking, and gait velocity was increased from 37.06 ± 15.57 m/min at baseline to 42.03 ± 14.02 m/min when naming animals while walking. In the single-task gait trials, which consisted only of walking at their usual pace or at a fast pace, gait velocity was not increased by rivastigmine administration.
CONCLUSIONS
Our findings indicated that rivastigmine improved gait in subjects with mild to moderate Alzheimer's disease during dual-task trials. The observed enhancement of dual-task gait might be caused by an improvement of cognitive function rather than motor function.
BACKGROUND
UMIN, UMIN000025869. Registered December 16, 2016, https://upload.umin.ac.jp/cgi-open-bin/icdr/ctr_view.cgi?recptno=R000029744.
Background
Alzheimer’s disease (AD) is the most common neurodegenerative disorder and one of the leading causes of death in old age [1]. AD affects a variety of functional areas, including cognitive and motor functions [1]. Recently, the relationship between motor activity and dementia has received increasing research attention [2]. Gait abnormalities are commonly observed in patients with AD and increase in frequency and severity over time [3]. Gait disorders decrease mobility and increase the risk of falling [4]. The consequences of gait disorders and associated falls can be severe, including fractures, worsening of mobility, loss of independence, and increased cardiovascular morbidity and mortality [5]. The presence of gait abnormalities in AD is important for predicting faster cognitive decline, institutionalization, and death [6].
Gait disturbance in patients with AD is particularly evident under dual-task conditions [7, 8], e.g., in simple tasks performed while walking such as counting backward or in more complex tasks such as verbal fluency [2]. As dual-task gait assessments isolate the cognitive cost of maintaining a safe gait while distracted, they have been used to indicate that impairments in cognition lead to deficits in gait control that are independent of the decline in muscle strength and osteoarticular function that accompanies aging [9]. Specifically, higher-level motor control requires cognition to produce the complex motor responses that are adapted to multiple sensory inputs and environmental challenges. Thus, impaired cognitive abilities, especially attention and executive function, compromise postural and gait stability [10]. The dual-task paradigm can be used to study the allocation of attentional resources during a motor task and to separate the cognitive and motor components of executing a movement [2].
Previous studies suggest that cholinesterase inhibitors (ChEIs), a current treatment for the symptoms of AD, may improve gait performance [11–13]. Since, cholinesterase inhibition improves attention and executive function in patients with AD [14], which are both associated with gait quality [15], we hypothesized that the acetylcholinesterase inhibitor (AChEI) rivastigmine would improve gait quality, as quantified by gait velocity, stride length, and cadence, in single- and dual-task gait trials.
Methods
Participant flow
Patient flow in the study is described in Fig. 1.
Fig. 1 CONSORT 2010 Flow Diagram
Participants and procedure
The participants were recruited from December 2016 to June 2018 from the Memory Clinic at Juntendo University Urayasu Hospital. Newly diagnosed older adults with mild to moderate AD who were prescribed a rivastigmine patch were approached for recruitment. The participants were eligible to enter the trial if they met all of the following criteria at baseline: diagnosis of probable AD according to the criteria of the National Institute of Neurologic and Communicative Disorder and Stroke-AD and Related Disorders Association; Mini-Mental State Examination (MMSE) score greater than 14 to be considered mild or moderate AD; had a caregiver who could assist the participant with medication; and had the ability to walk independently, i.e., without a walking aid or without assistance from other people. Participants aged 65 years or older were recruited. Subjects were not included if they had a history of head trauma with loss of consciousness and concomitant medication including benzodiazepines or antipsychotics. We also excluded patients with any neurological disorder with motor residual deficits including parkinsonism, stroke, and polyneuropathy that influenced their ability to carry out a walking task. All participants received magnetic resonance imaging or computed tomography, and an N-isopropyl-p-(123 I)-iodoamphetamine single photon emission computed tomography cerebral blood flow test was performed in all participants. The absence of a large lesion, i.e., infarction, tumor, and inflammation, was confirmed in all participants. We also confirmed the presence of hypoperfusion in the parietal lobe, which is consistent with a diagnosis of AD.
Design
Baseline cognitive and gait assessments were performed on the day before rivastigmine was administered. The participants received 9 mg/day rivastigmine for 4 weeks and 18 mg/day by transdermal patch for the subsequent 8 weeks of follow-up. Gait, cognitive, and psychological functions and AChE activity in plasma were analyzed at baseline, 4 weeks, and 12 weeks.
Cognitive and psychological assessments
We administered the MMSE, Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS-ADL), Functional Assessment Staging (FAST), and Geriatric Depression Scale (GDS) to all participants.
Gait assessment
Quantitative gait variables were assessed using a portable gait rhythmograph (MG-M 1110; LSI Medience Corporation, Tokyo, Japan), which is a small device (8 × 6 × 2 cm; weight, 80 g) with an accelerometer. The portable gait rhythmograph measures the acceleration accompanied by limb and trunk movements and acceleration induced by step-in and kick-off during gait in three dimensions (ax, ay, az). Its accuracy has been verified previously [16].
Gait speed, average step length, acceleration, and cadence, which is the number of steps per minute, were measured in single- and dual-task gait trials. The single-task trials consisted of normal gait at a self-selected usual pace and fast gait. For the dual-task trials, the participants walked while counting backward from 100 in steps of 7 or while naming animals aloud. Ten-meter-walk tests were performed on the level floor of the hospital in the presence of two investigators (SA and HS). The order of gait analysis was normal gait for the first trial, fast gait for the second trial, counting backward by seven for the third trial, and animal naming for the fourth trial. The participants briefly practiced dual-task walking before the first assessment. The participants did not practice dual-task walking during the study period.
Gait analysis
Using the portable gait rhythmograph, gait-induced acceleration was extracted from limb and trunk movements with an automatic gait detection algorithm [16, 17]. The portable gait rhythmograph performs three-dimensional measurements of acceleration associated with voluntary limb and trunk movements, heel strike, and toe-off when walking. Data were collected at a sampling frequency of 100 Hz and stored on a microSD card in the device for subsequent analysis. When recording was complete, the absolute values of the acceleration vectors were calculated and displayed graphically on a PC.
Statistical analysis
A paired Student’s t-test was used to detect group differences before and at 12 weeks after rivastigmine treatment for gait speed, average step length, acceleration, and cadence in single- and dual-task gait trials. Statistical significance was considered for P-values less than 0.05.
Standard protocol approval registration and patient consent
This study was conducted in accordance with the ethical standards set forth in the Declaration of Helsinki (1983). This study was approved by the local ethics committee of Juntendo University Urayasu Hospital. Each participant provided written informed consent. If a participant had impaired decisional capacity, their family provided consent and the participants provided assent.
Results
Subject characteristics and follow-up
Thirty participants with mild to moderate AD were initially enrolled, of which 21 completed the full study and were included in the analyses. The nine subjects who withdrew did so for the following reasons: two did not use rivastigmine properly, two were no longer interested in participating, two suffered a fracture, one did not visit our hospital because their caregiver suffered a fracture, one developed mild pneumonia, and one could not continue using the rivastigmine patch because of dermatitis.
Adverse events
One participant collided with another person while riding a crowded train and fractured his left humerus; he underwent open fusion for the fracture and recovered without sequelae. Another patient suffered a lumbar compression fracture by bumping into another person while walking; she was hospitalized for 1 month and recovered without sequelae. Both of these patients continued to use rivastigmine. One participant was withdrawn due to medication intolerance by dermatitis (as stated in the previous section).
Baseline characteristics and outcomes after intervention
The baseline characteristics of the subjects are presented in Table 1. At baseline, the subjects had a mean single-task gait velocity of 59.21 m/min, which is considered normal gait velocity. Dual-task gait velocity while counting backward by seven was decreased to 40.59 m/min compared to single-task gait, and decreased to 37.06 m/min when naming animals (Table 1).
Table 1 Baseline Characteristics of the Subjects
Age (mean, SD) 79.03 (6.89)
Sex (female; n, %) 13 (61.9%)
Mini-Mental State Examination (mean, SD) 19.62 (4.71)
Geriatric Depression Scale (mean, SD) 2.76 (1.09)
Functional Assessment Staging (mean, SD) 4.24 (0.83)
Alzheimer’s Disease Cooperative Study Activities of Daily Living (mean, SD) 63.14 (8.6)
Single-task gait trials velocity (m/min) stride length (cm) cadence (steps/min)
Normal gait (mean, SD) 59.21 (12.21) 50.11 (7.52) 117.69 (12.26)
Fast gait (mean, SD) 70.33 (16.06) 54.64 (8.58) 127.69 (13.37)
Dual-task gait trials
Counting backward by 7 40.59 (13.59) 46 (9.29) 95.38 (23.88)
Naming animals 37.06 (15.57) 46.25 (9.24) 80.46 (27.15)
SD Standard deviation
Gait assessment
In single-task gait analysis, the gait velocity, stride length, and cadence of the subjects did not significantly change from baseline to after 12 weeks intervention. In dual-task gait analysis, the subjects increased their gait velocity when counting backward by seven from 40.59 ± 13.59 at baseline to 46.88 ± 12.73 m/min at 12 weeks (p = 0.025), and their gait velocity when naming animals increased from 37.06 ± 15.57 at baseline to 42.03 ± 14.02 m/min at 12 weeks (p = 0.036). The subjects also increased their cadence when counting backward by seven from 89.37 ± 24.64 at baseline to 99.35 ± 18.02 at 12 weeks (p = 0.048). Stride length did not significantly change from baseline to after 12 weeks intervention (Table 2).
Table 2 Gait Assessment
Baseline 12 weeks p-value (12 weeks vs. baseline)
Rivastigmine 0 mg 18 mg/day
Single-task gait trials
Normal gait (mean, SD)
velocity (m/min) 59.21 (12.21) 59.82 (11.46) 0.733
stride length (cm) 50.11 (7.52) 51.68 (7.27) 0.111
cadence (steps/min) 117.69 (12.26) 115.55 (13.26) 0.412
Fast gait (mean, SD)
velocity (m/min) 70.33 (16.06) 69.44 (12.62) 0.691
stride length (cm) 54.64 (8.58) 55.5 (7.95) 0.367
cadence (steps/min) 127.69 (13.37) 125.11 (13.17) 0.406
Dual-task gait trials
Counting backward by 7 s
velocity (m/min) 40.59 (13.59) 46.88 (12.73) 0.025*
stride length (cm) 46 (9.29) 46.37 (6.61) 0.716
cadence (steps/min) 89.37 (24.64) 99.35 (18.02) 0.048*
Naming animals
velocity (m/min) 37.06 (15.57) 42.03 (14.02) 0.036*
stride length (cm) 46.25 (9.24) 47.55 (7.46) 0.199
cadence (steps/min) 80.46 (27.15) 88.76 (23.42) 0.076
Paired sample t-test: *p < 0.05
SD Standard deviation
Cognitive and psychological assessments
The subjects showed an improvement in the MMSE score from 19.62 ± 4.71 at baseline to 20.29 ± 4.66 at 12 weeks (p = 0.001). However, there was no significant improvement of the scores for FAST, GDS, and ADCS-ADL (Table 3).
Table 3 Cognitive and Psychological Assessments and Acetylcholinesterase Activity
Baseline 12 weeks p-value (12 weeks vs. baseline)
MMSE 19.62 ± 4.71 20.29 ± 4.66 0.001*
FAST 4.24 ± 0.83 4.14 ± 0.85 0.16
ADCS-ADL 63.14 ± 8.6 63.29 ± 8.17 0.48
GDS 2.76 ± 1.09 2.86 ± 1.11 0.16
AChE activity (IU/L) 276.81 ± 56.28 159.81 ± 60.25 < 0.001*
Paired sample t-test: *p < 0.05
AChE Acetylcholinesterase, ADCS-ADL Alzheimer’s Disease Cooperative Study Activities of Daily Living, FAST Functional Assessment Staging, GDS Geriatric Depression Scale, MMSE Mini-Mental State Examination
AChE activity
AChE activity was significantly decreased from 276.81 ± 56.28 IU/L at baseline to 159.81 ± 60.25 IU/L at 12 weeks (Table 3), indicating that the subjects took rivastigmine as prescribed.
Discussion
The present study showed that rivastigmine improved gait velocity under dual-task conditions in subjects with mild to moderate AD. Conversely, rivastigmine did not improve gait velocity, cadence, and stride length under single-task conditions.
AChEIs stabilize cognitive function and delay functional decrease [18]. Although it is not clear by which mechanism AChEIs have this effect, it is recognized that they improve not only cognitive function but also motor function. Acetylcholine has an important role in cognitive function and in controlling gait and balance [19]. AChEIs are thought to contribute to the initiation and maintenance of gait by improving executive function and attention and the control of step length and gait velocity. A limited number of studies have shown that ChEIs improved gait performance in patients with AD. Donepezil significantly improved gait velocity in subjects with mild AD under single- and dual-task conditions measured using an electronic walkway [20]. Galantamine improved dual-task stride time in a small number of patients with moderate AD [12]. In the present study, rivastigmine significantly improved gait velocity under dual-task conditions in 21 subjects with mild to moderate AD.
Cognitive enhancers could improve gait by a number of mechanisms. Cognitive function and neural control of gait share brain cortical networks and neurotransmitters [2]. The neurotransmitter acetylcholine has an important role in cognitive function and in controlling gait and balance [13]. Specifically, thalamic activity is derived mainly from the brainstem pedunculopontine nucleus, which plays a central role in the generation of movement, gait, and balance control [21]. Cholinergic forebrain projections from the nucleus basalis of Meynert also have a specific role in the control of selective attention, which is an important factor in the cost of dual-tasking while walking in subjects with AD. ChEIs stabilize and improve attention and executive function in patients with AD and other neurodegenerative disorders [22]. There may be cognitive- and non-cognitive-related enhancement mechanisms by which ChEIs improve gait and potentially improve gait performance.
In our study, rivastigmine increased gait velocity in the dual-task trials, but not in the single-task trials. The principle dual-task paradigm involving gait is the creation of an attention-demanding task [23]. A decline in gait performance while performing a dual task when compared to a single task is usually interpreted as interference due to competing demands for attention between both tasks [23]. Thus, gait performance while dual tasking appears to be more dependent on cortical cholinergic levels than while performing a single task [24], suggesting that cognitive enhancement may have affected the increase of gait velocity in our subjects rather than non-cognitive enhancement. The increase in gait velocity during the dual task was mainly due to an increase in cadence, but not stride length, in our study. We speculate that motor function may be more involved in stride length than cognitive function as compared with cadence. Although both the animal naming test and the counting backward by seven test are associated with prefrontal and anterior cortex regions, there was a significant improvement in cadence when counting backward rather than when naming animals. The participants were faster and more accurate when counting backward than when naming animals. Baseline cadence data were better when the participants counted backward than when naming animals, which may be related to the fact that cadence was significantly improved when the participants counted backward. Cadence did improve slightly during the animal naming test, but not significantly so. The reason for this discrepancy between the two dual tasks should be examined in future studies.
Rivastigmine also significantly improved the MMSE score, but this improvement was negligible. Rivastigmine did not significantly improve the scores for FAST, GDS, and ADCS-ADL. The AChE activity of all subjects was decreased. These results indicate that rivastigmine did not greatly improve the cognitive function of the participants in this study.
Some limitations of this study need to be considered. Firstly, we used a single-arm open-label design with no randomization and no placebo group. Future studies will be needed with a placebo group. Second, there is a possibility of a learning effect due to the repetition of the dual tasks and MMSE, which may have affected the results of these tests. Third, the small number of participants from one clinic may be unrepresentative of the general population of patients with AD. Fourth, although we were able to control for changes of gait and treatment, residual confounders (e.g., physical condition or motivation) might still be present.
Two participants suffered a fracture during the study period. The contribution of rivastigmine to fracture cannot be ruled out completely, but we believe that any direct effect is small as both fractures occurred by accidental collision.
Conclusions
In conclusion, we found a rivastigmine-related increase in gait velocity of patients with AD in dual-task trials. This improvement may contribute to gait function in patients with AD. This study had a single arm design with a small number of participants and the statistical strength of the study was not strong. Double blind randomized placebo-controlled parallel trial testing is necessary to confirm the effectiveness of rivastigmine on gait disorders in patients with AD in the future.
Abbreviations
AChEIAcetylcholinesterase inhibitor
ADAlzheimer’s disease
ADCS-ADLAlzheimer’s Disease Cooperative Study Activities of Daily Living
FASTFunctional Assessment Staging
GDSGeriatric Depression Scale
MMSEMini-Mental State Examination
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We are grateful to the participants and their families for their cooperation.
Authors’ contributions
HS, SA, and AH participated in designing the study and writing and reviewing the manuscript. NH and TU participated in reviewing the manuscript. All authors read and approved the final manuscript.
Funding
The study was financially supported by the Ono Pharmaceutical company. The sponsors had no role in the design and conduct of the study, in the collection, management, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
This study was approved by the local ethics committee of Juntendo University Urayasu Hospital. Each participant provided written informed consent. The study was prospectively registered with UMIN, UMIN000025869. Registered December 16, 2016, https://upload.umin.ac.jp/cgi-open-bin/icdr/ctr_view.cgi?recptno=R000029744.
Consent for publication
Not applicable.
Competing interests
All authors declare that they have no competing interests. | RIVASTIGMINE | DrugsGivenReaction | CC BY | 33568083 | 17,267,567 | 2021-02-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Interstitial lung disease'. | Rivastigmine improves dual-task gait velocity in patients with Alzheimer's disease.
BACKGROUND
Gait impairments are common in patients with Alzheimer's disease. Cholinesterase inhibitors are used to treat the symptoms of patients with Alzheimer's disease, but they have not been shown to reduce the severity of Alzheimer's disease-related gait disorders.
METHODS
This was a prospective, single-arm, open-label, non-randomized study. The aim of the present study was to determine the effect of the acetylcholinesterase inhibitor rivastigmine on gait in 21 newly diagnosed patients with mild to moderate Alzheimer's disease. The outcome variables were velocity, stride length, and cadence during single-task and dual-task gait trials. The subjects were also assessed with the Mini-Mental State Examination, Alzheimer's Disease Cooperative Study Activities of Daily Living, Functional Assessment Staging, and Geriatric Depression Scale.
RESULTS
After 12 weeks of treatment with rivastigmine, gait velocity was significantly improved in the dual-task gait trials; gait velocity was increased from 40.59 ± 13.59 m/min at baseline to 46.88 ± 12.73 m/min when counting backward from 100 in steps of 7 while walking, and gait velocity was increased from 37.06 ± 15.57 m/min at baseline to 42.03 ± 14.02 m/min when naming animals while walking. In the single-task gait trials, which consisted only of walking at their usual pace or at a fast pace, gait velocity was not increased by rivastigmine administration.
CONCLUSIONS
Our findings indicated that rivastigmine improved gait in subjects with mild to moderate Alzheimer's disease during dual-task trials. The observed enhancement of dual-task gait might be caused by an improvement of cognitive function rather than motor function.
BACKGROUND
UMIN, UMIN000025869. Registered December 16, 2016, https://upload.umin.ac.jp/cgi-open-bin/icdr/ctr_view.cgi?recptno=R000029744.
Background
Alzheimer’s disease (AD) is the most common neurodegenerative disorder and one of the leading causes of death in old age [1]. AD affects a variety of functional areas, including cognitive and motor functions [1]. Recently, the relationship between motor activity and dementia has received increasing research attention [2]. Gait abnormalities are commonly observed in patients with AD and increase in frequency and severity over time [3]. Gait disorders decrease mobility and increase the risk of falling [4]. The consequences of gait disorders and associated falls can be severe, including fractures, worsening of mobility, loss of independence, and increased cardiovascular morbidity and mortality [5]. The presence of gait abnormalities in AD is important for predicting faster cognitive decline, institutionalization, and death [6].
Gait disturbance in patients with AD is particularly evident under dual-task conditions [7, 8], e.g., in simple tasks performed while walking such as counting backward or in more complex tasks such as verbal fluency [2]. As dual-task gait assessments isolate the cognitive cost of maintaining a safe gait while distracted, they have been used to indicate that impairments in cognition lead to deficits in gait control that are independent of the decline in muscle strength and osteoarticular function that accompanies aging [9]. Specifically, higher-level motor control requires cognition to produce the complex motor responses that are adapted to multiple sensory inputs and environmental challenges. Thus, impaired cognitive abilities, especially attention and executive function, compromise postural and gait stability [10]. The dual-task paradigm can be used to study the allocation of attentional resources during a motor task and to separate the cognitive and motor components of executing a movement [2].
Previous studies suggest that cholinesterase inhibitors (ChEIs), a current treatment for the symptoms of AD, may improve gait performance [11–13]. Since, cholinesterase inhibition improves attention and executive function in patients with AD [14], which are both associated with gait quality [15], we hypothesized that the acetylcholinesterase inhibitor (AChEI) rivastigmine would improve gait quality, as quantified by gait velocity, stride length, and cadence, in single- and dual-task gait trials.
Methods
Participant flow
Patient flow in the study is described in Fig. 1.
Fig. 1 CONSORT 2010 Flow Diagram
Participants and procedure
The participants were recruited from December 2016 to June 2018 from the Memory Clinic at Juntendo University Urayasu Hospital. Newly diagnosed older adults with mild to moderate AD who were prescribed a rivastigmine patch were approached for recruitment. The participants were eligible to enter the trial if they met all of the following criteria at baseline: diagnosis of probable AD according to the criteria of the National Institute of Neurologic and Communicative Disorder and Stroke-AD and Related Disorders Association; Mini-Mental State Examination (MMSE) score greater than 14 to be considered mild or moderate AD; had a caregiver who could assist the participant with medication; and had the ability to walk independently, i.e., without a walking aid or without assistance from other people. Participants aged 65 years or older were recruited. Subjects were not included if they had a history of head trauma with loss of consciousness and concomitant medication including benzodiazepines or antipsychotics. We also excluded patients with any neurological disorder with motor residual deficits including parkinsonism, stroke, and polyneuropathy that influenced their ability to carry out a walking task. All participants received magnetic resonance imaging or computed tomography, and an N-isopropyl-p-(123 I)-iodoamphetamine single photon emission computed tomography cerebral blood flow test was performed in all participants. The absence of a large lesion, i.e., infarction, tumor, and inflammation, was confirmed in all participants. We also confirmed the presence of hypoperfusion in the parietal lobe, which is consistent with a diagnosis of AD.
Design
Baseline cognitive and gait assessments were performed on the day before rivastigmine was administered. The participants received 9 mg/day rivastigmine for 4 weeks and 18 mg/day by transdermal patch for the subsequent 8 weeks of follow-up. Gait, cognitive, and psychological functions and AChE activity in plasma were analyzed at baseline, 4 weeks, and 12 weeks.
Cognitive and psychological assessments
We administered the MMSE, Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS-ADL), Functional Assessment Staging (FAST), and Geriatric Depression Scale (GDS) to all participants.
Gait assessment
Quantitative gait variables were assessed using a portable gait rhythmograph (MG-M 1110; LSI Medience Corporation, Tokyo, Japan), which is a small device (8 × 6 × 2 cm; weight, 80 g) with an accelerometer. The portable gait rhythmograph measures the acceleration accompanied by limb and trunk movements and acceleration induced by step-in and kick-off during gait in three dimensions (ax, ay, az). Its accuracy has been verified previously [16].
Gait speed, average step length, acceleration, and cadence, which is the number of steps per minute, were measured in single- and dual-task gait trials. The single-task trials consisted of normal gait at a self-selected usual pace and fast gait. For the dual-task trials, the participants walked while counting backward from 100 in steps of 7 or while naming animals aloud. Ten-meter-walk tests were performed on the level floor of the hospital in the presence of two investigators (SA and HS). The order of gait analysis was normal gait for the first trial, fast gait for the second trial, counting backward by seven for the third trial, and animal naming for the fourth trial. The participants briefly practiced dual-task walking before the first assessment. The participants did not practice dual-task walking during the study period.
Gait analysis
Using the portable gait rhythmograph, gait-induced acceleration was extracted from limb and trunk movements with an automatic gait detection algorithm [16, 17]. The portable gait rhythmograph performs three-dimensional measurements of acceleration associated with voluntary limb and trunk movements, heel strike, and toe-off when walking. Data were collected at a sampling frequency of 100 Hz and stored on a microSD card in the device for subsequent analysis. When recording was complete, the absolute values of the acceleration vectors were calculated and displayed graphically on a PC.
Statistical analysis
A paired Student’s t-test was used to detect group differences before and at 12 weeks after rivastigmine treatment for gait speed, average step length, acceleration, and cadence in single- and dual-task gait trials. Statistical significance was considered for P-values less than 0.05.
Standard protocol approval registration and patient consent
This study was conducted in accordance with the ethical standards set forth in the Declaration of Helsinki (1983). This study was approved by the local ethics committee of Juntendo University Urayasu Hospital. Each participant provided written informed consent. If a participant had impaired decisional capacity, their family provided consent and the participants provided assent.
Results
Subject characteristics and follow-up
Thirty participants with mild to moderate AD were initially enrolled, of which 21 completed the full study and were included in the analyses. The nine subjects who withdrew did so for the following reasons: two did not use rivastigmine properly, two were no longer interested in participating, two suffered a fracture, one did not visit our hospital because their caregiver suffered a fracture, one developed mild pneumonia, and one could not continue using the rivastigmine patch because of dermatitis.
Adverse events
One participant collided with another person while riding a crowded train and fractured his left humerus; he underwent open fusion for the fracture and recovered without sequelae. Another patient suffered a lumbar compression fracture by bumping into another person while walking; she was hospitalized for 1 month and recovered without sequelae. Both of these patients continued to use rivastigmine. One participant was withdrawn due to medication intolerance by dermatitis (as stated in the previous section).
Baseline characteristics and outcomes after intervention
The baseline characteristics of the subjects are presented in Table 1. At baseline, the subjects had a mean single-task gait velocity of 59.21 m/min, which is considered normal gait velocity. Dual-task gait velocity while counting backward by seven was decreased to 40.59 m/min compared to single-task gait, and decreased to 37.06 m/min when naming animals (Table 1).
Table 1 Baseline Characteristics of the Subjects
Age (mean, SD) 79.03 (6.89)
Sex (female; n, %) 13 (61.9%)
Mini-Mental State Examination (mean, SD) 19.62 (4.71)
Geriatric Depression Scale (mean, SD) 2.76 (1.09)
Functional Assessment Staging (mean, SD) 4.24 (0.83)
Alzheimer’s Disease Cooperative Study Activities of Daily Living (mean, SD) 63.14 (8.6)
Single-task gait trials velocity (m/min) stride length (cm) cadence (steps/min)
Normal gait (mean, SD) 59.21 (12.21) 50.11 (7.52) 117.69 (12.26)
Fast gait (mean, SD) 70.33 (16.06) 54.64 (8.58) 127.69 (13.37)
Dual-task gait trials
Counting backward by 7 40.59 (13.59) 46 (9.29) 95.38 (23.88)
Naming animals 37.06 (15.57) 46.25 (9.24) 80.46 (27.15)
SD Standard deviation
Gait assessment
In single-task gait analysis, the gait velocity, stride length, and cadence of the subjects did not significantly change from baseline to after 12 weeks intervention. In dual-task gait analysis, the subjects increased their gait velocity when counting backward by seven from 40.59 ± 13.59 at baseline to 46.88 ± 12.73 m/min at 12 weeks (p = 0.025), and their gait velocity when naming animals increased from 37.06 ± 15.57 at baseline to 42.03 ± 14.02 m/min at 12 weeks (p = 0.036). The subjects also increased their cadence when counting backward by seven from 89.37 ± 24.64 at baseline to 99.35 ± 18.02 at 12 weeks (p = 0.048). Stride length did not significantly change from baseline to after 12 weeks intervention (Table 2).
Table 2 Gait Assessment
Baseline 12 weeks p-value (12 weeks vs. baseline)
Rivastigmine 0 mg 18 mg/day
Single-task gait trials
Normal gait (mean, SD)
velocity (m/min) 59.21 (12.21) 59.82 (11.46) 0.733
stride length (cm) 50.11 (7.52) 51.68 (7.27) 0.111
cadence (steps/min) 117.69 (12.26) 115.55 (13.26) 0.412
Fast gait (mean, SD)
velocity (m/min) 70.33 (16.06) 69.44 (12.62) 0.691
stride length (cm) 54.64 (8.58) 55.5 (7.95) 0.367
cadence (steps/min) 127.69 (13.37) 125.11 (13.17) 0.406
Dual-task gait trials
Counting backward by 7 s
velocity (m/min) 40.59 (13.59) 46.88 (12.73) 0.025*
stride length (cm) 46 (9.29) 46.37 (6.61) 0.716
cadence (steps/min) 89.37 (24.64) 99.35 (18.02) 0.048*
Naming animals
velocity (m/min) 37.06 (15.57) 42.03 (14.02) 0.036*
stride length (cm) 46.25 (9.24) 47.55 (7.46) 0.199
cadence (steps/min) 80.46 (27.15) 88.76 (23.42) 0.076
Paired sample t-test: *p < 0.05
SD Standard deviation
Cognitive and psychological assessments
The subjects showed an improvement in the MMSE score from 19.62 ± 4.71 at baseline to 20.29 ± 4.66 at 12 weeks (p = 0.001). However, there was no significant improvement of the scores for FAST, GDS, and ADCS-ADL (Table 3).
Table 3 Cognitive and Psychological Assessments and Acetylcholinesterase Activity
Baseline 12 weeks p-value (12 weeks vs. baseline)
MMSE 19.62 ± 4.71 20.29 ± 4.66 0.001*
FAST 4.24 ± 0.83 4.14 ± 0.85 0.16
ADCS-ADL 63.14 ± 8.6 63.29 ± 8.17 0.48
GDS 2.76 ± 1.09 2.86 ± 1.11 0.16
AChE activity (IU/L) 276.81 ± 56.28 159.81 ± 60.25 < 0.001*
Paired sample t-test: *p < 0.05
AChE Acetylcholinesterase, ADCS-ADL Alzheimer’s Disease Cooperative Study Activities of Daily Living, FAST Functional Assessment Staging, GDS Geriatric Depression Scale, MMSE Mini-Mental State Examination
AChE activity
AChE activity was significantly decreased from 276.81 ± 56.28 IU/L at baseline to 159.81 ± 60.25 IU/L at 12 weeks (Table 3), indicating that the subjects took rivastigmine as prescribed.
Discussion
The present study showed that rivastigmine improved gait velocity under dual-task conditions in subjects with mild to moderate AD. Conversely, rivastigmine did not improve gait velocity, cadence, and stride length under single-task conditions.
AChEIs stabilize cognitive function and delay functional decrease [18]. Although it is not clear by which mechanism AChEIs have this effect, it is recognized that they improve not only cognitive function but also motor function. Acetylcholine has an important role in cognitive function and in controlling gait and balance [19]. AChEIs are thought to contribute to the initiation and maintenance of gait by improving executive function and attention and the control of step length and gait velocity. A limited number of studies have shown that ChEIs improved gait performance in patients with AD. Donepezil significantly improved gait velocity in subjects with mild AD under single- and dual-task conditions measured using an electronic walkway [20]. Galantamine improved dual-task stride time in a small number of patients with moderate AD [12]. In the present study, rivastigmine significantly improved gait velocity under dual-task conditions in 21 subjects with mild to moderate AD.
Cognitive enhancers could improve gait by a number of mechanisms. Cognitive function and neural control of gait share brain cortical networks and neurotransmitters [2]. The neurotransmitter acetylcholine has an important role in cognitive function and in controlling gait and balance [13]. Specifically, thalamic activity is derived mainly from the brainstem pedunculopontine nucleus, which plays a central role in the generation of movement, gait, and balance control [21]. Cholinergic forebrain projections from the nucleus basalis of Meynert also have a specific role in the control of selective attention, which is an important factor in the cost of dual-tasking while walking in subjects with AD. ChEIs stabilize and improve attention and executive function in patients with AD and other neurodegenerative disorders [22]. There may be cognitive- and non-cognitive-related enhancement mechanisms by which ChEIs improve gait and potentially improve gait performance.
In our study, rivastigmine increased gait velocity in the dual-task trials, but not in the single-task trials. The principle dual-task paradigm involving gait is the creation of an attention-demanding task [23]. A decline in gait performance while performing a dual task when compared to a single task is usually interpreted as interference due to competing demands for attention between both tasks [23]. Thus, gait performance while dual tasking appears to be more dependent on cortical cholinergic levels than while performing a single task [24], suggesting that cognitive enhancement may have affected the increase of gait velocity in our subjects rather than non-cognitive enhancement. The increase in gait velocity during the dual task was mainly due to an increase in cadence, but not stride length, in our study. We speculate that motor function may be more involved in stride length than cognitive function as compared with cadence. Although both the animal naming test and the counting backward by seven test are associated with prefrontal and anterior cortex regions, there was a significant improvement in cadence when counting backward rather than when naming animals. The participants were faster and more accurate when counting backward than when naming animals. Baseline cadence data were better when the participants counted backward than when naming animals, which may be related to the fact that cadence was significantly improved when the participants counted backward. Cadence did improve slightly during the animal naming test, but not significantly so. The reason for this discrepancy between the two dual tasks should be examined in future studies.
Rivastigmine also significantly improved the MMSE score, but this improvement was negligible. Rivastigmine did not significantly improve the scores for FAST, GDS, and ADCS-ADL. The AChE activity of all subjects was decreased. These results indicate that rivastigmine did not greatly improve the cognitive function of the participants in this study.
Some limitations of this study need to be considered. Firstly, we used a single-arm open-label design with no randomization and no placebo group. Future studies will be needed with a placebo group. Second, there is a possibility of a learning effect due to the repetition of the dual tasks and MMSE, which may have affected the results of these tests. Third, the small number of participants from one clinic may be unrepresentative of the general population of patients with AD. Fourth, although we were able to control for changes of gait and treatment, residual confounders (e.g., physical condition or motivation) might still be present.
Two participants suffered a fracture during the study period. The contribution of rivastigmine to fracture cannot be ruled out completely, but we believe that any direct effect is small as both fractures occurred by accidental collision.
Conclusions
In conclusion, we found a rivastigmine-related increase in gait velocity of patients with AD in dual-task trials. This improvement may contribute to gait function in patients with AD. This study had a single arm design with a small number of participants and the statistical strength of the study was not strong. Double blind randomized placebo-controlled parallel trial testing is necessary to confirm the effectiveness of rivastigmine on gait disorders in patients with AD in the future.
Abbreviations
AChEIAcetylcholinesterase inhibitor
ADAlzheimer’s disease
ADCS-ADLAlzheimer’s Disease Cooperative Study Activities of Daily Living
FASTFunctional Assessment Staging
GDSGeriatric Depression Scale
MMSEMini-Mental State Examination
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We are grateful to the participants and their families for their cooperation.
Authors’ contributions
HS, SA, and AH participated in designing the study and writing and reviewing the manuscript. NH and TU participated in reviewing the manuscript. All authors read and approved the final manuscript.
Funding
The study was financially supported by the Ono Pharmaceutical company. The sponsors had no role in the design and conduct of the study, in the collection, management, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
This study was approved by the local ethics committee of Juntendo University Urayasu Hospital. Each participant provided written informed consent. The study was prospectively registered with UMIN, UMIN000025869. Registered December 16, 2016, https://upload.umin.ac.jp/cgi-open-bin/icdr/ctr_view.cgi?recptno=R000029744.
Consent for publication
Not applicable.
Competing interests
All authors declare that they have no competing interests. | RIVASTIGMINE | DrugsGivenReaction | CC BY | 33568083 | 15,730,979 | 2021-02-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pulmonary fibrosis'. | Rivastigmine improves dual-task gait velocity in patients with Alzheimer's disease.
BACKGROUND
Gait impairments are common in patients with Alzheimer's disease. Cholinesterase inhibitors are used to treat the symptoms of patients with Alzheimer's disease, but they have not been shown to reduce the severity of Alzheimer's disease-related gait disorders.
METHODS
This was a prospective, single-arm, open-label, non-randomized study. The aim of the present study was to determine the effect of the acetylcholinesterase inhibitor rivastigmine on gait in 21 newly diagnosed patients with mild to moderate Alzheimer's disease. The outcome variables were velocity, stride length, and cadence during single-task and dual-task gait trials. The subjects were also assessed with the Mini-Mental State Examination, Alzheimer's Disease Cooperative Study Activities of Daily Living, Functional Assessment Staging, and Geriatric Depression Scale.
RESULTS
After 12 weeks of treatment with rivastigmine, gait velocity was significantly improved in the dual-task gait trials; gait velocity was increased from 40.59 ± 13.59 m/min at baseline to 46.88 ± 12.73 m/min when counting backward from 100 in steps of 7 while walking, and gait velocity was increased from 37.06 ± 15.57 m/min at baseline to 42.03 ± 14.02 m/min when naming animals while walking. In the single-task gait trials, which consisted only of walking at their usual pace or at a fast pace, gait velocity was not increased by rivastigmine administration.
CONCLUSIONS
Our findings indicated that rivastigmine improved gait in subjects with mild to moderate Alzheimer's disease during dual-task trials. The observed enhancement of dual-task gait might be caused by an improvement of cognitive function rather than motor function.
BACKGROUND
UMIN, UMIN000025869. Registered December 16, 2016, https://upload.umin.ac.jp/cgi-open-bin/icdr/ctr_view.cgi?recptno=R000029744.
Background
Alzheimer’s disease (AD) is the most common neurodegenerative disorder and one of the leading causes of death in old age [1]. AD affects a variety of functional areas, including cognitive and motor functions [1]. Recently, the relationship between motor activity and dementia has received increasing research attention [2]. Gait abnormalities are commonly observed in patients with AD and increase in frequency and severity over time [3]. Gait disorders decrease mobility and increase the risk of falling [4]. The consequences of gait disorders and associated falls can be severe, including fractures, worsening of mobility, loss of independence, and increased cardiovascular morbidity and mortality [5]. The presence of gait abnormalities in AD is important for predicting faster cognitive decline, institutionalization, and death [6].
Gait disturbance in patients with AD is particularly evident under dual-task conditions [7, 8], e.g., in simple tasks performed while walking such as counting backward or in more complex tasks such as verbal fluency [2]. As dual-task gait assessments isolate the cognitive cost of maintaining a safe gait while distracted, they have been used to indicate that impairments in cognition lead to deficits in gait control that are independent of the decline in muscle strength and osteoarticular function that accompanies aging [9]. Specifically, higher-level motor control requires cognition to produce the complex motor responses that are adapted to multiple sensory inputs and environmental challenges. Thus, impaired cognitive abilities, especially attention and executive function, compromise postural and gait stability [10]. The dual-task paradigm can be used to study the allocation of attentional resources during a motor task and to separate the cognitive and motor components of executing a movement [2].
Previous studies suggest that cholinesterase inhibitors (ChEIs), a current treatment for the symptoms of AD, may improve gait performance [11–13]. Since, cholinesterase inhibition improves attention and executive function in patients with AD [14], which are both associated with gait quality [15], we hypothesized that the acetylcholinesterase inhibitor (AChEI) rivastigmine would improve gait quality, as quantified by gait velocity, stride length, and cadence, in single- and dual-task gait trials.
Methods
Participant flow
Patient flow in the study is described in Fig. 1.
Fig. 1 CONSORT 2010 Flow Diagram
Participants and procedure
The participants were recruited from December 2016 to June 2018 from the Memory Clinic at Juntendo University Urayasu Hospital. Newly diagnosed older adults with mild to moderate AD who were prescribed a rivastigmine patch were approached for recruitment. The participants were eligible to enter the trial if they met all of the following criteria at baseline: diagnosis of probable AD according to the criteria of the National Institute of Neurologic and Communicative Disorder and Stroke-AD and Related Disorders Association; Mini-Mental State Examination (MMSE) score greater than 14 to be considered mild or moderate AD; had a caregiver who could assist the participant with medication; and had the ability to walk independently, i.e., without a walking aid or without assistance from other people. Participants aged 65 years or older were recruited. Subjects were not included if they had a history of head trauma with loss of consciousness and concomitant medication including benzodiazepines or antipsychotics. We also excluded patients with any neurological disorder with motor residual deficits including parkinsonism, stroke, and polyneuropathy that influenced their ability to carry out a walking task. All participants received magnetic resonance imaging or computed tomography, and an N-isopropyl-p-(123 I)-iodoamphetamine single photon emission computed tomography cerebral blood flow test was performed in all participants. The absence of a large lesion, i.e., infarction, tumor, and inflammation, was confirmed in all participants. We also confirmed the presence of hypoperfusion in the parietal lobe, which is consistent with a diagnosis of AD.
Design
Baseline cognitive and gait assessments were performed on the day before rivastigmine was administered. The participants received 9 mg/day rivastigmine for 4 weeks and 18 mg/day by transdermal patch for the subsequent 8 weeks of follow-up. Gait, cognitive, and psychological functions and AChE activity in plasma were analyzed at baseline, 4 weeks, and 12 weeks.
Cognitive and psychological assessments
We administered the MMSE, Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS-ADL), Functional Assessment Staging (FAST), and Geriatric Depression Scale (GDS) to all participants.
Gait assessment
Quantitative gait variables were assessed using a portable gait rhythmograph (MG-M 1110; LSI Medience Corporation, Tokyo, Japan), which is a small device (8 × 6 × 2 cm; weight, 80 g) with an accelerometer. The portable gait rhythmograph measures the acceleration accompanied by limb and trunk movements and acceleration induced by step-in and kick-off during gait in three dimensions (ax, ay, az). Its accuracy has been verified previously [16].
Gait speed, average step length, acceleration, and cadence, which is the number of steps per minute, were measured in single- and dual-task gait trials. The single-task trials consisted of normal gait at a self-selected usual pace and fast gait. For the dual-task trials, the participants walked while counting backward from 100 in steps of 7 or while naming animals aloud. Ten-meter-walk tests were performed on the level floor of the hospital in the presence of two investigators (SA and HS). The order of gait analysis was normal gait for the first trial, fast gait for the second trial, counting backward by seven for the third trial, and animal naming for the fourth trial. The participants briefly practiced dual-task walking before the first assessment. The participants did not practice dual-task walking during the study period.
Gait analysis
Using the portable gait rhythmograph, gait-induced acceleration was extracted from limb and trunk movements with an automatic gait detection algorithm [16, 17]. The portable gait rhythmograph performs three-dimensional measurements of acceleration associated with voluntary limb and trunk movements, heel strike, and toe-off when walking. Data were collected at a sampling frequency of 100 Hz and stored on a microSD card in the device for subsequent analysis. When recording was complete, the absolute values of the acceleration vectors were calculated and displayed graphically on a PC.
Statistical analysis
A paired Student’s t-test was used to detect group differences before and at 12 weeks after rivastigmine treatment for gait speed, average step length, acceleration, and cadence in single- and dual-task gait trials. Statistical significance was considered for P-values less than 0.05.
Standard protocol approval registration and patient consent
This study was conducted in accordance with the ethical standards set forth in the Declaration of Helsinki (1983). This study was approved by the local ethics committee of Juntendo University Urayasu Hospital. Each participant provided written informed consent. If a participant had impaired decisional capacity, their family provided consent and the participants provided assent.
Results
Subject characteristics and follow-up
Thirty participants with mild to moderate AD were initially enrolled, of which 21 completed the full study and were included in the analyses. The nine subjects who withdrew did so for the following reasons: two did not use rivastigmine properly, two were no longer interested in participating, two suffered a fracture, one did not visit our hospital because their caregiver suffered a fracture, one developed mild pneumonia, and one could not continue using the rivastigmine patch because of dermatitis.
Adverse events
One participant collided with another person while riding a crowded train and fractured his left humerus; he underwent open fusion for the fracture and recovered without sequelae. Another patient suffered a lumbar compression fracture by bumping into another person while walking; she was hospitalized for 1 month and recovered without sequelae. Both of these patients continued to use rivastigmine. One participant was withdrawn due to medication intolerance by dermatitis (as stated in the previous section).
Baseline characteristics and outcomes after intervention
The baseline characteristics of the subjects are presented in Table 1. At baseline, the subjects had a mean single-task gait velocity of 59.21 m/min, which is considered normal gait velocity. Dual-task gait velocity while counting backward by seven was decreased to 40.59 m/min compared to single-task gait, and decreased to 37.06 m/min when naming animals (Table 1).
Table 1 Baseline Characteristics of the Subjects
Age (mean, SD) 79.03 (6.89)
Sex (female; n, %) 13 (61.9%)
Mini-Mental State Examination (mean, SD) 19.62 (4.71)
Geriatric Depression Scale (mean, SD) 2.76 (1.09)
Functional Assessment Staging (mean, SD) 4.24 (0.83)
Alzheimer’s Disease Cooperative Study Activities of Daily Living (mean, SD) 63.14 (8.6)
Single-task gait trials velocity (m/min) stride length (cm) cadence (steps/min)
Normal gait (mean, SD) 59.21 (12.21) 50.11 (7.52) 117.69 (12.26)
Fast gait (mean, SD) 70.33 (16.06) 54.64 (8.58) 127.69 (13.37)
Dual-task gait trials
Counting backward by 7 40.59 (13.59) 46 (9.29) 95.38 (23.88)
Naming animals 37.06 (15.57) 46.25 (9.24) 80.46 (27.15)
SD Standard deviation
Gait assessment
In single-task gait analysis, the gait velocity, stride length, and cadence of the subjects did not significantly change from baseline to after 12 weeks intervention. In dual-task gait analysis, the subjects increased their gait velocity when counting backward by seven from 40.59 ± 13.59 at baseline to 46.88 ± 12.73 m/min at 12 weeks (p = 0.025), and their gait velocity when naming animals increased from 37.06 ± 15.57 at baseline to 42.03 ± 14.02 m/min at 12 weeks (p = 0.036). The subjects also increased their cadence when counting backward by seven from 89.37 ± 24.64 at baseline to 99.35 ± 18.02 at 12 weeks (p = 0.048). Stride length did not significantly change from baseline to after 12 weeks intervention (Table 2).
Table 2 Gait Assessment
Baseline 12 weeks p-value (12 weeks vs. baseline)
Rivastigmine 0 mg 18 mg/day
Single-task gait trials
Normal gait (mean, SD)
velocity (m/min) 59.21 (12.21) 59.82 (11.46) 0.733
stride length (cm) 50.11 (7.52) 51.68 (7.27) 0.111
cadence (steps/min) 117.69 (12.26) 115.55 (13.26) 0.412
Fast gait (mean, SD)
velocity (m/min) 70.33 (16.06) 69.44 (12.62) 0.691
stride length (cm) 54.64 (8.58) 55.5 (7.95) 0.367
cadence (steps/min) 127.69 (13.37) 125.11 (13.17) 0.406
Dual-task gait trials
Counting backward by 7 s
velocity (m/min) 40.59 (13.59) 46.88 (12.73) 0.025*
stride length (cm) 46 (9.29) 46.37 (6.61) 0.716
cadence (steps/min) 89.37 (24.64) 99.35 (18.02) 0.048*
Naming animals
velocity (m/min) 37.06 (15.57) 42.03 (14.02) 0.036*
stride length (cm) 46.25 (9.24) 47.55 (7.46) 0.199
cadence (steps/min) 80.46 (27.15) 88.76 (23.42) 0.076
Paired sample t-test: *p < 0.05
SD Standard deviation
Cognitive and psychological assessments
The subjects showed an improvement in the MMSE score from 19.62 ± 4.71 at baseline to 20.29 ± 4.66 at 12 weeks (p = 0.001). However, there was no significant improvement of the scores for FAST, GDS, and ADCS-ADL (Table 3).
Table 3 Cognitive and Psychological Assessments and Acetylcholinesterase Activity
Baseline 12 weeks p-value (12 weeks vs. baseline)
MMSE 19.62 ± 4.71 20.29 ± 4.66 0.001*
FAST 4.24 ± 0.83 4.14 ± 0.85 0.16
ADCS-ADL 63.14 ± 8.6 63.29 ± 8.17 0.48
GDS 2.76 ± 1.09 2.86 ± 1.11 0.16
AChE activity (IU/L) 276.81 ± 56.28 159.81 ± 60.25 < 0.001*
Paired sample t-test: *p < 0.05
AChE Acetylcholinesterase, ADCS-ADL Alzheimer’s Disease Cooperative Study Activities of Daily Living, FAST Functional Assessment Staging, GDS Geriatric Depression Scale, MMSE Mini-Mental State Examination
AChE activity
AChE activity was significantly decreased from 276.81 ± 56.28 IU/L at baseline to 159.81 ± 60.25 IU/L at 12 weeks (Table 3), indicating that the subjects took rivastigmine as prescribed.
Discussion
The present study showed that rivastigmine improved gait velocity under dual-task conditions in subjects with mild to moderate AD. Conversely, rivastigmine did not improve gait velocity, cadence, and stride length under single-task conditions.
AChEIs stabilize cognitive function and delay functional decrease [18]. Although it is not clear by which mechanism AChEIs have this effect, it is recognized that they improve not only cognitive function but also motor function. Acetylcholine has an important role in cognitive function and in controlling gait and balance [19]. AChEIs are thought to contribute to the initiation and maintenance of gait by improving executive function and attention and the control of step length and gait velocity. A limited number of studies have shown that ChEIs improved gait performance in patients with AD. Donepezil significantly improved gait velocity in subjects with mild AD under single- and dual-task conditions measured using an electronic walkway [20]. Galantamine improved dual-task stride time in a small number of patients with moderate AD [12]. In the present study, rivastigmine significantly improved gait velocity under dual-task conditions in 21 subjects with mild to moderate AD.
Cognitive enhancers could improve gait by a number of mechanisms. Cognitive function and neural control of gait share brain cortical networks and neurotransmitters [2]. The neurotransmitter acetylcholine has an important role in cognitive function and in controlling gait and balance [13]. Specifically, thalamic activity is derived mainly from the brainstem pedunculopontine nucleus, which plays a central role in the generation of movement, gait, and balance control [21]. Cholinergic forebrain projections from the nucleus basalis of Meynert also have a specific role in the control of selective attention, which is an important factor in the cost of dual-tasking while walking in subjects with AD. ChEIs stabilize and improve attention and executive function in patients with AD and other neurodegenerative disorders [22]. There may be cognitive- and non-cognitive-related enhancement mechanisms by which ChEIs improve gait and potentially improve gait performance.
In our study, rivastigmine increased gait velocity in the dual-task trials, but not in the single-task trials. The principle dual-task paradigm involving gait is the creation of an attention-demanding task [23]. A decline in gait performance while performing a dual task when compared to a single task is usually interpreted as interference due to competing demands for attention between both tasks [23]. Thus, gait performance while dual tasking appears to be more dependent on cortical cholinergic levels than while performing a single task [24], suggesting that cognitive enhancement may have affected the increase of gait velocity in our subjects rather than non-cognitive enhancement. The increase in gait velocity during the dual task was mainly due to an increase in cadence, but not stride length, in our study. We speculate that motor function may be more involved in stride length than cognitive function as compared with cadence. Although both the animal naming test and the counting backward by seven test are associated with prefrontal and anterior cortex regions, there was a significant improvement in cadence when counting backward rather than when naming animals. The participants were faster and more accurate when counting backward than when naming animals. Baseline cadence data were better when the participants counted backward than when naming animals, which may be related to the fact that cadence was significantly improved when the participants counted backward. Cadence did improve slightly during the animal naming test, but not significantly so. The reason for this discrepancy between the two dual tasks should be examined in future studies.
Rivastigmine also significantly improved the MMSE score, but this improvement was negligible. Rivastigmine did not significantly improve the scores for FAST, GDS, and ADCS-ADL. The AChE activity of all subjects was decreased. These results indicate that rivastigmine did not greatly improve the cognitive function of the participants in this study.
Some limitations of this study need to be considered. Firstly, we used a single-arm open-label design with no randomization and no placebo group. Future studies will be needed with a placebo group. Second, there is a possibility of a learning effect due to the repetition of the dual tasks and MMSE, which may have affected the results of these tests. Third, the small number of participants from one clinic may be unrepresentative of the general population of patients with AD. Fourth, although we were able to control for changes of gait and treatment, residual confounders (e.g., physical condition or motivation) might still be present.
Two participants suffered a fracture during the study period. The contribution of rivastigmine to fracture cannot be ruled out completely, but we believe that any direct effect is small as both fractures occurred by accidental collision.
Conclusions
In conclusion, we found a rivastigmine-related increase in gait velocity of patients with AD in dual-task trials. This improvement may contribute to gait function in patients with AD. This study had a single arm design with a small number of participants and the statistical strength of the study was not strong. Double blind randomized placebo-controlled parallel trial testing is necessary to confirm the effectiveness of rivastigmine on gait disorders in patients with AD in the future.
Abbreviations
AChEIAcetylcholinesterase inhibitor
ADAlzheimer’s disease
ADCS-ADLAlzheimer’s Disease Cooperative Study Activities of Daily Living
FASTFunctional Assessment Staging
GDSGeriatric Depression Scale
MMSEMini-Mental State Examination
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We are grateful to the participants and their families for their cooperation.
Authors’ contributions
HS, SA, and AH participated in designing the study and writing and reviewing the manuscript. NH and TU participated in reviewing the manuscript. All authors read and approved the final manuscript.
Funding
The study was financially supported by the Ono Pharmaceutical company. The sponsors had no role in the design and conduct of the study, in the collection, management, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
This study was approved by the local ethics committee of Juntendo University Urayasu Hospital. Each participant provided written informed consent. The study was prospectively registered with UMIN, UMIN000025869. Registered December 16, 2016, https://upload.umin.ac.jp/cgi-open-bin/icdr/ctr_view.cgi?recptno=R000029744.
Consent for publication
Not applicable.
Competing interests
All authors declare that they have no competing interests. | RIVASTIGMINE | DrugsGivenReaction | CC BY | 33568083 | 15,730,979 | 2021-02-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Spinal compression fracture'. | Rivastigmine improves dual-task gait velocity in patients with Alzheimer's disease.
BACKGROUND
Gait impairments are common in patients with Alzheimer's disease. Cholinesterase inhibitors are used to treat the symptoms of patients with Alzheimer's disease, but they have not been shown to reduce the severity of Alzheimer's disease-related gait disorders.
METHODS
This was a prospective, single-arm, open-label, non-randomized study. The aim of the present study was to determine the effect of the acetylcholinesterase inhibitor rivastigmine on gait in 21 newly diagnosed patients with mild to moderate Alzheimer's disease. The outcome variables were velocity, stride length, and cadence during single-task and dual-task gait trials. The subjects were also assessed with the Mini-Mental State Examination, Alzheimer's Disease Cooperative Study Activities of Daily Living, Functional Assessment Staging, and Geriatric Depression Scale.
RESULTS
After 12 weeks of treatment with rivastigmine, gait velocity was significantly improved in the dual-task gait trials; gait velocity was increased from 40.59 ± 13.59 m/min at baseline to 46.88 ± 12.73 m/min when counting backward from 100 in steps of 7 while walking, and gait velocity was increased from 37.06 ± 15.57 m/min at baseline to 42.03 ± 14.02 m/min when naming animals while walking. In the single-task gait trials, which consisted only of walking at their usual pace or at a fast pace, gait velocity was not increased by rivastigmine administration.
CONCLUSIONS
Our findings indicated that rivastigmine improved gait in subjects with mild to moderate Alzheimer's disease during dual-task trials. The observed enhancement of dual-task gait might be caused by an improvement of cognitive function rather than motor function.
BACKGROUND
UMIN, UMIN000025869. Registered December 16, 2016, https://upload.umin.ac.jp/cgi-open-bin/icdr/ctr_view.cgi?recptno=R000029744.
Background
Alzheimer’s disease (AD) is the most common neurodegenerative disorder and one of the leading causes of death in old age [1]. AD affects a variety of functional areas, including cognitive and motor functions [1]. Recently, the relationship between motor activity and dementia has received increasing research attention [2]. Gait abnormalities are commonly observed in patients with AD and increase in frequency and severity over time [3]. Gait disorders decrease mobility and increase the risk of falling [4]. The consequences of gait disorders and associated falls can be severe, including fractures, worsening of mobility, loss of independence, and increased cardiovascular morbidity and mortality [5]. The presence of gait abnormalities in AD is important for predicting faster cognitive decline, institutionalization, and death [6].
Gait disturbance in patients with AD is particularly evident under dual-task conditions [7, 8], e.g., in simple tasks performed while walking such as counting backward or in more complex tasks such as verbal fluency [2]. As dual-task gait assessments isolate the cognitive cost of maintaining a safe gait while distracted, they have been used to indicate that impairments in cognition lead to deficits in gait control that are independent of the decline in muscle strength and osteoarticular function that accompanies aging [9]. Specifically, higher-level motor control requires cognition to produce the complex motor responses that are adapted to multiple sensory inputs and environmental challenges. Thus, impaired cognitive abilities, especially attention and executive function, compromise postural and gait stability [10]. The dual-task paradigm can be used to study the allocation of attentional resources during a motor task and to separate the cognitive and motor components of executing a movement [2].
Previous studies suggest that cholinesterase inhibitors (ChEIs), a current treatment for the symptoms of AD, may improve gait performance [11–13]. Since, cholinesterase inhibition improves attention and executive function in patients with AD [14], which are both associated with gait quality [15], we hypothesized that the acetylcholinesterase inhibitor (AChEI) rivastigmine would improve gait quality, as quantified by gait velocity, stride length, and cadence, in single- and dual-task gait trials.
Methods
Participant flow
Patient flow in the study is described in Fig. 1.
Fig. 1 CONSORT 2010 Flow Diagram
Participants and procedure
The participants were recruited from December 2016 to June 2018 from the Memory Clinic at Juntendo University Urayasu Hospital. Newly diagnosed older adults with mild to moderate AD who were prescribed a rivastigmine patch were approached for recruitment. The participants were eligible to enter the trial if they met all of the following criteria at baseline: diagnosis of probable AD according to the criteria of the National Institute of Neurologic and Communicative Disorder and Stroke-AD and Related Disorders Association; Mini-Mental State Examination (MMSE) score greater than 14 to be considered mild or moderate AD; had a caregiver who could assist the participant with medication; and had the ability to walk independently, i.e., without a walking aid or without assistance from other people. Participants aged 65 years or older were recruited. Subjects were not included if they had a history of head trauma with loss of consciousness and concomitant medication including benzodiazepines or antipsychotics. We also excluded patients with any neurological disorder with motor residual deficits including parkinsonism, stroke, and polyneuropathy that influenced their ability to carry out a walking task. All participants received magnetic resonance imaging or computed tomography, and an N-isopropyl-p-(123 I)-iodoamphetamine single photon emission computed tomography cerebral blood flow test was performed in all participants. The absence of a large lesion, i.e., infarction, tumor, and inflammation, was confirmed in all participants. We also confirmed the presence of hypoperfusion in the parietal lobe, which is consistent with a diagnosis of AD.
Design
Baseline cognitive and gait assessments were performed on the day before rivastigmine was administered. The participants received 9 mg/day rivastigmine for 4 weeks and 18 mg/day by transdermal patch for the subsequent 8 weeks of follow-up. Gait, cognitive, and psychological functions and AChE activity in plasma were analyzed at baseline, 4 weeks, and 12 weeks.
Cognitive and psychological assessments
We administered the MMSE, Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS-ADL), Functional Assessment Staging (FAST), and Geriatric Depression Scale (GDS) to all participants.
Gait assessment
Quantitative gait variables were assessed using a portable gait rhythmograph (MG-M 1110; LSI Medience Corporation, Tokyo, Japan), which is a small device (8 × 6 × 2 cm; weight, 80 g) with an accelerometer. The portable gait rhythmograph measures the acceleration accompanied by limb and trunk movements and acceleration induced by step-in and kick-off during gait in three dimensions (ax, ay, az). Its accuracy has been verified previously [16].
Gait speed, average step length, acceleration, and cadence, which is the number of steps per minute, were measured in single- and dual-task gait trials. The single-task trials consisted of normal gait at a self-selected usual pace and fast gait. For the dual-task trials, the participants walked while counting backward from 100 in steps of 7 or while naming animals aloud. Ten-meter-walk tests were performed on the level floor of the hospital in the presence of two investigators (SA and HS). The order of gait analysis was normal gait for the first trial, fast gait for the second trial, counting backward by seven for the third trial, and animal naming for the fourth trial. The participants briefly practiced dual-task walking before the first assessment. The participants did not practice dual-task walking during the study period.
Gait analysis
Using the portable gait rhythmograph, gait-induced acceleration was extracted from limb and trunk movements with an automatic gait detection algorithm [16, 17]. The portable gait rhythmograph performs three-dimensional measurements of acceleration associated with voluntary limb and trunk movements, heel strike, and toe-off when walking. Data were collected at a sampling frequency of 100 Hz and stored on a microSD card in the device for subsequent analysis. When recording was complete, the absolute values of the acceleration vectors were calculated and displayed graphically on a PC.
Statistical analysis
A paired Student’s t-test was used to detect group differences before and at 12 weeks after rivastigmine treatment for gait speed, average step length, acceleration, and cadence in single- and dual-task gait trials. Statistical significance was considered for P-values less than 0.05.
Standard protocol approval registration and patient consent
This study was conducted in accordance with the ethical standards set forth in the Declaration of Helsinki (1983). This study was approved by the local ethics committee of Juntendo University Urayasu Hospital. Each participant provided written informed consent. If a participant had impaired decisional capacity, their family provided consent and the participants provided assent.
Results
Subject characteristics and follow-up
Thirty participants with mild to moderate AD were initially enrolled, of which 21 completed the full study and were included in the analyses. The nine subjects who withdrew did so for the following reasons: two did not use rivastigmine properly, two were no longer interested in participating, two suffered a fracture, one did not visit our hospital because their caregiver suffered a fracture, one developed mild pneumonia, and one could not continue using the rivastigmine patch because of dermatitis.
Adverse events
One participant collided with another person while riding a crowded train and fractured his left humerus; he underwent open fusion for the fracture and recovered without sequelae. Another patient suffered a lumbar compression fracture by bumping into another person while walking; she was hospitalized for 1 month and recovered without sequelae. Both of these patients continued to use rivastigmine. One participant was withdrawn due to medication intolerance by dermatitis (as stated in the previous section).
Baseline characteristics and outcomes after intervention
The baseline characteristics of the subjects are presented in Table 1. At baseline, the subjects had a mean single-task gait velocity of 59.21 m/min, which is considered normal gait velocity. Dual-task gait velocity while counting backward by seven was decreased to 40.59 m/min compared to single-task gait, and decreased to 37.06 m/min when naming animals (Table 1).
Table 1 Baseline Characteristics of the Subjects
Age (mean, SD) 79.03 (6.89)
Sex (female; n, %) 13 (61.9%)
Mini-Mental State Examination (mean, SD) 19.62 (4.71)
Geriatric Depression Scale (mean, SD) 2.76 (1.09)
Functional Assessment Staging (mean, SD) 4.24 (0.83)
Alzheimer’s Disease Cooperative Study Activities of Daily Living (mean, SD) 63.14 (8.6)
Single-task gait trials velocity (m/min) stride length (cm) cadence (steps/min)
Normal gait (mean, SD) 59.21 (12.21) 50.11 (7.52) 117.69 (12.26)
Fast gait (mean, SD) 70.33 (16.06) 54.64 (8.58) 127.69 (13.37)
Dual-task gait trials
Counting backward by 7 40.59 (13.59) 46 (9.29) 95.38 (23.88)
Naming animals 37.06 (15.57) 46.25 (9.24) 80.46 (27.15)
SD Standard deviation
Gait assessment
In single-task gait analysis, the gait velocity, stride length, and cadence of the subjects did not significantly change from baseline to after 12 weeks intervention. In dual-task gait analysis, the subjects increased their gait velocity when counting backward by seven from 40.59 ± 13.59 at baseline to 46.88 ± 12.73 m/min at 12 weeks (p = 0.025), and their gait velocity when naming animals increased from 37.06 ± 15.57 at baseline to 42.03 ± 14.02 m/min at 12 weeks (p = 0.036). The subjects also increased their cadence when counting backward by seven from 89.37 ± 24.64 at baseline to 99.35 ± 18.02 at 12 weeks (p = 0.048). Stride length did not significantly change from baseline to after 12 weeks intervention (Table 2).
Table 2 Gait Assessment
Baseline 12 weeks p-value (12 weeks vs. baseline)
Rivastigmine 0 mg 18 mg/day
Single-task gait trials
Normal gait (mean, SD)
velocity (m/min) 59.21 (12.21) 59.82 (11.46) 0.733
stride length (cm) 50.11 (7.52) 51.68 (7.27) 0.111
cadence (steps/min) 117.69 (12.26) 115.55 (13.26) 0.412
Fast gait (mean, SD)
velocity (m/min) 70.33 (16.06) 69.44 (12.62) 0.691
stride length (cm) 54.64 (8.58) 55.5 (7.95) 0.367
cadence (steps/min) 127.69 (13.37) 125.11 (13.17) 0.406
Dual-task gait trials
Counting backward by 7 s
velocity (m/min) 40.59 (13.59) 46.88 (12.73) 0.025*
stride length (cm) 46 (9.29) 46.37 (6.61) 0.716
cadence (steps/min) 89.37 (24.64) 99.35 (18.02) 0.048*
Naming animals
velocity (m/min) 37.06 (15.57) 42.03 (14.02) 0.036*
stride length (cm) 46.25 (9.24) 47.55 (7.46) 0.199
cadence (steps/min) 80.46 (27.15) 88.76 (23.42) 0.076
Paired sample t-test: *p < 0.05
SD Standard deviation
Cognitive and psychological assessments
The subjects showed an improvement in the MMSE score from 19.62 ± 4.71 at baseline to 20.29 ± 4.66 at 12 weeks (p = 0.001). However, there was no significant improvement of the scores for FAST, GDS, and ADCS-ADL (Table 3).
Table 3 Cognitive and Psychological Assessments and Acetylcholinesterase Activity
Baseline 12 weeks p-value (12 weeks vs. baseline)
MMSE 19.62 ± 4.71 20.29 ± 4.66 0.001*
FAST 4.24 ± 0.83 4.14 ± 0.85 0.16
ADCS-ADL 63.14 ± 8.6 63.29 ± 8.17 0.48
GDS 2.76 ± 1.09 2.86 ± 1.11 0.16
AChE activity (IU/L) 276.81 ± 56.28 159.81 ± 60.25 < 0.001*
Paired sample t-test: *p < 0.05
AChE Acetylcholinesterase, ADCS-ADL Alzheimer’s Disease Cooperative Study Activities of Daily Living, FAST Functional Assessment Staging, GDS Geriatric Depression Scale, MMSE Mini-Mental State Examination
AChE activity
AChE activity was significantly decreased from 276.81 ± 56.28 IU/L at baseline to 159.81 ± 60.25 IU/L at 12 weeks (Table 3), indicating that the subjects took rivastigmine as prescribed.
Discussion
The present study showed that rivastigmine improved gait velocity under dual-task conditions in subjects with mild to moderate AD. Conversely, rivastigmine did not improve gait velocity, cadence, and stride length under single-task conditions.
AChEIs stabilize cognitive function and delay functional decrease [18]. Although it is not clear by which mechanism AChEIs have this effect, it is recognized that they improve not only cognitive function but also motor function. Acetylcholine has an important role in cognitive function and in controlling gait and balance [19]. AChEIs are thought to contribute to the initiation and maintenance of gait by improving executive function and attention and the control of step length and gait velocity. A limited number of studies have shown that ChEIs improved gait performance in patients with AD. Donepezil significantly improved gait velocity in subjects with mild AD under single- and dual-task conditions measured using an electronic walkway [20]. Galantamine improved dual-task stride time in a small number of patients with moderate AD [12]. In the present study, rivastigmine significantly improved gait velocity under dual-task conditions in 21 subjects with mild to moderate AD.
Cognitive enhancers could improve gait by a number of mechanisms. Cognitive function and neural control of gait share brain cortical networks and neurotransmitters [2]. The neurotransmitter acetylcholine has an important role in cognitive function and in controlling gait and balance [13]. Specifically, thalamic activity is derived mainly from the brainstem pedunculopontine nucleus, which plays a central role in the generation of movement, gait, and balance control [21]. Cholinergic forebrain projections from the nucleus basalis of Meynert also have a specific role in the control of selective attention, which is an important factor in the cost of dual-tasking while walking in subjects with AD. ChEIs stabilize and improve attention and executive function in patients with AD and other neurodegenerative disorders [22]. There may be cognitive- and non-cognitive-related enhancement mechanisms by which ChEIs improve gait and potentially improve gait performance.
In our study, rivastigmine increased gait velocity in the dual-task trials, but not in the single-task trials. The principle dual-task paradigm involving gait is the creation of an attention-demanding task [23]. A decline in gait performance while performing a dual task when compared to a single task is usually interpreted as interference due to competing demands for attention between both tasks [23]. Thus, gait performance while dual tasking appears to be more dependent on cortical cholinergic levels than while performing a single task [24], suggesting that cognitive enhancement may have affected the increase of gait velocity in our subjects rather than non-cognitive enhancement. The increase in gait velocity during the dual task was mainly due to an increase in cadence, but not stride length, in our study. We speculate that motor function may be more involved in stride length than cognitive function as compared with cadence. Although both the animal naming test and the counting backward by seven test are associated with prefrontal and anterior cortex regions, there was a significant improvement in cadence when counting backward rather than when naming animals. The participants were faster and more accurate when counting backward than when naming animals. Baseline cadence data were better when the participants counted backward than when naming animals, which may be related to the fact that cadence was significantly improved when the participants counted backward. Cadence did improve slightly during the animal naming test, but not significantly so. The reason for this discrepancy between the two dual tasks should be examined in future studies.
Rivastigmine also significantly improved the MMSE score, but this improvement was negligible. Rivastigmine did not significantly improve the scores for FAST, GDS, and ADCS-ADL. The AChE activity of all subjects was decreased. These results indicate that rivastigmine did not greatly improve the cognitive function of the participants in this study.
Some limitations of this study need to be considered. Firstly, we used a single-arm open-label design with no randomization and no placebo group. Future studies will be needed with a placebo group. Second, there is a possibility of a learning effect due to the repetition of the dual tasks and MMSE, which may have affected the results of these tests. Third, the small number of participants from one clinic may be unrepresentative of the general population of patients with AD. Fourth, although we were able to control for changes of gait and treatment, residual confounders (e.g., physical condition or motivation) might still be present.
Two participants suffered a fracture during the study period. The contribution of rivastigmine to fracture cannot be ruled out completely, but we believe that any direct effect is small as both fractures occurred by accidental collision.
Conclusions
In conclusion, we found a rivastigmine-related increase in gait velocity of patients with AD in dual-task trials. This improvement may contribute to gait function in patients with AD. This study had a single arm design with a small number of participants and the statistical strength of the study was not strong. Double blind randomized placebo-controlled parallel trial testing is necessary to confirm the effectiveness of rivastigmine on gait disorders in patients with AD in the future.
Abbreviations
AChEIAcetylcholinesterase inhibitor
ADAlzheimer’s disease
ADCS-ADLAlzheimer’s Disease Cooperative Study Activities of Daily Living
FASTFunctional Assessment Staging
GDSGeriatric Depression Scale
MMSEMini-Mental State Examination
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We are grateful to the participants and their families for their cooperation.
Authors’ contributions
HS, SA, and AH participated in designing the study and writing and reviewing the manuscript. NH and TU participated in reviewing the manuscript. All authors read and approved the final manuscript.
Funding
The study was financially supported by the Ono Pharmaceutical company. The sponsors had no role in the design and conduct of the study, in the collection, management, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
This study was approved by the local ethics committee of Juntendo University Urayasu Hospital. Each participant provided written informed consent. The study was prospectively registered with UMIN, UMIN000025869. Registered December 16, 2016, https://upload.umin.ac.jp/cgi-open-bin/icdr/ctr_view.cgi?recptno=R000029744.
Consent for publication
Not applicable.
Competing interests
All authors declare that they have no competing interests. | RIVASTIGMINE | DrugsGivenReaction | CC BY | 33568083 | 17,267,147 | 2021-02-10 |
What was the outcome of reaction 'Fall'? | Rivastigmine improves dual-task gait velocity in patients with Alzheimer's disease.
BACKGROUND
Gait impairments are common in patients with Alzheimer's disease. Cholinesterase inhibitors are used to treat the symptoms of patients with Alzheimer's disease, but they have not been shown to reduce the severity of Alzheimer's disease-related gait disorders.
METHODS
This was a prospective, single-arm, open-label, non-randomized study. The aim of the present study was to determine the effect of the acetylcholinesterase inhibitor rivastigmine on gait in 21 newly diagnosed patients with mild to moderate Alzheimer's disease. The outcome variables were velocity, stride length, and cadence during single-task and dual-task gait trials. The subjects were also assessed with the Mini-Mental State Examination, Alzheimer's Disease Cooperative Study Activities of Daily Living, Functional Assessment Staging, and Geriatric Depression Scale.
RESULTS
After 12 weeks of treatment with rivastigmine, gait velocity was significantly improved in the dual-task gait trials; gait velocity was increased from 40.59 ± 13.59 m/min at baseline to 46.88 ± 12.73 m/min when counting backward from 100 in steps of 7 while walking, and gait velocity was increased from 37.06 ± 15.57 m/min at baseline to 42.03 ± 14.02 m/min when naming animals while walking. In the single-task gait trials, which consisted only of walking at their usual pace or at a fast pace, gait velocity was not increased by rivastigmine administration.
CONCLUSIONS
Our findings indicated that rivastigmine improved gait in subjects with mild to moderate Alzheimer's disease during dual-task trials. The observed enhancement of dual-task gait might be caused by an improvement of cognitive function rather than motor function.
BACKGROUND
UMIN, UMIN000025869. Registered December 16, 2016, https://upload.umin.ac.jp/cgi-open-bin/icdr/ctr_view.cgi?recptno=R000029744.
Background
Alzheimer’s disease (AD) is the most common neurodegenerative disorder and one of the leading causes of death in old age [1]. AD affects a variety of functional areas, including cognitive and motor functions [1]. Recently, the relationship between motor activity and dementia has received increasing research attention [2]. Gait abnormalities are commonly observed in patients with AD and increase in frequency and severity over time [3]. Gait disorders decrease mobility and increase the risk of falling [4]. The consequences of gait disorders and associated falls can be severe, including fractures, worsening of mobility, loss of independence, and increased cardiovascular morbidity and mortality [5]. The presence of gait abnormalities in AD is important for predicting faster cognitive decline, institutionalization, and death [6].
Gait disturbance in patients with AD is particularly evident under dual-task conditions [7, 8], e.g., in simple tasks performed while walking such as counting backward or in more complex tasks such as verbal fluency [2]. As dual-task gait assessments isolate the cognitive cost of maintaining a safe gait while distracted, they have been used to indicate that impairments in cognition lead to deficits in gait control that are independent of the decline in muscle strength and osteoarticular function that accompanies aging [9]. Specifically, higher-level motor control requires cognition to produce the complex motor responses that are adapted to multiple sensory inputs and environmental challenges. Thus, impaired cognitive abilities, especially attention and executive function, compromise postural and gait stability [10]. The dual-task paradigm can be used to study the allocation of attentional resources during a motor task and to separate the cognitive and motor components of executing a movement [2].
Previous studies suggest that cholinesterase inhibitors (ChEIs), a current treatment for the symptoms of AD, may improve gait performance [11–13]. Since, cholinesterase inhibition improves attention and executive function in patients with AD [14], which are both associated with gait quality [15], we hypothesized that the acetylcholinesterase inhibitor (AChEI) rivastigmine would improve gait quality, as quantified by gait velocity, stride length, and cadence, in single- and dual-task gait trials.
Methods
Participant flow
Patient flow in the study is described in Fig. 1.
Fig. 1 CONSORT 2010 Flow Diagram
Participants and procedure
The participants were recruited from December 2016 to June 2018 from the Memory Clinic at Juntendo University Urayasu Hospital. Newly diagnosed older adults with mild to moderate AD who were prescribed a rivastigmine patch were approached for recruitment. The participants were eligible to enter the trial if they met all of the following criteria at baseline: diagnosis of probable AD according to the criteria of the National Institute of Neurologic and Communicative Disorder and Stroke-AD and Related Disorders Association; Mini-Mental State Examination (MMSE) score greater than 14 to be considered mild or moderate AD; had a caregiver who could assist the participant with medication; and had the ability to walk independently, i.e., without a walking aid or without assistance from other people. Participants aged 65 years or older were recruited. Subjects were not included if they had a history of head trauma with loss of consciousness and concomitant medication including benzodiazepines or antipsychotics. We also excluded patients with any neurological disorder with motor residual deficits including parkinsonism, stroke, and polyneuropathy that influenced their ability to carry out a walking task. All participants received magnetic resonance imaging or computed tomography, and an N-isopropyl-p-(123 I)-iodoamphetamine single photon emission computed tomography cerebral blood flow test was performed in all participants. The absence of a large lesion, i.e., infarction, tumor, and inflammation, was confirmed in all participants. We also confirmed the presence of hypoperfusion in the parietal lobe, which is consistent with a diagnosis of AD.
Design
Baseline cognitive and gait assessments were performed on the day before rivastigmine was administered. The participants received 9 mg/day rivastigmine for 4 weeks and 18 mg/day by transdermal patch for the subsequent 8 weeks of follow-up. Gait, cognitive, and psychological functions and AChE activity in plasma were analyzed at baseline, 4 weeks, and 12 weeks.
Cognitive and psychological assessments
We administered the MMSE, Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS-ADL), Functional Assessment Staging (FAST), and Geriatric Depression Scale (GDS) to all participants.
Gait assessment
Quantitative gait variables were assessed using a portable gait rhythmograph (MG-M 1110; LSI Medience Corporation, Tokyo, Japan), which is a small device (8 × 6 × 2 cm; weight, 80 g) with an accelerometer. The portable gait rhythmograph measures the acceleration accompanied by limb and trunk movements and acceleration induced by step-in and kick-off during gait in three dimensions (ax, ay, az). Its accuracy has been verified previously [16].
Gait speed, average step length, acceleration, and cadence, which is the number of steps per minute, were measured in single- and dual-task gait trials. The single-task trials consisted of normal gait at a self-selected usual pace and fast gait. For the dual-task trials, the participants walked while counting backward from 100 in steps of 7 or while naming animals aloud. Ten-meter-walk tests were performed on the level floor of the hospital in the presence of two investigators (SA and HS). The order of gait analysis was normal gait for the first trial, fast gait for the second trial, counting backward by seven for the third trial, and animal naming for the fourth trial. The participants briefly practiced dual-task walking before the first assessment. The participants did not practice dual-task walking during the study period.
Gait analysis
Using the portable gait rhythmograph, gait-induced acceleration was extracted from limb and trunk movements with an automatic gait detection algorithm [16, 17]. The portable gait rhythmograph performs three-dimensional measurements of acceleration associated with voluntary limb and trunk movements, heel strike, and toe-off when walking. Data were collected at a sampling frequency of 100 Hz and stored on a microSD card in the device for subsequent analysis. When recording was complete, the absolute values of the acceleration vectors were calculated and displayed graphically on a PC.
Statistical analysis
A paired Student’s t-test was used to detect group differences before and at 12 weeks after rivastigmine treatment for gait speed, average step length, acceleration, and cadence in single- and dual-task gait trials. Statistical significance was considered for P-values less than 0.05.
Standard protocol approval registration and patient consent
This study was conducted in accordance with the ethical standards set forth in the Declaration of Helsinki (1983). This study was approved by the local ethics committee of Juntendo University Urayasu Hospital. Each participant provided written informed consent. If a participant had impaired decisional capacity, their family provided consent and the participants provided assent.
Results
Subject characteristics and follow-up
Thirty participants with mild to moderate AD were initially enrolled, of which 21 completed the full study and were included in the analyses. The nine subjects who withdrew did so for the following reasons: two did not use rivastigmine properly, two were no longer interested in participating, two suffered a fracture, one did not visit our hospital because their caregiver suffered a fracture, one developed mild pneumonia, and one could not continue using the rivastigmine patch because of dermatitis.
Adverse events
One participant collided with another person while riding a crowded train and fractured his left humerus; he underwent open fusion for the fracture and recovered without sequelae. Another patient suffered a lumbar compression fracture by bumping into another person while walking; she was hospitalized for 1 month and recovered without sequelae. Both of these patients continued to use rivastigmine. One participant was withdrawn due to medication intolerance by dermatitis (as stated in the previous section).
Baseline characteristics and outcomes after intervention
The baseline characteristics of the subjects are presented in Table 1. At baseline, the subjects had a mean single-task gait velocity of 59.21 m/min, which is considered normal gait velocity. Dual-task gait velocity while counting backward by seven was decreased to 40.59 m/min compared to single-task gait, and decreased to 37.06 m/min when naming animals (Table 1).
Table 1 Baseline Characteristics of the Subjects
Age (mean, SD) 79.03 (6.89)
Sex (female; n, %) 13 (61.9%)
Mini-Mental State Examination (mean, SD) 19.62 (4.71)
Geriatric Depression Scale (mean, SD) 2.76 (1.09)
Functional Assessment Staging (mean, SD) 4.24 (0.83)
Alzheimer’s Disease Cooperative Study Activities of Daily Living (mean, SD) 63.14 (8.6)
Single-task gait trials velocity (m/min) stride length (cm) cadence (steps/min)
Normal gait (mean, SD) 59.21 (12.21) 50.11 (7.52) 117.69 (12.26)
Fast gait (mean, SD) 70.33 (16.06) 54.64 (8.58) 127.69 (13.37)
Dual-task gait trials
Counting backward by 7 40.59 (13.59) 46 (9.29) 95.38 (23.88)
Naming animals 37.06 (15.57) 46.25 (9.24) 80.46 (27.15)
SD Standard deviation
Gait assessment
In single-task gait analysis, the gait velocity, stride length, and cadence of the subjects did not significantly change from baseline to after 12 weeks intervention. In dual-task gait analysis, the subjects increased their gait velocity when counting backward by seven from 40.59 ± 13.59 at baseline to 46.88 ± 12.73 m/min at 12 weeks (p = 0.025), and their gait velocity when naming animals increased from 37.06 ± 15.57 at baseline to 42.03 ± 14.02 m/min at 12 weeks (p = 0.036). The subjects also increased their cadence when counting backward by seven from 89.37 ± 24.64 at baseline to 99.35 ± 18.02 at 12 weeks (p = 0.048). Stride length did not significantly change from baseline to after 12 weeks intervention (Table 2).
Table 2 Gait Assessment
Baseline 12 weeks p-value (12 weeks vs. baseline)
Rivastigmine 0 mg 18 mg/day
Single-task gait trials
Normal gait (mean, SD)
velocity (m/min) 59.21 (12.21) 59.82 (11.46) 0.733
stride length (cm) 50.11 (7.52) 51.68 (7.27) 0.111
cadence (steps/min) 117.69 (12.26) 115.55 (13.26) 0.412
Fast gait (mean, SD)
velocity (m/min) 70.33 (16.06) 69.44 (12.62) 0.691
stride length (cm) 54.64 (8.58) 55.5 (7.95) 0.367
cadence (steps/min) 127.69 (13.37) 125.11 (13.17) 0.406
Dual-task gait trials
Counting backward by 7 s
velocity (m/min) 40.59 (13.59) 46.88 (12.73) 0.025*
stride length (cm) 46 (9.29) 46.37 (6.61) 0.716
cadence (steps/min) 89.37 (24.64) 99.35 (18.02) 0.048*
Naming animals
velocity (m/min) 37.06 (15.57) 42.03 (14.02) 0.036*
stride length (cm) 46.25 (9.24) 47.55 (7.46) 0.199
cadence (steps/min) 80.46 (27.15) 88.76 (23.42) 0.076
Paired sample t-test: *p < 0.05
SD Standard deviation
Cognitive and psychological assessments
The subjects showed an improvement in the MMSE score from 19.62 ± 4.71 at baseline to 20.29 ± 4.66 at 12 weeks (p = 0.001). However, there was no significant improvement of the scores for FAST, GDS, and ADCS-ADL (Table 3).
Table 3 Cognitive and Psychological Assessments and Acetylcholinesterase Activity
Baseline 12 weeks p-value (12 weeks vs. baseline)
MMSE 19.62 ± 4.71 20.29 ± 4.66 0.001*
FAST 4.24 ± 0.83 4.14 ± 0.85 0.16
ADCS-ADL 63.14 ± 8.6 63.29 ± 8.17 0.48
GDS 2.76 ± 1.09 2.86 ± 1.11 0.16
AChE activity (IU/L) 276.81 ± 56.28 159.81 ± 60.25 < 0.001*
Paired sample t-test: *p < 0.05
AChE Acetylcholinesterase, ADCS-ADL Alzheimer’s Disease Cooperative Study Activities of Daily Living, FAST Functional Assessment Staging, GDS Geriatric Depression Scale, MMSE Mini-Mental State Examination
AChE activity
AChE activity was significantly decreased from 276.81 ± 56.28 IU/L at baseline to 159.81 ± 60.25 IU/L at 12 weeks (Table 3), indicating that the subjects took rivastigmine as prescribed.
Discussion
The present study showed that rivastigmine improved gait velocity under dual-task conditions in subjects with mild to moderate AD. Conversely, rivastigmine did not improve gait velocity, cadence, and stride length under single-task conditions.
AChEIs stabilize cognitive function and delay functional decrease [18]. Although it is not clear by which mechanism AChEIs have this effect, it is recognized that they improve not only cognitive function but also motor function. Acetylcholine has an important role in cognitive function and in controlling gait and balance [19]. AChEIs are thought to contribute to the initiation and maintenance of gait by improving executive function and attention and the control of step length and gait velocity. A limited number of studies have shown that ChEIs improved gait performance in patients with AD. Donepezil significantly improved gait velocity in subjects with mild AD under single- and dual-task conditions measured using an electronic walkway [20]. Galantamine improved dual-task stride time in a small number of patients with moderate AD [12]. In the present study, rivastigmine significantly improved gait velocity under dual-task conditions in 21 subjects with mild to moderate AD.
Cognitive enhancers could improve gait by a number of mechanisms. Cognitive function and neural control of gait share brain cortical networks and neurotransmitters [2]. The neurotransmitter acetylcholine has an important role in cognitive function and in controlling gait and balance [13]. Specifically, thalamic activity is derived mainly from the brainstem pedunculopontine nucleus, which plays a central role in the generation of movement, gait, and balance control [21]. Cholinergic forebrain projections from the nucleus basalis of Meynert also have a specific role in the control of selective attention, which is an important factor in the cost of dual-tasking while walking in subjects with AD. ChEIs stabilize and improve attention and executive function in patients with AD and other neurodegenerative disorders [22]. There may be cognitive- and non-cognitive-related enhancement mechanisms by which ChEIs improve gait and potentially improve gait performance.
In our study, rivastigmine increased gait velocity in the dual-task trials, but not in the single-task trials. The principle dual-task paradigm involving gait is the creation of an attention-demanding task [23]. A decline in gait performance while performing a dual task when compared to a single task is usually interpreted as interference due to competing demands for attention between both tasks [23]. Thus, gait performance while dual tasking appears to be more dependent on cortical cholinergic levels than while performing a single task [24], suggesting that cognitive enhancement may have affected the increase of gait velocity in our subjects rather than non-cognitive enhancement. The increase in gait velocity during the dual task was mainly due to an increase in cadence, but not stride length, in our study. We speculate that motor function may be more involved in stride length than cognitive function as compared with cadence. Although both the animal naming test and the counting backward by seven test are associated with prefrontal and anterior cortex regions, there was a significant improvement in cadence when counting backward rather than when naming animals. The participants were faster and more accurate when counting backward than when naming animals. Baseline cadence data were better when the participants counted backward than when naming animals, which may be related to the fact that cadence was significantly improved when the participants counted backward. Cadence did improve slightly during the animal naming test, but not significantly so. The reason for this discrepancy between the two dual tasks should be examined in future studies.
Rivastigmine also significantly improved the MMSE score, but this improvement was negligible. Rivastigmine did not significantly improve the scores for FAST, GDS, and ADCS-ADL. The AChE activity of all subjects was decreased. These results indicate that rivastigmine did not greatly improve the cognitive function of the participants in this study.
Some limitations of this study need to be considered. Firstly, we used a single-arm open-label design with no randomization and no placebo group. Future studies will be needed with a placebo group. Second, there is a possibility of a learning effect due to the repetition of the dual tasks and MMSE, which may have affected the results of these tests. Third, the small number of participants from one clinic may be unrepresentative of the general population of patients with AD. Fourth, although we were able to control for changes of gait and treatment, residual confounders (e.g., physical condition or motivation) might still be present.
Two participants suffered a fracture during the study period. The contribution of rivastigmine to fracture cannot be ruled out completely, but we believe that any direct effect is small as both fractures occurred by accidental collision.
Conclusions
In conclusion, we found a rivastigmine-related increase in gait velocity of patients with AD in dual-task trials. This improvement may contribute to gait function in patients with AD. This study had a single arm design with a small number of participants and the statistical strength of the study was not strong. Double blind randomized placebo-controlled parallel trial testing is necessary to confirm the effectiveness of rivastigmine on gait disorders in patients with AD in the future.
Abbreviations
AChEIAcetylcholinesterase inhibitor
ADAlzheimer’s disease
ADCS-ADLAlzheimer’s Disease Cooperative Study Activities of Daily Living
FASTFunctional Assessment Staging
GDSGeriatric Depression Scale
MMSEMini-Mental State Examination
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We are grateful to the participants and their families for their cooperation.
Authors’ contributions
HS, SA, and AH participated in designing the study and writing and reviewing the manuscript. NH and TU participated in reviewing the manuscript. All authors read and approved the final manuscript.
Funding
The study was financially supported by the Ono Pharmaceutical company. The sponsors had no role in the design and conduct of the study, in the collection, management, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
This study was approved by the local ethics committee of Juntendo University Urayasu Hospital. Each participant provided written informed consent. The study was prospectively registered with UMIN, UMIN000025869. Registered December 16, 2016, https://upload.umin.ac.jp/cgi-open-bin/icdr/ctr_view.cgi?recptno=R000029744.
Consent for publication
Not applicable.
Competing interests
All authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33568083 | 17,267,567 | 2021-02-10 |
What was the outcome of reaction 'Humerus fracture'? | Rivastigmine improves dual-task gait velocity in patients with Alzheimer's disease.
BACKGROUND
Gait impairments are common in patients with Alzheimer's disease. Cholinesterase inhibitors are used to treat the symptoms of patients with Alzheimer's disease, but they have not been shown to reduce the severity of Alzheimer's disease-related gait disorders.
METHODS
This was a prospective, single-arm, open-label, non-randomized study. The aim of the present study was to determine the effect of the acetylcholinesterase inhibitor rivastigmine on gait in 21 newly diagnosed patients with mild to moderate Alzheimer's disease. The outcome variables were velocity, stride length, and cadence during single-task and dual-task gait trials. The subjects were also assessed with the Mini-Mental State Examination, Alzheimer's Disease Cooperative Study Activities of Daily Living, Functional Assessment Staging, and Geriatric Depression Scale.
RESULTS
After 12 weeks of treatment with rivastigmine, gait velocity was significantly improved in the dual-task gait trials; gait velocity was increased from 40.59 ± 13.59 m/min at baseline to 46.88 ± 12.73 m/min when counting backward from 100 in steps of 7 while walking, and gait velocity was increased from 37.06 ± 15.57 m/min at baseline to 42.03 ± 14.02 m/min when naming animals while walking. In the single-task gait trials, which consisted only of walking at their usual pace or at a fast pace, gait velocity was not increased by rivastigmine administration.
CONCLUSIONS
Our findings indicated that rivastigmine improved gait in subjects with mild to moderate Alzheimer's disease during dual-task trials. The observed enhancement of dual-task gait might be caused by an improvement of cognitive function rather than motor function.
BACKGROUND
UMIN, UMIN000025869. Registered December 16, 2016, https://upload.umin.ac.jp/cgi-open-bin/icdr/ctr_view.cgi?recptno=R000029744.
Background
Alzheimer’s disease (AD) is the most common neurodegenerative disorder and one of the leading causes of death in old age [1]. AD affects a variety of functional areas, including cognitive and motor functions [1]. Recently, the relationship between motor activity and dementia has received increasing research attention [2]. Gait abnormalities are commonly observed in patients with AD and increase in frequency and severity over time [3]. Gait disorders decrease mobility and increase the risk of falling [4]. The consequences of gait disorders and associated falls can be severe, including fractures, worsening of mobility, loss of independence, and increased cardiovascular morbidity and mortality [5]. The presence of gait abnormalities in AD is important for predicting faster cognitive decline, institutionalization, and death [6].
Gait disturbance in patients with AD is particularly evident under dual-task conditions [7, 8], e.g., in simple tasks performed while walking such as counting backward or in more complex tasks such as verbal fluency [2]. As dual-task gait assessments isolate the cognitive cost of maintaining a safe gait while distracted, they have been used to indicate that impairments in cognition lead to deficits in gait control that are independent of the decline in muscle strength and osteoarticular function that accompanies aging [9]. Specifically, higher-level motor control requires cognition to produce the complex motor responses that are adapted to multiple sensory inputs and environmental challenges. Thus, impaired cognitive abilities, especially attention and executive function, compromise postural and gait stability [10]. The dual-task paradigm can be used to study the allocation of attentional resources during a motor task and to separate the cognitive and motor components of executing a movement [2].
Previous studies suggest that cholinesterase inhibitors (ChEIs), a current treatment for the symptoms of AD, may improve gait performance [11–13]. Since, cholinesterase inhibition improves attention and executive function in patients with AD [14], which are both associated with gait quality [15], we hypothesized that the acetylcholinesterase inhibitor (AChEI) rivastigmine would improve gait quality, as quantified by gait velocity, stride length, and cadence, in single- and dual-task gait trials.
Methods
Participant flow
Patient flow in the study is described in Fig. 1.
Fig. 1 CONSORT 2010 Flow Diagram
Participants and procedure
The participants were recruited from December 2016 to June 2018 from the Memory Clinic at Juntendo University Urayasu Hospital. Newly diagnosed older adults with mild to moderate AD who were prescribed a rivastigmine patch were approached for recruitment. The participants were eligible to enter the trial if they met all of the following criteria at baseline: diagnosis of probable AD according to the criteria of the National Institute of Neurologic and Communicative Disorder and Stroke-AD and Related Disorders Association; Mini-Mental State Examination (MMSE) score greater than 14 to be considered mild or moderate AD; had a caregiver who could assist the participant with medication; and had the ability to walk independently, i.e., without a walking aid or without assistance from other people. Participants aged 65 years or older were recruited. Subjects were not included if they had a history of head trauma with loss of consciousness and concomitant medication including benzodiazepines or antipsychotics. We also excluded patients with any neurological disorder with motor residual deficits including parkinsonism, stroke, and polyneuropathy that influenced their ability to carry out a walking task. All participants received magnetic resonance imaging or computed tomography, and an N-isopropyl-p-(123 I)-iodoamphetamine single photon emission computed tomography cerebral blood flow test was performed in all participants. The absence of a large lesion, i.e., infarction, tumor, and inflammation, was confirmed in all participants. We also confirmed the presence of hypoperfusion in the parietal lobe, which is consistent with a diagnosis of AD.
Design
Baseline cognitive and gait assessments were performed on the day before rivastigmine was administered. The participants received 9 mg/day rivastigmine for 4 weeks and 18 mg/day by transdermal patch for the subsequent 8 weeks of follow-up. Gait, cognitive, and psychological functions and AChE activity in plasma were analyzed at baseline, 4 weeks, and 12 weeks.
Cognitive and psychological assessments
We administered the MMSE, Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS-ADL), Functional Assessment Staging (FAST), and Geriatric Depression Scale (GDS) to all participants.
Gait assessment
Quantitative gait variables were assessed using a portable gait rhythmograph (MG-M 1110; LSI Medience Corporation, Tokyo, Japan), which is a small device (8 × 6 × 2 cm; weight, 80 g) with an accelerometer. The portable gait rhythmograph measures the acceleration accompanied by limb and trunk movements and acceleration induced by step-in and kick-off during gait in three dimensions (ax, ay, az). Its accuracy has been verified previously [16].
Gait speed, average step length, acceleration, and cadence, which is the number of steps per minute, were measured in single- and dual-task gait trials. The single-task trials consisted of normal gait at a self-selected usual pace and fast gait. For the dual-task trials, the participants walked while counting backward from 100 in steps of 7 or while naming animals aloud. Ten-meter-walk tests were performed on the level floor of the hospital in the presence of two investigators (SA and HS). The order of gait analysis was normal gait for the first trial, fast gait for the second trial, counting backward by seven for the third trial, and animal naming for the fourth trial. The participants briefly practiced dual-task walking before the first assessment. The participants did not practice dual-task walking during the study period.
Gait analysis
Using the portable gait rhythmograph, gait-induced acceleration was extracted from limb and trunk movements with an automatic gait detection algorithm [16, 17]. The portable gait rhythmograph performs three-dimensional measurements of acceleration associated with voluntary limb and trunk movements, heel strike, and toe-off when walking. Data were collected at a sampling frequency of 100 Hz and stored on a microSD card in the device for subsequent analysis. When recording was complete, the absolute values of the acceleration vectors were calculated and displayed graphically on a PC.
Statistical analysis
A paired Student’s t-test was used to detect group differences before and at 12 weeks after rivastigmine treatment for gait speed, average step length, acceleration, and cadence in single- and dual-task gait trials. Statistical significance was considered for P-values less than 0.05.
Standard protocol approval registration and patient consent
This study was conducted in accordance with the ethical standards set forth in the Declaration of Helsinki (1983). This study was approved by the local ethics committee of Juntendo University Urayasu Hospital. Each participant provided written informed consent. If a participant had impaired decisional capacity, their family provided consent and the participants provided assent.
Results
Subject characteristics and follow-up
Thirty participants with mild to moderate AD were initially enrolled, of which 21 completed the full study and were included in the analyses. The nine subjects who withdrew did so for the following reasons: two did not use rivastigmine properly, two were no longer interested in participating, two suffered a fracture, one did not visit our hospital because their caregiver suffered a fracture, one developed mild pneumonia, and one could not continue using the rivastigmine patch because of dermatitis.
Adverse events
One participant collided with another person while riding a crowded train and fractured his left humerus; he underwent open fusion for the fracture and recovered without sequelae. Another patient suffered a lumbar compression fracture by bumping into another person while walking; she was hospitalized for 1 month and recovered without sequelae. Both of these patients continued to use rivastigmine. One participant was withdrawn due to medication intolerance by dermatitis (as stated in the previous section).
Baseline characteristics and outcomes after intervention
The baseline characteristics of the subjects are presented in Table 1. At baseline, the subjects had a mean single-task gait velocity of 59.21 m/min, which is considered normal gait velocity. Dual-task gait velocity while counting backward by seven was decreased to 40.59 m/min compared to single-task gait, and decreased to 37.06 m/min when naming animals (Table 1).
Table 1 Baseline Characteristics of the Subjects
Age (mean, SD) 79.03 (6.89)
Sex (female; n, %) 13 (61.9%)
Mini-Mental State Examination (mean, SD) 19.62 (4.71)
Geriatric Depression Scale (mean, SD) 2.76 (1.09)
Functional Assessment Staging (mean, SD) 4.24 (0.83)
Alzheimer’s Disease Cooperative Study Activities of Daily Living (mean, SD) 63.14 (8.6)
Single-task gait trials velocity (m/min) stride length (cm) cadence (steps/min)
Normal gait (mean, SD) 59.21 (12.21) 50.11 (7.52) 117.69 (12.26)
Fast gait (mean, SD) 70.33 (16.06) 54.64 (8.58) 127.69 (13.37)
Dual-task gait trials
Counting backward by 7 40.59 (13.59) 46 (9.29) 95.38 (23.88)
Naming animals 37.06 (15.57) 46.25 (9.24) 80.46 (27.15)
SD Standard deviation
Gait assessment
In single-task gait analysis, the gait velocity, stride length, and cadence of the subjects did not significantly change from baseline to after 12 weeks intervention. In dual-task gait analysis, the subjects increased their gait velocity when counting backward by seven from 40.59 ± 13.59 at baseline to 46.88 ± 12.73 m/min at 12 weeks (p = 0.025), and their gait velocity when naming animals increased from 37.06 ± 15.57 at baseline to 42.03 ± 14.02 m/min at 12 weeks (p = 0.036). The subjects also increased their cadence when counting backward by seven from 89.37 ± 24.64 at baseline to 99.35 ± 18.02 at 12 weeks (p = 0.048). Stride length did not significantly change from baseline to after 12 weeks intervention (Table 2).
Table 2 Gait Assessment
Baseline 12 weeks p-value (12 weeks vs. baseline)
Rivastigmine 0 mg 18 mg/day
Single-task gait trials
Normal gait (mean, SD)
velocity (m/min) 59.21 (12.21) 59.82 (11.46) 0.733
stride length (cm) 50.11 (7.52) 51.68 (7.27) 0.111
cadence (steps/min) 117.69 (12.26) 115.55 (13.26) 0.412
Fast gait (mean, SD)
velocity (m/min) 70.33 (16.06) 69.44 (12.62) 0.691
stride length (cm) 54.64 (8.58) 55.5 (7.95) 0.367
cadence (steps/min) 127.69 (13.37) 125.11 (13.17) 0.406
Dual-task gait trials
Counting backward by 7 s
velocity (m/min) 40.59 (13.59) 46.88 (12.73) 0.025*
stride length (cm) 46 (9.29) 46.37 (6.61) 0.716
cadence (steps/min) 89.37 (24.64) 99.35 (18.02) 0.048*
Naming animals
velocity (m/min) 37.06 (15.57) 42.03 (14.02) 0.036*
stride length (cm) 46.25 (9.24) 47.55 (7.46) 0.199
cadence (steps/min) 80.46 (27.15) 88.76 (23.42) 0.076
Paired sample t-test: *p < 0.05
SD Standard deviation
Cognitive and psychological assessments
The subjects showed an improvement in the MMSE score from 19.62 ± 4.71 at baseline to 20.29 ± 4.66 at 12 weeks (p = 0.001). However, there was no significant improvement of the scores for FAST, GDS, and ADCS-ADL (Table 3).
Table 3 Cognitive and Psychological Assessments and Acetylcholinesterase Activity
Baseline 12 weeks p-value (12 weeks vs. baseline)
MMSE 19.62 ± 4.71 20.29 ± 4.66 0.001*
FAST 4.24 ± 0.83 4.14 ± 0.85 0.16
ADCS-ADL 63.14 ± 8.6 63.29 ± 8.17 0.48
GDS 2.76 ± 1.09 2.86 ± 1.11 0.16
AChE activity (IU/L) 276.81 ± 56.28 159.81 ± 60.25 < 0.001*
Paired sample t-test: *p < 0.05
AChE Acetylcholinesterase, ADCS-ADL Alzheimer’s Disease Cooperative Study Activities of Daily Living, FAST Functional Assessment Staging, GDS Geriatric Depression Scale, MMSE Mini-Mental State Examination
AChE activity
AChE activity was significantly decreased from 276.81 ± 56.28 IU/L at baseline to 159.81 ± 60.25 IU/L at 12 weeks (Table 3), indicating that the subjects took rivastigmine as prescribed.
Discussion
The present study showed that rivastigmine improved gait velocity under dual-task conditions in subjects with mild to moderate AD. Conversely, rivastigmine did not improve gait velocity, cadence, and stride length under single-task conditions.
AChEIs stabilize cognitive function and delay functional decrease [18]. Although it is not clear by which mechanism AChEIs have this effect, it is recognized that they improve not only cognitive function but also motor function. Acetylcholine has an important role in cognitive function and in controlling gait and balance [19]. AChEIs are thought to contribute to the initiation and maintenance of gait by improving executive function and attention and the control of step length and gait velocity. A limited number of studies have shown that ChEIs improved gait performance in patients with AD. Donepezil significantly improved gait velocity in subjects with mild AD under single- and dual-task conditions measured using an electronic walkway [20]. Galantamine improved dual-task stride time in a small number of patients with moderate AD [12]. In the present study, rivastigmine significantly improved gait velocity under dual-task conditions in 21 subjects with mild to moderate AD.
Cognitive enhancers could improve gait by a number of mechanisms. Cognitive function and neural control of gait share brain cortical networks and neurotransmitters [2]. The neurotransmitter acetylcholine has an important role in cognitive function and in controlling gait and balance [13]. Specifically, thalamic activity is derived mainly from the brainstem pedunculopontine nucleus, which plays a central role in the generation of movement, gait, and balance control [21]. Cholinergic forebrain projections from the nucleus basalis of Meynert also have a specific role in the control of selective attention, which is an important factor in the cost of dual-tasking while walking in subjects with AD. ChEIs stabilize and improve attention and executive function in patients with AD and other neurodegenerative disorders [22]. There may be cognitive- and non-cognitive-related enhancement mechanisms by which ChEIs improve gait and potentially improve gait performance.
In our study, rivastigmine increased gait velocity in the dual-task trials, but not in the single-task trials. The principle dual-task paradigm involving gait is the creation of an attention-demanding task [23]. A decline in gait performance while performing a dual task when compared to a single task is usually interpreted as interference due to competing demands for attention between both tasks [23]. Thus, gait performance while dual tasking appears to be more dependent on cortical cholinergic levels than while performing a single task [24], suggesting that cognitive enhancement may have affected the increase of gait velocity in our subjects rather than non-cognitive enhancement. The increase in gait velocity during the dual task was mainly due to an increase in cadence, but not stride length, in our study. We speculate that motor function may be more involved in stride length than cognitive function as compared with cadence. Although both the animal naming test and the counting backward by seven test are associated with prefrontal and anterior cortex regions, there was a significant improvement in cadence when counting backward rather than when naming animals. The participants were faster and more accurate when counting backward than when naming animals. Baseline cadence data were better when the participants counted backward than when naming animals, which may be related to the fact that cadence was significantly improved when the participants counted backward. Cadence did improve slightly during the animal naming test, but not significantly so. The reason for this discrepancy between the two dual tasks should be examined in future studies.
Rivastigmine also significantly improved the MMSE score, but this improvement was negligible. Rivastigmine did not significantly improve the scores for FAST, GDS, and ADCS-ADL. The AChE activity of all subjects was decreased. These results indicate that rivastigmine did not greatly improve the cognitive function of the participants in this study.
Some limitations of this study need to be considered. Firstly, we used a single-arm open-label design with no randomization and no placebo group. Future studies will be needed with a placebo group. Second, there is a possibility of a learning effect due to the repetition of the dual tasks and MMSE, which may have affected the results of these tests. Third, the small number of participants from one clinic may be unrepresentative of the general population of patients with AD. Fourth, although we were able to control for changes of gait and treatment, residual confounders (e.g., physical condition or motivation) might still be present.
Two participants suffered a fracture during the study period. The contribution of rivastigmine to fracture cannot be ruled out completely, but we believe that any direct effect is small as both fractures occurred by accidental collision.
Conclusions
In conclusion, we found a rivastigmine-related increase in gait velocity of patients with AD in dual-task trials. This improvement may contribute to gait function in patients with AD. This study had a single arm design with a small number of participants and the statistical strength of the study was not strong. Double blind randomized placebo-controlled parallel trial testing is necessary to confirm the effectiveness of rivastigmine on gait disorders in patients with AD in the future.
Abbreviations
AChEIAcetylcholinesterase inhibitor
ADAlzheimer’s disease
ADCS-ADLAlzheimer’s Disease Cooperative Study Activities of Daily Living
FASTFunctional Assessment Staging
GDSGeriatric Depression Scale
MMSEMini-Mental State Examination
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We are grateful to the participants and their families for their cooperation.
Authors’ contributions
HS, SA, and AH participated in designing the study and writing and reviewing the manuscript. NH and TU participated in reviewing the manuscript. All authors read and approved the final manuscript.
Funding
The study was financially supported by the Ono Pharmaceutical company. The sponsors had no role in the design and conduct of the study, in the collection, management, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
This study was approved by the local ethics committee of Juntendo University Urayasu Hospital. Each participant provided written informed consent. The study was prospectively registered with UMIN, UMIN000025869. Registered December 16, 2016, https://upload.umin.ac.jp/cgi-open-bin/icdr/ctr_view.cgi?recptno=R000029744.
Consent for publication
Not applicable.
Competing interests
All authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33568083 | 17,267,567 | 2021-02-10 |
What was the outcome of reaction 'Interstitial lung disease'? | Rivastigmine improves dual-task gait velocity in patients with Alzheimer's disease.
BACKGROUND
Gait impairments are common in patients with Alzheimer's disease. Cholinesterase inhibitors are used to treat the symptoms of patients with Alzheimer's disease, but they have not been shown to reduce the severity of Alzheimer's disease-related gait disorders.
METHODS
This was a prospective, single-arm, open-label, non-randomized study. The aim of the present study was to determine the effect of the acetylcholinesterase inhibitor rivastigmine on gait in 21 newly diagnosed patients with mild to moderate Alzheimer's disease. The outcome variables were velocity, stride length, and cadence during single-task and dual-task gait trials. The subjects were also assessed with the Mini-Mental State Examination, Alzheimer's Disease Cooperative Study Activities of Daily Living, Functional Assessment Staging, and Geriatric Depression Scale.
RESULTS
After 12 weeks of treatment with rivastigmine, gait velocity was significantly improved in the dual-task gait trials; gait velocity was increased from 40.59 ± 13.59 m/min at baseline to 46.88 ± 12.73 m/min when counting backward from 100 in steps of 7 while walking, and gait velocity was increased from 37.06 ± 15.57 m/min at baseline to 42.03 ± 14.02 m/min when naming animals while walking. In the single-task gait trials, which consisted only of walking at their usual pace or at a fast pace, gait velocity was not increased by rivastigmine administration.
CONCLUSIONS
Our findings indicated that rivastigmine improved gait in subjects with mild to moderate Alzheimer's disease during dual-task trials. The observed enhancement of dual-task gait might be caused by an improvement of cognitive function rather than motor function.
BACKGROUND
UMIN, UMIN000025869. Registered December 16, 2016, https://upload.umin.ac.jp/cgi-open-bin/icdr/ctr_view.cgi?recptno=R000029744.
Background
Alzheimer’s disease (AD) is the most common neurodegenerative disorder and one of the leading causes of death in old age [1]. AD affects a variety of functional areas, including cognitive and motor functions [1]. Recently, the relationship between motor activity and dementia has received increasing research attention [2]. Gait abnormalities are commonly observed in patients with AD and increase in frequency and severity over time [3]. Gait disorders decrease mobility and increase the risk of falling [4]. The consequences of gait disorders and associated falls can be severe, including fractures, worsening of mobility, loss of independence, and increased cardiovascular morbidity and mortality [5]. The presence of gait abnormalities in AD is important for predicting faster cognitive decline, institutionalization, and death [6].
Gait disturbance in patients with AD is particularly evident under dual-task conditions [7, 8], e.g., in simple tasks performed while walking such as counting backward or in more complex tasks such as verbal fluency [2]. As dual-task gait assessments isolate the cognitive cost of maintaining a safe gait while distracted, they have been used to indicate that impairments in cognition lead to deficits in gait control that are independent of the decline in muscle strength and osteoarticular function that accompanies aging [9]. Specifically, higher-level motor control requires cognition to produce the complex motor responses that are adapted to multiple sensory inputs and environmental challenges. Thus, impaired cognitive abilities, especially attention and executive function, compromise postural and gait stability [10]. The dual-task paradigm can be used to study the allocation of attentional resources during a motor task and to separate the cognitive and motor components of executing a movement [2].
Previous studies suggest that cholinesterase inhibitors (ChEIs), a current treatment for the symptoms of AD, may improve gait performance [11–13]. Since, cholinesterase inhibition improves attention and executive function in patients with AD [14], which are both associated with gait quality [15], we hypothesized that the acetylcholinesterase inhibitor (AChEI) rivastigmine would improve gait quality, as quantified by gait velocity, stride length, and cadence, in single- and dual-task gait trials.
Methods
Participant flow
Patient flow in the study is described in Fig. 1.
Fig. 1 CONSORT 2010 Flow Diagram
Participants and procedure
The participants were recruited from December 2016 to June 2018 from the Memory Clinic at Juntendo University Urayasu Hospital. Newly diagnosed older adults with mild to moderate AD who were prescribed a rivastigmine patch were approached for recruitment. The participants were eligible to enter the trial if they met all of the following criteria at baseline: diagnosis of probable AD according to the criteria of the National Institute of Neurologic and Communicative Disorder and Stroke-AD and Related Disorders Association; Mini-Mental State Examination (MMSE) score greater than 14 to be considered mild or moderate AD; had a caregiver who could assist the participant with medication; and had the ability to walk independently, i.e., without a walking aid or without assistance from other people. Participants aged 65 years or older were recruited. Subjects were not included if they had a history of head trauma with loss of consciousness and concomitant medication including benzodiazepines or antipsychotics. We also excluded patients with any neurological disorder with motor residual deficits including parkinsonism, stroke, and polyneuropathy that influenced their ability to carry out a walking task. All participants received magnetic resonance imaging or computed tomography, and an N-isopropyl-p-(123 I)-iodoamphetamine single photon emission computed tomography cerebral blood flow test was performed in all participants. The absence of a large lesion, i.e., infarction, tumor, and inflammation, was confirmed in all participants. We also confirmed the presence of hypoperfusion in the parietal lobe, which is consistent with a diagnosis of AD.
Design
Baseline cognitive and gait assessments were performed on the day before rivastigmine was administered. The participants received 9 mg/day rivastigmine for 4 weeks and 18 mg/day by transdermal patch for the subsequent 8 weeks of follow-up. Gait, cognitive, and psychological functions and AChE activity in plasma were analyzed at baseline, 4 weeks, and 12 weeks.
Cognitive and psychological assessments
We administered the MMSE, Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS-ADL), Functional Assessment Staging (FAST), and Geriatric Depression Scale (GDS) to all participants.
Gait assessment
Quantitative gait variables were assessed using a portable gait rhythmograph (MG-M 1110; LSI Medience Corporation, Tokyo, Japan), which is a small device (8 × 6 × 2 cm; weight, 80 g) with an accelerometer. The portable gait rhythmograph measures the acceleration accompanied by limb and trunk movements and acceleration induced by step-in and kick-off during gait in three dimensions (ax, ay, az). Its accuracy has been verified previously [16].
Gait speed, average step length, acceleration, and cadence, which is the number of steps per minute, were measured in single- and dual-task gait trials. The single-task trials consisted of normal gait at a self-selected usual pace and fast gait. For the dual-task trials, the participants walked while counting backward from 100 in steps of 7 or while naming animals aloud. Ten-meter-walk tests were performed on the level floor of the hospital in the presence of two investigators (SA and HS). The order of gait analysis was normal gait for the first trial, fast gait for the second trial, counting backward by seven for the third trial, and animal naming for the fourth trial. The participants briefly practiced dual-task walking before the first assessment. The participants did not practice dual-task walking during the study period.
Gait analysis
Using the portable gait rhythmograph, gait-induced acceleration was extracted from limb and trunk movements with an automatic gait detection algorithm [16, 17]. The portable gait rhythmograph performs three-dimensional measurements of acceleration associated with voluntary limb and trunk movements, heel strike, and toe-off when walking. Data were collected at a sampling frequency of 100 Hz and stored on a microSD card in the device for subsequent analysis. When recording was complete, the absolute values of the acceleration vectors were calculated and displayed graphically on a PC.
Statistical analysis
A paired Student’s t-test was used to detect group differences before and at 12 weeks after rivastigmine treatment for gait speed, average step length, acceleration, and cadence in single- and dual-task gait trials. Statistical significance was considered for P-values less than 0.05.
Standard protocol approval registration and patient consent
This study was conducted in accordance with the ethical standards set forth in the Declaration of Helsinki (1983). This study was approved by the local ethics committee of Juntendo University Urayasu Hospital. Each participant provided written informed consent. If a participant had impaired decisional capacity, their family provided consent and the participants provided assent.
Results
Subject characteristics and follow-up
Thirty participants with mild to moderate AD were initially enrolled, of which 21 completed the full study and were included in the analyses. The nine subjects who withdrew did so for the following reasons: two did not use rivastigmine properly, two were no longer interested in participating, two suffered a fracture, one did not visit our hospital because their caregiver suffered a fracture, one developed mild pneumonia, and one could not continue using the rivastigmine patch because of dermatitis.
Adverse events
One participant collided with another person while riding a crowded train and fractured his left humerus; he underwent open fusion for the fracture and recovered without sequelae. Another patient suffered a lumbar compression fracture by bumping into another person while walking; she was hospitalized for 1 month and recovered without sequelae. Both of these patients continued to use rivastigmine. One participant was withdrawn due to medication intolerance by dermatitis (as stated in the previous section).
Baseline characteristics and outcomes after intervention
The baseline characteristics of the subjects are presented in Table 1. At baseline, the subjects had a mean single-task gait velocity of 59.21 m/min, which is considered normal gait velocity. Dual-task gait velocity while counting backward by seven was decreased to 40.59 m/min compared to single-task gait, and decreased to 37.06 m/min when naming animals (Table 1).
Table 1 Baseline Characteristics of the Subjects
Age (mean, SD) 79.03 (6.89)
Sex (female; n, %) 13 (61.9%)
Mini-Mental State Examination (mean, SD) 19.62 (4.71)
Geriatric Depression Scale (mean, SD) 2.76 (1.09)
Functional Assessment Staging (mean, SD) 4.24 (0.83)
Alzheimer’s Disease Cooperative Study Activities of Daily Living (mean, SD) 63.14 (8.6)
Single-task gait trials velocity (m/min) stride length (cm) cadence (steps/min)
Normal gait (mean, SD) 59.21 (12.21) 50.11 (7.52) 117.69 (12.26)
Fast gait (mean, SD) 70.33 (16.06) 54.64 (8.58) 127.69 (13.37)
Dual-task gait trials
Counting backward by 7 40.59 (13.59) 46 (9.29) 95.38 (23.88)
Naming animals 37.06 (15.57) 46.25 (9.24) 80.46 (27.15)
SD Standard deviation
Gait assessment
In single-task gait analysis, the gait velocity, stride length, and cadence of the subjects did not significantly change from baseline to after 12 weeks intervention. In dual-task gait analysis, the subjects increased their gait velocity when counting backward by seven from 40.59 ± 13.59 at baseline to 46.88 ± 12.73 m/min at 12 weeks (p = 0.025), and their gait velocity when naming animals increased from 37.06 ± 15.57 at baseline to 42.03 ± 14.02 m/min at 12 weeks (p = 0.036). The subjects also increased their cadence when counting backward by seven from 89.37 ± 24.64 at baseline to 99.35 ± 18.02 at 12 weeks (p = 0.048). Stride length did not significantly change from baseline to after 12 weeks intervention (Table 2).
Table 2 Gait Assessment
Baseline 12 weeks p-value (12 weeks vs. baseline)
Rivastigmine 0 mg 18 mg/day
Single-task gait trials
Normal gait (mean, SD)
velocity (m/min) 59.21 (12.21) 59.82 (11.46) 0.733
stride length (cm) 50.11 (7.52) 51.68 (7.27) 0.111
cadence (steps/min) 117.69 (12.26) 115.55 (13.26) 0.412
Fast gait (mean, SD)
velocity (m/min) 70.33 (16.06) 69.44 (12.62) 0.691
stride length (cm) 54.64 (8.58) 55.5 (7.95) 0.367
cadence (steps/min) 127.69 (13.37) 125.11 (13.17) 0.406
Dual-task gait trials
Counting backward by 7 s
velocity (m/min) 40.59 (13.59) 46.88 (12.73) 0.025*
stride length (cm) 46 (9.29) 46.37 (6.61) 0.716
cadence (steps/min) 89.37 (24.64) 99.35 (18.02) 0.048*
Naming animals
velocity (m/min) 37.06 (15.57) 42.03 (14.02) 0.036*
stride length (cm) 46.25 (9.24) 47.55 (7.46) 0.199
cadence (steps/min) 80.46 (27.15) 88.76 (23.42) 0.076
Paired sample t-test: *p < 0.05
SD Standard deviation
Cognitive and psychological assessments
The subjects showed an improvement in the MMSE score from 19.62 ± 4.71 at baseline to 20.29 ± 4.66 at 12 weeks (p = 0.001). However, there was no significant improvement of the scores for FAST, GDS, and ADCS-ADL (Table 3).
Table 3 Cognitive and Psychological Assessments and Acetylcholinesterase Activity
Baseline 12 weeks p-value (12 weeks vs. baseline)
MMSE 19.62 ± 4.71 20.29 ± 4.66 0.001*
FAST 4.24 ± 0.83 4.14 ± 0.85 0.16
ADCS-ADL 63.14 ± 8.6 63.29 ± 8.17 0.48
GDS 2.76 ± 1.09 2.86 ± 1.11 0.16
AChE activity (IU/L) 276.81 ± 56.28 159.81 ± 60.25 < 0.001*
Paired sample t-test: *p < 0.05
AChE Acetylcholinesterase, ADCS-ADL Alzheimer’s Disease Cooperative Study Activities of Daily Living, FAST Functional Assessment Staging, GDS Geriatric Depression Scale, MMSE Mini-Mental State Examination
AChE activity
AChE activity was significantly decreased from 276.81 ± 56.28 IU/L at baseline to 159.81 ± 60.25 IU/L at 12 weeks (Table 3), indicating that the subjects took rivastigmine as prescribed.
Discussion
The present study showed that rivastigmine improved gait velocity under dual-task conditions in subjects with mild to moderate AD. Conversely, rivastigmine did not improve gait velocity, cadence, and stride length under single-task conditions.
AChEIs stabilize cognitive function and delay functional decrease [18]. Although it is not clear by which mechanism AChEIs have this effect, it is recognized that they improve not only cognitive function but also motor function. Acetylcholine has an important role in cognitive function and in controlling gait and balance [19]. AChEIs are thought to contribute to the initiation and maintenance of gait by improving executive function and attention and the control of step length and gait velocity. A limited number of studies have shown that ChEIs improved gait performance in patients with AD. Donepezil significantly improved gait velocity in subjects with mild AD under single- and dual-task conditions measured using an electronic walkway [20]. Galantamine improved dual-task stride time in a small number of patients with moderate AD [12]. In the present study, rivastigmine significantly improved gait velocity under dual-task conditions in 21 subjects with mild to moderate AD.
Cognitive enhancers could improve gait by a number of mechanisms. Cognitive function and neural control of gait share brain cortical networks and neurotransmitters [2]. The neurotransmitter acetylcholine has an important role in cognitive function and in controlling gait and balance [13]. Specifically, thalamic activity is derived mainly from the brainstem pedunculopontine nucleus, which plays a central role in the generation of movement, gait, and balance control [21]. Cholinergic forebrain projections from the nucleus basalis of Meynert also have a specific role in the control of selective attention, which is an important factor in the cost of dual-tasking while walking in subjects with AD. ChEIs stabilize and improve attention and executive function in patients with AD and other neurodegenerative disorders [22]. There may be cognitive- and non-cognitive-related enhancement mechanisms by which ChEIs improve gait and potentially improve gait performance.
In our study, rivastigmine increased gait velocity in the dual-task trials, but not in the single-task trials. The principle dual-task paradigm involving gait is the creation of an attention-demanding task [23]. A decline in gait performance while performing a dual task when compared to a single task is usually interpreted as interference due to competing demands for attention between both tasks [23]. Thus, gait performance while dual tasking appears to be more dependent on cortical cholinergic levels than while performing a single task [24], suggesting that cognitive enhancement may have affected the increase of gait velocity in our subjects rather than non-cognitive enhancement. The increase in gait velocity during the dual task was mainly due to an increase in cadence, but not stride length, in our study. We speculate that motor function may be more involved in stride length than cognitive function as compared with cadence. Although both the animal naming test and the counting backward by seven test are associated with prefrontal and anterior cortex regions, there was a significant improvement in cadence when counting backward rather than when naming animals. The participants were faster and more accurate when counting backward than when naming animals. Baseline cadence data were better when the participants counted backward than when naming animals, which may be related to the fact that cadence was significantly improved when the participants counted backward. Cadence did improve slightly during the animal naming test, but not significantly so. The reason for this discrepancy between the two dual tasks should be examined in future studies.
Rivastigmine also significantly improved the MMSE score, but this improvement was negligible. Rivastigmine did not significantly improve the scores for FAST, GDS, and ADCS-ADL. The AChE activity of all subjects was decreased. These results indicate that rivastigmine did not greatly improve the cognitive function of the participants in this study.
Some limitations of this study need to be considered. Firstly, we used a single-arm open-label design with no randomization and no placebo group. Future studies will be needed with a placebo group. Second, there is a possibility of a learning effect due to the repetition of the dual tasks and MMSE, which may have affected the results of these tests. Third, the small number of participants from one clinic may be unrepresentative of the general population of patients with AD. Fourth, although we were able to control for changes of gait and treatment, residual confounders (e.g., physical condition or motivation) might still be present.
Two participants suffered a fracture during the study period. The contribution of rivastigmine to fracture cannot be ruled out completely, but we believe that any direct effect is small as both fractures occurred by accidental collision.
Conclusions
In conclusion, we found a rivastigmine-related increase in gait velocity of patients with AD in dual-task trials. This improvement may contribute to gait function in patients with AD. This study had a single arm design with a small number of participants and the statistical strength of the study was not strong. Double blind randomized placebo-controlled parallel trial testing is necessary to confirm the effectiveness of rivastigmine on gait disorders in patients with AD in the future.
Abbreviations
AChEIAcetylcholinesterase inhibitor
ADAlzheimer’s disease
ADCS-ADLAlzheimer’s Disease Cooperative Study Activities of Daily Living
FASTFunctional Assessment Staging
GDSGeriatric Depression Scale
MMSEMini-Mental State Examination
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We are grateful to the participants and their families for their cooperation.
Authors’ contributions
HS, SA, and AH participated in designing the study and writing and reviewing the manuscript. NH and TU participated in reviewing the manuscript. All authors read and approved the final manuscript.
Funding
The study was financially supported by the Ono Pharmaceutical company. The sponsors had no role in the design and conduct of the study, in the collection, management, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
This study was approved by the local ethics committee of Juntendo University Urayasu Hospital. Each participant provided written informed consent. The study was prospectively registered with UMIN, UMIN000025869. Registered December 16, 2016, https://upload.umin.ac.jp/cgi-open-bin/icdr/ctr_view.cgi?recptno=R000029744.
Consent for publication
Not applicable.
Competing interests
All authors declare that they have no competing interests. | Not recovered | ReactionOutcome | CC BY | 33568083 | 15,730,979 | 2021-02-10 |
What was the outcome of reaction 'Pulmonary fibrosis'? | Rivastigmine improves dual-task gait velocity in patients with Alzheimer's disease.
BACKGROUND
Gait impairments are common in patients with Alzheimer's disease. Cholinesterase inhibitors are used to treat the symptoms of patients with Alzheimer's disease, but they have not been shown to reduce the severity of Alzheimer's disease-related gait disorders.
METHODS
This was a prospective, single-arm, open-label, non-randomized study. The aim of the present study was to determine the effect of the acetylcholinesterase inhibitor rivastigmine on gait in 21 newly diagnosed patients with mild to moderate Alzheimer's disease. The outcome variables were velocity, stride length, and cadence during single-task and dual-task gait trials. The subjects were also assessed with the Mini-Mental State Examination, Alzheimer's Disease Cooperative Study Activities of Daily Living, Functional Assessment Staging, and Geriatric Depression Scale.
RESULTS
After 12 weeks of treatment with rivastigmine, gait velocity was significantly improved in the dual-task gait trials; gait velocity was increased from 40.59 ± 13.59 m/min at baseline to 46.88 ± 12.73 m/min when counting backward from 100 in steps of 7 while walking, and gait velocity was increased from 37.06 ± 15.57 m/min at baseline to 42.03 ± 14.02 m/min when naming animals while walking. In the single-task gait trials, which consisted only of walking at their usual pace or at a fast pace, gait velocity was not increased by rivastigmine administration.
CONCLUSIONS
Our findings indicated that rivastigmine improved gait in subjects with mild to moderate Alzheimer's disease during dual-task trials. The observed enhancement of dual-task gait might be caused by an improvement of cognitive function rather than motor function.
BACKGROUND
UMIN, UMIN000025869. Registered December 16, 2016, https://upload.umin.ac.jp/cgi-open-bin/icdr/ctr_view.cgi?recptno=R000029744.
Background
Alzheimer’s disease (AD) is the most common neurodegenerative disorder and one of the leading causes of death in old age [1]. AD affects a variety of functional areas, including cognitive and motor functions [1]. Recently, the relationship between motor activity and dementia has received increasing research attention [2]. Gait abnormalities are commonly observed in patients with AD and increase in frequency and severity over time [3]. Gait disorders decrease mobility and increase the risk of falling [4]. The consequences of gait disorders and associated falls can be severe, including fractures, worsening of mobility, loss of independence, and increased cardiovascular morbidity and mortality [5]. The presence of gait abnormalities in AD is important for predicting faster cognitive decline, institutionalization, and death [6].
Gait disturbance in patients with AD is particularly evident under dual-task conditions [7, 8], e.g., in simple tasks performed while walking such as counting backward or in more complex tasks such as verbal fluency [2]. As dual-task gait assessments isolate the cognitive cost of maintaining a safe gait while distracted, they have been used to indicate that impairments in cognition lead to deficits in gait control that are independent of the decline in muscle strength and osteoarticular function that accompanies aging [9]. Specifically, higher-level motor control requires cognition to produce the complex motor responses that are adapted to multiple sensory inputs and environmental challenges. Thus, impaired cognitive abilities, especially attention and executive function, compromise postural and gait stability [10]. The dual-task paradigm can be used to study the allocation of attentional resources during a motor task and to separate the cognitive and motor components of executing a movement [2].
Previous studies suggest that cholinesterase inhibitors (ChEIs), a current treatment for the symptoms of AD, may improve gait performance [11–13]. Since, cholinesterase inhibition improves attention and executive function in patients with AD [14], which are both associated with gait quality [15], we hypothesized that the acetylcholinesterase inhibitor (AChEI) rivastigmine would improve gait quality, as quantified by gait velocity, stride length, and cadence, in single- and dual-task gait trials.
Methods
Participant flow
Patient flow in the study is described in Fig. 1.
Fig. 1 CONSORT 2010 Flow Diagram
Participants and procedure
The participants were recruited from December 2016 to June 2018 from the Memory Clinic at Juntendo University Urayasu Hospital. Newly diagnosed older adults with mild to moderate AD who were prescribed a rivastigmine patch were approached for recruitment. The participants were eligible to enter the trial if they met all of the following criteria at baseline: diagnosis of probable AD according to the criteria of the National Institute of Neurologic and Communicative Disorder and Stroke-AD and Related Disorders Association; Mini-Mental State Examination (MMSE) score greater than 14 to be considered mild or moderate AD; had a caregiver who could assist the participant with medication; and had the ability to walk independently, i.e., without a walking aid or without assistance from other people. Participants aged 65 years or older were recruited. Subjects were not included if they had a history of head trauma with loss of consciousness and concomitant medication including benzodiazepines or antipsychotics. We also excluded patients with any neurological disorder with motor residual deficits including parkinsonism, stroke, and polyneuropathy that influenced their ability to carry out a walking task. All participants received magnetic resonance imaging or computed tomography, and an N-isopropyl-p-(123 I)-iodoamphetamine single photon emission computed tomography cerebral blood flow test was performed in all participants. The absence of a large lesion, i.e., infarction, tumor, and inflammation, was confirmed in all participants. We also confirmed the presence of hypoperfusion in the parietal lobe, which is consistent with a diagnosis of AD.
Design
Baseline cognitive and gait assessments were performed on the day before rivastigmine was administered. The participants received 9 mg/day rivastigmine for 4 weeks and 18 mg/day by transdermal patch for the subsequent 8 weeks of follow-up. Gait, cognitive, and psychological functions and AChE activity in plasma were analyzed at baseline, 4 weeks, and 12 weeks.
Cognitive and psychological assessments
We administered the MMSE, Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS-ADL), Functional Assessment Staging (FAST), and Geriatric Depression Scale (GDS) to all participants.
Gait assessment
Quantitative gait variables were assessed using a portable gait rhythmograph (MG-M 1110; LSI Medience Corporation, Tokyo, Japan), which is a small device (8 × 6 × 2 cm; weight, 80 g) with an accelerometer. The portable gait rhythmograph measures the acceleration accompanied by limb and trunk movements and acceleration induced by step-in and kick-off during gait in three dimensions (ax, ay, az). Its accuracy has been verified previously [16].
Gait speed, average step length, acceleration, and cadence, which is the number of steps per minute, were measured in single- and dual-task gait trials. The single-task trials consisted of normal gait at a self-selected usual pace and fast gait. For the dual-task trials, the participants walked while counting backward from 100 in steps of 7 or while naming animals aloud. Ten-meter-walk tests were performed on the level floor of the hospital in the presence of two investigators (SA and HS). The order of gait analysis was normal gait for the first trial, fast gait for the second trial, counting backward by seven for the third trial, and animal naming for the fourth trial. The participants briefly practiced dual-task walking before the first assessment. The participants did not practice dual-task walking during the study period.
Gait analysis
Using the portable gait rhythmograph, gait-induced acceleration was extracted from limb and trunk movements with an automatic gait detection algorithm [16, 17]. The portable gait rhythmograph performs three-dimensional measurements of acceleration associated with voluntary limb and trunk movements, heel strike, and toe-off when walking. Data were collected at a sampling frequency of 100 Hz and stored on a microSD card in the device for subsequent analysis. When recording was complete, the absolute values of the acceleration vectors were calculated and displayed graphically on a PC.
Statistical analysis
A paired Student’s t-test was used to detect group differences before and at 12 weeks after rivastigmine treatment for gait speed, average step length, acceleration, and cadence in single- and dual-task gait trials. Statistical significance was considered for P-values less than 0.05.
Standard protocol approval registration and patient consent
This study was conducted in accordance with the ethical standards set forth in the Declaration of Helsinki (1983). This study was approved by the local ethics committee of Juntendo University Urayasu Hospital. Each participant provided written informed consent. If a participant had impaired decisional capacity, their family provided consent and the participants provided assent.
Results
Subject characteristics and follow-up
Thirty participants with mild to moderate AD were initially enrolled, of which 21 completed the full study and were included in the analyses. The nine subjects who withdrew did so for the following reasons: two did not use rivastigmine properly, two were no longer interested in participating, two suffered a fracture, one did not visit our hospital because their caregiver suffered a fracture, one developed mild pneumonia, and one could not continue using the rivastigmine patch because of dermatitis.
Adverse events
One participant collided with another person while riding a crowded train and fractured his left humerus; he underwent open fusion for the fracture and recovered without sequelae. Another patient suffered a lumbar compression fracture by bumping into another person while walking; she was hospitalized for 1 month and recovered without sequelae. Both of these patients continued to use rivastigmine. One participant was withdrawn due to medication intolerance by dermatitis (as stated in the previous section).
Baseline characteristics and outcomes after intervention
The baseline characteristics of the subjects are presented in Table 1. At baseline, the subjects had a mean single-task gait velocity of 59.21 m/min, which is considered normal gait velocity. Dual-task gait velocity while counting backward by seven was decreased to 40.59 m/min compared to single-task gait, and decreased to 37.06 m/min when naming animals (Table 1).
Table 1 Baseline Characteristics of the Subjects
Age (mean, SD) 79.03 (6.89)
Sex (female; n, %) 13 (61.9%)
Mini-Mental State Examination (mean, SD) 19.62 (4.71)
Geriatric Depression Scale (mean, SD) 2.76 (1.09)
Functional Assessment Staging (mean, SD) 4.24 (0.83)
Alzheimer’s Disease Cooperative Study Activities of Daily Living (mean, SD) 63.14 (8.6)
Single-task gait trials velocity (m/min) stride length (cm) cadence (steps/min)
Normal gait (mean, SD) 59.21 (12.21) 50.11 (7.52) 117.69 (12.26)
Fast gait (mean, SD) 70.33 (16.06) 54.64 (8.58) 127.69 (13.37)
Dual-task gait trials
Counting backward by 7 40.59 (13.59) 46 (9.29) 95.38 (23.88)
Naming animals 37.06 (15.57) 46.25 (9.24) 80.46 (27.15)
SD Standard deviation
Gait assessment
In single-task gait analysis, the gait velocity, stride length, and cadence of the subjects did not significantly change from baseline to after 12 weeks intervention. In dual-task gait analysis, the subjects increased their gait velocity when counting backward by seven from 40.59 ± 13.59 at baseline to 46.88 ± 12.73 m/min at 12 weeks (p = 0.025), and their gait velocity when naming animals increased from 37.06 ± 15.57 at baseline to 42.03 ± 14.02 m/min at 12 weeks (p = 0.036). The subjects also increased their cadence when counting backward by seven from 89.37 ± 24.64 at baseline to 99.35 ± 18.02 at 12 weeks (p = 0.048). Stride length did not significantly change from baseline to after 12 weeks intervention (Table 2).
Table 2 Gait Assessment
Baseline 12 weeks p-value (12 weeks vs. baseline)
Rivastigmine 0 mg 18 mg/day
Single-task gait trials
Normal gait (mean, SD)
velocity (m/min) 59.21 (12.21) 59.82 (11.46) 0.733
stride length (cm) 50.11 (7.52) 51.68 (7.27) 0.111
cadence (steps/min) 117.69 (12.26) 115.55 (13.26) 0.412
Fast gait (mean, SD)
velocity (m/min) 70.33 (16.06) 69.44 (12.62) 0.691
stride length (cm) 54.64 (8.58) 55.5 (7.95) 0.367
cadence (steps/min) 127.69 (13.37) 125.11 (13.17) 0.406
Dual-task gait trials
Counting backward by 7 s
velocity (m/min) 40.59 (13.59) 46.88 (12.73) 0.025*
stride length (cm) 46 (9.29) 46.37 (6.61) 0.716
cadence (steps/min) 89.37 (24.64) 99.35 (18.02) 0.048*
Naming animals
velocity (m/min) 37.06 (15.57) 42.03 (14.02) 0.036*
stride length (cm) 46.25 (9.24) 47.55 (7.46) 0.199
cadence (steps/min) 80.46 (27.15) 88.76 (23.42) 0.076
Paired sample t-test: *p < 0.05
SD Standard deviation
Cognitive and psychological assessments
The subjects showed an improvement in the MMSE score from 19.62 ± 4.71 at baseline to 20.29 ± 4.66 at 12 weeks (p = 0.001). However, there was no significant improvement of the scores for FAST, GDS, and ADCS-ADL (Table 3).
Table 3 Cognitive and Psychological Assessments and Acetylcholinesterase Activity
Baseline 12 weeks p-value (12 weeks vs. baseline)
MMSE 19.62 ± 4.71 20.29 ± 4.66 0.001*
FAST 4.24 ± 0.83 4.14 ± 0.85 0.16
ADCS-ADL 63.14 ± 8.6 63.29 ± 8.17 0.48
GDS 2.76 ± 1.09 2.86 ± 1.11 0.16
AChE activity (IU/L) 276.81 ± 56.28 159.81 ± 60.25 < 0.001*
Paired sample t-test: *p < 0.05
AChE Acetylcholinesterase, ADCS-ADL Alzheimer’s Disease Cooperative Study Activities of Daily Living, FAST Functional Assessment Staging, GDS Geriatric Depression Scale, MMSE Mini-Mental State Examination
AChE activity
AChE activity was significantly decreased from 276.81 ± 56.28 IU/L at baseline to 159.81 ± 60.25 IU/L at 12 weeks (Table 3), indicating that the subjects took rivastigmine as prescribed.
Discussion
The present study showed that rivastigmine improved gait velocity under dual-task conditions in subjects with mild to moderate AD. Conversely, rivastigmine did not improve gait velocity, cadence, and stride length under single-task conditions.
AChEIs stabilize cognitive function and delay functional decrease [18]. Although it is not clear by which mechanism AChEIs have this effect, it is recognized that they improve not only cognitive function but also motor function. Acetylcholine has an important role in cognitive function and in controlling gait and balance [19]. AChEIs are thought to contribute to the initiation and maintenance of gait by improving executive function and attention and the control of step length and gait velocity. A limited number of studies have shown that ChEIs improved gait performance in patients with AD. Donepezil significantly improved gait velocity in subjects with mild AD under single- and dual-task conditions measured using an electronic walkway [20]. Galantamine improved dual-task stride time in a small number of patients with moderate AD [12]. In the present study, rivastigmine significantly improved gait velocity under dual-task conditions in 21 subjects with mild to moderate AD.
Cognitive enhancers could improve gait by a number of mechanisms. Cognitive function and neural control of gait share brain cortical networks and neurotransmitters [2]. The neurotransmitter acetylcholine has an important role in cognitive function and in controlling gait and balance [13]. Specifically, thalamic activity is derived mainly from the brainstem pedunculopontine nucleus, which plays a central role in the generation of movement, gait, and balance control [21]. Cholinergic forebrain projections from the nucleus basalis of Meynert also have a specific role in the control of selective attention, which is an important factor in the cost of dual-tasking while walking in subjects with AD. ChEIs stabilize and improve attention and executive function in patients with AD and other neurodegenerative disorders [22]. There may be cognitive- and non-cognitive-related enhancement mechanisms by which ChEIs improve gait and potentially improve gait performance.
In our study, rivastigmine increased gait velocity in the dual-task trials, but not in the single-task trials. The principle dual-task paradigm involving gait is the creation of an attention-demanding task [23]. A decline in gait performance while performing a dual task when compared to a single task is usually interpreted as interference due to competing demands for attention between both tasks [23]. Thus, gait performance while dual tasking appears to be more dependent on cortical cholinergic levels than while performing a single task [24], suggesting that cognitive enhancement may have affected the increase of gait velocity in our subjects rather than non-cognitive enhancement. The increase in gait velocity during the dual task was mainly due to an increase in cadence, but not stride length, in our study. We speculate that motor function may be more involved in stride length than cognitive function as compared with cadence. Although both the animal naming test and the counting backward by seven test are associated with prefrontal and anterior cortex regions, there was a significant improvement in cadence when counting backward rather than when naming animals. The participants were faster and more accurate when counting backward than when naming animals. Baseline cadence data were better when the participants counted backward than when naming animals, which may be related to the fact that cadence was significantly improved when the participants counted backward. Cadence did improve slightly during the animal naming test, but not significantly so. The reason for this discrepancy between the two dual tasks should be examined in future studies.
Rivastigmine also significantly improved the MMSE score, but this improvement was negligible. Rivastigmine did not significantly improve the scores for FAST, GDS, and ADCS-ADL. The AChE activity of all subjects was decreased. These results indicate that rivastigmine did not greatly improve the cognitive function of the participants in this study.
Some limitations of this study need to be considered. Firstly, we used a single-arm open-label design with no randomization and no placebo group. Future studies will be needed with a placebo group. Second, there is a possibility of a learning effect due to the repetition of the dual tasks and MMSE, which may have affected the results of these tests. Third, the small number of participants from one clinic may be unrepresentative of the general population of patients with AD. Fourth, although we were able to control for changes of gait and treatment, residual confounders (e.g., physical condition or motivation) might still be present.
Two participants suffered a fracture during the study period. The contribution of rivastigmine to fracture cannot be ruled out completely, but we believe that any direct effect is small as both fractures occurred by accidental collision.
Conclusions
In conclusion, we found a rivastigmine-related increase in gait velocity of patients with AD in dual-task trials. This improvement may contribute to gait function in patients with AD. This study had a single arm design with a small number of participants and the statistical strength of the study was not strong. Double blind randomized placebo-controlled parallel trial testing is necessary to confirm the effectiveness of rivastigmine on gait disorders in patients with AD in the future.
Abbreviations
AChEIAcetylcholinesterase inhibitor
ADAlzheimer’s disease
ADCS-ADLAlzheimer’s Disease Cooperative Study Activities of Daily Living
FASTFunctional Assessment Staging
GDSGeriatric Depression Scale
MMSEMini-Mental State Examination
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We are grateful to the participants and their families for their cooperation.
Authors’ contributions
HS, SA, and AH participated in designing the study and writing and reviewing the manuscript. NH and TU participated in reviewing the manuscript. All authors read and approved the final manuscript.
Funding
The study was financially supported by the Ono Pharmaceutical company. The sponsors had no role in the design and conduct of the study, in the collection, management, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
This study was approved by the local ethics committee of Juntendo University Urayasu Hospital. Each participant provided written informed consent. The study was prospectively registered with UMIN, UMIN000025869. Registered December 16, 2016, https://upload.umin.ac.jp/cgi-open-bin/icdr/ctr_view.cgi?recptno=R000029744.
Consent for publication
Not applicable.
Competing interests
All authors declare that they have no competing interests. | Not recovered | ReactionOutcome | CC BY | 33568083 | 15,730,979 | 2021-02-10 |
What was the outcome of reaction 'Spinal compression fracture'? | Rivastigmine improves dual-task gait velocity in patients with Alzheimer's disease.
BACKGROUND
Gait impairments are common in patients with Alzheimer's disease. Cholinesterase inhibitors are used to treat the symptoms of patients with Alzheimer's disease, but they have not been shown to reduce the severity of Alzheimer's disease-related gait disorders.
METHODS
This was a prospective, single-arm, open-label, non-randomized study. The aim of the present study was to determine the effect of the acetylcholinesterase inhibitor rivastigmine on gait in 21 newly diagnosed patients with mild to moderate Alzheimer's disease. The outcome variables were velocity, stride length, and cadence during single-task and dual-task gait trials. The subjects were also assessed with the Mini-Mental State Examination, Alzheimer's Disease Cooperative Study Activities of Daily Living, Functional Assessment Staging, and Geriatric Depression Scale.
RESULTS
After 12 weeks of treatment with rivastigmine, gait velocity was significantly improved in the dual-task gait trials; gait velocity was increased from 40.59 ± 13.59 m/min at baseline to 46.88 ± 12.73 m/min when counting backward from 100 in steps of 7 while walking, and gait velocity was increased from 37.06 ± 15.57 m/min at baseline to 42.03 ± 14.02 m/min when naming animals while walking. In the single-task gait trials, which consisted only of walking at their usual pace or at a fast pace, gait velocity was not increased by rivastigmine administration.
CONCLUSIONS
Our findings indicated that rivastigmine improved gait in subjects with mild to moderate Alzheimer's disease during dual-task trials. The observed enhancement of dual-task gait might be caused by an improvement of cognitive function rather than motor function.
BACKGROUND
UMIN, UMIN000025869. Registered December 16, 2016, https://upload.umin.ac.jp/cgi-open-bin/icdr/ctr_view.cgi?recptno=R000029744.
Background
Alzheimer’s disease (AD) is the most common neurodegenerative disorder and one of the leading causes of death in old age [1]. AD affects a variety of functional areas, including cognitive and motor functions [1]. Recently, the relationship between motor activity and dementia has received increasing research attention [2]. Gait abnormalities are commonly observed in patients with AD and increase in frequency and severity over time [3]. Gait disorders decrease mobility and increase the risk of falling [4]. The consequences of gait disorders and associated falls can be severe, including fractures, worsening of mobility, loss of independence, and increased cardiovascular morbidity and mortality [5]. The presence of gait abnormalities in AD is important for predicting faster cognitive decline, institutionalization, and death [6].
Gait disturbance in patients with AD is particularly evident under dual-task conditions [7, 8], e.g., in simple tasks performed while walking such as counting backward or in more complex tasks such as verbal fluency [2]. As dual-task gait assessments isolate the cognitive cost of maintaining a safe gait while distracted, they have been used to indicate that impairments in cognition lead to deficits in gait control that are independent of the decline in muscle strength and osteoarticular function that accompanies aging [9]. Specifically, higher-level motor control requires cognition to produce the complex motor responses that are adapted to multiple sensory inputs and environmental challenges. Thus, impaired cognitive abilities, especially attention and executive function, compromise postural and gait stability [10]. The dual-task paradigm can be used to study the allocation of attentional resources during a motor task and to separate the cognitive and motor components of executing a movement [2].
Previous studies suggest that cholinesterase inhibitors (ChEIs), a current treatment for the symptoms of AD, may improve gait performance [11–13]. Since, cholinesterase inhibition improves attention and executive function in patients with AD [14], which are both associated with gait quality [15], we hypothesized that the acetylcholinesterase inhibitor (AChEI) rivastigmine would improve gait quality, as quantified by gait velocity, stride length, and cadence, in single- and dual-task gait trials.
Methods
Participant flow
Patient flow in the study is described in Fig. 1.
Fig. 1 CONSORT 2010 Flow Diagram
Participants and procedure
The participants were recruited from December 2016 to June 2018 from the Memory Clinic at Juntendo University Urayasu Hospital. Newly diagnosed older adults with mild to moderate AD who were prescribed a rivastigmine patch were approached for recruitment. The participants were eligible to enter the trial if they met all of the following criteria at baseline: diagnosis of probable AD according to the criteria of the National Institute of Neurologic and Communicative Disorder and Stroke-AD and Related Disorders Association; Mini-Mental State Examination (MMSE) score greater than 14 to be considered mild or moderate AD; had a caregiver who could assist the participant with medication; and had the ability to walk independently, i.e., without a walking aid or without assistance from other people. Participants aged 65 years or older were recruited. Subjects were not included if they had a history of head trauma with loss of consciousness and concomitant medication including benzodiazepines or antipsychotics. We also excluded patients with any neurological disorder with motor residual deficits including parkinsonism, stroke, and polyneuropathy that influenced their ability to carry out a walking task. All participants received magnetic resonance imaging or computed tomography, and an N-isopropyl-p-(123 I)-iodoamphetamine single photon emission computed tomography cerebral blood flow test was performed in all participants. The absence of a large lesion, i.e., infarction, tumor, and inflammation, was confirmed in all participants. We also confirmed the presence of hypoperfusion in the parietal lobe, which is consistent with a diagnosis of AD.
Design
Baseline cognitive and gait assessments were performed on the day before rivastigmine was administered. The participants received 9 mg/day rivastigmine for 4 weeks and 18 mg/day by transdermal patch for the subsequent 8 weeks of follow-up. Gait, cognitive, and psychological functions and AChE activity in plasma were analyzed at baseline, 4 weeks, and 12 weeks.
Cognitive and psychological assessments
We administered the MMSE, Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS-ADL), Functional Assessment Staging (FAST), and Geriatric Depression Scale (GDS) to all participants.
Gait assessment
Quantitative gait variables were assessed using a portable gait rhythmograph (MG-M 1110; LSI Medience Corporation, Tokyo, Japan), which is a small device (8 × 6 × 2 cm; weight, 80 g) with an accelerometer. The portable gait rhythmograph measures the acceleration accompanied by limb and trunk movements and acceleration induced by step-in and kick-off during gait in three dimensions (ax, ay, az). Its accuracy has been verified previously [16].
Gait speed, average step length, acceleration, and cadence, which is the number of steps per minute, were measured in single- and dual-task gait trials. The single-task trials consisted of normal gait at a self-selected usual pace and fast gait. For the dual-task trials, the participants walked while counting backward from 100 in steps of 7 or while naming animals aloud. Ten-meter-walk tests were performed on the level floor of the hospital in the presence of two investigators (SA and HS). The order of gait analysis was normal gait for the first trial, fast gait for the second trial, counting backward by seven for the third trial, and animal naming for the fourth trial. The participants briefly practiced dual-task walking before the first assessment. The participants did not practice dual-task walking during the study period.
Gait analysis
Using the portable gait rhythmograph, gait-induced acceleration was extracted from limb and trunk movements with an automatic gait detection algorithm [16, 17]. The portable gait rhythmograph performs three-dimensional measurements of acceleration associated with voluntary limb and trunk movements, heel strike, and toe-off when walking. Data were collected at a sampling frequency of 100 Hz and stored on a microSD card in the device for subsequent analysis. When recording was complete, the absolute values of the acceleration vectors were calculated and displayed graphically on a PC.
Statistical analysis
A paired Student’s t-test was used to detect group differences before and at 12 weeks after rivastigmine treatment for gait speed, average step length, acceleration, and cadence in single- and dual-task gait trials. Statistical significance was considered for P-values less than 0.05.
Standard protocol approval registration and patient consent
This study was conducted in accordance with the ethical standards set forth in the Declaration of Helsinki (1983). This study was approved by the local ethics committee of Juntendo University Urayasu Hospital. Each participant provided written informed consent. If a participant had impaired decisional capacity, their family provided consent and the participants provided assent.
Results
Subject characteristics and follow-up
Thirty participants with mild to moderate AD were initially enrolled, of which 21 completed the full study and were included in the analyses. The nine subjects who withdrew did so for the following reasons: two did not use rivastigmine properly, two were no longer interested in participating, two suffered a fracture, one did not visit our hospital because their caregiver suffered a fracture, one developed mild pneumonia, and one could not continue using the rivastigmine patch because of dermatitis.
Adverse events
One participant collided with another person while riding a crowded train and fractured his left humerus; he underwent open fusion for the fracture and recovered without sequelae. Another patient suffered a lumbar compression fracture by bumping into another person while walking; she was hospitalized for 1 month and recovered without sequelae. Both of these patients continued to use rivastigmine. One participant was withdrawn due to medication intolerance by dermatitis (as stated in the previous section).
Baseline characteristics and outcomes after intervention
The baseline characteristics of the subjects are presented in Table 1. At baseline, the subjects had a mean single-task gait velocity of 59.21 m/min, which is considered normal gait velocity. Dual-task gait velocity while counting backward by seven was decreased to 40.59 m/min compared to single-task gait, and decreased to 37.06 m/min when naming animals (Table 1).
Table 1 Baseline Characteristics of the Subjects
Age (mean, SD) 79.03 (6.89)
Sex (female; n, %) 13 (61.9%)
Mini-Mental State Examination (mean, SD) 19.62 (4.71)
Geriatric Depression Scale (mean, SD) 2.76 (1.09)
Functional Assessment Staging (mean, SD) 4.24 (0.83)
Alzheimer’s Disease Cooperative Study Activities of Daily Living (mean, SD) 63.14 (8.6)
Single-task gait trials velocity (m/min) stride length (cm) cadence (steps/min)
Normal gait (mean, SD) 59.21 (12.21) 50.11 (7.52) 117.69 (12.26)
Fast gait (mean, SD) 70.33 (16.06) 54.64 (8.58) 127.69 (13.37)
Dual-task gait trials
Counting backward by 7 40.59 (13.59) 46 (9.29) 95.38 (23.88)
Naming animals 37.06 (15.57) 46.25 (9.24) 80.46 (27.15)
SD Standard deviation
Gait assessment
In single-task gait analysis, the gait velocity, stride length, and cadence of the subjects did not significantly change from baseline to after 12 weeks intervention. In dual-task gait analysis, the subjects increased their gait velocity when counting backward by seven from 40.59 ± 13.59 at baseline to 46.88 ± 12.73 m/min at 12 weeks (p = 0.025), and their gait velocity when naming animals increased from 37.06 ± 15.57 at baseline to 42.03 ± 14.02 m/min at 12 weeks (p = 0.036). The subjects also increased their cadence when counting backward by seven from 89.37 ± 24.64 at baseline to 99.35 ± 18.02 at 12 weeks (p = 0.048). Stride length did not significantly change from baseline to after 12 weeks intervention (Table 2).
Table 2 Gait Assessment
Baseline 12 weeks p-value (12 weeks vs. baseline)
Rivastigmine 0 mg 18 mg/day
Single-task gait trials
Normal gait (mean, SD)
velocity (m/min) 59.21 (12.21) 59.82 (11.46) 0.733
stride length (cm) 50.11 (7.52) 51.68 (7.27) 0.111
cadence (steps/min) 117.69 (12.26) 115.55 (13.26) 0.412
Fast gait (mean, SD)
velocity (m/min) 70.33 (16.06) 69.44 (12.62) 0.691
stride length (cm) 54.64 (8.58) 55.5 (7.95) 0.367
cadence (steps/min) 127.69 (13.37) 125.11 (13.17) 0.406
Dual-task gait trials
Counting backward by 7 s
velocity (m/min) 40.59 (13.59) 46.88 (12.73) 0.025*
stride length (cm) 46 (9.29) 46.37 (6.61) 0.716
cadence (steps/min) 89.37 (24.64) 99.35 (18.02) 0.048*
Naming animals
velocity (m/min) 37.06 (15.57) 42.03 (14.02) 0.036*
stride length (cm) 46.25 (9.24) 47.55 (7.46) 0.199
cadence (steps/min) 80.46 (27.15) 88.76 (23.42) 0.076
Paired sample t-test: *p < 0.05
SD Standard deviation
Cognitive and psychological assessments
The subjects showed an improvement in the MMSE score from 19.62 ± 4.71 at baseline to 20.29 ± 4.66 at 12 weeks (p = 0.001). However, there was no significant improvement of the scores for FAST, GDS, and ADCS-ADL (Table 3).
Table 3 Cognitive and Psychological Assessments and Acetylcholinesterase Activity
Baseline 12 weeks p-value (12 weeks vs. baseline)
MMSE 19.62 ± 4.71 20.29 ± 4.66 0.001*
FAST 4.24 ± 0.83 4.14 ± 0.85 0.16
ADCS-ADL 63.14 ± 8.6 63.29 ± 8.17 0.48
GDS 2.76 ± 1.09 2.86 ± 1.11 0.16
AChE activity (IU/L) 276.81 ± 56.28 159.81 ± 60.25 < 0.001*
Paired sample t-test: *p < 0.05
AChE Acetylcholinesterase, ADCS-ADL Alzheimer’s Disease Cooperative Study Activities of Daily Living, FAST Functional Assessment Staging, GDS Geriatric Depression Scale, MMSE Mini-Mental State Examination
AChE activity
AChE activity was significantly decreased from 276.81 ± 56.28 IU/L at baseline to 159.81 ± 60.25 IU/L at 12 weeks (Table 3), indicating that the subjects took rivastigmine as prescribed.
Discussion
The present study showed that rivastigmine improved gait velocity under dual-task conditions in subjects with mild to moderate AD. Conversely, rivastigmine did not improve gait velocity, cadence, and stride length under single-task conditions.
AChEIs stabilize cognitive function and delay functional decrease [18]. Although it is not clear by which mechanism AChEIs have this effect, it is recognized that they improve not only cognitive function but also motor function. Acetylcholine has an important role in cognitive function and in controlling gait and balance [19]. AChEIs are thought to contribute to the initiation and maintenance of gait by improving executive function and attention and the control of step length and gait velocity. A limited number of studies have shown that ChEIs improved gait performance in patients with AD. Donepezil significantly improved gait velocity in subjects with mild AD under single- and dual-task conditions measured using an electronic walkway [20]. Galantamine improved dual-task stride time in a small number of patients with moderate AD [12]. In the present study, rivastigmine significantly improved gait velocity under dual-task conditions in 21 subjects with mild to moderate AD.
Cognitive enhancers could improve gait by a number of mechanisms. Cognitive function and neural control of gait share brain cortical networks and neurotransmitters [2]. The neurotransmitter acetylcholine has an important role in cognitive function and in controlling gait and balance [13]. Specifically, thalamic activity is derived mainly from the brainstem pedunculopontine nucleus, which plays a central role in the generation of movement, gait, and balance control [21]. Cholinergic forebrain projections from the nucleus basalis of Meynert also have a specific role in the control of selective attention, which is an important factor in the cost of dual-tasking while walking in subjects with AD. ChEIs stabilize and improve attention and executive function in patients with AD and other neurodegenerative disorders [22]. There may be cognitive- and non-cognitive-related enhancement mechanisms by which ChEIs improve gait and potentially improve gait performance.
In our study, rivastigmine increased gait velocity in the dual-task trials, but not in the single-task trials. The principle dual-task paradigm involving gait is the creation of an attention-demanding task [23]. A decline in gait performance while performing a dual task when compared to a single task is usually interpreted as interference due to competing demands for attention between both tasks [23]. Thus, gait performance while dual tasking appears to be more dependent on cortical cholinergic levels than while performing a single task [24], suggesting that cognitive enhancement may have affected the increase of gait velocity in our subjects rather than non-cognitive enhancement. The increase in gait velocity during the dual task was mainly due to an increase in cadence, but not stride length, in our study. We speculate that motor function may be more involved in stride length than cognitive function as compared with cadence. Although both the animal naming test and the counting backward by seven test are associated with prefrontal and anterior cortex regions, there was a significant improvement in cadence when counting backward rather than when naming animals. The participants were faster and more accurate when counting backward than when naming animals. Baseline cadence data were better when the participants counted backward than when naming animals, which may be related to the fact that cadence was significantly improved when the participants counted backward. Cadence did improve slightly during the animal naming test, but not significantly so. The reason for this discrepancy between the two dual tasks should be examined in future studies.
Rivastigmine also significantly improved the MMSE score, but this improvement was negligible. Rivastigmine did not significantly improve the scores for FAST, GDS, and ADCS-ADL. The AChE activity of all subjects was decreased. These results indicate that rivastigmine did not greatly improve the cognitive function of the participants in this study.
Some limitations of this study need to be considered. Firstly, we used a single-arm open-label design with no randomization and no placebo group. Future studies will be needed with a placebo group. Second, there is a possibility of a learning effect due to the repetition of the dual tasks and MMSE, which may have affected the results of these tests. Third, the small number of participants from one clinic may be unrepresentative of the general population of patients with AD. Fourth, although we were able to control for changes of gait and treatment, residual confounders (e.g., physical condition or motivation) might still be present.
Two participants suffered a fracture during the study period. The contribution of rivastigmine to fracture cannot be ruled out completely, but we believe that any direct effect is small as both fractures occurred by accidental collision.
Conclusions
In conclusion, we found a rivastigmine-related increase in gait velocity of patients with AD in dual-task trials. This improvement may contribute to gait function in patients with AD. This study had a single arm design with a small number of participants and the statistical strength of the study was not strong. Double blind randomized placebo-controlled parallel trial testing is necessary to confirm the effectiveness of rivastigmine on gait disorders in patients with AD in the future.
Abbreviations
AChEIAcetylcholinesterase inhibitor
ADAlzheimer’s disease
ADCS-ADLAlzheimer’s Disease Cooperative Study Activities of Daily Living
FASTFunctional Assessment Staging
GDSGeriatric Depression Scale
MMSEMini-Mental State Examination
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We are grateful to the participants and their families for their cooperation.
Authors’ contributions
HS, SA, and AH participated in designing the study and writing and reviewing the manuscript. NH and TU participated in reviewing the manuscript. All authors read and approved the final manuscript.
Funding
The study was financially supported by the Ono Pharmaceutical company. The sponsors had no role in the design and conduct of the study, in the collection, management, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript.
Availability of data and materials
Not applicable.
Ethics approval and consent to participate
This study was approved by the local ethics committee of Juntendo University Urayasu Hospital. Each participant provided written informed consent. The study was prospectively registered with UMIN, UMIN000025869. Registered December 16, 2016, https://upload.umin.ac.jp/cgi-open-bin/icdr/ctr_view.cgi?recptno=R000029744.
Consent for publication
Not applicable.
Competing interests
All authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33568083 | 17,267,147 | 2021-02-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cheilitis'. | Clonal expansion of CD4+CD8+ T cells in an adult patient with Mycoplasma pneumoniae-associated Erythema multiforme majus.
BACKGROUND
Erythema multiforme (EM) is an acute, immune-mediated mucocutaneous disease, most often preceded by herpes simplex virus (HSV) infection or reactivation. Mycoplasma pneumoniae (Mp) is considered the second major trigger of EM and is often associated with an atypical and more severe presentation of disease, characterized by prominent mucosal involvement. However, contrary to HSV-associated Erythema multiforme (HAEM), immunological mechanisms of Mp-associated EM remain unclear.
METHODS
We present the case of a 50-year-old male patient presenting with community-acquired pneumonia (CAP) and erythema multiforme majus (EMM). Acute Mp infection was diagnosed by seroconversion, with no evidence of HSV infection as a cause of EMM. We performed immune phenotyping of blister fluid (BF) and peripheral blood (PB) T cells and detected a clonally expanded TCRVβ2+ T cell population that was double positive for CD4 and CD8, and expressed the cytotoxic markers granulysin and perforin. This CD4+CD8+ population comprised up to 50.7% of BF T cells and 24.9% of PB T cells. Two years prior to the onset of disease, the frequency of PB CD4+CD8+T cells had been within normal range and it gradually returned to baseline levels with the resolution of symptoms, suggesting an involvement of this population in EMM disease pathophysiology.
CONCLUSIONS
This report is the first to provide a phenotypic description of lesional T cells in Mp-associated EMM. Characterizing the local immune response might help to address pathophysiological questions and warrants further systematic research.
Background
Erythema multiforme (EM) is an acute, immune-mediated mucocutaneous disease characterized by typical target or raised atypical target lesions, typically with an acral distribution [1]. EM can occur in patients of all ages, but it is most prevalent in young adults and shows a predominance for the male sex [2, 3]. EM comprises a minor and a major form, with ≤ 1 (Erythema multiforme minus, EMm) or ≥ 2 (Erythema multiforme majus, EMM) mucosal sites involved, respectively [1]. EMM may also be accompanied by general illness such as fever or fatigue [2, 3]. In most cases, EM is preceded by infection/reactivation with herpes simplex virus (HSV) and is thought to be caused by HSV DNA fragments, transported to the skin by Langerhans cell precursors [4, 5]. Expression of certain HSV genes, notably DNA polymerase (pol), by keratinocytes leads to an inflammatory immune response initiated by HSV-antigen specific CD4+ T helper cell type 1 cells whose T cell receptor (TCR) repertoire is usually skewed towards usage of the TCRVβ2 chain [5]. EM is self-limited, but may recur in up to 30% of EMm and 10% of EMM patients, respectively [3].
Besides HSV, other pathogens have been associated with EM as well [6], especially Mycoplasma pneumoniae (Mp), which is considered the second major cause of EM and the primary cause of EM in children [3]. Mp-associated EM presentation is often atypical and more severe than HSV-associated EM (HAEM), with prominent mucositis and either a non-acral distribution of atypical (larger) targets [3, 7] or only very sparse or even absent cutaneous involvement. The latter condition is referred to as “Fuchs Syndrome” or “Mucosal EMM” [3]. Mucosal sequelae affecting the ocular or genital region are more frequent in patients with Mp-associated EM than among patients with non-Mp-associated EM [7].
EM needs to be distinguished from Stevens-Johnson syndrome/Toxical Epidermal Necrolysis (SJS/TEN). EM and SJS/TEN were previously viewed as two shades of a shared syndrome, but are now considered two different disease entities [1, 8]. Both may affect mucous membranes but can be distinguished by the morphology of the skin lesions. Contrary to EM, lesions in SJS/TEN consist of macules and atypical flat targets or detachment of large epithelial sheets of the skin affecting < 10% of the body surface area in SJS, 10–30% in overlap SJS-TEN and > 30% in TEN [1]. Drugs represent the main triggers of SJS/TEN, leading to an immune response driven by drug-antigen specific, clonally expanded cytotoxic CD8+ T cells [9]. Of interest however, Mp has not only been described as a trigger of EM, but also as a potential trigger [10–13] or co-trigger [14] of SJS/TEN.
Canavan et al. reviewed 202 documented cases of Mp-associated EM, SJS/TEN and mucositis, published between 1922 and 2013 [15]. Based on the observed clinical pattern, they proposed that mucocutaneous disease in the context of Mp infection constitutes a syndrome different from EM and SJS/TEN, and suggested the term Mycoplasma pneumoniae-induced rash and mucositis (MIRM) [15]. The concept of MIRM as a separate entity has since been adopted by different authors [16–21]. However, the concept has been rejected by others [3] and so far, there is no consensus on MIRM as a separate entity, nor has this concept been validated in further studies.
In contrast to HAEM, the pathophysiology of Mp-associated EM remains elusive. Here, we present the case of a patient with Mp infection and mucocutaneous disease characteristic of EMM. A characterization of lesional T cell responses in Mp-associated EMM has not been previously reported.
Case description
A 50-year-old man of European descent presented to the emergency department with a six-day history of productive cough with putrid secretion, fever up to 39 °C and a pounding headache. C-reactive protein (CRP) levels were elevated (188.7 mg/l, normal range < 5 mg/l), and chest X-Ray showed a slight infiltration in the left lower lobe. A diagnosis of non-severe community acquired pneumonia (CAP) was established. Oral treatment with amoxicillin/clavulanic acid and clarithromycin was prescribed and the patient was discharged. Two days later, he presented again to the emergency department. His condition had worsened, and he had developed severe erosive stomatitis, cheilitis and conjunctivitis with photophobia on both eyes (Figs. 1a, b, 2). According to the patient, conjunctivitis was observed prior to the first dose of oral antibiotics. He also complained of dysuria (urethritis) and rapidly developed vesiculobullous lesions on his trunk (first lesions), palms, and the scrotum (Fig. 1c–f). He was admitted to the infectious diseases ward. Antibiotic treatment was changed to levofloxacin, and due to the severity and rapid expansion of the mucocutaneous lesions, a supportive treatment with intravenous prednisolone was initiated by the consultant dermatologist (Fig. 2).Fig. 1 Involvement of different cutaneous and mucosal sites. a Conjunctivitis. b Erosive stomatitis and cheilitis. c Example of an early cutaneous blister. d Confluent area of epithelial detachment at the scrotal skin. e, f Widespread distribution of cutaneous lesions over the trunk (e) and extremities (f)
Fig. 2 Timeline. Timeline of symptoms, drug exposure and treatment, including C-reactive protein (CRP) levels (dark grey line, normal range: < 5 mg/l, scale on the left side), total leukocyte count (light grey line, normal range: 3.9–10.5 /nl, scale on the right side) and percentage of CD4+CD8+ T cells (among total T cells) in peripheral blood (PB, orange) and blister fluid (BF, red). When percentage of CD4+CD8+ T cells was determined by two panels at the same day, the mean was calculated. Dosage of medication was 2 × 875/125 mg/d for amoxicillin-clavulanic acid (AMC), 2 × 250 mg/d for clarithromycin (CLR) and 2 × 500 mg/d for levofloxacin (LVX). Paracetamole, ibuprofen, and metamizole were taken successively, however, exact dosage could not be evaluated retrospectively. Further abbreviations: CAP: community-aquired pneumonia, EMM: Erythema multiforme majus, d: day, w: week, y: year
The medical history revealed that the patient had previously suffered from recurring respiratory tract infections, mainly bronchitis, up to five times per year. He had known allergies to grass-pollen and house dust mite with mild symptoms of allergic rhino-conjunctivitis. Of note, he had previously suffered from recurring enoral aphthous ulcers and recurring conjunctivitis in the past, the latter of which almost exclusively occurred in conjunction with respiratory infections. The family history revealed that his father, sister and son also suffered from recurring aphthous stomatitis. Immunological testing performed two years prior to the onset of mucocutaneous disease had not shown abnormal findings, with the exception of an isolated mannose-binding lectin deficiency (37.6 ng/ml; values > 50 ng/ml were considered normal) and slightly elevated serum levels of serum IgE (368.8 kU/l, values < 100 kU/l were considered normal).
In the days prior to presenting to the emergency department, the patient had taken the following medication; paracetamol (started six days prior to conjunctivitis, which was the first sign of mucocutaneous disease), ibuprofen (started four days prior to conjunctivits) and metamizole (started two days prior to conjunctivitis) (Fig. 2), a non-opioid analgesic commonly used in Germany but not available in all countries. He reported that he had taken paracetamol several times in the past without any adverse reactions to the drug. In contrast, he reported that it was his first-time exposure to ibuprofen and metamizole. Extensive microbiological and virological testing revealed weakly positive polymerase chain reaction (PCR) results for Bordetella parapertussis (B. parapertussis) in pharyngeal swabs, positive Mycoplasma pneumoniae serology and subsequent seroconversion (on admission: IgM 11.2, IgG negative; seven weeks later: IgM 35.0, IgG 19.1, values < 8.5 were considered normal) and marginally positive Human Herpesvirus 6 (HHV6)-IgM serology. Neither of these pathogens (B. parapertussis, Mp and HHV-6) could be detected by PCR in cutaneous blister fluid (BF). All other microbiological and virological analyses, including HSV-1/2 (PCR in peripheral blood (PB), BF, throat wash and eye smear negative, HSV1/2-IgM and IgG negative, serology negative also 2 years before), Epstein-Barr virus (EBV, DNA in PB 2260 copies/ml, limit of detection 1000 copies/ml, PCR in BF and throat wash negative, EBNA1-IgG 72,9; VCA-IgG > 750; EBV-IgM negative, tested twice 3 days apart), cytomegalovirus (CMV, PCR negative in PB, BF and throat wash), were not indicative of infection or reactivation.
The clinical presentation was characteristic of EMM, with mainly round target lesions showing central blistering and mucosal involvement of two mucosal sites (oral and ocular mucosa) (Fig. 1a, b). As there was no indication of recent HSV infection/reactivation and neither HHV-6, nor B. parapertussis have been reported as causes of EMM in the literature, Mp was considered the most likely trigger of mucocutaneous disease. Drugs have also been associated with EM [6], however, in retrospect these associations were often misclassified [22]. Therefore, drugs may not be considered likely triggers in a patient with EM lesions. In our patient, antibiotics could be excluded as causative triggers, since first symptoms (conjunctivitis) appeared prior to first exposure. Since the patient had been previously exposed to paracetamol without adverse reactions, this drug was also considered an unlikely trigger of the eruptions. Ibuprofen and metamizole, which were taken four days (ibuprofen) and two days (metamizole) before onset of conjunctivitis, cannot be completely ruled out as (co-) triggers—especially as it has been reported that Mp and non-opioid analgesics might also synergistically trigger disease [14]. Lymphocyte transformation testing (LTT) to assess for potential drug involvement was not conclusive when performed during the acute phase, as the positive control tested negative, potentially due to systemic high-dose corticosteroid (CS) treatment, and it did not retrieve positive results for any of the drugs four months after the acute phase. LTT often produces negative results after the acute phase and, therefore, it does not exclude drug causality [23].
The skin lesions as well as stomatitis and cheilitis slowly receded over the course of several weeks on symptomatic treatment and systemic CS. Pneumonic infiltration in chest X-ray had also largely dissolved at the time of discharge. In contrast, ocular lesions persisted and required prolonged treatment with topical CS and locally administered cyclosporine. The patient also reported a persistent dry cough over five months after discharge, as well as exertional dyspnea (which he had not experienced before) and pulmonary function test abnormalities (hyperinflation and airflow obstruction) that did not respond to treatment with systemic or inhaled CS and long-acting beta-2 agonists and were still present 1.5 years after the acute phase.
In order to better characterize the immunological changes, we analyzed the immune cell composition in PB and in cutaneous BF. Flow cytometry analyses on day five after initiation of CS treatment revealed that the inflammatory infiltrate in blisters was dominated by neutrophils (52%) and T cells (32%), with only minor representation of monocytes (6.9%), eosinophils (3.5%) and Natural Killer (NK) cells (1.5%). B cells (0.08%) were virtually absent in BF. We found that approximately 50% of BF T cells were double positive for CD4 and CD8 (48.5% three days, and 50.7% five days after initiation of CS treatment, Fig. 3a). A similarly expanded CD4+CD8+ T cell population was also detected in the patient’s PB (24.9% of all T cells before CS treatment, Fig. 3b; 13.4% (panel 1) or 11.0% (panel 2) five days after initiation of CS, Fig. 3a). This finding was verified by independent staining panels (Fig. 3a), largely excluding technical artefacts. CD4+CD8+ T cells belonged to the CD4lowCD8high subgroup of CD4+CD8+ T cells (Fig. 3a, b) and therefore likely might have derived from mature CD8+ T cells [24, 25]. TCRVβ clonotyping revealed that nearly all of the CD4+CD8+ T cells were TCRVβ2+ cells (99.2% in BF, 92.6% in PB, Fig. 3c), indicating a mono- (or oligo-) clonal expansion of the CD4+CD8+ T cells. A previous assessment two years before the onset of disease had shown a normal percentage of CD4+CD8+ T cells in PB (1.86% of T cells, Figs. 2, 3b). Over time, and potentially under the influence of systemic CS, which are known to decrease T cell activation and proliferation [26], the population size of CD4+CD8+ T cells in PB gradually declined to baseline levels (Figs. 2, 3b), along with the regression of mucocutaneous lesions (Fig. 2). We therefore hypothesize that this clonally expanded CD4+CD8+ T cell population was involved in disease pathophysiology in our patient.Fig. 3 Detection of a clonally expanded CD4+CD8+ T cell population in blister fluid and peripheral blood. a CD4+CD8+ T cell frequencies within blister fluid (BF) and peripheral blood (PB) in two different flow cytometry staining panels (panel 1 and panel 2) 3–5 days after the initiation of corticosteroid (CS) treatment. b Frequencies of CD4+CD8+ T cells within PB 2 years prior to onset of disease, during the acute phase before initiation of CS treatment and 19 weeks after the acute stage. c Flow cytometry analysis of the frequency of TCRVβ2+ cells among CD4+CD8−, CD4−CD8 + and CD4+CD8+ T cell subsets at day 5 after initiation of CS treatment. Antibody against TCRVβ2 was labeled to FITC and PE at equal amounts. d Flow cytometry analysis of the frequency of PB T cells expressing the cytotoxic mediators granulysin and perforin among CD4+CD8−, CD4−CD8+ and CD4+CD8+ T cell subsets, assessed 10 days after initiation of CS treatment. The most relevant findings are highlighted in red
Granulysin has been identified as an important effector molecule in bullous skin disorders mediated by cytotoxic T cells [27–29], including EMM [27, 28]. CD4+CD8+ T cells in BF in our patient expressed high levels of granulysin, along with perforin, and the frequency of cells expressing these cytotoxic markers among CD4+CD8+ was higher than among CD4+ or CD8+ single positive T cells (37,6% of cells among vs. 10,8% among CD4−CD8+ and 0,02% among CD4+CD8− T cells, Fig. 3d), further indicating a pathogenic role of these cells in disease pathophysiology.
BF T cells displayed a highly activated (CD69+, HLA-DR+, CD11a+), highly differentiated (CD28−, CD57+) and Natural Killer T (NKT) cell -like (CD16/56+) phenotype (Table 1). Their counterpart population in PB displayed a similar phenotype, yet with different expression patterns of the activation marker CD69 and CD45RA (Table 1).Table 1 Phenotype of T cells in blister fluid (BF) and peripheral blood (PB)
Total CD3+ CD4+CD8− CD4−CD8+ CD4 +CD8+
BF PB BF PB BF PB BF PB
TRM cell marker
CD69+ 68.4 3.30 67.4 0.52 66.9 5.91 68.2 1.26
CD69+CD103 + 6.23 NA 3.56 NA 8.33 NA 6.91 NA
MAIT cell marker
MR1+ (5-OP-RU) 1.25 2.09 0.50 0.28 3.16 4.36 0.34 0.46
NKT cell marker
CD16/56+ 64.6 24.4 1.41 1.14 67.2 36.3 87.9 86.1
Memory marker
CD45RA+ 11.5 68.2 0.67 62.7 20.7 78.4 10.6 61.1
Naive (CD45RA+CCR7 +) NA 41.3 NA 62.4 NA 32.8 NA 4.06
TEMRA (CD45RA+CCR7− NA 26.9 NA 0.27 NA 45.6 NA 57.0
TCM (CD45RA−CCR7+) NA 10.0 NA 20.7 NA 1.08 NA 0.55
TEM (CD45RA−CCR7−) NA 21.8 NA 16.6 NA 20.6 NA 38.4
Activation/differentiation marker
CD69+ 68.4 3.30 67.4 0.52 66.9 5.91 68.2 1.26
HLA-DR+ 37.3 19.0 25.4 4.76 24.6 20.3 52.6 65.7
CD11ahigh 81.5 42.7 46.0 13.2 84.3 61.3 94.7 95.6
CD57+ 33.1 25.9 3.77 2.46 33.9 38.6 48.0 77.3
CD28+ 32.1 69.2 99.2 99.0 34.1 53.8 0.70 5.33
Phenotypic flow cytometry analyses were performed 3–5 days after initiation of CS treatment. NA not assessed. Numbers represent proportions (%) of cells expressing the respective markers among total T cells (CD3+) or among a subset of T cells (CD4+CD8− T cells, CD4−CD8 + T cells or CD4+CD8+ T cells)
More than half (57.0%) of CD4+CD8+ T cells in PB displayed a “T effector memory RA” (TEMRA, CCR7−CD45RA+) phenotype and were negative for CD69, whereas most BF CD4+CD8+ T cells did not express CD45RA and were CD69+ (Table 1). Only a minority of BF T cells was CD69+CD103+ (6,23% of total BF T cells, 6,91% of CD4+CD8+ BF T cells, Table 1), indicating that BF T cells did not represent “classical” long term Tissue Resident Memory T cells (TRM) of the epithelium [30], which have been previously implicated as potential triggers of tissue-specific restriction of symptoms in mucocutaneous diseases such as SJS/TEN [31]. Mucosal-Associated Invariant T (MAIT) cells, a semi-invariant T cell population that has been shown to display high cytotoxicity against bacterially infected epithelial cells [32] were also present only in low frequencies (1,25% of total BF T cells, Table 1).
Conclusions
To the best of our knowledge, this is the first report of a large clonal expansion of CD4+CD8+ T cells in BF and PB of a patient with Mp-associated EMM. In the published literature, we could only find one other report describing BF immune cells in mucocutaneous disease in the context of Mp infection, which reported “elevated CD4+ /CD8+ (697/558 × 105/L) T cells with absence of B cells” in a pediatric patient with widespread epithelial detachment of the skin, reminiscent of SJS/TEN [33]. This report did not provide primary flow cytometry data and lacked further phenotypical characterization of T cells.
CD4lowCD8high T cells have been studied in the context of various viral infections such as HHV-6 [34], EBV [35, 36] and CMV [36] and there is solid published evidence that stimulation of CD8+ T cells via their TCR in combination with CD28 costimulation, but none of those signals alone, can lead to de novo expression of CD4 [37–40]. The role of other signals in this process and the stability of CD4 expression is unknown. If CD4/CD8 co-expression is of direct pathophysiologic relevance remains unclear. In line with our findings of higher cytotoxic mediator content in CD4+CD8+ cells (Fig. 3d), it has been found, that ligation of CD4 augments the cytotoxic potential of CD4lowCD8high T cells [39, 41]. Interestingly, CD4+CD8+ carbamazepine-specific T cell clones could be generated from patients with carbamazepine hypersensitivity [42]. Some of these clones—in contrast to CD4+ or CD8+ single positive clones—displayed drug antigen-specific proliferation even in the absence of antigen-presenting cells or the presence of MHC class I and II blocking antibodies in vitro [42].
Extrapulmonary Mp manifestation in general can be classified according to different pathomechanisms as of i) a direct type (bacterium present at the site of inflammation), ii) an indirect type (bacterium not present at the site of inflammation) and iii) a vascular occlusion type [43]. Direct culture of Mp from vesicular skin lesions has been reported in several early case descriptions of Mp-associated EM [44] and SJS/TEN [45, 46], pointing towards a direct bacterial involvement in the pathophysiology. However, Mp was not detectable via PCR (targeting the Mp P1 adhesion gene) in lesional biopsies of patients with Mp-associated EM in a more recent study [7] and indirect pathomechanisms such as polyclonal B-cell activation, cross-reacting autoantibodies resulting from molecular mimicry, akin to Mp-associated Guillain-Barré syndrome, immune complex deposition and complement activation, have all been discussed and seem to be favored in the current literature [15–17, 43, 47, 48]. However, there is no direct evidence for any of these pathomechanisms in the literature. Our observation that lesional T cells were clonally enriched for one TCRVβ family and expressed cytotoxic molecules like granulysin and perforin, indicates a clonal T cell response directed against a defined antigen, similar to what has been observed in HAEM and in drug-induced SJS/TEN. Furthermore, the majority of the CD4+CD8+ T cells showed a TEMRA phenotype (CCR7−CD45RA+) in PB, but nearly all of the CD4+CD8+ T cells had lost CD45RA in BF, which has been reported for CD8+ TEMRA upon antigenic encounter [49]. This finding supports the hypothesis that circulating CD4+CD8+ TEMRA were recruited to mucosal and epithelial sites, where they downregulated CD45RA expression upon exposure to a defined antigen. This antigen could be an antigen of Mp, a neo- or autoantigen, or a viral or drug-derived antigen, in which case Mp would represent a co-stimulus rather than the primary cause of disease. Identifying the nature and the source of the causative antigen will be a critical step towards a targeted treatment.
No general conclusions can be drawn from observations in a single patient. However, in rare conditions such as Mp-associated EMM, observations made in single cases might be critical to generate hypotheses, disseminate knowledge and spur further systematic research.
Material and methods
Cell isolation and flow cytometry
Flow cytometry analyses of BF and PB (T) cells were performed in the diagnostic laboratory (Labor Berlin—Charité Vivantes GmbH) and in the research laboratory of our institution, according to standard protocols for isolation and surface staining of immune cells. BF immune cells were classified by granularity and size (side and forward scatter area) and expression levels of CD45, CD14 (monocytes), CD16/CD56 (neutrophils, proinflammatory monocytes, NK/NKT cells), CD19 (B cells), CD3 (T cells) following standard gating strategies used in routine diagnostics. T cells were then further characterized as shown in Table 1. TCRVβ clonotyping was performed using the IOTest Beta Mark TCR Vβ Repertoire Kit (Beckman Coulter). Fluorophore-conjugated 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU)-loaded Major Histocompatibility Complex class I related molecule 1 (MR1) tetramers were used to identify MAIT cells, 6-formylpterin (6-FP)-loaded MR1 tetramers were used as a negative control. For analysis of granulysin and perforin expression (Fig. 3d) peripheral blood mononuclear cells (PBMC) were cultured in a humidified incubator in the presence of brefeldin A and monensin for 2 h before intracellular cytokine staining. Cells were not restimulated with Phorbol-12-myristat-13-acetat (PMA)/Ionomycin, to prevent PMA/Ionomycin induced downregulation of the CD4 molecule and secretion of granulysin and perforin. All flow cytometry analyses were performed on fresh PBMC processed immediately or kept at 4 °C overnight. Flow cytometry was performed on a BD FACS Canto II cytometer or Beckman Coulter 10-color Navios. Data was analyzed using FlowJo software Version 10 (Treestar).
Abbreviations
BFBlister fluid
B. parapertussisBordetella parapertussis
CAPCommunity-aquired pneumonia
CMVCytomegalovirus
CRPC-reactive protein
CSCorticosteroid(s)
EBNA1Epstein–Barr nuclear antigen 1
EBVEpstein-Barr virus
EMErythema multiforme
EMmErythema multiforme minus
EMMErythema multiforme majus
HHV-6Human Herpesvirus 6
HAEMHSV-associated erythema multiforme
HLAHuman Leukocyte Antigen
HSVHerpes Simplex virus
LTTLymphocyte transformation testing
MAIT cellMucosal-Associated Invariant T cell
MIRMMycoplasma pneumoniae-induced rash and mucositis
MpMycoplasma pneumonia
MR1Major Histocompatibility Complex class I related molecule 1
NK cellNatural Killer cell
NKT cellNatural Killer T cell
PBPeripheral blood
PBMCPeripheral blood mononuclear cells
PCRPolymerase chain reaction
PMAPhorbol-12-myristat-13-acetat
SJSStevens-Johnson syndrome
SJS/TENStevens-Johnson syndrome/Toxical Epidermal Necrolysis
TCRT cell receptor
TENToxical Epidermal Necrolysis
TEMRAT effector memory RA
TRMTissue Resident Memory T cells
VCAViral-capsid antigen
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Acknowledgements
We thank Dr. Cornelia Doebis, Sarah Altekrüger and Dr. Volker von Baehr from the “Institut für Medizinische Diagnostik Berlin” for performing LTT twice. The MR1 tetramer technology used for the detection of MAIT cells was developed jointly by Dr. James McCluskey, Dr. Jamie Rossjohn, and Dr. David Fairlie, and the material was produced by the NIH Tetramer Core Facility as permitted to be distributed by the University of Melbourne.
Authors’ contributions
S.M.V. conducted and interpreted immunological analyses, collected data and performed literature research. C.M. provided additional FACS data and provided important immunological insights and data interpretation. D.T. and G.J.B. interpreted clinical images of skin lesions and provided important dermatological insights. D.S., N.S. and L.E.S. took care of the patient and provided clinical data. S.M.V. and L.E.S wrote the manuscript. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL. This report was supported by the German Research Council (DFG, SFB-TR84 TP C08 and TP C10 to L.E.S., C09 to N.S.) and the Jürgen Manchot Foundation (doctoral fellowship to S.M.V.).
Availability of data and material
The datasets of this report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Written and oral informed consent to participate has been obtained from the patient and may be requested to see a copy at any stage.
Consent for publication
Written informed consent for publication of his clinical details and/or clinical images was obtained from the patient. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests. | ACETAMINOPHEN, IBUPROFEN, METAMIZOLE | DrugsGivenReaction | CC BY | 33568212 | 19,681,953 | 2021-02-10 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Conjunctivitis'. | Clonal expansion of CD4+CD8+ T cells in an adult patient with Mycoplasma pneumoniae-associated Erythema multiforme majus.
BACKGROUND
Erythema multiforme (EM) is an acute, immune-mediated mucocutaneous disease, most often preceded by herpes simplex virus (HSV) infection or reactivation. Mycoplasma pneumoniae (Mp) is considered the second major trigger of EM and is often associated with an atypical and more severe presentation of disease, characterized by prominent mucosal involvement. However, contrary to HSV-associated Erythema multiforme (HAEM), immunological mechanisms of Mp-associated EM remain unclear.
METHODS
We present the case of a 50-year-old male patient presenting with community-acquired pneumonia (CAP) and erythema multiforme majus (EMM). Acute Mp infection was diagnosed by seroconversion, with no evidence of HSV infection as a cause of EMM. We performed immune phenotyping of blister fluid (BF) and peripheral blood (PB) T cells and detected a clonally expanded TCRVβ2+ T cell population that was double positive for CD4 and CD8, and expressed the cytotoxic markers granulysin and perforin. This CD4+CD8+ population comprised up to 50.7% of BF T cells and 24.9% of PB T cells. Two years prior to the onset of disease, the frequency of PB CD4+CD8+T cells had been within normal range and it gradually returned to baseline levels with the resolution of symptoms, suggesting an involvement of this population in EMM disease pathophysiology.
CONCLUSIONS
This report is the first to provide a phenotypic description of lesional T cells in Mp-associated EMM. Characterizing the local immune response might help to address pathophysiological questions and warrants further systematic research.
Background
Erythema multiforme (EM) is an acute, immune-mediated mucocutaneous disease characterized by typical target or raised atypical target lesions, typically with an acral distribution [1]. EM can occur in patients of all ages, but it is most prevalent in young adults and shows a predominance for the male sex [2, 3]. EM comprises a minor and a major form, with ≤ 1 (Erythema multiforme minus, EMm) or ≥ 2 (Erythema multiforme majus, EMM) mucosal sites involved, respectively [1]. EMM may also be accompanied by general illness such as fever or fatigue [2, 3]. In most cases, EM is preceded by infection/reactivation with herpes simplex virus (HSV) and is thought to be caused by HSV DNA fragments, transported to the skin by Langerhans cell precursors [4, 5]. Expression of certain HSV genes, notably DNA polymerase (pol), by keratinocytes leads to an inflammatory immune response initiated by HSV-antigen specific CD4+ T helper cell type 1 cells whose T cell receptor (TCR) repertoire is usually skewed towards usage of the TCRVβ2 chain [5]. EM is self-limited, but may recur in up to 30% of EMm and 10% of EMM patients, respectively [3].
Besides HSV, other pathogens have been associated with EM as well [6], especially Mycoplasma pneumoniae (Mp), which is considered the second major cause of EM and the primary cause of EM in children [3]. Mp-associated EM presentation is often atypical and more severe than HSV-associated EM (HAEM), with prominent mucositis and either a non-acral distribution of atypical (larger) targets [3, 7] or only very sparse or even absent cutaneous involvement. The latter condition is referred to as “Fuchs Syndrome” or “Mucosal EMM” [3]. Mucosal sequelae affecting the ocular or genital region are more frequent in patients with Mp-associated EM than among patients with non-Mp-associated EM [7].
EM needs to be distinguished from Stevens-Johnson syndrome/Toxical Epidermal Necrolysis (SJS/TEN). EM and SJS/TEN were previously viewed as two shades of a shared syndrome, but are now considered two different disease entities [1, 8]. Both may affect mucous membranes but can be distinguished by the morphology of the skin lesions. Contrary to EM, lesions in SJS/TEN consist of macules and atypical flat targets or detachment of large epithelial sheets of the skin affecting < 10% of the body surface area in SJS, 10–30% in overlap SJS-TEN and > 30% in TEN [1]. Drugs represent the main triggers of SJS/TEN, leading to an immune response driven by drug-antigen specific, clonally expanded cytotoxic CD8+ T cells [9]. Of interest however, Mp has not only been described as a trigger of EM, but also as a potential trigger [10–13] or co-trigger [14] of SJS/TEN.
Canavan et al. reviewed 202 documented cases of Mp-associated EM, SJS/TEN and mucositis, published between 1922 and 2013 [15]. Based on the observed clinical pattern, they proposed that mucocutaneous disease in the context of Mp infection constitutes a syndrome different from EM and SJS/TEN, and suggested the term Mycoplasma pneumoniae-induced rash and mucositis (MIRM) [15]. The concept of MIRM as a separate entity has since been adopted by different authors [16–21]. However, the concept has been rejected by others [3] and so far, there is no consensus on MIRM as a separate entity, nor has this concept been validated in further studies.
In contrast to HAEM, the pathophysiology of Mp-associated EM remains elusive. Here, we present the case of a patient with Mp infection and mucocutaneous disease characteristic of EMM. A characterization of lesional T cell responses in Mp-associated EMM has not been previously reported.
Case description
A 50-year-old man of European descent presented to the emergency department with a six-day history of productive cough with putrid secretion, fever up to 39 °C and a pounding headache. C-reactive protein (CRP) levels were elevated (188.7 mg/l, normal range < 5 mg/l), and chest X-Ray showed a slight infiltration in the left lower lobe. A diagnosis of non-severe community acquired pneumonia (CAP) was established. Oral treatment with amoxicillin/clavulanic acid and clarithromycin was prescribed and the patient was discharged. Two days later, he presented again to the emergency department. His condition had worsened, and he had developed severe erosive stomatitis, cheilitis and conjunctivitis with photophobia on both eyes (Figs. 1a, b, 2). According to the patient, conjunctivitis was observed prior to the first dose of oral antibiotics. He also complained of dysuria (urethritis) and rapidly developed vesiculobullous lesions on his trunk (first lesions), palms, and the scrotum (Fig. 1c–f). He was admitted to the infectious diseases ward. Antibiotic treatment was changed to levofloxacin, and due to the severity and rapid expansion of the mucocutaneous lesions, a supportive treatment with intravenous prednisolone was initiated by the consultant dermatologist (Fig. 2).Fig. 1 Involvement of different cutaneous and mucosal sites. a Conjunctivitis. b Erosive stomatitis and cheilitis. c Example of an early cutaneous blister. d Confluent area of epithelial detachment at the scrotal skin. e, f Widespread distribution of cutaneous lesions over the trunk (e) and extremities (f)
Fig. 2 Timeline. Timeline of symptoms, drug exposure and treatment, including C-reactive protein (CRP) levels (dark grey line, normal range: < 5 mg/l, scale on the left side), total leukocyte count (light grey line, normal range: 3.9–10.5 /nl, scale on the right side) and percentage of CD4+CD8+ T cells (among total T cells) in peripheral blood (PB, orange) and blister fluid (BF, red). When percentage of CD4+CD8+ T cells was determined by two panels at the same day, the mean was calculated. Dosage of medication was 2 × 875/125 mg/d for amoxicillin-clavulanic acid (AMC), 2 × 250 mg/d for clarithromycin (CLR) and 2 × 500 mg/d for levofloxacin (LVX). Paracetamole, ibuprofen, and metamizole were taken successively, however, exact dosage could not be evaluated retrospectively. Further abbreviations: CAP: community-aquired pneumonia, EMM: Erythema multiforme majus, d: day, w: week, y: year
The medical history revealed that the patient had previously suffered from recurring respiratory tract infections, mainly bronchitis, up to five times per year. He had known allergies to grass-pollen and house dust mite with mild symptoms of allergic rhino-conjunctivitis. Of note, he had previously suffered from recurring enoral aphthous ulcers and recurring conjunctivitis in the past, the latter of which almost exclusively occurred in conjunction with respiratory infections. The family history revealed that his father, sister and son also suffered from recurring aphthous stomatitis. Immunological testing performed two years prior to the onset of mucocutaneous disease had not shown abnormal findings, with the exception of an isolated mannose-binding lectin deficiency (37.6 ng/ml; values > 50 ng/ml were considered normal) and slightly elevated serum levels of serum IgE (368.8 kU/l, values < 100 kU/l were considered normal).
In the days prior to presenting to the emergency department, the patient had taken the following medication; paracetamol (started six days prior to conjunctivitis, which was the first sign of mucocutaneous disease), ibuprofen (started four days prior to conjunctivits) and metamizole (started two days prior to conjunctivitis) (Fig. 2), a non-opioid analgesic commonly used in Germany but not available in all countries. He reported that he had taken paracetamol several times in the past without any adverse reactions to the drug. In contrast, he reported that it was his first-time exposure to ibuprofen and metamizole. Extensive microbiological and virological testing revealed weakly positive polymerase chain reaction (PCR) results for Bordetella parapertussis (B. parapertussis) in pharyngeal swabs, positive Mycoplasma pneumoniae serology and subsequent seroconversion (on admission: IgM 11.2, IgG negative; seven weeks later: IgM 35.0, IgG 19.1, values < 8.5 were considered normal) and marginally positive Human Herpesvirus 6 (HHV6)-IgM serology. Neither of these pathogens (B. parapertussis, Mp and HHV-6) could be detected by PCR in cutaneous blister fluid (BF). All other microbiological and virological analyses, including HSV-1/2 (PCR in peripheral blood (PB), BF, throat wash and eye smear negative, HSV1/2-IgM and IgG negative, serology negative also 2 years before), Epstein-Barr virus (EBV, DNA in PB 2260 copies/ml, limit of detection 1000 copies/ml, PCR in BF and throat wash negative, EBNA1-IgG 72,9; VCA-IgG > 750; EBV-IgM negative, tested twice 3 days apart), cytomegalovirus (CMV, PCR negative in PB, BF and throat wash), were not indicative of infection or reactivation.
The clinical presentation was characteristic of EMM, with mainly round target lesions showing central blistering and mucosal involvement of two mucosal sites (oral and ocular mucosa) (Fig. 1a, b). As there was no indication of recent HSV infection/reactivation and neither HHV-6, nor B. parapertussis have been reported as causes of EMM in the literature, Mp was considered the most likely trigger of mucocutaneous disease. Drugs have also been associated with EM [6], however, in retrospect these associations were often misclassified [22]. Therefore, drugs may not be considered likely triggers in a patient with EM lesions. In our patient, antibiotics could be excluded as causative triggers, since first symptoms (conjunctivitis) appeared prior to first exposure. Since the patient had been previously exposed to paracetamol without adverse reactions, this drug was also considered an unlikely trigger of the eruptions. Ibuprofen and metamizole, which were taken four days (ibuprofen) and two days (metamizole) before onset of conjunctivitis, cannot be completely ruled out as (co-) triggers—especially as it has been reported that Mp and non-opioid analgesics might also synergistically trigger disease [14]. Lymphocyte transformation testing (LTT) to assess for potential drug involvement was not conclusive when performed during the acute phase, as the positive control tested negative, potentially due to systemic high-dose corticosteroid (CS) treatment, and it did not retrieve positive results for any of the drugs four months after the acute phase. LTT often produces negative results after the acute phase and, therefore, it does not exclude drug causality [23].
The skin lesions as well as stomatitis and cheilitis slowly receded over the course of several weeks on symptomatic treatment and systemic CS. Pneumonic infiltration in chest X-ray had also largely dissolved at the time of discharge. In contrast, ocular lesions persisted and required prolonged treatment with topical CS and locally administered cyclosporine. The patient also reported a persistent dry cough over five months after discharge, as well as exertional dyspnea (which he had not experienced before) and pulmonary function test abnormalities (hyperinflation and airflow obstruction) that did not respond to treatment with systemic or inhaled CS and long-acting beta-2 agonists and were still present 1.5 years after the acute phase.
In order to better characterize the immunological changes, we analyzed the immune cell composition in PB and in cutaneous BF. Flow cytometry analyses on day five after initiation of CS treatment revealed that the inflammatory infiltrate in blisters was dominated by neutrophils (52%) and T cells (32%), with only minor representation of monocytes (6.9%), eosinophils (3.5%) and Natural Killer (NK) cells (1.5%). B cells (0.08%) were virtually absent in BF. We found that approximately 50% of BF T cells were double positive for CD4 and CD8 (48.5% three days, and 50.7% five days after initiation of CS treatment, Fig. 3a). A similarly expanded CD4+CD8+ T cell population was also detected in the patient’s PB (24.9% of all T cells before CS treatment, Fig. 3b; 13.4% (panel 1) or 11.0% (panel 2) five days after initiation of CS, Fig. 3a). This finding was verified by independent staining panels (Fig. 3a), largely excluding technical artefacts. CD4+CD8+ T cells belonged to the CD4lowCD8high subgroup of CD4+CD8+ T cells (Fig. 3a, b) and therefore likely might have derived from mature CD8+ T cells [24, 25]. TCRVβ clonotyping revealed that nearly all of the CD4+CD8+ T cells were TCRVβ2+ cells (99.2% in BF, 92.6% in PB, Fig. 3c), indicating a mono- (or oligo-) clonal expansion of the CD4+CD8+ T cells. A previous assessment two years before the onset of disease had shown a normal percentage of CD4+CD8+ T cells in PB (1.86% of T cells, Figs. 2, 3b). Over time, and potentially under the influence of systemic CS, which are known to decrease T cell activation and proliferation [26], the population size of CD4+CD8+ T cells in PB gradually declined to baseline levels (Figs. 2, 3b), along with the regression of mucocutaneous lesions (Fig. 2). We therefore hypothesize that this clonally expanded CD4+CD8+ T cell population was involved in disease pathophysiology in our patient.Fig. 3 Detection of a clonally expanded CD4+CD8+ T cell population in blister fluid and peripheral blood. a CD4+CD8+ T cell frequencies within blister fluid (BF) and peripheral blood (PB) in two different flow cytometry staining panels (panel 1 and panel 2) 3–5 days after the initiation of corticosteroid (CS) treatment. b Frequencies of CD4+CD8+ T cells within PB 2 years prior to onset of disease, during the acute phase before initiation of CS treatment and 19 weeks after the acute stage. c Flow cytometry analysis of the frequency of TCRVβ2+ cells among CD4+CD8−, CD4−CD8 + and CD4+CD8+ T cell subsets at day 5 after initiation of CS treatment. Antibody against TCRVβ2 was labeled to FITC and PE at equal amounts. d Flow cytometry analysis of the frequency of PB T cells expressing the cytotoxic mediators granulysin and perforin among CD4+CD8−, CD4−CD8+ and CD4+CD8+ T cell subsets, assessed 10 days after initiation of CS treatment. The most relevant findings are highlighted in red
Granulysin has been identified as an important effector molecule in bullous skin disorders mediated by cytotoxic T cells [27–29], including EMM [27, 28]. CD4+CD8+ T cells in BF in our patient expressed high levels of granulysin, along with perforin, and the frequency of cells expressing these cytotoxic markers among CD4+CD8+ was higher than among CD4+ or CD8+ single positive T cells (37,6% of cells among vs. 10,8% among CD4−CD8+ and 0,02% among CD4+CD8− T cells, Fig. 3d), further indicating a pathogenic role of these cells in disease pathophysiology.
BF T cells displayed a highly activated (CD69+, HLA-DR+, CD11a+), highly differentiated (CD28−, CD57+) and Natural Killer T (NKT) cell -like (CD16/56+) phenotype (Table 1). Their counterpart population in PB displayed a similar phenotype, yet with different expression patterns of the activation marker CD69 and CD45RA (Table 1).Table 1 Phenotype of T cells in blister fluid (BF) and peripheral blood (PB)
Total CD3+ CD4+CD8− CD4−CD8+ CD4 +CD8+
BF PB BF PB BF PB BF PB
TRM cell marker
CD69+ 68.4 3.30 67.4 0.52 66.9 5.91 68.2 1.26
CD69+CD103 + 6.23 NA 3.56 NA 8.33 NA 6.91 NA
MAIT cell marker
MR1+ (5-OP-RU) 1.25 2.09 0.50 0.28 3.16 4.36 0.34 0.46
NKT cell marker
CD16/56+ 64.6 24.4 1.41 1.14 67.2 36.3 87.9 86.1
Memory marker
CD45RA+ 11.5 68.2 0.67 62.7 20.7 78.4 10.6 61.1
Naive (CD45RA+CCR7 +) NA 41.3 NA 62.4 NA 32.8 NA 4.06
TEMRA (CD45RA+CCR7− NA 26.9 NA 0.27 NA 45.6 NA 57.0
TCM (CD45RA−CCR7+) NA 10.0 NA 20.7 NA 1.08 NA 0.55
TEM (CD45RA−CCR7−) NA 21.8 NA 16.6 NA 20.6 NA 38.4
Activation/differentiation marker
CD69+ 68.4 3.30 67.4 0.52 66.9 5.91 68.2 1.26
HLA-DR+ 37.3 19.0 25.4 4.76 24.6 20.3 52.6 65.7
CD11ahigh 81.5 42.7 46.0 13.2 84.3 61.3 94.7 95.6
CD57+ 33.1 25.9 3.77 2.46 33.9 38.6 48.0 77.3
CD28+ 32.1 69.2 99.2 99.0 34.1 53.8 0.70 5.33
Phenotypic flow cytometry analyses were performed 3–5 days after initiation of CS treatment. NA not assessed. Numbers represent proportions (%) of cells expressing the respective markers among total T cells (CD3+) or among a subset of T cells (CD4+CD8− T cells, CD4−CD8 + T cells or CD4+CD8+ T cells)
More than half (57.0%) of CD4+CD8+ T cells in PB displayed a “T effector memory RA” (TEMRA, CCR7−CD45RA+) phenotype and were negative for CD69, whereas most BF CD4+CD8+ T cells did not express CD45RA and were CD69+ (Table 1). Only a minority of BF T cells was CD69+CD103+ (6,23% of total BF T cells, 6,91% of CD4+CD8+ BF T cells, Table 1), indicating that BF T cells did not represent “classical” long term Tissue Resident Memory T cells (TRM) of the epithelium [30], which have been previously implicated as potential triggers of tissue-specific restriction of symptoms in mucocutaneous diseases such as SJS/TEN [31]. Mucosal-Associated Invariant T (MAIT) cells, a semi-invariant T cell population that has been shown to display high cytotoxicity against bacterially infected epithelial cells [32] were also present only in low frequencies (1,25% of total BF T cells, Table 1).
Conclusions
To the best of our knowledge, this is the first report of a large clonal expansion of CD4+CD8+ T cells in BF and PB of a patient with Mp-associated EMM. In the published literature, we could only find one other report describing BF immune cells in mucocutaneous disease in the context of Mp infection, which reported “elevated CD4+ /CD8+ (697/558 × 105/L) T cells with absence of B cells” in a pediatric patient with widespread epithelial detachment of the skin, reminiscent of SJS/TEN [33]. This report did not provide primary flow cytometry data and lacked further phenotypical characterization of T cells.
CD4lowCD8high T cells have been studied in the context of various viral infections such as HHV-6 [34], EBV [35, 36] and CMV [36] and there is solid published evidence that stimulation of CD8+ T cells via their TCR in combination with CD28 costimulation, but none of those signals alone, can lead to de novo expression of CD4 [37–40]. The role of other signals in this process and the stability of CD4 expression is unknown. If CD4/CD8 co-expression is of direct pathophysiologic relevance remains unclear. In line with our findings of higher cytotoxic mediator content in CD4+CD8+ cells (Fig. 3d), it has been found, that ligation of CD4 augments the cytotoxic potential of CD4lowCD8high T cells [39, 41]. Interestingly, CD4+CD8+ carbamazepine-specific T cell clones could be generated from patients with carbamazepine hypersensitivity [42]. Some of these clones—in contrast to CD4+ or CD8+ single positive clones—displayed drug antigen-specific proliferation even in the absence of antigen-presenting cells or the presence of MHC class I and II blocking antibodies in vitro [42].
Extrapulmonary Mp manifestation in general can be classified according to different pathomechanisms as of i) a direct type (bacterium present at the site of inflammation), ii) an indirect type (bacterium not present at the site of inflammation) and iii) a vascular occlusion type [43]. Direct culture of Mp from vesicular skin lesions has been reported in several early case descriptions of Mp-associated EM [44] and SJS/TEN [45, 46], pointing towards a direct bacterial involvement in the pathophysiology. However, Mp was not detectable via PCR (targeting the Mp P1 adhesion gene) in lesional biopsies of patients with Mp-associated EM in a more recent study [7] and indirect pathomechanisms such as polyclonal B-cell activation, cross-reacting autoantibodies resulting from molecular mimicry, akin to Mp-associated Guillain-Barré syndrome, immune complex deposition and complement activation, have all been discussed and seem to be favored in the current literature [15–17, 43, 47, 48]. However, there is no direct evidence for any of these pathomechanisms in the literature. Our observation that lesional T cells were clonally enriched for one TCRVβ family and expressed cytotoxic molecules like granulysin and perforin, indicates a clonal T cell response directed against a defined antigen, similar to what has been observed in HAEM and in drug-induced SJS/TEN. Furthermore, the majority of the CD4+CD8+ T cells showed a TEMRA phenotype (CCR7−CD45RA+) in PB, but nearly all of the CD4+CD8+ T cells had lost CD45RA in BF, which has been reported for CD8+ TEMRA upon antigenic encounter [49]. This finding supports the hypothesis that circulating CD4+CD8+ TEMRA were recruited to mucosal and epithelial sites, where they downregulated CD45RA expression upon exposure to a defined antigen. This antigen could be an antigen of Mp, a neo- or autoantigen, or a viral or drug-derived antigen, in which case Mp would represent a co-stimulus rather than the primary cause of disease. Identifying the nature and the source of the causative antigen will be a critical step towards a targeted treatment.
No general conclusions can be drawn from observations in a single patient. However, in rare conditions such as Mp-associated EMM, observations made in single cases might be critical to generate hypotheses, disseminate knowledge and spur further systematic research.
Material and methods
Cell isolation and flow cytometry
Flow cytometry analyses of BF and PB (T) cells were performed in the diagnostic laboratory (Labor Berlin—Charité Vivantes GmbH) and in the research laboratory of our institution, according to standard protocols for isolation and surface staining of immune cells. BF immune cells were classified by granularity and size (side and forward scatter area) and expression levels of CD45, CD14 (monocytes), CD16/CD56 (neutrophils, proinflammatory monocytes, NK/NKT cells), CD19 (B cells), CD3 (T cells) following standard gating strategies used in routine diagnostics. T cells were then further characterized as shown in Table 1. TCRVβ clonotyping was performed using the IOTest Beta Mark TCR Vβ Repertoire Kit (Beckman Coulter). Fluorophore-conjugated 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU)-loaded Major Histocompatibility Complex class I related molecule 1 (MR1) tetramers were used to identify MAIT cells, 6-formylpterin (6-FP)-loaded MR1 tetramers were used as a negative control. For analysis of granulysin and perforin expression (Fig. 3d) peripheral blood mononuclear cells (PBMC) were cultured in a humidified incubator in the presence of brefeldin A and monensin for 2 h before intracellular cytokine staining. Cells were not restimulated with Phorbol-12-myristat-13-acetat (PMA)/Ionomycin, to prevent PMA/Ionomycin induced downregulation of the CD4 molecule and secretion of granulysin and perforin. All flow cytometry analyses were performed on fresh PBMC processed immediately or kept at 4 °C overnight. Flow cytometry was performed on a BD FACS Canto II cytometer or Beckman Coulter 10-color Navios. Data was analyzed using FlowJo software Version 10 (Treestar).
Abbreviations
BFBlister fluid
B. parapertussisBordetella parapertussis
CAPCommunity-aquired pneumonia
CMVCytomegalovirus
CRPC-reactive protein
CSCorticosteroid(s)
EBNA1Epstein–Barr nuclear antigen 1
EBVEpstein-Barr virus
EMErythema multiforme
EMmErythema multiforme minus
EMMErythema multiforme majus
HHV-6Human Herpesvirus 6
HAEMHSV-associated erythema multiforme
HLAHuman Leukocyte Antigen
HSVHerpes Simplex virus
LTTLymphocyte transformation testing
MAIT cellMucosal-Associated Invariant T cell
MIRMMycoplasma pneumoniae-induced rash and mucositis
MpMycoplasma pneumonia
MR1Major Histocompatibility Complex class I related molecule 1
NK cellNatural Killer cell
NKT cellNatural Killer T cell
PBPeripheral blood
PBMCPeripheral blood mononuclear cells
PCRPolymerase chain reaction
PMAPhorbol-12-myristat-13-acetat
SJSStevens-Johnson syndrome
SJS/TENStevens-Johnson syndrome/Toxical Epidermal Necrolysis
TCRT cell receptor
TENToxical Epidermal Necrolysis
TEMRAT effector memory RA
TRMTissue Resident Memory T cells
VCAViral-capsid antigen
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Acknowledgements
We thank Dr. Cornelia Doebis, Sarah Altekrüger and Dr. Volker von Baehr from the “Institut für Medizinische Diagnostik Berlin” for performing LTT twice. The MR1 tetramer technology used for the detection of MAIT cells was developed jointly by Dr. James McCluskey, Dr. Jamie Rossjohn, and Dr. David Fairlie, and the material was produced by the NIH Tetramer Core Facility as permitted to be distributed by the University of Melbourne.
Authors’ contributions
S.M.V. conducted and interpreted immunological analyses, collected data and performed literature research. C.M. provided additional FACS data and provided important immunological insights and data interpretation. D.T. and G.J.B. interpreted clinical images of skin lesions and provided important dermatological insights. D.S., N.S. and L.E.S. took care of the patient and provided clinical data. S.M.V. and L.E.S wrote the manuscript. All authors read and approved the final manuscript.
Funding
Open Access funding enabled and organized by Projekt DEAL. This report was supported by the German Research Council (DFG, SFB-TR84 TP C08 and TP C10 to L.E.S., C09 to N.S.) and the Jürgen Manchot Foundation (doctoral fellowship to S.M.V.).
Availability of data and material
The datasets of this report are available from the corresponding author on reasonable request.
Ethics approval and consent to participate
Written and oral informed consent to participate has been obtained from the patient and may be requested to see a copy at any stage.
Consent for publication
Written informed consent for publication of his clinical details and/or clinical images was obtained from the patient. A copy of the consent form is available for review by the Editor of this journal.
Competing interests
The authors declare that they have no competing interests. | ACETAMINOPHEN, IBUPROFEN, METAMIZOLE | DrugsGivenReaction | CC BY | 33568212 | 19,681,953 | 2021-02-10 |
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