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What was the outcome of reaction 'Anticoagulation drug level above therapeutic'? | Mechanical valve replacement without anticoagulation: a case report.
For patients who undergo mechanical valve replacement, the greatest disadvantage is that they require long-term or permanent use of anticoagulant therapy to prevent thromboembolism. To date, mechanical valve replacement without anticoagulation has been published in the literature.
We present the case of a 75-year-old female who underwent mechanical mitral valve replacement (MVR) on mid-June, 2007. However, this patient had not been taking anticoagulant medication since she experienced warfarin overdose in the first month after the operation. She had been well without using any anticoagulation, and there were no complications of the mechanical valve.
There was no thrombosis for such a long period of time because she suffered from FX deficiency. To the best of our knowledge, she may be the only patient who has been well without any anticoagulation since not taking warfarin 12 years ago.
Learning points
The patient suffers Factor X (FX) deficiency.
To the best of our knowledge, she may be the only patient who has been well without any anticoagulation since not taking warfarin 12 years ago.
Introduction
Prosthetic heart valve replacement is recommended for patients with severe cardiac valve disease and is performed in many patients worldwide every year.1 Mechanical valves are more durable than bioprosthetic valves,2 but patients with these valves require lifelong anticoagulant therapy. Warfarin provide excellent protection against thrombo-embolic complications in patients with mechanical heart valves,3 but these patients require lifelong monitoring of coagulation studies. Because excessive or insufficient anti-coagulant effects may cause severe clinical symptoms such as bleeding and thrombo-embolic events, it is difficult for clinicians to estimate the optimal initial dosage of warfarin to attain such a narrow therapeutic international normalized ratio (INR) range for every patient.
Timeline
Dates Presentation Investigations Findings
14 June 2007 Progressive dyspnoea Echocardiography Severe mitral regurgitation
July 2007
July 2007 to October 2019
October 2019
Skin purpura
Asymptomatic
Oedema of the legs
Monitor anticoagulant function
Telephone and outpatient follow-up
Echocardiography
Excessive anticoagulation without bleeding
She was well without any anticoagulation
Right ventricular dysfunction
Case presentation
A 75-year-old Chinese woman was admitted to the hospital with symptoms of progressive oedema of the lower limbs. On physical exam, her head exam revealed a normocephalic, atraumatic head with no palpable or visible masses. A neck exam revealed no lymphadenopathy, jugular venous distention, or carotid bruits. A cardiovascular exam was significant for abnormal S1 and S2 but no murmurs or thrills on auscultation. Breath sounds were clear and symmetric bilaterally, without any crackles, wheezes, or rhonchi. Her abdomen was soft, non-distended, and non-tender, with normal bowel sounds and no organomegaly.
The patient underwent mechanical mitral valve (GK-3 tilting disc, 27 mm, made in China) replacement surgery on mid-June, 2007. She had a history of hypertension for 15 years. At this time, she was admitted to our hospital again because of right ventricular dysfunction. The patient was discharged after symptoms of shortness of breath, leg swelling had been improved with diuretic therapy.
We found that the patient had been taking 0.625 mg warfarin per day since one month after surgery, but due to excessive anticoagulation, she suffered from skin purpura without bleeding and neurological complications. Therefore, she had stopped taking warfarin and other anticoagulant treatments since she experienced excessive anticoagulation. Interestingly, her INR had always remained in the range of 2.0–2.5 until now without any anticoagulants. Follow-up interval for her will be half a year in the future.
Repeat echocardiography showed a normal-functioning mechanical mitral prosthesis (Figure 1). On 29 September 2019, transthoracic echocardiography showed right ventricular enlargement (Figure 2) and normal left ventricular function (Figure 3), and the mitral valve was working well without any vegetation (Videos 1 and 2). There was no thrombosis in the heart valve or left atrium. The preoperative PT and INR of this patient were 22.5 s and 2.02, respectively. Warfarin-related genes were tested (Table 1). These genes were normal. We found that the patient suffered from factor X (FX) deficiency (Table 2). Therefore, we considered that this patient, without any anticoagulants, did not have thrombo-embolic complications due to the FX deficiency.
Figure 1 Transthoracic echocardiography showing a normal-functioning mechanical mitral prosthesis.
Figure 2 Transthoracic echocardiography showing right ventricular dysfunction.
Figure 3 Transthoracic echocardiography showing normal left ventricular function.
Table 1 Gene studies of the patient
Gene Genotype Result
MTHFR (C677T) CC, CT, TT CC
PAI-1 (5G/4G) 5G/5G, 5G/4G, 4G/4G 5G/5G
CYP2C9*2 (R144C, C→T) CC, CT, TT CC
CYP2C9*3 (I359L, A→C) AA, AC, CC AA
VKORC1 (G-1639A) GG, GA, AA AA
Table 2 Coagulation factor studies of the patient
Factor Result Normal
II: C 76.40% ↓ 79–131%
V: C 105.10% 62–139%
VII: C 75.30% 50–129%
VIII: C 126.70% 50–150%
IX: C 113.90% 65–150%
X: C 7.10% ↓↓ 77–131%
XI: C 83.70% 65–150%
XII: C 71.80% 50–150%
PT 24.60 s ↑ 9.9–12.8 s
APTT 48.00 s ↑ 25.1–36.5 s
INR 2.22
Discussion
Cardiac valve replacement is one of the most effective methods for the treatment of mid- to late-stage cardiac valvular diseases. In China, cardiac valve replacements account for 30% of cardiac procedures.4 With the continuous improvements in perioperative management and surgical techniques, heart valve surgery has lower mortality. However, there is a high incidence of thrombo-embolic events of approximately 1–4% per year.5 The bleeding risk is significant, ranging from 2% to 9% per year.6 Therefore, the greatest disadvantage of this surgery is that patients require long-term or permanent use of anticoagulant therapy to prevent thrombo-embolic events.
Warfarin is an effective drug for addressing this problem but increases the risk of major bleeding at the same time.7 Warfarin interferes with the hepatic synthesis of vitamin K-dependent clotting factors II, VII, IX, and X, resulting in their eventual depletion and a prolongation in the clotting time, as measured by the PT and INR. Compared with other drugs, warfarin has been viewed as the most frequently used clinical oral anticoagulant drug due to its relatively low cost.8,9 However, the toxic dose of warfarin is close to the dosage required to achieve a pharmaceutical effect. The warfarin dosage response is related to demographic, environmental, clinical and, especially, genetic factors.10 Due to the narrow therapeutic range as well as interactions and genetic variants, patients who experience warfarin overdose need genetic testing for the initial estimate of warfarin dose and the close monitoring of the intensity of anticoagulation with warfarin.11 In our hospital, we have been able to widely perform warfarin-related gene testing in patients with abnormal coagulation function. If a patient with a mechanical heart valve presents with warfarin overdose, vitamin K and fresh-frozen plasma should be given. The American College of Chest Physicians (2008) guidelines recommend oral doses of 1–2.5 mg vitamin K for an INR between 5 and 9 and 2.5–5 mg for all patients with an INR ≥ 9 but with no significant bleeding.12 The INR is then monitored every 4–6 h after administering vitamin K. When the INR is <3, the lowest dose of warfarin is given to prevent thrombosis.12
Factor X, a vitamin K-dependent plasma glycoprotein, plays a pivotal role in the coagulation cascade. Factor X is the first enzyme in the common pathway of thrombin formation. Factor X deficiency is a rare, recessively inherited bleeding disorder representing 10% of all rare bleeding diseases and affecting 1 in every 1 000 000 people.13 Factor X deficiency can be congenital or acquired.14 The diagnosis of factor X deficiency is usually suspected when both the prothrombin time and activated partial thromboplastin time are abnormal and are corrected upon mixing 1:1 with normal plasma.15 The functional activity of Factor X (FX: C) is quantified by performing a prothrombin time-based assay using rabbit thromboplastin and factor X-deficient plasma. Accordingly, patients are classified into three groups: severe (FX: C, <1%), moderate (FX: C, 1–4%), and mild (FX: C, 6–10%).16
Rivaroxaban is a direct and selective coagulation factor Xa inhibitor. Indications for the use of these agents include the prevention of stroke in non-valvular atrial fibrillation and for the prevention and treatment of deep vein thrombosis and pulmonary embolism as well as the prevention of venous thrombosis after orthopaedic surgery, but these agents are not indicated for patients undergoing cardiac valve replacement.17 There was a case report where a patient who underwent mechanical aortic valve replacement was administered the oral anticoagulant rivaroxaban instead of warfarin, which caused a significant gradient and thrombosis on one leaflet of the valve.18 This patient died due to complications from the thrombotic valve. However, for this patient with FX deficiency, she had not been taking any anticoagulants and did not have any complications due to the mechanical valve.
Conclusion
We believe that there was no thrombosis for such a long period of time because she suffered from FX deficiency. We have not found out other mechanisms to explain this phenomenon so far.
Lead author biography
I am a cardiac surgeon and have two English papers.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing these cases and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytaa566_Supplementary_Data Click here for additional data file. | Recovered | ReactionOutcome | CC BY | 33644653 | 19,008,280 | 2021-01 |
What was the outcome of reaction 'Factor X deficiency'? | Mechanical valve replacement without anticoagulation: a case report.
For patients who undergo mechanical valve replacement, the greatest disadvantage is that they require long-term or permanent use of anticoagulant therapy to prevent thromboembolism. To date, mechanical valve replacement without anticoagulation has been published in the literature.
We present the case of a 75-year-old female who underwent mechanical mitral valve replacement (MVR) on mid-June, 2007. However, this patient had not been taking anticoagulant medication since she experienced warfarin overdose in the first month after the operation. She had been well without using any anticoagulation, and there were no complications of the mechanical valve.
There was no thrombosis for such a long period of time because she suffered from FX deficiency. To the best of our knowledge, she may be the only patient who has been well without any anticoagulation since not taking warfarin 12 years ago.
Learning points
The patient suffers Factor X (FX) deficiency.
To the best of our knowledge, she may be the only patient who has been well without any anticoagulation since not taking warfarin 12 years ago.
Introduction
Prosthetic heart valve replacement is recommended for patients with severe cardiac valve disease and is performed in many patients worldwide every year.1 Mechanical valves are more durable than bioprosthetic valves,2 but patients with these valves require lifelong anticoagulant therapy. Warfarin provide excellent protection against thrombo-embolic complications in patients with mechanical heart valves,3 but these patients require lifelong monitoring of coagulation studies. Because excessive or insufficient anti-coagulant effects may cause severe clinical symptoms such as bleeding and thrombo-embolic events, it is difficult for clinicians to estimate the optimal initial dosage of warfarin to attain such a narrow therapeutic international normalized ratio (INR) range for every patient.
Timeline
Dates Presentation Investigations Findings
14 June 2007 Progressive dyspnoea Echocardiography Severe mitral regurgitation
July 2007
July 2007 to October 2019
October 2019
Skin purpura
Asymptomatic
Oedema of the legs
Monitor anticoagulant function
Telephone and outpatient follow-up
Echocardiography
Excessive anticoagulation without bleeding
She was well without any anticoagulation
Right ventricular dysfunction
Case presentation
A 75-year-old Chinese woman was admitted to the hospital with symptoms of progressive oedema of the lower limbs. On physical exam, her head exam revealed a normocephalic, atraumatic head with no palpable or visible masses. A neck exam revealed no lymphadenopathy, jugular venous distention, or carotid bruits. A cardiovascular exam was significant for abnormal S1 and S2 but no murmurs or thrills on auscultation. Breath sounds were clear and symmetric bilaterally, without any crackles, wheezes, or rhonchi. Her abdomen was soft, non-distended, and non-tender, with normal bowel sounds and no organomegaly.
The patient underwent mechanical mitral valve (GK-3 tilting disc, 27 mm, made in China) replacement surgery on mid-June, 2007. She had a history of hypertension for 15 years. At this time, she was admitted to our hospital again because of right ventricular dysfunction. The patient was discharged after symptoms of shortness of breath, leg swelling had been improved with diuretic therapy.
We found that the patient had been taking 0.625 mg warfarin per day since one month after surgery, but due to excessive anticoagulation, she suffered from skin purpura without bleeding and neurological complications. Therefore, she had stopped taking warfarin and other anticoagulant treatments since she experienced excessive anticoagulation. Interestingly, her INR had always remained in the range of 2.0–2.5 until now without any anticoagulants. Follow-up interval for her will be half a year in the future.
Repeat echocardiography showed a normal-functioning mechanical mitral prosthesis (Figure 1). On 29 September 2019, transthoracic echocardiography showed right ventricular enlargement (Figure 2) and normal left ventricular function (Figure 3), and the mitral valve was working well without any vegetation (Videos 1 and 2). There was no thrombosis in the heart valve or left atrium. The preoperative PT and INR of this patient were 22.5 s and 2.02, respectively. Warfarin-related genes were tested (Table 1). These genes were normal. We found that the patient suffered from factor X (FX) deficiency (Table 2). Therefore, we considered that this patient, without any anticoagulants, did not have thrombo-embolic complications due to the FX deficiency.
Figure 1 Transthoracic echocardiography showing a normal-functioning mechanical mitral prosthesis.
Figure 2 Transthoracic echocardiography showing right ventricular dysfunction.
Figure 3 Transthoracic echocardiography showing normal left ventricular function.
Table 1 Gene studies of the patient
Gene Genotype Result
MTHFR (C677T) CC, CT, TT CC
PAI-1 (5G/4G) 5G/5G, 5G/4G, 4G/4G 5G/5G
CYP2C9*2 (R144C, C→T) CC, CT, TT CC
CYP2C9*3 (I359L, A→C) AA, AC, CC AA
VKORC1 (G-1639A) GG, GA, AA AA
Table 2 Coagulation factor studies of the patient
Factor Result Normal
II: C 76.40% ↓ 79–131%
V: C 105.10% 62–139%
VII: C 75.30% 50–129%
VIII: C 126.70% 50–150%
IX: C 113.90% 65–150%
X: C 7.10% ↓↓ 77–131%
XI: C 83.70% 65–150%
XII: C 71.80% 50–150%
PT 24.60 s ↑ 9.9–12.8 s
APTT 48.00 s ↑ 25.1–36.5 s
INR 2.22
Discussion
Cardiac valve replacement is one of the most effective methods for the treatment of mid- to late-stage cardiac valvular diseases. In China, cardiac valve replacements account for 30% of cardiac procedures.4 With the continuous improvements in perioperative management and surgical techniques, heart valve surgery has lower mortality. However, there is a high incidence of thrombo-embolic events of approximately 1–4% per year.5 The bleeding risk is significant, ranging from 2% to 9% per year.6 Therefore, the greatest disadvantage of this surgery is that patients require long-term or permanent use of anticoagulant therapy to prevent thrombo-embolic events.
Warfarin is an effective drug for addressing this problem but increases the risk of major bleeding at the same time.7 Warfarin interferes with the hepatic synthesis of vitamin K-dependent clotting factors II, VII, IX, and X, resulting in their eventual depletion and a prolongation in the clotting time, as measured by the PT and INR. Compared with other drugs, warfarin has been viewed as the most frequently used clinical oral anticoagulant drug due to its relatively low cost.8,9 However, the toxic dose of warfarin is close to the dosage required to achieve a pharmaceutical effect. The warfarin dosage response is related to demographic, environmental, clinical and, especially, genetic factors.10 Due to the narrow therapeutic range as well as interactions and genetic variants, patients who experience warfarin overdose need genetic testing for the initial estimate of warfarin dose and the close monitoring of the intensity of anticoagulation with warfarin.11 In our hospital, we have been able to widely perform warfarin-related gene testing in patients with abnormal coagulation function. If a patient with a mechanical heart valve presents with warfarin overdose, vitamin K and fresh-frozen plasma should be given. The American College of Chest Physicians (2008) guidelines recommend oral doses of 1–2.5 mg vitamin K for an INR between 5 and 9 and 2.5–5 mg for all patients with an INR ≥ 9 but with no significant bleeding.12 The INR is then monitored every 4–6 h after administering vitamin K. When the INR is <3, the lowest dose of warfarin is given to prevent thrombosis.12
Factor X, a vitamin K-dependent plasma glycoprotein, plays a pivotal role in the coagulation cascade. Factor X is the first enzyme in the common pathway of thrombin formation. Factor X deficiency is a rare, recessively inherited bleeding disorder representing 10% of all rare bleeding diseases and affecting 1 in every 1 000 000 people.13 Factor X deficiency can be congenital or acquired.14 The diagnosis of factor X deficiency is usually suspected when both the prothrombin time and activated partial thromboplastin time are abnormal and are corrected upon mixing 1:1 with normal plasma.15 The functional activity of Factor X (FX: C) is quantified by performing a prothrombin time-based assay using rabbit thromboplastin and factor X-deficient plasma. Accordingly, patients are classified into three groups: severe (FX: C, <1%), moderate (FX: C, 1–4%), and mild (FX: C, 6–10%).16
Rivaroxaban is a direct and selective coagulation factor Xa inhibitor. Indications for the use of these agents include the prevention of stroke in non-valvular atrial fibrillation and for the prevention and treatment of deep vein thrombosis and pulmonary embolism as well as the prevention of venous thrombosis after orthopaedic surgery, but these agents are not indicated for patients undergoing cardiac valve replacement.17 There was a case report where a patient who underwent mechanical aortic valve replacement was administered the oral anticoagulant rivaroxaban instead of warfarin, which caused a significant gradient and thrombosis on one leaflet of the valve.18 This patient died due to complications from the thrombotic valve. However, for this patient with FX deficiency, she had not been taking any anticoagulants and did not have any complications due to the mechanical valve.
Conclusion
We believe that there was no thrombosis for such a long period of time because she suffered from FX deficiency. We have not found out other mechanisms to explain this phenomenon so far.
Lead author biography
I am a cardiac surgeon and have two English papers.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing these cases and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytaa566_Supplementary_Data Click here for additional data file. | Recovered | ReactionOutcome | CC BY | 33644653 | 19,008,280 | 2021-01 |
What was the outcome of reaction 'Neurological symptom'? | Mechanical valve replacement without anticoagulation: a case report.
For patients who undergo mechanical valve replacement, the greatest disadvantage is that they require long-term or permanent use of anticoagulant therapy to prevent thromboembolism. To date, mechanical valve replacement without anticoagulation has been published in the literature.
We present the case of a 75-year-old female who underwent mechanical mitral valve replacement (MVR) on mid-June, 2007. However, this patient had not been taking anticoagulant medication since she experienced warfarin overdose in the first month after the operation. She had been well without using any anticoagulation, and there were no complications of the mechanical valve.
There was no thrombosis for such a long period of time because she suffered from FX deficiency. To the best of our knowledge, she may be the only patient who has been well without any anticoagulation since not taking warfarin 12 years ago.
Learning points
The patient suffers Factor X (FX) deficiency.
To the best of our knowledge, she may be the only patient who has been well without any anticoagulation since not taking warfarin 12 years ago.
Introduction
Prosthetic heart valve replacement is recommended for patients with severe cardiac valve disease and is performed in many patients worldwide every year.1 Mechanical valves are more durable than bioprosthetic valves,2 but patients with these valves require lifelong anticoagulant therapy. Warfarin provide excellent protection against thrombo-embolic complications in patients with mechanical heart valves,3 but these patients require lifelong monitoring of coagulation studies. Because excessive or insufficient anti-coagulant effects may cause severe clinical symptoms such as bleeding and thrombo-embolic events, it is difficult for clinicians to estimate the optimal initial dosage of warfarin to attain such a narrow therapeutic international normalized ratio (INR) range for every patient.
Timeline
Dates Presentation Investigations Findings
14 June 2007 Progressive dyspnoea Echocardiography Severe mitral regurgitation
July 2007
July 2007 to October 2019
October 2019
Skin purpura
Asymptomatic
Oedema of the legs
Monitor anticoagulant function
Telephone and outpatient follow-up
Echocardiography
Excessive anticoagulation without bleeding
She was well without any anticoagulation
Right ventricular dysfunction
Case presentation
A 75-year-old Chinese woman was admitted to the hospital with symptoms of progressive oedema of the lower limbs. On physical exam, her head exam revealed a normocephalic, atraumatic head with no palpable or visible masses. A neck exam revealed no lymphadenopathy, jugular venous distention, or carotid bruits. A cardiovascular exam was significant for abnormal S1 and S2 but no murmurs or thrills on auscultation. Breath sounds were clear and symmetric bilaterally, without any crackles, wheezes, or rhonchi. Her abdomen was soft, non-distended, and non-tender, with normal bowel sounds and no organomegaly.
The patient underwent mechanical mitral valve (GK-3 tilting disc, 27 mm, made in China) replacement surgery on mid-June, 2007. She had a history of hypertension for 15 years. At this time, she was admitted to our hospital again because of right ventricular dysfunction. The patient was discharged after symptoms of shortness of breath, leg swelling had been improved with diuretic therapy.
We found that the patient had been taking 0.625 mg warfarin per day since one month after surgery, but due to excessive anticoagulation, she suffered from skin purpura without bleeding and neurological complications. Therefore, she had stopped taking warfarin and other anticoagulant treatments since she experienced excessive anticoagulation. Interestingly, her INR had always remained in the range of 2.0–2.5 until now without any anticoagulants. Follow-up interval for her will be half a year in the future.
Repeat echocardiography showed a normal-functioning mechanical mitral prosthesis (Figure 1). On 29 September 2019, transthoracic echocardiography showed right ventricular enlargement (Figure 2) and normal left ventricular function (Figure 3), and the mitral valve was working well without any vegetation (Videos 1 and 2). There was no thrombosis in the heart valve or left atrium. The preoperative PT and INR of this patient were 22.5 s and 2.02, respectively. Warfarin-related genes were tested (Table 1). These genes were normal. We found that the patient suffered from factor X (FX) deficiency (Table 2). Therefore, we considered that this patient, without any anticoagulants, did not have thrombo-embolic complications due to the FX deficiency.
Figure 1 Transthoracic echocardiography showing a normal-functioning mechanical mitral prosthesis.
Figure 2 Transthoracic echocardiography showing right ventricular dysfunction.
Figure 3 Transthoracic echocardiography showing normal left ventricular function.
Table 1 Gene studies of the patient
Gene Genotype Result
MTHFR (C677T) CC, CT, TT CC
PAI-1 (5G/4G) 5G/5G, 5G/4G, 4G/4G 5G/5G
CYP2C9*2 (R144C, C→T) CC, CT, TT CC
CYP2C9*3 (I359L, A→C) AA, AC, CC AA
VKORC1 (G-1639A) GG, GA, AA AA
Table 2 Coagulation factor studies of the patient
Factor Result Normal
II: C 76.40% ↓ 79–131%
V: C 105.10% 62–139%
VII: C 75.30% 50–129%
VIII: C 126.70% 50–150%
IX: C 113.90% 65–150%
X: C 7.10% ↓↓ 77–131%
XI: C 83.70% 65–150%
XII: C 71.80% 50–150%
PT 24.60 s ↑ 9.9–12.8 s
APTT 48.00 s ↑ 25.1–36.5 s
INR 2.22
Discussion
Cardiac valve replacement is one of the most effective methods for the treatment of mid- to late-stage cardiac valvular diseases. In China, cardiac valve replacements account for 30% of cardiac procedures.4 With the continuous improvements in perioperative management and surgical techniques, heart valve surgery has lower mortality. However, there is a high incidence of thrombo-embolic events of approximately 1–4% per year.5 The bleeding risk is significant, ranging from 2% to 9% per year.6 Therefore, the greatest disadvantage of this surgery is that patients require long-term or permanent use of anticoagulant therapy to prevent thrombo-embolic events.
Warfarin is an effective drug for addressing this problem but increases the risk of major bleeding at the same time.7 Warfarin interferes with the hepatic synthesis of vitamin K-dependent clotting factors II, VII, IX, and X, resulting in their eventual depletion and a prolongation in the clotting time, as measured by the PT and INR. Compared with other drugs, warfarin has been viewed as the most frequently used clinical oral anticoagulant drug due to its relatively low cost.8,9 However, the toxic dose of warfarin is close to the dosage required to achieve a pharmaceutical effect. The warfarin dosage response is related to demographic, environmental, clinical and, especially, genetic factors.10 Due to the narrow therapeutic range as well as interactions and genetic variants, patients who experience warfarin overdose need genetic testing for the initial estimate of warfarin dose and the close monitoring of the intensity of anticoagulation with warfarin.11 In our hospital, we have been able to widely perform warfarin-related gene testing in patients with abnormal coagulation function. If a patient with a mechanical heart valve presents with warfarin overdose, vitamin K and fresh-frozen plasma should be given. The American College of Chest Physicians (2008) guidelines recommend oral doses of 1–2.5 mg vitamin K for an INR between 5 and 9 and 2.5–5 mg for all patients with an INR ≥ 9 but with no significant bleeding.12 The INR is then monitored every 4–6 h after administering vitamin K. When the INR is <3, the lowest dose of warfarin is given to prevent thrombosis.12
Factor X, a vitamin K-dependent plasma glycoprotein, plays a pivotal role in the coagulation cascade. Factor X is the first enzyme in the common pathway of thrombin formation. Factor X deficiency is a rare, recessively inherited bleeding disorder representing 10% of all rare bleeding diseases and affecting 1 in every 1 000 000 people.13 Factor X deficiency can be congenital or acquired.14 The diagnosis of factor X deficiency is usually suspected when both the prothrombin time and activated partial thromboplastin time are abnormal and are corrected upon mixing 1:1 with normal plasma.15 The functional activity of Factor X (FX: C) is quantified by performing a prothrombin time-based assay using rabbit thromboplastin and factor X-deficient plasma. Accordingly, patients are classified into three groups: severe (FX: C, <1%), moderate (FX: C, 1–4%), and mild (FX: C, 6–10%).16
Rivaroxaban is a direct and selective coagulation factor Xa inhibitor. Indications for the use of these agents include the prevention of stroke in non-valvular atrial fibrillation and for the prevention and treatment of deep vein thrombosis and pulmonary embolism as well as the prevention of venous thrombosis after orthopaedic surgery, but these agents are not indicated for patients undergoing cardiac valve replacement.17 There was a case report where a patient who underwent mechanical aortic valve replacement was administered the oral anticoagulant rivaroxaban instead of warfarin, which caused a significant gradient and thrombosis on one leaflet of the valve.18 This patient died due to complications from the thrombotic valve. However, for this patient with FX deficiency, she had not been taking any anticoagulants and did not have any complications due to the mechanical valve.
Conclusion
We believe that there was no thrombosis for such a long period of time because she suffered from FX deficiency. We have not found out other mechanisms to explain this phenomenon so far.
Lead author biography
I am a cardiac surgeon and have two English papers.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing these cases and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytaa566_Supplementary_Data Click here for additional data file. | Recovered | ReactionOutcome | CC BY | 33644653 | 19,008,280 | 2021-01 |
What was the outcome of reaction 'Purpura'? | Mechanical valve replacement without anticoagulation: a case report.
For patients who undergo mechanical valve replacement, the greatest disadvantage is that they require long-term or permanent use of anticoagulant therapy to prevent thromboembolism. To date, mechanical valve replacement without anticoagulation has been published in the literature.
We present the case of a 75-year-old female who underwent mechanical mitral valve replacement (MVR) on mid-June, 2007. However, this patient had not been taking anticoagulant medication since she experienced warfarin overdose in the first month after the operation. She had been well without using any anticoagulation, and there were no complications of the mechanical valve.
There was no thrombosis for such a long period of time because she suffered from FX deficiency. To the best of our knowledge, she may be the only patient who has been well without any anticoagulation since not taking warfarin 12 years ago.
Learning points
The patient suffers Factor X (FX) deficiency.
To the best of our knowledge, she may be the only patient who has been well without any anticoagulation since not taking warfarin 12 years ago.
Introduction
Prosthetic heart valve replacement is recommended for patients with severe cardiac valve disease and is performed in many patients worldwide every year.1 Mechanical valves are more durable than bioprosthetic valves,2 but patients with these valves require lifelong anticoagulant therapy. Warfarin provide excellent protection against thrombo-embolic complications in patients with mechanical heart valves,3 but these patients require lifelong monitoring of coagulation studies. Because excessive or insufficient anti-coagulant effects may cause severe clinical symptoms such as bleeding and thrombo-embolic events, it is difficult for clinicians to estimate the optimal initial dosage of warfarin to attain such a narrow therapeutic international normalized ratio (INR) range for every patient.
Timeline
Dates Presentation Investigations Findings
14 June 2007 Progressive dyspnoea Echocardiography Severe mitral regurgitation
July 2007
July 2007 to October 2019
October 2019
Skin purpura
Asymptomatic
Oedema of the legs
Monitor anticoagulant function
Telephone and outpatient follow-up
Echocardiography
Excessive anticoagulation without bleeding
She was well without any anticoagulation
Right ventricular dysfunction
Case presentation
A 75-year-old Chinese woman was admitted to the hospital with symptoms of progressive oedema of the lower limbs. On physical exam, her head exam revealed a normocephalic, atraumatic head with no palpable or visible masses. A neck exam revealed no lymphadenopathy, jugular venous distention, or carotid bruits. A cardiovascular exam was significant for abnormal S1 and S2 but no murmurs or thrills on auscultation. Breath sounds were clear and symmetric bilaterally, without any crackles, wheezes, or rhonchi. Her abdomen was soft, non-distended, and non-tender, with normal bowel sounds and no organomegaly.
The patient underwent mechanical mitral valve (GK-3 tilting disc, 27 mm, made in China) replacement surgery on mid-June, 2007. She had a history of hypertension for 15 years. At this time, she was admitted to our hospital again because of right ventricular dysfunction. The patient was discharged after symptoms of shortness of breath, leg swelling had been improved with diuretic therapy.
We found that the patient had been taking 0.625 mg warfarin per day since one month after surgery, but due to excessive anticoagulation, she suffered from skin purpura without bleeding and neurological complications. Therefore, she had stopped taking warfarin and other anticoagulant treatments since she experienced excessive anticoagulation. Interestingly, her INR had always remained in the range of 2.0–2.5 until now without any anticoagulants. Follow-up interval for her will be half a year in the future.
Repeat echocardiography showed a normal-functioning mechanical mitral prosthesis (Figure 1). On 29 September 2019, transthoracic echocardiography showed right ventricular enlargement (Figure 2) and normal left ventricular function (Figure 3), and the mitral valve was working well without any vegetation (Videos 1 and 2). There was no thrombosis in the heart valve or left atrium. The preoperative PT and INR of this patient were 22.5 s and 2.02, respectively. Warfarin-related genes were tested (Table 1). These genes were normal. We found that the patient suffered from factor X (FX) deficiency (Table 2). Therefore, we considered that this patient, without any anticoagulants, did not have thrombo-embolic complications due to the FX deficiency.
Figure 1 Transthoracic echocardiography showing a normal-functioning mechanical mitral prosthesis.
Figure 2 Transthoracic echocardiography showing right ventricular dysfunction.
Figure 3 Transthoracic echocardiography showing normal left ventricular function.
Table 1 Gene studies of the patient
Gene Genotype Result
MTHFR (C677T) CC, CT, TT CC
PAI-1 (5G/4G) 5G/5G, 5G/4G, 4G/4G 5G/5G
CYP2C9*2 (R144C, C→T) CC, CT, TT CC
CYP2C9*3 (I359L, A→C) AA, AC, CC AA
VKORC1 (G-1639A) GG, GA, AA AA
Table 2 Coagulation factor studies of the patient
Factor Result Normal
II: C 76.40% ↓ 79–131%
V: C 105.10% 62–139%
VII: C 75.30% 50–129%
VIII: C 126.70% 50–150%
IX: C 113.90% 65–150%
X: C 7.10% ↓↓ 77–131%
XI: C 83.70% 65–150%
XII: C 71.80% 50–150%
PT 24.60 s ↑ 9.9–12.8 s
APTT 48.00 s ↑ 25.1–36.5 s
INR 2.22
Discussion
Cardiac valve replacement is one of the most effective methods for the treatment of mid- to late-stage cardiac valvular diseases. In China, cardiac valve replacements account for 30% of cardiac procedures.4 With the continuous improvements in perioperative management and surgical techniques, heart valve surgery has lower mortality. However, there is a high incidence of thrombo-embolic events of approximately 1–4% per year.5 The bleeding risk is significant, ranging from 2% to 9% per year.6 Therefore, the greatest disadvantage of this surgery is that patients require long-term or permanent use of anticoagulant therapy to prevent thrombo-embolic events.
Warfarin is an effective drug for addressing this problem but increases the risk of major bleeding at the same time.7 Warfarin interferes with the hepatic synthesis of vitamin K-dependent clotting factors II, VII, IX, and X, resulting in their eventual depletion and a prolongation in the clotting time, as measured by the PT and INR. Compared with other drugs, warfarin has been viewed as the most frequently used clinical oral anticoagulant drug due to its relatively low cost.8,9 However, the toxic dose of warfarin is close to the dosage required to achieve a pharmaceutical effect. The warfarin dosage response is related to demographic, environmental, clinical and, especially, genetic factors.10 Due to the narrow therapeutic range as well as interactions and genetic variants, patients who experience warfarin overdose need genetic testing for the initial estimate of warfarin dose and the close monitoring of the intensity of anticoagulation with warfarin.11 In our hospital, we have been able to widely perform warfarin-related gene testing in patients with abnormal coagulation function. If a patient with a mechanical heart valve presents with warfarin overdose, vitamin K and fresh-frozen plasma should be given. The American College of Chest Physicians (2008) guidelines recommend oral doses of 1–2.5 mg vitamin K for an INR between 5 and 9 and 2.5–5 mg for all patients with an INR ≥ 9 but with no significant bleeding.12 The INR is then monitored every 4–6 h after administering vitamin K. When the INR is <3, the lowest dose of warfarin is given to prevent thrombosis.12
Factor X, a vitamin K-dependent plasma glycoprotein, plays a pivotal role in the coagulation cascade. Factor X is the first enzyme in the common pathway of thrombin formation. Factor X deficiency is a rare, recessively inherited bleeding disorder representing 10% of all rare bleeding diseases and affecting 1 in every 1 000 000 people.13 Factor X deficiency can be congenital or acquired.14 The diagnosis of factor X deficiency is usually suspected when both the prothrombin time and activated partial thromboplastin time are abnormal and are corrected upon mixing 1:1 with normal plasma.15 The functional activity of Factor X (FX: C) is quantified by performing a prothrombin time-based assay using rabbit thromboplastin and factor X-deficient plasma. Accordingly, patients are classified into three groups: severe (FX: C, <1%), moderate (FX: C, 1–4%), and mild (FX: C, 6–10%).16
Rivaroxaban is a direct and selective coagulation factor Xa inhibitor. Indications for the use of these agents include the prevention of stroke in non-valvular atrial fibrillation and for the prevention and treatment of deep vein thrombosis and pulmonary embolism as well as the prevention of venous thrombosis after orthopaedic surgery, but these agents are not indicated for patients undergoing cardiac valve replacement.17 There was a case report where a patient who underwent mechanical aortic valve replacement was administered the oral anticoagulant rivaroxaban instead of warfarin, which caused a significant gradient and thrombosis on one leaflet of the valve.18 This patient died due to complications from the thrombotic valve. However, for this patient with FX deficiency, she had not been taking any anticoagulants and did not have any complications due to the mechanical valve.
Conclusion
We believe that there was no thrombosis for such a long period of time because she suffered from FX deficiency. We have not found out other mechanisms to explain this phenomenon so far.
Lead author biography
I am a cardiac surgeon and have two English papers.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing these cases and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytaa566_Supplementary_Data Click here for additional data file. | Recovered | ReactionOutcome | CC BY | 33644653 | 19,008,280 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Refractory constrictive pericarditis caused by an immune checkpoint inhibitor properly managed with infliximab: a case report.
Immune checkpoint inhibitors (ICIs) can cause cardiac immune-related adverse events (irAEs), including pericarditis. Cardiovascular events related to pericardial irAE are less frequent, but fulminant forms can be fatal. However, the diagnosis and treatment strategies for pericardial irAE have not established.
A 58-year-old man was diagnosed with advanced non-small-cell lung cancer and nivolumab was administered as 5th-line therapy. Eighteen months after the initiation of nivolumab, the patient developed limb oedema and increased body weight. Although a favourable response of the cancer was observed, pericardial thickening and effusion were newly detected. He was diagnosed with irAE pericarditis after excluding other causes of pericarditis. Nivolumab was suspended and a high-dose corticosteroid was initiated. However, right heart failure (RHF) symptoms were exacerbated during the tapering of corticosteroid because acute pericarditis developed to steroid-refractory constrictive pericarditis. To suppress sustained inflammation of the pericardium, infliximab, a tumour necrosis factor-alfa inhibitor, was initiated. After the initiation of infliximab, the corticosteroid dose was tapered without deterioration of RHF. Exacerbation of lung cancer by irAE treatment including infliximab was not observed.
IrAE should be considered when pericarditis develops after the administration of ICI even after a long period from its initiation. Infliximab rescue therapy may be considered as a 2nd-line therapy for steroid-refractory irAE pericarditis even with constrictive physiology.
For the podcast associated with this article, please visit https://academic.oup.com/ehjcr/pages/podcast
Learning points
Immune-related adverse event (irAE) pericarditis can develop long after the initiation of immune checkpoint inhibitors and progress to constrictive pericarditis.
Early initiation of immune-suppressive therapy for irAE should be considered when it is refractory to corticosteroids.
Introduction
Immune checkpoint inhibitors (ICIs) have markedly improved the survival of cancer patients.1 However, immune-related adverse events (irAEs) by ICIs have been increasingly reported.2 Cardiac irAEs are rare (up to 2%), but 50% of the patients with irAE myocarditis and 21% of those with irAE pericarditis die, making them the ‘Achilles heel’ of ICI treatment.3 IrAEs are often diagnosed early after the initiation of ICI, but their delayed manifestation and progression can occur.4 We report a case of late-onset irAE pericarditis that developed to steroid-refractory constrictive pericarditis.
Timeline
July 2015 Age 58 The patient was diagnosed with advanced non-small-cell lung cancer, and anticancer chemotherapies were initiated. No cardiac disorder was identified.
December 2016 Age 60 Nivolumab (3 mg/kg every 2 weeks) was administered for 5th line therapy.
June 2018 Age 61 The patient complained of right heart failure (RHF) symptoms, and pericardial effusion was detected. Immune-related adverse event pericarditis was diagnosed.
July 2018 Age 61 RHF ameliorated with prednisolone but flared up at reduced dose, requiring increased dose of prednisolone.
September 2018 Age 62 Prednisolone was suspended and subsequently body weight gradually increased.
January 2019 Age 62 RHF was re-exacerbated, and echocardiography and right heart catheterization detected constrictive pericarditis. Steroid pulse therapy was performed.
March 2019 Age 62 RHF was re-re-exacerbated and repeated infliximab therapy was initiated.
February 2020 Age 63 Corticosteroid was tapered to a lower dose without the aggravation of RHF.
Case presentation
A 58-year-old man was diagnosed with stage IV (cT2N0M1) non-small-cell lung cancer comprising adenocarcinoma. The patient had no past medical history, including cardiovascular diseases. Prior to anticancer therapy, jugular venous distension and limb oedema were not detected, and heart sounds were normal. Electrocardiography demonstrated normal sinus rhythm, and computed tomography (CT) revealed no cardiomegaly or pericardial effusion. Lung cancer was aggravated despite anticancer chemotherapies, including cisplatin and pemetrexed as the 1st-line, docetaxel as the 2nd-line, tegafur/gimeracil/oteracil as the 3rd-line, and amrubicin as the 4th-line therapy. Nivolumab (3 mg/kg every 2 weeks), a programmed death-1 (PD-1) inhibitor, was administered as 5th-line therapy. Eighteen months after the initiation of nivolumab (after the 35th-cycle), the patient developed fatigue, limb oedema, and increased body weight (BW).
Physical examination revealed jugular venous distension and limb pitting oedema. The serum creatinine level was 0.77 mg/dL (normal range: 0.6–1.0 mg/dL). No electrocardiographic abnormalities were found. On echocardiography, ventricular systolic function on both sides and left ventricular diastolic function were preserved (abnormal relaxation pattern, Table 1), but mild pericardial effusion was detected (Figure 1A). The diameter of the pericardial echo-free space was 9 mm in the anterior right ventricle. CT revealed pericardial thickening, and trivial effusion in the pericardium and pleura (Figure 2B). As the patient was haemodynamically stable and the volume of pericardial effusion was mild, pericardiocentesis was planned to be performed if effusion increased. Favourable response of the lung cancer to treatment on CT suggested a non-malignant cause. Viral or purulent pericarditis was unlikely because the patient had no fever, a normal white blood cell count (6570/μL; normal range: 3300–8600/μL), and a negative blood culture test. Autoantibodies were all negative. Liver biopsy for the examination of liver enzymes revealed T-cell lymphocytic infiltration. Therefore, the patient was diagnosed with irAE hepatitis. Based on these findings, the patient was diagnosed with irAE pericarditis with constrictive features.
Figure 1 Chronological change in echocardiography. (A) Pericardial effusion detected at the time of diagnosis of pericarditis (arrow). (B–D) Pericardial adhesion to the right ventricular wall (B; arrow), significant reduction of the mitral peak E velocity in the inspiratory phase (C), and high peak e′ using tissue Doppler (D; arrow) were detected at 6 months after the diagnosis of pericarditis.
Figure 2 Clinical course and CT images. (A) Doses of steroid, the administration point of infliximab, body weight, the point of computed tomography (CT), and right heart failure (RHF) exacerbation events are described over time. (B) Pericardial thickening and effusion (arrow) on CT at the time of the diagnosis of pericarditis. (C) Pericardial effusion decreased after corticosteroid therapy (arrow) at 3 months after the diagnosis of pericarditis. (D) Trivial pericardial effusion (arrow) and massive pleural effusion (arrowhead) at 6 months after the diagnosis of pericarditis.
Table 1 Parameters of left ventricular diastolic function
Time after the diagnosis (months) 0 6 13 19
E (cm/s) 55.0 81.0 71.1 83.2
A (cm/s) 86.0 48.0 43.8 51.0
E/A 0.6 1.7 1.6 1.6
Deceleration time (ms) 161.0 117.0 109.0 121.0
E′ (cm/s) 7.8 13.3 10.6 9.9
E/E′ 7.1 6.1 6.7 8.4
Nivolumab was suspended and a high-dose corticosteroid, prednisolone at 0.5 mg/kg, was initiated. Right heart failure (RHF) symptoms were gradually ameliorated and the serum C-reactive protein level decreased from 4.08 mg/dL to 1.93 mg/dL (normal range: 0.00–0.14 mg/dL). However, RHF was exacerbated during the tapering of prednisolone (Figure 2A, 1st RHF exacerbation). Therefore, the dose of prednisolone was increased to the initial dose and re-tapered carefully. At the time of cessation of prednisolone, pericardial effusion was significantly reduced (Figure 2C). For a few months, the BW gradually increased with furosemide at 10 mg/day and quickly increased 3 months after the cessation of prednisolone (Figure 2A, 2nd RHF exacerbation), and the patient was positive for Kussmaul’s sign. Trivial pericardial effusion and massive pleural effusion were noted on CT (Figure 2D). In addition, echocardiography revealed pericardial adhesion (Figure 1B), aggravation of left ventricular diastolic function to a restrictive pattern (Table 1), significant reduction of the mitral peak E wave velocity in the inspiratory phase (Figure 1C), and septal bounce (Video 1). A higher peak e′ velocity on tissue Doppler (>8 cm/s) suggested a lower likelihood of restrictive cardiomyopathy (Figure 1D). Right heart catheterization demonstrated a W-shaped right atrial pressure waveform (Figure 3A). Simultaneous recording of biventricular pressures revealed a dip and plateau pattern in both ventricles, low end-diastolic pressure difference between the left and right ventricle (1 mmHg; cut-off: 5 mmHg), and high systolic area index (1.11; cut-off: 1.1), which suggested discordant changes in right and left ventricular filling during respiration (Figure 3B).5 As the amount of pericardial effusion was slight, pericardiocentesis was not performed. The serum troponin-T level was high (0.123 ng/mL; normal range: <0.014 ng/mL), but there was no evidence of active myocarditis by endomyocardial biopsy. Cardiac magnetic resonance imaging demonstrated pericardial thickening, but there was no myocardial oedema or significant late gadolinium enhancement in the pericardium or myocardium. At this point, the patient was diagnosed with constrictive pericarditis (CP) with myopericarditis. The dose of furosemide was increased to 40 mg/day and tolvaptan at 15 mg/day was added, but these did not ameliorate RHF symptoms. Consequently, methylprednisolone at 1 g/day for 3 days and subsequent prednisolone at 1 mg/kg were administered. RHF symptoms were transiently ameliorated, but they exacerbated again after the tapering of prednisolone (Figure 2A, 3rd RHF exacerbation). As pericarditis recurred repeatedly and progressed to CP despite corticosteroid therapy, infliximab (5 mg/kg) was initiated. Infliximab was administered 2 and 6 weeks after the 1st administration, and every 8 weeks thereafter in accordance with the regimen for the treatment of connective tissue disease (Figure 2A).
Figure 3 Haemodynamic assessment on cardiac catheterization. (A) High right atrial (RA) pressure with a W-shaped waveform. (B) A dip and plateau pattern and high systolic area index (SAI) were detected on simultaneous biventricular pressure recording.
After the initiation of infliximab, the BW decreased from 82 to 75 kg despite a reduction in the dose of diuretics (tolvaptan 7.5 mg/day), and the serum troponin-T level decreased to 0.020 ng/mL. Although CP findings were still present by echocardiography (Table 1), prednisolone was able to be tapered to a lower dose (0.15 mg/kg) without aggravation of RHF; therefore, pericardiectomy was not performed. The patient was administered low-dose prednisolone and repeated infliximab for 11 months after the 3rd RHF exacerbation without worsening RHF (Figure 2A).
Discussion
Cardiac irAEs are rare, but they do occur and can be fatal; therefore, they require appropriate treatment. As patients with pericardial irAE usually achieve improvement after the administration of corticosteroids,6 the effects of infliximab on pericarditis have not been reported. This is the 1st case demonstrating the efficacy of infliximab for corticosteroid-refractory pericardial irAE.
An important process in the diagnosis of irAE pericarditis is to exclude other causes of pericarditis. The Naranjo Scale score, which helps assess causality of adverse drug reactions, was six points in this case, suggesting that pericarditis was a probable adverse event of nivolumab.7 In this case, infection, autoimmune disorders, and metastasis of lung cancer were excluded by the patient’s history and examinations. In addition, concurrent hepatic irAE suggested that ICI-induced inflammation was the cause of pericarditis.3 Considering the RHF symptoms at the time of the initial diagnosis of pericarditis, the pericarditis had constrictive features when pericardial effusion developed. Left ventricular diastolic function on echocardiography deteriorated over time and CP-specific haemodynamics were demonstrated on cardiac catheterization at 6 months after the initial diagnosis of pericarditis.5,8 Increased serum troponin suggested myocardial inflammation accompanied by severe inflammation at the pericardium. Although cardiac irAE usually develops within 3 months after the initiation of ICI,3 this patient was diagnosed with pericarditis 18 months after the introduction of nivolumab. In addition, pericardial inflammation was sustained for a long time after the cessation of nivolumab. The delayed manifestation and sustained exacerbation of irAE pericarditis in this case can be partly explained by the pharmacodynamics of anti-PD-1 blockade, as demonstrated by the initial single nivolumab administration occupying >70% of PD-1 molecules on T cells for 85 days and this occupancy remained at 40% for more than 8 months after the last dose.9
Immune-suppressive therapy is recommended for serious irAEs refractory to high-dose corticosteroids.2 Infliximab, mycophenolate, or antithymocyte globulin are recommended as additional immune-suppressive therapy, but the differences in therapeutic effects among these drugs have not been assessed in the treatment of irAE pericarditis.2 Infliximab, a monoclonal antibody tumour necrosis factor-α inhibitor, reduces the expression of several proinflammatory molecules and mucosal cytokines. It is generally used for inflammatory bowel disease or connective tissue disease.10 In addition, Infliximab is effective for irAE colitis and is covered by insurance for the treatment of rheumatoid arthritis in our country, thus we administered it for irAE pericarditis in this patient within the approved dosage range for rheumatoid arthritis; 5 mg/kg at Weeks 0, 2, and 6 as induction therapy, then every 8 weeks as maintenance therapy.10,11 Infliximab was effective at relieving pericardial inflammation in this case, demonstrated by the reduced need for diuretics and prednisolone for the control of RHF after the initiation of infliximab concomitant with a decrease in serum troponin. Although the RHF status improved, CP remained after the initiation of infliximab according to echocardiography (Table 1). The treatment for irAEs did not affect the overall survival or time to treatment failure in cancer patients.12 Thus, considering the progressive course of pericarditis in this case, immune-suppressive therapy at an earlier stage of steroid-refractory pericarditis should be considered. Further studies are warranted to clarify the benefits of infliximab for irAE pericarditis.
Conclusion
ICI-related pericarditis potentially develops into CP. Therefore, early therapeutic intervention should be considered. Immune-suppressive drugs represented by infliximab are a promising therapeutic option for the treatment of steroid-refractory pericarditis.
Lead author biography
Dr Shohei Moriyama is a medical doctor at Kyushu University Hospital (Japan) and acquired a medical degree at Kyushu University in Fukuoka. Specialization: Cardio-Oncology. Membership: Japanese Circulation Society, Japanese Society of Medical Oncology, and Japanese Onco-Cardiology society.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytab002_Supplementary_Data Click here for additional data file. | FUROSEMIDE, INFLIXIMAB, METHYLPREDNISOLONE, NIVOLUMAB, PREDNISOLONE, TOLVAPTAN | DrugsGivenReaction | CC BY-NC | 33644656 | 19,399,337 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hepatitis'. | Refractory constrictive pericarditis caused by an immune checkpoint inhibitor properly managed with infliximab: a case report.
Immune checkpoint inhibitors (ICIs) can cause cardiac immune-related adverse events (irAEs), including pericarditis. Cardiovascular events related to pericardial irAE are less frequent, but fulminant forms can be fatal. However, the diagnosis and treatment strategies for pericardial irAE have not established.
A 58-year-old man was diagnosed with advanced non-small-cell lung cancer and nivolumab was administered as 5th-line therapy. Eighteen months after the initiation of nivolumab, the patient developed limb oedema and increased body weight. Although a favourable response of the cancer was observed, pericardial thickening and effusion were newly detected. He was diagnosed with irAE pericarditis after excluding other causes of pericarditis. Nivolumab was suspended and a high-dose corticosteroid was initiated. However, right heart failure (RHF) symptoms were exacerbated during the tapering of corticosteroid because acute pericarditis developed to steroid-refractory constrictive pericarditis. To suppress sustained inflammation of the pericardium, infliximab, a tumour necrosis factor-alfa inhibitor, was initiated. After the initiation of infliximab, the corticosteroid dose was tapered without deterioration of RHF. Exacerbation of lung cancer by irAE treatment including infliximab was not observed.
IrAE should be considered when pericarditis develops after the administration of ICI even after a long period from its initiation. Infliximab rescue therapy may be considered as a 2nd-line therapy for steroid-refractory irAE pericarditis even with constrictive physiology.
For the podcast associated with this article, please visit https://academic.oup.com/ehjcr/pages/podcast
Learning points
Immune-related adverse event (irAE) pericarditis can develop long after the initiation of immune checkpoint inhibitors and progress to constrictive pericarditis.
Early initiation of immune-suppressive therapy for irAE should be considered when it is refractory to corticosteroids.
Introduction
Immune checkpoint inhibitors (ICIs) have markedly improved the survival of cancer patients.1 However, immune-related adverse events (irAEs) by ICIs have been increasingly reported.2 Cardiac irAEs are rare (up to 2%), but 50% of the patients with irAE myocarditis and 21% of those with irAE pericarditis die, making them the ‘Achilles heel’ of ICI treatment.3 IrAEs are often diagnosed early after the initiation of ICI, but their delayed manifestation and progression can occur.4 We report a case of late-onset irAE pericarditis that developed to steroid-refractory constrictive pericarditis.
Timeline
July 2015 Age 58 The patient was diagnosed with advanced non-small-cell lung cancer, and anticancer chemotherapies were initiated. No cardiac disorder was identified.
December 2016 Age 60 Nivolumab (3 mg/kg every 2 weeks) was administered for 5th line therapy.
June 2018 Age 61 The patient complained of right heart failure (RHF) symptoms, and pericardial effusion was detected. Immune-related adverse event pericarditis was diagnosed.
July 2018 Age 61 RHF ameliorated with prednisolone but flared up at reduced dose, requiring increased dose of prednisolone.
September 2018 Age 62 Prednisolone was suspended and subsequently body weight gradually increased.
January 2019 Age 62 RHF was re-exacerbated, and echocardiography and right heart catheterization detected constrictive pericarditis. Steroid pulse therapy was performed.
March 2019 Age 62 RHF was re-re-exacerbated and repeated infliximab therapy was initiated.
February 2020 Age 63 Corticosteroid was tapered to a lower dose without the aggravation of RHF.
Case presentation
A 58-year-old man was diagnosed with stage IV (cT2N0M1) non-small-cell lung cancer comprising adenocarcinoma. The patient had no past medical history, including cardiovascular diseases. Prior to anticancer therapy, jugular venous distension and limb oedema were not detected, and heart sounds were normal. Electrocardiography demonstrated normal sinus rhythm, and computed tomography (CT) revealed no cardiomegaly or pericardial effusion. Lung cancer was aggravated despite anticancer chemotherapies, including cisplatin and pemetrexed as the 1st-line, docetaxel as the 2nd-line, tegafur/gimeracil/oteracil as the 3rd-line, and amrubicin as the 4th-line therapy. Nivolumab (3 mg/kg every 2 weeks), a programmed death-1 (PD-1) inhibitor, was administered as 5th-line therapy. Eighteen months after the initiation of nivolumab (after the 35th-cycle), the patient developed fatigue, limb oedema, and increased body weight (BW).
Physical examination revealed jugular venous distension and limb pitting oedema. The serum creatinine level was 0.77 mg/dL (normal range: 0.6–1.0 mg/dL). No electrocardiographic abnormalities were found. On echocardiography, ventricular systolic function on both sides and left ventricular diastolic function were preserved (abnormal relaxation pattern, Table 1), but mild pericardial effusion was detected (Figure 1A). The diameter of the pericardial echo-free space was 9 mm in the anterior right ventricle. CT revealed pericardial thickening, and trivial effusion in the pericardium and pleura (Figure 2B). As the patient was haemodynamically stable and the volume of pericardial effusion was mild, pericardiocentesis was planned to be performed if effusion increased. Favourable response of the lung cancer to treatment on CT suggested a non-malignant cause. Viral or purulent pericarditis was unlikely because the patient had no fever, a normal white blood cell count (6570/μL; normal range: 3300–8600/μL), and a negative blood culture test. Autoantibodies were all negative. Liver biopsy for the examination of liver enzymes revealed T-cell lymphocytic infiltration. Therefore, the patient was diagnosed with irAE hepatitis. Based on these findings, the patient was diagnosed with irAE pericarditis with constrictive features.
Figure 1 Chronological change in echocardiography. (A) Pericardial effusion detected at the time of diagnosis of pericarditis (arrow). (B–D) Pericardial adhesion to the right ventricular wall (B; arrow), significant reduction of the mitral peak E velocity in the inspiratory phase (C), and high peak e′ using tissue Doppler (D; arrow) were detected at 6 months after the diagnosis of pericarditis.
Figure 2 Clinical course and CT images. (A) Doses of steroid, the administration point of infliximab, body weight, the point of computed tomography (CT), and right heart failure (RHF) exacerbation events are described over time. (B) Pericardial thickening and effusion (arrow) on CT at the time of the diagnosis of pericarditis. (C) Pericardial effusion decreased after corticosteroid therapy (arrow) at 3 months after the diagnosis of pericarditis. (D) Trivial pericardial effusion (arrow) and massive pleural effusion (arrowhead) at 6 months after the diagnosis of pericarditis.
Table 1 Parameters of left ventricular diastolic function
Time after the diagnosis (months) 0 6 13 19
E (cm/s) 55.0 81.0 71.1 83.2
A (cm/s) 86.0 48.0 43.8 51.0
E/A 0.6 1.7 1.6 1.6
Deceleration time (ms) 161.0 117.0 109.0 121.0
E′ (cm/s) 7.8 13.3 10.6 9.9
E/E′ 7.1 6.1 6.7 8.4
Nivolumab was suspended and a high-dose corticosteroid, prednisolone at 0.5 mg/kg, was initiated. Right heart failure (RHF) symptoms were gradually ameliorated and the serum C-reactive protein level decreased from 4.08 mg/dL to 1.93 mg/dL (normal range: 0.00–0.14 mg/dL). However, RHF was exacerbated during the tapering of prednisolone (Figure 2A, 1st RHF exacerbation). Therefore, the dose of prednisolone was increased to the initial dose and re-tapered carefully. At the time of cessation of prednisolone, pericardial effusion was significantly reduced (Figure 2C). For a few months, the BW gradually increased with furosemide at 10 mg/day and quickly increased 3 months after the cessation of prednisolone (Figure 2A, 2nd RHF exacerbation), and the patient was positive for Kussmaul’s sign. Trivial pericardial effusion and massive pleural effusion were noted on CT (Figure 2D). In addition, echocardiography revealed pericardial adhesion (Figure 1B), aggravation of left ventricular diastolic function to a restrictive pattern (Table 1), significant reduction of the mitral peak E wave velocity in the inspiratory phase (Figure 1C), and septal bounce (Video 1). A higher peak e′ velocity on tissue Doppler (>8 cm/s) suggested a lower likelihood of restrictive cardiomyopathy (Figure 1D). Right heart catheterization demonstrated a W-shaped right atrial pressure waveform (Figure 3A). Simultaneous recording of biventricular pressures revealed a dip and plateau pattern in both ventricles, low end-diastolic pressure difference between the left and right ventricle (1 mmHg; cut-off: 5 mmHg), and high systolic area index (1.11; cut-off: 1.1), which suggested discordant changes in right and left ventricular filling during respiration (Figure 3B).5 As the amount of pericardial effusion was slight, pericardiocentesis was not performed. The serum troponin-T level was high (0.123 ng/mL; normal range: <0.014 ng/mL), but there was no evidence of active myocarditis by endomyocardial biopsy. Cardiac magnetic resonance imaging demonstrated pericardial thickening, but there was no myocardial oedema or significant late gadolinium enhancement in the pericardium or myocardium. At this point, the patient was diagnosed with constrictive pericarditis (CP) with myopericarditis. The dose of furosemide was increased to 40 mg/day and tolvaptan at 15 mg/day was added, but these did not ameliorate RHF symptoms. Consequently, methylprednisolone at 1 g/day for 3 days and subsequent prednisolone at 1 mg/kg were administered. RHF symptoms were transiently ameliorated, but they exacerbated again after the tapering of prednisolone (Figure 2A, 3rd RHF exacerbation). As pericarditis recurred repeatedly and progressed to CP despite corticosteroid therapy, infliximab (5 mg/kg) was initiated. Infliximab was administered 2 and 6 weeks after the 1st administration, and every 8 weeks thereafter in accordance with the regimen for the treatment of connective tissue disease (Figure 2A).
Figure 3 Haemodynamic assessment on cardiac catheterization. (A) High right atrial (RA) pressure with a W-shaped waveform. (B) A dip and plateau pattern and high systolic area index (SAI) were detected on simultaneous biventricular pressure recording.
After the initiation of infliximab, the BW decreased from 82 to 75 kg despite a reduction in the dose of diuretics (tolvaptan 7.5 mg/day), and the serum troponin-T level decreased to 0.020 ng/mL. Although CP findings were still present by echocardiography (Table 1), prednisolone was able to be tapered to a lower dose (0.15 mg/kg) without aggravation of RHF; therefore, pericardiectomy was not performed. The patient was administered low-dose prednisolone and repeated infliximab for 11 months after the 3rd RHF exacerbation without worsening RHF (Figure 2A).
Discussion
Cardiac irAEs are rare, but they do occur and can be fatal; therefore, they require appropriate treatment. As patients with pericardial irAE usually achieve improvement after the administration of corticosteroids,6 the effects of infliximab on pericarditis have not been reported. This is the 1st case demonstrating the efficacy of infliximab for corticosteroid-refractory pericardial irAE.
An important process in the diagnosis of irAE pericarditis is to exclude other causes of pericarditis. The Naranjo Scale score, which helps assess causality of adverse drug reactions, was six points in this case, suggesting that pericarditis was a probable adverse event of nivolumab.7 In this case, infection, autoimmune disorders, and metastasis of lung cancer were excluded by the patient’s history and examinations. In addition, concurrent hepatic irAE suggested that ICI-induced inflammation was the cause of pericarditis.3 Considering the RHF symptoms at the time of the initial diagnosis of pericarditis, the pericarditis had constrictive features when pericardial effusion developed. Left ventricular diastolic function on echocardiography deteriorated over time and CP-specific haemodynamics were demonstrated on cardiac catheterization at 6 months after the initial diagnosis of pericarditis.5,8 Increased serum troponin suggested myocardial inflammation accompanied by severe inflammation at the pericardium. Although cardiac irAE usually develops within 3 months after the initiation of ICI,3 this patient was diagnosed with pericarditis 18 months after the introduction of nivolumab. In addition, pericardial inflammation was sustained for a long time after the cessation of nivolumab. The delayed manifestation and sustained exacerbation of irAE pericarditis in this case can be partly explained by the pharmacodynamics of anti-PD-1 blockade, as demonstrated by the initial single nivolumab administration occupying >70% of PD-1 molecules on T cells for 85 days and this occupancy remained at 40% for more than 8 months after the last dose.9
Immune-suppressive therapy is recommended for serious irAEs refractory to high-dose corticosteroids.2 Infliximab, mycophenolate, or antithymocyte globulin are recommended as additional immune-suppressive therapy, but the differences in therapeutic effects among these drugs have not been assessed in the treatment of irAE pericarditis.2 Infliximab, a monoclonal antibody tumour necrosis factor-α inhibitor, reduces the expression of several proinflammatory molecules and mucosal cytokines. It is generally used for inflammatory bowel disease or connective tissue disease.10 In addition, Infliximab is effective for irAE colitis and is covered by insurance for the treatment of rheumatoid arthritis in our country, thus we administered it for irAE pericarditis in this patient within the approved dosage range for rheumatoid arthritis; 5 mg/kg at Weeks 0, 2, and 6 as induction therapy, then every 8 weeks as maintenance therapy.10,11 Infliximab was effective at relieving pericardial inflammation in this case, demonstrated by the reduced need for diuretics and prednisolone for the control of RHF after the initiation of infliximab concomitant with a decrease in serum troponin. Although the RHF status improved, CP remained after the initiation of infliximab according to echocardiography (Table 1). The treatment for irAEs did not affect the overall survival or time to treatment failure in cancer patients.12 Thus, considering the progressive course of pericarditis in this case, immune-suppressive therapy at an earlier stage of steroid-refractory pericarditis should be considered. Further studies are warranted to clarify the benefits of infliximab for irAE pericarditis.
Conclusion
ICI-related pericarditis potentially develops into CP. Therefore, early therapeutic intervention should be considered. Immune-suppressive drugs represented by infliximab are a promising therapeutic option for the treatment of steroid-refractory pericarditis.
Lead author biography
Dr Shohei Moriyama is a medical doctor at Kyushu University Hospital (Japan) and acquired a medical degree at Kyushu University in Fukuoka. Specialization: Cardio-Oncology. Membership: Japanese Circulation Society, Japanese Society of Medical Oncology, and Japanese Onco-Cardiology society.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytab002_Supplementary_Data Click here for additional data file. | FUROSEMIDE, INFLIXIMAB, METHYLPREDNISOLONE, NIVOLUMAB, PREDNISOLONE, TOLVAPTAN | DrugsGivenReaction | CC BY-NC | 33644656 | 19,426,929 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Myocarditis'. | Refractory constrictive pericarditis caused by an immune checkpoint inhibitor properly managed with infliximab: a case report.
Immune checkpoint inhibitors (ICIs) can cause cardiac immune-related adverse events (irAEs), including pericarditis. Cardiovascular events related to pericardial irAE are less frequent, but fulminant forms can be fatal. However, the diagnosis and treatment strategies for pericardial irAE have not established.
A 58-year-old man was diagnosed with advanced non-small-cell lung cancer and nivolumab was administered as 5th-line therapy. Eighteen months after the initiation of nivolumab, the patient developed limb oedema and increased body weight. Although a favourable response of the cancer was observed, pericardial thickening and effusion were newly detected. He was diagnosed with irAE pericarditis after excluding other causes of pericarditis. Nivolumab was suspended and a high-dose corticosteroid was initiated. However, right heart failure (RHF) symptoms were exacerbated during the tapering of corticosteroid because acute pericarditis developed to steroid-refractory constrictive pericarditis. To suppress sustained inflammation of the pericardium, infliximab, a tumour necrosis factor-alfa inhibitor, was initiated. After the initiation of infliximab, the corticosteroid dose was tapered without deterioration of RHF. Exacerbation of lung cancer by irAE treatment including infliximab was not observed.
IrAE should be considered when pericarditis develops after the administration of ICI even after a long period from its initiation. Infliximab rescue therapy may be considered as a 2nd-line therapy for steroid-refractory irAE pericarditis even with constrictive physiology.
For the podcast associated with this article, please visit https://academic.oup.com/ehjcr/pages/podcast
Learning points
Immune-related adverse event (irAE) pericarditis can develop long after the initiation of immune checkpoint inhibitors and progress to constrictive pericarditis.
Early initiation of immune-suppressive therapy for irAE should be considered when it is refractory to corticosteroids.
Introduction
Immune checkpoint inhibitors (ICIs) have markedly improved the survival of cancer patients.1 However, immune-related adverse events (irAEs) by ICIs have been increasingly reported.2 Cardiac irAEs are rare (up to 2%), but 50% of the patients with irAE myocarditis and 21% of those with irAE pericarditis die, making them the ‘Achilles heel’ of ICI treatment.3 IrAEs are often diagnosed early after the initiation of ICI, but their delayed manifestation and progression can occur.4 We report a case of late-onset irAE pericarditis that developed to steroid-refractory constrictive pericarditis.
Timeline
July 2015 Age 58 The patient was diagnosed with advanced non-small-cell lung cancer, and anticancer chemotherapies were initiated. No cardiac disorder was identified.
December 2016 Age 60 Nivolumab (3 mg/kg every 2 weeks) was administered for 5th line therapy.
June 2018 Age 61 The patient complained of right heart failure (RHF) symptoms, and pericardial effusion was detected. Immune-related adverse event pericarditis was diagnosed.
July 2018 Age 61 RHF ameliorated with prednisolone but flared up at reduced dose, requiring increased dose of prednisolone.
September 2018 Age 62 Prednisolone was suspended and subsequently body weight gradually increased.
January 2019 Age 62 RHF was re-exacerbated, and echocardiography and right heart catheterization detected constrictive pericarditis. Steroid pulse therapy was performed.
March 2019 Age 62 RHF was re-re-exacerbated and repeated infliximab therapy was initiated.
February 2020 Age 63 Corticosteroid was tapered to a lower dose without the aggravation of RHF.
Case presentation
A 58-year-old man was diagnosed with stage IV (cT2N0M1) non-small-cell lung cancer comprising adenocarcinoma. The patient had no past medical history, including cardiovascular diseases. Prior to anticancer therapy, jugular venous distension and limb oedema were not detected, and heart sounds were normal. Electrocardiography demonstrated normal sinus rhythm, and computed tomography (CT) revealed no cardiomegaly or pericardial effusion. Lung cancer was aggravated despite anticancer chemotherapies, including cisplatin and pemetrexed as the 1st-line, docetaxel as the 2nd-line, tegafur/gimeracil/oteracil as the 3rd-line, and amrubicin as the 4th-line therapy. Nivolumab (3 mg/kg every 2 weeks), a programmed death-1 (PD-1) inhibitor, was administered as 5th-line therapy. Eighteen months after the initiation of nivolumab (after the 35th-cycle), the patient developed fatigue, limb oedema, and increased body weight (BW).
Physical examination revealed jugular venous distension and limb pitting oedema. The serum creatinine level was 0.77 mg/dL (normal range: 0.6–1.0 mg/dL). No electrocardiographic abnormalities were found. On echocardiography, ventricular systolic function on both sides and left ventricular diastolic function were preserved (abnormal relaxation pattern, Table 1), but mild pericardial effusion was detected (Figure 1A). The diameter of the pericardial echo-free space was 9 mm in the anterior right ventricle. CT revealed pericardial thickening, and trivial effusion in the pericardium and pleura (Figure 2B). As the patient was haemodynamically stable and the volume of pericardial effusion was mild, pericardiocentesis was planned to be performed if effusion increased. Favourable response of the lung cancer to treatment on CT suggested a non-malignant cause. Viral or purulent pericarditis was unlikely because the patient had no fever, a normal white blood cell count (6570/μL; normal range: 3300–8600/μL), and a negative blood culture test. Autoantibodies were all negative. Liver biopsy for the examination of liver enzymes revealed T-cell lymphocytic infiltration. Therefore, the patient was diagnosed with irAE hepatitis. Based on these findings, the patient was diagnosed with irAE pericarditis with constrictive features.
Figure 1 Chronological change in echocardiography. (A) Pericardial effusion detected at the time of diagnosis of pericarditis (arrow). (B–D) Pericardial adhesion to the right ventricular wall (B; arrow), significant reduction of the mitral peak E velocity in the inspiratory phase (C), and high peak e′ using tissue Doppler (D; arrow) were detected at 6 months after the diagnosis of pericarditis.
Figure 2 Clinical course and CT images. (A) Doses of steroid, the administration point of infliximab, body weight, the point of computed tomography (CT), and right heart failure (RHF) exacerbation events are described over time. (B) Pericardial thickening and effusion (arrow) on CT at the time of the diagnosis of pericarditis. (C) Pericardial effusion decreased after corticosteroid therapy (arrow) at 3 months after the diagnosis of pericarditis. (D) Trivial pericardial effusion (arrow) and massive pleural effusion (arrowhead) at 6 months after the diagnosis of pericarditis.
Table 1 Parameters of left ventricular diastolic function
Time after the diagnosis (months) 0 6 13 19
E (cm/s) 55.0 81.0 71.1 83.2
A (cm/s) 86.0 48.0 43.8 51.0
E/A 0.6 1.7 1.6 1.6
Deceleration time (ms) 161.0 117.0 109.0 121.0
E′ (cm/s) 7.8 13.3 10.6 9.9
E/E′ 7.1 6.1 6.7 8.4
Nivolumab was suspended and a high-dose corticosteroid, prednisolone at 0.5 mg/kg, was initiated. Right heart failure (RHF) symptoms were gradually ameliorated and the serum C-reactive protein level decreased from 4.08 mg/dL to 1.93 mg/dL (normal range: 0.00–0.14 mg/dL). However, RHF was exacerbated during the tapering of prednisolone (Figure 2A, 1st RHF exacerbation). Therefore, the dose of prednisolone was increased to the initial dose and re-tapered carefully. At the time of cessation of prednisolone, pericardial effusion was significantly reduced (Figure 2C). For a few months, the BW gradually increased with furosemide at 10 mg/day and quickly increased 3 months after the cessation of prednisolone (Figure 2A, 2nd RHF exacerbation), and the patient was positive for Kussmaul’s sign. Trivial pericardial effusion and massive pleural effusion were noted on CT (Figure 2D). In addition, echocardiography revealed pericardial adhesion (Figure 1B), aggravation of left ventricular diastolic function to a restrictive pattern (Table 1), significant reduction of the mitral peak E wave velocity in the inspiratory phase (Figure 1C), and septal bounce (Video 1). A higher peak e′ velocity on tissue Doppler (>8 cm/s) suggested a lower likelihood of restrictive cardiomyopathy (Figure 1D). Right heart catheterization demonstrated a W-shaped right atrial pressure waveform (Figure 3A). Simultaneous recording of biventricular pressures revealed a dip and plateau pattern in both ventricles, low end-diastolic pressure difference between the left and right ventricle (1 mmHg; cut-off: 5 mmHg), and high systolic area index (1.11; cut-off: 1.1), which suggested discordant changes in right and left ventricular filling during respiration (Figure 3B).5 As the amount of pericardial effusion was slight, pericardiocentesis was not performed. The serum troponin-T level was high (0.123 ng/mL; normal range: <0.014 ng/mL), but there was no evidence of active myocarditis by endomyocardial biopsy. Cardiac magnetic resonance imaging demonstrated pericardial thickening, but there was no myocardial oedema or significant late gadolinium enhancement in the pericardium or myocardium. At this point, the patient was diagnosed with constrictive pericarditis (CP) with myopericarditis. The dose of furosemide was increased to 40 mg/day and tolvaptan at 15 mg/day was added, but these did not ameliorate RHF symptoms. Consequently, methylprednisolone at 1 g/day for 3 days and subsequent prednisolone at 1 mg/kg were administered. RHF symptoms were transiently ameliorated, but they exacerbated again after the tapering of prednisolone (Figure 2A, 3rd RHF exacerbation). As pericarditis recurred repeatedly and progressed to CP despite corticosteroid therapy, infliximab (5 mg/kg) was initiated. Infliximab was administered 2 and 6 weeks after the 1st administration, and every 8 weeks thereafter in accordance with the regimen for the treatment of connective tissue disease (Figure 2A).
Figure 3 Haemodynamic assessment on cardiac catheterization. (A) High right atrial (RA) pressure with a W-shaped waveform. (B) A dip and plateau pattern and high systolic area index (SAI) were detected on simultaneous biventricular pressure recording.
After the initiation of infliximab, the BW decreased from 82 to 75 kg despite a reduction in the dose of diuretics (tolvaptan 7.5 mg/day), and the serum troponin-T level decreased to 0.020 ng/mL. Although CP findings were still present by echocardiography (Table 1), prednisolone was able to be tapered to a lower dose (0.15 mg/kg) without aggravation of RHF; therefore, pericardiectomy was not performed. The patient was administered low-dose prednisolone and repeated infliximab for 11 months after the 3rd RHF exacerbation without worsening RHF (Figure 2A).
Discussion
Cardiac irAEs are rare, but they do occur and can be fatal; therefore, they require appropriate treatment. As patients with pericardial irAE usually achieve improvement after the administration of corticosteroids,6 the effects of infliximab on pericarditis have not been reported. This is the 1st case demonstrating the efficacy of infliximab for corticosteroid-refractory pericardial irAE.
An important process in the diagnosis of irAE pericarditis is to exclude other causes of pericarditis. The Naranjo Scale score, which helps assess causality of adverse drug reactions, was six points in this case, suggesting that pericarditis was a probable adverse event of nivolumab.7 In this case, infection, autoimmune disorders, and metastasis of lung cancer were excluded by the patient’s history and examinations. In addition, concurrent hepatic irAE suggested that ICI-induced inflammation was the cause of pericarditis.3 Considering the RHF symptoms at the time of the initial diagnosis of pericarditis, the pericarditis had constrictive features when pericardial effusion developed. Left ventricular diastolic function on echocardiography deteriorated over time and CP-specific haemodynamics were demonstrated on cardiac catheterization at 6 months after the initial diagnosis of pericarditis.5,8 Increased serum troponin suggested myocardial inflammation accompanied by severe inflammation at the pericardium. Although cardiac irAE usually develops within 3 months after the initiation of ICI,3 this patient was diagnosed with pericarditis 18 months after the introduction of nivolumab. In addition, pericardial inflammation was sustained for a long time after the cessation of nivolumab. The delayed manifestation and sustained exacerbation of irAE pericarditis in this case can be partly explained by the pharmacodynamics of anti-PD-1 blockade, as demonstrated by the initial single nivolumab administration occupying >70% of PD-1 molecules on T cells for 85 days and this occupancy remained at 40% for more than 8 months after the last dose.9
Immune-suppressive therapy is recommended for serious irAEs refractory to high-dose corticosteroids.2 Infliximab, mycophenolate, or antithymocyte globulin are recommended as additional immune-suppressive therapy, but the differences in therapeutic effects among these drugs have not been assessed in the treatment of irAE pericarditis.2 Infliximab, a monoclonal antibody tumour necrosis factor-α inhibitor, reduces the expression of several proinflammatory molecules and mucosal cytokines. It is generally used for inflammatory bowel disease or connective tissue disease.10 In addition, Infliximab is effective for irAE colitis and is covered by insurance for the treatment of rheumatoid arthritis in our country, thus we administered it for irAE pericarditis in this patient within the approved dosage range for rheumatoid arthritis; 5 mg/kg at Weeks 0, 2, and 6 as induction therapy, then every 8 weeks as maintenance therapy.10,11 Infliximab was effective at relieving pericardial inflammation in this case, demonstrated by the reduced need for diuretics and prednisolone for the control of RHF after the initiation of infliximab concomitant with a decrease in serum troponin. Although the RHF status improved, CP remained after the initiation of infliximab according to echocardiography (Table 1). The treatment for irAEs did not affect the overall survival or time to treatment failure in cancer patients.12 Thus, considering the progressive course of pericarditis in this case, immune-suppressive therapy at an earlier stage of steroid-refractory pericarditis should be considered. Further studies are warranted to clarify the benefits of infliximab for irAE pericarditis.
Conclusion
ICI-related pericarditis potentially develops into CP. Therefore, early therapeutic intervention should be considered. Immune-suppressive drugs represented by infliximab are a promising therapeutic option for the treatment of steroid-refractory pericarditis.
Lead author biography
Dr Shohei Moriyama is a medical doctor at Kyushu University Hospital (Japan) and acquired a medical degree at Kyushu University in Fukuoka. Specialization: Cardio-Oncology. Membership: Japanese Circulation Society, Japanese Society of Medical Oncology, and Japanese Onco-Cardiology society.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytab002_Supplementary_Data Click here for additional data file. | FUROSEMIDE, INFLIXIMAB, METHYLPREDNISOLONE, NIVOLUMAB, PREDNISOLONE, TOLVAPTAN | DrugsGivenReaction | CC BY-NC | 33644656 | 19,426,929 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Refractory constrictive pericarditis caused by an immune checkpoint inhibitor properly managed with infliximab: a case report.
Immune checkpoint inhibitors (ICIs) can cause cardiac immune-related adverse events (irAEs), including pericarditis. Cardiovascular events related to pericardial irAE are less frequent, but fulminant forms can be fatal. However, the diagnosis and treatment strategies for pericardial irAE have not established.
A 58-year-old man was diagnosed with advanced non-small-cell lung cancer and nivolumab was administered as 5th-line therapy. Eighteen months after the initiation of nivolumab, the patient developed limb oedema and increased body weight. Although a favourable response of the cancer was observed, pericardial thickening and effusion were newly detected. He was diagnosed with irAE pericarditis after excluding other causes of pericarditis. Nivolumab was suspended and a high-dose corticosteroid was initiated. However, right heart failure (RHF) symptoms were exacerbated during the tapering of corticosteroid because acute pericarditis developed to steroid-refractory constrictive pericarditis. To suppress sustained inflammation of the pericardium, infliximab, a tumour necrosis factor-alfa inhibitor, was initiated. After the initiation of infliximab, the corticosteroid dose was tapered without deterioration of RHF. Exacerbation of lung cancer by irAE treatment including infliximab was not observed.
IrAE should be considered when pericarditis develops after the administration of ICI even after a long period from its initiation. Infliximab rescue therapy may be considered as a 2nd-line therapy for steroid-refractory irAE pericarditis even with constrictive physiology.
For the podcast associated with this article, please visit https://academic.oup.com/ehjcr/pages/podcast
Learning points
Immune-related adverse event (irAE) pericarditis can develop long after the initiation of immune checkpoint inhibitors and progress to constrictive pericarditis.
Early initiation of immune-suppressive therapy for irAE should be considered when it is refractory to corticosteroids.
Introduction
Immune checkpoint inhibitors (ICIs) have markedly improved the survival of cancer patients.1 However, immune-related adverse events (irAEs) by ICIs have been increasingly reported.2 Cardiac irAEs are rare (up to 2%), but 50% of the patients with irAE myocarditis and 21% of those with irAE pericarditis die, making them the ‘Achilles heel’ of ICI treatment.3 IrAEs are often diagnosed early after the initiation of ICI, but their delayed manifestation and progression can occur.4 We report a case of late-onset irAE pericarditis that developed to steroid-refractory constrictive pericarditis.
Timeline
July 2015 Age 58 The patient was diagnosed with advanced non-small-cell lung cancer, and anticancer chemotherapies were initiated. No cardiac disorder was identified.
December 2016 Age 60 Nivolumab (3 mg/kg every 2 weeks) was administered for 5th line therapy.
June 2018 Age 61 The patient complained of right heart failure (RHF) symptoms, and pericardial effusion was detected. Immune-related adverse event pericarditis was diagnosed.
July 2018 Age 61 RHF ameliorated with prednisolone but flared up at reduced dose, requiring increased dose of prednisolone.
September 2018 Age 62 Prednisolone was suspended and subsequently body weight gradually increased.
January 2019 Age 62 RHF was re-exacerbated, and echocardiography and right heart catheterization detected constrictive pericarditis. Steroid pulse therapy was performed.
March 2019 Age 62 RHF was re-re-exacerbated and repeated infliximab therapy was initiated.
February 2020 Age 63 Corticosteroid was tapered to a lower dose without the aggravation of RHF.
Case presentation
A 58-year-old man was diagnosed with stage IV (cT2N0M1) non-small-cell lung cancer comprising adenocarcinoma. The patient had no past medical history, including cardiovascular diseases. Prior to anticancer therapy, jugular venous distension and limb oedema were not detected, and heart sounds were normal. Electrocardiography demonstrated normal sinus rhythm, and computed tomography (CT) revealed no cardiomegaly or pericardial effusion. Lung cancer was aggravated despite anticancer chemotherapies, including cisplatin and pemetrexed as the 1st-line, docetaxel as the 2nd-line, tegafur/gimeracil/oteracil as the 3rd-line, and amrubicin as the 4th-line therapy. Nivolumab (3 mg/kg every 2 weeks), a programmed death-1 (PD-1) inhibitor, was administered as 5th-line therapy. Eighteen months after the initiation of nivolumab (after the 35th-cycle), the patient developed fatigue, limb oedema, and increased body weight (BW).
Physical examination revealed jugular venous distension and limb pitting oedema. The serum creatinine level was 0.77 mg/dL (normal range: 0.6–1.0 mg/dL). No electrocardiographic abnormalities were found. On echocardiography, ventricular systolic function on both sides and left ventricular diastolic function were preserved (abnormal relaxation pattern, Table 1), but mild pericardial effusion was detected (Figure 1A). The diameter of the pericardial echo-free space was 9 mm in the anterior right ventricle. CT revealed pericardial thickening, and trivial effusion in the pericardium and pleura (Figure 2B). As the patient was haemodynamically stable and the volume of pericardial effusion was mild, pericardiocentesis was planned to be performed if effusion increased. Favourable response of the lung cancer to treatment on CT suggested a non-malignant cause. Viral or purulent pericarditis was unlikely because the patient had no fever, a normal white blood cell count (6570/μL; normal range: 3300–8600/μL), and a negative blood culture test. Autoantibodies were all negative. Liver biopsy for the examination of liver enzymes revealed T-cell lymphocytic infiltration. Therefore, the patient was diagnosed with irAE hepatitis. Based on these findings, the patient was diagnosed with irAE pericarditis with constrictive features.
Figure 1 Chronological change in echocardiography. (A) Pericardial effusion detected at the time of diagnosis of pericarditis (arrow). (B–D) Pericardial adhesion to the right ventricular wall (B; arrow), significant reduction of the mitral peak E velocity in the inspiratory phase (C), and high peak e′ using tissue Doppler (D; arrow) were detected at 6 months after the diagnosis of pericarditis.
Figure 2 Clinical course and CT images. (A) Doses of steroid, the administration point of infliximab, body weight, the point of computed tomography (CT), and right heart failure (RHF) exacerbation events are described over time. (B) Pericardial thickening and effusion (arrow) on CT at the time of the diagnosis of pericarditis. (C) Pericardial effusion decreased after corticosteroid therapy (arrow) at 3 months after the diagnosis of pericarditis. (D) Trivial pericardial effusion (arrow) and massive pleural effusion (arrowhead) at 6 months after the diagnosis of pericarditis.
Table 1 Parameters of left ventricular diastolic function
Time after the diagnosis (months) 0 6 13 19
E (cm/s) 55.0 81.0 71.1 83.2
A (cm/s) 86.0 48.0 43.8 51.0
E/A 0.6 1.7 1.6 1.6
Deceleration time (ms) 161.0 117.0 109.0 121.0
E′ (cm/s) 7.8 13.3 10.6 9.9
E/E′ 7.1 6.1 6.7 8.4
Nivolumab was suspended and a high-dose corticosteroid, prednisolone at 0.5 mg/kg, was initiated. Right heart failure (RHF) symptoms were gradually ameliorated and the serum C-reactive protein level decreased from 4.08 mg/dL to 1.93 mg/dL (normal range: 0.00–0.14 mg/dL). However, RHF was exacerbated during the tapering of prednisolone (Figure 2A, 1st RHF exacerbation). Therefore, the dose of prednisolone was increased to the initial dose and re-tapered carefully. At the time of cessation of prednisolone, pericardial effusion was significantly reduced (Figure 2C). For a few months, the BW gradually increased with furosemide at 10 mg/day and quickly increased 3 months after the cessation of prednisolone (Figure 2A, 2nd RHF exacerbation), and the patient was positive for Kussmaul’s sign. Trivial pericardial effusion and massive pleural effusion were noted on CT (Figure 2D). In addition, echocardiography revealed pericardial adhesion (Figure 1B), aggravation of left ventricular diastolic function to a restrictive pattern (Table 1), significant reduction of the mitral peak E wave velocity in the inspiratory phase (Figure 1C), and septal bounce (Video 1). A higher peak e′ velocity on tissue Doppler (>8 cm/s) suggested a lower likelihood of restrictive cardiomyopathy (Figure 1D). Right heart catheterization demonstrated a W-shaped right atrial pressure waveform (Figure 3A). Simultaneous recording of biventricular pressures revealed a dip and plateau pattern in both ventricles, low end-diastolic pressure difference between the left and right ventricle (1 mmHg; cut-off: 5 mmHg), and high systolic area index (1.11; cut-off: 1.1), which suggested discordant changes in right and left ventricular filling during respiration (Figure 3B).5 As the amount of pericardial effusion was slight, pericardiocentesis was not performed. The serum troponin-T level was high (0.123 ng/mL; normal range: <0.014 ng/mL), but there was no evidence of active myocarditis by endomyocardial biopsy. Cardiac magnetic resonance imaging demonstrated pericardial thickening, but there was no myocardial oedema or significant late gadolinium enhancement in the pericardium or myocardium. At this point, the patient was diagnosed with constrictive pericarditis (CP) with myopericarditis. The dose of furosemide was increased to 40 mg/day and tolvaptan at 15 mg/day was added, but these did not ameliorate RHF symptoms. Consequently, methylprednisolone at 1 g/day for 3 days and subsequent prednisolone at 1 mg/kg were administered. RHF symptoms were transiently ameliorated, but they exacerbated again after the tapering of prednisolone (Figure 2A, 3rd RHF exacerbation). As pericarditis recurred repeatedly and progressed to CP despite corticosteroid therapy, infliximab (5 mg/kg) was initiated. Infliximab was administered 2 and 6 weeks after the 1st administration, and every 8 weeks thereafter in accordance with the regimen for the treatment of connective tissue disease (Figure 2A).
Figure 3 Haemodynamic assessment on cardiac catheterization. (A) High right atrial (RA) pressure with a W-shaped waveform. (B) A dip and plateau pattern and high systolic area index (SAI) were detected on simultaneous biventricular pressure recording.
After the initiation of infliximab, the BW decreased from 82 to 75 kg despite a reduction in the dose of diuretics (tolvaptan 7.5 mg/day), and the serum troponin-T level decreased to 0.020 ng/mL. Although CP findings were still present by echocardiography (Table 1), prednisolone was able to be tapered to a lower dose (0.15 mg/kg) without aggravation of RHF; therefore, pericardiectomy was not performed. The patient was administered low-dose prednisolone and repeated infliximab for 11 months after the 3rd RHF exacerbation without worsening RHF (Figure 2A).
Discussion
Cardiac irAEs are rare, but they do occur and can be fatal; therefore, they require appropriate treatment. As patients with pericardial irAE usually achieve improvement after the administration of corticosteroids,6 the effects of infliximab on pericarditis have not been reported. This is the 1st case demonstrating the efficacy of infliximab for corticosteroid-refractory pericardial irAE.
An important process in the diagnosis of irAE pericarditis is to exclude other causes of pericarditis. The Naranjo Scale score, which helps assess causality of adverse drug reactions, was six points in this case, suggesting that pericarditis was a probable adverse event of nivolumab.7 In this case, infection, autoimmune disorders, and metastasis of lung cancer were excluded by the patient’s history and examinations. In addition, concurrent hepatic irAE suggested that ICI-induced inflammation was the cause of pericarditis.3 Considering the RHF symptoms at the time of the initial diagnosis of pericarditis, the pericarditis had constrictive features when pericardial effusion developed. Left ventricular diastolic function on echocardiography deteriorated over time and CP-specific haemodynamics were demonstrated on cardiac catheterization at 6 months after the initial diagnosis of pericarditis.5,8 Increased serum troponin suggested myocardial inflammation accompanied by severe inflammation at the pericardium. Although cardiac irAE usually develops within 3 months after the initiation of ICI,3 this patient was diagnosed with pericarditis 18 months after the introduction of nivolumab. In addition, pericardial inflammation was sustained for a long time after the cessation of nivolumab. The delayed manifestation and sustained exacerbation of irAE pericarditis in this case can be partly explained by the pharmacodynamics of anti-PD-1 blockade, as demonstrated by the initial single nivolumab administration occupying >70% of PD-1 molecules on T cells for 85 days and this occupancy remained at 40% for more than 8 months after the last dose.9
Immune-suppressive therapy is recommended for serious irAEs refractory to high-dose corticosteroids.2 Infliximab, mycophenolate, or antithymocyte globulin are recommended as additional immune-suppressive therapy, but the differences in therapeutic effects among these drugs have not been assessed in the treatment of irAE pericarditis.2 Infliximab, a monoclonal antibody tumour necrosis factor-α inhibitor, reduces the expression of several proinflammatory molecules and mucosal cytokines. It is generally used for inflammatory bowel disease or connective tissue disease.10 In addition, Infliximab is effective for irAE colitis and is covered by insurance for the treatment of rheumatoid arthritis in our country, thus we administered it for irAE pericarditis in this patient within the approved dosage range for rheumatoid arthritis; 5 mg/kg at Weeks 0, 2, and 6 as induction therapy, then every 8 weeks as maintenance therapy.10,11 Infliximab was effective at relieving pericardial inflammation in this case, demonstrated by the reduced need for diuretics and prednisolone for the control of RHF after the initiation of infliximab concomitant with a decrease in serum troponin. Although the RHF status improved, CP remained after the initiation of infliximab according to echocardiography (Table 1). The treatment for irAEs did not affect the overall survival or time to treatment failure in cancer patients.12 Thus, considering the progressive course of pericarditis in this case, immune-suppressive therapy at an earlier stage of steroid-refractory pericarditis should be considered. Further studies are warranted to clarify the benefits of infliximab for irAE pericarditis.
Conclusion
ICI-related pericarditis potentially develops into CP. Therefore, early therapeutic intervention should be considered. Immune-suppressive drugs represented by infliximab are a promising therapeutic option for the treatment of steroid-refractory pericarditis.
Lead author biography
Dr Shohei Moriyama is a medical doctor at Kyushu University Hospital (Japan) and acquired a medical degree at Kyushu University in Fukuoka. Specialization: Cardio-Oncology. Membership: Japanese Circulation Society, Japanese Society of Medical Oncology, and Japanese Onco-Cardiology society.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytab002_Supplementary_Data Click here for additional data file. | FUROSEMIDE, INFLIXIMAB, METHYLPREDNISOLONE, NIVOLUMAB, PREDNISOLONE, TOLVAPTAN | DrugsGivenReaction | CC BY-NC | 33644656 | 19,426,929 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pericarditis constrictive'. | Refractory constrictive pericarditis caused by an immune checkpoint inhibitor properly managed with infliximab: a case report.
Immune checkpoint inhibitors (ICIs) can cause cardiac immune-related adverse events (irAEs), including pericarditis. Cardiovascular events related to pericardial irAE are less frequent, but fulminant forms can be fatal. However, the diagnosis and treatment strategies for pericardial irAE have not established.
A 58-year-old man was diagnosed with advanced non-small-cell lung cancer and nivolumab was administered as 5th-line therapy. Eighteen months after the initiation of nivolumab, the patient developed limb oedema and increased body weight. Although a favourable response of the cancer was observed, pericardial thickening and effusion were newly detected. He was diagnosed with irAE pericarditis after excluding other causes of pericarditis. Nivolumab was suspended and a high-dose corticosteroid was initiated. However, right heart failure (RHF) symptoms were exacerbated during the tapering of corticosteroid because acute pericarditis developed to steroid-refractory constrictive pericarditis. To suppress sustained inflammation of the pericardium, infliximab, a tumour necrosis factor-alfa inhibitor, was initiated. After the initiation of infliximab, the corticosteroid dose was tapered without deterioration of RHF. Exacerbation of lung cancer by irAE treatment including infliximab was not observed.
IrAE should be considered when pericarditis develops after the administration of ICI even after a long period from its initiation. Infliximab rescue therapy may be considered as a 2nd-line therapy for steroid-refractory irAE pericarditis even with constrictive physiology.
For the podcast associated with this article, please visit https://academic.oup.com/ehjcr/pages/podcast
Learning points
Immune-related adverse event (irAE) pericarditis can develop long after the initiation of immune checkpoint inhibitors and progress to constrictive pericarditis.
Early initiation of immune-suppressive therapy for irAE should be considered when it is refractory to corticosteroids.
Introduction
Immune checkpoint inhibitors (ICIs) have markedly improved the survival of cancer patients.1 However, immune-related adverse events (irAEs) by ICIs have been increasingly reported.2 Cardiac irAEs are rare (up to 2%), but 50% of the patients with irAE myocarditis and 21% of those with irAE pericarditis die, making them the ‘Achilles heel’ of ICI treatment.3 IrAEs are often diagnosed early after the initiation of ICI, but their delayed manifestation and progression can occur.4 We report a case of late-onset irAE pericarditis that developed to steroid-refractory constrictive pericarditis.
Timeline
July 2015 Age 58 The patient was diagnosed with advanced non-small-cell lung cancer, and anticancer chemotherapies were initiated. No cardiac disorder was identified.
December 2016 Age 60 Nivolumab (3 mg/kg every 2 weeks) was administered for 5th line therapy.
June 2018 Age 61 The patient complained of right heart failure (RHF) symptoms, and pericardial effusion was detected. Immune-related adverse event pericarditis was diagnosed.
July 2018 Age 61 RHF ameliorated with prednisolone but flared up at reduced dose, requiring increased dose of prednisolone.
September 2018 Age 62 Prednisolone was suspended and subsequently body weight gradually increased.
January 2019 Age 62 RHF was re-exacerbated, and echocardiography and right heart catheterization detected constrictive pericarditis. Steroid pulse therapy was performed.
March 2019 Age 62 RHF was re-re-exacerbated and repeated infliximab therapy was initiated.
February 2020 Age 63 Corticosteroid was tapered to a lower dose without the aggravation of RHF.
Case presentation
A 58-year-old man was diagnosed with stage IV (cT2N0M1) non-small-cell lung cancer comprising adenocarcinoma. The patient had no past medical history, including cardiovascular diseases. Prior to anticancer therapy, jugular venous distension and limb oedema were not detected, and heart sounds were normal. Electrocardiography demonstrated normal sinus rhythm, and computed tomography (CT) revealed no cardiomegaly or pericardial effusion. Lung cancer was aggravated despite anticancer chemotherapies, including cisplatin and pemetrexed as the 1st-line, docetaxel as the 2nd-line, tegafur/gimeracil/oteracil as the 3rd-line, and amrubicin as the 4th-line therapy. Nivolumab (3 mg/kg every 2 weeks), a programmed death-1 (PD-1) inhibitor, was administered as 5th-line therapy. Eighteen months after the initiation of nivolumab (after the 35th-cycle), the patient developed fatigue, limb oedema, and increased body weight (BW).
Physical examination revealed jugular venous distension and limb pitting oedema. The serum creatinine level was 0.77 mg/dL (normal range: 0.6–1.0 mg/dL). No electrocardiographic abnormalities were found. On echocardiography, ventricular systolic function on both sides and left ventricular diastolic function were preserved (abnormal relaxation pattern, Table 1), but mild pericardial effusion was detected (Figure 1A). The diameter of the pericardial echo-free space was 9 mm in the anterior right ventricle. CT revealed pericardial thickening, and trivial effusion in the pericardium and pleura (Figure 2B). As the patient was haemodynamically stable and the volume of pericardial effusion was mild, pericardiocentesis was planned to be performed if effusion increased. Favourable response of the lung cancer to treatment on CT suggested a non-malignant cause. Viral or purulent pericarditis was unlikely because the patient had no fever, a normal white blood cell count (6570/μL; normal range: 3300–8600/μL), and a negative blood culture test. Autoantibodies were all negative. Liver biopsy for the examination of liver enzymes revealed T-cell lymphocytic infiltration. Therefore, the patient was diagnosed with irAE hepatitis. Based on these findings, the patient was diagnosed with irAE pericarditis with constrictive features.
Figure 1 Chronological change in echocardiography. (A) Pericardial effusion detected at the time of diagnosis of pericarditis (arrow). (B–D) Pericardial adhesion to the right ventricular wall (B; arrow), significant reduction of the mitral peak E velocity in the inspiratory phase (C), and high peak e′ using tissue Doppler (D; arrow) were detected at 6 months after the diagnosis of pericarditis.
Figure 2 Clinical course and CT images. (A) Doses of steroid, the administration point of infliximab, body weight, the point of computed tomography (CT), and right heart failure (RHF) exacerbation events are described over time. (B) Pericardial thickening and effusion (arrow) on CT at the time of the diagnosis of pericarditis. (C) Pericardial effusion decreased after corticosteroid therapy (arrow) at 3 months after the diagnosis of pericarditis. (D) Trivial pericardial effusion (arrow) and massive pleural effusion (arrowhead) at 6 months after the diagnosis of pericarditis.
Table 1 Parameters of left ventricular diastolic function
Time after the diagnosis (months) 0 6 13 19
E (cm/s) 55.0 81.0 71.1 83.2
A (cm/s) 86.0 48.0 43.8 51.0
E/A 0.6 1.7 1.6 1.6
Deceleration time (ms) 161.0 117.0 109.0 121.0
E′ (cm/s) 7.8 13.3 10.6 9.9
E/E′ 7.1 6.1 6.7 8.4
Nivolumab was suspended and a high-dose corticosteroid, prednisolone at 0.5 mg/kg, was initiated. Right heart failure (RHF) symptoms were gradually ameliorated and the serum C-reactive protein level decreased from 4.08 mg/dL to 1.93 mg/dL (normal range: 0.00–0.14 mg/dL). However, RHF was exacerbated during the tapering of prednisolone (Figure 2A, 1st RHF exacerbation). Therefore, the dose of prednisolone was increased to the initial dose and re-tapered carefully. At the time of cessation of prednisolone, pericardial effusion was significantly reduced (Figure 2C). For a few months, the BW gradually increased with furosemide at 10 mg/day and quickly increased 3 months after the cessation of prednisolone (Figure 2A, 2nd RHF exacerbation), and the patient was positive for Kussmaul’s sign. Trivial pericardial effusion and massive pleural effusion were noted on CT (Figure 2D). In addition, echocardiography revealed pericardial adhesion (Figure 1B), aggravation of left ventricular diastolic function to a restrictive pattern (Table 1), significant reduction of the mitral peak E wave velocity in the inspiratory phase (Figure 1C), and septal bounce (Video 1). A higher peak e′ velocity on tissue Doppler (>8 cm/s) suggested a lower likelihood of restrictive cardiomyopathy (Figure 1D). Right heart catheterization demonstrated a W-shaped right atrial pressure waveform (Figure 3A). Simultaneous recording of biventricular pressures revealed a dip and plateau pattern in both ventricles, low end-diastolic pressure difference between the left and right ventricle (1 mmHg; cut-off: 5 mmHg), and high systolic area index (1.11; cut-off: 1.1), which suggested discordant changes in right and left ventricular filling during respiration (Figure 3B).5 As the amount of pericardial effusion was slight, pericardiocentesis was not performed. The serum troponin-T level was high (0.123 ng/mL; normal range: <0.014 ng/mL), but there was no evidence of active myocarditis by endomyocardial biopsy. Cardiac magnetic resonance imaging demonstrated pericardial thickening, but there was no myocardial oedema or significant late gadolinium enhancement in the pericardium or myocardium. At this point, the patient was diagnosed with constrictive pericarditis (CP) with myopericarditis. The dose of furosemide was increased to 40 mg/day and tolvaptan at 15 mg/day was added, but these did not ameliorate RHF symptoms. Consequently, methylprednisolone at 1 g/day for 3 days and subsequent prednisolone at 1 mg/kg were administered. RHF symptoms were transiently ameliorated, but they exacerbated again after the tapering of prednisolone (Figure 2A, 3rd RHF exacerbation). As pericarditis recurred repeatedly and progressed to CP despite corticosteroid therapy, infliximab (5 mg/kg) was initiated. Infliximab was administered 2 and 6 weeks after the 1st administration, and every 8 weeks thereafter in accordance with the regimen for the treatment of connective tissue disease (Figure 2A).
Figure 3 Haemodynamic assessment on cardiac catheterization. (A) High right atrial (RA) pressure with a W-shaped waveform. (B) A dip and plateau pattern and high systolic area index (SAI) were detected on simultaneous biventricular pressure recording.
After the initiation of infliximab, the BW decreased from 82 to 75 kg despite a reduction in the dose of diuretics (tolvaptan 7.5 mg/day), and the serum troponin-T level decreased to 0.020 ng/mL. Although CP findings were still present by echocardiography (Table 1), prednisolone was able to be tapered to a lower dose (0.15 mg/kg) without aggravation of RHF; therefore, pericardiectomy was not performed. The patient was administered low-dose prednisolone and repeated infliximab for 11 months after the 3rd RHF exacerbation without worsening RHF (Figure 2A).
Discussion
Cardiac irAEs are rare, but they do occur and can be fatal; therefore, they require appropriate treatment. As patients with pericardial irAE usually achieve improvement after the administration of corticosteroids,6 the effects of infliximab on pericarditis have not been reported. This is the 1st case demonstrating the efficacy of infliximab for corticosteroid-refractory pericardial irAE.
An important process in the diagnosis of irAE pericarditis is to exclude other causes of pericarditis. The Naranjo Scale score, which helps assess causality of adverse drug reactions, was six points in this case, suggesting that pericarditis was a probable adverse event of nivolumab.7 In this case, infection, autoimmune disorders, and metastasis of lung cancer were excluded by the patient’s history and examinations. In addition, concurrent hepatic irAE suggested that ICI-induced inflammation was the cause of pericarditis.3 Considering the RHF symptoms at the time of the initial diagnosis of pericarditis, the pericarditis had constrictive features when pericardial effusion developed. Left ventricular diastolic function on echocardiography deteriorated over time and CP-specific haemodynamics were demonstrated on cardiac catheterization at 6 months after the initial diagnosis of pericarditis.5,8 Increased serum troponin suggested myocardial inflammation accompanied by severe inflammation at the pericardium. Although cardiac irAE usually develops within 3 months after the initiation of ICI,3 this patient was diagnosed with pericarditis 18 months after the introduction of nivolumab. In addition, pericardial inflammation was sustained for a long time after the cessation of nivolumab. The delayed manifestation and sustained exacerbation of irAE pericarditis in this case can be partly explained by the pharmacodynamics of anti-PD-1 blockade, as demonstrated by the initial single nivolumab administration occupying >70% of PD-1 molecules on T cells for 85 days and this occupancy remained at 40% for more than 8 months after the last dose.9
Immune-suppressive therapy is recommended for serious irAEs refractory to high-dose corticosteroids.2 Infliximab, mycophenolate, or antithymocyte globulin are recommended as additional immune-suppressive therapy, but the differences in therapeutic effects among these drugs have not been assessed in the treatment of irAE pericarditis.2 Infliximab, a monoclonal antibody tumour necrosis factor-α inhibitor, reduces the expression of several proinflammatory molecules and mucosal cytokines. It is generally used for inflammatory bowel disease or connective tissue disease.10 In addition, Infliximab is effective for irAE colitis and is covered by insurance for the treatment of rheumatoid arthritis in our country, thus we administered it for irAE pericarditis in this patient within the approved dosage range for rheumatoid arthritis; 5 mg/kg at Weeks 0, 2, and 6 as induction therapy, then every 8 weeks as maintenance therapy.10,11 Infliximab was effective at relieving pericardial inflammation in this case, demonstrated by the reduced need for diuretics and prednisolone for the control of RHF after the initiation of infliximab concomitant with a decrease in serum troponin. Although the RHF status improved, CP remained after the initiation of infliximab according to echocardiography (Table 1). The treatment for irAEs did not affect the overall survival or time to treatment failure in cancer patients.12 Thus, considering the progressive course of pericarditis in this case, immune-suppressive therapy at an earlier stage of steroid-refractory pericarditis should be considered. Further studies are warranted to clarify the benefits of infliximab for irAE pericarditis.
Conclusion
ICI-related pericarditis potentially develops into CP. Therefore, early therapeutic intervention should be considered. Immune-suppressive drugs represented by infliximab are a promising therapeutic option for the treatment of steroid-refractory pericarditis.
Lead author biography
Dr Shohei Moriyama is a medical doctor at Kyushu University Hospital (Japan) and acquired a medical degree at Kyushu University in Fukuoka. Specialization: Cardio-Oncology. Membership: Japanese Circulation Society, Japanese Society of Medical Oncology, and Japanese Onco-Cardiology society.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytab002_Supplementary_Data Click here for additional data file. | FUROSEMIDE, INFLIXIMAB, METHYLPREDNISOLONE, NIVOLUMAB, PREDNISOLONE, TOLVAPTAN | DrugsGivenReaction | CC BY-NC | 33644656 | 19,426,929 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Right ventricular failure'. | Refractory constrictive pericarditis caused by an immune checkpoint inhibitor properly managed with infliximab: a case report.
Immune checkpoint inhibitors (ICIs) can cause cardiac immune-related adverse events (irAEs), including pericarditis. Cardiovascular events related to pericardial irAE are less frequent, but fulminant forms can be fatal. However, the diagnosis and treatment strategies for pericardial irAE have not established.
A 58-year-old man was diagnosed with advanced non-small-cell lung cancer and nivolumab was administered as 5th-line therapy. Eighteen months after the initiation of nivolumab, the patient developed limb oedema and increased body weight. Although a favourable response of the cancer was observed, pericardial thickening and effusion were newly detected. He was diagnosed with irAE pericarditis after excluding other causes of pericarditis. Nivolumab was suspended and a high-dose corticosteroid was initiated. However, right heart failure (RHF) symptoms were exacerbated during the tapering of corticosteroid because acute pericarditis developed to steroid-refractory constrictive pericarditis. To suppress sustained inflammation of the pericardium, infliximab, a tumour necrosis factor-alfa inhibitor, was initiated. After the initiation of infliximab, the corticosteroid dose was tapered without deterioration of RHF. Exacerbation of lung cancer by irAE treatment including infliximab was not observed.
IrAE should be considered when pericarditis develops after the administration of ICI even after a long period from its initiation. Infliximab rescue therapy may be considered as a 2nd-line therapy for steroid-refractory irAE pericarditis even with constrictive physiology.
For the podcast associated with this article, please visit https://academic.oup.com/ehjcr/pages/podcast
Learning points
Immune-related adverse event (irAE) pericarditis can develop long after the initiation of immune checkpoint inhibitors and progress to constrictive pericarditis.
Early initiation of immune-suppressive therapy for irAE should be considered when it is refractory to corticosteroids.
Introduction
Immune checkpoint inhibitors (ICIs) have markedly improved the survival of cancer patients.1 However, immune-related adverse events (irAEs) by ICIs have been increasingly reported.2 Cardiac irAEs are rare (up to 2%), but 50% of the patients with irAE myocarditis and 21% of those with irAE pericarditis die, making them the ‘Achilles heel’ of ICI treatment.3 IrAEs are often diagnosed early after the initiation of ICI, but their delayed manifestation and progression can occur.4 We report a case of late-onset irAE pericarditis that developed to steroid-refractory constrictive pericarditis.
Timeline
July 2015 Age 58 The patient was diagnosed with advanced non-small-cell lung cancer, and anticancer chemotherapies were initiated. No cardiac disorder was identified.
December 2016 Age 60 Nivolumab (3 mg/kg every 2 weeks) was administered for 5th line therapy.
June 2018 Age 61 The patient complained of right heart failure (RHF) symptoms, and pericardial effusion was detected. Immune-related adverse event pericarditis was diagnosed.
July 2018 Age 61 RHF ameliorated with prednisolone but flared up at reduced dose, requiring increased dose of prednisolone.
September 2018 Age 62 Prednisolone was suspended and subsequently body weight gradually increased.
January 2019 Age 62 RHF was re-exacerbated, and echocardiography and right heart catheterization detected constrictive pericarditis. Steroid pulse therapy was performed.
March 2019 Age 62 RHF was re-re-exacerbated and repeated infliximab therapy was initiated.
February 2020 Age 63 Corticosteroid was tapered to a lower dose without the aggravation of RHF.
Case presentation
A 58-year-old man was diagnosed with stage IV (cT2N0M1) non-small-cell lung cancer comprising adenocarcinoma. The patient had no past medical history, including cardiovascular diseases. Prior to anticancer therapy, jugular venous distension and limb oedema were not detected, and heart sounds were normal. Electrocardiography demonstrated normal sinus rhythm, and computed tomography (CT) revealed no cardiomegaly or pericardial effusion. Lung cancer was aggravated despite anticancer chemotherapies, including cisplatin and pemetrexed as the 1st-line, docetaxel as the 2nd-line, tegafur/gimeracil/oteracil as the 3rd-line, and amrubicin as the 4th-line therapy. Nivolumab (3 mg/kg every 2 weeks), a programmed death-1 (PD-1) inhibitor, was administered as 5th-line therapy. Eighteen months after the initiation of nivolumab (after the 35th-cycle), the patient developed fatigue, limb oedema, and increased body weight (BW).
Physical examination revealed jugular venous distension and limb pitting oedema. The serum creatinine level was 0.77 mg/dL (normal range: 0.6–1.0 mg/dL). No electrocardiographic abnormalities were found. On echocardiography, ventricular systolic function on both sides and left ventricular diastolic function were preserved (abnormal relaxation pattern, Table 1), but mild pericardial effusion was detected (Figure 1A). The diameter of the pericardial echo-free space was 9 mm in the anterior right ventricle. CT revealed pericardial thickening, and trivial effusion in the pericardium and pleura (Figure 2B). As the patient was haemodynamically stable and the volume of pericardial effusion was mild, pericardiocentesis was planned to be performed if effusion increased. Favourable response of the lung cancer to treatment on CT suggested a non-malignant cause. Viral or purulent pericarditis was unlikely because the patient had no fever, a normal white blood cell count (6570/μL; normal range: 3300–8600/μL), and a negative blood culture test. Autoantibodies were all negative. Liver biopsy for the examination of liver enzymes revealed T-cell lymphocytic infiltration. Therefore, the patient was diagnosed with irAE hepatitis. Based on these findings, the patient was diagnosed with irAE pericarditis with constrictive features.
Figure 1 Chronological change in echocardiography. (A) Pericardial effusion detected at the time of diagnosis of pericarditis (arrow). (B–D) Pericardial adhesion to the right ventricular wall (B; arrow), significant reduction of the mitral peak E velocity in the inspiratory phase (C), and high peak e′ using tissue Doppler (D; arrow) were detected at 6 months after the diagnosis of pericarditis.
Figure 2 Clinical course and CT images. (A) Doses of steroid, the administration point of infliximab, body weight, the point of computed tomography (CT), and right heart failure (RHF) exacerbation events are described over time. (B) Pericardial thickening and effusion (arrow) on CT at the time of the diagnosis of pericarditis. (C) Pericardial effusion decreased after corticosteroid therapy (arrow) at 3 months after the diagnosis of pericarditis. (D) Trivial pericardial effusion (arrow) and massive pleural effusion (arrowhead) at 6 months after the diagnosis of pericarditis.
Table 1 Parameters of left ventricular diastolic function
Time after the diagnosis (months) 0 6 13 19
E (cm/s) 55.0 81.0 71.1 83.2
A (cm/s) 86.0 48.0 43.8 51.0
E/A 0.6 1.7 1.6 1.6
Deceleration time (ms) 161.0 117.0 109.0 121.0
E′ (cm/s) 7.8 13.3 10.6 9.9
E/E′ 7.1 6.1 6.7 8.4
Nivolumab was suspended and a high-dose corticosteroid, prednisolone at 0.5 mg/kg, was initiated. Right heart failure (RHF) symptoms were gradually ameliorated and the serum C-reactive protein level decreased from 4.08 mg/dL to 1.93 mg/dL (normal range: 0.00–0.14 mg/dL). However, RHF was exacerbated during the tapering of prednisolone (Figure 2A, 1st RHF exacerbation). Therefore, the dose of prednisolone was increased to the initial dose and re-tapered carefully. At the time of cessation of prednisolone, pericardial effusion was significantly reduced (Figure 2C). For a few months, the BW gradually increased with furosemide at 10 mg/day and quickly increased 3 months after the cessation of prednisolone (Figure 2A, 2nd RHF exacerbation), and the patient was positive for Kussmaul’s sign. Trivial pericardial effusion and massive pleural effusion were noted on CT (Figure 2D). In addition, echocardiography revealed pericardial adhesion (Figure 1B), aggravation of left ventricular diastolic function to a restrictive pattern (Table 1), significant reduction of the mitral peak E wave velocity in the inspiratory phase (Figure 1C), and septal bounce (Video 1). A higher peak e′ velocity on tissue Doppler (>8 cm/s) suggested a lower likelihood of restrictive cardiomyopathy (Figure 1D). Right heart catheterization demonstrated a W-shaped right atrial pressure waveform (Figure 3A). Simultaneous recording of biventricular pressures revealed a dip and plateau pattern in both ventricles, low end-diastolic pressure difference between the left and right ventricle (1 mmHg; cut-off: 5 mmHg), and high systolic area index (1.11; cut-off: 1.1), which suggested discordant changes in right and left ventricular filling during respiration (Figure 3B).5 As the amount of pericardial effusion was slight, pericardiocentesis was not performed. The serum troponin-T level was high (0.123 ng/mL; normal range: <0.014 ng/mL), but there was no evidence of active myocarditis by endomyocardial biopsy. Cardiac magnetic resonance imaging demonstrated pericardial thickening, but there was no myocardial oedema or significant late gadolinium enhancement in the pericardium or myocardium. At this point, the patient was diagnosed with constrictive pericarditis (CP) with myopericarditis. The dose of furosemide was increased to 40 mg/day and tolvaptan at 15 mg/day was added, but these did not ameliorate RHF symptoms. Consequently, methylprednisolone at 1 g/day for 3 days and subsequent prednisolone at 1 mg/kg were administered. RHF symptoms were transiently ameliorated, but they exacerbated again after the tapering of prednisolone (Figure 2A, 3rd RHF exacerbation). As pericarditis recurred repeatedly and progressed to CP despite corticosteroid therapy, infliximab (5 mg/kg) was initiated. Infliximab was administered 2 and 6 weeks after the 1st administration, and every 8 weeks thereafter in accordance with the regimen for the treatment of connective tissue disease (Figure 2A).
Figure 3 Haemodynamic assessment on cardiac catheterization. (A) High right atrial (RA) pressure with a W-shaped waveform. (B) A dip and plateau pattern and high systolic area index (SAI) were detected on simultaneous biventricular pressure recording.
After the initiation of infliximab, the BW decreased from 82 to 75 kg despite a reduction in the dose of diuretics (tolvaptan 7.5 mg/day), and the serum troponin-T level decreased to 0.020 ng/mL. Although CP findings were still present by echocardiography (Table 1), prednisolone was able to be tapered to a lower dose (0.15 mg/kg) without aggravation of RHF; therefore, pericardiectomy was not performed. The patient was administered low-dose prednisolone and repeated infliximab for 11 months after the 3rd RHF exacerbation without worsening RHF (Figure 2A).
Discussion
Cardiac irAEs are rare, but they do occur and can be fatal; therefore, they require appropriate treatment. As patients with pericardial irAE usually achieve improvement after the administration of corticosteroids,6 the effects of infliximab on pericarditis have not been reported. This is the 1st case demonstrating the efficacy of infliximab for corticosteroid-refractory pericardial irAE.
An important process in the diagnosis of irAE pericarditis is to exclude other causes of pericarditis. The Naranjo Scale score, which helps assess causality of adverse drug reactions, was six points in this case, suggesting that pericarditis was a probable adverse event of nivolumab.7 In this case, infection, autoimmune disorders, and metastasis of lung cancer were excluded by the patient’s history and examinations. In addition, concurrent hepatic irAE suggested that ICI-induced inflammation was the cause of pericarditis.3 Considering the RHF symptoms at the time of the initial diagnosis of pericarditis, the pericarditis had constrictive features when pericardial effusion developed. Left ventricular diastolic function on echocardiography deteriorated over time and CP-specific haemodynamics were demonstrated on cardiac catheterization at 6 months after the initial diagnosis of pericarditis.5,8 Increased serum troponin suggested myocardial inflammation accompanied by severe inflammation at the pericardium. Although cardiac irAE usually develops within 3 months after the initiation of ICI,3 this patient was diagnosed with pericarditis 18 months after the introduction of nivolumab. In addition, pericardial inflammation was sustained for a long time after the cessation of nivolumab. The delayed manifestation and sustained exacerbation of irAE pericarditis in this case can be partly explained by the pharmacodynamics of anti-PD-1 blockade, as demonstrated by the initial single nivolumab administration occupying >70% of PD-1 molecules on T cells for 85 days and this occupancy remained at 40% for more than 8 months after the last dose.9
Immune-suppressive therapy is recommended for serious irAEs refractory to high-dose corticosteroids.2 Infliximab, mycophenolate, or antithymocyte globulin are recommended as additional immune-suppressive therapy, but the differences in therapeutic effects among these drugs have not been assessed in the treatment of irAE pericarditis.2 Infliximab, a monoclonal antibody tumour necrosis factor-α inhibitor, reduces the expression of several proinflammatory molecules and mucosal cytokines. It is generally used for inflammatory bowel disease or connective tissue disease.10 In addition, Infliximab is effective for irAE colitis and is covered by insurance for the treatment of rheumatoid arthritis in our country, thus we administered it for irAE pericarditis in this patient within the approved dosage range for rheumatoid arthritis; 5 mg/kg at Weeks 0, 2, and 6 as induction therapy, then every 8 weeks as maintenance therapy.10,11 Infliximab was effective at relieving pericardial inflammation in this case, demonstrated by the reduced need for diuretics and prednisolone for the control of RHF after the initiation of infliximab concomitant with a decrease in serum troponin. Although the RHF status improved, CP remained after the initiation of infliximab according to echocardiography (Table 1). The treatment for irAEs did not affect the overall survival or time to treatment failure in cancer patients.12 Thus, considering the progressive course of pericarditis in this case, immune-suppressive therapy at an earlier stage of steroid-refractory pericarditis should be considered. Further studies are warranted to clarify the benefits of infliximab for irAE pericarditis.
Conclusion
ICI-related pericarditis potentially develops into CP. Therefore, early therapeutic intervention should be considered. Immune-suppressive drugs represented by infliximab are a promising therapeutic option for the treatment of steroid-refractory pericarditis.
Lead author biography
Dr Shohei Moriyama is a medical doctor at Kyushu University Hospital (Japan) and acquired a medical degree at Kyushu University in Fukuoka. Specialization: Cardio-Oncology. Membership: Japanese Circulation Society, Japanese Society of Medical Oncology, and Japanese Onco-Cardiology society.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytab002_Supplementary_Data Click here for additional data file. | FUROSEMIDE, INFLIXIMAB, METHYLPREDNISOLONE, NIVOLUMAB, PREDNISOLONE, TOLVAPTAN | DrugsGivenReaction | CC BY-NC | 33644656 | 19,426,929 | 2021-01 |
What was the dosage of drug 'METHYLPREDNISOLONE'? | Refractory constrictive pericarditis caused by an immune checkpoint inhibitor properly managed with infliximab: a case report.
Immune checkpoint inhibitors (ICIs) can cause cardiac immune-related adverse events (irAEs), including pericarditis. Cardiovascular events related to pericardial irAE are less frequent, but fulminant forms can be fatal. However, the diagnosis and treatment strategies for pericardial irAE have not established.
A 58-year-old man was diagnosed with advanced non-small-cell lung cancer and nivolumab was administered as 5th-line therapy. Eighteen months after the initiation of nivolumab, the patient developed limb oedema and increased body weight. Although a favourable response of the cancer was observed, pericardial thickening and effusion were newly detected. He was diagnosed with irAE pericarditis after excluding other causes of pericarditis. Nivolumab was suspended and a high-dose corticosteroid was initiated. However, right heart failure (RHF) symptoms were exacerbated during the tapering of corticosteroid because acute pericarditis developed to steroid-refractory constrictive pericarditis. To suppress sustained inflammation of the pericardium, infliximab, a tumour necrosis factor-alfa inhibitor, was initiated. After the initiation of infliximab, the corticosteroid dose was tapered without deterioration of RHF. Exacerbation of lung cancer by irAE treatment including infliximab was not observed.
IrAE should be considered when pericarditis develops after the administration of ICI even after a long period from its initiation. Infliximab rescue therapy may be considered as a 2nd-line therapy for steroid-refractory irAE pericarditis even with constrictive physiology.
For the podcast associated with this article, please visit https://academic.oup.com/ehjcr/pages/podcast
Learning points
Immune-related adverse event (irAE) pericarditis can develop long after the initiation of immune checkpoint inhibitors and progress to constrictive pericarditis.
Early initiation of immune-suppressive therapy for irAE should be considered when it is refractory to corticosteroids.
Introduction
Immune checkpoint inhibitors (ICIs) have markedly improved the survival of cancer patients.1 However, immune-related adverse events (irAEs) by ICIs have been increasingly reported.2 Cardiac irAEs are rare (up to 2%), but 50% of the patients with irAE myocarditis and 21% of those with irAE pericarditis die, making them the ‘Achilles heel’ of ICI treatment.3 IrAEs are often diagnosed early after the initiation of ICI, but their delayed manifestation and progression can occur.4 We report a case of late-onset irAE pericarditis that developed to steroid-refractory constrictive pericarditis.
Timeline
July 2015 Age 58 The patient was diagnosed with advanced non-small-cell lung cancer, and anticancer chemotherapies were initiated. No cardiac disorder was identified.
December 2016 Age 60 Nivolumab (3 mg/kg every 2 weeks) was administered for 5th line therapy.
June 2018 Age 61 The patient complained of right heart failure (RHF) symptoms, and pericardial effusion was detected. Immune-related adverse event pericarditis was diagnosed.
July 2018 Age 61 RHF ameliorated with prednisolone but flared up at reduced dose, requiring increased dose of prednisolone.
September 2018 Age 62 Prednisolone was suspended and subsequently body weight gradually increased.
January 2019 Age 62 RHF was re-exacerbated, and echocardiography and right heart catheterization detected constrictive pericarditis. Steroid pulse therapy was performed.
March 2019 Age 62 RHF was re-re-exacerbated and repeated infliximab therapy was initiated.
February 2020 Age 63 Corticosteroid was tapered to a lower dose without the aggravation of RHF.
Case presentation
A 58-year-old man was diagnosed with stage IV (cT2N0M1) non-small-cell lung cancer comprising adenocarcinoma. The patient had no past medical history, including cardiovascular diseases. Prior to anticancer therapy, jugular venous distension and limb oedema were not detected, and heart sounds were normal. Electrocardiography demonstrated normal sinus rhythm, and computed tomography (CT) revealed no cardiomegaly or pericardial effusion. Lung cancer was aggravated despite anticancer chemotherapies, including cisplatin and pemetrexed as the 1st-line, docetaxel as the 2nd-line, tegafur/gimeracil/oteracil as the 3rd-line, and amrubicin as the 4th-line therapy. Nivolumab (3 mg/kg every 2 weeks), a programmed death-1 (PD-1) inhibitor, was administered as 5th-line therapy. Eighteen months after the initiation of nivolumab (after the 35th-cycle), the patient developed fatigue, limb oedema, and increased body weight (BW).
Physical examination revealed jugular venous distension and limb pitting oedema. The serum creatinine level was 0.77 mg/dL (normal range: 0.6–1.0 mg/dL). No electrocardiographic abnormalities were found. On echocardiography, ventricular systolic function on both sides and left ventricular diastolic function were preserved (abnormal relaxation pattern, Table 1), but mild pericardial effusion was detected (Figure 1A). The diameter of the pericardial echo-free space was 9 mm in the anterior right ventricle. CT revealed pericardial thickening, and trivial effusion in the pericardium and pleura (Figure 2B). As the patient was haemodynamically stable and the volume of pericardial effusion was mild, pericardiocentesis was planned to be performed if effusion increased. Favourable response of the lung cancer to treatment on CT suggested a non-malignant cause. Viral or purulent pericarditis was unlikely because the patient had no fever, a normal white blood cell count (6570/μL; normal range: 3300–8600/μL), and a negative blood culture test. Autoantibodies were all negative. Liver biopsy for the examination of liver enzymes revealed T-cell lymphocytic infiltration. Therefore, the patient was diagnosed with irAE hepatitis. Based on these findings, the patient was diagnosed with irAE pericarditis with constrictive features.
Figure 1 Chronological change in echocardiography. (A) Pericardial effusion detected at the time of diagnosis of pericarditis (arrow). (B–D) Pericardial adhesion to the right ventricular wall (B; arrow), significant reduction of the mitral peak E velocity in the inspiratory phase (C), and high peak e′ using tissue Doppler (D; arrow) were detected at 6 months after the diagnosis of pericarditis.
Figure 2 Clinical course and CT images. (A) Doses of steroid, the administration point of infliximab, body weight, the point of computed tomography (CT), and right heart failure (RHF) exacerbation events are described over time. (B) Pericardial thickening and effusion (arrow) on CT at the time of the diagnosis of pericarditis. (C) Pericardial effusion decreased after corticosteroid therapy (arrow) at 3 months after the diagnosis of pericarditis. (D) Trivial pericardial effusion (arrow) and massive pleural effusion (arrowhead) at 6 months after the diagnosis of pericarditis.
Table 1 Parameters of left ventricular diastolic function
Time after the diagnosis (months) 0 6 13 19
E (cm/s) 55.0 81.0 71.1 83.2
A (cm/s) 86.0 48.0 43.8 51.0
E/A 0.6 1.7 1.6 1.6
Deceleration time (ms) 161.0 117.0 109.0 121.0
E′ (cm/s) 7.8 13.3 10.6 9.9
E/E′ 7.1 6.1 6.7 8.4
Nivolumab was suspended and a high-dose corticosteroid, prednisolone at 0.5 mg/kg, was initiated. Right heart failure (RHF) symptoms were gradually ameliorated and the serum C-reactive protein level decreased from 4.08 mg/dL to 1.93 mg/dL (normal range: 0.00–0.14 mg/dL). However, RHF was exacerbated during the tapering of prednisolone (Figure 2A, 1st RHF exacerbation). Therefore, the dose of prednisolone was increased to the initial dose and re-tapered carefully. At the time of cessation of prednisolone, pericardial effusion was significantly reduced (Figure 2C). For a few months, the BW gradually increased with furosemide at 10 mg/day and quickly increased 3 months after the cessation of prednisolone (Figure 2A, 2nd RHF exacerbation), and the patient was positive for Kussmaul’s sign. Trivial pericardial effusion and massive pleural effusion were noted on CT (Figure 2D). In addition, echocardiography revealed pericardial adhesion (Figure 1B), aggravation of left ventricular diastolic function to a restrictive pattern (Table 1), significant reduction of the mitral peak E wave velocity in the inspiratory phase (Figure 1C), and septal bounce (Video 1). A higher peak e′ velocity on tissue Doppler (>8 cm/s) suggested a lower likelihood of restrictive cardiomyopathy (Figure 1D). Right heart catheterization demonstrated a W-shaped right atrial pressure waveform (Figure 3A). Simultaneous recording of biventricular pressures revealed a dip and plateau pattern in both ventricles, low end-diastolic pressure difference between the left and right ventricle (1 mmHg; cut-off: 5 mmHg), and high systolic area index (1.11; cut-off: 1.1), which suggested discordant changes in right and left ventricular filling during respiration (Figure 3B).5 As the amount of pericardial effusion was slight, pericardiocentesis was not performed. The serum troponin-T level was high (0.123 ng/mL; normal range: <0.014 ng/mL), but there was no evidence of active myocarditis by endomyocardial biopsy. Cardiac magnetic resonance imaging demonstrated pericardial thickening, but there was no myocardial oedema or significant late gadolinium enhancement in the pericardium or myocardium. At this point, the patient was diagnosed with constrictive pericarditis (CP) with myopericarditis. The dose of furosemide was increased to 40 mg/day and tolvaptan at 15 mg/day was added, but these did not ameliorate RHF symptoms. Consequently, methylprednisolone at 1 g/day for 3 days and subsequent prednisolone at 1 mg/kg were administered. RHF symptoms were transiently ameliorated, but they exacerbated again after the tapering of prednisolone (Figure 2A, 3rd RHF exacerbation). As pericarditis recurred repeatedly and progressed to CP despite corticosteroid therapy, infliximab (5 mg/kg) was initiated. Infliximab was administered 2 and 6 weeks after the 1st administration, and every 8 weeks thereafter in accordance with the regimen for the treatment of connective tissue disease (Figure 2A).
Figure 3 Haemodynamic assessment on cardiac catheterization. (A) High right atrial (RA) pressure with a W-shaped waveform. (B) A dip and plateau pattern and high systolic area index (SAI) were detected on simultaneous biventricular pressure recording.
After the initiation of infliximab, the BW decreased from 82 to 75 kg despite a reduction in the dose of diuretics (tolvaptan 7.5 mg/day), and the serum troponin-T level decreased to 0.020 ng/mL. Although CP findings were still present by echocardiography (Table 1), prednisolone was able to be tapered to a lower dose (0.15 mg/kg) without aggravation of RHF; therefore, pericardiectomy was not performed. The patient was administered low-dose prednisolone and repeated infliximab for 11 months after the 3rd RHF exacerbation without worsening RHF (Figure 2A).
Discussion
Cardiac irAEs are rare, but they do occur and can be fatal; therefore, they require appropriate treatment. As patients with pericardial irAE usually achieve improvement after the administration of corticosteroids,6 the effects of infliximab on pericarditis have not been reported. This is the 1st case demonstrating the efficacy of infliximab for corticosteroid-refractory pericardial irAE.
An important process in the diagnosis of irAE pericarditis is to exclude other causes of pericarditis. The Naranjo Scale score, which helps assess causality of adverse drug reactions, was six points in this case, suggesting that pericarditis was a probable adverse event of nivolumab.7 In this case, infection, autoimmune disorders, and metastasis of lung cancer were excluded by the patient’s history and examinations. In addition, concurrent hepatic irAE suggested that ICI-induced inflammation was the cause of pericarditis.3 Considering the RHF symptoms at the time of the initial diagnosis of pericarditis, the pericarditis had constrictive features when pericardial effusion developed. Left ventricular diastolic function on echocardiography deteriorated over time and CP-specific haemodynamics were demonstrated on cardiac catheterization at 6 months after the initial diagnosis of pericarditis.5,8 Increased serum troponin suggested myocardial inflammation accompanied by severe inflammation at the pericardium. Although cardiac irAE usually develops within 3 months after the initiation of ICI,3 this patient was diagnosed with pericarditis 18 months after the introduction of nivolumab. In addition, pericardial inflammation was sustained for a long time after the cessation of nivolumab. The delayed manifestation and sustained exacerbation of irAE pericarditis in this case can be partly explained by the pharmacodynamics of anti-PD-1 blockade, as demonstrated by the initial single nivolumab administration occupying >70% of PD-1 molecules on T cells for 85 days and this occupancy remained at 40% for more than 8 months after the last dose.9
Immune-suppressive therapy is recommended for serious irAEs refractory to high-dose corticosteroids.2 Infliximab, mycophenolate, or antithymocyte globulin are recommended as additional immune-suppressive therapy, but the differences in therapeutic effects among these drugs have not been assessed in the treatment of irAE pericarditis.2 Infliximab, a monoclonal antibody tumour necrosis factor-α inhibitor, reduces the expression of several proinflammatory molecules and mucosal cytokines. It is generally used for inflammatory bowel disease or connective tissue disease.10 In addition, Infliximab is effective for irAE colitis and is covered by insurance for the treatment of rheumatoid arthritis in our country, thus we administered it for irAE pericarditis in this patient within the approved dosage range for rheumatoid arthritis; 5 mg/kg at Weeks 0, 2, and 6 as induction therapy, then every 8 weeks as maintenance therapy.10,11 Infliximab was effective at relieving pericardial inflammation in this case, demonstrated by the reduced need for diuretics and prednisolone for the control of RHF after the initiation of infliximab concomitant with a decrease in serum troponin. Although the RHF status improved, CP remained after the initiation of infliximab according to echocardiography (Table 1). The treatment for irAEs did not affect the overall survival or time to treatment failure in cancer patients.12 Thus, considering the progressive course of pericarditis in this case, immune-suppressive therapy at an earlier stage of steroid-refractory pericarditis should be considered. Further studies are warranted to clarify the benefits of infliximab for irAE pericarditis.
Conclusion
ICI-related pericarditis potentially develops into CP. Therefore, early therapeutic intervention should be considered. Immune-suppressive drugs represented by infliximab are a promising therapeutic option for the treatment of steroid-refractory pericarditis.
Lead author biography
Dr Shohei Moriyama is a medical doctor at Kyushu University Hospital (Japan) and acquired a medical degree at Kyushu University in Fukuoka. Specialization: Cardio-Oncology. Membership: Japanese Circulation Society, Japanese Society of Medical Oncology, and Japanese Onco-Cardiology society.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytab002_Supplementary_Data Click here for additional data file. | 1 GRAM DAILY; | DrugDosageText | CC BY-NC | 33644656 | 19,426,929 | 2021-01 |
What was the dosage of drug 'TOLVAPTAN'? | Refractory constrictive pericarditis caused by an immune checkpoint inhibitor properly managed with infliximab: a case report.
Immune checkpoint inhibitors (ICIs) can cause cardiac immune-related adverse events (irAEs), including pericarditis. Cardiovascular events related to pericardial irAE are less frequent, but fulminant forms can be fatal. However, the diagnosis and treatment strategies for pericardial irAE have not established.
A 58-year-old man was diagnosed with advanced non-small-cell lung cancer and nivolumab was administered as 5th-line therapy. Eighteen months after the initiation of nivolumab, the patient developed limb oedema and increased body weight. Although a favourable response of the cancer was observed, pericardial thickening and effusion were newly detected. He was diagnosed with irAE pericarditis after excluding other causes of pericarditis. Nivolumab was suspended and a high-dose corticosteroid was initiated. However, right heart failure (RHF) symptoms were exacerbated during the tapering of corticosteroid because acute pericarditis developed to steroid-refractory constrictive pericarditis. To suppress sustained inflammation of the pericardium, infliximab, a tumour necrosis factor-alfa inhibitor, was initiated. After the initiation of infliximab, the corticosteroid dose was tapered without deterioration of RHF. Exacerbation of lung cancer by irAE treatment including infliximab was not observed.
IrAE should be considered when pericarditis develops after the administration of ICI even after a long period from its initiation. Infliximab rescue therapy may be considered as a 2nd-line therapy for steroid-refractory irAE pericarditis even with constrictive physiology.
For the podcast associated with this article, please visit https://academic.oup.com/ehjcr/pages/podcast
Learning points
Immune-related adverse event (irAE) pericarditis can develop long after the initiation of immune checkpoint inhibitors and progress to constrictive pericarditis.
Early initiation of immune-suppressive therapy for irAE should be considered when it is refractory to corticosteroids.
Introduction
Immune checkpoint inhibitors (ICIs) have markedly improved the survival of cancer patients.1 However, immune-related adverse events (irAEs) by ICIs have been increasingly reported.2 Cardiac irAEs are rare (up to 2%), but 50% of the patients with irAE myocarditis and 21% of those with irAE pericarditis die, making them the ‘Achilles heel’ of ICI treatment.3 IrAEs are often diagnosed early after the initiation of ICI, but their delayed manifestation and progression can occur.4 We report a case of late-onset irAE pericarditis that developed to steroid-refractory constrictive pericarditis.
Timeline
July 2015 Age 58 The patient was diagnosed with advanced non-small-cell lung cancer, and anticancer chemotherapies were initiated. No cardiac disorder was identified.
December 2016 Age 60 Nivolumab (3 mg/kg every 2 weeks) was administered for 5th line therapy.
June 2018 Age 61 The patient complained of right heart failure (RHF) symptoms, and pericardial effusion was detected. Immune-related adverse event pericarditis was diagnosed.
July 2018 Age 61 RHF ameliorated with prednisolone but flared up at reduced dose, requiring increased dose of prednisolone.
September 2018 Age 62 Prednisolone was suspended and subsequently body weight gradually increased.
January 2019 Age 62 RHF was re-exacerbated, and echocardiography and right heart catheterization detected constrictive pericarditis. Steroid pulse therapy was performed.
March 2019 Age 62 RHF was re-re-exacerbated and repeated infliximab therapy was initiated.
February 2020 Age 63 Corticosteroid was tapered to a lower dose without the aggravation of RHF.
Case presentation
A 58-year-old man was diagnosed with stage IV (cT2N0M1) non-small-cell lung cancer comprising adenocarcinoma. The patient had no past medical history, including cardiovascular diseases. Prior to anticancer therapy, jugular venous distension and limb oedema were not detected, and heart sounds were normal. Electrocardiography demonstrated normal sinus rhythm, and computed tomography (CT) revealed no cardiomegaly or pericardial effusion. Lung cancer was aggravated despite anticancer chemotherapies, including cisplatin and pemetrexed as the 1st-line, docetaxel as the 2nd-line, tegafur/gimeracil/oteracil as the 3rd-line, and amrubicin as the 4th-line therapy. Nivolumab (3 mg/kg every 2 weeks), a programmed death-1 (PD-1) inhibitor, was administered as 5th-line therapy. Eighteen months after the initiation of nivolumab (after the 35th-cycle), the patient developed fatigue, limb oedema, and increased body weight (BW).
Physical examination revealed jugular venous distension and limb pitting oedema. The serum creatinine level was 0.77 mg/dL (normal range: 0.6–1.0 mg/dL). No electrocardiographic abnormalities were found. On echocardiography, ventricular systolic function on both sides and left ventricular diastolic function were preserved (abnormal relaxation pattern, Table 1), but mild pericardial effusion was detected (Figure 1A). The diameter of the pericardial echo-free space was 9 mm in the anterior right ventricle. CT revealed pericardial thickening, and trivial effusion in the pericardium and pleura (Figure 2B). As the patient was haemodynamically stable and the volume of pericardial effusion was mild, pericardiocentesis was planned to be performed if effusion increased. Favourable response of the lung cancer to treatment on CT suggested a non-malignant cause. Viral or purulent pericarditis was unlikely because the patient had no fever, a normal white blood cell count (6570/μL; normal range: 3300–8600/μL), and a negative blood culture test. Autoantibodies were all negative. Liver biopsy for the examination of liver enzymes revealed T-cell lymphocytic infiltration. Therefore, the patient was diagnosed with irAE hepatitis. Based on these findings, the patient was diagnosed with irAE pericarditis with constrictive features.
Figure 1 Chronological change in echocardiography. (A) Pericardial effusion detected at the time of diagnosis of pericarditis (arrow). (B–D) Pericardial adhesion to the right ventricular wall (B; arrow), significant reduction of the mitral peak E velocity in the inspiratory phase (C), and high peak e′ using tissue Doppler (D; arrow) were detected at 6 months after the diagnosis of pericarditis.
Figure 2 Clinical course and CT images. (A) Doses of steroid, the administration point of infliximab, body weight, the point of computed tomography (CT), and right heart failure (RHF) exacerbation events are described over time. (B) Pericardial thickening and effusion (arrow) on CT at the time of the diagnosis of pericarditis. (C) Pericardial effusion decreased after corticosteroid therapy (arrow) at 3 months after the diagnosis of pericarditis. (D) Trivial pericardial effusion (arrow) and massive pleural effusion (arrowhead) at 6 months after the diagnosis of pericarditis.
Table 1 Parameters of left ventricular diastolic function
Time after the diagnosis (months) 0 6 13 19
E (cm/s) 55.0 81.0 71.1 83.2
A (cm/s) 86.0 48.0 43.8 51.0
E/A 0.6 1.7 1.6 1.6
Deceleration time (ms) 161.0 117.0 109.0 121.0
E′ (cm/s) 7.8 13.3 10.6 9.9
E/E′ 7.1 6.1 6.7 8.4
Nivolumab was suspended and a high-dose corticosteroid, prednisolone at 0.5 mg/kg, was initiated. Right heart failure (RHF) symptoms were gradually ameliorated and the serum C-reactive protein level decreased from 4.08 mg/dL to 1.93 mg/dL (normal range: 0.00–0.14 mg/dL). However, RHF was exacerbated during the tapering of prednisolone (Figure 2A, 1st RHF exacerbation). Therefore, the dose of prednisolone was increased to the initial dose and re-tapered carefully. At the time of cessation of prednisolone, pericardial effusion was significantly reduced (Figure 2C). For a few months, the BW gradually increased with furosemide at 10 mg/day and quickly increased 3 months after the cessation of prednisolone (Figure 2A, 2nd RHF exacerbation), and the patient was positive for Kussmaul’s sign. Trivial pericardial effusion and massive pleural effusion were noted on CT (Figure 2D). In addition, echocardiography revealed pericardial adhesion (Figure 1B), aggravation of left ventricular diastolic function to a restrictive pattern (Table 1), significant reduction of the mitral peak E wave velocity in the inspiratory phase (Figure 1C), and septal bounce (Video 1). A higher peak e′ velocity on tissue Doppler (>8 cm/s) suggested a lower likelihood of restrictive cardiomyopathy (Figure 1D). Right heart catheterization demonstrated a W-shaped right atrial pressure waveform (Figure 3A). Simultaneous recording of biventricular pressures revealed a dip and plateau pattern in both ventricles, low end-diastolic pressure difference between the left and right ventricle (1 mmHg; cut-off: 5 mmHg), and high systolic area index (1.11; cut-off: 1.1), which suggested discordant changes in right and left ventricular filling during respiration (Figure 3B).5 As the amount of pericardial effusion was slight, pericardiocentesis was not performed. The serum troponin-T level was high (0.123 ng/mL; normal range: <0.014 ng/mL), but there was no evidence of active myocarditis by endomyocardial biopsy. Cardiac magnetic resonance imaging demonstrated pericardial thickening, but there was no myocardial oedema or significant late gadolinium enhancement in the pericardium or myocardium. At this point, the patient was diagnosed with constrictive pericarditis (CP) with myopericarditis. The dose of furosemide was increased to 40 mg/day and tolvaptan at 15 mg/day was added, but these did not ameliorate RHF symptoms. Consequently, methylprednisolone at 1 g/day for 3 days and subsequent prednisolone at 1 mg/kg were administered. RHF symptoms were transiently ameliorated, but they exacerbated again after the tapering of prednisolone (Figure 2A, 3rd RHF exacerbation). As pericarditis recurred repeatedly and progressed to CP despite corticosteroid therapy, infliximab (5 mg/kg) was initiated. Infliximab was administered 2 and 6 weeks after the 1st administration, and every 8 weeks thereafter in accordance with the regimen for the treatment of connective tissue disease (Figure 2A).
Figure 3 Haemodynamic assessment on cardiac catheterization. (A) High right atrial (RA) pressure with a W-shaped waveform. (B) A dip and plateau pattern and high systolic area index (SAI) were detected on simultaneous biventricular pressure recording.
After the initiation of infliximab, the BW decreased from 82 to 75 kg despite a reduction in the dose of diuretics (tolvaptan 7.5 mg/day), and the serum troponin-T level decreased to 0.020 ng/mL. Although CP findings were still present by echocardiography (Table 1), prednisolone was able to be tapered to a lower dose (0.15 mg/kg) without aggravation of RHF; therefore, pericardiectomy was not performed. The patient was administered low-dose prednisolone and repeated infliximab for 11 months after the 3rd RHF exacerbation without worsening RHF (Figure 2A).
Discussion
Cardiac irAEs are rare, but they do occur and can be fatal; therefore, they require appropriate treatment. As patients with pericardial irAE usually achieve improvement after the administration of corticosteroids,6 the effects of infliximab on pericarditis have not been reported. This is the 1st case demonstrating the efficacy of infliximab for corticosteroid-refractory pericardial irAE.
An important process in the diagnosis of irAE pericarditis is to exclude other causes of pericarditis. The Naranjo Scale score, which helps assess causality of adverse drug reactions, was six points in this case, suggesting that pericarditis was a probable adverse event of nivolumab.7 In this case, infection, autoimmune disorders, and metastasis of lung cancer were excluded by the patient’s history and examinations. In addition, concurrent hepatic irAE suggested that ICI-induced inflammation was the cause of pericarditis.3 Considering the RHF symptoms at the time of the initial diagnosis of pericarditis, the pericarditis had constrictive features when pericardial effusion developed. Left ventricular diastolic function on echocardiography deteriorated over time and CP-specific haemodynamics were demonstrated on cardiac catheterization at 6 months after the initial diagnosis of pericarditis.5,8 Increased serum troponin suggested myocardial inflammation accompanied by severe inflammation at the pericardium. Although cardiac irAE usually develops within 3 months after the initiation of ICI,3 this patient was diagnosed with pericarditis 18 months after the introduction of nivolumab. In addition, pericardial inflammation was sustained for a long time after the cessation of nivolumab. The delayed manifestation and sustained exacerbation of irAE pericarditis in this case can be partly explained by the pharmacodynamics of anti-PD-1 blockade, as demonstrated by the initial single nivolumab administration occupying >70% of PD-1 molecules on T cells for 85 days and this occupancy remained at 40% for more than 8 months after the last dose.9
Immune-suppressive therapy is recommended for serious irAEs refractory to high-dose corticosteroids.2 Infliximab, mycophenolate, or antithymocyte globulin are recommended as additional immune-suppressive therapy, but the differences in therapeutic effects among these drugs have not been assessed in the treatment of irAE pericarditis.2 Infliximab, a monoclonal antibody tumour necrosis factor-α inhibitor, reduces the expression of several proinflammatory molecules and mucosal cytokines. It is generally used for inflammatory bowel disease or connective tissue disease.10 In addition, Infliximab is effective for irAE colitis and is covered by insurance for the treatment of rheumatoid arthritis in our country, thus we administered it for irAE pericarditis in this patient within the approved dosage range for rheumatoid arthritis; 5 mg/kg at Weeks 0, 2, and 6 as induction therapy, then every 8 weeks as maintenance therapy.10,11 Infliximab was effective at relieving pericardial inflammation in this case, demonstrated by the reduced need for diuretics and prednisolone for the control of RHF after the initiation of infliximab concomitant with a decrease in serum troponin. Although the RHF status improved, CP remained after the initiation of infliximab according to echocardiography (Table 1). The treatment for irAEs did not affect the overall survival or time to treatment failure in cancer patients.12 Thus, considering the progressive course of pericarditis in this case, immune-suppressive therapy at an earlier stage of steroid-refractory pericarditis should be considered. Further studies are warranted to clarify the benefits of infliximab for irAE pericarditis.
Conclusion
ICI-related pericarditis potentially develops into CP. Therefore, early therapeutic intervention should be considered. Immune-suppressive drugs represented by infliximab are a promising therapeutic option for the treatment of steroid-refractory pericarditis.
Lead author biography
Dr Shohei Moriyama is a medical doctor at Kyushu University Hospital (Japan) and acquired a medical degree at Kyushu University in Fukuoka. Specialization: Cardio-Oncology. Membership: Japanese Circulation Society, Japanese Society of Medical Oncology, and Japanese Onco-Cardiology society.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytab002_Supplementary_Data Click here for additional data file. | 15 MILLIGRAM DAILY; | DrugDosageText | CC BY-NC | 33644656 | 19,426,929 | 2021-01 |
What was the outcome of reaction 'Pericarditis constrictive'? | Refractory constrictive pericarditis caused by an immune checkpoint inhibitor properly managed with infliximab: a case report.
Immune checkpoint inhibitors (ICIs) can cause cardiac immune-related adverse events (irAEs), including pericarditis. Cardiovascular events related to pericardial irAE are less frequent, but fulminant forms can be fatal. However, the diagnosis and treatment strategies for pericardial irAE have not established.
A 58-year-old man was diagnosed with advanced non-small-cell lung cancer and nivolumab was administered as 5th-line therapy. Eighteen months after the initiation of nivolumab, the patient developed limb oedema and increased body weight. Although a favourable response of the cancer was observed, pericardial thickening and effusion were newly detected. He was diagnosed with irAE pericarditis after excluding other causes of pericarditis. Nivolumab was suspended and a high-dose corticosteroid was initiated. However, right heart failure (RHF) symptoms were exacerbated during the tapering of corticosteroid because acute pericarditis developed to steroid-refractory constrictive pericarditis. To suppress sustained inflammation of the pericardium, infliximab, a tumour necrosis factor-alfa inhibitor, was initiated. After the initiation of infliximab, the corticosteroid dose was tapered without deterioration of RHF. Exacerbation of lung cancer by irAE treatment including infliximab was not observed.
IrAE should be considered when pericarditis develops after the administration of ICI even after a long period from its initiation. Infliximab rescue therapy may be considered as a 2nd-line therapy for steroid-refractory irAE pericarditis even with constrictive physiology.
For the podcast associated with this article, please visit https://academic.oup.com/ehjcr/pages/podcast
Learning points
Immune-related adverse event (irAE) pericarditis can develop long after the initiation of immune checkpoint inhibitors and progress to constrictive pericarditis.
Early initiation of immune-suppressive therapy for irAE should be considered when it is refractory to corticosteroids.
Introduction
Immune checkpoint inhibitors (ICIs) have markedly improved the survival of cancer patients.1 However, immune-related adverse events (irAEs) by ICIs have been increasingly reported.2 Cardiac irAEs are rare (up to 2%), but 50% of the patients with irAE myocarditis and 21% of those with irAE pericarditis die, making them the ‘Achilles heel’ of ICI treatment.3 IrAEs are often diagnosed early after the initiation of ICI, but their delayed manifestation and progression can occur.4 We report a case of late-onset irAE pericarditis that developed to steroid-refractory constrictive pericarditis.
Timeline
July 2015 Age 58 The patient was diagnosed with advanced non-small-cell lung cancer, and anticancer chemotherapies were initiated. No cardiac disorder was identified.
December 2016 Age 60 Nivolumab (3 mg/kg every 2 weeks) was administered for 5th line therapy.
June 2018 Age 61 The patient complained of right heart failure (RHF) symptoms, and pericardial effusion was detected. Immune-related adverse event pericarditis was diagnosed.
July 2018 Age 61 RHF ameliorated with prednisolone but flared up at reduced dose, requiring increased dose of prednisolone.
September 2018 Age 62 Prednisolone was suspended and subsequently body weight gradually increased.
January 2019 Age 62 RHF was re-exacerbated, and echocardiography and right heart catheterization detected constrictive pericarditis. Steroid pulse therapy was performed.
March 2019 Age 62 RHF was re-re-exacerbated and repeated infliximab therapy was initiated.
February 2020 Age 63 Corticosteroid was tapered to a lower dose without the aggravation of RHF.
Case presentation
A 58-year-old man was diagnosed with stage IV (cT2N0M1) non-small-cell lung cancer comprising adenocarcinoma. The patient had no past medical history, including cardiovascular diseases. Prior to anticancer therapy, jugular venous distension and limb oedema were not detected, and heart sounds were normal. Electrocardiography demonstrated normal sinus rhythm, and computed tomography (CT) revealed no cardiomegaly or pericardial effusion. Lung cancer was aggravated despite anticancer chemotherapies, including cisplatin and pemetrexed as the 1st-line, docetaxel as the 2nd-line, tegafur/gimeracil/oteracil as the 3rd-line, and amrubicin as the 4th-line therapy. Nivolumab (3 mg/kg every 2 weeks), a programmed death-1 (PD-1) inhibitor, was administered as 5th-line therapy. Eighteen months after the initiation of nivolumab (after the 35th-cycle), the patient developed fatigue, limb oedema, and increased body weight (BW).
Physical examination revealed jugular venous distension and limb pitting oedema. The serum creatinine level was 0.77 mg/dL (normal range: 0.6–1.0 mg/dL). No electrocardiographic abnormalities were found. On echocardiography, ventricular systolic function on both sides and left ventricular diastolic function were preserved (abnormal relaxation pattern, Table 1), but mild pericardial effusion was detected (Figure 1A). The diameter of the pericardial echo-free space was 9 mm in the anterior right ventricle. CT revealed pericardial thickening, and trivial effusion in the pericardium and pleura (Figure 2B). As the patient was haemodynamically stable and the volume of pericardial effusion was mild, pericardiocentesis was planned to be performed if effusion increased. Favourable response of the lung cancer to treatment on CT suggested a non-malignant cause. Viral or purulent pericarditis was unlikely because the patient had no fever, a normal white blood cell count (6570/μL; normal range: 3300–8600/μL), and a negative blood culture test. Autoantibodies were all negative. Liver biopsy for the examination of liver enzymes revealed T-cell lymphocytic infiltration. Therefore, the patient was diagnosed with irAE hepatitis. Based on these findings, the patient was diagnosed with irAE pericarditis with constrictive features.
Figure 1 Chronological change in echocardiography. (A) Pericardial effusion detected at the time of diagnosis of pericarditis (arrow). (B–D) Pericardial adhesion to the right ventricular wall (B; arrow), significant reduction of the mitral peak E velocity in the inspiratory phase (C), and high peak e′ using tissue Doppler (D; arrow) were detected at 6 months after the diagnosis of pericarditis.
Figure 2 Clinical course and CT images. (A) Doses of steroid, the administration point of infliximab, body weight, the point of computed tomography (CT), and right heart failure (RHF) exacerbation events are described over time. (B) Pericardial thickening and effusion (arrow) on CT at the time of the diagnosis of pericarditis. (C) Pericardial effusion decreased after corticosteroid therapy (arrow) at 3 months after the diagnosis of pericarditis. (D) Trivial pericardial effusion (arrow) and massive pleural effusion (arrowhead) at 6 months after the diagnosis of pericarditis.
Table 1 Parameters of left ventricular diastolic function
Time after the diagnosis (months) 0 6 13 19
E (cm/s) 55.0 81.0 71.1 83.2
A (cm/s) 86.0 48.0 43.8 51.0
E/A 0.6 1.7 1.6 1.6
Deceleration time (ms) 161.0 117.0 109.0 121.0
E′ (cm/s) 7.8 13.3 10.6 9.9
E/E′ 7.1 6.1 6.7 8.4
Nivolumab was suspended and a high-dose corticosteroid, prednisolone at 0.5 mg/kg, was initiated. Right heart failure (RHF) symptoms were gradually ameliorated and the serum C-reactive protein level decreased from 4.08 mg/dL to 1.93 mg/dL (normal range: 0.00–0.14 mg/dL). However, RHF was exacerbated during the tapering of prednisolone (Figure 2A, 1st RHF exacerbation). Therefore, the dose of prednisolone was increased to the initial dose and re-tapered carefully. At the time of cessation of prednisolone, pericardial effusion was significantly reduced (Figure 2C). For a few months, the BW gradually increased with furosemide at 10 mg/day and quickly increased 3 months after the cessation of prednisolone (Figure 2A, 2nd RHF exacerbation), and the patient was positive for Kussmaul’s sign. Trivial pericardial effusion and massive pleural effusion were noted on CT (Figure 2D). In addition, echocardiography revealed pericardial adhesion (Figure 1B), aggravation of left ventricular diastolic function to a restrictive pattern (Table 1), significant reduction of the mitral peak E wave velocity in the inspiratory phase (Figure 1C), and septal bounce (Video 1). A higher peak e′ velocity on tissue Doppler (>8 cm/s) suggested a lower likelihood of restrictive cardiomyopathy (Figure 1D). Right heart catheterization demonstrated a W-shaped right atrial pressure waveform (Figure 3A). Simultaneous recording of biventricular pressures revealed a dip and plateau pattern in both ventricles, low end-diastolic pressure difference between the left and right ventricle (1 mmHg; cut-off: 5 mmHg), and high systolic area index (1.11; cut-off: 1.1), which suggested discordant changes in right and left ventricular filling during respiration (Figure 3B).5 As the amount of pericardial effusion was slight, pericardiocentesis was not performed. The serum troponin-T level was high (0.123 ng/mL; normal range: <0.014 ng/mL), but there was no evidence of active myocarditis by endomyocardial biopsy. Cardiac magnetic resonance imaging demonstrated pericardial thickening, but there was no myocardial oedema or significant late gadolinium enhancement in the pericardium or myocardium. At this point, the patient was diagnosed with constrictive pericarditis (CP) with myopericarditis. The dose of furosemide was increased to 40 mg/day and tolvaptan at 15 mg/day was added, but these did not ameliorate RHF symptoms. Consequently, methylprednisolone at 1 g/day for 3 days and subsequent prednisolone at 1 mg/kg were administered. RHF symptoms were transiently ameliorated, but they exacerbated again after the tapering of prednisolone (Figure 2A, 3rd RHF exacerbation). As pericarditis recurred repeatedly and progressed to CP despite corticosteroid therapy, infliximab (5 mg/kg) was initiated. Infliximab was administered 2 and 6 weeks after the 1st administration, and every 8 weeks thereafter in accordance with the regimen for the treatment of connective tissue disease (Figure 2A).
Figure 3 Haemodynamic assessment on cardiac catheterization. (A) High right atrial (RA) pressure with a W-shaped waveform. (B) A dip and plateau pattern and high systolic area index (SAI) were detected on simultaneous biventricular pressure recording.
After the initiation of infliximab, the BW decreased from 82 to 75 kg despite a reduction in the dose of diuretics (tolvaptan 7.5 mg/day), and the serum troponin-T level decreased to 0.020 ng/mL. Although CP findings were still present by echocardiography (Table 1), prednisolone was able to be tapered to a lower dose (0.15 mg/kg) without aggravation of RHF; therefore, pericardiectomy was not performed. The patient was administered low-dose prednisolone and repeated infliximab for 11 months after the 3rd RHF exacerbation without worsening RHF (Figure 2A).
Discussion
Cardiac irAEs are rare, but they do occur and can be fatal; therefore, they require appropriate treatment. As patients with pericardial irAE usually achieve improvement after the administration of corticosteroids,6 the effects of infliximab on pericarditis have not been reported. This is the 1st case demonstrating the efficacy of infliximab for corticosteroid-refractory pericardial irAE.
An important process in the diagnosis of irAE pericarditis is to exclude other causes of pericarditis. The Naranjo Scale score, which helps assess causality of adverse drug reactions, was six points in this case, suggesting that pericarditis was a probable adverse event of nivolumab.7 In this case, infection, autoimmune disorders, and metastasis of lung cancer were excluded by the patient’s history and examinations. In addition, concurrent hepatic irAE suggested that ICI-induced inflammation was the cause of pericarditis.3 Considering the RHF symptoms at the time of the initial diagnosis of pericarditis, the pericarditis had constrictive features when pericardial effusion developed. Left ventricular diastolic function on echocardiography deteriorated over time and CP-specific haemodynamics were demonstrated on cardiac catheterization at 6 months after the initial diagnosis of pericarditis.5,8 Increased serum troponin suggested myocardial inflammation accompanied by severe inflammation at the pericardium. Although cardiac irAE usually develops within 3 months after the initiation of ICI,3 this patient was diagnosed with pericarditis 18 months after the introduction of nivolumab. In addition, pericardial inflammation was sustained for a long time after the cessation of nivolumab. The delayed manifestation and sustained exacerbation of irAE pericarditis in this case can be partly explained by the pharmacodynamics of anti-PD-1 blockade, as demonstrated by the initial single nivolumab administration occupying >70% of PD-1 molecules on T cells for 85 days and this occupancy remained at 40% for more than 8 months after the last dose.9
Immune-suppressive therapy is recommended for serious irAEs refractory to high-dose corticosteroids.2 Infliximab, mycophenolate, or antithymocyte globulin are recommended as additional immune-suppressive therapy, but the differences in therapeutic effects among these drugs have not been assessed in the treatment of irAE pericarditis.2 Infliximab, a monoclonal antibody tumour necrosis factor-α inhibitor, reduces the expression of several proinflammatory molecules and mucosal cytokines. It is generally used for inflammatory bowel disease or connective tissue disease.10 In addition, Infliximab is effective for irAE colitis and is covered by insurance for the treatment of rheumatoid arthritis in our country, thus we administered it for irAE pericarditis in this patient within the approved dosage range for rheumatoid arthritis; 5 mg/kg at Weeks 0, 2, and 6 as induction therapy, then every 8 weeks as maintenance therapy.10,11 Infliximab was effective at relieving pericardial inflammation in this case, demonstrated by the reduced need for diuretics and prednisolone for the control of RHF after the initiation of infliximab concomitant with a decrease in serum troponin. Although the RHF status improved, CP remained after the initiation of infliximab according to echocardiography (Table 1). The treatment for irAEs did not affect the overall survival or time to treatment failure in cancer patients.12 Thus, considering the progressive course of pericarditis in this case, immune-suppressive therapy at an earlier stage of steroid-refractory pericarditis should be considered. Further studies are warranted to clarify the benefits of infliximab for irAE pericarditis.
Conclusion
ICI-related pericarditis potentially develops into CP. Therefore, early therapeutic intervention should be considered. Immune-suppressive drugs represented by infliximab are a promising therapeutic option for the treatment of steroid-refractory pericarditis.
Lead author biography
Dr Shohei Moriyama is a medical doctor at Kyushu University Hospital (Japan) and acquired a medical degree at Kyushu University in Fukuoka. Specialization: Cardio-Oncology. Membership: Japanese Circulation Society, Japanese Society of Medical Oncology, and Japanese Onco-Cardiology society.
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: None declared.
Funding: None declared.
Supplementary Material
ytab002_Supplementary_Data Click here for additional data file. | Recovering | ReactionOutcome | CC BY-NC | 33644656 | 19,426,929 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Myalgia'. | Liver Injury Associated With Ezetimibe Monotherapy.
Statin intolerance, primarily myalgia, is not uncommon in patients treated for elevated low-density lipoprotein cholesterol. Nonstatin drugs, such as ezetimibe, can spare patients from statin exposure, while still reducing low-density lipoprotein cholesterol. Ezetimibe is generally very well tolerated, although gastrointestinal and musculoskeletal symptoms have been occasionally reported. We describe an extremely rare case of an ezetimibe-associated liver injury who required protracted treatment with prednisone and azathioprine. Ezetimibe-associated liver injury should be suspected with development of hepatic abnormalities concurrent with the timing of ezetimibe treatment and in the absence of other possible precipitating factors.
Statins are the cornerstone therapy to reduce low-density lipoprotein (LDL) cholesterol levels and its associated risk of atherosclerotic cardiovascular disease.1 However, statin intolerance, primarily statin-associated muscle symptoms affect 2.5%-5% of patients.2 Nonstatin drugs are thus essential to spare affected patients from statin exposure, while still reducing LDL cholesterol.1 Treatment guidelines endorse the use of both ezetimibe and inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) as safe and effective second-line LDL-lowering treatments to consider in response to statin intolerance.1 Ezetimibe lowers LDL cholesterol by blocking sterol uptake via the Niemann-Pick C1-like 1 protein (NPC1L1) in the upper small intestine.3 It has been available in Canada since 2003. Ezetimibe is generally very well tolerated, although gastrointestinal and musculoskeletal symptoms have been reported in approximately 0.1%-2% of patients.4, 5, 6, 7 Although no cases of ezetimibe-induced liver injury were observed in randomized clinical trials, there are a few case reports of this complication.4, 5, 6, 7 We describe an extremely rare case of an ezetimibe-associated liver injury.
Case Report
A 59-year-old asymptomatic man of European descent was referred to the lipid clinic with high LDL cholesterol levels. His medical history was positive only for appendectomy and he was not taking any medication including neither natural health products nor supplements. He had no history of the use of either alcohol or recreational drugs. His family history was positive for dyslipidemia in 2 brothers, one of whom died of a myocardial infarction at age 67. The patient’s father and mother each also died from sudden cardiac events at ages 62 and 80, respectively. On physical examination, his height was 180 cm, weight was 81.5 kg, body mass index (BMI) was 25.2 kg/m2, supine blood pressure was 104/60 mm Hg, and radial pulse was 75 beats/min. No physical stigmata of familial hypercholesterolemia were detected, that is, no xanthomas, xanthelasmas, or corneal arcus. There was no hepatosplenomegaly, and cardiovascular examination was normal.
His lipid profile showed total cholesterol, triglyceride, high-density lipoprotein cholesterol, and LDL cholesterol of 5.62, 1.12, 1.02, and 4.09 mmol/L, respectively. His apolipoprotein B level was 1.41 g/L (target < 0.8 g/L) and lipoprotein (a) was normal at < 10 mg/dL.1 His 2008 Framingham 10-year risk of cardiovascular disease was 11.2%.1 Baseline liver enzymes included alanine transaminase (ALT) 54 U/L (normal < 46 U/L), aspartate transaminase (AST) 33 U/L (normal < 37 U/L), bilirubin 10.2 μmol/L (normal 3.4-17.1 μmol/L), and alkaline phosphatase (ALP) 68 U/L (normal 40-129 U/L). Creatine kinase was 94 U/L (normal < 190 U/L). His mean carotid intima medial thickness was at the 50th percentile for age and sex. Targeted DNA sequencing found no pathogenic familial hypercholesterolemia mutation but showed a high polygenic score for LDL cholesterol (unweighted 15/20, or the 92nd percentile). His clinical and biochemical pictures were thus consistent with polygenic hypercholesterolemia, with a positive family history of early atherosclerotic cardiovascular disease and intermediate Framingham cardiovascular risk.
The patient was prescribed atorvastatin 20 mg daily but discontinued this treatment after 8 weeks because of severe myalgia, with normal creatine kinase at 103 U/L. After discussion, his preference was to avoid another statin and instead to try the PCSK9 inhibitor alirocumab 75 mg subcutaneously biweekly. As monotherapy, this treatment effectively reduced his plasma LDL cholesterol level to 1.41 mmol/L (55 mg/dL) within 8 weeks with no adverse effects (Fig. 1). Unfortunately, after 18 months, the patient's medical insurer declined to continue coverage of alirocumab therapy until a 3-month trial of ezetimibe 10 mg daily had been completed.Figure 1 Timeline showing liver function tests. Periods of medication (doses described in text) are shown with the horizontal lines. Azathioprine was still taken at the time of last assessment. ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate aminotransferase.
Within a month of starting ezetimibe therapy, the patient began to experience progressive and eventually debilitating frontal headaches, which led him to discontinue the medication within 8 weeks. After stopping ezetimibe, his headaches abated, but his health continued to deteriorate. One month after ezetimibe therapy had been stopped, he presented to the emergency department with anorexia, right upper quadrant abdominal pain radiating to the back, profound pruritus with no obvious rash, diarrhoea, debilitating sleeping difficulties, and new-onset arthralgia. His BMI had decreased to 23.4 kg/m2. His liver was palpable 4 cm below the right costal margin. ALT, AST, and ALP were 300, 129, and 1344 U/L, respectively. Bilirubin and international normalized ratio were normal at 14 μmol/L and 1.0, respectively. Viral serology was negative for hepatitis A, B, and C, and HIV. The antinuclear antibody test was positive. There were no other contributing factors that may have precipitated acute liver injury after ezetimibe discontinuation.
A trial of ursodiol and cholestyramine resulted in no significant improvement in pruritus. He was prescribed hydromorphone for pain. A month later, his BMI was further reduced to 22.8 kg/m2. ALT, AST, and ALP were 300, 158, and 1600 U/L, respectively. Fibroscan of the liver was 12.9 kPa, which was consistent with fibrosis and/or severe inflammation. A liver biopsy showed active parenchymal inflammation and bile duct injury, but without fibrosis. A causal relationship was assessed using the Roussel Uclaf Causality Assessment Method causality scale,8 which is a well-established and commonly used tool to determine causality in cases of suspected drug-induced liver injury, by quantitatively assessing factors such as age, time of onset, liver function, drug use, and other comorbidities. In this case, ezetimibe-induced liver injury was determined as being probable for this patient with a score of 8. He was prescribed prednisone 40 mg daily and azathioprine 100 mg daily. Within 1 month, his ALT, AST, ALP, and bilirubin each decreased by > 50%. Prednisone was gradually tapered and stopped after a total of 7 months, but azathioprine was maintained (Fig. 1). After stopping prednisone, his BMI was 24.7 kg/m2 and his liver function tests had returned to the normal range. He restarted alirocumab 75 mg daily subcutaneously biweekly. Six months after stopping prednisone, on azathioprine 100 mg daily and alirocumab, his total cholesterol, triglyceride, high-density lipoprotein and LDL cholesterol were 3.63, 1.51, 0.86 and 2.08, respectively. His ALT, AST, and ALP were 12, 10, and 91 U/L, respectively, whereas total bilirubin was 7.0 μmol/L. He felt improved overall, although he still reported fatigue with exertion.
Discussion
We report a patient with severe ezetimibe-induced liver injury lasting several months after discontinuation of the medication. Suggestive features include the development of hepatic abnormalities in relation to the timing of ezetimibe treatment, and the absence of other possible precipitating agents and causes of acute liver injury. He remained symptomatic for more than 7 weeks after discontinuation of ezetimibe and in the acute stage of illness was at high risk for liver failure. Despite the severe ALP elevation, liver biopsy showed active parenchymal inflammation. Ursodiol was initially used because of the early predominance of the ALP elevation, but inflammation observed on liver biopsy led to switch to prednisone plus azathioprine. He required prednisone for a total of 7 months together with ongoing azathioprine before biochemical and clinical resolution, and has now returned close to his baseline state of health.
Ezetimibe is a useful second-line therapy for hypercholesterolemia that produces a modest reduction in LDL cholesterol compared with statin therapy.3 Severe side effects are very rare, particularly when the drug is used as monotherapy in patients with statin intolerance.2,3 Most previous published cases of ezetimibe-induced liver injury have been reported in combination with a statin.4,5 Indeed, the drug label warns of possible liver enzyme elevation when ezetimibe is prescribed in combination with a statin, but with no mention of such effects when used as monotherapy. Only 2 case reports describe liver injury when ezetimibe was used as monotherapy, but both subjects had other medical conditions such as treated hypertension.6,7 In contrast, our subject was on ezetimibe monotherapy solely, without any other medication or underlying condition except for hypercholesterolemia.
It remains unclear how ezetimibe induced the liver injury observed here. Ezetimibe does not interact with cytochrome P450 system or liver enzymes.3 However, ezetimibe circulates enterohepatically and likely blocks sterol absorption from hepatocytes via the inhibition of hepatic NPC1L1.3 Thus, there is some plausible connection to the liver as a site of action. This unique patient's history illustrates an extremely rare but potentially life-threatening hazard of ezetimibe monotherapy.Novel Teaching Points
• Although very rare, ezetimibe-associated liver injury is a potentially serious complication.
• With hepatic inflammation due to ezetimibe, discontinue treatment and consider systemic steroids and anti-inflammatory agents, with weekly monitoring of liver function tests (ALT, AST, ALP, total bilirubin).
• Inhibitors of PCSK9 may be safe and effective alternatives to consider for LDL lowering in certain patients intolerant to statins and ezetimibe.
Acknowledgements
We gratefully acknowledge the written consent, support, and cooperation of the patient in preparation of this report.
Funding Sources
J.L. is supported by the Canadian Institutes of Health Research (Doctoral Research Award) and the Schulich School of Medicine and Dentistry (Cobban Student Award in Heart and Stroke Research). RAH is supported by the Jacob J. Wolfe Distinguished Medical Research Chair, the Edith Schulich Vinet Research Chair in Human Genetics, and the Martha G. Blackburn Chair in Cardiovascular Research. R.A.H. has also received operating grants from the Canadian Institutes of Health Research (Foundation award), the Heart and Stroke Foundation of Ontario (G-18-0022147).
Disclosures
R.A.H. reports consulting fees from Acasti, Aegerion, Akcea/Ionis, Amgen, HLS Therapeutics Novartis, Regeneron, and Sanofi. The rest of the authors have no conflicts of interest to disclose.
Ethics Statement: The research reported has adhered to ethical guidelines (Western University protocol 0379).
See page 197 for disclosure information. | ALIROCUMAB, ATORVASTATIN, EZETIMIBE | DrugsGivenReaction | CC BY-NC-ND | 33644733 | 19,114,043 | 2021-02 |
What was the administration route of drug 'ALIROCUMAB'? | Liver Injury Associated With Ezetimibe Monotherapy.
Statin intolerance, primarily myalgia, is not uncommon in patients treated for elevated low-density lipoprotein cholesterol. Nonstatin drugs, such as ezetimibe, can spare patients from statin exposure, while still reducing low-density lipoprotein cholesterol. Ezetimibe is generally very well tolerated, although gastrointestinal and musculoskeletal symptoms have been occasionally reported. We describe an extremely rare case of an ezetimibe-associated liver injury who required protracted treatment with prednisone and azathioprine. Ezetimibe-associated liver injury should be suspected with development of hepatic abnormalities concurrent with the timing of ezetimibe treatment and in the absence of other possible precipitating factors.
Statins are the cornerstone therapy to reduce low-density lipoprotein (LDL) cholesterol levels and its associated risk of atherosclerotic cardiovascular disease.1 However, statin intolerance, primarily statin-associated muscle symptoms affect 2.5%-5% of patients.2 Nonstatin drugs are thus essential to spare affected patients from statin exposure, while still reducing LDL cholesterol.1 Treatment guidelines endorse the use of both ezetimibe and inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) as safe and effective second-line LDL-lowering treatments to consider in response to statin intolerance.1 Ezetimibe lowers LDL cholesterol by blocking sterol uptake via the Niemann-Pick C1-like 1 protein (NPC1L1) in the upper small intestine.3 It has been available in Canada since 2003. Ezetimibe is generally very well tolerated, although gastrointestinal and musculoskeletal symptoms have been reported in approximately 0.1%-2% of patients.4, 5, 6, 7 Although no cases of ezetimibe-induced liver injury were observed in randomized clinical trials, there are a few case reports of this complication.4, 5, 6, 7 We describe an extremely rare case of an ezetimibe-associated liver injury.
Case Report
A 59-year-old asymptomatic man of European descent was referred to the lipid clinic with high LDL cholesterol levels. His medical history was positive only for appendectomy and he was not taking any medication including neither natural health products nor supplements. He had no history of the use of either alcohol or recreational drugs. His family history was positive for dyslipidemia in 2 brothers, one of whom died of a myocardial infarction at age 67. The patient’s father and mother each also died from sudden cardiac events at ages 62 and 80, respectively. On physical examination, his height was 180 cm, weight was 81.5 kg, body mass index (BMI) was 25.2 kg/m2, supine blood pressure was 104/60 mm Hg, and radial pulse was 75 beats/min. No physical stigmata of familial hypercholesterolemia were detected, that is, no xanthomas, xanthelasmas, or corneal arcus. There was no hepatosplenomegaly, and cardiovascular examination was normal.
His lipid profile showed total cholesterol, triglyceride, high-density lipoprotein cholesterol, and LDL cholesterol of 5.62, 1.12, 1.02, and 4.09 mmol/L, respectively. His apolipoprotein B level was 1.41 g/L (target < 0.8 g/L) and lipoprotein (a) was normal at < 10 mg/dL.1 His 2008 Framingham 10-year risk of cardiovascular disease was 11.2%.1 Baseline liver enzymes included alanine transaminase (ALT) 54 U/L (normal < 46 U/L), aspartate transaminase (AST) 33 U/L (normal < 37 U/L), bilirubin 10.2 μmol/L (normal 3.4-17.1 μmol/L), and alkaline phosphatase (ALP) 68 U/L (normal 40-129 U/L). Creatine kinase was 94 U/L (normal < 190 U/L). His mean carotid intima medial thickness was at the 50th percentile for age and sex. Targeted DNA sequencing found no pathogenic familial hypercholesterolemia mutation but showed a high polygenic score for LDL cholesterol (unweighted 15/20, or the 92nd percentile). His clinical and biochemical pictures were thus consistent with polygenic hypercholesterolemia, with a positive family history of early atherosclerotic cardiovascular disease and intermediate Framingham cardiovascular risk.
The patient was prescribed atorvastatin 20 mg daily but discontinued this treatment after 8 weeks because of severe myalgia, with normal creatine kinase at 103 U/L. After discussion, his preference was to avoid another statin and instead to try the PCSK9 inhibitor alirocumab 75 mg subcutaneously biweekly. As monotherapy, this treatment effectively reduced his plasma LDL cholesterol level to 1.41 mmol/L (55 mg/dL) within 8 weeks with no adverse effects (Fig. 1). Unfortunately, after 18 months, the patient's medical insurer declined to continue coverage of alirocumab therapy until a 3-month trial of ezetimibe 10 mg daily had been completed.Figure 1 Timeline showing liver function tests. Periods of medication (doses described in text) are shown with the horizontal lines. Azathioprine was still taken at the time of last assessment. ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate aminotransferase.
Within a month of starting ezetimibe therapy, the patient began to experience progressive and eventually debilitating frontal headaches, which led him to discontinue the medication within 8 weeks. After stopping ezetimibe, his headaches abated, but his health continued to deteriorate. One month after ezetimibe therapy had been stopped, he presented to the emergency department with anorexia, right upper quadrant abdominal pain radiating to the back, profound pruritus with no obvious rash, diarrhoea, debilitating sleeping difficulties, and new-onset arthralgia. His BMI had decreased to 23.4 kg/m2. His liver was palpable 4 cm below the right costal margin. ALT, AST, and ALP were 300, 129, and 1344 U/L, respectively. Bilirubin and international normalized ratio were normal at 14 μmol/L and 1.0, respectively. Viral serology was negative for hepatitis A, B, and C, and HIV. The antinuclear antibody test was positive. There were no other contributing factors that may have precipitated acute liver injury after ezetimibe discontinuation.
A trial of ursodiol and cholestyramine resulted in no significant improvement in pruritus. He was prescribed hydromorphone for pain. A month later, his BMI was further reduced to 22.8 kg/m2. ALT, AST, and ALP were 300, 158, and 1600 U/L, respectively. Fibroscan of the liver was 12.9 kPa, which was consistent with fibrosis and/or severe inflammation. A liver biopsy showed active parenchymal inflammation and bile duct injury, but without fibrosis. A causal relationship was assessed using the Roussel Uclaf Causality Assessment Method causality scale,8 which is a well-established and commonly used tool to determine causality in cases of suspected drug-induced liver injury, by quantitatively assessing factors such as age, time of onset, liver function, drug use, and other comorbidities. In this case, ezetimibe-induced liver injury was determined as being probable for this patient with a score of 8. He was prescribed prednisone 40 mg daily and azathioprine 100 mg daily. Within 1 month, his ALT, AST, ALP, and bilirubin each decreased by > 50%. Prednisone was gradually tapered and stopped after a total of 7 months, but azathioprine was maintained (Fig. 1). After stopping prednisone, his BMI was 24.7 kg/m2 and his liver function tests had returned to the normal range. He restarted alirocumab 75 mg daily subcutaneously biweekly. Six months after stopping prednisone, on azathioprine 100 mg daily and alirocumab, his total cholesterol, triglyceride, high-density lipoprotein and LDL cholesterol were 3.63, 1.51, 0.86 and 2.08, respectively. His ALT, AST, and ALP were 12, 10, and 91 U/L, respectively, whereas total bilirubin was 7.0 μmol/L. He felt improved overall, although he still reported fatigue with exertion.
Discussion
We report a patient with severe ezetimibe-induced liver injury lasting several months after discontinuation of the medication. Suggestive features include the development of hepatic abnormalities in relation to the timing of ezetimibe treatment, and the absence of other possible precipitating agents and causes of acute liver injury. He remained symptomatic for more than 7 weeks after discontinuation of ezetimibe and in the acute stage of illness was at high risk for liver failure. Despite the severe ALP elevation, liver biopsy showed active parenchymal inflammation. Ursodiol was initially used because of the early predominance of the ALP elevation, but inflammation observed on liver biopsy led to switch to prednisone plus azathioprine. He required prednisone for a total of 7 months together with ongoing azathioprine before biochemical and clinical resolution, and has now returned close to his baseline state of health.
Ezetimibe is a useful second-line therapy for hypercholesterolemia that produces a modest reduction in LDL cholesterol compared with statin therapy.3 Severe side effects are very rare, particularly when the drug is used as monotherapy in patients with statin intolerance.2,3 Most previous published cases of ezetimibe-induced liver injury have been reported in combination with a statin.4,5 Indeed, the drug label warns of possible liver enzyme elevation when ezetimibe is prescribed in combination with a statin, but with no mention of such effects when used as monotherapy. Only 2 case reports describe liver injury when ezetimibe was used as monotherapy, but both subjects had other medical conditions such as treated hypertension.6,7 In contrast, our subject was on ezetimibe monotherapy solely, without any other medication or underlying condition except for hypercholesterolemia.
It remains unclear how ezetimibe induced the liver injury observed here. Ezetimibe does not interact with cytochrome P450 system or liver enzymes.3 However, ezetimibe circulates enterohepatically and likely blocks sterol absorption from hepatocytes via the inhibition of hepatic NPC1L1.3 Thus, there is some plausible connection to the liver as a site of action. This unique patient's history illustrates an extremely rare but potentially life-threatening hazard of ezetimibe monotherapy.Novel Teaching Points
• Although very rare, ezetimibe-associated liver injury is a potentially serious complication.
• With hepatic inflammation due to ezetimibe, discontinue treatment and consider systemic steroids and anti-inflammatory agents, with weekly monitoring of liver function tests (ALT, AST, ALP, total bilirubin).
• Inhibitors of PCSK9 may be safe and effective alternatives to consider for LDL lowering in certain patients intolerant to statins and ezetimibe.
Acknowledgements
We gratefully acknowledge the written consent, support, and cooperation of the patient in preparation of this report.
Funding Sources
J.L. is supported by the Canadian Institutes of Health Research (Doctoral Research Award) and the Schulich School of Medicine and Dentistry (Cobban Student Award in Heart and Stroke Research). RAH is supported by the Jacob J. Wolfe Distinguished Medical Research Chair, the Edith Schulich Vinet Research Chair in Human Genetics, and the Martha G. Blackburn Chair in Cardiovascular Research. R.A.H. has also received operating grants from the Canadian Institutes of Health Research (Foundation award), the Heart and Stroke Foundation of Ontario (G-18-0022147).
Disclosures
R.A.H. reports consulting fees from Acasti, Aegerion, Akcea/Ionis, Amgen, HLS Therapeutics Novartis, Regeneron, and Sanofi. The rest of the authors have no conflicts of interest to disclose.
Ethics Statement: The research reported has adhered to ethical guidelines (Western University protocol 0379).
See page 197 for disclosure information. | Subcutaneous | DrugAdministrationRoute | CC BY-NC-ND | 33644733 | 19,114,043 | 2021-02 |
What was the outcome of reaction 'Drug-induced liver injury'? | Liver Injury Associated With Ezetimibe Monotherapy.
Statin intolerance, primarily myalgia, is not uncommon in patients treated for elevated low-density lipoprotein cholesterol. Nonstatin drugs, such as ezetimibe, can spare patients from statin exposure, while still reducing low-density lipoprotein cholesterol. Ezetimibe is generally very well tolerated, although gastrointestinal and musculoskeletal symptoms have been occasionally reported. We describe an extremely rare case of an ezetimibe-associated liver injury who required protracted treatment with prednisone and azathioprine. Ezetimibe-associated liver injury should be suspected with development of hepatic abnormalities concurrent with the timing of ezetimibe treatment and in the absence of other possible precipitating factors.
Statins are the cornerstone therapy to reduce low-density lipoprotein (LDL) cholesterol levels and its associated risk of atherosclerotic cardiovascular disease.1 However, statin intolerance, primarily statin-associated muscle symptoms affect 2.5%-5% of patients.2 Nonstatin drugs are thus essential to spare affected patients from statin exposure, while still reducing LDL cholesterol.1 Treatment guidelines endorse the use of both ezetimibe and inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) as safe and effective second-line LDL-lowering treatments to consider in response to statin intolerance.1 Ezetimibe lowers LDL cholesterol by blocking sterol uptake via the Niemann-Pick C1-like 1 protein (NPC1L1) in the upper small intestine.3 It has been available in Canada since 2003. Ezetimibe is generally very well tolerated, although gastrointestinal and musculoskeletal symptoms have been reported in approximately 0.1%-2% of patients.4, 5, 6, 7 Although no cases of ezetimibe-induced liver injury were observed in randomized clinical trials, there are a few case reports of this complication.4, 5, 6, 7 We describe an extremely rare case of an ezetimibe-associated liver injury.
Case Report
A 59-year-old asymptomatic man of European descent was referred to the lipid clinic with high LDL cholesterol levels. His medical history was positive only for appendectomy and he was not taking any medication including neither natural health products nor supplements. He had no history of the use of either alcohol or recreational drugs. His family history was positive for dyslipidemia in 2 brothers, one of whom died of a myocardial infarction at age 67. The patient’s father and mother each also died from sudden cardiac events at ages 62 and 80, respectively. On physical examination, his height was 180 cm, weight was 81.5 kg, body mass index (BMI) was 25.2 kg/m2, supine blood pressure was 104/60 mm Hg, and radial pulse was 75 beats/min. No physical stigmata of familial hypercholesterolemia were detected, that is, no xanthomas, xanthelasmas, or corneal arcus. There was no hepatosplenomegaly, and cardiovascular examination was normal.
His lipid profile showed total cholesterol, triglyceride, high-density lipoprotein cholesterol, and LDL cholesterol of 5.62, 1.12, 1.02, and 4.09 mmol/L, respectively. His apolipoprotein B level was 1.41 g/L (target < 0.8 g/L) and lipoprotein (a) was normal at < 10 mg/dL.1 His 2008 Framingham 10-year risk of cardiovascular disease was 11.2%.1 Baseline liver enzymes included alanine transaminase (ALT) 54 U/L (normal < 46 U/L), aspartate transaminase (AST) 33 U/L (normal < 37 U/L), bilirubin 10.2 μmol/L (normal 3.4-17.1 μmol/L), and alkaline phosphatase (ALP) 68 U/L (normal 40-129 U/L). Creatine kinase was 94 U/L (normal < 190 U/L). His mean carotid intima medial thickness was at the 50th percentile for age and sex. Targeted DNA sequencing found no pathogenic familial hypercholesterolemia mutation but showed a high polygenic score for LDL cholesterol (unweighted 15/20, or the 92nd percentile). His clinical and biochemical pictures were thus consistent with polygenic hypercholesterolemia, with a positive family history of early atherosclerotic cardiovascular disease and intermediate Framingham cardiovascular risk.
The patient was prescribed atorvastatin 20 mg daily but discontinued this treatment after 8 weeks because of severe myalgia, with normal creatine kinase at 103 U/L. After discussion, his preference was to avoid another statin and instead to try the PCSK9 inhibitor alirocumab 75 mg subcutaneously biweekly. As monotherapy, this treatment effectively reduced his plasma LDL cholesterol level to 1.41 mmol/L (55 mg/dL) within 8 weeks with no adverse effects (Fig. 1). Unfortunately, after 18 months, the patient's medical insurer declined to continue coverage of alirocumab therapy until a 3-month trial of ezetimibe 10 mg daily had been completed.Figure 1 Timeline showing liver function tests. Periods of medication (doses described in text) are shown with the horizontal lines. Azathioprine was still taken at the time of last assessment. ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate aminotransferase.
Within a month of starting ezetimibe therapy, the patient began to experience progressive and eventually debilitating frontal headaches, which led him to discontinue the medication within 8 weeks. After stopping ezetimibe, his headaches abated, but his health continued to deteriorate. One month after ezetimibe therapy had been stopped, he presented to the emergency department with anorexia, right upper quadrant abdominal pain radiating to the back, profound pruritus with no obvious rash, diarrhoea, debilitating sleeping difficulties, and new-onset arthralgia. His BMI had decreased to 23.4 kg/m2. His liver was palpable 4 cm below the right costal margin. ALT, AST, and ALP were 300, 129, and 1344 U/L, respectively. Bilirubin and international normalized ratio were normal at 14 μmol/L and 1.0, respectively. Viral serology was negative for hepatitis A, B, and C, and HIV. The antinuclear antibody test was positive. There were no other contributing factors that may have precipitated acute liver injury after ezetimibe discontinuation.
A trial of ursodiol and cholestyramine resulted in no significant improvement in pruritus. He was prescribed hydromorphone for pain. A month later, his BMI was further reduced to 22.8 kg/m2. ALT, AST, and ALP were 300, 158, and 1600 U/L, respectively. Fibroscan of the liver was 12.9 kPa, which was consistent with fibrosis and/or severe inflammation. A liver biopsy showed active parenchymal inflammation and bile duct injury, but without fibrosis. A causal relationship was assessed using the Roussel Uclaf Causality Assessment Method causality scale,8 which is a well-established and commonly used tool to determine causality in cases of suspected drug-induced liver injury, by quantitatively assessing factors such as age, time of onset, liver function, drug use, and other comorbidities. In this case, ezetimibe-induced liver injury was determined as being probable for this patient with a score of 8. He was prescribed prednisone 40 mg daily and azathioprine 100 mg daily. Within 1 month, his ALT, AST, ALP, and bilirubin each decreased by > 50%. Prednisone was gradually tapered and stopped after a total of 7 months, but azathioprine was maintained (Fig. 1). After stopping prednisone, his BMI was 24.7 kg/m2 and his liver function tests had returned to the normal range. He restarted alirocumab 75 mg daily subcutaneously biweekly. Six months after stopping prednisone, on azathioprine 100 mg daily and alirocumab, his total cholesterol, triglyceride, high-density lipoprotein and LDL cholesterol were 3.63, 1.51, 0.86 and 2.08, respectively. His ALT, AST, and ALP were 12, 10, and 91 U/L, respectively, whereas total bilirubin was 7.0 μmol/L. He felt improved overall, although he still reported fatigue with exertion.
Discussion
We report a patient with severe ezetimibe-induced liver injury lasting several months after discontinuation of the medication. Suggestive features include the development of hepatic abnormalities in relation to the timing of ezetimibe treatment, and the absence of other possible precipitating agents and causes of acute liver injury. He remained symptomatic for more than 7 weeks after discontinuation of ezetimibe and in the acute stage of illness was at high risk for liver failure. Despite the severe ALP elevation, liver biopsy showed active parenchymal inflammation. Ursodiol was initially used because of the early predominance of the ALP elevation, but inflammation observed on liver biopsy led to switch to prednisone plus azathioprine. He required prednisone for a total of 7 months together with ongoing azathioprine before biochemical and clinical resolution, and has now returned close to his baseline state of health.
Ezetimibe is a useful second-line therapy for hypercholesterolemia that produces a modest reduction in LDL cholesterol compared with statin therapy.3 Severe side effects are very rare, particularly when the drug is used as monotherapy in patients with statin intolerance.2,3 Most previous published cases of ezetimibe-induced liver injury have been reported in combination with a statin.4,5 Indeed, the drug label warns of possible liver enzyme elevation when ezetimibe is prescribed in combination with a statin, but with no mention of such effects when used as monotherapy. Only 2 case reports describe liver injury when ezetimibe was used as monotherapy, but both subjects had other medical conditions such as treated hypertension.6,7 In contrast, our subject was on ezetimibe monotherapy solely, without any other medication or underlying condition except for hypercholesterolemia.
It remains unclear how ezetimibe induced the liver injury observed here. Ezetimibe does not interact with cytochrome P450 system or liver enzymes.3 However, ezetimibe circulates enterohepatically and likely blocks sterol absorption from hepatocytes via the inhibition of hepatic NPC1L1.3 Thus, there is some plausible connection to the liver as a site of action. This unique patient's history illustrates an extremely rare but potentially life-threatening hazard of ezetimibe monotherapy.Novel Teaching Points
• Although very rare, ezetimibe-associated liver injury is a potentially serious complication.
• With hepatic inflammation due to ezetimibe, discontinue treatment and consider systemic steroids and anti-inflammatory agents, with weekly monitoring of liver function tests (ALT, AST, ALP, total bilirubin).
• Inhibitors of PCSK9 may be safe and effective alternatives to consider for LDL lowering in certain patients intolerant to statins and ezetimibe.
Acknowledgements
We gratefully acknowledge the written consent, support, and cooperation of the patient in preparation of this report.
Funding Sources
J.L. is supported by the Canadian Institutes of Health Research (Doctoral Research Award) and the Schulich School of Medicine and Dentistry (Cobban Student Award in Heart and Stroke Research). RAH is supported by the Jacob J. Wolfe Distinguished Medical Research Chair, the Edith Schulich Vinet Research Chair in Human Genetics, and the Martha G. Blackburn Chair in Cardiovascular Research. R.A.H. has also received operating grants from the Canadian Institutes of Health Research (Foundation award), the Heart and Stroke Foundation of Ontario (G-18-0022147).
Disclosures
R.A.H. reports consulting fees from Acasti, Aegerion, Akcea/Ionis, Amgen, HLS Therapeutics Novartis, Regeneron, and Sanofi. The rest of the authors have no conflicts of interest to disclose.
Ethics Statement: The research reported has adhered to ethical guidelines (Western University protocol 0379).
See page 197 for disclosure information. | Recovered | ReactionOutcome | CC BY-NC-ND | 33644733 | 19,025,447 | 2021-02 |
What was the outcome of reaction 'Headache'? | Liver Injury Associated With Ezetimibe Monotherapy.
Statin intolerance, primarily myalgia, is not uncommon in patients treated for elevated low-density lipoprotein cholesterol. Nonstatin drugs, such as ezetimibe, can spare patients from statin exposure, while still reducing low-density lipoprotein cholesterol. Ezetimibe is generally very well tolerated, although gastrointestinal and musculoskeletal symptoms have been occasionally reported. We describe an extremely rare case of an ezetimibe-associated liver injury who required protracted treatment with prednisone and azathioprine. Ezetimibe-associated liver injury should be suspected with development of hepatic abnormalities concurrent with the timing of ezetimibe treatment and in the absence of other possible precipitating factors.
Statins are the cornerstone therapy to reduce low-density lipoprotein (LDL) cholesterol levels and its associated risk of atherosclerotic cardiovascular disease.1 However, statin intolerance, primarily statin-associated muscle symptoms affect 2.5%-5% of patients.2 Nonstatin drugs are thus essential to spare affected patients from statin exposure, while still reducing LDL cholesterol.1 Treatment guidelines endorse the use of both ezetimibe and inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) as safe and effective second-line LDL-lowering treatments to consider in response to statin intolerance.1 Ezetimibe lowers LDL cholesterol by blocking sterol uptake via the Niemann-Pick C1-like 1 protein (NPC1L1) in the upper small intestine.3 It has been available in Canada since 2003. Ezetimibe is generally very well tolerated, although gastrointestinal and musculoskeletal symptoms have been reported in approximately 0.1%-2% of patients.4, 5, 6, 7 Although no cases of ezetimibe-induced liver injury were observed in randomized clinical trials, there are a few case reports of this complication.4, 5, 6, 7 We describe an extremely rare case of an ezetimibe-associated liver injury.
Case Report
A 59-year-old asymptomatic man of European descent was referred to the lipid clinic with high LDL cholesterol levels. His medical history was positive only for appendectomy and he was not taking any medication including neither natural health products nor supplements. He had no history of the use of either alcohol or recreational drugs. His family history was positive for dyslipidemia in 2 brothers, one of whom died of a myocardial infarction at age 67. The patient’s father and mother each also died from sudden cardiac events at ages 62 and 80, respectively. On physical examination, his height was 180 cm, weight was 81.5 kg, body mass index (BMI) was 25.2 kg/m2, supine blood pressure was 104/60 mm Hg, and radial pulse was 75 beats/min. No physical stigmata of familial hypercholesterolemia were detected, that is, no xanthomas, xanthelasmas, or corneal arcus. There was no hepatosplenomegaly, and cardiovascular examination was normal.
His lipid profile showed total cholesterol, triglyceride, high-density lipoprotein cholesterol, and LDL cholesterol of 5.62, 1.12, 1.02, and 4.09 mmol/L, respectively. His apolipoprotein B level was 1.41 g/L (target < 0.8 g/L) and lipoprotein (a) was normal at < 10 mg/dL.1 His 2008 Framingham 10-year risk of cardiovascular disease was 11.2%.1 Baseline liver enzymes included alanine transaminase (ALT) 54 U/L (normal < 46 U/L), aspartate transaminase (AST) 33 U/L (normal < 37 U/L), bilirubin 10.2 μmol/L (normal 3.4-17.1 μmol/L), and alkaline phosphatase (ALP) 68 U/L (normal 40-129 U/L). Creatine kinase was 94 U/L (normal < 190 U/L). His mean carotid intima medial thickness was at the 50th percentile for age and sex. Targeted DNA sequencing found no pathogenic familial hypercholesterolemia mutation but showed a high polygenic score for LDL cholesterol (unweighted 15/20, or the 92nd percentile). His clinical and biochemical pictures were thus consistent with polygenic hypercholesterolemia, with a positive family history of early atherosclerotic cardiovascular disease and intermediate Framingham cardiovascular risk.
The patient was prescribed atorvastatin 20 mg daily but discontinued this treatment after 8 weeks because of severe myalgia, with normal creatine kinase at 103 U/L. After discussion, his preference was to avoid another statin and instead to try the PCSK9 inhibitor alirocumab 75 mg subcutaneously biweekly. As monotherapy, this treatment effectively reduced his plasma LDL cholesterol level to 1.41 mmol/L (55 mg/dL) within 8 weeks with no adverse effects (Fig. 1). Unfortunately, after 18 months, the patient's medical insurer declined to continue coverage of alirocumab therapy until a 3-month trial of ezetimibe 10 mg daily had been completed.Figure 1 Timeline showing liver function tests. Periods of medication (doses described in text) are shown with the horizontal lines. Azathioprine was still taken at the time of last assessment. ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate aminotransferase.
Within a month of starting ezetimibe therapy, the patient began to experience progressive and eventually debilitating frontal headaches, which led him to discontinue the medication within 8 weeks. After stopping ezetimibe, his headaches abated, but his health continued to deteriorate. One month after ezetimibe therapy had been stopped, he presented to the emergency department with anorexia, right upper quadrant abdominal pain radiating to the back, profound pruritus with no obvious rash, diarrhoea, debilitating sleeping difficulties, and new-onset arthralgia. His BMI had decreased to 23.4 kg/m2. His liver was palpable 4 cm below the right costal margin. ALT, AST, and ALP were 300, 129, and 1344 U/L, respectively. Bilirubin and international normalized ratio were normal at 14 μmol/L and 1.0, respectively. Viral serology was negative for hepatitis A, B, and C, and HIV. The antinuclear antibody test was positive. There were no other contributing factors that may have precipitated acute liver injury after ezetimibe discontinuation.
A trial of ursodiol and cholestyramine resulted in no significant improvement in pruritus. He was prescribed hydromorphone for pain. A month later, his BMI was further reduced to 22.8 kg/m2. ALT, AST, and ALP were 300, 158, and 1600 U/L, respectively. Fibroscan of the liver was 12.9 kPa, which was consistent with fibrosis and/or severe inflammation. A liver biopsy showed active parenchymal inflammation and bile duct injury, but without fibrosis. A causal relationship was assessed using the Roussel Uclaf Causality Assessment Method causality scale,8 which is a well-established and commonly used tool to determine causality in cases of suspected drug-induced liver injury, by quantitatively assessing factors such as age, time of onset, liver function, drug use, and other comorbidities. In this case, ezetimibe-induced liver injury was determined as being probable for this patient with a score of 8. He was prescribed prednisone 40 mg daily and azathioprine 100 mg daily. Within 1 month, his ALT, AST, ALP, and bilirubin each decreased by > 50%. Prednisone was gradually tapered and stopped after a total of 7 months, but azathioprine was maintained (Fig. 1). After stopping prednisone, his BMI was 24.7 kg/m2 and his liver function tests had returned to the normal range. He restarted alirocumab 75 mg daily subcutaneously biweekly. Six months after stopping prednisone, on azathioprine 100 mg daily and alirocumab, his total cholesterol, triglyceride, high-density lipoprotein and LDL cholesterol were 3.63, 1.51, 0.86 and 2.08, respectively. His ALT, AST, and ALP were 12, 10, and 91 U/L, respectively, whereas total bilirubin was 7.0 μmol/L. He felt improved overall, although he still reported fatigue with exertion.
Discussion
We report a patient with severe ezetimibe-induced liver injury lasting several months after discontinuation of the medication. Suggestive features include the development of hepatic abnormalities in relation to the timing of ezetimibe treatment, and the absence of other possible precipitating agents and causes of acute liver injury. He remained symptomatic for more than 7 weeks after discontinuation of ezetimibe and in the acute stage of illness was at high risk for liver failure. Despite the severe ALP elevation, liver biopsy showed active parenchymal inflammation. Ursodiol was initially used because of the early predominance of the ALP elevation, but inflammation observed on liver biopsy led to switch to prednisone plus azathioprine. He required prednisone for a total of 7 months together with ongoing azathioprine before biochemical and clinical resolution, and has now returned close to his baseline state of health.
Ezetimibe is a useful second-line therapy for hypercholesterolemia that produces a modest reduction in LDL cholesterol compared with statin therapy.3 Severe side effects are very rare, particularly when the drug is used as monotherapy in patients with statin intolerance.2,3 Most previous published cases of ezetimibe-induced liver injury have been reported in combination with a statin.4,5 Indeed, the drug label warns of possible liver enzyme elevation when ezetimibe is prescribed in combination with a statin, but with no mention of such effects when used as monotherapy. Only 2 case reports describe liver injury when ezetimibe was used as monotherapy, but both subjects had other medical conditions such as treated hypertension.6,7 In contrast, our subject was on ezetimibe monotherapy solely, without any other medication or underlying condition except for hypercholesterolemia.
It remains unclear how ezetimibe induced the liver injury observed here. Ezetimibe does not interact with cytochrome P450 system or liver enzymes.3 However, ezetimibe circulates enterohepatically and likely blocks sterol absorption from hepatocytes via the inhibition of hepatic NPC1L1.3 Thus, there is some plausible connection to the liver as a site of action. This unique patient's history illustrates an extremely rare but potentially life-threatening hazard of ezetimibe monotherapy.Novel Teaching Points
• Although very rare, ezetimibe-associated liver injury is a potentially serious complication.
• With hepatic inflammation due to ezetimibe, discontinue treatment and consider systemic steroids and anti-inflammatory agents, with weekly monitoring of liver function tests (ALT, AST, ALP, total bilirubin).
• Inhibitors of PCSK9 may be safe and effective alternatives to consider for LDL lowering in certain patients intolerant to statins and ezetimibe.
Acknowledgements
We gratefully acknowledge the written consent, support, and cooperation of the patient in preparation of this report.
Funding Sources
J.L. is supported by the Canadian Institutes of Health Research (Doctoral Research Award) and the Schulich School of Medicine and Dentistry (Cobban Student Award in Heart and Stroke Research). RAH is supported by the Jacob J. Wolfe Distinguished Medical Research Chair, the Edith Schulich Vinet Research Chair in Human Genetics, and the Martha G. Blackburn Chair in Cardiovascular Research. R.A.H. has also received operating grants from the Canadian Institutes of Health Research (Foundation award), the Heart and Stroke Foundation of Ontario (G-18-0022147).
Disclosures
R.A.H. reports consulting fees from Acasti, Aegerion, Akcea/Ionis, Amgen, HLS Therapeutics Novartis, Regeneron, and Sanofi. The rest of the authors have no conflicts of interest to disclose.
Ethics Statement: The research reported has adhered to ethical guidelines (Western University protocol 0379).
See page 197 for disclosure information. | Recovered | ReactionOutcome | CC BY-NC-ND | 33644733 | 19,025,447 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Disseminated Bacillus Calmette-Guerin infection'. | A 56-Year-Old Male With Weight Loss, Night Sweats, Dyspnea, and Bladder Cancer.
A 56-year-old man presented with subacute night sweats, fever, and weight loss with worsening dyspnea. Computed tomography (CT) scan demonstrated miliary pattern of nodules evenly distributed throughout all lung fields. Given the patient's CT findings and temporal association with Bacille Calmette-Guerin (BCG) immunotherapy for bladder cancer, the patient was diagnosed with disseminated Mycobacterium bovis secondary to BCG bladder instillations.
Introduction
Disseminated Mycobacterium bovis is a rare complication of intravesical Bacille Calmette-Guerin (BCG) immunotherapy. This phenomenon is most often associated with pulmonary and hepatic involvement, though a variety of other organs can be involved as well. The 2 pulmonary complications are pneumonitis and miliary dissemination, which combined occur in less than 0.5% of intravesical BCG immunotherapy complications.1 Either pulmonary complication can occur at any point during therapy with case reviews showing a mean of 8.3 instillations before dissemination with a range of 3 to 16 instillations.2
Symptoms typically include acute or subacute onset of fever, malaise, weight loss, cough, and dyspnea.3 Risk factors include active urinary tract infections, genitourinary trauma, or hematuria in immunocompetent hosts. Administration of intravesical BCG stimulates a localized antitumor effect through patient’s cell-mediated immunity. As such, any patient with a defect in this pathway is at risk for dissemination. Immunosuppressed patients are at higher risk as well, and it is a relative contraindication to intravesical therapy.3
Chest imaging findings typically show diffuse micronodular pattern or interstitial disease, and bronchoalveolar lavage (BAL) samples are rarely positive for acid-fast bacilli by smear or culture.4 If transbronchial or other lung biopsies are obtained, noncaseating granulomas are often seen. We describe the case of a patient who developed disseminated BCG due to bladder instillations and was successfully treated despite liver involvement.
Case Description
A 56-year-old man presents to clinic with 4 weeks of night sweats, fevers, 10-pound weight loss, and progressive dyspnea. He denies cough, hemoptysis, rash, or arthralgias. He has a 2-pack year smoking history as a teenager, drinks approximately 15 alcoholic beverages per week, and denies any illicit drug use. He denies tuberculosis risk factors or exposure to farm soil. His past medical history is notable for bladder cancer, treated with transurethral resection of bladder tumor 2 years prior. He subsequently was started on BCG immunotherapy 1 year prior, tolerating 15 instillations without complications. His last installation was 2 weeks prior to the onset of the aforementioned symptoms. His vitals are all within normal limits. His physical examination reveals diffuse alveolar breath sounds with no adventitious sounds. The remainder of his examination is normal. Chest X-ray shows a diffuse nodular pattern, and subsequent computed tomography (CT) scan shows innumerable, small, dense nodules throughout all lobes without notable hilar or mediastinal lymphadenopathy (Figure 1). Laboratory testing shows a mixed hepatocellular/cholestatic transaminitis with alkaline phosphatase 271 U/L (normal 35-115 U/L), aspartate aminotransferase 100 U/L (normal 15-43 U/L), and alanine aminotransferase 179 U/L (normal 6-63 U/L; Table 1). Interferon-γ (IFN-γ) release assay is negative; however, a purified protein derivative (PPD) is measured as 10 mm. Coccidioides serologies are positive immunoglobulin M (IgM) by immunodiffusion, but negative by complement fixation. CT and ultrasound imaging of the liver do not show abnormalities. Bronchoscopy with BAL of the right middle lobe reveal a lymphocytic preponderance of white blood cells (475 cells/mm3 with 70% lymphocytes; normal: <1% lymphocytes and >95% macrophages) and negative bacterial, fungal, and mycobacterial cultures. Transbronchial biopsies of the right lower lobe reveal noncaseating granulomas with negative acid-fast bacilli and fungal stains. After the diagnosis of disseminated Mycobacterium bovis was made based on imaging and clinical findings, the patient immediately started on rifampin, isoniazid, and ethambutol. Bronchoscopy was performed after coccidioidomycosis IgM positivity was demonstrated. BAL gram stain showed no spherules, and fungal cultures were negative. After 3 months of triple therapy, his symptoms, transaminitis, and pulmonary findings completely resolved.
Figure 1. CT chest findids of miliary nodular pattern diffusely in all lung fields.
Table 1. Pertinent hepatic serum levels from initiation of anti-mycobacterial therapy (day 0) on through the completion of treatment (4 months).
Laboratory value (normal range) Day 0 2 weeks 4 weeks 8 weeks 4 months
Alkaline phosphatase (35-115 U/L) 271 U/L 192 145 86 56
Aspartate aminotransferase (15-43 U/L) 100 U/L 54 44 35 32
Alanine aminotransferase (6-63 U/L) 179 U/L 107 107 41 30
Discussion
Disseminated M bovis is a rare but described complication of BCG bladder installation. Patients given the intradermal BCG vaccine are well known to have false-positive tuberculin skin test (TST) reactions. The typical administered dose for the intradermal vaccine is 0.05 to 0.1 mg; however, the intravesical dose is considerably higher at 81 mg given in multiple weekly doses. Bladder instillation has an observed TST conversion rate of 65% to 68%. IFN-γ T-cell-based assays target Mycobacterium tuberculosis proteins CFP-10 and ESAT-6, which are not present in the BCG vaccine. This assay was created to improve specificity testing for presumed M tuberculosis. Thus, a positive TST and negative IFN-γ test significantly increases the likelihood of disseminated BCG over miliary tuberculous infection. Overall, the diagnosis is clinically made with supporting laboratory, TST, and imaging results.5
The vaccine’s origins are like that of the smallpox vaccine by Edward Jenner who used the less virulent Vaccinia virus to create protective antibodies to the highly virulent Variola virus. After Robert Koch differentiated M bovis from M tuberculosis, a 19th century attempt was made in Italy to create protective antibodies to M tuberculosis through inoculation with M bovis. This was met with significant patient death as the M bovis strains were still highly virulent. This changed with Albert Calmette and Camille Guerin who created an avirulent strain of M bovis through 230 growth cycles on glycerinated bile potato medium.2
A variety of different strains have been produced around the world for region-specific vaccination programs, though nearly all substrains in use today originated from the Calmette laboratory in the 1920s.6 Of note, these strains of M bovis are intrinsically resistant to pyrazinamide. Nearly all strains are susceptible to other first-line antimycobacterial therapies—rifampin, rifabutin, and ethambutol. As such, a 3-drug combination of any first-line antimycobacterial drugs or fluoroquinolone with the exception of pyrazinamide is sufficient with courses varying from 3 to 9 months depending on the clinical course. Outcomes with treatment are generally good with few deaths reported, as long as treatment is initiated in a timely manner.7
The positive coccidiomycosis IgM was likely a false positive as the patient lacked a clear exposure aside from living at the outside edge of the endemic range of the fungus. Furthermore, his clinical presentation was more consistent with disseminated M bovis. False-positive coccidioidomycosis IgM has been reported to be in the range of 13.5% depending on the titer cutoff used.8 The Infectious Disease Society of America recommends only treating positive serologies in the presence of disabling symptoms due to large amount of self-resolution.9
This is a case of disseminated M bovis due to BCG bladder installation. Despite liver involvement, liver function tests improved despite administration of medications with potential hepatotoxic side effects.
Authors’ Note: This study was presented as an abstract at the American Thoracic Society in May 2019.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Our institution does not require ethical approval for reporting individual cases or case series.
Informed Consent: Verbal informed consent was obtained from the patient(s) for their anonymized information to be published in this article.
ORCID iD: Brooks T. Kuhn https://orcid.org/0000-0003-0036-1300 | BACILLUS CALMETTE-GUERIN SUBSTRAIN TICE LIVE ANTIGEN | DrugsGivenReaction | CC BY-NC | 33645301 | 17,263,115 | 2021 |
What was the administration route of drug 'BACILLUS CALMETTE-GUERIN SUBSTRAIN TICE LIVE ANTIGEN'? | A 56-Year-Old Male With Weight Loss, Night Sweats, Dyspnea, and Bladder Cancer.
A 56-year-old man presented with subacute night sweats, fever, and weight loss with worsening dyspnea. Computed tomography (CT) scan demonstrated miliary pattern of nodules evenly distributed throughout all lung fields. Given the patient's CT findings and temporal association with Bacille Calmette-Guerin (BCG) immunotherapy for bladder cancer, the patient was diagnosed with disseminated Mycobacterium bovis secondary to BCG bladder instillations.
Introduction
Disseminated Mycobacterium bovis is a rare complication of intravesical Bacille Calmette-Guerin (BCG) immunotherapy. This phenomenon is most often associated with pulmonary and hepatic involvement, though a variety of other organs can be involved as well. The 2 pulmonary complications are pneumonitis and miliary dissemination, which combined occur in less than 0.5% of intravesical BCG immunotherapy complications.1 Either pulmonary complication can occur at any point during therapy with case reviews showing a mean of 8.3 instillations before dissemination with a range of 3 to 16 instillations.2
Symptoms typically include acute or subacute onset of fever, malaise, weight loss, cough, and dyspnea.3 Risk factors include active urinary tract infections, genitourinary trauma, or hematuria in immunocompetent hosts. Administration of intravesical BCG stimulates a localized antitumor effect through patient’s cell-mediated immunity. As such, any patient with a defect in this pathway is at risk for dissemination. Immunosuppressed patients are at higher risk as well, and it is a relative contraindication to intravesical therapy.3
Chest imaging findings typically show diffuse micronodular pattern or interstitial disease, and bronchoalveolar lavage (BAL) samples are rarely positive for acid-fast bacilli by smear or culture.4 If transbronchial or other lung biopsies are obtained, noncaseating granulomas are often seen. We describe the case of a patient who developed disseminated BCG due to bladder instillations and was successfully treated despite liver involvement.
Case Description
A 56-year-old man presents to clinic with 4 weeks of night sweats, fevers, 10-pound weight loss, and progressive dyspnea. He denies cough, hemoptysis, rash, or arthralgias. He has a 2-pack year smoking history as a teenager, drinks approximately 15 alcoholic beverages per week, and denies any illicit drug use. He denies tuberculosis risk factors or exposure to farm soil. His past medical history is notable for bladder cancer, treated with transurethral resection of bladder tumor 2 years prior. He subsequently was started on BCG immunotherapy 1 year prior, tolerating 15 instillations without complications. His last installation was 2 weeks prior to the onset of the aforementioned symptoms. His vitals are all within normal limits. His physical examination reveals diffuse alveolar breath sounds with no adventitious sounds. The remainder of his examination is normal. Chest X-ray shows a diffuse nodular pattern, and subsequent computed tomography (CT) scan shows innumerable, small, dense nodules throughout all lobes without notable hilar or mediastinal lymphadenopathy (Figure 1). Laboratory testing shows a mixed hepatocellular/cholestatic transaminitis with alkaline phosphatase 271 U/L (normal 35-115 U/L), aspartate aminotransferase 100 U/L (normal 15-43 U/L), and alanine aminotransferase 179 U/L (normal 6-63 U/L; Table 1). Interferon-γ (IFN-γ) release assay is negative; however, a purified protein derivative (PPD) is measured as 10 mm. Coccidioides serologies are positive immunoglobulin M (IgM) by immunodiffusion, but negative by complement fixation. CT and ultrasound imaging of the liver do not show abnormalities. Bronchoscopy with BAL of the right middle lobe reveal a lymphocytic preponderance of white blood cells (475 cells/mm3 with 70% lymphocytes; normal: <1% lymphocytes and >95% macrophages) and negative bacterial, fungal, and mycobacterial cultures. Transbronchial biopsies of the right lower lobe reveal noncaseating granulomas with negative acid-fast bacilli and fungal stains. After the diagnosis of disseminated Mycobacterium bovis was made based on imaging and clinical findings, the patient immediately started on rifampin, isoniazid, and ethambutol. Bronchoscopy was performed after coccidioidomycosis IgM positivity was demonstrated. BAL gram stain showed no spherules, and fungal cultures were negative. After 3 months of triple therapy, his symptoms, transaminitis, and pulmonary findings completely resolved.
Figure 1. CT chest findids of miliary nodular pattern diffusely in all lung fields.
Table 1. Pertinent hepatic serum levels from initiation of anti-mycobacterial therapy (day 0) on through the completion of treatment (4 months).
Laboratory value (normal range) Day 0 2 weeks 4 weeks 8 weeks 4 months
Alkaline phosphatase (35-115 U/L) 271 U/L 192 145 86 56
Aspartate aminotransferase (15-43 U/L) 100 U/L 54 44 35 32
Alanine aminotransferase (6-63 U/L) 179 U/L 107 107 41 30
Discussion
Disseminated M bovis is a rare but described complication of BCG bladder installation. Patients given the intradermal BCG vaccine are well known to have false-positive tuberculin skin test (TST) reactions. The typical administered dose for the intradermal vaccine is 0.05 to 0.1 mg; however, the intravesical dose is considerably higher at 81 mg given in multiple weekly doses. Bladder instillation has an observed TST conversion rate of 65% to 68%. IFN-γ T-cell-based assays target Mycobacterium tuberculosis proteins CFP-10 and ESAT-6, which are not present in the BCG vaccine. This assay was created to improve specificity testing for presumed M tuberculosis. Thus, a positive TST and negative IFN-γ test significantly increases the likelihood of disseminated BCG over miliary tuberculous infection. Overall, the diagnosis is clinically made with supporting laboratory, TST, and imaging results.5
The vaccine’s origins are like that of the smallpox vaccine by Edward Jenner who used the less virulent Vaccinia virus to create protective antibodies to the highly virulent Variola virus. After Robert Koch differentiated M bovis from M tuberculosis, a 19th century attempt was made in Italy to create protective antibodies to M tuberculosis through inoculation with M bovis. This was met with significant patient death as the M bovis strains were still highly virulent. This changed with Albert Calmette and Camille Guerin who created an avirulent strain of M bovis through 230 growth cycles on glycerinated bile potato medium.2
A variety of different strains have been produced around the world for region-specific vaccination programs, though nearly all substrains in use today originated from the Calmette laboratory in the 1920s.6 Of note, these strains of M bovis are intrinsically resistant to pyrazinamide. Nearly all strains are susceptible to other first-line antimycobacterial therapies—rifampin, rifabutin, and ethambutol. As such, a 3-drug combination of any first-line antimycobacterial drugs or fluoroquinolone with the exception of pyrazinamide is sufficient with courses varying from 3 to 9 months depending on the clinical course. Outcomes with treatment are generally good with few deaths reported, as long as treatment is initiated in a timely manner.7
The positive coccidiomycosis IgM was likely a false positive as the patient lacked a clear exposure aside from living at the outside edge of the endemic range of the fungus. Furthermore, his clinical presentation was more consistent with disseminated M bovis. False-positive coccidioidomycosis IgM has been reported to be in the range of 13.5% depending on the titer cutoff used.8 The Infectious Disease Society of America recommends only treating positive serologies in the presence of disabling symptoms due to large amount of self-resolution.9
This is a case of disseminated M bovis due to BCG bladder installation. Despite liver involvement, liver function tests improved despite administration of medications with potential hepatotoxic side effects.
Authors’ Note: This study was presented as an abstract at the American Thoracic Society in May 2019.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Our institution does not require ethical approval for reporting individual cases or case series.
Informed Consent: Verbal informed consent was obtained from the patient(s) for their anonymized information to be published in this article.
ORCID iD: Brooks T. Kuhn https://orcid.org/0000-0003-0036-1300 | Intravesical | DrugAdministrationRoute | CC BY-NC | 33645301 | 17,263,115 | 2021 |
What was the dosage of drug 'BACILLUS CALMETTE-GUERIN SUBSTRAIN TICE LIVE ANTIGEN'? | A 56-Year-Old Male With Weight Loss, Night Sweats, Dyspnea, and Bladder Cancer.
A 56-year-old man presented with subacute night sweats, fever, and weight loss with worsening dyspnea. Computed tomography (CT) scan demonstrated miliary pattern of nodules evenly distributed throughout all lung fields. Given the patient's CT findings and temporal association with Bacille Calmette-Guerin (BCG) immunotherapy for bladder cancer, the patient was diagnosed with disseminated Mycobacterium bovis secondary to BCG bladder instillations.
Introduction
Disseminated Mycobacterium bovis is a rare complication of intravesical Bacille Calmette-Guerin (BCG) immunotherapy. This phenomenon is most often associated with pulmonary and hepatic involvement, though a variety of other organs can be involved as well. The 2 pulmonary complications are pneumonitis and miliary dissemination, which combined occur in less than 0.5% of intravesical BCG immunotherapy complications.1 Either pulmonary complication can occur at any point during therapy with case reviews showing a mean of 8.3 instillations before dissemination with a range of 3 to 16 instillations.2
Symptoms typically include acute or subacute onset of fever, malaise, weight loss, cough, and dyspnea.3 Risk factors include active urinary tract infections, genitourinary trauma, or hematuria in immunocompetent hosts. Administration of intravesical BCG stimulates a localized antitumor effect through patient’s cell-mediated immunity. As such, any patient with a defect in this pathway is at risk for dissemination. Immunosuppressed patients are at higher risk as well, and it is a relative contraindication to intravesical therapy.3
Chest imaging findings typically show diffuse micronodular pattern or interstitial disease, and bronchoalveolar lavage (BAL) samples are rarely positive for acid-fast bacilli by smear or culture.4 If transbronchial or other lung biopsies are obtained, noncaseating granulomas are often seen. We describe the case of a patient who developed disseminated BCG due to bladder instillations and was successfully treated despite liver involvement.
Case Description
A 56-year-old man presents to clinic with 4 weeks of night sweats, fevers, 10-pound weight loss, and progressive dyspnea. He denies cough, hemoptysis, rash, or arthralgias. He has a 2-pack year smoking history as a teenager, drinks approximately 15 alcoholic beverages per week, and denies any illicit drug use. He denies tuberculosis risk factors or exposure to farm soil. His past medical history is notable for bladder cancer, treated with transurethral resection of bladder tumor 2 years prior. He subsequently was started on BCG immunotherapy 1 year prior, tolerating 15 instillations without complications. His last installation was 2 weeks prior to the onset of the aforementioned symptoms. His vitals are all within normal limits. His physical examination reveals diffuse alveolar breath sounds with no adventitious sounds. The remainder of his examination is normal. Chest X-ray shows a diffuse nodular pattern, and subsequent computed tomography (CT) scan shows innumerable, small, dense nodules throughout all lobes without notable hilar or mediastinal lymphadenopathy (Figure 1). Laboratory testing shows a mixed hepatocellular/cholestatic transaminitis with alkaline phosphatase 271 U/L (normal 35-115 U/L), aspartate aminotransferase 100 U/L (normal 15-43 U/L), and alanine aminotransferase 179 U/L (normal 6-63 U/L; Table 1). Interferon-γ (IFN-γ) release assay is negative; however, a purified protein derivative (PPD) is measured as 10 mm. Coccidioides serologies are positive immunoglobulin M (IgM) by immunodiffusion, but negative by complement fixation. CT and ultrasound imaging of the liver do not show abnormalities. Bronchoscopy with BAL of the right middle lobe reveal a lymphocytic preponderance of white blood cells (475 cells/mm3 with 70% lymphocytes; normal: <1% lymphocytes and >95% macrophages) and negative bacterial, fungal, and mycobacterial cultures. Transbronchial biopsies of the right lower lobe reveal noncaseating granulomas with negative acid-fast bacilli and fungal stains. After the diagnosis of disseminated Mycobacterium bovis was made based on imaging and clinical findings, the patient immediately started on rifampin, isoniazid, and ethambutol. Bronchoscopy was performed after coccidioidomycosis IgM positivity was demonstrated. BAL gram stain showed no spherules, and fungal cultures were negative. After 3 months of triple therapy, his symptoms, transaminitis, and pulmonary findings completely resolved.
Figure 1. CT chest findids of miliary nodular pattern diffusely in all lung fields.
Table 1. Pertinent hepatic serum levels from initiation of anti-mycobacterial therapy (day 0) on through the completion of treatment (4 months).
Laboratory value (normal range) Day 0 2 weeks 4 weeks 8 weeks 4 months
Alkaline phosphatase (35-115 U/L) 271 U/L 192 145 86 56
Aspartate aminotransferase (15-43 U/L) 100 U/L 54 44 35 32
Alanine aminotransferase (6-63 U/L) 179 U/L 107 107 41 30
Discussion
Disseminated M bovis is a rare but described complication of BCG bladder installation. Patients given the intradermal BCG vaccine are well known to have false-positive tuberculin skin test (TST) reactions. The typical administered dose for the intradermal vaccine is 0.05 to 0.1 mg; however, the intravesical dose is considerably higher at 81 mg given in multiple weekly doses. Bladder instillation has an observed TST conversion rate of 65% to 68%. IFN-γ T-cell-based assays target Mycobacterium tuberculosis proteins CFP-10 and ESAT-6, which are not present in the BCG vaccine. This assay was created to improve specificity testing for presumed M tuberculosis. Thus, a positive TST and negative IFN-γ test significantly increases the likelihood of disseminated BCG over miliary tuberculous infection. Overall, the diagnosis is clinically made with supporting laboratory, TST, and imaging results.5
The vaccine’s origins are like that of the smallpox vaccine by Edward Jenner who used the less virulent Vaccinia virus to create protective antibodies to the highly virulent Variola virus. After Robert Koch differentiated M bovis from M tuberculosis, a 19th century attempt was made in Italy to create protective antibodies to M tuberculosis through inoculation with M bovis. This was met with significant patient death as the M bovis strains were still highly virulent. This changed with Albert Calmette and Camille Guerin who created an avirulent strain of M bovis through 230 growth cycles on glycerinated bile potato medium.2
A variety of different strains have been produced around the world for region-specific vaccination programs, though nearly all substrains in use today originated from the Calmette laboratory in the 1920s.6 Of note, these strains of M bovis are intrinsically resistant to pyrazinamide. Nearly all strains are susceptible to other first-line antimycobacterial therapies—rifampin, rifabutin, and ethambutol. As such, a 3-drug combination of any first-line antimycobacterial drugs or fluoroquinolone with the exception of pyrazinamide is sufficient with courses varying from 3 to 9 months depending on the clinical course. Outcomes with treatment are generally good with few deaths reported, as long as treatment is initiated in a timely manner.7
The positive coccidiomycosis IgM was likely a false positive as the patient lacked a clear exposure aside from living at the outside edge of the endemic range of the fungus. Furthermore, his clinical presentation was more consistent with disseminated M bovis. False-positive coccidioidomycosis IgM has been reported to be in the range of 13.5% depending on the titer cutoff used.8 The Infectious Disease Society of America recommends only treating positive serologies in the presence of disabling symptoms due to large amount of self-resolution.9
This is a case of disseminated M bovis due to BCG bladder installation. Despite liver involvement, liver function tests improved despite administration of medications with potential hepatotoxic side effects.
Authors’ Note: This study was presented as an abstract at the American Thoracic Society in May 2019.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Our institution does not require ethical approval for reporting individual cases or case series.
Informed Consent: Verbal informed consent was obtained from the patient(s) for their anonymized information to be published in this article.
ORCID iD: Brooks T. Kuhn https://orcid.org/0000-0003-0036-1300 | 15 INSTILLATIONS | DrugDosageText | CC BY-NC | 33645301 | 17,263,115 | 2021 |
What was the outcome of reaction 'Disseminated Bacillus Calmette-Guerin infection'? | A 56-Year-Old Male With Weight Loss, Night Sweats, Dyspnea, and Bladder Cancer.
A 56-year-old man presented with subacute night sweats, fever, and weight loss with worsening dyspnea. Computed tomography (CT) scan demonstrated miliary pattern of nodules evenly distributed throughout all lung fields. Given the patient's CT findings and temporal association with Bacille Calmette-Guerin (BCG) immunotherapy for bladder cancer, the patient was diagnosed with disseminated Mycobacterium bovis secondary to BCG bladder instillations.
Introduction
Disseminated Mycobacterium bovis is a rare complication of intravesical Bacille Calmette-Guerin (BCG) immunotherapy. This phenomenon is most often associated with pulmonary and hepatic involvement, though a variety of other organs can be involved as well. The 2 pulmonary complications are pneumonitis and miliary dissemination, which combined occur in less than 0.5% of intravesical BCG immunotherapy complications.1 Either pulmonary complication can occur at any point during therapy with case reviews showing a mean of 8.3 instillations before dissemination with a range of 3 to 16 instillations.2
Symptoms typically include acute or subacute onset of fever, malaise, weight loss, cough, and dyspnea.3 Risk factors include active urinary tract infections, genitourinary trauma, or hematuria in immunocompetent hosts. Administration of intravesical BCG stimulates a localized antitumor effect through patient’s cell-mediated immunity. As such, any patient with a defect in this pathway is at risk for dissemination. Immunosuppressed patients are at higher risk as well, and it is a relative contraindication to intravesical therapy.3
Chest imaging findings typically show diffuse micronodular pattern or interstitial disease, and bronchoalveolar lavage (BAL) samples are rarely positive for acid-fast bacilli by smear or culture.4 If transbronchial or other lung biopsies are obtained, noncaseating granulomas are often seen. We describe the case of a patient who developed disseminated BCG due to bladder instillations and was successfully treated despite liver involvement.
Case Description
A 56-year-old man presents to clinic with 4 weeks of night sweats, fevers, 10-pound weight loss, and progressive dyspnea. He denies cough, hemoptysis, rash, or arthralgias. He has a 2-pack year smoking history as a teenager, drinks approximately 15 alcoholic beverages per week, and denies any illicit drug use. He denies tuberculosis risk factors or exposure to farm soil. His past medical history is notable for bladder cancer, treated with transurethral resection of bladder tumor 2 years prior. He subsequently was started on BCG immunotherapy 1 year prior, tolerating 15 instillations without complications. His last installation was 2 weeks prior to the onset of the aforementioned symptoms. His vitals are all within normal limits. His physical examination reveals diffuse alveolar breath sounds with no adventitious sounds. The remainder of his examination is normal. Chest X-ray shows a diffuse nodular pattern, and subsequent computed tomography (CT) scan shows innumerable, small, dense nodules throughout all lobes without notable hilar or mediastinal lymphadenopathy (Figure 1). Laboratory testing shows a mixed hepatocellular/cholestatic transaminitis with alkaline phosphatase 271 U/L (normal 35-115 U/L), aspartate aminotransferase 100 U/L (normal 15-43 U/L), and alanine aminotransferase 179 U/L (normal 6-63 U/L; Table 1). Interferon-γ (IFN-γ) release assay is negative; however, a purified protein derivative (PPD) is measured as 10 mm. Coccidioides serologies are positive immunoglobulin M (IgM) by immunodiffusion, but negative by complement fixation. CT and ultrasound imaging of the liver do not show abnormalities. Bronchoscopy with BAL of the right middle lobe reveal a lymphocytic preponderance of white blood cells (475 cells/mm3 with 70% lymphocytes; normal: <1% lymphocytes and >95% macrophages) and negative bacterial, fungal, and mycobacterial cultures. Transbronchial biopsies of the right lower lobe reveal noncaseating granulomas with negative acid-fast bacilli and fungal stains. After the diagnosis of disseminated Mycobacterium bovis was made based on imaging and clinical findings, the patient immediately started on rifampin, isoniazid, and ethambutol. Bronchoscopy was performed after coccidioidomycosis IgM positivity was demonstrated. BAL gram stain showed no spherules, and fungal cultures were negative. After 3 months of triple therapy, his symptoms, transaminitis, and pulmonary findings completely resolved.
Figure 1. CT chest findids of miliary nodular pattern diffusely in all lung fields.
Table 1. Pertinent hepatic serum levels from initiation of anti-mycobacterial therapy (day 0) on through the completion of treatment (4 months).
Laboratory value (normal range) Day 0 2 weeks 4 weeks 8 weeks 4 months
Alkaline phosphatase (35-115 U/L) 271 U/L 192 145 86 56
Aspartate aminotransferase (15-43 U/L) 100 U/L 54 44 35 32
Alanine aminotransferase (6-63 U/L) 179 U/L 107 107 41 30
Discussion
Disseminated M bovis is a rare but described complication of BCG bladder installation. Patients given the intradermal BCG vaccine are well known to have false-positive tuberculin skin test (TST) reactions. The typical administered dose for the intradermal vaccine is 0.05 to 0.1 mg; however, the intravesical dose is considerably higher at 81 mg given in multiple weekly doses. Bladder instillation has an observed TST conversion rate of 65% to 68%. IFN-γ T-cell-based assays target Mycobacterium tuberculosis proteins CFP-10 and ESAT-6, which are not present in the BCG vaccine. This assay was created to improve specificity testing for presumed M tuberculosis. Thus, a positive TST and negative IFN-γ test significantly increases the likelihood of disseminated BCG over miliary tuberculous infection. Overall, the diagnosis is clinically made with supporting laboratory, TST, and imaging results.5
The vaccine’s origins are like that of the smallpox vaccine by Edward Jenner who used the less virulent Vaccinia virus to create protective antibodies to the highly virulent Variola virus. After Robert Koch differentiated M bovis from M tuberculosis, a 19th century attempt was made in Italy to create protective antibodies to M tuberculosis through inoculation with M bovis. This was met with significant patient death as the M bovis strains were still highly virulent. This changed with Albert Calmette and Camille Guerin who created an avirulent strain of M bovis through 230 growth cycles on glycerinated bile potato medium.2
A variety of different strains have been produced around the world for region-specific vaccination programs, though nearly all substrains in use today originated from the Calmette laboratory in the 1920s.6 Of note, these strains of M bovis are intrinsically resistant to pyrazinamide. Nearly all strains are susceptible to other first-line antimycobacterial therapies—rifampin, rifabutin, and ethambutol. As such, a 3-drug combination of any first-line antimycobacterial drugs or fluoroquinolone with the exception of pyrazinamide is sufficient with courses varying from 3 to 9 months depending on the clinical course. Outcomes with treatment are generally good with few deaths reported, as long as treatment is initiated in a timely manner.7
The positive coccidiomycosis IgM was likely a false positive as the patient lacked a clear exposure aside from living at the outside edge of the endemic range of the fungus. Furthermore, his clinical presentation was more consistent with disseminated M bovis. False-positive coccidioidomycosis IgM has been reported to be in the range of 13.5% depending on the titer cutoff used.8 The Infectious Disease Society of America recommends only treating positive serologies in the presence of disabling symptoms due to large amount of self-resolution.9
This is a case of disseminated M bovis due to BCG bladder installation. Despite liver involvement, liver function tests improved despite administration of medications with potential hepatotoxic side effects.
Authors’ Note: This study was presented as an abstract at the American Thoracic Society in May 2019.
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval: Our institution does not require ethical approval for reporting individual cases or case series.
Informed Consent: Verbal informed consent was obtained from the patient(s) for their anonymized information to be published in this article.
ORCID iD: Brooks T. Kuhn https://orcid.org/0000-0003-0036-1300 | Recovered | ReactionOutcome | CC BY-NC | 33645301 | 17,263,115 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Neutropenic sepsis'. | Hemophagocytic lymphohistiocytosis and myelodysplastic syndrome: a case report and review of the literature.
BACKGROUND
Hemophagocytic lymphohistiocytosis (HLH) is characterized by hyperinflammation and life-threatening cytopenias. Survival is poor, and management is pivotal on rapid identification of the disease. HLH is associated with hematologic malignancies, however correlation with myelodysplastic syndromes (MDS) is exceedingly unusual. Although minimizing overwhelming hyperinflammation by treating hemophagocytosis are central for HLH outcome, there is urgent necessity to identify potential initiating mechanisms that could assist in therapy design.
METHODS
Here, we describe an elderly African American patient who developed rapid onset of cytopenias and coagulopathy associated with hepatic and bone marrow hemophagocytosis. We analyze four additional similar cases to isolate clinical, laboratory and cytogenetic findings expected in patients exhibiting concurrent HLH and MDS. HLH linked with MDS retains common HLH features associated with systemic hyperinflammation such as fever, hypotension, hepatosplenomegaly, hyperferritinemia, coagulopathy and rapidly evolving cytopenias. Typical MDS chromosomic abnormality such as trisomy 8 was frequently observed in our studied cases.
CONCLUSIONS
Our case describes difficulties while managing HLH in MDS patients. Diagnosis should be based on identifying HLH appropriate criteria and if possible karyotypic abnormalities normally observed in MDS.
Introduction
Hemophagocytic lymphohistiocytosis (HLH) is characterized by deregulated immunity and end organ damage. Primary HLH is linked with autosomal recessive and X-linked mutations. Secondary HLH results from predisposing conditions. Both primary and secondary HLH may be activated by an infections and malignancies. [1] The association of HLH with hematologic malignancies is accepted. However, HLH initiated by myelodysplastic syndrome (MDS) is exceedingly unusual. Although dysplasia is observed in patients with hemophagocytosis, a hyperinflammatory entity characterized by dysplastic cytopenias, MDS like karyotypic abnormality and hemophagocytosis suggests a different spectrum of disease, in which HLH originates from a clonal disorder. In this report, we present an elderly female who fulfilled HLH 2004 criteria exhibiting erythroid and megakaryocytic dysplasia associated with trisomy 8 [+ 8]. Additionally, we examine published cases in English literature to identify clinical, laboratory and cytogenetic features observed in MDS patients fulfilling HLH 2004 criteria.
Case presentation
An 83-year-old African American female presented with lethargy, temperature of 102.9° F and tachycardia. After 9 days of broad-spectrum antibiotics, she developed hemodynamic instability requiring vasopressors, worsening liver function (peak bilirubin of 12.5 mg/dL, Aspartate aminotransferase (AST) of 689 IU/L, Alanine aminotransferase (ALT) of 239 IU/L) and leukocytosis of 16,000/uL. Her hemoglobin was 8.9/uL and platelets had fallen to 26,000/uL. Disseminated intravascular coagulation (DIC) was considered given progressive severe thrombocytopenia of 13,000 U/L, fibrinogen < 70 mg/dL and d-dimer of 12.4 mg/L. Her ferritin was 9479 ng/mL and fasting triglycerides (TAG) were 321 mg/dL. Soluble interleukin-2Rα (CD25) was < 38 pg/dL. Her human immunodeficiency virus (HIV), rapid influenza A/B, hepatitis B/C serologies were all negative. Epstein-barr virus (EBV) viral load was negative. Given concern autoimmune hepatitis, a liver biopsy showed Kupffer cell hypertrophy with hemophagocytosis. Bone marrow biopsy demonstrated hemophagocytosis (Fig 1a, b). In addition, significant erythroid nuclear fragmentation and karyorrhexis were observed (Fig 1c). Marrow cytogenetics showed 47, XX +8 [6], 46, XX [5]. Next generation sequencing (NGS) including CSFR1, SF3B1, SRSF2, U2AF1, NRAS, KRAS, FLT3, JAK2, KIT, PHF6, PDGFRA, CDKN2A, IDH1, IDH2, TET2, EZH2, CEBPA, EP300, PTPN11, P53, CREBBP, IKZF1, IKZF3, NOTCH1, RUNX1, WT1 and NPM1 showed DNMT3A p.Arg736His (c.2207G>A) and DNMT3A p.Leu859Ter (c.2576T>A) at allele frequencies of 2.7 and 2.4 %, respectively. In view of her hemophagocytosis, cytopenias, high temperature, abnormal liver function test, low fibrinogen and elevated fasting triglycerides and ferritin, she fulfilled 5/8 HLH 2004 criteria. HLH-94 regimen was initiated with dexamethasone and etoposide. She developed neutropenic sepsis and etoposide was stopped. Blood cultures were positive for Escherichia coli. Patient expired after developing hemodynamic instability.Figure 1. Bone marrow hemophagocytosis and dysplastic changes in a trisomy 8 myelodysplastic syndrome patient. a Bone marrow aspirate smear revealing active hemophagocytosis. Erythroid cells are phagocytized by histiocytic cells. b Bone marrow aspirate showing neutrophil phagocytized by histiocytic cell. Peripherally to hemophagocytosis, erythroid precursor shows megaloblastic changes. Additionally, hyposegmented neutrophils are observed. c Nucleated red cell showing nuclear fragmentation with dysmorphic features suggesting dysplasia
Methods
In addition to our case, three additional previously published reports were included in our reviewed cases. Clinical, laboratory and karyotypic data was analyzed to investigate potential features commonly observed in patients presenting with hyperinflammation and MDS. Data aggregation from four cases presenting with HLH and MDS allowed identification of clinical outcome in patients receiving HLH directed therapy or alternative regimens.
Cohort analysis
HLH is a deadly syndrome. If untreated, survival is less than 2 months [2]. Here, we describe an elderly female exhibiting hyperinflammation, refractory cytopenias, erythroid dysplasia, expansion of + 8 metaphases and bone marrow/hepatic hemophagocytosis suggesting HLH associated with MDS (HLH-MDS). In addition to our patient, three previously published HLH cases associated with MDS were included in study cohort (Table 1). 7/8 HLH criteria were observed in two (50%), and one (25%) case with 6/8 and 5/8 criteria, each. Our report and published cases are novel since 3 of 4 (75%) patients harbored a karyotypic abnormality highlighting the clonal nature of the disease. A detectable chromosomic abnormality suggests that HLH was systemically initiated by MDS rather than representing a reactive phenomenon [3-5]. In reviewed cases, patients were older than 60 years with exception of one pediatric patient. International prognostic score system (IPSS) was intermediate-1 and high-risk (2 cases, each). + 8 was detected as sole abnormality or within a complex metaphase in 75% of cases. Most of the patients succumbed to the disease, except one case treated with high dose methylprednisolone, cyclosporine (CSA) decitabine. Tamamyan et al. described 33 cases of HLH, of which 3(9%) exhibited concurrent MDS, although only one was identified by HLH 2004 [6]. Karyotypic abnormalities were not reported. As in our case, the author reported that HLH linked with MDS represented a fatal condition.Table 1 Myelodysplastic syndrome cases associated with hemophagocytic Lymphohistiocytosis (HLH)
Age (years) Fever ANC (/mL) Hb (g/dL) Platelet (K/UL) Ferritin (ng/dL) Fibrinogen (mg/dL) TAG (mg/dL) IL-2 (pg/dL) Hemophagocytosis Marrow blast (%) Karyotype R-IPSS Hepatomegaly/splenomegaly HLH-2004 (points) Outcome
1 8 Yes 400 10.6 49 1070 256 306 4250 Yes 2.2 46, XX, + 8 [20] Inter-mediate Yes/yes 5 Alive
2 60 Yes 6800 6.5 14 649 NA NA 4054 Yes 2 Complex [including + 8]a Very high Yes/yes 5 Alive
3 68 NA NA 10.5 45 24,316 129 NA 1025 Yes 0 46, XY Low No/yes 5 Died
Case 83 Yes 8900 8.9 13 9479 70 321 34 Yes 0 47, XX, + 8 [6], 46, XX [5] Low No/no 6 Died
ANC absolute neutrophil count, Hb hemoglobin, TAG triglycerides, IL2 Interleukin 2 soluble receptor, IPSS International Prognostic Score System, NA not available
aPatient karyotype = 54-57,XY + 1 [2], + 3 [2], + [4], + 8 [4].add (9) (p22) [2], + 11[3].add (15) (p.11.2) [4], add (16) (q24) [4], add (19) (p13.1) [4], add (20) (p13) [4],?21 [2],2–5mar[cp4]/46,XY [8]
Conclusions
Efforts to elucidate pathogenesis of HLH demonstrate that expansion of CD8+ cytotoxic T cells, low Treg frequencies and cytokine storm are frequently observed [7]. In MDS, similar clonal T cell expansion and decreased Treg frequencies results in stem cell/progenitor apoptosis in low-risk disease. Rather than hyperinflammation normally found in HLH patients, chronic low-grade inflammation develops associated with tumor-necrosis factor-alpha (TNF-α), interleukin 1-beta (IL-1β) and IL-6 upregulation. Cytokine abnormalities in MDS leads to increased apoptosis and marrow hypercellularity. However, decreased marrow cellularity can develop in fraction of MDS patients harboring trisomy 8 karyotypic abnormality. Interestingly, our patient and two previously published cases harbored + 8 in their metaphase analysis at MDS diagnosis while HLH had developed [3, 5]. + 8 cells induce autologous T-cell oligoclonal expansion capable to target MDS precursor/progenitors resulting in characteristic marrow hypoplasia [8, 9]. In most of MDS cases, disease propagation depends on somatic mutations acquisition allowing dysplastic transformation. Mutations in perforin-dependent cytotoxicity are classically described in primary HLH. In our case, it is conceivable that myeloid mutations induced apoptotic and differentiation defects, and “facilitated” acquisition of HLH-like phenotype.
The preferred HLH treatment is HLH-94 protocol, but its administration is limited by MDS-induced cytopenias, as was the case with our patient. This is largely due to hemopoietic progenitor depletion initiated MDS and likely aggravated by HLH. Daitoku et al. reports superior outcome in a HLH-MDS patient treated with Methylprednisolone, CSA and decitabine[4]. Indeed, in vivo administration of hypomethylating agents (HMA) induce Foxp3+ Tregs expansion leading to immune suppression, and attenuates graft-versus-host disease [10]. The combination of HMA and immunosuppressive therapy may be promising treatment in HLH-MDS cases as suggested by the interesting outcomes in the case described by Daitoku et al.
We acknowledge limitations to our interpretation. It is possible that hyperinflammation initiated by HLH led to marrow dysplasia. However, the evidence of +8 strongly suggests a clonal etiology supporting MDS induced HLH. Secondly, sequencing did not include HLH like mutations such as PRF1, STX11, UNC13D, STXBP2, RAB27A, SH2D1A, BIRC4, LYST, ITK, SLC7A7, XMEN, HPS, among others. This may affect our ability to assign HLH as culprit for hyperinflammation in our case. However, Rui et al. recently demonstrated that epigenetic perturbations induced by DNMT3A mutations results in aberrant stem cell gene-expression associated with immune deregulation, which may have contributed to inflammatory manifestations in our case [11]. Additionally, recent data demonstrated that myeloid specific mutations including TET2, ASXL1, and DNMT3A can induce inflammasome activation in myelodysplasia and exacerbate inflammation [12-15]. In summary, HLH associated with MDS is an aggressive entity and should prompt careful evaluation hyperinflammatory signs. It is possible that targeting MDS hematopoiesis with hypomethylating agents in combination with immunosuppressive therapy to minimize hyperinflammation could improve life-threatening HLH in MDS patients.
Abbreviations
HLHHemophagocytic lymphohistiocytosis
MDSMyelodysplastic syndrome
HMAHypomethylating agent
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Financial support for this study was provided by the Texas Golfers against Cancer grant funding.
Authors’ contribution
YS and GR contributed equally to manuscript writing. BYM sequenced marrow cells and provided analysis for next generation sequencing. CB provided morphologic details of marrow. GR, YS and RS designed plan for investigation and report of the case and studied cohort. RG conceived the study; RG and SY designed the research; RG, SY, MBY, RS, BC performed the research; RG and SY analysed and interpreted the results; RG, SY, MBY, RS and BC wrote, reviewed and approved the manuscript. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and supporting materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Ethic approval and consent to participate
Institutional Review Board (IRB) approval was obtained for publication.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interest
Dr. Sun, Dr. Blieden, Dr. Merritt, Dr. Sosa and Dr. Rivero reported no conflict of interest. | DEXAMETHASONE, ETOPOSIDE | DrugsGivenReaction | CC BY | 33648567 | 19,811,533 | 2021-03-01 |
What was the dosage of drug 'DEXAMETHASONE'? | Hemophagocytic lymphohistiocytosis and myelodysplastic syndrome: a case report and review of the literature.
BACKGROUND
Hemophagocytic lymphohistiocytosis (HLH) is characterized by hyperinflammation and life-threatening cytopenias. Survival is poor, and management is pivotal on rapid identification of the disease. HLH is associated with hematologic malignancies, however correlation with myelodysplastic syndromes (MDS) is exceedingly unusual. Although minimizing overwhelming hyperinflammation by treating hemophagocytosis are central for HLH outcome, there is urgent necessity to identify potential initiating mechanisms that could assist in therapy design.
METHODS
Here, we describe an elderly African American patient who developed rapid onset of cytopenias and coagulopathy associated with hepatic and bone marrow hemophagocytosis. We analyze four additional similar cases to isolate clinical, laboratory and cytogenetic findings expected in patients exhibiting concurrent HLH and MDS. HLH linked with MDS retains common HLH features associated with systemic hyperinflammation such as fever, hypotension, hepatosplenomegaly, hyperferritinemia, coagulopathy and rapidly evolving cytopenias. Typical MDS chromosomic abnormality such as trisomy 8 was frequently observed in our studied cases.
CONCLUSIONS
Our case describes difficulties while managing HLH in MDS patients. Diagnosis should be based on identifying HLH appropriate criteria and if possible karyotypic abnormalities normally observed in MDS.
Introduction
Hemophagocytic lymphohistiocytosis (HLH) is characterized by deregulated immunity and end organ damage. Primary HLH is linked with autosomal recessive and X-linked mutations. Secondary HLH results from predisposing conditions. Both primary and secondary HLH may be activated by an infections and malignancies. [1] The association of HLH with hematologic malignancies is accepted. However, HLH initiated by myelodysplastic syndrome (MDS) is exceedingly unusual. Although dysplasia is observed in patients with hemophagocytosis, a hyperinflammatory entity characterized by dysplastic cytopenias, MDS like karyotypic abnormality and hemophagocytosis suggests a different spectrum of disease, in which HLH originates from a clonal disorder. In this report, we present an elderly female who fulfilled HLH 2004 criteria exhibiting erythroid and megakaryocytic dysplasia associated with trisomy 8 [+ 8]. Additionally, we examine published cases in English literature to identify clinical, laboratory and cytogenetic features observed in MDS patients fulfilling HLH 2004 criteria.
Case presentation
An 83-year-old African American female presented with lethargy, temperature of 102.9° F and tachycardia. After 9 days of broad-spectrum antibiotics, she developed hemodynamic instability requiring vasopressors, worsening liver function (peak bilirubin of 12.5 mg/dL, Aspartate aminotransferase (AST) of 689 IU/L, Alanine aminotransferase (ALT) of 239 IU/L) and leukocytosis of 16,000/uL. Her hemoglobin was 8.9/uL and platelets had fallen to 26,000/uL. Disseminated intravascular coagulation (DIC) was considered given progressive severe thrombocytopenia of 13,000 U/L, fibrinogen < 70 mg/dL and d-dimer of 12.4 mg/L. Her ferritin was 9479 ng/mL and fasting triglycerides (TAG) were 321 mg/dL. Soluble interleukin-2Rα (CD25) was < 38 pg/dL. Her human immunodeficiency virus (HIV), rapid influenza A/B, hepatitis B/C serologies were all negative. Epstein-barr virus (EBV) viral load was negative. Given concern autoimmune hepatitis, a liver biopsy showed Kupffer cell hypertrophy with hemophagocytosis. Bone marrow biopsy demonstrated hemophagocytosis (Fig 1a, b). In addition, significant erythroid nuclear fragmentation and karyorrhexis were observed (Fig 1c). Marrow cytogenetics showed 47, XX +8 [6], 46, XX [5]. Next generation sequencing (NGS) including CSFR1, SF3B1, SRSF2, U2AF1, NRAS, KRAS, FLT3, JAK2, KIT, PHF6, PDGFRA, CDKN2A, IDH1, IDH2, TET2, EZH2, CEBPA, EP300, PTPN11, P53, CREBBP, IKZF1, IKZF3, NOTCH1, RUNX1, WT1 and NPM1 showed DNMT3A p.Arg736His (c.2207G>A) and DNMT3A p.Leu859Ter (c.2576T>A) at allele frequencies of 2.7 and 2.4 %, respectively. In view of her hemophagocytosis, cytopenias, high temperature, abnormal liver function test, low fibrinogen and elevated fasting triglycerides and ferritin, she fulfilled 5/8 HLH 2004 criteria. HLH-94 regimen was initiated with dexamethasone and etoposide. She developed neutropenic sepsis and etoposide was stopped. Blood cultures were positive for Escherichia coli. Patient expired after developing hemodynamic instability.Figure 1. Bone marrow hemophagocytosis and dysplastic changes in a trisomy 8 myelodysplastic syndrome patient. a Bone marrow aspirate smear revealing active hemophagocytosis. Erythroid cells are phagocytized by histiocytic cells. b Bone marrow aspirate showing neutrophil phagocytized by histiocytic cell. Peripherally to hemophagocytosis, erythroid precursor shows megaloblastic changes. Additionally, hyposegmented neutrophils are observed. c Nucleated red cell showing nuclear fragmentation with dysmorphic features suggesting dysplasia
Methods
In addition to our case, three additional previously published reports were included in our reviewed cases. Clinical, laboratory and karyotypic data was analyzed to investigate potential features commonly observed in patients presenting with hyperinflammation and MDS. Data aggregation from four cases presenting with HLH and MDS allowed identification of clinical outcome in patients receiving HLH directed therapy or alternative regimens.
Cohort analysis
HLH is a deadly syndrome. If untreated, survival is less than 2 months [2]. Here, we describe an elderly female exhibiting hyperinflammation, refractory cytopenias, erythroid dysplasia, expansion of + 8 metaphases and bone marrow/hepatic hemophagocytosis suggesting HLH associated with MDS (HLH-MDS). In addition to our patient, three previously published HLH cases associated with MDS were included in study cohort (Table 1). 7/8 HLH criteria were observed in two (50%), and one (25%) case with 6/8 and 5/8 criteria, each. Our report and published cases are novel since 3 of 4 (75%) patients harbored a karyotypic abnormality highlighting the clonal nature of the disease. A detectable chromosomic abnormality suggests that HLH was systemically initiated by MDS rather than representing a reactive phenomenon [3-5]. In reviewed cases, patients were older than 60 years with exception of one pediatric patient. International prognostic score system (IPSS) was intermediate-1 and high-risk (2 cases, each). + 8 was detected as sole abnormality or within a complex metaphase in 75% of cases. Most of the patients succumbed to the disease, except one case treated with high dose methylprednisolone, cyclosporine (CSA) decitabine. Tamamyan et al. described 33 cases of HLH, of which 3(9%) exhibited concurrent MDS, although only one was identified by HLH 2004 [6]. Karyotypic abnormalities were not reported. As in our case, the author reported that HLH linked with MDS represented a fatal condition.Table 1 Myelodysplastic syndrome cases associated with hemophagocytic Lymphohistiocytosis (HLH)
Age (years) Fever ANC (/mL) Hb (g/dL) Platelet (K/UL) Ferritin (ng/dL) Fibrinogen (mg/dL) TAG (mg/dL) IL-2 (pg/dL) Hemophagocytosis Marrow blast (%) Karyotype R-IPSS Hepatomegaly/splenomegaly HLH-2004 (points) Outcome
1 8 Yes 400 10.6 49 1070 256 306 4250 Yes 2.2 46, XX, + 8 [20] Inter-mediate Yes/yes 5 Alive
2 60 Yes 6800 6.5 14 649 NA NA 4054 Yes 2 Complex [including + 8]a Very high Yes/yes 5 Alive
3 68 NA NA 10.5 45 24,316 129 NA 1025 Yes 0 46, XY Low No/yes 5 Died
Case 83 Yes 8900 8.9 13 9479 70 321 34 Yes 0 47, XX, + 8 [6], 46, XX [5] Low No/no 6 Died
ANC absolute neutrophil count, Hb hemoglobin, TAG triglycerides, IL2 Interleukin 2 soluble receptor, IPSS International Prognostic Score System, NA not available
aPatient karyotype = 54-57,XY + 1 [2], + 3 [2], + [4], + 8 [4].add (9) (p22) [2], + 11[3].add (15) (p.11.2) [4], add (16) (q24) [4], add (19) (p13.1) [4], add (20) (p13) [4],?21 [2],2–5mar[cp4]/46,XY [8]
Conclusions
Efforts to elucidate pathogenesis of HLH demonstrate that expansion of CD8+ cytotoxic T cells, low Treg frequencies and cytokine storm are frequently observed [7]. In MDS, similar clonal T cell expansion and decreased Treg frequencies results in stem cell/progenitor apoptosis in low-risk disease. Rather than hyperinflammation normally found in HLH patients, chronic low-grade inflammation develops associated with tumor-necrosis factor-alpha (TNF-α), interleukin 1-beta (IL-1β) and IL-6 upregulation. Cytokine abnormalities in MDS leads to increased apoptosis and marrow hypercellularity. However, decreased marrow cellularity can develop in fraction of MDS patients harboring trisomy 8 karyotypic abnormality. Interestingly, our patient and two previously published cases harbored + 8 in their metaphase analysis at MDS diagnosis while HLH had developed [3, 5]. + 8 cells induce autologous T-cell oligoclonal expansion capable to target MDS precursor/progenitors resulting in characteristic marrow hypoplasia [8, 9]. In most of MDS cases, disease propagation depends on somatic mutations acquisition allowing dysplastic transformation. Mutations in perforin-dependent cytotoxicity are classically described in primary HLH. In our case, it is conceivable that myeloid mutations induced apoptotic and differentiation defects, and “facilitated” acquisition of HLH-like phenotype.
The preferred HLH treatment is HLH-94 protocol, but its administration is limited by MDS-induced cytopenias, as was the case with our patient. This is largely due to hemopoietic progenitor depletion initiated MDS and likely aggravated by HLH. Daitoku et al. reports superior outcome in a HLH-MDS patient treated with Methylprednisolone, CSA and decitabine[4]. Indeed, in vivo administration of hypomethylating agents (HMA) induce Foxp3+ Tregs expansion leading to immune suppression, and attenuates graft-versus-host disease [10]. The combination of HMA and immunosuppressive therapy may be promising treatment in HLH-MDS cases as suggested by the interesting outcomes in the case described by Daitoku et al.
We acknowledge limitations to our interpretation. It is possible that hyperinflammation initiated by HLH led to marrow dysplasia. However, the evidence of +8 strongly suggests a clonal etiology supporting MDS induced HLH. Secondly, sequencing did not include HLH like mutations such as PRF1, STX11, UNC13D, STXBP2, RAB27A, SH2D1A, BIRC4, LYST, ITK, SLC7A7, XMEN, HPS, among others. This may affect our ability to assign HLH as culprit for hyperinflammation in our case. However, Rui et al. recently demonstrated that epigenetic perturbations induced by DNMT3A mutations results in aberrant stem cell gene-expression associated with immune deregulation, which may have contributed to inflammatory manifestations in our case [11]. Additionally, recent data demonstrated that myeloid specific mutations including TET2, ASXL1, and DNMT3A can induce inflammasome activation in myelodysplasia and exacerbate inflammation [12-15]. In summary, HLH associated with MDS is an aggressive entity and should prompt careful evaluation hyperinflammatory signs. It is possible that targeting MDS hematopoiesis with hypomethylating agents in combination with immunosuppressive therapy to minimize hyperinflammation could improve life-threatening HLH in MDS patients.
Abbreviations
HLHHemophagocytic lymphohistiocytosis
MDSMyelodysplastic syndrome
HMAHypomethylating agent
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Financial support for this study was provided by the Texas Golfers against Cancer grant funding.
Authors’ contribution
YS and GR contributed equally to manuscript writing. BYM sequenced marrow cells and provided analysis for next generation sequencing. CB provided morphologic details of marrow. GR, YS and RS designed plan for investigation and report of the case and studied cohort. RG conceived the study; RG and SY designed the research; RG, SY, MBY, RS, BC performed the research; RG and SY analysed and interpreted the results; RG, SY, MBY, RS and BC wrote, reviewed and approved the manuscript. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and supporting materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Ethic approval and consent to participate
Institutional Review Board (IRB) approval was obtained for publication.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interest
Dr. Sun, Dr. Blieden, Dr. Merritt, Dr. Sosa and Dr. Rivero reported no conflict of interest. | UNKNOWN | DrugDosageText | CC BY | 33648567 | 19,811,533 | 2021-03-01 |
What was the dosage of drug 'ETOPOSIDE'? | Hemophagocytic lymphohistiocytosis and myelodysplastic syndrome: a case report and review of the literature.
BACKGROUND
Hemophagocytic lymphohistiocytosis (HLH) is characterized by hyperinflammation and life-threatening cytopenias. Survival is poor, and management is pivotal on rapid identification of the disease. HLH is associated with hematologic malignancies, however correlation with myelodysplastic syndromes (MDS) is exceedingly unusual. Although minimizing overwhelming hyperinflammation by treating hemophagocytosis are central for HLH outcome, there is urgent necessity to identify potential initiating mechanisms that could assist in therapy design.
METHODS
Here, we describe an elderly African American patient who developed rapid onset of cytopenias and coagulopathy associated with hepatic and bone marrow hemophagocytosis. We analyze four additional similar cases to isolate clinical, laboratory and cytogenetic findings expected in patients exhibiting concurrent HLH and MDS. HLH linked with MDS retains common HLH features associated with systemic hyperinflammation such as fever, hypotension, hepatosplenomegaly, hyperferritinemia, coagulopathy and rapidly evolving cytopenias. Typical MDS chromosomic abnormality such as trisomy 8 was frequently observed in our studied cases.
CONCLUSIONS
Our case describes difficulties while managing HLH in MDS patients. Diagnosis should be based on identifying HLH appropriate criteria and if possible karyotypic abnormalities normally observed in MDS.
Introduction
Hemophagocytic lymphohistiocytosis (HLH) is characterized by deregulated immunity and end organ damage. Primary HLH is linked with autosomal recessive and X-linked mutations. Secondary HLH results from predisposing conditions. Both primary and secondary HLH may be activated by an infections and malignancies. [1] The association of HLH with hematologic malignancies is accepted. However, HLH initiated by myelodysplastic syndrome (MDS) is exceedingly unusual. Although dysplasia is observed in patients with hemophagocytosis, a hyperinflammatory entity characterized by dysplastic cytopenias, MDS like karyotypic abnormality and hemophagocytosis suggests a different spectrum of disease, in which HLH originates from a clonal disorder. In this report, we present an elderly female who fulfilled HLH 2004 criteria exhibiting erythroid and megakaryocytic dysplasia associated with trisomy 8 [+ 8]. Additionally, we examine published cases in English literature to identify clinical, laboratory and cytogenetic features observed in MDS patients fulfilling HLH 2004 criteria.
Case presentation
An 83-year-old African American female presented with lethargy, temperature of 102.9° F and tachycardia. After 9 days of broad-spectrum antibiotics, she developed hemodynamic instability requiring vasopressors, worsening liver function (peak bilirubin of 12.5 mg/dL, Aspartate aminotransferase (AST) of 689 IU/L, Alanine aminotransferase (ALT) of 239 IU/L) and leukocytosis of 16,000/uL. Her hemoglobin was 8.9/uL and platelets had fallen to 26,000/uL. Disseminated intravascular coagulation (DIC) was considered given progressive severe thrombocytopenia of 13,000 U/L, fibrinogen < 70 mg/dL and d-dimer of 12.4 mg/L. Her ferritin was 9479 ng/mL and fasting triglycerides (TAG) were 321 mg/dL. Soluble interleukin-2Rα (CD25) was < 38 pg/dL. Her human immunodeficiency virus (HIV), rapid influenza A/B, hepatitis B/C serologies were all negative. Epstein-barr virus (EBV) viral load was negative. Given concern autoimmune hepatitis, a liver biopsy showed Kupffer cell hypertrophy with hemophagocytosis. Bone marrow biopsy demonstrated hemophagocytosis (Fig 1a, b). In addition, significant erythroid nuclear fragmentation and karyorrhexis were observed (Fig 1c). Marrow cytogenetics showed 47, XX +8 [6], 46, XX [5]. Next generation sequencing (NGS) including CSFR1, SF3B1, SRSF2, U2AF1, NRAS, KRAS, FLT3, JAK2, KIT, PHF6, PDGFRA, CDKN2A, IDH1, IDH2, TET2, EZH2, CEBPA, EP300, PTPN11, P53, CREBBP, IKZF1, IKZF3, NOTCH1, RUNX1, WT1 and NPM1 showed DNMT3A p.Arg736His (c.2207G>A) and DNMT3A p.Leu859Ter (c.2576T>A) at allele frequencies of 2.7 and 2.4 %, respectively. In view of her hemophagocytosis, cytopenias, high temperature, abnormal liver function test, low fibrinogen and elevated fasting triglycerides and ferritin, she fulfilled 5/8 HLH 2004 criteria. HLH-94 regimen was initiated with dexamethasone and etoposide. She developed neutropenic sepsis and etoposide was stopped. Blood cultures were positive for Escherichia coli. Patient expired after developing hemodynamic instability.Figure 1. Bone marrow hemophagocytosis and dysplastic changes in a trisomy 8 myelodysplastic syndrome patient. a Bone marrow aspirate smear revealing active hemophagocytosis. Erythroid cells are phagocytized by histiocytic cells. b Bone marrow aspirate showing neutrophil phagocytized by histiocytic cell. Peripherally to hemophagocytosis, erythroid precursor shows megaloblastic changes. Additionally, hyposegmented neutrophils are observed. c Nucleated red cell showing nuclear fragmentation with dysmorphic features suggesting dysplasia
Methods
In addition to our case, three additional previously published reports were included in our reviewed cases. Clinical, laboratory and karyotypic data was analyzed to investigate potential features commonly observed in patients presenting with hyperinflammation and MDS. Data aggregation from four cases presenting with HLH and MDS allowed identification of clinical outcome in patients receiving HLH directed therapy or alternative regimens.
Cohort analysis
HLH is a deadly syndrome. If untreated, survival is less than 2 months [2]. Here, we describe an elderly female exhibiting hyperinflammation, refractory cytopenias, erythroid dysplasia, expansion of + 8 metaphases and bone marrow/hepatic hemophagocytosis suggesting HLH associated with MDS (HLH-MDS). In addition to our patient, three previously published HLH cases associated with MDS were included in study cohort (Table 1). 7/8 HLH criteria were observed in two (50%), and one (25%) case with 6/8 and 5/8 criteria, each. Our report and published cases are novel since 3 of 4 (75%) patients harbored a karyotypic abnormality highlighting the clonal nature of the disease. A detectable chromosomic abnormality suggests that HLH was systemically initiated by MDS rather than representing a reactive phenomenon [3-5]. In reviewed cases, patients were older than 60 years with exception of one pediatric patient. International prognostic score system (IPSS) was intermediate-1 and high-risk (2 cases, each). + 8 was detected as sole abnormality or within a complex metaphase in 75% of cases. Most of the patients succumbed to the disease, except one case treated with high dose methylprednisolone, cyclosporine (CSA) decitabine. Tamamyan et al. described 33 cases of HLH, of which 3(9%) exhibited concurrent MDS, although only one was identified by HLH 2004 [6]. Karyotypic abnormalities were not reported. As in our case, the author reported that HLH linked with MDS represented a fatal condition.Table 1 Myelodysplastic syndrome cases associated with hemophagocytic Lymphohistiocytosis (HLH)
Age (years) Fever ANC (/mL) Hb (g/dL) Platelet (K/UL) Ferritin (ng/dL) Fibrinogen (mg/dL) TAG (mg/dL) IL-2 (pg/dL) Hemophagocytosis Marrow blast (%) Karyotype R-IPSS Hepatomegaly/splenomegaly HLH-2004 (points) Outcome
1 8 Yes 400 10.6 49 1070 256 306 4250 Yes 2.2 46, XX, + 8 [20] Inter-mediate Yes/yes 5 Alive
2 60 Yes 6800 6.5 14 649 NA NA 4054 Yes 2 Complex [including + 8]a Very high Yes/yes 5 Alive
3 68 NA NA 10.5 45 24,316 129 NA 1025 Yes 0 46, XY Low No/yes 5 Died
Case 83 Yes 8900 8.9 13 9479 70 321 34 Yes 0 47, XX, + 8 [6], 46, XX [5] Low No/no 6 Died
ANC absolute neutrophil count, Hb hemoglobin, TAG triglycerides, IL2 Interleukin 2 soluble receptor, IPSS International Prognostic Score System, NA not available
aPatient karyotype = 54-57,XY + 1 [2], + 3 [2], + [4], + 8 [4].add (9) (p22) [2], + 11[3].add (15) (p.11.2) [4], add (16) (q24) [4], add (19) (p13.1) [4], add (20) (p13) [4],?21 [2],2–5mar[cp4]/46,XY [8]
Conclusions
Efforts to elucidate pathogenesis of HLH demonstrate that expansion of CD8+ cytotoxic T cells, low Treg frequencies and cytokine storm are frequently observed [7]. In MDS, similar clonal T cell expansion and decreased Treg frequencies results in stem cell/progenitor apoptosis in low-risk disease. Rather than hyperinflammation normally found in HLH patients, chronic low-grade inflammation develops associated with tumor-necrosis factor-alpha (TNF-α), interleukin 1-beta (IL-1β) and IL-6 upregulation. Cytokine abnormalities in MDS leads to increased apoptosis and marrow hypercellularity. However, decreased marrow cellularity can develop in fraction of MDS patients harboring trisomy 8 karyotypic abnormality. Interestingly, our patient and two previously published cases harbored + 8 in their metaphase analysis at MDS diagnosis while HLH had developed [3, 5]. + 8 cells induce autologous T-cell oligoclonal expansion capable to target MDS precursor/progenitors resulting in characteristic marrow hypoplasia [8, 9]. In most of MDS cases, disease propagation depends on somatic mutations acquisition allowing dysplastic transformation. Mutations in perforin-dependent cytotoxicity are classically described in primary HLH. In our case, it is conceivable that myeloid mutations induced apoptotic and differentiation defects, and “facilitated” acquisition of HLH-like phenotype.
The preferred HLH treatment is HLH-94 protocol, but its administration is limited by MDS-induced cytopenias, as was the case with our patient. This is largely due to hemopoietic progenitor depletion initiated MDS and likely aggravated by HLH. Daitoku et al. reports superior outcome in a HLH-MDS patient treated with Methylprednisolone, CSA and decitabine[4]. Indeed, in vivo administration of hypomethylating agents (HMA) induce Foxp3+ Tregs expansion leading to immune suppression, and attenuates graft-versus-host disease [10]. The combination of HMA and immunosuppressive therapy may be promising treatment in HLH-MDS cases as suggested by the interesting outcomes in the case described by Daitoku et al.
We acknowledge limitations to our interpretation. It is possible that hyperinflammation initiated by HLH led to marrow dysplasia. However, the evidence of +8 strongly suggests a clonal etiology supporting MDS induced HLH. Secondly, sequencing did not include HLH like mutations such as PRF1, STX11, UNC13D, STXBP2, RAB27A, SH2D1A, BIRC4, LYST, ITK, SLC7A7, XMEN, HPS, among others. This may affect our ability to assign HLH as culprit for hyperinflammation in our case. However, Rui et al. recently demonstrated that epigenetic perturbations induced by DNMT3A mutations results in aberrant stem cell gene-expression associated with immune deregulation, which may have contributed to inflammatory manifestations in our case [11]. Additionally, recent data demonstrated that myeloid specific mutations including TET2, ASXL1, and DNMT3A can induce inflammasome activation in myelodysplasia and exacerbate inflammation [12-15]. In summary, HLH associated with MDS is an aggressive entity and should prompt careful evaluation hyperinflammatory signs. It is possible that targeting MDS hematopoiesis with hypomethylating agents in combination with immunosuppressive therapy to minimize hyperinflammation could improve life-threatening HLH in MDS patients.
Abbreviations
HLHHemophagocytic lymphohistiocytosis
MDSMyelodysplastic syndrome
HMAHypomethylating agent
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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Financial support for this study was provided by the Texas Golfers against Cancer grant funding.
Authors’ contribution
YS and GR contributed equally to manuscript writing. BYM sequenced marrow cells and provided analysis for next generation sequencing. CB provided morphologic details of marrow. GR, YS and RS designed plan for investigation and report of the case and studied cohort. RG conceived the study; RG and SY designed the research; RG, SY, MBY, RS, BC performed the research; RG and SY analysed and interpreted the results; RG, SY, MBY, RS and BC wrote, reviewed and approved the manuscript. All authors read and approved the final manuscript.
Funding
Not applicable.
Availability of data and supporting materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
Ethic approval and consent to participate
Institutional Review Board (IRB) approval was obtained for publication.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interest
Dr. Sun, Dr. Blieden, Dr. Merritt, Dr. Sosa and Dr. Rivero reported no conflict of interest. | UNKNOWN | DrugDosageText | CC BY | 33648567 | 19,811,533 | 2021-03-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Exposure during pregnancy'. | A COVID-19 pregnant patient with thrombotic thrombocytopenic purpura: a case report.
BACKGROUND
Pregnancy seems to increase the risk of thrombotic thrombocytopenic purpura (TTP) relapses and make the TTP more severe in any of the pregnancy trimesters, or even during the postpartum period.
METHODS
This study highlights details of treating a COVID-19 pregnant patient who survived. This 21-year addicted White woman was admitted at her 29th week and delivered a stillbirth. She was transferred to another hospital after showing signs of TTP, which was caused by a viral infection.
CONCLUSIONS
This viral infection caused fever and dyspnea, and the patient was tested positive for COVID-19 infection. A chest computed tomography scan showed diffuse multiple bilateral consolidations and interlobar septal thickening. She stayed at the Intensive Care Unit for 20 days and treated with plasmapheresis. As far as we know, this is the first report of a TTP pregnant patient with COVID-19 infection.
Introduction
Pregnancy seems to increase the risk of thrombotic thrombocytopenic purpura (TTP) relapses and make the TTP more severe in any pregnancy trimesters or even during the postpartum period [1]. TTP is diagnosed when a patient has at least three of the following symptoms: thrombocytopenia, microangiopathic hemolytic anemia (MAHA), end‑organ damage (mostly renal insufficiency), neurologic phenomena (such as seizures, strokes), and fever. It is rare to see all the symptoms in a patient [2, 3]. TTP is usually triggered by bacterial or viral infections, autoimmune diseases such as lupus, and malignancy [4].
Acquired TTP presents as a severe MAHA and thrombocytopenia in a healthy individual. In a patient with MAHA, who has a hemoglobin level lower than ten and the platelet level lower than 30,000, the patinaed will be diagnosed as a TTP patient. Lactate dehydrogenase (LDH) level and ADAMTS13 activity level can achieve the same result [5, 6]. Differential diagnoses in pregnancy involve other conditions that contribute to having MAHA. These conditions include severe preeclampsia, HELLP syndrome, and disseminated intravascular coagulation (DIC) [7].
The most important therapy for TTP is doing plasma exchange to remove anti-ADAMTS13 autoantibodies. Plasma exchange should be administrated to reach at least 150,000/mm3 of platelets for 3 successive days, and LDH level of at most 500 U/l [8]. Introducing this treatment was a big jump, which reduced the mortality rate of TTP to 20% compared to the previously reported 90% [9]. Glucocorticoid therapy is a second treatment for TTP patients that can reduce the creation of the anti-ADAMTS13 autoantibody [10].
This study delves into finding how COVID-19 affects the pregnancy outcome in a rare condition. It focuses on viral infections as one of the causes of TTP. We report a drug-addicted TTP patient affected by COVID-19, who just delivered her baby, and we discuss the postpartum conditions in detail. We are going to share our case to increase knowledge on how to treat TTP patients with such complicated conditions.
Case study
A 21 years old White woman with gravida 1 and para 1 and intra uterine fetal death, who had a 29-week gestation, was admitted to RobatKarim Hospital, Tehran, Iran on March 20, 2020. The patient did not have a history of hospitalization, and she did not report any health issues among her family members. She was a housewife from a middle-class family who was living with his husband. Also, she was not a relative of her husband. She vaginally delivered a macerated male baby with 1300 g. As she stated, the pregnancy was unintended, and there was not any documented treatment found during the pregnancy months. The TTP patient who delivered her child and had a COVID-19 infection. As she stated, she did not have any severe preeclampsia signs, such as headaches and visual changes. She had fever, and sporadic dry coughs starting a week before the due date. She was tested positive for COVID 19.
She was a heavy smoker (did not take alcoholic beverages) and addicted to methamphetamine (for example, crystal) for a long time, and as she declared, she stopped taking methamphetamine during the last month before giving birth. She was treated with one loading dose of magnesium sulfate (4 g/IV (Intravenous)/stat), as well as antibiotics, such as ampicillin (2 g/IV/every 6 hours), Clindamycin (600 mg/IV/every 8 hours) and gentamicin (80 mg/IV/every 12 hours). Her condition deteriorated as the laboratory tests showed; the creatinine level became 5.6 mg/dl, the platelet was decreased to 23,000/mm3 and hemoglobin was decreased to 8.9 g/dl.
On March 21, 2020, she was sent to Firoozgar teaching hospital, Tehran, Iran, which Iran University of Medical Sciences administrated. At the time of admission, she was awake, conscious, and had a normal mental state. Her neurological examination, including cranial nerves, motor, sensory and cerebellar examination, were within normal ranges. Her blood pressure and body temperature and respiratory rate and pulse rate were 125/80 mmHg, 38.4 ℃ (oral), 26/minute, and 110/minute, respectively. Auscultation of both lungs and the heart showed fine crackles and tachycardia. Uterus was contracted, and we did not see any tenderness in liver palpation in the abdominal examination, and extremities examination showed that she had petechia on the inner surface of the arms.
The electrocardiogram was normal and Chest X-ray showed that both lungs had signs of diffused opacity. Chest computerized tomography (CT) showed signs of ground glass lung opacities (Fig. 1a), diffuse multiple bilateral consolidations (Fig. 1b), and diffuse bilateral fine interlobar septal thickening (Fig. 1c). As the literature shows, these are evidence for having viral lung infection and positive COVID-19 [11, 12].Fig. 1. Chest computerized tomography scan of the patient; a Ground glass lung opacities, b diffuse multiple bilateral consolidations, and c diffuse bilateral interlobar septal thickening
Figure 2 shows peripheral blood smear anomalies, including anemia, thrombocytopenia, anisocytosis, poikilocytosis, macrocytosis and schistocytes.Fig. 2. Peripheral blood smear anomalies
Polymerase chain reaction (PCR) test obtained by nasopharyngeal swabs specimen confirmed that she was positive for COVID-19. She did not have genetic testing for TTP. The viral infection tests, including Human Immunodeficiency Virus (HIV) antibody, Hepatitis B Surface (HBS) antigen, anti-HCV (Hepatitis C Virus) anti body were negative. The lupus blood test showed that anti double strand DNA, anti-coagulant, and anti-cardiolipin anti body were negative. The complement of C3 and C4 were in the normal range (C3 was equal to 101 mg/dl, and C4 was equal to 19 mg/dl).
Table 1 provides the results of laboratory tests for 5 days. As it shows for the second day, she had leukocytosis (Leukocyte was equal to 21,600 count/mm3), low hemoglobin level (4.9 g/dl), low platelets level (25,000/mm3), high serum creatinine level (4.7 mg/dl), and high lactate dehydrogenase level (1050 U/l).Table 1 Laboratory results of the patient
Hospitalization day Day 1 Day 2 Day 3 Day 4 Day5
Hemoglobin g/dl 5.0 4.9 6.1 7.9 8.1
Leukocyte count/mm3 11,000 21,600 29,000 28,800 18,600
Platelets /mm3 21,000 25,000 20,000 42,000 99,000
Fasting blood sugar mg/dl 98 87 85 87 100
Urea mg/dl 271 140 109 92 64
Creatinine mg/dl 5.6 4.7 2.3 1.3 1
Sodium mEq/l 134 143 137 142 138
Potassium mEq/l 5.7 4.7 3.6 3.4 4.2
AST u/l 24 30 33 31 36
ALT u/l 10 30 22 20 23
Bilirubin mg/dl 1.8 1.6 1.5 1.3 1.1
Albumin g/dl 2.3 3.2 3 3.5 3.7
Lactate dehydrogenase u/l 1,910 1,050 889 745 669
D-Dimer Negative N/A N/A N/A N/A
Serum bicarbonate mmol/l 15.1 19.3 18.8 17.3 22.0
Urine analysis (protein) Negative N/A N/A 1+ N/A
Urine analysis (blood) 2+ N/A N/A 3+ N/A
Fibrinogen mg/dl 403 N/A N/A N/A N/A
PT (seconds) 13.5 13 12.5 13.5 13
PTT (seconds) 24 33 25 30 28
INR 1 1.5 1.1 1.2 1.1
CRP (mg/ dl) 24 N/A N/A N/A 4
AST Aspartate Aminotransferase; ALT Alanine Transaminase; PT Prothrombin Time; PTT Partial Thromboplastin Time; INR International Normalized Ratio; CPR Cardiopulmonary Resuscitation; N/A No information was collected
Her hemoglobin level dropped to 5.0 g/dl and we transfused the packed red blood cells. Hematologists suggested taking Dexamethasone at the rate of 8 mg/day. She had premature membrane rupture along with malodor vaginal discharge and endometritis, so she took antibiotics, including Clindamycin in the rate of 600 mg/IV/(every 8 hours), Meropenem at the rate of 500 mg/(every 12 hours). It should be mentioned that the doses were adjusted to creatinine clearance. She also got dialysis treatment for 2 successive days as the serum creatinine level was raised.
Infectious disease specialists started to treat the patient with Kaletra (in one combined dosage of Lopinavir in the rate of 100 mg and Ritonavir in the rate of 400 mg) and Hydroxychloroquine 400 mg/stat followed by a continuous dose of it at the rate of 200 mg/ (every 12 hours) for14 days.
Due to the presence of thrombocytopenia and an increase in LDH level to 1910 U/l, the hematologist treated her with plasmapheresis. The hematologist suggested exchanging 2.5 l of plasma with 2 l of fresh frozen plasma for 5 consecutive days, which resulted in achieving platelet to 155,000 per cubic millimeter and lowering LDH level to 450 U/l.
Our multi-disciplinary health team strived to save the patient, and finally the patient started to feel better as the body temperature returned to normal (i.e., break the fever). The patient did not have any signs of dyspnea on the 20th day of ICU hospitalization. Additionally, the leukocyte level returned to normal, and the kidney started to function healthily. She was in ICU for 24 days until March 27, 2020, and then she was transferred to the Gynecological ward. This patient was finally discharged after 8 days. The patient is cured at the moment and does not show any TTP symptoms afterwards. Her hemoglobin is 11 g/dl, platelet is 220,000/mm3, LDH is 200 U/l, and creatinine is 0.9 mg/dl.
Discussion
World Health Organization declared COVID 19 a global pandemic on March 11, 2020 [13]. COVID 19 can cause complicated situations for patients who have underlying medical conditions. A 21 years old drug-addicted woman was admitted to a hospital. She was tested positive for COVID 19 at the time of admission and delivered a stillbirth fetus. Then, she showed the early symptoms of TTP, including haemoglobin level of 5 g/dl, platelet of 23,000/mm3, and creatinine level of 5.6 mg/dl, and schistocytes in the peripheral blood smear. She did not have any symptoms of TTP before hospitalization. And she showed the symptoms for the first time during her pregnancy. Also, this patient had normal liver enzymes, and she did not have any severe preeclampsia symptoms. She responded to plasmapheresis and was cured. Moreover, at the moment, which is 6 months after her delivery, she does not have any TTP symptoms. By taking all these factors into account, we believe that her TTP was acquired.
Literature found that pregnant women are going through some physiological changes that affect their immune systems. This affection may predispose such people to viral respiratory infections such as COVID-19, a cause of TTP [14–16]. This study summarizes the challenges that the medical team faced during this process in order to find how COVID-19 affects the pregnancy outcome in a rare condition. As we are learning how COVID-19 interferes with organs’ functions, we share the diagnosis and treatment steps for curing a TTP pregnant woman as of the first study of its kind.
Karami et al., in March 2020, reported a 27 years pregnant woman with COVID-19 symptoms such as fever, myalgia, and cough, which are similar to our case. [17] Our case has leukocytosis, which could be a positive sign for her survival; however, the 27 years case suffered from leukopenia and lymphopenia. In both of the cases, Reverse Transcription Polymerase Chain Reaction confirmed the presence of COVID-19 infection. However, the results of the Chest CT scan at the time of hospitalization were different between these studies, as the CT of our patient was similar to the CT of COVID-19 patients. Both cases started treatment for COVID 19, and both cases had a stillbirth. Literature listed Intrauterine fetal death as an outcome of infection with a family cluster of coronaviruses such as MERS (Middle Eastern Respiratory Syndrome Coronavirus)-COV and SARS(Severe Acute Respiratory Syndrome)-COV [14–16, 18]. Since we admitted our patient to the ICU sooner, she survived, while the 27 years patient died due to the multi-organ failure.
Another study took nine pregnant women with gestational ages greater than or equal to 36 weeks with COVID-19 infection, each of them had only one symptom from the typical symptoms [12] (i.e., fever, cough, myalgia, and dyspnea). Our patient was in her 29th week and had all of the common symptoms, and she survived while the patient died in this study. Each of the cases had a stillbirth, which can be explained in the case of infection. In more severe cases with COVID-19 infection, the virus may cause pneumonia that reduces the lungs’ capacity. This reduction in the capacity develops hypoxia in a pregnant patient that stops oxygen delivery to the fetus [15]. This causes Intrauterine Fetal Death (IUFD), which was happened in our case. We have a rich literature discuss the effect of influenza and other known respiratory infections in pregnancy [14], which happened to be similar in our patient who had COVID-19.
Another study considered 13 pregnant women with COVID-19; 10 cases undergone cesarean section due to the complicated conditions, such as fetal distress and premature rupture of the membrane (PROM) [15, 19]. Our case vaginally delivered a stillbirth, and the mother survived, while this study reports the death of one of the patients who had a stillbirth. This patient experienced multiple organ damages, including acute kidney injury, acute hepatic failure, and septic shock. Additionally, she went to ICU, and she was intubated due to the occurrence of acute respiratory distress syndrome [19].
Other studies treated a pregnant TTP patient effectively with plasmapheresis and glucocorticoid [20]. The major difference between this study and ours is that this study knew that the patient had TTP who finally suffered a relapse, while our patient was not previously treated for TTP. In our case, we believe that COVID-19, as a viral infection, stimulated anti-ADAMTS13 autoantibodies.
Another study treated a pregnant TTP patient who only had HELLP syndrome without COVID-19 infection [21]. The blood pressure of our case was normal, which ruled out the presence of HELLP syndrome. In both cases, high LDH, anemia, and thrombocytopenia confirm that the patients had MAHA, which is one of the hallmarks of TTP. In our case, Fig. 2 confirms this information as it visualizes fragmented erythrocytes in the shape of teardrops. To treat the TTP, our patient took Hydrocortisone 100 mg/IV/stat and then Dexamethasone 4 mg/IV/(every 8 hours) as well as having plasmapheresis daily for 5 days. It should be noted that we applied this treatment due to the severe condition of our patient, as even measuring the ADAMTS13 activities could not be suggested as a reliable diagnostic test at the acute phase [21].
Conclusion
To summarize our case, pregnancy and the presence of the viral infection could be the triggers of TTP [6, 22, 23], which causes a critical risk for both mother and the child [24]. Literature shows that infections such as influenza, SARS-COV, and MERS-COV could increase the risk of maternal mortality, spontaneous miscarriage, preterm labor, and intrauterine growth restriction during pregnancy [15, 25]. In our case, we believe that the COVID-19 behaves similarly to other viral infections. Thus, we can consider TTP or COVID-19 as different etiologies engender the IUFD. It should be mentioned that COVID-19 does not have a proven treatment. Frontline workers are treating patients with potential therapy, such as antiviral drugs and immunotherapies. We believe that if our patient was hospitalized sooner, she could have saved the baby, as the medical procedure we followed to save this TTP patient could benefit the baby as well. We recommend to other colleagues to consider this approach while they admit a pregnant patient.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We appreciate the assistance from Ahmadreza Mahmoudzadeh at Texas A&M University, who helped us in drafting and revising the manuscript.
Authors' contributions
SA was responsible for writing the first draft and review, supervising the project, and analyzing the data. NA and SN were involved in writing the initial draft. OMN was responsible for data collection and FM was responsible for writing the initial draft. All authors read and approved the final manuscript.
Funding
The authors did not receive any funding for this study.
Availability of data and materials
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.
Ethics approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | HYDROXYCHLOROQUINE | DrugsGivenReaction | CC BY | 33648584 | 19,174,507 | 2021-03-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | A COVID-19 pregnant patient with thrombotic thrombocytopenic purpura: a case report.
BACKGROUND
Pregnancy seems to increase the risk of thrombotic thrombocytopenic purpura (TTP) relapses and make the TTP more severe in any of the pregnancy trimesters, or even during the postpartum period.
METHODS
This study highlights details of treating a COVID-19 pregnant patient who survived. This 21-year addicted White woman was admitted at her 29th week and delivered a stillbirth. She was transferred to another hospital after showing signs of TTP, which was caused by a viral infection.
CONCLUSIONS
This viral infection caused fever and dyspnea, and the patient was tested positive for COVID-19 infection. A chest computed tomography scan showed diffuse multiple bilateral consolidations and interlobar septal thickening. She stayed at the Intensive Care Unit for 20 days and treated with plasmapheresis. As far as we know, this is the first report of a TTP pregnant patient with COVID-19 infection.
Introduction
Pregnancy seems to increase the risk of thrombotic thrombocytopenic purpura (TTP) relapses and make the TTP more severe in any pregnancy trimesters or even during the postpartum period [1]. TTP is diagnosed when a patient has at least three of the following symptoms: thrombocytopenia, microangiopathic hemolytic anemia (MAHA), end‑organ damage (mostly renal insufficiency), neurologic phenomena (such as seizures, strokes), and fever. It is rare to see all the symptoms in a patient [2, 3]. TTP is usually triggered by bacterial or viral infections, autoimmune diseases such as lupus, and malignancy [4].
Acquired TTP presents as a severe MAHA and thrombocytopenia in a healthy individual. In a patient with MAHA, who has a hemoglobin level lower than ten and the platelet level lower than 30,000, the patinaed will be diagnosed as a TTP patient. Lactate dehydrogenase (LDH) level and ADAMTS13 activity level can achieve the same result [5, 6]. Differential diagnoses in pregnancy involve other conditions that contribute to having MAHA. These conditions include severe preeclampsia, HELLP syndrome, and disseminated intravascular coagulation (DIC) [7].
The most important therapy for TTP is doing plasma exchange to remove anti-ADAMTS13 autoantibodies. Plasma exchange should be administrated to reach at least 150,000/mm3 of platelets for 3 successive days, and LDH level of at most 500 U/l [8]. Introducing this treatment was a big jump, which reduced the mortality rate of TTP to 20% compared to the previously reported 90% [9]. Glucocorticoid therapy is a second treatment for TTP patients that can reduce the creation of the anti-ADAMTS13 autoantibody [10].
This study delves into finding how COVID-19 affects the pregnancy outcome in a rare condition. It focuses on viral infections as one of the causes of TTP. We report a drug-addicted TTP patient affected by COVID-19, who just delivered her baby, and we discuss the postpartum conditions in detail. We are going to share our case to increase knowledge on how to treat TTP patients with such complicated conditions.
Case study
A 21 years old White woman with gravida 1 and para 1 and intra uterine fetal death, who had a 29-week gestation, was admitted to RobatKarim Hospital, Tehran, Iran on March 20, 2020. The patient did not have a history of hospitalization, and she did not report any health issues among her family members. She was a housewife from a middle-class family who was living with his husband. Also, she was not a relative of her husband. She vaginally delivered a macerated male baby with 1300 g. As she stated, the pregnancy was unintended, and there was not any documented treatment found during the pregnancy months. The TTP patient who delivered her child and had a COVID-19 infection. As she stated, she did not have any severe preeclampsia signs, such as headaches and visual changes. She had fever, and sporadic dry coughs starting a week before the due date. She was tested positive for COVID 19.
She was a heavy smoker (did not take alcoholic beverages) and addicted to methamphetamine (for example, crystal) for a long time, and as she declared, she stopped taking methamphetamine during the last month before giving birth. She was treated with one loading dose of magnesium sulfate (4 g/IV (Intravenous)/stat), as well as antibiotics, such as ampicillin (2 g/IV/every 6 hours), Clindamycin (600 mg/IV/every 8 hours) and gentamicin (80 mg/IV/every 12 hours). Her condition deteriorated as the laboratory tests showed; the creatinine level became 5.6 mg/dl, the platelet was decreased to 23,000/mm3 and hemoglobin was decreased to 8.9 g/dl.
On March 21, 2020, she was sent to Firoozgar teaching hospital, Tehran, Iran, which Iran University of Medical Sciences administrated. At the time of admission, she was awake, conscious, and had a normal mental state. Her neurological examination, including cranial nerves, motor, sensory and cerebellar examination, were within normal ranges. Her blood pressure and body temperature and respiratory rate and pulse rate were 125/80 mmHg, 38.4 ℃ (oral), 26/minute, and 110/minute, respectively. Auscultation of both lungs and the heart showed fine crackles and tachycardia. Uterus was contracted, and we did not see any tenderness in liver palpation in the abdominal examination, and extremities examination showed that she had petechia on the inner surface of the arms.
The electrocardiogram was normal and Chest X-ray showed that both lungs had signs of diffused opacity. Chest computerized tomography (CT) showed signs of ground glass lung opacities (Fig. 1a), diffuse multiple bilateral consolidations (Fig. 1b), and diffuse bilateral fine interlobar septal thickening (Fig. 1c). As the literature shows, these are evidence for having viral lung infection and positive COVID-19 [11, 12].Fig. 1. Chest computerized tomography scan of the patient; a Ground glass lung opacities, b diffuse multiple bilateral consolidations, and c diffuse bilateral interlobar septal thickening
Figure 2 shows peripheral blood smear anomalies, including anemia, thrombocytopenia, anisocytosis, poikilocytosis, macrocytosis and schistocytes.Fig. 2. Peripheral blood smear anomalies
Polymerase chain reaction (PCR) test obtained by nasopharyngeal swabs specimen confirmed that she was positive for COVID-19. She did not have genetic testing for TTP. The viral infection tests, including Human Immunodeficiency Virus (HIV) antibody, Hepatitis B Surface (HBS) antigen, anti-HCV (Hepatitis C Virus) anti body were negative. The lupus blood test showed that anti double strand DNA, anti-coagulant, and anti-cardiolipin anti body were negative. The complement of C3 and C4 were in the normal range (C3 was equal to 101 mg/dl, and C4 was equal to 19 mg/dl).
Table 1 provides the results of laboratory tests for 5 days. As it shows for the second day, she had leukocytosis (Leukocyte was equal to 21,600 count/mm3), low hemoglobin level (4.9 g/dl), low platelets level (25,000/mm3), high serum creatinine level (4.7 mg/dl), and high lactate dehydrogenase level (1050 U/l).Table 1 Laboratory results of the patient
Hospitalization day Day 1 Day 2 Day 3 Day 4 Day5
Hemoglobin g/dl 5.0 4.9 6.1 7.9 8.1
Leukocyte count/mm3 11,000 21,600 29,000 28,800 18,600
Platelets /mm3 21,000 25,000 20,000 42,000 99,000
Fasting blood sugar mg/dl 98 87 85 87 100
Urea mg/dl 271 140 109 92 64
Creatinine mg/dl 5.6 4.7 2.3 1.3 1
Sodium mEq/l 134 143 137 142 138
Potassium mEq/l 5.7 4.7 3.6 3.4 4.2
AST u/l 24 30 33 31 36
ALT u/l 10 30 22 20 23
Bilirubin mg/dl 1.8 1.6 1.5 1.3 1.1
Albumin g/dl 2.3 3.2 3 3.5 3.7
Lactate dehydrogenase u/l 1,910 1,050 889 745 669
D-Dimer Negative N/A N/A N/A N/A
Serum bicarbonate mmol/l 15.1 19.3 18.8 17.3 22.0
Urine analysis (protein) Negative N/A N/A 1+ N/A
Urine analysis (blood) 2+ N/A N/A 3+ N/A
Fibrinogen mg/dl 403 N/A N/A N/A N/A
PT (seconds) 13.5 13 12.5 13.5 13
PTT (seconds) 24 33 25 30 28
INR 1 1.5 1.1 1.2 1.1
CRP (mg/ dl) 24 N/A N/A N/A 4
AST Aspartate Aminotransferase; ALT Alanine Transaminase; PT Prothrombin Time; PTT Partial Thromboplastin Time; INR International Normalized Ratio; CPR Cardiopulmonary Resuscitation; N/A No information was collected
Her hemoglobin level dropped to 5.0 g/dl and we transfused the packed red blood cells. Hematologists suggested taking Dexamethasone at the rate of 8 mg/day. She had premature membrane rupture along with malodor vaginal discharge and endometritis, so she took antibiotics, including Clindamycin in the rate of 600 mg/IV/(every 8 hours), Meropenem at the rate of 500 mg/(every 12 hours). It should be mentioned that the doses were adjusted to creatinine clearance. She also got dialysis treatment for 2 successive days as the serum creatinine level was raised.
Infectious disease specialists started to treat the patient with Kaletra (in one combined dosage of Lopinavir in the rate of 100 mg and Ritonavir in the rate of 400 mg) and Hydroxychloroquine 400 mg/stat followed by a continuous dose of it at the rate of 200 mg/ (every 12 hours) for14 days.
Due to the presence of thrombocytopenia and an increase in LDH level to 1910 U/l, the hematologist treated her with plasmapheresis. The hematologist suggested exchanging 2.5 l of plasma with 2 l of fresh frozen plasma for 5 consecutive days, which resulted in achieving platelet to 155,000 per cubic millimeter and lowering LDH level to 450 U/l.
Our multi-disciplinary health team strived to save the patient, and finally the patient started to feel better as the body temperature returned to normal (i.e., break the fever). The patient did not have any signs of dyspnea on the 20th day of ICU hospitalization. Additionally, the leukocyte level returned to normal, and the kidney started to function healthily. She was in ICU for 24 days until March 27, 2020, and then she was transferred to the Gynecological ward. This patient was finally discharged after 8 days. The patient is cured at the moment and does not show any TTP symptoms afterwards. Her hemoglobin is 11 g/dl, platelet is 220,000/mm3, LDH is 200 U/l, and creatinine is 0.9 mg/dl.
Discussion
World Health Organization declared COVID 19 a global pandemic on March 11, 2020 [13]. COVID 19 can cause complicated situations for patients who have underlying medical conditions. A 21 years old drug-addicted woman was admitted to a hospital. She was tested positive for COVID 19 at the time of admission and delivered a stillbirth fetus. Then, she showed the early symptoms of TTP, including haemoglobin level of 5 g/dl, platelet of 23,000/mm3, and creatinine level of 5.6 mg/dl, and schistocytes in the peripheral blood smear. She did not have any symptoms of TTP before hospitalization. And she showed the symptoms for the first time during her pregnancy. Also, this patient had normal liver enzymes, and she did not have any severe preeclampsia symptoms. She responded to plasmapheresis and was cured. Moreover, at the moment, which is 6 months after her delivery, she does not have any TTP symptoms. By taking all these factors into account, we believe that her TTP was acquired.
Literature found that pregnant women are going through some physiological changes that affect their immune systems. This affection may predispose such people to viral respiratory infections such as COVID-19, a cause of TTP [14–16]. This study summarizes the challenges that the medical team faced during this process in order to find how COVID-19 affects the pregnancy outcome in a rare condition. As we are learning how COVID-19 interferes with organs’ functions, we share the diagnosis and treatment steps for curing a TTP pregnant woman as of the first study of its kind.
Karami et al., in March 2020, reported a 27 years pregnant woman with COVID-19 symptoms such as fever, myalgia, and cough, which are similar to our case. [17] Our case has leukocytosis, which could be a positive sign for her survival; however, the 27 years case suffered from leukopenia and lymphopenia. In both of the cases, Reverse Transcription Polymerase Chain Reaction confirmed the presence of COVID-19 infection. However, the results of the Chest CT scan at the time of hospitalization were different between these studies, as the CT of our patient was similar to the CT of COVID-19 patients. Both cases started treatment for COVID 19, and both cases had a stillbirth. Literature listed Intrauterine fetal death as an outcome of infection with a family cluster of coronaviruses such as MERS (Middle Eastern Respiratory Syndrome Coronavirus)-COV and SARS(Severe Acute Respiratory Syndrome)-COV [14–16, 18]. Since we admitted our patient to the ICU sooner, she survived, while the 27 years patient died due to the multi-organ failure.
Another study took nine pregnant women with gestational ages greater than or equal to 36 weeks with COVID-19 infection, each of them had only one symptom from the typical symptoms [12] (i.e., fever, cough, myalgia, and dyspnea). Our patient was in her 29th week and had all of the common symptoms, and she survived while the patient died in this study. Each of the cases had a stillbirth, which can be explained in the case of infection. In more severe cases with COVID-19 infection, the virus may cause pneumonia that reduces the lungs’ capacity. This reduction in the capacity develops hypoxia in a pregnant patient that stops oxygen delivery to the fetus [15]. This causes Intrauterine Fetal Death (IUFD), which was happened in our case. We have a rich literature discuss the effect of influenza and other known respiratory infections in pregnancy [14], which happened to be similar in our patient who had COVID-19.
Another study considered 13 pregnant women with COVID-19; 10 cases undergone cesarean section due to the complicated conditions, such as fetal distress and premature rupture of the membrane (PROM) [15, 19]. Our case vaginally delivered a stillbirth, and the mother survived, while this study reports the death of one of the patients who had a stillbirth. This patient experienced multiple organ damages, including acute kidney injury, acute hepatic failure, and septic shock. Additionally, she went to ICU, and she was intubated due to the occurrence of acute respiratory distress syndrome [19].
Other studies treated a pregnant TTP patient effectively with plasmapheresis and glucocorticoid [20]. The major difference between this study and ours is that this study knew that the patient had TTP who finally suffered a relapse, while our patient was not previously treated for TTP. In our case, we believe that COVID-19, as a viral infection, stimulated anti-ADAMTS13 autoantibodies.
Another study treated a pregnant TTP patient who only had HELLP syndrome without COVID-19 infection [21]. The blood pressure of our case was normal, which ruled out the presence of HELLP syndrome. In both cases, high LDH, anemia, and thrombocytopenia confirm that the patients had MAHA, which is one of the hallmarks of TTP. In our case, Fig. 2 confirms this information as it visualizes fragmented erythrocytes in the shape of teardrops. To treat the TTP, our patient took Hydrocortisone 100 mg/IV/stat and then Dexamethasone 4 mg/IV/(every 8 hours) as well as having plasmapheresis daily for 5 days. It should be noted that we applied this treatment due to the severe condition of our patient, as even measuring the ADAMTS13 activities could not be suggested as a reliable diagnostic test at the acute phase [21].
Conclusion
To summarize our case, pregnancy and the presence of the viral infection could be the triggers of TTP [6, 22, 23], which causes a critical risk for both mother and the child [24]. Literature shows that infections such as influenza, SARS-COV, and MERS-COV could increase the risk of maternal mortality, spontaneous miscarriage, preterm labor, and intrauterine growth restriction during pregnancy [15, 25]. In our case, we believe that the COVID-19 behaves similarly to other viral infections. Thus, we can consider TTP or COVID-19 as different etiologies engender the IUFD. It should be mentioned that COVID-19 does not have a proven treatment. Frontline workers are treating patients with potential therapy, such as antiviral drugs and immunotherapies. We believe that if our patient was hospitalized sooner, she could have saved the baby, as the medical procedure we followed to save this TTP patient could benefit the baby as well. We recommend to other colleagues to consider this approach while they admit a pregnant patient.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We appreciate the assistance from Ahmadreza Mahmoudzadeh at Texas A&M University, who helped us in drafting and revising the manuscript.
Authors' contributions
SA was responsible for writing the first draft and review, supervising the project, and analyzing the data. NA and SN were involved in writing the initial draft. OMN was responsible for data collection and FM was responsible for writing the initial draft. All authors read and approved the final manuscript.
Funding
The authors did not receive any funding for this study.
Availability of data and materials
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.
Ethics approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | HYDROXYCHLOROQUINE | DrugsGivenReaction | CC BY | 33648584 | 19,174,507 | 2021-03-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Stillbirth'. | A COVID-19 pregnant patient with thrombotic thrombocytopenic purpura: a case report.
BACKGROUND
Pregnancy seems to increase the risk of thrombotic thrombocytopenic purpura (TTP) relapses and make the TTP more severe in any of the pregnancy trimesters, or even during the postpartum period.
METHODS
This study highlights details of treating a COVID-19 pregnant patient who survived. This 21-year addicted White woman was admitted at her 29th week and delivered a stillbirth. She was transferred to another hospital after showing signs of TTP, which was caused by a viral infection.
CONCLUSIONS
This viral infection caused fever and dyspnea, and the patient was tested positive for COVID-19 infection. A chest computed tomography scan showed diffuse multiple bilateral consolidations and interlobar septal thickening. She stayed at the Intensive Care Unit for 20 days and treated with plasmapheresis. As far as we know, this is the first report of a TTP pregnant patient with COVID-19 infection.
Introduction
Pregnancy seems to increase the risk of thrombotic thrombocytopenic purpura (TTP) relapses and make the TTP more severe in any pregnancy trimesters or even during the postpartum period [1]. TTP is diagnosed when a patient has at least three of the following symptoms: thrombocytopenia, microangiopathic hemolytic anemia (MAHA), end‑organ damage (mostly renal insufficiency), neurologic phenomena (such as seizures, strokes), and fever. It is rare to see all the symptoms in a patient [2, 3]. TTP is usually triggered by bacterial or viral infections, autoimmune diseases such as lupus, and malignancy [4].
Acquired TTP presents as a severe MAHA and thrombocytopenia in a healthy individual. In a patient with MAHA, who has a hemoglobin level lower than ten and the platelet level lower than 30,000, the patinaed will be diagnosed as a TTP patient. Lactate dehydrogenase (LDH) level and ADAMTS13 activity level can achieve the same result [5, 6]. Differential diagnoses in pregnancy involve other conditions that contribute to having MAHA. These conditions include severe preeclampsia, HELLP syndrome, and disseminated intravascular coagulation (DIC) [7].
The most important therapy for TTP is doing plasma exchange to remove anti-ADAMTS13 autoantibodies. Plasma exchange should be administrated to reach at least 150,000/mm3 of platelets for 3 successive days, and LDH level of at most 500 U/l [8]. Introducing this treatment was a big jump, which reduced the mortality rate of TTP to 20% compared to the previously reported 90% [9]. Glucocorticoid therapy is a second treatment for TTP patients that can reduce the creation of the anti-ADAMTS13 autoantibody [10].
This study delves into finding how COVID-19 affects the pregnancy outcome in a rare condition. It focuses on viral infections as one of the causes of TTP. We report a drug-addicted TTP patient affected by COVID-19, who just delivered her baby, and we discuss the postpartum conditions in detail. We are going to share our case to increase knowledge on how to treat TTP patients with such complicated conditions.
Case study
A 21 years old White woman with gravida 1 and para 1 and intra uterine fetal death, who had a 29-week gestation, was admitted to RobatKarim Hospital, Tehran, Iran on March 20, 2020. The patient did not have a history of hospitalization, and she did not report any health issues among her family members. She was a housewife from a middle-class family who was living with his husband. Also, she was not a relative of her husband. She vaginally delivered a macerated male baby with 1300 g. As she stated, the pregnancy was unintended, and there was not any documented treatment found during the pregnancy months. The TTP patient who delivered her child and had a COVID-19 infection. As she stated, she did not have any severe preeclampsia signs, such as headaches and visual changes. She had fever, and sporadic dry coughs starting a week before the due date. She was tested positive for COVID 19.
She was a heavy smoker (did not take alcoholic beverages) and addicted to methamphetamine (for example, crystal) for a long time, and as she declared, she stopped taking methamphetamine during the last month before giving birth. She was treated with one loading dose of magnesium sulfate (4 g/IV (Intravenous)/stat), as well as antibiotics, such as ampicillin (2 g/IV/every 6 hours), Clindamycin (600 mg/IV/every 8 hours) and gentamicin (80 mg/IV/every 12 hours). Her condition deteriorated as the laboratory tests showed; the creatinine level became 5.6 mg/dl, the platelet was decreased to 23,000/mm3 and hemoglobin was decreased to 8.9 g/dl.
On March 21, 2020, she was sent to Firoozgar teaching hospital, Tehran, Iran, which Iran University of Medical Sciences administrated. At the time of admission, she was awake, conscious, and had a normal mental state. Her neurological examination, including cranial nerves, motor, sensory and cerebellar examination, were within normal ranges. Her blood pressure and body temperature and respiratory rate and pulse rate were 125/80 mmHg, 38.4 ℃ (oral), 26/minute, and 110/minute, respectively. Auscultation of both lungs and the heart showed fine crackles and tachycardia. Uterus was contracted, and we did not see any tenderness in liver palpation in the abdominal examination, and extremities examination showed that she had petechia on the inner surface of the arms.
The electrocardiogram was normal and Chest X-ray showed that both lungs had signs of diffused opacity. Chest computerized tomography (CT) showed signs of ground glass lung opacities (Fig. 1a), diffuse multiple bilateral consolidations (Fig. 1b), and diffuse bilateral fine interlobar septal thickening (Fig. 1c). As the literature shows, these are evidence for having viral lung infection and positive COVID-19 [11, 12].Fig. 1. Chest computerized tomography scan of the patient; a Ground glass lung opacities, b diffuse multiple bilateral consolidations, and c diffuse bilateral interlobar septal thickening
Figure 2 shows peripheral blood smear anomalies, including anemia, thrombocytopenia, anisocytosis, poikilocytosis, macrocytosis and schistocytes.Fig. 2. Peripheral blood smear anomalies
Polymerase chain reaction (PCR) test obtained by nasopharyngeal swabs specimen confirmed that she was positive for COVID-19. She did not have genetic testing for TTP. The viral infection tests, including Human Immunodeficiency Virus (HIV) antibody, Hepatitis B Surface (HBS) antigen, anti-HCV (Hepatitis C Virus) anti body were negative. The lupus blood test showed that anti double strand DNA, anti-coagulant, and anti-cardiolipin anti body were negative. The complement of C3 and C4 were in the normal range (C3 was equal to 101 mg/dl, and C4 was equal to 19 mg/dl).
Table 1 provides the results of laboratory tests for 5 days. As it shows for the second day, she had leukocytosis (Leukocyte was equal to 21,600 count/mm3), low hemoglobin level (4.9 g/dl), low platelets level (25,000/mm3), high serum creatinine level (4.7 mg/dl), and high lactate dehydrogenase level (1050 U/l).Table 1 Laboratory results of the patient
Hospitalization day Day 1 Day 2 Day 3 Day 4 Day5
Hemoglobin g/dl 5.0 4.9 6.1 7.9 8.1
Leukocyte count/mm3 11,000 21,600 29,000 28,800 18,600
Platelets /mm3 21,000 25,000 20,000 42,000 99,000
Fasting blood sugar mg/dl 98 87 85 87 100
Urea mg/dl 271 140 109 92 64
Creatinine mg/dl 5.6 4.7 2.3 1.3 1
Sodium mEq/l 134 143 137 142 138
Potassium mEq/l 5.7 4.7 3.6 3.4 4.2
AST u/l 24 30 33 31 36
ALT u/l 10 30 22 20 23
Bilirubin mg/dl 1.8 1.6 1.5 1.3 1.1
Albumin g/dl 2.3 3.2 3 3.5 3.7
Lactate dehydrogenase u/l 1,910 1,050 889 745 669
D-Dimer Negative N/A N/A N/A N/A
Serum bicarbonate mmol/l 15.1 19.3 18.8 17.3 22.0
Urine analysis (protein) Negative N/A N/A 1+ N/A
Urine analysis (blood) 2+ N/A N/A 3+ N/A
Fibrinogen mg/dl 403 N/A N/A N/A N/A
PT (seconds) 13.5 13 12.5 13.5 13
PTT (seconds) 24 33 25 30 28
INR 1 1.5 1.1 1.2 1.1
CRP (mg/ dl) 24 N/A N/A N/A 4
AST Aspartate Aminotransferase; ALT Alanine Transaminase; PT Prothrombin Time; PTT Partial Thromboplastin Time; INR International Normalized Ratio; CPR Cardiopulmonary Resuscitation; N/A No information was collected
Her hemoglobin level dropped to 5.0 g/dl and we transfused the packed red blood cells. Hematologists suggested taking Dexamethasone at the rate of 8 mg/day. She had premature membrane rupture along with malodor vaginal discharge and endometritis, so she took antibiotics, including Clindamycin in the rate of 600 mg/IV/(every 8 hours), Meropenem at the rate of 500 mg/(every 12 hours). It should be mentioned that the doses were adjusted to creatinine clearance. She also got dialysis treatment for 2 successive days as the serum creatinine level was raised.
Infectious disease specialists started to treat the patient with Kaletra (in one combined dosage of Lopinavir in the rate of 100 mg and Ritonavir in the rate of 400 mg) and Hydroxychloroquine 400 mg/stat followed by a continuous dose of it at the rate of 200 mg/ (every 12 hours) for14 days.
Due to the presence of thrombocytopenia and an increase in LDH level to 1910 U/l, the hematologist treated her with plasmapheresis. The hematologist suggested exchanging 2.5 l of plasma with 2 l of fresh frozen plasma for 5 consecutive days, which resulted in achieving platelet to 155,000 per cubic millimeter and lowering LDH level to 450 U/l.
Our multi-disciplinary health team strived to save the patient, and finally the patient started to feel better as the body temperature returned to normal (i.e., break the fever). The patient did not have any signs of dyspnea on the 20th day of ICU hospitalization. Additionally, the leukocyte level returned to normal, and the kidney started to function healthily. She was in ICU for 24 days until March 27, 2020, and then she was transferred to the Gynecological ward. This patient was finally discharged after 8 days. The patient is cured at the moment and does not show any TTP symptoms afterwards. Her hemoglobin is 11 g/dl, platelet is 220,000/mm3, LDH is 200 U/l, and creatinine is 0.9 mg/dl.
Discussion
World Health Organization declared COVID 19 a global pandemic on March 11, 2020 [13]. COVID 19 can cause complicated situations for patients who have underlying medical conditions. A 21 years old drug-addicted woman was admitted to a hospital. She was tested positive for COVID 19 at the time of admission and delivered a stillbirth fetus. Then, she showed the early symptoms of TTP, including haemoglobin level of 5 g/dl, platelet of 23,000/mm3, and creatinine level of 5.6 mg/dl, and schistocytes in the peripheral blood smear. She did not have any symptoms of TTP before hospitalization. And she showed the symptoms for the first time during her pregnancy. Also, this patient had normal liver enzymes, and she did not have any severe preeclampsia symptoms. She responded to plasmapheresis and was cured. Moreover, at the moment, which is 6 months after her delivery, she does not have any TTP symptoms. By taking all these factors into account, we believe that her TTP was acquired.
Literature found that pregnant women are going through some physiological changes that affect their immune systems. This affection may predispose such people to viral respiratory infections such as COVID-19, a cause of TTP [14–16]. This study summarizes the challenges that the medical team faced during this process in order to find how COVID-19 affects the pregnancy outcome in a rare condition. As we are learning how COVID-19 interferes with organs’ functions, we share the diagnosis and treatment steps for curing a TTP pregnant woman as of the first study of its kind.
Karami et al., in March 2020, reported a 27 years pregnant woman with COVID-19 symptoms such as fever, myalgia, and cough, which are similar to our case. [17] Our case has leukocytosis, which could be a positive sign for her survival; however, the 27 years case suffered from leukopenia and lymphopenia. In both of the cases, Reverse Transcription Polymerase Chain Reaction confirmed the presence of COVID-19 infection. However, the results of the Chest CT scan at the time of hospitalization were different between these studies, as the CT of our patient was similar to the CT of COVID-19 patients. Both cases started treatment for COVID 19, and both cases had a stillbirth. Literature listed Intrauterine fetal death as an outcome of infection with a family cluster of coronaviruses such as MERS (Middle Eastern Respiratory Syndrome Coronavirus)-COV and SARS(Severe Acute Respiratory Syndrome)-COV [14–16, 18]. Since we admitted our patient to the ICU sooner, she survived, while the 27 years patient died due to the multi-organ failure.
Another study took nine pregnant women with gestational ages greater than or equal to 36 weeks with COVID-19 infection, each of them had only one symptom from the typical symptoms [12] (i.e., fever, cough, myalgia, and dyspnea). Our patient was in her 29th week and had all of the common symptoms, and she survived while the patient died in this study. Each of the cases had a stillbirth, which can be explained in the case of infection. In more severe cases with COVID-19 infection, the virus may cause pneumonia that reduces the lungs’ capacity. This reduction in the capacity develops hypoxia in a pregnant patient that stops oxygen delivery to the fetus [15]. This causes Intrauterine Fetal Death (IUFD), which was happened in our case. We have a rich literature discuss the effect of influenza and other known respiratory infections in pregnancy [14], which happened to be similar in our patient who had COVID-19.
Another study considered 13 pregnant women with COVID-19; 10 cases undergone cesarean section due to the complicated conditions, such as fetal distress and premature rupture of the membrane (PROM) [15, 19]. Our case vaginally delivered a stillbirth, and the mother survived, while this study reports the death of one of the patients who had a stillbirth. This patient experienced multiple organ damages, including acute kidney injury, acute hepatic failure, and septic shock. Additionally, she went to ICU, and she was intubated due to the occurrence of acute respiratory distress syndrome [19].
Other studies treated a pregnant TTP patient effectively with plasmapheresis and glucocorticoid [20]. The major difference between this study and ours is that this study knew that the patient had TTP who finally suffered a relapse, while our patient was not previously treated for TTP. In our case, we believe that COVID-19, as a viral infection, stimulated anti-ADAMTS13 autoantibodies.
Another study treated a pregnant TTP patient who only had HELLP syndrome without COVID-19 infection [21]. The blood pressure of our case was normal, which ruled out the presence of HELLP syndrome. In both cases, high LDH, anemia, and thrombocytopenia confirm that the patients had MAHA, which is one of the hallmarks of TTP. In our case, Fig. 2 confirms this information as it visualizes fragmented erythrocytes in the shape of teardrops. To treat the TTP, our patient took Hydrocortisone 100 mg/IV/stat and then Dexamethasone 4 mg/IV/(every 8 hours) as well as having plasmapheresis daily for 5 days. It should be noted that we applied this treatment due to the severe condition of our patient, as even measuring the ADAMTS13 activities could not be suggested as a reliable diagnostic test at the acute phase [21].
Conclusion
To summarize our case, pregnancy and the presence of the viral infection could be the triggers of TTP [6, 22, 23], which causes a critical risk for both mother and the child [24]. Literature shows that infections such as influenza, SARS-COV, and MERS-COV could increase the risk of maternal mortality, spontaneous miscarriage, preterm labor, and intrauterine growth restriction during pregnancy [15, 25]. In our case, we believe that the COVID-19 behaves similarly to other viral infections. Thus, we can consider TTP or COVID-19 as different etiologies engender the IUFD. It should be mentioned that COVID-19 does not have a proven treatment. Frontline workers are treating patients with potential therapy, such as antiviral drugs and immunotherapies. We believe that if our patient was hospitalized sooner, she could have saved the baby, as the medical procedure we followed to save this TTP patient could benefit the baby as well. We recommend to other colleagues to consider this approach while they admit a pregnant patient.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
We appreciate the assistance from Ahmadreza Mahmoudzadeh at Texas A&M University, who helped us in drafting and revising the manuscript.
Authors' contributions
SA was responsible for writing the first draft and review, supervising the project, and analyzing the data. NA and SN were involved in writing the initial draft. OMN was responsible for data collection and FM was responsible for writing the initial draft. All authors read and approved the final manuscript.
Funding
The authors did not receive any funding for this study.
Availability of data and materials
Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.
Ethics approval and consent to participate
This study was conducted in accordance with the fundamental principles of the Declaration of Helsinki.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Competing interests
The authors declare that they have no competing interests. | HYDROXYCHLOROQUINE | DrugsGivenReaction | CC BY | 33648584 | 19,174,507 | 2021-03-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Epstein-Barr virus associated lymphoproliferative disorder'. | Post-transplant lymphoproliferative disorder as a cause of oesophageal ulceration and stricture: case report and literature review.
Post-transplant lymphoproliferative disorder (PTLD) of the oesophagus is a rare complication of solid organ transplant that requires a high index of suspicion to diagnose. A literature review conducted on Ovid Medline database retrieved 24 articles, among which five previous cases of oesophageal PTLD were identified. Development of oesophageal strictures related to PTLD has not been reported in the literature. We report a case of oesophageal PTLD following lung transplant, presenting with extensive, circumferential ulceration in the oesophagus. PTLD was successfully treated with chemotherapy but subsequently, this patient developed a severe oesophageal stricture at the site of her PTLD. She presented with an episode of food bolus impaction requiring endoscopic retrieval. In the following years, our patient required multiple endoscopic dilatations of this PTLD-related oesophageal stricture.
Introduction
Post-transplant lymphoproliferative disorder (PTLD) is one of many serious complications that follow transplantation of solid organs or haematologic stem cells. Development of PTLD is commonly a result of uncontrolled B cell proliferation in the context of Epstein-Barr virus (EBV) infection.1
The clinical presentation of PTLD is variable, with some patients being completely asymptomatic and others presenting in critical condition with multiorgan involvement. Common organ involvement in PTLD includes lymph nodes, the central nervous system and gastrointestinal system.2
Although gastric, colonic and small bowel involvement with PTLD have been reported in the literature with an estimated prevalence of 25% of all PTLD in paediatric patients,2 isolated oesophageal PTLD is exceedingly rare.
A literature review has discovered five reported cases1–5 of isolated oesophageal PTLD. We present a case of oesophageal PTLD that was complicated by stricture formation which required multiple endoscopic dilations over the follow-up period.
Case
A 35-year-old woman with a history of mixed connective tissue disease, Raynaud’s phenomenon, arthritis, progressive interstitial lung disease resulted in respiratory compromise that required a double lung transplant. One year following her transplant, she was referred to the gastroenterology service with a 2-week history of worsening odynophagia and dysphagia.
Her symptoms were predominantly caused by solids with the need to over-chew or to drink large quantities of liquids to push food down the oesophagus. She lost 4 kg. She reported occasional nausea and regurgitation of food and pills, but no vomiting. There were no other gastrointestinal symptoms. She reported no fever or night sweats.
Her immunosuppressive medications included prednisone, tacrolimus and mycophenolate.
She had no allergies. There was no history of smoking, excessive alcohol consumption or recreational drug use.
There was no family history of malignancies.
Physical examination did not reveal any skin rashes or lymphadenopathy. Abdominal examination was normal.
Investigation
A complete blood count revealed haemoglobin of 87 g/L (normal range: 120–160), low lymphocytes of 1.01×109/L (normal range: 1.50–4.00), high monocytes at 1.15×109/L (normal range: 0.20–0.80) and elevated platelet at 560×109/L (normal range: 150–400). Lactate dehydrogenase was elevated at 368 U/L (normal range: 120–220).
An upper endoscopy demonstrated extensive, ulcerations involving most of the oesophagus except the distal 3–4 cm, occupying at least 70% of the circumference, with minimal normal intervening mucosa. Oesophageal ulcers were wide and deep with rolled edges and a whitish base (figure 1). The distal 3–4 cm of the oesophagus was spared and showed no oesophagitis or Barret’s oesophagus. Endoscopic examination of the stomach and the duodenum was unremarkable.
Figure 1 Endoscopic image showing deep, extensive ulceration in the oesophagus.
Biopsies from the edges of the ulcers showed granulation tissue and inflammatory exudate with no evidence of viral cytopathic effects. Brushing was positive for Candida albicans.
Work-up for the differential diagnosis included Cytomegalo virus blood PCR which was negative. Blood PCR for EBV was detected at 7.88E+03 copies of DNA/mL (negative if less than 600 copies of DNA/mL).
A course of antifungal therapy for oesophageal candidiasis was completed but symptoms persisted. A repeat endoscopy revealed that the oesophagus was unchanged. Biopsies were obtained from the bases of ulcers and revealed EBV-positive large B cell lymphoproliferative disorder consistent with monomorphic PTLD. There was multifocal necrosis and high apoptotic rate. Duodenal and stomach biopsies were normal.
CT of the thorax showed circumferential, irregular thickening of a long segment of the oesophagus associated with some mildly enlarged lymph nodes in the mediastinum. The remainder of the staging work-up including a bone marrow biopsy and CT scans of the head, neck, abdomen and pelvis showed no evidence of PTLD elsewhere. Colonoscopy was not indicated given lack of clinical symptoms of colonic PTLD and negative imaging.
Rituximab single agent treatment was started initially, but did not result in complete remission of PTLD. Therefore, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine/(oncovin) and prednisone) chemotherapy was initiated. Subsequent to that, the patient had resolution of dysphagia and odynophagia, negative blood EBV PCR, decreased oesophageal thickening on CT and confirmed healing oesophageal ulcers on endoscopy.
However, a few weeks after completion of chemotherapy, she developed sudden-onset dysphagia with sensation of food impaction in her oesophagus and presented to the hospital. A barium swallow showed a severe stricture in the mid-oesophagus for about 3.5 cm, with the narrowest part of the lumen measuring 4 mm (figure 2). Endoscopy revealed significant dilatation in the upper oesophagus with a food bolus noted. This bolus required endoscopic retrieval using a Roth net. Distal to this, there was a stenotic area which was non-traversable by the gastroscope and measured about 4.5 mm in diameter. CRE balloon dilation was performed (from 8 mm to 10 mm). Biopsies from the stenotic segment and from the dilated upper oesophagus were obtained and were negative for PTLD.
Figure 2 Barium study demonstrating severe stricture in the mid-thoracic oesophagus for about 3.5 cm, with the narrowest part of the lumen measuring 4 mm.
A 24-hour pH monitoring showed no episodes of acid reflux and no symptoms were recorded during the study.
Follow-up
Over the span of the following years, this patient required multiple endoscopic dilatations to allow for relief of dysphagia. Repeated oesophageal biopsies were negative for recurrent lymphoma. CT scans remained stable with no evidence of PTLD.
Learning points
Presence of oesophageal Candida and/or viral (Cytomegalo virus) infections have been co-incidentally reported in patients with oesophageal PTLD.
Maintain a high index of suspicion for PTLD in immunosuppressed patients with clinical symptoms refractory to treatment with antimicrobials.
Repeat endoscopy with deep biopsies from ulcer base may increase the yield for PTLD detection.
Discussion
The association between EBV infection, the cumulative burden of immunosuppressive treatment (specifically T cell depleting strategies) and the higher risk of PTLD is well established.1
A literature review conducted on Ovid Medline database retrieved 24 articles, among which five previous cases of oesophageal PTLD were identified (online supplemental material).1–5 There were four adult cases1 3–5 and one paediatric case.2 During the pre-transplant work-up, all of the adult recipients were EBV positive. Interestingly; however, the 8-year-old transplant recipient was EBV negative but developed acute tonsillitis 4 months after his transplant from an EBV-positive donor.2
10.1136/bmjgast-2021-000602.supp1 Supplementary data
All of these oesophageal PTLD cases followed solid organ transplantation and were EBV-driven as confirmed by pathology and/or serology. The interval for PTLD development ranged from 6 months2 to 31 years5 following transplant.
In conclusion, we describe a case of PTLD primarily involving the oesophagus. After PTLD was treated, an oesophageal stricture occurred at the site of previous PTLD involvement, likely as a result of scar tissue formation after healing of circumferential ulcers. To the best of our knowledge, this is the first case in the literature with PTLD leading to an oesophageal stricture.
In our case, the initial endoscopic biopsies were non-specific and brushings were positive for oesophageal candidiasis; however, the endoscopic appearance was atypical for Candida infection and patient’s symptoms did not respond to antifungal therapy. Therefore, we elected to repeat endoscopy and obtain more biopsies from the ulcer base, and this eventually confirmed PTLD. This underlines the importance of maintaining a high index of suspicion and the value of repeat endoscopy and biopsies in cases where endoscopic findings are atypical and whenever there is no resolution of symptoms despite treatment.
Contributors: MSM and SLW contributed to the planning of this case report, equally. MSM conducted the literature review and wrote the case report. SLW reviewed/edited the manuscript, and provided supervision. SLW arranged clinical follow-up with the patient and obtained consent. MSM submitted the report and edited the submission according to the review comments.
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: Not required.
Provenance and peer review: Not commissioned; externally peer reviewed.
Data availability statement: Data sharing not applicable as no datasets generated and/or analysed for this study.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | MYCOPHENOLIC ACID, PREDNISONE, TACROLIMUS | DrugsGivenReaction | CC BY-NC | 33648984 | 19,513,483 | 2021-02 |
What was the administration route of drug 'MYCOPHENOLATE SODIUM'? | Post-transplant lymphoproliferative disorder as a cause of oesophageal ulceration and stricture: case report and literature review.
Post-transplant lymphoproliferative disorder (PTLD) of the oesophagus is a rare complication of solid organ transplant that requires a high index of suspicion to diagnose. A literature review conducted on Ovid Medline database retrieved 24 articles, among which five previous cases of oesophageal PTLD were identified. Development of oesophageal strictures related to PTLD has not been reported in the literature. We report a case of oesophageal PTLD following lung transplant, presenting with extensive, circumferential ulceration in the oesophagus. PTLD was successfully treated with chemotherapy but subsequently, this patient developed a severe oesophageal stricture at the site of her PTLD. She presented with an episode of food bolus impaction requiring endoscopic retrieval. In the following years, our patient required multiple endoscopic dilatations of this PTLD-related oesophageal stricture.
Introduction
Post-transplant lymphoproliferative disorder (PTLD) is one of many serious complications that follow transplantation of solid organs or haematologic stem cells. Development of PTLD is commonly a result of uncontrolled B cell proliferation in the context of Epstein-Barr virus (EBV) infection.1
The clinical presentation of PTLD is variable, with some patients being completely asymptomatic and others presenting in critical condition with multiorgan involvement. Common organ involvement in PTLD includes lymph nodes, the central nervous system and gastrointestinal system.2
Although gastric, colonic and small bowel involvement with PTLD have been reported in the literature with an estimated prevalence of 25% of all PTLD in paediatric patients,2 isolated oesophageal PTLD is exceedingly rare.
A literature review has discovered five reported cases1–5 of isolated oesophageal PTLD. We present a case of oesophageal PTLD that was complicated by stricture formation which required multiple endoscopic dilations over the follow-up period.
Case
A 35-year-old woman with a history of mixed connective tissue disease, Raynaud’s phenomenon, arthritis, progressive interstitial lung disease resulted in respiratory compromise that required a double lung transplant. One year following her transplant, she was referred to the gastroenterology service with a 2-week history of worsening odynophagia and dysphagia.
Her symptoms were predominantly caused by solids with the need to over-chew or to drink large quantities of liquids to push food down the oesophagus. She lost 4 kg. She reported occasional nausea and regurgitation of food and pills, but no vomiting. There were no other gastrointestinal symptoms. She reported no fever or night sweats.
Her immunosuppressive medications included prednisone, tacrolimus and mycophenolate.
She had no allergies. There was no history of smoking, excessive alcohol consumption or recreational drug use.
There was no family history of malignancies.
Physical examination did not reveal any skin rashes or lymphadenopathy. Abdominal examination was normal.
Investigation
A complete blood count revealed haemoglobin of 87 g/L (normal range: 120–160), low lymphocytes of 1.01×109/L (normal range: 1.50–4.00), high monocytes at 1.15×109/L (normal range: 0.20–0.80) and elevated platelet at 560×109/L (normal range: 150–400). Lactate dehydrogenase was elevated at 368 U/L (normal range: 120–220).
An upper endoscopy demonstrated extensive, ulcerations involving most of the oesophagus except the distal 3–4 cm, occupying at least 70% of the circumference, with minimal normal intervening mucosa. Oesophageal ulcers were wide and deep with rolled edges and a whitish base (figure 1). The distal 3–4 cm of the oesophagus was spared and showed no oesophagitis or Barret’s oesophagus. Endoscopic examination of the stomach and the duodenum was unremarkable.
Figure 1 Endoscopic image showing deep, extensive ulceration in the oesophagus.
Biopsies from the edges of the ulcers showed granulation tissue and inflammatory exudate with no evidence of viral cytopathic effects. Brushing was positive for Candida albicans.
Work-up for the differential diagnosis included Cytomegalo virus blood PCR which was negative. Blood PCR for EBV was detected at 7.88E+03 copies of DNA/mL (negative if less than 600 copies of DNA/mL).
A course of antifungal therapy for oesophageal candidiasis was completed but symptoms persisted. A repeat endoscopy revealed that the oesophagus was unchanged. Biopsies were obtained from the bases of ulcers and revealed EBV-positive large B cell lymphoproliferative disorder consistent with monomorphic PTLD. There was multifocal necrosis and high apoptotic rate. Duodenal and stomach biopsies were normal.
CT of the thorax showed circumferential, irregular thickening of a long segment of the oesophagus associated with some mildly enlarged lymph nodes in the mediastinum. The remainder of the staging work-up including a bone marrow biopsy and CT scans of the head, neck, abdomen and pelvis showed no evidence of PTLD elsewhere. Colonoscopy was not indicated given lack of clinical symptoms of colonic PTLD and negative imaging.
Rituximab single agent treatment was started initially, but did not result in complete remission of PTLD. Therefore, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine/(oncovin) and prednisone) chemotherapy was initiated. Subsequent to that, the patient had resolution of dysphagia and odynophagia, negative blood EBV PCR, decreased oesophageal thickening on CT and confirmed healing oesophageal ulcers on endoscopy.
However, a few weeks after completion of chemotherapy, she developed sudden-onset dysphagia with sensation of food impaction in her oesophagus and presented to the hospital. A barium swallow showed a severe stricture in the mid-oesophagus for about 3.5 cm, with the narrowest part of the lumen measuring 4 mm (figure 2). Endoscopy revealed significant dilatation in the upper oesophagus with a food bolus noted. This bolus required endoscopic retrieval using a Roth net. Distal to this, there was a stenotic area which was non-traversable by the gastroscope and measured about 4.5 mm in diameter. CRE balloon dilation was performed (from 8 mm to 10 mm). Biopsies from the stenotic segment and from the dilated upper oesophagus were obtained and were negative for PTLD.
Figure 2 Barium study demonstrating severe stricture in the mid-thoracic oesophagus for about 3.5 cm, with the narrowest part of the lumen measuring 4 mm.
A 24-hour pH monitoring showed no episodes of acid reflux and no symptoms were recorded during the study.
Follow-up
Over the span of the following years, this patient required multiple endoscopic dilatations to allow for relief of dysphagia. Repeated oesophageal biopsies were negative for recurrent lymphoma. CT scans remained stable with no evidence of PTLD.
Learning points
Presence of oesophageal Candida and/or viral (Cytomegalo virus) infections have been co-incidentally reported in patients with oesophageal PTLD.
Maintain a high index of suspicion for PTLD in immunosuppressed patients with clinical symptoms refractory to treatment with antimicrobials.
Repeat endoscopy with deep biopsies from ulcer base may increase the yield for PTLD detection.
Discussion
The association between EBV infection, the cumulative burden of immunosuppressive treatment (specifically T cell depleting strategies) and the higher risk of PTLD is well established.1
A literature review conducted on Ovid Medline database retrieved 24 articles, among which five previous cases of oesophageal PTLD were identified (online supplemental material).1–5 There were four adult cases1 3–5 and one paediatric case.2 During the pre-transplant work-up, all of the adult recipients were EBV positive. Interestingly; however, the 8-year-old transplant recipient was EBV negative but developed acute tonsillitis 4 months after his transplant from an EBV-positive donor.2
10.1136/bmjgast-2021-000602.supp1 Supplementary data
All of these oesophageal PTLD cases followed solid organ transplantation and were EBV-driven as confirmed by pathology and/or serology. The interval for PTLD development ranged from 6 months2 to 31 years5 following transplant.
In conclusion, we describe a case of PTLD primarily involving the oesophagus. After PTLD was treated, an oesophageal stricture occurred at the site of previous PTLD involvement, likely as a result of scar tissue formation after healing of circumferential ulcers. To the best of our knowledge, this is the first case in the literature with PTLD leading to an oesophageal stricture.
In our case, the initial endoscopic biopsies were non-specific and brushings were positive for oesophageal candidiasis; however, the endoscopic appearance was atypical for Candida infection and patient’s symptoms did not respond to antifungal therapy. Therefore, we elected to repeat endoscopy and obtain more biopsies from the ulcer base, and this eventually confirmed PTLD. This underlines the importance of maintaining a high index of suspicion and the value of repeat endoscopy and biopsies in cases where endoscopic findings are atypical and whenever there is no resolution of symptoms despite treatment.
Contributors: MSM and SLW contributed to the planning of this case report, equally. MSM conducted the literature review and wrote the case report. SLW reviewed/edited the manuscript, and provided supervision. SLW arranged clinical follow-up with the patient and obtained consent. MSM submitted the report and edited the submission according to the review comments.
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: Not required.
Provenance and peer review: Not commissioned; externally peer reviewed.
Data availability statement: Data sharing not applicable as no datasets generated and/or analysed for this study.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | Oral | DrugAdministrationRoute | CC BY-NC | 33648984 | 19,520,660 | 2021-02 |
What was the administration route of drug 'PREDNISONE'? | Post-transplant lymphoproliferative disorder as a cause of oesophageal ulceration and stricture: case report and literature review.
Post-transplant lymphoproliferative disorder (PTLD) of the oesophagus is a rare complication of solid organ transplant that requires a high index of suspicion to diagnose. A literature review conducted on Ovid Medline database retrieved 24 articles, among which five previous cases of oesophageal PTLD were identified. Development of oesophageal strictures related to PTLD has not been reported in the literature. We report a case of oesophageal PTLD following lung transplant, presenting with extensive, circumferential ulceration in the oesophagus. PTLD was successfully treated with chemotherapy but subsequently, this patient developed a severe oesophageal stricture at the site of her PTLD. She presented with an episode of food bolus impaction requiring endoscopic retrieval. In the following years, our patient required multiple endoscopic dilatations of this PTLD-related oesophageal stricture.
Introduction
Post-transplant lymphoproliferative disorder (PTLD) is one of many serious complications that follow transplantation of solid organs or haematologic stem cells. Development of PTLD is commonly a result of uncontrolled B cell proliferation in the context of Epstein-Barr virus (EBV) infection.1
The clinical presentation of PTLD is variable, with some patients being completely asymptomatic and others presenting in critical condition with multiorgan involvement. Common organ involvement in PTLD includes lymph nodes, the central nervous system and gastrointestinal system.2
Although gastric, colonic and small bowel involvement with PTLD have been reported in the literature with an estimated prevalence of 25% of all PTLD in paediatric patients,2 isolated oesophageal PTLD is exceedingly rare.
A literature review has discovered five reported cases1–5 of isolated oesophageal PTLD. We present a case of oesophageal PTLD that was complicated by stricture formation which required multiple endoscopic dilations over the follow-up period.
Case
A 35-year-old woman with a history of mixed connective tissue disease, Raynaud’s phenomenon, arthritis, progressive interstitial lung disease resulted in respiratory compromise that required a double lung transplant. One year following her transplant, she was referred to the gastroenterology service with a 2-week history of worsening odynophagia and dysphagia.
Her symptoms were predominantly caused by solids with the need to over-chew or to drink large quantities of liquids to push food down the oesophagus. She lost 4 kg. She reported occasional nausea and regurgitation of food and pills, but no vomiting. There were no other gastrointestinal symptoms. She reported no fever or night sweats.
Her immunosuppressive medications included prednisone, tacrolimus and mycophenolate.
She had no allergies. There was no history of smoking, excessive alcohol consumption or recreational drug use.
There was no family history of malignancies.
Physical examination did not reveal any skin rashes or lymphadenopathy. Abdominal examination was normal.
Investigation
A complete blood count revealed haemoglobin of 87 g/L (normal range: 120–160), low lymphocytes of 1.01×109/L (normal range: 1.50–4.00), high monocytes at 1.15×109/L (normal range: 0.20–0.80) and elevated platelet at 560×109/L (normal range: 150–400). Lactate dehydrogenase was elevated at 368 U/L (normal range: 120–220).
An upper endoscopy demonstrated extensive, ulcerations involving most of the oesophagus except the distal 3–4 cm, occupying at least 70% of the circumference, with minimal normal intervening mucosa. Oesophageal ulcers were wide and deep with rolled edges and a whitish base (figure 1). The distal 3–4 cm of the oesophagus was spared and showed no oesophagitis or Barret’s oesophagus. Endoscopic examination of the stomach and the duodenum was unremarkable.
Figure 1 Endoscopic image showing deep, extensive ulceration in the oesophagus.
Biopsies from the edges of the ulcers showed granulation tissue and inflammatory exudate with no evidence of viral cytopathic effects. Brushing was positive for Candida albicans.
Work-up for the differential diagnosis included Cytomegalo virus blood PCR which was negative. Blood PCR for EBV was detected at 7.88E+03 copies of DNA/mL (negative if less than 600 copies of DNA/mL).
A course of antifungal therapy for oesophageal candidiasis was completed but symptoms persisted. A repeat endoscopy revealed that the oesophagus was unchanged. Biopsies were obtained from the bases of ulcers and revealed EBV-positive large B cell lymphoproliferative disorder consistent with monomorphic PTLD. There was multifocal necrosis and high apoptotic rate. Duodenal and stomach biopsies were normal.
CT of the thorax showed circumferential, irregular thickening of a long segment of the oesophagus associated with some mildly enlarged lymph nodes in the mediastinum. The remainder of the staging work-up including a bone marrow biopsy and CT scans of the head, neck, abdomen and pelvis showed no evidence of PTLD elsewhere. Colonoscopy was not indicated given lack of clinical symptoms of colonic PTLD and negative imaging.
Rituximab single agent treatment was started initially, but did not result in complete remission of PTLD. Therefore, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine/(oncovin) and prednisone) chemotherapy was initiated. Subsequent to that, the patient had resolution of dysphagia and odynophagia, negative blood EBV PCR, decreased oesophageal thickening on CT and confirmed healing oesophageal ulcers on endoscopy.
However, a few weeks after completion of chemotherapy, she developed sudden-onset dysphagia with sensation of food impaction in her oesophagus and presented to the hospital. A barium swallow showed a severe stricture in the mid-oesophagus for about 3.5 cm, with the narrowest part of the lumen measuring 4 mm (figure 2). Endoscopy revealed significant dilatation in the upper oesophagus with a food bolus noted. This bolus required endoscopic retrieval using a Roth net. Distal to this, there was a stenotic area which was non-traversable by the gastroscope and measured about 4.5 mm in diameter. CRE balloon dilation was performed (from 8 mm to 10 mm). Biopsies from the stenotic segment and from the dilated upper oesophagus were obtained and were negative for PTLD.
Figure 2 Barium study demonstrating severe stricture in the mid-thoracic oesophagus for about 3.5 cm, with the narrowest part of the lumen measuring 4 mm.
A 24-hour pH monitoring showed no episodes of acid reflux and no symptoms were recorded during the study.
Follow-up
Over the span of the following years, this patient required multiple endoscopic dilatations to allow for relief of dysphagia. Repeated oesophageal biopsies were negative for recurrent lymphoma. CT scans remained stable with no evidence of PTLD.
Learning points
Presence of oesophageal Candida and/or viral (Cytomegalo virus) infections have been co-incidentally reported in patients with oesophageal PTLD.
Maintain a high index of suspicion for PTLD in immunosuppressed patients with clinical symptoms refractory to treatment with antimicrobials.
Repeat endoscopy with deep biopsies from ulcer base may increase the yield for PTLD detection.
Discussion
The association between EBV infection, the cumulative burden of immunosuppressive treatment (specifically T cell depleting strategies) and the higher risk of PTLD is well established.1
A literature review conducted on Ovid Medline database retrieved 24 articles, among which five previous cases of oesophageal PTLD were identified (online supplemental material).1–5 There were four adult cases1 3–5 and one paediatric case.2 During the pre-transplant work-up, all of the adult recipients were EBV positive. Interestingly; however, the 8-year-old transplant recipient was EBV negative but developed acute tonsillitis 4 months after his transplant from an EBV-positive donor.2
10.1136/bmjgast-2021-000602.supp1 Supplementary data
All of these oesophageal PTLD cases followed solid organ transplantation and were EBV-driven as confirmed by pathology and/or serology. The interval for PTLD development ranged from 6 months2 to 31 years5 following transplant.
In conclusion, we describe a case of PTLD primarily involving the oesophagus. After PTLD was treated, an oesophageal stricture occurred at the site of previous PTLD involvement, likely as a result of scar tissue formation after healing of circumferential ulcers. To the best of our knowledge, this is the first case in the literature with PTLD leading to an oesophageal stricture.
In our case, the initial endoscopic biopsies were non-specific and brushings were positive for oesophageal candidiasis; however, the endoscopic appearance was atypical for Candida infection and patient’s symptoms did not respond to antifungal therapy. Therefore, we elected to repeat endoscopy and obtain more biopsies from the ulcer base, and this eventually confirmed PTLD. This underlines the importance of maintaining a high index of suspicion and the value of repeat endoscopy and biopsies in cases where endoscopic findings are atypical and whenever there is no resolution of symptoms despite treatment.
Contributors: MSM and SLW contributed to the planning of this case report, equally. MSM conducted the literature review and wrote the case report. SLW reviewed/edited the manuscript, and provided supervision. SLW arranged clinical follow-up with the patient and obtained consent. MSM submitted the report and edited the submission according to the review comments.
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: Not required.
Provenance and peer review: Not commissioned; externally peer reviewed.
Data availability statement: Data sharing not applicable as no datasets generated and/or analysed for this study.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | Oral | DrugAdministrationRoute | CC BY-NC | 33648984 | 19,520,660 | 2021-02 |
What was the administration route of drug 'TACROLIMUS'? | Post-transplant lymphoproliferative disorder as a cause of oesophageal ulceration and stricture: case report and literature review.
Post-transplant lymphoproliferative disorder (PTLD) of the oesophagus is a rare complication of solid organ transplant that requires a high index of suspicion to diagnose. A literature review conducted on Ovid Medline database retrieved 24 articles, among which five previous cases of oesophageal PTLD were identified. Development of oesophageal strictures related to PTLD has not been reported in the literature. We report a case of oesophageal PTLD following lung transplant, presenting with extensive, circumferential ulceration in the oesophagus. PTLD was successfully treated with chemotherapy but subsequently, this patient developed a severe oesophageal stricture at the site of her PTLD. She presented with an episode of food bolus impaction requiring endoscopic retrieval. In the following years, our patient required multiple endoscopic dilatations of this PTLD-related oesophageal stricture.
Introduction
Post-transplant lymphoproliferative disorder (PTLD) is one of many serious complications that follow transplantation of solid organs or haematologic stem cells. Development of PTLD is commonly a result of uncontrolled B cell proliferation in the context of Epstein-Barr virus (EBV) infection.1
The clinical presentation of PTLD is variable, with some patients being completely asymptomatic and others presenting in critical condition with multiorgan involvement. Common organ involvement in PTLD includes lymph nodes, the central nervous system and gastrointestinal system.2
Although gastric, colonic and small bowel involvement with PTLD have been reported in the literature with an estimated prevalence of 25% of all PTLD in paediatric patients,2 isolated oesophageal PTLD is exceedingly rare.
A literature review has discovered five reported cases1–5 of isolated oesophageal PTLD. We present a case of oesophageal PTLD that was complicated by stricture formation which required multiple endoscopic dilations over the follow-up period.
Case
A 35-year-old woman with a history of mixed connective tissue disease, Raynaud’s phenomenon, arthritis, progressive interstitial lung disease resulted in respiratory compromise that required a double lung transplant. One year following her transplant, she was referred to the gastroenterology service with a 2-week history of worsening odynophagia and dysphagia.
Her symptoms were predominantly caused by solids with the need to over-chew or to drink large quantities of liquids to push food down the oesophagus. She lost 4 kg. She reported occasional nausea and regurgitation of food and pills, but no vomiting. There were no other gastrointestinal symptoms. She reported no fever or night sweats.
Her immunosuppressive medications included prednisone, tacrolimus and mycophenolate.
She had no allergies. There was no history of smoking, excessive alcohol consumption or recreational drug use.
There was no family history of malignancies.
Physical examination did not reveal any skin rashes or lymphadenopathy. Abdominal examination was normal.
Investigation
A complete blood count revealed haemoglobin of 87 g/L (normal range: 120–160), low lymphocytes of 1.01×109/L (normal range: 1.50–4.00), high monocytes at 1.15×109/L (normal range: 0.20–0.80) and elevated platelet at 560×109/L (normal range: 150–400). Lactate dehydrogenase was elevated at 368 U/L (normal range: 120–220).
An upper endoscopy demonstrated extensive, ulcerations involving most of the oesophagus except the distal 3–4 cm, occupying at least 70% of the circumference, with minimal normal intervening mucosa. Oesophageal ulcers were wide and deep with rolled edges and a whitish base (figure 1). The distal 3–4 cm of the oesophagus was spared and showed no oesophagitis or Barret’s oesophagus. Endoscopic examination of the stomach and the duodenum was unremarkable.
Figure 1 Endoscopic image showing deep, extensive ulceration in the oesophagus.
Biopsies from the edges of the ulcers showed granulation tissue and inflammatory exudate with no evidence of viral cytopathic effects. Brushing was positive for Candida albicans.
Work-up for the differential diagnosis included Cytomegalo virus blood PCR which was negative. Blood PCR for EBV was detected at 7.88E+03 copies of DNA/mL (negative if less than 600 copies of DNA/mL).
A course of antifungal therapy for oesophageal candidiasis was completed but symptoms persisted. A repeat endoscopy revealed that the oesophagus was unchanged. Biopsies were obtained from the bases of ulcers and revealed EBV-positive large B cell lymphoproliferative disorder consistent with monomorphic PTLD. There was multifocal necrosis and high apoptotic rate. Duodenal and stomach biopsies were normal.
CT of the thorax showed circumferential, irregular thickening of a long segment of the oesophagus associated with some mildly enlarged lymph nodes in the mediastinum. The remainder of the staging work-up including a bone marrow biopsy and CT scans of the head, neck, abdomen and pelvis showed no evidence of PTLD elsewhere. Colonoscopy was not indicated given lack of clinical symptoms of colonic PTLD and negative imaging.
Rituximab single agent treatment was started initially, but did not result in complete remission of PTLD. Therefore, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine/(oncovin) and prednisone) chemotherapy was initiated. Subsequent to that, the patient had resolution of dysphagia and odynophagia, negative blood EBV PCR, decreased oesophageal thickening on CT and confirmed healing oesophageal ulcers on endoscopy.
However, a few weeks after completion of chemotherapy, she developed sudden-onset dysphagia with sensation of food impaction in her oesophagus and presented to the hospital. A barium swallow showed a severe stricture in the mid-oesophagus for about 3.5 cm, with the narrowest part of the lumen measuring 4 mm (figure 2). Endoscopy revealed significant dilatation in the upper oesophagus with a food bolus noted. This bolus required endoscopic retrieval using a Roth net. Distal to this, there was a stenotic area which was non-traversable by the gastroscope and measured about 4.5 mm in diameter. CRE balloon dilation was performed (from 8 mm to 10 mm). Biopsies from the stenotic segment and from the dilated upper oesophagus were obtained and were negative for PTLD.
Figure 2 Barium study demonstrating severe stricture in the mid-thoracic oesophagus for about 3.5 cm, with the narrowest part of the lumen measuring 4 mm.
A 24-hour pH monitoring showed no episodes of acid reflux and no symptoms were recorded during the study.
Follow-up
Over the span of the following years, this patient required multiple endoscopic dilatations to allow for relief of dysphagia. Repeated oesophageal biopsies were negative for recurrent lymphoma. CT scans remained stable with no evidence of PTLD.
Learning points
Presence of oesophageal Candida and/or viral (Cytomegalo virus) infections have been co-incidentally reported in patients with oesophageal PTLD.
Maintain a high index of suspicion for PTLD in immunosuppressed patients with clinical symptoms refractory to treatment with antimicrobials.
Repeat endoscopy with deep biopsies from ulcer base may increase the yield for PTLD detection.
Discussion
The association between EBV infection, the cumulative burden of immunosuppressive treatment (specifically T cell depleting strategies) and the higher risk of PTLD is well established.1
A literature review conducted on Ovid Medline database retrieved 24 articles, among which five previous cases of oesophageal PTLD were identified (online supplemental material).1–5 There were four adult cases1 3–5 and one paediatric case.2 During the pre-transplant work-up, all of the adult recipients were EBV positive. Interestingly; however, the 8-year-old transplant recipient was EBV negative but developed acute tonsillitis 4 months after his transplant from an EBV-positive donor.2
10.1136/bmjgast-2021-000602.supp1 Supplementary data
All of these oesophageal PTLD cases followed solid organ transplantation and were EBV-driven as confirmed by pathology and/or serology. The interval for PTLD development ranged from 6 months2 to 31 years5 following transplant.
In conclusion, we describe a case of PTLD primarily involving the oesophagus. After PTLD was treated, an oesophageal stricture occurred at the site of previous PTLD involvement, likely as a result of scar tissue formation after healing of circumferential ulcers. To the best of our knowledge, this is the first case in the literature with PTLD leading to an oesophageal stricture.
In our case, the initial endoscopic biopsies were non-specific and brushings were positive for oesophageal candidiasis; however, the endoscopic appearance was atypical for Candida infection and patient’s symptoms did not respond to antifungal therapy. Therefore, we elected to repeat endoscopy and obtain more biopsies from the ulcer base, and this eventually confirmed PTLD. This underlines the importance of maintaining a high index of suspicion and the value of repeat endoscopy and biopsies in cases where endoscopic findings are atypical and whenever there is no resolution of symptoms despite treatment.
Contributors: MSM and SLW contributed to the planning of this case report, equally. MSM conducted the literature review and wrote the case report. SLW reviewed/edited the manuscript, and provided supervision. SLW arranged clinical follow-up with the patient and obtained consent. MSM submitted the report and edited the submission according to the review comments.
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: Not required.
Provenance and peer review: Not commissioned; externally peer reviewed.
Data availability statement: Data sharing not applicable as no datasets generated and/or analysed for this study.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | Oral | DrugAdministrationRoute | CC BY-NC | 33648984 | 19,520,660 | 2021-02 |
What was the outcome of reaction 'Epstein-Barr virus associated lymphoproliferative disorder'? | Post-transplant lymphoproliferative disorder as a cause of oesophageal ulceration and stricture: case report and literature review.
Post-transplant lymphoproliferative disorder (PTLD) of the oesophagus is a rare complication of solid organ transplant that requires a high index of suspicion to diagnose. A literature review conducted on Ovid Medline database retrieved 24 articles, among which five previous cases of oesophageal PTLD were identified. Development of oesophageal strictures related to PTLD has not been reported in the literature. We report a case of oesophageal PTLD following lung transplant, presenting with extensive, circumferential ulceration in the oesophagus. PTLD was successfully treated with chemotherapy but subsequently, this patient developed a severe oesophageal stricture at the site of her PTLD. She presented with an episode of food bolus impaction requiring endoscopic retrieval. In the following years, our patient required multiple endoscopic dilatations of this PTLD-related oesophageal stricture.
Introduction
Post-transplant lymphoproliferative disorder (PTLD) is one of many serious complications that follow transplantation of solid organs or haematologic stem cells. Development of PTLD is commonly a result of uncontrolled B cell proliferation in the context of Epstein-Barr virus (EBV) infection.1
The clinical presentation of PTLD is variable, with some patients being completely asymptomatic and others presenting in critical condition with multiorgan involvement. Common organ involvement in PTLD includes lymph nodes, the central nervous system and gastrointestinal system.2
Although gastric, colonic and small bowel involvement with PTLD have been reported in the literature with an estimated prevalence of 25% of all PTLD in paediatric patients,2 isolated oesophageal PTLD is exceedingly rare.
A literature review has discovered five reported cases1–5 of isolated oesophageal PTLD. We present a case of oesophageal PTLD that was complicated by stricture formation which required multiple endoscopic dilations over the follow-up period.
Case
A 35-year-old woman with a history of mixed connective tissue disease, Raynaud’s phenomenon, arthritis, progressive interstitial lung disease resulted in respiratory compromise that required a double lung transplant. One year following her transplant, she was referred to the gastroenterology service with a 2-week history of worsening odynophagia and dysphagia.
Her symptoms were predominantly caused by solids with the need to over-chew or to drink large quantities of liquids to push food down the oesophagus. She lost 4 kg. She reported occasional nausea and regurgitation of food and pills, but no vomiting. There were no other gastrointestinal symptoms. She reported no fever or night sweats.
Her immunosuppressive medications included prednisone, tacrolimus and mycophenolate.
She had no allergies. There was no history of smoking, excessive alcohol consumption or recreational drug use.
There was no family history of malignancies.
Physical examination did not reveal any skin rashes or lymphadenopathy. Abdominal examination was normal.
Investigation
A complete blood count revealed haemoglobin of 87 g/L (normal range: 120–160), low lymphocytes of 1.01×109/L (normal range: 1.50–4.00), high monocytes at 1.15×109/L (normal range: 0.20–0.80) and elevated platelet at 560×109/L (normal range: 150–400). Lactate dehydrogenase was elevated at 368 U/L (normal range: 120–220).
An upper endoscopy demonstrated extensive, ulcerations involving most of the oesophagus except the distal 3–4 cm, occupying at least 70% of the circumference, with minimal normal intervening mucosa. Oesophageal ulcers were wide and deep with rolled edges and a whitish base (figure 1). The distal 3–4 cm of the oesophagus was spared and showed no oesophagitis or Barret’s oesophagus. Endoscopic examination of the stomach and the duodenum was unremarkable.
Figure 1 Endoscopic image showing deep, extensive ulceration in the oesophagus.
Biopsies from the edges of the ulcers showed granulation tissue and inflammatory exudate with no evidence of viral cytopathic effects. Brushing was positive for Candida albicans.
Work-up for the differential diagnosis included Cytomegalo virus blood PCR which was negative. Blood PCR for EBV was detected at 7.88E+03 copies of DNA/mL (negative if less than 600 copies of DNA/mL).
A course of antifungal therapy for oesophageal candidiasis was completed but symptoms persisted. A repeat endoscopy revealed that the oesophagus was unchanged. Biopsies were obtained from the bases of ulcers and revealed EBV-positive large B cell lymphoproliferative disorder consistent with monomorphic PTLD. There was multifocal necrosis and high apoptotic rate. Duodenal and stomach biopsies were normal.
CT of the thorax showed circumferential, irregular thickening of a long segment of the oesophagus associated with some mildly enlarged lymph nodes in the mediastinum. The remainder of the staging work-up including a bone marrow biopsy and CT scans of the head, neck, abdomen and pelvis showed no evidence of PTLD elsewhere. Colonoscopy was not indicated given lack of clinical symptoms of colonic PTLD and negative imaging.
Rituximab single agent treatment was started initially, but did not result in complete remission of PTLD. Therefore, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine/(oncovin) and prednisone) chemotherapy was initiated. Subsequent to that, the patient had resolution of dysphagia and odynophagia, negative blood EBV PCR, decreased oesophageal thickening on CT and confirmed healing oesophageal ulcers on endoscopy.
However, a few weeks after completion of chemotherapy, she developed sudden-onset dysphagia with sensation of food impaction in her oesophagus and presented to the hospital. A barium swallow showed a severe stricture in the mid-oesophagus for about 3.5 cm, with the narrowest part of the lumen measuring 4 mm (figure 2). Endoscopy revealed significant dilatation in the upper oesophagus with a food bolus noted. This bolus required endoscopic retrieval using a Roth net. Distal to this, there was a stenotic area which was non-traversable by the gastroscope and measured about 4.5 mm in diameter. CRE balloon dilation was performed (from 8 mm to 10 mm). Biopsies from the stenotic segment and from the dilated upper oesophagus were obtained and were negative for PTLD.
Figure 2 Barium study demonstrating severe stricture in the mid-thoracic oesophagus for about 3.5 cm, with the narrowest part of the lumen measuring 4 mm.
A 24-hour pH monitoring showed no episodes of acid reflux and no symptoms were recorded during the study.
Follow-up
Over the span of the following years, this patient required multiple endoscopic dilatations to allow for relief of dysphagia. Repeated oesophageal biopsies were negative for recurrent lymphoma. CT scans remained stable with no evidence of PTLD.
Learning points
Presence of oesophageal Candida and/or viral (Cytomegalo virus) infections have been co-incidentally reported in patients with oesophageal PTLD.
Maintain a high index of suspicion for PTLD in immunosuppressed patients with clinical symptoms refractory to treatment with antimicrobials.
Repeat endoscopy with deep biopsies from ulcer base may increase the yield for PTLD detection.
Discussion
The association between EBV infection, the cumulative burden of immunosuppressive treatment (specifically T cell depleting strategies) and the higher risk of PTLD is well established.1
A literature review conducted on Ovid Medline database retrieved 24 articles, among which five previous cases of oesophageal PTLD were identified (online supplemental material).1–5 There were four adult cases1 3–5 and one paediatric case.2 During the pre-transplant work-up, all of the adult recipients were EBV positive. Interestingly; however, the 8-year-old transplant recipient was EBV negative but developed acute tonsillitis 4 months after his transplant from an EBV-positive donor.2
10.1136/bmjgast-2021-000602.supp1 Supplementary data
All of these oesophageal PTLD cases followed solid organ transplantation and were EBV-driven as confirmed by pathology and/or serology. The interval for PTLD development ranged from 6 months2 to 31 years5 following transplant.
In conclusion, we describe a case of PTLD primarily involving the oesophagus. After PTLD was treated, an oesophageal stricture occurred at the site of previous PTLD involvement, likely as a result of scar tissue formation after healing of circumferential ulcers. To the best of our knowledge, this is the first case in the literature with PTLD leading to an oesophageal stricture.
In our case, the initial endoscopic biopsies were non-specific and brushings were positive for oesophageal candidiasis; however, the endoscopic appearance was atypical for Candida infection and patient’s symptoms did not respond to antifungal therapy. Therefore, we elected to repeat endoscopy and obtain more biopsies from the ulcer base, and this eventually confirmed PTLD. This underlines the importance of maintaining a high index of suspicion and the value of repeat endoscopy and biopsies in cases where endoscopic findings are atypical and whenever there is no resolution of symptoms despite treatment.
Contributors: MSM and SLW contributed to the planning of this case report, equally. MSM conducted the literature review and wrote the case report. SLW reviewed/edited the manuscript, and provided supervision. SLW arranged clinical follow-up with the patient and obtained consent. MSM submitted the report and edited the submission according to the review comments.
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: Not required.
Provenance and peer review: Not commissioned; externally peer reviewed.
Data availability statement: Data sharing not applicable as no datasets generated and/or analysed for this study.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | Recovered | ReactionOutcome | CC BY-NC | 33648984 | 19,513,483 | 2021-02 |
What was the outcome of reaction 'Oesophageal candidiasis'? | Post-transplant lymphoproliferative disorder as a cause of oesophageal ulceration and stricture: case report and literature review.
Post-transplant lymphoproliferative disorder (PTLD) of the oesophagus is a rare complication of solid organ transplant that requires a high index of suspicion to diagnose. A literature review conducted on Ovid Medline database retrieved 24 articles, among which five previous cases of oesophageal PTLD were identified. Development of oesophageal strictures related to PTLD has not been reported in the literature. We report a case of oesophageal PTLD following lung transplant, presenting with extensive, circumferential ulceration in the oesophagus. PTLD was successfully treated with chemotherapy but subsequently, this patient developed a severe oesophageal stricture at the site of her PTLD. She presented with an episode of food bolus impaction requiring endoscopic retrieval. In the following years, our patient required multiple endoscopic dilatations of this PTLD-related oesophageal stricture.
Introduction
Post-transplant lymphoproliferative disorder (PTLD) is one of many serious complications that follow transplantation of solid organs or haematologic stem cells. Development of PTLD is commonly a result of uncontrolled B cell proliferation in the context of Epstein-Barr virus (EBV) infection.1
The clinical presentation of PTLD is variable, with some patients being completely asymptomatic and others presenting in critical condition with multiorgan involvement. Common organ involvement in PTLD includes lymph nodes, the central nervous system and gastrointestinal system.2
Although gastric, colonic and small bowel involvement with PTLD have been reported in the literature with an estimated prevalence of 25% of all PTLD in paediatric patients,2 isolated oesophageal PTLD is exceedingly rare.
A literature review has discovered five reported cases1–5 of isolated oesophageal PTLD. We present a case of oesophageal PTLD that was complicated by stricture formation which required multiple endoscopic dilations over the follow-up period.
Case
A 35-year-old woman with a history of mixed connective tissue disease, Raynaud’s phenomenon, arthritis, progressive interstitial lung disease resulted in respiratory compromise that required a double lung transplant. One year following her transplant, she was referred to the gastroenterology service with a 2-week history of worsening odynophagia and dysphagia.
Her symptoms were predominantly caused by solids with the need to over-chew or to drink large quantities of liquids to push food down the oesophagus. She lost 4 kg. She reported occasional nausea and regurgitation of food and pills, but no vomiting. There were no other gastrointestinal symptoms. She reported no fever or night sweats.
Her immunosuppressive medications included prednisone, tacrolimus and mycophenolate.
She had no allergies. There was no history of smoking, excessive alcohol consumption or recreational drug use.
There was no family history of malignancies.
Physical examination did not reveal any skin rashes or lymphadenopathy. Abdominal examination was normal.
Investigation
A complete blood count revealed haemoglobin of 87 g/L (normal range: 120–160), low lymphocytes of 1.01×109/L (normal range: 1.50–4.00), high monocytes at 1.15×109/L (normal range: 0.20–0.80) and elevated platelet at 560×109/L (normal range: 150–400). Lactate dehydrogenase was elevated at 368 U/L (normal range: 120–220).
An upper endoscopy demonstrated extensive, ulcerations involving most of the oesophagus except the distal 3–4 cm, occupying at least 70% of the circumference, with minimal normal intervening mucosa. Oesophageal ulcers were wide and deep with rolled edges and a whitish base (figure 1). The distal 3–4 cm of the oesophagus was spared and showed no oesophagitis or Barret’s oesophagus. Endoscopic examination of the stomach and the duodenum was unremarkable.
Figure 1 Endoscopic image showing deep, extensive ulceration in the oesophagus.
Biopsies from the edges of the ulcers showed granulation tissue and inflammatory exudate with no evidence of viral cytopathic effects. Brushing was positive for Candida albicans.
Work-up for the differential diagnosis included Cytomegalo virus blood PCR which was negative. Blood PCR for EBV was detected at 7.88E+03 copies of DNA/mL (negative if less than 600 copies of DNA/mL).
A course of antifungal therapy for oesophageal candidiasis was completed but symptoms persisted. A repeat endoscopy revealed that the oesophagus was unchanged. Biopsies were obtained from the bases of ulcers and revealed EBV-positive large B cell lymphoproliferative disorder consistent with monomorphic PTLD. There was multifocal necrosis and high apoptotic rate. Duodenal and stomach biopsies were normal.
CT of the thorax showed circumferential, irregular thickening of a long segment of the oesophagus associated with some mildly enlarged lymph nodes in the mediastinum. The remainder of the staging work-up including a bone marrow biopsy and CT scans of the head, neck, abdomen and pelvis showed no evidence of PTLD elsewhere. Colonoscopy was not indicated given lack of clinical symptoms of colonic PTLD and negative imaging.
Rituximab single agent treatment was started initially, but did not result in complete remission of PTLD. Therefore, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine/(oncovin) and prednisone) chemotherapy was initiated. Subsequent to that, the patient had resolution of dysphagia and odynophagia, negative blood EBV PCR, decreased oesophageal thickening on CT and confirmed healing oesophageal ulcers on endoscopy.
However, a few weeks after completion of chemotherapy, she developed sudden-onset dysphagia with sensation of food impaction in her oesophagus and presented to the hospital. A barium swallow showed a severe stricture in the mid-oesophagus for about 3.5 cm, with the narrowest part of the lumen measuring 4 mm (figure 2). Endoscopy revealed significant dilatation in the upper oesophagus with a food bolus noted. This bolus required endoscopic retrieval using a Roth net. Distal to this, there was a stenotic area which was non-traversable by the gastroscope and measured about 4.5 mm in diameter. CRE balloon dilation was performed (from 8 mm to 10 mm). Biopsies from the stenotic segment and from the dilated upper oesophagus were obtained and were negative for PTLD.
Figure 2 Barium study demonstrating severe stricture in the mid-thoracic oesophagus for about 3.5 cm, with the narrowest part of the lumen measuring 4 mm.
A 24-hour pH monitoring showed no episodes of acid reflux and no symptoms were recorded during the study.
Follow-up
Over the span of the following years, this patient required multiple endoscopic dilatations to allow for relief of dysphagia. Repeated oesophageal biopsies were negative for recurrent lymphoma. CT scans remained stable with no evidence of PTLD.
Learning points
Presence of oesophageal Candida and/or viral (Cytomegalo virus) infections have been co-incidentally reported in patients with oesophageal PTLD.
Maintain a high index of suspicion for PTLD in immunosuppressed patients with clinical symptoms refractory to treatment with antimicrobials.
Repeat endoscopy with deep biopsies from ulcer base may increase the yield for PTLD detection.
Discussion
The association between EBV infection, the cumulative burden of immunosuppressive treatment (specifically T cell depleting strategies) and the higher risk of PTLD is well established.1
A literature review conducted on Ovid Medline database retrieved 24 articles, among which five previous cases of oesophageal PTLD were identified (online supplemental material).1–5 There were four adult cases1 3–5 and one paediatric case.2 During the pre-transplant work-up, all of the adult recipients were EBV positive. Interestingly; however, the 8-year-old transplant recipient was EBV negative but developed acute tonsillitis 4 months after his transplant from an EBV-positive donor.2
10.1136/bmjgast-2021-000602.supp1 Supplementary data
All of these oesophageal PTLD cases followed solid organ transplantation and were EBV-driven as confirmed by pathology and/or serology. The interval for PTLD development ranged from 6 months2 to 31 years5 following transplant.
In conclusion, we describe a case of PTLD primarily involving the oesophagus. After PTLD was treated, an oesophageal stricture occurred at the site of previous PTLD involvement, likely as a result of scar tissue formation after healing of circumferential ulcers. To the best of our knowledge, this is the first case in the literature with PTLD leading to an oesophageal stricture.
In our case, the initial endoscopic biopsies were non-specific and brushings were positive for oesophageal candidiasis; however, the endoscopic appearance was atypical for Candida infection and patient’s symptoms did not respond to antifungal therapy. Therefore, we elected to repeat endoscopy and obtain more biopsies from the ulcer base, and this eventually confirmed PTLD. This underlines the importance of maintaining a high index of suspicion and the value of repeat endoscopy and biopsies in cases where endoscopic findings are atypical and whenever there is no resolution of symptoms despite treatment.
Contributors: MSM and SLW contributed to the planning of this case report, equally. MSM conducted the literature review and wrote the case report. SLW reviewed/edited the manuscript, and provided supervision. SLW arranged clinical follow-up with the patient and obtained consent. MSM submitted the report and edited the submission according to the review comments.
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: Not required.
Provenance and peer review: Not commissioned; externally peer reviewed.
Data availability statement: Data sharing not applicable as no datasets generated and/or analysed for this study.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | Recovered | ReactionOutcome | CC BY-NC | 33648984 | 19,551,529 | 2021-02 |
What was the outcome of reaction 'Oesophageal ulcer'? | Post-transplant lymphoproliferative disorder as a cause of oesophageal ulceration and stricture: case report and literature review.
Post-transplant lymphoproliferative disorder (PTLD) of the oesophagus is a rare complication of solid organ transplant that requires a high index of suspicion to diagnose. A literature review conducted on Ovid Medline database retrieved 24 articles, among which five previous cases of oesophageal PTLD were identified. Development of oesophageal strictures related to PTLD has not been reported in the literature. We report a case of oesophageal PTLD following lung transplant, presenting with extensive, circumferential ulceration in the oesophagus. PTLD was successfully treated with chemotherapy but subsequently, this patient developed a severe oesophageal stricture at the site of her PTLD. She presented with an episode of food bolus impaction requiring endoscopic retrieval. In the following years, our patient required multiple endoscopic dilatations of this PTLD-related oesophageal stricture.
Introduction
Post-transplant lymphoproliferative disorder (PTLD) is one of many serious complications that follow transplantation of solid organs or haematologic stem cells. Development of PTLD is commonly a result of uncontrolled B cell proliferation in the context of Epstein-Barr virus (EBV) infection.1
The clinical presentation of PTLD is variable, with some patients being completely asymptomatic and others presenting in critical condition with multiorgan involvement. Common organ involvement in PTLD includes lymph nodes, the central nervous system and gastrointestinal system.2
Although gastric, colonic and small bowel involvement with PTLD have been reported in the literature with an estimated prevalence of 25% of all PTLD in paediatric patients,2 isolated oesophageal PTLD is exceedingly rare.
A literature review has discovered five reported cases1–5 of isolated oesophageal PTLD. We present a case of oesophageal PTLD that was complicated by stricture formation which required multiple endoscopic dilations over the follow-up period.
Case
A 35-year-old woman with a history of mixed connective tissue disease, Raynaud’s phenomenon, arthritis, progressive interstitial lung disease resulted in respiratory compromise that required a double lung transplant. One year following her transplant, she was referred to the gastroenterology service with a 2-week history of worsening odynophagia and dysphagia.
Her symptoms were predominantly caused by solids with the need to over-chew or to drink large quantities of liquids to push food down the oesophagus. She lost 4 kg. She reported occasional nausea and regurgitation of food and pills, but no vomiting. There were no other gastrointestinal symptoms. She reported no fever or night sweats.
Her immunosuppressive medications included prednisone, tacrolimus and mycophenolate.
She had no allergies. There was no history of smoking, excessive alcohol consumption or recreational drug use.
There was no family history of malignancies.
Physical examination did not reveal any skin rashes or lymphadenopathy. Abdominal examination was normal.
Investigation
A complete blood count revealed haemoglobin of 87 g/L (normal range: 120–160), low lymphocytes of 1.01×109/L (normal range: 1.50–4.00), high monocytes at 1.15×109/L (normal range: 0.20–0.80) and elevated platelet at 560×109/L (normal range: 150–400). Lactate dehydrogenase was elevated at 368 U/L (normal range: 120–220).
An upper endoscopy demonstrated extensive, ulcerations involving most of the oesophagus except the distal 3–4 cm, occupying at least 70% of the circumference, with minimal normal intervening mucosa. Oesophageal ulcers were wide and deep with rolled edges and a whitish base (figure 1). The distal 3–4 cm of the oesophagus was spared and showed no oesophagitis or Barret’s oesophagus. Endoscopic examination of the stomach and the duodenum was unremarkable.
Figure 1 Endoscopic image showing deep, extensive ulceration in the oesophagus.
Biopsies from the edges of the ulcers showed granulation tissue and inflammatory exudate with no evidence of viral cytopathic effects. Brushing was positive for Candida albicans.
Work-up for the differential diagnosis included Cytomegalo virus blood PCR which was negative. Blood PCR for EBV was detected at 7.88E+03 copies of DNA/mL (negative if less than 600 copies of DNA/mL).
A course of antifungal therapy for oesophageal candidiasis was completed but symptoms persisted. A repeat endoscopy revealed that the oesophagus was unchanged. Biopsies were obtained from the bases of ulcers and revealed EBV-positive large B cell lymphoproliferative disorder consistent with monomorphic PTLD. There was multifocal necrosis and high apoptotic rate. Duodenal and stomach biopsies were normal.
CT of the thorax showed circumferential, irregular thickening of a long segment of the oesophagus associated with some mildly enlarged lymph nodes in the mediastinum. The remainder of the staging work-up including a bone marrow biopsy and CT scans of the head, neck, abdomen and pelvis showed no evidence of PTLD elsewhere. Colonoscopy was not indicated given lack of clinical symptoms of colonic PTLD and negative imaging.
Rituximab single agent treatment was started initially, but did not result in complete remission of PTLD. Therefore, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine/(oncovin) and prednisone) chemotherapy was initiated. Subsequent to that, the patient had resolution of dysphagia and odynophagia, negative blood EBV PCR, decreased oesophageal thickening on CT and confirmed healing oesophageal ulcers on endoscopy.
However, a few weeks after completion of chemotherapy, she developed sudden-onset dysphagia with sensation of food impaction in her oesophagus and presented to the hospital. A barium swallow showed a severe stricture in the mid-oesophagus for about 3.5 cm, with the narrowest part of the lumen measuring 4 mm (figure 2). Endoscopy revealed significant dilatation in the upper oesophagus with a food bolus noted. This bolus required endoscopic retrieval using a Roth net. Distal to this, there was a stenotic area which was non-traversable by the gastroscope and measured about 4.5 mm in diameter. CRE balloon dilation was performed (from 8 mm to 10 mm). Biopsies from the stenotic segment and from the dilated upper oesophagus were obtained and were negative for PTLD.
Figure 2 Barium study demonstrating severe stricture in the mid-thoracic oesophagus for about 3.5 cm, with the narrowest part of the lumen measuring 4 mm.
A 24-hour pH monitoring showed no episodes of acid reflux and no symptoms were recorded during the study.
Follow-up
Over the span of the following years, this patient required multiple endoscopic dilatations to allow for relief of dysphagia. Repeated oesophageal biopsies were negative for recurrent lymphoma. CT scans remained stable with no evidence of PTLD.
Learning points
Presence of oesophageal Candida and/or viral (Cytomegalo virus) infections have been co-incidentally reported in patients with oesophageal PTLD.
Maintain a high index of suspicion for PTLD in immunosuppressed patients with clinical symptoms refractory to treatment with antimicrobials.
Repeat endoscopy with deep biopsies from ulcer base may increase the yield for PTLD detection.
Discussion
The association between EBV infection, the cumulative burden of immunosuppressive treatment (specifically T cell depleting strategies) and the higher risk of PTLD is well established.1
A literature review conducted on Ovid Medline database retrieved 24 articles, among which five previous cases of oesophageal PTLD were identified (online supplemental material).1–5 There were four adult cases1 3–5 and one paediatric case.2 During the pre-transplant work-up, all of the adult recipients were EBV positive. Interestingly; however, the 8-year-old transplant recipient was EBV negative but developed acute tonsillitis 4 months after his transplant from an EBV-positive donor.2
10.1136/bmjgast-2021-000602.supp1 Supplementary data
All of these oesophageal PTLD cases followed solid organ transplantation and were EBV-driven as confirmed by pathology and/or serology. The interval for PTLD development ranged from 6 months2 to 31 years5 following transplant.
In conclusion, we describe a case of PTLD primarily involving the oesophagus. After PTLD was treated, an oesophageal stricture occurred at the site of previous PTLD involvement, likely as a result of scar tissue formation after healing of circumferential ulcers. To the best of our knowledge, this is the first case in the literature with PTLD leading to an oesophageal stricture.
In our case, the initial endoscopic biopsies were non-specific and brushings were positive for oesophageal candidiasis; however, the endoscopic appearance was atypical for Candida infection and patient’s symptoms did not respond to antifungal therapy. Therefore, we elected to repeat endoscopy and obtain more biopsies from the ulcer base, and this eventually confirmed PTLD. This underlines the importance of maintaining a high index of suspicion and the value of repeat endoscopy and biopsies in cases where endoscopic findings are atypical and whenever there is no resolution of symptoms despite treatment.
Contributors: MSM and SLW contributed to the planning of this case report, equally. MSM conducted the literature review and wrote the case report. SLW reviewed/edited the manuscript, and provided supervision. SLW arranged clinical follow-up with the patient and obtained consent. MSM submitted the report and edited the submission according to the review comments.
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: Not required.
Provenance and peer review: Not commissioned; externally peer reviewed.
Data availability statement: Data sharing not applicable as no datasets generated and/or analysed for this study.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | Recovered | ReactionOutcome | CC BY-NC | 33648984 | 19,520,660 | 2021-02 |
What was the outcome of reaction 'Post transplant lymphoproliferative disorder'? | Post-transplant lymphoproliferative disorder as a cause of oesophageal ulceration and stricture: case report and literature review.
Post-transplant lymphoproliferative disorder (PTLD) of the oesophagus is a rare complication of solid organ transplant that requires a high index of suspicion to diagnose. A literature review conducted on Ovid Medline database retrieved 24 articles, among which five previous cases of oesophageal PTLD were identified. Development of oesophageal strictures related to PTLD has not been reported in the literature. We report a case of oesophageal PTLD following lung transplant, presenting with extensive, circumferential ulceration in the oesophagus. PTLD was successfully treated with chemotherapy but subsequently, this patient developed a severe oesophageal stricture at the site of her PTLD. She presented with an episode of food bolus impaction requiring endoscopic retrieval. In the following years, our patient required multiple endoscopic dilatations of this PTLD-related oesophageal stricture.
Introduction
Post-transplant lymphoproliferative disorder (PTLD) is one of many serious complications that follow transplantation of solid organs or haematologic stem cells. Development of PTLD is commonly a result of uncontrolled B cell proliferation in the context of Epstein-Barr virus (EBV) infection.1
The clinical presentation of PTLD is variable, with some patients being completely asymptomatic and others presenting in critical condition with multiorgan involvement. Common organ involvement in PTLD includes lymph nodes, the central nervous system and gastrointestinal system.2
Although gastric, colonic and small bowel involvement with PTLD have been reported in the literature with an estimated prevalence of 25% of all PTLD in paediatric patients,2 isolated oesophageal PTLD is exceedingly rare.
A literature review has discovered five reported cases1–5 of isolated oesophageal PTLD. We present a case of oesophageal PTLD that was complicated by stricture formation which required multiple endoscopic dilations over the follow-up period.
Case
A 35-year-old woman with a history of mixed connective tissue disease, Raynaud’s phenomenon, arthritis, progressive interstitial lung disease resulted in respiratory compromise that required a double lung transplant. One year following her transplant, she was referred to the gastroenterology service with a 2-week history of worsening odynophagia and dysphagia.
Her symptoms were predominantly caused by solids with the need to over-chew or to drink large quantities of liquids to push food down the oesophagus. She lost 4 kg. She reported occasional nausea and regurgitation of food and pills, but no vomiting. There were no other gastrointestinal symptoms. She reported no fever or night sweats.
Her immunosuppressive medications included prednisone, tacrolimus and mycophenolate.
She had no allergies. There was no history of smoking, excessive alcohol consumption or recreational drug use.
There was no family history of malignancies.
Physical examination did not reveal any skin rashes or lymphadenopathy. Abdominal examination was normal.
Investigation
A complete blood count revealed haemoglobin of 87 g/L (normal range: 120–160), low lymphocytes of 1.01×109/L (normal range: 1.50–4.00), high monocytes at 1.15×109/L (normal range: 0.20–0.80) and elevated platelet at 560×109/L (normal range: 150–400). Lactate dehydrogenase was elevated at 368 U/L (normal range: 120–220).
An upper endoscopy demonstrated extensive, ulcerations involving most of the oesophagus except the distal 3–4 cm, occupying at least 70% of the circumference, with minimal normal intervening mucosa. Oesophageal ulcers were wide and deep with rolled edges and a whitish base (figure 1). The distal 3–4 cm of the oesophagus was spared and showed no oesophagitis or Barret’s oesophagus. Endoscopic examination of the stomach and the duodenum was unremarkable.
Figure 1 Endoscopic image showing deep, extensive ulceration in the oesophagus.
Biopsies from the edges of the ulcers showed granulation tissue and inflammatory exudate with no evidence of viral cytopathic effects. Brushing was positive for Candida albicans.
Work-up for the differential diagnosis included Cytomegalo virus blood PCR which was negative. Blood PCR for EBV was detected at 7.88E+03 copies of DNA/mL (negative if less than 600 copies of DNA/mL).
A course of antifungal therapy for oesophageal candidiasis was completed but symptoms persisted. A repeat endoscopy revealed that the oesophagus was unchanged. Biopsies were obtained from the bases of ulcers and revealed EBV-positive large B cell lymphoproliferative disorder consistent with monomorphic PTLD. There was multifocal necrosis and high apoptotic rate. Duodenal and stomach biopsies were normal.
CT of the thorax showed circumferential, irregular thickening of a long segment of the oesophagus associated with some mildly enlarged lymph nodes in the mediastinum. The remainder of the staging work-up including a bone marrow biopsy and CT scans of the head, neck, abdomen and pelvis showed no evidence of PTLD elsewhere. Colonoscopy was not indicated given lack of clinical symptoms of colonic PTLD and negative imaging.
Rituximab single agent treatment was started initially, but did not result in complete remission of PTLD. Therefore, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine/(oncovin) and prednisone) chemotherapy was initiated. Subsequent to that, the patient had resolution of dysphagia and odynophagia, negative blood EBV PCR, decreased oesophageal thickening on CT and confirmed healing oesophageal ulcers on endoscopy.
However, a few weeks after completion of chemotherapy, she developed sudden-onset dysphagia with sensation of food impaction in her oesophagus and presented to the hospital. A barium swallow showed a severe stricture in the mid-oesophagus for about 3.5 cm, with the narrowest part of the lumen measuring 4 mm (figure 2). Endoscopy revealed significant dilatation in the upper oesophagus with a food bolus noted. This bolus required endoscopic retrieval using a Roth net. Distal to this, there was a stenotic area which was non-traversable by the gastroscope and measured about 4.5 mm in diameter. CRE balloon dilation was performed (from 8 mm to 10 mm). Biopsies from the stenotic segment and from the dilated upper oesophagus were obtained and were negative for PTLD.
Figure 2 Barium study demonstrating severe stricture in the mid-thoracic oesophagus for about 3.5 cm, with the narrowest part of the lumen measuring 4 mm.
A 24-hour pH monitoring showed no episodes of acid reflux and no symptoms were recorded during the study.
Follow-up
Over the span of the following years, this patient required multiple endoscopic dilatations to allow for relief of dysphagia. Repeated oesophageal biopsies were negative for recurrent lymphoma. CT scans remained stable with no evidence of PTLD.
Learning points
Presence of oesophageal Candida and/or viral (Cytomegalo virus) infections have been co-incidentally reported in patients with oesophageal PTLD.
Maintain a high index of suspicion for PTLD in immunosuppressed patients with clinical symptoms refractory to treatment with antimicrobials.
Repeat endoscopy with deep biopsies from ulcer base may increase the yield for PTLD detection.
Discussion
The association between EBV infection, the cumulative burden of immunosuppressive treatment (specifically T cell depleting strategies) and the higher risk of PTLD is well established.1
A literature review conducted on Ovid Medline database retrieved 24 articles, among which five previous cases of oesophageal PTLD were identified (online supplemental material).1–5 There were four adult cases1 3–5 and one paediatric case.2 During the pre-transplant work-up, all of the adult recipients were EBV positive. Interestingly; however, the 8-year-old transplant recipient was EBV negative but developed acute tonsillitis 4 months after his transplant from an EBV-positive donor.2
10.1136/bmjgast-2021-000602.supp1 Supplementary data
All of these oesophageal PTLD cases followed solid organ transplantation and were EBV-driven as confirmed by pathology and/or serology. The interval for PTLD development ranged from 6 months2 to 31 years5 following transplant.
In conclusion, we describe a case of PTLD primarily involving the oesophagus. After PTLD was treated, an oesophageal stricture occurred at the site of previous PTLD involvement, likely as a result of scar tissue formation after healing of circumferential ulcers. To the best of our knowledge, this is the first case in the literature with PTLD leading to an oesophageal stricture.
In our case, the initial endoscopic biopsies were non-specific and brushings were positive for oesophageal candidiasis; however, the endoscopic appearance was atypical for Candida infection and patient’s symptoms did not respond to antifungal therapy. Therefore, we elected to repeat endoscopy and obtain more biopsies from the ulcer base, and this eventually confirmed PTLD. This underlines the importance of maintaining a high index of suspicion and the value of repeat endoscopy and biopsies in cases where endoscopic findings are atypical and whenever there is no resolution of symptoms despite treatment.
Contributors: MSM and SLW contributed to the planning of this case report, equally. MSM conducted the literature review and wrote the case report. SLW reviewed/edited the manuscript, and provided supervision. SLW arranged clinical follow-up with the patient and obtained consent. MSM submitted the report and edited the submission according to the review comments.
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: Not required.
Provenance and peer review: Not commissioned; externally peer reviewed.
Data availability statement: Data sharing not applicable as no datasets generated and/or analysed for this study.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise. | Recovered | ReactionOutcome | CC BY-NC | 33648984 | 19,551,529 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Kounis syndrome'. | Uncommon but imperative cause of repeated acute stent thrombosis: Kounis syndrome type III.
A 69-year-old woman with a history of allergic reactions to unknown metals who presented 1 year prior with acute coronary syndrome complicated by acute stent thrombosis (ST) was admitted due to new-onset chest pain during mild exercise. She electively underwent coronary angiography, revealing a newly developed stenosis in the fourth branch of the posterior descending artery, treated with an everolimus-eluting stent. One hour later, she reported of sudden chest tightness and nausea; ECG revealed significant ST-segment elevation in the II, III and aVF leads. We suspected ST-segment elevation myocardial infarction resulting from an allergic reaction (ie, Kounis syndrome type III) and managed it properly by eliminating other potential causes. The tentative diagnosis was confirmed by pathological examination of aspirated materials. Kounis syndrome type III may be a frequently undiagnosed clinical entity, emphasising the importance of pathological examination of aspirated materials when implanting coronary stents and history-taking of allergies to stent metals.
BACKGROUND
The Kounis syndrome was first reported in 1991 as an acute coronary syndrome, including coronary spasm (type I), atheromatous plaque erosion or rupture (type II) and stent thrombosis (ST) (type III), resulting from allergic or hypersensitivity reactions, or anaphylactic or anaphylactoid insults.1 In type III, all three components of drug-eluting stents (stent metals, polymers and eluted drugs) could be responsible for inducing allergic reactions and ST.2 To make an accurate diagnosis of Kounis syndrome type III, an urgent aspiration of intrastent thrombus, followed by histological examination of aspirated material and staining for eosinophils (H&E) and mast cells (Giemsa) can be mandatory.3 Concerning this point, Kounis syndrome type III may not be an uncommon disease but an infrequently misdiagnosed entity, which, however, has clinical significance because of the wide range of triggers and possible fatal consequences, unless promptly recognised. Herein, we report a novel case of repeated acute ST following a local allergic reaction diagnosed that was managed properly in a patient with a history of metal allergy.
Case presentation
A 69-year-old woman with a medical history of hypertension was admitted to our heart centre with symptoms of chest pain during exercise. Mild allergic reactions to unknown metals were reported 30 years prior but had not been investigated further. Her medical history was noteworthy for acute coronary syndrome, 1 year before admission, complicated by acute ST in the proximal left anterior descending artery (LAD). This occurred 1 hour (figure 1A) after the primary percutaneous coronary intervention (PCI) with a 2.5×26 mm zotarolimus-eluting stent (Resolute Onyx; Medtronic, Santa Rosa, California, USA) under the guidance of intravascular ultrasound (IVUS).
Figure 1 Coronary artery angiography. (A) Acute stent thrombosis of the left anterior descending coronary artery (LAD) following implantation of a stent (red arrow) 1 year prior. (B) Left coronary artery angiography without signs of restenosis (red arrow heads) in the proximal LAD where the acute stent thrombosis had developed 1 year prior. (C) Tight stenotic lesions (yellow arrowheads) in the distal right coronary artery (RCA) are noted.
After admission, she electively underwent coronary angiography (CAG) on hospital day 2 to determine the cause of her chest pain. CAG revealed no in-stent restenosis in the proximal LAD (figure 1B) and critical stenosis in the fourth branch of the posterior descending artery (figure 1C). To treat the stenosis, which was thought to be the culprit lesion for her angina, a 2.25×38 mm everolimus-eluting stent (XIENCE Sierra; Abbott Vascular, Santa Clara, California, USA) was implanted (figure 2A, B) the same day. Aspirin (100 mg) and clopidogrel (75 mg) were administered daily as maintenance treatment 7 days prior to implantation. An IVUS (AltaView; Terumo Corporation, Tokyo, Japan) was performed to optimise the stenting by probing that no stent complications such as under-expansion, malposition or stent fracture were observed (figure 2C, D). One hour after the final angiogram, the patient reported of sudden chest tightness and nausea. There was no generalised itching or cutaneous erythema, and her vital signs were as follows: blood pressure, 173/86 mm Hg; heart rate, 76 beats/min and oxygen saturation, 98%. An ECG revealed significant ST-segment elevation in the II, III and aVF leads (figure 3).
Figure 2 Elective percutaneous coronary intervention and intracoronary imaging findings. (A) A drug-eluting stent (2.25×38 mm) was deployed in the distal right coronary artery; the kissing balloon technique was not employed. (B) Stent placement provided excellent results in the final angiogram. The red arrows denote the areas shown in panels C and D, respectively. (C, D) Intravascular ultrasound imaging confirmed optimal stent expansion in the distal right coronary artery (C, stent proximal; D, stent distal). (E) One hour after the final angiogram, angiographic appearance of multiple thrombi in the stent (yellow arrowheads) is noted. The red arrows denote the areas shown in panels F and G, respectively. (F, G) Optical frequency domain imaging confirming the presence of the thrombus mainly in the proximal (F) and distal (G) regions of the implanted stent.
Figure 3 ECG during the stent thrombosis (ST) event showing ST-segment elevation in leads II, III and aVF and ST-segment depression in leads V 1–3, I and aVL.
Differential diagnosis
ST-segment elevation myocardial infarction/acute stent thrombosis resulting from
Procedure related (stent under-expansion, incomplete stent apposition and coronary artery dissection).
Kounis syndrome (type III).
Heparin-induced thrombocytopenia (HIT).
Clopidogrel resistance.
Plasma factors influencing the thrombophilic propensity (protein C, protein S, antithrombin III, activated protein C, antiphospholipid antibodies and anticardiolipin antibodies, etc).
Treatment
We suspected ST-segment elevation myocardial infarction resulting from an allergic reaction (ie, Kounis syndrome type III). Intravenous hydrocortisone (125 mg), oxygen and saline were immediately administered. Emergent CAG confirmed a thrombotic semi-occlusion of the stent site (figure 2E). Optical frequency domain imaging (OFDI) (LUNAWAVE, Terumo Corporation, Tokyo, Japan) revealed a residual thrombus overlying the stent struts (figure 2F, G). Aspiration thrombectomy and subsequent balloon angioplasty with a 3 mm non-compliant balloon were performed, which resulted in an improvement from thrombolysis in myocardial infarction (TIMI) flow grade 1–2 (figure 4A). The intra-aortic balloon was left in place for 3 days, during which time the TIMI flow grade in the right coronary artery was 3, as determined via CAG (figure 4B).
Figure 4 Final angiogram after thrombus aspiration and balloon angioplasty (A). Absence of the thrombus in the distal right coronary artery following a 3-day use of the intra-aortic balloon pump (B).
Investigations
After the bailout procedure, the peak troponin I and creatine kinase-MB levels were 27.8 pg/mL and 73.7 U/L, respectively. The lowest platelet count after thrombectomy and angiography was 180 x109/L (initial platelet count, 195 x109/L). The blood eosinophil percentage was 0.5% at 5 hours after the onset. As we suspected clopidogrel resistance, we replaced clopidogrel with prasugrel (20 mg as the loading dose, followed by 3.75 mg as the maintenance dose) during the bailout PCI.
Pathological examination of the thrombotic aspirate (figure 5A) revealed platelet aggregates, fibrin and white cells, including eosinophils and neutrophils (figure 5B); mast cells were not detected (figure 5C). CYP2C19*2 and CYP2C19*3 genotyping via polymerase chain reaction-restriction fragment length polymorphism analysis revealed that the patient was an intermediate metaboliser (CYP2C19 *1/*3 genotype). The activities of protein C, protein S, antithrombin III, activated protein C and α2-antiplasmin were within normal limits according to haematological tests. Antiphospholipid and anticardiolipin antibodies were negative. The above-mentioned findings were compatible with acute ST due to an allergic reaction. A patch test for metal allergies was strongly positive for nickel and cobalt, which are the main components of the patient’s two implanted coronary stents.
Figure 5 (A) Thrombotic material is aspirated from the right coronary artery. (B) The aspirate consists of platelet aggregates, fibrin and white cells, including eosinophils (yellow arrows) and neutrophils (blue arrows). H&E. (C) Mast cells are not present in the aspirate—Giemsa stain.
Outcome and follow-up
The patient’s clinical course was uneventful afterward, and she was discharged on hospital day 12 and had no symptoms at the 3-month follow-up visit.
Discussion
Type III Kounis syndrome is defined as ST with eosinophils and mast cells in the aspirated thrombus.2 The lack of mast cells in our patient’s thrombotic material may have been due to the very short period between symptom onset and aspiration. In most previously reported cases with mast cells observed in implanted stent sites, histological analyses were performed several hours after the event or even during the autopsy.4 All components of drug-eluting coronary stents can potentially cause allergic reactions and Kounis syndrome type III along with possibly concomitant oral antiplatelet drugs and environmental exposures.2 Our patient had a positive allergic patch test response to nickel and cobalt, which are the two main components of two different stents (everolimus-eluting and zotarolimus-eluting stents) that were implanted separately. Hence, hypersensitivity to these metals likely accounted for her apparent repeated acute ST.5 Notably, her clinical course included focal hypersensitivity to the coronary stent that resulted in acute ST immediately following stent implantation. Less commonly, she did not demonstrate typical systemic allergic reactions, such as skin itching, pruritus, dyspnoea, and hypotension.6
The mechanisms underlying ST are multifactorial. Before concluding acute ST resulting from allergic reactions after the implantation of drug-eluting stents, we should explore other potential mechanisms, such as patient-related, procedural and postprocedural factors (including type and duration of antiplatelet therapy) as discussed previously.4 In our case, procedural factors, such as stent under-expansion, incomplete apposition and fracture, were unlikely to cause acute ST because the procedure was carefully performed via IVUS guidance and we also safely confirmed that these stent-related causes were much less likely via OFDI during the bailout PCI. HIT was a differential diagnosis if the patient administered heparin presented with thrombocytopenia or thrombosis. While the platelet count in this patient was within the normal limit and the relative change in platelets was not definitive to diagnose HIT, although the HIT test showed a weakly positive reaction. Similarly, plasma factors influencing the thrombophilic propensity, such as protein C, protein S, antithrombin III, activated protein C, antiphospholipid antibodies and anticardiolipin antibodies, were all within the normal range. Clopidogrel resistance is associated with subacute ST.7 We immediately switched 75 mg of clopidogrel to 3.75 mg of prasugrel, a third generation thienopyridine agent with greater platelet inhibition, and later, the patient disclosed not carrying CYP2C19 loss of-function alleles, which are seen more frequently in Japanese population.8 Overall, the above-mentioned findings were compatible with acute repeated ST due to an allergic reaction.
To the best of our knowledge, this is the first report of repetitive acute ST induced by an allergic reaction, highlighting eosinophilic infiltration in the aspirated thrombus on pathological examination. Using intradermal skin tests, we identified nickel and cobalt as the causes of the allergic reaction and consequent Kounis syndrome. Herein, this novel case conveys a significant message that Kounis syndrome type III should be considered when implanting coronary stents. Rather than being a rare disease, Kounis syndrome type III is a frequently undiagnosed clinical entity. Hence, we emphasise the importance of the pathological examination of aspirated materials and history-taking of previous allergic reactions to stent metals in cases of idiopathic ST.
Patient’s perspective
I am greatly engaged and interested in this clinical research of this especially unusual but important medical problem that I was suffering from. This novel report could hopefully contribute not only to improve my health condition in the future but also to deepen the understanding of the Kounis syndrome, leading to the further development of specific treatments for this clinical entity.
Learning points
Kounis syndrome is an acute coronary syndrome caused by an allergic reaction to various drugs or substances.
Kounis syndrome type III may be a frequently undiagnosed clinical entity when implanting coronary stents.
Kounis syndrome type III warrants careful consideration, emphasising the importance of pathological examination of aspirated materials and history-taking of previous allergic reactions to stent metals.
Contributors: SM was involved in the case selection, the main manuscript writing and the collection of references. TY revised the manuscript critically for important intellectual content and gave the final approval for the version published. MM conducted pathological examinations. NGK supervised the case presentation and reviewed the entire manuscript.
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. | ASPIRIN, CLOPIDOGREL BISULFATE, EVEROLIMUS, ZOTAROLIMUS | DrugsGivenReaction | CC BY-NC | 33649028 | 19,809,536 | 2021-03-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Treatment failure'. | Uncommon but imperative cause of repeated acute stent thrombosis: Kounis syndrome type III.
A 69-year-old woman with a history of allergic reactions to unknown metals who presented 1 year prior with acute coronary syndrome complicated by acute stent thrombosis (ST) was admitted due to new-onset chest pain during mild exercise. She electively underwent coronary angiography, revealing a newly developed stenosis in the fourth branch of the posterior descending artery, treated with an everolimus-eluting stent. One hour later, she reported of sudden chest tightness and nausea; ECG revealed significant ST-segment elevation in the II, III and aVF leads. We suspected ST-segment elevation myocardial infarction resulting from an allergic reaction (ie, Kounis syndrome type III) and managed it properly by eliminating other potential causes. The tentative diagnosis was confirmed by pathological examination of aspirated materials. Kounis syndrome type III may be a frequently undiagnosed clinical entity, emphasising the importance of pathological examination of aspirated materials when implanting coronary stents and history-taking of allergies to stent metals.
BACKGROUND
The Kounis syndrome was first reported in 1991 as an acute coronary syndrome, including coronary spasm (type I), atheromatous plaque erosion or rupture (type II) and stent thrombosis (ST) (type III), resulting from allergic or hypersensitivity reactions, or anaphylactic or anaphylactoid insults.1 In type III, all three components of drug-eluting stents (stent metals, polymers and eluted drugs) could be responsible for inducing allergic reactions and ST.2 To make an accurate diagnosis of Kounis syndrome type III, an urgent aspiration of intrastent thrombus, followed by histological examination of aspirated material and staining for eosinophils (H&E) and mast cells (Giemsa) can be mandatory.3 Concerning this point, Kounis syndrome type III may not be an uncommon disease but an infrequently misdiagnosed entity, which, however, has clinical significance because of the wide range of triggers and possible fatal consequences, unless promptly recognised. Herein, we report a novel case of repeated acute ST following a local allergic reaction diagnosed that was managed properly in a patient with a history of metal allergy.
Case presentation
A 69-year-old woman with a medical history of hypertension was admitted to our heart centre with symptoms of chest pain during exercise. Mild allergic reactions to unknown metals were reported 30 years prior but had not been investigated further. Her medical history was noteworthy for acute coronary syndrome, 1 year before admission, complicated by acute ST in the proximal left anterior descending artery (LAD). This occurred 1 hour (figure 1A) after the primary percutaneous coronary intervention (PCI) with a 2.5×26 mm zotarolimus-eluting stent (Resolute Onyx; Medtronic, Santa Rosa, California, USA) under the guidance of intravascular ultrasound (IVUS).
Figure 1 Coronary artery angiography. (A) Acute stent thrombosis of the left anterior descending coronary artery (LAD) following implantation of a stent (red arrow) 1 year prior. (B) Left coronary artery angiography without signs of restenosis (red arrow heads) in the proximal LAD where the acute stent thrombosis had developed 1 year prior. (C) Tight stenotic lesions (yellow arrowheads) in the distal right coronary artery (RCA) are noted.
After admission, she electively underwent coronary angiography (CAG) on hospital day 2 to determine the cause of her chest pain. CAG revealed no in-stent restenosis in the proximal LAD (figure 1B) and critical stenosis in the fourth branch of the posterior descending artery (figure 1C). To treat the stenosis, which was thought to be the culprit lesion for her angina, a 2.25×38 mm everolimus-eluting stent (XIENCE Sierra; Abbott Vascular, Santa Clara, California, USA) was implanted (figure 2A, B) the same day. Aspirin (100 mg) and clopidogrel (75 mg) were administered daily as maintenance treatment 7 days prior to implantation. An IVUS (AltaView; Terumo Corporation, Tokyo, Japan) was performed to optimise the stenting by probing that no stent complications such as under-expansion, malposition or stent fracture were observed (figure 2C, D). One hour after the final angiogram, the patient reported of sudden chest tightness and nausea. There was no generalised itching or cutaneous erythema, and her vital signs were as follows: blood pressure, 173/86 mm Hg; heart rate, 76 beats/min and oxygen saturation, 98%. An ECG revealed significant ST-segment elevation in the II, III and aVF leads (figure 3).
Figure 2 Elective percutaneous coronary intervention and intracoronary imaging findings. (A) A drug-eluting stent (2.25×38 mm) was deployed in the distal right coronary artery; the kissing balloon technique was not employed. (B) Stent placement provided excellent results in the final angiogram. The red arrows denote the areas shown in panels C and D, respectively. (C, D) Intravascular ultrasound imaging confirmed optimal stent expansion in the distal right coronary artery (C, stent proximal; D, stent distal). (E) One hour after the final angiogram, angiographic appearance of multiple thrombi in the stent (yellow arrowheads) is noted. The red arrows denote the areas shown in panels F and G, respectively. (F, G) Optical frequency domain imaging confirming the presence of the thrombus mainly in the proximal (F) and distal (G) regions of the implanted stent.
Figure 3 ECG during the stent thrombosis (ST) event showing ST-segment elevation in leads II, III and aVF and ST-segment depression in leads V 1–3, I and aVL.
Differential diagnosis
ST-segment elevation myocardial infarction/acute stent thrombosis resulting from
Procedure related (stent under-expansion, incomplete stent apposition and coronary artery dissection).
Kounis syndrome (type III).
Heparin-induced thrombocytopenia (HIT).
Clopidogrel resistance.
Plasma factors influencing the thrombophilic propensity (protein C, protein S, antithrombin III, activated protein C, antiphospholipid antibodies and anticardiolipin antibodies, etc).
Treatment
We suspected ST-segment elevation myocardial infarction resulting from an allergic reaction (ie, Kounis syndrome type III). Intravenous hydrocortisone (125 mg), oxygen and saline were immediately administered. Emergent CAG confirmed a thrombotic semi-occlusion of the stent site (figure 2E). Optical frequency domain imaging (OFDI) (LUNAWAVE, Terumo Corporation, Tokyo, Japan) revealed a residual thrombus overlying the stent struts (figure 2F, G). Aspiration thrombectomy and subsequent balloon angioplasty with a 3 mm non-compliant balloon were performed, which resulted in an improvement from thrombolysis in myocardial infarction (TIMI) flow grade 1–2 (figure 4A). The intra-aortic balloon was left in place for 3 days, during which time the TIMI flow grade in the right coronary artery was 3, as determined via CAG (figure 4B).
Figure 4 Final angiogram after thrombus aspiration and balloon angioplasty (A). Absence of the thrombus in the distal right coronary artery following a 3-day use of the intra-aortic balloon pump (B).
Investigations
After the bailout procedure, the peak troponin I and creatine kinase-MB levels were 27.8 pg/mL and 73.7 U/L, respectively. The lowest platelet count after thrombectomy and angiography was 180 x109/L (initial platelet count, 195 x109/L). The blood eosinophil percentage was 0.5% at 5 hours after the onset. As we suspected clopidogrel resistance, we replaced clopidogrel with prasugrel (20 mg as the loading dose, followed by 3.75 mg as the maintenance dose) during the bailout PCI.
Pathological examination of the thrombotic aspirate (figure 5A) revealed platelet aggregates, fibrin and white cells, including eosinophils and neutrophils (figure 5B); mast cells were not detected (figure 5C). CYP2C19*2 and CYP2C19*3 genotyping via polymerase chain reaction-restriction fragment length polymorphism analysis revealed that the patient was an intermediate metaboliser (CYP2C19 *1/*3 genotype). The activities of protein C, protein S, antithrombin III, activated protein C and α2-antiplasmin were within normal limits according to haematological tests. Antiphospholipid and anticardiolipin antibodies were negative. The above-mentioned findings were compatible with acute ST due to an allergic reaction. A patch test for metal allergies was strongly positive for nickel and cobalt, which are the main components of the patient’s two implanted coronary stents.
Figure 5 (A) Thrombotic material is aspirated from the right coronary artery. (B) The aspirate consists of platelet aggregates, fibrin and white cells, including eosinophils (yellow arrows) and neutrophils (blue arrows). H&E. (C) Mast cells are not present in the aspirate—Giemsa stain.
Outcome and follow-up
The patient’s clinical course was uneventful afterward, and she was discharged on hospital day 12 and had no symptoms at the 3-month follow-up visit.
Discussion
Type III Kounis syndrome is defined as ST with eosinophils and mast cells in the aspirated thrombus.2 The lack of mast cells in our patient’s thrombotic material may have been due to the very short period between symptom onset and aspiration. In most previously reported cases with mast cells observed in implanted stent sites, histological analyses were performed several hours after the event or even during the autopsy.4 All components of drug-eluting coronary stents can potentially cause allergic reactions and Kounis syndrome type III along with possibly concomitant oral antiplatelet drugs and environmental exposures.2 Our patient had a positive allergic patch test response to nickel and cobalt, which are the two main components of two different stents (everolimus-eluting and zotarolimus-eluting stents) that were implanted separately. Hence, hypersensitivity to these metals likely accounted for her apparent repeated acute ST.5 Notably, her clinical course included focal hypersensitivity to the coronary stent that resulted in acute ST immediately following stent implantation. Less commonly, she did not demonstrate typical systemic allergic reactions, such as skin itching, pruritus, dyspnoea, and hypotension.6
The mechanisms underlying ST are multifactorial. Before concluding acute ST resulting from allergic reactions after the implantation of drug-eluting stents, we should explore other potential mechanisms, such as patient-related, procedural and postprocedural factors (including type and duration of antiplatelet therapy) as discussed previously.4 In our case, procedural factors, such as stent under-expansion, incomplete apposition and fracture, were unlikely to cause acute ST because the procedure was carefully performed via IVUS guidance and we also safely confirmed that these stent-related causes were much less likely via OFDI during the bailout PCI. HIT was a differential diagnosis if the patient administered heparin presented with thrombocytopenia or thrombosis. While the platelet count in this patient was within the normal limit and the relative change in platelets was not definitive to diagnose HIT, although the HIT test showed a weakly positive reaction. Similarly, plasma factors influencing the thrombophilic propensity, such as protein C, protein S, antithrombin III, activated protein C, antiphospholipid antibodies and anticardiolipin antibodies, were all within the normal range. Clopidogrel resistance is associated with subacute ST.7 We immediately switched 75 mg of clopidogrel to 3.75 mg of prasugrel, a third generation thienopyridine agent with greater platelet inhibition, and later, the patient disclosed not carrying CYP2C19 loss of-function alleles, which are seen more frequently in Japanese population.8 Overall, the above-mentioned findings were compatible with acute repeated ST due to an allergic reaction.
To the best of our knowledge, this is the first report of repetitive acute ST induced by an allergic reaction, highlighting eosinophilic infiltration in the aspirated thrombus on pathological examination. Using intradermal skin tests, we identified nickel and cobalt as the causes of the allergic reaction and consequent Kounis syndrome. Herein, this novel case conveys a significant message that Kounis syndrome type III should be considered when implanting coronary stents. Rather than being a rare disease, Kounis syndrome type III is a frequently undiagnosed clinical entity. Hence, we emphasise the importance of the pathological examination of aspirated materials and history-taking of previous allergic reactions to stent metals in cases of idiopathic ST.
Patient’s perspective
I am greatly engaged and interested in this clinical research of this especially unusual but important medical problem that I was suffering from. This novel report could hopefully contribute not only to improve my health condition in the future but also to deepen the understanding of the Kounis syndrome, leading to the further development of specific treatments for this clinical entity.
Learning points
Kounis syndrome is an acute coronary syndrome caused by an allergic reaction to various drugs or substances.
Kounis syndrome type III may be a frequently undiagnosed clinical entity when implanting coronary stents.
Kounis syndrome type III warrants careful consideration, emphasising the importance of pathological examination of aspirated materials and history-taking of previous allergic reactions to stent metals.
Contributors: SM was involved in the case selection, the main manuscript writing and the collection of references. TY revised the manuscript critically for important intellectual content and gave the final approval for the version published. MM conducted pathological examinations. NGK supervised the case presentation and reviewed the entire manuscript.
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. | ASPIRIN, CLOPIDOGREL BISULFATE, EVEROLIMUS, ZOTAROLIMUS | DrugsGivenReaction | CC BY-NC | 33649028 | 19,809,536 | 2021-03-01 |
What was the outcome of reaction 'Kounis syndrome'? | Uncommon but imperative cause of repeated acute stent thrombosis: Kounis syndrome type III.
A 69-year-old woman with a history of allergic reactions to unknown metals who presented 1 year prior with acute coronary syndrome complicated by acute stent thrombosis (ST) was admitted due to new-onset chest pain during mild exercise. She electively underwent coronary angiography, revealing a newly developed stenosis in the fourth branch of the posterior descending artery, treated with an everolimus-eluting stent. One hour later, she reported of sudden chest tightness and nausea; ECG revealed significant ST-segment elevation in the II, III and aVF leads. We suspected ST-segment elevation myocardial infarction resulting from an allergic reaction (ie, Kounis syndrome type III) and managed it properly by eliminating other potential causes. The tentative diagnosis was confirmed by pathological examination of aspirated materials. Kounis syndrome type III may be a frequently undiagnosed clinical entity, emphasising the importance of pathological examination of aspirated materials when implanting coronary stents and history-taking of allergies to stent metals.
BACKGROUND
The Kounis syndrome was first reported in 1991 as an acute coronary syndrome, including coronary spasm (type I), atheromatous plaque erosion or rupture (type II) and stent thrombosis (ST) (type III), resulting from allergic or hypersensitivity reactions, or anaphylactic or anaphylactoid insults.1 In type III, all three components of drug-eluting stents (stent metals, polymers and eluted drugs) could be responsible for inducing allergic reactions and ST.2 To make an accurate diagnosis of Kounis syndrome type III, an urgent aspiration of intrastent thrombus, followed by histological examination of aspirated material and staining for eosinophils (H&E) and mast cells (Giemsa) can be mandatory.3 Concerning this point, Kounis syndrome type III may not be an uncommon disease but an infrequently misdiagnosed entity, which, however, has clinical significance because of the wide range of triggers and possible fatal consequences, unless promptly recognised. Herein, we report a novel case of repeated acute ST following a local allergic reaction diagnosed that was managed properly in a patient with a history of metal allergy.
Case presentation
A 69-year-old woman with a medical history of hypertension was admitted to our heart centre with symptoms of chest pain during exercise. Mild allergic reactions to unknown metals were reported 30 years prior but had not been investigated further. Her medical history was noteworthy for acute coronary syndrome, 1 year before admission, complicated by acute ST in the proximal left anterior descending artery (LAD). This occurred 1 hour (figure 1A) after the primary percutaneous coronary intervention (PCI) with a 2.5×26 mm zotarolimus-eluting stent (Resolute Onyx; Medtronic, Santa Rosa, California, USA) under the guidance of intravascular ultrasound (IVUS).
Figure 1 Coronary artery angiography. (A) Acute stent thrombosis of the left anterior descending coronary artery (LAD) following implantation of a stent (red arrow) 1 year prior. (B) Left coronary artery angiography without signs of restenosis (red arrow heads) in the proximal LAD where the acute stent thrombosis had developed 1 year prior. (C) Tight stenotic lesions (yellow arrowheads) in the distal right coronary artery (RCA) are noted.
After admission, she electively underwent coronary angiography (CAG) on hospital day 2 to determine the cause of her chest pain. CAG revealed no in-stent restenosis in the proximal LAD (figure 1B) and critical stenosis in the fourth branch of the posterior descending artery (figure 1C). To treat the stenosis, which was thought to be the culprit lesion for her angina, a 2.25×38 mm everolimus-eluting stent (XIENCE Sierra; Abbott Vascular, Santa Clara, California, USA) was implanted (figure 2A, B) the same day. Aspirin (100 mg) and clopidogrel (75 mg) were administered daily as maintenance treatment 7 days prior to implantation. An IVUS (AltaView; Terumo Corporation, Tokyo, Japan) was performed to optimise the stenting by probing that no stent complications such as under-expansion, malposition or stent fracture were observed (figure 2C, D). One hour after the final angiogram, the patient reported of sudden chest tightness and nausea. There was no generalised itching or cutaneous erythema, and her vital signs were as follows: blood pressure, 173/86 mm Hg; heart rate, 76 beats/min and oxygen saturation, 98%. An ECG revealed significant ST-segment elevation in the II, III and aVF leads (figure 3).
Figure 2 Elective percutaneous coronary intervention and intracoronary imaging findings. (A) A drug-eluting stent (2.25×38 mm) was deployed in the distal right coronary artery; the kissing balloon technique was not employed. (B) Stent placement provided excellent results in the final angiogram. The red arrows denote the areas shown in panels C and D, respectively. (C, D) Intravascular ultrasound imaging confirmed optimal stent expansion in the distal right coronary artery (C, stent proximal; D, stent distal). (E) One hour after the final angiogram, angiographic appearance of multiple thrombi in the stent (yellow arrowheads) is noted. The red arrows denote the areas shown in panels F and G, respectively. (F, G) Optical frequency domain imaging confirming the presence of the thrombus mainly in the proximal (F) and distal (G) regions of the implanted stent.
Figure 3 ECG during the stent thrombosis (ST) event showing ST-segment elevation in leads II, III and aVF and ST-segment depression in leads V 1–3, I and aVL.
Differential diagnosis
ST-segment elevation myocardial infarction/acute stent thrombosis resulting from
Procedure related (stent under-expansion, incomplete stent apposition and coronary artery dissection).
Kounis syndrome (type III).
Heparin-induced thrombocytopenia (HIT).
Clopidogrel resistance.
Plasma factors influencing the thrombophilic propensity (protein C, protein S, antithrombin III, activated protein C, antiphospholipid antibodies and anticardiolipin antibodies, etc).
Treatment
We suspected ST-segment elevation myocardial infarction resulting from an allergic reaction (ie, Kounis syndrome type III). Intravenous hydrocortisone (125 mg), oxygen and saline were immediately administered. Emergent CAG confirmed a thrombotic semi-occlusion of the stent site (figure 2E). Optical frequency domain imaging (OFDI) (LUNAWAVE, Terumo Corporation, Tokyo, Japan) revealed a residual thrombus overlying the stent struts (figure 2F, G). Aspiration thrombectomy and subsequent balloon angioplasty with a 3 mm non-compliant balloon were performed, which resulted in an improvement from thrombolysis in myocardial infarction (TIMI) flow grade 1–2 (figure 4A). The intra-aortic balloon was left in place for 3 days, during which time the TIMI flow grade in the right coronary artery was 3, as determined via CAG (figure 4B).
Figure 4 Final angiogram after thrombus aspiration and balloon angioplasty (A). Absence of the thrombus in the distal right coronary artery following a 3-day use of the intra-aortic balloon pump (B).
Investigations
After the bailout procedure, the peak troponin I and creatine kinase-MB levels were 27.8 pg/mL and 73.7 U/L, respectively. The lowest platelet count after thrombectomy and angiography was 180 x109/L (initial platelet count, 195 x109/L). The blood eosinophil percentage was 0.5% at 5 hours after the onset. As we suspected clopidogrel resistance, we replaced clopidogrel with prasugrel (20 mg as the loading dose, followed by 3.75 mg as the maintenance dose) during the bailout PCI.
Pathological examination of the thrombotic aspirate (figure 5A) revealed platelet aggregates, fibrin and white cells, including eosinophils and neutrophils (figure 5B); mast cells were not detected (figure 5C). CYP2C19*2 and CYP2C19*3 genotyping via polymerase chain reaction-restriction fragment length polymorphism analysis revealed that the patient was an intermediate metaboliser (CYP2C19 *1/*3 genotype). The activities of protein C, protein S, antithrombin III, activated protein C and α2-antiplasmin were within normal limits according to haematological tests. Antiphospholipid and anticardiolipin antibodies were negative. The above-mentioned findings were compatible with acute ST due to an allergic reaction. A patch test for metal allergies was strongly positive for nickel and cobalt, which are the main components of the patient’s two implanted coronary stents.
Figure 5 (A) Thrombotic material is aspirated from the right coronary artery. (B) The aspirate consists of platelet aggregates, fibrin and white cells, including eosinophils (yellow arrows) and neutrophils (blue arrows). H&E. (C) Mast cells are not present in the aspirate—Giemsa stain.
Outcome and follow-up
The patient’s clinical course was uneventful afterward, and she was discharged on hospital day 12 and had no symptoms at the 3-month follow-up visit.
Discussion
Type III Kounis syndrome is defined as ST with eosinophils and mast cells in the aspirated thrombus.2 The lack of mast cells in our patient’s thrombotic material may have been due to the very short period between symptom onset and aspiration. In most previously reported cases with mast cells observed in implanted stent sites, histological analyses were performed several hours after the event or even during the autopsy.4 All components of drug-eluting coronary stents can potentially cause allergic reactions and Kounis syndrome type III along with possibly concomitant oral antiplatelet drugs and environmental exposures.2 Our patient had a positive allergic patch test response to nickel and cobalt, which are the two main components of two different stents (everolimus-eluting and zotarolimus-eluting stents) that were implanted separately. Hence, hypersensitivity to these metals likely accounted for her apparent repeated acute ST.5 Notably, her clinical course included focal hypersensitivity to the coronary stent that resulted in acute ST immediately following stent implantation. Less commonly, she did not demonstrate typical systemic allergic reactions, such as skin itching, pruritus, dyspnoea, and hypotension.6
The mechanisms underlying ST are multifactorial. Before concluding acute ST resulting from allergic reactions after the implantation of drug-eluting stents, we should explore other potential mechanisms, such as patient-related, procedural and postprocedural factors (including type and duration of antiplatelet therapy) as discussed previously.4 In our case, procedural factors, such as stent under-expansion, incomplete apposition and fracture, were unlikely to cause acute ST because the procedure was carefully performed via IVUS guidance and we also safely confirmed that these stent-related causes were much less likely via OFDI during the bailout PCI. HIT was a differential diagnosis if the patient administered heparin presented with thrombocytopenia or thrombosis. While the platelet count in this patient was within the normal limit and the relative change in platelets was not definitive to diagnose HIT, although the HIT test showed a weakly positive reaction. Similarly, plasma factors influencing the thrombophilic propensity, such as protein C, protein S, antithrombin III, activated protein C, antiphospholipid antibodies and anticardiolipin antibodies, were all within the normal range. Clopidogrel resistance is associated with subacute ST.7 We immediately switched 75 mg of clopidogrel to 3.75 mg of prasugrel, a third generation thienopyridine agent with greater platelet inhibition, and later, the patient disclosed not carrying CYP2C19 loss of-function alleles, which are seen more frequently in Japanese population.8 Overall, the above-mentioned findings were compatible with acute repeated ST due to an allergic reaction.
To the best of our knowledge, this is the first report of repetitive acute ST induced by an allergic reaction, highlighting eosinophilic infiltration in the aspirated thrombus on pathological examination. Using intradermal skin tests, we identified nickel and cobalt as the causes of the allergic reaction and consequent Kounis syndrome. Herein, this novel case conveys a significant message that Kounis syndrome type III should be considered when implanting coronary stents. Rather than being a rare disease, Kounis syndrome type III is a frequently undiagnosed clinical entity. Hence, we emphasise the importance of the pathological examination of aspirated materials and history-taking of previous allergic reactions to stent metals in cases of idiopathic ST.
Patient’s perspective
I am greatly engaged and interested in this clinical research of this especially unusual but important medical problem that I was suffering from. This novel report could hopefully contribute not only to improve my health condition in the future but also to deepen the understanding of the Kounis syndrome, leading to the further development of specific treatments for this clinical entity.
Learning points
Kounis syndrome is an acute coronary syndrome caused by an allergic reaction to various drugs or substances.
Kounis syndrome type III may be a frequently undiagnosed clinical entity when implanting coronary stents.
Kounis syndrome type III warrants careful consideration, emphasising the importance of pathological examination of aspirated materials and history-taking of previous allergic reactions to stent metals.
Contributors: SM was involved in the case selection, the main manuscript writing and the collection of references. TY revised the manuscript critically for important intellectual content and gave the final approval for the version published. MM conducted pathological examinations. NGK supervised the case presentation and reviewed the entire manuscript.
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. | Recovering | ReactionOutcome | CC BY-NC | 33649028 | 19,809,536 | 2021-03-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pneumatosis intestinalis'. | Pneumatosis intestinalis in a radioactive iodine-refractory metastasic thyroid papillary carcinoma with BRAFV600E mutation treated with dabrafenib-trametinib: a case report.
BACKGROUND
Pneumatosis intestinalis (PI) is a rare entity which refers to the presence of gas within the wall of the small bowel or colon which is a radiographic sign. The etiology and clinical presentation are variable. Patients with PI may present either with chronic mild non-specific symptoms or with acute abdominal pain with peritonitis. Some cases of intestinal pneumatosis have been reported as adverse events of new oncological treatments such as targeted therapies that are widely used in multiple tumors.
METHODS
A 59-year-old caucasian female with radioactive iodine-refractory metastatic thyroid papillary carcinoma with BRAFV600E mutation was treated with dabrafenib and trametinib as a compassionate use. After 4 months treatment, positron emission tomography-computed tomography (PET-CT) showed PI. At the time of diagnosis, the patient was asymptomatic without signs of peritonitis. The initial treatment was conservative and no specific treatment for PI was needed. Unfortunately, after dabrafenib-trametinib withdrawal, the patient developed tumor progression with significant clinical worsening.
CONCLUSIONS
This case report is, in our knowledge, the first description of PI in a patient treated with dabrafenib-trametinib. Conservative treatment is feasible if there are no abdominal symptoms.
Background
Pneumatosis intestinalis is a rare condition characterized by the presence of subserosal and submucosal gas, with air-filled cysts occurring anywhere in the gastrointestinal tract [1]. PI often presents as an incidental finding on abdominal imaging in asymptomatic patients, but it may occur in the context of life-threatening intestinal pathology, such as acute intestinal ischemia [2]. The pathogenesis is poorly understood and PI is associated with a wide range of etiologies. Chemotherapy has been defined as a well-known predisposing factor by oncologists [3]. Nowadays, due to the increased use of targeted therapies, PI has also been described as a side effect of multiple targeted anticancer drugs [4]. This entity is one of the few conditions where a pneumoperitoneum has no mandatory indication for laparotomy [5]. Although the association of tyrosine kinase inhibitors with PI is rare, its knowledge and management are essential in the era of these targeted therapies.
Case presentation
A 59-year-old caucasian female was diagnosed with thyroid papillary carcinoma after total thyroidectomy in 2001. Diagnosed with postsurgical hypothyroidism under treatment with levothyroxine, 100 micrograms per day. There was no other previous medical history of interest. The patient did not consume tobacco or alcohol.
In 2008, a computerized tomography scan (CT) showed locoregional relapse and surgery was performed with resection of locoregional recurrence and left cervical lymphadenectomy. In November 2011, pulmonary relapse was treated with I-131 since November 2011 until March 2012 (total accumulated dose: 850 mCi). In October 2016, a CT scan showed a progression of the disease with cervical and pulmonary progression. The patient started sorafenib, 400 mg twice a day. Stable disease was maintained during 20 months. In June 2018, patient presented an episode of abrupt instability and cervical pain. The magnetic resonance imaging (MRI) (Fig. 1) showed a new metastatic lesion in the skull base with destruction of bony structures of the left occipital-petrous region. At this point, a molecular study of the cervical node was performed and a mutation in BRAFV600E was found.Fig. 1 Magnetic resonance imaging June 2018 showing metastatic lesion in the skull base with destruction of bony structures
Due to the lack of alternative therapeutic options, treatment with vemurafenib–trametinib was requested as a compassionate use. In August 2018, patient was started on the combination of dabrafenib 150 mg twice a day and trametinib 2 mg once a day. MRI in October 2018 showed a slight decrease of the metastatic lesion in the skull base (Fig. 2). In addition, the patient showed evident clinical improvement with decreased initial headache and cervicalgia.Fig. 2 Magnetic resonance imaging October 2018 showing a slight decrease of the metastatic lesion at the base of the skull
A follow-up PET–CT scan was performed in January 2019. Tumor was on radiological partial response. In addition, there was intestinal pneumatosis with mild sign of pneumoperitoneum (Fig. 3). Patient had no digestive symptoms and the abdominal medical examination was completely normal. Also normal neurological examination was verified. Routine physical examination showed blood pressure 110/60 mmHg, heart rate 80 bpm and 36.5 degree centigrade temperature. Blood test showed normal liver function: AST 21 U/L, ALT 16 U/L, bilirubin 0.19 mg/dL and normal renal function: creatinine 0.7 and glomerular filtrate > 90 mL/min. Blood count values were normal: leukocytes 7.6 × 1000/µL, hemoglobin 12 g/dL and platelets 417 × 1000/µL.Fig. 3 Positron emission tomography–computed tomography January 2019. (Images a and b show radiological signs of PI with mild sign of pneumoperitoneum showed in image c.)
The surgery department recommended conservative treatment unless new abdominal signs or symptoms were seen. Intravenous metoclopramide 10 mg/8 h and paracetamol 1000 mg/8 h were administrated. Both drugs, dabrafenib and trametinib, were discontinued after the PI diagnosis.
Only 10 days after the discontinuation of targeted therapy, tumor progression was shown with clinical deterioration due to intracranial hypertension and the patient died 4 weeks later because of intracranial disease progression. Because the cause of death was related with tumor progression, autopsy was not performed.
Discussion
Despite PI being related to targeted therapies, we have not found any report in patients receiving dabrafenib–trametinib. Here, we presented a case of a 59-year-old woman who developed PI 5 months after starting the combination treatment with those drugs.
Papillary thyroid cancer is the most common type among all thyroid tumors. Outcome of refractory radioactive iodine tumors is poor, the 10-year survival is 10% from the time of detection of metastasis [6]. About half of papillary thyroid cancers harbor the BRAFV600E mutation. Although the value of this mutation is still under investigation, thyroid cancer harboring BRAFV600E mutation have worse prognosis [7]. In the last decade, tyrosine kinase inhibitors have been approved and used for radioactive iodine-refractory patients.
Vemurafenib and dabrafenib potently inhibit BRAF proteins containing the V600E mutation and are indicated for patients with non-resectable or metastatic melanoma associated with this mutation [8]. Both drugs act in the RAS–RAF–MEK–ERK pathway which is overactivated by oncogenic mutation in the BRAF protein, triggering overactivation of this pathway and increasing cell proliferation, cell survival and angiogenesis [9]. Dabrafenib inhibits mutated BRAF proteins and trametinib inhibits MEK. Neither dabrafenib nor trametinib is currently approved for papillary thyroid cancer, however responses have been observed to those drugs in thyroid tumors carrying the BRAFV600 mutation.
In the last decade, the extended use of those targeted therapies has caused new types of toxicities. PI is a multifactorial entity with a wide range of etiologies: changes of the intestinal wall, peritonitis, bowel distention and corticosteroid therapy are some of the described etiologies [10].
A wide study evaluating the association of targeted therapies with PI and bowel perforation was published by Shinagare AB et al. These authors retrospectively reviewed 48 patients with cancer who developed one of these abdominal complications. Twenty-four patients were receiving molecular targeted therapies and have no other risk factors for PI or bowel perforation. Investigators showed that bevacizumab (n = 14) and sunitinib (n = 6) were the most common drugs associated with PI. Other drugs included were sorafenib, cetuximab, erlotinib and ipilimumab [11]. In the context of those treatments, the precise mechanism that leads to the association between targeted therapies and PI is currently unknown. In the case of antiangiogenics, bevacizumab, an anti-VEGF monoclonal antibody, has been shown to compromise the bowel wall integrity, producing intestinal wall disruption due to necrosis of the serosa and PI [11].
Conclusion
Despite the existence of other targeted therapies associated with PI, to our knowledge, this is the first report of PI in a patient receiving dabrafenib–trametinib. Conservative treatment is feasible if there are no abdominal signs or symptoms. However, the discontinuation of the cancer treatment led to a clinical deterioration and progression of the thyroid cancer. Understanding the toxicity of novel treatments is crucial in the management of our patients. In patients who are receiving targeted therapies it is possible that PI, if it appears, determines the vital prognosis and it should be considered a severe adverse event.
Abbreviations
PIPneumatosis intestinalis
PET–CTPositron emission tomography–computed tomography
CTComputed tomography
MRIMagnetic resonance imaging
VEGFVascular endothelial growth factor
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
All authors have approved the manuscript, including the conflict of interest statements, for submission for publication. All the authors have been involved in review of previous bibliography and review of successive drafts of the manuscript and have approved the manuscript.
Funding
There was no funding received for this project
Ethics approval and consent to participate
This case report study was carried out respecting the Declaration of Helsinki in its current version. The study of a case report is exempt from ethical approval in our institution.
Consent for publication
Written informed consent was obtained from the patient’s next of kin for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Availability of data and materials
This case report corresponds to a real case diagnosed and treated in our clinical center. Clinical and radiological data presented correspond to real data. The datasets supporting this article are stored in Hospital 12 Octubre medical records.
Competing interests
The authors included in this case report declare that they have no conflict of interest. | DABRAFENIB, TRAMETINIB | DrugsGivenReaction | CC BY | 33653337 | 19,092,829 | 2021-03-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Therapy partial responder'. | Pneumatosis intestinalis in a radioactive iodine-refractory metastasic thyroid papillary carcinoma with BRAFV600E mutation treated with dabrafenib-trametinib: a case report.
BACKGROUND
Pneumatosis intestinalis (PI) is a rare entity which refers to the presence of gas within the wall of the small bowel or colon which is a radiographic sign. The etiology and clinical presentation are variable. Patients with PI may present either with chronic mild non-specific symptoms or with acute abdominal pain with peritonitis. Some cases of intestinal pneumatosis have been reported as adverse events of new oncological treatments such as targeted therapies that are widely used in multiple tumors.
METHODS
A 59-year-old caucasian female with radioactive iodine-refractory metastatic thyroid papillary carcinoma with BRAFV600E mutation was treated with dabrafenib and trametinib as a compassionate use. After 4 months treatment, positron emission tomography-computed tomography (PET-CT) showed PI. At the time of diagnosis, the patient was asymptomatic without signs of peritonitis. The initial treatment was conservative and no specific treatment for PI was needed. Unfortunately, after dabrafenib-trametinib withdrawal, the patient developed tumor progression with significant clinical worsening.
CONCLUSIONS
This case report is, in our knowledge, the first description of PI in a patient treated with dabrafenib-trametinib. Conservative treatment is feasible if there are no abdominal symptoms.
Background
Pneumatosis intestinalis is a rare condition characterized by the presence of subserosal and submucosal gas, with air-filled cysts occurring anywhere in the gastrointestinal tract [1]. PI often presents as an incidental finding on abdominal imaging in asymptomatic patients, but it may occur in the context of life-threatening intestinal pathology, such as acute intestinal ischemia [2]. The pathogenesis is poorly understood and PI is associated with a wide range of etiologies. Chemotherapy has been defined as a well-known predisposing factor by oncologists [3]. Nowadays, due to the increased use of targeted therapies, PI has also been described as a side effect of multiple targeted anticancer drugs [4]. This entity is one of the few conditions where a pneumoperitoneum has no mandatory indication for laparotomy [5]. Although the association of tyrosine kinase inhibitors with PI is rare, its knowledge and management are essential in the era of these targeted therapies.
Case presentation
A 59-year-old caucasian female was diagnosed with thyroid papillary carcinoma after total thyroidectomy in 2001. Diagnosed with postsurgical hypothyroidism under treatment with levothyroxine, 100 micrograms per day. There was no other previous medical history of interest. The patient did not consume tobacco or alcohol.
In 2008, a computerized tomography scan (CT) showed locoregional relapse and surgery was performed with resection of locoregional recurrence and left cervical lymphadenectomy. In November 2011, pulmonary relapse was treated with I-131 since November 2011 until March 2012 (total accumulated dose: 850 mCi). In October 2016, a CT scan showed a progression of the disease with cervical and pulmonary progression. The patient started sorafenib, 400 mg twice a day. Stable disease was maintained during 20 months. In June 2018, patient presented an episode of abrupt instability and cervical pain. The magnetic resonance imaging (MRI) (Fig. 1) showed a new metastatic lesion in the skull base with destruction of bony structures of the left occipital-petrous region. At this point, a molecular study of the cervical node was performed and a mutation in BRAFV600E was found.Fig. 1 Magnetic resonance imaging June 2018 showing metastatic lesion in the skull base with destruction of bony structures
Due to the lack of alternative therapeutic options, treatment with vemurafenib–trametinib was requested as a compassionate use. In August 2018, patient was started on the combination of dabrafenib 150 mg twice a day and trametinib 2 mg once a day. MRI in October 2018 showed a slight decrease of the metastatic lesion in the skull base (Fig. 2). In addition, the patient showed evident clinical improvement with decreased initial headache and cervicalgia.Fig. 2 Magnetic resonance imaging October 2018 showing a slight decrease of the metastatic lesion at the base of the skull
A follow-up PET–CT scan was performed in January 2019. Tumor was on radiological partial response. In addition, there was intestinal pneumatosis with mild sign of pneumoperitoneum (Fig. 3). Patient had no digestive symptoms and the abdominal medical examination was completely normal. Also normal neurological examination was verified. Routine physical examination showed blood pressure 110/60 mmHg, heart rate 80 bpm and 36.5 degree centigrade temperature. Blood test showed normal liver function: AST 21 U/L, ALT 16 U/L, bilirubin 0.19 mg/dL and normal renal function: creatinine 0.7 and glomerular filtrate > 90 mL/min. Blood count values were normal: leukocytes 7.6 × 1000/µL, hemoglobin 12 g/dL and platelets 417 × 1000/µL.Fig. 3 Positron emission tomography–computed tomography January 2019. (Images a and b show radiological signs of PI with mild sign of pneumoperitoneum showed in image c.)
The surgery department recommended conservative treatment unless new abdominal signs or symptoms were seen. Intravenous metoclopramide 10 mg/8 h and paracetamol 1000 mg/8 h were administrated. Both drugs, dabrafenib and trametinib, were discontinued after the PI diagnosis.
Only 10 days after the discontinuation of targeted therapy, tumor progression was shown with clinical deterioration due to intracranial hypertension and the patient died 4 weeks later because of intracranial disease progression. Because the cause of death was related with tumor progression, autopsy was not performed.
Discussion
Despite PI being related to targeted therapies, we have not found any report in patients receiving dabrafenib–trametinib. Here, we presented a case of a 59-year-old woman who developed PI 5 months after starting the combination treatment with those drugs.
Papillary thyroid cancer is the most common type among all thyroid tumors. Outcome of refractory radioactive iodine tumors is poor, the 10-year survival is 10% from the time of detection of metastasis [6]. About half of papillary thyroid cancers harbor the BRAFV600E mutation. Although the value of this mutation is still under investigation, thyroid cancer harboring BRAFV600E mutation have worse prognosis [7]. In the last decade, tyrosine kinase inhibitors have been approved and used for radioactive iodine-refractory patients.
Vemurafenib and dabrafenib potently inhibit BRAF proteins containing the V600E mutation and are indicated for patients with non-resectable or metastatic melanoma associated with this mutation [8]. Both drugs act in the RAS–RAF–MEK–ERK pathway which is overactivated by oncogenic mutation in the BRAF protein, triggering overactivation of this pathway and increasing cell proliferation, cell survival and angiogenesis [9]. Dabrafenib inhibits mutated BRAF proteins and trametinib inhibits MEK. Neither dabrafenib nor trametinib is currently approved for papillary thyroid cancer, however responses have been observed to those drugs in thyroid tumors carrying the BRAFV600 mutation.
In the last decade, the extended use of those targeted therapies has caused new types of toxicities. PI is a multifactorial entity with a wide range of etiologies: changes of the intestinal wall, peritonitis, bowel distention and corticosteroid therapy are some of the described etiologies [10].
A wide study evaluating the association of targeted therapies with PI and bowel perforation was published by Shinagare AB et al. These authors retrospectively reviewed 48 patients with cancer who developed one of these abdominal complications. Twenty-four patients were receiving molecular targeted therapies and have no other risk factors for PI or bowel perforation. Investigators showed that bevacizumab (n = 14) and sunitinib (n = 6) were the most common drugs associated with PI. Other drugs included were sorafenib, cetuximab, erlotinib and ipilimumab [11]. In the context of those treatments, the precise mechanism that leads to the association between targeted therapies and PI is currently unknown. In the case of antiangiogenics, bevacizumab, an anti-VEGF monoclonal antibody, has been shown to compromise the bowel wall integrity, producing intestinal wall disruption due to necrosis of the serosa and PI [11].
Conclusion
Despite the existence of other targeted therapies associated with PI, to our knowledge, this is the first report of PI in a patient receiving dabrafenib–trametinib. Conservative treatment is feasible if there are no abdominal signs or symptoms. However, the discontinuation of the cancer treatment led to a clinical deterioration and progression of the thyroid cancer. Understanding the toxicity of novel treatments is crucial in the management of our patients. In patients who are receiving targeted therapies it is possible that PI, if it appears, determines the vital prognosis and it should be considered a severe adverse event.
Abbreviations
PIPneumatosis intestinalis
PET–CTPositron emission tomography–computed tomography
CTComputed tomography
MRIMagnetic resonance imaging
VEGFVascular endothelial growth factor
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Acknowledgements
Not applicable.
Authors’ contributions
All authors have approved the manuscript, including the conflict of interest statements, for submission for publication. All the authors have been involved in review of previous bibliography and review of successive drafts of the manuscript and have approved the manuscript.
Funding
There was no funding received for this project
Ethics approval and consent to participate
This case report study was carried out respecting the Declaration of Helsinki in its current version. The study of a case report is exempt from ethical approval in our institution.
Consent for publication
Written informed consent was obtained from the patient’s next of kin for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Availability of data and materials
This case report corresponds to a real case diagnosed and treated in our clinical center. Clinical and radiological data presented correspond to real data. The datasets supporting this article are stored in Hospital 12 Octubre medical records.
Competing interests
The authors included in this case report declare that they have no conflict of interest. | DABRAFENIB, TRAMETINIB | DrugsGivenReaction | CC BY | 33653337 | 19,092,829 | 2021-03-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Dizziness'. | Combination therapy of midodrine and droxidopa for refractory hypotension in heart failure with preserved ejection fraction per a pharmacist's proposal: a case report.
BACKGROUND
Patients with chronic heart failure (CHF) are often treated using many diuretics for symptom relief; however, diuretic use may have to continue despite hypotension development in these patients. Here, we present a case of heart failure with preserved ejection fraction (HFpEF), which is defined as ejection fraction ≥50% in CHF, and refractory hypotension, which was treated with midodrine and droxidopa to normalize blood pressure.
METHODS
The patient was a 62-year-old man with a history of HFpEF due to mitral regurgitation and complaints of dyspnea on exertion. He had been prescribed multiple medications at an outpatient clinic for CHF management, including azosemide 60 mg/day, bisoprolol 2.5 mg/day, enalapril 2.5 mg/day, spironolactone 50 mg/day, and tolvaptan 15 mg/day. The systolic blood pressure (SBP) of the patient remained at 70-80 mmHg because the use of the diuretic could not be reduced or discontinued owing to edema and weight gain. He was hospitalized for the exacerbation of CHF. Although midodrine 8 mg/day was administered to improve hypotension, the SBP of the patient increased only up to 90 mmHg. On the 35th day after hospitalization, the urine volume decreased significantly (< 100 mL/day) due to hypotension. When droxidopa 200 mg/day replaced intravenous noradrenaline on the 47th day, the SBP remained at 100-120 mmHg and the urine volume increased.
CONCLUSIONS
Oral combination treatment with midodrine and droxidopa might contribute to the maintenance of blood pressure and diuretic activity in HFpEF patients with refractory hypotension. However, further long-term studies evaluating the safety and efficacy of this combination therapy for patients with HFpEF are needed.
Background
While it is well-known that diuretic treatment is crucial to improve the prognosis and symptoms among patients with chronic heart failure (CHF) [1–3], a diminished diuretic response is common in these patients, increasing the required diuretic dose [4]. Hypotension has been defined as systolic blood pressure (SBP) < 90 mmHg and/or diastolic blood pressure (DBP) < 60 mmHg [5]. In particular, diuretic-induced hypotension causes dizziness [6]. However, the administration of diuretics in these patients cannot be stopped as this would likely result in the progression of heart failure [7].
Many reports have shown that droxidopa, a noradrenaline (NA) prodrug, improves the symptoms of orthostatic hypotension in patients with Parkinson disease, multiple system atrophy, and pure autonomic failure [8–10]. While extensive evidence is available regarding neurogenic hypotension, information on the efficacy and safety of droxidopa for refractory hypotension with CHF is insufficient. Midodrine is widely used for the management of orthostatic blood pressure [11]; however, there is no evidence available on the efficacy of the combination of midodrine and droxidopa. In recent years, drug treatment has been reported to improve prognosis in heart failure with reduced ejection fraction (HFrEF), in which ejection fraction (EF) is < 40% [1–3]. However, guidelines for the treatment of heart failure with preserved ejection fraction (HFpEF), in which EF is ≥50%, are not available. Here, we describe the case of a patient with HFpEF who was successfully treated for refractory hypotension.
Case presentation
The patient was a 62-year-old man with a history of CHF due to mitral regurgitation and complaints of dyspnea on exertion (New York Heart Association functional class III). After mitral annuloplasty, he was prescribed multiple medications at an outpatient clinic for the management of CHF, including azosemide 60 mg/day, bisoprolol 2.5 mg/day, enalapril 2.5 mg/day, spironolactone 50 mg/day, and tolvaptan 15 mg/day. The SBP of the patient remained at 70–80 mmHg because diuretic use could not be reduced or discontinued due to the possible effects of edema and weight gain. He was hospitalized for exacerbation of heart failure. On admission, his SBP and DBP were 83 and 47, respectively, and his heart rate (HR) was 88 beats/min. On the 3rd day after hospitalization, a pharmacist proposed midodrine 4 mg/day, an oral pressor with a weak effect on HR [12], to the attending doctor, after which drug administration was started (Fig. 1). The EF was measured on the 8th day and was 53.4%, which is categorized as HFpEF. Furosemide 20 mg/day was started because the urine volume was low on the 8th day. Over a 9-day period after the initiation of midodrine treatment, the dose was increased to 8 mg/day; however, SBP increased only up to 90 mmHg. Although amezinium 20 mg/day was administered on the 25th day for further pressor action, it was discontinued on the 29th day due to the onset of tachycardia (Fig. 1).
Fig. 1 Clinical course of the hospitalized patient in this study. Up-titration and down-titration of medications while in the hospital are shown, along with the daily urine volume, intake volume, blood pressure, and HR. BP, blood pressure; CHDF, continuous hemodiafiltration; DBP, diastolic blood pressure; DOA, dopamine; hANP, human atrial natriuretic peptide; HR, heart rate; NA, noradrenaline; SBP, systolic blood pressure. The unit γ shows μg/kg/min. SBP, DBP, and HR are shown as the mean ± standard deviation (SD)
In HFrEF, enalapril has been shown to contribute to improved prognosis [13], whereas it is unknown if this effect is present in HFpEF. However, because in HFpEF it may also be highly beneficial to continue with renin-angiotensin system inhibitors, we changed the drug regimen to losartan, which is reported to have a weak hypertensive effect among the angiotensin II receptor blockers [14]. From the 35th day of hospitalization, blood pressure decreased and urine volume decreased significantly (< 100 mL/day), and losartan was discontinued on the 36th day. Consequently, the patient underwent continuous hemodiafiltration (CHDF) on the 36th day only. As shown in Fig. 1, continuous intravenous infusion of dopamine from the 35th day and NA and human atrial natriuretic peptide from the 36th day gradually increased the blood pressure and urine volume. However, it was suggested that it would not be possible to maintain blood pressure upon NA discontinuation. Therefore, the attending doctor consulted a pharmacist regarding the switch from NA to oral pressor drugs. On the basis of some case reports [8–10], the pharmacist suggested switching from intravenous NA to droxidopa, which is converted to NA in vivo, on the 47th day. When the dosage of droxidopa was increased from 200 mg/day to 300 mg/day on the 49th day of hospitalization, SBP and DBP increased to 100–120 mmHg and 60–80 mmHg, respectively. As blood pressure increased, urine volume could be maintained at an average of 3000 mL/day. Seven days after the start of this combination therapy, the EF was 60.1% (Day 53), and no decrease was observed compared to the findings on the Day 8 (EF = 53.4%). In addition, this combination therapy also did not affect cardiothoracic ratio (CTR) (Day 8: CTR = 58% and Day 60: CTR = 58%) (Fig. 2). After discharge, the patient’s SBP and DBP were maintained using a combination of midodrine 8 mg/day and droxidopa 300 mg/day therapy, and his dizziness disappeared.
Fig. 2 Chest X-ray of the patient pre- and post-combination therapy with midodrine and droxidopa. Cardiothoracic ratio (CTR, %) was calculated as (a/b) × 100. A Chest X-ray showing pre-combination therapy status on the 8th day of hospitalization with a CTR of 58%. B Chest X-ray showing post-combination therapy status on the 60th day of hospitalization with a CTR of 58%
Discussion and conclusions
Hypotension is one of the most serious side effects of diuretics in patients with CHF [6]. It causes not only dizziness, but also reduction of diuretic activity because of decreased blood flow [4]. Therefore, it is suggested that improving hypotension may contribute to ensuring diuretic responsiveness. In the case of our patient with HFpEF and refractory hypotension, combination therapy of midodrine and droxidopa increased blood pressure and improved diuretic responsiveness.
While a β-blocker may have potential to improve prognosis in HFpEF [15], bisoprolol decreases blood pressure [16]. In this case, because bisoprolol was used to control tachycardia, we continued to administer bisoprolol at the lowest possible dose while monitoring the HR.
Midodrine is an oral alpha-1 adrenergic agonist that acts as a blood pressor [11] and decreases HR [12]. Although the sample size was small, it was also reported that midodrine elevates EF significantly in HFrEF [17]. Considering this evidence, midodrine might be considered suitable as an oral pressor for patients with HFpEF. Midodrine can elevate SBP and DBP by approximately 20 mmHg [17], and the degree of increase in blood pressure in our patient was similar to that reported previously [17]. Although amezinium was administered on the 25th day, the HR of the patient increased (Fig. 1). Katoh et al. [18] revealed that amezinium elevated HR. Tachycardia is known to be an exacerbating prognostic factor for heart failure [19], suggesting that midodrine, but not amezinium, may show efficacy as an oral pressor in patients with HFpEF.
Despite the administration of midodrine, the urine volume decreased due to excessive hypotension on the 34th and 35th days of hospitalization, and CHDF was performed on the 36th day. It was speculated that the blood pressure might be insufficiently maintained. Because droxidopa is metabolized by L-aromatic-amino-acid decarboxylase to NA, which mediates a pressor response [20], it may be useful to switch from intravenous to oral NA treatment due to hypotension. As expected, up-titration of droxidopa from 200 to 300 mg/day combined with 8 mg/day midodrine rapidly and significantly improved hypotension. Because the blood pressure of the patient could be maintained using this combination therapy, it is considered that the responsiveness to diuretics increased. Therefore, it may be possible to reduce the dose of diuretics such as furosemide. In a double-blind, 4-period crossover study, there were no clinically relevant effects of droxidopa on HR [21]. While the cardiovascular safety of droxidopa has been reported in patients with neurogenic hypotension [22], the detailed safety profile in patients with a history of HFpEF remains unknown. No adverse effects of the combination therapy were noted over the short term in this case. To the best of our knowledge, there is no information regarding the efficacy and safety of droxidopa combined with midodrine in HFpEF patients over the long term. Accordingly, further studies evaluating the safety and efficacy of long-term combination therapy of droxidopa and midodrine for HFpEF patients are needed.
Based on our findings, the combination therapy of midodrine and droxidopa might be safely and effectively administered to HFpEF patients with refractory hypotension, but further studies need to be conducted. In general, diuretic use should be reduced or discontinued if hypotension develops in patients with CHF. If the administration of diuretics must be continued owing to CHF progression, it is advisable to first start midodrine and then add droxidopa if hypotension cannot be effectively controlled.
Abbreviations
CHDFContinuous hemodiafiltration
CHFChronic heart failure
CTRCardiothoracic ratio
DBPDiastolic blood pressure
EFEjection fraction
HFpEFHeart failure with preserved ejection fraction
HFrEFHeart failure with reduced ejection fraction
HRHeart rate
NANoradrenaline
SBPSystolic blood pressure
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Not applicable.
Authors’ contributions
All authors edited the manuscript and approved the final version. Participated in research design: Asai, Sato, Yamamoto, Kito, Hioki, Urata, Abe. Wrote or contributed to the writing of the manuscript: Asai, Abe.
Funding
Not applicable.
Availability of data and materials
All the data generated or analyzed in this study are included in the published article.
Ethics approval and consent to participate
Because this is a case report, ethics review was deemed unnecessary at the discretion of the Ethics Review Committee of the National Hospital Organization Mie Chuo Medical Center.
Consent for publication
Written informed consent was obtained from the patient afterwards.
Competing interests
The authors declare that they have no competing interests. | AMEZINIUM METILSULFATE, AZOSEMIDE, BISOPROLOL, DOPAMINE HYDROCHLORIDE, ENALAPRIL, FUROSEMIDE, LOSARTAN, MIDODRINE, NOREPINEPHRINE, SPIRONOLACTONE, TOLVAPTAN | DrugsGivenReaction | CC BY | 33653416 | 19,980,597 | 2021-03-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Combination therapy of midodrine and droxidopa for refractory hypotension in heart failure with preserved ejection fraction per a pharmacist's proposal: a case report.
BACKGROUND
Patients with chronic heart failure (CHF) are often treated using many diuretics for symptom relief; however, diuretic use may have to continue despite hypotension development in these patients. Here, we present a case of heart failure with preserved ejection fraction (HFpEF), which is defined as ejection fraction ≥50% in CHF, and refractory hypotension, which was treated with midodrine and droxidopa to normalize blood pressure.
METHODS
The patient was a 62-year-old man with a history of HFpEF due to mitral regurgitation and complaints of dyspnea on exertion. He had been prescribed multiple medications at an outpatient clinic for CHF management, including azosemide 60 mg/day, bisoprolol 2.5 mg/day, enalapril 2.5 mg/day, spironolactone 50 mg/day, and tolvaptan 15 mg/day. The systolic blood pressure (SBP) of the patient remained at 70-80 mmHg because the use of the diuretic could not be reduced or discontinued owing to edema and weight gain. He was hospitalized for the exacerbation of CHF. Although midodrine 8 mg/day was administered to improve hypotension, the SBP of the patient increased only up to 90 mmHg. On the 35th day after hospitalization, the urine volume decreased significantly (< 100 mL/day) due to hypotension. When droxidopa 200 mg/day replaced intravenous noradrenaline on the 47th day, the SBP remained at 100-120 mmHg and the urine volume increased.
CONCLUSIONS
Oral combination treatment with midodrine and droxidopa might contribute to the maintenance of blood pressure and diuretic activity in HFpEF patients with refractory hypotension. However, further long-term studies evaluating the safety and efficacy of this combination therapy for patients with HFpEF are needed.
Background
While it is well-known that diuretic treatment is crucial to improve the prognosis and symptoms among patients with chronic heart failure (CHF) [1–3], a diminished diuretic response is common in these patients, increasing the required diuretic dose [4]. Hypotension has been defined as systolic blood pressure (SBP) < 90 mmHg and/or diastolic blood pressure (DBP) < 60 mmHg [5]. In particular, diuretic-induced hypotension causes dizziness [6]. However, the administration of diuretics in these patients cannot be stopped as this would likely result in the progression of heart failure [7].
Many reports have shown that droxidopa, a noradrenaline (NA) prodrug, improves the symptoms of orthostatic hypotension in patients with Parkinson disease, multiple system atrophy, and pure autonomic failure [8–10]. While extensive evidence is available regarding neurogenic hypotension, information on the efficacy and safety of droxidopa for refractory hypotension with CHF is insufficient. Midodrine is widely used for the management of orthostatic blood pressure [11]; however, there is no evidence available on the efficacy of the combination of midodrine and droxidopa. In recent years, drug treatment has been reported to improve prognosis in heart failure with reduced ejection fraction (HFrEF), in which ejection fraction (EF) is < 40% [1–3]. However, guidelines for the treatment of heart failure with preserved ejection fraction (HFpEF), in which EF is ≥50%, are not available. Here, we describe the case of a patient with HFpEF who was successfully treated for refractory hypotension.
Case presentation
The patient was a 62-year-old man with a history of CHF due to mitral regurgitation and complaints of dyspnea on exertion (New York Heart Association functional class III). After mitral annuloplasty, he was prescribed multiple medications at an outpatient clinic for the management of CHF, including azosemide 60 mg/day, bisoprolol 2.5 mg/day, enalapril 2.5 mg/day, spironolactone 50 mg/day, and tolvaptan 15 mg/day. The SBP of the patient remained at 70–80 mmHg because diuretic use could not be reduced or discontinued due to the possible effects of edema and weight gain. He was hospitalized for exacerbation of heart failure. On admission, his SBP and DBP were 83 and 47, respectively, and his heart rate (HR) was 88 beats/min. On the 3rd day after hospitalization, a pharmacist proposed midodrine 4 mg/day, an oral pressor with a weak effect on HR [12], to the attending doctor, after which drug administration was started (Fig. 1). The EF was measured on the 8th day and was 53.4%, which is categorized as HFpEF. Furosemide 20 mg/day was started because the urine volume was low on the 8th day. Over a 9-day period after the initiation of midodrine treatment, the dose was increased to 8 mg/day; however, SBP increased only up to 90 mmHg. Although amezinium 20 mg/day was administered on the 25th day for further pressor action, it was discontinued on the 29th day due to the onset of tachycardia (Fig. 1).
Fig. 1 Clinical course of the hospitalized patient in this study. Up-titration and down-titration of medications while in the hospital are shown, along with the daily urine volume, intake volume, blood pressure, and HR. BP, blood pressure; CHDF, continuous hemodiafiltration; DBP, diastolic blood pressure; DOA, dopamine; hANP, human atrial natriuretic peptide; HR, heart rate; NA, noradrenaline; SBP, systolic blood pressure. The unit γ shows μg/kg/min. SBP, DBP, and HR are shown as the mean ± standard deviation (SD)
In HFrEF, enalapril has been shown to contribute to improved prognosis [13], whereas it is unknown if this effect is present in HFpEF. However, because in HFpEF it may also be highly beneficial to continue with renin-angiotensin system inhibitors, we changed the drug regimen to losartan, which is reported to have a weak hypertensive effect among the angiotensin II receptor blockers [14]. From the 35th day of hospitalization, blood pressure decreased and urine volume decreased significantly (< 100 mL/day), and losartan was discontinued on the 36th day. Consequently, the patient underwent continuous hemodiafiltration (CHDF) on the 36th day only. As shown in Fig. 1, continuous intravenous infusion of dopamine from the 35th day and NA and human atrial natriuretic peptide from the 36th day gradually increased the blood pressure and urine volume. However, it was suggested that it would not be possible to maintain blood pressure upon NA discontinuation. Therefore, the attending doctor consulted a pharmacist regarding the switch from NA to oral pressor drugs. On the basis of some case reports [8–10], the pharmacist suggested switching from intravenous NA to droxidopa, which is converted to NA in vivo, on the 47th day. When the dosage of droxidopa was increased from 200 mg/day to 300 mg/day on the 49th day of hospitalization, SBP and DBP increased to 100–120 mmHg and 60–80 mmHg, respectively. As blood pressure increased, urine volume could be maintained at an average of 3000 mL/day. Seven days after the start of this combination therapy, the EF was 60.1% (Day 53), and no decrease was observed compared to the findings on the Day 8 (EF = 53.4%). In addition, this combination therapy also did not affect cardiothoracic ratio (CTR) (Day 8: CTR = 58% and Day 60: CTR = 58%) (Fig. 2). After discharge, the patient’s SBP and DBP were maintained using a combination of midodrine 8 mg/day and droxidopa 300 mg/day therapy, and his dizziness disappeared.
Fig. 2 Chest X-ray of the patient pre- and post-combination therapy with midodrine and droxidopa. Cardiothoracic ratio (CTR, %) was calculated as (a/b) × 100. A Chest X-ray showing pre-combination therapy status on the 8th day of hospitalization with a CTR of 58%. B Chest X-ray showing post-combination therapy status on the 60th day of hospitalization with a CTR of 58%
Discussion and conclusions
Hypotension is one of the most serious side effects of diuretics in patients with CHF [6]. It causes not only dizziness, but also reduction of diuretic activity because of decreased blood flow [4]. Therefore, it is suggested that improving hypotension may contribute to ensuring diuretic responsiveness. In the case of our patient with HFpEF and refractory hypotension, combination therapy of midodrine and droxidopa increased blood pressure and improved diuretic responsiveness.
While a β-blocker may have potential to improve prognosis in HFpEF [15], bisoprolol decreases blood pressure [16]. In this case, because bisoprolol was used to control tachycardia, we continued to administer bisoprolol at the lowest possible dose while monitoring the HR.
Midodrine is an oral alpha-1 adrenergic agonist that acts as a blood pressor [11] and decreases HR [12]. Although the sample size was small, it was also reported that midodrine elevates EF significantly in HFrEF [17]. Considering this evidence, midodrine might be considered suitable as an oral pressor for patients with HFpEF. Midodrine can elevate SBP and DBP by approximately 20 mmHg [17], and the degree of increase in blood pressure in our patient was similar to that reported previously [17]. Although amezinium was administered on the 25th day, the HR of the patient increased (Fig. 1). Katoh et al. [18] revealed that amezinium elevated HR. Tachycardia is known to be an exacerbating prognostic factor for heart failure [19], suggesting that midodrine, but not amezinium, may show efficacy as an oral pressor in patients with HFpEF.
Despite the administration of midodrine, the urine volume decreased due to excessive hypotension on the 34th and 35th days of hospitalization, and CHDF was performed on the 36th day. It was speculated that the blood pressure might be insufficiently maintained. Because droxidopa is metabolized by L-aromatic-amino-acid decarboxylase to NA, which mediates a pressor response [20], it may be useful to switch from intravenous to oral NA treatment due to hypotension. As expected, up-titration of droxidopa from 200 to 300 mg/day combined with 8 mg/day midodrine rapidly and significantly improved hypotension. Because the blood pressure of the patient could be maintained using this combination therapy, it is considered that the responsiveness to diuretics increased. Therefore, it may be possible to reduce the dose of diuretics such as furosemide. In a double-blind, 4-period crossover study, there were no clinically relevant effects of droxidopa on HR [21]. While the cardiovascular safety of droxidopa has been reported in patients with neurogenic hypotension [22], the detailed safety profile in patients with a history of HFpEF remains unknown. No adverse effects of the combination therapy were noted over the short term in this case. To the best of our knowledge, there is no information regarding the efficacy and safety of droxidopa combined with midodrine in HFpEF patients over the long term. Accordingly, further studies evaluating the safety and efficacy of long-term combination therapy of droxidopa and midodrine for HFpEF patients are needed.
Based on our findings, the combination therapy of midodrine and droxidopa might be safely and effectively administered to HFpEF patients with refractory hypotension, but further studies need to be conducted. In general, diuretic use should be reduced or discontinued if hypotension develops in patients with CHF. If the administration of diuretics must be continued owing to CHF progression, it is advisable to first start midodrine and then add droxidopa if hypotension cannot be effectively controlled.
Abbreviations
CHDFContinuous hemodiafiltration
CHFChronic heart failure
CTRCardiothoracic ratio
DBPDiastolic blood pressure
EFEjection fraction
HFpEFHeart failure with preserved ejection fraction
HFrEFHeart failure with reduced ejection fraction
HRHeart rate
NANoradrenaline
SBPSystolic blood pressure
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Not applicable.
Authors’ contributions
All authors edited the manuscript and approved the final version. Participated in research design: Asai, Sato, Yamamoto, Kito, Hioki, Urata, Abe. Wrote or contributed to the writing of the manuscript: Asai, Abe.
Funding
Not applicable.
Availability of data and materials
All the data generated or analyzed in this study are included in the published article.
Ethics approval and consent to participate
Because this is a case report, ethics review was deemed unnecessary at the discretion of the Ethics Review Committee of the National Hospital Organization Mie Chuo Medical Center.
Consent for publication
Written informed consent was obtained from the patient afterwards.
Competing interests
The authors declare that they have no competing interests. | AMEZINIUM METILSULFATE, AZOSEMIDE, BISOPROLOL, DOPAMINE HYDROCHLORIDE, ENALAPRIL, FUROSEMIDE, LOSARTAN, MIDODRINE, NOREPINEPHRINE, SPIRONOLACTONE, TOLVAPTAN | DrugsGivenReaction | CC BY | 33653416 | 19,980,597 | 2021-03-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypotension'. | Combination therapy of midodrine and droxidopa for refractory hypotension in heart failure with preserved ejection fraction per a pharmacist's proposal: a case report.
BACKGROUND
Patients with chronic heart failure (CHF) are often treated using many diuretics for symptom relief; however, diuretic use may have to continue despite hypotension development in these patients. Here, we present a case of heart failure with preserved ejection fraction (HFpEF), which is defined as ejection fraction ≥50% in CHF, and refractory hypotension, which was treated with midodrine and droxidopa to normalize blood pressure.
METHODS
The patient was a 62-year-old man with a history of HFpEF due to mitral regurgitation and complaints of dyspnea on exertion. He had been prescribed multiple medications at an outpatient clinic for CHF management, including azosemide 60 mg/day, bisoprolol 2.5 mg/day, enalapril 2.5 mg/day, spironolactone 50 mg/day, and tolvaptan 15 mg/day. The systolic blood pressure (SBP) of the patient remained at 70-80 mmHg because the use of the diuretic could not be reduced or discontinued owing to edema and weight gain. He was hospitalized for the exacerbation of CHF. Although midodrine 8 mg/day was administered to improve hypotension, the SBP of the patient increased only up to 90 mmHg. On the 35th day after hospitalization, the urine volume decreased significantly (< 100 mL/day) due to hypotension. When droxidopa 200 mg/day replaced intravenous noradrenaline on the 47th day, the SBP remained at 100-120 mmHg and the urine volume increased.
CONCLUSIONS
Oral combination treatment with midodrine and droxidopa might contribute to the maintenance of blood pressure and diuretic activity in HFpEF patients with refractory hypotension. However, further long-term studies evaluating the safety and efficacy of this combination therapy for patients with HFpEF are needed.
Background
While it is well-known that diuretic treatment is crucial to improve the prognosis and symptoms among patients with chronic heart failure (CHF) [1–3], a diminished diuretic response is common in these patients, increasing the required diuretic dose [4]. Hypotension has been defined as systolic blood pressure (SBP) < 90 mmHg and/or diastolic blood pressure (DBP) < 60 mmHg [5]. In particular, diuretic-induced hypotension causes dizziness [6]. However, the administration of diuretics in these patients cannot be stopped as this would likely result in the progression of heart failure [7].
Many reports have shown that droxidopa, a noradrenaline (NA) prodrug, improves the symptoms of orthostatic hypotension in patients with Parkinson disease, multiple system atrophy, and pure autonomic failure [8–10]. While extensive evidence is available regarding neurogenic hypotension, information on the efficacy and safety of droxidopa for refractory hypotension with CHF is insufficient. Midodrine is widely used for the management of orthostatic blood pressure [11]; however, there is no evidence available on the efficacy of the combination of midodrine and droxidopa. In recent years, drug treatment has been reported to improve prognosis in heart failure with reduced ejection fraction (HFrEF), in which ejection fraction (EF) is < 40% [1–3]. However, guidelines for the treatment of heart failure with preserved ejection fraction (HFpEF), in which EF is ≥50%, are not available. Here, we describe the case of a patient with HFpEF who was successfully treated for refractory hypotension.
Case presentation
The patient was a 62-year-old man with a history of CHF due to mitral regurgitation and complaints of dyspnea on exertion (New York Heart Association functional class III). After mitral annuloplasty, he was prescribed multiple medications at an outpatient clinic for the management of CHF, including azosemide 60 mg/day, bisoprolol 2.5 mg/day, enalapril 2.5 mg/day, spironolactone 50 mg/day, and tolvaptan 15 mg/day. The SBP of the patient remained at 70–80 mmHg because diuretic use could not be reduced or discontinued due to the possible effects of edema and weight gain. He was hospitalized for exacerbation of heart failure. On admission, his SBP and DBP were 83 and 47, respectively, and his heart rate (HR) was 88 beats/min. On the 3rd day after hospitalization, a pharmacist proposed midodrine 4 mg/day, an oral pressor with a weak effect on HR [12], to the attending doctor, after which drug administration was started (Fig. 1). The EF was measured on the 8th day and was 53.4%, which is categorized as HFpEF. Furosemide 20 mg/day was started because the urine volume was low on the 8th day. Over a 9-day period after the initiation of midodrine treatment, the dose was increased to 8 mg/day; however, SBP increased only up to 90 mmHg. Although amezinium 20 mg/day was administered on the 25th day for further pressor action, it was discontinued on the 29th day due to the onset of tachycardia (Fig. 1).
Fig. 1 Clinical course of the hospitalized patient in this study. Up-titration and down-titration of medications while in the hospital are shown, along with the daily urine volume, intake volume, blood pressure, and HR. BP, blood pressure; CHDF, continuous hemodiafiltration; DBP, diastolic blood pressure; DOA, dopamine; hANP, human atrial natriuretic peptide; HR, heart rate; NA, noradrenaline; SBP, systolic blood pressure. The unit γ shows μg/kg/min. SBP, DBP, and HR are shown as the mean ± standard deviation (SD)
In HFrEF, enalapril has been shown to contribute to improved prognosis [13], whereas it is unknown if this effect is present in HFpEF. However, because in HFpEF it may also be highly beneficial to continue with renin-angiotensin system inhibitors, we changed the drug regimen to losartan, which is reported to have a weak hypertensive effect among the angiotensin II receptor blockers [14]. From the 35th day of hospitalization, blood pressure decreased and urine volume decreased significantly (< 100 mL/day), and losartan was discontinued on the 36th day. Consequently, the patient underwent continuous hemodiafiltration (CHDF) on the 36th day only. As shown in Fig. 1, continuous intravenous infusion of dopamine from the 35th day and NA and human atrial natriuretic peptide from the 36th day gradually increased the blood pressure and urine volume. However, it was suggested that it would not be possible to maintain blood pressure upon NA discontinuation. Therefore, the attending doctor consulted a pharmacist regarding the switch from NA to oral pressor drugs. On the basis of some case reports [8–10], the pharmacist suggested switching from intravenous NA to droxidopa, which is converted to NA in vivo, on the 47th day. When the dosage of droxidopa was increased from 200 mg/day to 300 mg/day on the 49th day of hospitalization, SBP and DBP increased to 100–120 mmHg and 60–80 mmHg, respectively. As blood pressure increased, urine volume could be maintained at an average of 3000 mL/day. Seven days after the start of this combination therapy, the EF was 60.1% (Day 53), and no decrease was observed compared to the findings on the Day 8 (EF = 53.4%). In addition, this combination therapy also did not affect cardiothoracic ratio (CTR) (Day 8: CTR = 58% and Day 60: CTR = 58%) (Fig. 2). After discharge, the patient’s SBP and DBP were maintained using a combination of midodrine 8 mg/day and droxidopa 300 mg/day therapy, and his dizziness disappeared.
Fig. 2 Chest X-ray of the patient pre- and post-combination therapy with midodrine and droxidopa. Cardiothoracic ratio (CTR, %) was calculated as (a/b) × 100. A Chest X-ray showing pre-combination therapy status on the 8th day of hospitalization with a CTR of 58%. B Chest X-ray showing post-combination therapy status on the 60th day of hospitalization with a CTR of 58%
Discussion and conclusions
Hypotension is one of the most serious side effects of diuretics in patients with CHF [6]. It causes not only dizziness, but also reduction of diuretic activity because of decreased blood flow [4]. Therefore, it is suggested that improving hypotension may contribute to ensuring diuretic responsiveness. In the case of our patient with HFpEF and refractory hypotension, combination therapy of midodrine and droxidopa increased blood pressure and improved diuretic responsiveness.
While a β-blocker may have potential to improve prognosis in HFpEF [15], bisoprolol decreases blood pressure [16]. In this case, because bisoprolol was used to control tachycardia, we continued to administer bisoprolol at the lowest possible dose while monitoring the HR.
Midodrine is an oral alpha-1 adrenergic agonist that acts as a blood pressor [11] and decreases HR [12]. Although the sample size was small, it was also reported that midodrine elevates EF significantly in HFrEF [17]. Considering this evidence, midodrine might be considered suitable as an oral pressor for patients with HFpEF. Midodrine can elevate SBP and DBP by approximately 20 mmHg [17], and the degree of increase in blood pressure in our patient was similar to that reported previously [17]. Although amezinium was administered on the 25th day, the HR of the patient increased (Fig. 1). Katoh et al. [18] revealed that amezinium elevated HR. Tachycardia is known to be an exacerbating prognostic factor for heart failure [19], suggesting that midodrine, but not amezinium, may show efficacy as an oral pressor in patients with HFpEF.
Despite the administration of midodrine, the urine volume decreased due to excessive hypotension on the 34th and 35th days of hospitalization, and CHDF was performed on the 36th day. It was speculated that the blood pressure might be insufficiently maintained. Because droxidopa is metabolized by L-aromatic-amino-acid decarboxylase to NA, which mediates a pressor response [20], it may be useful to switch from intravenous to oral NA treatment due to hypotension. As expected, up-titration of droxidopa from 200 to 300 mg/day combined with 8 mg/day midodrine rapidly and significantly improved hypotension. Because the blood pressure of the patient could be maintained using this combination therapy, it is considered that the responsiveness to diuretics increased. Therefore, it may be possible to reduce the dose of diuretics such as furosemide. In a double-blind, 4-period crossover study, there were no clinically relevant effects of droxidopa on HR [21]. While the cardiovascular safety of droxidopa has been reported in patients with neurogenic hypotension [22], the detailed safety profile in patients with a history of HFpEF remains unknown. No adverse effects of the combination therapy were noted over the short term in this case. To the best of our knowledge, there is no information regarding the efficacy and safety of droxidopa combined with midodrine in HFpEF patients over the long term. Accordingly, further studies evaluating the safety and efficacy of long-term combination therapy of droxidopa and midodrine for HFpEF patients are needed.
Based on our findings, the combination therapy of midodrine and droxidopa might be safely and effectively administered to HFpEF patients with refractory hypotension, but further studies need to be conducted. In general, diuretic use should be reduced or discontinued if hypotension develops in patients with CHF. If the administration of diuretics must be continued owing to CHF progression, it is advisable to first start midodrine and then add droxidopa if hypotension cannot be effectively controlled.
Abbreviations
CHDFContinuous hemodiafiltration
CHFChronic heart failure
CTRCardiothoracic ratio
DBPDiastolic blood pressure
EFEjection fraction
HFpEFHeart failure with preserved ejection fraction
HFrEFHeart failure with reduced ejection fraction
HRHeart rate
NANoradrenaline
SBPSystolic blood pressure
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Not applicable.
Authors’ contributions
All authors edited the manuscript and approved the final version. Participated in research design: Asai, Sato, Yamamoto, Kito, Hioki, Urata, Abe. Wrote or contributed to the writing of the manuscript: Asai, Abe.
Funding
Not applicable.
Availability of data and materials
All the data generated or analyzed in this study are included in the published article.
Ethics approval and consent to participate
Because this is a case report, ethics review was deemed unnecessary at the discretion of the Ethics Review Committee of the National Hospital Organization Mie Chuo Medical Center.
Consent for publication
Written informed consent was obtained from the patient afterwards.
Competing interests
The authors declare that they have no competing interests. | AMEZINIUM METILSULFATE, AZOSEMIDE, BISOPROLOL, DOPAMINE HYDROCHLORIDE, ENALAPRIL, FUROSEMIDE, LOSARTAN, MIDODRINE, NOREPINEPHRINE, SPIRONOLACTONE, TOLVAPTAN | DrugsGivenReaction | CC BY | 33653416 | 19,980,597 | 2021-03-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Tachycardia'. | Combination therapy of midodrine and droxidopa for refractory hypotension in heart failure with preserved ejection fraction per a pharmacist's proposal: a case report.
BACKGROUND
Patients with chronic heart failure (CHF) are often treated using many diuretics for symptom relief; however, diuretic use may have to continue despite hypotension development in these patients. Here, we present a case of heart failure with preserved ejection fraction (HFpEF), which is defined as ejection fraction ≥50% in CHF, and refractory hypotension, which was treated with midodrine and droxidopa to normalize blood pressure.
METHODS
The patient was a 62-year-old man with a history of HFpEF due to mitral regurgitation and complaints of dyspnea on exertion. He had been prescribed multiple medications at an outpatient clinic for CHF management, including azosemide 60 mg/day, bisoprolol 2.5 mg/day, enalapril 2.5 mg/day, spironolactone 50 mg/day, and tolvaptan 15 mg/day. The systolic blood pressure (SBP) of the patient remained at 70-80 mmHg because the use of the diuretic could not be reduced or discontinued owing to edema and weight gain. He was hospitalized for the exacerbation of CHF. Although midodrine 8 mg/day was administered to improve hypotension, the SBP of the patient increased only up to 90 mmHg. On the 35th day after hospitalization, the urine volume decreased significantly (< 100 mL/day) due to hypotension. When droxidopa 200 mg/day replaced intravenous noradrenaline on the 47th day, the SBP remained at 100-120 mmHg and the urine volume increased.
CONCLUSIONS
Oral combination treatment with midodrine and droxidopa might contribute to the maintenance of blood pressure and diuretic activity in HFpEF patients with refractory hypotension. However, further long-term studies evaluating the safety and efficacy of this combination therapy for patients with HFpEF are needed.
Background
While it is well-known that diuretic treatment is crucial to improve the prognosis and symptoms among patients with chronic heart failure (CHF) [1–3], a diminished diuretic response is common in these patients, increasing the required diuretic dose [4]. Hypotension has been defined as systolic blood pressure (SBP) < 90 mmHg and/or diastolic blood pressure (DBP) < 60 mmHg [5]. In particular, diuretic-induced hypotension causes dizziness [6]. However, the administration of diuretics in these patients cannot be stopped as this would likely result in the progression of heart failure [7].
Many reports have shown that droxidopa, a noradrenaline (NA) prodrug, improves the symptoms of orthostatic hypotension in patients with Parkinson disease, multiple system atrophy, and pure autonomic failure [8–10]. While extensive evidence is available regarding neurogenic hypotension, information on the efficacy and safety of droxidopa for refractory hypotension with CHF is insufficient. Midodrine is widely used for the management of orthostatic blood pressure [11]; however, there is no evidence available on the efficacy of the combination of midodrine and droxidopa. In recent years, drug treatment has been reported to improve prognosis in heart failure with reduced ejection fraction (HFrEF), in which ejection fraction (EF) is < 40% [1–3]. However, guidelines for the treatment of heart failure with preserved ejection fraction (HFpEF), in which EF is ≥50%, are not available. Here, we describe the case of a patient with HFpEF who was successfully treated for refractory hypotension.
Case presentation
The patient was a 62-year-old man with a history of CHF due to mitral regurgitation and complaints of dyspnea on exertion (New York Heart Association functional class III). After mitral annuloplasty, he was prescribed multiple medications at an outpatient clinic for the management of CHF, including azosemide 60 mg/day, bisoprolol 2.5 mg/day, enalapril 2.5 mg/day, spironolactone 50 mg/day, and tolvaptan 15 mg/day. The SBP of the patient remained at 70–80 mmHg because diuretic use could not be reduced or discontinued due to the possible effects of edema and weight gain. He was hospitalized for exacerbation of heart failure. On admission, his SBP and DBP were 83 and 47, respectively, and his heart rate (HR) was 88 beats/min. On the 3rd day after hospitalization, a pharmacist proposed midodrine 4 mg/day, an oral pressor with a weak effect on HR [12], to the attending doctor, after which drug administration was started (Fig. 1). The EF was measured on the 8th day and was 53.4%, which is categorized as HFpEF. Furosemide 20 mg/day was started because the urine volume was low on the 8th day. Over a 9-day period after the initiation of midodrine treatment, the dose was increased to 8 mg/day; however, SBP increased only up to 90 mmHg. Although amezinium 20 mg/day was administered on the 25th day for further pressor action, it was discontinued on the 29th day due to the onset of tachycardia (Fig. 1).
Fig. 1 Clinical course of the hospitalized patient in this study. Up-titration and down-titration of medications while in the hospital are shown, along with the daily urine volume, intake volume, blood pressure, and HR. BP, blood pressure; CHDF, continuous hemodiafiltration; DBP, diastolic blood pressure; DOA, dopamine; hANP, human atrial natriuretic peptide; HR, heart rate; NA, noradrenaline; SBP, systolic blood pressure. The unit γ shows μg/kg/min. SBP, DBP, and HR are shown as the mean ± standard deviation (SD)
In HFrEF, enalapril has been shown to contribute to improved prognosis [13], whereas it is unknown if this effect is present in HFpEF. However, because in HFpEF it may also be highly beneficial to continue with renin-angiotensin system inhibitors, we changed the drug regimen to losartan, which is reported to have a weak hypertensive effect among the angiotensin II receptor blockers [14]. From the 35th day of hospitalization, blood pressure decreased and urine volume decreased significantly (< 100 mL/day), and losartan was discontinued on the 36th day. Consequently, the patient underwent continuous hemodiafiltration (CHDF) on the 36th day only. As shown in Fig. 1, continuous intravenous infusion of dopamine from the 35th day and NA and human atrial natriuretic peptide from the 36th day gradually increased the blood pressure and urine volume. However, it was suggested that it would not be possible to maintain blood pressure upon NA discontinuation. Therefore, the attending doctor consulted a pharmacist regarding the switch from NA to oral pressor drugs. On the basis of some case reports [8–10], the pharmacist suggested switching from intravenous NA to droxidopa, which is converted to NA in vivo, on the 47th day. When the dosage of droxidopa was increased from 200 mg/day to 300 mg/day on the 49th day of hospitalization, SBP and DBP increased to 100–120 mmHg and 60–80 mmHg, respectively. As blood pressure increased, urine volume could be maintained at an average of 3000 mL/day. Seven days after the start of this combination therapy, the EF was 60.1% (Day 53), and no decrease was observed compared to the findings on the Day 8 (EF = 53.4%). In addition, this combination therapy also did not affect cardiothoracic ratio (CTR) (Day 8: CTR = 58% and Day 60: CTR = 58%) (Fig. 2). After discharge, the patient’s SBP and DBP were maintained using a combination of midodrine 8 mg/day and droxidopa 300 mg/day therapy, and his dizziness disappeared.
Fig. 2 Chest X-ray of the patient pre- and post-combination therapy with midodrine and droxidopa. Cardiothoracic ratio (CTR, %) was calculated as (a/b) × 100. A Chest X-ray showing pre-combination therapy status on the 8th day of hospitalization with a CTR of 58%. B Chest X-ray showing post-combination therapy status on the 60th day of hospitalization with a CTR of 58%
Discussion and conclusions
Hypotension is one of the most serious side effects of diuretics in patients with CHF [6]. It causes not only dizziness, but also reduction of diuretic activity because of decreased blood flow [4]. Therefore, it is suggested that improving hypotension may contribute to ensuring diuretic responsiveness. In the case of our patient with HFpEF and refractory hypotension, combination therapy of midodrine and droxidopa increased blood pressure and improved diuretic responsiveness.
While a β-blocker may have potential to improve prognosis in HFpEF [15], bisoprolol decreases blood pressure [16]. In this case, because bisoprolol was used to control tachycardia, we continued to administer bisoprolol at the lowest possible dose while monitoring the HR.
Midodrine is an oral alpha-1 adrenergic agonist that acts as a blood pressor [11] and decreases HR [12]. Although the sample size was small, it was also reported that midodrine elevates EF significantly in HFrEF [17]. Considering this evidence, midodrine might be considered suitable as an oral pressor for patients with HFpEF. Midodrine can elevate SBP and DBP by approximately 20 mmHg [17], and the degree of increase in blood pressure in our patient was similar to that reported previously [17]. Although amezinium was administered on the 25th day, the HR of the patient increased (Fig. 1). Katoh et al. [18] revealed that amezinium elevated HR. Tachycardia is known to be an exacerbating prognostic factor for heart failure [19], suggesting that midodrine, but not amezinium, may show efficacy as an oral pressor in patients with HFpEF.
Despite the administration of midodrine, the urine volume decreased due to excessive hypotension on the 34th and 35th days of hospitalization, and CHDF was performed on the 36th day. It was speculated that the blood pressure might be insufficiently maintained. Because droxidopa is metabolized by L-aromatic-amino-acid decarboxylase to NA, which mediates a pressor response [20], it may be useful to switch from intravenous to oral NA treatment due to hypotension. As expected, up-titration of droxidopa from 200 to 300 mg/day combined with 8 mg/day midodrine rapidly and significantly improved hypotension. Because the blood pressure of the patient could be maintained using this combination therapy, it is considered that the responsiveness to diuretics increased. Therefore, it may be possible to reduce the dose of diuretics such as furosemide. In a double-blind, 4-period crossover study, there were no clinically relevant effects of droxidopa on HR [21]. While the cardiovascular safety of droxidopa has been reported in patients with neurogenic hypotension [22], the detailed safety profile in patients with a history of HFpEF remains unknown. No adverse effects of the combination therapy were noted over the short term in this case. To the best of our knowledge, there is no information regarding the efficacy and safety of droxidopa combined with midodrine in HFpEF patients over the long term. Accordingly, further studies evaluating the safety and efficacy of long-term combination therapy of droxidopa and midodrine for HFpEF patients are needed.
Based on our findings, the combination therapy of midodrine and droxidopa might be safely and effectively administered to HFpEF patients with refractory hypotension, but further studies need to be conducted. In general, diuretic use should be reduced or discontinued if hypotension develops in patients with CHF. If the administration of diuretics must be continued owing to CHF progression, it is advisable to first start midodrine and then add droxidopa if hypotension cannot be effectively controlled.
Abbreviations
CHDFContinuous hemodiafiltration
CHFChronic heart failure
CTRCardiothoracic ratio
DBPDiastolic blood pressure
EFEjection fraction
HFpEFHeart failure with preserved ejection fraction
HFrEFHeart failure with reduced ejection fraction
HRHeart rate
NANoradrenaline
SBPSystolic blood pressure
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Not applicable.
Authors’ contributions
All authors edited the manuscript and approved the final version. Participated in research design: Asai, Sato, Yamamoto, Kito, Hioki, Urata, Abe. Wrote or contributed to the writing of the manuscript: Asai, Abe.
Funding
Not applicable.
Availability of data and materials
All the data generated or analyzed in this study are included in the published article.
Ethics approval and consent to participate
Because this is a case report, ethics review was deemed unnecessary at the discretion of the Ethics Review Committee of the National Hospital Organization Mie Chuo Medical Center.
Consent for publication
Written informed consent was obtained from the patient afterwards.
Competing interests
The authors declare that they have no competing interests. | AMEZINIUM METILSULFATE, AZOSEMIDE, BISOPROLOL, DOPAMINE HYDROCHLORIDE, ENALAPRIL, FUROSEMIDE, LOSARTAN, MIDODRINE, NOREPINEPHRINE, SPIRONOLACTONE, TOLVAPTAN | DrugsGivenReaction | CC BY | 33653416 | 19,980,597 | 2021-03-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Urine output decreased'. | Combination therapy of midodrine and droxidopa for refractory hypotension in heart failure with preserved ejection fraction per a pharmacist's proposal: a case report.
BACKGROUND
Patients with chronic heart failure (CHF) are often treated using many diuretics for symptom relief; however, diuretic use may have to continue despite hypotension development in these patients. Here, we present a case of heart failure with preserved ejection fraction (HFpEF), which is defined as ejection fraction ≥50% in CHF, and refractory hypotension, which was treated with midodrine and droxidopa to normalize blood pressure.
METHODS
The patient was a 62-year-old man with a history of HFpEF due to mitral regurgitation and complaints of dyspnea on exertion. He had been prescribed multiple medications at an outpatient clinic for CHF management, including azosemide 60 mg/day, bisoprolol 2.5 mg/day, enalapril 2.5 mg/day, spironolactone 50 mg/day, and tolvaptan 15 mg/day. The systolic blood pressure (SBP) of the patient remained at 70-80 mmHg because the use of the diuretic could not be reduced or discontinued owing to edema and weight gain. He was hospitalized for the exacerbation of CHF. Although midodrine 8 mg/day was administered to improve hypotension, the SBP of the patient increased only up to 90 mmHg. On the 35th day after hospitalization, the urine volume decreased significantly (< 100 mL/day) due to hypotension. When droxidopa 200 mg/day replaced intravenous noradrenaline on the 47th day, the SBP remained at 100-120 mmHg and the urine volume increased.
CONCLUSIONS
Oral combination treatment with midodrine and droxidopa might contribute to the maintenance of blood pressure and diuretic activity in HFpEF patients with refractory hypotension. However, further long-term studies evaluating the safety and efficacy of this combination therapy for patients with HFpEF are needed.
Background
While it is well-known that diuretic treatment is crucial to improve the prognosis and symptoms among patients with chronic heart failure (CHF) [1–3], a diminished diuretic response is common in these patients, increasing the required diuretic dose [4]. Hypotension has been defined as systolic blood pressure (SBP) < 90 mmHg and/or diastolic blood pressure (DBP) < 60 mmHg [5]. In particular, diuretic-induced hypotension causes dizziness [6]. However, the administration of diuretics in these patients cannot be stopped as this would likely result in the progression of heart failure [7].
Many reports have shown that droxidopa, a noradrenaline (NA) prodrug, improves the symptoms of orthostatic hypotension in patients with Parkinson disease, multiple system atrophy, and pure autonomic failure [8–10]. While extensive evidence is available regarding neurogenic hypotension, information on the efficacy and safety of droxidopa for refractory hypotension with CHF is insufficient. Midodrine is widely used for the management of orthostatic blood pressure [11]; however, there is no evidence available on the efficacy of the combination of midodrine and droxidopa. In recent years, drug treatment has been reported to improve prognosis in heart failure with reduced ejection fraction (HFrEF), in which ejection fraction (EF) is < 40% [1–3]. However, guidelines for the treatment of heart failure with preserved ejection fraction (HFpEF), in which EF is ≥50%, are not available. Here, we describe the case of a patient with HFpEF who was successfully treated for refractory hypotension.
Case presentation
The patient was a 62-year-old man with a history of CHF due to mitral regurgitation and complaints of dyspnea on exertion (New York Heart Association functional class III). After mitral annuloplasty, he was prescribed multiple medications at an outpatient clinic for the management of CHF, including azosemide 60 mg/day, bisoprolol 2.5 mg/day, enalapril 2.5 mg/day, spironolactone 50 mg/day, and tolvaptan 15 mg/day. The SBP of the patient remained at 70–80 mmHg because diuretic use could not be reduced or discontinued due to the possible effects of edema and weight gain. He was hospitalized for exacerbation of heart failure. On admission, his SBP and DBP were 83 and 47, respectively, and his heart rate (HR) was 88 beats/min. On the 3rd day after hospitalization, a pharmacist proposed midodrine 4 mg/day, an oral pressor with a weak effect on HR [12], to the attending doctor, after which drug administration was started (Fig. 1). The EF was measured on the 8th day and was 53.4%, which is categorized as HFpEF. Furosemide 20 mg/day was started because the urine volume was low on the 8th day. Over a 9-day period after the initiation of midodrine treatment, the dose was increased to 8 mg/day; however, SBP increased only up to 90 mmHg. Although amezinium 20 mg/day was administered on the 25th day for further pressor action, it was discontinued on the 29th day due to the onset of tachycardia (Fig. 1).
Fig. 1 Clinical course of the hospitalized patient in this study. Up-titration and down-titration of medications while in the hospital are shown, along with the daily urine volume, intake volume, blood pressure, and HR. BP, blood pressure; CHDF, continuous hemodiafiltration; DBP, diastolic blood pressure; DOA, dopamine; hANP, human atrial natriuretic peptide; HR, heart rate; NA, noradrenaline; SBP, systolic blood pressure. The unit γ shows μg/kg/min. SBP, DBP, and HR are shown as the mean ± standard deviation (SD)
In HFrEF, enalapril has been shown to contribute to improved prognosis [13], whereas it is unknown if this effect is present in HFpEF. However, because in HFpEF it may also be highly beneficial to continue with renin-angiotensin system inhibitors, we changed the drug regimen to losartan, which is reported to have a weak hypertensive effect among the angiotensin II receptor blockers [14]. From the 35th day of hospitalization, blood pressure decreased and urine volume decreased significantly (< 100 mL/day), and losartan was discontinued on the 36th day. Consequently, the patient underwent continuous hemodiafiltration (CHDF) on the 36th day only. As shown in Fig. 1, continuous intravenous infusion of dopamine from the 35th day and NA and human atrial natriuretic peptide from the 36th day gradually increased the blood pressure and urine volume. However, it was suggested that it would not be possible to maintain blood pressure upon NA discontinuation. Therefore, the attending doctor consulted a pharmacist regarding the switch from NA to oral pressor drugs. On the basis of some case reports [8–10], the pharmacist suggested switching from intravenous NA to droxidopa, which is converted to NA in vivo, on the 47th day. When the dosage of droxidopa was increased from 200 mg/day to 300 mg/day on the 49th day of hospitalization, SBP and DBP increased to 100–120 mmHg and 60–80 mmHg, respectively. As blood pressure increased, urine volume could be maintained at an average of 3000 mL/day. Seven days after the start of this combination therapy, the EF was 60.1% (Day 53), and no decrease was observed compared to the findings on the Day 8 (EF = 53.4%). In addition, this combination therapy also did not affect cardiothoracic ratio (CTR) (Day 8: CTR = 58% and Day 60: CTR = 58%) (Fig. 2). After discharge, the patient’s SBP and DBP were maintained using a combination of midodrine 8 mg/day and droxidopa 300 mg/day therapy, and his dizziness disappeared.
Fig. 2 Chest X-ray of the patient pre- and post-combination therapy with midodrine and droxidopa. Cardiothoracic ratio (CTR, %) was calculated as (a/b) × 100. A Chest X-ray showing pre-combination therapy status on the 8th day of hospitalization with a CTR of 58%. B Chest X-ray showing post-combination therapy status on the 60th day of hospitalization with a CTR of 58%
Discussion and conclusions
Hypotension is one of the most serious side effects of diuretics in patients with CHF [6]. It causes not only dizziness, but also reduction of diuretic activity because of decreased blood flow [4]. Therefore, it is suggested that improving hypotension may contribute to ensuring diuretic responsiveness. In the case of our patient with HFpEF and refractory hypotension, combination therapy of midodrine and droxidopa increased blood pressure and improved diuretic responsiveness.
While a β-blocker may have potential to improve prognosis in HFpEF [15], bisoprolol decreases blood pressure [16]. In this case, because bisoprolol was used to control tachycardia, we continued to administer bisoprolol at the lowest possible dose while monitoring the HR.
Midodrine is an oral alpha-1 adrenergic agonist that acts as a blood pressor [11] and decreases HR [12]. Although the sample size was small, it was also reported that midodrine elevates EF significantly in HFrEF [17]. Considering this evidence, midodrine might be considered suitable as an oral pressor for patients with HFpEF. Midodrine can elevate SBP and DBP by approximately 20 mmHg [17], and the degree of increase in blood pressure in our patient was similar to that reported previously [17]. Although amezinium was administered on the 25th day, the HR of the patient increased (Fig. 1). Katoh et al. [18] revealed that amezinium elevated HR. Tachycardia is known to be an exacerbating prognostic factor for heart failure [19], suggesting that midodrine, but not amezinium, may show efficacy as an oral pressor in patients with HFpEF.
Despite the administration of midodrine, the urine volume decreased due to excessive hypotension on the 34th and 35th days of hospitalization, and CHDF was performed on the 36th day. It was speculated that the blood pressure might be insufficiently maintained. Because droxidopa is metabolized by L-aromatic-amino-acid decarboxylase to NA, which mediates a pressor response [20], it may be useful to switch from intravenous to oral NA treatment due to hypotension. As expected, up-titration of droxidopa from 200 to 300 mg/day combined with 8 mg/day midodrine rapidly and significantly improved hypotension. Because the blood pressure of the patient could be maintained using this combination therapy, it is considered that the responsiveness to diuretics increased. Therefore, it may be possible to reduce the dose of diuretics such as furosemide. In a double-blind, 4-period crossover study, there were no clinically relevant effects of droxidopa on HR [21]. While the cardiovascular safety of droxidopa has been reported in patients with neurogenic hypotension [22], the detailed safety profile in patients with a history of HFpEF remains unknown. No adverse effects of the combination therapy were noted over the short term in this case. To the best of our knowledge, there is no information regarding the efficacy and safety of droxidopa combined with midodrine in HFpEF patients over the long term. Accordingly, further studies evaluating the safety and efficacy of long-term combination therapy of droxidopa and midodrine for HFpEF patients are needed.
Based on our findings, the combination therapy of midodrine and droxidopa might be safely and effectively administered to HFpEF patients with refractory hypotension, but further studies need to be conducted. In general, diuretic use should be reduced or discontinued if hypotension develops in patients with CHF. If the administration of diuretics must be continued owing to CHF progression, it is advisable to first start midodrine and then add droxidopa if hypotension cannot be effectively controlled.
Abbreviations
CHDFContinuous hemodiafiltration
CHFChronic heart failure
CTRCardiothoracic ratio
DBPDiastolic blood pressure
EFEjection fraction
HFpEFHeart failure with preserved ejection fraction
HFrEFHeart failure with reduced ejection fraction
HRHeart rate
NANoradrenaline
SBPSystolic blood pressure
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Not applicable.
Authors’ contributions
All authors edited the manuscript and approved the final version. Participated in research design: Asai, Sato, Yamamoto, Kito, Hioki, Urata, Abe. Wrote or contributed to the writing of the manuscript: Asai, Abe.
Funding
Not applicable.
Availability of data and materials
All the data generated or analyzed in this study are included in the published article.
Ethics approval and consent to participate
Because this is a case report, ethics review was deemed unnecessary at the discretion of the Ethics Review Committee of the National Hospital Organization Mie Chuo Medical Center.
Consent for publication
Written informed consent was obtained from the patient afterwards.
Competing interests
The authors declare that they have no competing interests. | AMEZINIUM METILSULFATE, AZOSEMIDE, BISOPROLOL, DOPAMINE HYDROCHLORIDE, ENALAPRIL, FUROSEMIDE, LOSARTAN, MIDODRINE, NOREPINEPHRINE, SPIRONOLACTONE, TOLVAPTAN | DrugsGivenReaction | CC BY | 33653416 | 19,980,597 | 2021-03-03 |
What was the administration route of drug 'AMEZINIUM METILSULFATE'? | Combination therapy of midodrine and droxidopa for refractory hypotension in heart failure with preserved ejection fraction per a pharmacist's proposal: a case report.
BACKGROUND
Patients with chronic heart failure (CHF) are often treated using many diuretics for symptom relief; however, diuretic use may have to continue despite hypotension development in these patients. Here, we present a case of heart failure with preserved ejection fraction (HFpEF), which is defined as ejection fraction ≥50% in CHF, and refractory hypotension, which was treated with midodrine and droxidopa to normalize blood pressure.
METHODS
The patient was a 62-year-old man with a history of HFpEF due to mitral regurgitation and complaints of dyspnea on exertion. He had been prescribed multiple medications at an outpatient clinic for CHF management, including azosemide 60 mg/day, bisoprolol 2.5 mg/day, enalapril 2.5 mg/day, spironolactone 50 mg/day, and tolvaptan 15 mg/day. The systolic blood pressure (SBP) of the patient remained at 70-80 mmHg because the use of the diuretic could not be reduced or discontinued owing to edema and weight gain. He was hospitalized for the exacerbation of CHF. Although midodrine 8 mg/day was administered to improve hypotension, the SBP of the patient increased only up to 90 mmHg. On the 35th day after hospitalization, the urine volume decreased significantly (< 100 mL/day) due to hypotension. When droxidopa 200 mg/day replaced intravenous noradrenaline on the 47th day, the SBP remained at 100-120 mmHg and the urine volume increased.
CONCLUSIONS
Oral combination treatment with midodrine and droxidopa might contribute to the maintenance of blood pressure and diuretic activity in HFpEF patients with refractory hypotension. However, further long-term studies evaluating the safety and efficacy of this combination therapy for patients with HFpEF are needed.
Background
While it is well-known that diuretic treatment is crucial to improve the prognosis and symptoms among patients with chronic heart failure (CHF) [1–3], a diminished diuretic response is common in these patients, increasing the required diuretic dose [4]. Hypotension has been defined as systolic blood pressure (SBP) < 90 mmHg and/or diastolic blood pressure (DBP) < 60 mmHg [5]. In particular, diuretic-induced hypotension causes dizziness [6]. However, the administration of diuretics in these patients cannot be stopped as this would likely result in the progression of heart failure [7].
Many reports have shown that droxidopa, a noradrenaline (NA) prodrug, improves the symptoms of orthostatic hypotension in patients with Parkinson disease, multiple system atrophy, and pure autonomic failure [8–10]. While extensive evidence is available regarding neurogenic hypotension, information on the efficacy and safety of droxidopa for refractory hypotension with CHF is insufficient. Midodrine is widely used for the management of orthostatic blood pressure [11]; however, there is no evidence available on the efficacy of the combination of midodrine and droxidopa. In recent years, drug treatment has been reported to improve prognosis in heart failure with reduced ejection fraction (HFrEF), in which ejection fraction (EF) is < 40% [1–3]. However, guidelines for the treatment of heart failure with preserved ejection fraction (HFpEF), in which EF is ≥50%, are not available. Here, we describe the case of a patient with HFpEF who was successfully treated for refractory hypotension.
Case presentation
The patient was a 62-year-old man with a history of CHF due to mitral regurgitation and complaints of dyspnea on exertion (New York Heart Association functional class III). After mitral annuloplasty, he was prescribed multiple medications at an outpatient clinic for the management of CHF, including azosemide 60 mg/day, bisoprolol 2.5 mg/day, enalapril 2.5 mg/day, spironolactone 50 mg/day, and tolvaptan 15 mg/day. The SBP of the patient remained at 70–80 mmHg because diuretic use could not be reduced or discontinued due to the possible effects of edema and weight gain. He was hospitalized for exacerbation of heart failure. On admission, his SBP and DBP were 83 and 47, respectively, and his heart rate (HR) was 88 beats/min. On the 3rd day after hospitalization, a pharmacist proposed midodrine 4 mg/day, an oral pressor with a weak effect on HR [12], to the attending doctor, after which drug administration was started (Fig. 1). The EF was measured on the 8th day and was 53.4%, which is categorized as HFpEF. Furosemide 20 mg/day was started because the urine volume was low on the 8th day. Over a 9-day period after the initiation of midodrine treatment, the dose was increased to 8 mg/day; however, SBP increased only up to 90 mmHg. Although amezinium 20 mg/day was administered on the 25th day for further pressor action, it was discontinued on the 29th day due to the onset of tachycardia (Fig. 1).
Fig. 1 Clinical course of the hospitalized patient in this study. Up-titration and down-titration of medications while in the hospital are shown, along with the daily urine volume, intake volume, blood pressure, and HR. BP, blood pressure; CHDF, continuous hemodiafiltration; DBP, diastolic blood pressure; DOA, dopamine; hANP, human atrial natriuretic peptide; HR, heart rate; NA, noradrenaline; SBP, systolic blood pressure. The unit γ shows μg/kg/min. SBP, DBP, and HR are shown as the mean ± standard deviation (SD)
In HFrEF, enalapril has been shown to contribute to improved prognosis [13], whereas it is unknown if this effect is present in HFpEF. However, because in HFpEF it may also be highly beneficial to continue with renin-angiotensin system inhibitors, we changed the drug regimen to losartan, which is reported to have a weak hypertensive effect among the angiotensin II receptor blockers [14]. From the 35th day of hospitalization, blood pressure decreased and urine volume decreased significantly (< 100 mL/day), and losartan was discontinued on the 36th day. Consequently, the patient underwent continuous hemodiafiltration (CHDF) on the 36th day only. As shown in Fig. 1, continuous intravenous infusion of dopamine from the 35th day and NA and human atrial natriuretic peptide from the 36th day gradually increased the blood pressure and urine volume. However, it was suggested that it would not be possible to maintain blood pressure upon NA discontinuation. Therefore, the attending doctor consulted a pharmacist regarding the switch from NA to oral pressor drugs. On the basis of some case reports [8–10], the pharmacist suggested switching from intravenous NA to droxidopa, which is converted to NA in vivo, on the 47th day. When the dosage of droxidopa was increased from 200 mg/day to 300 mg/day on the 49th day of hospitalization, SBP and DBP increased to 100–120 mmHg and 60–80 mmHg, respectively. As blood pressure increased, urine volume could be maintained at an average of 3000 mL/day. Seven days after the start of this combination therapy, the EF was 60.1% (Day 53), and no decrease was observed compared to the findings on the Day 8 (EF = 53.4%). In addition, this combination therapy also did not affect cardiothoracic ratio (CTR) (Day 8: CTR = 58% and Day 60: CTR = 58%) (Fig. 2). After discharge, the patient’s SBP and DBP were maintained using a combination of midodrine 8 mg/day and droxidopa 300 mg/day therapy, and his dizziness disappeared.
Fig. 2 Chest X-ray of the patient pre- and post-combination therapy with midodrine and droxidopa. Cardiothoracic ratio (CTR, %) was calculated as (a/b) × 100. A Chest X-ray showing pre-combination therapy status on the 8th day of hospitalization with a CTR of 58%. B Chest X-ray showing post-combination therapy status on the 60th day of hospitalization with a CTR of 58%
Discussion and conclusions
Hypotension is one of the most serious side effects of diuretics in patients with CHF [6]. It causes not only dizziness, but also reduction of diuretic activity because of decreased blood flow [4]. Therefore, it is suggested that improving hypotension may contribute to ensuring diuretic responsiveness. In the case of our patient with HFpEF and refractory hypotension, combination therapy of midodrine and droxidopa increased blood pressure and improved diuretic responsiveness.
While a β-blocker may have potential to improve prognosis in HFpEF [15], bisoprolol decreases blood pressure [16]. In this case, because bisoprolol was used to control tachycardia, we continued to administer bisoprolol at the lowest possible dose while monitoring the HR.
Midodrine is an oral alpha-1 adrenergic agonist that acts as a blood pressor [11] and decreases HR [12]. Although the sample size was small, it was also reported that midodrine elevates EF significantly in HFrEF [17]. Considering this evidence, midodrine might be considered suitable as an oral pressor for patients with HFpEF. Midodrine can elevate SBP and DBP by approximately 20 mmHg [17], and the degree of increase in blood pressure in our patient was similar to that reported previously [17]. Although amezinium was administered on the 25th day, the HR of the patient increased (Fig. 1). Katoh et al. [18] revealed that amezinium elevated HR. Tachycardia is known to be an exacerbating prognostic factor for heart failure [19], suggesting that midodrine, but not amezinium, may show efficacy as an oral pressor in patients with HFpEF.
Despite the administration of midodrine, the urine volume decreased due to excessive hypotension on the 34th and 35th days of hospitalization, and CHDF was performed on the 36th day. It was speculated that the blood pressure might be insufficiently maintained. Because droxidopa is metabolized by L-aromatic-amino-acid decarboxylase to NA, which mediates a pressor response [20], it may be useful to switch from intravenous to oral NA treatment due to hypotension. As expected, up-titration of droxidopa from 200 to 300 mg/day combined with 8 mg/day midodrine rapidly and significantly improved hypotension. Because the blood pressure of the patient could be maintained using this combination therapy, it is considered that the responsiveness to diuretics increased. Therefore, it may be possible to reduce the dose of diuretics such as furosemide. In a double-blind, 4-period crossover study, there were no clinically relevant effects of droxidopa on HR [21]. While the cardiovascular safety of droxidopa has been reported in patients with neurogenic hypotension [22], the detailed safety profile in patients with a history of HFpEF remains unknown. No adverse effects of the combination therapy were noted over the short term in this case. To the best of our knowledge, there is no information regarding the efficacy and safety of droxidopa combined with midodrine in HFpEF patients over the long term. Accordingly, further studies evaluating the safety and efficacy of long-term combination therapy of droxidopa and midodrine for HFpEF patients are needed.
Based on our findings, the combination therapy of midodrine and droxidopa might be safely and effectively administered to HFpEF patients with refractory hypotension, but further studies need to be conducted. In general, diuretic use should be reduced or discontinued if hypotension develops in patients with CHF. If the administration of diuretics must be continued owing to CHF progression, it is advisable to first start midodrine and then add droxidopa if hypotension cannot be effectively controlled.
Abbreviations
CHDFContinuous hemodiafiltration
CHFChronic heart failure
CTRCardiothoracic ratio
DBPDiastolic blood pressure
EFEjection fraction
HFpEFHeart failure with preserved ejection fraction
HFrEFHeart failure with reduced ejection fraction
HRHeart rate
NANoradrenaline
SBPSystolic blood pressure
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Not applicable.
Authors’ contributions
All authors edited the manuscript and approved the final version. Participated in research design: Asai, Sato, Yamamoto, Kito, Hioki, Urata, Abe. Wrote or contributed to the writing of the manuscript: Asai, Abe.
Funding
Not applicable.
Availability of data and materials
All the data generated or analyzed in this study are included in the published article.
Ethics approval and consent to participate
Because this is a case report, ethics review was deemed unnecessary at the discretion of the Ethics Review Committee of the National Hospital Organization Mie Chuo Medical Center.
Consent for publication
Written informed consent was obtained from the patient afterwards.
Competing interests
The authors declare that they have no competing interests. | Oral | DrugAdministrationRoute | CC BY | 33653416 | 19,980,597 | 2021-03-03 |
What was the administration route of drug 'AZOSEMIDE'? | Combination therapy of midodrine and droxidopa for refractory hypotension in heart failure with preserved ejection fraction per a pharmacist's proposal: a case report.
BACKGROUND
Patients with chronic heart failure (CHF) are often treated using many diuretics for symptom relief; however, diuretic use may have to continue despite hypotension development in these patients. Here, we present a case of heart failure with preserved ejection fraction (HFpEF), which is defined as ejection fraction ≥50% in CHF, and refractory hypotension, which was treated with midodrine and droxidopa to normalize blood pressure.
METHODS
The patient was a 62-year-old man with a history of HFpEF due to mitral regurgitation and complaints of dyspnea on exertion. He had been prescribed multiple medications at an outpatient clinic for CHF management, including azosemide 60 mg/day, bisoprolol 2.5 mg/day, enalapril 2.5 mg/day, spironolactone 50 mg/day, and tolvaptan 15 mg/day. The systolic blood pressure (SBP) of the patient remained at 70-80 mmHg because the use of the diuretic could not be reduced or discontinued owing to edema and weight gain. He was hospitalized for the exacerbation of CHF. Although midodrine 8 mg/day was administered to improve hypotension, the SBP of the patient increased only up to 90 mmHg. On the 35th day after hospitalization, the urine volume decreased significantly (< 100 mL/day) due to hypotension. When droxidopa 200 mg/day replaced intravenous noradrenaline on the 47th day, the SBP remained at 100-120 mmHg and the urine volume increased.
CONCLUSIONS
Oral combination treatment with midodrine and droxidopa might contribute to the maintenance of blood pressure and diuretic activity in HFpEF patients with refractory hypotension. However, further long-term studies evaluating the safety and efficacy of this combination therapy for patients with HFpEF are needed.
Background
While it is well-known that diuretic treatment is crucial to improve the prognosis and symptoms among patients with chronic heart failure (CHF) [1–3], a diminished diuretic response is common in these patients, increasing the required diuretic dose [4]. Hypotension has been defined as systolic blood pressure (SBP) < 90 mmHg and/or diastolic blood pressure (DBP) < 60 mmHg [5]. In particular, diuretic-induced hypotension causes dizziness [6]. However, the administration of diuretics in these patients cannot be stopped as this would likely result in the progression of heart failure [7].
Many reports have shown that droxidopa, a noradrenaline (NA) prodrug, improves the symptoms of orthostatic hypotension in patients with Parkinson disease, multiple system atrophy, and pure autonomic failure [8–10]. While extensive evidence is available regarding neurogenic hypotension, information on the efficacy and safety of droxidopa for refractory hypotension with CHF is insufficient. Midodrine is widely used for the management of orthostatic blood pressure [11]; however, there is no evidence available on the efficacy of the combination of midodrine and droxidopa. In recent years, drug treatment has been reported to improve prognosis in heart failure with reduced ejection fraction (HFrEF), in which ejection fraction (EF) is < 40% [1–3]. However, guidelines for the treatment of heart failure with preserved ejection fraction (HFpEF), in which EF is ≥50%, are not available. Here, we describe the case of a patient with HFpEF who was successfully treated for refractory hypotension.
Case presentation
The patient was a 62-year-old man with a history of CHF due to mitral regurgitation and complaints of dyspnea on exertion (New York Heart Association functional class III). After mitral annuloplasty, he was prescribed multiple medications at an outpatient clinic for the management of CHF, including azosemide 60 mg/day, bisoprolol 2.5 mg/day, enalapril 2.5 mg/day, spironolactone 50 mg/day, and tolvaptan 15 mg/day. The SBP of the patient remained at 70–80 mmHg because diuretic use could not be reduced or discontinued due to the possible effects of edema and weight gain. He was hospitalized for exacerbation of heart failure. On admission, his SBP and DBP were 83 and 47, respectively, and his heart rate (HR) was 88 beats/min. On the 3rd day after hospitalization, a pharmacist proposed midodrine 4 mg/day, an oral pressor with a weak effect on HR [12], to the attending doctor, after which drug administration was started (Fig. 1). The EF was measured on the 8th day and was 53.4%, which is categorized as HFpEF. Furosemide 20 mg/day was started because the urine volume was low on the 8th day. Over a 9-day period after the initiation of midodrine treatment, the dose was increased to 8 mg/day; however, SBP increased only up to 90 mmHg. Although amezinium 20 mg/day was administered on the 25th day for further pressor action, it was discontinued on the 29th day due to the onset of tachycardia (Fig. 1).
Fig. 1 Clinical course of the hospitalized patient in this study. Up-titration and down-titration of medications while in the hospital are shown, along with the daily urine volume, intake volume, blood pressure, and HR. BP, blood pressure; CHDF, continuous hemodiafiltration; DBP, diastolic blood pressure; DOA, dopamine; hANP, human atrial natriuretic peptide; HR, heart rate; NA, noradrenaline; SBP, systolic blood pressure. The unit γ shows μg/kg/min. SBP, DBP, and HR are shown as the mean ± standard deviation (SD)
In HFrEF, enalapril has been shown to contribute to improved prognosis [13], whereas it is unknown if this effect is present in HFpEF. However, because in HFpEF it may also be highly beneficial to continue with renin-angiotensin system inhibitors, we changed the drug regimen to losartan, which is reported to have a weak hypertensive effect among the angiotensin II receptor blockers [14]. From the 35th day of hospitalization, blood pressure decreased and urine volume decreased significantly (< 100 mL/day), and losartan was discontinued on the 36th day. Consequently, the patient underwent continuous hemodiafiltration (CHDF) on the 36th day only. As shown in Fig. 1, continuous intravenous infusion of dopamine from the 35th day and NA and human atrial natriuretic peptide from the 36th day gradually increased the blood pressure and urine volume. However, it was suggested that it would not be possible to maintain blood pressure upon NA discontinuation. Therefore, the attending doctor consulted a pharmacist regarding the switch from NA to oral pressor drugs. On the basis of some case reports [8–10], the pharmacist suggested switching from intravenous NA to droxidopa, which is converted to NA in vivo, on the 47th day. When the dosage of droxidopa was increased from 200 mg/day to 300 mg/day on the 49th day of hospitalization, SBP and DBP increased to 100–120 mmHg and 60–80 mmHg, respectively. As blood pressure increased, urine volume could be maintained at an average of 3000 mL/day. Seven days after the start of this combination therapy, the EF was 60.1% (Day 53), and no decrease was observed compared to the findings on the Day 8 (EF = 53.4%). In addition, this combination therapy also did not affect cardiothoracic ratio (CTR) (Day 8: CTR = 58% and Day 60: CTR = 58%) (Fig. 2). After discharge, the patient’s SBP and DBP were maintained using a combination of midodrine 8 mg/day and droxidopa 300 mg/day therapy, and his dizziness disappeared.
Fig. 2 Chest X-ray of the patient pre- and post-combination therapy with midodrine and droxidopa. Cardiothoracic ratio (CTR, %) was calculated as (a/b) × 100. A Chest X-ray showing pre-combination therapy status on the 8th day of hospitalization with a CTR of 58%. B Chest X-ray showing post-combination therapy status on the 60th day of hospitalization with a CTR of 58%
Discussion and conclusions
Hypotension is one of the most serious side effects of diuretics in patients with CHF [6]. It causes not only dizziness, but also reduction of diuretic activity because of decreased blood flow [4]. Therefore, it is suggested that improving hypotension may contribute to ensuring diuretic responsiveness. In the case of our patient with HFpEF and refractory hypotension, combination therapy of midodrine and droxidopa increased blood pressure and improved diuretic responsiveness.
While a β-blocker may have potential to improve prognosis in HFpEF [15], bisoprolol decreases blood pressure [16]. In this case, because bisoprolol was used to control tachycardia, we continued to administer bisoprolol at the lowest possible dose while monitoring the HR.
Midodrine is an oral alpha-1 adrenergic agonist that acts as a blood pressor [11] and decreases HR [12]. Although the sample size was small, it was also reported that midodrine elevates EF significantly in HFrEF [17]. Considering this evidence, midodrine might be considered suitable as an oral pressor for patients with HFpEF. Midodrine can elevate SBP and DBP by approximately 20 mmHg [17], and the degree of increase in blood pressure in our patient was similar to that reported previously [17]. Although amezinium was administered on the 25th day, the HR of the patient increased (Fig. 1). Katoh et al. [18] revealed that amezinium elevated HR. Tachycardia is known to be an exacerbating prognostic factor for heart failure [19], suggesting that midodrine, but not amezinium, may show efficacy as an oral pressor in patients with HFpEF.
Despite the administration of midodrine, the urine volume decreased due to excessive hypotension on the 34th and 35th days of hospitalization, and CHDF was performed on the 36th day. It was speculated that the blood pressure might be insufficiently maintained. Because droxidopa is metabolized by L-aromatic-amino-acid decarboxylase to NA, which mediates a pressor response [20], it may be useful to switch from intravenous to oral NA treatment due to hypotension. As expected, up-titration of droxidopa from 200 to 300 mg/day combined with 8 mg/day midodrine rapidly and significantly improved hypotension. Because the blood pressure of the patient could be maintained using this combination therapy, it is considered that the responsiveness to diuretics increased. Therefore, it may be possible to reduce the dose of diuretics such as furosemide. In a double-blind, 4-period crossover study, there were no clinically relevant effects of droxidopa on HR [21]. While the cardiovascular safety of droxidopa has been reported in patients with neurogenic hypotension [22], the detailed safety profile in patients with a history of HFpEF remains unknown. No adverse effects of the combination therapy were noted over the short term in this case. To the best of our knowledge, there is no information regarding the efficacy and safety of droxidopa combined with midodrine in HFpEF patients over the long term. Accordingly, further studies evaluating the safety and efficacy of long-term combination therapy of droxidopa and midodrine for HFpEF patients are needed.
Based on our findings, the combination therapy of midodrine and droxidopa might be safely and effectively administered to HFpEF patients with refractory hypotension, but further studies need to be conducted. In general, diuretic use should be reduced or discontinued if hypotension develops in patients with CHF. If the administration of diuretics must be continued owing to CHF progression, it is advisable to first start midodrine and then add droxidopa if hypotension cannot be effectively controlled.
Abbreviations
CHDFContinuous hemodiafiltration
CHFChronic heart failure
CTRCardiothoracic ratio
DBPDiastolic blood pressure
EFEjection fraction
HFpEFHeart failure with preserved ejection fraction
HFrEFHeart failure with reduced ejection fraction
HRHeart rate
NANoradrenaline
SBPSystolic blood pressure
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Not applicable.
Authors’ contributions
All authors edited the manuscript and approved the final version. Participated in research design: Asai, Sato, Yamamoto, Kito, Hioki, Urata, Abe. Wrote or contributed to the writing of the manuscript: Asai, Abe.
Funding
Not applicable.
Availability of data and materials
All the data generated or analyzed in this study are included in the published article.
Ethics approval and consent to participate
Because this is a case report, ethics review was deemed unnecessary at the discretion of the Ethics Review Committee of the National Hospital Organization Mie Chuo Medical Center.
Consent for publication
Written informed consent was obtained from the patient afterwards.
Competing interests
The authors declare that they have no competing interests. | Oral | DrugAdministrationRoute | CC BY | 33653416 | 19,980,597 | 2021-03-03 |
What was the administration route of drug 'BISOPROLOL'? | Combination therapy of midodrine and droxidopa for refractory hypotension in heart failure with preserved ejection fraction per a pharmacist's proposal: a case report.
BACKGROUND
Patients with chronic heart failure (CHF) are often treated using many diuretics for symptom relief; however, diuretic use may have to continue despite hypotension development in these patients. Here, we present a case of heart failure with preserved ejection fraction (HFpEF), which is defined as ejection fraction ≥50% in CHF, and refractory hypotension, which was treated with midodrine and droxidopa to normalize blood pressure.
METHODS
The patient was a 62-year-old man with a history of HFpEF due to mitral regurgitation and complaints of dyspnea on exertion. He had been prescribed multiple medications at an outpatient clinic for CHF management, including azosemide 60 mg/day, bisoprolol 2.5 mg/day, enalapril 2.5 mg/day, spironolactone 50 mg/day, and tolvaptan 15 mg/day. The systolic blood pressure (SBP) of the patient remained at 70-80 mmHg because the use of the diuretic could not be reduced or discontinued owing to edema and weight gain. He was hospitalized for the exacerbation of CHF. Although midodrine 8 mg/day was administered to improve hypotension, the SBP of the patient increased only up to 90 mmHg. On the 35th day after hospitalization, the urine volume decreased significantly (< 100 mL/day) due to hypotension. When droxidopa 200 mg/day replaced intravenous noradrenaline on the 47th day, the SBP remained at 100-120 mmHg and the urine volume increased.
CONCLUSIONS
Oral combination treatment with midodrine and droxidopa might contribute to the maintenance of blood pressure and diuretic activity in HFpEF patients with refractory hypotension. However, further long-term studies evaluating the safety and efficacy of this combination therapy for patients with HFpEF are needed.
Background
While it is well-known that diuretic treatment is crucial to improve the prognosis and symptoms among patients with chronic heart failure (CHF) [1–3], a diminished diuretic response is common in these patients, increasing the required diuretic dose [4]. Hypotension has been defined as systolic blood pressure (SBP) < 90 mmHg and/or diastolic blood pressure (DBP) < 60 mmHg [5]. In particular, diuretic-induced hypotension causes dizziness [6]. However, the administration of diuretics in these patients cannot be stopped as this would likely result in the progression of heart failure [7].
Many reports have shown that droxidopa, a noradrenaline (NA) prodrug, improves the symptoms of orthostatic hypotension in patients with Parkinson disease, multiple system atrophy, and pure autonomic failure [8–10]. While extensive evidence is available regarding neurogenic hypotension, information on the efficacy and safety of droxidopa for refractory hypotension with CHF is insufficient. Midodrine is widely used for the management of orthostatic blood pressure [11]; however, there is no evidence available on the efficacy of the combination of midodrine and droxidopa. In recent years, drug treatment has been reported to improve prognosis in heart failure with reduced ejection fraction (HFrEF), in which ejection fraction (EF) is < 40% [1–3]. However, guidelines for the treatment of heart failure with preserved ejection fraction (HFpEF), in which EF is ≥50%, are not available. Here, we describe the case of a patient with HFpEF who was successfully treated for refractory hypotension.
Case presentation
The patient was a 62-year-old man with a history of CHF due to mitral regurgitation and complaints of dyspnea on exertion (New York Heart Association functional class III). After mitral annuloplasty, he was prescribed multiple medications at an outpatient clinic for the management of CHF, including azosemide 60 mg/day, bisoprolol 2.5 mg/day, enalapril 2.5 mg/day, spironolactone 50 mg/day, and tolvaptan 15 mg/day. The SBP of the patient remained at 70–80 mmHg because diuretic use could not be reduced or discontinued due to the possible effects of edema and weight gain. He was hospitalized for exacerbation of heart failure. On admission, his SBP and DBP were 83 and 47, respectively, and his heart rate (HR) was 88 beats/min. On the 3rd day after hospitalization, a pharmacist proposed midodrine 4 mg/day, an oral pressor with a weak effect on HR [12], to the attending doctor, after which drug administration was started (Fig. 1). The EF was measured on the 8th day and was 53.4%, which is categorized as HFpEF. Furosemide 20 mg/day was started because the urine volume was low on the 8th day. Over a 9-day period after the initiation of midodrine treatment, the dose was increased to 8 mg/day; however, SBP increased only up to 90 mmHg. Although amezinium 20 mg/day was administered on the 25th day for further pressor action, it was discontinued on the 29th day due to the onset of tachycardia (Fig. 1).
Fig. 1 Clinical course of the hospitalized patient in this study. Up-titration and down-titration of medications while in the hospital are shown, along with the daily urine volume, intake volume, blood pressure, and HR. BP, blood pressure; CHDF, continuous hemodiafiltration; DBP, diastolic blood pressure; DOA, dopamine; hANP, human atrial natriuretic peptide; HR, heart rate; NA, noradrenaline; SBP, systolic blood pressure. The unit γ shows μg/kg/min. SBP, DBP, and HR are shown as the mean ± standard deviation (SD)
In HFrEF, enalapril has been shown to contribute to improved prognosis [13], whereas it is unknown if this effect is present in HFpEF. However, because in HFpEF it may also be highly beneficial to continue with renin-angiotensin system inhibitors, we changed the drug regimen to losartan, which is reported to have a weak hypertensive effect among the angiotensin II receptor blockers [14]. From the 35th day of hospitalization, blood pressure decreased and urine volume decreased significantly (< 100 mL/day), and losartan was discontinued on the 36th day. Consequently, the patient underwent continuous hemodiafiltration (CHDF) on the 36th day only. As shown in Fig. 1, continuous intravenous infusion of dopamine from the 35th day and NA and human atrial natriuretic peptide from the 36th day gradually increased the blood pressure and urine volume. However, it was suggested that it would not be possible to maintain blood pressure upon NA discontinuation. Therefore, the attending doctor consulted a pharmacist regarding the switch from NA to oral pressor drugs. On the basis of some case reports [8–10], the pharmacist suggested switching from intravenous NA to droxidopa, which is converted to NA in vivo, on the 47th day. When the dosage of droxidopa was increased from 200 mg/day to 300 mg/day on the 49th day of hospitalization, SBP and DBP increased to 100–120 mmHg and 60–80 mmHg, respectively. As blood pressure increased, urine volume could be maintained at an average of 3000 mL/day. Seven days after the start of this combination therapy, the EF was 60.1% (Day 53), and no decrease was observed compared to the findings on the Day 8 (EF = 53.4%). In addition, this combination therapy also did not affect cardiothoracic ratio (CTR) (Day 8: CTR = 58% and Day 60: CTR = 58%) (Fig. 2). After discharge, the patient’s SBP and DBP were maintained using a combination of midodrine 8 mg/day and droxidopa 300 mg/day therapy, and his dizziness disappeared.
Fig. 2 Chest X-ray of the patient pre- and post-combination therapy with midodrine and droxidopa. Cardiothoracic ratio (CTR, %) was calculated as (a/b) × 100. A Chest X-ray showing pre-combination therapy status on the 8th day of hospitalization with a CTR of 58%. B Chest X-ray showing post-combination therapy status on the 60th day of hospitalization with a CTR of 58%
Discussion and conclusions
Hypotension is one of the most serious side effects of diuretics in patients with CHF [6]. It causes not only dizziness, but also reduction of diuretic activity because of decreased blood flow [4]. Therefore, it is suggested that improving hypotension may contribute to ensuring diuretic responsiveness. In the case of our patient with HFpEF and refractory hypotension, combination therapy of midodrine and droxidopa increased blood pressure and improved diuretic responsiveness.
While a β-blocker may have potential to improve prognosis in HFpEF [15], bisoprolol decreases blood pressure [16]. In this case, because bisoprolol was used to control tachycardia, we continued to administer bisoprolol at the lowest possible dose while monitoring the HR.
Midodrine is an oral alpha-1 adrenergic agonist that acts as a blood pressor [11] and decreases HR [12]. Although the sample size was small, it was also reported that midodrine elevates EF significantly in HFrEF [17]. Considering this evidence, midodrine might be considered suitable as an oral pressor for patients with HFpEF. Midodrine can elevate SBP and DBP by approximately 20 mmHg [17], and the degree of increase in blood pressure in our patient was similar to that reported previously [17]. Although amezinium was administered on the 25th day, the HR of the patient increased (Fig. 1). Katoh et al. [18] revealed that amezinium elevated HR. Tachycardia is known to be an exacerbating prognostic factor for heart failure [19], suggesting that midodrine, but not amezinium, may show efficacy as an oral pressor in patients with HFpEF.
Despite the administration of midodrine, the urine volume decreased due to excessive hypotension on the 34th and 35th days of hospitalization, and CHDF was performed on the 36th day. It was speculated that the blood pressure might be insufficiently maintained. Because droxidopa is metabolized by L-aromatic-amino-acid decarboxylase to NA, which mediates a pressor response [20], it may be useful to switch from intravenous to oral NA treatment due to hypotension. As expected, up-titration of droxidopa from 200 to 300 mg/day combined with 8 mg/day midodrine rapidly and significantly improved hypotension. Because the blood pressure of the patient could be maintained using this combination therapy, it is considered that the responsiveness to diuretics increased. Therefore, it may be possible to reduce the dose of diuretics such as furosemide. In a double-blind, 4-period crossover study, there were no clinically relevant effects of droxidopa on HR [21]. While the cardiovascular safety of droxidopa has been reported in patients with neurogenic hypotension [22], the detailed safety profile in patients with a history of HFpEF remains unknown. No adverse effects of the combination therapy were noted over the short term in this case. To the best of our knowledge, there is no information regarding the efficacy and safety of droxidopa combined with midodrine in HFpEF patients over the long term. Accordingly, further studies evaluating the safety and efficacy of long-term combination therapy of droxidopa and midodrine for HFpEF patients are needed.
Based on our findings, the combination therapy of midodrine and droxidopa might be safely and effectively administered to HFpEF patients with refractory hypotension, but further studies need to be conducted. In general, diuretic use should be reduced or discontinued if hypotension develops in patients with CHF. If the administration of diuretics must be continued owing to CHF progression, it is advisable to first start midodrine and then add droxidopa if hypotension cannot be effectively controlled.
Abbreviations
CHDFContinuous hemodiafiltration
CHFChronic heart failure
CTRCardiothoracic ratio
DBPDiastolic blood pressure
EFEjection fraction
HFpEFHeart failure with preserved ejection fraction
HFrEFHeart failure with reduced ejection fraction
HRHeart rate
NANoradrenaline
SBPSystolic blood pressure
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Not applicable.
Authors’ contributions
All authors edited the manuscript and approved the final version. Participated in research design: Asai, Sato, Yamamoto, Kito, Hioki, Urata, Abe. Wrote or contributed to the writing of the manuscript: Asai, Abe.
Funding
Not applicable.
Availability of data and materials
All the data generated or analyzed in this study are included in the published article.
Ethics approval and consent to participate
Because this is a case report, ethics review was deemed unnecessary at the discretion of the Ethics Review Committee of the National Hospital Organization Mie Chuo Medical Center.
Consent for publication
Written informed consent was obtained from the patient afterwards.
Competing interests
The authors declare that they have no competing interests. | Oral | DrugAdministrationRoute | CC BY | 33653416 | 19,980,597 | 2021-03-03 |
What was the administration route of drug 'DOPAMINE HYDROCHLORIDE'? | Combination therapy of midodrine and droxidopa for refractory hypotension in heart failure with preserved ejection fraction per a pharmacist's proposal: a case report.
BACKGROUND
Patients with chronic heart failure (CHF) are often treated using many diuretics for symptom relief; however, diuretic use may have to continue despite hypotension development in these patients. Here, we present a case of heart failure with preserved ejection fraction (HFpEF), which is defined as ejection fraction ≥50% in CHF, and refractory hypotension, which was treated with midodrine and droxidopa to normalize blood pressure.
METHODS
The patient was a 62-year-old man with a history of HFpEF due to mitral regurgitation and complaints of dyspnea on exertion. He had been prescribed multiple medications at an outpatient clinic for CHF management, including azosemide 60 mg/day, bisoprolol 2.5 mg/day, enalapril 2.5 mg/day, spironolactone 50 mg/day, and tolvaptan 15 mg/day. The systolic blood pressure (SBP) of the patient remained at 70-80 mmHg because the use of the diuretic could not be reduced or discontinued owing to edema and weight gain. He was hospitalized for the exacerbation of CHF. Although midodrine 8 mg/day was administered to improve hypotension, the SBP of the patient increased only up to 90 mmHg. On the 35th day after hospitalization, the urine volume decreased significantly (< 100 mL/day) due to hypotension. When droxidopa 200 mg/day replaced intravenous noradrenaline on the 47th day, the SBP remained at 100-120 mmHg and the urine volume increased.
CONCLUSIONS
Oral combination treatment with midodrine and droxidopa might contribute to the maintenance of blood pressure and diuretic activity in HFpEF patients with refractory hypotension. However, further long-term studies evaluating the safety and efficacy of this combination therapy for patients with HFpEF are needed.
Background
While it is well-known that diuretic treatment is crucial to improve the prognosis and symptoms among patients with chronic heart failure (CHF) [1–3], a diminished diuretic response is common in these patients, increasing the required diuretic dose [4]. Hypotension has been defined as systolic blood pressure (SBP) < 90 mmHg and/or diastolic blood pressure (DBP) < 60 mmHg [5]. In particular, diuretic-induced hypotension causes dizziness [6]. However, the administration of diuretics in these patients cannot be stopped as this would likely result in the progression of heart failure [7].
Many reports have shown that droxidopa, a noradrenaline (NA) prodrug, improves the symptoms of orthostatic hypotension in patients with Parkinson disease, multiple system atrophy, and pure autonomic failure [8–10]. While extensive evidence is available regarding neurogenic hypotension, information on the efficacy and safety of droxidopa for refractory hypotension with CHF is insufficient. Midodrine is widely used for the management of orthostatic blood pressure [11]; however, there is no evidence available on the efficacy of the combination of midodrine and droxidopa. In recent years, drug treatment has been reported to improve prognosis in heart failure with reduced ejection fraction (HFrEF), in which ejection fraction (EF) is < 40% [1–3]. However, guidelines for the treatment of heart failure with preserved ejection fraction (HFpEF), in which EF is ≥50%, are not available. Here, we describe the case of a patient with HFpEF who was successfully treated for refractory hypotension.
Case presentation
The patient was a 62-year-old man with a history of CHF due to mitral regurgitation and complaints of dyspnea on exertion (New York Heart Association functional class III). After mitral annuloplasty, he was prescribed multiple medications at an outpatient clinic for the management of CHF, including azosemide 60 mg/day, bisoprolol 2.5 mg/day, enalapril 2.5 mg/day, spironolactone 50 mg/day, and tolvaptan 15 mg/day. The SBP of the patient remained at 70–80 mmHg because diuretic use could not be reduced or discontinued due to the possible effects of edema and weight gain. He was hospitalized for exacerbation of heart failure. On admission, his SBP and DBP were 83 and 47, respectively, and his heart rate (HR) was 88 beats/min. On the 3rd day after hospitalization, a pharmacist proposed midodrine 4 mg/day, an oral pressor with a weak effect on HR [12], to the attending doctor, after which drug administration was started (Fig. 1). The EF was measured on the 8th day and was 53.4%, which is categorized as HFpEF. Furosemide 20 mg/day was started because the urine volume was low on the 8th day. Over a 9-day period after the initiation of midodrine treatment, the dose was increased to 8 mg/day; however, SBP increased only up to 90 mmHg. Although amezinium 20 mg/day was administered on the 25th day for further pressor action, it was discontinued on the 29th day due to the onset of tachycardia (Fig. 1).
Fig. 1 Clinical course of the hospitalized patient in this study. Up-titration and down-titration of medications while in the hospital are shown, along with the daily urine volume, intake volume, blood pressure, and HR. BP, blood pressure; CHDF, continuous hemodiafiltration; DBP, diastolic blood pressure; DOA, dopamine; hANP, human atrial natriuretic peptide; HR, heart rate; NA, noradrenaline; SBP, systolic blood pressure. The unit γ shows μg/kg/min. SBP, DBP, and HR are shown as the mean ± standard deviation (SD)
In HFrEF, enalapril has been shown to contribute to improved prognosis [13], whereas it is unknown if this effect is present in HFpEF. However, because in HFpEF it may also be highly beneficial to continue with renin-angiotensin system inhibitors, we changed the drug regimen to losartan, which is reported to have a weak hypertensive effect among the angiotensin II receptor blockers [14]. From the 35th day of hospitalization, blood pressure decreased and urine volume decreased significantly (< 100 mL/day), and losartan was discontinued on the 36th day. Consequently, the patient underwent continuous hemodiafiltration (CHDF) on the 36th day only. As shown in Fig. 1, continuous intravenous infusion of dopamine from the 35th day and NA and human atrial natriuretic peptide from the 36th day gradually increased the blood pressure and urine volume. However, it was suggested that it would not be possible to maintain blood pressure upon NA discontinuation. Therefore, the attending doctor consulted a pharmacist regarding the switch from NA to oral pressor drugs. On the basis of some case reports [8–10], the pharmacist suggested switching from intravenous NA to droxidopa, which is converted to NA in vivo, on the 47th day. When the dosage of droxidopa was increased from 200 mg/day to 300 mg/day on the 49th day of hospitalization, SBP and DBP increased to 100–120 mmHg and 60–80 mmHg, respectively. As blood pressure increased, urine volume could be maintained at an average of 3000 mL/day. Seven days after the start of this combination therapy, the EF was 60.1% (Day 53), and no decrease was observed compared to the findings on the Day 8 (EF = 53.4%). In addition, this combination therapy also did not affect cardiothoracic ratio (CTR) (Day 8: CTR = 58% and Day 60: CTR = 58%) (Fig. 2). After discharge, the patient’s SBP and DBP were maintained using a combination of midodrine 8 mg/day and droxidopa 300 mg/day therapy, and his dizziness disappeared.
Fig. 2 Chest X-ray of the patient pre- and post-combination therapy with midodrine and droxidopa. Cardiothoracic ratio (CTR, %) was calculated as (a/b) × 100. A Chest X-ray showing pre-combination therapy status on the 8th day of hospitalization with a CTR of 58%. B Chest X-ray showing post-combination therapy status on the 60th day of hospitalization with a CTR of 58%
Discussion and conclusions
Hypotension is one of the most serious side effects of diuretics in patients with CHF [6]. It causes not only dizziness, but also reduction of diuretic activity because of decreased blood flow [4]. Therefore, it is suggested that improving hypotension may contribute to ensuring diuretic responsiveness. In the case of our patient with HFpEF and refractory hypotension, combination therapy of midodrine and droxidopa increased blood pressure and improved diuretic responsiveness.
While a β-blocker may have potential to improve prognosis in HFpEF [15], bisoprolol decreases blood pressure [16]. In this case, because bisoprolol was used to control tachycardia, we continued to administer bisoprolol at the lowest possible dose while monitoring the HR.
Midodrine is an oral alpha-1 adrenergic agonist that acts as a blood pressor [11] and decreases HR [12]. Although the sample size was small, it was also reported that midodrine elevates EF significantly in HFrEF [17]. Considering this evidence, midodrine might be considered suitable as an oral pressor for patients with HFpEF. Midodrine can elevate SBP and DBP by approximately 20 mmHg [17], and the degree of increase in blood pressure in our patient was similar to that reported previously [17]. Although amezinium was administered on the 25th day, the HR of the patient increased (Fig. 1). Katoh et al. [18] revealed that amezinium elevated HR. Tachycardia is known to be an exacerbating prognostic factor for heart failure [19], suggesting that midodrine, but not amezinium, may show efficacy as an oral pressor in patients with HFpEF.
Despite the administration of midodrine, the urine volume decreased due to excessive hypotension on the 34th and 35th days of hospitalization, and CHDF was performed on the 36th day. It was speculated that the blood pressure might be insufficiently maintained. Because droxidopa is metabolized by L-aromatic-amino-acid decarboxylase to NA, which mediates a pressor response [20], it may be useful to switch from intravenous to oral NA treatment due to hypotension. As expected, up-titration of droxidopa from 200 to 300 mg/day combined with 8 mg/day midodrine rapidly and significantly improved hypotension. Because the blood pressure of the patient could be maintained using this combination therapy, it is considered that the responsiveness to diuretics increased. Therefore, it may be possible to reduce the dose of diuretics such as furosemide. In a double-blind, 4-period crossover study, there were no clinically relevant effects of droxidopa on HR [21]. While the cardiovascular safety of droxidopa has been reported in patients with neurogenic hypotension [22], the detailed safety profile in patients with a history of HFpEF remains unknown. No adverse effects of the combination therapy were noted over the short term in this case. To the best of our knowledge, there is no information regarding the efficacy and safety of droxidopa combined with midodrine in HFpEF patients over the long term. Accordingly, further studies evaluating the safety and efficacy of long-term combination therapy of droxidopa and midodrine for HFpEF patients are needed.
Based on our findings, the combination therapy of midodrine and droxidopa might be safely and effectively administered to HFpEF patients with refractory hypotension, but further studies need to be conducted. In general, diuretic use should be reduced or discontinued if hypotension develops in patients with CHF. If the administration of diuretics must be continued owing to CHF progression, it is advisable to first start midodrine and then add droxidopa if hypotension cannot be effectively controlled.
Abbreviations
CHDFContinuous hemodiafiltration
CHFChronic heart failure
CTRCardiothoracic ratio
DBPDiastolic blood pressure
EFEjection fraction
HFpEFHeart failure with preserved ejection fraction
HFrEFHeart failure with reduced ejection fraction
HRHeart rate
NANoradrenaline
SBPSystolic blood pressure
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Not applicable.
Authors’ contributions
All authors edited the manuscript and approved the final version. Participated in research design: Asai, Sato, Yamamoto, Kito, Hioki, Urata, Abe. Wrote or contributed to the writing of the manuscript: Asai, Abe.
Funding
Not applicable.
Availability of data and materials
All the data generated or analyzed in this study are included in the published article.
Ethics approval and consent to participate
Because this is a case report, ethics review was deemed unnecessary at the discretion of the Ethics Review Committee of the National Hospital Organization Mie Chuo Medical Center.
Consent for publication
Written informed consent was obtained from the patient afterwards.
Competing interests
The authors declare that they have no competing interests. | Intravenous drip | DrugAdministrationRoute | CC BY | 33653416 | 19,980,597 | 2021-03-03 |
What was the administration route of drug 'ENALAPRIL'? | Combination therapy of midodrine and droxidopa for refractory hypotension in heart failure with preserved ejection fraction per a pharmacist's proposal: a case report.
BACKGROUND
Patients with chronic heart failure (CHF) are often treated using many diuretics for symptom relief; however, diuretic use may have to continue despite hypotension development in these patients. Here, we present a case of heart failure with preserved ejection fraction (HFpEF), which is defined as ejection fraction ≥50% in CHF, and refractory hypotension, which was treated with midodrine and droxidopa to normalize blood pressure.
METHODS
The patient was a 62-year-old man with a history of HFpEF due to mitral regurgitation and complaints of dyspnea on exertion. He had been prescribed multiple medications at an outpatient clinic for CHF management, including azosemide 60 mg/day, bisoprolol 2.5 mg/day, enalapril 2.5 mg/day, spironolactone 50 mg/day, and tolvaptan 15 mg/day. The systolic blood pressure (SBP) of the patient remained at 70-80 mmHg because the use of the diuretic could not be reduced or discontinued owing to edema and weight gain. He was hospitalized for the exacerbation of CHF. Although midodrine 8 mg/day was administered to improve hypotension, the SBP of the patient increased only up to 90 mmHg. On the 35th day after hospitalization, the urine volume decreased significantly (< 100 mL/day) due to hypotension. When droxidopa 200 mg/day replaced intravenous noradrenaline on the 47th day, the SBP remained at 100-120 mmHg and the urine volume increased.
CONCLUSIONS
Oral combination treatment with midodrine and droxidopa might contribute to the maintenance of blood pressure and diuretic activity in HFpEF patients with refractory hypotension. However, further long-term studies evaluating the safety and efficacy of this combination therapy for patients with HFpEF are needed.
Background
While it is well-known that diuretic treatment is crucial to improve the prognosis and symptoms among patients with chronic heart failure (CHF) [1–3], a diminished diuretic response is common in these patients, increasing the required diuretic dose [4]. Hypotension has been defined as systolic blood pressure (SBP) < 90 mmHg and/or diastolic blood pressure (DBP) < 60 mmHg [5]. In particular, diuretic-induced hypotension causes dizziness [6]. However, the administration of diuretics in these patients cannot be stopped as this would likely result in the progression of heart failure [7].
Many reports have shown that droxidopa, a noradrenaline (NA) prodrug, improves the symptoms of orthostatic hypotension in patients with Parkinson disease, multiple system atrophy, and pure autonomic failure [8–10]. While extensive evidence is available regarding neurogenic hypotension, information on the efficacy and safety of droxidopa for refractory hypotension with CHF is insufficient. Midodrine is widely used for the management of orthostatic blood pressure [11]; however, there is no evidence available on the efficacy of the combination of midodrine and droxidopa. In recent years, drug treatment has been reported to improve prognosis in heart failure with reduced ejection fraction (HFrEF), in which ejection fraction (EF) is < 40% [1–3]. However, guidelines for the treatment of heart failure with preserved ejection fraction (HFpEF), in which EF is ≥50%, are not available. Here, we describe the case of a patient with HFpEF who was successfully treated for refractory hypotension.
Case presentation
The patient was a 62-year-old man with a history of CHF due to mitral regurgitation and complaints of dyspnea on exertion (New York Heart Association functional class III). After mitral annuloplasty, he was prescribed multiple medications at an outpatient clinic for the management of CHF, including azosemide 60 mg/day, bisoprolol 2.5 mg/day, enalapril 2.5 mg/day, spironolactone 50 mg/day, and tolvaptan 15 mg/day. The SBP of the patient remained at 70–80 mmHg because diuretic use could not be reduced or discontinued due to the possible effects of edema and weight gain. He was hospitalized for exacerbation of heart failure. On admission, his SBP and DBP were 83 and 47, respectively, and his heart rate (HR) was 88 beats/min. On the 3rd day after hospitalization, a pharmacist proposed midodrine 4 mg/day, an oral pressor with a weak effect on HR [12], to the attending doctor, after which drug administration was started (Fig. 1). The EF was measured on the 8th day and was 53.4%, which is categorized as HFpEF. Furosemide 20 mg/day was started because the urine volume was low on the 8th day. Over a 9-day period after the initiation of midodrine treatment, the dose was increased to 8 mg/day; however, SBP increased only up to 90 mmHg. Although amezinium 20 mg/day was administered on the 25th day for further pressor action, it was discontinued on the 29th day due to the onset of tachycardia (Fig. 1).
Fig. 1 Clinical course of the hospitalized patient in this study. Up-titration and down-titration of medications while in the hospital are shown, along with the daily urine volume, intake volume, blood pressure, and HR. BP, blood pressure; CHDF, continuous hemodiafiltration; DBP, diastolic blood pressure; DOA, dopamine; hANP, human atrial natriuretic peptide; HR, heart rate; NA, noradrenaline; SBP, systolic blood pressure. The unit γ shows μg/kg/min. SBP, DBP, and HR are shown as the mean ± standard deviation (SD)
In HFrEF, enalapril has been shown to contribute to improved prognosis [13], whereas it is unknown if this effect is present in HFpEF. However, because in HFpEF it may also be highly beneficial to continue with renin-angiotensin system inhibitors, we changed the drug regimen to losartan, which is reported to have a weak hypertensive effect among the angiotensin II receptor blockers [14]. From the 35th day of hospitalization, blood pressure decreased and urine volume decreased significantly (< 100 mL/day), and losartan was discontinued on the 36th day. Consequently, the patient underwent continuous hemodiafiltration (CHDF) on the 36th day only. As shown in Fig. 1, continuous intravenous infusion of dopamine from the 35th day and NA and human atrial natriuretic peptide from the 36th day gradually increased the blood pressure and urine volume. However, it was suggested that it would not be possible to maintain blood pressure upon NA discontinuation. Therefore, the attending doctor consulted a pharmacist regarding the switch from NA to oral pressor drugs. On the basis of some case reports [8–10], the pharmacist suggested switching from intravenous NA to droxidopa, which is converted to NA in vivo, on the 47th day. When the dosage of droxidopa was increased from 200 mg/day to 300 mg/day on the 49th day of hospitalization, SBP and DBP increased to 100–120 mmHg and 60–80 mmHg, respectively. As blood pressure increased, urine volume could be maintained at an average of 3000 mL/day. Seven days after the start of this combination therapy, the EF was 60.1% (Day 53), and no decrease was observed compared to the findings on the Day 8 (EF = 53.4%). In addition, this combination therapy also did not affect cardiothoracic ratio (CTR) (Day 8: CTR = 58% and Day 60: CTR = 58%) (Fig. 2). After discharge, the patient’s SBP and DBP were maintained using a combination of midodrine 8 mg/day and droxidopa 300 mg/day therapy, and his dizziness disappeared.
Fig. 2 Chest X-ray of the patient pre- and post-combination therapy with midodrine and droxidopa. Cardiothoracic ratio (CTR, %) was calculated as (a/b) × 100. A Chest X-ray showing pre-combination therapy status on the 8th day of hospitalization with a CTR of 58%. B Chest X-ray showing post-combination therapy status on the 60th day of hospitalization with a CTR of 58%
Discussion and conclusions
Hypotension is one of the most serious side effects of diuretics in patients with CHF [6]. It causes not only dizziness, but also reduction of diuretic activity because of decreased blood flow [4]. Therefore, it is suggested that improving hypotension may contribute to ensuring diuretic responsiveness. In the case of our patient with HFpEF and refractory hypotension, combination therapy of midodrine and droxidopa increased blood pressure and improved diuretic responsiveness.
While a β-blocker may have potential to improve prognosis in HFpEF [15], bisoprolol decreases blood pressure [16]. In this case, because bisoprolol was used to control tachycardia, we continued to administer bisoprolol at the lowest possible dose while monitoring the HR.
Midodrine is an oral alpha-1 adrenergic agonist that acts as a blood pressor [11] and decreases HR [12]. Although the sample size was small, it was also reported that midodrine elevates EF significantly in HFrEF [17]. Considering this evidence, midodrine might be considered suitable as an oral pressor for patients with HFpEF. Midodrine can elevate SBP and DBP by approximately 20 mmHg [17], and the degree of increase in blood pressure in our patient was similar to that reported previously [17]. Although amezinium was administered on the 25th day, the HR of the patient increased (Fig. 1). Katoh et al. [18] revealed that amezinium elevated HR. Tachycardia is known to be an exacerbating prognostic factor for heart failure [19], suggesting that midodrine, but not amezinium, may show efficacy as an oral pressor in patients with HFpEF.
Despite the administration of midodrine, the urine volume decreased due to excessive hypotension on the 34th and 35th days of hospitalization, and CHDF was performed on the 36th day. It was speculated that the blood pressure might be insufficiently maintained. Because droxidopa is metabolized by L-aromatic-amino-acid decarboxylase to NA, which mediates a pressor response [20], it may be useful to switch from intravenous to oral NA treatment due to hypotension. As expected, up-titration of droxidopa from 200 to 300 mg/day combined with 8 mg/day midodrine rapidly and significantly improved hypotension. Because the blood pressure of the patient could be maintained using this combination therapy, it is considered that the responsiveness to diuretics increased. Therefore, it may be possible to reduce the dose of diuretics such as furosemide. In a double-blind, 4-period crossover study, there were no clinically relevant effects of droxidopa on HR [21]. While the cardiovascular safety of droxidopa has been reported in patients with neurogenic hypotension [22], the detailed safety profile in patients with a history of HFpEF remains unknown. No adverse effects of the combination therapy were noted over the short term in this case. To the best of our knowledge, there is no information regarding the efficacy and safety of droxidopa combined with midodrine in HFpEF patients over the long term. Accordingly, further studies evaluating the safety and efficacy of long-term combination therapy of droxidopa and midodrine for HFpEF patients are needed.
Based on our findings, the combination therapy of midodrine and droxidopa might be safely and effectively administered to HFpEF patients with refractory hypotension, but further studies need to be conducted. In general, diuretic use should be reduced or discontinued if hypotension develops in patients with CHF. If the administration of diuretics must be continued owing to CHF progression, it is advisable to first start midodrine and then add droxidopa if hypotension cannot be effectively controlled.
Abbreviations
CHDFContinuous hemodiafiltration
CHFChronic heart failure
CTRCardiothoracic ratio
DBPDiastolic blood pressure
EFEjection fraction
HFpEFHeart failure with preserved ejection fraction
HFrEFHeart failure with reduced ejection fraction
HRHeart rate
NANoradrenaline
SBPSystolic blood pressure
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Not applicable.
Authors’ contributions
All authors edited the manuscript and approved the final version. Participated in research design: Asai, Sato, Yamamoto, Kito, Hioki, Urata, Abe. Wrote or contributed to the writing of the manuscript: Asai, Abe.
Funding
Not applicable.
Availability of data and materials
All the data generated or analyzed in this study are included in the published article.
Ethics approval and consent to participate
Because this is a case report, ethics review was deemed unnecessary at the discretion of the Ethics Review Committee of the National Hospital Organization Mie Chuo Medical Center.
Consent for publication
Written informed consent was obtained from the patient afterwards.
Competing interests
The authors declare that they have no competing interests. | Oral | DrugAdministrationRoute | CC BY | 33653416 | 19,980,597 | 2021-03-03 |
What was the administration route of drug 'FUROSEMIDE'? | Combination therapy of midodrine and droxidopa for refractory hypotension in heart failure with preserved ejection fraction per a pharmacist's proposal: a case report.
BACKGROUND
Patients with chronic heart failure (CHF) are often treated using many diuretics for symptom relief; however, diuretic use may have to continue despite hypotension development in these patients. Here, we present a case of heart failure with preserved ejection fraction (HFpEF), which is defined as ejection fraction ≥50% in CHF, and refractory hypotension, which was treated with midodrine and droxidopa to normalize blood pressure.
METHODS
The patient was a 62-year-old man with a history of HFpEF due to mitral regurgitation and complaints of dyspnea on exertion. He had been prescribed multiple medications at an outpatient clinic for CHF management, including azosemide 60 mg/day, bisoprolol 2.5 mg/day, enalapril 2.5 mg/day, spironolactone 50 mg/day, and tolvaptan 15 mg/day. The systolic blood pressure (SBP) of the patient remained at 70-80 mmHg because the use of the diuretic could not be reduced or discontinued owing to edema and weight gain. He was hospitalized for the exacerbation of CHF. Although midodrine 8 mg/day was administered to improve hypotension, the SBP of the patient increased only up to 90 mmHg. On the 35th day after hospitalization, the urine volume decreased significantly (< 100 mL/day) due to hypotension. When droxidopa 200 mg/day replaced intravenous noradrenaline on the 47th day, the SBP remained at 100-120 mmHg and the urine volume increased.
CONCLUSIONS
Oral combination treatment with midodrine and droxidopa might contribute to the maintenance of blood pressure and diuretic activity in HFpEF patients with refractory hypotension. However, further long-term studies evaluating the safety and efficacy of this combination therapy for patients with HFpEF are needed.
Background
While it is well-known that diuretic treatment is crucial to improve the prognosis and symptoms among patients with chronic heart failure (CHF) [1–3], a diminished diuretic response is common in these patients, increasing the required diuretic dose [4]. Hypotension has been defined as systolic blood pressure (SBP) < 90 mmHg and/or diastolic blood pressure (DBP) < 60 mmHg [5]. In particular, diuretic-induced hypotension causes dizziness [6]. However, the administration of diuretics in these patients cannot be stopped as this would likely result in the progression of heart failure [7].
Many reports have shown that droxidopa, a noradrenaline (NA) prodrug, improves the symptoms of orthostatic hypotension in patients with Parkinson disease, multiple system atrophy, and pure autonomic failure [8–10]. While extensive evidence is available regarding neurogenic hypotension, information on the efficacy and safety of droxidopa for refractory hypotension with CHF is insufficient. Midodrine is widely used for the management of orthostatic blood pressure [11]; however, there is no evidence available on the efficacy of the combination of midodrine and droxidopa. In recent years, drug treatment has been reported to improve prognosis in heart failure with reduced ejection fraction (HFrEF), in which ejection fraction (EF) is < 40% [1–3]. However, guidelines for the treatment of heart failure with preserved ejection fraction (HFpEF), in which EF is ≥50%, are not available. Here, we describe the case of a patient with HFpEF who was successfully treated for refractory hypotension.
Case presentation
The patient was a 62-year-old man with a history of CHF due to mitral regurgitation and complaints of dyspnea on exertion (New York Heart Association functional class III). After mitral annuloplasty, he was prescribed multiple medications at an outpatient clinic for the management of CHF, including azosemide 60 mg/day, bisoprolol 2.5 mg/day, enalapril 2.5 mg/day, spironolactone 50 mg/day, and tolvaptan 15 mg/day. The SBP of the patient remained at 70–80 mmHg because diuretic use could not be reduced or discontinued due to the possible effects of edema and weight gain. He was hospitalized for exacerbation of heart failure. On admission, his SBP and DBP were 83 and 47, respectively, and his heart rate (HR) was 88 beats/min. On the 3rd day after hospitalization, a pharmacist proposed midodrine 4 mg/day, an oral pressor with a weak effect on HR [12], to the attending doctor, after which drug administration was started (Fig. 1). The EF was measured on the 8th day and was 53.4%, which is categorized as HFpEF. Furosemide 20 mg/day was started because the urine volume was low on the 8th day. Over a 9-day period after the initiation of midodrine treatment, the dose was increased to 8 mg/day; however, SBP increased only up to 90 mmHg. Although amezinium 20 mg/day was administered on the 25th day for further pressor action, it was discontinued on the 29th day due to the onset of tachycardia (Fig. 1).
Fig. 1 Clinical course of the hospitalized patient in this study. Up-titration and down-titration of medications while in the hospital are shown, along with the daily urine volume, intake volume, blood pressure, and HR. BP, blood pressure; CHDF, continuous hemodiafiltration; DBP, diastolic blood pressure; DOA, dopamine; hANP, human atrial natriuretic peptide; HR, heart rate; NA, noradrenaline; SBP, systolic blood pressure. The unit γ shows μg/kg/min. SBP, DBP, and HR are shown as the mean ± standard deviation (SD)
In HFrEF, enalapril has been shown to contribute to improved prognosis [13], whereas it is unknown if this effect is present in HFpEF. However, because in HFpEF it may also be highly beneficial to continue with renin-angiotensin system inhibitors, we changed the drug regimen to losartan, which is reported to have a weak hypertensive effect among the angiotensin II receptor blockers [14]. From the 35th day of hospitalization, blood pressure decreased and urine volume decreased significantly (< 100 mL/day), and losartan was discontinued on the 36th day. Consequently, the patient underwent continuous hemodiafiltration (CHDF) on the 36th day only. As shown in Fig. 1, continuous intravenous infusion of dopamine from the 35th day and NA and human atrial natriuretic peptide from the 36th day gradually increased the blood pressure and urine volume. However, it was suggested that it would not be possible to maintain blood pressure upon NA discontinuation. Therefore, the attending doctor consulted a pharmacist regarding the switch from NA to oral pressor drugs. On the basis of some case reports [8–10], the pharmacist suggested switching from intravenous NA to droxidopa, which is converted to NA in vivo, on the 47th day. When the dosage of droxidopa was increased from 200 mg/day to 300 mg/day on the 49th day of hospitalization, SBP and DBP increased to 100–120 mmHg and 60–80 mmHg, respectively. As blood pressure increased, urine volume could be maintained at an average of 3000 mL/day. Seven days after the start of this combination therapy, the EF was 60.1% (Day 53), and no decrease was observed compared to the findings on the Day 8 (EF = 53.4%). In addition, this combination therapy also did not affect cardiothoracic ratio (CTR) (Day 8: CTR = 58% and Day 60: CTR = 58%) (Fig. 2). After discharge, the patient’s SBP and DBP were maintained using a combination of midodrine 8 mg/day and droxidopa 300 mg/day therapy, and his dizziness disappeared.
Fig. 2 Chest X-ray of the patient pre- and post-combination therapy with midodrine and droxidopa. Cardiothoracic ratio (CTR, %) was calculated as (a/b) × 100. A Chest X-ray showing pre-combination therapy status on the 8th day of hospitalization with a CTR of 58%. B Chest X-ray showing post-combination therapy status on the 60th day of hospitalization with a CTR of 58%
Discussion and conclusions
Hypotension is one of the most serious side effects of diuretics in patients with CHF [6]. It causes not only dizziness, but also reduction of diuretic activity because of decreased blood flow [4]. Therefore, it is suggested that improving hypotension may contribute to ensuring diuretic responsiveness. In the case of our patient with HFpEF and refractory hypotension, combination therapy of midodrine and droxidopa increased blood pressure and improved diuretic responsiveness.
While a β-blocker may have potential to improve prognosis in HFpEF [15], bisoprolol decreases blood pressure [16]. In this case, because bisoprolol was used to control tachycardia, we continued to administer bisoprolol at the lowest possible dose while monitoring the HR.
Midodrine is an oral alpha-1 adrenergic agonist that acts as a blood pressor [11] and decreases HR [12]. Although the sample size was small, it was also reported that midodrine elevates EF significantly in HFrEF [17]. Considering this evidence, midodrine might be considered suitable as an oral pressor for patients with HFpEF. Midodrine can elevate SBP and DBP by approximately 20 mmHg [17], and the degree of increase in blood pressure in our patient was similar to that reported previously [17]. Although amezinium was administered on the 25th day, the HR of the patient increased (Fig. 1). Katoh et al. [18] revealed that amezinium elevated HR. Tachycardia is known to be an exacerbating prognostic factor for heart failure [19], suggesting that midodrine, but not amezinium, may show efficacy as an oral pressor in patients with HFpEF.
Despite the administration of midodrine, the urine volume decreased due to excessive hypotension on the 34th and 35th days of hospitalization, and CHDF was performed on the 36th day. It was speculated that the blood pressure might be insufficiently maintained. Because droxidopa is metabolized by L-aromatic-amino-acid decarboxylase to NA, which mediates a pressor response [20], it may be useful to switch from intravenous to oral NA treatment due to hypotension. As expected, up-titration of droxidopa from 200 to 300 mg/day combined with 8 mg/day midodrine rapidly and significantly improved hypotension. Because the blood pressure of the patient could be maintained using this combination therapy, it is considered that the responsiveness to diuretics increased. Therefore, it may be possible to reduce the dose of diuretics such as furosemide. In a double-blind, 4-period crossover study, there were no clinically relevant effects of droxidopa on HR [21]. While the cardiovascular safety of droxidopa has been reported in patients with neurogenic hypotension [22], the detailed safety profile in patients with a history of HFpEF remains unknown. No adverse effects of the combination therapy were noted over the short term in this case. To the best of our knowledge, there is no information regarding the efficacy and safety of droxidopa combined with midodrine in HFpEF patients over the long term. Accordingly, further studies evaluating the safety and efficacy of long-term combination therapy of droxidopa and midodrine for HFpEF patients are needed.
Based on our findings, the combination therapy of midodrine and droxidopa might be safely and effectively administered to HFpEF patients with refractory hypotension, but further studies need to be conducted. In general, diuretic use should be reduced or discontinued if hypotension develops in patients with CHF. If the administration of diuretics must be continued owing to CHF progression, it is advisable to first start midodrine and then add droxidopa if hypotension cannot be effectively controlled.
Abbreviations
CHDFContinuous hemodiafiltration
CHFChronic heart failure
CTRCardiothoracic ratio
DBPDiastolic blood pressure
EFEjection fraction
HFpEFHeart failure with preserved ejection fraction
HFrEFHeart failure with reduced ejection fraction
HRHeart rate
NANoradrenaline
SBPSystolic blood pressure
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Not applicable.
Authors’ contributions
All authors edited the manuscript and approved the final version. Participated in research design: Asai, Sato, Yamamoto, Kito, Hioki, Urata, Abe. Wrote or contributed to the writing of the manuscript: Asai, Abe.
Funding
Not applicable.
Availability of data and materials
All the data generated or analyzed in this study are included in the published article.
Ethics approval and consent to participate
Because this is a case report, ethics review was deemed unnecessary at the discretion of the Ethics Review Committee of the National Hospital Organization Mie Chuo Medical Center.
Consent for publication
Written informed consent was obtained from the patient afterwards.
Competing interests
The authors declare that they have no competing interests. | Oral | DrugAdministrationRoute | CC BY | 33653416 | 19,980,597 | 2021-03-03 |
What was the administration route of drug 'LOSARTAN'? | Combination therapy of midodrine and droxidopa for refractory hypotension in heart failure with preserved ejection fraction per a pharmacist's proposal: a case report.
BACKGROUND
Patients with chronic heart failure (CHF) are often treated using many diuretics for symptom relief; however, diuretic use may have to continue despite hypotension development in these patients. Here, we present a case of heart failure with preserved ejection fraction (HFpEF), which is defined as ejection fraction ≥50% in CHF, and refractory hypotension, which was treated with midodrine and droxidopa to normalize blood pressure.
METHODS
The patient was a 62-year-old man with a history of HFpEF due to mitral regurgitation and complaints of dyspnea on exertion. He had been prescribed multiple medications at an outpatient clinic for CHF management, including azosemide 60 mg/day, bisoprolol 2.5 mg/day, enalapril 2.5 mg/day, spironolactone 50 mg/day, and tolvaptan 15 mg/day. The systolic blood pressure (SBP) of the patient remained at 70-80 mmHg because the use of the diuretic could not be reduced or discontinued owing to edema and weight gain. He was hospitalized for the exacerbation of CHF. Although midodrine 8 mg/day was administered to improve hypotension, the SBP of the patient increased only up to 90 mmHg. On the 35th day after hospitalization, the urine volume decreased significantly (< 100 mL/day) due to hypotension. When droxidopa 200 mg/day replaced intravenous noradrenaline on the 47th day, the SBP remained at 100-120 mmHg and the urine volume increased.
CONCLUSIONS
Oral combination treatment with midodrine and droxidopa might contribute to the maintenance of blood pressure and diuretic activity in HFpEF patients with refractory hypotension. However, further long-term studies evaluating the safety and efficacy of this combination therapy for patients with HFpEF are needed.
Background
While it is well-known that diuretic treatment is crucial to improve the prognosis and symptoms among patients with chronic heart failure (CHF) [1–3], a diminished diuretic response is common in these patients, increasing the required diuretic dose [4]. Hypotension has been defined as systolic blood pressure (SBP) < 90 mmHg and/or diastolic blood pressure (DBP) < 60 mmHg [5]. In particular, diuretic-induced hypotension causes dizziness [6]. However, the administration of diuretics in these patients cannot be stopped as this would likely result in the progression of heart failure [7].
Many reports have shown that droxidopa, a noradrenaline (NA) prodrug, improves the symptoms of orthostatic hypotension in patients with Parkinson disease, multiple system atrophy, and pure autonomic failure [8–10]. While extensive evidence is available regarding neurogenic hypotension, information on the efficacy and safety of droxidopa for refractory hypotension with CHF is insufficient. Midodrine is widely used for the management of orthostatic blood pressure [11]; however, there is no evidence available on the efficacy of the combination of midodrine and droxidopa. In recent years, drug treatment has been reported to improve prognosis in heart failure with reduced ejection fraction (HFrEF), in which ejection fraction (EF) is < 40% [1–3]. However, guidelines for the treatment of heart failure with preserved ejection fraction (HFpEF), in which EF is ≥50%, are not available. Here, we describe the case of a patient with HFpEF who was successfully treated for refractory hypotension.
Case presentation
The patient was a 62-year-old man with a history of CHF due to mitral regurgitation and complaints of dyspnea on exertion (New York Heart Association functional class III). After mitral annuloplasty, he was prescribed multiple medications at an outpatient clinic for the management of CHF, including azosemide 60 mg/day, bisoprolol 2.5 mg/day, enalapril 2.5 mg/day, spironolactone 50 mg/day, and tolvaptan 15 mg/day. The SBP of the patient remained at 70–80 mmHg because diuretic use could not be reduced or discontinued due to the possible effects of edema and weight gain. He was hospitalized for exacerbation of heart failure. On admission, his SBP and DBP were 83 and 47, respectively, and his heart rate (HR) was 88 beats/min. On the 3rd day after hospitalization, a pharmacist proposed midodrine 4 mg/day, an oral pressor with a weak effect on HR [12], to the attending doctor, after which drug administration was started (Fig. 1). The EF was measured on the 8th day and was 53.4%, which is categorized as HFpEF. Furosemide 20 mg/day was started because the urine volume was low on the 8th day. Over a 9-day period after the initiation of midodrine treatment, the dose was increased to 8 mg/day; however, SBP increased only up to 90 mmHg. Although amezinium 20 mg/day was administered on the 25th day for further pressor action, it was discontinued on the 29th day due to the onset of tachycardia (Fig. 1).
Fig. 1 Clinical course of the hospitalized patient in this study. Up-titration and down-titration of medications while in the hospital are shown, along with the daily urine volume, intake volume, blood pressure, and HR. BP, blood pressure; CHDF, continuous hemodiafiltration; DBP, diastolic blood pressure; DOA, dopamine; hANP, human atrial natriuretic peptide; HR, heart rate; NA, noradrenaline; SBP, systolic blood pressure. The unit γ shows μg/kg/min. SBP, DBP, and HR are shown as the mean ± standard deviation (SD)
In HFrEF, enalapril has been shown to contribute to improved prognosis [13], whereas it is unknown if this effect is present in HFpEF. However, because in HFpEF it may also be highly beneficial to continue with renin-angiotensin system inhibitors, we changed the drug regimen to losartan, which is reported to have a weak hypertensive effect among the angiotensin II receptor blockers [14]. From the 35th day of hospitalization, blood pressure decreased and urine volume decreased significantly (< 100 mL/day), and losartan was discontinued on the 36th day. Consequently, the patient underwent continuous hemodiafiltration (CHDF) on the 36th day only. As shown in Fig. 1, continuous intravenous infusion of dopamine from the 35th day and NA and human atrial natriuretic peptide from the 36th day gradually increased the blood pressure and urine volume. However, it was suggested that it would not be possible to maintain blood pressure upon NA discontinuation. Therefore, the attending doctor consulted a pharmacist regarding the switch from NA to oral pressor drugs. On the basis of some case reports [8–10], the pharmacist suggested switching from intravenous NA to droxidopa, which is converted to NA in vivo, on the 47th day. When the dosage of droxidopa was increased from 200 mg/day to 300 mg/day on the 49th day of hospitalization, SBP and DBP increased to 100–120 mmHg and 60–80 mmHg, respectively. As blood pressure increased, urine volume could be maintained at an average of 3000 mL/day. Seven days after the start of this combination therapy, the EF was 60.1% (Day 53), and no decrease was observed compared to the findings on the Day 8 (EF = 53.4%). In addition, this combination therapy also did not affect cardiothoracic ratio (CTR) (Day 8: CTR = 58% and Day 60: CTR = 58%) (Fig. 2). After discharge, the patient’s SBP and DBP were maintained using a combination of midodrine 8 mg/day and droxidopa 300 mg/day therapy, and his dizziness disappeared.
Fig. 2 Chest X-ray of the patient pre- and post-combination therapy with midodrine and droxidopa. Cardiothoracic ratio (CTR, %) was calculated as (a/b) × 100. A Chest X-ray showing pre-combination therapy status on the 8th day of hospitalization with a CTR of 58%. B Chest X-ray showing post-combination therapy status on the 60th day of hospitalization with a CTR of 58%
Discussion and conclusions
Hypotension is one of the most serious side effects of diuretics in patients with CHF [6]. It causes not only dizziness, but also reduction of diuretic activity because of decreased blood flow [4]. Therefore, it is suggested that improving hypotension may contribute to ensuring diuretic responsiveness. In the case of our patient with HFpEF and refractory hypotension, combination therapy of midodrine and droxidopa increased blood pressure and improved diuretic responsiveness.
While a β-blocker may have potential to improve prognosis in HFpEF [15], bisoprolol decreases blood pressure [16]. In this case, because bisoprolol was used to control tachycardia, we continued to administer bisoprolol at the lowest possible dose while monitoring the HR.
Midodrine is an oral alpha-1 adrenergic agonist that acts as a blood pressor [11] and decreases HR [12]. Although the sample size was small, it was also reported that midodrine elevates EF significantly in HFrEF [17]. Considering this evidence, midodrine might be considered suitable as an oral pressor for patients with HFpEF. Midodrine can elevate SBP and DBP by approximately 20 mmHg [17], and the degree of increase in blood pressure in our patient was similar to that reported previously [17]. Although amezinium was administered on the 25th day, the HR of the patient increased (Fig. 1). Katoh et al. [18] revealed that amezinium elevated HR. Tachycardia is known to be an exacerbating prognostic factor for heart failure [19], suggesting that midodrine, but not amezinium, may show efficacy as an oral pressor in patients with HFpEF.
Despite the administration of midodrine, the urine volume decreased due to excessive hypotension on the 34th and 35th days of hospitalization, and CHDF was performed on the 36th day. It was speculated that the blood pressure might be insufficiently maintained. Because droxidopa is metabolized by L-aromatic-amino-acid decarboxylase to NA, which mediates a pressor response [20], it may be useful to switch from intravenous to oral NA treatment due to hypotension. As expected, up-titration of droxidopa from 200 to 300 mg/day combined with 8 mg/day midodrine rapidly and significantly improved hypotension. Because the blood pressure of the patient could be maintained using this combination therapy, it is considered that the responsiveness to diuretics increased. Therefore, it may be possible to reduce the dose of diuretics such as furosemide. In a double-blind, 4-period crossover study, there were no clinically relevant effects of droxidopa on HR [21]. While the cardiovascular safety of droxidopa has been reported in patients with neurogenic hypotension [22], the detailed safety profile in patients with a history of HFpEF remains unknown. No adverse effects of the combination therapy were noted over the short term in this case. To the best of our knowledge, there is no information regarding the efficacy and safety of droxidopa combined with midodrine in HFpEF patients over the long term. Accordingly, further studies evaluating the safety and efficacy of long-term combination therapy of droxidopa and midodrine for HFpEF patients are needed.
Based on our findings, the combination therapy of midodrine and droxidopa might be safely and effectively administered to HFpEF patients with refractory hypotension, but further studies need to be conducted. In general, diuretic use should be reduced or discontinued if hypotension develops in patients with CHF. If the administration of diuretics must be continued owing to CHF progression, it is advisable to first start midodrine and then add droxidopa if hypotension cannot be effectively controlled.
Abbreviations
CHDFContinuous hemodiafiltration
CHFChronic heart failure
CTRCardiothoracic ratio
DBPDiastolic blood pressure
EFEjection fraction
HFpEFHeart failure with preserved ejection fraction
HFrEFHeart failure with reduced ejection fraction
HRHeart rate
NANoradrenaline
SBPSystolic blood pressure
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Not applicable.
Authors’ contributions
All authors edited the manuscript and approved the final version. Participated in research design: Asai, Sato, Yamamoto, Kito, Hioki, Urata, Abe. Wrote or contributed to the writing of the manuscript: Asai, Abe.
Funding
Not applicable.
Availability of data and materials
All the data generated or analyzed in this study are included in the published article.
Ethics approval and consent to participate
Because this is a case report, ethics review was deemed unnecessary at the discretion of the Ethics Review Committee of the National Hospital Organization Mie Chuo Medical Center.
Consent for publication
Written informed consent was obtained from the patient afterwards.
Competing interests
The authors declare that they have no competing interests. | Oral | DrugAdministrationRoute | CC BY | 33653416 | 19,980,597 | 2021-03-03 |
What was the administration route of drug 'MIDODRINE'? | Combination therapy of midodrine and droxidopa for refractory hypotension in heart failure with preserved ejection fraction per a pharmacist's proposal: a case report.
BACKGROUND
Patients with chronic heart failure (CHF) are often treated using many diuretics for symptom relief; however, diuretic use may have to continue despite hypotension development in these patients. Here, we present a case of heart failure with preserved ejection fraction (HFpEF), which is defined as ejection fraction ≥50% in CHF, and refractory hypotension, which was treated with midodrine and droxidopa to normalize blood pressure.
METHODS
The patient was a 62-year-old man with a history of HFpEF due to mitral regurgitation and complaints of dyspnea on exertion. He had been prescribed multiple medications at an outpatient clinic for CHF management, including azosemide 60 mg/day, bisoprolol 2.5 mg/day, enalapril 2.5 mg/day, spironolactone 50 mg/day, and tolvaptan 15 mg/day. The systolic blood pressure (SBP) of the patient remained at 70-80 mmHg because the use of the diuretic could not be reduced or discontinued owing to edema and weight gain. He was hospitalized for the exacerbation of CHF. Although midodrine 8 mg/day was administered to improve hypotension, the SBP of the patient increased only up to 90 mmHg. On the 35th day after hospitalization, the urine volume decreased significantly (< 100 mL/day) due to hypotension. When droxidopa 200 mg/day replaced intravenous noradrenaline on the 47th day, the SBP remained at 100-120 mmHg and the urine volume increased.
CONCLUSIONS
Oral combination treatment with midodrine and droxidopa might contribute to the maintenance of blood pressure and diuretic activity in HFpEF patients with refractory hypotension. However, further long-term studies evaluating the safety and efficacy of this combination therapy for patients with HFpEF are needed.
Background
While it is well-known that diuretic treatment is crucial to improve the prognosis and symptoms among patients with chronic heart failure (CHF) [1–3], a diminished diuretic response is common in these patients, increasing the required diuretic dose [4]. Hypotension has been defined as systolic blood pressure (SBP) < 90 mmHg and/or diastolic blood pressure (DBP) < 60 mmHg [5]. In particular, diuretic-induced hypotension causes dizziness [6]. However, the administration of diuretics in these patients cannot be stopped as this would likely result in the progression of heart failure [7].
Many reports have shown that droxidopa, a noradrenaline (NA) prodrug, improves the symptoms of orthostatic hypotension in patients with Parkinson disease, multiple system atrophy, and pure autonomic failure [8–10]. While extensive evidence is available regarding neurogenic hypotension, information on the efficacy and safety of droxidopa for refractory hypotension with CHF is insufficient. Midodrine is widely used for the management of orthostatic blood pressure [11]; however, there is no evidence available on the efficacy of the combination of midodrine and droxidopa. In recent years, drug treatment has been reported to improve prognosis in heart failure with reduced ejection fraction (HFrEF), in which ejection fraction (EF) is < 40% [1–3]. However, guidelines for the treatment of heart failure with preserved ejection fraction (HFpEF), in which EF is ≥50%, are not available. Here, we describe the case of a patient with HFpEF who was successfully treated for refractory hypotension.
Case presentation
The patient was a 62-year-old man with a history of CHF due to mitral regurgitation and complaints of dyspnea on exertion (New York Heart Association functional class III). After mitral annuloplasty, he was prescribed multiple medications at an outpatient clinic for the management of CHF, including azosemide 60 mg/day, bisoprolol 2.5 mg/day, enalapril 2.5 mg/day, spironolactone 50 mg/day, and tolvaptan 15 mg/day. The SBP of the patient remained at 70–80 mmHg because diuretic use could not be reduced or discontinued due to the possible effects of edema and weight gain. He was hospitalized for exacerbation of heart failure. On admission, his SBP and DBP were 83 and 47, respectively, and his heart rate (HR) was 88 beats/min. On the 3rd day after hospitalization, a pharmacist proposed midodrine 4 mg/day, an oral pressor with a weak effect on HR [12], to the attending doctor, after which drug administration was started (Fig. 1). The EF was measured on the 8th day and was 53.4%, which is categorized as HFpEF. Furosemide 20 mg/day was started because the urine volume was low on the 8th day. Over a 9-day period after the initiation of midodrine treatment, the dose was increased to 8 mg/day; however, SBP increased only up to 90 mmHg. Although amezinium 20 mg/day was administered on the 25th day for further pressor action, it was discontinued on the 29th day due to the onset of tachycardia (Fig. 1).
Fig. 1 Clinical course of the hospitalized patient in this study. Up-titration and down-titration of medications while in the hospital are shown, along with the daily urine volume, intake volume, blood pressure, and HR. BP, blood pressure; CHDF, continuous hemodiafiltration; DBP, diastolic blood pressure; DOA, dopamine; hANP, human atrial natriuretic peptide; HR, heart rate; NA, noradrenaline; SBP, systolic blood pressure. The unit γ shows μg/kg/min. SBP, DBP, and HR are shown as the mean ± standard deviation (SD)
In HFrEF, enalapril has been shown to contribute to improved prognosis [13], whereas it is unknown if this effect is present in HFpEF. However, because in HFpEF it may also be highly beneficial to continue with renin-angiotensin system inhibitors, we changed the drug regimen to losartan, which is reported to have a weak hypertensive effect among the angiotensin II receptor blockers [14]. From the 35th day of hospitalization, blood pressure decreased and urine volume decreased significantly (< 100 mL/day), and losartan was discontinued on the 36th day. Consequently, the patient underwent continuous hemodiafiltration (CHDF) on the 36th day only. As shown in Fig. 1, continuous intravenous infusion of dopamine from the 35th day and NA and human atrial natriuretic peptide from the 36th day gradually increased the blood pressure and urine volume. However, it was suggested that it would not be possible to maintain blood pressure upon NA discontinuation. Therefore, the attending doctor consulted a pharmacist regarding the switch from NA to oral pressor drugs. On the basis of some case reports [8–10], the pharmacist suggested switching from intravenous NA to droxidopa, which is converted to NA in vivo, on the 47th day. When the dosage of droxidopa was increased from 200 mg/day to 300 mg/day on the 49th day of hospitalization, SBP and DBP increased to 100–120 mmHg and 60–80 mmHg, respectively. As blood pressure increased, urine volume could be maintained at an average of 3000 mL/day. Seven days after the start of this combination therapy, the EF was 60.1% (Day 53), and no decrease was observed compared to the findings on the Day 8 (EF = 53.4%). In addition, this combination therapy also did not affect cardiothoracic ratio (CTR) (Day 8: CTR = 58% and Day 60: CTR = 58%) (Fig. 2). After discharge, the patient’s SBP and DBP were maintained using a combination of midodrine 8 mg/day and droxidopa 300 mg/day therapy, and his dizziness disappeared.
Fig. 2 Chest X-ray of the patient pre- and post-combination therapy with midodrine and droxidopa. Cardiothoracic ratio (CTR, %) was calculated as (a/b) × 100. A Chest X-ray showing pre-combination therapy status on the 8th day of hospitalization with a CTR of 58%. B Chest X-ray showing post-combination therapy status on the 60th day of hospitalization with a CTR of 58%
Discussion and conclusions
Hypotension is one of the most serious side effects of diuretics in patients with CHF [6]. It causes not only dizziness, but also reduction of diuretic activity because of decreased blood flow [4]. Therefore, it is suggested that improving hypotension may contribute to ensuring diuretic responsiveness. In the case of our patient with HFpEF and refractory hypotension, combination therapy of midodrine and droxidopa increased blood pressure and improved diuretic responsiveness.
While a β-blocker may have potential to improve prognosis in HFpEF [15], bisoprolol decreases blood pressure [16]. In this case, because bisoprolol was used to control tachycardia, we continued to administer bisoprolol at the lowest possible dose while monitoring the HR.
Midodrine is an oral alpha-1 adrenergic agonist that acts as a blood pressor [11] and decreases HR [12]. Although the sample size was small, it was also reported that midodrine elevates EF significantly in HFrEF [17]. Considering this evidence, midodrine might be considered suitable as an oral pressor for patients with HFpEF. Midodrine can elevate SBP and DBP by approximately 20 mmHg [17], and the degree of increase in blood pressure in our patient was similar to that reported previously [17]. Although amezinium was administered on the 25th day, the HR of the patient increased (Fig. 1). Katoh et al. [18] revealed that amezinium elevated HR. Tachycardia is known to be an exacerbating prognostic factor for heart failure [19], suggesting that midodrine, but not amezinium, may show efficacy as an oral pressor in patients with HFpEF.
Despite the administration of midodrine, the urine volume decreased due to excessive hypotension on the 34th and 35th days of hospitalization, and CHDF was performed on the 36th day. It was speculated that the blood pressure might be insufficiently maintained. Because droxidopa is metabolized by L-aromatic-amino-acid decarboxylase to NA, which mediates a pressor response [20], it may be useful to switch from intravenous to oral NA treatment due to hypotension. As expected, up-titration of droxidopa from 200 to 300 mg/day combined with 8 mg/day midodrine rapidly and significantly improved hypotension. Because the blood pressure of the patient could be maintained using this combination therapy, it is considered that the responsiveness to diuretics increased. Therefore, it may be possible to reduce the dose of diuretics such as furosemide. In a double-blind, 4-period crossover study, there were no clinically relevant effects of droxidopa on HR [21]. While the cardiovascular safety of droxidopa has been reported in patients with neurogenic hypotension [22], the detailed safety profile in patients with a history of HFpEF remains unknown. No adverse effects of the combination therapy were noted over the short term in this case. To the best of our knowledge, there is no information regarding the efficacy and safety of droxidopa combined with midodrine in HFpEF patients over the long term. Accordingly, further studies evaluating the safety and efficacy of long-term combination therapy of droxidopa and midodrine for HFpEF patients are needed.
Based on our findings, the combination therapy of midodrine and droxidopa might be safely and effectively administered to HFpEF patients with refractory hypotension, but further studies need to be conducted. In general, diuretic use should be reduced or discontinued if hypotension develops in patients with CHF. If the administration of diuretics must be continued owing to CHF progression, it is advisable to first start midodrine and then add droxidopa if hypotension cannot be effectively controlled.
Abbreviations
CHDFContinuous hemodiafiltration
CHFChronic heart failure
CTRCardiothoracic ratio
DBPDiastolic blood pressure
EFEjection fraction
HFpEFHeart failure with preserved ejection fraction
HFrEFHeart failure with reduced ejection fraction
HRHeart rate
NANoradrenaline
SBPSystolic blood pressure
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Not applicable.
Authors’ contributions
All authors edited the manuscript and approved the final version. Participated in research design: Asai, Sato, Yamamoto, Kito, Hioki, Urata, Abe. Wrote or contributed to the writing of the manuscript: Asai, Abe.
Funding
Not applicable.
Availability of data and materials
All the data generated or analyzed in this study are included in the published article.
Ethics approval and consent to participate
Because this is a case report, ethics review was deemed unnecessary at the discretion of the Ethics Review Committee of the National Hospital Organization Mie Chuo Medical Center.
Consent for publication
Written informed consent was obtained from the patient afterwards.
Competing interests
The authors declare that they have no competing interests. | Oral | DrugAdministrationRoute | CC BY | 33653416 | 19,980,597 | 2021-03-03 |
What was the administration route of drug 'NOREPINEPHRINE'? | Combination therapy of midodrine and droxidopa for refractory hypotension in heart failure with preserved ejection fraction per a pharmacist's proposal: a case report.
BACKGROUND
Patients with chronic heart failure (CHF) are often treated using many diuretics for symptom relief; however, diuretic use may have to continue despite hypotension development in these patients. Here, we present a case of heart failure with preserved ejection fraction (HFpEF), which is defined as ejection fraction ≥50% in CHF, and refractory hypotension, which was treated with midodrine and droxidopa to normalize blood pressure.
METHODS
The patient was a 62-year-old man with a history of HFpEF due to mitral regurgitation and complaints of dyspnea on exertion. He had been prescribed multiple medications at an outpatient clinic for CHF management, including azosemide 60 mg/day, bisoprolol 2.5 mg/day, enalapril 2.5 mg/day, spironolactone 50 mg/day, and tolvaptan 15 mg/day. The systolic blood pressure (SBP) of the patient remained at 70-80 mmHg because the use of the diuretic could not be reduced or discontinued owing to edema and weight gain. He was hospitalized for the exacerbation of CHF. Although midodrine 8 mg/day was administered to improve hypotension, the SBP of the patient increased only up to 90 mmHg. On the 35th day after hospitalization, the urine volume decreased significantly (< 100 mL/day) due to hypotension. When droxidopa 200 mg/day replaced intravenous noradrenaline on the 47th day, the SBP remained at 100-120 mmHg and the urine volume increased.
CONCLUSIONS
Oral combination treatment with midodrine and droxidopa might contribute to the maintenance of blood pressure and diuretic activity in HFpEF patients with refractory hypotension. However, further long-term studies evaluating the safety and efficacy of this combination therapy for patients with HFpEF are needed.
Background
While it is well-known that diuretic treatment is crucial to improve the prognosis and symptoms among patients with chronic heart failure (CHF) [1–3], a diminished diuretic response is common in these patients, increasing the required diuretic dose [4]. Hypotension has been defined as systolic blood pressure (SBP) < 90 mmHg and/or diastolic blood pressure (DBP) < 60 mmHg [5]. In particular, diuretic-induced hypotension causes dizziness [6]. However, the administration of diuretics in these patients cannot be stopped as this would likely result in the progression of heart failure [7].
Many reports have shown that droxidopa, a noradrenaline (NA) prodrug, improves the symptoms of orthostatic hypotension in patients with Parkinson disease, multiple system atrophy, and pure autonomic failure [8–10]. While extensive evidence is available regarding neurogenic hypotension, information on the efficacy and safety of droxidopa for refractory hypotension with CHF is insufficient. Midodrine is widely used for the management of orthostatic blood pressure [11]; however, there is no evidence available on the efficacy of the combination of midodrine and droxidopa. In recent years, drug treatment has been reported to improve prognosis in heart failure with reduced ejection fraction (HFrEF), in which ejection fraction (EF) is < 40% [1–3]. However, guidelines for the treatment of heart failure with preserved ejection fraction (HFpEF), in which EF is ≥50%, are not available. Here, we describe the case of a patient with HFpEF who was successfully treated for refractory hypotension.
Case presentation
The patient was a 62-year-old man with a history of CHF due to mitral regurgitation and complaints of dyspnea on exertion (New York Heart Association functional class III). After mitral annuloplasty, he was prescribed multiple medications at an outpatient clinic for the management of CHF, including azosemide 60 mg/day, bisoprolol 2.5 mg/day, enalapril 2.5 mg/day, spironolactone 50 mg/day, and tolvaptan 15 mg/day. The SBP of the patient remained at 70–80 mmHg because diuretic use could not be reduced or discontinued due to the possible effects of edema and weight gain. He was hospitalized for exacerbation of heart failure. On admission, his SBP and DBP were 83 and 47, respectively, and his heart rate (HR) was 88 beats/min. On the 3rd day after hospitalization, a pharmacist proposed midodrine 4 mg/day, an oral pressor with a weak effect on HR [12], to the attending doctor, after which drug administration was started (Fig. 1). The EF was measured on the 8th day and was 53.4%, which is categorized as HFpEF. Furosemide 20 mg/day was started because the urine volume was low on the 8th day. Over a 9-day period after the initiation of midodrine treatment, the dose was increased to 8 mg/day; however, SBP increased only up to 90 mmHg. Although amezinium 20 mg/day was administered on the 25th day for further pressor action, it was discontinued on the 29th day due to the onset of tachycardia (Fig. 1).
Fig. 1 Clinical course of the hospitalized patient in this study. Up-titration and down-titration of medications while in the hospital are shown, along with the daily urine volume, intake volume, blood pressure, and HR. BP, blood pressure; CHDF, continuous hemodiafiltration; DBP, diastolic blood pressure; DOA, dopamine; hANP, human atrial natriuretic peptide; HR, heart rate; NA, noradrenaline; SBP, systolic blood pressure. The unit γ shows μg/kg/min. SBP, DBP, and HR are shown as the mean ± standard deviation (SD)
In HFrEF, enalapril has been shown to contribute to improved prognosis [13], whereas it is unknown if this effect is present in HFpEF. However, because in HFpEF it may also be highly beneficial to continue with renin-angiotensin system inhibitors, we changed the drug regimen to losartan, which is reported to have a weak hypertensive effect among the angiotensin II receptor blockers [14]. From the 35th day of hospitalization, blood pressure decreased and urine volume decreased significantly (< 100 mL/day), and losartan was discontinued on the 36th day. Consequently, the patient underwent continuous hemodiafiltration (CHDF) on the 36th day only. As shown in Fig. 1, continuous intravenous infusion of dopamine from the 35th day and NA and human atrial natriuretic peptide from the 36th day gradually increased the blood pressure and urine volume. However, it was suggested that it would not be possible to maintain blood pressure upon NA discontinuation. Therefore, the attending doctor consulted a pharmacist regarding the switch from NA to oral pressor drugs. On the basis of some case reports [8–10], the pharmacist suggested switching from intravenous NA to droxidopa, which is converted to NA in vivo, on the 47th day. When the dosage of droxidopa was increased from 200 mg/day to 300 mg/day on the 49th day of hospitalization, SBP and DBP increased to 100–120 mmHg and 60–80 mmHg, respectively. As blood pressure increased, urine volume could be maintained at an average of 3000 mL/day. Seven days after the start of this combination therapy, the EF was 60.1% (Day 53), and no decrease was observed compared to the findings on the Day 8 (EF = 53.4%). In addition, this combination therapy also did not affect cardiothoracic ratio (CTR) (Day 8: CTR = 58% and Day 60: CTR = 58%) (Fig. 2). After discharge, the patient’s SBP and DBP were maintained using a combination of midodrine 8 mg/day and droxidopa 300 mg/day therapy, and his dizziness disappeared.
Fig. 2 Chest X-ray of the patient pre- and post-combination therapy with midodrine and droxidopa. Cardiothoracic ratio (CTR, %) was calculated as (a/b) × 100. A Chest X-ray showing pre-combination therapy status on the 8th day of hospitalization with a CTR of 58%. B Chest X-ray showing post-combination therapy status on the 60th day of hospitalization with a CTR of 58%
Discussion and conclusions
Hypotension is one of the most serious side effects of diuretics in patients with CHF [6]. It causes not only dizziness, but also reduction of diuretic activity because of decreased blood flow [4]. Therefore, it is suggested that improving hypotension may contribute to ensuring diuretic responsiveness. In the case of our patient with HFpEF and refractory hypotension, combination therapy of midodrine and droxidopa increased blood pressure and improved diuretic responsiveness.
While a β-blocker may have potential to improve prognosis in HFpEF [15], bisoprolol decreases blood pressure [16]. In this case, because bisoprolol was used to control tachycardia, we continued to administer bisoprolol at the lowest possible dose while monitoring the HR.
Midodrine is an oral alpha-1 adrenergic agonist that acts as a blood pressor [11] and decreases HR [12]. Although the sample size was small, it was also reported that midodrine elevates EF significantly in HFrEF [17]. Considering this evidence, midodrine might be considered suitable as an oral pressor for patients with HFpEF. Midodrine can elevate SBP and DBP by approximately 20 mmHg [17], and the degree of increase in blood pressure in our patient was similar to that reported previously [17]. Although amezinium was administered on the 25th day, the HR of the patient increased (Fig. 1). Katoh et al. [18] revealed that amezinium elevated HR. Tachycardia is known to be an exacerbating prognostic factor for heart failure [19], suggesting that midodrine, but not amezinium, may show efficacy as an oral pressor in patients with HFpEF.
Despite the administration of midodrine, the urine volume decreased due to excessive hypotension on the 34th and 35th days of hospitalization, and CHDF was performed on the 36th day. It was speculated that the blood pressure might be insufficiently maintained. Because droxidopa is metabolized by L-aromatic-amino-acid decarboxylase to NA, which mediates a pressor response [20], it may be useful to switch from intravenous to oral NA treatment due to hypotension. As expected, up-titration of droxidopa from 200 to 300 mg/day combined with 8 mg/day midodrine rapidly and significantly improved hypotension. Because the blood pressure of the patient could be maintained using this combination therapy, it is considered that the responsiveness to diuretics increased. Therefore, it may be possible to reduce the dose of diuretics such as furosemide. In a double-blind, 4-period crossover study, there were no clinically relevant effects of droxidopa on HR [21]. While the cardiovascular safety of droxidopa has been reported in patients with neurogenic hypotension [22], the detailed safety profile in patients with a history of HFpEF remains unknown. No adverse effects of the combination therapy were noted over the short term in this case. To the best of our knowledge, there is no information regarding the efficacy and safety of droxidopa combined with midodrine in HFpEF patients over the long term. Accordingly, further studies evaluating the safety and efficacy of long-term combination therapy of droxidopa and midodrine for HFpEF patients are needed.
Based on our findings, the combination therapy of midodrine and droxidopa might be safely and effectively administered to HFpEF patients with refractory hypotension, but further studies need to be conducted. In general, diuretic use should be reduced or discontinued if hypotension develops in patients with CHF. If the administration of diuretics must be continued owing to CHF progression, it is advisable to first start midodrine and then add droxidopa if hypotension cannot be effectively controlled.
Abbreviations
CHDFContinuous hemodiafiltration
CHFChronic heart failure
CTRCardiothoracic ratio
DBPDiastolic blood pressure
EFEjection fraction
HFpEFHeart failure with preserved ejection fraction
HFrEFHeart failure with reduced ejection fraction
HRHeart rate
NANoradrenaline
SBPSystolic blood pressure
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Not applicable.
Authors’ contributions
All authors edited the manuscript and approved the final version. Participated in research design: Asai, Sato, Yamamoto, Kito, Hioki, Urata, Abe. Wrote or contributed to the writing of the manuscript: Asai, Abe.
Funding
Not applicable.
Availability of data and materials
All the data generated or analyzed in this study are included in the published article.
Ethics approval and consent to participate
Because this is a case report, ethics review was deemed unnecessary at the discretion of the Ethics Review Committee of the National Hospital Organization Mie Chuo Medical Center.
Consent for publication
Written informed consent was obtained from the patient afterwards.
Competing interests
The authors declare that they have no competing interests. | Intravenous drip | DrugAdministrationRoute | CC BY | 33653416 | 19,980,597 | 2021-03-03 |
What was the administration route of drug 'SPIRONOLACTONE'? | Combination therapy of midodrine and droxidopa for refractory hypotension in heart failure with preserved ejection fraction per a pharmacist's proposal: a case report.
BACKGROUND
Patients with chronic heart failure (CHF) are often treated using many diuretics for symptom relief; however, diuretic use may have to continue despite hypotension development in these patients. Here, we present a case of heart failure with preserved ejection fraction (HFpEF), which is defined as ejection fraction ≥50% in CHF, and refractory hypotension, which was treated with midodrine and droxidopa to normalize blood pressure.
METHODS
The patient was a 62-year-old man with a history of HFpEF due to mitral regurgitation and complaints of dyspnea on exertion. He had been prescribed multiple medications at an outpatient clinic for CHF management, including azosemide 60 mg/day, bisoprolol 2.5 mg/day, enalapril 2.5 mg/day, spironolactone 50 mg/day, and tolvaptan 15 mg/day. The systolic blood pressure (SBP) of the patient remained at 70-80 mmHg because the use of the diuretic could not be reduced or discontinued owing to edema and weight gain. He was hospitalized for the exacerbation of CHF. Although midodrine 8 mg/day was administered to improve hypotension, the SBP of the patient increased only up to 90 mmHg. On the 35th day after hospitalization, the urine volume decreased significantly (< 100 mL/day) due to hypotension. When droxidopa 200 mg/day replaced intravenous noradrenaline on the 47th day, the SBP remained at 100-120 mmHg and the urine volume increased.
CONCLUSIONS
Oral combination treatment with midodrine and droxidopa might contribute to the maintenance of blood pressure and diuretic activity in HFpEF patients with refractory hypotension. However, further long-term studies evaluating the safety and efficacy of this combination therapy for patients with HFpEF are needed.
Background
While it is well-known that diuretic treatment is crucial to improve the prognosis and symptoms among patients with chronic heart failure (CHF) [1–3], a diminished diuretic response is common in these patients, increasing the required diuretic dose [4]. Hypotension has been defined as systolic blood pressure (SBP) < 90 mmHg and/or diastolic blood pressure (DBP) < 60 mmHg [5]. In particular, diuretic-induced hypotension causes dizziness [6]. However, the administration of diuretics in these patients cannot be stopped as this would likely result in the progression of heart failure [7].
Many reports have shown that droxidopa, a noradrenaline (NA) prodrug, improves the symptoms of orthostatic hypotension in patients with Parkinson disease, multiple system atrophy, and pure autonomic failure [8–10]. While extensive evidence is available regarding neurogenic hypotension, information on the efficacy and safety of droxidopa for refractory hypotension with CHF is insufficient. Midodrine is widely used for the management of orthostatic blood pressure [11]; however, there is no evidence available on the efficacy of the combination of midodrine and droxidopa. In recent years, drug treatment has been reported to improve prognosis in heart failure with reduced ejection fraction (HFrEF), in which ejection fraction (EF) is < 40% [1–3]. However, guidelines for the treatment of heart failure with preserved ejection fraction (HFpEF), in which EF is ≥50%, are not available. Here, we describe the case of a patient with HFpEF who was successfully treated for refractory hypotension.
Case presentation
The patient was a 62-year-old man with a history of CHF due to mitral regurgitation and complaints of dyspnea on exertion (New York Heart Association functional class III). After mitral annuloplasty, he was prescribed multiple medications at an outpatient clinic for the management of CHF, including azosemide 60 mg/day, bisoprolol 2.5 mg/day, enalapril 2.5 mg/day, spironolactone 50 mg/day, and tolvaptan 15 mg/day. The SBP of the patient remained at 70–80 mmHg because diuretic use could not be reduced or discontinued due to the possible effects of edema and weight gain. He was hospitalized for exacerbation of heart failure. On admission, his SBP and DBP were 83 and 47, respectively, and his heart rate (HR) was 88 beats/min. On the 3rd day after hospitalization, a pharmacist proposed midodrine 4 mg/day, an oral pressor with a weak effect on HR [12], to the attending doctor, after which drug administration was started (Fig. 1). The EF was measured on the 8th day and was 53.4%, which is categorized as HFpEF. Furosemide 20 mg/day was started because the urine volume was low on the 8th day. Over a 9-day period after the initiation of midodrine treatment, the dose was increased to 8 mg/day; however, SBP increased only up to 90 mmHg. Although amezinium 20 mg/day was administered on the 25th day for further pressor action, it was discontinued on the 29th day due to the onset of tachycardia (Fig. 1).
Fig. 1 Clinical course of the hospitalized patient in this study. Up-titration and down-titration of medications while in the hospital are shown, along with the daily urine volume, intake volume, blood pressure, and HR. BP, blood pressure; CHDF, continuous hemodiafiltration; DBP, diastolic blood pressure; DOA, dopamine; hANP, human atrial natriuretic peptide; HR, heart rate; NA, noradrenaline; SBP, systolic blood pressure. The unit γ shows μg/kg/min. SBP, DBP, and HR are shown as the mean ± standard deviation (SD)
In HFrEF, enalapril has been shown to contribute to improved prognosis [13], whereas it is unknown if this effect is present in HFpEF. However, because in HFpEF it may also be highly beneficial to continue with renin-angiotensin system inhibitors, we changed the drug regimen to losartan, which is reported to have a weak hypertensive effect among the angiotensin II receptor blockers [14]. From the 35th day of hospitalization, blood pressure decreased and urine volume decreased significantly (< 100 mL/day), and losartan was discontinued on the 36th day. Consequently, the patient underwent continuous hemodiafiltration (CHDF) on the 36th day only. As shown in Fig. 1, continuous intravenous infusion of dopamine from the 35th day and NA and human atrial natriuretic peptide from the 36th day gradually increased the blood pressure and urine volume. However, it was suggested that it would not be possible to maintain blood pressure upon NA discontinuation. Therefore, the attending doctor consulted a pharmacist regarding the switch from NA to oral pressor drugs. On the basis of some case reports [8–10], the pharmacist suggested switching from intravenous NA to droxidopa, which is converted to NA in vivo, on the 47th day. When the dosage of droxidopa was increased from 200 mg/day to 300 mg/day on the 49th day of hospitalization, SBP and DBP increased to 100–120 mmHg and 60–80 mmHg, respectively. As blood pressure increased, urine volume could be maintained at an average of 3000 mL/day. Seven days after the start of this combination therapy, the EF was 60.1% (Day 53), and no decrease was observed compared to the findings on the Day 8 (EF = 53.4%). In addition, this combination therapy also did not affect cardiothoracic ratio (CTR) (Day 8: CTR = 58% and Day 60: CTR = 58%) (Fig. 2). After discharge, the patient’s SBP and DBP were maintained using a combination of midodrine 8 mg/day and droxidopa 300 mg/day therapy, and his dizziness disappeared.
Fig. 2 Chest X-ray of the patient pre- and post-combination therapy with midodrine and droxidopa. Cardiothoracic ratio (CTR, %) was calculated as (a/b) × 100. A Chest X-ray showing pre-combination therapy status on the 8th day of hospitalization with a CTR of 58%. B Chest X-ray showing post-combination therapy status on the 60th day of hospitalization with a CTR of 58%
Discussion and conclusions
Hypotension is one of the most serious side effects of diuretics in patients with CHF [6]. It causes not only dizziness, but also reduction of diuretic activity because of decreased blood flow [4]. Therefore, it is suggested that improving hypotension may contribute to ensuring diuretic responsiveness. In the case of our patient with HFpEF and refractory hypotension, combination therapy of midodrine and droxidopa increased blood pressure and improved diuretic responsiveness.
While a β-blocker may have potential to improve prognosis in HFpEF [15], bisoprolol decreases blood pressure [16]. In this case, because bisoprolol was used to control tachycardia, we continued to administer bisoprolol at the lowest possible dose while monitoring the HR.
Midodrine is an oral alpha-1 adrenergic agonist that acts as a blood pressor [11] and decreases HR [12]. Although the sample size was small, it was also reported that midodrine elevates EF significantly in HFrEF [17]. Considering this evidence, midodrine might be considered suitable as an oral pressor for patients with HFpEF. Midodrine can elevate SBP and DBP by approximately 20 mmHg [17], and the degree of increase in blood pressure in our patient was similar to that reported previously [17]. Although amezinium was administered on the 25th day, the HR of the patient increased (Fig. 1). Katoh et al. [18] revealed that amezinium elevated HR. Tachycardia is known to be an exacerbating prognostic factor for heart failure [19], suggesting that midodrine, but not amezinium, may show efficacy as an oral pressor in patients with HFpEF.
Despite the administration of midodrine, the urine volume decreased due to excessive hypotension on the 34th and 35th days of hospitalization, and CHDF was performed on the 36th day. It was speculated that the blood pressure might be insufficiently maintained. Because droxidopa is metabolized by L-aromatic-amino-acid decarboxylase to NA, which mediates a pressor response [20], it may be useful to switch from intravenous to oral NA treatment due to hypotension. As expected, up-titration of droxidopa from 200 to 300 mg/day combined with 8 mg/day midodrine rapidly and significantly improved hypotension. Because the blood pressure of the patient could be maintained using this combination therapy, it is considered that the responsiveness to diuretics increased. Therefore, it may be possible to reduce the dose of diuretics such as furosemide. In a double-blind, 4-period crossover study, there were no clinically relevant effects of droxidopa on HR [21]. While the cardiovascular safety of droxidopa has been reported in patients with neurogenic hypotension [22], the detailed safety profile in patients with a history of HFpEF remains unknown. No adverse effects of the combination therapy were noted over the short term in this case. To the best of our knowledge, there is no information regarding the efficacy and safety of droxidopa combined with midodrine in HFpEF patients over the long term. Accordingly, further studies evaluating the safety and efficacy of long-term combination therapy of droxidopa and midodrine for HFpEF patients are needed.
Based on our findings, the combination therapy of midodrine and droxidopa might be safely and effectively administered to HFpEF patients with refractory hypotension, but further studies need to be conducted. In general, diuretic use should be reduced or discontinued if hypotension develops in patients with CHF. If the administration of diuretics must be continued owing to CHF progression, it is advisable to first start midodrine and then add droxidopa if hypotension cannot be effectively controlled.
Abbreviations
CHDFContinuous hemodiafiltration
CHFChronic heart failure
CTRCardiothoracic ratio
DBPDiastolic blood pressure
EFEjection fraction
HFpEFHeart failure with preserved ejection fraction
HFrEFHeart failure with reduced ejection fraction
HRHeart rate
NANoradrenaline
SBPSystolic blood pressure
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Not applicable.
Authors’ contributions
All authors edited the manuscript and approved the final version. Participated in research design: Asai, Sato, Yamamoto, Kito, Hioki, Urata, Abe. Wrote or contributed to the writing of the manuscript: Asai, Abe.
Funding
Not applicable.
Availability of data and materials
All the data generated or analyzed in this study are included in the published article.
Ethics approval and consent to participate
Because this is a case report, ethics review was deemed unnecessary at the discretion of the Ethics Review Committee of the National Hospital Organization Mie Chuo Medical Center.
Consent for publication
Written informed consent was obtained from the patient afterwards.
Competing interests
The authors declare that they have no competing interests. | Oral | DrugAdministrationRoute | CC BY | 33653416 | 19,980,597 | 2021-03-03 |
What was the administration route of drug 'TOLVAPTAN'? | Combination therapy of midodrine and droxidopa for refractory hypotension in heart failure with preserved ejection fraction per a pharmacist's proposal: a case report.
BACKGROUND
Patients with chronic heart failure (CHF) are often treated using many diuretics for symptom relief; however, diuretic use may have to continue despite hypotension development in these patients. Here, we present a case of heart failure with preserved ejection fraction (HFpEF), which is defined as ejection fraction ≥50% in CHF, and refractory hypotension, which was treated with midodrine and droxidopa to normalize blood pressure.
METHODS
The patient was a 62-year-old man with a history of HFpEF due to mitral regurgitation and complaints of dyspnea on exertion. He had been prescribed multiple medications at an outpatient clinic for CHF management, including azosemide 60 mg/day, bisoprolol 2.5 mg/day, enalapril 2.5 mg/day, spironolactone 50 mg/day, and tolvaptan 15 mg/day. The systolic blood pressure (SBP) of the patient remained at 70-80 mmHg because the use of the diuretic could not be reduced or discontinued owing to edema and weight gain. He was hospitalized for the exacerbation of CHF. Although midodrine 8 mg/day was administered to improve hypotension, the SBP of the patient increased only up to 90 mmHg. On the 35th day after hospitalization, the urine volume decreased significantly (< 100 mL/day) due to hypotension. When droxidopa 200 mg/day replaced intravenous noradrenaline on the 47th day, the SBP remained at 100-120 mmHg and the urine volume increased.
CONCLUSIONS
Oral combination treatment with midodrine and droxidopa might contribute to the maintenance of blood pressure and diuretic activity in HFpEF patients with refractory hypotension. However, further long-term studies evaluating the safety and efficacy of this combination therapy for patients with HFpEF are needed.
Background
While it is well-known that diuretic treatment is crucial to improve the prognosis and symptoms among patients with chronic heart failure (CHF) [1–3], a diminished diuretic response is common in these patients, increasing the required diuretic dose [4]. Hypotension has been defined as systolic blood pressure (SBP) < 90 mmHg and/or diastolic blood pressure (DBP) < 60 mmHg [5]. In particular, diuretic-induced hypotension causes dizziness [6]. However, the administration of diuretics in these patients cannot be stopped as this would likely result in the progression of heart failure [7].
Many reports have shown that droxidopa, a noradrenaline (NA) prodrug, improves the symptoms of orthostatic hypotension in patients with Parkinson disease, multiple system atrophy, and pure autonomic failure [8–10]. While extensive evidence is available regarding neurogenic hypotension, information on the efficacy and safety of droxidopa for refractory hypotension with CHF is insufficient. Midodrine is widely used for the management of orthostatic blood pressure [11]; however, there is no evidence available on the efficacy of the combination of midodrine and droxidopa. In recent years, drug treatment has been reported to improve prognosis in heart failure with reduced ejection fraction (HFrEF), in which ejection fraction (EF) is < 40% [1–3]. However, guidelines for the treatment of heart failure with preserved ejection fraction (HFpEF), in which EF is ≥50%, are not available. Here, we describe the case of a patient with HFpEF who was successfully treated for refractory hypotension.
Case presentation
The patient was a 62-year-old man with a history of CHF due to mitral regurgitation and complaints of dyspnea on exertion (New York Heart Association functional class III). After mitral annuloplasty, he was prescribed multiple medications at an outpatient clinic for the management of CHF, including azosemide 60 mg/day, bisoprolol 2.5 mg/day, enalapril 2.5 mg/day, spironolactone 50 mg/day, and tolvaptan 15 mg/day. The SBP of the patient remained at 70–80 mmHg because diuretic use could not be reduced or discontinued due to the possible effects of edema and weight gain. He was hospitalized for exacerbation of heart failure. On admission, his SBP and DBP were 83 and 47, respectively, and his heart rate (HR) was 88 beats/min. On the 3rd day after hospitalization, a pharmacist proposed midodrine 4 mg/day, an oral pressor with a weak effect on HR [12], to the attending doctor, after which drug administration was started (Fig. 1). The EF was measured on the 8th day and was 53.4%, which is categorized as HFpEF. Furosemide 20 mg/day was started because the urine volume was low on the 8th day. Over a 9-day period after the initiation of midodrine treatment, the dose was increased to 8 mg/day; however, SBP increased only up to 90 mmHg. Although amezinium 20 mg/day was administered on the 25th day for further pressor action, it was discontinued on the 29th day due to the onset of tachycardia (Fig. 1).
Fig. 1 Clinical course of the hospitalized patient in this study. Up-titration and down-titration of medications while in the hospital are shown, along with the daily urine volume, intake volume, blood pressure, and HR. BP, blood pressure; CHDF, continuous hemodiafiltration; DBP, diastolic blood pressure; DOA, dopamine; hANP, human atrial natriuretic peptide; HR, heart rate; NA, noradrenaline; SBP, systolic blood pressure. The unit γ shows μg/kg/min. SBP, DBP, and HR are shown as the mean ± standard deviation (SD)
In HFrEF, enalapril has been shown to contribute to improved prognosis [13], whereas it is unknown if this effect is present in HFpEF. However, because in HFpEF it may also be highly beneficial to continue with renin-angiotensin system inhibitors, we changed the drug regimen to losartan, which is reported to have a weak hypertensive effect among the angiotensin II receptor blockers [14]. From the 35th day of hospitalization, blood pressure decreased and urine volume decreased significantly (< 100 mL/day), and losartan was discontinued on the 36th day. Consequently, the patient underwent continuous hemodiafiltration (CHDF) on the 36th day only. As shown in Fig. 1, continuous intravenous infusion of dopamine from the 35th day and NA and human atrial natriuretic peptide from the 36th day gradually increased the blood pressure and urine volume. However, it was suggested that it would not be possible to maintain blood pressure upon NA discontinuation. Therefore, the attending doctor consulted a pharmacist regarding the switch from NA to oral pressor drugs. On the basis of some case reports [8–10], the pharmacist suggested switching from intravenous NA to droxidopa, which is converted to NA in vivo, on the 47th day. When the dosage of droxidopa was increased from 200 mg/day to 300 mg/day on the 49th day of hospitalization, SBP and DBP increased to 100–120 mmHg and 60–80 mmHg, respectively. As blood pressure increased, urine volume could be maintained at an average of 3000 mL/day. Seven days after the start of this combination therapy, the EF was 60.1% (Day 53), and no decrease was observed compared to the findings on the Day 8 (EF = 53.4%). In addition, this combination therapy also did not affect cardiothoracic ratio (CTR) (Day 8: CTR = 58% and Day 60: CTR = 58%) (Fig. 2). After discharge, the patient’s SBP and DBP were maintained using a combination of midodrine 8 mg/day and droxidopa 300 mg/day therapy, and his dizziness disappeared.
Fig. 2 Chest X-ray of the patient pre- and post-combination therapy with midodrine and droxidopa. Cardiothoracic ratio (CTR, %) was calculated as (a/b) × 100. A Chest X-ray showing pre-combination therapy status on the 8th day of hospitalization with a CTR of 58%. B Chest X-ray showing post-combination therapy status on the 60th day of hospitalization with a CTR of 58%
Discussion and conclusions
Hypotension is one of the most serious side effects of diuretics in patients with CHF [6]. It causes not only dizziness, but also reduction of diuretic activity because of decreased blood flow [4]. Therefore, it is suggested that improving hypotension may contribute to ensuring diuretic responsiveness. In the case of our patient with HFpEF and refractory hypotension, combination therapy of midodrine and droxidopa increased blood pressure and improved diuretic responsiveness.
While a β-blocker may have potential to improve prognosis in HFpEF [15], bisoprolol decreases blood pressure [16]. In this case, because bisoprolol was used to control tachycardia, we continued to administer bisoprolol at the lowest possible dose while monitoring the HR.
Midodrine is an oral alpha-1 adrenergic agonist that acts as a blood pressor [11] and decreases HR [12]. Although the sample size was small, it was also reported that midodrine elevates EF significantly in HFrEF [17]. Considering this evidence, midodrine might be considered suitable as an oral pressor for patients with HFpEF. Midodrine can elevate SBP and DBP by approximately 20 mmHg [17], and the degree of increase in blood pressure in our patient was similar to that reported previously [17]. Although amezinium was administered on the 25th day, the HR of the patient increased (Fig. 1). Katoh et al. [18] revealed that amezinium elevated HR. Tachycardia is known to be an exacerbating prognostic factor for heart failure [19], suggesting that midodrine, but not amezinium, may show efficacy as an oral pressor in patients with HFpEF.
Despite the administration of midodrine, the urine volume decreased due to excessive hypotension on the 34th and 35th days of hospitalization, and CHDF was performed on the 36th day. It was speculated that the blood pressure might be insufficiently maintained. Because droxidopa is metabolized by L-aromatic-amino-acid decarboxylase to NA, which mediates a pressor response [20], it may be useful to switch from intravenous to oral NA treatment due to hypotension. As expected, up-titration of droxidopa from 200 to 300 mg/day combined with 8 mg/day midodrine rapidly and significantly improved hypotension. Because the blood pressure of the patient could be maintained using this combination therapy, it is considered that the responsiveness to diuretics increased. Therefore, it may be possible to reduce the dose of diuretics such as furosemide. In a double-blind, 4-period crossover study, there were no clinically relevant effects of droxidopa on HR [21]. While the cardiovascular safety of droxidopa has been reported in patients with neurogenic hypotension [22], the detailed safety profile in patients with a history of HFpEF remains unknown. No adverse effects of the combination therapy were noted over the short term in this case. To the best of our knowledge, there is no information regarding the efficacy and safety of droxidopa combined with midodrine in HFpEF patients over the long term. Accordingly, further studies evaluating the safety and efficacy of long-term combination therapy of droxidopa and midodrine for HFpEF patients are needed.
Based on our findings, the combination therapy of midodrine and droxidopa might be safely and effectively administered to HFpEF patients with refractory hypotension, but further studies need to be conducted. In general, diuretic use should be reduced or discontinued if hypotension develops in patients with CHF. If the administration of diuretics must be continued owing to CHF progression, it is advisable to first start midodrine and then add droxidopa if hypotension cannot be effectively controlled.
Abbreviations
CHDFContinuous hemodiafiltration
CHFChronic heart failure
CTRCardiothoracic ratio
DBPDiastolic blood pressure
EFEjection fraction
HFpEFHeart failure with preserved ejection fraction
HFrEFHeart failure with reduced ejection fraction
HRHeart rate
NANoradrenaline
SBPSystolic blood pressure
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Not applicable.
Authors’ contributions
All authors edited the manuscript and approved the final version. Participated in research design: Asai, Sato, Yamamoto, Kito, Hioki, Urata, Abe. Wrote or contributed to the writing of the manuscript: Asai, Abe.
Funding
Not applicable.
Availability of data and materials
All the data generated or analyzed in this study are included in the published article.
Ethics approval and consent to participate
Because this is a case report, ethics review was deemed unnecessary at the discretion of the Ethics Review Committee of the National Hospital Organization Mie Chuo Medical Center.
Consent for publication
Written informed consent was obtained from the patient afterwards.
Competing interests
The authors declare that they have no competing interests. | Oral | DrugAdministrationRoute | CC BY | 33653416 | 19,980,597 | 2021-03-03 |
What was the outcome of reaction 'Dizziness'? | Combination therapy of midodrine and droxidopa for refractory hypotension in heart failure with preserved ejection fraction per a pharmacist's proposal: a case report.
BACKGROUND
Patients with chronic heart failure (CHF) are often treated using many diuretics for symptom relief; however, diuretic use may have to continue despite hypotension development in these patients. Here, we present a case of heart failure with preserved ejection fraction (HFpEF), which is defined as ejection fraction ≥50% in CHF, and refractory hypotension, which was treated with midodrine and droxidopa to normalize blood pressure.
METHODS
The patient was a 62-year-old man with a history of HFpEF due to mitral regurgitation and complaints of dyspnea on exertion. He had been prescribed multiple medications at an outpatient clinic for CHF management, including azosemide 60 mg/day, bisoprolol 2.5 mg/day, enalapril 2.5 mg/day, spironolactone 50 mg/day, and tolvaptan 15 mg/day. The systolic blood pressure (SBP) of the patient remained at 70-80 mmHg because the use of the diuretic could not be reduced or discontinued owing to edema and weight gain. He was hospitalized for the exacerbation of CHF. Although midodrine 8 mg/day was administered to improve hypotension, the SBP of the patient increased only up to 90 mmHg. On the 35th day after hospitalization, the urine volume decreased significantly (< 100 mL/day) due to hypotension. When droxidopa 200 mg/day replaced intravenous noradrenaline on the 47th day, the SBP remained at 100-120 mmHg and the urine volume increased.
CONCLUSIONS
Oral combination treatment with midodrine and droxidopa might contribute to the maintenance of blood pressure and diuretic activity in HFpEF patients with refractory hypotension. However, further long-term studies evaluating the safety and efficacy of this combination therapy for patients with HFpEF are needed.
Background
While it is well-known that diuretic treatment is crucial to improve the prognosis and symptoms among patients with chronic heart failure (CHF) [1–3], a diminished diuretic response is common in these patients, increasing the required diuretic dose [4]. Hypotension has been defined as systolic blood pressure (SBP) < 90 mmHg and/or diastolic blood pressure (DBP) < 60 mmHg [5]. In particular, diuretic-induced hypotension causes dizziness [6]. However, the administration of diuretics in these patients cannot be stopped as this would likely result in the progression of heart failure [7].
Many reports have shown that droxidopa, a noradrenaline (NA) prodrug, improves the symptoms of orthostatic hypotension in patients with Parkinson disease, multiple system atrophy, and pure autonomic failure [8–10]. While extensive evidence is available regarding neurogenic hypotension, information on the efficacy and safety of droxidopa for refractory hypotension with CHF is insufficient. Midodrine is widely used for the management of orthostatic blood pressure [11]; however, there is no evidence available on the efficacy of the combination of midodrine and droxidopa. In recent years, drug treatment has been reported to improve prognosis in heart failure with reduced ejection fraction (HFrEF), in which ejection fraction (EF) is < 40% [1–3]. However, guidelines for the treatment of heart failure with preserved ejection fraction (HFpEF), in which EF is ≥50%, are not available. Here, we describe the case of a patient with HFpEF who was successfully treated for refractory hypotension.
Case presentation
The patient was a 62-year-old man with a history of CHF due to mitral regurgitation and complaints of dyspnea on exertion (New York Heart Association functional class III). After mitral annuloplasty, he was prescribed multiple medications at an outpatient clinic for the management of CHF, including azosemide 60 mg/day, bisoprolol 2.5 mg/day, enalapril 2.5 mg/day, spironolactone 50 mg/day, and tolvaptan 15 mg/day. The SBP of the patient remained at 70–80 mmHg because diuretic use could not be reduced or discontinued due to the possible effects of edema and weight gain. He was hospitalized for exacerbation of heart failure. On admission, his SBP and DBP were 83 and 47, respectively, and his heart rate (HR) was 88 beats/min. On the 3rd day after hospitalization, a pharmacist proposed midodrine 4 mg/day, an oral pressor with a weak effect on HR [12], to the attending doctor, after which drug administration was started (Fig. 1). The EF was measured on the 8th day and was 53.4%, which is categorized as HFpEF. Furosemide 20 mg/day was started because the urine volume was low on the 8th day. Over a 9-day period after the initiation of midodrine treatment, the dose was increased to 8 mg/day; however, SBP increased only up to 90 mmHg. Although amezinium 20 mg/day was administered on the 25th day for further pressor action, it was discontinued on the 29th day due to the onset of tachycardia (Fig. 1).
Fig. 1 Clinical course of the hospitalized patient in this study. Up-titration and down-titration of medications while in the hospital are shown, along with the daily urine volume, intake volume, blood pressure, and HR. BP, blood pressure; CHDF, continuous hemodiafiltration; DBP, diastolic blood pressure; DOA, dopamine; hANP, human atrial natriuretic peptide; HR, heart rate; NA, noradrenaline; SBP, systolic blood pressure. The unit γ shows μg/kg/min. SBP, DBP, and HR are shown as the mean ± standard deviation (SD)
In HFrEF, enalapril has been shown to contribute to improved prognosis [13], whereas it is unknown if this effect is present in HFpEF. However, because in HFpEF it may also be highly beneficial to continue with renin-angiotensin system inhibitors, we changed the drug regimen to losartan, which is reported to have a weak hypertensive effect among the angiotensin II receptor blockers [14]. From the 35th day of hospitalization, blood pressure decreased and urine volume decreased significantly (< 100 mL/day), and losartan was discontinued on the 36th day. Consequently, the patient underwent continuous hemodiafiltration (CHDF) on the 36th day only. As shown in Fig. 1, continuous intravenous infusion of dopamine from the 35th day and NA and human atrial natriuretic peptide from the 36th day gradually increased the blood pressure and urine volume. However, it was suggested that it would not be possible to maintain blood pressure upon NA discontinuation. Therefore, the attending doctor consulted a pharmacist regarding the switch from NA to oral pressor drugs. On the basis of some case reports [8–10], the pharmacist suggested switching from intravenous NA to droxidopa, which is converted to NA in vivo, on the 47th day. When the dosage of droxidopa was increased from 200 mg/day to 300 mg/day on the 49th day of hospitalization, SBP and DBP increased to 100–120 mmHg and 60–80 mmHg, respectively. As blood pressure increased, urine volume could be maintained at an average of 3000 mL/day. Seven days after the start of this combination therapy, the EF was 60.1% (Day 53), and no decrease was observed compared to the findings on the Day 8 (EF = 53.4%). In addition, this combination therapy also did not affect cardiothoracic ratio (CTR) (Day 8: CTR = 58% and Day 60: CTR = 58%) (Fig. 2). After discharge, the patient’s SBP and DBP were maintained using a combination of midodrine 8 mg/day and droxidopa 300 mg/day therapy, and his dizziness disappeared.
Fig. 2 Chest X-ray of the patient pre- and post-combination therapy with midodrine and droxidopa. Cardiothoracic ratio (CTR, %) was calculated as (a/b) × 100. A Chest X-ray showing pre-combination therapy status on the 8th day of hospitalization with a CTR of 58%. B Chest X-ray showing post-combination therapy status on the 60th day of hospitalization with a CTR of 58%
Discussion and conclusions
Hypotension is one of the most serious side effects of diuretics in patients with CHF [6]. It causes not only dizziness, but also reduction of diuretic activity because of decreased blood flow [4]. Therefore, it is suggested that improving hypotension may contribute to ensuring diuretic responsiveness. In the case of our patient with HFpEF and refractory hypotension, combination therapy of midodrine and droxidopa increased blood pressure and improved diuretic responsiveness.
While a β-blocker may have potential to improve prognosis in HFpEF [15], bisoprolol decreases blood pressure [16]. In this case, because bisoprolol was used to control tachycardia, we continued to administer bisoprolol at the lowest possible dose while monitoring the HR.
Midodrine is an oral alpha-1 adrenergic agonist that acts as a blood pressor [11] and decreases HR [12]. Although the sample size was small, it was also reported that midodrine elevates EF significantly in HFrEF [17]. Considering this evidence, midodrine might be considered suitable as an oral pressor for patients with HFpEF. Midodrine can elevate SBP and DBP by approximately 20 mmHg [17], and the degree of increase in blood pressure in our patient was similar to that reported previously [17]. Although amezinium was administered on the 25th day, the HR of the patient increased (Fig. 1). Katoh et al. [18] revealed that amezinium elevated HR. Tachycardia is known to be an exacerbating prognostic factor for heart failure [19], suggesting that midodrine, but not amezinium, may show efficacy as an oral pressor in patients with HFpEF.
Despite the administration of midodrine, the urine volume decreased due to excessive hypotension on the 34th and 35th days of hospitalization, and CHDF was performed on the 36th day. It was speculated that the blood pressure might be insufficiently maintained. Because droxidopa is metabolized by L-aromatic-amino-acid decarboxylase to NA, which mediates a pressor response [20], it may be useful to switch from intravenous to oral NA treatment due to hypotension. As expected, up-titration of droxidopa from 200 to 300 mg/day combined with 8 mg/day midodrine rapidly and significantly improved hypotension. Because the blood pressure of the patient could be maintained using this combination therapy, it is considered that the responsiveness to diuretics increased. Therefore, it may be possible to reduce the dose of diuretics such as furosemide. In a double-blind, 4-period crossover study, there were no clinically relevant effects of droxidopa on HR [21]. While the cardiovascular safety of droxidopa has been reported in patients with neurogenic hypotension [22], the detailed safety profile in patients with a history of HFpEF remains unknown. No adverse effects of the combination therapy were noted over the short term in this case. To the best of our knowledge, there is no information regarding the efficacy and safety of droxidopa combined with midodrine in HFpEF patients over the long term. Accordingly, further studies evaluating the safety and efficacy of long-term combination therapy of droxidopa and midodrine for HFpEF patients are needed.
Based on our findings, the combination therapy of midodrine and droxidopa might be safely and effectively administered to HFpEF patients with refractory hypotension, but further studies need to be conducted. In general, diuretic use should be reduced or discontinued if hypotension develops in patients with CHF. If the administration of diuretics must be continued owing to CHF progression, it is advisable to first start midodrine and then add droxidopa if hypotension cannot be effectively controlled.
Abbreviations
CHDFContinuous hemodiafiltration
CHFChronic heart failure
CTRCardiothoracic ratio
DBPDiastolic blood pressure
EFEjection fraction
HFpEFHeart failure with preserved ejection fraction
HFrEFHeart failure with reduced ejection fraction
HRHeart rate
NANoradrenaline
SBPSystolic blood pressure
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Not applicable.
Authors’ contributions
All authors edited the manuscript and approved the final version. Participated in research design: Asai, Sato, Yamamoto, Kito, Hioki, Urata, Abe. Wrote or contributed to the writing of the manuscript: Asai, Abe.
Funding
Not applicable.
Availability of data and materials
All the data generated or analyzed in this study are included in the published article.
Ethics approval and consent to participate
Because this is a case report, ethics review was deemed unnecessary at the discretion of the Ethics Review Committee of the National Hospital Organization Mie Chuo Medical Center.
Consent for publication
Written informed consent was obtained from the patient afterwards.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33653416 | 19,980,597 | 2021-03-03 |
What was the outcome of reaction 'Hypotension'? | Combination therapy of midodrine and droxidopa for refractory hypotension in heart failure with preserved ejection fraction per a pharmacist's proposal: a case report.
BACKGROUND
Patients with chronic heart failure (CHF) are often treated using many diuretics for symptom relief; however, diuretic use may have to continue despite hypotension development in these patients. Here, we present a case of heart failure with preserved ejection fraction (HFpEF), which is defined as ejection fraction ≥50% in CHF, and refractory hypotension, which was treated with midodrine and droxidopa to normalize blood pressure.
METHODS
The patient was a 62-year-old man with a history of HFpEF due to mitral regurgitation and complaints of dyspnea on exertion. He had been prescribed multiple medications at an outpatient clinic for CHF management, including azosemide 60 mg/day, bisoprolol 2.5 mg/day, enalapril 2.5 mg/day, spironolactone 50 mg/day, and tolvaptan 15 mg/day. The systolic blood pressure (SBP) of the patient remained at 70-80 mmHg because the use of the diuretic could not be reduced or discontinued owing to edema and weight gain. He was hospitalized for the exacerbation of CHF. Although midodrine 8 mg/day was administered to improve hypotension, the SBP of the patient increased only up to 90 mmHg. On the 35th day after hospitalization, the urine volume decreased significantly (< 100 mL/day) due to hypotension. When droxidopa 200 mg/day replaced intravenous noradrenaline on the 47th day, the SBP remained at 100-120 mmHg and the urine volume increased.
CONCLUSIONS
Oral combination treatment with midodrine and droxidopa might contribute to the maintenance of blood pressure and diuretic activity in HFpEF patients with refractory hypotension. However, further long-term studies evaluating the safety and efficacy of this combination therapy for patients with HFpEF are needed.
Background
While it is well-known that diuretic treatment is crucial to improve the prognosis and symptoms among patients with chronic heart failure (CHF) [1–3], a diminished diuretic response is common in these patients, increasing the required diuretic dose [4]. Hypotension has been defined as systolic blood pressure (SBP) < 90 mmHg and/or diastolic blood pressure (DBP) < 60 mmHg [5]. In particular, diuretic-induced hypotension causes dizziness [6]. However, the administration of diuretics in these patients cannot be stopped as this would likely result in the progression of heart failure [7].
Many reports have shown that droxidopa, a noradrenaline (NA) prodrug, improves the symptoms of orthostatic hypotension in patients with Parkinson disease, multiple system atrophy, and pure autonomic failure [8–10]. While extensive evidence is available regarding neurogenic hypotension, information on the efficacy and safety of droxidopa for refractory hypotension with CHF is insufficient. Midodrine is widely used for the management of orthostatic blood pressure [11]; however, there is no evidence available on the efficacy of the combination of midodrine and droxidopa. In recent years, drug treatment has been reported to improve prognosis in heart failure with reduced ejection fraction (HFrEF), in which ejection fraction (EF) is < 40% [1–3]. However, guidelines for the treatment of heart failure with preserved ejection fraction (HFpEF), in which EF is ≥50%, are not available. Here, we describe the case of a patient with HFpEF who was successfully treated for refractory hypotension.
Case presentation
The patient was a 62-year-old man with a history of CHF due to mitral regurgitation and complaints of dyspnea on exertion (New York Heart Association functional class III). After mitral annuloplasty, he was prescribed multiple medications at an outpatient clinic for the management of CHF, including azosemide 60 mg/day, bisoprolol 2.5 mg/day, enalapril 2.5 mg/day, spironolactone 50 mg/day, and tolvaptan 15 mg/day. The SBP of the patient remained at 70–80 mmHg because diuretic use could not be reduced or discontinued due to the possible effects of edema and weight gain. He was hospitalized for exacerbation of heart failure. On admission, his SBP and DBP were 83 and 47, respectively, and his heart rate (HR) was 88 beats/min. On the 3rd day after hospitalization, a pharmacist proposed midodrine 4 mg/day, an oral pressor with a weak effect on HR [12], to the attending doctor, after which drug administration was started (Fig. 1). The EF was measured on the 8th day and was 53.4%, which is categorized as HFpEF. Furosemide 20 mg/day was started because the urine volume was low on the 8th day. Over a 9-day period after the initiation of midodrine treatment, the dose was increased to 8 mg/day; however, SBP increased only up to 90 mmHg. Although amezinium 20 mg/day was administered on the 25th day for further pressor action, it was discontinued on the 29th day due to the onset of tachycardia (Fig. 1).
Fig. 1 Clinical course of the hospitalized patient in this study. Up-titration and down-titration of medications while in the hospital are shown, along with the daily urine volume, intake volume, blood pressure, and HR. BP, blood pressure; CHDF, continuous hemodiafiltration; DBP, diastolic blood pressure; DOA, dopamine; hANP, human atrial natriuretic peptide; HR, heart rate; NA, noradrenaline; SBP, systolic blood pressure. The unit γ shows μg/kg/min. SBP, DBP, and HR are shown as the mean ± standard deviation (SD)
In HFrEF, enalapril has been shown to contribute to improved prognosis [13], whereas it is unknown if this effect is present in HFpEF. However, because in HFpEF it may also be highly beneficial to continue with renin-angiotensin system inhibitors, we changed the drug regimen to losartan, which is reported to have a weak hypertensive effect among the angiotensin II receptor blockers [14]. From the 35th day of hospitalization, blood pressure decreased and urine volume decreased significantly (< 100 mL/day), and losartan was discontinued on the 36th day. Consequently, the patient underwent continuous hemodiafiltration (CHDF) on the 36th day only. As shown in Fig. 1, continuous intravenous infusion of dopamine from the 35th day and NA and human atrial natriuretic peptide from the 36th day gradually increased the blood pressure and urine volume. However, it was suggested that it would not be possible to maintain blood pressure upon NA discontinuation. Therefore, the attending doctor consulted a pharmacist regarding the switch from NA to oral pressor drugs. On the basis of some case reports [8–10], the pharmacist suggested switching from intravenous NA to droxidopa, which is converted to NA in vivo, on the 47th day. When the dosage of droxidopa was increased from 200 mg/day to 300 mg/day on the 49th day of hospitalization, SBP and DBP increased to 100–120 mmHg and 60–80 mmHg, respectively. As blood pressure increased, urine volume could be maintained at an average of 3000 mL/day. Seven days after the start of this combination therapy, the EF was 60.1% (Day 53), and no decrease was observed compared to the findings on the Day 8 (EF = 53.4%). In addition, this combination therapy also did not affect cardiothoracic ratio (CTR) (Day 8: CTR = 58% and Day 60: CTR = 58%) (Fig. 2). After discharge, the patient’s SBP and DBP were maintained using a combination of midodrine 8 mg/day and droxidopa 300 mg/day therapy, and his dizziness disappeared.
Fig. 2 Chest X-ray of the patient pre- and post-combination therapy with midodrine and droxidopa. Cardiothoracic ratio (CTR, %) was calculated as (a/b) × 100. A Chest X-ray showing pre-combination therapy status on the 8th day of hospitalization with a CTR of 58%. B Chest X-ray showing post-combination therapy status on the 60th day of hospitalization with a CTR of 58%
Discussion and conclusions
Hypotension is one of the most serious side effects of diuretics in patients with CHF [6]. It causes not only dizziness, but also reduction of diuretic activity because of decreased blood flow [4]. Therefore, it is suggested that improving hypotension may contribute to ensuring diuretic responsiveness. In the case of our patient with HFpEF and refractory hypotension, combination therapy of midodrine and droxidopa increased blood pressure and improved diuretic responsiveness.
While a β-blocker may have potential to improve prognosis in HFpEF [15], bisoprolol decreases blood pressure [16]. In this case, because bisoprolol was used to control tachycardia, we continued to administer bisoprolol at the lowest possible dose while monitoring the HR.
Midodrine is an oral alpha-1 adrenergic agonist that acts as a blood pressor [11] and decreases HR [12]. Although the sample size was small, it was also reported that midodrine elevates EF significantly in HFrEF [17]. Considering this evidence, midodrine might be considered suitable as an oral pressor for patients with HFpEF. Midodrine can elevate SBP and DBP by approximately 20 mmHg [17], and the degree of increase in blood pressure in our patient was similar to that reported previously [17]. Although amezinium was administered on the 25th day, the HR of the patient increased (Fig. 1). Katoh et al. [18] revealed that amezinium elevated HR. Tachycardia is known to be an exacerbating prognostic factor for heart failure [19], suggesting that midodrine, but not amezinium, may show efficacy as an oral pressor in patients with HFpEF.
Despite the administration of midodrine, the urine volume decreased due to excessive hypotension on the 34th and 35th days of hospitalization, and CHDF was performed on the 36th day. It was speculated that the blood pressure might be insufficiently maintained. Because droxidopa is metabolized by L-aromatic-amino-acid decarboxylase to NA, which mediates a pressor response [20], it may be useful to switch from intravenous to oral NA treatment due to hypotension. As expected, up-titration of droxidopa from 200 to 300 mg/day combined with 8 mg/day midodrine rapidly and significantly improved hypotension. Because the blood pressure of the patient could be maintained using this combination therapy, it is considered that the responsiveness to diuretics increased. Therefore, it may be possible to reduce the dose of diuretics such as furosemide. In a double-blind, 4-period crossover study, there were no clinically relevant effects of droxidopa on HR [21]. While the cardiovascular safety of droxidopa has been reported in patients with neurogenic hypotension [22], the detailed safety profile in patients with a history of HFpEF remains unknown. No adverse effects of the combination therapy were noted over the short term in this case. To the best of our knowledge, there is no information regarding the efficacy and safety of droxidopa combined with midodrine in HFpEF patients over the long term. Accordingly, further studies evaluating the safety and efficacy of long-term combination therapy of droxidopa and midodrine for HFpEF patients are needed.
Based on our findings, the combination therapy of midodrine and droxidopa might be safely and effectively administered to HFpEF patients with refractory hypotension, but further studies need to be conducted. In general, diuretic use should be reduced or discontinued if hypotension develops in patients with CHF. If the administration of diuretics must be continued owing to CHF progression, it is advisable to first start midodrine and then add droxidopa if hypotension cannot be effectively controlled.
Abbreviations
CHDFContinuous hemodiafiltration
CHFChronic heart failure
CTRCardiothoracic ratio
DBPDiastolic blood pressure
EFEjection fraction
HFpEFHeart failure with preserved ejection fraction
HFrEFHeart failure with reduced ejection fraction
HRHeart rate
NANoradrenaline
SBPSystolic blood pressure
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Not applicable.
Authors’ contributions
All authors edited the manuscript and approved the final version. Participated in research design: Asai, Sato, Yamamoto, Kito, Hioki, Urata, Abe. Wrote or contributed to the writing of the manuscript: Asai, Abe.
Funding
Not applicable.
Availability of data and materials
All the data generated or analyzed in this study are included in the published article.
Ethics approval and consent to participate
Because this is a case report, ethics review was deemed unnecessary at the discretion of the Ethics Review Committee of the National Hospital Organization Mie Chuo Medical Center.
Consent for publication
Written informed consent was obtained from the patient afterwards.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33653416 | 19,980,597 | 2021-03-03 |
What was the outcome of reaction 'Urine output decreased'? | Combination therapy of midodrine and droxidopa for refractory hypotension in heart failure with preserved ejection fraction per a pharmacist's proposal: a case report.
BACKGROUND
Patients with chronic heart failure (CHF) are often treated using many diuretics for symptom relief; however, diuretic use may have to continue despite hypotension development in these patients. Here, we present a case of heart failure with preserved ejection fraction (HFpEF), which is defined as ejection fraction ≥50% in CHF, and refractory hypotension, which was treated with midodrine and droxidopa to normalize blood pressure.
METHODS
The patient was a 62-year-old man with a history of HFpEF due to mitral regurgitation and complaints of dyspnea on exertion. He had been prescribed multiple medications at an outpatient clinic for CHF management, including azosemide 60 mg/day, bisoprolol 2.5 mg/day, enalapril 2.5 mg/day, spironolactone 50 mg/day, and tolvaptan 15 mg/day. The systolic blood pressure (SBP) of the patient remained at 70-80 mmHg because the use of the diuretic could not be reduced or discontinued owing to edema and weight gain. He was hospitalized for the exacerbation of CHF. Although midodrine 8 mg/day was administered to improve hypotension, the SBP of the patient increased only up to 90 mmHg. On the 35th day after hospitalization, the urine volume decreased significantly (< 100 mL/day) due to hypotension. When droxidopa 200 mg/day replaced intravenous noradrenaline on the 47th day, the SBP remained at 100-120 mmHg and the urine volume increased.
CONCLUSIONS
Oral combination treatment with midodrine and droxidopa might contribute to the maintenance of blood pressure and diuretic activity in HFpEF patients with refractory hypotension. However, further long-term studies evaluating the safety and efficacy of this combination therapy for patients with HFpEF are needed.
Background
While it is well-known that diuretic treatment is crucial to improve the prognosis and symptoms among patients with chronic heart failure (CHF) [1–3], a diminished diuretic response is common in these patients, increasing the required diuretic dose [4]. Hypotension has been defined as systolic blood pressure (SBP) < 90 mmHg and/or diastolic blood pressure (DBP) < 60 mmHg [5]. In particular, diuretic-induced hypotension causes dizziness [6]. However, the administration of diuretics in these patients cannot be stopped as this would likely result in the progression of heart failure [7].
Many reports have shown that droxidopa, a noradrenaline (NA) prodrug, improves the symptoms of orthostatic hypotension in patients with Parkinson disease, multiple system atrophy, and pure autonomic failure [8–10]. While extensive evidence is available regarding neurogenic hypotension, information on the efficacy and safety of droxidopa for refractory hypotension with CHF is insufficient. Midodrine is widely used for the management of orthostatic blood pressure [11]; however, there is no evidence available on the efficacy of the combination of midodrine and droxidopa. In recent years, drug treatment has been reported to improve prognosis in heart failure with reduced ejection fraction (HFrEF), in which ejection fraction (EF) is < 40% [1–3]. However, guidelines for the treatment of heart failure with preserved ejection fraction (HFpEF), in which EF is ≥50%, are not available. Here, we describe the case of a patient with HFpEF who was successfully treated for refractory hypotension.
Case presentation
The patient was a 62-year-old man with a history of CHF due to mitral regurgitation and complaints of dyspnea on exertion (New York Heart Association functional class III). After mitral annuloplasty, he was prescribed multiple medications at an outpatient clinic for the management of CHF, including azosemide 60 mg/day, bisoprolol 2.5 mg/day, enalapril 2.5 mg/day, spironolactone 50 mg/day, and tolvaptan 15 mg/day. The SBP of the patient remained at 70–80 mmHg because diuretic use could not be reduced or discontinued due to the possible effects of edema and weight gain. He was hospitalized for exacerbation of heart failure. On admission, his SBP and DBP were 83 and 47, respectively, and his heart rate (HR) was 88 beats/min. On the 3rd day after hospitalization, a pharmacist proposed midodrine 4 mg/day, an oral pressor with a weak effect on HR [12], to the attending doctor, after which drug administration was started (Fig. 1). The EF was measured on the 8th day and was 53.4%, which is categorized as HFpEF. Furosemide 20 mg/day was started because the urine volume was low on the 8th day. Over a 9-day period after the initiation of midodrine treatment, the dose was increased to 8 mg/day; however, SBP increased only up to 90 mmHg. Although amezinium 20 mg/day was administered on the 25th day for further pressor action, it was discontinued on the 29th day due to the onset of tachycardia (Fig. 1).
Fig. 1 Clinical course of the hospitalized patient in this study. Up-titration and down-titration of medications while in the hospital are shown, along with the daily urine volume, intake volume, blood pressure, and HR. BP, blood pressure; CHDF, continuous hemodiafiltration; DBP, diastolic blood pressure; DOA, dopamine; hANP, human atrial natriuretic peptide; HR, heart rate; NA, noradrenaline; SBP, systolic blood pressure. The unit γ shows μg/kg/min. SBP, DBP, and HR are shown as the mean ± standard deviation (SD)
In HFrEF, enalapril has been shown to contribute to improved prognosis [13], whereas it is unknown if this effect is present in HFpEF. However, because in HFpEF it may also be highly beneficial to continue with renin-angiotensin system inhibitors, we changed the drug regimen to losartan, which is reported to have a weak hypertensive effect among the angiotensin II receptor blockers [14]. From the 35th day of hospitalization, blood pressure decreased and urine volume decreased significantly (< 100 mL/day), and losartan was discontinued on the 36th day. Consequently, the patient underwent continuous hemodiafiltration (CHDF) on the 36th day only. As shown in Fig. 1, continuous intravenous infusion of dopamine from the 35th day and NA and human atrial natriuretic peptide from the 36th day gradually increased the blood pressure and urine volume. However, it was suggested that it would not be possible to maintain blood pressure upon NA discontinuation. Therefore, the attending doctor consulted a pharmacist regarding the switch from NA to oral pressor drugs. On the basis of some case reports [8–10], the pharmacist suggested switching from intravenous NA to droxidopa, which is converted to NA in vivo, on the 47th day. When the dosage of droxidopa was increased from 200 mg/day to 300 mg/day on the 49th day of hospitalization, SBP and DBP increased to 100–120 mmHg and 60–80 mmHg, respectively. As blood pressure increased, urine volume could be maintained at an average of 3000 mL/day. Seven days after the start of this combination therapy, the EF was 60.1% (Day 53), and no decrease was observed compared to the findings on the Day 8 (EF = 53.4%). In addition, this combination therapy also did not affect cardiothoracic ratio (CTR) (Day 8: CTR = 58% and Day 60: CTR = 58%) (Fig. 2). After discharge, the patient’s SBP and DBP were maintained using a combination of midodrine 8 mg/day and droxidopa 300 mg/day therapy, and his dizziness disappeared.
Fig. 2 Chest X-ray of the patient pre- and post-combination therapy with midodrine and droxidopa. Cardiothoracic ratio (CTR, %) was calculated as (a/b) × 100. A Chest X-ray showing pre-combination therapy status on the 8th day of hospitalization with a CTR of 58%. B Chest X-ray showing post-combination therapy status on the 60th day of hospitalization with a CTR of 58%
Discussion and conclusions
Hypotension is one of the most serious side effects of diuretics in patients with CHF [6]. It causes not only dizziness, but also reduction of diuretic activity because of decreased blood flow [4]. Therefore, it is suggested that improving hypotension may contribute to ensuring diuretic responsiveness. In the case of our patient with HFpEF and refractory hypotension, combination therapy of midodrine and droxidopa increased blood pressure and improved diuretic responsiveness.
While a β-blocker may have potential to improve prognosis in HFpEF [15], bisoprolol decreases blood pressure [16]. In this case, because bisoprolol was used to control tachycardia, we continued to administer bisoprolol at the lowest possible dose while monitoring the HR.
Midodrine is an oral alpha-1 adrenergic agonist that acts as a blood pressor [11] and decreases HR [12]. Although the sample size was small, it was also reported that midodrine elevates EF significantly in HFrEF [17]. Considering this evidence, midodrine might be considered suitable as an oral pressor for patients with HFpEF. Midodrine can elevate SBP and DBP by approximately 20 mmHg [17], and the degree of increase in blood pressure in our patient was similar to that reported previously [17]. Although amezinium was administered on the 25th day, the HR of the patient increased (Fig. 1). Katoh et al. [18] revealed that amezinium elevated HR. Tachycardia is known to be an exacerbating prognostic factor for heart failure [19], suggesting that midodrine, but not amezinium, may show efficacy as an oral pressor in patients with HFpEF.
Despite the administration of midodrine, the urine volume decreased due to excessive hypotension on the 34th and 35th days of hospitalization, and CHDF was performed on the 36th day. It was speculated that the blood pressure might be insufficiently maintained. Because droxidopa is metabolized by L-aromatic-amino-acid decarboxylase to NA, which mediates a pressor response [20], it may be useful to switch from intravenous to oral NA treatment due to hypotension. As expected, up-titration of droxidopa from 200 to 300 mg/day combined with 8 mg/day midodrine rapidly and significantly improved hypotension. Because the blood pressure of the patient could be maintained using this combination therapy, it is considered that the responsiveness to diuretics increased. Therefore, it may be possible to reduce the dose of diuretics such as furosemide. In a double-blind, 4-period crossover study, there were no clinically relevant effects of droxidopa on HR [21]. While the cardiovascular safety of droxidopa has been reported in patients with neurogenic hypotension [22], the detailed safety profile in patients with a history of HFpEF remains unknown. No adverse effects of the combination therapy were noted over the short term in this case. To the best of our knowledge, there is no information regarding the efficacy and safety of droxidopa combined with midodrine in HFpEF patients over the long term. Accordingly, further studies evaluating the safety and efficacy of long-term combination therapy of droxidopa and midodrine for HFpEF patients are needed.
Based on our findings, the combination therapy of midodrine and droxidopa might be safely and effectively administered to HFpEF patients with refractory hypotension, but further studies need to be conducted. In general, diuretic use should be reduced or discontinued if hypotension develops in patients with CHF. If the administration of diuretics must be continued owing to CHF progression, it is advisable to first start midodrine and then add droxidopa if hypotension cannot be effectively controlled.
Abbreviations
CHDFContinuous hemodiafiltration
CHFChronic heart failure
CTRCardiothoracic ratio
DBPDiastolic blood pressure
EFEjection fraction
HFpEFHeart failure with preserved ejection fraction
HFrEFHeart failure with reduced ejection fraction
HRHeart rate
NANoradrenaline
SBPSystolic blood pressure
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Not applicable.
Authors’ contributions
All authors edited the manuscript and approved the final version. Participated in research design: Asai, Sato, Yamamoto, Kito, Hioki, Urata, Abe. Wrote or contributed to the writing of the manuscript: Asai, Abe.
Funding
Not applicable.
Availability of data and materials
All the data generated or analyzed in this study are included in the published article.
Ethics approval and consent to participate
Because this is a case report, ethics review was deemed unnecessary at the discretion of the Ethics Review Committee of the National Hospital Organization Mie Chuo Medical Center.
Consent for publication
Written informed consent was obtained from the patient afterwards.
Competing interests
The authors declare that they have no competing interests. | Recovered | ReactionOutcome | CC BY | 33653416 | 19,980,597 | 2021-03-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pneumonia bacterial'. | Pneumonia due to Mycobacterium cosmeticum in a renal transplant recipient.
A 69-year-old man renal transplant recipient for 4 years, presented with 4-day history of cough and dyspnoea. He was diagnosed with community-acquired pneumonia and treated accordingly. He deteriorated requiring intensive care unit admission and intubation. Mycobacterial culture from bronchoalveolar lavage grew colonies within 7 days of incubation while Mycobacterium tuberculosis PCR was negative. The antibiotic regimen was adjusted to cover for rapidly growing mycobacteria with imipenem, amikacin and clarithromycin. The final culture reported Mycobacterium cosmeticum He improved on the antibiotic regimen given which the organism turned to be sensitive to. We reported the second case with M. cosmeticum that fulfilled the diagnostic criteria for non-tuberculous mycobacterial lung infection. Improvement of patient's lung infection on appropriate antibiotics points to a causal relationship.
Background
Although relatively rare, non-tuberculous mycobacterial (NTM) infections remain clinically relevant, especially in immunosuppressed patients. Among solid organ transplant recipients, they are most prevalent among lung transplant recipients with lung and pleura being the most common sites of infection.1 2 Identification is associated with a significantly increased mortality rate in transplant recipients.3 Timely identification and diagnosis will help direct appropriate management of these patients. As NTM are ubiquitous in the environment, diagnostic criteria were developed to help differentiate true infection from contamination or colonisation.
Mycobacterium cosmeticum is a rapidly growing NTM. It has been rarely reported in the literature as a cause of different infections mostly in immunocompromised patients. Its role as a cause of lung infection has been reported only once. We report herein a case of a renal transplant recipient who developed pneumonia secondary to M. cosmeticum. This adds to the growing literature about this rarely reported organism.
Case presentation
A 69-year-old man presented to the emergency department with 4-day history of dry cough, progressive shortness of breath, fever with chills and progressive fatigue. The patient had a history of urinary schistosomiasis complicated with reflux nephropathy and end-stage renal failure. He was on haemodialysis for 6 years before he underwent a successful living-related renal transplant 4 years before presentation with good graft function. The patient was hypertensive and also had a history of empyema secondary to parapneumonic effusion and right lung decortication 3 years ago.
He was on nifedipine 120 mg once daily, lisinopril 10 mg once daily, mycophenolate 750 mg two times per day, prednisolone 5 mg once daily and tacrolimus 0.5 mg two times per day (all orally).
On admission, he was pale, tachypneic (22 breaths/min), had O2 saturation of 92% on room air and had bilateral fine crackles, more in the right lower zone.
His initial investigations showed leucopenia with white cell count of 3.31×109/L, neutrophils 45.1%, lymphocytes 38.2%, monocytes 7.1% and eosinophils 8.4%, anaemia with haemoglobin of 93 g/L, hyponatremia of 130 mEq/L and an erythrocyte sedimentation rate of 51 mm/hour. Screening of viral pathogens and sputum culture were negative. HIV serology was negative. Our patient was presented before the COVID-19 pandemic. Chest X-ray (CXR) revealed diffuse reticulonodular infiltrates with opacity in the right lower zone (figure 1).
Figure 1 Chest X-ray on admission showed diffuse reticulo-nodular infiltrates with irregular opacity in the right lower zone.
The patient was treated for community-acquired pneumonia with levofloxacin. Over the next few days, the patient’s condition worsened. Repeated CXR showed worsening bilateral infiltrates (figure 2). Chest CT showed a diffuse bilateral airspace consolidation, reticulation and ground glass appearance with lower lobes predominance (figure 3). Piperacillin/tazobactam was added, and the patient was shifted to the intensive care unit (ICU), intubated and ventilated.
Figure 2 Chest X-ray on fourth day of admission showed increase of bilateral pulmonary infiltrates.
Figure 3 CT chest showed a diffuse bilateral air space consolidation, reticulation and ground glass appearance with lower lobes predominance.
Bronchoalveolar lavage (BAL) and new microbiological investigations were performed. The results for gram stain, bacterial and fungal cultures, cytology for Pneumocystis jiroveci, acid-fast bacilli (AFB) staining, respiratory viruses and Mycobacterium tuberculosis PCR were negative. However, on the seventh day of incubation, AFB were noted in BAL mycobacterial culture. Assuming rapid growing NTM infection, he was started on imipenem, amikacin and clarithromycin. Cultures were sent for species identification (at Mayo Clinic Laboratories, Rochester, Minnesota, USA). M. cosmeticum was identified. It was sensitive to clarithromycin and amikacin.
Outcome and follow-up
The patient improved markedly (figure 4), extubated and shifted from ICU after 26 days. He was treated with this antibiotic regimen for 4 weeks and discharged home on oral antibiotics and home oxygen after 36 days of hospitalisation. Repeated mycobacterial culture from BAL 6 weeks after starting treatment was negative which suggests a good response.
Figure 4 Chest X-ray after treatment showed improvement of bilateral pulmonary infiltrates.
Discussion
NTM comprise more than 150 different species and are distributed worldwide.4 Many of these bacteria can lead to opportunistic infections with different clinical manifestations. According to Runyon classification, NTM are divided into slowly growing mycobacteria and rapidly growing mycobacteria.5 Rapidly growing mycobacteria form colonies within 7 days of inoculation in solid culture media.
As NTMs are ubiquitous environmental organisms, diagnostic criteria were developed to distinguish true infection from contamination or colonisation. The American Thoracic Society and Infectious Disease Society of America (ATS/IDSA) definition of NTM pulmonary disease require clinical and microbiological criteria to be fulfilled. Clinical criteria include pulmonary symptoms, nodular or cavitary opacities on chest radiograph, or a high-resolution CT scan that shows multifocal bronchiectasis with multiple small nodules and appropriate exclusion of other diagnoses. Microbiological criteria include at least two positive sputum cultures, at least one bronchial wash/lavage or biopsy with compatible histopathological features and positive culture.6
Transplanted patients are more susceptible to opportunistic and atypical infections as they are immunosuppressed. NTM infections are relatively rare among solid organ transplant patients and most commonly affect lung transplant recipients.1 2 The incidence of NTM in renal transplant recipients is between 0.16% and 0.38%.7 A retrospective study of solid organ transplant patients by Longworth et al2 found that Mycobacterium avium complex and Mycobacterium abscessus to be the most prevalent NTM infections with lung and pleura to be the most common site of infection.
In case of non-resolving or atypical infections, NTM infections have to be suspected and investigated in transplant recipients as they are associated with significantly increased mortality, 50% at 3 years versus 13% in solid organ transplant recipients without NTM infection.3 Patients with NTM infections typically need a prolonged course of antibiotics which differ depending on the organism and site of infection.
M. cosmeticum is a rapidly growing mycobacterium that was first isolated from a sink in a nail salon in the USA,8 then from monument sandstones9 and household potable water.10 Its role as a human pathogen was first described in 2004 after the isolation from a granulomatous subdermal lesion of a female patient in Venezuela.8 Similar cases were later reported in the literature.11 12
M. cosmeticum has been described to cause other infections as catheter-related bloodstream infection,13 granulomatous colitis,14 ascites,15 16 and was described to cause bacteremia in a preterm patient.17
The role of M. cosmeticum as a respiratory pathogen is not well established. It was isolated first from the sputum of an HIV patient in addition to Mycobacterium scrofulaceum. It was not mentioned in the report by Cooksey et al13 if the patient had evidence of lung infection or not. More recently, M. cosmeticum was reported in sputum of two patients from Saudi Arabia.18 One of them was post lung transplant and fulfilled the criteria of NTM lung disease according to the ATS/IDSA diagnostic criteria.6
We report the second case of M. cosmeticum pneumonia that has fulfilled the diagnostic criteria. First, the patient had symptoms and signs of pulmonary infection. Second, all routine tests for common pathogens were negative and the patient did not respond to initial broad-spectrum empiric antimicrobial therapy. Third, the culture of BAL was positive for M. cosmeticum. The combination of being a transplant recipient on immunosuppressive medications and possibly previous lung decortication surgery have contributed to his lung NTM lung infection.
In our patient, M. cosmeticum was the only organism that was isolated, and the improvement following appropriate antibiotic therapy points to a causal relationship. Differential diagnosis includes infection with a resistant unidentified organism that was covered with increasing the spectrum of antibiotic coverage. Use of culture-independent techniques as sequencing could have detected a potentially pathogenic microorganism as they are associated with increased sensitivity.19 20
Learning points
Mycobacterium cosmeticum, a rapidly growing non-tuberculous mycobacterium (NTM), that was initially described to cause skin and soft tissue infection, can be a cause of lung infection.
Although relatively rare, NTM lung infection should be suspected and investigated in immunocompromised patients who do not improve on initial empiric therapy.
Rapidly growing mycobacteria form colonies within 7 days of incubation in solid culture media.
Clinical and microbiologic diagnostic criteria have to be fulfilled to diagnose NTM lung disease.
More research is needed regarding the clinical use of culture-independent techniques in respiratory infections to improve the diagnostic yield, especially in critically ill patients.
Improved basic science understanding is needed to better identify factors that cause NTM infections to be pathogenic in some patients.
Contributors: AA contributed to planing, reviewing and reporting. MK contributed to planning and review of the article. MA contributed to review and reporting of case.
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: Next of kin consent obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | LISINOPRIL, MYCOPHENOLIC ACID, NIFEDIPINE, PREDNISOLONE, TACROLIMUS | DrugsGivenReaction | CC BY-NC | 33653829 | 19,811,129 | 2021-03-02 |
What was the administration route of drug 'LISINOPRIL'? | Pneumonia due to Mycobacterium cosmeticum in a renal transplant recipient.
A 69-year-old man renal transplant recipient for 4 years, presented with 4-day history of cough and dyspnoea. He was diagnosed with community-acquired pneumonia and treated accordingly. He deteriorated requiring intensive care unit admission and intubation. Mycobacterial culture from bronchoalveolar lavage grew colonies within 7 days of incubation while Mycobacterium tuberculosis PCR was negative. The antibiotic regimen was adjusted to cover for rapidly growing mycobacteria with imipenem, amikacin and clarithromycin. The final culture reported Mycobacterium cosmeticum He improved on the antibiotic regimen given which the organism turned to be sensitive to. We reported the second case with M. cosmeticum that fulfilled the diagnostic criteria for non-tuberculous mycobacterial lung infection. Improvement of patient's lung infection on appropriate antibiotics points to a causal relationship.
Background
Although relatively rare, non-tuberculous mycobacterial (NTM) infections remain clinically relevant, especially in immunosuppressed patients. Among solid organ transplant recipients, they are most prevalent among lung transplant recipients with lung and pleura being the most common sites of infection.1 2 Identification is associated with a significantly increased mortality rate in transplant recipients.3 Timely identification and diagnosis will help direct appropriate management of these patients. As NTM are ubiquitous in the environment, diagnostic criteria were developed to help differentiate true infection from contamination or colonisation.
Mycobacterium cosmeticum is a rapidly growing NTM. It has been rarely reported in the literature as a cause of different infections mostly in immunocompromised patients. Its role as a cause of lung infection has been reported only once. We report herein a case of a renal transplant recipient who developed pneumonia secondary to M. cosmeticum. This adds to the growing literature about this rarely reported organism.
Case presentation
A 69-year-old man presented to the emergency department with 4-day history of dry cough, progressive shortness of breath, fever with chills and progressive fatigue. The patient had a history of urinary schistosomiasis complicated with reflux nephropathy and end-stage renal failure. He was on haemodialysis for 6 years before he underwent a successful living-related renal transplant 4 years before presentation with good graft function. The patient was hypertensive and also had a history of empyema secondary to parapneumonic effusion and right lung decortication 3 years ago.
He was on nifedipine 120 mg once daily, lisinopril 10 mg once daily, mycophenolate 750 mg two times per day, prednisolone 5 mg once daily and tacrolimus 0.5 mg two times per day (all orally).
On admission, he was pale, tachypneic (22 breaths/min), had O2 saturation of 92% on room air and had bilateral fine crackles, more in the right lower zone.
His initial investigations showed leucopenia with white cell count of 3.31×109/L, neutrophils 45.1%, lymphocytes 38.2%, monocytes 7.1% and eosinophils 8.4%, anaemia with haemoglobin of 93 g/L, hyponatremia of 130 mEq/L and an erythrocyte sedimentation rate of 51 mm/hour. Screening of viral pathogens and sputum culture were negative. HIV serology was negative. Our patient was presented before the COVID-19 pandemic. Chest X-ray (CXR) revealed diffuse reticulonodular infiltrates with opacity in the right lower zone (figure 1).
Figure 1 Chest X-ray on admission showed diffuse reticulo-nodular infiltrates with irregular opacity in the right lower zone.
The patient was treated for community-acquired pneumonia with levofloxacin. Over the next few days, the patient’s condition worsened. Repeated CXR showed worsening bilateral infiltrates (figure 2). Chest CT showed a diffuse bilateral airspace consolidation, reticulation and ground glass appearance with lower lobes predominance (figure 3). Piperacillin/tazobactam was added, and the patient was shifted to the intensive care unit (ICU), intubated and ventilated.
Figure 2 Chest X-ray on fourth day of admission showed increase of bilateral pulmonary infiltrates.
Figure 3 CT chest showed a diffuse bilateral air space consolidation, reticulation and ground glass appearance with lower lobes predominance.
Bronchoalveolar lavage (BAL) and new microbiological investigations were performed. The results for gram stain, bacterial and fungal cultures, cytology for Pneumocystis jiroveci, acid-fast bacilli (AFB) staining, respiratory viruses and Mycobacterium tuberculosis PCR were negative. However, on the seventh day of incubation, AFB were noted in BAL mycobacterial culture. Assuming rapid growing NTM infection, he was started on imipenem, amikacin and clarithromycin. Cultures were sent for species identification (at Mayo Clinic Laboratories, Rochester, Minnesota, USA). M. cosmeticum was identified. It was sensitive to clarithromycin and amikacin.
Outcome and follow-up
The patient improved markedly (figure 4), extubated and shifted from ICU after 26 days. He was treated with this antibiotic regimen for 4 weeks and discharged home on oral antibiotics and home oxygen after 36 days of hospitalisation. Repeated mycobacterial culture from BAL 6 weeks after starting treatment was negative which suggests a good response.
Figure 4 Chest X-ray after treatment showed improvement of bilateral pulmonary infiltrates.
Discussion
NTM comprise more than 150 different species and are distributed worldwide.4 Many of these bacteria can lead to opportunistic infections with different clinical manifestations. According to Runyon classification, NTM are divided into slowly growing mycobacteria and rapidly growing mycobacteria.5 Rapidly growing mycobacteria form colonies within 7 days of inoculation in solid culture media.
As NTMs are ubiquitous environmental organisms, diagnostic criteria were developed to distinguish true infection from contamination or colonisation. The American Thoracic Society and Infectious Disease Society of America (ATS/IDSA) definition of NTM pulmonary disease require clinical and microbiological criteria to be fulfilled. Clinical criteria include pulmonary symptoms, nodular or cavitary opacities on chest radiograph, or a high-resolution CT scan that shows multifocal bronchiectasis with multiple small nodules and appropriate exclusion of other diagnoses. Microbiological criteria include at least two positive sputum cultures, at least one bronchial wash/lavage or biopsy with compatible histopathological features and positive culture.6
Transplanted patients are more susceptible to opportunistic and atypical infections as they are immunosuppressed. NTM infections are relatively rare among solid organ transplant patients and most commonly affect lung transplant recipients.1 2 The incidence of NTM in renal transplant recipients is between 0.16% and 0.38%.7 A retrospective study of solid organ transplant patients by Longworth et al2 found that Mycobacterium avium complex and Mycobacterium abscessus to be the most prevalent NTM infections with lung and pleura to be the most common site of infection.
In case of non-resolving or atypical infections, NTM infections have to be suspected and investigated in transplant recipients as they are associated with significantly increased mortality, 50% at 3 years versus 13% in solid organ transplant recipients without NTM infection.3 Patients with NTM infections typically need a prolonged course of antibiotics which differ depending on the organism and site of infection.
M. cosmeticum is a rapidly growing mycobacterium that was first isolated from a sink in a nail salon in the USA,8 then from monument sandstones9 and household potable water.10 Its role as a human pathogen was first described in 2004 after the isolation from a granulomatous subdermal lesion of a female patient in Venezuela.8 Similar cases were later reported in the literature.11 12
M. cosmeticum has been described to cause other infections as catheter-related bloodstream infection,13 granulomatous colitis,14 ascites,15 16 and was described to cause bacteremia in a preterm patient.17
The role of M. cosmeticum as a respiratory pathogen is not well established. It was isolated first from the sputum of an HIV patient in addition to Mycobacterium scrofulaceum. It was not mentioned in the report by Cooksey et al13 if the patient had evidence of lung infection or not. More recently, M. cosmeticum was reported in sputum of two patients from Saudi Arabia.18 One of them was post lung transplant and fulfilled the criteria of NTM lung disease according to the ATS/IDSA diagnostic criteria.6
We report the second case of M. cosmeticum pneumonia that has fulfilled the diagnostic criteria. First, the patient had symptoms and signs of pulmonary infection. Second, all routine tests for common pathogens were negative and the patient did not respond to initial broad-spectrum empiric antimicrobial therapy. Third, the culture of BAL was positive for M. cosmeticum. The combination of being a transplant recipient on immunosuppressive medications and possibly previous lung decortication surgery have contributed to his lung NTM lung infection.
In our patient, M. cosmeticum was the only organism that was isolated, and the improvement following appropriate antibiotic therapy points to a causal relationship. Differential diagnosis includes infection with a resistant unidentified organism that was covered with increasing the spectrum of antibiotic coverage. Use of culture-independent techniques as sequencing could have detected a potentially pathogenic microorganism as they are associated with increased sensitivity.19 20
Learning points
Mycobacterium cosmeticum, a rapidly growing non-tuberculous mycobacterium (NTM), that was initially described to cause skin and soft tissue infection, can be a cause of lung infection.
Although relatively rare, NTM lung infection should be suspected and investigated in immunocompromised patients who do not improve on initial empiric therapy.
Rapidly growing mycobacteria form colonies within 7 days of incubation in solid culture media.
Clinical and microbiologic diagnostic criteria have to be fulfilled to diagnose NTM lung disease.
More research is needed regarding the clinical use of culture-independent techniques in respiratory infections to improve the diagnostic yield, especially in critically ill patients.
Improved basic science understanding is needed to better identify factors that cause NTM infections to be pathogenic in some patients.
Contributors: AA contributed to planing, reviewing and reporting. MK contributed to planning and review of the article. MA contributed to review and reporting of case.
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: Next of kin consent obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Oral | DrugAdministrationRoute | CC BY-NC | 33653829 | 19,811,129 | 2021-03-02 |
What was the administration route of drug 'MYCOPHENOLIC ACID'? | Pneumonia due to Mycobacterium cosmeticum in a renal transplant recipient.
A 69-year-old man renal transplant recipient for 4 years, presented with 4-day history of cough and dyspnoea. He was diagnosed with community-acquired pneumonia and treated accordingly. He deteriorated requiring intensive care unit admission and intubation. Mycobacterial culture from bronchoalveolar lavage grew colonies within 7 days of incubation while Mycobacterium tuberculosis PCR was negative. The antibiotic regimen was adjusted to cover for rapidly growing mycobacteria with imipenem, amikacin and clarithromycin. The final culture reported Mycobacterium cosmeticum He improved on the antibiotic regimen given which the organism turned to be sensitive to. We reported the second case with M. cosmeticum that fulfilled the diagnostic criteria for non-tuberculous mycobacterial lung infection. Improvement of patient's lung infection on appropriate antibiotics points to a causal relationship.
Background
Although relatively rare, non-tuberculous mycobacterial (NTM) infections remain clinically relevant, especially in immunosuppressed patients. Among solid organ transplant recipients, they are most prevalent among lung transplant recipients with lung and pleura being the most common sites of infection.1 2 Identification is associated with a significantly increased mortality rate in transplant recipients.3 Timely identification and diagnosis will help direct appropriate management of these patients. As NTM are ubiquitous in the environment, diagnostic criteria were developed to help differentiate true infection from contamination or colonisation.
Mycobacterium cosmeticum is a rapidly growing NTM. It has been rarely reported in the literature as a cause of different infections mostly in immunocompromised patients. Its role as a cause of lung infection has been reported only once. We report herein a case of a renal transplant recipient who developed pneumonia secondary to M. cosmeticum. This adds to the growing literature about this rarely reported organism.
Case presentation
A 69-year-old man presented to the emergency department with 4-day history of dry cough, progressive shortness of breath, fever with chills and progressive fatigue. The patient had a history of urinary schistosomiasis complicated with reflux nephropathy and end-stage renal failure. He was on haemodialysis for 6 years before he underwent a successful living-related renal transplant 4 years before presentation with good graft function. The patient was hypertensive and also had a history of empyema secondary to parapneumonic effusion and right lung decortication 3 years ago.
He was on nifedipine 120 mg once daily, lisinopril 10 mg once daily, mycophenolate 750 mg two times per day, prednisolone 5 mg once daily and tacrolimus 0.5 mg two times per day (all orally).
On admission, he was pale, tachypneic (22 breaths/min), had O2 saturation of 92% on room air and had bilateral fine crackles, more in the right lower zone.
His initial investigations showed leucopenia with white cell count of 3.31×109/L, neutrophils 45.1%, lymphocytes 38.2%, monocytes 7.1% and eosinophils 8.4%, anaemia with haemoglobin of 93 g/L, hyponatremia of 130 mEq/L and an erythrocyte sedimentation rate of 51 mm/hour. Screening of viral pathogens and sputum culture were negative. HIV serology was negative. Our patient was presented before the COVID-19 pandemic. Chest X-ray (CXR) revealed diffuse reticulonodular infiltrates with opacity in the right lower zone (figure 1).
Figure 1 Chest X-ray on admission showed diffuse reticulo-nodular infiltrates with irregular opacity in the right lower zone.
The patient was treated for community-acquired pneumonia with levofloxacin. Over the next few days, the patient’s condition worsened. Repeated CXR showed worsening bilateral infiltrates (figure 2). Chest CT showed a diffuse bilateral airspace consolidation, reticulation and ground glass appearance with lower lobes predominance (figure 3). Piperacillin/tazobactam was added, and the patient was shifted to the intensive care unit (ICU), intubated and ventilated.
Figure 2 Chest X-ray on fourth day of admission showed increase of bilateral pulmonary infiltrates.
Figure 3 CT chest showed a diffuse bilateral air space consolidation, reticulation and ground glass appearance with lower lobes predominance.
Bronchoalveolar lavage (BAL) and new microbiological investigations were performed. The results for gram stain, bacterial and fungal cultures, cytology for Pneumocystis jiroveci, acid-fast bacilli (AFB) staining, respiratory viruses and Mycobacterium tuberculosis PCR were negative. However, on the seventh day of incubation, AFB were noted in BAL mycobacterial culture. Assuming rapid growing NTM infection, he was started on imipenem, amikacin and clarithromycin. Cultures were sent for species identification (at Mayo Clinic Laboratories, Rochester, Minnesota, USA). M. cosmeticum was identified. It was sensitive to clarithromycin and amikacin.
Outcome and follow-up
The patient improved markedly (figure 4), extubated and shifted from ICU after 26 days. He was treated with this antibiotic regimen for 4 weeks and discharged home on oral antibiotics and home oxygen after 36 days of hospitalisation. Repeated mycobacterial culture from BAL 6 weeks after starting treatment was negative which suggests a good response.
Figure 4 Chest X-ray after treatment showed improvement of bilateral pulmonary infiltrates.
Discussion
NTM comprise more than 150 different species and are distributed worldwide.4 Many of these bacteria can lead to opportunistic infections with different clinical manifestations. According to Runyon classification, NTM are divided into slowly growing mycobacteria and rapidly growing mycobacteria.5 Rapidly growing mycobacteria form colonies within 7 days of inoculation in solid culture media.
As NTMs are ubiquitous environmental organisms, diagnostic criteria were developed to distinguish true infection from contamination or colonisation. The American Thoracic Society and Infectious Disease Society of America (ATS/IDSA) definition of NTM pulmonary disease require clinical and microbiological criteria to be fulfilled. Clinical criteria include pulmonary symptoms, nodular or cavitary opacities on chest radiograph, or a high-resolution CT scan that shows multifocal bronchiectasis with multiple small nodules and appropriate exclusion of other diagnoses. Microbiological criteria include at least two positive sputum cultures, at least one bronchial wash/lavage or biopsy with compatible histopathological features and positive culture.6
Transplanted patients are more susceptible to opportunistic and atypical infections as they are immunosuppressed. NTM infections are relatively rare among solid organ transplant patients and most commonly affect lung transplant recipients.1 2 The incidence of NTM in renal transplant recipients is between 0.16% and 0.38%.7 A retrospective study of solid organ transplant patients by Longworth et al2 found that Mycobacterium avium complex and Mycobacterium abscessus to be the most prevalent NTM infections with lung and pleura to be the most common site of infection.
In case of non-resolving or atypical infections, NTM infections have to be suspected and investigated in transplant recipients as they are associated with significantly increased mortality, 50% at 3 years versus 13% in solid organ transplant recipients without NTM infection.3 Patients with NTM infections typically need a prolonged course of antibiotics which differ depending on the organism and site of infection.
M. cosmeticum is a rapidly growing mycobacterium that was first isolated from a sink in a nail salon in the USA,8 then from monument sandstones9 and household potable water.10 Its role as a human pathogen was first described in 2004 after the isolation from a granulomatous subdermal lesion of a female patient in Venezuela.8 Similar cases were later reported in the literature.11 12
M. cosmeticum has been described to cause other infections as catheter-related bloodstream infection,13 granulomatous colitis,14 ascites,15 16 and was described to cause bacteremia in a preterm patient.17
The role of M. cosmeticum as a respiratory pathogen is not well established. It was isolated first from the sputum of an HIV patient in addition to Mycobacterium scrofulaceum. It was not mentioned in the report by Cooksey et al13 if the patient had evidence of lung infection or not. More recently, M. cosmeticum was reported in sputum of two patients from Saudi Arabia.18 One of them was post lung transplant and fulfilled the criteria of NTM lung disease according to the ATS/IDSA diagnostic criteria.6
We report the second case of M. cosmeticum pneumonia that has fulfilled the diagnostic criteria. First, the patient had symptoms and signs of pulmonary infection. Second, all routine tests for common pathogens were negative and the patient did not respond to initial broad-spectrum empiric antimicrobial therapy. Third, the culture of BAL was positive for M. cosmeticum. The combination of being a transplant recipient on immunosuppressive medications and possibly previous lung decortication surgery have contributed to his lung NTM lung infection.
In our patient, M. cosmeticum was the only organism that was isolated, and the improvement following appropriate antibiotic therapy points to a causal relationship. Differential diagnosis includes infection with a resistant unidentified organism that was covered with increasing the spectrum of antibiotic coverage. Use of culture-independent techniques as sequencing could have detected a potentially pathogenic microorganism as they are associated with increased sensitivity.19 20
Learning points
Mycobacterium cosmeticum, a rapidly growing non-tuberculous mycobacterium (NTM), that was initially described to cause skin and soft tissue infection, can be a cause of lung infection.
Although relatively rare, NTM lung infection should be suspected and investigated in immunocompromised patients who do not improve on initial empiric therapy.
Rapidly growing mycobacteria form colonies within 7 days of incubation in solid culture media.
Clinical and microbiologic diagnostic criteria have to be fulfilled to diagnose NTM lung disease.
More research is needed regarding the clinical use of culture-independent techniques in respiratory infections to improve the diagnostic yield, especially in critically ill patients.
Improved basic science understanding is needed to better identify factors that cause NTM infections to be pathogenic in some patients.
Contributors: AA contributed to planing, reviewing and reporting. MK contributed to planning and review of the article. MA contributed to review and reporting of case.
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: Next of kin consent obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Oral | DrugAdministrationRoute | CC BY-NC | 33653829 | 19,811,129 | 2021-03-02 |
What was the administration route of drug 'NIFEDIPINE'? | Pneumonia due to Mycobacterium cosmeticum in a renal transplant recipient.
A 69-year-old man renal transplant recipient for 4 years, presented with 4-day history of cough and dyspnoea. He was diagnosed with community-acquired pneumonia and treated accordingly. He deteriorated requiring intensive care unit admission and intubation. Mycobacterial culture from bronchoalveolar lavage grew colonies within 7 days of incubation while Mycobacterium tuberculosis PCR was negative. The antibiotic regimen was adjusted to cover for rapidly growing mycobacteria with imipenem, amikacin and clarithromycin. The final culture reported Mycobacterium cosmeticum He improved on the antibiotic regimen given which the organism turned to be sensitive to. We reported the second case with M. cosmeticum that fulfilled the diagnostic criteria for non-tuberculous mycobacterial lung infection. Improvement of patient's lung infection on appropriate antibiotics points to a causal relationship.
Background
Although relatively rare, non-tuberculous mycobacterial (NTM) infections remain clinically relevant, especially in immunosuppressed patients. Among solid organ transplant recipients, they are most prevalent among lung transplant recipients with lung and pleura being the most common sites of infection.1 2 Identification is associated with a significantly increased mortality rate in transplant recipients.3 Timely identification and diagnosis will help direct appropriate management of these patients. As NTM are ubiquitous in the environment, diagnostic criteria were developed to help differentiate true infection from contamination or colonisation.
Mycobacterium cosmeticum is a rapidly growing NTM. It has been rarely reported in the literature as a cause of different infections mostly in immunocompromised patients. Its role as a cause of lung infection has been reported only once. We report herein a case of a renal transplant recipient who developed pneumonia secondary to M. cosmeticum. This adds to the growing literature about this rarely reported organism.
Case presentation
A 69-year-old man presented to the emergency department with 4-day history of dry cough, progressive shortness of breath, fever with chills and progressive fatigue. The patient had a history of urinary schistosomiasis complicated with reflux nephropathy and end-stage renal failure. He was on haemodialysis for 6 years before he underwent a successful living-related renal transplant 4 years before presentation with good graft function. The patient was hypertensive and also had a history of empyema secondary to parapneumonic effusion and right lung decortication 3 years ago.
He was on nifedipine 120 mg once daily, lisinopril 10 mg once daily, mycophenolate 750 mg two times per day, prednisolone 5 mg once daily and tacrolimus 0.5 mg two times per day (all orally).
On admission, he was pale, tachypneic (22 breaths/min), had O2 saturation of 92% on room air and had bilateral fine crackles, more in the right lower zone.
His initial investigations showed leucopenia with white cell count of 3.31×109/L, neutrophils 45.1%, lymphocytes 38.2%, monocytes 7.1% and eosinophils 8.4%, anaemia with haemoglobin of 93 g/L, hyponatremia of 130 mEq/L and an erythrocyte sedimentation rate of 51 mm/hour. Screening of viral pathogens and sputum culture were negative. HIV serology was negative. Our patient was presented before the COVID-19 pandemic. Chest X-ray (CXR) revealed diffuse reticulonodular infiltrates with opacity in the right lower zone (figure 1).
Figure 1 Chest X-ray on admission showed diffuse reticulo-nodular infiltrates with irregular opacity in the right lower zone.
The patient was treated for community-acquired pneumonia with levofloxacin. Over the next few days, the patient’s condition worsened. Repeated CXR showed worsening bilateral infiltrates (figure 2). Chest CT showed a diffuse bilateral airspace consolidation, reticulation and ground glass appearance with lower lobes predominance (figure 3). Piperacillin/tazobactam was added, and the patient was shifted to the intensive care unit (ICU), intubated and ventilated.
Figure 2 Chest X-ray on fourth day of admission showed increase of bilateral pulmonary infiltrates.
Figure 3 CT chest showed a diffuse bilateral air space consolidation, reticulation and ground glass appearance with lower lobes predominance.
Bronchoalveolar lavage (BAL) and new microbiological investigations were performed. The results for gram stain, bacterial and fungal cultures, cytology for Pneumocystis jiroveci, acid-fast bacilli (AFB) staining, respiratory viruses and Mycobacterium tuberculosis PCR were negative. However, on the seventh day of incubation, AFB were noted in BAL mycobacterial culture. Assuming rapid growing NTM infection, he was started on imipenem, amikacin and clarithromycin. Cultures were sent for species identification (at Mayo Clinic Laboratories, Rochester, Minnesota, USA). M. cosmeticum was identified. It was sensitive to clarithromycin and amikacin.
Outcome and follow-up
The patient improved markedly (figure 4), extubated and shifted from ICU after 26 days. He was treated with this antibiotic regimen for 4 weeks and discharged home on oral antibiotics and home oxygen after 36 days of hospitalisation. Repeated mycobacterial culture from BAL 6 weeks after starting treatment was negative which suggests a good response.
Figure 4 Chest X-ray after treatment showed improvement of bilateral pulmonary infiltrates.
Discussion
NTM comprise more than 150 different species and are distributed worldwide.4 Many of these bacteria can lead to opportunistic infections with different clinical manifestations. According to Runyon classification, NTM are divided into slowly growing mycobacteria and rapidly growing mycobacteria.5 Rapidly growing mycobacteria form colonies within 7 days of inoculation in solid culture media.
As NTMs are ubiquitous environmental organisms, diagnostic criteria were developed to distinguish true infection from contamination or colonisation. The American Thoracic Society and Infectious Disease Society of America (ATS/IDSA) definition of NTM pulmonary disease require clinical and microbiological criteria to be fulfilled. Clinical criteria include pulmonary symptoms, nodular or cavitary opacities on chest radiograph, or a high-resolution CT scan that shows multifocal bronchiectasis with multiple small nodules and appropriate exclusion of other diagnoses. Microbiological criteria include at least two positive sputum cultures, at least one bronchial wash/lavage or biopsy with compatible histopathological features and positive culture.6
Transplanted patients are more susceptible to opportunistic and atypical infections as they are immunosuppressed. NTM infections are relatively rare among solid organ transplant patients and most commonly affect lung transplant recipients.1 2 The incidence of NTM in renal transplant recipients is between 0.16% and 0.38%.7 A retrospective study of solid organ transplant patients by Longworth et al2 found that Mycobacterium avium complex and Mycobacterium abscessus to be the most prevalent NTM infections with lung and pleura to be the most common site of infection.
In case of non-resolving or atypical infections, NTM infections have to be suspected and investigated in transplant recipients as they are associated with significantly increased mortality, 50% at 3 years versus 13% in solid organ transplant recipients without NTM infection.3 Patients with NTM infections typically need a prolonged course of antibiotics which differ depending on the organism and site of infection.
M. cosmeticum is a rapidly growing mycobacterium that was first isolated from a sink in a nail salon in the USA,8 then from monument sandstones9 and household potable water.10 Its role as a human pathogen was first described in 2004 after the isolation from a granulomatous subdermal lesion of a female patient in Venezuela.8 Similar cases were later reported in the literature.11 12
M. cosmeticum has been described to cause other infections as catheter-related bloodstream infection,13 granulomatous colitis,14 ascites,15 16 and was described to cause bacteremia in a preterm patient.17
The role of M. cosmeticum as a respiratory pathogen is not well established. It was isolated first from the sputum of an HIV patient in addition to Mycobacterium scrofulaceum. It was not mentioned in the report by Cooksey et al13 if the patient had evidence of lung infection or not. More recently, M. cosmeticum was reported in sputum of two patients from Saudi Arabia.18 One of them was post lung transplant and fulfilled the criteria of NTM lung disease according to the ATS/IDSA diagnostic criteria.6
We report the second case of M. cosmeticum pneumonia that has fulfilled the diagnostic criteria. First, the patient had symptoms and signs of pulmonary infection. Second, all routine tests for common pathogens were negative and the patient did not respond to initial broad-spectrum empiric antimicrobial therapy. Third, the culture of BAL was positive for M. cosmeticum. The combination of being a transplant recipient on immunosuppressive medications and possibly previous lung decortication surgery have contributed to his lung NTM lung infection.
In our patient, M. cosmeticum was the only organism that was isolated, and the improvement following appropriate antibiotic therapy points to a causal relationship. Differential diagnosis includes infection with a resistant unidentified organism that was covered with increasing the spectrum of antibiotic coverage. Use of culture-independent techniques as sequencing could have detected a potentially pathogenic microorganism as they are associated with increased sensitivity.19 20
Learning points
Mycobacterium cosmeticum, a rapidly growing non-tuberculous mycobacterium (NTM), that was initially described to cause skin and soft tissue infection, can be a cause of lung infection.
Although relatively rare, NTM lung infection should be suspected and investigated in immunocompromised patients who do not improve on initial empiric therapy.
Rapidly growing mycobacteria form colonies within 7 days of incubation in solid culture media.
Clinical and microbiologic diagnostic criteria have to be fulfilled to diagnose NTM lung disease.
More research is needed regarding the clinical use of culture-independent techniques in respiratory infections to improve the diagnostic yield, especially in critically ill patients.
Improved basic science understanding is needed to better identify factors that cause NTM infections to be pathogenic in some patients.
Contributors: AA contributed to planing, reviewing and reporting. MK contributed to planning and review of the article. MA contributed to review and reporting of case.
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: Next of kin consent obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Oral | DrugAdministrationRoute | CC BY-NC | 33653829 | 19,811,129 | 2021-03-02 |
What was the administration route of drug 'PREDNISOLONE'? | Pneumonia due to Mycobacterium cosmeticum in a renal transplant recipient.
A 69-year-old man renal transplant recipient for 4 years, presented with 4-day history of cough and dyspnoea. He was diagnosed with community-acquired pneumonia and treated accordingly. He deteriorated requiring intensive care unit admission and intubation. Mycobacterial culture from bronchoalveolar lavage grew colonies within 7 days of incubation while Mycobacterium tuberculosis PCR was negative. The antibiotic regimen was adjusted to cover for rapidly growing mycobacteria with imipenem, amikacin and clarithromycin. The final culture reported Mycobacterium cosmeticum He improved on the antibiotic regimen given which the organism turned to be sensitive to. We reported the second case with M. cosmeticum that fulfilled the diagnostic criteria for non-tuberculous mycobacterial lung infection. Improvement of patient's lung infection on appropriate antibiotics points to a causal relationship.
Background
Although relatively rare, non-tuberculous mycobacterial (NTM) infections remain clinically relevant, especially in immunosuppressed patients. Among solid organ transplant recipients, they are most prevalent among lung transplant recipients with lung and pleura being the most common sites of infection.1 2 Identification is associated with a significantly increased mortality rate in transplant recipients.3 Timely identification and diagnosis will help direct appropriate management of these patients. As NTM are ubiquitous in the environment, diagnostic criteria were developed to help differentiate true infection from contamination or colonisation.
Mycobacterium cosmeticum is a rapidly growing NTM. It has been rarely reported in the literature as a cause of different infections mostly in immunocompromised patients. Its role as a cause of lung infection has been reported only once. We report herein a case of a renal transplant recipient who developed pneumonia secondary to M. cosmeticum. This adds to the growing literature about this rarely reported organism.
Case presentation
A 69-year-old man presented to the emergency department with 4-day history of dry cough, progressive shortness of breath, fever with chills and progressive fatigue. The patient had a history of urinary schistosomiasis complicated with reflux nephropathy and end-stage renal failure. He was on haemodialysis for 6 years before he underwent a successful living-related renal transplant 4 years before presentation with good graft function. The patient was hypertensive and also had a history of empyema secondary to parapneumonic effusion and right lung decortication 3 years ago.
He was on nifedipine 120 mg once daily, lisinopril 10 mg once daily, mycophenolate 750 mg two times per day, prednisolone 5 mg once daily and tacrolimus 0.5 mg two times per day (all orally).
On admission, he was pale, tachypneic (22 breaths/min), had O2 saturation of 92% on room air and had bilateral fine crackles, more in the right lower zone.
His initial investigations showed leucopenia with white cell count of 3.31×109/L, neutrophils 45.1%, lymphocytes 38.2%, monocytes 7.1% and eosinophils 8.4%, anaemia with haemoglobin of 93 g/L, hyponatremia of 130 mEq/L and an erythrocyte sedimentation rate of 51 mm/hour. Screening of viral pathogens and sputum culture were negative. HIV serology was negative. Our patient was presented before the COVID-19 pandemic. Chest X-ray (CXR) revealed diffuse reticulonodular infiltrates with opacity in the right lower zone (figure 1).
Figure 1 Chest X-ray on admission showed diffuse reticulo-nodular infiltrates with irregular opacity in the right lower zone.
The patient was treated for community-acquired pneumonia with levofloxacin. Over the next few days, the patient’s condition worsened. Repeated CXR showed worsening bilateral infiltrates (figure 2). Chest CT showed a diffuse bilateral airspace consolidation, reticulation and ground glass appearance with lower lobes predominance (figure 3). Piperacillin/tazobactam was added, and the patient was shifted to the intensive care unit (ICU), intubated and ventilated.
Figure 2 Chest X-ray on fourth day of admission showed increase of bilateral pulmonary infiltrates.
Figure 3 CT chest showed a diffuse bilateral air space consolidation, reticulation and ground glass appearance with lower lobes predominance.
Bronchoalveolar lavage (BAL) and new microbiological investigations were performed. The results for gram stain, bacterial and fungal cultures, cytology for Pneumocystis jiroveci, acid-fast bacilli (AFB) staining, respiratory viruses and Mycobacterium tuberculosis PCR were negative. However, on the seventh day of incubation, AFB were noted in BAL mycobacterial culture. Assuming rapid growing NTM infection, he was started on imipenem, amikacin and clarithromycin. Cultures were sent for species identification (at Mayo Clinic Laboratories, Rochester, Minnesota, USA). M. cosmeticum was identified. It was sensitive to clarithromycin and amikacin.
Outcome and follow-up
The patient improved markedly (figure 4), extubated and shifted from ICU after 26 days. He was treated with this antibiotic regimen for 4 weeks and discharged home on oral antibiotics and home oxygen after 36 days of hospitalisation. Repeated mycobacterial culture from BAL 6 weeks after starting treatment was negative which suggests a good response.
Figure 4 Chest X-ray after treatment showed improvement of bilateral pulmonary infiltrates.
Discussion
NTM comprise more than 150 different species and are distributed worldwide.4 Many of these bacteria can lead to opportunistic infections with different clinical manifestations. According to Runyon classification, NTM are divided into slowly growing mycobacteria and rapidly growing mycobacteria.5 Rapidly growing mycobacteria form colonies within 7 days of inoculation in solid culture media.
As NTMs are ubiquitous environmental organisms, diagnostic criteria were developed to distinguish true infection from contamination or colonisation. The American Thoracic Society and Infectious Disease Society of America (ATS/IDSA) definition of NTM pulmonary disease require clinical and microbiological criteria to be fulfilled. Clinical criteria include pulmonary symptoms, nodular or cavitary opacities on chest radiograph, or a high-resolution CT scan that shows multifocal bronchiectasis with multiple small nodules and appropriate exclusion of other diagnoses. Microbiological criteria include at least two positive sputum cultures, at least one bronchial wash/lavage or biopsy with compatible histopathological features and positive culture.6
Transplanted patients are more susceptible to opportunistic and atypical infections as they are immunosuppressed. NTM infections are relatively rare among solid organ transplant patients and most commonly affect lung transplant recipients.1 2 The incidence of NTM in renal transplant recipients is between 0.16% and 0.38%.7 A retrospective study of solid organ transplant patients by Longworth et al2 found that Mycobacterium avium complex and Mycobacterium abscessus to be the most prevalent NTM infections with lung and pleura to be the most common site of infection.
In case of non-resolving or atypical infections, NTM infections have to be suspected and investigated in transplant recipients as they are associated with significantly increased mortality, 50% at 3 years versus 13% in solid organ transplant recipients without NTM infection.3 Patients with NTM infections typically need a prolonged course of antibiotics which differ depending on the organism and site of infection.
M. cosmeticum is a rapidly growing mycobacterium that was first isolated from a sink in a nail salon in the USA,8 then from monument sandstones9 and household potable water.10 Its role as a human pathogen was first described in 2004 after the isolation from a granulomatous subdermal lesion of a female patient in Venezuela.8 Similar cases were later reported in the literature.11 12
M. cosmeticum has been described to cause other infections as catheter-related bloodstream infection,13 granulomatous colitis,14 ascites,15 16 and was described to cause bacteremia in a preterm patient.17
The role of M. cosmeticum as a respiratory pathogen is not well established. It was isolated first from the sputum of an HIV patient in addition to Mycobacterium scrofulaceum. It was not mentioned in the report by Cooksey et al13 if the patient had evidence of lung infection or not. More recently, M. cosmeticum was reported in sputum of two patients from Saudi Arabia.18 One of them was post lung transplant and fulfilled the criteria of NTM lung disease according to the ATS/IDSA diagnostic criteria.6
We report the second case of M. cosmeticum pneumonia that has fulfilled the diagnostic criteria. First, the patient had symptoms and signs of pulmonary infection. Second, all routine tests for common pathogens were negative and the patient did not respond to initial broad-spectrum empiric antimicrobial therapy. Third, the culture of BAL was positive for M. cosmeticum. The combination of being a transplant recipient on immunosuppressive medications and possibly previous lung decortication surgery have contributed to his lung NTM lung infection.
In our patient, M. cosmeticum was the only organism that was isolated, and the improvement following appropriate antibiotic therapy points to a causal relationship. Differential diagnosis includes infection with a resistant unidentified organism that was covered with increasing the spectrum of antibiotic coverage. Use of culture-independent techniques as sequencing could have detected a potentially pathogenic microorganism as they are associated with increased sensitivity.19 20
Learning points
Mycobacterium cosmeticum, a rapidly growing non-tuberculous mycobacterium (NTM), that was initially described to cause skin and soft tissue infection, can be a cause of lung infection.
Although relatively rare, NTM lung infection should be suspected and investigated in immunocompromised patients who do not improve on initial empiric therapy.
Rapidly growing mycobacteria form colonies within 7 days of incubation in solid culture media.
Clinical and microbiologic diagnostic criteria have to be fulfilled to diagnose NTM lung disease.
More research is needed regarding the clinical use of culture-independent techniques in respiratory infections to improve the diagnostic yield, especially in critically ill patients.
Improved basic science understanding is needed to better identify factors that cause NTM infections to be pathogenic in some patients.
Contributors: AA contributed to planing, reviewing and reporting. MK contributed to planning and review of the article. MA contributed to review and reporting of case.
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: Next of kin consent obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Oral | DrugAdministrationRoute | CC BY-NC | 33653829 | 19,811,129 | 2021-03-02 |
What was the administration route of drug 'TACROLIMUS'? | Pneumonia due to Mycobacterium cosmeticum in a renal transplant recipient.
A 69-year-old man renal transplant recipient for 4 years, presented with 4-day history of cough and dyspnoea. He was diagnosed with community-acquired pneumonia and treated accordingly. He deteriorated requiring intensive care unit admission and intubation. Mycobacterial culture from bronchoalveolar lavage grew colonies within 7 days of incubation while Mycobacterium tuberculosis PCR was negative. The antibiotic regimen was adjusted to cover for rapidly growing mycobacteria with imipenem, amikacin and clarithromycin. The final culture reported Mycobacterium cosmeticum He improved on the antibiotic regimen given which the organism turned to be sensitive to. We reported the second case with M. cosmeticum that fulfilled the diagnostic criteria for non-tuberculous mycobacterial lung infection. Improvement of patient's lung infection on appropriate antibiotics points to a causal relationship.
Background
Although relatively rare, non-tuberculous mycobacterial (NTM) infections remain clinically relevant, especially in immunosuppressed patients. Among solid organ transplant recipients, they are most prevalent among lung transplant recipients with lung and pleura being the most common sites of infection.1 2 Identification is associated with a significantly increased mortality rate in transplant recipients.3 Timely identification and diagnosis will help direct appropriate management of these patients. As NTM are ubiquitous in the environment, diagnostic criteria were developed to help differentiate true infection from contamination or colonisation.
Mycobacterium cosmeticum is a rapidly growing NTM. It has been rarely reported in the literature as a cause of different infections mostly in immunocompromised patients. Its role as a cause of lung infection has been reported only once. We report herein a case of a renal transplant recipient who developed pneumonia secondary to M. cosmeticum. This adds to the growing literature about this rarely reported organism.
Case presentation
A 69-year-old man presented to the emergency department with 4-day history of dry cough, progressive shortness of breath, fever with chills and progressive fatigue. The patient had a history of urinary schistosomiasis complicated with reflux nephropathy and end-stage renal failure. He was on haemodialysis for 6 years before he underwent a successful living-related renal transplant 4 years before presentation with good graft function. The patient was hypertensive and also had a history of empyema secondary to parapneumonic effusion and right lung decortication 3 years ago.
He was on nifedipine 120 mg once daily, lisinopril 10 mg once daily, mycophenolate 750 mg two times per day, prednisolone 5 mg once daily and tacrolimus 0.5 mg two times per day (all orally).
On admission, he was pale, tachypneic (22 breaths/min), had O2 saturation of 92% on room air and had bilateral fine crackles, more in the right lower zone.
His initial investigations showed leucopenia with white cell count of 3.31×109/L, neutrophils 45.1%, lymphocytes 38.2%, monocytes 7.1% and eosinophils 8.4%, anaemia with haemoglobin of 93 g/L, hyponatremia of 130 mEq/L and an erythrocyte sedimentation rate of 51 mm/hour. Screening of viral pathogens and sputum culture were negative. HIV serology was negative. Our patient was presented before the COVID-19 pandemic. Chest X-ray (CXR) revealed diffuse reticulonodular infiltrates with opacity in the right lower zone (figure 1).
Figure 1 Chest X-ray on admission showed diffuse reticulo-nodular infiltrates with irregular opacity in the right lower zone.
The patient was treated for community-acquired pneumonia with levofloxacin. Over the next few days, the patient’s condition worsened. Repeated CXR showed worsening bilateral infiltrates (figure 2). Chest CT showed a diffuse bilateral airspace consolidation, reticulation and ground glass appearance with lower lobes predominance (figure 3). Piperacillin/tazobactam was added, and the patient was shifted to the intensive care unit (ICU), intubated and ventilated.
Figure 2 Chest X-ray on fourth day of admission showed increase of bilateral pulmonary infiltrates.
Figure 3 CT chest showed a diffuse bilateral air space consolidation, reticulation and ground glass appearance with lower lobes predominance.
Bronchoalveolar lavage (BAL) and new microbiological investigations were performed. The results for gram stain, bacterial and fungal cultures, cytology for Pneumocystis jiroveci, acid-fast bacilli (AFB) staining, respiratory viruses and Mycobacterium tuberculosis PCR were negative. However, on the seventh day of incubation, AFB were noted in BAL mycobacterial culture. Assuming rapid growing NTM infection, he was started on imipenem, amikacin and clarithromycin. Cultures were sent for species identification (at Mayo Clinic Laboratories, Rochester, Minnesota, USA). M. cosmeticum was identified. It was sensitive to clarithromycin and amikacin.
Outcome and follow-up
The patient improved markedly (figure 4), extubated and shifted from ICU after 26 days. He was treated with this antibiotic regimen for 4 weeks and discharged home on oral antibiotics and home oxygen after 36 days of hospitalisation. Repeated mycobacterial culture from BAL 6 weeks after starting treatment was negative which suggests a good response.
Figure 4 Chest X-ray after treatment showed improvement of bilateral pulmonary infiltrates.
Discussion
NTM comprise more than 150 different species and are distributed worldwide.4 Many of these bacteria can lead to opportunistic infections with different clinical manifestations. According to Runyon classification, NTM are divided into slowly growing mycobacteria and rapidly growing mycobacteria.5 Rapidly growing mycobacteria form colonies within 7 days of inoculation in solid culture media.
As NTMs are ubiquitous environmental organisms, diagnostic criteria were developed to distinguish true infection from contamination or colonisation. The American Thoracic Society and Infectious Disease Society of America (ATS/IDSA) definition of NTM pulmonary disease require clinical and microbiological criteria to be fulfilled. Clinical criteria include pulmonary symptoms, nodular or cavitary opacities on chest radiograph, or a high-resolution CT scan that shows multifocal bronchiectasis with multiple small nodules and appropriate exclusion of other diagnoses. Microbiological criteria include at least two positive sputum cultures, at least one bronchial wash/lavage or biopsy with compatible histopathological features and positive culture.6
Transplanted patients are more susceptible to opportunistic and atypical infections as they are immunosuppressed. NTM infections are relatively rare among solid organ transplant patients and most commonly affect lung transplant recipients.1 2 The incidence of NTM in renal transplant recipients is between 0.16% and 0.38%.7 A retrospective study of solid organ transplant patients by Longworth et al2 found that Mycobacterium avium complex and Mycobacterium abscessus to be the most prevalent NTM infections with lung and pleura to be the most common site of infection.
In case of non-resolving or atypical infections, NTM infections have to be suspected and investigated in transplant recipients as they are associated with significantly increased mortality, 50% at 3 years versus 13% in solid organ transplant recipients without NTM infection.3 Patients with NTM infections typically need a prolonged course of antibiotics which differ depending on the organism and site of infection.
M. cosmeticum is a rapidly growing mycobacterium that was first isolated from a sink in a nail salon in the USA,8 then from monument sandstones9 and household potable water.10 Its role as a human pathogen was first described in 2004 after the isolation from a granulomatous subdermal lesion of a female patient in Venezuela.8 Similar cases were later reported in the literature.11 12
M. cosmeticum has been described to cause other infections as catheter-related bloodstream infection,13 granulomatous colitis,14 ascites,15 16 and was described to cause bacteremia in a preterm patient.17
The role of M. cosmeticum as a respiratory pathogen is not well established. It was isolated first from the sputum of an HIV patient in addition to Mycobacterium scrofulaceum. It was not mentioned in the report by Cooksey et al13 if the patient had evidence of lung infection or not. More recently, M. cosmeticum was reported in sputum of two patients from Saudi Arabia.18 One of them was post lung transplant and fulfilled the criteria of NTM lung disease according to the ATS/IDSA diagnostic criteria.6
We report the second case of M. cosmeticum pneumonia that has fulfilled the diagnostic criteria. First, the patient had symptoms and signs of pulmonary infection. Second, all routine tests for common pathogens were negative and the patient did not respond to initial broad-spectrum empiric antimicrobial therapy. Third, the culture of BAL was positive for M. cosmeticum. The combination of being a transplant recipient on immunosuppressive medications and possibly previous lung decortication surgery have contributed to his lung NTM lung infection.
In our patient, M. cosmeticum was the only organism that was isolated, and the improvement following appropriate antibiotic therapy points to a causal relationship. Differential diagnosis includes infection with a resistant unidentified organism that was covered with increasing the spectrum of antibiotic coverage. Use of culture-independent techniques as sequencing could have detected a potentially pathogenic microorganism as they are associated with increased sensitivity.19 20
Learning points
Mycobacterium cosmeticum, a rapidly growing non-tuberculous mycobacterium (NTM), that was initially described to cause skin and soft tissue infection, can be a cause of lung infection.
Although relatively rare, NTM lung infection should be suspected and investigated in immunocompromised patients who do not improve on initial empiric therapy.
Rapidly growing mycobacteria form colonies within 7 days of incubation in solid culture media.
Clinical and microbiologic diagnostic criteria have to be fulfilled to diagnose NTM lung disease.
More research is needed regarding the clinical use of culture-independent techniques in respiratory infections to improve the diagnostic yield, especially in critically ill patients.
Improved basic science understanding is needed to better identify factors that cause NTM infections to be pathogenic in some patients.
Contributors: AA contributed to planing, reviewing and reporting. MK contributed to planning and review of the article. MA contributed to review and reporting of case.
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: Next of kin consent obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Oral | DrugAdministrationRoute | CC BY-NC | 33653829 | 19,811,129 | 2021-03-02 |
What was the outcome of reaction 'Pneumonia bacterial'? | Pneumonia due to Mycobacterium cosmeticum in a renal transplant recipient.
A 69-year-old man renal transplant recipient for 4 years, presented with 4-day history of cough and dyspnoea. He was diagnosed with community-acquired pneumonia and treated accordingly. He deteriorated requiring intensive care unit admission and intubation. Mycobacterial culture from bronchoalveolar lavage grew colonies within 7 days of incubation while Mycobacterium tuberculosis PCR was negative. The antibiotic regimen was adjusted to cover for rapidly growing mycobacteria with imipenem, amikacin and clarithromycin. The final culture reported Mycobacterium cosmeticum He improved on the antibiotic regimen given which the organism turned to be sensitive to. We reported the second case with M. cosmeticum that fulfilled the diagnostic criteria for non-tuberculous mycobacterial lung infection. Improvement of patient's lung infection on appropriate antibiotics points to a causal relationship.
Background
Although relatively rare, non-tuberculous mycobacterial (NTM) infections remain clinically relevant, especially in immunosuppressed patients. Among solid organ transplant recipients, they are most prevalent among lung transplant recipients with lung and pleura being the most common sites of infection.1 2 Identification is associated with a significantly increased mortality rate in transplant recipients.3 Timely identification and diagnosis will help direct appropriate management of these patients. As NTM are ubiquitous in the environment, diagnostic criteria were developed to help differentiate true infection from contamination or colonisation.
Mycobacterium cosmeticum is a rapidly growing NTM. It has been rarely reported in the literature as a cause of different infections mostly in immunocompromised patients. Its role as a cause of lung infection has been reported only once. We report herein a case of a renal transplant recipient who developed pneumonia secondary to M. cosmeticum. This adds to the growing literature about this rarely reported organism.
Case presentation
A 69-year-old man presented to the emergency department with 4-day history of dry cough, progressive shortness of breath, fever with chills and progressive fatigue. The patient had a history of urinary schistosomiasis complicated with reflux nephropathy and end-stage renal failure. He was on haemodialysis for 6 years before he underwent a successful living-related renal transplant 4 years before presentation with good graft function. The patient was hypertensive and also had a history of empyema secondary to parapneumonic effusion and right lung decortication 3 years ago.
He was on nifedipine 120 mg once daily, lisinopril 10 mg once daily, mycophenolate 750 mg two times per day, prednisolone 5 mg once daily and tacrolimus 0.5 mg two times per day (all orally).
On admission, he was pale, tachypneic (22 breaths/min), had O2 saturation of 92% on room air and had bilateral fine crackles, more in the right lower zone.
His initial investigations showed leucopenia with white cell count of 3.31×109/L, neutrophils 45.1%, lymphocytes 38.2%, monocytes 7.1% and eosinophils 8.4%, anaemia with haemoglobin of 93 g/L, hyponatremia of 130 mEq/L and an erythrocyte sedimentation rate of 51 mm/hour. Screening of viral pathogens and sputum culture were negative. HIV serology was negative. Our patient was presented before the COVID-19 pandemic. Chest X-ray (CXR) revealed diffuse reticulonodular infiltrates with opacity in the right lower zone (figure 1).
Figure 1 Chest X-ray on admission showed diffuse reticulo-nodular infiltrates with irregular opacity in the right lower zone.
The patient was treated for community-acquired pneumonia with levofloxacin. Over the next few days, the patient’s condition worsened. Repeated CXR showed worsening bilateral infiltrates (figure 2). Chest CT showed a diffuse bilateral airspace consolidation, reticulation and ground glass appearance with lower lobes predominance (figure 3). Piperacillin/tazobactam was added, and the patient was shifted to the intensive care unit (ICU), intubated and ventilated.
Figure 2 Chest X-ray on fourth day of admission showed increase of bilateral pulmonary infiltrates.
Figure 3 CT chest showed a diffuse bilateral air space consolidation, reticulation and ground glass appearance with lower lobes predominance.
Bronchoalveolar lavage (BAL) and new microbiological investigations were performed. The results for gram stain, bacterial and fungal cultures, cytology for Pneumocystis jiroveci, acid-fast bacilli (AFB) staining, respiratory viruses and Mycobacterium tuberculosis PCR were negative. However, on the seventh day of incubation, AFB were noted in BAL mycobacterial culture. Assuming rapid growing NTM infection, he was started on imipenem, amikacin and clarithromycin. Cultures were sent for species identification (at Mayo Clinic Laboratories, Rochester, Minnesota, USA). M. cosmeticum was identified. It was sensitive to clarithromycin and amikacin.
Outcome and follow-up
The patient improved markedly (figure 4), extubated and shifted from ICU after 26 days. He was treated with this antibiotic regimen for 4 weeks and discharged home on oral antibiotics and home oxygen after 36 days of hospitalisation. Repeated mycobacterial culture from BAL 6 weeks after starting treatment was negative which suggests a good response.
Figure 4 Chest X-ray after treatment showed improvement of bilateral pulmonary infiltrates.
Discussion
NTM comprise more than 150 different species and are distributed worldwide.4 Many of these bacteria can lead to opportunistic infections with different clinical manifestations. According to Runyon classification, NTM are divided into slowly growing mycobacteria and rapidly growing mycobacteria.5 Rapidly growing mycobacteria form colonies within 7 days of inoculation in solid culture media.
As NTMs are ubiquitous environmental organisms, diagnostic criteria were developed to distinguish true infection from contamination or colonisation. The American Thoracic Society and Infectious Disease Society of America (ATS/IDSA) definition of NTM pulmonary disease require clinical and microbiological criteria to be fulfilled. Clinical criteria include pulmonary symptoms, nodular or cavitary opacities on chest radiograph, or a high-resolution CT scan that shows multifocal bronchiectasis with multiple small nodules and appropriate exclusion of other diagnoses. Microbiological criteria include at least two positive sputum cultures, at least one bronchial wash/lavage or biopsy with compatible histopathological features and positive culture.6
Transplanted patients are more susceptible to opportunistic and atypical infections as they are immunosuppressed. NTM infections are relatively rare among solid organ transplant patients and most commonly affect lung transplant recipients.1 2 The incidence of NTM in renal transplant recipients is between 0.16% and 0.38%.7 A retrospective study of solid organ transplant patients by Longworth et al2 found that Mycobacterium avium complex and Mycobacterium abscessus to be the most prevalent NTM infections with lung and pleura to be the most common site of infection.
In case of non-resolving or atypical infections, NTM infections have to be suspected and investigated in transplant recipients as they are associated with significantly increased mortality, 50% at 3 years versus 13% in solid organ transplant recipients without NTM infection.3 Patients with NTM infections typically need a prolonged course of antibiotics which differ depending on the organism and site of infection.
M. cosmeticum is a rapidly growing mycobacterium that was first isolated from a sink in a nail salon in the USA,8 then from monument sandstones9 and household potable water.10 Its role as a human pathogen was first described in 2004 after the isolation from a granulomatous subdermal lesion of a female patient in Venezuela.8 Similar cases were later reported in the literature.11 12
M. cosmeticum has been described to cause other infections as catheter-related bloodstream infection,13 granulomatous colitis,14 ascites,15 16 and was described to cause bacteremia in a preterm patient.17
The role of M. cosmeticum as a respiratory pathogen is not well established. It was isolated first from the sputum of an HIV patient in addition to Mycobacterium scrofulaceum. It was not mentioned in the report by Cooksey et al13 if the patient had evidence of lung infection or not. More recently, M. cosmeticum was reported in sputum of two patients from Saudi Arabia.18 One of them was post lung transplant and fulfilled the criteria of NTM lung disease according to the ATS/IDSA diagnostic criteria.6
We report the second case of M. cosmeticum pneumonia that has fulfilled the diagnostic criteria. First, the patient had symptoms and signs of pulmonary infection. Second, all routine tests for common pathogens were negative and the patient did not respond to initial broad-spectrum empiric antimicrobial therapy. Third, the culture of BAL was positive for M. cosmeticum. The combination of being a transplant recipient on immunosuppressive medications and possibly previous lung decortication surgery have contributed to his lung NTM lung infection.
In our patient, M. cosmeticum was the only organism that was isolated, and the improvement following appropriate antibiotic therapy points to a causal relationship. Differential diagnosis includes infection with a resistant unidentified organism that was covered with increasing the spectrum of antibiotic coverage. Use of culture-independent techniques as sequencing could have detected a potentially pathogenic microorganism as they are associated with increased sensitivity.19 20
Learning points
Mycobacterium cosmeticum, a rapidly growing non-tuberculous mycobacterium (NTM), that was initially described to cause skin and soft tissue infection, can be a cause of lung infection.
Although relatively rare, NTM lung infection should be suspected and investigated in immunocompromised patients who do not improve on initial empiric therapy.
Rapidly growing mycobacteria form colonies within 7 days of incubation in solid culture media.
Clinical and microbiologic diagnostic criteria have to be fulfilled to diagnose NTM lung disease.
More research is needed regarding the clinical use of culture-independent techniques in respiratory infections to improve the diagnostic yield, especially in critically ill patients.
Improved basic science understanding is needed to better identify factors that cause NTM infections to be pathogenic in some patients.
Contributors: AA contributed to planing, reviewing and reporting. MK contributed to planning and review of the article. MA contributed to review and reporting of case.
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: Next of kin consent obtained.
Provenance and peer review: Not commissioned; externally peer reviewed. | Recovered | ReactionOutcome | CC BY-NC | 33653829 | 19,811,129 | 2021-03-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Acute kidney injury'. | A case of ramucirumab-induced renal failure with nephrotic-range proteinuria and its pathological findings.
Ramucirumab-induced renal dysfunction is rarely reported. The pathology of ramucirumab-associated nephropathy in past reports primarily shows thrombotic microangiopathy (TMA) lesions but podocytopathy is not yet known. We report a case of kidney injury induced by ramucirumab in a 71-year-old man with cecal cancer. He was referred to our department for increasing serum creatinine (Cr) levels from 1.08 mg/dL to 2.56 mg/dL after changing anticancer drugs from bevacizumab to ramucirumab. He showed nephrotic-range proteinuria (12.1 g/gCr). A renal biopsy revealed endothelial cell injuries, such as TMA and podocytopathy with epithelial cell hyperplasia, which looked like a crescent. After discontinuing ramucirumab, his renal function and proteinuria improved, as seen by his Cr levels and proteinuria which decreased to 1.74 mg/dL and 1.21 g/gCr, respectively, in 3 months. Unlike previous reports, we found that ramucirumab caused podocyte injuries.
Background
Currently, inhibiting vascular endothelial growth factor (VEGF) signalling is one of the most efficient ways to treat cancers. Ramucirumab is a fully humanised monoclonal antibody targeting VEGF receptor-2 (VEGFR-2) and it inhibits downstream signalling.1 In the last decade, antiangiogenic agents for solid cancers have caused renal dysfunction.2 However, renal dysfunction induced by ramucirumab is rarely reported3 and its specific clinical course is still unknown.
We present the case of a 71-year-old man who had acute kidney injury with nephrotic-range proteinuria after ramucirumab administration. Past reports showed only thrombotic microangiopathy (TMA) in renal pathological changes,3 but his pathological findings suggested ramucirumab induced TMA and podocytopathy, which included a crescent-like lesion.
Case presentation
A 71-year-old man diagnosed with cecal cancer with lymph node metastasis underwent an ileocecal resection and received chemotherapy. He completed his therapy and remained stable for the next few years. When imaging studies showed a progressive disease, he restarted chemotherapy with folinic acid, fluorouracil, irinotecan and bevacizumab. With bevacizumab, he showed proteinuria 3+ in a dipstick test; therefore, he was closely monitored. After a year, because he presented with a progressive disease, bevacizumab was changed to ramucirumab. After 2 weeks, he was admitted to our department because of oedema exacerbation. He had high blood pressure, which was 172/83 mm Hg, although he had already been taking medication for hypertension. His blood pressure was usually controlled at approximately 150/80 mm Hg with an angiotensin II receptor blocker and a calcium channel blocker. His weight was 68 kg, although his usual weight was 61 kg. He showed pitting oedema.
Investigations
The laboratory data (table 1) showed worsening renal function and nephrotic-range proteinuria of 12.1 g/gCr. Serum creatinine (Cr) levels were increased from 1.08 mg/dL to 2.56 mg/dL. Serum albumin decreased from 3.9 g/dL to 3.2 g/dL. The kidney sizes were 108×56 mm (right) and 117×56 mm (left).
Table 1 Blood and Urinary tests are shown
Patient values Reference range Interpretation
Blood test
White cell count 3.6109/L 3.5109–9.1109/L Normal
Haemoglobin 115 g/L 113–152 g/L Normal
Platelet count 90×109/L 130×109–369×109/L Normal
C reactive protein 0.1 mg/dL 0–0.3 mg/dL Normal
Albumin 3.2 g/dL 4–5 g/dL Decreased
Total protein 5.6 g/dL 6.7–8.3 g/dL Decreased
Blood urea nitrogen 32.4 mg/dL 6–20 mg/dL Normal
Creatinine 1.2 mg/dL 0.47–0.79 mg/dL Elevated
LDL cholesterol 126 mg/dL 70–139 mg/dL Normal
Urinary test
Urinary red blood cell 5–9/HPF <1/HPF Elevated
Urinary protein 12.1 g/gCr <0.15 g/gCr Elevated
Bence Jones protein − − Normal
Urinary β2-microglobulin 6777 µg/L 0–259 µg/L Elevated
Selectivity index 0.39 <0.2 (high selectivity) Elevated
HPF, high power field; LDL, low-density lipoproteins.
A kidney biopsy was performed. The renal biopsy specimen contained 18 glomeruli. Two glomeruli showed global sclerosis. The mesangial matrix proliferated in all glomeruli, and the mesangial cells partly proliferated. The glomerular basement membrane showed thickening in all glomeruli, and half of them showed a double contour that circumscribed fibrin such as an eosinophilic substance (figure 1A, B). TMA caused these changes. No spike formation was detected. Four glomeruli were collapsed with epithelial cell hyperplasia which looks like a crescent lesion (figure 2A, B). These changes were similar to collapsing glomeruli with a ‘pseudocrescent’,4 which suggested podocytopathy. Immunofluorescence studies indicated positive staining of the glomerular capillaries and mesangium for C3, C4 and C1q. A part of the mesangium was also positive for IgG, IgM and IgA. Electron microscopy revealed endothelial cell hyperplasia and non-specific dense substances around the mesangium. Some of the foot processes vanished, but no podocytes were detached. Tubular atrophy and interstitial fibrosis were observed in approximately half of the total area.
Figure 1 The glomerular basement membrane showed thickening in all glomeruli, and half of them showed a double contour with fibrinous exudates. (A): H&E stain, (B): Periodic acid-methenamine silver stain).
Figure 2 Glomeruli with epithelial cell hyperplasia, which looks like a ‘crescent’, show capillary wall collapse. (A, B: Periodic acid-methenamine silver stain).
Differential diagnosis
We considered the effect of bevacizumab, which is an anti-VEGF-A drug. In this case, several injections of bevacizumab already caused proteinuria. Bevacizumab may have damaged endothelial cells in the glomeruli. However, it was clear that ramucirumab was a key drug because renal failure and pitting oedema had not been shown before its administration.
It is known that bevacizumab mainly causes TMA.5 His pathology showed not only TMA but also glomerular collapse with a crescent-like lesion. This also suggested that the renal dysfunction could not be explained only by bevacizumab.
Treatment
We discontinued ramucirumab and continued an angiotensin II receptor blocker to reduce proteinuria. We did not use immune therapies such as corticosteroids.
Outcome and follow-up
After discontinuation of ramucirumab, the serum Cr gradually decreased to 1.79 mg/dL, and proteinuria also decreased to 3.21 g/gCr 3 months later (figure 3). Proteinuria decreased to 1.21 g/gCr about 7 months later.
Figure 3 There was an improvement with the discontinuation of the medication, but some renal impairment remained.
Discussion
Many anticancer drugs have been developed to inhibit VEGF signalling because it plays a vital role in controlling neovascular processes in neoplasms.2 In the kidney, podocytes and endothelial cells are significant sources of VEGF. It acts in autocrine and paracrine fashions and contributes to maintaining homeostasis.6 The VEGF receptor family, which is a tyrosine kinase receptor, consists of three subtypes: VEGFR-1, VEGFR-2 and VEGFR-3. Among them, VEGFR-2 is predominantly expressed in podocytes, mesangium, endothelial cells and tubular capillaries.5 6 Ramucirumab is a VEGFR-2 binding monoclonal antibody that has been widely used for gastric, lung and colorectal cancer as a second-line therapy.1 A previous study showed adverse renal effects of ramucirumab involving hypertension (21%) and proteinuria (9%).7 Although other VEGF inhibitory drugs, such as the anti-VEGF monoclonal body (bevacizumab), tyrosine kinase inhibitors (sunitinib, axitinib, sorafenib and cediranib) and VEGF-Trap (aflibercept) have been known to cause nephrotic-range proteinuria and renal dysfunction, ramucirumab has been reported in only one case report8 and one single-centre case report.3
Anti-VEGF/VEGFR therapy reportedly accounts for two primary forms of renal pathological changes: minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS), which suggests podocytopathy, and TMA, which suggests endothelial cell injury.5 There is a different tendency for TMA or MCD/FSGS to occur depending on the type of anti-VEGF/VEGFR drug. For example, it is well known that VEGFR is abundant in endothelial cells and inhibition of VEGFR–VEGF crosstalk by anti-VEGF drugs, such as bevacizumab cause TMA.5 On the other hand, VEGFR tyrosine kinase inhibitors (RTKI) cause MCD/FSGS more often than TMA. Previous studies suggested that RTKI inhibits NF-κB activity, leading to c-mip overexpression, and induces MCD or FSGS.5 In two previous studies on ramucirumab-induced nephropathy, three cases of renal pathology were reported3 8 and all of them were reported as TMA. The development of renal impairment characterised the three previous cases after switching from bevacizumab to ramucirumab, as in this case. It is possible that TMA could be caused or exacerbated due to endothelial damage caused by ramucirumab because it is known that the interaction of VEGF with VEGFR-2 is necessary to maintain endothelial cells.9 Since double contours of the glomerular basement membrane were chronic lesions of TMA10 and bevacizumab was administered before ramucirumab, the effect of bevacizumab on TMA could not be ignored. Compared with previous reports, we think this case is characterised by collapsing glomeruli with epithelial cell hyperplasia. A previous report showed that collapsing glomeruli with ‘pseudocrescents’ are caused by podocyte damage.4 The clinical course of marked nephrotic-range proteinuria is also consistent with podocytopathy rather than TMA. A previous study showed that VEGFR-2 is also expressed in podocytes in vivo and that VEGF and VEGFR-2, through autocrine actions, regulate podocyte survival.11 Bertuccio et al12 demonstrated a direct interaction between VEGFR-2 and nephrin in vitro and proposed VEGF signalling via the VEGFR-2–nephrin complex has an essential role in podocyte foot process effacement.
Moreover, ramucirumab inhibits the start of VEGFR-2 signalling, which is the target of RTKI,7 so ramucirumab would cause podocytopathy in the same way as RTKI. These findings suggest that VEGFR-2 plays an important role in podocytes. As mentioned above, renal injury occurred in the three previously reported cases as well as in this case after switching from bevacizumab therapy and this suggests the synergistic effect of ramucirumab and bevacizumab. Müller-Deile et al6 showed that VEGF-A and VEGF-C both interact with VEGFR-2 and play important roles in podocyte survival. They showed that when VEGF-A is inhibited by bevacizumab, VEGF-C plays an important role in suppressing podocyte apoptosis. Another study showed that when bevacizumab inhibits VEGF-A, VEGF-C maintains VEGFR-2 activation in glioblastomas.13 In our case, ramucirumab was considered to have inhibited the interaction between VEGFR-2 and VEGF-C, and this may have resulted in a synergistic effect. The pathology of this case suggests that the presence of chronic TMA caused by bevacizumab may have been combined with podocyte damage from ramucirumab, leading to severe damage to the kidney. This case suggests that VEGFR-2 plays an essential role in the maintenance of podocytes as well as endothelial cells.
We report a rare case of ramucirumab-induced severe proteinuria and renal dysfunction with just one dose. The pathology showed not only TMA lesions but also collapsing glomeruli with crescent-like lesions due to epithelial cell hyperplasia caused by podocyte injury. Given that ramucirumab can cause podocytopathy, which is uncommon in bevacizumab, the change from bevacizumab to ramucirumab should be made carefully. When ramucirumab is used, proteinuria and renal function should be strictly monitored. We also found that proteinuria and serum Cr levels decreased without corticosteroids after ramucirumab treatment was discontinued. Once ramucirumab causes renal involvement, ramucirumab should be discontinued for some time.
Learning points
Compared with other antivascular endothelial growth factor (anti-VEGF) drugs, the pathology of ramucirumab-induced renal failure is still unknown. Only a few reports suggest ramucirumab can present thrombotic microangiopathy, but we found that ramucirumab can also injure podocytes.
Although rare, ramucirumab can cause severe proteinuria and renal dysfunction with just one dose. When used, we must follow-up carefully.
If ramucirumab is a possible causative agent, it should be discontinued. As with other VEGF inhibitors, proteinuria and renal impairment may improve with discontinuation.
Ramucirumab and bevacizumab may have synergistic side effects. Care must be taken when switching between both drugs.
The authors would like to acknowledge Dr Atsuki Ohashi, Dr Eriko Kanehisa and Dr Megumi Yamamuro for their cooperation in medical practice.
Contributors: YN wrote the manuscript with support from HF. JK and KN gave advice about pathological interpretation.
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: Consent obtained from next of kin.
Provenance and peer review: Not commissioned; externally peer reviewed. | BEVACIZUMAB, FLUOROURACIL, IRINOTECAN, LEUCOVORIN, RAMUCIRUMAB | DrugsGivenReaction | CC BY-NC | 33653851 | 19,945,647 | 2021-03-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug interaction'. | A case of ramucirumab-induced renal failure with nephrotic-range proteinuria and its pathological findings.
Ramucirumab-induced renal dysfunction is rarely reported. The pathology of ramucirumab-associated nephropathy in past reports primarily shows thrombotic microangiopathy (TMA) lesions but podocytopathy is not yet known. We report a case of kidney injury induced by ramucirumab in a 71-year-old man with cecal cancer. He was referred to our department for increasing serum creatinine (Cr) levels from 1.08 mg/dL to 2.56 mg/dL after changing anticancer drugs from bevacizumab to ramucirumab. He showed nephrotic-range proteinuria (12.1 g/gCr). A renal biopsy revealed endothelial cell injuries, such as TMA and podocytopathy with epithelial cell hyperplasia, which looked like a crescent. After discontinuing ramucirumab, his renal function and proteinuria improved, as seen by his Cr levels and proteinuria which decreased to 1.74 mg/dL and 1.21 g/gCr, respectively, in 3 months. Unlike previous reports, we found that ramucirumab caused podocyte injuries.
Background
Currently, inhibiting vascular endothelial growth factor (VEGF) signalling is one of the most efficient ways to treat cancers. Ramucirumab is a fully humanised monoclonal antibody targeting VEGF receptor-2 (VEGFR-2) and it inhibits downstream signalling.1 In the last decade, antiangiogenic agents for solid cancers have caused renal dysfunction.2 However, renal dysfunction induced by ramucirumab is rarely reported3 and its specific clinical course is still unknown.
We present the case of a 71-year-old man who had acute kidney injury with nephrotic-range proteinuria after ramucirumab administration. Past reports showed only thrombotic microangiopathy (TMA) in renal pathological changes,3 but his pathological findings suggested ramucirumab induced TMA and podocytopathy, which included a crescent-like lesion.
Case presentation
A 71-year-old man diagnosed with cecal cancer with lymph node metastasis underwent an ileocecal resection and received chemotherapy. He completed his therapy and remained stable for the next few years. When imaging studies showed a progressive disease, he restarted chemotherapy with folinic acid, fluorouracil, irinotecan and bevacizumab. With bevacizumab, he showed proteinuria 3+ in a dipstick test; therefore, he was closely monitored. After a year, because he presented with a progressive disease, bevacizumab was changed to ramucirumab. After 2 weeks, he was admitted to our department because of oedema exacerbation. He had high blood pressure, which was 172/83 mm Hg, although he had already been taking medication for hypertension. His blood pressure was usually controlled at approximately 150/80 mm Hg with an angiotensin II receptor blocker and a calcium channel blocker. His weight was 68 kg, although his usual weight was 61 kg. He showed pitting oedema.
Investigations
The laboratory data (table 1) showed worsening renal function and nephrotic-range proteinuria of 12.1 g/gCr. Serum creatinine (Cr) levels were increased from 1.08 mg/dL to 2.56 mg/dL. Serum albumin decreased from 3.9 g/dL to 3.2 g/dL. The kidney sizes were 108×56 mm (right) and 117×56 mm (left).
Table 1 Blood and Urinary tests are shown
Patient values Reference range Interpretation
Blood test
White cell count 3.6109/L 3.5109–9.1109/L Normal
Haemoglobin 115 g/L 113–152 g/L Normal
Platelet count 90×109/L 130×109–369×109/L Normal
C reactive protein 0.1 mg/dL 0–0.3 mg/dL Normal
Albumin 3.2 g/dL 4–5 g/dL Decreased
Total protein 5.6 g/dL 6.7–8.3 g/dL Decreased
Blood urea nitrogen 32.4 mg/dL 6–20 mg/dL Normal
Creatinine 1.2 mg/dL 0.47–0.79 mg/dL Elevated
LDL cholesterol 126 mg/dL 70–139 mg/dL Normal
Urinary test
Urinary red blood cell 5–9/HPF <1/HPF Elevated
Urinary protein 12.1 g/gCr <0.15 g/gCr Elevated
Bence Jones protein − − Normal
Urinary β2-microglobulin 6777 µg/L 0–259 µg/L Elevated
Selectivity index 0.39 <0.2 (high selectivity) Elevated
HPF, high power field; LDL, low-density lipoproteins.
A kidney biopsy was performed. The renal biopsy specimen contained 18 glomeruli. Two glomeruli showed global sclerosis. The mesangial matrix proliferated in all glomeruli, and the mesangial cells partly proliferated. The glomerular basement membrane showed thickening in all glomeruli, and half of them showed a double contour that circumscribed fibrin such as an eosinophilic substance (figure 1A, B). TMA caused these changes. No spike formation was detected. Four glomeruli were collapsed with epithelial cell hyperplasia which looks like a crescent lesion (figure 2A, B). These changes were similar to collapsing glomeruli with a ‘pseudocrescent’,4 which suggested podocytopathy. Immunofluorescence studies indicated positive staining of the glomerular capillaries and mesangium for C3, C4 and C1q. A part of the mesangium was also positive for IgG, IgM and IgA. Electron microscopy revealed endothelial cell hyperplasia and non-specific dense substances around the mesangium. Some of the foot processes vanished, but no podocytes were detached. Tubular atrophy and interstitial fibrosis were observed in approximately half of the total area.
Figure 1 The glomerular basement membrane showed thickening in all glomeruli, and half of them showed a double contour with fibrinous exudates. (A): H&E stain, (B): Periodic acid-methenamine silver stain).
Figure 2 Glomeruli with epithelial cell hyperplasia, which looks like a ‘crescent’, show capillary wall collapse. (A, B: Periodic acid-methenamine silver stain).
Differential diagnosis
We considered the effect of bevacizumab, which is an anti-VEGF-A drug. In this case, several injections of bevacizumab already caused proteinuria. Bevacizumab may have damaged endothelial cells in the glomeruli. However, it was clear that ramucirumab was a key drug because renal failure and pitting oedema had not been shown before its administration.
It is known that bevacizumab mainly causes TMA.5 His pathology showed not only TMA but also glomerular collapse with a crescent-like lesion. This also suggested that the renal dysfunction could not be explained only by bevacizumab.
Treatment
We discontinued ramucirumab and continued an angiotensin II receptor blocker to reduce proteinuria. We did not use immune therapies such as corticosteroids.
Outcome and follow-up
After discontinuation of ramucirumab, the serum Cr gradually decreased to 1.79 mg/dL, and proteinuria also decreased to 3.21 g/gCr 3 months later (figure 3). Proteinuria decreased to 1.21 g/gCr about 7 months later.
Figure 3 There was an improvement with the discontinuation of the medication, but some renal impairment remained.
Discussion
Many anticancer drugs have been developed to inhibit VEGF signalling because it plays a vital role in controlling neovascular processes in neoplasms.2 In the kidney, podocytes and endothelial cells are significant sources of VEGF. It acts in autocrine and paracrine fashions and contributes to maintaining homeostasis.6 The VEGF receptor family, which is a tyrosine kinase receptor, consists of three subtypes: VEGFR-1, VEGFR-2 and VEGFR-3. Among them, VEGFR-2 is predominantly expressed in podocytes, mesangium, endothelial cells and tubular capillaries.5 6 Ramucirumab is a VEGFR-2 binding monoclonal antibody that has been widely used for gastric, lung and colorectal cancer as a second-line therapy.1 A previous study showed adverse renal effects of ramucirumab involving hypertension (21%) and proteinuria (9%).7 Although other VEGF inhibitory drugs, such as the anti-VEGF monoclonal body (bevacizumab), tyrosine kinase inhibitors (sunitinib, axitinib, sorafenib and cediranib) and VEGF-Trap (aflibercept) have been known to cause nephrotic-range proteinuria and renal dysfunction, ramucirumab has been reported in only one case report8 and one single-centre case report.3
Anti-VEGF/VEGFR therapy reportedly accounts for two primary forms of renal pathological changes: minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS), which suggests podocytopathy, and TMA, which suggests endothelial cell injury.5 There is a different tendency for TMA or MCD/FSGS to occur depending on the type of anti-VEGF/VEGFR drug. For example, it is well known that VEGFR is abundant in endothelial cells and inhibition of VEGFR–VEGF crosstalk by anti-VEGF drugs, such as bevacizumab cause TMA.5 On the other hand, VEGFR tyrosine kinase inhibitors (RTKI) cause MCD/FSGS more often than TMA. Previous studies suggested that RTKI inhibits NF-κB activity, leading to c-mip overexpression, and induces MCD or FSGS.5 In two previous studies on ramucirumab-induced nephropathy, three cases of renal pathology were reported3 8 and all of them were reported as TMA. The development of renal impairment characterised the three previous cases after switching from bevacizumab to ramucirumab, as in this case. It is possible that TMA could be caused or exacerbated due to endothelial damage caused by ramucirumab because it is known that the interaction of VEGF with VEGFR-2 is necessary to maintain endothelial cells.9 Since double contours of the glomerular basement membrane were chronic lesions of TMA10 and bevacizumab was administered before ramucirumab, the effect of bevacizumab on TMA could not be ignored. Compared with previous reports, we think this case is characterised by collapsing glomeruli with epithelial cell hyperplasia. A previous report showed that collapsing glomeruli with ‘pseudocrescents’ are caused by podocyte damage.4 The clinical course of marked nephrotic-range proteinuria is also consistent with podocytopathy rather than TMA. A previous study showed that VEGFR-2 is also expressed in podocytes in vivo and that VEGF and VEGFR-2, through autocrine actions, regulate podocyte survival.11 Bertuccio et al12 demonstrated a direct interaction between VEGFR-2 and nephrin in vitro and proposed VEGF signalling via the VEGFR-2–nephrin complex has an essential role in podocyte foot process effacement.
Moreover, ramucirumab inhibits the start of VEGFR-2 signalling, which is the target of RTKI,7 so ramucirumab would cause podocytopathy in the same way as RTKI. These findings suggest that VEGFR-2 plays an important role in podocytes. As mentioned above, renal injury occurred in the three previously reported cases as well as in this case after switching from bevacizumab therapy and this suggests the synergistic effect of ramucirumab and bevacizumab. Müller-Deile et al6 showed that VEGF-A and VEGF-C both interact with VEGFR-2 and play important roles in podocyte survival. They showed that when VEGF-A is inhibited by bevacizumab, VEGF-C plays an important role in suppressing podocyte apoptosis. Another study showed that when bevacizumab inhibits VEGF-A, VEGF-C maintains VEGFR-2 activation in glioblastomas.13 In our case, ramucirumab was considered to have inhibited the interaction between VEGFR-2 and VEGF-C, and this may have resulted in a synergistic effect. The pathology of this case suggests that the presence of chronic TMA caused by bevacizumab may have been combined with podocyte damage from ramucirumab, leading to severe damage to the kidney. This case suggests that VEGFR-2 plays an essential role in the maintenance of podocytes as well as endothelial cells.
We report a rare case of ramucirumab-induced severe proteinuria and renal dysfunction with just one dose. The pathology showed not only TMA lesions but also collapsing glomeruli with crescent-like lesions due to epithelial cell hyperplasia caused by podocyte injury. Given that ramucirumab can cause podocytopathy, which is uncommon in bevacizumab, the change from bevacizumab to ramucirumab should be made carefully. When ramucirumab is used, proteinuria and renal function should be strictly monitored. We also found that proteinuria and serum Cr levels decreased without corticosteroids after ramucirumab treatment was discontinued. Once ramucirumab causes renal involvement, ramucirumab should be discontinued for some time.
Learning points
Compared with other antivascular endothelial growth factor (anti-VEGF) drugs, the pathology of ramucirumab-induced renal failure is still unknown. Only a few reports suggest ramucirumab can present thrombotic microangiopathy, but we found that ramucirumab can also injure podocytes.
Although rare, ramucirumab can cause severe proteinuria and renal dysfunction with just one dose. When used, we must follow-up carefully.
If ramucirumab is a possible causative agent, it should be discontinued. As with other VEGF inhibitors, proteinuria and renal impairment may improve with discontinuation.
Ramucirumab and bevacizumab may have synergistic side effects. Care must be taken when switching between both drugs.
The authors would like to acknowledge Dr Atsuki Ohashi, Dr Eriko Kanehisa and Dr Megumi Yamamuro for their cooperation in medical practice.
Contributors: YN wrote the manuscript with support from HF. JK and KN gave advice about pathological interpretation.
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: Consent obtained from next of kin.
Provenance and peer review: Not commissioned; externally peer reviewed. | BEVACIZUMAB, FLUOROURACIL, IRINOTECAN, LEUCOVORIN, RAMUCIRUMAB | DrugsGivenReaction | CC BY-NC | 33653851 | 19,945,647 | 2021-03-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Proteinuria'. | A case of ramucirumab-induced renal failure with nephrotic-range proteinuria and its pathological findings.
Ramucirumab-induced renal dysfunction is rarely reported. The pathology of ramucirumab-associated nephropathy in past reports primarily shows thrombotic microangiopathy (TMA) lesions but podocytopathy is not yet known. We report a case of kidney injury induced by ramucirumab in a 71-year-old man with cecal cancer. He was referred to our department for increasing serum creatinine (Cr) levels from 1.08 mg/dL to 2.56 mg/dL after changing anticancer drugs from bevacizumab to ramucirumab. He showed nephrotic-range proteinuria (12.1 g/gCr). A renal biopsy revealed endothelial cell injuries, such as TMA and podocytopathy with epithelial cell hyperplasia, which looked like a crescent. After discontinuing ramucirumab, his renal function and proteinuria improved, as seen by his Cr levels and proteinuria which decreased to 1.74 mg/dL and 1.21 g/gCr, respectively, in 3 months. Unlike previous reports, we found that ramucirumab caused podocyte injuries.
Background
Currently, inhibiting vascular endothelial growth factor (VEGF) signalling is one of the most efficient ways to treat cancers. Ramucirumab is a fully humanised monoclonal antibody targeting VEGF receptor-2 (VEGFR-2) and it inhibits downstream signalling.1 In the last decade, antiangiogenic agents for solid cancers have caused renal dysfunction.2 However, renal dysfunction induced by ramucirumab is rarely reported3 and its specific clinical course is still unknown.
We present the case of a 71-year-old man who had acute kidney injury with nephrotic-range proteinuria after ramucirumab administration. Past reports showed only thrombotic microangiopathy (TMA) in renal pathological changes,3 but his pathological findings suggested ramucirumab induced TMA and podocytopathy, which included a crescent-like lesion.
Case presentation
A 71-year-old man diagnosed with cecal cancer with lymph node metastasis underwent an ileocecal resection and received chemotherapy. He completed his therapy and remained stable for the next few years. When imaging studies showed a progressive disease, he restarted chemotherapy with folinic acid, fluorouracil, irinotecan and bevacizumab. With bevacizumab, he showed proteinuria 3+ in a dipstick test; therefore, he was closely monitored. After a year, because he presented with a progressive disease, bevacizumab was changed to ramucirumab. After 2 weeks, he was admitted to our department because of oedema exacerbation. He had high blood pressure, which was 172/83 mm Hg, although he had already been taking medication for hypertension. His blood pressure was usually controlled at approximately 150/80 mm Hg with an angiotensin II receptor blocker and a calcium channel blocker. His weight was 68 kg, although his usual weight was 61 kg. He showed pitting oedema.
Investigations
The laboratory data (table 1) showed worsening renal function and nephrotic-range proteinuria of 12.1 g/gCr. Serum creatinine (Cr) levels were increased from 1.08 mg/dL to 2.56 mg/dL. Serum albumin decreased from 3.9 g/dL to 3.2 g/dL. The kidney sizes were 108×56 mm (right) and 117×56 mm (left).
Table 1 Blood and Urinary tests are shown
Patient values Reference range Interpretation
Blood test
White cell count 3.6109/L 3.5109–9.1109/L Normal
Haemoglobin 115 g/L 113–152 g/L Normal
Platelet count 90×109/L 130×109–369×109/L Normal
C reactive protein 0.1 mg/dL 0–0.3 mg/dL Normal
Albumin 3.2 g/dL 4–5 g/dL Decreased
Total protein 5.6 g/dL 6.7–8.3 g/dL Decreased
Blood urea nitrogen 32.4 mg/dL 6–20 mg/dL Normal
Creatinine 1.2 mg/dL 0.47–0.79 mg/dL Elevated
LDL cholesterol 126 mg/dL 70–139 mg/dL Normal
Urinary test
Urinary red blood cell 5–9/HPF <1/HPF Elevated
Urinary protein 12.1 g/gCr <0.15 g/gCr Elevated
Bence Jones protein − − Normal
Urinary β2-microglobulin 6777 µg/L 0–259 µg/L Elevated
Selectivity index 0.39 <0.2 (high selectivity) Elevated
HPF, high power field; LDL, low-density lipoproteins.
A kidney biopsy was performed. The renal biopsy specimen contained 18 glomeruli. Two glomeruli showed global sclerosis. The mesangial matrix proliferated in all glomeruli, and the mesangial cells partly proliferated. The glomerular basement membrane showed thickening in all glomeruli, and half of them showed a double contour that circumscribed fibrin such as an eosinophilic substance (figure 1A, B). TMA caused these changes. No spike formation was detected. Four glomeruli were collapsed with epithelial cell hyperplasia which looks like a crescent lesion (figure 2A, B). These changes were similar to collapsing glomeruli with a ‘pseudocrescent’,4 which suggested podocytopathy. Immunofluorescence studies indicated positive staining of the glomerular capillaries and mesangium for C3, C4 and C1q. A part of the mesangium was also positive for IgG, IgM and IgA. Electron microscopy revealed endothelial cell hyperplasia and non-specific dense substances around the mesangium. Some of the foot processes vanished, but no podocytes were detached. Tubular atrophy and interstitial fibrosis were observed in approximately half of the total area.
Figure 1 The glomerular basement membrane showed thickening in all glomeruli, and half of them showed a double contour with fibrinous exudates. (A): H&E stain, (B): Periodic acid-methenamine silver stain).
Figure 2 Glomeruli with epithelial cell hyperplasia, which looks like a ‘crescent’, show capillary wall collapse. (A, B: Periodic acid-methenamine silver stain).
Differential diagnosis
We considered the effect of bevacizumab, which is an anti-VEGF-A drug. In this case, several injections of bevacizumab already caused proteinuria. Bevacizumab may have damaged endothelial cells in the glomeruli. However, it was clear that ramucirumab was a key drug because renal failure and pitting oedema had not been shown before its administration.
It is known that bevacizumab mainly causes TMA.5 His pathology showed not only TMA but also glomerular collapse with a crescent-like lesion. This also suggested that the renal dysfunction could not be explained only by bevacizumab.
Treatment
We discontinued ramucirumab and continued an angiotensin II receptor blocker to reduce proteinuria. We did not use immune therapies such as corticosteroids.
Outcome and follow-up
After discontinuation of ramucirumab, the serum Cr gradually decreased to 1.79 mg/dL, and proteinuria also decreased to 3.21 g/gCr 3 months later (figure 3). Proteinuria decreased to 1.21 g/gCr about 7 months later.
Figure 3 There was an improvement with the discontinuation of the medication, but some renal impairment remained.
Discussion
Many anticancer drugs have been developed to inhibit VEGF signalling because it plays a vital role in controlling neovascular processes in neoplasms.2 In the kidney, podocytes and endothelial cells are significant sources of VEGF. It acts in autocrine and paracrine fashions and contributes to maintaining homeostasis.6 The VEGF receptor family, which is a tyrosine kinase receptor, consists of three subtypes: VEGFR-1, VEGFR-2 and VEGFR-3. Among them, VEGFR-2 is predominantly expressed in podocytes, mesangium, endothelial cells and tubular capillaries.5 6 Ramucirumab is a VEGFR-2 binding monoclonal antibody that has been widely used for gastric, lung and colorectal cancer as a second-line therapy.1 A previous study showed adverse renal effects of ramucirumab involving hypertension (21%) and proteinuria (9%).7 Although other VEGF inhibitory drugs, such as the anti-VEGF monoclonal body (bevacizumab), tyrosine kinase inhibitors (sunitinib, axitinib, sorafenib and cediranib) and VEGF-Trap (aflibercept) have been known to cause nephrotic-range proteinuria and renal dysfunction, ramucirumab has been reported in only one case report8 and one single-centre case report.3
Anti-VEGF/VEGFR therapy reportedly accounts for two primary forms of renal pathological changes: minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS), which suggests podocytopathy, and TMA, which suggests endothelial cell injury.5 There is a different tendency for TMA or MCD/FSGS to occur depending on the type of anti-VEGF/VEGFR drug. For example, it is well known that VEGFR is abundant in endothelial cells and inhibition of VEGFR–VEGF crosstalk by anti-VEGF drugs, such as bevacizumab cause TMA.5 On the other hand, VEGFR tyrosine kinase inhibitors (RTKI) cause MCD/FSGS more often than TMA. Previous studies suggested that RTKI inhibits NF-κB activity, leading to c-mip overexpression, and induces MCD or FSGS.5 In two previous studies on ramucirumab-induced nephropathy, three cases of renal pathology were reported3 8 and all of them were reported as TMA. The development of renal impairment characterised the three previous cases after switching from bevacizumab to ramucirumab, as in this case. It is possible that TMA could be caused or exacerbated due to endothelial damage caused by ramucirumab because it is known that the interaction of VEGF with VEGFR-2 is necessary to maintain endothelial cells.9 Since double contours of the glomerular basement membrane were chronic lesions of TMA10 and bevacizumab was administered before ramucirumab, the effect of bevacizumab on TMA could not be ignored. Compared with previous reports, we think this case is characterised by collapsing glomeruli with epithelial cell hyperplasia. A previous report showed that collapsing glomeruli with ‘pseudocrescents’ are caused by podocyte damage.4 The clinical course of marked nephrotic-range proteinuria is also consistent with podocytopathy rather than TMA. A previous study showed that VEGFR-2 is also expressed in podocytes in vivo and that VEGF and VEGFR-2, through autocrine actions, regulate podocyte survival.11 Bertuccio et al12 demonstrated a direct interaction between VEGFR-2 and nephrin in vitro and proposed VEGF signalling via the VEGFR-2–nephrin complex has an essential role in podocyte foot process effacement.
Moreover, ramucirumab inhibits the start of VEGFR-2 signalling, which is the target of RTKI,7 so ramucirumab would cause podocytopathy in the same way as RTKI. These findings suggest that VEGFR-2 plays an important role in podocytes. As mentioned above, renal injury occurred in the three previously reported cases as well as in this case after switching from bevacizumab therapy and this suggests the synergistic effect of ramucirumab and bevacizumab. Müller-Deile et al6 showed that VEGF-A and VEGF-C both interact with VEGFR-2 and play important roles in podocyte survival. They showed that when VEGF-A is inhibited by bevacizumab, VEGF-C plays an important role in suppressing podocyte apoptosis. Another study showed that when bevacizumab inhibits VEGF-A, VEGF-C maintains VEGFR-2 activation in glioblastomas.13 In our case, ramucirumab was considered to have inhibited the interaction between VEGFR-2 and VEGF-C, and this may have resulted in a synergistic effect. The pathology of this case suggests that the presence of chronic TMA caused by bevacizumab may have been combined with podocyte damage from ramucirumab, leading to severe damage to the kidney. This case suggests that VEGFR-2 plays an essential role in the maintenance of podocytes as well as endothelial cells.
We report a rare case of ramucirumab-induced severe proteinuria and renal dysfunction with just one dose. The pathology showed not only TMA lesions but also collapsing glomeruli with crescent-like lesions due to epithelial cell hyperplasia caused by podocyte injury. Given that ramucirumab can cause podocytopathy, which is uncommon in bevacizumab, the change from bevacizumab to ramucirumab should be made carefully. When ramucirumab is used, proteinuria and renal function should be strictly monitored. We also found that proteinuria and serum Cr levels decreased without corticosteroids after ramucirumab treatment was discontinued. Once ramucirumab causes renal involvement, ramucirumab should be discontinued for some time.
Learning points
Compared with other antivascular endothelial growth factor (anti-VEGF) drugs, the pathology of ramucirumab-induced renal failure is still unknown. Only a few reports suggest ramucirumab can present thrombotic microangiopathy, but we found that ramucirumab can also injure podocytes.
Although rare, ramucirumab can cause severe proteinuria and renal dysfunction with just one dose. When used, we must follow-up carefully.
If ramucirumab is a possible causative agent, it should be discontinued. As with other VEGF inhibitors, proteinuria and renal impairment may improve with discontinuation.
Ramucirumab and bevacizumab may have synergistic side effects. Care must be taken when switching between both drugs.
The authors would like to acknowledge Dr Atsuki Ohashi, Dr Eriko Kanehisa and Dr Megumi Yamamuro for their cooperation in medical practice.
Contributors: YN wrote the manuscript with support from HF. JK and KN gave advice about pathological interpretation.
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: Consent obtained from next of kin.
Provenance and peer review: Not commissioned; externally peer reviewed. | BEVACIZUMAB, FLUOROURACIL, IRINOTECAN, LEUCOVORIN, RAMUCIRUMAB | DrugsGivenReaction | CC BY-NC | 33653851 | 19,945,647 | 2021-03-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Thrombotic microangiopathy'. | A case of ramucirumab-induced renal failure with nephrotic-range proteinuria and its pathological findings.
Ramucirumab-induced renal dysfunction is rarely reported. The pathology of ramucirumab-associated nephropathy in past reports primarily shows thrombotic microangiopathy (TMA) lesions but podocytopathy is not yet known. We report a case of kidney injury induced by ramucirumab in a 71-year-old man with cecal cancer. He was referred to our department for increasing serum creatinine (Cr) levels from 1.08 mg/dL to 2.56 mg/dL after changing anticancer drugs from bevacizumab to ramucirumab. He showed nephrotic-range proteinuria (12.1 g/gCr). A renal biopsy revealed endothelial cell injuries, such as TMA and podocytopathy with epithelial cell hyperplasia, which looked like a crescent. After discontinuing ramucirumab, his renal function and proteinuria improved, as seen by his Cr levels and proteinuria which decreased to 1.74 mg/dL and 1.21 g/gCr, respectively, in 3 months. Unlike previous reports, we found that ramucirumab caused podocyte injuries.
Background
Currently, inhibiting vascular endothelial growth factor (VEGF) signalling is one of the most efficient ways to treat cancers. Ramucirumab is a fully humanised monoclonal antibody targeting VEGF receptor-2 (VEGFR-2) and it inhibits downstream signalling.1 In the last decade, antiangiogenic agents for solid cancers have caused renal dysfunction.2 However, renal dysfunction induced by ramucirumab is rarely reported3 and its specific clinical course is still unknown.
We present the case of a 71-year-old man who had acute kidney injury with nephrotic-range proteinuria after ramucirumab administration. Past reports showed only thrombotic microangiopathy (TMA) in renal pathological changes,3 but his pathological findings suggested ramucirumab induced TMA and podocytopathy, which included a crescent-like lesion.
Case presentation
A 71-year-old man diagnosed with cecal cancer with lymph node metastasis underwent an ileocecal resection and received chemotherapy. He completed his therapy and remained stable for the next few years. When imaging studies showed a progressive disease, he restarted chemotherapy with folinic acid, fluorouracil, irinotecan and bevacizumab. With bevacizumab, he showed proteinuria 3+ in a dipstick test; therefore, he was closely monitored. After a year, because he presented with a progressive disease, bevacizumab was changed to ramucirumab. After 2 weeks, he was admitted to our department because of oedema exacerbation. He had high blood pressure, which was 172/83 mm Hg, although he had already been taking medication for hypertension. His blood pressure was usually controlled at approximately 150/80 mm Hg with an angiotensin II receptor blocker and a calcium channel blocker. His weight was 68 kg, although his usual weight was 61 kg. He showed pitting oedema.
Investigations
The laboratory data (table 1) showed worsening renal function and nephrotic-range proteinuria of 12.1 g/gCr. Serum creatinine (Cr) levels were increased from 1.08 mg/dL to 2.56 mg/dL. Serum albumin decreased from 3.9 g/dL to 3.2 g/dL. The kidney sizes were 108×56 mm (right) and 117×56 mm (left).
Table 1 Blood and Urinary tests are shown
Patient values Reference range Interpretation
Blood test
White cell count 3.6109/L 3.5109–9.1109/L Normal
Haemoglobin 115 g/L 113–152 g/L Normal
Platelet count 90×109/L 130×109–369×109/L Normal
C reactive protein 0.1 mg/dL 0–0.3 mg/dL Normal
Albumin 3.2 g/dL 4–5 g/dL Decreased
Total protein 5.6 g/dL 6.7–8.3 g/dL Decreased
Blood urea nitrogen 32.4 mg/dL 6–20 mg/dL Normal
Creatinine 1.2 mg/dL 0.47–0.79 mg/dL Elevated
LDL cholesterol 126 mg/dL 70–139 mg/dL Normal
Urinary test
Urinary red blood cell 5–9/HPF <1/HPF Elevated
Urinary protein 12.1 g/gCr <0.15 g/gCr Elevated
Bence Jones protein − − Normal
Urinary β2-microglobulin 6777 µg/L 0–259 µg/L Elevated
Selectivity index 0.39 <0.2 (high selectivity) Elevated
HPF, high power field; LDL, low-density lipoproteins.
A kidney biopsy was performed. The renal biopsy specimen contained 18 glomeruli. Two glomeruli showed global sclerosis. The mesangial matrix proliferated in all glomeruli, and the mesangial cells partly proliferated. The glomerular basement membrane showed thickening in all glomeruli, and half of them showed a double contour that circumscribed fibrin such as an eosinophilic substance (figure 1A, B). TMA caused these changes. No spike formation was detected. Four glomeruli were collapsed with epithelial cell hyperplasia which looks like a crescent lesion (figure 2A, B). These changes were similar to collapsing glomeruli with a ‘pseudocrescent’,4 which suggested podocytopathy. Immunofluorescence studies indicated positive staining of the glomerular capillaries and mesangium for C3, C4 and C1q. A part of the mesangium was also positive for IgG, IgM and IgA. Electron microscopy revealed endothelial cell hyperplasia and non-specific dense substances around the mesangium. Some of the foot processes vanished, but no podocytes were detached. Tubular atrophy and interstitial fibrosis were observed in approximately half of the total area.
Figure 1 The glomerular basement membrane showed thickening in all glomeruli, and half of them showed a double contour with fibrinous exudates. (A): H&E stain, (B): Periodic acid-methenamine silver stain).
Figure 2 Glomeruli with epithelial cell hyperplasia, which looks like a ‘crescent’, show capillary wall collapse. (A, B: Periodic acid-methenamine silver stain).
Differential diagnosis
We considered the effect of bevacizumab, which is an anti-VEGF-A drug. In this case, several injections of bevacizumab already caused proteinuria. Bevacizumab may have damaged endothelial cells in the glomeruli. However, it was clear that ramucirumab was a key drug because renal failure and pitting oedema had not been shown before its administration.
It is known that bevacizumab mainly causes TMA.5 His pathology showed not only TMA but also glomerular collapse with a crescent-like lesion. This also suggested that the renal dysfunction could not be explained only by bevacizumab.
Treatment
We discontinued ramucirumab and continued an angiotensin II receptor blocker to reduce proteinuria. We did not use immune therapies such as corticosteroids.
Outcome and follow-up
After discontinuation of ramucirumab, the serum Cr gradually decreased to 1.79 mg/dL, and proteinuria also decreased to 3.21 g/gCr 3 months later (figure 3). Proteinuria decreased to 1.21 g/gCr about 7 months later.
Figure 3 There was an improvement with the discontinuation of the medication, but some renal impairment remained.
Discussion
Many anticancer drugs have been developed to inhibit VEGF signalling because it plays a vital role in controlling neovascular processes in neoplasms.2 In the kidney, podocytes and endothelial cells are significant sources of VEGF. It acts in autocrine and paracrine fashions and contributes to maintaining homeostasis.6 The VEGF receptor family, which is a tyrosine kinase receptor, consists of three subtypes: VEGFR-1, VEGFR-2 and VEGFR-3. Among them, VEGFR-2 is predominantly expressed in podocytes, mesangium, endothelial cells and tubular capillaries.5 6 Ramucirumab is a VEGFR-2 binding monoclonal antibody that has been widely used for gastric, lung and colorectal cancer as a second-line therapy.1 A previous study showed adverse renal effects of ramucirumab involving hypertension (21%) and proteinuria (9%).7 Although other VEGF inhibitory drugs, such as the anti-VEGF monoclonal body (bevacizumab), tyrosine kinase inhibitors (sunitinib, axitinib, sorafenib and cediranib) and VEGF-Trap (aflibercept) have been known to cause nephrotic-range proteinuria and renal dysfunction, ramucirumab has been reported in only one case report8 and one single-centre case report.3
Anti-VEGF/VEGFR therapy reportedly accounts for two primary forms of renal pathological changes: minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS), which suggests podocytopathy, and TMA, which suggests endothelial cell injury.5 There is a different tendency for TMA or MCD/FSGS to occur depending on the type of anti-VEGF/VEGFR drug. For example, it is well known that VEGFR is abundant in endothelial cells and inhibition of VEGFR–VEGF crosstalk by anti-VEGF drugs, such as bevacizumab cause TMA.5 On the other hand, VEGFR tyrosine kinase inhibitors (RTKI) cause MCD/FSGS more often than TMA. Previous studies suggested that RTKI inhibits NF-κB activity, leading to c-mip overexpression, and induces MCD or FSGS.5 In two previous studies on ramucirumab-induced nephropathy, three cases of renal pathology were reported3 8 and all of them were reported as TMA. The development of renal impairment characterised the three previous cases after switching from bevacizumab to ramucirumab, as in this case. It is possible that TMA could be caused or exacerbated due to endothelial damage caused by ramucirumab because it is known that the interaction of VEGF with VEGFR-2 is necessary to maintain endothelial cells.9 Since double contours of the glomerular basement membrane were chronic lesions of TMA10 and bevacizumab was administered before ramucirumab, the effect of bevacizumab on TMA could not be ignored. Compared with previous reports, we think this case is characterised by collapsing glomeruli with epithelial cell hyperplasia. A previous report showed that collapsing glomeruli with ‘pseudocrescents’ are caused by podocyte damage.4 The clinical course of marked nephrotic-range proteinuria is also consistent with podocytopathy rather than TMA. A previous study showed that VEGFR-2 is also expressed in podocytes in vivo and that VEGF and VEGFR-2, through autocrine actions, regulate podocyte survival.11 Bertuccio et al12 demonstrated a direct interaction between VEGFR-2 and nephrin in vitro and proposed VEGF signalling via the VEGFR-2–nephrin complex has an essential role in podocyte foot process effacement.
Moreover, ramucirumab inhibits the start of VEGFR-2 signalling, which is the target of RTKI,7 so ramucirumab would cause podocytopathy in the same way as RTKI. These findings suggest that VEGFR-2 plays an important role in podocytes. As mentioned above, renal injury occurred in the three previously reported cases as well as in this case after switching from bevacizumab therapy and this suggests the synergistic effect of ramucirumab and bevacizumab. Müller-Deile et al6 showed that VEGF-A and VEGF-C both interact with VEGFR-2 and play important roles in podocyte survival. They showed that when VEGF-A is inhibited by bevacizumab, VEGF-C plays an important role in suppressing podocyte apoptosis. Another study showed that when bevacizumab inhibits VEGF-A, VEGF-C maintains VEGFR-2 activation in glioblastomas.13 In our case, ramucirumab was considered to have inhibited the interaction between VEGFR-2 and VEGF-C, and this may have resulted in a synergistic effect. The pathology of this case suggests that the presence of chronic TMA caused by bevacizumab may have been combined with podocyte damage from ramucirumab, leading to severe damage to the kidney. This case suggests that VEGFR-2 plays an essential role in the maintenance of podocytes as well as endothelial cells.
We report a rare case of ramucirumab-induced severe proteinuria and renal dysfunction with just one dose. The pathology showed not only TMA lesions but also collapsing glomeruli with crescent-like lesions due to epithelial cell hyperplasia caused by podocyte injury. Given that ramucirumab can cause podocytopathy, which is uncommon in bevacizumab, the change from bevacizumab to ramucirumab should be made carefully. When ramucirumab is used, proteinuria and renal function should be strictly monitored. We also found that proteinuria and serum Cr levels decreased without corticosteroids after ramucirumab treatment was discontinued. Once ramucirumab causes renal involvement, ramucirumab should be discontinued for some time.
Learning points
Compared with other antivascular endothelial growth factor (anti-VEGF) drugs, the pathology of ramucirumab-induced renal failure is still unknown. Only a few reports suggest ramucirumab can present thrombotic microangiopathy, but we found that ramucirumab can also injure podocytes.
Although rare, ramucirumab can cause severe proteinuria and renal dysfunction with just one dose. When used, we must follow-up carefully.
If ramucirumab is a possible causative agent, it should be discontinued. As with other VEGF inhibitors, proteinuria and renal impairment may improve with discontinuation.
Ramucirumab and bevacizumab may have synergistic side effects. Care must be taken when switching between both drugs.
The authors would like to acknowledge Dr Atsuki Ohashi, Dr Eriko Kanehisa and Dr Megumi Yamamuro for their cooperation in medical practice.
Contributors: YN wrote the manuscript with support from HF. JK and KN gave advice about pathological interpretation.
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: Consent obtained from next of kin.
Provenance and peer review: Not commissioned; externally peer reviewed. | BEVACIZUMAB, FLUOROURACIL, IRINOTECAN, LEUCOVORIN, RAMUCIRUMAB | DrugsGivenReaction | CC BY-NC | 33653851 | 19,945,647 | 2021-03-02 |
What is the weight of the patient? | A case of ramucirumab-induced renal failure with nephrotic-range proteinuria and its pathological findings.
Ramucirumab-induced renal dysfunction is rarely reported. The pathology of ramucirumab-associated nephropathy in past reports primarily shows thrombotic microangiopathy (TMA) lesions but podocytopathy is not yet known. We report a case of kidney injury induced by ramucirumab in a 71-year-old man with cecal cancer. He was referred to our department for increasing serum creatinine (Cr) levels from 1.08 mg/dL to 2.56 mg/dL after changing anticancer drugs from bevacizumab to ramucirumab. He showed nephrotic-range proteinuria (12.1 g/gCr). A renal biopsy revealed endothelial cell injuries, such as TMA and podocytopathy with epithelial cell hyperplasia, which looked like a crescent. After discontinuing ramucirumab, his renal function and proteinuria improved, as seen by his Cr levels and proteinuria which decreased to 1.74 mg/dL and 1.21 g/gCr, respectively, in 3 months. Unlike previous reports, we found that ramucirumab caused podocyte injuries.
Background
Currently, inhibiting vascular endothelial growth factor (VEGF) signalling is one of the most efficient ways to treat cancers. Ramucirumab is a fully humanised monoclonal antibody targeting VEGF receptor-2 (VEGFR-2) and it inhibits downstream signalling.1 In the last decade, antiangiogenic agents for solid cancers have caused renal dysfunction.2 However, renal dysfunction induced by ramucirumab is rarely reported3 and its specific clinical course is still unknown.
We present the case of a 71-year-old man who had acute kidney injury with nephrotic-range proteinuria after ramucirumab administration. Past reports showed only thrombotic microangiopathy (TMA) in renal pathological changes,3 but his pathological findings suggested ramucirumab induced TMA and podocytopathy, which included a crescent-like lesion.
Case presentation
A 71-year-old man diagnosed with cecal cancer with lymph node metastasis underwent an ileocecal resection and received chemotherapy. He completed his therapy and remained stable for the next few years. When imaging studies showed a progressive disease, he restarted chemotherapy with folinic acid, fluorouracil, irinotecan and bevacizumab. With bevacizumab, he showed proteinuria 3+ in a dipstick test; therefore, he was closely monitored. After a year, because he presented with a progressive disease, bevacizumab was changed to ramucirumab. After 2 weeks, he was admitted to our department because of oedema exacerbation. He had high blood pressure, which was 172/83 mm Hg, although he had already been taking medication for hypertension. His blood pressure was usually controlled at approximately 150/80 mm Hg with an angiotensin II receptor blocker and a calcium channel blocker. His weight was 68 kg, although his usual weight was 61 kg. He showed pitting oedema.
Investigations
The laboratory data (table 1) showed worsening renal function and nephrotic-range proteinuria of 12.1 g/gCr. Serum creatinine (Cr) levels were increased from 1.08 mg/dL to 2.56 mg/dL. Serum albumin decreased from 3.9 g/dL to 3.2 g/dL. The kidney sizes were 108×56 mm (right) and 117×56 mm (left).
Table 1 Blood and Urinary tests are shown
Patient values Reference range Interpretation
Blood test
White cell count 3.6109/L 3.5109–9.1109/L Normal
Haemoglobin 115 g/L 113–152 g/L Normal
Platelet count 90×109/L 130×109–369×109/L Normal
C reactive protein 0.1 mg/dL 0–0.3 mg/dL Normal
Albumin 3.2 g/dL 4–5 g/dL Decreased
Total protein 5.6 g/dL 6.7–8.3 g/dL Decreased
Blood urea nitrogen 32.4 mg/dL 6–20 mg/dL Normal
Creatinine 1.2 mg/dL 0.47–0.79 mg/dL Elevated
LDL cholesterol 126 mg/dL 70–139 mg/dL Normal
Urinary test
Urinary red blood cell 5–9/HPF <1/HPF Elevated
Urinary protein 12.1 g/gCr <0.15 g/gCr Elevated
Bence Jones protein − − Normal
Urinary β2-microglobulin 6777 µg/L 0–259 µg/L Elevated
Selectivity index 0.39 <0.2 (high selectivity) Elevated
HPF, high power field; LDL, low-density lipoproteins.
A kidney biopsy was performed. The renal biopsy specimen contained 18 glomeruli. Two glomeruli showed global sclerosis. The mesangial matrix proliferated in all glomeruli, and the mesangial cells partly proliferated. The glomerular basement membrane showed thickening in all glomeruli, and half of them showed a double contour that circumscribed fibrin such as an eosinophilic substance (figure 1A, B). TMA caused these changes. No spike formation was detected. Four glomeruli were collapsed with epithelial cell hyperplasia which looks like a crescent lesion (figure 2A, B). These changes were similar to collapsing glomeruli with a ‘pseudocrescent’,4 which suggested podocytopathy. Immunofluorescence studies indicated positive staining of the glomerular capillaries and mesangium for C3, C4 and C1q. A part of the mesangium was also positive for IgG, IgM and IgA. Electron microscopy revealed endothelial cell hyperplasia and non-specific dense substances around the mesangium. Some of the foot processes vanished, but no podocytes were detached. Tubular atrophy and interstitial fibrosis were observed in approximately half of the total area.
Figure 1 The glomerular basement membrane showed thickening in all glomeruli, and half of them showed a double contour with fibrinous exudates. (A): H&E stain, (B): Periodic acid-methenamine silver stain).
Figure 2 Glomeruli with epithelial cell hyperplasia, which looks like a ‘crescent’, show capillary wall collapse. (A, B: Periodic acid-methenamine silver stain).
Differential diagnosis
We considered the effect of bevacizumab, which is an anti-VEGF-A drug. In this case, several injections of bevacizumab already caused proteinuria. Bevacizumab may have damaged endothelial cells in the glomeruli. However, it was clear that ramucirumab was a key drug because renal failure and pitting oedema had not been shown before its administration.
It is known that bevacizumab mainly causes TMA.5 His pathology showed not only TMA but also glomerular collapse with a crescent-like lesion. This also suggested that the renal dysfunction could not be explained only by bevacizumab.
Treatment
We discontinued ramucirumab and continued an angiotensin II receptor blocker to reduce proteinuria. We did not use immune therapies such as corticosteroids.
Outcome and follow-up
After discontinuation of ramucirumab, the serum Cr gradually decreased to 1.79 mg/dL, and proteinuria also decreased to 3.21 g/gCr 3 months later (figure 3). Proteinuria decreased to 1.21 g/gCr about 7 months later.
Figure 3 There was an improvement with the discontinuation of the medication, but some renal impairment remained.
Discussion
Many anticancer drugs have been developed to inhibit VEGF signalling because it plays a vital role in controlling neovascular processes in neoplasms.2 In the kidney, podocytes and endothelial cells are significant sources of VEGF. It acts in autocrine and paracrine fashions and contributes to maintaining homeostasis.6 The VEGF receptor family, which is a tyrosine kinase receptor, consists of three subtypes: VEGFR-1, VEGFR-2 and VEGFR-3. Among them, VEGFR-2 is predominantly expressed in podocytes, mesangium, endothelial cells and tubular capillaries.5 6 Ramucirumab is a VEGFR-2 binding monoclonal antibody that has been widely used for gastric, lung and colorectal cancer as a second-line therapy.1 A previous study showed adverse renal effects of ramucirumab involving hypertension (21%) and proteinuria (9%).7 Although other VEGF inhibitory drugs, such as the anti-VEGF monoclonal body (bevacizumab), tyrosine kinase inhibitors (sunitinib, axitinib, sorafenib and cediranib) and VEGF-Trap (aflibercept) have been known to cause nephrotic-range proteinuria and renal dysfunction, ramucirumab has been reported in only one case report8 and one single-centre case report.3
Anti-VEGF/VEGFR therapy reportedly accounts for two primary forms of renal pathological changes: minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS), which suggests podocytopathy, and TMA, which suggests endothelial cell injury.5 There is a different tendency for TMA or MCD/FSGS to occur depending on the type of anti-VEGF/VEGFR drug. For example, it is well known that VEGFR is abundant in endothelial cells and inhibition of VEGFR–VEGF crosstalk by anti-VEGF drugs, such as bevacizumab cause TMA.5 On the other hand, VEGFR tyrosine kinase inhibitors (RTKI) cause MCD/FSGS more often than TMA. Previous studies suggested that RTKI inhibits NF-κB activity, leading to c-mip overexpression, and induces MCD or FSGS.5 In two previous studies on ramucirumab-induced nephropathy, three cases of renal pathology were reported3 8 and all of them were reported as TMA. The development of renal impairment characterised the three previous cases after switching from bevacizumab to ramucirumab, as in this case. It is possible that TMA could be caused or exacerbated due to endothelial damage caused by ramucirumab because it is known that the interaction of VEGF with VEGFR-2 is necessary to maintain endothelial cells.9 Since double contours of the glomerular basement membrane were chronic lesions of TMA10 and bevacizumab was administered before ramucirumab, the effect of bevacizumab on TMA could not be ignored. Compared with previous reports, we think this case is characterised by collapsing glomeruli with epithelial cell hyperplasia. A previous report showed that collapsing glomeruli with ‘pseudocrescents’ are caused by podocyte damage.4 The clinical course of marked nephrotic-range proteinuria is also consistent with podocytopathy rather than TMA. A previous study showed that VEGFR-2 is also expressed in podocytes in vivo and that VEGF and VEGFR-2, through autocrine actions, regulate podocyte survival.11 Bertuccio et al12 demonstrated a direct interaction between VEGFR-2 and nephrin in vitro and proposed VEGF signalling via the VEGFR-2–nephrin complex has an essential role in podocyte foot process effacement.
Moreover, ramucirumab inhibits the start of VEGFR-2 signalling, which is the target of RTKI,7 so ramucirumab would cause podocytopathy in the same way as RTKI. These findings suggest that VEGFR-2 plays an important role in podocytes. As mentioned above, renal injury occurred in the three previously reported cases as well as in this case after switching from bevacizumab therapy and this suggests the synergistic effect of ramucirumab and bevacizumab. Müller-Deile et al6 showed that VEGF-A and VEGF-C both interact with VEGFR-2 and play important roles in podocyte survival. They showed that when VEGF-A is inhibited by bevacizumab, VEGF-C plays an important role in suppressing podocyte apoptosis. Another study showed that when bevacizumab inhibits VEGF-A, VEGF-C maintains VEGFR-2 activation in glioblastomas.13 In our case, ramucirumab was considered to have inhibited the interaction between VEGFR-2 and VEGF-C, and this may have resulted in a synergistic effect. The pathology of this case suggests that the presence of chronic TMA caused by bevacizumab may have been combined with podocyte damage from ramucirumab, leading to severe damage to the kidney. This case suggests that VEGFR-2 plays an essential role in the maintenance of podocytes as well as endothelial cells.
We report a rare case of ramucirumab-induced severe proteinuria and renal dysfunction with just one dose. The pathology showed not only TMA lesions but also collapsing glomeruli with crescent-like lesions due to epithelial cell hyperplasia caused by podocyte injury. Given that ramucirumab can cause podocytopathy, which is uncommon in bevacizumab, the change from bevacizumab to ramucirumab should be made carefully. When ramucirumab is used, proteinuria and renal function should be strictly monitored. We also found that proteinuria and serum Cr levels decreased without corticosteroids after ramucirumab treatment was discontinued. Once ramucirumab causes renal involvement, ramucirumab should be discontinued for some time.
Learning points
Compared with other antivascular endothelial growth factor (anti-VEGF) drugs, the pathology of ramucirumab-induced renal failure is still unknown. Only a few reports suggest ramucirumab can present thrombotic microangiopathy, but we found that ramucirumab can also injure podocytes.
Although rare, ramucirumab can cause severe proteinuria and renal dysfunction with just one dose. When used, we must follow-up carefully.
If ramucirumab is a possible causative agent, it should be discontinued. As with other VEGF inhibitors, proteinuria and renal impairment may improve with discontinuation.
Ramucirumab and bevacizumab may have synergistic side effects. Care must be taken when switching between both drugs.
The authors would like to acknowledge Dr Atsuki Ohashi, Dr Eriko Kanehisa and Dr Megumi Yamamuro for their cooperation in medical practice.
Contributors: YN wrote the manuscript with support from HF. JK and KN gave advice about pathological interpretation.
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: Consent obtained from next of kin.
Provenance and peer review: Not commissioned; externally peer reviewed. | 68 kg. | Weight | CC BY-NC | 33653851 | 19,945,647 | 2021-03-02 |
What was the outcome of reaction 'Acute kidney injury'? | A case of ramucirumab-induced renal failure with nephrotic-range proteinuria and its pathological findings.
Ramucirumab-induced renal dysfunction is rarely reported. The pathology of ramucirumab-associated nephropathy in past reports primarily shows thrombotic microangiopathy (TMA) lesions but podocytopathy is not yet known. We report a case of kidney injury induced by ramucirumab in a 71-year-old man with cecal cancer. He was referred to our department for increasing serum creatinine (Cr) levels from 1.08 mg/dL to 2.56 mg/dL after changing anticancer drugs from bevacizumab to ramucirumab. He showed nephrotic-range proteinuria (12.1 g/gCr). A renal biopsy revealed endothelial cell injuries, such as TMA and podocytopathy with epithelial cell hyperplasia, which looked like a crescent. After discontinuing ramucirumab, his renal function and proteinuria improved, as seen by his Cr levels and proteinuria which decreased to 1.74 mg/dL and 1.21 g/gCr, respectively, in 3 months. Unlike previous reports, we found that ramucirumab caused podocyte injuries.
Background
Currently, inhibiting vascular endothelial growth factor (VEGF) signalling is one of the most efficient ways to treat cancers. Ramucirumab is a fully humanised monoclonal antibody targeting VEGF receptor-2 (VEGFR-2) and it inhibits downstream signalling.1 In the last decade, antiangiogenic agents for solid cancers have caused renal dysfunction.2 However, renal dysfunction induced by ramucirumab is rarely reported3 and its specific clinical course is still unknown.
We present the case of a 71-year-old man who had acute kidney injury with nephrotic-range proteinuria after ramucirumab administration. Past reports showed only thrombotic microangiopathy (TMA) in renal pathological changes,3 but his pathological findings suggested ramucirumab induced TMA and podocytopathy, which included a crescent-like lesion.
Case presentation
A 71-year-old man diagnosed with cecal cancer with lymph node metastasis underwent an ileocecal resection and received chemotherapy. He completed his therapy and remained stable for the next few years. When imaging studies showed a progressive disease, he restarted chemotherapy with folinic acid, fluorouracil, irinotecan and bevacizumab. With bevacizumab, he showed proteinuria 3+ in a dipstick test; therefore, he was closely monitored. After a year, because he presented with a progressive disease, bevacizumab was changed to ramucirumab. After 2 weeks, he was admitted to our department because of oedema exacerbation. He had high blood pressure, which was 172/83 mm Hg, although he had already been taking medication for hypertension. His blood pressure was usually controlled at approximately 150/80 mm Hg with an angiotensin II receptor blocker and a calcium channel blocker. His weight was 68 kg, although his usual weight was 61 kg. He showed pitting oedema.
Investigations
The laboratory data (table 1) showed worsening renal function and nephrotic-range proteinuria of 12.1 g/gCr. Serum creatinine (Cr) levels were increased from 1.08 mg/dL to 2.56 mg/dL. Serum albumin decreased from 3.9 g/dL to 3.2 g/dL. The kidney sizes were 108×56 mm (right) and 117×56 mm (left).
Table 1 Blood and Urinary tests are shown
Patient values Reference range Interpretation
Blood test
White cell count 3.6109/L 3.5109–9.1109/L Normal
Haemoglobin 115 g/L 113–152 g/L Normal
Platelet count 90×109/L 130×109–369×109/L Normal
C reactive protein 0.1 mg/dL 0–0.3 mg/dL Normal
Albumin 3.2 g/dL 4–5 g/dL Decreased
Total protein 5.6 g/dL 6.7–8.3 g/dL Decreased
Blood urea nitrogen 32.4 mg/dL 6–20 mg/dL Normal
Creatinine 1.2 mg/dL 0.47–0.79 mg/dL Elevated
LDL cholesterol 126 mg/dL 70–139 mg/dL Normal
Urinary test
Urinary red blood cell 5–9/HPF <1/HPF Elevated
Urinary protein 12.1 g/gCr <0.15 g/gCr Elevated
Bence Jones protein − − Normal
Urinary β2-microglobulin 6777 µg/L 0–259 µg/L Elevated
Selectivity index 0.39 <0.2 (high selectivity) Elevated
HPF, high power field; LDL, low-density lipoproteins.
A kidney biopsy was performed. The renal biopsy specimen contained 18 glomeruli. Two glomeruli showed global sclerosis. The mesangial matrix proliferated in all glomeruli, and the mesangial cells partly proliferated. The glomerular basement membrane showed thickening in all glomeruli, and half of them showed a double contour that circumscribed fibrin such as an eosinophilic substance (figure 1A, B). TMA caused these changes. No spike formation was detected. Four glomeruli were collapsed with epithelial cell hyperplasia which looks like a crescent lesion (figure 2A, B). These changes were similar to collapsing glomeruli with a ‘pseudocrescent’,4 which suggested podocytopathy. Immunofluorescence studies indicated positive staining of the glomerular capillaries and mesangium for C3, C4 and C1q. A part of the mesangium was also positive for IgG, IgM and IgA. Electron microscopy revealed endothelial cell hyperplasia and non-specific dense substances around the mesangium. Some of the foot processes vanished, but no podocytes were detached. Tubular atrophy and interstitial fibrosis were observed in approximately half of the total area.
Figure 1 The glomerular basement membrane showed thickening in all glomeruli, and half of them showed a double contour with fibrinous exudates. (A): H&E stain, (B): Periodic acid-methenamine silver stain).
Figure 2 Glomeruli with epithelial cell hyperplasia, which looks like a ‘crescent’, show capillary wall collapse. (A, B: Periodic acid-methenamine silver stain).
Differential diagnosis
We considered the effect of bevacizumab, which is an anti-VEGF-A drug. In this case, several injections of bevacizumab already caused proteinuria. Bevacizumab may have damaged endothelial cells in the glomeruli. However, it was clear that ramucirumab was a key drug because renal failure and pitting oedema had not been shown before its administration.
It is known that bevacizumab mainly causes TMA.5 His pathology showed not only TMA but also glomerular collapse with a crescent-like lesion. This also suggested that the renal dysfunction could not be explained only by bevacizumab.
Treatment
We discontinued ramucirumab and continued an angiotensin II receptor blocker to reduce proteinuria. We did not use immune therapies such as corticosteroids.
Outcome and follow-up
After discontinuation of ramucirumab, the serum Cr gradually decreased to 1.79 mg/dL, and proteinuria also decreased to 3.21 g/gCr 3 months later (figure 3). Proteinuria decreased to 1.21 g/gCr about 7 months later.
Figure 3 There was an improvement with the discontinuation of the medication, but some renal impairment remained.
Discussion
Many anticancer drugs have been developed to inhibit VEGF signalling because it plays a vital role in controlling neovascular processes in neoplasms.2 In the kidney, podocytes and endothelial cells are significant sources of VEGF. It acts in autocrine and paracrine fashions and contributes to maintaining homeostasis.6 The VEGF receptor family, which is a tyrosine kinase receptor, consists of three subtypes: VEGFR-1, VEGFR-2 and VEGFR-3. Among them, VEGFR-2 is predominantly expressed in podocytes, mesangium, endothelial cells and tubular capillaries.5 6 Ramucirumab is a VEGFR-2 binding monoclonal antibody that has been widely used for gastric, lung and colorectal cancer as a second-line therapy.1 A previous study showed adverse renal effects of ramucirumab involving hypertension (21%) and proteinuria (9%).7 Although other VEGF inhibitory drugs, such as the anti-VEGF monoclonal body (bevacizumab), tyrosine kinase inhibitors (sunitinib, axitinib, sorafenib and cediranib) and VEGF-Trap (aflibercept) have been known to cause nephrotic-range proteinuria and renal dysfunction, ramucirumab has been reported in only one case report8 and one single-centre case report.3
Anti-VEGF/VEGFR therapy reportedly accounts for two primary forms of renal pathological changes: minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS), which suggests podocytopathy, and TMA, which suggests endothelial cell injury.5 There is a different tendency for TMA or MCD/FSGS to occur depending on the type of anti-VEGF/VEGFR drug. For example, it is well known that VEGFR is abundant in endothelial cells and inhibition of VEGFR–VEGF crosstalk by anti-VEGF drugs, such as bevacizumab cause TMA.5 On the other hand, VEGFR tyrosine kinase inhibitors (RTKI) cause MCD/FSGS more often than TMA. Previous studies suggested that RTKI inhibits NF-κB activity, leading to c-mip overexpression, and induces MCD or FSGS.5 In two previous studies on ramucirumab-induced nephropathy, three cases of renal pathology were reported3 8 and all of them were reported as TMA. The development of renal impairment characterised the three previous cases after switching from bevacizumab to ramucirumab, as in this case. It is possible that TMA could be caused or exacerbated due to endothelial damage caused by ramucirumab because it is known that the interaction of VEGF with VEGFR-2 is necessary to maintain endothelial cells.9 Since double contours of the glomerular basement membrane were chronic lesions of TMA10 and bevacizumab was administered before ramucirumab, the effect of bevacizumab on TMA could not be ignored. Compared with previous reports, we think this case is characterised by collapsing glomeruli with epithelial cell hyperplasia. A previous report showed that collapsing glomeruli with ‘pseudocrescents’ are caused by podocyte damage.4 The clinical course of marked nephrotic-range proteinuria is also consistent with podocytopathy rather than TMA. A previous study showed that VEGFR-2 is also expressed in podocytes in vivo and that VEGF and VEGFR-2, through autocrine actions, regulate podocyte survival.11 Bertuccio et al12 demonstrated a direct interaction between VEGFR-2 and nephrin in vitro and proposed VEGF signalling via the VEGFR-2–nephrin complex has an essential role in podocyte foot process effacement.
Moreover, ramucirumab inhibits the start of VEGFR-2 signalling, which is the target of RTKI,7 so ramucirumab would cause podocytopathy in the same way as RTKI. These findings suggest that VEGFR-2 plays an important role in podocytes. As mentioned above, renal injury occurred in the three previously reported cases as well as in this case after switching from bevacizumab therapy and this suggests the synergistic effect of ramucirumab and bevacizumab. Müller-Deile et al6 showed that VEGF-A and VEGF-C both interact with VEGFR-2 and play important roles in podocyte survival. They showed that when VEGF-A is inhibited by bevacizumab, VEGF-C plays an important role in suppressing podocyte apoptosis. Another study showed that when bevacizumab inhibits VEGF-A, VEGF-C maintains VEGFR-2 activation in glioblastomas.13 In our case, ramucirumab was considered to have inhibited the interaction between VEGFR-2 and VEGF-C, and this may have resulted in a synergistic effect. The pathology of this case suggests that the presence of chronic TMA caused by bevacizumab may have been combined with podocyte damage from ramucirumab, leading to severe damage to the kidney. This case suggests that VEGFR-2 plays an essential role in the maintenance of podocytes as well as endothelial cells.
We report a rare case of ramucirumab-induced severe proteinuria and renal dysfunction with just one dose. The pathology showed not only TMA lesions but also collapsing glomeruli with crescent-like lesions due to epithelial cell hyperplasia caused by podocyte injury. Given that ramucirumab can cause podocytopathy, which is uncommon in bevacizumab, the change from bevacizumab to ramucirumab should be made carefully. When ramucirumab is used, proteinuria and renal function should be strictly monitored. We also found that proteinuria and serum Cr levels decreased without corticosteroids after ramucirumab treatment was discontinued. Once ramucirumab causes renal involvement, ramucirumab should be discontinued for some time.
Learning points
Compared with other antivascular endothelial growth factor (anti-VEGF) drugs, the pathology of ramucirumab-induced renal failure is still unknown. Only a few reports suggest ramucirumab can present thrombotic microangiopathy, but we found that ramucirumab can also injure podocytes.
Although rare, ramucirumab can cause severe proteinuria and renal dysfunction with just one dose. When used, we must follow-up carefully.
If ramucirumab is a possible causative agent, it should be discontinued. As with other VEGF inhibitors, proteinuria and renal impairment may improve with discontinuation.
Ramucirumab and bevacizumab may have synergistic side effects. Care must be taken when switching between both drugs.
The authors would like to acknowledge Dr Atsuki Ohashi, Dr Eriko Kanehisa and Dr Megumi Yamamuro for their cooperation in medical practice.
Contributors: YN wrote the manuscript with support from HF. JK and KN gave advice about pathological interpretation.
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: Consent obtained from next of kin.
Provenance and peer review: Not commissioned; externally peer reviewed. | Recovering | ReactionOutcome | CC BY-NC | 33653851 | 19,945,647 | 2021-03-02 |
What was the outcome of reaction 'Drug interaction'? | A case of ramucirumab-induced renal failure with nephrotic-range proteinuria and its pathological findings.
Ramucirumab-induced renal dysfunction is rarely reported. The pathology of ramucirumab-associated nephropathy in past reports primarily shows thrombotic microangiopathy (TMA) lesions but podocytopathy is not yet known. We report a case of kidney injury induced by ramucirumab in a 71-year-old man with cecal cancer. He was referred to our department for increasing serum creatinine (Cr) levels from 1.08 mg/dL to 2.56 mg/dL after changing anticancer drugs from bevacizumab to ramucirumab. He showed nephrotic-range proteinuria (12.1 g/gCr). A renal biopsy revealed endothelial cell injuries, such as TMA and podocytopathy with epithelial cell hyperplasia, which looked like a crescent. After discontinuing ramucirumab, his renal function and proteinuria improved, as seen by his Cr levels and proteinuria which decreased to 1.74 mg/dL and 1.21 g/gCr, respectively, in 3 months. Unlike previous reports, we found that ramucirumab caused podocyte injuries.
Background
Currently, inhibiting vascular endothelial growth factor (VEGF) signalling is one of the most efficient ways to treat cancers. Ramucirumab is a fully humanised monoclonal antibody targeting VEGF receptor-2 (VEGFR-2) and it inhibits downstream signalling.1 In the last decade, antiangiogenic agents for solid cancers have caused renal dysfunction.2 However, renal dysfunction induced by ramucirumab is rarely reported3 and its specific clinical course is still unknown.
We present the case of a 71-year-old man who had acute kidney injury with nephrotic-range proteinuria after ramucirumab administration. Past reports showed only thrombotic microangiopathy (TMA) in renal pathological changes,3 but his pathological findings suggested ramucirumab induced TMA and podocytopathy, which included a crescent-like lesion.
Case presentation
A 71-year-old man diagnosed with cecal cancer with lymph node metastasis underwent an ileocecal resection and received chemotherapy. He completed his therapy and remained stable for the next few years. When imaging studies showed a progressive disease, he restarted chemotherapy with folinic acid, fluorouracil, irinotecan and bevacizumab. With bevacizumab, he showed proteinuria 3+ in a dipstick test; therefore, he was closely monitored. After a year, because he presented with a progressive disease, bevacizumab was changed to ramucirumab. After 2 weeks, he was admitted to our department because of oedema exacerbation. He had high blood pressure, which was 172/83 mm Hg, although he had already been taking medication for hypertension. His blood pressure was usually controlled at approximately 150/80 mm Hg with an angiotensin II receptor blocker and a calcium channel blocker. His weight was 68 kg, although his usual weight was 61 kg. He showed pitting oedema.
Investigations
The laboratory data (table 1) showed worsening renal function and nephrotic-range proteinuria of 12.1 g/gCr. Serum creatinine (Cr) levels were increased from 1.08 mg/dL to 2.56 mg/dL. Serum albumin decreased from 3.9 g/dL to 3.2 g/dL. The kidney sizes were 108×56 mm (right) and 117×56 mm (left).
Table 1 Blood and Urinary tests are shown
Patient values Reference range Interpretation
Blood test
White cell count 3.6109/L 3.5109–9.1109/L Normal
Haemoglobin 115 g/L 113–152 g/L Normal
Platelet count 90×109/L 130×109–369×109/L Normal
C reactive protein 0.1 mg/dL 0–0.3 mg/dL Normal
Albumin 3.2 g/dL 4–5 g/dL Decreased
Total protein 5.6 g/dL 6.7–8.3 g/dL Decreased
Blood urea nitrogen 32.4 mg/dL 6–20 mg/dL Normal
Creatinine 1.2 mg/dL 0.47–0.79 mg/dL Elevated
LDL cholesterol 126 mg/dL 70–139 mg/dL Normal
Urinary test
Urinary red blood cell 5–9/HPF <1/HPF Elevated
Urinary protein 12.1 g/gCr <0.15 g/gCr Elevated
Bence Jones protein − − Normal
Urinary β2-microglobulin 6777 µg/L 0–259 µg/L Elevated
Selectivity index 0.39 <0.2 (high selectivity) Elevated
HPF, high power field; LDL, low-density lipoproteins.
A kidney biopsy was performed. The renal biopsy specimen contained 18 glomeruli. Two glomeruli showed global sclerosis. The mesangial matrix proliferated in all glomeruli, and the mesangial cells partly proliferated. The glomerular basement membrane showed thickening in all glomeruli, and half of them showed a double contour that circumscribed fibrin such as an eosinophilic substance (figure 1A, B). TMA caused these changes. No spike formation was detected. Four glomeruli were collapsed with epithelial cell hyperplasia which looks like a crescent lesion (figure 2A, B). These changes were similar to collapsing glomeruli with a ‘pseudocrescent’,4 which suggested podocytopathy. Immunofluorescence studies indicated positive staining of the glomerular capillaries and mesangium for C3, C4 and C1q. A part of the mesangium was also positive for IgG, IgM and IgA. Electron microscopy revealed endothelial cell hyperplasia and non-specific dense substances around the mesangium. Some of the foot processes vanished, but no podocytes were detached. Tubular atrophy and interstitial fibrosis were observed in approximately half of the total area.
Figure 1 The glomerular basement membrane showed thickening in all glomeruli, and half of them showed a double contour with fibrinous exudates. (A): H&E stain, (B): Periodic acid-methenamine silver stain).
Figure 2 Glomeruli with epithelial cell hyperplasia, which looks like a ‘crescent’, show capillary wall collapse. (A, B: Periodic acid-methenamine silver stain).
Differential diagnosis
We considered the effect of bevacizumab, which is an anti-VEGF-A drug. In this case, several injections of bevacizumab already caused proteinuria. Bevacizumab may have damaged endothelial cells in the glomeruli. However, it was clear that ramucirumab was a key drug because renal failure and pitting oedema had not been shown before its administration.
It is known that bevacizumab mainly causes TMA.5 His pathology showed not only TMA but also glomerular collapse with a crescent-like lesion. This also suggested that the renal dysfunction could not be explained only by bevacizumab.
Treatment
We discontinued ramucirumab and continued an angiotensin II receptor blocker to reduce proteinuria. We did not use immune therapies such as corticosteroids.
Outcome and follow-up
After discontinuation of ramucirumab, the serum Cr gradually decreased to 1.79 mg/dL, and proteinuria also decreased to 3.21 g/gCr 3 months later (figure 3). Proteinuria decreased to 1.21 g/gCr about 7 months later.
Figure 3 There was an improvement with the discontinuation of the medication, but some renal impairment remained.
Discussion
Many anticancer drugs have been developed to inhibit VEGF signalling because it plays a vital role in controlling neovascular processes in neoplasms.2 In the kidney, podocytes and endothelial cells are significant sources of VEGF. It acts in autocrine and paracrine fashions and contributes to maintaining homeostasis.6 The VEGF receptor family, which is a tyrosine kinase receptor, consists of three subtypes: VEGFR-1, VEGFR-2 and VEGFR-3. Among them, VEGFR-2 is predominantly expressed in podocytes, mesangium, endothelial cells and tubular capillaries.5 6 Ramucirumab is a VEGFR-2 binding monoclonal antibody that has been widely used for gastric, lung and colorectal cancer as a second-line therapy.1 A previous study showed adverse renal effects of ramucirumab involving hypertension (21%) and proteinuria (9%).7 Although other VEGF inhibitory drugs, such as the anti-VEGF monoclonal body (bevacizumab), tyrosine kinase inhibitors (sunitinib, axitinib, sorafenib and cediranib) and VEGF-Trap (aflibercept) have been known to cause nephrotic-range proteinuria and renal dysfunction, ramucirumab has been reported in only one case report8 and one single-centre case report.3
Anti-VEGF/VEGFR therapy reportedly accounts for two primary forms of renal pathological changes: minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS), which suggests podocytopathy, and TMA, which suggests endothelial cell injury.5 There is a different tendency for TMA or MCD/FSGS to occur depending on the type of anti-VEGF/VEGFR drug. For example, it is well known that VEGFR is abundant in endothelial cells and inhibition of VEGFR–VEGF crosstalk by anti-VEGF drugs, such as bevacizumab cause TMA.5 On the other hand, VEGFR tyrosine kinase inhibitors (RTKI) cause MCD/FSGS more often than TMA. Previous studies suggested that RTKI inhibits NF-κB activity, leading to c-mip overexpression, and induces MCD or FSGS.5 In two previous studies on ramucirumab-induced nephropathy, three cases of renal pathology were reported3 8 and all of them were reported as TMA. The development of renal impairment characterised the three previous cases after switching from bevacizumab to ramucirumab, as in this case. It is possible that TMA could be caused or exacerbated due to endothelial damage caused by ramucirumab because it is known that the interaction of VEGF with VEGFR-2 is necessary to maintain endothelial cells.9 Since double contours of the glomerular basement membrane were chronic lesions of TMA10 and bevacizumab was administered before ramucirumab, the effect of bevacizumab on TMA could not be ignored. Compared with previous reports, we think this case is characterised by collapsing glomeruli with epithelial cell hyperplasia. A previous report showed that collapsing glomeruli with ‘pseudocrescents’ are caused by podocyte damage.4 The clinical course of marked nephrotic-range proteinuria is also consistent with podocytopathy rather than TMA. A previous study showed that VEGFR-2 is also expressed in podocytes in vivo and that VEGF and VEGFR-2, through autocrine actions, regulate podocyte survival.11 Bertuccio et al12 demonstrated a direct interaction between VEGFR-2 and nephrin in vitro and proposed VEGF signalling via the VEGFR-2–nephrin complex has an essential role in podocyte foot process effacement.
Moreover, ramucirumab inhibits the start of VEGFR-2 signalling, which is the target of RTKI,7 so ramucirumab would cause podocytopathy in the same way as RTKI. These findings suggest that VEGFR-2 plays an important role in podocytes. As mentioned above, renal injury occurred in the three previously reported cases as well as in this case after switching from bevacizumab therapy and this suggests the synergistic effect of ramucirumab and bevacizumab. Müller-Deile et al6 showed that VEGF-A and VEGF-C both interact with VEGFR-2 and play important roles in podocyte survival. They showed that when VEGF-A is inhibited by bevacizumab, VEGF-C plays an important role in suppressing podocyte apoptosis. Another study showed that when bevacizumab inhibits VEGF-A, VEGF-C maintains VEGFR-2 activation in glioblastomas.13 In our case, ramucirumab was considered to have inhibited the interaction between VEGFR-2 and VEGF-C, and this may have resulted in a synergistic effect. The pathology of this case suggests that the presence of chronic TMA caused by bevacizumab may have been combined with podocyte damage from ramucirumab, leading to severe damage to the kidney. This case suggests that VEGFR-2 plays an essential role in the maintenance of podocytes as well as endothelial cells.
We report a rare case of ramucirumab-induced severe proteinuria and renal dysfunction with just one dose. The pathology showed not only TMA lesions but also collapsing glomeruli with crescent-like lesions due to epithelial cell hyperplasia caused by podocyte injury. Given that ramucirumab can cause podocytopathy, which is uncommon in bevacizumab, the change from bevacizumab to ramucirumab should be made carefully. When ramucirumab is used, proteinuria and renal function should be strictly monitored. We also found that proteinuria and serum Cr levels decreased without corticosteroids after ramucirumab treatment was discontinued. Once ramucirumab causes renal involvement, ramucirumab should be discontinued for some time.
Learning points
Compared with other antivascular endothelial growth factor (anti-VEGF) drugs, the pathology of ramucirumab-induced renal failure is still unknown. Only a few reports suggest ramucirumab can present thrombotic microangiopathy, but we found that ramucirumab can also injure podocytes.
Although rare, ramucirumab can cause severe proteinuria and renal dysfunction with just one dose. When used, we must follow-up carefully.
If ramucirumab is a possible causative agent, it should be discontinued. As with other VEGF inhibitors, proteinuria and renal impairment may improve with discontinuation.
Ramucirumab and bevacizumab may have synergistic side effects. Care must be taken when switching between both drugs.
The authors would like to acknowledge Dr Atsuki Ohashi, Dr Eriko Kanehisa and Dr Megumi Yamamuro for their cooperation in medical practice.
Contributors: YN wrote the manuscript with support from HF. JK and KN gave advice about pathological interpretation.
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: Consent obtained from next of kin.
Provenance and peer review: Not commissioned; externally peer reviewed. | Recovering | ReactionOutcome | CC BY-NC | 33653851 | 19,945,647 | 2021-03-02 |
What was the outcome of reaction 'Proteinuria'? | A case of ramucirumab-induced renal failure with nephrotic-range proteinuria and its pathological findings.
Ramucirumab-induced renal dysfunction is rarely reported. The pathology of ramucirumab-associated nephropathy in past reports primarily shows thrombotic microangiopathy (TMA) lesions but podocytopathy is not yet known. We report a case of kidney injury induced by ramucirumab in a 71-year-old man with cecal cancer. He was referred to our department for increasing serum creatinine (Cr) levels from 1.08 mg/dL to 2.56 mg/dL after changing anticancer drugs from bevacizumab to ramucirumab. He showed nephrotic-range proteinuria (12.1 g/gCr). A renal biopsy revealed endothelial cell injuries, such as TMA and podocytopathy with epithelial cell hyperplasia, which looked like a crescent. After discontinuing ramucirumab, his renal function and proteinuria improved, as seen by his Cr levels and proteinuria which decreased to 1.74 mg/dL and 1.21 g/gCr, respectively, in 3 months. Unlike previous reports, we found that ramucirumab caused podocyte injuries.
Background
Currently, inhibiting vascular endothelial growth factor (VEGF) signalling is one of the most efficient ways to treat cancers. Ramucirumab is a fully humanised monoclonal antibody targeting VEGF receptor-2 (VEGFR-2) and it inhibits downstream signalling.1 In the last decade, antiangiogenic agents for solid cancers have caused renal dysfunction.2 However, renal dysfunction induced by ramucirumab is rarely reported3 and its specific clinical course is still unknown.
We present the case of a 71-year-old man who had acute kidney injury with nephrotic-range proteinuria after ramucirumab administration. Past reports showed only thrombotic microangiopathy (TMA) in renal pathological changes,3 but his pathological findings suggested ramucirumab induced TMA and podocytopathy, which included a crescent-like lesion.
Case presentation
A 71-year-old man diagnosed with cecal cancer with lymph node metastasis underwent an ileocecal resection and received chemotherapy. He completed his therapy and remained stable for the next few years. When imaging studies showed a progressive disease, he restarted chemotherapy with folinic acid, fluorouracil, irinotecan and bevacizumab. With bevacizumab, he showed proteinuria 3+ in a dipstick test; therefore, he was closely monitored. After a year, because he presented with a progressive disease, bevacizumab was changed to ramucirumab. After 2 weeks, he was admitted to our department because of oedema exacerbation. He had high blood pressure, which was 172/83 mm Hg, although he had already been taking medication for hypertension. His blood pressure was usually controlled at approximately 150/80 mm Hg with an angiotensin II receptor blocker and a calcium channel blocker. His weight was 68 kg, although his usual weight was 61 kg. He showed pitting oedema.
Investigations
The laboratory data (table 1) showed worsening renal function and nephrotic-range proteinuria of 12.1 g/gCr. Serum creatinine (Cr) levels were increased from 1.08 mg/dL to 2.56 mg/dL. Serum albumin decreased from 3.9 g/dL to 3.2 g/dL. The kidney sizes were 108×56 mm (right) and 117×56 mm (left).
Table 1 Blood and Urinary tests are shown
Patient values Reference range Interpretation
Blood test
White cell count 3.6109/L 3.5109–9.1109/L Normal
Haemoglobin 115 g/L 113–152 g/L Normal
Platelet count 90×109/L 130×109–369×109/L Normal
C reactive protein 0.1 mg/dL 0–0.3 mg/dL Normal
Albumin 3.2 g/dL 4–5 g/dL Decreased
Total protein 5.6 g/dL 6.7–8.3 g/dL Decreased
Blood urea nitrogen 32.4 mg/dL 6–20 mg/dL Normal
Creatinine 1.2 mg/dL 0.47–0.79 mg/dL Elevated
LDL cholesterol 126 mg/dL 70–139 mg/dL Normal
Urinary test
Urinary red blood cell 5–9/HPF <1/HPF Elevated
Urinary protein 12.1 g/gCr <0.15 g/gCr Elevated
Bence Jones protein − − Normal
Urinary β2-microglobulin 6777 µg/L 0–259 µg/L Elevated
Selectivity index 0.39 <0.2 (high selectivity) Elevated
HPF, high power field; LDL, low-density lipoproteins.
A kidney biopsy was performed. The renal biopsy specimen contained 18 glomeruli. Two glomeruli showed global sclerosis. The mesangial matrix proliferated in all glomeruli, and the mesangial cells partly proliferated. The glomerular basement membrane showed thickening in all glomeruli, and half of them showed a double contour that circumscribed fibrin such as an eosinophilic substance (figure 1A, B). TMA caused these changes. No spike formation was detected. Four glomeruli were collapsed with epithelial cell hyperplasia which looks like a crescent lesion (figure 2A, B). These changes were similar to collapsing glomeruli with a ‘pseudocrescent’,4 which suggested podocytopathy. Immunofluorescence studies indicated positive staining of the glomerular capillaries and mesangium for C3, C4 and C1q. A part of the mesangium was also positive for IgG, IgM and IgA. Electron microscopy revealed endothelial cell hyperplasia and non-specific dense substances around the mesangium. Some of the foot processes vanished, but no podocytes were detached. Tubular atrophy and interstitial fibrosis were observed in approximately half of the total area.
Figure 1 The glomerular basement membrane showed thickening in all glomeruli, and half of them showed a double contour with fibrinous exudates. (A): H&E stain, (B): Periodic acid-methenamine silver stain).
Figure 2 Glomeruli with epithelial cell hyperplasia, which looks like a ‘crescent’, show capillary wall collapse. (A, B: Periodic acid-methenamine silver stain).
Differential diagnosis
We considered the effect of bevacizumab, which is an anti-VEGF-A drug. In this case, several injections of bevacizumab already caused proteinuria. Bevacizumab may have damaged endothelial cells in the glomeruli. However, it was clear that ramucirumab was a key drug because renal failure and pitting oedema had not been shown before its administration.
It is known that bevacizumab mainly causes TMA.5 His pathology showed not only TMA but also glomerular collapse with a crescent-like lesion. This also suggested that the renal dysfunction could not be explained only by bevacizumab.
Treatment
We discontinued ramucirumab and continued an angiotensin II receptor blocker to reduce proteinuria. We did not use immune therapies such as corticosteroids.
Outcome and follow-up
After discontinuation of ramucirumab, the serum Cr gradually decreased to 1.79 mg/dL, and proteinuria also decreased to 3.21 g/gCr 3 months later (figure 3). Proteinuria decreased to 1.21 g/gCr about 7 months later.
Figure 3 There was an improvement with the discontinuation of the medication, but some renal impairment remained.
Discussion
Many anticancer drugs have been developed to inhibit VEGF signalling because it plays a vital role in controlling neovascular processes in neoplasms.2 In the kidney, podocytes and endothelial cells are significant sources of VEGF. It acts in autocrine and paracrine fashions and contributes to maintaining homeostasis.6 The VEGF receptor family, which is a tyrosine kinase receptor, consists of three subtypes: VEGFR-1, VEGFR-2 and VEGFR-3. Among them, VEGFR-2 is predominantly expressed in podocytes, mesangium, endothelial cells and tubular capillaries.5 6 Ramucirumab is a VEGFR-2 binding monoclonal antibody that has been widely used for gastric, lung and colorectal cancer as a second-line therapy.1 A previous study showed adverse renal effects of ramucirumab involving hypertension (21%) and proteinuria (9%).7 Although other VEGF inhibitory drugs, such as the anti-VEGF monoclonal body (bevacizumab), tyrosine kinase inhibitors (sunitinib, axitinib, sorafenib and cediranib) and VEGF-Trap (aflibercept) have been known to cause nephrotic-range proteinuria and renal dysfunction, ramucirumab has been reported in only one case report8 and one single-centre case report.3
Anti-VEGF/VEGFR therapy reportedly accounts for two primary forms of renal pathological changes: minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS), which suggests podocytopathy, and TMA, which suggests endothelial cell injury.5 There is a different tendency for TMA or MCD/FSGS to occur depending on the type of anti-VEGF/VEGFR drug. For example, it is well known that VEGFR is abundant in endothelial cells and inhibition of VEGFR–VEGF crosstalk by anti-VEGF drugs, such as bevacizumab cause TMA.5 On the other hand, VEGFR tyrosine kinase inhibitors (RTKI) cause MCD/FSGS more often than TMA. Previous studies suggested that RTKI inhibits NF-κB activity, leading to c-mip overexpression, and induces MCD or FSGS.5 In two previous studies on ramucirumab-induced nephropathy, three cases of renal pathology were reported3 8 and all of them were reported as TMA. The development of renal impairment characterised the three previous cases after switching from bevacizumab to ramucirumab, as in this case. It is possible that TMA could be caused or exacerbated due to endothelial damage caused by ramucirumab because it is known that the interaction of VEGF with VEGFR-2 is necessary to maintain endothelial cells.9 Since double contours of the glomerular basement membrane were chronic lesions of TMA10 and bevacizumab was administered before ramucirumab, the effect of bevacizumab on TMA could not be ignored. Compared with previous reports, we think this case is characterised by collapsing glomeruli with epithelial cell hyperplasia. A previous report showed that collapsing glomeruli with ‘pseudocrescents’ are caused by podocyte damage.4 The clinical course of marked nephrotic-range proteinuria is also consistent with podocytopathy rather than TMA. A previous study showed that VEGFR-2 is also expressed in podocytes in vivo and that VEGF and VEGFR-2, through autocrine actions, regulate podocyte survival.11 Bertuccio et al12 demonstrated a direct interaction between VEGFR-2 and nephrin in vitro and proposed VEGF signalling via the VEGFR-2–nephrin complex has an essential role in podocyte foot process effacement.
Moreover, ramucirumab inhibits the start of VEGFR-2 signalling, which is the target of RTKI,7 so ramucirumab would cause podocytopathy in the same way as RTKI. These findings suggest that VEGFR-2 plays an important role in podocytes. As mentioned above, renal injury occurred in the three previously reported cases as well as in this case after switching from bevacizumab therapy and this suggests the synergistic effect of ramucirumab and bevacizumab. Müller-Deile et al6 showed that VEGF-A and VEGF-C both interact with VEGFR-2 and play important roles in podocyte survival. They showed that when VEGF-A is inhibited by bevacizumab, VEGF-C plays an important role in suppressing podocyte apoptosis. Another study showed that when bevacizumab inhibits VEGF-A, VEGF-C maintains VEGFR-2 activation in glioblastomas.13 In our case, ramucirumab was considered to have inhibited the interaction between VEGFR-2 and VEGF-C, and this may have resulted in a synergistic effect. The pathology of this case suggests that the presence of chronic TMA caused by bevacizumab may have been combined with podocyte damage from ramucirumab, leading to severe damage to the kidney. This case suggests that VEGFR-2 plays an essential role in the maintenance of podocytes as well as endothelial cells.
We report a rare case of ramucirumab-induced severe proteinuria and renal dysfunction with just one dose. The pathology showed not only TMA lesions but also collapsing glomeruli with crescent-like lesions due to epithelial cell hyperplasia caused by podocyte injury. Given that ramucirumab can cause podocytopathy, which is uncommon in bevacizumab, the change from bevacizumab to ramucirumab should be made carefully. When ramucirumab is used, proteinuria and renal function should be strictly monitored. We also found that proteinuria and serum Cr levels decreased without corticosteroids after ramucirumab treatment was discontinued. Once ramucirumab causes renal involvement, ramucirumab should be discontinued for some time.
Learning points
Compared with other antivascular endothelial growth factor (anti-VEGF) drugs, the pathology of ramucirumab-induced renal failure is still unknown. Only a few reports suggest ramucirumab can present thrombotic microangiopathy, but we found that ramucirumab can also injure podocytes.
Although rare, ramucirumab can cause severe proteinuria and renal dysfunction with just one dose. When used, we must follow-up carefully.
If ramucirumab is a possible causative agent, it should be discontinued. As with other VEGF inhibitors, proteinuria and renal impairment may improve with discontinuation.
Ramucirumab and bevacizumab may have synergistic side effects. Care must be taken when switching between both drugs.
The authors would like to acknowledge Dr Atsuki Ohashi, Dr Eriko Kanehisa and Dr Megumi Yamamuro for their cooperation in medical practice.
Contributors: YN wrote the manuscript with support from HF. JK and KN gave advice about pathological interpretation.
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: Consent obtained from next of kin.
Provenance and peer review: Not commissioned; externally peer reviewed. | Recovering | ReactionOutcome | CC BY-NC | 33653851 | 19,945,647 | 2021-03-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cerebral palsy'. | Emergency Thrombolysis During Cardiac Arrest Due to Pulmonary Thromboembolism: Our Experience Over 6 Years.
Cardiac arrest (CA) is one of the leading causes of death worldwide. Among patients with CA, pulmonary embolism (PE) accounts for approximately 10% of all cases.
To compare the outcomes after cardiopulmonary-cerebral resuscitation (CCPR) with and without thrombolytic therapy (TT) in patients with CA secondary to PE.
We included patients older than 17 years admitted to our hospital between 2013 and 2017 with a diagnosis of CA with confirmed or highly suspected PE who received CCPR with or without TT. Measures of central tendency were used to depict the data.
The study comprised 16 patients, 8 of whom received CCPR and thrombolysis with alteplase, whereas the remaining patients received CCPR without TT. The most frequent rhythm of CA in both groups was pulseless electrical activity. Return of spontaneous circulation (ROSC) occurred in 100% of patients who received TT and in 88% of non-thrombolysed patients. The mortality rate of patients who received TT and non-thrombolysed patients at 24 hours was 25% and 50%, respectively. However, at the time of hospital discharge, the mortality was the same in both groups (62%). In patients who received TT, mortality was related to sepsis and hemorrhage whereas in non-thrombolysed patients, mortality was due to myocardial dysfunction.
Intra-arrest thrombolysis resulted in a higher likelihood of ROSC and a higher 24-hour survival in adults with CA secondary to acute PE. Overall, the survival at hospital discharge was the same in the two groups.
Introduction
Cardiac arrest (CA) is one of the leading causes of death worldwide, with an incidence of 28–54 per 100,000 person-years.1 Cardiovascular-related causes, especially acute myocardial infarction, are responsible for more than 70% of all CA.2 Pulmonary embolism (PE) accounts for approximately 10% of cases.3 Mortality of patients with CA secondary to PE continues to be high, ranging between 65%-88%, despite all the recommended Cardiopulmonary-Cerebral Resuscitation (CCPR) strategies.4,5 Between 60% and 74% of survivors have a good neurological outcome, with a score of 1–2 on the cerebral performance category (CPC) scale.6,7
Advanced CCPR can be supplemented with thrombolysis in patients with CA secondary to PE as a reperfusion therapy. However, its use in cases of CA remains controversial.8 This intervention has been extrapolated from the treatment indicated in patients with high-risk PE defined by hemodynamic instability with arterial hypotension or shock. Thrombolytic therapy (TT) has been associated with reduced mortality in such patients.9,10 Thrombolysis has been found to be beneficial in return of spontaneous circulation (ROSC) in prospective studies on patients with CA due to all cardiovascular-related causes.11,12 Other cohort studies that assessed outcomes with TT in the subgroup of CA secondary to PE found higher rate of ROSC in 24-hour survival and survival to discharge from hospital.6,13–15 Conversely, a recent clinical trial found no statistically significant differences in survival nor neurological outcomes with the use of thrombolysis in CA in the subgroup of CA secondary to PE.16 International CCPR guidelines consider the use of TT in cases of presumed PE as cause of CA in high-risk patients, being a IIb recommendation, with a C-Limited Data level of evidence.17
In Colombia, only case reports with successful outcomes have been published.18,19 However, there are no case-control studies to evaluate the use or non-use of TT in CA secondary to PE. Therefore, the purpose of this study was to assess the outcomes of patients with CA secondary to PE who received CCPR with or without TT upon presentation to the emergency department of a tertiary care center/referral university hospital.
Methodology
Setting and Data Source
This retrospective observational study was conducted at Fundación Valle del Lili (FVL) University Hospital. The FVL hospital is a non-profit university hospital affiliated with the Icesi University School of Medicine in Cali, Colombia. It serves as a referral facility for critically ill patients from the Southwest region of the country and has an emergency department volume of approximately 70,000 patients per year.
The data for this study were obtained from the FVL institutional registry on cardiac arrest CRECA (Colombian REgistry of Cardiac Arrest). This registry was launched in 2017 to retrospectively collect information of patients with non-traumatic CA. Data collected included demographics, clinical features, resource utilization, and patients’ outcomes. The registry searched for data of patients admitted to the emergency department from 2013 to 2017. Information from the registry was complemented by reviewing individual medical charts. This study was approved by our institutional IRB (Register No. 263) and adhered to the standards of the STROBE guidelines (Strengthening the Reporting of Observational studies in Epidemiology). It was approved by the FVL ethics committee in biomedical research, approved on October 21, 2016. Institutional act No. 21 of October 19, 2016, protocol number 1040. According to resolution 8430 of 1993 of the Colombian Ministry of Health, this study was classified as “no risk”; since it is documentary in nature and the researchers do not assign biological, psychological or social exposures to patients. Therefore, the ethics committee omitted the use of informed consent. All patient data accessed complied with relevant data protection and privacy regulations.
Participants
Eligibility criteria included patients older than 17 years of both genders from the institutional registry of CA, CRECA, with confirmed or highly suspected PE as the primary cause of the CA and who had received CCPR with or without emergency thrombolysis. Exclusion criteria were non-cardiovascular-related causes of CA, trauma, cancer, or prolonged arrest. Confirmed PE was considered in subjects with documented venous embolism of the pulmonary arteries by computed tomography (CT) angiography. Highly suspected PE was considered in patients with suggestive clinical findings, associated risk factors, and ultrasound criteria.
Case presentation suggestive of PE included symptoms such as dyspnea, pleuritic chest pain, cough, or syncope, and the presence of high-risk factors such as previous venous thromboembolism, immobilization, recent surgery, limb pain, hormonal therapy, or recent childbirth. The ultrasound criteria used were as follows: right ventricle dilation, hypokinesia of the right ventricular wall, flattening of the interventricular septum accompanied by paradoxical motion, and a D-shaped left ventricle.
Variables and Outcomes
Clinical variables used in the characterization of the study participants included age, gender, medical history, cardiac rhythm, and in- or out-of-hospital CA. To characterize the resuscitation therapy, variables such as medications, dosage, and use or non-use of TT were evaluated. The administration of a thrombolytic agent resulted from a deliberate decision of the emergency physician and the team managing each case. Alteplase, a recombinant tissue plasminogen activator, was used in all patients with TT.
Outcome variables were evaluated in terms of ROSC, 24-hour survival, survival to hospital discharge, neurological performance, and adverse events derived from the use of a thrombolytic agent. Neurological performance was measured using the CPC disability scale. In essence, the CPC scale classifies patients into five categories: 1) Good cerebral performance = conscious, alert, and able to work; 2) Moderate cerebral disability = conscious, independent with regard to activities of daily living and able to work in a sheltered environment. Patients may present with hemiplegia, seizures, ataxia, dysarthria, dysphasia, or memory or mental changes; 3) Severe cerebral disability = conscious and dependent on others for daily activities; 4) Coma or vegetative state; and 5) Brain death = apnea, areflexia, and EEG silence.
Data Analysis
Categorical variables were described using frequencies and percentages, and quantitative variables using median and interquartile range (IQR). These descriptions were made by subgroups according to resuscitation decision making, with or without TT. Pearson Chi-2 test and Mann–Whitney U-test were used for comparison of categorical and continuous variables, respectively. Analysis was performed using Microsoft© Excel (Version 16.24, Santa Rosa, California).
Results
During the study period, 298 patients with CA were treated in the FVL Emergency Department, 16 of whom suffered from acute PE as the cause of the CA. Eight patients received CCPR in addition to emergency TT with alteplase, and the remaining eight received CCPR without thrombolysis (Figure 1).Figure 1 Code blue registration.
All patients were older than 50 years, and half of them were male. Among the patients who received TT, the median age was 68 (IQR, 52–80) years, and among the non-thrombolysed patients, the median age was 80 (IQR, 50–85) years. Seven subjects (87.5%) within the group receiving thrombolysis and six (75%) from the non-thrombolysed group presented with out-of-hospital CA; of these, four patients within the TT group and one from non-thrombolysed group received CCPR before admission to the hospital. The most frequent CA rhythm in both groups was pulseless electrical activity in 75% of patients, followed by asystole. A history of hypertension was present in 50% of the TT group and 75% of patients in the group without TT. Table 1 shows patients’ features according to management.Table 1 Clinical Features of Patients According to the Use of Thrombolytic Therapy During Cardiopulmonary Resuscitation
Features TT, n = 8 (%) Without TT, n = 8 (%) p value
Age, median in years (IQR) 68 (52–80) 80 (50–85) 0.61
Male gender 5 (62.5) 4 (50) 0.61
Confirmatory study 0
CT angiography 4 (50) 4 (50) 1.00
FOCUS peri-arrest 6 (75) 5 (62.5) 0.59
Initial cardiac arrest rhythm 0
Ventricular fibrillation 1 (12.5) 0 (0) 0.30
Pulseless ventricular tachycardia 0 (0) 0 (0) 1.00
Pulseless electrical activity 6 (75) 6 (75) 1.00
Asystole 1 (12.5) 2 (25) 0.52
Cardiac arrest 0
Out-of-hospital 7 (87.5) 6 (75) 0.52
CCPR prior to admission 4/7 1/6 0.10
Medication prior to admission 3/7 1/6 0.24
Medical record
Current smoker 1 (12.5) 3 (37.5) 0.24
Arterial hypertension 4 (50) 6 (75) 0.30
Coronary heart disease 1 (12.5) 3 (37.5) 0.24
Diabetes 0 (0) 3 (37.5) 0.06
Heart failure 0 (0) 1 (12.5) 0.30
Lung disease 2 (25) 3 (37.5) 0.59
Neurological disease 0 (0) 3 (37.5) 0.06
Note: All data, except age, are expressed in terms of frequency (%).
Abbreviations: CCPR, cerebro-cardio-pulmonary resuscitation; CT, computed tomography; FOCUS, focused cardiac ultrasound; IQR, interquartile range; LV, left ventricle; RV, right ventricle; TT, thrombolytic therapy.
A peri-arrest ultrasound study was performed in 6/8 patients in the group receiving TT and in 5/8 patients in the non-thrombolysed group (Table 2). Signs of right ventricular dysfunction were not found in 1/5 patients. Thrombus in the pulmonary artery was reported in one patient from the TT group. PE was confirmed by computed tomography pulmonary angiogram (CTPA) in 7/16 patients. In 9/16 patients it was confirmed by transthoracic echocardiogram and focused cardiac ultrasound.Table 2 Findings of Emergency Ultrasound
TT, n = 6 (%) Without TT, n = 5 (%) p value
RV hypokinesia 6/6 4/5
Ratio RV>LV 6/6 4/5 0.59
Septal flattening 5/6 4/5
Pulmonary artery thrombus 1/6 0/5
FOCUS on the peri-cardiac arrest 6 (75) 5 (62.5) 0.31
Abbreviations: LV, left ventricle; RV, right ventricle; TT, thrombolytic therapy.
ROSC occurred in 100% of patients undergoing thrombolysis and in 88% of non-thrombolysed patients; 24-hour mortality rates were 25% and 50%, respectively. However, at the time of hospital discharge and at 30-days mortality was equal between TT and non-TT patients. All the survivors showed a good neurological performance according to the CPC scale, except for one patient in the thrombolysis group, who had moderate disability. A surviving patient from the non-thrombolysed group was lost to follow-up after hospital discharge. In the group receiving TT mortality was not related to cardiac dysfunction; two deaths were attributed to sepsis and another to intracranial bleeding. In the non-thrombolysed group, mortality was mainly associated with cardiac dysfunction (Table 3).Table 3 Mortality, Neurological Functionality, and Adverse Events Related to the Use of Thrombolysis During Cardiopulmonary Resuscitation
Outcomes TT, n = 8 (%) Without TT, n = 8 (%) p value
ROSC (%) 8 (100) 7 (87.5) 0.30
Mortality 0
At 24 hours 2 (25) 4 (50) 0.30
Upon discharge from the ICU 5 (62.5) 5 (62.5) 1.00
To hospital discharge 5 (62.5) 5 (62.5) 1.00
At 30 days 5 (62.5) 5/7* 1.00
Causes of death 0
Cardiac 2/5 4/5 0.31
Others (e.g., sepsis) 3/5 1/5 0.24
Neurological outcome 0
No cerebral disability (CPC 1) 2/3 3/3 0.59
Moderate cerebral disability (CPC 2) 1/3 0/3 0.30
Severe cerebral disability/coma/brain death (CPC 3–5) 0/3 0/3 1.00
Hemorrhagic complications 0
Intracerebral hemorrhage 1 (12.5) 0 (0) 0.30
Other hemorrhages 1 (12.5) 0 (0) 0.30
Notes: Data expressed as absolute (%). *1 Lost at follow-up.
Abbreviations: CPC, cerebral performance categories; ICU, intensive care unit; ROSC, return of spontaneous circulation; TT, thrombolytic therapy.
Post-interventional adverse events analysis showed two hemorrhagic events occurred in the thrombolysis group; one patient had a minor urinary tract bleed, and the second experienced a fatal intracranial bleeding. In the non-thrombolysed group, no hemorrhagic events were documented.
Discussion
This study aimed to compare the outcomes of CCPR with and without thrombolysis in patients with CA secondary to PE, identifying a higher ROSC and 24-hour survival in those patients who received TT. However, no changes in survival or neurological performance at hospital discharge could be observed.
Our results are similar to those by Bottiger in 2001 and Bozeman in 2006 regarding the increase in ROSC.11,12 Bottiger et al conducted a prospective study on 90 CA patients in whom ROSC could not be achieved within the first 15 minutes of CCPR and compared the administration of unfractionated heparin with the use of TT. The group that received TT presented with a higher ROSC rate (68% vs. 44%, p = 0.026), a higher 24-hour survival rate (35% vs. 22%, p = 0.171), and higher survival to hospital discharge rate (15% vs. 8%, p = 0.1).11 Subsequently, Bozeman et al conducted a prospective study comparing thrombolysis in 50 CA patients who did not respond to CCPR, against standard CCPR in 113 additional patients. ROSC was higher in the thrombolysed group as compared with control group (26% vs. 12.4%, p = 0.04); however, there were no differences in 24-hour survival or in survival to discharge from hospital. All survivors had a good neurological performance (CPC 1–2).12
Small cohort studies from reference centers with similar facilities have found a higher ROSC rate and a higher 24-hour survival rate and survival to hospital discharge rate when administering intra-arrest thrombolysis in patients with PE.6,13–15 For example, Lederer et al observed a significant increase in the 24-hour survival rate (48.1 vs. 32.9%, p = 0.003).15 Conversely, our study found no difference in the mortality to hospital discharge rate.
The TROICA trial published in 2008 by Bottiger et al is perhaps the study that has majorly dismissed the use of intra-arrest thrombolysis. This study included 1050 patients with CA from cardiovascular-related causes; 85 (8%) of whom presented with documented PE. Further, 525 patients received TT and the remaining patients received a placebo. On comparing the thrombolysed group with the placebo group, they found no statistically significant differences for the primary outcome at the 30-day survival mark (14.7% vs. 17%, p = 0.36). In the subgroup of CA secondary to PE, survival was 13.3% (2/15) in the thrombolysed group compared with 0% (0/22) in the placebo group (p = 0.31). Our study yields similar results to those in the TROICA study in that no differences were found in neurological outcomes assessed with the CPC scale.16
Our cohort study presented one case of intracranial hemorrhage from the subjects who received thrombolysis and none from the non-thrombolysed group. This association of TT with an increased risk of hemorrhage is consistent with other findings in literature, with a low rate of intracranial hemorrhage of less than 5%.12,13,15,16
Deaths from the non-thrombolysed group occurred within 24 hours and were mostly due to cardiogenic shock, whereas deaths from patients who received thrombolysis were late and followed non-cardiac complications, mainly septic shock and cerebral hemorrhage. This finding has not been previously observed. This could mean that greater caution must be taken in the post-arrest state in order to prevent such complications and initiate timely management.
In 2019, Karsten Keller et al investigated the use of systemic thrombolysis in hospitalized patients with acute PE in Germany from 2005 to 2015, and analyzed its possible impact on early prognosis. 885 806 patients were diagnosed with acute PE. In total, systemic thrombolysis was administered to 36,917 (4.2%) PE patients.
Among hemodynamically unstable PE patients (excluding those with CCPR), case fatality rates were lower in patients who received thrombolysis compared with those without this reperfusion treatment (28.6% vs. 49.9%; P < 0.001). Overall, intracerebral bleeding was more frequent in patients who received systemic thrombolysis compared with those who did not (1.7% vs. 0.5%, P < 0.001).17 Our study shows similar outcomes in terms of mortality and complications related to TT; however, it does not meet the statistical power for the generation of hypotheses and analysis of correlation of variables is small.
Focused cardiac ultrasound results in a reliable tool for the diagnosis of PE and as a quick guide for decision making, especially in the unstable patient not tolerating transfer to the CT room. Although its usefulness has not been well established in CA, it should be considered whenever skilled human resource is available and its use does not interfere with standard cardiopulmonary resuscitation. The CTPA was not performed in all patients because of their clinical conditions (high estimated bleeding risk by physician, comorbidities, hemodynamic instability) and the imminent death in the transfer to the CT room.
In our study, the decision for thrombolysis was based on medical criteria. No predictive bleeding scale was used to make this decision. The specialists did not perform the thrombolysis if the patients had contraindications such as active bleeding, predominantly anticoagulation.
Our study has certain limitations, and results should be interpreted in the context of a case series. The small number of cases of CA secondary to PE in this study was 7%, similar to the prevalence reported for other patients with CA treated in an emergency department.3,13,16 Decision making of emergency physicians regarding the administration of TT to their patients is based on their clinical judgment, and this represents a high risk of selection bias. However, it is possible that many factors not intended in this analysis, such as witnessed CA, elapsed time from out-of-hospital CA, and CCPR duration, were considered.
Conclusion
Intra-arrest thrombolysis resulted in a greater likelihood of ROSC and a higher 24-hour survival rate in adults with CA secondary to acute PE, although it was not associated with better survival rate to hospital discharge. In our study, thrombolysis was associated with a higher risk of bleeding and sepsis, but a lower likelihood of death from cardiogenic shock as was observed in the non-thrombolysed group during CA. Thus, we recommend that special attention must be taken on strategies that may reduce these complications when thrombolysis is considered. Subsequent studies are needed in this field.
Acknowledgments
Meetings: CIMER (Congreso Internacional de Medicina de Emergencias y Reanimación CIMER 2019). Emergency Service, Fundación Valle del Lili Cra. 98 # 18–49, Cali 760032, Cali, Valle del Cauca, Colombia.
Author Contributions
All authors contributed to data analysis, drafting or revising the article, have agreed on the journal to which the article will be submitted, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.
Disclosure
Fredy Ariza report honoraries for scientific consultation from Octapharma, outside the submitted work. The authors report no other potential conflicts of interest for this work. | ALTEPLASE | DrugsGivenReaction | CC BY-NC | 33654439 | 19,030,646 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Asthenia'. | Diclofenac-Induced Immune Hemolytic Anemia: A Case Report and Review of Literature.
Non-steroidal anti-inflammatory drugs are widely used for pain management. Most frequently, adverse reactions affect the gastrointestinal tract and hematological side effects usually relate to the gastrointestinal manifestations. Drug-induced immune hemolytic anemia is a rare and frequently underdiagnosed complication that is associated with poor outcomes including organ failure and even death. A 76-year-old female patient was treated with intramuscular diclofenac, thiocolchicoside, and diazepam for low back pain. Five days following diclofenac exposure, the patient was admitted to the Emergency Department with complaints of asthenia, nausea, vomiting, and diarrhea. Hemolysis and a positive direct antiglobulin test were detected on laboratory testing. Further causes of hemolytic anemia were excluded and a diagnosis of diclofenac-induced immune hemolytic anemia was established. Glucocorticoid therapy initiated on admission and drug eviction led to complete recovery. Long-term follow-up showed no recurrence of anemia. Here, we present the unusual case of a successful recovery of a 76-year-old patient with diclofenac-induced immune hemolytic anemia, a rare but immediate life-threatening condition of a frequently used drug in clinical practice.
Introduction
Autoimmune hemolytic anemia (AIHA) ensues when the host’s immune system acts against its own red cell antigens and has an estimated prevalence of approximately 1 in 100,000 individuals [1]. Approximately 50% of the cases refer to primary or idiopathic AIHA, where an associated disorder is not found [2]. Secondary causes of AIHA depend on the studied population. Current series estimate that half are associated with hematological malignancy, a third with infection, a sixth with collagen vascular disorders, and a tenth with drug-induced immune hemolytic anemia (DIIHA), the latter reaching an estimated incidence of one per million per year [1,3].
Diclofenac is one of the non-steroidal anti-inflammatory drugs (NSAIDs) most used for the treatment of rheumatoid arthritis and osteoarthritis [4]. Though generally well tolerated, over 400 adverse reactions have been documented. Most frequently, adverse reactions affect the gastrointestinal tract, the skin, and the central nervous system [5]. Direct hematological side effects such as leukopenia, thrombocytopenia, and aplastic anemia have been described only in limited cases [6-9].
We present the case of a 76-year-old patient with diclofenac DIIHA and a summary of the pathophysiology and therapeutic options.
Case presentation
A 76-year-old woman presented to the Emergency Department (ED) with recent onset of fatigue. She had a previous medical history of essential arterial hypertension, dyslipidemia, and spinal osteoarthritis with sporadic episodes of lumbosciatic pain. Regular medications initiated several years prior included perindopril 8 mg and rosuvastatin 10 mg. No allergies, alcohol, tobacco, toxins, or animal exposures were known, and she had no other relevant personal or familiar history.
Three weeks before admission the patient had an exacerbation of right lumbosciatic pain. This episode was similar to the previous ones, for which she usually was prescribed oral NSAIDs, acetaminophen, general physical therapy, massages, and rest with complete recovery. However, this time the pain was refractory to general measures, and eight days before admission, she was prescribed a combination of a daily intramuscular administration of 4 mg thiocolchicoside, 75 mg diclofenac, and 5 mg diazepam for a total of six days.
On the fifth day of treatment, she developed generalized malaise, fatigue, nausea, postprandial vomiting, and diarrhea with up to six soft, brownish dejections per day.
Despite resolution of nausea, vomiting, and diarrhea, she experienced progressive worsening of fatigue and was admitted to the ED. Detailed medical history was negative for other symptoms, namely, fever, coluria, acholia, melena, and other evident blood losses, either on admission or in the past.
Physical examination revealed jaundice and pallor of the skin and mucous membranes. No epistaxis, gingivorrhagia, adenopathies, ecchymosis, or other skin lesions were found. Blood pressure was 137/62 mmHg and heart rate was 96 beats per minute, respiratory rate was 16 beats per minute, and peripheral oxygenation saturation was 96%. No fever or other abnormalities were noted.
Blood examination showed normocytic normochromic anemia (hemoglobin: 7.9 g/dL, reference median globular volume: 88 fL), reticulocytosis (9.2%), leucocytosis (white blood cells: 13.8 × 10 9/L), hyperbilirubinemia at the expense of unconjugated bilirubin (total bilirubin: 4.09 mg/dL, conjugated bilirubin: 0.97 mg/dL), elevated lactic dehydrogenase (805 UI/L), and sedimentation rate (VS: 76 mm). Serum iron concentration, ferritin, total iron-binding capacity, folic acid, or vitamin B12 showed no significant changes and haptoglobin levels were undetectable. Peripheral blood smear revealed exuberant erythrocyte rouleaux and spherocytes. The direct antiglobulin test (DAT) was positive for immunoglobulin G (IgG). Chest radiography, abdominal ultrasound, and electrocardiogram performed in the ED were normal.
The hypothesis of AIHA was considered in the ED. The patient was started on 60 mg of prednisolone per day (1 mg/kg/day) and was admitted to the medical ward.
The hypothesis of secondary AIHA to an infectious or a connective tissue disease was ruled out. Gastrointestinal complaints were compatible with side effects of NSAIDs, viral serologies, blood cultures, rheumatoid factor, antinuclear antibody, antineutrophil cytoplasmic antibodies, and cyclic citrullinated peptide antibody were negative, and complement (both C3 and C4 studies) was normal. Lymphoproliferative disease was excluded due to the absence of adenopathies both on physical examination and in imaging studies, as well as normal immunoglobulin levels (IgG, IgM, and IgA) and a normal serum protein electrophoresis. Inflammatory bowel disease and digestive tract tumors were also excluded by endoscopic observation and anatomopathological analysis of biopsies made in macroscopically normal mucosa.
During hospitalization, glucocorticoid therapy was maintained, and folic acid supplementation of 5 mg per day was started. The patient had clinical improvement with resolution of asthenia and jaundice, as well as progressive normalization of the hemoglobin and bilirubin values. On discharge, 13 days after admission, anemia was mild (hemoglobin: 11 g/dL) and no signs of hemolysis were noted. Table 1 shows the laboratory data during hospitalization.
Table 1 Laboratory data during hospitalization.
ALP: alkaline phosphatase; ALT: alanine aminotransferase; ANA: antinuclear antibodies; ANCA: antineutrophil cytoplasmic antibody; anti-CCP: anti-cyclic citrullinated peptides; AST: aspartate aminotransferase; GGT: gamma-glutamyl transferase; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; Ig: immunoglobulin; LDH: lactate dehydrogenase, MCV: mean corpuscular volume, TIBC: total iron binding capacity
Results
Variable Reference range (adults) Day 1 Day 2 Day 5 Day 7 Day 9 Day 13
Hemoglobin (g/dL) 11.8-15.8 7.9 7.8 8.2 9.1 10.3 11
Hematocrit (%) 36.0-46.0 21.9 22.1 24.4 26.7 30.6 33
Red blood cells (106/µL) 4.2-5.4 2.47 2.42 2.48 2.63 2.97 3.14
MCV (fL) 80.4-96.4 88.7 91.3 98.4 101.5 103 105.1
White cell count (103/µL) 4.0-10.0 13.88 12.49 18.09 15.62 11.43 11.82
Differential cell count (103/L)
Neutrophils 1.5-8.0 9.1 8.3 11.448 9.4 5.9 7.2
Lymphocytes 0.8-4.0 3.3 2.7 5.5 5.2 4.7 3.8
Platelet count (103/µL) 150-400 353 353 381 377 392 362
Reticulocytes (%) 0.5-1.5 9.22
Sedimentation rate (mm) 4-10 103 9
C-reactive protein (mg/dL) <0.51 3.23 2.67 0.69 0.41 0.23 0.14
Urea (mg/dL) 17.0-43.0 40 31 39 35 29 33
Creatinine (mg/dL) 0.6-1.0 0.84 0.78 0.8 0.78 0.84 0.79
Sodium (mmol/L) 136-145 140 141 138 143 141 142
Potassium (mmol/L) 3.5-5.1 4.2 4.2 3 3.7 4 3.9
Calcium (mg/dL) 8.6-10.3 8.7
Uric acid (mg/dL) 2.6-6 7
Bilirubin (mg/dL)
Total 0.3-1.2 4.09 4.01 2.16 2.29 2.27 1.28
Direct <0.5 0.07 0.82 0.71 0.75 0.75 0.46
LDH (UI/L) 125-220 805 632 467 436 388 309
ALP (UI/L) 30-120 152 135 96 93 90 76
GGT (UI/L) <38 83 70 55 56 54 43
ALT (UI/L) 7-45 44 19 23 30 31
AST (UI/L) 8-35 30 22 15 21 21 23
Iron (µ/dL) 70-180 124
TIBC (µ/dL) 250-245 300
Folic acid (ng/mL) 2.34-17.56 5.8
Vitamin B12 (pg/mL) 187-883 414
Haptoglobin (mg/dL) 35-250 <8
Direct antiglobulin test Positive for IgG
Protein electrophoresis No monoclonal spikes
Total proteins (g/dL) 6.4-8.2 6.1
Albumin (g/dL) 3.5-5.2 3.6
Immunoglobulins
IgA (mg/dL) 60-400 192
IgG (mg/dL) 70-1,600 1,008
IgM (mg/dL) 40-230 131
ANA Negative
ANCA Negative
Rheumatoid factor Negative
anti-CCP Negative
Serology
HIV Negative
HBV Negative
HCV Negative
Given the acute clinical context after diclofenac intake and absence of evidence for other secondary etiologies, the diagnosis of acquired hemolytic anemia secondary to NSAIDs was made. Follow-up three years later found the patient asymptomatic with no recurrence of anemia or hemolysis.
Discussion
Drugs are generally small molecules unable to elicit an immune response, however, they can function as haptens, bind to larger proteins, become immunogenic, and lead to antibody production. These antibodies can be further classified as drug-induced, drug-dependent, and drug-independent antibodies. Drug-induced antibodies can bind to red blood cells (RBCs) and lead to hemolysis by non-immunological modification of erythrocyte membranes known as adsorption of non-immunological proteins. Drug-dependent antibodies bind to RBCs only in the presence of the drug or its metabolites, causing abrupt complement-mediated intravascular hemolysis. In vitro tests searching for lysis, DAT, or indirect antiglobulin test can be performed to confirm the diagnosis using the offending drug or its metabolites and the patient’s plasma or serum. Drug-independent antibodies can react with RBCs even in the absence of the drug and, therefore, are indistinguishable from autoantibodies mediating warm autoimmune hemolytic anemia (WAIHA) [1,10,11].
WAIHA is named after warm agglutinins, usually IgG autoantibodies, that bind to antigens on erythrocytes at a temperature of 37°C, leading to RBC destruction and a chronic or relapsing disease with an almost pathognomonic positive DAT [2].
Patients are treated with glucocorticoids 1 to 2 mg/kg of body weight/day of prednisone administered orally or an equivalent dose of methylprednisolone administered intravenously. Though most patients recover to an hemoglobin level above 10 g/dL within two to three weeks of treatment, relapse after treatment discontinuation is common, with retrospective case studies suggesting long-term remission rates as low as 20% to 30% [2].
DIIHA is identified by clinical evidence of hemolysis associated with drug therapy. Although many drugs have anedoctally reported isolated cases of DIIHA, over 130 drugs have reasonable evidence that supports an immune etiology [12]. It has been speculated that DIIHA is far more common than previously estimated, as most reports usually refer to more severe cases, either presenting with shock, multiorgan damage, or renal failure, and most mild cases being unreported [6].
Drugs most frequently associated with DIIHA are second and third generation of cephalosporins, diclofenac, oxaliplatin, and fludarabine. In European cohorts where diclofenac is the most frequently used NSAID, case reviews reported diclofenac as the most frequently implicated drug, with a fatal outcome being estimated in 15% to 21% of the reported cases [6,12-16]. Diclofenac-induced immune hemolytic anemia has been demonstrated in few cases, where the exposure to the drug or its metabolites lead to developing both drug-independent IgG autoantibodies and antibodies that reacted with diclofenac and its metabolites [8].
Signs and symptoms of DIIHA, as any other hemolytic anemia, are proportional to the degree and time of onset and can present withing hours to weeks of drug exposure. These include fatigue, dyspnea, and thoracic or abdominal pain. Late symptoms are usually due to complications of decompensated hemolysis, usually shock or renal failure. Laboratory abnormalities include low hemoglobin and haptoglobin levels, elevated lactate dehydrogenase and indirect bilirubin levels, reticulocytosis, and a positive DAT [1,10].
The DAT is positive in all the described forms of DIIHA, either for IgG, C3, or both. Rare cases with negative DAT reported either low antibody density, massive intravascular hemolysis, or red cell transfusion administered prior to testing [1,10]. When approaching a case where there is evidence of hemolysis and an established temporal relationship with a drug known to induce autoantibody production, investigation for drug-dependent antibodies can be performed in adequate laboratory settings, with quality ensured expertise and appropriate controls [1,3].
As there are no defining clinical features and drug-induced autoantibodies are indistinguishable from idiopathic autoantibodies, misdiagnosis in DIIHA is extremely common, with some patients dying because of late diagnosis. Furthermore, hemolysis and serological results can persist for up to months after withdrawal of the drug, leading to erroneous attribution of recovery on the administered treatment and not to the interruption of the drug [6].
If DIIHA is suspected, relevant medication should be withdrawn immediately. In mild cases, recovery usually happens within one to two weeks after drug suspension, with no other necessary measures. As most drugs have a relatively short half-life, even a strong drug-dependent antibody loses its effect shortly after drug suspension [1]. Failure to recognize DIIHA can have disastrous consequences, especially when patients present complaints for which the offending drug was prescribed. Regarding diclofenac DIIHA, some cases have been reported of patients receiving the drug again for “low back pain” during the early onset of hemolysis [9].
In acute severe DIIHA, recommendations suggest close monitoring of clinical and laboratory signs, early intravenous access, and fluid resuscitation. Blood transfusion should not be withheld in patients with severe anemia [3]. Even though crossmatch-compatible blood can be difficult to find, a review of 134 patients showed that 68 (55%) patients received blood transfusions. Though most patients (85%) received glucocorticoids, its benefit is uncertain and its routine use is not recommended as drug eviction is usually enough to stop the immune response [14].
Applying the criteria of the World Health Organization causality assessment method to assess a possible drug‐induced etiology of IHA we are confident the most likely diagnosis for our patient was diclofenac-induced IHA [17]. Our analysis is supported by: (a) the presence of autoantibodies in the patient’s eluate was demonstrated; (b) diclofenac is known to induce DIIHA; (c) there is a chronological relationship between hemolysis and diclofenac administration; (d) a review of the literature failed to show cases of DIIHA induced by any of the other drugs taken by the patient; (e) symptoms and laboratory signs significantly improved after discontinuation of diclofenac; (f) no coexistent neoplastic, autoimmune, or infectious diseases known to be secondary causes of AIHA were found after systematic and comprehensive studies; and (g) though glucocorticoids were started on admission, no recurrence of anemia was verified in a three-year follow-up period, which would be uncommon if the patient suffered from WAIHA.
Conclusions
As a potentially fatal complication of a widely used drug in clinical practice such as diclofenac, early and correct diagnosis of DIIHA and prompt removal of the offending drug is crucial for the patient’s recovery. Our case highlights the need for both prescribing physicians and patients to be aware of this frequently underreported and usually misdiagnosed entity.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
Appendices
Table 2 Causality categories. Adapted from the WHO-UMC system for standardized case causality assessment. The usual approach is to choose one of the causality terms’ categories and to test if the various criteria fit the content of the case report. All assessment criteria should be reasonably complied to assume a category. The WHO-UMC causality assessment system can be used for the assessment of case reports of adverse drug reactions or drug-drug interactions.
WHO-UMC, World Health Organization-Uppsala Monitoring Centre
Causality term Assessment criteria
Certain • Event or laboratory test abnormality, with plausible time relationship to drug intake • Cannot be explained by disease or other drugs • Response to withdrawal plausible (pharmacologically, pathologically) • Event definitive pharmacologically or phenomenologically (i.e., an objective and specific medical disorder or a recognized pharmacological phenomenon) • Rechallenge satisfactory, if necessary
Probable/Likely • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Unlikely to be attributed to disease or other drugs • Response to withdrawal clinically reasonable • Rechallenge not required
Possible • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Could also be explained by disease or other drugs • Information on drug withdrawal may be lacking or unclear
Unlikely • Event or laboratory test abnormality, with a time to drug intake that makes a relationship improbable (but not impossible) • Disease or other drugs provide plausible explanations
Conditional/Unclassified • Event or laboratory test abnormality • More data for proper assessment needed • Additional data under examination
Unassessable/Unclassifiable • Report suggesting an adverse reaction • Cannot be judged because information is insufficient or contradictory • Data cannot be supplemented or verified | ACETAMINOPHEN, DIAZEPAM, DICLOFENAC, PERINDOPRIL, ROSUVASTATIN, THIOCOLCHICOSIDE | DrugsGivenReaction | CC BY | 33654588 | 19,027,243 | 2021-01-25 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Diarrhoea'. | Diclofenac-Induced Immune Hemolytic Anemia: A Case Report and Review of Literature.
Non-steroidal anti-inflammatory drugs are widely used for pain management. Most frequently, adverse reactions affect the gastrointestinal tract and hematological side effects usually relate to the gastrointestinal manifestations. Drug-induced immune hemolytic anemia is a rare and frequently underdiagnosed complication that is associated with poor outcomes including organ failure and even death. A 76-year-old female patient was treated with intramuscular diclofenac, thiocolchicoside, and diazepam for low back pain. Five days following diclofenac exposure, the patient was admitted to the Emergency Department with complaints of asthenia, nausea, vomiting, and diarrhea. Hemolysis and a positive direct antiglobulin test were detected on laboratory testing. Further causes of hemolytic anemia were excluded and a diagnosis of diclofenac-induced immune hemolytic anemia was established. Glucocorticoid therapy initiated on admission and drug eviction led to complete recovery. Long-term follow-up showed no recurrence of anemia. Here, we present the unusual case of a successful recovery of a 76-year-old patient with diclofenac-induced immune hemolytic anemia, a rare but immediate life-threatening condition of a frequently used drug in clinical practice.
Introduction
Autoimmune hemolytic anemia (AIHA) ensues when the host’s immune system acts against its own red cell antigens and has an estimated prevalence of approximately 1 in 100,000 individuals [1]. Approximately 50% of the cases refer to primary or idiopathic AIHA, where an associated disorder is not found [2]. Secondary causes of AIHA depend on the studied population. Current series estimate that half are associated with hematological malignancy, a third with infection, a sixth with collagen vascular disorders, and a tenth with drug-induced immune hemolytic anemia (DIIHA), the latter reaching an estimated incidence of one per million per year [1,3].
Diclofenac is one of the non-steroidal anti-inflammatory drugs (NSAIDs) most used for the treatment of rheumatoid arthritis and osteoarthritis [4]. Though generally well tolerated, over 400 adverse reactions have been documented. Most frequently, adverse reactions affect the gastrointestinal tract, the skin, and the central nervous system [5]. Direct hematological side effects such as leukopenia, thrombocytopenia, and aplastic anemia have been described only in limited cases [6-9].
We present the case of a 76-year-old patient with diclofenac DIIHA and a summary of the pathophysiology and therapeutic options.
Case presentation
A 76-year-old woman presented to the Emergency Department (ED) with recent onset of fatigue. She had a previous medical history of essential arterial hypertension, dyslipidemia, and spinal osteoarthritis with sporadic episodes of lumbosciatic pain. Regular medications initiated several years prior included perindopril 8 mg and rosuvastatin 10 mg. No allergies, alcohol, tobacco, toxins, or animal exposures were known, and she had no other relevant personal or familiar history.
Three weeks before admission the patient had an exacerbation of right lumbosciatic pain. This episode was similar to the previous ones, for which she usually was prescribed oral NSAIDs, acetaminophen, general physical therapy, massages, and rest with complete recovery. However, this time the pain was refractory to general measures, and eight days before admission, she was prescribed a combination of a daily intramuscular administration of 4 mg thiocolchicoside, 75 mg diclofenac, and 5 mg diazepam for a total of six days.
On the fifth day of treatment, she developed generalized malaise, fatigue, nausea, postprandial vomiting, and diarrhea with up to six soft, brownish dejections per day.
Despite resolution of nausea, vomiting, and diarrhea, she experienced progressive worsening of fatigue and was admitted to the ED. Detailed medical history was negative for other symptoms, namely, fever, coluria, acholia, melena, and other evident blood losses, either on admission or in the past.
Physical examination revealed jaundice and pallor of the skin and mucous membranes. No epistaxis, gingivorrhagia, adenopathies, ecchymosis, or other skin lesions were found. Blood pressure was 137/62 mmHg and heart rate was 96 beats per minute, respiratory rate was 16 beats per minute, and peripheral oxygenation saturation was 96%. No fever or other abnormalities were noted.
Blood examination showed normocytic normochromic anemia (hemoglobin: 7.9 g/dL, reference median globular volume: 88 fL), reticulocytosis (9.2%), leucocytosis (white blood cells: 13.8 × 10 9/L), hyperbilirubinemia at the expense of unconjugated bilirubin (total bilirubin: 4.09 mg/dL, conjugated bilirubin: 0.97 mg/dL), elevated lactic dehydrogenase (805 UI/L), and sedimentation rate (VS: 76 mm). Serum iron concentration, ferritin, total iron-binding capacity, folic acid, or vitamin B12 showed no significant changes and haptoglobin levels were undetectable. Peripheral blood smear revealed exuberant erythrocyte rouleaux and spherocytes. The direct antiglobulin test (DAT) was positive for immunoglobulin G (IgG). Chest radiography, abdominal ultrasound, and electrocardiogram performed in the ED were normal.
The hypothesis of AIHA was considered in the ED. The patient was started on 60 mg of prednisolone per day (1 mg/kg/day) and was admitted to the medical ward.
The hypothesis of secondary AIHA to an infectious or a connective tissue disease was ruled out. Gastrointestinal complaints were compatible with side effects of NSAIDs, viral serologies, blood cultures, rheumatoid factor, antinuclear antibody, antineutrophil cytoplasmic antibodies, and cyclic citrullinated peptide antibody were negative, and complement (both C3 and C4 studies) was normal. Lymphoproliferative disease was excluded due to the absence of adenopathies both on physical examination and in imaging studies, as well as normal immunoglobulin levels (IgG, IgM, and IgA) and a normal serum protein electrophoresis. Inflammatory bowel disease and digestive tract tumors were also excluded by endoscopic observation and anatomopathological analysis of biopsies made in macroscopically normal mucosa.
During hospitalization, glucocorticoid therapy was maintained, and folic acid supplementation of 5 mg per day was started. The patient had clinical improvement with resolution of asthenia and jaundice, as well as progressive normalization of the hemoglobin and bilirubin values. On discharge, 13 days after admission, anemia was mild (hemoglobin: 11 g/dL) and no signs of hemolysis were noted. Table 1 shows the laboratory data during hospitalization.
Table 1 Laboratory data during hospitalization.
ALP: alkaline phosphatase; ALT: alanine aminotransferase; ANA: antinuclear antibodies; ANCA: antineutrophil cytoplasmic antibody; anti-CCP: anti-cyclic citrullinated peptides; AST: aspartate aminotransferase; GGT: gamma-glutamyl transferase; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; Ig: immunoglobulin; LDH: lactate dehydrogenase, MCV: mean corpuscular volume, TIBC: total iron binding capacity
Results
Variable Reference range (adults) Day 1 Day 2 Day 5 Day 7 Day 9 Day 13
Hemoglobin (g/dL) 11.8-15.8 7.9 7.8 8.2 9.1 10.3 11
Hematocrit (%) 36.0-46.0 21.9 22.1 24.4 26.7 30.6 33
Red blood cells (106/µL) 4.2-5.4 2.47 2.42 2.48 2.63 2.97 3.14
MCV (fL) 80.4-96.4 88.7 91.3 98.4 101.5 103 105.1
White cell count (103/µL) 4.0-10.0 13.88 12.49 18.09 15.62 11.43 11.82
Differential cell count (103/L)
Neutrophils 1.5-8.0 9.1 8.3 11.448 9.4 5.9 7.2
Lymphocytes 0.8-4.0 3.3 2.7 5.5 5.2 4.7 3.8
Platelet count (103/µL) 150-400 353 353 381 377 392 362
Reticulocytes (%) 0.5-1.5 9.22
Sedimentation rate (mm) 4-10 103 9
C-reactive protein (mg/dL) <0.51 3.23 2.67 0.69 0.41 0.23 0.14
Urea (mg/dL) 17.0-43.0 40 31 39 35 29 33
Creatinine (mg/dL) 0.6-1.0 0.84 0.78 0.8 0.78 0.84 0.79
Sodium (mmol/L) 136-145 140 141 138 143 141 142
Potassium (mmol/L) 3.5-5.1 4.2 4.2 3 3.7 4 3.9
Calcium (mg/dL) 8.6-10.3 8.7
Uric acid (mg/dL) 2.6-6 7
Bilirubin (mg/dL)
Total 0.3-1.2 4.09 4.01 2.16 2.29 2.27 1.28
Direct <0.5 0.07 0.82 0.71 0.75 0.75 0.46
LDH (UI/L) 125-220 805 632 467 436 388 309
ALP (UI/L) 30-120 152 135 96 93 90 76
GGT (UI/L) <38 83 70 55 56 54 43
ALT (UI/L) 7-45 44 19 23 30 31
AST (UI/L) 8-35 30 22 15 21 21 23
Iron (µ/dL) 70-180 124
TIBC (µ/dL) 250-245 300
Folic acid (ng/mL) 2.34-17.56 5.8
Vitamin B12 (pg/mL) 187-883 414
Haptoglobin (mg/dL) 35-250 <8
Direct antiglobulin test Positive for IgG
Protein electrophoresis No monoclonal spikes
Total proteins (g/dL) 6.4-8.2 6.1
Albumin (g/dL) 3.5-5.2 3.6
Immunoglobulins
IgA (mg/dL) 60-400 192
IgG (mg/dL) 70-1,600 1,008
IgM (mg/dL) 40-230 131
ANA Negative
ANCA Negative
Rheumatoid factor Negative
anti-CCP Negative
Serology
HIV Negative
HBV Negative
HCV Negative
Given the acute clinical context after diclofenac intake and absence of evidence for other secondary etiologies, the diagnosis of acquired hemolytic anemia secondary to NSAIDs was made. Follow-up three years later found the patient asymptomatic with no recurrence of anemia or hemolysis.
Discussion
Drugs are generally small molecules unable to elicit an immune response, however, they can function as haptens, bind to larger proteins, become immunogenic, and lead to antibody production. These antibodies can be further classified as drug-induced, drug-dependent, and drug-independent antibodies. Drug-induced antibodies can bind to red blood cells (RBCs) and lead to hemolysis by non-immunological modification of erythrocyte membranes known as adsorption of non-immunological proteins. Drug-dependent antibodies bind to RBCs only in the presence of the drug or its metabolites, causing abrupt complement-mediated intravascular hemolysis. In vitro tests searching for lysis, DAT, or indirect antiglobulin test can be performed to confirm the diagnosis using the offending drug or its metabolites and the patient’s plasma or serum. Drug-independent antibodies can react with RBCs even in the absence of the drug and, therefore, are indistinguishable from autoantibodies mediating warm autoimmune hemolytic anemia (WAIHA) [1,10,11].
WAIHA is named after warm agglutinins, usually IgG autoantibodies, that bind to antigens on erythrocytes at a temperature of 37°C, leading to RBC destruction and a chronic or relapsing disease with an almost pathognomonic positive DAT [2].
Patients are treated with glucocorticoids 1 to 2 mg/kg of body weight/day of prednisone administered orally or an equivalent dose of methylprednisolone administered intravenously. Though most patients recover to an hemoglobin level above 10 g/dL within two to three weeks of treatment, relapse after treatment discontinuation is common, with retrospective case studies suggesting long-term remission rates as low as 20% to 30% [2].
DIIHA is identified by clinical evidence of hemolysis associated with drug therapy. Although many drugs have anedoctally reported isolated cases of DIIHA, over 130 drugs have reasonable evidence that supports an immune etiology [12]. It has been speculated that DIIHA is far more common than previously estimated, as most reports usually refer to more severe cases, either presenting with shock, multiorgan damage, or renal failure, and most mild cases being unreported [6].
Drugs most frequently associated with DIIHA are second and third generation of cephalosporins, diclofenac, oxaliplatin, and fludarabine. In European cohorts where diclofenac is the most frequently used NSAID, case reviews reported diclofenac as the most frequently implicated drug, with a fatal outcome being estimated in 15% to 21% of the reported cases [6,12-16]. Diclofenac-induced immune hemolytic anemia has been demonstrated in few cases, where the exposure to the drug or its metabolites lead to developing both drug-independent IgG autoantibodies and antibodies that reacted with diclofenac and its metabolites [8].
Signs and symptoms of DIIHA, as any other hemolytic anemia, are proportional to the degree and time of onset and can present withing hours to weeks of drug exposure. These include fatigue, dyspnea, and thoracic or abdominal pain. Late symptoms are usually due to complications of decompensated hemolysis, usually shock or renal failure. Laboratory abnormalities include low hemoglobin and haptoglobin levels, elevated lactate dehydrogenase and indirect bilirubin levels, reticulocytosis, and a positive DAT [1,10].
The DAT is positive in all the described forms of DIIHA, either for IgG, C3, or both. Rare cases with negative DAT reported either low antibody density, massive intravascular hemolysis, or red cell transfusion administered prior to testing [1,10]. When approaching a case where there is evidence of hemolysis and an established temporal relationship with a drug known to induce autoantibody production, investigation for drug-dependent antibodies can be performed in adequate laboratory settings, with quality ensured expertise and appropriate controls [1,3].
As there are no defining clinical features and drug-induced autoantibodies are indistinguishable from idiopathic autoantibodies, misdiagnosis in DIIHA is extremely common, with some patients dying because of late diagnosis. Furthermore, hemolysis and serological results can persist for up to months after withdrawal of the drug, leading to erroneous attribution of recovery on the administered treatment and not to the interruption of the drug [6].
If DIIHA is suspected, relevant medication should be withdrawn immediately. In mild cases, recovery usually happens within one to two weeks after drug suspension, with no other necessary measures. As most drugs have a relatively short half-life, even a strong drug-dependent antibody loses its effect shortly after drug suspension [1]. Failure to recognize DIIHA can have disastrous consequences, especially when patients present complaints for which the offending drug was prescribed. Regarding diclofenac DIIHA, some cases have been reported of patients receiving the drug again for “low back pain” during the early onset of hemolysis [9].
In acute severe DIIHA, recommendations suggest close monitoring of clinical and laboratory signs, early intravenous access, and fluid resuscitation. Blood transfusion should not be withheld in patients with severe anemia [3]. Even though crossmatch-compatible blood can be difficult to find, a review of 134 patients showed that 68 (55%) patients received blood transfusions. Though most patients (85%) received glucocorticoids, its benefit is uncertain and its routine use is not recommended as drug eviction is usually enough to stop the immune response [14].
Applying the criteria of the World Health Organization causality assessment method to assess a possible drug‐induced etiology of IHA we are confident the most likely diagnosis for our patient was diclofenac-induced IHA [17]. Our analysis is supported by: (a) the presence of autoantibodies in the patient’s eluate was demonstrated; (b) diclofenac is known to induce DIIHA; (c) there is a chronological relationship between hemolysis and diclofenac administration; (d) a review of the literature failed to show cases of DIIHA induced by any of the other drugs taken by the patient; (e) symptoms and laboratory signs significantly improved after discontinuation of diclofenac; (f) no coexistent neoplastic, autoimmune, or infectious diseases known to be secondary causes of AIHA were found after systematic and comprehensive studies; and (g) though glucocorticoids were started on admission, no recurrence of anemia was verified in a three-year follow-up period, which would be uncommon if the patient suffered from WAIHA.
Conclusions
As a potentially fatal complication of a widely used drug in clinical practice such as diclofenac, early and correct diagnosis of DIIHA and prompt removal of the offending drug is crucial for the patient’s recovery. Our case highlights the need for both prescribing physicians and patients to be aware of this frequently underreported and usually misdiagnosed entity.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
Appendices
Table 2 Causality categories. Adapted from the WHO-UMC system for standardized case causality assessment. The usual approach is to choose one of the causality terms’ categories and to test if the various criteria fit the content of the case report. All assessment criteria should be reasonably complied to assume a category. The WHO-UMC causality assessment system can be used for the assessment of case reports of adverse drug reactions or drug-drug interactions.
WHO-UMC, World Health Organization-Uppsala Monitoring Centre
Causality term Assessment criteria
Certain • Event or laboratory test abnormality, with plausible time relationship to drug intake • Cannot be explained by disease or other drugs • Response to withdrawal plausible (pharmacologically, pathologically) • Event definitive pharmacologically or phenomenologically (i.e., an objective and specific medical disorder or a recognized pharmacological phenomenon) • Rechallenge satisfactory, if necessary
Probable/Likely • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Unlikely to be attributed to disease or other drugs • Response to withdrawal clinically reasonable • Rechallenge not required
Possible • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Could also be explained by disease or other drugs • Information on drug withdrawal may be lacking or unclear
Unlikely • Event or laboratory test abnormality, with a time to drug intake that makes a relationship improbable (but not impossible) • Disease or other drugs provide plausible explanations
Conditional/Unclassified • Event or laboratory test abnormality • More data for proper assessment needed • Additional data under examination
Unassessable/Unclassifiable • Report suggesting an adverse reaction • Cannot be judged because information is insufficient or contradictory • Data cannot be supplemented or verified | ACETAMINOPHEN, DIAZEPAM, DICLOFENAC, PERINDOPRIL, ROSUVASTATIN, THIOCOLCHICOSIDE | DrugsGivenReaction | CC BY | 33654588 | 19,027,243 | 2021-01-25 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Fatigue'. | Diclofenac-Induced Immune Hemolytic Anemia: A Case Report and Review of Literature.
Non-steroidal anti-inflammatory drugs are widely used for pain management. Most frequently, adverse reactions affect the gastrointestinal tract and hematological side effects usually relate to the gastrointestinal manifestations. Drug-induced immune hemolytic anemia is a rare and frequently underdiagnosed complication that is associated with poor outcomes including organ failure and even death. A 76-year-old female patient was treated with intramuscular diclofenac, thiocolchicoside, and diazepam for low back pain. Five days following diclofenac exposure, the patient was admitted to the Emergency Department with complaints of asthenia, nausea, vomiting, and diarrhea. Hemolysis and a positive direct antiglobulin test were detected on laboratory testing. Further causes of hemolytic anemia were excluded and a diagnosis of diclofenac-induced immune hemolytic anemia was established. Glucocorticoid therapy initiated on admission and drug eviction led to complete recovery. Long-term follow-up showed no recurrence of anemia. Here, we present the unusual case of a successful recovery of a 76-year-old patient with diclofenac-induced immune hemolytic anemia, a rare but immediate life-threatening condition of a frequently used drug in clinical practice.
Introduction
Autoimmune hemolytic anemia (AIHA) ensues when the host’s immune system acts against its own red cell antigens and has an estimated prevalence of approximately 1 in 100,000 individuals [1]. Approximately 50% of the cases refer to primary or idiopathic AIHA, where an associated disorder is not found [2]. Secondary causes of AIHA depend on the studied population. Current series estimate that half are associated with hematological malignancy, a third with infection, a sixth with collagen vascular disorders, and a tenth with drug-induced immune hemolytic anemia (DIIHA), the latter reaching an estimated incidence of one per million per year [1,3].
Diclofenac is one of the non-steroidal anti-inflammatory drugs (NSAIDs) most used for the treatment of rheumatoid arthritis and osteoarthritis [4]. Though generally well tolerated, over 400 adverse reactions have been documented. Most frequently, adverse reactions affect the gastrointestinal tract, the skin, and the central nervous system [5]. Direct hematological side effects such as leukopenia, thrombocytopenia, and aplastic anemia have been described only in limited cases [6-9].
We present the case of a 76-year-old patient with diclofenac DIIHA and a summary of the pathophysiology and therapeutic options.
Case presentation
A 76-year-old woman presented to the Emergency Department (ED) with recent onset of fatigue. She had a previous medical history of essential arterial hypertension, dyslipidemia, and spinal osteoarthritis with sporadic episodes of lumbosciatic pain. Regular medications initiated several years prior included perindopril 8 mg and rosuvastatin 10 mg. No allergies, alcohol, tobacco, toxins, or animal exposures were known, and she had no other relevant personal or familiar history.
Three weeks before admission the patient had an exacerbation of right lumbosciatic pain. This episode was similar to the previous ones, for which she usually was prescribed oral NSAIDs, acetaminophen, general physical therapy, massages, and rest with complete recovery. However, this time the pain was refractory to general measures, and eight days before admission, she was prescribed a combination of a daily intramuscular administration of 4 mg thiocolchicoside, 75 mg diclofenac, and 5 mg diazepam for a total of six days.
On the fifth day of treatment, she developed generalized malaise, fatigue, nausea, postprandial vomiting, and diarrhea with up to six soft, brownish dejections per day.
Despite resolution of nausea, vomiting, and diarrhea, she experienced progressive worsening of fatigue and was admitted to the ED. Detailed medical history was negative for other symptoms, namely, fever, coluria, acholia, melena, and other evident blood losses, either on admission or in the past.
Physical examination revealed jaundice and pallor of the skin and mucous membranes. No epistaxis, gingivorrhagia, adenopathies, ecchymosis, or other skin lesions were found. Blood pressure was 137/62 mmHg and heart rate was 96 beats per minute, respiratory rate was 16 beats per minute, and peripheral oxygenation saturation was 96%. No fever or other abnormalities were noted.
Blood examination showed normocytic normochromic anemia (hemoglobin: 7.9 g/dL, reference median globular volume: 88 fL), reticulocytosis (9.2%), leucocytosis (white blood cells: 13.8 × 10 9/L), hyperbilirubinemia at the expense of unconjugated bilirubin (total bilirubin: 4.09 mg/dL, conjugated bilirubin: 0.97 mg/dL), elevated lactic dehydrogenase (805 UI/L), and sedimentation rate (VS: 76 mm). Serum iron concentration, ferritin, total iron-binding capacity, folic acid, or vitamin B12 showed no significant changes and haptoglobin levels were undetectable. Peripheral blood smear revealed exuberant erythrocyte rouleaux and spherocytes. The direct antiglobulin test (DAT) was positive for immunoglobulin G (IgG). Chest radiography, abdominal ultrasound, and electrocardiogram performed in the ED were normal.
The hypothesis of AIHA was considered in the ED. The patient was started on 60 mg of prednisolone per day (1 mg/kg/day) and was admitted to the medical ward.
The hypothesis of secondary AIHA to an infectious or a connective tissue disease was ruled out. Gastrointestinal complaints were compatible with side effects of NSAIDs, viral serologies, blood cultures, rheumatoid factor, antinuclear antibody, antineutrophil cytoplasmic antibodies, and cyclic citrullinated peptide antibody were negative, and complement (both C3 and C4 studies) was normal. Lymphoproliferative disease was excluded due to the absence of adenopathies both on physical examination and in imaging studies, as well as normal immunoglobulin levels (IgG, IgM, and IgA) and a normal serum protein electrophoresis. Inflammatory bowel disease and digestive tract tumors were also excluded by endoscopic observation and anatomopathological analysis of biopsies made in macroscopically normal mucosa.
During hospitalization, glucocorticoid therapy was maintained, and folic acid supplementation of 5 mg per day was started. The patient had clinical improvement with resolution of asthenia and jaundice, as well as progressive normalization of the hemoglobin and bilirubin values. On discharge, 13 days after admission, anemia was mild (hemoglobin: 11 g/dL) and no signs of hemolysis were noted. Table 1 shows the laboratory data during hospitalization.
Table 1 Laboratory data during hospitalization.
ALP: alkaline phosphatase; ALT: alanine aminotransferase; ANA: antinuclear antibodies; ANCA: antineutrophil cytoplasmic antibody; anti-CCP: anti-cyclic citrullinated peptides; AST: aspartate aminotransferase; GGT: gamma-glutamyl transferase; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; Ig: immunoglobulin; LDH: lactate dehydrogenase, MCV: mean corpuscular volume, TIBC: total iron binding capacity
Results
Variable Reference range (adults) Day 1 Day 2 Day 5 Day 7 Day 9 Day 13
Hemoglobin (g/dL) 11.8-15.8 7.9 7.8 8.2 9.1 10.3 11
Hematocrit (%) 36.0-46.0 21.9 22.1 24.4 26.7 30.6 33
Red blood cells (106/µL) 4.2-5.4 2.47 2.42 2.48 2.63 2.97 3.14
MCV (fL) 80.4-96.4 88.7 91.3 98.4 101.5 103 105.1
White cell count (103/µL) 4.0-10.0 13.88 12.49 18.09 15.62 11.43 11.82
Differential cell count (103/L)
Neutrophils 1.5-8.0 9.1 8.3 11.448 9.4 5.9 7.2
Lymphocytes 0.8-4.0 3.3 2.7 5.5 5.2 4.7 3.8
Platelet count (103/µL) 150-400 353 353 381 377 392 362
Reticulocytes (%) 0.5-1.5 9.22
Sedimentation rate (mm) 4-10 103 9
C-reactive protein (mg/dL) <0.51 3.23 2.67 0.69 0.41 0.23 0.14
Urea (mg/dL) 17.0-43.0 40 31 39 35 29 33
Creatinine (mg/dL) 0.6-1.0 0.84 0.78 0.8 0.78 0.84 0.79
Sodium (mmol/L) 136-145 140 141 138 143 141 142
Potassium (mmol/L) 3.5-5.1 4.2 4.2 3 3.7 4 3.9
Calcium (mg/dL) 8.6-10.3 8.7
Uric acid (mg/dL) 2.6-6 7
Bilirubin (mg/dL)
Total 0.3-1.2 4.09 4.01 2.16 2.29 2.27 1.28
Direct <0.5 0.07 0.82 0.71 0.75 0.75 0.46
LDH (UI/L) 125-220 805 632 467 436 388 309
ALP (UI/L) 30-120 152 135 96 93 90 76
GGT (UI/L) <38 83 70 55 56 54 43
ALT (UI/L) 7-45 44 19 23 30 31
AST (UI/L) 8-35 30 22 15 21 21 23
Iron (µ/dL) 70-180 124
TIBC (µ/dL) 250-245 300
Folic acid (ng/mL) 2.34-17.56 5.8
Vitamin B12 (pg/mL) 187-883 414
Haptoglobin (mg/dL) 35-250 <8
Direct antiglobulin test Positive for IgG
Protein electrophoresis No monoclonal spikes
Total proteins (g/dL) 6.4-8.2 6.1
Albumin (g/dL) 3.5-5.2 3.6
Immunoglobulins
IgA (mg/dL) 60-400 192
IgG (mg/dL) 70-1,600 1,008
IgM (mg/dL) 40-230 131
ANA Negative
ANCA Negative
Rheumatoid factor Negative
anti-CCP Negative
Serology
HIV Negative
HBV Negative
HCV Negative
Given the acute clinical context after diclofenac intake and absence of evidence for other secondary etiologies, the diagnosis of acquired hemolytic anemia secondary to NSAIDs was made. Follow-up three years later found the patient asymptomatic with no recurrence of anemia or hemolysis.
Discussion
Drugs are generally small molecules unable to elicit an immune response, however, they can function as haptens, bind to larger proteins, become immunogenic, and lead to antibody production. These antibodies can be further classified as drug-induced, drug-dependent, and drug-independent antibodies. Drug-induced antibodies can bind to red blood cells (RBCs) and lead to hemolysis by non-immunological modification of erythrocyte membranes known as adsorption of non-immunological proteins. Drug-dependent antibodies bind to RBCs only in the presence of the drug or its metabolites, causing abrupt complement-mediated intravascular hemolysis. In vitro tests searching for lysis, DAT, or indirect antiglobulin test can be performed to confirm the diagnosis using the offending drug or its metabolites and the patient’s plasma or serum. Drug-independent antibodies can react with RBCs even in the absence of the drug and, therefore, are indistinguishable from autoantibodies mediating warm autoimmune hemolytic anemia (WAIHA) [1,10,11].
WAIHA is named after warm agglutinins, usually IgG autoantibodies, that bind to antigens on erythrocytes at a temperature of 37°C, leading to RBC destruction and a chronic or relapsing disease with an almost pathognomonic positive DAT [2].
Patients are treated with glucocorticoids 1 to 2 mg/kg of body weight/day of prednisone administered orally or an equivalent dose of methylprednisolone administered intravenously. Though most patients recover to an hemoglobin level above 10 g/dL within two to three weeks of treatment, relapse after treatment discontinuation is common, with retrospective case studies suggesting long-term remission rates as low as 20% to 30% [2].
DIIHA is identified by clinical evidence of hemolysis associated with drug therapy. Although many drugs have anedoctally reported isolated cases of DIIHA, over 130 drugs have reasonable evidence that supports an immune etiology [12]. It has been speculated that DIIHA is far more common than previously estimated, as most reports usually refer to more severe cases, either presenting with shock, multiorgan damage, or renal failure, and most mild cases being unreported [6].
Drugs most frequently associated with DIIHA are second and third generation of cephalosporins, diclofenac, oxaliplatin, and fludarabine. In European cohorts where diclofenac is the most frequently used NSAID, case reviews reported diclofenac as the most frequently implicated drug, with a fatal outcome being estimated in 15% to 21% of the reported cases [6,12-16]. Diclofenac-induced immune hemolytic anemia has been demonstrated in few cases, where the exposure to the drug or its metabolites lead to developing both drug-independent IgG autoantibodies and antibodies that reacted with diclofenac and its metabolites [8].
Signs and symptoms of DIIHA, as any other hemolytic anemia, are proportional to the degree and time of onset and can present withing hours to weeks of drug exposure. These include fatigue, dyspnea, and thoracic or abdominal pain. Late symptoms are usually due to complications of decompensated hemolysis, usually shock or renal failure. Laboratory abnormalities include low hemoglobin and haptoglobin levels, elevated lactate dehydrogenase and indirect bilirubin levels, reticulocytosis, and a positive DAT [1,10].
The DAT is positive in all the described forms of DIIHA, either for IgG, C3, or both. Rare cases with negative DAT reported either low antibody density, massive intravascular hemolysis, or red cell transfusion administered prior to testing [1,10]. When approaching a case where there is evidence of hemolysis and an established temporal relationship with a drug known to induce autoantibody production, investigation for drug-dependent antibodies can be performed in adequate laboratory settings, with quality ensured expertise and appropriate controls [1,3].
As there are no defining clinical features and drug-induced autoantibodies are indistinguishable from idiopathic autoantibodies, misdiagnosis in DIIHA is extremely common, with some patients dying because of late diagnosis. Furthermore, hemolysis and serological results can persist for up to months after withdrawal of the drug, leading to erroneous attribution of recovery on the administered treatment and not to the interruption of the drug [6].
If DIIHA is suspected, relevant medication should be withdrawn immediately. In mild cases, recovery usually happens within one to two weeks after drug suspension, with no other necessary measures. As most drugs have a relatively short half-life, even a strong drug-dependent antibody loses its effect shortly after drug suspension [1]. Failure to recognize DIIHA can have disastrous consequences, especially when patients present complaints for which the offending drug was prescribed. Regarding diclofenac DIIHA, some cases have been reported of patients receiving the drug again for “low back pain” during the early onset of hemolysis [9].
In acute severe DIIHA, recommendations suggest close monitoring of clinical and laboratory signs, early intravenous access, and fluid resuscitation. Blood transfusion should not be withheld in patients with severe anemia [3]. Even though crossmatch-compatible blood can be difficult to find, a review of 134 patients showed that 68 (55%) patients received blood transfusions. Though most patients (85%) received glucocorticoids, its benefit is uncertain and its routine use is not recommended as drug eviction is usually enough to stop the immune response [14].
Applying the criteria of the World Health Organization causality assessment method to assess a possible drug‐induced etiology of IHA we are confident the most likely diagnosis for our patient was diclofenac-induced IHA [17]. Our analysis is supported by: (a) the presence of autoantibodies in the patient’s eluate was demonstrated; (b) diclofenac is known to induce DIIHA; (c) there is a chronological relationship between hemolysis and diclofenac administration; (d) a review of the literature failed to show cases of DIIHA induced by any of the other drugs taken by the patient; (e) symptoms and laboratory signs significantly improved after discontinuation of diclofenac; (f) no coexistent neoplastic, autoimmune, or infectious diseases known to be secondary causes of AIHA were found after systematic and comprehensive studies; and (g) though glucocorticoids were started on admission, no recurrence of anemia was verified in a three-year follow-up period, which would be uncommon if the patient suffered from WAIHA.
Conclusions
As a potentially fatal complication of a widely used drug in clinical practice such as diclofenac, early and correct diagnosis of DIIHA and prompt removal of the offending drug is crucial for the patient’s recovery. Our case highlights the need for both prescribing physicians and patients to be aware of this frequently underreported and usually misdiagnosed entity.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
Appendices
Table 2 Causality categories. Adapted from the WHO-UMC system for standardized case causality assessment. The usual approach is to choose one of the causality terms’ categories and to test if the various criteria fit the content of the case report. All assessment criteria should be reasonably complied to assume a category. The WHO-UMC causality assessment system can be used for the assessment of case reports of adverse drug reactions or drug-drug interactions.
WHO-UMC, World Health Organization-Uppsala Monitoring Centre
Causality term Assessment criteria
Certain • Event or laboratory test abnormality, with plausible time relationship to drug intake • Cannot be explained by disease or other drugs • Response to withdrawal plausible (pharmacologically, pathologically) • Event definitive pharmacologically or phenomenologically (i.e., an objective and specific medical disorder or a recognized pharmacological phenomenon) • Rechallenge satisfactory, if necessary
Probable/Likely • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Unlikely to be attributed to disease or other drugs • Response to withdrawal clinically reasonable • Rechallenge not required
Possible • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Could also be explained by disease or other drugs • Information on drug withdrawal may be lacking or unclear
Unlikely • Event or laboratory test abnormality, with a time to drug intake that makes a relationship improbable (but not impossible) • Disease or other drugs provide plausible explanations
Conditional/Unclassified • Event or laboratory test abnormality • More data for proper assessment needed • Additional data under examination
Unassessable/Unclassifiable • Report suggesting an adverse reaction • Cannot be judged because information is insufficient or contradictory • Data cannot be supplemented or verified | ACETAMINOPHEN, DIAZEPAM, DICLOFENAC, PERINDOPRIL, ROSUVASTATIN, THIOCOLCHICOSIDE | DrugsGivenReaction | CC BY | 33654588 | 19,027,243 | 2021-01-25 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Haemolytic anaemia'. | Diclofenac-Induced Immune Hemolytic Anemia: A Case Report and Review of Literature.
Non-steroidal anti-inflammatory drugs are widely used for pain management. Most frequently, adverse reactions affect the gastrointestinal tract and hematological side effects usually relate to the gastrointestinal manifestations. Drug-induced immune hemolytic anemia is a rare and frequently underdiagnosed complication that is associated with poor outcomes including organ failure and even death. A 76-year-old female patient was treated with intramuscular diclofenac, thiocolchicoside, and diazepam for low back pain. Five days following diclofenac exposure, the patient was admitted to the Emergency Department with complaints of asthenia, nausea, vomiting, and diarrhea. Hemolysis and a positive direct antiglobulin test were detected on laboratory testing. Further causes of hemolytic anemia were excluded and a diagnosis of diclofenac-induced immune hemolytic anemia was established. Glucocorticoid therapy initiated on admission and drug eviction led to complete recovery. Long-term follow-up showed no recurrence of anemia. Here, we present the unusual case of a successful recovery of a 76-year-old patient with diclofenac-induced immune hemolytic anemia, a rare but immediate life-threatening condition of a frequently used drug in clinical practice.
Introduction
Autoimmune hemolytic anemia (AIHA) ensues when the host’s immune system acts against its own red cell antigens and has an estimated prevalence of approximately 1 in 100,000 individuals [1]. Approximately 50% of the cases refer to primary or idiopathic AIHA, where an associated disorder is not found [2]. Secondary causes of AIHA depend on the studied population. Current series estimate that half are associated with hematological malignancy, a third with infection, a sixth with collagen vascular disorders, and a tenth with drug-induced immune hemolytic anemia (DIIHA), the latter reaching an estimated incidence of one per million per year [1,3].
Diclofenac is one of the non-steroidal anti-inflammatory drugs (NSAIDs) most used for the treatment of rheumatoid arthritis and osteoarthritis [4]. Though generally well tolerated, over 400 adverse reactions have been documented. Most frequently, adverse reactions affect the gastrointestinal tract, the skin, and the central nervous system [5]. Direct hematological side effects such as leukopenia, thrombocytopenia, and aplastic anemia have been described only in limited cases [6-9].
We present the case of a 76-year-old patient with diclofenac DIIHA and a summary of the pathophysiology and therapeutic options.
Case presentation
A 76-year-old woman presented to the Emergency Department (ED) with recent onset of fatigue. She had a previous medical history of essential arterial hypertension, dyslipidemia, and spinal osteoarthritis with sporadic episodes of lumbosciatic pain. Regular medications initiated several years prior included perindopril 8 mg and rosuvastatin 10 mg. No allergies, alcohol, tobacco, toxins, or animal exposures were known, and she had no other relevant personal or familiar history.
Three weeks before admission the patient had an exacerbation of right lumbosciatic pain. This episode was similar to the previous ones, for which she usually was prescribed oral NSAIDs, acetaminophen, general physical therapy, massages, and rest with complete recovery. However, this time the pain was refractory to general measures, and eight days before admission, she was prescribed a combination of a daily intramuscular administration of 4 mg thiocolchicoside, 75 mg diclofenac, and 5 mg diazepam for a total of six days.
On the fifth day of treatment, she developed generalized malaise, fatigue, nausea, postprandial vomiting, and diarrhea with up to six soft, brownish dejections per day.
Despite resolution of nausea, vomiting, and diarrhea, she experienced progressive worsening of fatigue and was admitted to the ED. Detailed medical history was negative for other symptoms, namely, fever, coluria, acholia, melena, and other evident blood losses, either on admission or in the past.
Physical examination revealed jaundice and pallor of the skin and mucous membranes. No epistaxis, gingivorrhagia, adenopathies, ecchymosis, or other skin lesions were found. Blood pressure was 137/62 mmHg and heart rate was 96 beats per minute, respiratory rate was 16 beats per minute, and peripheral oxygenation saturation was 96%. No fever or other abnormalities were noted.
Blood examination showed normocytic normochromic anemia (hemoglobin: 7.9 g/dL, reference median globular volume: 88 fL), reticulocytosis (9.2%), leucocytosis (white blood cells: 13.8 × 10 9/L), hyperbilirubinemia at the expense of unconjugated bilirubin (total bilirubin: 4.09 mg/dL, conjugated bilirubin: 0.97 mg/dL), elevated lactic dehydrogenase (805 UI/L), and sedimentation rate (VS: 76 mm). Serum iron concentration, ferritin, total iron-binding capacity, folic acid, or vitamin B12 showed no significant changes and haptoglobin levels were undetectable. Peripheral blood smear revealed exuberant erythrocyte rouleaux and spherocytes. The direct antiglobulin test (DAT) was positive for immunoglobulin G (IgG). Chest radiography, abdominal ultrasound, and electrocardiogram performed in the ED were normal.
The hypothesis of AIHA was considered in the ED. The patient was started on 60 mg of prednisolone per day (1 mg/kg/day) and was admitted to the medical ward.
The hypothesis of secondary AIHA to an infectious or a connective tissue disease was ruled out. Gastrointestinal complaints were compatible with side effects of NSAIDs, viral serologies, blood cultures, rheumatoid factor, antinuclear antibody, antineutrophil cytoplasmic antibodies, and cyclic citrullinated peptide antibody were negative, and complement (both C3 and C4 studies) was normal. Lymphoproliferative disease was excluded due to the absence of adenopathies both on physical examination and in imaging studies, as well as normal immunoglobulin levels (IgG, IgM, and IgA) and a normal serum protein electrophoresis. Inflammatory bowel disease and digestive tract tumors were also excluded by endoscopic observation and anatomopathological analysis of biopsies made in macroscopically normal mucosa.
During hospitalization, glucocorticoid therapy was maintained, and folic acid supplementation of 5 mg per day was started. The patient had clinical improvement with resolution of asthenia and jaundice, as well as progressive normalization of the hemoglobin and bilirubin values. On discharge, 13 days after admission, anemia was mild (hemoglobin: 11 g/dL) and no signs of hemolysis were noted. Table 1 shows the laboratory data during hospitalization.
Table 1 Laboratory data during hospitalization.
ALP: alkaline phosphatase; ALT: alanine aminotransferase; ANA: antinuclear antibodies; ANCA: antineutrophil cytoplasmic antibody; anti-CCP: anti-cyclic citrullinated peptides; AST: aspartate aminotransferase; GGT: gamma-glutamyl transferase; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; Ig: immunoglobulin; LDH: lactate dehydrogenase, MCV: mean corpuscular volume, TIBC: total iron binding capacity
Results
Variable Reference range (adults) Day 1 Day 2 Day 5 Day 7 Day 9 Day 13
Hemoglobin (g/dL) 11.8-15.8 7.9 7.8 8.2 9.1 10.3 11
Hematocrit (%) 36.0-46.0 21.9 22.1 24.4 26.7 30.6 33
Red blood cells (106/µL) 4.2-5.4 2.47 2.42 2.48 2.63 2.97 3.14
MCV (fL) 80.4-96.4 88.7 91.3 98.4 101.5 103 105.1
White cell count (103/µL) 4.0-10.0 13.88 12.49 18.09 15.62 11.43 11.82
Differential cell count (103/L)
Neutrophils 1.5-8.0 9.1 8.3 11.448 9.4 5.9 7.2
Lymphocytes 0.8-4.0 3.3 2.7 5.5 5.2 4.7 3.8
Platelet count (103/µL) 150-400 353 353 381 377 392 362
Reticulocytes (%) 0.5-1.5 9.22
Sedimentation rate (mm) 4-10 103 9
C-reactive protein (mg/dL) <0.51 3.23 2.67 0.69 0.41 0.23 0.14
Urea (mg/dL) 17.0-43.0 40 31 39 35 29 33
Creatinine (mg/dL) 0.6-1.0 0.84 0.78 0.8 0.78 0.84 0.79
Sodium (mmol/L) 136-145 140 141 138 143 141 142
Potassium (mmol/L) 3.5-5.1 4.2 4.2 3 3.7 4 3.9
Calcium (mg/dL) 8.6-10.3 8.7
Uric acid (mg/dL) 2.6-6 7
Bilirubin (mg/dL)
Total 0.3-1.2 4.09 4.01 2.16 2.29 2.27 1.28
Direct <0.5 0.07 0.82 0.71 0.75 0.75 0.46
LDH (UI/L) 125-220 805 632 467 436 388 309
ALP (UI/L) 30-120 152 135 96 93 90 76
GGT (UI/L) <38 83 70 55 56 54 43
ALT (UI/L) 7-45 44 19 23 30 31
AST (UI/L) 8-35 30 22 15 21 21 23
Iron (µ/dL) 70-180 124
TIBC (µ/dL) 250-245 300
Folic acid (ng/mL) 2.34-17.56 5.8
Vitamin B12 (pg/mL) 187-883 414
Haptoglobin (mg/dL) 35-250 <8
Direct antiglobulin test Positive for IgG
Protein electrophoresis No monoclonal spikes
Total proteins (g/dL) 6.4-8.2 6.1
Albumin (g/dL) 3.5-5.2 3.6
Immunoglobulins
IgA (mg/dL) 60-400 192
IgG (mg/dL) 70-1,600 1,008
IgM (mg/dL) 40-230 131
ANA Negative
ANCA Negative
Rheumatoid factor Negative
anti-CCP Negative
Serology
HIV Negative
HBV Negative
HCV Negative
Given the acute clinical context after diclofenac intake and absence of evidence for other secondary etiologies, the diagnosis of acquired hemolytic anemia secondary to NSAIDs was made. Follow-up three years later found the patient asymptomatic with no recurrence of anemia or hemolysis.
Discussion
Drugs are generally small molecules unable to elicit an immune response, however, they can function as haptens, bind to larger proteins, become immunogenic, and lead to antibody production. These antibodies can be further classified as drug-induced, drug-dependent, and drug-independent antibodies. Drug-induced antibodies can bind to red blood cells (RBCs) and lead to hemolysis by non-immunological modification of erythrocyte membranes known as adsorption of non-immunological proteins. Drug-dependent antibodies bind to RBCs only in the presence of the drug or its metabolites, causing abrupt complement-mediated intravascular hemolysis. In vitro tests searching for lysis, DAT, or indirect antiglobulin test can be performed to confirm the diagnosis using the offending drug or its metabolites and the patient’s plasma or serum. Drug-independent antibodies can react with RBCs even in the absence of the drug and, therefore, are indistinguishable from autoantibodies mediating warm autoimmune hemolytic anemia (WAIHA) [1,10,11].
WAIHA is named after warm agglutinins, usually IgG autoantibodies, that bind to antigens on erythrocytes at a temperature of 37°C, leading to RBC destruction and a chronic or relapsing disease with an almost pathognomonic positive DAT [2].
Patients are treated with glucocorticoids 1 to 2 mg/kg of body weight/day of prednisone administered orally or an equivalent dose of methylprednisolone administered intravenously. Though most patients recover to an hemoglobin level above 10 g/dL within two to three weeks of treatment, relapse after treatment discontinuation is common, with retrospective case studies suggesting long-term remission rates as low as 20% to 30% [2].
DIIHA is identified by clinical evidence of hemolysis associated with drug therapy. Although many drugs have anedoctally reported isolated cases of DIIHA, over 130 drugs have reasonable evidence that supports an immune etiology [12]. It has been speculated that DIIHA is far more common than previously estimated, as most reports usually refer to more severe cases, either presenting with shock, multiorgan damage, or renal failure, and most mild cases being unreported [6].
Drugs most frequently associated with DIIHA are second and third generation of cephalosporins, diclofenac, oxaliplatin, and fludarabine. In European cohorts where diclofenac is the most frequently used NSAID, case reviews reported diclofenac as the most frequently implicated drug, with a fatal outcome being estimated in 15% to 21% of the reported cases [6,12-16]. Diclofenac-induced immune hemolytic anemia has been demonstrated in few cases, where the exposure to the drug or its metabolites lead to developing both drug-independent IgG autoantibodies and antibodies that reacted with diclofenac and its metabolites [8].
Signs and symptoms of DIIHA, as any other hemolytic anemia, are proportional to the degree and time of onset and can present withing hours to weeks of drug exposure. These include fatigue, dyspnea, and thoracic or abdominal pain. Late symptoms are usually due to complications of decompensated hemolysis, usually shock or renal failure. Laboratory abnormalities include low hemoglobin and haptoglobin levels, elevated lactate dehydrogenase and indirect bilirubin levels, reticulocytosis, and a positive DAT [1,10].
The DAT is positive in all the described forms of DIIHA, either for IgG, C3, or both. Rare cases with negative DAT reported either low antibody density, massive intravascular hemolysis, or red cell transfusion administered prior to testing [1,10]. When approaching a case where there is evidence of hemolysis and an established temporal relationship with a drug known to induce autoantibody production, investigation for drug-dependent antibodies can be performed in adequate laboratory settings, with quality ensured expertise and appropriate controls [1,3].
As there are no defining clinical features and drug-induced autoantibodies are indistinguishable from idiopathic autoantibodies, misdiagnosis in DIIHA is extremely common, with some patients dying because of late diagnosis. Furthermore, hemolysis and serological results can persist for up to months after withdrawal of the drug, leading to erroneous attribution of recovery on the administered treatment and not to the interruption of the drug [6].
If DIIHA is suspected, relevant medication should be withdrawn immediately. In mild cases, recovery usually happens within one to two weeks after drug suspension, with no other necessary measures. As most drugs have a relatively short half-life, even a strong drug-dependent antibody loses its effect shortly after drug suspension [1]. Failure to recognize DIIHA can have disastrous consequences, especially when patients present complaints for which the offending drug was prescribed. Regarding diclofenac DIIHA, some cases have been reported of patients receiving the drug again for “low back pain” during the early onset of hemolysis [9].
In acute severe DIIHA, recommendations suggest close monitoring of clinical and laboratory signs, early intravenous access, and fluid resuscitation. Blood transfusion should not be withheld in patients with severe anemia [3]. Even though crossmatch-compatible blood can be difficult to find, a review of 134 patients showed that 68 (55%) patients received blood transfusions. Though most patients (85%) received glucocorticoids, its benefit is uncertain and its routine use is not recommended as drug eviction is usually enough to stop the immune response [14].
Applying the criteria of the World Health Organization causality assessment method to assess a possible drug‐induced etiology of IHA we are confident the most likely diagnosis for our patient was diclofenac-induced IHA [17]. Our analysis is supported by: (a) the presence of autoantibodies in the patient’s eluate was demonstrated; (b) diclofenac is known to induce DIIHA; (c) there is a chronological relationship between hemolysis and diclofenac administration; (d) a review of the literature failed to show cases of DIIHA induced by any of the other drugs taken by the patient; (e) symptoms and laboratory signs significantly improved after discontinuation of diclofenac; (f) no coexistent neoplastic, autoimmune, or infectious diseases known to be secondary causes of AIHA were found after systematic and comprehensive studies; and (g) though glucocorticoids were started on admission, no recurrence of anemia was verified in a three-year follow-up period, which would be uncommon if the patient suffered from WAIHA.
Conclusions
As a potentially fatal complication of a widely used drug in clinical practice such as diclofenac, early and correct diagnosis of DIIHA and prompt removal of the offending drug is crucial for the patient’s recovery. Our case highlights the need for both prescribing physicians and patients to be aware of this frequently underreported and usually misdiagnosed entity.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
Appendices
Table 2 Causality categories. Adapted from the WHO-UMC system for standardized case causality assessment. The usual approach is to choose one of the causality terms’ categories and to test if the various criteria fit the content of the case report. All assessment criteria should be reasonably complied to assume a category. The WHO-UMC causality assessment system can be used for the assessment of case reports of adverse drug reactions or drug-drug interactions.
WHO-UMC, World Health Organization-Uppsala Monitoring Centre
Causality term Assessment criteria
Certain • Event or laboratory test abnormality, with plausible time relationship to drug intake • Cannot be explained by disease or other drugs • Response to withdrawal plausible (pharmacologically, pathologically) • Event definitive pharmacologically or phenomenologically (i.e., an objective and specific medical disorder or a recognized pharmacological phenomenon) • Rechallenge satisfactory, if necessary
Probable/Likely • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Unlikely to be attributed to disease or other drugs • Response to withdrawal clinically reasonable • Rechallenge not required
Possible • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Could also be explained by disease or other drugs • Information on drug withdrawal may be lacking or unclear
Unlikely • Event or laboratory test abnormality, with a time to drug intake that makes a relationship improbable (but not impossible) • Disease or other drugs provide plausible explanations
Conditional/Unclassified • Event or laboratory test abnormality • More data for proper assessment needed • Additional data under examination
Unassessable/Unclassifiable • Report suggesting an adverse reaction • Cannot be judged because information is insufficient or contradictory • Data cannot be supplemented or verified | ACETAMINOPHEN, DIAZEPAM, DICLOFENAC, PERINDOPRIL, ROSUVASTATIN, THIOCOLCHICOSIDE | DrugsGivenReaction | CC BY | 33654588 | 19,027,243 | 2021-01-25 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Jaundice'. | Diclofenac-Induced Immune Hemolytic Anemia: A Case Report and Review of Literature.
Non-steroidal anti-inflammatory drugs are widely used for pain management. Most frequently, adverse reactions affect the gastrointestinal tract and hematological side effects usually relate to the gastrointestinal manifestations. Drug-induced immune hemolytic anemia is a rare and frequently underdiagnosed complication that is associated with poor outcomes including organ failure and even death. A 76-year-old female patient was treated with intramuscular diclofenac, thiocolchicoside, and diazepam for low back pain. Five days following diclofenac exposure, the patient was admitted to the Emergency Department with complaints of asthenia, nausea, vomiting, and diarrhea. Hemolysis and a positive direct antiglobulin test were detected on laboratory testing. Further causes of hemolytic anemia were excluded and a diagnosis of diclofenac-induced immune hemolytic anemia was established. Glucocorticoid therapy initiated on admission and drug eviction led to complete recovery. Long-term follow-up showed no recurrence of anemia. Here, we present the unusual case of a successful recovery of a 76-year-old patient with diclofenac-induced immune hemolytic anemia, a rare but immediate life-threatening condition of a frequently used drug in clinical practice.
Introduction
Autoimmune hemolytic anemia (AIHA) ensues when the host’s immune system acts against its own red cell antigens and has an estimated prevalence of approximately 1 in 100,000 individuals [1]. Approximately 50% of the cases refer to primary or idiopathic AIHA, where an associated disorder is not found [2]. Secondary causes of AIHA depend on the studied population. Current series estimate that half are associated with hematological malignancy, a third with infection, a sixth with collagen vascular disorders, and a tenth with drug-induced immune hemolytic anemia (DIIHA), the latter reaching an estimated incidence of one per million per year [1,3].
Diclofenac is one of the non-steroidal anti-inflammatory drugs (NSAIDs) most used for the treatment of rheumatoid arthritis and osteoarthritis [4]. Though generally well tolerated, over 400 adverse reactions have been documented. Most frequently, adverse reactions affect the gastrointestinal tract, the skin, and the central nervous system [5]. Direct hematological side effects such as leukopenia, thrombocytopenia, and aplastic anemia have been described only in limited cases [6-9].
We present the case of a 76-year-old patient with diclofenac DIIHA and a summary of the pathophysiology and therapeutic options.
Case presentation
A 76-year-old woman presented to the Emergency Department (ED) with recent onset of fatigue. She had a previous medical history of essential arterial hypertension, dyslipidemia, and spinal osteoarthritis with sporadic episodes of lumbosciatic pain. Regular medications initiated several years prior included perindopril 8 mg and rosuvastatin 10 mg. No allergies, alcohol, tobacco, toxins, or animal exposures were known, and she had no other relevant personal or familiar history.
Three weeks before admission the patient had an exacerbation of right lumbosciatic pain. This episode was similar to the previous ones, for which she usually was prescribed oral NSAIDs, acetaminophen, general physical therapy, massages, and rest with complete recovery. However, this time the pain was refractory to general measures, and eight days before admission, she was prescribed a combination of a daily intramuscular administration of 4 mg thiocolchicoside, 75 mg diclofenac, and 5 mg diazepam for a total of six days.
On the fifth day of treatment, she developed generalized malaise, fatigue, nausea, postprandial vomiting, and diarrhea with up to six soft, brownish dejections per day.
Despite resolution of nausea, vomiting, and diarrhea, she experienced progressive worsening of fatigue and was admitted to the ED. Detailed medical history was negative for other symptoms, namely, fever, coluria, acholia, melena, and other evident blood losses, either on admission or in the past.
Physical examination revealed jaundice and pallor of the skin and mucous membranes. No epistaxis, gingivorrhagia, adenopathies, ecchymosis, or other skin lesions were found. Blood pressure was 137/62 mmHg and heart rate was 96 beats per minute, respiratory rate was 16 beats per minute, and peripheral oxygenation saturation was 96%. No fever or other abnormalities were noted.
Blood examination showed normocytic normochromic anemia (hemoglobin: 7.9 g/dL, reference median globular volume: 88 fL), reticulocytosis (9.2%), leucocytosis (white blood cells: 13.8 × 10 9/L), hyperbilirubinemia at the expense of unconjugated bilirubin (total bilirubin: 4.09 mg/dL, conjugated bilirubin: 0.97 mg/dL), elevated lactic dehydrogenase (805 UI/L), and sedimentation rate (VS: 76 mm). Serum iron concentration, ferritin, total iron-binding capacity, folic acid, or vitamin B12 showed no significant changes and haptoglobin levels were undetectable. Peripheral blood smear revealed exuberant erythrocyte rouleaux and spherocytes. The direct antiglobulin test (DAT) was positive for immunoglobulin G (IgG). Chest radiography, abdominal ultrasound, and electrocardiogram performed in the ED were normal.
The hypothesis of AIHA was considered in the ED. The patient was started on 60 mg of prednisolone per day (1 mg/kg/day) and was admitted to the medical ward.
The hypothesis of secondary AIHA to an infectious or a connective tissue disease was ruled out. Gastrointestinal complaints were compatible with side effects of NSAIDs, viral serologies, blood cultures, rheumatoid factor, antinuclear antibody, antineutrophil cytoplasmic antibodies, and cyclic citrullinated peptide antibody were negative, and complement (both C3 and C4 studies) was normal. Lymphoproliferative disease was excluded due to the absence of adenopathies both on physical examination and in imaging studies, as well as normal immunoglobulin levels (IgG, IgM, and IgA) and a normal serum protein electrophoresis. Inflammatory bowel disease and digestive tract tumors were also excluded by endoscopic observation and anatomopathological analysis of biopsies made in macroscopically normal mucosa.
During hospitalization, glucocorticoid therapy was maintained, and folic acid supplementation of 5 mg per day was started. The patient had clinical improvement with resolution of asthenia and jaundice, as well as progressive normalization of the hemoglobin and bilirubin values. On discharge, 13 days after admission, anemia was mild (hemoglobin: 11 g/dL) and no signs of hemolysis were noted. Table 1 shows the laboratory data during hospitalization.
Table 1 Laboratory data during hospitalization.
ALP: alkaline phosphatase; ALT: alanine aminotransferase; ANA: antinuclear antibodies; ANCA: antineutrophil cytoplasmic antibody; anti-CCP: anti-cyclic citrullinated peptides; AST: aspartate aminotransferase; GGT: gamma-glutamyl transferase; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; Ig: immunoglobulin; LDH: lactate dehydrogenase, MCV: mean corpuscular volume, TIBC: total iron binding capacity
Results
Variable Reference range (adults) Day 1 Day 2 Day 5 Day 7 Day 9 Day 13
Hemoglobin (g/dL) 11.8-15.8 7.9 7.8 8.2 9.1 10.3 11
Hematocrit (%) 36.0-46.0 21.9 22.1 24.4 26.7 30.6 33
Red blood cells (106/µL) 4.2-5.4 2.47 2.42 2.48 2.63 2.97 3.14
MCV (fL) 80.4-96.4 88.7 91.3 98.4 101.5 103 105.1
White cell count (103/µL) 4.0-10.0 13.88 12.49 18.09 15.62 11.43 11.82
Differential cell count (103/L)
Neutrophils 1.5-8.0 9.1 8.3 11.448 9.4 5.9 7.2
Lymphocytes 0.8-4.0 3.3 2.7 5.5 5.2 4.7 3.8
Platelet count (103/µL) 150-400 353 353 381 377 392 362
Reticulocytes (%) 0.5-1.5 9.22
Sedimentation rate (mm) 4-10 103 9
C-reactive protein (mg/dL) <0.51 3.23 2.67 0.69 0.41 0.23 0.14
Urea (mg/dL) 17.0-43.0 40 31 39 35 29 33
Creatinine (mg/dL) 0.6-1.0 0.84 0.78 0.8 0.78 0.84 0.79
Sodium (mmol/L) 136-145 140 141 138 143 141 142
Potassium (mmol/L) 3.5-5.1 4.2 4.2 3 3.7 4 3.9
Calcium (mg/dL) 8.6-10.3 8.7
Uric acid (mg/dL) 2.6-6 7
Bilirubin (mg/dL)
Total 0.3-1.2 4.09 4.01 2.16 2.29 2.27 1.28
Direct <0.5 0.07 0.82 0.71 0.75 0.75 0.46
LDH (UI/L) 125-220 805 632 467 436 388 309
ALP (UI/L) 30-120 152 135 96 93 90 76
GGT (UI/L) <38 83 70 55 56 54 43
ALT (UI/L) 7-45 44 19 23 30 31
AST (UI/L) 8-35 30 22 15 21 21 23
Iron (µ/dL) 70-180 124
TIBC (µ/dL) 250-245 300
Folic acid (ng/mL) 2.34-17.56 5.8
Vitamin B12 (pg/mL) 187-883 414
Haptoglobin (mg/dL) 35-250 <8
Direct antiglobulin test Positive for IgG
Protein electrophoresis No monoclonal spikes
Total proteins (g/dL) 6.4-8.2 6.1
Albumin (g/dL) 3.5-5.2 3.6
Immunoglobulins
IgA (mg/dL) 60-400 192
IgG (mg/dL) 70-1,600 1,008
IgM (mg/dL) 40-230 131
ANA Negative
ANCA Negative
Rheumatoid factor Negative
anti-CCP Negative
Serology
HIV Negative
HBV Negative
HCV Negative
Given the acute clinical context after diclofenac intake and absence of evidence for other secondary etiologies, the diagnosis of acquired hemolytic anemia secondary to NSAIDs was made. Follow-up three years later found the patient asymptomatic with no recurrence of anemia or hemolysis.
Discussion
Drugs are generally small molecules unable to elicit an immune response, however, they can function as haptens, bind to larger proteins, become immunogenic, and lead to antibody production. These antibodies can be further classified as drug-induced, drug-dependent, and drug-independent antibodies. Drug-induced antibodies can bind to red blood cells (RBCs) and lead to hemolysis by non-immunological modification of erythrocyte membranes known as adsorption of non-immunological proteins. Drug-dependent antibodies bind to RBCs only in the presence of the drug or its metabolites, causing abrupt complement-mediated intravascular hemolysis. In vitro tests searching for lysis, DAT, or indirect antiglobulin test can be performed to confirm the diagnosis using the offending drug or its metabolites and the patient’s plasma or serum. Drug-independent antibodies can react with RBCs even in the absence of the drug and, therefore, are indistinguishable from autoantibodies mediating warm autoimmune hemolytic anemia (WAIHA) [1,10,11].
WAIHA is named after warm agglutinins, usually IgG autoantibodies, that bind to antigens on erythrocytes at a temperature of 37°C, leading to RBC destruction and a chronic or relapsing disease with an almost pathognomonic positive DAT [2].
Patients are treated with glucocorticoids 1 to 2 mg/kg of body weight/day of prednisone administered orally or an equivalent dose of methylprednisolone administered intravenously. Though most patients recover to an hemoglobin level above 10 g/dL within two to three weeks of treatment, relapse after treatment discontinuation is common, with retrospective case studies suggesting long-term remission rates as low as 20% to 30% [2].
DIIHA is identified by clinical evidence of hemolysis associated with drug therapy. Although many drugs have anedoctally reported isolated cases of DIIHA, over 130 drugs have reasonable evidence that supports an immune etiology [12]. It has been speculated that DIIHA is far more common than previously estimated, as most reports usually refer to more severe cases, either presenting with shock, multiorgan damage, or renal failure, and most mild cases being unreported [6].
Drugs most frequently associated with DIIHA are second and third generation of cephalosporins, diclofenac, oxaliplatin, and fludarabine. In European cohorts where diclofenac is the most frequently used NSAID, case reviews reported diclofenac as the most frequently implicated drug, with a fatal outcome being estimated in 15% to 21% of the reported cases [6,12-16]. Diclofenac-induced immune hemolytic anemia has been demonstrated in few cases, where the exposure to the drug or its metabolites lead to developing both drug-independent IgG autoantibodies and antibodies that reacted with diclofenac and its metabolites [8].
Signs and symptoms of DIIHA, as any other hemolytic anemia, are proportional to the degree and time of onset and can present withing hours to weeks of drug exposure. These include fatigue, dyspnea, and thoracic or abdominal pain. Late symptoms are usually due to complications of decompensated hemolysis, usually shock or renal failure. Laboratory abnormalities include low hemoglobin and haptoglobin levels, elevated lactate dehydrogenase and indirect bilirubin levels, reticulocytosis, and a positive DAT [1,10].
The DAT is positive in all the described forms of DIIHA, either for IgG, C3, or both. Rare cases with negative DAT reported either low antibody density, massive intravascular hemolysis, or red cell transfusion administered prior to testing [1,10]. When approaching a case where there is evidence of hemolysis and an established temporal relationship with a drug known to induce autoantibody production, investigation for drug-dependent antibodies can be performed in adequate laboratory settings, with quality ensured expertise and appropriate controls [1,3].
As there are no defining clinical features and drug-induced autoantibodies are indistinguishable from idiopathic autoantibodies, misdiagnosis in DIIHA is extremely common, with some patients dying because of late diagnosis. Furthermore, hemolysis and serological results can persist for up to months after withdrawal of the drug, leading to erroneous attribution of recovery on the administered treatment and not to the interruption of the drug [6].
If DIIHA is suspected, relevant medication should be withdrawn immediately. In mild cases, recovery usually happens within one to two weeks after drug suspension, with no other necessary measures. As most drugs have a relatively short half-life, even a strong drug-dependent antibody loses its effect shortly after drug suspension [1]. Failure to recognize DIIHA can have disastrous consequences, especially when patients present complaints for which the offending drug was prescribed. Regarding diclofenac DIIHA, some cases have been reported of patients receiving the drug again for “low back pain” during the early onset of hemolysis [9].
In acute severe DIIHA, recommendations suggest close monitoring of clinical and laboratory signs, early intravenous access, and fluid resuscitation. Blood transfusion should not be withheld in patients with severe anemia [3]. Even though crossmatch-compatible blood can be difficult to find, a review of 134 patients showed that 68 (55%) patients received blood transfusions. Though most patients (85%) received glucocorticoids, its benefit is uncertain and its routine use is not recommended as drug eviction is usually enough to stop the immune response [14].
Applying the criteria of the World Health Organization causality assessment method to assess a possible drug‐induced etiology of IHA we are confident the most likely diagnosis for our patient was diclofenac-induced IHA [17]. Our analysis is supported by: (a) the presence of autoantibodies in the patient’s eluate was demonstrated; (b) diclofenac is known to induce DIIHA; (c) there is a chronological relationship between hemolysis and diclofenac administration; (d) a review of the literature failed to show cases of DIIHA induced by any of the other drugs taken by the patient; (e) symptoms and laboratory signs significantly improved after discontinuation of diclofenac; (f) no coexistent neoplastic, autoimmune, or infectious diseases known to be secondary causes of AIHA were found after systematic and comprehensive studies; and (g) though glucocorticoids were started on admission, no recurrence of anemia was verified in a three-year follow-up period, which would be uncommon if the patient suffered from WAIHA.
Conclusions
As a potentially fatal complication of a widely used drug in clinical practice such as diclofenac, early and correct diagnosis of DIIHA and prompt removal of the offending drug is crucial for the patient’s recovery. Our case highlights the need for both prescribing physicians and patients to be aware of this frequently underreported and usually misdiagnosed entity.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
Appendices
Table 2 Causality categories. Adapted from the WHO-UMC system for standardized case causality assessment. The usual approach is to choose one of the causality terms’ categories and to test if the various criteria fit the content of the case report. All assessment criteria should be reasonably complied to assume a category. The WHO-UMC causality assessment system can be used for the assessment of case reports of adverse drug reactions or drug-drug interactions.
WHO-UMC, World Health Organization-Uppsala Monitoring Centre
Causality term Assessment criteria
Certain • Event or laboratory test abnormality, with plausible time relationship to drug intake • Cannot be explained by disease or other drugs • Response to withdrawal plausible (pharmacologically, pathologically) • Event definitive pharmacologically or phenomenologically (i.e., an objective and specific medical disorder or a recognized pharmacological phenomenon) • Rechallenge satisfactory, if necessary
Probable/Likely • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Unlikely to be attributed to disease or other drugs • Response to withdrawal clinically reasonable • Rechallenge not required
Possible • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Could also be explained by disease or other drugs • Information on drug withdrawal may be lacking or unclear
Unlikely • Event or laboratory test abnormality, with a time to drug intake that makes a relationship improbable (but not impossible) • Disease or other drugs provide plausible explanations
Conditional/Unclassified • Event or laboratory test abnormality • More data for proper assessment needed • Additional data under examination
Unassessable/Unclassifiable • Report suggesting an adverse reaction • Cannot be judged because information is insufficient or contradictory • Data cannot be supplemented or verified | ACETAMINOPHEN, DIAZEPAM, DICLOFENAC, PERINDOPRIL, ROSUVASTATIN, THIOCOLCHICOSIDE | DrugsGivenReaction | CC BY | 33654588 | 19,027,243 | 2021-01-25 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Malaise'. | Diclofenac-Induced Immune Hemolytic Anemia: A Case Report and Review of Literature.
Non-steroidal anti-inflammatory drugs are widely used for pain management. Most frequently, adverse reactions affect the gastrointestinal tract and hematological side effects usually relate to the gastrointestinal manifestations. Drug-induced immune hemolytic anemia is a rare and frequently underdiagnosed complication that is associated with poor outcomes including organ failure and even death. A 76-year-old female patient was treated with intramuscular diclofenac, thiocolchicoside, and diazepam for low back pain. Five days following diclofenac exposure, the patient was admitted to the Emergency Department with complaints of asthenia, nausea, vomiting, and diarrhea. Hemolysis and a positive direct antiglobulin test were detected on laboratory testing. Further causes of hemolytic anemia were excluded and a diagnosis of diclofenac-induced immune hemolytic anemia was established. Glucocorticoid therapy initiated on admission and drug eviction led to complete recovery. Long-term follow-up showed no recurrence of anemia. Here, we present the unusual case of a successful recovery of a 76-year-old patient with diclofenac-induced immune hemolytic anemia, a rare but immediate life-threatening condition of a frequently used drug in clinical practice.
Introduction
Autoimmune hemolytic anemia (AIHA) ensues when the host’s immune system acts against its own red cell antigens and has an estimated prevalence of approximately 1 in 100,000 individuals [1]. Approximately 50% of the cases refer to primary or idiopathic AIHA, where an associated disorder is not found [2]. Secondary causes of AIHA depend on the studied population. Current series estimate that half are associated with hematological malignancy, a third with infection, a sixth with collagen vascular disorders, and a tenth with drug-induced immune hemolytic anemia (DIIHA), the latter reaching an estimated incidence of one per million per year [1,3].
Diclofenac is one of the non-steroidal anti-inflammatory drugs (NSAIDs) most used for the treatment of rheumatoid arthritis and osteoarthritis [4]. Though generally well tolerated, over 400 adverse reactions have been documented. Most frequently, adverse reactions affect the gastrointestinal tract, the skin, and the central nervous system [5]. Direct hematological side effects such as leukopenia, thrombocytopenia, and aplastic anemia have been described only in limited cases [6-9].
We present the case of a 76-year-old patient with diclofenac DIIHA and a summary of the pathophysiology and therapeutic options.
Case presentation
A 76-year-old woman presented to the Emergency Department (ED) with recent onset of fatigue. She had a previous medical history of essential arterial hypertension, dyslipidemia, and spinal osteoarthritis with sporadic episodes of lumbosciatic pain. Regular medications initiated several years prior included perindopril 8 mg and rosuvastatin 10 mg. No allergies, alcohol, tobacco, toxins, or animal exposures were known, and she had no other relevant personal or familiar history.
Three weeks before admission the patient had an exacerbation of right lumbosciatic pain. This episode was similar to the previous ones, for which she usually was prescribed oral NSAIDs, acetaminophen, general physical therapy, massages, and rest with complete recovery. However, this time the pain was refractory to general measures, and eight days before admission, she was prescribed a combination of a daily intramuscular administration of 4 mg thiocolchicoside, 75 mg diclofenac, and 5 mg diazepam for a total of six days.
On the fifth day of treatment, she developed generalized malaise, fatigue, nausea, postprandial vomiting, and diarrhea with up to six soft, brownish dejections per day.
Despite resolution of nausea, vomiting, and diarrhea, she experienced progressive worsening of fatigue and was admitted to the ED. Detailed medical history was negative for other symptoms, namely, fever, coluria, acholia, melena, and other evident blood losses, either on admission or in the past.
Physical examination revealed jaundice and pallor of the skin and mucous membranes. No epistaxis, gingivorrhagia, adenopathies, ecchymosis, or other skin lesions were found. Blood pressure was 137/62 mmHg and heart rate was 96 beats per minute, respiratory rate was 16 beats per minute, and peripheral oxygenation saturation was 96%. No fever or other abnormalities were noted.
Blood examination showed normocytic normochromic anemia (hemoglobin: 7.9 g/dL, reference median globular volume: 88 fL), reticulocytosis (9.2%), leucocytosis (white blood cells: 13.8 × 10 9/L), hyperbilirubinemia at the expense of unconjugated bilirubin (total bilirubin: 4.09 mg/dL, conjugated bilirubin: 0.97 mg/dL), elevated lactic dehydrogenase (805 UI/L), and sedimentation rate (VS: 76 mm). Serum iron concentration, ferritin, total iron-binding capacity, folic acid, or vitamin B12 showed no significant changes and haptoglobin levels were undetectable. Peripheral blood smear revealed exuberant erythrocyte rouleaux and spherocytes. The direct antiglobulin test (DAT) was positive for immunoglobulin G (IgG). Chest radiography, abdominal ultrasound, and electrocardiogram performed in the ED were normal.
The hypothesis of AIHA was considered in the ED. The patient was started on 60 mg of prednisolone per day (1 mg/kg/day) and was admitted to the medical ward.
The hypothesis of secondary AIHA to an infectious or a connective tissue disease was ruled out. Gastrointestinal complaints were compatible with side effects of NSAIDs, viral serologies, blood cultures, rheumatoid factor, antinuclear antibody, antineutrophil cytoplasmic antibodies, and cyclic citrullinated peptide antibody were negative, and complement (both C3 and C4 studies) was normal. Lymphoproliferative disease was excluded due to the absence of adenopathies both on physical examination and in imaging studies, as well as normal immunoglobulin levels (IgG, IgM, and IgA) and a normal serum protein electrophoresis. Inflammatory bowel disease and digestive tract tumors were also excluded by endoscopic observation and anatomopathological analysis of biopsies made in macroscopically normal mucosa.
During hospitalization, glucocorticoid therapy was maintained, and folic acid supplementation of 5 mg per day was started. The patient had clinical improvement with resolution of asthenia and jaundice, as well as progressive normalization of the hemoglobin and bilirubin values. On discharge, 13 days after admission, anemia was mild (hemoglobin: 11 g/dL) and no signs of hemolysis were noted. Table 1 shows the laboratory data during hospitalization.
Table 1 Laboratory data during hospitalization.
ALP: alkaline phosphatase; ALT: alanine aminotransferase; ANA: antinuclear antibodies; ANCA: antineutrophil cytoplasmic antibody; anti-CCP: anti-cyclic citrullinated peptides; AST: aspartate aminotransferase; GGT: gamma-glutamyl transferase; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; Ig: immunoglobulin; LDH: lactate dehydrogenase, MCV: mean corpuscular volume, TIBC: total iron binding capacity
Results
Variable Reference range (adults) Day 1 Day 2 Day 5 Day 7 Day 9 Day 13
Hemoglobin (g/dL) 11.8-15.8 7.9 7.8 8.2 9.1 10.3 11
Hematocrit (%) 36.0-46.0 21.9 22.1 24.4 26.7 30.6 33
Red blood cells (106/µL) 4.2-5.4 2.47 2.42 2.48 2.63 2.97 3.14
MCV (fL) 80.4-96.4 88.7 91.3 98.4 101.5 103 105.1
White cell count (103/µL) 4.0-10.0 13.88 12.49 18.09 15.62 11.43 11.82
Differential cell count (103/L)
Neutrophils 1.5-8.0 9.1 8.3 11.448 9.4 5.9 7.2
Lymphocytes 0.8-4.0 3.3 2.7 5.5 5.2 4.7 3.8
Platelet count (103/µL) 150-400 353 353 381 377 392 362
Reticulocytes (%) 0.5-1.5 9.22
Sedimentation rate (mm) 4-10 103 9
C-reactive protein (mg/dL) <0.51 3.23 2.67 0.69 0.41 0.23 0.14
Urea (mg/dL) 17.0-43.0 40 31 39 35 29 33
Creatinine (mg/dL) 0.6-1.0 0.84 0.78 0.8 0.78 0.84 0.79
Sodium (mmol/L) 136-145 140 141 138 143 141 142
Potassium (mmol/L) 3.5-5.1 4.2 4.2 3 3.7 4 3.9
Calcium (mg/dL) 8.6-10.3 8.7
Uric acid (mg/dL) 2.6-6 7
Bilirubin (mg/dL)
Total 0.3-1.2 4.09 4.01 2.16 2.29 2.27 1.28
Direct <0.5 0.07 0.82 0.71 0.75 0.75 0.46
LDH (UI/L) 125-220 805 632 467 436 388 309
ALP (UI/L) 30-120 152 135 96 93 90 76
GGT (UI/L) <38 83 70 55 56 54 43
ALT (UI/L) 7-45 44 19 23 30 31
AST (UI/L) 8-35 30 22 15 21 21 23
Iron (µ/dL) 70-180 124
TIBC (µ/dL) 250-245 300
Folic acid (ng/mL) 2.34-17.56 5.8
Vitamin B12 (pg/mL) 187-883 414
Haptoglobin (mg/dL) 35-250 <8
Direct antiglobulin test Positive for IgG
Protein electrophoresis No monoclonal spikes
Total proteins (g/dL) 6.4-8.2 6.1
Albumin (g/dL) 3.5-5.2 3.6
Immunoglobulins
IgA (mg/dL) 60-400 192
IgG (mg/dL) 70-1,600 1,008
IgM (mg/dL) 40-230 131
ANA Negative
ANCA Negative
Rheumatoid factor Negative
anti-CCP Negative
Serology
HIV Negative
HBV Negative
HCV Negative
Given the acute clinical context after diclofenac intake and absence of evidence for other secondary etiologies, the diagnosis of acquired hemolytic anemia secondary to NSAIDs was made. Follow-up three years later found the patient asymptomatic with no recurrence of anemia or hemolysis.
Discussion
Drugs are generally small molecules unable to elicit an immune response, however, they can function as haptens, bind to larger proteins, become immunogenic, and lead to antibody production. These antibodies can be further classified as drug-induced, drug-dependent, and drug-independent antibodies. Drug-induced antibodies can bind to red blood cells (RBCs) and lead to hemolysis by non-immunological modification of erythrocyte membranes known as adsorption of non-immunological proteins. Drug-dependent antibodies bind to RBCs only in the presence of the drug or its metabolites, causing abrupt complement-mediated intravascular hemolysis. In vitro tests searching for lysis, DAT, or indirect antiglobulin test can be performed to confirm the diagnosis using the offending drug or its metabolites and the patient’s plasma or serum. Drug-independent antibodies can react with RBCs even in the absence of the drug and, therefore, are indistinguishable from autoantibodies mediating warm autoimmune hemolytic anemia (WAIHA) [1,10,11].
WAIHA is named after warm agglutinins, usually IgG autoantibodies, that bind to antigens on erythrocytes at a temperature of 37°C, leading to RBC destruction and a chronic or relapsing disease with an almost pathognomonic positive DAT [2].
Patients are treated with glucocorticoids 1 to 2 mg/kg of body weight/day of prednisone administered orally or an equivalent dose of methylprednisolone administered intravenously. Though most patients recover to an hemoglobin level above 10 g/dL within two to three weeks of treatment, relapse after treatment discontinuation is common, with retrospective case studies suggesting long-term remission rates as low as 20% to 30% [2].
DIIHA is identified by clinical evidence of hemolysis associated with drug therapy. Although many drugs have anedoctally reported isolated cases of DIIHA, over 130 drugs have reasonable evidence that supports an immune etiology [12]. It has been speculated that DIIHA is far more common than previously estimated, as most reports usually refer to more severe cases, either presenting with shock, multiorgan damage, or renal failure, and most mild cases being unreported [6].
Drugs most frequently associated with DIIHA are second and third generation of cephalosporins, diclofenac, oxaliplatin, and fludarabine. In European cohorts where diclofenac is the most frequently used NSAID, case reviews reported diclofenac as the most frequently implicated drug, with a fatal outcome being estimated in 15% to 21% of the reported cases [6,12-16]. Diclofenac-induced immune hemolytic anemia has been demonstrated in few cases, where the exposure to the drug or its metabolites lead to developing both drug-independent IgG autoantibodies and antibodies that reacted with diclofenac and its metabolites [8].
Signs and symptoms of DIIHA, as any other hemolytic anemia, are proportional to the degree and time of onset and can present withing hours to weeks of drug exposure. These include fatigue, dyspnea, and thoracic or abdominal pain. Late symptoms are usually due to complications of decompensated hemolysis, usually shock or renal failure. Laboratory abnormalities include low hemoglobin and haptoglobin levels, elevated lactate dehydrogenase and indirect bilirubin levels, reticulocytosis, and a positive DAT [1,10].
The DAT is positive in all the described forms of DIIHA, either for IgG, C3, or both. Rare cases with negative DAT reported either low antibody density, massive intravascular hemolysis, or red cell transfusion administered prior to testing [1,10]. When approaching a case where there is evidence of hemolysis and an established temporal relationship with a drug known to induce autoantibody production, investigation for drug-dependent antibodies can be performed in adequate laboratory settings, with quality ensured expertise and appropriate controls [1,3].
As there are no defining clinical features and drug-induced autoantibodies are indistinguishable from idiopathic autoantibodies, misdiagnosis in DIIHA is extremely common, with some patients dying because of late diagnosis. Furthermore, hemolysis and serological results can persist for up to months after withdrawal of the drug, leading to erroneous attribution of recovery on the administered treatment and not to the interruption of the drug [6].
If DIIHA is suspected, relevant medication should be withdrawn immediately. In mild cases, recovery usually happens within one to two weeks after drug suspension, with no other necessary measures. As most drugs have a relatively short half-life, even a strong drug-dependent antibody loses its effect shortly after drug suspension [1]. Failure to recognize DIIHA can have disastrous consequences, especially when patients present complaints for which the offending drug was prescribed. Regarding diclofenac DIIHA, some cases have been reported of patients receiving the drug again for “low back pain” during the early onset of hemolysis [9].
In acute severe DIIHA, recommendations suggest close monitoring of clinical and laboratory signs, early intravenous access, and fluid resuscitation. Blood transfusion should not be withheld in patients with severe anemia [3]. Even though crossmatch-compatible blood can be difficult to find, a review of 134 patients showed that 68 (55%) patients received blood transfusions. Though most patients (85%) received glucocorticoids, its benefit is uncertain and its routine use is not recommended as drug eviction is usually enough to stop the immune response [14].
Applying the criteria of the World Health Organization causality assessment method to assess a possible drug‐induced etiology of IHA we are confident the most likely diagnosis for our patient was diclofenac-induced IHA [17]. Our analysis is supported by: (a) the presence of autoantibodies in the patient’s eluate was demonstrated; (b) diclofenac is known to induce DIIHA; (c) there is a chronological relationship between hemolysis and diclofenac administration; (d) a review of the literature failed to show cases of DIIHA induced by any of the other drugs taken by the patient; (e) symptoms and laboratory signs significantly improved after discontinuation of diclofenac; (f) no coexistent neoplastic, autoimmune, or infectious diseases known to be secondary causes of AIHA were found after systematic and comprehensive studies; and (g) though glucocorticoids were started on admission, no recurrence of anemia was verified in a three-year follow-up period, which would be uncommon if the patient suffered from WAIHA.
Conclusions
As a potentially fatal complication of a widely used drug in clinical practice such as diclofenac, early and correct diagnosis of DIIHA and prompt removal of the offending drug is crucial for the patient’s recovery. Our case highlights the need for both prescribing physicians and patients to be aware of this frequently underreported and usually misdiagnosed entity.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
Appendices
Table 2 Causality categories. Adapted from the WHO-UMC system for standardized case causality assessment. The usual approach is to choose one of the causality terms’ categories and to test if the various criteria fit the content of the case report. All assessment criteria should be reasonably complied to assume a category. The WHO-UMC causality assessment system can be used for the assessment of case reports of adverse drug reactions or drug-drug interactions.
WHO-UMC, World Health Organization-Uppsala Monitoring Centre
Causality term Assessment criteria
Certain • Event or laboratory test abnormality, with plausible time relationship to drug intake • Cannot be explained by disease or other drugs • Response to withdrawal plausible (pharmacologically, pathologically) • Event definitive pharmacologically or phenomenologically (i.e., an objective and specific medical disorder or a recognized pharmacological phenomenon) • Rechallenge satisfactory, if necessary
Probable/Likely • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Unlikely to be attributed to disease or other drugs • Response to withdrawal clinically reasonable • Rechallenge not required
Possible • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Could also be explained by disease or other drugs • Information on drug withdrawal may be lacking or unclear
Unlikely • Event or laboratory test abnormality, with a time to drug intake that makes a relationship improbable (but not impossible) • Disease or other drugs provide plausible explanations
Conditional/Unclassified • Event or laboratory test abnormality • More data for proper assessment needed • Additional data under examination
Unassessable/Unclassifiable • Report suggesting an adverse reaction • Cannot be judged because information is insufficient or contradictory • Data cannot be supplemented or verified | ACETAMINOPHEN, DIAZEPAM, DICLOFENAC, PERINDOPRIL, ROSUVASTATIN, THIOCOLCHICOSIDE | DrugsGivenReaction | CC BY | 33654588 | 19,027,243 | 2021-01-25 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nausea'. | Diclofenac-Induced Immune Hemolytic Anemia: A Case Report and Review of Literature.
Non-steroidal anti-inflammatory drugs are widely used for pain management. Most frequently, adverse reactions affect the gastrointestinal tract and hematological side effects usually relate to the gastrointestinal manifestations. Drug-induced immune hemolytic anemia is a rare and frequently underdiagnosed complication that is associated with poor outcomes including organ failure and even death. A 76-year-old female patient was treated with intramuscular diclofenac, thiocolchicoside, and diazepam for low back pain. Five days following diclofenac exposure, the patient was admitted to the Emergency Department with complaints of asthenia, nausea, vomiting, and diarrhea. Hemolysis and a positive direct antiglobulin test were detected on laboratory testing. Further causes of hemolytic anemia were excluded and a diagnosis of diclofenac-induced immune hemolytic anemia was established. Glucocorticoid therapy initiated on admission and drug eviction led to complete recovery. Long-term follow-up showed no recurrence of anemia. Here, we present the unusual case of a successful recovery of a 76-year-old patient with diclofenac-induced immune hemolytic anemia, a rare but immediate life-threatening condition of a frequently used drug in clinical practice.
Introduction
Autoimmune hemolytic anemia (AIHA) ensues when the host’s immune system acts against its own red cell antigens and has an estimated prevalence of approximately 1 in 100,000 individuals [1]. Approximately 50% of the cases refer to primary or idiopathic AIHA, where an associated disorder is not found [2]. Secondary causes of AIHA depend on the studied population. Current series estimate that half are associated with hematological malignancy, a third with infection, a sixth with collagen vascular disorders, and a tenth with drug-induced immune hemolytic anemia (DIIHA), the latter reaching an estimated incidence of one per million per year [1,3].
Diclofenac is one of the non-steroidal anti-inflammatory drugs (NSAIDs) most used for the treatment of rheumatoid arthritis and osteoarthritis [4]. Though generally well tolerated, over 400 adverse reactions have been documented. Most frequently, adverse reactions affect the gastrointestinal tract, the skin, and the central nervous system [5]. Direct hematological side effects such as leukopenia, thrombocytopenia, and aplastic anemia have been described only in limited cases [6-9].
We present the case of a 76-year-old patient with diclofenac DIIHA and a summary of the pathophysiology and therapeutic options.
Case presentation
A 76-year-old woman presented to the Emergency Department (ED) with recent onset of fatigue. She had a previous medical history of essential arterial hypertension, dyslipidemia, and spinal osteoarthritis with sporadic episodes of lumbosciatic pain. Regular medications initiated several years prior included perindopril 8 mg and rosuvastatin 10 mg. No allergies, alcohol, tobacco, toxins, or animal exposures were known, and she had no other relevant personal or familiar history.
Three weeks before admission the patient had an exacerbation of right lumbosciatic pain. This episode was similar to the previous ones, for which she usually was prescribed oral NSAIDs, acetaminophen, general physical therapy, massages, and rest with complete recovery. However, this time the pain was refractory to general measures, and eight days before admission, she was prescribed a combination of a daily intramuscular administration of 4 mg thiocolchicoside, 75 mg diclofenac, and 5 mg diazepam for a total of six days.
On the fifth day of treatment, she developed generalized malaise, fatigue, nausea, postprandial vomiting, and diarrhea with up to six soft, brownish dejections per day.
Despite resolution of nausea, vomiting, and diarrhea, she experienced progressive worsening of fatigue and was admitted to the ED. Detailed medical history was negative for other symptoms, namely, fever, coluria, acholia, melena, and other evident blood losses, either on admission or in the past.
Physical examination revealed jaundice and pallor of the skin and mucous membranes. No epistaxis, gingivorrhagia, adenopathies, ecchymosis, or other skin lesions were found. Blood pressure was 137/62 mmHg and heart rate was 96 beats per minute, respiratory rate was 16 beats per minute, and peripheral oxygenation saturation was 96%. No fever or other abnormalities were noted.
Blood examination showed normocytic normochromic anemia (hemoglobin: 7.9 g/dL, reference median globular volume: 88 fL), reticulocytosis (9.2%), leucocytosis (white blood cells: 13.8 × 10 9/L), hyperbilirubinemia at the expense of unconjugated bilirubin (total bilirubin: 4.09 mg/dL, conjugated bilirubin: 0.97 mg/dL), elevated lactic dehydrogenase (805 UI/L), and sedimentation rate (VS: 76 mm). Serum iron concentration, ferritin, total iron-binding capacity, folic acid, or vitamin B12 showed no significant changes and haptoglobin levels were undetectable. Peripheral blood smear revealed exuberant erythrocyte rouleaux and spherocytes. The direct antiglobulin test (DAT) was positive for immunoglobulin G (IgG). Chest radiography, abdominal ultrasound, and electrocardiogram performed in the ED were normal.
The hypothesis of AIHA was considered in the ED. The patient was started on 60 mg of prednisolone per day (1 mg/kg/day) and was admitted to the medical ward.
The hypothesis of secondary AIHA to an infectious or a connective tissue disease was ruled out. Gastrointestinal complaints were compatible with side effects of NSAIDs, viral serologies, blood cultures, rheumatoid factor, antinuclear antibody, antineutrophil cytoplasmic antibodies, and cyclic citrullinated peptide antibody were negative, and complement (both C3 and C4 studies) was normal. Lymphoproliferative disease was excluded due to the absence of adenopathies both on physical examination and in imaging studies, as well as normal immunoglobulin levels (IgG, IgM, and IgA) and a normal serum protein electrophoresis. Inflammatory bowel disease and digestive tract tumors were also excluded by endoscopic observation and anatomopathological analysis of biopsies made in macroscopically normal mucosa.
During hospitalization, glucocorticoid therapy was maintained, and folic acid supplementation of 5 mg per day was started. The patient had clinical improvement with resolution of asthenia and jaundice, as well as progressive normalization of the hemoglobin and bilirubin values. On discharge, 13 days after admission, anemia was mild (hemoglobin: 11 g/dL) and no signs of hemolysis were noted. Table 1 shows the laboratory data during hospitalization.
Table 1 Laboratory data during hospitalization.
ALP: alkaline phosphatase; ALT: alanine aminotransferase; ANA: antinuclear antibodies; ANCA: antineutrophil cytoplasmic antibody; anti-CCP: anti-cyclic citrullinated peptides; AST: aspartate aminotransferase; GGT: gamma-glutamyl transferase; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; Ig: immunoglobulin; LDH: lactate dehydrogenase, MCV: mean corpuscular volume, TIBC: total iron binding capacity
Results
Variable Reference range (adults) Day 1 Day 2 Day 5 Day 7 Day 9 Day 13
Hemoglobin (g/dL) 11.8-15.8 7.9 7.8 8.2 9.1 10.3 11
Hematocrit (%) 36.0-46.0 21.9 22.1 24.4 26.7 30.6 33
Red blood cells (106/µL) 4.2-5.4 2.47 2.42 2.48 2.63 2.97 3.14
MCV (fL) 80.4-96.4 88.7 91.3 98.4 101.5 103 105.1
White cell count (103/µL) 4.0-10.0 13.88 12.49 18.09 15.62 11.43 11.82
Differential cell count (103/L)
Neutrophils 1.5-8.0 9.1 8.3 11.448 9.4 5.9 7.2
Lymphocytes 0.8-4.0 3.3 2.7 5.5 5.2 4.7 3.8
Platelet count (103/µL) 150-400 353 353 381 377 392 362
Reticulocytes (%) 0.5-1.5 9.22
Sedimentation rate (mm) 4-10 103 9
C-reactive protein (mg/dL) <0.51 3.23 2.67 0.69 0.41 0.23 0.14
Urea (mg/dL) 17.0-43.0 40 31 39 35 29 33
Creatinine (mg/dL) 0.6-1.0 0.84 0.78 0.8 0.78 0.84 0.79
Sodium (mmol/L) 136-145 140 141 138 143 141 142
Potassium (mmol/L) 3.5-5.1 4.2 4.2 3 3.7 4 3.9
Calcium (mg/dL) 8.6-10.3 8.7
Uric acid (mg/dL) 2.6-6 7
Bilirubin (mg/dL)
Total 0.3-1.2 4.09 4.01 2.16 2.29 2.27 1.28
Direct <0.5 0.07 0.82 0.71 0.75 0.75 0.46
LDH (UI/L) 125-220 805 632 467 436 388 309
ALP (UI/L) 30-120 152 135 96 93 90 76
GGT (UI/L) <38 83 70 55 56 54 43
ALT (UI/L) 7-45 44 19 23 30 31
AST (UI/L) 8-35 30 22 15 21 21 23
Iron (µ/dL) 70-180 124
TIBC (µ/dL) 250-245 300
Folic acid (ng/mL) 2.34-17.56 5.8
Vitamin B12 (pg/mL) 187-883 414
Haptoglobin (mg/dL) 35-250 <8
Direct antiglobulin test Positive for IgG
Protein electrophoresis No monoclonal spikes
Total proteins (g/dL) 6.4-8.2 6.1
Albumin (g/dL) 3.5-5.2 3.6
Immunoglobulins
IgA (mg/dL) 60-400 192
IgG (mg/dL) 70-1,600 1,008
IgM (mg/dL) 40-230 131
ANA Negative
ANCA Negative
Rheumatoid factor Negative
anti-CCP Negative
Serology
HIV Negative
HBV Negative
HCV Negative
Given the acute clinical context after diclofenac intake and absence of evidence for other secondary etiologies, the diagnosis of acquired hemolytic anemia secondary to NSAIDs was made. Follow-up three years later found the patient asymptomatic with no recurrence of anemia or hemolysis.
Discussion
Drugs are generally small molecules unable to elicit an immune response, however, they can function as haptens, bind to larger proteins, become immunogenic, and lead to antibody production. These antibodies can be further classified as drug-induced, drug-dependent, and drug-independent antibodies. Drug-induced antibodies can bind to red blood cells (RBCs) and lead to hemolysis by non-immunological modification of erythrocyte membranes known as adsorption of non-immunological proteins. Drug-dependent antibodies bind to RBCs only in the presence of the drug or its metabolites, causing abrupt complement-mediated intravascular hemolysis. In vitro tests searching for lysis, DAT, or indirect antiglobulin test can be performed to confirm the diagnosis using the offending drug or its metabolites and the patient’s plasma or serum. Drug-independent antibodies can react with RBCs even in the absence of the drug and, therefore, are indistinguishable from autoantibodies mediating warm autoimmune hemolytic anemia (WAIHA) [1,10,11].
WAIHA is named after warm agglutinins, usually IgG autoantibodies, that bind to antigens on erythrocytes at a temperature of 37°C, leading to RBC destruction and a chronic or relapsing disease with an almost pathognomonic positive DAT [2].
Patients are treated with glucocorticoids 1 to 2 mg/kg of body weight/day of prednisone administered orally or an equivalent dose of methylprednisolone administered intravenously. Though most patients recover to an hemoglobin level above 10 g/dL within two to three weeks of treatment, relapse after treatment discontinuation is common, with retrospective case studies suggesting long-term remission rates as low as 20% to 30% [2].
DIIHA is identified by clinical evidence of hemolysis associated with drug therapy. Although many drugs have anedoctally reported isolated cases of DIIHA, over 130 drugs have reasonable evidence that supports an immune etiology [12]. It has been speculated that DIIHA is far more common than previously estimated, as most reports usually refer to more severe cases, either presenting with shock, multiorgan damage, or renal failure, and most mild cases being unreported [6].
Drugs most frequently associated with DIIHA are second and third generation of cephalosporins, diclofenac, oxaliplatin, and fludarabine. In European cohorts where diclofenac is the most frequently used NSAID, case reviews reported diclofenac as the most frequently implicated drug, with a fatal outcome being estimated in 15% to 21% of the reported cases [6,12-16]. Diclofenac-induced immune hemolytic anemia has been demonstrated in few cases, where the exposure to the drug or its metabolites lead to developing both drug-independent IgG autoantibodies and antibodies that reacted with diclofenac and its metabolites [8].
Signs and symptoms of DIIHA, as any other hemolytic anemia, are proportional to the degree and time of onset and can present withing hours to weeks of drug exposure. These include fatigue, dyspnea, and thoracic or abdominal pain. Late symptoms are usually due to complications of decompensated hemolysis, usually shock or renal failure. Laboratory abnormalities include low hemoglobin and haptoglobin levels, elevated lactate dehydrogenase and indirect bilirubin levels, reticulocytosis, and a positive DAT [1,10].
The DAT is positive in all the described forms of DIIHA, either for IgG, C3, or both. Rare cases with negative DAT reported either low antibody density, massive intravascular hemolysis, or red cell transfusion administered prior to testing [1,10]. When approaching a case where there is evidence of hemolysis and an established temporal relationship with a drug known to induce autoantibody production, investigation for drug-dependent antibodies can be performed in adequate laboratory settings, with quality ensured expertise and appropriate controls [1,3].
As there are no defining clinical features and drug-induced autoantibodies are indistinguishable from idiopathic autoantibodies, misdiagnosis in DIIHA is extremely common, with some patients dying because of late diagnosis. Furthermore, hemolysis and serological results can persist for up to months after withdrawal of the drug, leading to erroneous attribution of recovery on the administered treatment and not to the interruption of the drug [6].
If DIIHA is suspected, relevant medication should be withdrawn immediately. In mild cases, recovery usually happens within one to two weeks after drug suspension, with no other necessary measures. As most drugs have a relatively short half-life, even a strong drug-dependent antibody loses its effect shortly after drug suspension [1]. Failure to recognize DIIHA can have disastrous consequences, especially when patients present complaints for which the offending drug was prescribed. Regarding diclofenac DIIHA, some cases have been reported of patients receiving the drug again for “low back pain” during the early onset of hemolysis [9].
In acute severe DIIHA, recommendations suggest close monitoring of clinical and laboratory signs, early intravenous access, and fluid resuscitation. Blood transfusion should not be withheld in patients with severe anemia [3]. Even though crossmatch-compatible blood can be difficult to find, a review of 134 patients showed that 68 (55%) patients received blood transfusions. Though most patients (85%) received glucocorticoids, its benefit is uncertain and its routine use is not recommended as drug eviction is usually enough to stop the immune response [14].
Applying the criteria of the World Health Organization causality assessment method to assess a possible drug‐induced etiology of IHA we are confident the most likely diagnosis for our patient was diclofenac-induced IHA [17]. Our analysis is supported by: (a) the presence of autoantibodies in the patient’s eluate was demonstrated; (b) diclofenac is known to induce DIIHA; (c) there is a chronological relationship between hemolysis and diclofenac administration; (d) a review of the literature failed to show cases of DIIHA induced by any of the other drugs taken by the patient; (e) symptoms and laboratory signs significantly improved after discontinuation of diclofenac; (f) no coexistent neoplastic, autoimmune, or infectious diseases known to be secondary causes of AIHA were found after systematic and comprehensive studies; and (g) though glucocorticoids were started on admission, no recurrence of anemia was verified in a three-year follow-up period, which would be uncommon if the patient suffered from WAIHA.
Conclusions
As a potentially fatal complication of a widely used drug in clinical practice such as diclofenac, early and correct diagnosis of DIIHA and prompt removal of the offending drug is crucial for the patient’s recovery. Our case highlights the need for both prescribing physicians and patients to be aware of this frequently underreported and usually misdiagnosed entity.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
Appendices
Table 2 Causality categories. Adapted from the WHO-UMC system for standardized case causality assessment. The usual approach is to choose one of the causality terms’ categories and to test if the various criteria fit the content of the case report. All assessment criteria should be reasonably complied to assume a category. The WHO-UMC causality assessment system can be used for the assessment of case reports of adverse drug reactions or drug-drug interactions.
WHO-UMC, World Health Organization-Uppsala Monitoring Centre
Causality term Assessment criteria
Certain • Event or laboratory test abnormality, with plausible time relationship to drug intake • Cannot be explained by disease or other drugs • Response to withdrawal plausible (pharmacologically, pathologically) • Event definitive pharmacologically or phenomenologically (i.e., an objective and specific medical disorder or a recognized pharmacological phenomenon) • Rechallenge satisfactory, if necessary
Probable/Likely • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Unlikely to be attributed to disease or other drugs • Response to withdrawal clinically reasonable • Rechallenge not required
Possible • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Could also be explained by disease or other drugs • Information on drug withdrawal may be lacking or unclear
Unlikely • Event or laboratory test abnormality, with a time to drug intake that makes a relationship improbable (but not impossible) • Disease or other drugs provide plausible explanations
Conditional/Unclassified • Event or laboratory test abnormality • More data for proper assessment needed • Additional data under examination
Unassessable/Unclassifiable • Report suggesting an adverse reaction • Cannot be judged because information is insufficient or contradictory • Data cannot be supplemented or verified | ACETAMINOPHEN, DIAZEPAM, DICLOFENAC, PERINDOPRIL, ROSUVASTATIN, THIOCOLCHICOSIDE | DrugsGivenReaction | CC BY | 33654588 | 19,027,243 | 2021-01-25 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Normochromic normocytic anaemia'. | Diclofenac-Induced Immune Hemolytic Anemia: A Case Report and Review of Literature.
Non-steroidal anti-inflammatory drugs are widely used for pain management. Most frequently, adverse reactions affect the gastrointestinal tract and hematological side effects usually relate to the gastrointestinal manifestations. Drug-induced immune hemolytic anemia is a rare and frequently underdiagnosed complication that is associated with poor outcomes including organ failure and even death. A 76-year-old female patient was treated with intramuscular diclofenac, thiocolchicoside, and diazepam for low back pain. Five days following diclofenac exposure, the patient was admitted to the Emergency Department with complaints of asthenia, nausea, vomiting, and diarrhea. Hemolysis and a positive direct antiglobulin test were detected on laboratory testing. Further causes of hemolytic anemia were excluded and a diagnosis of diclofenac-induced immune hemolytic anemia was established. Glucocorticoid therapy initiated on admission and drug eviction led to complete recovery. Long-term follow-up showed no recurrence of anemia. Here, we present the unusual case of a successful recovery of a 76-year-old patient with diclofenac-induced immune hemolytic anemia, a rare but immediate life-threatening condition of a frequently used drug in clinical practice.
Introduction
Autoimmune hemolytic anemia (AIHA) ensues when the host’s immune system acts against its own red cell antigens and has an estimated prevalence of approximately 1 in 100,000 individuals [1]. Approximately 50% of the cases refer to primary or idiopathic AIHA, where an associated disorder is not found [2]. Secondary causes of AIHA depend on the studied population. Current series estimate that half are associated with hematological malignancy, a third with infection, a sixth with collagen vascular disorders, and a tenth with drug-induced immune hemolytic anemia (DIIHA), the latter reaching an estimated incidence of one per million per year [1,3].
Diclofenac is one of the non-steroidal anti-inflammatory drugs (NSAIDs) most used for the treatment of rheumatoid arthritis and osteoarthritis [4]. Though generally well tolerated, over 400 adverse reactions have been documented. Most frequently, adverse reactions affect the gastrointestinal tract, the skin, and the central nervous system [5]. Direct hematological side effects such as leukopenia, thrombocytopenia, and aplastic anemia have been described only in limited cases [6-9].
We present the case of a 76-year-old patient with diclofenac DIIHA and a summary of the pathophysiology and therapeutic options.
Case presentation
A 76-year-old woman presented to the Emergency Department (ED) with recent onset of fatigue. She had a previous medical history of essential arterial hypertension, dyslipidemia, and spinal osteoarthritis with sporadic episodes of lumbosciatic pain. Regular medications initiated several years prior included perindopril 8 mg and rosuvastatin 10 mg. No allergies, alcohol, tobacco, toxins, or animal exposures were known, and she had no other relevant personal or familiar history.
Three weeks before admission the patient had an exacerbation of right lumbosciatic pain. This episode was similar to the previous ones, for which she usually was prescribed oral NSAIDs, acetaminophen, general physical therapy, massages, and rest with complete recovery. However, this time the pain was refractory to general measures, and eight days before admission, she was prescribed a combination of a daily intramuscular administration of 4 mg thiocolchicoside, 75 mg diclofenac, and 5 mg diazepam for a total of six days.
On the fifth day of treatment, she developed generalized malaise, fatigue, nausea, postprandial vomiting, and diarrhea with up to six soft, brownish dejections per day.
Despite resolution of nausea, vomiting, and diarrhea, she experienced progressive worsening of fatigue and was admitted to the ED. Detailed medical history was negative for other symptoms, namely, fever, coluria, acholia, melena, and other evident blood losses, either on admission or in the past.
Physical examination revealed jaundice and pallor of the skin and mucous membranes. No epistaxis, gingivorrhagia, adenopathies, ecchymosis, or other skin lesions were found. Blood pressure was 137/62 mmHg and heart rate was 96 beats per minute, respiratory rate was 16 beats per minute, and peripheral oxygenation saturation was 96%. No fever or other abnormalities were noted.
Blood examination showed normocytic normochromic anemia (hemoglobin: 7.9 g/dL, reference median globular volume: 88 fL), reticulocytosis (9.2%), leucocytosis (white blood cells: 13.8 × 10 9/L), hyperbilirubinemia at the expense of unconjugated bilirubin (total bilirubin: 4.09 mg/dL, conjugated bilirubin: 0.97 mg/dL), elevated lactic dehydrogenase (805 UI/L), and sedimentation rate (VS: 76 mm). Serum iron concentration, ferritin, total iron-binding capacity, folic acid, or vitamin B12 showed no significant changes and haptoglobin levels were undetectable. Peripheral blood smear revealed exuberant erythrocyte rouleaux and spherocytes. The direct antiglobulin test (DAT) was positive for immunoglobulin G (IgG). Chest radiography, abdominal ultrasound, and electrocardiogram performed in the ED were normal.
The hypothesis of AIHA was considered in the ED. The patient was started on 60 mg of prednisolone per day (1 mg/kg/day) and was admitted to the medical ward.
The hypothesis of secondary AIHA to an infectious or a connective tissue disease was ruled out. Gastrointestinal complaints were compatible with side effects of NSAIDs, viral serologies, blood cultures, rheumatoid factor, antinuclear antibody, antineutrophil cytoplasmic antibodies, and cyclic citrullinated peptide antibody were negative, and complement (both C3 and C4 studies) was normal. Lymphoproliferative disease was excluded due to the absence of adenopathies both on physical examination and in imaging studies, as well as normal immunoglobulin levels (IgG, IgM, and IgA) and a normal serum protein electrophoresis. Inflammatory bowel disease and digestive tract tumors were also excluded by endoscopic observation and anatomopathological analysis of biopsies made in macroscopically normal mucosa.
During hospitalization, glucocorticoid therapy was maintained, and folic acid supplementation of 5 mg per day was started. The patient had clinical improvement with resolution of asthenia and jaundice, as well as progressive normalization of the hemoglobin and bilirubin values. On discharge, 13 days after admission, anemia was mild (hemoglobin: 11 g/dL) and no signs of hemolysis were noted. Table 1 shows the laboratory data during hospitalization.
Table 1 Laboratory data during hospitalization.
ALP: alkaline phosphatase; ALT: alanine aminotransferase; ANA: antinuclear antibodies; ANCA: antineutrophil cytoplasmic antibody; anti-CCP: anti-cyclic citrullinated peptides; AST: aspartate aminotransferase; GGT: gamma-glutamyl transferase; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; Ig: immunoglobulin; LDH: lactate dehydrogenase, MCV: mean corpuscular volume, TIBC: total iron binding capacity
Results
Variable Reference range (adults) Day 1 Day 2 Day 5 Day 7 Day 9 Day 13
Hemoglobin (g/dL) 11.8-15.8 7.9 7.8 8.2 9.1 10.3 11
Hematocrit (%) 36.0-46.0 21.9 22.1 24.4 26.7 30.6 33
Red blood cells (106/µL) 4.2-5.4 2.47 2.42 2.48 2.63 2.97 3.14
MCV (fL) 80.4-96.4 88.7 91.3 98.4 101.5 103 105.1
White cell count (103/µL) 4.0-10.0 13.88 12.49 18.09 15.62 11.43 11.82
Differential cell count (103/L)
Neutrophils 1.5-8.0 9.1 8.3 11.448 9.4 5.9 7.2
Lymphocytes 0.8-4.0 3.3 2.7 5.5 5.2 4.7 3.8
Platelet count (103/µL) 150-400 353 353 381 377 392 362
Reticulocytes (%) 0.5-1.5 9.22
Sedimentation rate (mm) 4-10 103 9
C-reactive protein (mg/dL) <0.51 3.23 2.67 0.69 0.41 0.23 0.14
Urea (mg/dL) 17.0-43.0 40 31 39 35 29 33
Creatinine (mg/dL) 0.6-1.0 0.84 0.78 0.8 0.78 0.84 0.79
Sodium (mmol/L) 136-145 140 141 138 143 141 142
Potassium (mmol/L) 3.5-5.1 4.2 4.2 3 3.7 4 3.9
Calcium (mg/dL) 8.6-10.3 8.7
Uric acid (mg/dL) 2.6-6 7
Bilirubin (mg/dL)
Total 0.3-1.2 4.09 4.01 2.16 2.29 2.27 1.28
Direct <0.5 0.07 0.82 0.71 0.75 0.75 0.46
LDH (UI/L) 125-220 805 632 467 436 388 309
ALP (UI/L) 30-120 152 135 96 93 90 76
GGT (UI/L) <38 83 70 55 56 54 43
ALT (UI/L) 7-45 44 19 23 30 31
AST (UI/L) 8-35 30 22 15 21 21 23
Iron (µ/dL) 70-180 124
TIBC (µ/dL) 250-245 300
Folic acid (ng/mL) 2.34-17.56 5.8
Vitamin B12 (pg/mL) 187-883 414
Haptoglobin (mg/dL) 35-250 <8
Direct antiglobulin test Positive for IgG
Protein electrophoresis No monoclonal spikes
Total proteins (g/dL) 6.4-8.2 6.1
Albumin (g/dL) 3.5-5.2 3.6
Immunoglobulins
IgA (mg/dL) 60-400 192
IgG (mg/dL) 70-1,600 1,008
IgM (mg/dL) 40-230 131
ANA Negative
ANCA Negative
Rheumatoid factor Negative
anti-CCP Negative
Serology
HIV Negative
HBV Negative
HCV Negative
Given the acute clinical context after diclofenac intake and absence of evidence for other secondary etiologies, the diagnosis of acquired hemolytic anemia secondary to NSAIDs was made. Follow-up three years later found the patient asymptomatic with no recurrence of anemia or hemolysis.
Discussion
Drugs are generally small molecules unable to elicit an immune response, however, they can function as haptens, bind to larger proteins, become immunogenic, and lead to antibody production. These antibodies can be further classified as drug-induced, drug-dependent, and drug-independent antibodies. Drug-induced antibodies can bind to red blood cells (RBCs) and lead to hemolysis by non-immunological modification of erythrocyte membranes known as adsorption of non-immunological proteins. Drug-dependent antibodies bind to RBCs only in the presence of the drug or its metabolites, causing abrupt complement-mediated intravascular hemolysis. In vitro tests searching for lysis, DAT, or indirect antiglobulin test can be performed to confirm the diagnosis using the offending drug or its metabolites and the patient’s plasma or serum. Drug-independent antibodies can react with RBCs even in the absence of the drug and, therefore, are indistinguishable from autoantibodies mediating warm autoimmune hemolytic anemia (WAIHA) [1,10,11].
WAIHA is named after warm agglutinins, usually IgG autoantibodies, that bind to antigens on erythrocytes at a temperature of 37°C, leading to RBC destruction and a chronic or relapsing disease with an almost pathognomonic positive DAT [2].
Patients are treated with glucocorticoids 1 to 2 mg/kg of body weight/day of prednisone administered orally or an equivalent dose of methylprednisolone administered intravenously. Though most patients recover to an hemoglobin level above 10 g/dL within two to three weeks of treatment, relapse after treatment discontinuation is common, with retrospective case studies suggesting long-term remission rates as low as 20% to 30% [2].
DIIHA is identified by clinical evidence of hemolysis associated with drug therapy. Although many drugs have anedoctally reported isolated cases of DIIHA, over 130 drugs have reasonable evidence that supports an immune etiology [12]. It has been speculated that DIIHA is far more common than previously estimated, as most reports usually refer to more severe cases, either presenting with shock, multiorgan damage, or renal failure, and most mild cases being unreported [6].
Drugs most frequently associated with DIIHA are second and third generation of cephalosporins, diclofenac, oxaliplatin, and fludarabine. In European cohorts where diclofenac is the most frequently used NSAID, case reviews reported diclofenac as the most frequently implicated drug, with a fatal outcome being estimated in 15% to 21% of the reported cases [6,12-16]. Diclofenac-induced immune hemolytic anemia has been demonstrated in few cases, where the exposure to the drug or its metabolites lead to developing both drug-independent IgG autoantibodies and antibodies that reacted with diclofenac and its metabolites [8].
Signs and symptoms of DIIHA, as any other hemolytic anemia, are proportional to the degree and time of onset and can present withing hours to weeks of drug exposure. These include fatigue, dyspnea, and thoracic or abdominal pain. Late symptoms are usually due to complications of decompensated hemolysis, usually shock or renal failure. Laboratory abnormalities include low hemoglobin and haptoglobin levels, elevated lactate dehydrogenase and indirect bilirubin levels, reticulocytosis, and a positive DAT [1,10].
The DAT is positive in all the described forms of DIIHA, either for IgG, C3, or both. Rare cases with negative DAT reported either low antibody density, massive intravascular hemolysis, or red cell transfusion administered prior to testing [1,10]. When approaching a case where there is evidence of hemolysis and an established temporal relationship with a drug known to induce autoantibody production, investigation for drug-dependent antibodies can be performed in adequate laboratory settings, with quality ensured expertise and appropriate controls [1,3].
As there are no defining clinical features and drug-induced autoantibodies are indistinguishable from idiopathic autoantibodies, misdiagnosis in DIIHA is extremely common, with some patients dying because of late diagnosis. Furthermore, hemolysis and serological results can persist for up to months after withdrawal of the drug, leading to erroneous attribution of recovery on the administered treatment and not to the interruption of the drug [6].
If DIIHA is suspected, relevant medication should be withdrawn immediately. In mild cases, recovery usually happens within one to two weeks after drug suspension, with no other necessary measures. As most drugs have a relatively short half-life, even a strong drug-dependent antibody loses its effect shortly after drug suspension [1]. Failure to recognize DIIHA can have disastrous consequences, especially when patients present complaints for which the offending drug was prescribed. Regarding diclofenac DIIHA, some cases have been reported of patients receiving the drug again for “low back pain” during the early onset of hemolysis [9].
In acute severe DIIHA, recommendations suggest close monitoring of clinical and laboratory signs, early intravenous access, and fluid resuscitation. Blood transfusion should not be withheld in patients with severe anemia [3]. Even though crossmatch-compatible blood can be difficult to find, a review of 134 patients showed that 68 (55%) patients received blood transfusions. Though most patients (85%) received glucocorticoids, its benefit is uncertain and its routine use is not recommended as drug eviction is usually enough to stop the immune response [14].
Applying the criteria of the World Health Organization causality assessment method to assess a possible drug‐induced etiology of IHA we are confident the most likely diagnosis for our patient was diclofenac-induced IHA [17]. Our analysis is supported by: (a) the presence of autoantibodies in the patient’s eluate was demonstrated; (b) diclofenac is known to induce DIIHA; (c) there is a chronological relationship between hemolysis and diclofenac administration; (d) a review of the literature failed to show cases of DIIHA induced by any of the other drugs taken by the patient; (e) symptoms and laboratory signs significantly improved after discontinuation of diclofenac; (f) no coexistent neoplastic, autoimmune, or infectious diseases known to be secondary causes of AIHA were found after systematic and comprehensive studies; and (g) though glucocorticoids were started on admission, no recurrence of anemia was verified in a three-year follow-up period, which would be uncommon if the patient suffered from WAIHA.
Conclusions
As a potentially fatal complication of a widely used drug in clinical practice such as diclofenac, early and correct diagnosis of DIIHA and prompt removal of the offending drug is crucial for the patient’s recovery. Our case highlights the need for both prescribing physicians and patients to be aware of this frequently underreported and usually misdiagnosed entity.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
Appendices
Table 2 Causality categories. Adapted from the WHO-UMC system for standardized case causality assessment. The usual approach is to choose one of the causality terms’ categories and to test if the various criteria fit the content of the case report. All assessment criteria should be reasonably complied to assume a category. The WHO-UMC causality assessment system can be used for the assessment of case reports of adverse drug reactions or drug-drug interactions.
WHO-UMC, World Health Organization-Uppsala Monitoring Centre
Causality term Assessment criteria
Certain • Event or laboratory test abnormality, with plausible time relationship to drug intake • Cannot be explained by disease or other drugs • Response to withdrawal plausible (pharmacologically, pathologically) • Event definitive pharmacologically or phenomenologically (i.e., an objective and specific medical disorder or a recognized pharmacological phenomenon) • Rechallenge satisfactory, if necessary
Probable/Likely • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Unlikely to be attributed to disease or other drugs • Response to withdrawal clinically reasonable • Rechallenge not required
Possible • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Could also be explained by disease or other drugs • Information on drug withdrawal may be lacking or unclear
Unlikely • Event or laboratory test abnormality, with a time to drug intake that makes a relationship improbable (but not impossible) • Disease or other drugs provide plausible explanations
Conditional/Unclassified • Event or laboratory test abnormality • More data for proper assessment needed • Additional data under examination
Unassessable/Unclassifiable • Report suggesting an adverse reaction • Cannot be judged because information is insufficient or contradictory • Data cannot be supplemented or verified | ACETAMINOPHEN, DIAZEPAM, DICLOFENAC, PERINDOPRIL, ROSUVASTATIN, THIOCOLCHICOSIDE | DrugsGivenReaction | CC BY | 33654588 | 19,027,243 | 2021-01-25 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pallor'. | Diclofenac-Induced Immune Hemolytic Anemia: A Case Report and Review of Literature.
Non-steroidal anti-inflammatory drugs are widely used for pain management. Most frequently, adverse reactions affect the gastrointestinal tract and hematological side effects usually relate to the gastrointestinal manifestations. Drug-induced immune hemolytic anemia is a rare and frequently underdiagnosed complication that is associated with poor outcomes including organ failure and even death. A 76-year-old female patient was treated with intramuscular diclofenac, thiocolchicoside, and diazepam for low back pain. Five days following diclofenac exposure, the patient was admitted to the Emergency Department with complaints of asthenia, nausea, vomiting, and diarrhea. Hemolysis and a positive direct antiglobulin test were detected on laboratory testing. Further causes of hemolytic anemia were excluded and a diagnosis of diclofenac-induced immune hemolytic anemia was established. Glucocorticoid therapy initiated on admission and drug eviction led to complete recovery. Long-term follow-up showed no recurrence of anemia. Here, we present the unusual case of a successful recovery of a 76-year-old patient with diclofenac-induced immune hemolytic anemia, a rare but immediate life-threatening condition of a frequently used drug in clinical practice.
Introduction
Autoimmune hemolytic anemia (AIHA) ensues when the host’s immune system acts against its own red cell antigens and has an estimated prevalence of approximately 1 in 100,000 individuals [1]. Approximately 50% of the cases refer to primary or idiopathic AIHA, where an associated disorder is not found [2]. Secondary causes of AIHA depend on the studied population. Current series estimate that half are associated with hematological malignancy, a third with infection, a sixth with collagen vascular disorders, and a tenth with drug-induced immune hemolytic anemia (DIIHA), the latter reaching an estimated incidence of one per million per year [1,3].
Diclofenac is one of the non-steroidal anti-inflammatory drugs (NSAIDs) most used for the treatment of rheumatoid arthritis and osteoarthritis [4]. Though generally well tolerated, over 400 adverse reactions have been documented. Most frequently, adverse reactions affect the gastrointestinal tract, the skin, and the central nervous system [5]. Direct hematological side effects such as leukopenia, thrombocytopenia, and aplastic anemia have been described only in limited cases [6-9].
We present the case of a 76-year-old patient with diclofenac DIIHA and a summary of the pathophysiology and therapeutic options.
Case presentation
A 76-year-old woman presented to the Emergency Department (ED) with recent onset of fatigue. She had a previous medical history of essential arterial hypertension, dyslipidemia, and spinal osteoarthritis with sporadic episodes of lumbosciatic pain. Regular medications initiated several years prior included perindopril 8 mg and rosuvastatin 10 mg. No allergies, alcohol, tobacco, toxins, or animal exposures were known, and she had no other relevant personal or familiar history.
Three weeks before admission the patient had an exacerbation of right lumbosciatic pain. This episode was similar to the previous ones, for which she usually was prescribed oral NSAIDs, acetaminophen, general physical therapy, massages, and rest with complete recovery. However, this time the pain was refractory to general measures, and eight days before admission, she was prescribed a combination of a daily intramuscular administration of 4 mg thiocolchicoside, 75 mg diclofenac, and 5 mg diazepam for a total of six days.
On the fifth day of treatment, she developed generalized malaise, fatigue, nausea, postprandial vomiting, and diarrhea with up to six soft, brownish dejections per day.
Despite resolution of nausea, vomiting, and diarrhea, she experienced progressive worsening of fatigue and was admitted to the ED. Detailed medical history was negative for other symptoms, namely, fever, coluria, acholia, melena, and other evident blood losses, either on admission or in the past.
Physical examination revealed jaundice and pallor of the skin and mucous membranes. No epistaxis, gingivorrhagia, adenopathies, ecchymosis, or other skin lesions were found. Blood pressure was 137/62 mmHg and heart rate was 96 beats per minute, respiratory rate was 16 beats per minute, and peripheral oxygenation saturation was 96%. No fever or other abnormalities were noted.
Blood examination showed normocytic normochromic anemia (hemoglobin: 7.9 g/dL, reference median globular volume: 88 fL), reticulocytosis (9.2%), leucocytosis (white blood cells: 13.8 × 10 9/L), hyperbilirubinemia at the expense of unconjugated bilirubin (total bilirubin: 4.09 mg/dL, conjugated bilirubin: 0.97 mg/dL), elevated lactic dehydrogenase (805 UI/L), and sedimentation rate (VS: 76 mm). Serum iron concentration, ferritin, total iron-binding capacity, folic acid, or vitamin B12 showed no significant changes and haptoglobin levels were undetectable. Peripheral blood smear revealed exuberant erythrocyte rouleaux and spherocytes. The direct antiglobulin test (DAT) was positive for immunoglobulin G (IgG). Chest radiography, abdominal ultrasound, and electrocardiogram performed in the ED were normal.
The hypothesis of AIHA was considered in the ED. The patient was started on 60 mg of prednisolone per day (1 mg/kg/day) and was admitted to the medical ward.
The hypothesis of secondary AIHA to an infectious or a connective tissue disease was ruled out. Gastrointestinal complaints were compatible with side effects of NSAIDs, viral serologies, blood cultures, rheumatoid factor, antinuclear antibody, antineutrophil cytoplasmic antibodies, and cyclic citrullinated peptide antibody were negative, and complement (both C3 and C4 studies) was normal. Lymphoproliferative disease was excluded due to the absence of adenopathies both on physical examination and in imaging studies, as well as normal immunoglobulin levels (IgG, IgM, and IgA) and a normal serum protein electrophoresis. Inflammatory bowel disease and digestive tract tumors were also excluded by endoscopic observation and anatomopathological analysis of biopsies made in macroscopically normal mucosa.
During hospitalization, glucocorticoid therapy was maintained, and folic acid supplementation of 5 mg per day was started. The patient had clinical improvement with resolution of asthenia and jaundice, as well as progressive normalization of the hemoglobin and bilirubin values. On discharge, 13 days after admission, anemia was mild (hemoglobin: 11 g/dL) and no signs of hemolysis were noted. Table 1 shows the laboratory data during hospitalization.
Table 1 Laboratory data during hospitalization.
ALP: alkaline phosphatase; ALT: alanine aminotransferase; ANA: antinuclear antibodies; ANCA: antineutrophil cytoplasmic antibody; anti-CCP: anti-cyclic citrullinated peptides; AST: aspartate aminotransferase; GGT: gamma-glutamyl transferase; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; Ig: immunoglobulin; LDH: lactate dehydrogenase, MCV: mean corpuscular volume, TIBC: total iron binding capacity
Results
Variable Reference range (adults) Day 1 Day 2 Day 5 Day 7 Day 9 Day 13
Hemoglobin (g/dL) 11.8-15.8 7.9 7.8 8.2 9.1 10.3 11
Hematocrit (%) 36.0-46.0 21.9 22.1 24.4 26.7 30.6 33
Red blood cells (106/µL) 4.2-5.4 2.47 2.42 2.48 2.63 2.97 3.14
MCV (fL) 80.4-96.4 88.7 91.3 98.4 101.5 103 105.1
White cell count (103/µL) 4.0-10.0 13.88 12.49 18.09 15.62 11.43 11.82
Differential cell count (103/L)
Neutrophils 1.5-8.0 9.1 8.3 11.448 9.4 5.9 7.2
Lymphocytes 0.8-4.0 3.3 2.7 5.5 5.2 4.7 3.8
Platelet count (103/µL) 150-400 353 353 381 377 392 362
Reticulocytes (%) 0.5-1.5 9.22
Sedimentation rate (mm) 4-10 103 9
C-reactive protein (mg/dL) <0.51 3.23 2.67 0.69 0.41 0.23 0.14
Urea (mg/dL) 17.0-43.0 40 31 39 35 29 33
Creatinine (mg/dL) 0.6-1.0 0.84 0.78 0.8 0.78 0.84 0.79
Sodium (mmol/L) 136-145 140 141 138 143 141 142
Potassium (mmol/L) 3.5-5.1 4.2 4.2 3 3.7 4 3.9
Calcium (mg/dL) 8.6-10.3 8.7
Uric acid (mg/dL) 2.6-6 7
Bilirubin (mg/dL)
Total 0.3-1.2 4.09 4.01 2.16 2.29 2.27 1.28
Direct <0.5 0.07 0.82 0.71 0.75 0.75 0.46
LDH (UI/L) 125-220 805 632 467 436 388 309
ALP (UI/L) 30-120 152 135 96 93 90 76
GGT (UI/L) <38 83 70 55 56 54 43
ALT (UI/L) 7-45 44 19 23 30 31
AST (UI/L) 8-35 30 22 15 21 21 23
Iron (µ/dL) 70-180 124
TIBC (µ/dL) 250-245 300
Folic acid (ng/mL) 2.34-17.56 5.8
Vitamin B12 (pg/mL) 187-883 414
Haptoglobin (mg/dL) 35-250 <8
Direct antiglobulin test Positive for IgG
Protein electrophoresis No monoclonal spikes
Total proteins (g/dL) 6.4-8.2 6.1
Albumin (g/dL) 3.5-5.2 3.6
Immunoglobulins
IgA (mg/dL) 60-400 192
IgG (mg/dL) 70-1,600 1,008
IgM (mg/dL) 40-230 131
ANA Negative
ANCA Negative
Rheumatoid factor Negative
anti-CCP Negative
Serology
HIV Negative
HBV Negative
HCV Negative
Given the acute clinical context after diclofenac intake and absence of evidence for other secondary etiologies, the diagnosis of acquired hemolytic anemia secondary to NSAIDs was made. Follow-up three years later found the patient asymptomatic with no recurrence of anemia or hemolysis.
Discussion
Drugs are generally small molecules unable to elicit an immune response, however, they can function as haptens, bind to larger proteins, become immunogenic, and lead to antibody production. These antibodies can be further classified as drug-induced, drug-dependent, and drug-independent antibodies. Drug-induced antibodies can bind to red blood cells (RBCs) and lead to hemolysis by non-immunological modification of erythrocyte membranes known as adsorption of non-immunological proteins. Drug-dependent antibodies bind to RBCs only in the presence of the drug or its metabolites, causing abrupt complement-mediated intravascular hemolysis. In vitro tests searching for lysis, DAT, or indirect antiglobulin test can be performed to confirm the diagnosis using the offending drug or its metabolites and the patient’s plasma or serum. Drug-independent antibodies can react with RBCs even in the absence of the drug and, therefore, are indistinguishable from autoantibodies mediating warm autoimmune hemolytic anemia (WAIHA) [1,10,11].
WAIHA is named after warm agglutinins, usually IgG autoantibodies, that bind to antigens on erythrocytes at a temperature of 37°C, leading to RBC destruction and a chronic or relapsing disease with an almost pathognomonic positive DAT [2].
Patients are treated with glucocorticoids 1 to 2 mg/kg of body weight/day of prednisone administered orally or an equivalent dose of methylprednisolone administered intravenously. Though most patients recover to an hemoglobin level above 10 g/dL within two to three weeks of treatment, relapse after treatment discontinuation is common, with retrospective case studies suggesting long-term remission rates as low as 20% to 30% [2].
DIIHA is identified by clinical evidence of hemolysis associated with drug therapy. Although many drugs have anedoctally reported isolated cases of DIIHA, over 130 drugs have reasonable evidence that supports an immune etiology [12]. It has been speculated that DIIHA is far more common than previously estimated, as most reports usually refer to more severe cases, either presenting with shock, multiorgan damage, or renal failure, and most mild cases being unreported [6].
Drugs most frequently associated with DIIHA are second and third generation of cephalosporins, diclofenac, oxaliplatin, and fludarabine. In European cohorts where diclofenac is the most frequently used NSAID, case reviews reported diclofenac as the most frequently implicated drug, with a fatal outcome being estimated in 15% to 21% of the reported cases [6,12-16]. Diclofenac-induced immune hemolytic anemia has been demonstrated in few cases, where the exposure to the drug or its metabolites lead to developing both drug-independent IgG autoantibodies and antibodies that reacted with diclofenac and its metabolites [8].
Signs and symptoms of DIIHA, as any other hemolytic anemia, are proportional to the degree and time of onset and can present withing hours to weeks of drug exposure. These include fatigue, dyspnea, and thoracic or abdominal pain. Late symptoms are usually due to complications of decompensated hemolysis, usually shock or renal failure. Laboratory abnormalities include low hemoglobin and haptoglobin levels, elevated lactate dehydrogenase and indirect bilirubin levels, reticulocytosis, and a positive DAT [1,10].
The DAT is positive in all the described forms of DIIHA, either for IgG, C3, or both. Rare cases with negative DAT reported either low antibody density, massive intravascular hemolysis, or red cell transfusion administered prior to testing [1,10]. When approaching a case where there is evidence of hemolysis and an established temporal relationship with a drug known to induce autoantibody production, investigation for drug-dependent antibodies can be performed in adequate laboratory settings, with quality ensured expertise and appropriate controls [1,3].
As there are no defining clinical features and drug-induced autoantibodies are indistinguishable from idiopathic autoantibodies, misdiagnosis in DIIHA is extremely common, with some patients dying because of late diagnosis. Furthermore, hemolysis and serological results can persist for up to months after withdrawal of the drug, leading to erroneous attribution of recovery on the administered treatment and not to the interruption of the drug [6].
If DIIHA is suspected, relevant medication should be withdrawn immediately. In mild cases, recovery usually happens within one to two weeks after drug suspension, with no other necessary measures. As most drugs have a relatively short half-life, even a strong drug-dependent antibody loses its effect shortly after drug suspension [1]. Failure to recognize DIIHA can have disastrous consequences, especially when patients present complaints for which the offending drug was prescribed. Regarding diclofenac DIIHA, some cases have been reported of patients receiving the drug again for “low back pain” during the early onset of hemolysis [9].
In acute severe DIIHA, recommendations suggest close monitoring of clinical and laboratory signs, early intravenous access, and fluid resuscitation. Blood transfusion should not be withheld in patients with severe anemia [3]. Even though crossmatch-compatible blood can be difficult to find, a review of 134 patients showed that 68 (55%) patients received blood transfusions. Though most patients (85%) received glucocorticoids, its benefit is uncertain and its routine use is not recommended as drug eviction is usually enough to stop the immune response [14].
Applying the criteria of the World Health Organization causality assessment method to assess a possible drug‐induced etiology of IHA we are confident the most likely diagnosis for our patient was diclofenac-induced IHA [17]. Our analysis is supported by: (a) the presence of autoantibodies in the patient’s eluate was demonstrated; (b) diclofenac is known to induce DIIHA; (c) there is a chronological relationship between hemolysis and diclofenac administration; (d) a review of the literature failed to show cases of DIIHA induced by any of the other drugs taken by the patient; (e) symptoms and laboratory signs significantly improved after discontinuation of diclofenac; (f) no coexistent neoplastic, autoimmune, or infectious diseases known to be secondary causes of AIHA were found after systematic and comprehensive studies; and (g) though glucocorticoids were started on admission, no recurrence of anemia was verified in a three-year follow-up period, which would be uncommon if the patient suffered from WAIHA.
Conclusions
As a potentially fatal complication of a widely used drug in clinical practice such as diclofenac, early and correct diagnosis of DIIHA and prompt removal of the offending drug is crucial for the patient’s recovery. Our case highlights the need for both prescribing physicians and patients to be aware of this frequently underreported and usually misdiagnosed entity.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
Appendices
Table 2 Causality categories. Adapted from the WHO-UMC system for standardized case causality assessment. The usual approach is to choose one of the causality terms’ categories and to test if the various criteria fit the content of the case report. All assessment criteria should be reasonably complied to assume a category. The WHO-UMC causality assessment system can be used for the assessment of case reports of adverse drug reactions or drug-drug interactions.
WHO-UMC, World Health Organization-Uppsala Monitoring Centre
Causality term Assessment criteria
Certain • Event or laboratory test abnormality, with plausible time relationship to drug intake • Cannot be explained by disease or other drugs • Response to withdrawal plausible (pharmacologically, pathologically) • Event definitive pharmacologically or phenomenologically (i.e., an objective and specific medical disorder or a recognized pharmacological phenomenon) • Rechallenge satisfactory, if necessary
Probable/Likely • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Unlikely to be attributed to disease or other drugs • Response to withdrawal clinically reasonable • Rechallenge not required
Possible • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Could also be explained by disease or other drugs • Information on drug withdrawal may be lacking or unclear
Unlikely • Event or laboratory test abnormality, with a time to drug intake that makes a relationship improbable (but not impossible) • Disease or other drugs provide plausible explanations
Conditional/Unclassified • Event or laboratory test abnormality • More data for proper assessment needed • Additional data under examination
Unassessable/Unclassifiable • Report suggesting an adverse reaction • Cannot be judged because information is insufficient or contradictory • Data cannot be supplemented or verified | ACETAMINOPHEN, DIAZEPAM, DICLOFENAC, PERINDOPRIL, ROSUVASTATIN, THIOCOLCHICOSIDE | DrugsGivenReaction | CC BY | 33654588 | 19,027,243 | 2021-01-25 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Vomiting'. | Diclofenac-Induced Immune Hemolytic Anemia: A Case Report and Review of Literature.
Non-steroidal anti-inflammatory drugs are widely used for pain management. Most frequently, adverse reactions affect the gastrointestinal tract and hematological side effects usually relate to the gastrointestinal manifestations. Drug-induced immune hemolytic anemia is a rare and frequently underdiagnosed complication that is associated with poor outcomes including organ failure and even death. A 76-year-old female patient was treated with intramuscular diclofenac, thiocolchicoside, and diazepam for low back pain. Five days following diclofenac exposure, the patient was admitted to the Emergency Department with complaints of asthenia, nausea, vomiting, and diarrhea. Hemolysis and a positive direct antiglobulin test were detected on laboratory testing. Further causes of hemolytic anemia were excluded and a diagnosis of diclofenac-induced immune hemolytic anemia was established. Glucocorticoid therapy initiated on admission and drug eviction led to complete recovery. Long-term follow-up showed no recurrence of anemia. Here, we present the unusual case of a successful recovery of a 76-year-old patient with diclofenac-induced immune hemolytic anemia, a rare but immediate life-threatening condition of a frequently used drug in clinical practice.
Introduction
Autoimmune hemolytic anemia (AIHA) ensues when the host’s immune system acts against its own red cell antigens and has an estimated prevalence of approximately 1 in 100,000 individuals [1]. Approximately 50% of the cases refer to primary or idiopathic AIHA, where an associated disorder is not found [2]. Secondary causes of AIHA depend on the studied population. Current series estimate that half are associated with hematological malignancy, a third with infection, a sixth with collagen vascular disorders, and a tenth with drug-induced immune hemolytic anemia (DIIHA), the latter reaching an estimated incidence of one per million per year [1,3].
Diclofenac is one of the non-steroidal anti-inflammatory drugs (NSAIDs) most used for the treatment of rheumatoid arthritis and osteoarthritis [4]. Though generally well tolerated, over 400 adverse reactions have been documented. Most frequently, adverse reactions affect the gastrointestinal tract, the skin, and the central nervous system [5]. Direct hematological side effects such as leukopenia, thrombocytopenia, and aplastic anemia have been described only in limited cases [6-9].
We present the case of a 76-year-old patient with diclofenac DIIHA and a summary of the pathophysiology and therapeutic options.
Case presentation
A 76-year-old woman presented to the Emergency Department (ED) with recent onset of fatigue. She had a previous medical history of essential arterial hypertension, dyslipidemia, and spinal osteoarthritis with sporadic episodes of lumbosciatic pain. Regular medications initiated several years prior included perindopril 8 mg and rosuvastatin 10 mg. No allergies, alcohol, tobacco, toxins, or animal exposures were known, and she had no other relevant personal or familiar history.
Three weeks before admission the patient had an exacerbation of right lumbosciatic pain. This episode was similar to the previous ones, for which she usually was prescribed oral NSAIDs, acetaminophen, general physical therapy, massages, and rest with complete recovery. However, this time the pain was refractory to general measures, and eight days before admission, she was prescribed a combination of a daily intramuscular administration of 4 mg thiocolchicoside, 75 mg diclofenac, and 5 mg diazepam for a total of six days.
On the fifth day of treatment, she developed generalized malaise, fatigue, nausea, postprandial vomiting, and diarrhea with up to six soft, brownish dejections per day.
Despite resolution of nausea, vomiting, and diarrhea, she experienced progressive worsening of fatigue and was admitted to the ED. Detailed medical history was negative for other symptoms, namely, fever, coluria, acholia, melena, and other evident blood losses, either on admission or in the past.
Physical examination revealed jaundice and pallor of the skin and mucous membranes. No epistaxis, gingivorrhagia, adenopathies, ecchymosis, or other skin lesions were found. Blood pressure was 137/62 mmHg and heart rate was 96 beats per minute, respiratory rate was 16 beats per minute, and peripheral oxygenation saturation was 96%. No fever or other abnormalities were noted.
Blood examination showed normocytic normochromic anemia (hemoglobin: 7.9 g/dL, reference median globular volume: 88 fL), reticulocytosis (9.2%), leucocytosis (white blood cells: 13.8 × 10 9/L), hyperbilirubinemia at the expense of unconjugated bilirubin (total bilirubin: 4.09 mg/dL, conjugated bilirubin: 0.97 mg/dL), elevated lactic dehydrogenase (805 UI/L), and sedimentation rate (VS: 76 mm). Serum iron concentration, ferritin, total iron-binding capacity, folic acid, or vitamin B12 showed no significant changes and haptoglobin levels were undetectable. Peripheral blood smear revealed exuberant erythrocyte rouleaux and spherocytes. The direct antiglobulin test (DAT) was positive for immunoglobulin G (IgG). Chest radiography, abdominal ultrasound, and electrocardiogram performed in the ED were normal.
The hypothesis of AIHA was considered in the ED. The patient was started on 60 mg of prednisolone per day (1 mg/kg/day) and was admitted to the medical ward.
The hypothesis of secondary AIHA to an infectious or a connective tissue disease was ruled out. Gastrointestinal complaints were compatible with side effects of NSAIDs, viral serologies, blood cultures, rheumatoid factor, antinuclear antibody, antineutrophil cytoplasmic antibodies, and cyclic citrullinated peptide antibody were negative, and complement (both C3 and C4 studies) was normal. Lymphoproliferative disease was excluded due to the absence of adenopathies both on physical examination and in imaging studies, as well as normal immunoglobulin levels (IgG, IgM, and IgA) and a normal serum protein electrophoresis. Inflammatory bowel disease and digestive tract tumors were also excluded by endoscopic observation and anatomopathological analysis of biopsies made in macroscopically normal mucosa.
During hospitalization, glucocorticoid therapy was maintained, and folic acid supplementation of 5 mg per day was started. The patient had clinical improvement with resolution of asthenia and jaundice, as well as progressive normalization of the hemoglobin and bilirubin values. On discharge, 13 days after admission, anemia was mild (hemoglobin: 11 g/dL) and no signs of hemolysis were noted. Table 1 shows the laboratory data during hospitalization.
Table 1 Laboratory data during hospitalization.
ALP: alkaline phosphatase; ALT: alanine aminotransferase; ANA: antinuclear antibodies; ANCA: antineutrophil cytoplasmic antibody; anti-CCP: anti-cyclic citrullinated peptides; AST: aspartate aminotransferase; GGT: gamma-glutamyl transferase; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; Ig: immunoglobulin; LDH: lactate dehydrogenase, MCV: mean corpuscular volume, TIBC: total iron binding capacity
Results
Variable Reference range (adults) Day 1 Day 2 Day 5 Day 7 Day 9 Day 13
Hemoglobin (g/dL) 11.8-15.8 7.9 7.8 8.2 9.1 10.3 11
Hematocrit (%) 36.0-46.0 21.9 22.1 24.4 26.7 30.6 33
Red blood cells (106/µL) 4.2-5.4 2.47 2.42 2.48 2.63 2.97 3.14
MCV (fL) 80.4-96.4 88.7 91.3 98.4 101.5 103 105.1
White cell count (103/µL) 4.0-10.0 13.88 12.49 18.09 15.62 11.43 11.82
Differential cell count (103/L)
Neutrophils 1.5-8.0 9.1 8.3 11.448 9.4 5.9 7.2
Lymphocytes 0.8-4.0 3.3 2.7 5.5 5.2 4.7 3.8
Platelet count (103/µL) 150-400 353 353 381 377 392 362
Reticulocytes (%) 0.5-1.5 9.22
Sedimentation rate (mm) 4-10 103 9
C-reactive protein (mg/dL) <0.51 3.23 2.67 0.69 0.41 0.23 0.14
Urea (mg/dL) 17.0-43.0 40 31 39 35 29 33
Creatinine (mg/dL) 0.6-1.0 0.84 0.78 0.8 0.78 0.84 0.79
Sodium (mmol/L) 136-145 140 141 138 143 141 142
Potassium (mmol/L) 3.5-5.1 4.2 4.2 3 3.7 4 3.9
Calcium (mg/dL) 8.6-10.3 8.7
Uric acid (mg/dL) 2.6-6 7
Bilirubin (mg/dL)
Total 0.3-1.2 4.09 4.01 2.16 2.29 2.27 1.28
Direct <0.5 0.07 0.82 0.71 0.75 0.75 0.46
LDH (UI/L) 125-220 805 632 467 436 388 309
ALP (UI/L) 30-120 152 135 96 93 90 76
GGT (UI/L) <38 83 70 55 56 54 43
ALT (UI/L) 7-45 44 19 23 30 31
AST (UI/L) 8-35 30 22 15 21 21 23
Iron (µ/dL) 70-180 124
TIBC (µ/dL) 250-245 300
Folic acid (ng/mL) 2.34-17.56 5.8
Vitamin B12 (pg/mL) 187-883 414
Haptoglobin (mg/dL) 35-250 <8
Direct antiglobulin test Positive for IgG
Protein electrophoresis No monoclonal spikes
Total proteins (g/dL) 6.4-8.2 6.1
Albumin (g/dL) 3.5-5.2 3.6
Immunoglobulins
IgA (mg/dL) 60-400 192
IgG (mg/dL) 70-1,600 1,008
IgM (mg/dL) 40-230 131
ANA Negative
ANCA Negative
Rheumatoid factor Negative
anti-CCP Negative
Serology
HIV Negative
HBV Negative
HCV Negative
Given the acute clinical context after diclofenac intake and absence of evidence for other secondary etiologies, the diagnosis of acquired hemolytic anemia secondary to NSAIDs was made. Follow-up three years later found the patient asymptomatic with no recurrence of anemia or hemolysis.
Discussion
Drugs are generally small molecules unable to elicit an immune response, however, they can function as haptens, bind to larger proteins, become immunogenic, and lead to antibody production. These antibodies can be further classified as drug-induced, drug-dependent, and drug-independent antibodies. Drug-induced antibodies can bind to red blood cells (RBCs) and lead to hemolysis by non-immunological modification of erythrocyte membranes known as adsorption of non-immunological proteins. Drug-dependent antibodies bind to RBCs only in the presence of the drug or its metabolites, causing abrupt complement-mediated intravascular hemolysis. In vitro tests searching for lysis, DAT, or indirect antiglobulin test can be performed to confirm the diagnosis using the offending drug or its metabolites and the patient’s plasma or serum. Drug-independent antibodies can react with RBCs even in the absence of the drug and, therefore, are indistinguishable from autoantibodies mediating warm autoimmune hemolytic anemia (WAIHA) [1,10,11].
WAIHA is named after warm agglutinins, usually IgG autoantibodies, that bind to antigens on erythrocytes at a temperature of 37°C, leading to RBC destruction and a chronic or relapsing disease with an almost pathognomonic positive DAT [2].
Patients are treated with glucocorticoids 1 to 2 mg/kg of body weight/day of prednisone administered orally or an equivalent dose of methylprednisolone administered intravenously. Though most patients recover to an hemoglobin level above 10 g/dL within two to three weeks of treatment, relapse after treatment discontinuation is common, with retrospective case studies suggesting long-term remission rates as low as 20% to 30% [2].
DIIHA is identified by clinical evidence of hemolysis associated with drug therapy. Although many drugs have anedoctally reported isolated cases of DIIHA, over 130 drugs have reasonable evidence that supports an immune etiology [12]. It has been speculated that DIIHA is far more common than previously estimated, as most reports usually refer to more severe cases, either presenting with shock, multiorgan damage, or renal failure, and most mild cases being unreported [6].
Drugs most frequently associated with DIIHA are second and third generation of cephalosporins, diclofenac, oxaliplatin, and fludarabine. In European cohorts where diclofenac is the most frequently used NSAID, case reviews reported diclofenac as the most frequently implicated drug, with a fatal outcome being estimated in 15% to 21% of the reported cases [6,12-16]. Diclofenac-induced immune hemolytic anemia has been demonstrated in few cases, where the exposure to the drug or its metabolites lead to developing both drug-independent IgG autoantibodies and antibodies that reacted with diclofenac and its metabolites [8].
Signs and symptoms of DIIHA, as any other hemolytic anemia, are proportional to the degree and time of onset and can present withing hours to weeks of drug exposure. These include fatigue, dyspnea, and thoracic or abdominal pain. Late symptoms are usually due to complications of decompensated hemolysis, usually shock or renal failure. Laboratory abnormalities include low hemoglobin and haptoglobin levels, elevated lactate dehydrogenase and indirect bilirubin levels, reticulocytosis, and a positive DAT [1,10].
The DAT is positive in all the described forms of DIIHA, either for IgG, C3, or both. Rare cases with negative DAT reported either low antibody density, massive intravascular hemolysis, or red cell transfusion administered prior to testing [1,10]. When approaching a case where there is evidence of hemolysis and an established temporal relationship with a drug known to induce autoantibody production, investigation for drug-dependent antibodies can be performed in adequate laboratory settings, with quality ensured expertise and appropriate controls [1,3].
As there are no defining clinical features and drug-induced autoantibodies are indistinguishable from idiopathic autoantibodies, misdiagnosis in DIIHA is extremely common, with some patients dying because of late diagnosis. Furthermore, hemolysis and serological results can persist for up to months after withdrawal of the drug, leading to erroneous attribution of recovery on the administered treatment and not to the interruption of the drug [6].
If DIIHA is suspected, relevant medication should be withdrawn immediately. In mild cases, recovery usually happens within one to two weeks after drug suspension, with no other necessary measures. As most drugs have a relatively short half-life, even a strong drug-dependent antibody loses its effect shortly after drug suspension [1]. Failure to recognize DIIHA can have disastrous consequences, especially when patients present complaints for which the offending drug was prescribed. Regarding diclofenac DIIHA, some cases have been reported of patients receiving the drug again for “low back pain” during the early onset of hemolysis [9].
In acute severe DIIHA, recommendations suggest close monitoring of clinical and laboratory signs, early intravenous access, and fluid resuscitation. Blood transfusion should not be withheld in patients with severe anemia [3]. Even though crossmatch-compatible blood can be difficult to find, a review of 134 patients showed that 68 (55%) patients received blood transfusions. Though most patients (85%) received glucocorticoids, its benefit is uncertain and its routine use is not recommended as drug eviction is usually enough to stop the immune response [14].
Applying the criteria of the World Health Organization causality assessment method to assess a possible drug‐induced etiology of IHA we are confident the most likely diagnosis for our patient was diclofenac-induced IHA [17]. Our analysis is supported by: (a) the presence of autoantibodies in the patient’s eluate was demonstrated; (b) diclofenac is known to induce DIIHA; (c) there is a chronological relationship between hemolysis and diclofenac administration; (d) a review of the literature failed to show cases of DIIHA induced by any of the other drugs taken by the patient; (e) symptoms and laboratory signs significantly improved after discontinuation of diclofenac; (f) no coexistent neoplastic, autoimmune, or infectious diseases known to be secondary causes of AIHA were found after systematic and comprehensive studies; and (g) though glucocorticoids were started on admission, no recurrence of anemia was verified in a three-year follow-up period, which would be uncommon if the patient suffered from WAIHA.
Conclusions
As a potentially fatal complication of a widely used drug in clinical practice such as diclofenac, early and correct diagnosis of DIIHA and prompt removal of the offending drug is crucial for the patient’s recovery. Our case highlights the need for both prescribing physicians and patients to be aware of this frequently underreported and usually misdiagnosed entity.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
Appendices
Table 2 Causality categories. Adapted from the WHO-UMC system for standardized case causality assessment. The usual approach is to choose one of the causality terms’ categories and to test if the various criteria fit the content of the case report. All assessment criteria should be reasonably complied to assume a category. The WHO-UMC causality assessment system can be used for the assessment of case reports of adverse drug reactions or drug-drug interactions.
WHO-UMC, World Health Organization-Uppsala Monitoring Centre
Causality term Assessment criteria
Certain • Event or laboratory test abnormality, with plausible time relationship to drug intake • Cannot be explained by disease or other drugs • Response to withdrawal plausible (pharmacologically, pathologically) • Event definitive pharmacologically or phenomenologically (i.e., an objective and specific medical disorder or a recognized pharmacological phenomenon) • Rechallenge satisfactory, if necessary
Probable/Likely • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Unlikely to be attributed to disease or other drugs • Response to withdrawal clinically reasonable • Rechallenge not required
Possible • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Could also be explained by disease or other drugs • Information on drug withdrawal may be lacking or unclear
Unlikely • Event or laboratory test abnormality, with a time to drug intake that makes a relationship improbable (but not impossible) • Disease or other drugs provide plausible explanations
Conditional/Unclassified • Event or laboratory test abnormality • More data for proper assessment needed • Additional data under examination
Unassessable/Unclassifiable • Report suggesting an adverse reaction • Cannot be judged because information is insufficient or contradictory • Data cannot be supplemented or verified | ACETAMINOPHEN, DIAZEPAM, DICLOFENAC, PERINDOPRIL, ROSUVASTATIN, THIOCOLCHICOSIDE | DrugsGivenReaction | CC BY | 33654588 | 19,027,243 | 2021-01-25 |
What was the administration route of drug 'DIAZEPAM'? | Diclofenac-Induced Immune Hemolytic Anemia: A Case Report and Review of Literature.
Non-steroidal anti-inflammatory drugs are widely used for pain management. Most frequently, adverse reactions affect the gastrointestinal tract and hematological side effects usually relate to the gastrointestinal manifestations. Drug-induced immune hemolytic anemia is a rare and frequently underdiagnosed complication that is associated with poor outcomes including organ failure and even death. A 76-year-old female patient was treated with intramuscular diclofenac, thiocolchicoside, and diazepam for low back pain. Five days following diclofenac exposure, the patient was admitted to the Emergency Department with complaints of asthenia, nausea, vomiting, and diarrhea. Hemolysis and a positive direct antiglobulin test were detected on laboratory testing. Further causes of hemolytic anemia were excluded and a diagnosis of diclofenac-induced immune hemolytic anemia was established. Glucocorticoid therapy initiated on admission and drug eviction led to complete recovery. Long-term follow-up showed no recurrence of anemia. Here, we present the unusual case of a successful recovery of a 76-year-old patient with diclofenac-induced immune hemolytic anemia, a rare but immediate life-threatening condition of a frequently used drug in clinical practice.
Introduction
Autoimmune hemolytic anemia (AIHA) ensues when the host’s immune system acts against its own red cell antigens and has an estimated prevalence of approximately 1 in 100,000 individuals [1]. Approximately 50% of the cases refer to primary or idiopathic AIHA, where an associated disorder is not found [2]. Secondary causes of AIHA depend on the studied population. Current series estimate that half are associated with hematological malignancy, a third with infection, a sixth with collagen vascular disorders, and a tenth with drug-induced immune hemolytic anemia (DIIHA), the latter reaching an estimated incidence of one per million per year [1,3].
Diclofenac is one of the non-steroidal anti-inflammatory drugs (NSAIDs) most used for the treatment of rheumatoid arthritis and osteoarthritis [4]. Though generally well tolerated, over 400 adverse reactions have been documented. Most frequently, adverse reactions affect the gastrointestinal tract, the skin, and the central nervous system [5]. Direct hematological side effects such as leukopenia, thrombocytopenia, and aplastic anemia have been described only in limited cases [6-9].
We present the case of a 76-year-old patient with diclofenac DIIHA and a summary of the pathophysiology and therapeutic options.
Case presentation
A 76-year-old woman presented to the Emergency Department (ED) with recent onset of fatigue. She had a previous medical history of essential arterial hypertension, dyslipidemia, and spinal osteoarthritis with sporadic episodes of lumbosciatic pain. Regular medications initiated several years prior included perindopril 8 mg and rosuvastatin 10 mg. No allergies, alcohol, tobacco, toxins, or animal exposures were known, and she had no other relevant personal or familiar history.
Three weeks before admission the patient had an exacerbation of right lumbosciatic pain. This episode was similar to the previous ones, for which she usually was prescribed oral NSAIDs, acetaminophen, general physical therapy, massages, and rest with complete recovery. However, this time the pain was refractory to general measures, and eight days before admission, she was prescribed a combination of a daily intramuscular administration of 4 mg thiocolchicoside, 75 mg diclofenac, and 5 mg diazepam for a total of six days.
On the fifth day of treatment, she developed generalized malaise, fatigue, nausea, postprandial vomiting, and diarrhea with up to six soft, brownish dejections per day.
Despite resolution of nausea, vomiting, and diarrhea, she experienced progressive worsening of fatigue and was admitted to the ED. Detailed medical history was negative for other symptoms, namely, fever, coluria, acholia, melena, and other evident blood losses, either on admission or in the past.
Physical examination revealed jaundice and pallor of the skin and mucous membranes. No epistaxis, gingivorrhagia, adenopathies, ecchymosis, or other skin lesions were found. Blood pressure was 137/62 mmHg and heart rate was 96 beats per minute, respiratory rate was 16 beats per minute, and peripheral oxygenation saturation was 96%. No fever or other abnormalities were noted.
Blood examination showed normocytic normochromic anemia (hemoglobin: 7.9 g/dL, reference median globular volume: 88 fL), reticulocytosis (9.2%), leucocytosis (white blood cells: 13.8 × 10 9/L), hyperbilirubinemia at the expense of unconjugated bilirubin (total bilirubin: 4.09 mg/dL, conjugated bilirubin: 0.97 mg/dL), elevated lactic dehydrogenase (805 UI/L), and sedimentation rate (VS: 76 mm). Serum iron concentration, ferritin, total iron-binding capacity, folic acid, or vitamin B12 showed no significant changes and haptoglobin levels were undetectable. Peripheral blood smear revealed exuberant erythrocyte rouleaux and spherocytes. The direct antiglobulin test (DAT) was positive for immunoglobulin G (IgG). Chest radiography, abdominal ultrasound, and electrocardiogram performed in the ED were normal.
The hypothesis of AIHA was considered in the ED. The patient was started on 60 mg of prednisolone per day (1 mg/kg/day) and was admitted to the medical ward.
The hypothesis of secondary AIHA to an infectious or a connective tissue disease was ruled out. Gastrointestinal complaints were compatible with side effects of NSAIDs, viral serologies, blood cultures, rheumatoid factor, antinuclear antibody, antineutrophil cytoplasmic antibodies, and cyclic citrullinated peptide antibody were negative, and complement (both C3 and C4 studies) was normal. Lymphoproliferative disease was excluded due to the absence of adenopathies both on physical examination and in imaging studies, as well as normal immunoglobulin levels (IgG, IgM, and IgA) and a normal serum protein electrophoresis. Inflammatory bowel disease and digestive tract tumors were also excluded by endoscopic observation and anatomopathological analysis of biopsies made in macroscopically normal mucosa.
During hospitalization, glucocorticoid therapy was maintained, and folic acid supplementation of 5 mg per day was started. The patient had clinical improvement with resolution of asthenia and jaundice, as well as progressive normalization of the hemoglobin and bilirubin values. On discharge, 13 days after admission, anemia was mild (hemoglobin: 11 g/dL) and no signs of hemolysis were noted. Table 1 shows the laboratory data during hospitalization.
Table 1 Laboratory data during hospitalization.
ALP: alkaline phosphatase; ALT: alanine aminotransferase; ANA: antinuclear antibodies; ANCA: antineutrophil cytoplasmic antibody; anti-CCP: anti-cyclic citrullinated peptides; AST: aspartate aminotransferase; GGT: gamma-glutamyl transferase; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; Ig: immunoglobulin; LDH: lactate dehydrogenase, MCV: mean corpuscular volume, TIBC: total iron binding capacity
Results
Variable Reference range (adults) Day 1 Day 2 Day 5 Day 7 Day 9 Day 13
Hemoglobin (g/dL) 11.8-15.8 7.9 7.8 8.2 9.1 10.3 11
Hematocrit (%) 36.0-46.0 21.9 22.1 24.4 26.7 30.6 33
Red blood cells (106/µL) 4.2-5.4 2.47 2.42 2.48 2.63 2.97 3.14
MCV (fL) 80.4-96.4 88.7 91.3 98.4 101.5 103 105.1
White cell count (103/µL) 4.0-10.0 13.88 12.49 18.09 15.62 11.43 11.82
Differential cell count (103/L)
Neutrophils 1.5-8.0 9.1 8.3 11.448 9.4 5.9 7.2
Lymphocytes 0.8-4.0 3.3 2.7 5.5 5.2 4.7 3.8
Platelet count (103/µL) 150-400 353 353 381 377 392 362
Reticulocytes (%) 0.5-1.5 9.22
Sedimentation rate (mm) 4-10 103 9
C-reactive protein (mg/dL) <0.51 3.23 2.67 0.69 0.41 0.23 0.14
Urea (mg/dL) 17.0-43.0 40 31 39 35 29 33
Creatinine (mg/dL) 0.6-1.0 0.84 0.78 0.8 0.78 0.84 0.79
Sodium (mmol/L) 136-145 140 141 138 143 141 142
Potassium (mmol/L) 3.5-5.1 4.2 4.2 3 3.7 4 3.9
Calcium (mg/dL) 8.6-10.3 8.7
Uric acid (mg/dL) 2.6-6 7
Bilirubin (mg/dL)
Total 0.3-1.2 4.09 4.01 2.16 2.29 2.27 1.28
Direct <0.5 0.07 0.82 0.71 0.75 0.75 0.46
LDH (UI/L) 125-220 805 632 467 436 388 309
ALP (UI/L) 30-120 152 135 96 93 90 76
GGT (UI/L) <38 83 70 55 56 54 43
ALT (UI/L) 7-45 44 19 23 30 31
AST (UI/L) 8-35 30 22 15 21 21 23
Iron (µ/dL) 70-180 124
TIBC (µ/dL) 250-245 300
Folic acid (ng/mL) 2.34-17.56 5.8
Vitamin B12 (pg/mL) 187-883 414
Haptoglobin (mg/dL) 35-250 <8
Direct antiglobulin test Positive for IgG
Protein electrophoresis No monoclonal spikes
Total proteins (g/dL) 6.4-8.2 6.1
Albumin (g/dL) 3.5-5.2 3.6
Immunoglobulins
IgA (mg/dL) 60-400 192
IgG (mg/dL) 70-1,600 1,008
IgM (mg/dL) 40-230 131
ANA Negative
ANCA Negative
Rheumatoid factor Negative
anti-CCP Negative
Serology
HIV Negative
HBV Negative
HCV Negative
Given the acute clinical context after diclofenac intake and absence of evidence for other secondary etiologies, the diagnosis of acquired hemolytic anemia secondary to NSAIDs was made. Follow-up three years later found the patient asymptomatic with no recurrence of anemia or hemolysis.
Discussion
Drugs are generally small molecules unable to elicit an immune response, however, they can function as haptens, bind to larger proteins, become immunogenic, and lead to antibody production. These antibodies can be further classified as drug-induced, drug-dependent, and drug-independent antibodies. Drug-induced antibodies can bind to red blood cells (RBCs) and lead to hemolysis by non-immunological modification of erythrocyte membranes known as adsorption of non-immunological proteins. Drug-dependent antibodies bind to RBCs only in the presence of the drug or its metabolites, causing abrupt complement-mediated intravascular hemolysis. In vitro tests searching for lysis, DAT, or indirect antiglobulin test can be performed to confirm the diagnosis using the offending drug or its metabolites and the patient’s plasma or serum. Drug-independent antibodies can react with RBCs even in the absence of the drug and, therefore, are indistinguishable from autoantibodies mediating warm autoimmune hemolytic anemia (WAIHA) [1,10,11].
WAIHA is named after warm agglutinins, usually IgG autoantibodies, that bind to antigens on erythrocytes at a temperature of 37°C, leading to RBC destruction and a chronic or relapsing disease with an almost pathognomonic positive DAT [2].
Patients are treated with glucocorticoids 1 to 2 mg/kg of body weight/day of prednisone administered orally or an equivalent dose of methylprednisolone administered intravenously. Though most patients recover to an hemoglobin level above 10 g/dL within two to three weeks of treatment, relapse after treatment discontinuation is common, with retrospective case studies suggesting long-term remission rates as low as 20% to 30% [2].
DIIHA is identified by clinical evidence of hemolysis associated with drug therapy. Although many drugs have anedoctally reported isolated cases of DIIHA, over 130 drugs have reasonable evidence that supports an immune etiology [12]. It has been speculated that DIIHA is far more common than previously estimated, as most reports usually refer to more severe cases, either presenting with shock, multiorgan damage, or renal failure, and most mild cases being unreported [6].
Drugs most frequently associated with DIIHA are second and third generation of cephalosporins, diclofenac, oxaliplatin, and fludarabine. In European cohorts where diclofenac is the most frequently used NSAID, case reviews reported diclofenac as the most frequently implicated drug, with a fatal outcome being estimated in 15% to 21% of the reported cases [6,12-16]. Diclofenac-induced immune hemolytic anemia has been demonstrated in few cases, where the exposure to the drug or its metabolites lead to developing both drug-independent IgG autoantibodies and antibodies that reacted with diclofenac and its metabolites [8].
Signs and symptoms of DIIHA, as any other hemolytic anemia, are proportional to the degree and time of onset and can present withing hours to weeks of drug exposure. These include fatigue, dyspnea, and thoracic or abdominal pain. Late symptoms are usually due to complications of decompensated hemolysis, usually shock or renal failure. Laboratory abnormalities include low hemoglobin and haptoglobin levels, elevated lactate dehydrogenase and indirect bilirubin levels, reticulocytosis, and a positive DAT [1,10].
The DAT is positive in all the described forms of DIIHA, either for IgG, C3, or both. Rare cases with negative DAT reported either low antibody density, massive intravascular hemolysis, or red cell transfusion administered prior to testing [1,10]. When approaching a case where there is evidence of hemolysis and an established temporal relationship with a drug known to induce autoantibody production, investigation for drug-dependent antibodies can be performed in adequate laboratory settings, with quality ensured expertise and appropriate controls [1,3].
As there are no defining clinical features and drug-induced autoantibodies are indistinguishable from idiopathic autoantibodies, misdiagnosis in DIIHA is extremely common, with some patients dying because of late diagnosis. Furthermore, hemolysis and serological results can persist for up to months after withdrawal of the drug, leading to erroneous attribution of recovery on the administered treatment and not to the interruption of the drug [6].
If DIIHA is suspected, relevant medication should be withdrawn immediately. In mild cases, recovery usually happens within one to two weeks after drug suspension, with no other necessary measures. As most drugs have a relatively short half-life, even a strong drug-dependent antibody loses its effect shortly after drug suspension [1]. Failure to recognize DIIHA can have disastrous consequences, especially when patients present complaints for which the offending drug was prescribed. Regarding diclofenac DIIHA, some cases have been reported of patients receiving the drug again for “low back pain” during the early onset of hemolysis [9].
In acute severe DIIHA, recommendations suggest close monitoring of clinical and laboratory signs, early intravenous access, and fluid resuscitation. Blood transfusion should not be withheld in patients with severe anemia [3]. Even though crossmatch-compatible blood can be difficult to find, a review of 134 patients showed that 68 (55%) patients received blood transfusions. Though most patients (85%) received glucocorticoids, its benefit is uncertain and its routine use is not recommended as drug eviction is usually enough to stop the immune response [14].
Applying the criteria of the World Health Organization causality assessment method to assess a possible drug‐induced etiology of IHA we are confident the most likely diagnosis for our patient was diclofenac-induced IHA [17]. Our analysis is supported by: (a) the presence of autoantibodies in the patient’s eluate was demonstrated; (b) diclofenac is known to induce DIIHA; (c) there is a chronological relationship between hemolysis and diclofenac administration; (d) a review of the literature failed to show cases of DIIHA induced by any of the other drugs taken by the patient; (e) symptoms and laboratory signs significantly improved after discontinuation of diclofenac; (f) no coexistent neoplastic, autoimmune, or infectious diseases known to be secondary causes of AIHA were found after systematic and comprehensive studies; and (g) though glucocorticoids were started on admission, no recurrence of anemia was verified in a three-year follow-up period, which would be uncommon if the patient suffered from WAIHA.
Conclusions
As a potentially fatal complication of a widely used drug in clinical practice such as diclofenac, early and correct diagnosis of DIIHA and prompt removal of the offending drug is crucial for the patient’s recovery. Our case highlights the need for both prescribing physicians and patients to be aware of this frequently underreported and usually misdiagnosed entity.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
Appendices
Table 2 Causality categories. Adapted from the WHO-UMC system for standardized case causality assessment. The usual approach is to choose one of the causality terms’ categories and to test if the various criteria fit the content of the case report. All assessment criteria should be reasonably complied to assume a category. The WHO-UMC causality assessment system can be used for the assessment of case reports of adverse drug reactions or drug-drug interactions.
WHO-UMC, World Health Organization-Uppsala Monitoring Centre
Causality term Assessment criteria
Certain • Event or laboratory test abnormality, with plausible time relationship to drug intake • Cannot be explained by disease or other drugs • Response to withdrawal plausible (pharmacologically, pathologically) • Event definitive pharmacologically or phenomenologically (i.e., an objective and specific medical disorder or a recognized pharmacological phenomenon) • Rechallenge satisfactory, if necessary
Probable/Likely • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Unlikely to be attributed to disease or other drugs • Response to withdrawal clinically reasonable • Rechallenge not required
Possible • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Could also be explained by disease or other drugs • Information on drug withdrawal may be lacking or unclear
Unlikely • Event or laboratory test abnormality, with a time to drug intake that makes a relationship improbable (but not impossible) • Disease or other drugs provide plausible explanations
Conditional/Unclassified • Event or laboratory test abnormality • More data for proper assessment needed • Additional data under examination
Unassessable/Unclassifiable • Report suggesting an adverse reaction • Cannot be judged because information is insufficient or contradictory • Data cannot be supplemented or verified | Intramuscular | DrugAdministrationRoute | CC BY | 33654588 | 19,027,243 | 2021-01-25 |
What was the administration route of drug 'DICLOFENAC'? | Diclofenac-Induced Immune Hemolytic Anemia: A Case Report and Review of Literature.
Non-steroidal anti-inflammatory drugs are widely used for pain management. Most frequently, adverse reactions affect the gastrointestinal tract and hematological side effects usually relate to the gastrointestinal manifestations. Drug-induced immune hemolytic anemia is a rare and frequently underdiagnosed complication that is associated with poor outcomes including organ failure and even death. A 76-year-old female patient was treated with intramuscular diclofenac, thiocolchicoside, and diazepam for low back pain. Five days following diclofenac exposure, the patient was admitted to the Emergency Department with complaints of asthenia, nausea, vomiting, and diarrhea. Hemolysis and a positive direct antiglobulin test were detected on laboratory testing. Further causes of hemolytic anemia were excluded and a diagnosis of diclofenac-induced immune hemolytic anemia was established. Glucocorticoid therapy initiated on admission and drug eviction led to complete recovery. Long-term follow-up showed no recurrence of anemia. Here, we present the unusual case of a successful recovery of a 76-year-old patient with diclofenac-induced immune hemolytic anemia, a rare but immediate life-threatening condition of a frequently used drug in clinical practice.
Introduction
Autoimmune hemolytic anemia (AIHA) ensues when the host’s immune system acts against its own red cell antigens and has an estimated prevalence of approximately 1 in 100,000 individuals [1]. Approximately 50% of the cases refer to primary or idiopathic AIHA, where an associated disorder is not found [2]. Secondary causes of AIHA depend on the studied population. Current series estimate that half are associated with hematological malignancy, a third with infection, a sixth with collagen vascular disorders, and a tenth with drug-induced immune hemolytic anemia (DIIHA), the latter reaching an estimated incidence of one per million per year [1,3].
Diclofenac is one of the non-steroidal anti-inflammatory drugs (NSAIDs) most used for the treatment of rheumatoid arthritis and osteoarthritis [4]. Though generally well tolerated, over 400 adverse reactions have been documented. Most frequently, adverse reactions affect the gastrointestinal tract, the skin, and the central nervous system [5]. Direct hematological side effects such as leukopenia, thrombocytopenia, and aplastic anemia have been described only in limited cases [6-9].
We present the case of a 76-year-old patient with diclofenac DIIHA and a summary of the pathophysiology and therapeutic options.
Case presentation
A 76-year-old woman presented to the Emergency Department (ED) with recent onset of fatigue. She had a previous medical history of essential arterial hypertension, dyslipidemia, and spinal osteoarthritis with sporadic episodes of lumbosciatic pain. Regular medications initiated several years prior included perindopril 8 mg and rosuvastatin 10 mg. No allergies, alcohol, tobacco, toxins, or animal exposures were known, and she had no other relevant personal or familiar history.
Three weeks before admission the patient had an exacerbation of right lumbosciatic pain. This episode was similar to the previous ones, for which she usually was prescribed oral NSAIDs, acetaminophen, general physical therapy, massages, and rest with complete recovery. However, this time the pain was refractory to general measures, and eight days before admission, she was prescribed a combination of a daily intramuscular administration of 4 mg thiocolchicoside, 75 mg diclofenac, and 5 mg diazepam for a total of six days.
On the fifth day of treatment, she developed generalized malaise, fatigue, nausea, postprandial vomiting, and diarrhea with up to six soft, brownish dejections per day.
Despite resolution of nausea, vomiting, and diarrhea, she experienced progressive worsening of fatigue and was admitted to the ED. Detailed medical history was negative for other symptoms, namely, fever, coluria, acholia, melena, and other evident blood losses, either on admission or in the past.
Physical examination revealed jaundice and pallor of the skin and mucous membranes. No epistaxis, gingivorrhagia, adenopathies, ecchymosis, or other skin lesions were found. Blood pressure was 137/62 mmHg and heart rate was 96 beats per minute, respiratory rate was 16 beats per minute, and peripheral oxygenation saturation was 96%. No fever or other abnormalities were noted.
Blood examination showed normocytic normochromic anemia (hemoglobin: 7.9 g/dL, reference median globular volume: 88 fL), reticulocytosis (9.2%), leucocytosis (white blood cells: 13.8 × 10 9/L), hyperbilirubinemia at the expense of unconjugated bilirubin (total bilirubin: 4.09 mg/dL, conjugated bilirubin: 0.97 mg/dL), elevated lactic dehydrogenase (805 UI/L), and sedimentation rate (VS: 76 mm). Serum iron concentration, ferritin, total iron-binding capacity, folic acid, or vitamin B12 showed no significant changes and haptoglobin levels were undetectable. Peripheral blood smear revealed exuberant erythrocyte rouleaux and spherocytes. The direct antiglobulin test (DAT) was positive for immunoglobulin G (IgG). Chest radiography, abdominal ultrasound, and electrocardiogram performed in the ED were normal.
The hypothesis of AIHA was considered in the ED. The patient was started on 60 mg of prednisolone per day (1 mg/kg/day) and was admitted to the medical ward.
The hypothesis of secondary AIHA to an infectious or a connective tissue disease was ruled out. Gastrointestinal complaints were compatible with side effects of NSAIDs, viral serologies, blood cultures, rheumatoid factor, antinuclear antibody, antineutrophil cytoplasmic antibodies, and cyclic citrullinated peptide antibody were negative, and complement (both C3 and C4 studies) was normal. Lymphoproliferative disease was excluded due to the absence of adenopathies both on physical examination and in imaging studies, as well as normal immunoglobulin levels (IgG, IgM, and IgA) and a normal serum protein electrophoresis. Inflammatory bowel disease and digestive tract tumors were also excluded by endoscopic observation and anatomopathological analysis of biopsies made in macroscopically normal mucosa.
During hospitalization, glucocorticoid therapy was maintained, and folic acid supplementation of 5 mg per day was started. The patient had clinical improvement with resolution of asthenia and jaundice, as well as progressive normalization of the hemoglobin and bilirubin values. On discharge, 13 days after admission, anemia was mild (hemoglobin: 11 g/dL) and no signs of hemolysis were noted. Table 1 shows the laboratory data during hospitalization.
Table 1 Laboratory data during hospitalization.
ALP: alkaline phosphatase; ALT: alanine aminotransferase; ANA: antinuclear antibodies; ANCA: antineutrophil cytoplasmic antibody; anti-CCP: anti-cyclic citrullinated peptides; AST: aspartate aminotransferase; GGT: gamma-glutamyl transferase; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; Ig: immunoglobulin; LDH: lactate dehydrogenase, MCV: mean corpuscular volume, TIBC: total iron binding capacity
Results
Variable Reference range (adults) Day 1 Day 2 Day 5 Day 7 Day 9 Day 13
Hemoglobin (g/dL) 11.8-15.8 7.9 7.8 8.2 9.1 10.3 11
Hematocrit (%) 36.0-46.0 21.9 22.1 24.4 26.7 30.6 33
Red blood cells (106/µL) 4.2-5.4 2.47 2.42 2.48 2.63 2.97 3.14
MCV (fL) 80.4-96.4 88.7 91.3 98.4 101.5 103 105.1
White cell count (103/µL) 4.0-10.0 13.88 12.49 18.09 15.62 11.43 11.82
Differential cell count (103/L)
Neutrophils 1.5-8.0 9.1 8.3 11.448 9.4 5.9 7.2
Lymphocytes 0.8-4.0 3.3 2.7 5.5 5.2 4.7 3.8
Platelet count (103/µL) 150-400 353 353 381 377 392 362
Reticulocytes (%) 0.5-1.5 9.22
Sedimentation rate (mm) 4-10 103 9
C-reactive protein (mg/dL) <0.51 3.23 2.67 0.69 0.41 0.23 0.14
Urea (mg/dL) 17.0-43.0 40 31 39 35 29 33
Creatinine (mg/dL) 0.6-1.0 0.84 0.78 0.8 0.78 0.84 0.79
Sodium (mmol/L) 136-145 140 141 138 143 141 142
Potassium (mmol/L) 3.5-5.1 4.2 4.2 3 3.7 4 3.9
Calcium (mg/dL) 8.6-10.3 8.7
Uric acid (mg/dL) 2.6-6 7
Bilirubin (mg/dL)
Total 0.3-1.2 4.09 4.01 2.16 2.29 2.27 1.28
Direct <0.5 0.07 0.82 0.71 0.75 0.75 0.46
LDH (UI/L) 125-220 805 632 467 436 388 309
ALP (UI/L) 30-120 152 135 96 93 90 76
GGT (UI/L) <38 83 70 55 56 54 43
ALT (UI/L) 7-45 44 19 23 30 31
AST (UI/L) 8-35 30 22 15 21 21 23
Iron (µ/dL) 70-180 124
TIBC (µ/dL) 250-245 300
Folic acid (ng/mL) 2.34-17.56 5.8
Vitamin B12 (pg/mL) 187-883 414
Haptoglobin (mg/dL) 35-250 <8
Direct antiglobulin test Positive for IgG
Protein electrophoresis No monoclonal spikes
Total proteins (g/dL) 6.4-8.2 6.1
Albumin (g/dL) 3.5-5.2 3.6
Immunoglobulins
IgA (mg/dL) 60-400 192
IgG (mg/dL) 70-1,600 1,008
IgM (mg/dL) 40-230 131
ANA Negative
ANCA Negative
Rheumatoid factor Negative
anti-CCP Negative
Serology
HIV Negative
HBV Negative
HCV Negative
Given the acute clinical context after diclofenac intake and absence of evidence for other secondary etiologies, the diagnosis of acquired hemolytic anemia secondary to NSAIDs was made. Follow-up three years later found the patient asymptomatic with no recurrence of anemia or hemolysis.
Discussion
Drugs are generally small molecules unable to elicit an immune response, however, they can function as haptens, bind to larger proteins, become immunogenic, and lead to antibody production. These antibodies can be further classified as drug-induced, drug-dependent, and drug-independent antibodies. Drug-induced antibodies can bind to red blood cells (RBCs) and lead to hemolysis by non-immunological modification of erythrocyte membranes known as adsorption of non-immunological proteins. Drug-dependent antibodies bind to RBCs only in the presence of the drug or its metabolites, causing abrupt complement-mediated intravascular hemolysis. In vitro tests searching for lysis, DAT, or indirect antiglobulin test can be performed to confirm the diagnosis using the offending drug or its metabolites and the patient’s plasma or serum. Drug-independent antibodies can react with RBCs even in the absence of the drug and, therefore, are indistinguishable from autoantibodies mediating warm autoimmune hemolytic anemia (WAIHA) [1,10,11].
WAIHA is named after warm agglutinins, usually IgG autoantibodies, that bind to antigens on erythrocytes at a temperature of 37°C, leading to RBC destruction and a chronic or relapsing disease with an almost pathognomonic positive DAT [2].
Patients are treated with glucocorticoids 1 to 2 mg/kg of body weight/day of prednisone administered orally or an equivalent dose of methylprednisolone administered intravenously. Though most patients recover to an hemoglobin level above 10 g/dL within two to three weeks of treatment, relapse after treatment discontinuation is common, with retrospective case studies suggesting long-term remission rates as low as 20% to 30% [2].
DIIHA is identified by clinical evidence of hemolysis associated with drug therapy. Although many drugs have anedoctally reported isolated cases of DIIHA, over 130 drugs have reasonable evidence that supports an immune etiology [12]. It has been speculated that DIIHA is far more common than previously estimated, as most reports usually refer to more severe cases, either presenting with shock, multiorgan damage, or renal failure, and most mild cases being unreported [6].
Drugs most frequently associated with DIIHA are second and third generation of cephalosporins, diclofenac, oxaliplatin, and fludarabine. In European cohorts where diclofenac is the most frequently used NSAID, case reviews reported diclofenac as the most frequently implicated drug, with a fatal outcome being estimated in 15% to 21% of the reported cases [6,12-16]. Diclofenac-induced immune hemolytic anemia has been demonstrated in few cases, where the exposure to the drug or its metabolites lead to developing both drug-independent IgG autoantibodies and antibodies that reacted with diclofenac and its metabolites [8].
Signs and symptoms of DIIHA, as any other hemolytic anemia, are proportional to the degree and time of onset and can present withing hours to weeks of drug exposure. These include fatigue, dyspnea, and thoracic or abdominal pain. Late symptoms are usually due to complications of decompensated hemolysis, usually shock or renal failure. Laboratory abnormalities include low hemoglobin and haptoglobin levels, elevated lactate dehydrogenase and indirect bilirubin levels, reticulocytosis, and a positive DAT [1,10].
The DAT is positive in all the described forms of DIIHA, either for IgG, C3, or both. Rare cases with negative DAT reported either low antibody density, massive intravascular hemolysis, or red cell transfusion administered prior to testing [1,10]. When approaching a case where there is evidence of hemolysis and an established temporal relationship with a drug known to induce autoantibody production, investigation for drug-dependent antibodies can be performed in adequate laboratory settings, with quality ensured expertise and appropriate controls [1,3].
As there are no defining clinical features and drug-induced autoantibodies are indistinguishable from idiopathic autoantibodies, misdiagnosis in DIIHA is extremely common, with some patients dying because of late diagnosis. Furthermore, hemolysis and serological results can persist for up to months after withdrawal of the drug, leading to erroneous attribution of recovery on the administered treatment and not to the interruption of the drug [6].
If DIIHA is suspected, relevant medication should be withdrawn immediately. In mild cases, recovery usually happens within one to two weeks after drug suspension, with no other necessary measures. As most drugs have a relatively short half-life, even a strong drug-dependent antibody loses its effect shortly after drug suspension [1]. Failure to recognize DIIHA can have disastrous consequences, especially when patients present complaints for which the offending drug was prescribed. Regarding diclofenac DIIHA, some cases have been reported of patients receiving the drug again for “low back pain” during the early onset of hemolysis [9].
In acute severe DIIHA, recommendations suggest close monitoring of clinical and laboratory signs, early intravenous access, and fluid resuscitation. Blood transfusion should not be withheld in patients with severe anemia [3]. Even though crossmatch-compatible blood can be difficult to find, a review of 134 patients showed that 68 (55%) patients received blood transfusions. Though most patients (85%) received glucocorticoids, its benefit is uncertain and its routine use is not recommended as drug eviction is usually enough to stop the immune response [14].
Applying the criteria of the World Health Organization causality assessment method to assess a possible drug‐induced etiology of IHA we are confident the most likely diagnosis for our patient was diclofenac-induced IHA [17]. Our analysis is supported by: (a) the presence of autoantibodies in the patient’s eluate was demonstrated; (b) diclofenac is known to induce DIIHA; (c) there is a chronological relationship between hemolysis and diclofenac administration; (d) a review of the literature failed to show cases of DIIHA induced by any of the other drugs taken by the patient; (e) symptoms and laboratory signs significantly improved after discontinuation of diclofenac; (f) no coexistent neoplastic, autoimmune, or infectious diseases known to be secondary causes of AIHA were found after systematic and comprehensive studies; and (g) though glucocorticoids were started on admission, no recurrence of anemia was verified in a three-year follow-up period, which would be uncommon if the patient suffered from WAIHA.
Conclusions
As a potentially fatal complication of a widely used drug in clinical practice such as diclofenac, early and correct diagnosis of DIIHA and prompt removal of the offending drug is crucial for the patient’s recovery. Our case highlights the need for both prescribing physicians and patients to be aware of this frequently underreported and usually misdiagnosed entity.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
Appendices
Table 2 Causality categories. Adapted from the WHO-UMC system for standardized case causality assessment. The usual approach is to choose one of the causality terms’ categories and to test if the various criteria fit the content of the case report. All assessment criteria should be reasonably complied to assume a category. The WHO-UMC causality assessment system can be used for the assessment of case reports of adverse drug reactions or drug-drug interactions.
WHO-UMC, World Health Organization-Uppsala Monitoring Centre
Causality term Assessment criteria
Certain • Event or laboratory test abnormality, with plausible time relationship to drug intake • Cannot be explained by disease or other drugs • Response to withdrawal plausible (pharmacologically, pathologically) • Event definitive pharmacologically or phenomenologically (i.e., an objective and specific medical disorder or a recognized pharmacological phenomenon) • Rechallenge satisfactory, if necessary
Probable/Likely • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Unlikely to be attributed to disease or other drugs • Response to withdrawal clinically reasonable • Rechallenge not required
Possible • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Could also be explained by disease or other drugs • Information on drug withdrawal may be lacking or unclear
Unlikely • Event or laboratory test abnormality, with a time to drug intake that makes a relationship improbable (but not impossible) • Disease or other drugs provide plausible explanations
Conditional/Unclassified • Event or laboratory test abnormality • More data for proper assessment needed • Additional data under examination
Unassessable/Unclassifiable • Report suggesting an adverse reaction • Cannot be judged because information is insufficient or contradictory • Data cannot be supplemented or verified | Intramuscular | DrugAdministrationRoute | CC BY | 33654588 | 19,027,243 | 2021-01-25 |
What was the administration route of drug 'THIOCOLCHICOSIDE'? | Diclofenac-Induced Immune Hemolytic Anemia: A Case Report and Review of Literature.
Non-steroidal anti-inflammatory drugs are widely used for pain management. Most frequently, adverse reactions affect the gastrointestinal tract and hematological side effects usually relate to the gastrointestinal manifestations. Drug-induced immune hemolytic anemia is a rare and frequently underdiagnosed complication that is associated with poor outcomes including organ failure and even death. A 76-year-old female patient was treated with intramuscular diclofenac, thiocolchicoside, and diazepam for low back pain. Five days following diclofenac exposure, the patient was admitted to the Emergency Department with complaints of asthenia, nausea, vomiting, and diarrhea. Hemolysis and a positive direct antiglobulin test were detected on laboratory testing. Further causes of hemolytic anemia were excluded and a diagnosis of diclofenac-induced immune hemolytic anemia was established. Glucocorticoid therapy initiated on admission and drug eviction led to complete recovery. Long-term follow-up showed no recurrence of anemia. Here, we present the unusual case of a successful recovery of a 76-year-old patient with diclofenac-induced immune hemolytic anemia, a rare but immediate life-threatening condition of a frequently used drug in clinical practice.
Introduction
Autoimmune hemolytic anemia (AIHA) ensues when the host’s immune system acts against its own red cell antigens and has an estimated prevalence of approximately 1 in 100,000 individuals [1]. Approximately 50% of the cases refer to primary or idiopathic AIHA, where an associated disorder is not found [2]. Secondary causes of AIHA depend on the studied population. Current series estimate that half are associated with hematological malignancy, a third with infection, a sixth with collagen vascular disorders, and a tenth with drug-induced immune hemolytic anemia (DIIHA), the latter reaching an estimated incidence of one per million per year [1,3].
Diclofenac is one of the non-steroidal anti-inflammatory drugs (NSAIDs) most used for the treatment of rheumatoid arthritis and osteoarthritis [4]. Though generally well tolerated, over 400 adverse reactions have been documented. Most frequently, adverse reactions affect the gastrointestinal tract, the skin, and the central nervous system [5]. Direct hematological side effects such as leukopenia, thrombocytopenia, and aplastic anemia have been described only in limited cases [6-9].
We present the case of a 76-year-old patient with diclofenac DIIHA and a summary of the pathophysiology and therapeutic options.
Case presentation
A 76-year-old woman presented to the Emergency Department (ED) with recent onset of fatigue. She had a previous medical history of essential arterial hypertension, dyslipidemia, and spinal osteoarthritis with sporadic episodes of lumbosciatic pain. Regular medications initiated several years prior included perindopril 8 mg and rosuvastatin 10 mg. No allergies, alcohol, tobacco, toxins, or animal exposures were known, and she had no other relevant personal or familiar history.
Three weeks before admission the patient had an exacerbation of right lumbosciatic pain. This episode was similar to the previous ones, for which she usually was prescribed oral NSAIDs, acetaminophen, general physical therapy, massages, and rest with complete recovery. However, this time the pain was refractory to general measures, and eight days before admission, she was prescribed a combination of a daily intramuscular administration of 4 mg thiocolchicoside, 75 mg diclofenac, and 5 mg diazepam for a total of six days.
On the fifth day of treatment, she developed generalized malaise, fatigue, nausea, postprandial vomiting, and diarrhea with up to six soft, brownish dejections per day.
Despite resolution of nausea, vomiting, and diarrhea, she experienced progressive worsening of fatigue and was admitted to the ED. Detailed medical history was negative for other symptoms, namely, fever, coluria, acholia, melena, and other evident blood losses, either on admission or in the past.
Physical examination revealed jaundice and pallor of the skin and mucous membranes. No epistaxis, gingivorrhagia, adenopathies, ecchymosis, or other skin lesions were found. Blood pressure was 137/62 mmHg and heart rate was 96 beats per minute, respiratory rate was 16 beats per minute, and peripheral oxygenation saturation was 96%. No fever or other abnormalities were noted.
Blood examination showed normocytic normochromic anemia (hemoglobin: 7.9 g/dL, reference median globular volume: 88 fL), reticulocytosis (9.2%), leucocytosis (white blood cells: 13.8 × 10 9/L), hyperbilirubinemia at the expense of unconjugated bilirubin (total bilirubin: 4.09 mg/dL, conjugated bilirubin: 0.97 mg/dL), elevated lactic dehydrogenase (805 UI/L), and sedimentation rate (VS: 76 mm). Serum iron concentration, ferritin, total iron-binding capacity, folic acid, or vitamin B12 showed no significant changes and haptoglobin levels were undetectable. Peripheral blood smear revealed exuberant erythrocyte rouleaux and spherocytes. The direct antiglobulin test (DAT) was positive for immunoglobulin G (IgG). Chest radiography, abdominal ultrasound, and electrocardiogram performed in the ED were normal.
The hypothesis of AIHA was considered in the ED. The patient was started on 60 mg of prednisolone per day (1 mg/kg/day) and was admitted to the medical ward.
The hypothesis of secondary AIHA to an infectious or a connective tissue disease was ruled out. Gastrointestinal complaints were compatible with side effects of NSAIDs, viral serologies, blood cultures, rheumatoid factor, antinuclear antibody, antineutrophil cytoplasmic antibodies, and cyclic citrullinated peptide antibody were negative, and complement (both C3 and C4 studies) was normal. Lymphoproliferative disease was excluded due to the absence of adenopathies both on physical examination and in imaging studies, as well as normal immunoglobulin levels (IgG, IgM, and IgA) and a normal serum protein electrophoresis. Inflammatory bowel disease and digestive tract tumors were also excluded by endoscopic observation and anatomopathological analysis of biopsies made in macroscopically normal mucosa.
During hospitalization, glucocorticoid therapy was maintained, and folic acid supplementation of 5 mg per day was started. The patient had clinical improvement with resolution of asthenia and jaundice, as well as progressive normalization of the hemoglobin and bilirubin values. On discharge, 13 days after admission, anemia was mild (hemoglobin: 11 g/dL) and no signs of hemolysis were noted. Table 1 shows the laboratory data during hospitalization.
Table 1 Laboratory data during hospitalization.
ALP: alkaline phosphatase; ALT: alanine aminotransferase; ANA: antinuclear antibodies; ANCA: antineutrophil cytoplasmic antibody; anti-CCP: anti-cyclic citrullinated peptides; AST: aspartate aminotransferase; GGT: gamma-glutamyl transferase; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; Ig: immunoglobulin; LDH: lactate dehydrogenase, MCV: mean corpuscular volume, TIBC: total iron binding capacity
Results
Variable Reference range (adults) Day 1 Day 2 Day 5 Day 7 Day 9 Day 13
Hemoglobin (g/dL) 11.8-15.8 7.9 7.8 8.2 9.1 10.3 11
Hematocrit (%) 36.0-46.0 21.9 22.1 24.4 26.7 30.6 33
Red blood cells (106/µL) 4.2-5.4 2.47 2.42 2.48 2.63 2.97 3.14
MCV (fL) 80.4-96.4 88.7 91.3 98.4 101.5 103 105.1
White cell count (103/µL) 4.0-10.0 13.88 12.49 18.09 15.62 11.43 11.82
Differential cell count (103/L)
Neutrophils 1.5-8.0 9.1 8.3 11.448 9.4 5.9 7.2
Lymphocytes 0.8-4.0 3.3 2.7 5.5 5.2 4.7 3.8
Platelet count (103/µL) 150-400 353 353 381 377 392 362
Reticulocytes (%) 0.5-1.5 9.22
Sedimentation rate (mm) 4-10 103 9
C-reactive protein (mg/dL) <0.51 3.23 2.67 0.69 0.41 0.23 0.14
Urea (mg/dL) 17.0-43.0 40 31 39 35 29 33
Creatinine (mg/dL) 0.6-1.0 0.84 0.78 0.8 0.78 0.84 0.79
Sodium (mmol/L) 136-145 140 141 138 143 141 142
Potassium (mmol/L) 3.5-5.1 4.2 4.2 3 3.7 4 3.9
Calcium (mg/dL) 8.6-10.3 8.7
Uric acid (mg/dL) 2.6-6 7
Bilirubin (mg/dL)
Total 0.3-1.2 4.09 4.01 2.16 2.29 2.27 1.28
Direct <0.5 0.07 0.82 0.71 0.75 0.75 0.46
LDH (UI/L) 125-220 805 632 467 436 388 309
ALP (UI/L) 30-120 152 135 96 93 90 76
GGT (UI/L) <38 83 70 55 56 54 43
ALT (UI/L) 7-45 44 19 23 30 31
AST (UI/L) 8-35 30 22 15 21 21 23
Iron (µ/dL) 70-180 124
TIBC (µ/dL) 250-245 300
Folic acid (ng/mL) 2.34-17.56 5.8
Vitamin B12 (pg/mL) 187-883 414
Haptoglobin (mg/dL) 35-250 <8
Direct antiglobulin test Positive for IgG
Protein electrophoresis No monoclonal spikes
Total proteins (g/dL) 6.4-8.2 6.1
Albumin (g/dL) 3.5-5.2 3.6
Immunoglobulins
IgA (mg/dL) 60-400 192
IgG (mg/dL) 70-1,600 1,008
IgM (mg/dL) 40-230 131
ANA Negative
ANCA Negative
Rheumatoid factor Negative
anti-CCP Negative
Serology
HIV Negative
HBV Negative
HCV Negative
Given the acute clinical context after diclofenac intake and absence of evidence for other secondary etiologies, the diagnosis of acquired hemolytic anemia secondary to NSAIDs was made. Follow-up three years later found the patient asymptomatic with no recurrence of anemia or hemolysis.
Discussion
Drugs are generally small molecules unable to elicit an immune response, however, they can function as haptens, bind to larger proteins, become immunogenic, and lead to antibody production. These antibodies can be further classified as drug-induced, drug-dependent, and drug-independent antibodies. Drug-induced antibodies can bind to red blood cells (RBCs) and lead to hemolysis by non-immunological modification of erythrocyte membranes known as adsorption of non-immunological proteins. Drug-dependent antibodies bind to RBCs only in the presence of the drug or its metabolites, causing abrupt complement-mediated intravascular hemolysis. In vitro tests searching for lysis, DAT, or indirect antiglobulin test can be performed to confirm the diagnosis using the offending drug or its metabolites and the patient’s plasma or serum. Drug-independent antibodies can react with RBCs even in the absence of the drug and, therefore, are indistinguishable from autoantibodies mediating warm autoimmune hemolytic anemia (WAIHA) [1,10,11].
WAIHA is named after warm agglutinins, usually IgG autoantibodies, that bind to antigens on erythrocytes at a temperature of 37°C, leading to RBC destruction and a chronic or relapsing disease with an almost pathognomonic positive DAT [2].
Patients are treated with glucocorticoids 1 to 2 mg/kg of body weight/day of prednisone administered orally or an equivalent dose of methylprednisolone administered intravenously. Though most patients recover to an hemoglobin level above 10 g/dL within two to three weeks of treatment, relapse after treatment discontinuation is common, with retrospective case studies suggesting long-term remission rates as low as 20% to 30% [2].
DIIHA is identified by clinical evidence of hemolysis associated with drug therapy. Although many drugs have anedoctally reported isolated cases of DIIHA, over 130 drugs have reasonable evidence that supports an immune etiology [12]. It has been speculated that DIIHA is far more common than previously estimated, as most reports usually refer to more severe cases, either presenting with shock, multiorgan damage, or renal failure, and most mild cases being unreported [6].
Drugs most frequently associated with DIIHA are second and third generation of cephalosporins, diclofenac, oxaliplatin, and fludarabine. In European cohorts where diclofenac is the most frequently used NSAID, case reviews reported diclofenac as the most frequently implicated drug, with a fatal outcome being estimated in 15% to 21% of the reported cases [6,12-16]. Diclofenac-induced immune hemolytic anemia has been demonstrated in few cases, where the exposure to the drug or its metabolites lead to developing both drug-independent IgG autoantibodies and antibodies that reacted with diclofenac and its metabolites [8].
Signs and symptoms of DIIHA, as any other hemolytic anemia, are proportional to the degree and time of onset and can present withing hours to weeks of drug exposure. These include fatigue, dyspnea, and thoracic or abdominal pain. Late symptoms are usually due to complications of decompensated hemolysis, usually shock or renal failure. Laboratory abnormalities include low hemoglobin and haptoglobin levels, elevated lactate dehydrogenase and indirect bilirubin levels, reticulocytosis, and a positive DAT [1,10].
The DAT is positive in all the described forms of DIIHA, either for IgG, C3, or both. Rare cases with negative DAT reported either low antibody density, massive intravascular hemolysis, or red cell transfusion administered prior to testing [1,10]. When approaching a case where there is evidence of hemolysis and an established temporal relationship with a drug known to induce autoantibody production, investigation for drug-dependent antibodies can be performed in adequate laboratory settings, with quality ensured expertise and appropriate controls [1,3].
As there are no defining clinical features and drug-induced autoantibodies are indistinguishable from idiopathic autoantibodies, misdiagnosis in DIIHA is extremely common, with some patients dying because of late diagnosis. Furthermore, hemolysis and serological results can persist for up to months after withdrawal of the drug, leading to erroneous attribution of recovery on the administered treatment and not to the interruption of the drug [6].
If DIIHA is suspected, relevant medication should be withdrawn immediately. In mild cases, recovery usually happens within one to two weeks after drug suspension, with no other necessary measures. As most drugs have a relatively short half-life, even a strong drug-dependent antibody loses its effect shortly after drug suspension [1]. Failure to recognize DIIHA can have disastrous consequences, especially when patients present complaints for which the offending drug was prescribed. Regarding diclofenac DIIHA, some cases have been reported of patients receiving the drug again for “low back pain” during the early onset of hemolysis [9].
In acute severe DIIHA, recommendations suggest close monitoring of clinical and laboratory signs, early intravenous access, and fluid resuscitation. Blood transfusion should not be withheld in patients with severe anemia [3]. Even though crossmatch-compatible blood can be difficult to find, a review of 134 patients showed that 68 (55%) patients received blood transfusions. Though most patients (85%) received glucocorticoids, its benefit is uncertain and its routine use is not recommended as drug eviction is usually enough to stop the immune response [14].
Applying the criteria of the World Health Organization causality assessment method to assess a possible drug‐induced etiology of IHA we are confident the most likely diagnosis for our patient was diclofenac-induced IHA [17]. Our analysis is supported by: (a) the presence of autoantibodies in the patient’s eluate was demonstrated; (b) diclofenac is known to induce DIIHA; (c) there is a chronological relationship between hemolysis and diclofenac administration; (d) a review of the literature failed to show cases of DIIHA induced by any of the other drugs taken by the patient; (e) symptoms and laboratory signs significantly improved after discontinuation of diclofenac; (f) no coexistent neoplastic, autoimmune, or infectious diseases known to be secondary causes of AIHA were found after systematic and comprehensive studies; and (g) though glucocorticoids were started on admission, no recurrence of anemia was verified in a three-year follow-up period, which would be uncommon if the patient suffered from WAIHA.
Conclusions
As a potentially fatal complication of a widely used drug in clinical practice such as diclofenac, early and correct diagnosis of DIIHA and prompt removal of the offending drug is crucial for the patient’s recovery. Our case highlights the need for both prescribing physicians and patients to be aware of this frequently underreported and usually misdiagnosed entity.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
Appendices
Table 2 Causality categories. Adapted from the WHO-UMC system for standardized case causality assessment. The usual approach is to choose one of the causality terms’ categories and to test if the various criteria fit the content of the case report. All assessment criteria should be reasonably complied to assume a category. The WHO-UMC causality assessment system can be used for the assessment of case reports of adverse drug reactions or drug-drug interactions.
WHO-UMC, World Health Organization-Uppsala Monitoring Centre
Causality term Assessment criteria
Certain • Event or laboratory test abnormality, with plausible time relationship to drug intake • Cannot be explained by disease or other drugs • Response to withdrawal plausible (pharmacologically, pathologically) • Event definitive pharmacologically or phenomenologically (i.e., an objective and specific medical disorder or a recognized pharmacological phenomenon) • Rechallenge satisfactory, if necessary
Probable/Likely • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Unlikely to be attributed to disease or other drugs • Response to withdrawal clinically reasonable • Rechallenge not required
Possible • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Could also be explained by disease or other drugs • Information on drug withdrawal may be lacking or unclear
Unlikely • Event or laboratory test abnormality, with a time to drug intake that makes a relationship improbable (but not impossible) • Disease or other drugs provide plausible explanations
Conditional/Unclassified • Event or laboratory test abnormality • More data for proper assessment needed • Additional data under examination
Unassessable/Unclassifiable • Report suggesting an adverse reaction • Cannot be judged because information is insufficient or contradictory • Data cannot be supplemented or verified | Intramuscular | DrugAdministrationRoute | CC BY | 33654588 | 19,027,243 | 2021-01-25 |
What was the outcome of reaction 'Asthenia'? | Diclofenac-Induced Immune Hemolytic Anemia: A Case Report and Review of Literature.
Non-steroidal anti-inflammatory drugs are widely used for pain management. Most frequently, adverse reactions affect the gastrointestinal tract and hematological side effects usually relate to the gastrointestinal manifestations. Drug-induced immune hemolytic anemia is a rare and frequently underdiagnosed complication that is associated with poor outcomes including organ failure and even death. A 76-year-old female patient was treated with intramuscular diclofenac, thiocolchicoside, and diazepam for low back pain. Five days following diclofenac exposure, the patient was admitted to the Emergency Department with complaints of asthenia, nausea, vomiting, and diarrhea. Hemolysis and a positive direct antiglobulin test were detected on laboratory testing. Further causes of hemolytic anemia were excluded and a diagnosis of diclofenac-induced immune hemolytic anemia was established. Glucocorticoid therapy initiated on admission and drug eviction led to complete recovery. Long-term follow-up showed no recurrence of anemia. Here, we present the unusual case of a successful recovery of a 76-year-old patient with diclofenac-induced immune hemolytic anemia, a rare but immediate life-threatening condition of a frequently used drug in clinical practice.
Introduction
Autoimmune hemolytic anemia (AIHA) ensues when the host’s immune system acts against its own red cell antigens and has an estimated prevalence of approximately 1 in 100,000 individuals [1]. Approximately 50% of the cases refer to primary or idiopathic AIHA, where an associated disorder is not found [2]. Secondary causes of AIHA depend on the studied population. Current series estimate that half are associated with hematological malignancy, a third with infection, a sixth with collagen vascular disorders, and a tenth with drug-induced immune hemolytic anemia (DIIHA), the latter reaching an estimated incidence of one per million per year [1,3].
Diclofenac is one of the non-steroidal anti-inflammatory drugs (NSAIDs) most used for the treatment of rheumatoid arthritis and osteoarthritis [4]. Though generally well tolerated, over 400 adverse reactions have been documented. Most frequently, adverse reactions affect the gastrointestinal tract, the skin, and the central nervous system [5]. Direct hematological side effects such as leukopenia, thrombocytopenia, and aplastic anemia have been described only in limited cases [6-9].
We present the case of a 76-year-old patient with diclofenac DIIHA and a summary of the pathophysiology and therapeutic options.
Case presentation
A 76-year-old woman presented to the Emergency Department (ED) with recent onset of fatigue. She had a previous medical history of essential arterial hypertension, dyslipidemia, and spinal osteoarthritis with sporadic episodes of lumbosciatic pain. Regular medications initiated several years prior included perindopril 8 mg and rosuvastatin 10 mg. No allergies, alcohol, tobacco, toxins, or animal exposures were known, and she had no other relevant personal or familiar history.
Three weeks before admission the patient had an exacerbation of right lumbosciatic pain. This episode was similar to the previous ones, for which she usually was prescribed oral NSAIDs, acetaminophen, general physical therapy, massages, and rest with complete recovery. However, this time the pain was refractory to general measures, and eight days before admission, she was prescribed a combination of a daily intramuscular administration of 4 mg thiocolchicoside, 75 mg diclofenac, and 5 mg diazepam for a total of six days.
On the fifth day of treatment, she developed generalized malaise, fatigue, nausea, postprandial vomiting, and diarrhea with up to six soft, brownish dejections per day.
Despite resolution of nausea, vomiting, and diarrhea, she experienced progressive worsening of fatigue and was admitted to the ED. Detailed medical history was negative for other symptoms, namely, fever, coluria, acholia, melena, and other evident blood losses, either on admission or in the past.
Physical examination revealed jaundice and pallor of the skin and mucous membranes. No epistaxis, gingivorrhagia, adenopathies, ecchymosis, or other skin lesions were found. Blood pressure was 137/62 mmHg and heart rate was 96 beats per minute, respiratory rate was 16 beats per minute, and peripheral oxygenation saturation was 96%. No fever or other abnormalities were noted.
Blood examination showed normocytic normochromic anemia (hemoglobin: 7.9 g/dL, reference median globular volume: 88 fL), reticulocytosis (9.2%), leucocytosis (white blood cells: 13.8 × 10 9/L), hyperbilirubinemia at the expense of unconjugated bilirubin (total bilirubin: 4.09 mg/dL, conjugated bilirubin: 0.97 mg/dL), elevated lactic dehydrogenase (805 UI/L), and sedimentation rate (VS: 76 mm). Serum iron concentration, ferritin, total iron-binding capacity, folic acid, or vitamin B12 showed no significant changes and haptoglobin levels were undetectable. Peripheral blood smear revealed exuberant erythrocyte rouleaux and spherocytes. The direct antiglobulin test (DAT) was positive for immunoglobulin G (IgG). Chest radiography, abdominal ultrasound, and electrocardiogram performed in the ED were normal.
The hypothesis of AIHA was considered in the ED. The patient was started on 60 mg of prednisolone per day (1 mg/kg/day) and was admitted to the medical ward.
The hypothesis of secondary AIHA to an infectious or a connective tissue disease was ruled out. Gastrointestinal complaints were compatible with side effects of NSAIDs, viral serologies, blood cultures, rheumatoid factor, antinuclear antibody, antineutrophil cytoplasmic antibodies, and cyclic citrullinated peptide antibody were negative, and complement (both C3 and C4 studies) was normal. Lymphoproliferative disease was excluded due to the absence of adenopathies both on physical examination and in imaging studies, as well as normal immunoglobulin levels (IgG, IgM, and IgA) and a normal serum protein electrophoresis. Inflammatory bowel disease and digestive tract tumors were also excluded by endoscopic observation and anatomopathological analysis of biopsies made in macroscopically normal mucosa.
During hospitalization, glucocorticoid therapy was maintained, and folic acid supplementation of 5 mg per day was started. The patient had clinical improvement with resolution of asthenia and jaundice, as well as progressive normalization of the hemoglobin and bilirubin values. On discharge, 13 days after admission, anemia was mild (hemoglobin: 11 g/dL) and no signs of hemolysis were noted. Table 1 shows the laboratory data during hospitalization.
Table 1 Laboratory data during hospitalization.
ALP: alkaline phosphatase; ALT: alanine aminotransferase; ANA: antinuclear antibodies; ANCA: antineutrophil cytoplasmic antibody; anti-CCP: anti-cyclic citrullinated peptides; AST: aspartate aminotransferase; GGT: gamma-glutamyl transferase; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; Ig: immunoglobulin; LDH: lactate dehydrogenase, MCV: mean corpuscular volume, TIBC: total iron binding capacity
Results
Variable Reference range (adults) Day 1 Day 2 Day 5 Day 7 Day 9 Day 13
Hemoglobin (g/dL) 11.8-15.8 7.9 7.8 8.2 9.1 10.3 11
Hematocrit (%) 36.0-46.0 21.9 22.1 24.4 26.7 30.6 33
Red blood cells (106/µL) 4.2-5.4 2.47 2.42 2.48 2.63 2.97 3.14
MCV (fL) 80.4-96.4 88.7 91.3 98.4 101.5 103 105.1
White cell count (103/µL) 4.0-10.0 13.88 12.49 18.09 15.62 11.43 11.82
Differential cell count (103/L)
Neutrophils 1.5-8.0 9.1 8.3 11.448 9.4 5.9 7.2
Lymphocytes 0.8-4.0 3.3 2.7 5.5 5.2 4.7 3.8
Platelet count (103/µL) 150-400 353 353 381 377 392 362
Reticulocytes (%) 0.5-1.5 9.22
Sedimentation rate (mm) 4-10 103 9
C-reactive protein (mg/dL) <0.51 3.23 2.67 0.69 0.41 0.23 0.14
Urea (mg/dL) 17.0-43.0 40 31 39 35 29 33
Creatinine (mg/dL) 0.6-1.0 0.84 0.78 0.8 0.78 0.84 0.79
Sodium (mmol/L) 136-145 140 141 138 143 141 142
Potassium (mmol/L) 3.5-5.1 4.2 4.2 3 3.7 4 3.9
Calcium (mg/dL) 8.6-10.3 8.7
Uric acid (mg/dL) 2.6-6 7
Bilirubin (mg/dL)
Total 0.3-1.2 4.09 4.01 2.16 2.29 2.27 1.28
Direct <0.5 0.07 0.82 0.71 0.75 0.75 0.46
LDH (UI/L) 125-220 805 632 467 436 388 309
ALP (UI/L) 30-120 152 135 96 93 90 76
GGT (UI/L) <38 83 70 55 56 54 43
ALT (UI/L) 7-45 44 19 23 30 31
AST (UI/L) 8-35 30 22 15 21 21 23
Iron (µ/dL) 70-180 124
TIBC (µ/dL) 250-245 300
Folic acid (ng/mL) 2.34-17.56 5.8
Vitamin B12 (pg/mL) 187-883 414
Haptoglobin (mg/dL) 35-250 <8
Direct antiglobulin test Positive for IgG
Protein electrophoresis No monoclonal spikes
Total proteins (g/dL) 6.4-8.2 6.1
Albumin (g/dL) 3.5-5.2 3.6
Immunoglobulins
IgA (mg/dL) 60-400 192
IgG (mg/dL) 70-1,600 1,008
IgM (mg/dL) 40-230 131
ANA Negative
ANCA Negative
Rheumatoid factor Negative
anti-CCP Negative
Serology
HIV Negative
HBV Negative
HCV Negative
Given the acute clinical context after diclofenac intake and absence of evidence for other secondary etiologies, the diagnosis of acquired hemolytic anemia secondary to NSAIDs was made. Follow-up three years later found the patient asymptomatic with no recurrence of anemia or hemolysis.
Discussion
Drugs are generally small molecules unable to elicit an immune response, however, they can function as haptens, bind to larger proteins, become immunogenic, and lead to antibody production. These antibodies can be further classified as drug-induced, drug-dependent, and drug-independent antibodies. Drug-induced antibodies can bind to red blood cells (RBCs) and lead to hemolysis by non-immunological modification of erythrocyte membranes known as adsorption of non-immunological proteins. Drug-dependent antibodies bind to RBCs only in the presence of the drug or its metabolites, causing abrupt complement-mediated intravascular hemolysis. In vitro tests searching for lysis, DAT, or indirect antiglobulin test can be performed to confirm the diagnosis using the offending drug or its metabolites and the patient’s plasma or serum. Drug-independent antibodies can react with RBCs even in the absence of the drug and, therefore, are indistinguishable from autoantibodies mediating warm autoimmune hemolytic anemia (WAIHA) [1,10,11].
WAIHA is named after warm agglutinins, usually IgG autoantibodies, that bind to antigens on erythrocytes at a temperature of 37°C, leading to RBC destruction and a chronic or relapsing disease with an almost pathognomonic positive DAT [2].
Patients are treated with glucocorticoids 1 to 2 mg/kg of body weight/day of prednisone administered orally or an equivalent dose of methylprednisolone administered intravenously. Though most patients recover to an hemoglobin level above 10 g/dL within two to three weeks of treatment, relapse after treatment discontinuation is common, with retrospective case studies suggesting long-term remission rates as low as 20% to 30% [2].
DIIHA is identified by clinical evidence of hemolysis associated with drug therapy. Although many drugs have anedoctally reported isolated cases of DIIHA, over 130 drugs have reasonable evidence that supports an immune etiology [12]. It has been speculated that DIIHA is far more common than previously estimated, as most reports usually refer to more severe cases, either presenting with shock, multiorgan damage, or renal failure, and most mild cases being unreported [6].
Drugs most frequently associated with DIIHA are second and third generation of cephalosporins, diclofenac, oxaliplatin, and fludarabine. In European cohorts where diclofenac is the most frequently used NSAID, case reviews reported diclofenac as the most frequently implicated drug, with a fatal outcome being estimated in 15% to 21% of the reported cases [6,12-16]. Diclofenac-induced immune hemolytic anemia has been demonstrated in few cases, where the exposure to the drug or its metabolites lead to developing both drug-independent IgG autoantibodies and antibodies that reacted with diclofenac and its metabolites [8].
Signs and symptoms of DIIHA, as any other hemolytic anemia, are proportional to the degree and time of onset and can present withing hours to weeks of drug exposure. These include fatigue, dyspnea, and thoracic or abdominal pain. Late symptoms are usually due to complications of decompensated hemolysis, usually shock or renal failure. Laboratory abnormalities include low hemoglobin and haptoglobin levels, elevated lactate dehydrogenase and indirect bilirubin levels, reticulocytosis, and a positive DAT [1,10].
The DAT is positive in all the described forms of DIIHA, either for IgG, C3, or both. Rare cases with negative DAT reported either low antibody density, massive intravascular hemolysis, or red cell transfusion administered prior to testing [1,10]. When approaching a case where there is evidence of hemolysis and an established temporal relationship with a drug known to induce autoantibody production, investigation for drug-dependent antibodies can be performed in adequate laboratory settings, with quality ensured expertise and appropriate controls [1,3].
As there are no defining clinical features and drug-induced autoantibodies are indistinguishable from idiopathic autoantibodies, misdiagnosis in DIIHA is extremely common, with some patients dying because of late diagnosis. Furthermore, hemolysis and serological results can persist for up to months after withdrawal of the drug, leading to erroneous attribution of recovery on the administered treatment and not to the interruption of the drug [6].
If DIIHA is suspected, relevant medication should be withdrawn immediately. In mild cases, recovery usually happens within one to two weeks after drug suspension, with no other necessary measures. As most drugs have a relatively short half-life, even a strong drug-dependent antibody loses its effect shortly after drug suspension [1]. Failure to recognize DIIHA can have disastrous consequences, especially when patients present complaints for which the offending drug was prescribed. Regarding diclofenac DIIHA, some cases have been reported of patients receiving the drug again for “low back pain” during the early onset of hemolysis [9].
In acute severe DIIHA, recommendations suggest close monitoring of clinical and laboratory signs, early intravenous access, and fluid resuscitation. Blood transfusion should not be withheld in patients with severe anemia [3]. Even though crossmatch-compatible blood can be difficult to find, a review of 134 patients showed that 68 (55%) patients received blood transfusions. Though most patients (85%) received glucocorticoids, its benefit is uncertain and its routine use is not recommended as drug eviction is usually enough to stop the immune response [14].
Applying the criteria of the World Health Organization causality assessment method to assess a possible drug‐induced etiology of IHA we are confident the most likely diagnosis for our patient was diclofenac-induced IHA [17]. Our analysis is supported by: (a) the presence of autoantibodies in the patient’s eluate was demonstrated; (b) diclofenac is known to induce DIIHA; (c) there is a chronological relationship between hemolysis and diclofenac administration; (d) a review of the literature failed to show cases of DIIHA induced by any of the other drugs taken by the patient; (e) symptoms and laboratory signs significantly improved after discontinuation of diclofenac; (f) no coexistent neoplastic, autoimmune, or infectious diseases known to be secondary causes of AIHA were found after systematic and comprehensive studies; and (g) though glucocorticoids were started on admission, no recurrence of anemia was verified in a three-year follow-up period, which would be uncommon if the patient suffered from WAIHA.
Conclusions
As a potentially fatal complication of a widely used drug in clinical practice such as diclofenac, early and correct diagnosis of DIIHA and prompt removal of the offending drug is crucial for the patient’s recovery. Our case highlights the need for both prescribing physicians and patients to be aware of this frequently underreported and usually misdiagnosed entity.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
Appendices
Table 2 Causality categories. Adapted from the WHO-UMC system for standardized case causality assessment. The usual approach is to choose one of the causality terms’ categories and to test if the various criteria fit the content of the case report. All assessment criteria should be reasonably complied to assume a category. The WHO-UMC causality assessment system can be used for the assessment of case reports of adverse drug reactions or drug-drug interactions.
WHO-UMC, World Health Organization-Uppsala Monitoring Centre
Causality term Assessment criteria
Certain • Event or laboratory test abnormality, with plausible time relationship to drug intake • Cannot be explained by disease or other drugs • Response to withdrawal plausible (pharmacologically, pathologically) • Event definitive pharmacologically or phenomenologically (i.e., an objective and specific medical disorder or a recognized pharmacological phenomenon) • Rechallenge satisfactory, if necessary
Probable/Likely • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Unlikely to be attributed to disease or other drugs • Response to withdrawal clinically reasonable • Rechallenge not required
Possible • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Could also be explained by disease or other drugs • Information on drug withdrawal may be lacking or unclear
Unlikely • Event or laboratory test abnormality, with a time to drug intake that makes a relationship improbable (but not impossible) • Disease or other drugs provide plausible explanations
Conditional/Unclassified • Event or laboratory test abnormality • More data for proper assessment needed • Additional data under examination
Unassessable/Unclassifiable • Report suggesting an adverse reaction • Cannot be judged because information is insufficient or contradictory • Data cannot be supplemented or verified | Recovered | ReactionOutcome | CC BY | 33654588 | 19,027,243 | 2021-01-25 |
What was the outcome of reaction 'Diarrhoea'? | Diclofenac-Induced Immune Hemolytic Anemia: A Case Report and Review of Literature.
Non-steroidal anti-inflammatory drugs are widely used for pain management. Most frequently, adverse reactions affect the gastrointestinal tract and hematological side effects usually relate to the gastrointestinal manifestations. Drug-induced immune hemolytic anemia is a rare and frequently underdiagnosed complication that is associated with poor outcomes including organ failure and even death. A 76-year-old female patient was treated with intramuscular diclofenac, thiocolchicoside, and diazepam for low back pain. Five days following diclofenac exposure, the patient was admitted to the Emergency Department with complaints of asthenia, nausea, vomiting, and diarrhea. Hemolysis and a positive direct antiglobulin test were detected on laboratory testing. Further causes of hemolytic anemia were excluded and a diagnosis of diclofenac-induced immune hemolytic anemia was established. Glucocorticoid therapy initiated on admission and drug eviction led to complete recovery. Long-term follow-up showed no recurrence of anemia. Here, we present the unusual case of a successful recovery of a 76-year-old patient with diclofenac-induced immune hemolytic anemia, a rare but immediate life-threatening condition of a frequently used drug in clinical practice.
Introduction
Autoimmune hemolytic anemia (AIHA) ensues when the host’s immune system acts against its own red cell antigens and has an estimated prevalence of approximately 1 in 100,000 individuals [1]. Approximately 50% of the cases refer to primary or idiopathic AIHA, where an associated disorder is not found [2]. Secondary causes of AIHA depend on the studied population. Current series estimate that half are associated with hematological malignancy, a third with infection, a sixth with collagen vascular disorders, and a tenth with drug-induced immune hemolytic anemia (DIIHA), the latter reaching an estimated incidence of one per million per year [1,3].
Diclofenac is one of the non-steroidal anti-inflammatory drugs (NSAIDs) most used for the treatment of rheumatoid arthritis and osteoarthritis [4]. Though generally well tolerated, over 400 adverse reactions have been documented. Most frequently, adverse reactions affect the gastrointestinal tract, the skin, and the central nervous system [5]. Direct hematological side effects such as leukopenia, thrombocytopenia, and aplastic anemia have been described only in limited cases [6-9].
We present the case of a 76-year-old patient with diclofenac DIIHA and a summary of the pathophysiology and therapeutic options.
Case presentation
A 76-year-old woman presented to the Emergency Department (ED) with recent onset of fatigue. She had a previous medical history of essential arterial hypertension, dyslipidemia, and spinal osteoarthritis with sporadic episodes of lumbosciatic pain. Regular medications initiated several years prior included perindopril 8 mg and rosuvastatin 10 mg. No allergies, alcohol, tobacco, toxins, or animal exposures were known, and she had no other relevant personal or familiar history.
Three weeks before admission the patient had an exacerbation of right lumbosciatic pain. This episode was similar to the previous ones, for which she usually was prescribed oral NSAIDs, acetaminophen, general physical therapy, massages, and rest with complete recovery. However, this time the pain was refractory to general measures, and eight days before admission, she was prescribed a combination of a daily intramuscular administration of 4 mg thiocolchicoside, 75 mg diclofenac, and 5 mg diazepam for a total of six days.
On the fifth day of treatment, she developed generalized malaise, fatigue, nausea, postprandial vomiting, and diarrhea with up to six soft, brownish dejections per day.
Despite resolution of nausea, vomiting, and diarrhea, she experienced progressive worsening of fatigue and was admitted to the ED. Detailed medical history was negative for other symptoms, namely, fever, coluria, acholia, melena, and other evident blood losses, either on admission or in the past.
Physical examination revealed jaundice and pallor of the skin and mucous membranes. No epistaxis, gingivorrhagia, adenopathies, ecchymosis, or other skin lesions were found. Blood pressure was 137/62 mmHg and heart rate was 96 beats per minute, respiratory rate was 16 beats per minute, and peripheral oxygenation saturation was 96%. No fever or other abnormalities were noted.
Blood examination showed normocytic normochromic anemia (hemoglobin: 7.9 g/dL, reference median globular volume: 88 fL), reticulocytosis (9.2%), leucocytosis (white blood cells: 13.8 × 10 9/L), hyperbilirubinemia at the expense of unconjugated bilirubin (total bilirubin: 4.09 mg/dL, conjugated bilirubin: 0.97 mg/dL), elevated lactic dehydrogenase (805 UI/L), and sedimentation rate (VS: 76 mm). Serum iron concentration, ferritin, total iron-binding capacity, folic acid, or vitamin B12 showed no significant changes and haptoglobin levels were undetectable. Peripheral blood smear revealed exuberant erythrocyte rouleaux and spherocytes. The direct antiglobulin test (DAT) was positive for immunoglobulin G (IgG). Chest radiography, abdominal ultrasound, and electrocardiogram performed in the ED were normal.
The hypothesis of AIHA was considered in the ED. The patient was started on 60 mg of prednisolone per day (1 mg/kg/day) and was admitted to the medical ward.
The hypothesis of secondary AIHA to an infectious or a connective tissue disease was ruled out. Gastrointestinal complaints were compatible with side effects of NSAIDs, viral serologies, blood cultures, rheumatoid factor, antinuclear antibody, antineutrophil cytoplasmic antibodies, and cyclic citrullinated peptide antibody were negative, and complement (both C3 and C4 studies) was normal. Lymphoproliferative disease was excluded due to the absence of adenopathies both on physical examination and in imaging studies, as well as normal immunoglobulin levels (IgG, IgM, and IgA) and a normal serum protein electrophoresis. Inflammatory bowel disease and digestive tract tumors were also excluded by endoscopic observation and anatomopathological analysis of biopsies made in macroscopically normal mucosa.
During hospitalization, glucocorticoid therapy was maintained, and folic acid supplementation of 5 mg per day was started. The patient had clinical improvement with resolution of asthenia and jaundice, as well as progressive normalization of the hemoglobin and bilirubin values. On discharge, 13 days after admission, anemia was mild (hemoglobin: 11 g/dL) and no signs of hemolysis were noted. Table 1 shows the laboratory data during hospitalization.
Table 1 Laboratory data during hospitalization.
ALP: alkaline phosphatase; ALT: alanine aminotransferase; ANA: antinuclear antibodies; ANCA: antineutrophil cytoplasmic antibody; anti-CCP: anti-cyclic citrullinated peptides; AST: aspartate aminotransferase; GGT: gamma-glutamyl transferase; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; Ig: immunoglobulin; LDH: lactate dehydrogenase, MCV: mean corpuscular volume, TIBC: total iron binding capacity
Results
Variable Reference range (adults) Day 1 Day 2 Day 5 Day 7 Day 9 Day 13
Hemoglobin (g/dL) 11.8-15.8 7.9 7.8 8.2 9.1 10.3 11
Hematocrit (%) 36.0-46.0 21.9 22.1 24.4 26.7 30.6 33
Red blood cells (106/µL) 4.2-5.4 2.47 2.42 2.48 2.63 2.97 3.14
MCV (fL) 80.4-96.4 88.7 91.3 98.4 101.5 103 105.1
White cell count (103/µL) 4.0-10.0 13.88 12.49 18.09 15.62 11.43 11.82
Differential cell count (103/L)
Neutrophils 1.5-8.0 9.1 8.3 11.448 9.4 5.9 7.2
Lymphocytes 0.8-4.0 3.3 2.7 5.5 5.2 4.7 3.8
Platelet count (103/µL) 150-400 353 353 381 377 392 362
Reticulocytes (%) 0.5-1.5 9.22
Sedimentation rate (mm) 4-10 103 9
C-reactive protein (mg/dL) <0.51 3.23 2.67 0.69 0.41 0.23 0.14
Urea (mg/dL) 17.0-43.0 40 31 39 35 29 33
Creatinine (mg/dL) 0.6-1.0 0.84 0.78 0.8 0.78 0.84 0.79
Sodium (mmol/L) 136-145 140 141 138 143 141 142
Potassium (mmol/L) 3.5-5.1 4.2 4.2 3 3.7 4 3.9
Calcium (mg/dL) 8.6-10.3 8.7
Uric acid (mg/dL) 2.6-6 7
Bilirubin (mg/dL)
Total 0.3-1.2 4.09 4.01 2.16 2.29 2.27 1.28
Direct <0.5 0.07 0.82 0.71 0.75 0.75 0.46
LDH (UI/L) 125-220 805 632 467 436 388 309
ALP (UI/L) 30-120 152 135 96 93 90 76
GGT (UI/L) <38 83 70 55 56 54 43
ALT (UI/L) 7-45 44 19 23 30 31
AST (UI/L) 8-35 30 22 15 21 21 23
Iron (µ/dL) 70-180 124
TIBC (µ/dL) 250-245 300
Folic acid (ng/mL) 2.34-17.56 5.8
Vitamin B12 (pg/mL) 187-883 414
Haptoglobin (mg/dL) 35-250 <8
Direct antiglobulin test Positive for IgG
Protein electrophoresis No monoclonal spikes
Total proteins (g/dL) 6.4-8.2 6.1
Albumin (g/dL) 3.5-5.2 3.6
Immunoglobulins
IgA (mg/dL) 60-400 192
IgG (mg/dL) 70-1,600 1,008
IgM (mg/dL) 40-230 131
ANA Negative
ANCA Negative
Rheumatoid factor Negative
anti-CCP Negative
Serology
HIV Negative
HBV Negative
HCV Negative
Given the acute clinical context after diclofenac intake and absence of evidence for other secondary etiologies, the diagnosis of acquired hemolytic anemia secondary to NSAIDs was made. Follow-up three years later found the patient asymptomatic with no recurrence of anemia or hemolysis.
Discussion
Drugs are generally small molecules unable to elicit an immune response, however, they can function as haptens, bind to larger proteins, become immunogenic, and lead to antibody production. These antibodies can be further classified as drug-induced, drug-dependent, and drug-independent antibodies. Drug-induced antibodies can bind to red blood cells (RBCs) and lead to hemolysis by non-immunological modification of erythrocyte membranes known as adsorption of non-immunological proteins. Drug-dependent antibodies bind to RBCs only in the presence of the drug or its metabolites, causing abrupt complement-mediated intravascular hemolysis. In vitro tests searching for lysis, DAT, or indirect antiglobulin test can be performed to confirm the diagnosis using the offending drug or its metabolites and the patient’s plasma or serum. Drug-independent antibodies can react with RBCs even in the absence of the drug and, therefore, are indistinguishable from autoantibodies mediating warm autoimmune hemolytic anemia (WAIHA) [1,10,11].
WAIHA is named after warm agglutinins, usually IgG autoantibodies, that bind to antigens on erythrocytes at a temperature of 37°C, leading to RBC destruction and a chronic or relapsing disease with an almost pathognomonic positive DAT [2].
Patients are treated with glucocorticoids 1 to 2 mg/kg of body weight/day of prednisone administered orally or an equivalent dose of methylprednisolone administered intravenously. Though most patients recover to an hemoglobin level above 10 g/dL within two to three weeks of treatment, relapse after treatment discontinuation is common, with retrospective case studies suggesting long-term remission rates as low as 20% to 30% [2].
DIIHA is identified by clinical evidence of hemolysis associated with drug therapy. Although many drugs have anedoctally reported isolated cases of DIIHA, over 130 drugs have reasonable evidence that supports an immune etiology [12]. It has been speculated that DIIHA is far more common than previously estimated, as most reports usually refer to more severe cases, either presenting with shock, multiorgan damage, or renal failure, and most mild cases being unreported [6].
Drugs most frequently associated with DIIHA are second and third generation of cephalosporins, diclofenac, oxaliplatin, and fludarabine. In European cohorts where diclofenac is the most frequently used NSAID, case reviews reported diclofenac as the most frequently implicated drug, with a fatal outcome being estimated in 15% to 21% of the reported cases [6,12-16]. Diclofenac-induced immune hemolytic anemia has been demonstrated in few cases, where the exposure to the drug or its metabolites lead to developing both drug-independent IgG autoantibodies and antibodies that reacted with diclofenac and its metabolites [8].
Signs and symptoms of DIIHA, as any other hemolytic anemia, are proportional to the degree and time of onset and can present withing hours to weeks of drug exposure. These include fatigue, dyspnea, and thoracic or abdominal pain. Late symptoms are usually due to complications of decompensated hemolysis, usually shock or renal failure. Laboratory abnormalities include low hemoglobin and haptoglobin levels, elevated lactate dehydrogenase and indirect bilirubin levels, reticulocytosis, and a positive DAT [1,10].
The DAT is positive in all the described forms of DIIHA, either for IgG, C3, or both. Rare cases with negative DAT reported either low antibody density, massive intravascular hemolysis, or red cell transfusion administered prior to testing [1,10]. When approaching a case where there is evidence of hemolysis and an established temporal relationship with a drug known to induce autoantibody production, investigation for drug-dependent antibodies can be performed in adequate laboratory settings, with quality ensured expertise and appropriate controls [1,3].
As there are no defining clinical features and drug-induced autoantibodies are indistinguishable from idiopathic autoantibodies, misdiagnosis in DIIHA is extremely common, with some patients dying because of late diagnosis. Furthermore, hemolysis and serological results can persist for up to months after withdrawal of the drug, leading to erroneous attribution of recovery on the administered treatment and not to the interruption of the drug [6].
If DIIHA is suspected, relevant medication should be withdrawn immediately. In mild cases, recovery usually happens within one to two weeks after drug suspension, with no other necessary measures. As most drugs have a relatively short half-life, even a strong drug-dependent antibody loses its effect shortly after drug suspension [1]. Failure to recognize DIIHA can have disastrous consequences, especially when patients present complaints for which the offending drug was prescribed. Regarding diclofenac DIIHA, some cases have been reported of patients receiving the drug again for “low back pain” during the early onset of hemolysis [9].
In acute severe DIIHA, recommendations suggest close monitoring of clinical and laboratory signs, early intravenous access, and fluid resuscitation. Blood transfusion should not be withheld in patients with severe anemia [3]. Even though crossmatch-compatible blood can be difficult to find, a review of 134 patients showed that 68 (55%) patients received blood transfusions. Though most patients (85%) received glucocorticoids, its benefit is uncertain and its routine use is not recommended as drug eviction is usually enough to stop the immune response [14].
Applying the criteria of the World Health Organization causality assessment method to assess a possible drug‐induced etiology of IHA we are confident the most likely diagnosis for our patient was diclofenac-induced IHA [17]. Our analysis is supported by: (a) the presence of autoantibodies in the patient’s eluate was demonstrated; (b) diclofenac is known to induce DIIHA; (c) there is a chronological relationship between hemolysis and diclofenac administration; (d) a review of the literature failed to show cases of DIIHA induced by any of the other drugs taken by the patient; (e) symptoms and laboratory signs significantly improved after discontinuation of diclofenac; (f) no coexistent neoplastic, autoimmune, or infectious diseases known to be secondary causes of AIHA were found after systematic and comprehensive studies; and (g) though glucocorticoids were started on admission, no recurrence of anemia was verified in a three-year follow-up period, which would be uncommon if the patient suffered from WAIHA.
Conclusions
As a potentially fatal complication of a widely used drug in clinical practice such as diclofenac, early and correct diagnosis of DIIHA and prompt removal of the offending drug is crucial for the patient’s recovery. Our case highlights the need for both prescribing physicians and patients to be aware of this frequently underreported and usually misdiagnosed entity.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
Appendices
Table 2 Causality categories. Adapted from the WHO-UMC system for standardized case causality assessment. The usual approach is to choose one of the causality terms’ categories and to test if the various criteria fit the content of the case report. All assessment criteria should be reasonably complied to assume a category. The WHO-UMC causality assessment system can be used for the assessment of case reports of adverse drug reactions or drug-drug interactions.
WHO-UMC, World Health Organization-Uppsala Monitoring Centre
Causality term Assessment criteria
Certain • Event or laboratory test abnormality, with plausible time relationship to drug intake • Cannot be explained by disease or other drugs • Response to withdrawal plausible (pharmacologically, pathologically) • Event definitive pharmacologically or phenomenologically (i.e., an objective and specific medical disorder or a recognized pharmacological phenomenon) • Rechallenge satisfactory, if necessary
Probable/Likely • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Unlikely to be attributed to disease or other drugs • Response to withdrawal clinically reasonable • Rechallenge not required
Possible • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Could also be explained by disease or other drugs • Information on drug withdrawal may be lacking or unclear
Unlikely • Event or laboratory test abnormality, with a time to drug intake that makes a relationship improbable (but not impossible) • Disease or other drugs provide plausible explanations
Conditional/Unclassified • Event or laboratory test abnormality • More data for proper assessment needed • Additional data under examination
Unassessable/Unclassifiable • Report suggesting an adverse reaction • Cannot be judged because information is insufficient or contradictory • Data cannot be supplemented or verified | Recovered | ReactionOutcome | CC BY | 33654588 | 19,027,243 | 2021-01-25 |
What was the outcome of reaction 'Fatigue'? | Diclofenac-Induced Immune Hemolytic Anemia: A Case Report and Review of Literature.
Non-steroidal anti-inflammatory drugs are widely used for pain management. Most frequently, adverse reactions affect the gastrointestinal tract and hematological side effects usually relate to the gastrointestinal manifestations. Drug-induced immune hemolytic anemia is a rare and frequently underdiagnosed complication that is associated with poor outcomes including organ failure and even death. A 76-year-old female patient was treated with intramuscular diclofenac, thiocolchicoside, and diazepam for low back pain. Five days following diclofenac exposure, the patient was admitted to the Emergency Department with complaints of asthenia, nausea, vomiting, and diarrhea. Hemolysis and a positive direct antiglobulin test were detected on laboratory testing. Further causes of hemolytic anemia were excluded and a diagnosis of diclofenac-induced immune hemolytic anemia was established. Glucocorticoid therapy initiated on admission and drug eviction led to complete recovery. Long-term follow-up showed no recurrence of anemia. Here, we present the unusual case of a successful recovery of a 76-year-old patient with diclofenac-induced immune hemolytic anemia, a rare but immediate life-threatening condition of a frequently used drug in clinical practice.
Introduction
Autoimmune hemolytic anemia (AIHA) ensues when the host’s immune system acts against its own red cell antigens and has an estimated prevalence of approximately 1 in 100,000 individuals [1]. Approximately 50% of the cases refer to primary or idiopathic AIHA, where an associated disorder is not found [2]. Secondary causes of AIHA depend on the studied population. Current series estimate that half are associated with hematological malignancy, a third with infection, a sixth with collagen vascular disorders, and a tenth with drug-induced immune hemolytic anemia (DIIHA), the latter reaching an estimated incidence of one per million per year [1,3].
Diclofenac is one of the non-steroidal anti-inflammatory drugs (NSAIDs) most used for the treatment of rheumatoid arthritis and osteoarthritis [4]. Though generally well tolerated, over 400 adverse reactions have been documented. Most frequently, adverse reactions affect the gastrointestinal tract, the skin, and the central nervous system [5]. Direct hematological side effects such as leukopenia, thrombocytopenia, and aplastic anemia have been described only in limited cases [6-9].
We present the case of a 76-year-old patient with diclofenac DIIHA and a summary of the pathophysiology and therapeutic options.
Case presentation
A 76-year-old woman presented to the Emergency Department (ED) with recent onset of fatigue. She had a previous medical history of essential arterial hypertension, dyslipidemia, and spinal osteoarthritis with sporadic episodes of lumbosciatic pain. Regular medications initiated several years prior included perindopril 8 mg and rosuvastatin 10 mg. No allergies, alcohol, tobacco, toxins, or animal exposures were known, and she had no other relevant personal or familiar history.
Three weeks before admission the patient had an exacerbation of right lumbosciatic pain. This episode was similar to the previous ones, for which she usually was prescribed oral NSAIDs, acetaminophen, general physical therapy, massages, and rest with complete recovery. However, this time the pain was refractory to general measures, and eight days before admission, she was prescribed a combination of a daily intramuscular administration of 4 mg thiocolchicoside, 75 mg diclofenac, and 5 mg diazepam for a total of six days.
On the fifth day of treatment, she developed generalized malaise, fatigue, nausea, postprandial vomiting, and diarrhea with up to six soft, brownish dejections per day.
Despite resolution of nausea, vomiting, and diarrhea, she experienced progressive worsening of fatigue and was admitted to the ED. Detailed medical history was negative for other symptoms, namely, fever, coluria, acholia, melena, and other evident blood losses, either on admission or in the past.
Physical examination revealed jaundice and pallor of the skin and mucous membranes. No epistaxis, gingivorrhagia, adenopathies, ecchymosis, or other skin lesions were found. Blood pressure was 137/62 mmHg and heart rate was 96 beats per minute, respiratory rate was 16 beats per minute, and peripheral oxygenation saturation was 96%. No fever or other abnormalities were noted.
Blood examination showed normocytic normochromic anemia (hemoglobin: 7.9 g/dL, reference median globular volume: 88 fL), reticulocytosis (9.2%), leucocytosis (white blood cells: 13.8 × 10 9/L), hyperbilirubinemia at the expense of unconjugated bilirubin (total bilirubin: 4.09 mg/dL, conjugated bilirubin: 0.97 mg/dL), elevated lactic dehydrogenase (805 UI/L), and sedimentation rate (VS: 76 mm). Serum iron concentration, ferritin, total iron-binding capacity, folic acid, or vitamin B12 showed no significant changes and haptoglobin levels were undetectable. Peripheral blood smear revealed exuberant erythrocyte rouleaux and spherocytes. The direct antiglobulin test (DAT) was positive for immunoglobulin G (IgG). Chest radiography, abdominal ultrasound, and electrocardiogram performed in the ED were normal.
The hypothesis of AIHA was considered in the ED. The patient was started on 60 mg of prednisolone per day (1 mg/kg/day) and was admitted to the medical ward.
The hypothesis of secondary AIHA to an infectious or a connective tissue disease was ruled out. Gastrointestinal complaints were compatible with side effects of NSAIDs, viral serologies, blood cultures, rheumatoid factor, antinuclear antibody, antineutrophil cytoplasmic antibodies, and cyclic citrullinated peptide antibody were negative, and complement (both C3 and C4 studies) was normal. Lymphoproliferative disease was excluded due to the absence of adenopathies both on physical examination and in imaging studies, as well as normal immunoglobulin levels (IgG, IgM, and IgA) and a normal serum protein electrophoresis. Inflammatory bowel disease and digestive tract tumors were also excluded by endoscopic observation and anatomopathological analysis of biopsies made in macroscopically normal mucosa.
During hospitalization, glucocorticoid therapy was maintained, and folic acid supplementation of 5 mg per day was started. The patient had clinical improvement with resolution of asthenia and jaundice, as well as progressive normalization of the hemoglobin and bilirubin values. On discharge, 13 days after admission, anemia was mild (hemoglobin: 11 g/dL) and no signs of hemolysis were noted. Table 1 shows the laboratory data during hospitalization.
Table 1 Laboratory data during hospitalization.
ALP: alkaline phosphatase; ALT: alanine aminotransferase; ANA: antinuclear antibodies; ANCA: antineutrophil cytoplasmic antibody; anti-CCP: anti-cyclic citrullinated peptides; AST: aspartate aminotransferase; GGT: gamma-glutamyl transferase; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; Ig: immunoglobulin; LDH: lactate dehydrogenase, MCV: mean corpuscular volume, TIBC: total iron binding capacity
Results
Variable Reference range (adults) Day 1 Day 2 Day 5 Day 7 Day 9 Day 13
Hemoglobin (g/dL) 11.8-15.8 7.9 7.8 8.2 9.1 10.3 11
Hematocrit (%) 36.0-46.0 21.9 22.1 24.4 26.7 30.6 33
Red blood cells (106/µL) 4.2-5.4 2.47 2.42 2.48 2.63 2.97 3.14
MCV (fL) 80.4-96.4 88.7 91.3 98.4 101.5 103 105.1
White cell count (103/µL) 4.0-10.0 13.88 12.49 18.09 15.62 11.43 11.82
Differential cell count (103/L)
Neutrophils 1.5-8.0 9.1 8.3 11.448 9.4 5.9 7.2
Lymphocytes 0.8-4.0 3.3 2.7 5.5 5.2 4.7 3.8
Platelet count (103/µL) 150-400 353 353 381 377 392 362
Reticulocytes (%) 0.5-1.5 9.22
Sedimentation rate (mm) 4-10 103 9
C-reactive protein (mg/dL) <0.51 3.23 2.67 0.69 0.41 0.23 0.14
Urea (mg/dL) 17.0-43.0 40 31 39 35 29 33
Creatinine (mg/dL) 0.6-1.0 0.84 0.78 0.8 0.78 0.84 0.79
Sodium (mmol/L) 136-145 140 141 138 143 141 142
Potassium (mmol/L) 3.5-5.1 4.2 4.2 3 3.7 4 3.9
Calcium (mg/dL) 8.6-10.3 8.7
Uric acid (mg/dL) 2.6-6 7
Bilirubin (mg/dL)
Total 0.3-1.2 4.09 4.01 2.16 2.29 2.27 1.28
Direct <0.5 0.07 0.82 0.71 0.75 0.75 0.46
LDH (UI/L) 125-220 805 632 467 436 388 309
ALP (UI/L) 30-120 152 135 96 93 90 76
GGT (UI/L) <38 83 70 55 56 54 43
ALT (UI/L) 7-45 44 19 23 30 31
AST (UI/L) 8-35 30 22 15 21 21 23
Iron (µ/dL) 70-180 124
TIBC (µ/dL) 250-245 300
Folic acid (ng/mL) 2.34-17.56 5.8
Vitamin B12 (pg/mL) 187-883 414
Haptoglobin (mg/dL) 35-250 <8
Direct antiglobulin test Positive for IgG
Protein electrophoresis No monoclonal spikes
Total proteins (g/dL) 6.4-8.2 6.1
Albumin (g/dL) 3.5-5.2 3.6
Immunoglobulins
IgA (mg/dL) 60-400 192
IgG (mg/dL) 70-1,600 1,008
IgM (mg/dL) 40-230 131
ANA Negative
ANCA Negative
Rheumatoid factor Negative
anti-CCP Negative
Serology
HIV Negative
HBV Negative
HCV Negative
Given the acute clinical context after diclofenac intake and absence of evidence for other secondary etiologies, the diagnosis of acquired hemolytic anemia secondary to NSAIDs was made. Follow-up three years later found the patient asymptomatic with no recurrence of anemia or hemolysis.
Discussion
Drugs are generally small molecules unable to elicit an immune response, however, they can function as haptens, bind to larger proteins, become immunogenic, and lead to antibody production. These antibodies can be further classified as drug-induced, drug-dependent, and drug-independent antibodies. Drug-induced antibodies can bind to red blood cells (RBCs) and lead to hemolysis by non-immunological modification of erythrocyte membranes known as adsorption of non-immunological proteins. Drug-dependent antibodies bind to RBCs only in the presence of the drug or its metabolites, causing abrupt complement-mediated intravascular hemolysis. In vitro tests searching for lysis, DAT, or indirect antiglobulin test can be performed to confirm the diagnosis using the offending drug or its metabolites and the patient’s plasma or serum. Drug-independent antibodies can react with RBCs even in the absence of the drug and, therefore, are indistinguishable from autoantibodies mediating warm autoimmune hemolytic anemia (WAIHA) [1,10,11].
WAIHA is named after warm agglutinins, usually IgG autoantibodies, that bind to antigens on erythrocytes at a temperature of 37°C, leading to RBC destruction and a chronic or relapsing disease with an almost pathognomonic positive DAT [2].
Patients are treated with glucocorticoids 1 to 2 mg/kg of body weight/day of prednisone administered orally or an equivalent dose of methylprednisolone administered intravenously. Though most patients recover to an hemoglobin level above 10 g/dL within two to three weeks of treatment, relapse after treatment discontinuation is common, with retrospective case studies suggesting long-term remission rates as low as 20% to 30% [2].
DIIHA is identified by clinical evidence of hemolysis associated with drug therapy. Although many drugs have anedoctally reported isolated cases of DIIHA, over 130 drugs have reasonable evidence that supports an immune etiology [12]. It has been speculated that DIIHA is far more common than previously estimated, as most reports usually refer to more severe cases, either presenting with shock, multiorgan damage, or renal failure, and most mild cases being unreported [6].
Drugs most frequently associated with DIIHA are second and third generation of cephalosporins, diclofenac, oxaliplatin, and fludarabine. In European cohorts where diclofenac is the most frequently used NSAID, case reviews reported diclofenac as the most frequently implicated drug, with a fatal outcome being estimated in 15% to 21% of the reported cases [6,12-16]. Diclofenac-induced immune hemolytic anemia has been demonstrated in few cases, where the exposure to the drug or its metabolites lead to developing both drug-independent IgG autoantibodies and antibodies that reacted with diclofenac and its metabolites [8].
Signs and symptoms of DIIHA, as any other hemolytic anemia, are proportional to the degree and time of onset and can present withing hours to weeks of drug exposure. These include fatigue, dyspnea, and thoracic or abdominal pain. Late symptoms are usually due to complications of decompensated hemolysis, usually shock or renal failure. Laboratory abnormalities include low hemoglobin and haptoglobin levels, elevated lactate dehydrogenase and indirect bilirubin levels, reticulocytosis, and a positive DAT [1,10].
The DAT is positive in all the described forms of DIIHA, either for IgG, C3, or both. Rare cases with negative DAT reported either low antibody density, massive intravascular hemolysis, or red cell transfusion administered prior to testing [1,10]. When approaching a case where there is evidence of hemolysis and an established temporal relationship with a drug known to induce autoantibody production, investigation for drug-dependent antibodies can be performed in adequate laboratory settings, with quality ensured expertise and appropriate controls [1,3].
As there are no defining clinical features and drug-induced autoantibodies are indistinguishable from idiopathic autoantibodies, misdiagnosis in DIIHA is extremely common, with some patients dying because of late diagnosis. Furthermore, hemolysis and serological results can persist for up to months after withdrawal of the drug, leading to erroneous attribution of recovery on the administered treatment and not to the interruption of the drug [6].
If DIIHA is suspected, relevant medication should be withdrawn immediately. In mild cases, recovery usually happens within one to two weeks after drug suspension, with no other necessary measures. As most drugs have a relatively short half-life, even a strong drug-dependent antibody loses its effect shortly after drug suspension [1]. Failure to recognize DIIHA can have disastrous consequences, especially when patients present complaints for which the offending drug was prescribed. Regarding diclofenac DIIHA, some cases have been reported of patients receiving the drug again for “low back pain” during the early onset of hemolysis [9].
In acute severe DIIHA, recommendations suggest close monitoring of clinical and laboratory signs, early intravenous access, and fluid resuscitation. Blood transfusion should not be withheld in patients with severe anemia [3]. Even though crossmatch-compatible blood can be difficult to find, a review of 134 patients showed that 68 (55%) patients received blood transfusions. Though most patients (85%) received glucocorticoids, its benefit is uncertain and its routine use is not recommended as drug eviction is usually enough to stop the immune response [14].
Applying the criteria of the World Health Organization causality assessment method to assess a possible drug‐induced etiology of IHA we are confident the most likely diagnosis for our patient was diclofenac-induced IHA [17]. Our analysis is supported by: (a) the presence of autoantibodies in the patient’s eluate was demonstrated; (b) diclofenac is known to induce DIIHA; (c) there is a chronological relationship between hemolysis and diclofenac administration; (d) a review of the literature failed to show cases of DIIHA induced by any of the other drugs taken by the patient; (e) symptoms and laboratory signs significantly improved after discontinuation of diclofenac; (f) no coexistent neoplastic, autoimmune, or infectious diseases known to be secondary causes of AIHA were found after systematic and comprehensive studies; and (g) though glucocorticoids were started on admission, no recurrence of anemia was verified in a three-year follow-up period, which would be uncommon if the patient suffered from WAIHA.
Conclusions
As a potentially fatal complication of a widely used drug in clinical practice such as diclofenac, early and correct diagnosis of DIIHA and prompt removal of the offending drug is crucial for the patient’s recovery. Our case highlights the need for both prescribing physicians and patients to be aware of this frequently underreported and usually misdiagnosed entity.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
Appendices
Table 2 Causality categories. Adapted from the WHO-UMC system for standardized case causality assessment. The usual approach is to choose one of the causality terms’ categories and to test if the various criteria fit the content of the case report. All assessment criteria should be reasonably complied to assume a category. The WHO-UMC causality assessment system can be used for the assessment of case reports of adverse drug reactions or drug-drug interactions.
WHO-UMC, World Health Organization-Uppsala Monitoring Centre
Causality term Assessment criteria
Certain • Event or laboratory test abnormality, with plausible time relationship to drug intake • Cannot be explained by disease or other drugs • Response to withdrawal plausible (pharmacologically, pathologically) • Event definitive pharmacologically or phenomenologically (i.e., an objective and specific medical disorder or a recognized pharmacological phenomenon) • Rechallenge satisfactory, if necessary
Probable/Likely • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Unlikely to be attributed to disease or other drugs • Response to withdrawal clinically reasonable • Rechallenge not required
Possible • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Could also be explained by disease or other drugs • Information on drug withdrawal may be lacking or unclear
Unlikely • Event or laboratory test abnormality, with a time to drug intake that makes a relationship improbable (but not impossible) • Disease or other drugs provide plausible explanations
Conditional/Unclassified • Event or laboratory test abnormality • More data for proper assessment needed • Additional data under examination
Unassessable/Unclassifiable • Report suggesting an adverse reaction • Cannot be judged because information is insufficient or contradictory • Data cannot be supplemented or verified | Recovered | ReactionOutcome | CC BY | 33654588 | 19,027,243 | 2021-01-25 |
What was the outcome of reaction 'Haemolytic anaemia'? | Diclofenac-Induced Immune Hemolytic Anemia: A Case Report and Review of Literature.
Non-steroidal anti-inflammatory drugs are widely used for pain management. Most frequently, adverse reactions affect the gastrointestinal tract and hematological side effects usually relate to the gastrointestinal manifestations. Drug-induced immune hemolytic anemia is a rare and frequently underdiagnosed complication that is associated with poor outcomes including organ failure and even death. A 76-year-old female patient was treated with intramuscular diclofenac, thiocolchicoside, and diazepam for low back pain. Five days following diclofenac exposure, the patient was admitted to the Emergency Department with complaints of asthenia, nausea, vomiting, and diarrhea. Hemolysis and a positive direct antiglobulin test were detected on laboratory testing. Further causes of hemolytic anemia were excluded and a diagnosis of diclofenac-induced immune hemolytic anemia was established. Glucocorticoid therapy initiated on admission and drug eviction led to complete recovery. Long-term follow-up showed no recurrence of anemia. Here, we present the unusual case of a successful recovery of a 76-year-old patient with diclofenac-induced immune hemolytic anemia, a rare but immediate life-threatening condition of a frequently used drug in clinical practice.
Introduction
Autoimmune hemolytic anemia (AIHA) ensues when the host’s immune system acts against its own red cell antigens and has an estimated prevalence of approximately 1 in 100,000 individuals [1]. Approximately 50% of the cases refer to primary or idiopathic AIHA, where an associated disorder is not found [2]. Secondary causes of AIHA depend on the studied population. Current series estimate that half are associated with hematological malignancy, a third with infection, a sixth with collagen vascular disorders, and a tenth with drug-induced immune hemolytic anemia (DIIHA), the latter reaching an estimated incidence of one per million per year [1,3].
Diclofenac is one of the non-steroidal anti-inflammatory drugs (NSAIDs) most used for the treatment of rheumatoid arthritis and osteoarthritis [4]. Though generally well tolerated, over 400 adverse reactions have been documented. Most frequently, adverse reactions affect the gastrointestinal tract, the skin, and the central nervous system [5]. Direct hematological side effects such as leukopenia, thrombocytopenia, and aplastic anemia have been described only in limited cases [6-9].
We present the case of a 76-year-old patient with diclofenac DIIHA and a summary of the pathophysiology and therapeutic options.
Case presentation
A 76-year-old woman presented to the Emergency Department (ED) with recent onset of fatigue. She had a previous medical history of essential arterial hypertension, dyslipidemia, and spinal osteoarthritis with sporadic episodes of lumbosciatic pain. Regular medications initiated several years prior included perindopril 8 mg and rosuvastatin 10 mg. No allergies, alcohol, tobacco, toxins, or animal exposures were known, and she had no other relevant personal or familiar history.
Three weeks before admission the patient had an exacerbation of right lumbosciatic pain. This episode was similar to the previous ones, for which she usually was prescribed oral NSAIDs, acetaminophen, general physical therapy, massages, and rest with complete recovery. However, this time the pain was refractory to general measures, and eight days before admission, she was prescribed a combination of a daily intramuscular administration of 4 mg thiocolchicoside, 75 mg diclofenac, and 5 mg diazepam for a total of six days.
On the fifth day of treatment, she developed generalized malaise, fatigue, nausea, postprandial vomiting, and diarrhea with up to six soft, brownish dejections per day.
Despite resolution of nausea, vomiting, and diarrhea, she experienced progressive worsening of fatigue and was admitted to the ED. Detailed medical history was negative for other symptoms, namely, fever, coluria, acholia, melena, and other evident blood losses, either on admission or in the past.
Physical examination revealed jaundice and pallor of the skin and mucous membranes. No epistaxis, gingivorrhagia, adenopathies, ecchymosis, or other skin lesions were found. Blood pressure was 137/62 mmHg and heart rate was 96 beats per minute, respiratory rate was 16 beats per minute, and peripheral oxygenation saturation was 96%. No fever or other abnormalities were noted.
Blood examination showed normocytic normochromic anemia (hemoglobin: 7.9 g/dL, reference median globular volume: 88 fL), reticulocytosis (9.2%), leucocytosis (white blood cells: 13.8 × 10 9/L), hyperbilirubinemia at the expense of unconjugated bilirubin (total bilirubin: 4.09 mg/dL, conjugated bilirubin: 0.97 mg/dL), elevated lactic dehydrogenase (805 UI/L), and sedimentation rate (VS: 76 mm). Serum iron concentration, ferritin, total iron-binding capacity, folic acid, or vitamin B12 showed no significant changes and haptoglobin levels were undetectable. Peripheral blood smear revealed exuberant erythrocyte rouleaux and spherocytes. The direct antiglobulin test (DAT) was positive for immunoglobulin G (IgG). Chest radiography, abdominal ultrasound, and electrocardiogram performed in the ED were normal.
The hypothesis of AIHA was considered in the ED. The patient was started on 60 mg of prednisolone per day (1 mg/kg/day) and was admitted to the medical ward.
The hypothesis of secondary AIHA to an infectious or a connective tissue disease was ruled out. Gastrointestinal complaints were compatible with side effects of NSAIDs, viral serologies, blood cultures, rheumatoid factor, antinuclear antibody, antineutrophil cytoplasmic antibodies, and cyclic citrullinated peptide antibody were negative, and complement (both C3 and C4 studies) was normal. Lymphoproliferative disease was excluded due to the absence of adenopathies both on physical examination and in imaging studies, as well as normal immunoglobulin levels (IgG, IgM, and IgA) and a normal serum protein electrophoresis. Inflammatory bowel disease and digestive tract tumors were also excluded by endoscopic observation and anatomopathological analysis of biopsies made in macroscopically normal mucosa.
During hospitalization, glucocorticoid therapy was maintained, and folic acid supplementation of 5 mg per day was started. The patient had clinical improvement with resolution of asthenia and jaundice, as well as progressive normalization of the hemoglobin and bilirubin values. On discharge, 13 days after admission, anemia was mild (hemoglobin: 11 g/dL) and no signs of hemolysis were noted. Table 1 shows the laboratory data during hospitalization.
Table 1 Laboratory data during hospitalization.
ALP: alkaline phosphatase; ALT: alanine aminotransferase; ANA: antinuclear antibodies; ANCA: antineutrophil cytoplasmic antibody; anti-CCP: anti-cyclic citrullinated peptides; AST: aspartate aminotransferase; GGT: gamma-glutamyl transferase; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; Ig: immunoglobulin; LDH: lactate dehydrogenase, MCV: mean corpuscular volume, TIBC: total iron binding capacity
Results
Variable Reference range (adults) Day 1 Day 2 Day 5 Day 7 Day 9 Day 13
Hemoglobin (g/dL) 11.8-15.8 7.9 7.8 8.2 9.1 10.3 11
Hematocrit (%) 36.0-46.0 21.9 22.1 24.4 26.7 30.6 33
Red blood cells (106/µL) 4.2-5.4 2.47 2.42 2.48 2.63 2.97 3.14
MCV (fL) 80.4-96.4 88.7 91.3 98.4 101.5 103 105.1
White cell count (103/µL) 4.0-10.0 13.88 12.49 18.09 15.62 11.43 11.82
Differential cell count (103/L)
Neutrophils 1.5-8.0 9.1 8.3 11.448 9.4 5.9 7.2
Lymphocytes 0.8-4.0 3.3 2.7 5.5 5.2 4.7 3.8
Platelet count (103/µL) 150-400 353 353 381 377 392 362
Reticulocytes (%) 0.5-1.5 9.22
Sedimentation rate (mm) 4-10 103 9
C-reactive protein (mg/dL) <0.51 3.23 2.67 0.69 0.41 0.23 0.14
Urea (mg/dL) 17.0-43.0 40 31 39 35 29 33
Creatinine (mg/dL) 0.6-1.0 0.84 0.78 0.8 0.78 0.84 0.79
Sodium (mmol/L) 136-145 140 141 138 143 141 142
Potassium (mmol/L) 3.5-5.1 4.2 4.2 3 3.7 4 3.9
Calcium (mg/dL) 8.6-10.3 8.7
Uric acid (mg/dL) 2.6-6 7
Bilirubin (mg/dL)
Total 0.3-1.2 4.09 4.01 2.16 2.29 2.27 1.28
Direct <0.5 0.07 0.82 0.71 0.75 0.75 0.46
LDH (UI/L) 125-220 805 632 467 436 388 309
ALP (UI/L) 30-120 152 135 96 93 90 76
GGT (UI/L) <38 83 70 55 56 54 43
ALT (UI/L) 7-45 44 19 23 30 31
AST (UI/L) 8-35 30 22 15 21 21 23
Iron (µ/dL) 70-180 124
TIBC (µ/dL) 250-245 300
Folic acid (ng/mL) 2.34-17.56 5.8
Vitamin B12 (pg/mL) 187-883 414
Haptoglobin (mg/dL) 35-250 <8
Direct antiglobulin test Positive for IgG
Protein electrophoresis No monoclonal spikes
Total proteins (g/dL) 6.4-8.2 6.1
Albumin (g/dL) 3.5-5.2 3.6
Immunoglobulins
IgA (mg/dL) 60-400 192
IgG (mg/dL) 70-1,600 1,008
IgM (mg/dL) 40-230 131
ANA Negative
ANCA Negative
Rheumatoid factor Negative
anti-CCP Negative
Serology
HIV Negative
HBV Negative
HCV Negative
Given the acute clinical context after diclofenac intake and absence of evidence for other secondary etiologies, the diagnosis of acquired hemolytic anemia secondary to NSAIDs was made. Follow-up three years later found the patient asymptomatic with no recurrence of anemia or hemolysis.
Discussion
Drugs are generally small molecules unable to elicit an immune response, however, they can function as haptens, bind to larger proteins, become immunogenic, and lead to antibody production. These antibodies can be further classified as drug-induced, drug-dependent, and drug-independent antibodies. Drug-induced antibodies can bind to red blood cells (RBCs) and lead to hemolysis by non-immunological modification of erythrocyte membranes known as adsorption of non-immunological proteins. Drug-dependent antibodies bind to RBCs only in the presence of the drug or its metabolites, causing abrupt complement-mediated intravascular hemolysis. In vitro tests searching for lysis, DAT, or indirect antiglobulin test can be performed to confirm the diagnosis using the offending drug or its metabolites and the patient’s plasma or serum. Drug-independent antibodies can react with RBCs even in the absence of the drug and, therefore, are indistinguishable from autoantibodies mediating warm autoimmune hemolytic anemia (WAIHA) [1,10,11].
WAIHA is named after warm agglutinins, usually IgG autoantibodies, that bind to antigens on erythrocytes at a temperature of 37°C, leading to RBC destruction and a chronic or relapsing disease with an almost pathognomonic positive DAT [2].
Patients are treated with glucocorticoids 1 to 2 mg/kg of body weight/day of prednisone administered orally or an equivalent dose of methylprednisolone administered intravenously. Though most patients recover to an hemoglobin level above 10 g/dL within two to three weeks of treatment, relapse after treatment discontinuation is common, with retrospective case studies suggesting long-term remission rates as low as 20% to 30% [2].
DIIHA is identified by clinical evidence of hemolysis associated with drug therapy. Although many drugs have anedoctally reported isolated cases of DIIHA, over 130 drugs have reasonable evidence that supports an immune etiology [12]. It has been speculated that DIIHA is far more common than previously estimated, as most reports usually refer to more severe cases, either presenting with shock, multiorgan damage, or renal failure, and most mild cases being unreported [6].
Drugs most frequently associated with DIIHA are second and third generation of cephalosporins, diclofenac, oxaliplatin, and fludarabine. In European cohorts where diclofenac is the most frequently used NSAID, case reviews reported diclofenac as the most frequently implicated drug, with a fatal outcome being estimated in 15% to 21% of the reported cases [6,12-16]. Diclofenac-induced immune hemolytic anemia has been demonstrated in few cases, where the exposure to the drug or its metabolites lead to developing both drug-independent IgG autoantibodies and antibodies that reacted with diclofenac and its metabolites [8].
Signs and symptoms of DIIHA, as any other hemolytic anemia, are proportional to the degree and time of onset and can present withing hours to weeks of drug exposure. These include fatigue, dyspnea, and thoracic or abdominal pain. Late symptoms are usually due to complications of decompensated hemolysis, usually shock or renal failure. Laboratory abnormalities include low hemoglobin and haptoglobin levels, elevated lactate dehydrogenase and indirect bilirubin levels, reticulocytosis, and a positive DAT [1,10].
The DAT is positive in all the described forms of DIIHA, either for IgG, C3, or both. Rare cases with negative DAT reported either low antibody density, massive intravascular hemolysis, or red cell transfusion administered prior to testing [1,10]. When approaching a case where there is evidence of hemolysis and an established temporal relationship with a drug known to induce autoantibody production, investigation for drug-dependent antibodies can be performed in adequate laboratory settings, with quality ensured expertise and appropriate controls [1,3].
As there are no defining clinical features and drug-induced autoantibodies are indistinguishable from idiopathic autoantibodies, misdiagnosis in DIIHA is extremely common, with some patients dying because of late diagnosis. Furthermore, hemolysis and serological results can persist for up to months after withdrawal of the drug, leading to erroneous attribution of recovery on the administered treatment and not to the interruption of the drug [6].
If DIIHA is suspected, relevant medication should be withdrawn immediately. In mild cases, recovery usually happens within one to two weeks after drug suspension, with no other necessary measures. As most drugs have a relatively short half-life, even a strong drug-dependent antibody loses its effect shortly after drug suspension [1]. Failure to recognize DIIHA can have disastrous consequences, especially when patients present complaints for which the offending drug was prescribed. Regarding diclofenac DIIHA, some cases have been reported of patients receiving the drug again for “low back pain” during the early onset of hemolysis [9].
In acute severe DIIHA, recommendations suggest close monitoring of clinical and laboratory signs, early intravenous access, and fluid resuscitation. Blood transfusion should not be withheld in patients with severe anemia [3]. Even though crossmatch-compatible blood can be difficult to find, a review of 134 patients showed that 68 (55%) patients received blood transfusions. Though most patients (85%) received glucocorticoids, its benefit is uncertain and its routine use is not recommended as drug eviction is usually enough to stop the immune response [14].
Applying the criteria of the World Health Organization causality assessment method to assess a possible drug‐induced etiology of IHA we are confident the most likely diagnosis for our patient was diclofenac-induced IHA [17]. Our analysis is supported by: (a) the presence of autoantibodies in the patient’s eluate was demonstrated; (b) diclofenac is known to induce DIIHA; (c) there is a chronological relationship between hemolysis and diclofenac administration; (d) a review of the literature failed to show cases of DIIHA induced by any of the other drugs taken by the patient; (e) symptoms and laboratory signs significantly improved after discontinuation of diclofenac; (f) no coexistent neoplastic, autoimmune, or infectious diseases known to be secondary causes of AIHA were found after systematic and comprehensive studies; and (g) though glucocorticoids were started on admission, no recurrence of anemia was verified in a three-year follow-up period, which would be uncommon if the patient suffered from WAIHA.
Conclusions
As a potentially fatal complication of a widely used drug in clinical practice such as diclofenac, early and correct diagnosis of DIIHA and prompt removal of the offending drug is crucial for the patient’s recovery. Our case highlights the need for both prescribing physicians and patients to be aware of this frequently underreported and usually misdiagnosed entity.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
Appendices
Table 2 Causality categories. Adapted from the WHO-UMC system for standardized case causality assessment. The usual approach is to choose one of the causality terms’ categories and to test if the various criteria fit the content of the case report. All assessment criteria should be reasonably complied to assume a category. The WHO-UMC causality assessment system can be used for the assessment of case reports of adverse drug reactions or drug-drug interactions.
WHO-UMC, World Health Organization-Uppsala Monitoring Centre
Causality term Assessment criteria
Certain • Event or laboratory test abnormality, with plausible time relationship to drug intake • Cannot be explained by disease or other drugs • Response to withdrawal plausible (pharmacologically, pathologically) • Event definitive pharmacologically or phenomenologically (i.e., an objective and specific medical disorder or a recognized pharmacological phenomenon) • Rechallenge satisfactory, if necessary
Probable/Likely • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Unlikely to be attributed to disease or other drugs • Response to withdrawal clinically reasonable • Rechallenge not required
Possible • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Could also be explained by disease or other drugs • Information on drug withdrawal may be lacking or unclear
Unlikely • Event or laboratory test abnormality, with a time to drug intake that makes a relationship improbable (but not impossible) • Disease or other drugs provide plausible explanations
Conditional/Unclassified • Event or laboratory test abnormality • More data for proper assessment needed • Additional data under examination
Unassessable/Unclassifiable • Report suggesting an adverse reaction • Cannot be judged because information is insufficient or contradictory • Data cannot be supplemented or verified | Recovered | ReactionOutcome | CC BY | 33654588 | 19,027,243 | 2021-01-25 |
What was the outcome of reaction 'Jaundice'? | Diclofenac-Induced Immune Hemolytic Anemia: A Case Report and Review of Literature.
Non-steroidal anti-inflammatory drugs are widely used for pain management. Most frequently, adverse reactions affect the gastrointestinal tract and hematological side effects usually relate to the gastrointestinal manifestations. Drug-induced immune hemolytic anemia is a rare and frequently underdiagnosed complication that is associated with poor outcomes including organ failure and even death. A 76-year-old female patient was treated with intramuscular diclofenac, thiocolchicoside, and diazepam for low back pain. Five days following diclofenac exposure, the patient was admitted to the Emergency Department with complaints of asthenia, nausea, vomiting, and diarrhea. Hemolysis and a positive direct antiglobulin test were detected on laboratory testing. Further causes of hemolytic anemia were excluded and a diagnosis of diclofenac-induced immune hemolytic anemia was established. Glucocorticoid therapy initiated on admission and drug eviction led to complete recovery. Long-term follow-up showed no recurrence of anemia. Here, we present the unusual case of a successful recovery of a 76-year-old patient with diclofenac-induced immune hemolytic anemia, a rare but immediate life-threatening condition of a frequently used drug in clinical practice.
Introduction
Autoimmune hemolytic anemia (AIHA) ensues when the host’s immune system acts against its own red cell antigens and has an estimated prevalence of approximately 1 in 100,000 individuals [1]. Approximately 50% of the cases refer to primary or idiopathic AIHA, where an associated disorder is not found [2]. Secondary causes of AIHA depend on the studied population. Current series estimate that half are associated with hematological malignancy, a third with infection, a sixth with collagen vascular disorders, and a tenth with drug-induced immune hemolytic anemia (DIIHA), the latter reaching an estimated incidence of one per million per year [1,3].
Diclofenac is one of the non-steroidal anti-inflammatory drugs (NSAIDs) most used for the treatment of rheumatoid arthritis and osteoarthritis [4]. Though generally well tolerated, over 400 adverse reactions have been documented. Most frequently, adverse reactions affect the gastrointestinal tract, the skin, and the central nervous system [5]. Direct hematological side effects such as leukopenia, thrombocytopenia, and aplastic anemia have been described only in limited cases [6-9].
We present the case of a 76-year-old patient with diclofenac DIIHA and a summary of the pathophysiology and therapeutic options.
Case presentation
A 76-year-old woman presented to the Emergency Department (ED) with recent onset of fatigue. She had a previous medical history of essential arterial hypertension, dyslipidemia, and spinal osteoarthritis with sporadic episodes of lumbosciatic pain. Regular medications initiated several years prior included perindopril 8 mg and rosuvastatin 10 mg. No allergies, alcohol, tobacco, toxins, or animal exposures were known, and she had no other relevant personal or familiar history.
Three weeks before admission the patient had an exacerbation of right lumbosciatic pain. This episode was similar to the previous ones, for which she usually was prescribed oral NSAIDs, acetaminophen, general physical therapy, massages, and rest with complete recovery. However, this time the pain was refractory to general measures, and eight days before admission, she was prescribed a combination of a daily intramuscular administration of 4 mg thiocolchicoside, 75 mg diclofenac, and 5 mg diazepam for a total of six days.
On the fifth day of treatment, she developed generalized malaise, fatigue, nausea, postprandial vomiting, and diarrhea with up to six soft, brownish dejections per day.
Despite resolution of nausea, vomiting, and diarrhea, she experienced progressive worsening of fatigue and was admitted to the ED. Detailed medical history was negative for other symptoms, namely, fever, coluria, acholia, melena, and other evident blood losses, either on admission or in the past.
Physical examination revealed jaundice and pallor of the skin and mucous membranes. No epistaxis, gingivorrhagia, adenopathies, ecchymosis, or other skin lesions were found. Blood pressure was 137/62 mmHg and heart rate was 96 beats per minute, respiratory rate was 16 beats per minute, and peripheral oxygenation saturation was 96%. No fever or other abnormalities were noted.
Blood examination showed normocytic normochromic anemia (hemoglobin: 7.9 g/dL, reference median globular volume: 88 fL), reticulocytosis (9.2%), leucocytosis (white blood cells: 13.8 × 10 9/L), hyperbilirubinemia at the expense of unconjugated bilirubin (total bilirubin: 4.09 mg/dL, conjugated bilirubin: 0.97 mg/dL), elevated lactic dehydrogenase (805 UI/L), and sedimentation rate (VS: 76 mm). Serum iron concentration, ferritin, total iron-binding capacity, folic acid, or vitamin B12 showed no significant changes and haptoglobin levels were undetectable. Peripheral blood smear revealed exuberant erythrocyte rouleaux and spherocytes. The direct antiglobulin test (DAT) was positive for immunoglobulin G (IgG). Chest radiography, abdominal ultrasound, and electrocardiogram performed in the ED were normal.
The hypothesis of AIHA was considered in the ED. The patient was started on 60 mg of prednisolone per day (1 mg/kg/day) and was admitted to the medical ward.
The hypothesis of secondary AIHA to an infectious or a connective tissue disease was ruled out. Gastrointestinal complaints were compatible with side effects of NSAIDs, viral serologies, blood cultures, rheumatoid factor, antinuclear antibody, antineutrophil cytoplasmic antibodies, and cyclic citrullinated peptide antibody were negative, and complement (both C3 and C4 studies) was normal. Lymphoproliferative disease was excluded due to the absence of adenopathies both on physical examination and in imaging studies, as well as normal immunoglobulin levels (IgG, IgM, and IgA) and a normal serum protein electrophoresis. Inflammatory bowel disease and digestive tract tumors were also excluded by endoscopic observation and anatomopathological analysis of biopsies made in macroscopically normal mucosa.
During hospitalization, glucocorticoid therapy was maintained, and folic acid supplementation of 5 mg per day was started. The patient had clinical improvement with resolution of asthenia and jaundice, as well as progressive normalization of the hemoglobin and bilirubin values. On discharge, 13 days after admission, anemia was mild (hemoglobin: 11 g/dL) and no signs of hemolysis were noted. Table 1 shows the laboratory data during hospitalization.
Table 1 Laboratory data during hospitalization.
ALP: alkaline phosphatase; ALT: alanine aminotransferase; ANA: antinuclear antibodies; ANCA: antineutrophil cytoplasmic antibody; anti-CCP: anti-cyclic citrullinated peptides; AST: aspartate aminotransferase; GGT: gamma-glutamyl transferase; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; Ig: immunoglobulin; LDH: lactate dehydrogenase, MCV: mean corpuscular volume, TIBC: total iron binding capacity
Results
Variable Reference range (adults) Day 1 Day 2 Day 5 Day 7 Day 9 Day 13
Hemoglobin (g/dL) 11.8-15.8 7.9 7.8 8.2 9.1 10.3 11
Hematocrit (%) 36.0-46.0 21.9 22.1 24.4 26.7 30.6 33
Red blood cells (106/µL) 4.2-5.4 2.47 2.42 2.48 2.63 2.97 3.14
MCV (fL) 80.4-96.4 88.7 91.3 98.4 101.5 103 105.1
White cell count (103/µL) 4.0-10.0 13.88 12.49 18.09 15.62 11.43 11.82
Differential cell count (103/L)
Neutrophils 1.5-8.0 9.1 8.3 11.448 9.4 5.9 7.2
Lymphocytes 0.8-4.0 3.3 2.7 5.5 5.2 4.7 3.8
Platelet count (103/µL) 150-400 353 353 381 377 392 362
Reticulocytes (%) 0.5-1.5 9.22
Sedimentation rate (mm) 4-10 103 9
C-reactive protein (mg/dL) <0.51 3.23 2.67 0.69 0.41 0.23 0.14
Urea (mg/dL) 17.0-43.0 40 31 39 35 29 33
Creatinine (mg/dL) 0.6-1.0 0.84 0.78 0.8 0.78 0.84 0.79
Sodium (mmol/L) 136-145 140 141 138 143 141 142
Potassium (mmol/L) 3.5-5.1 4.2 4.2 3 3.7 4 3.9
Calcium (mg/dL) 8.6-10.3 8.7
Uric acid (mg/dL) 2.6-6 7
Bilirubin (mg/dL)
Total 0.3-1.2 4.09 4.01 2.16 2.29 2.27 1.28
Direct <0.5 0.07 0.82 0.71 0.75 0.75 0.46
LDH (UI/L) 125-220 805 632 467 436 388 309
ALP (UI/L) 30-120 152 135 96 93 90 76
GGT (UI/L) <38 83 70 55 56 54 43
ALT (UI/L) 7-45 44 19 23 30 31
AST (UI/L) 8-35 30 22 15 21 21 23
Iron (µ/dL) 70-180 124
TIBC (µ/dL) 250-245 300
Folic acid (ng/mL) 2.34-17.56 5.8
Vitamin B12 (pg/mL) 187-883 414
Haptoglobin (mg/dL) 35-250 <8
Direct antiglobulin test Positive for IgG
Protein electrophoresis No monoclonal spikes
Total proteins (g/dL) 6.4-8.2 6.1
Albumin (g/dL) 3.5-5.2 3.6
Immunoglobulins
IgA (mg/dL) 60-400 192
IgG (mg/dL) 70-1,600 1,008
IgM (mg/dL) 40-230 131
ANA Negative
ANCA Negative
Rheumatoid factor Negative
anti-CCP Negative
Serology
HIV Negative
HBV Negative
HCV Negative
Given the acute clinical context after diclofenac intake and absence of evidence for other secondary etiologies, the diagnosis of acquired hemolytic anemia secondary to NSAIDs was made. Follow-up three years later found the patient asymptomatic with no recurrence of anemia or hemolysis.
Discussion
Drugs are generally small molecules unable to elicit an immune response, however, they can function as haptens, bind to larger proteins, become immunogenic, and lead to antibody production. These antibodies can be further classified as drug-induced, drug-dependent, and drug-independent antibodies. Drug-induced antibodies can bind to red blood cells (RBCs) and lead to hemolysis by non-immunological modification of erythrocyte membranes known as adsorption of non-immunological proteins. Drug-dependent antibodies bind to RBCs only in the presence of the drug or its metabolites, causing abrupt complement-mediated intravascular hemolysis. In vitro tests searching for lysis, DAT, or indirect antiglobulin test can be performed to confirm the diagnosis using the offending drug or its metabolites and the patient’s plasma or serum. Drug-independent antibodies can react with RBCs even in the absence of the drug and, therefore, are indistinguishable from autoantibodies mediating warm autoimmune hemolytic anemia (WAIHA) [1,10,11].
WAIHA is named after warm agglutinins, usually IgG autoantibodies, that bind to antigens on erythrocytes at a temperature of 37°C, leading to RBC destruction and a chronic or relapsing disease with an almost pathognomonic positive DAT [2].
Patients are treated with glucocorticoids 1 to 2 mg/kg of body weight/day of prednisone administered orally or an equivalent dose of methylprednisolone administered intravenously. Though most patients recover to an hemoglobin level above 10 g/dL within two to three weeks of treatment, relapse after treatment discontinuation is common, with retrospective case studies suggesting long-term remission rates as low as 20% to 30% [2].
DIIHA is identified by clinical evidence of hemolysis associated with drug therapy. Although many drugs have anedoctally reported isolated cases of DIIHA, over 130 drugs have reasonable evidence that supports an immune etiology [12]. It has been speculated that DIIHA is far more common than previously estimated, as most reports usually refer to more severe cases, either presenting with shock, multiorgan damage, or renal failure, and most mild cases being unreported [6].
Drugs most frequently associated with DIIHA are second and third generation of cephalosporins, diclofenac, oxaliplatin, and fludarabine. In European cohorts where diclofenac is the most frequently used NSAID, case reviews reported diclofenac as the most frequently implicated drug, with a fatal outcome being estimated in 15% to 21% of the reported cases [6,12-16]. Diclofenac-induced immune hemolytic anemia has been demonstrated in few cases, where the exposure to the drug or its metabolites lead to developing both drug-independent IgG autoantibodies and antibodies that reacted with diclofenac and its metabolites [8].
Signs and symptoms of DIIHA, as any other hemolytic anemia, are proportional to the degree and time of onset and can present withing hours to weeks of drug exposure. These include fatigue, dyspnea, and thoracic or abdominal pain. Late symptoms are usually due to complications of decompensated hemolysis, usually shock or renal failure. Laboratory abnormalities include low hemoglobin and haptoglobin levels, elevated lactate dehydrogenase and indirect bilirubin levels, reticulocytosis, and a positive DAT [1,10].
The DAT is positive in all the described forms of DIIHA, either for IgG, C3, or both. Rare cases with negative DAT reported either low antibody density, massive intravascular hemolysis, or red cell transfusion administered prior to testing [1,10]. When approaching a case where there is evidence of hemolysis and an established temporal relationship with a drug known to induce autoantibody production, investigation for drug-dependent antibodies can be performed in adequate laboratory settings, with quality ensured expertise and appropriate controls [1,3].
As there are no defining clinical features and drug-induced autoantibodies are indistinguishable from idiopathic autoantibodies, misdiagnosis in DIIHA is extremely common, with some patients dying because of late diagnosis. Furthermore, hemolysis and serological results can persist for up to months after withdrawal of the drug, leading to erroneous attribution of recovery on the administered treatment and not to the interruption of the drug [6].
If DIIHA is suspected, relevant medication should be withdrawn immediately. In mild cases, recovery usually happens within one to two weeks after drug suspension, with no other necessary measures. As most drugs have a relatively short half-life, even a strong drug-dependent antibody loses its effect shortly after drug suspension [1]. Failure to recognize DIIHA can have disastrous consequences, especially when patients present complaints for which the offending drug was prescribed. Regarding diclofenac DIIHA, some cases have been reported of patients receiving the drug again for “low back pain” during the early onset of hemolysis [9].
In acute severe DIIHA, recommendations suggest close monitoring of clinical and laboratory signs, early intravenous access, and fluid resuscitation. Blood transfusion should not be withheld in patients with severe anemia [3]. Even though crossmatch-compatible blood can be difficult to find, a review of 134 patients showed that 68 (55%) patients received blood transfusions. Though most patients (85%) received glucocorticoids, its benefit is uncertain and its routine use is not recommended as drug eviction is usually enough to stop the immune response [14].
Applying the criteria of the World Health Organization causality assessment method to assess a possible drug‐induced etiology of IHA we are confident the most likely diagnosis for our patient was diclofenac-induced IHA [17]. Our analysis is supported by: (a) the presence of autoantibodies in the patient’s eluate was demonstrated; (b) diclofenac is known to induce DIIHA; (c) there is a chronological relationship between hemolysis and diclofenac administration; (d) a review of the literature failed to show cases of DIIHA induced by any of the other drugs taken by the patient; (e) symptoms and laboratory signs significantly improved after discontinuation of diclofenac; (f) no coexistent neoplastic, autoimmune, or infectious diseases known to be secondary causes of AIHA were found after systematic and comprehensive studies; and (g) though glucocorticoids were started on admission, no recurrence of anemia was verified in a three-year follow-up period, which would be uncommon if the patient suffered from WAIHA.
Conclusions
As a potentially fatal complication of a widely used drug in clinical practice such as diclofenac, early and correct diagnosis of DIIHA and prompt removal of the offending drug is crucial for the patient’s recovery. Our case highlights the need for both prescribing physicians and patients to be aware of this frequently underreported and usually misdiagnosed entity.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
Appendices
Table 2 Causality categories. Adapted from the WHO-UMC system for standardized case causality assessment. The usual approach is to choose one of the causality terms’ categories and to test if the various criteria fit the content of the case report. All assessment criteria should be reasonably complied to assume a category. The WHO-UMC causality assessment system can be used for the assessment of case reports of adverse drug reactions or drug-drug interactions.
WHO-UMC, World Health Organization-Uppsala Monitoring Centre
Causality term Assessment criteria
Certain • Event or laboratory test abnormality, with plausible time relationship to drug intake • Cannot be explained by disease or other drugs • Response to withdrawal plausible (pharmacologically, pathologically) • Event definitive pharmacologically or phenomenologically (i.e., an objective and specific medical disorder or a recognized pharmacological phenomenon) • Rechallenge satisfactory, if necessary
Probable/Likely • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Unlikely to be attributed to disease or other drugs • Response to withdrawal clinically reasonable • Rechallenge not required
Possible • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Could also be explained by disease or other drugs • Information on drug withdrawal may be lacking or unclear
Unlikely • Event or laboratory test abnormality, with a time to drug intake that makes a relationship improbable (but not impossible) • Disease or other drugs provide plausible explanations
Conditional/Unclassified • Event or laboratory test abnormality • More data for proper assessment needed • Additional data under examination
Unassessable/Unclassifiable • Report suggesting an adverse reaction • Cannot be judged because information is insufficient or contradictory • Data cannot be supplemented or verified | Recovered | ReactionOutcome | CC BY | 33654588 | 19,027,243 | 2021-01-25 |
What was the outcome of reaction 'Malaise'? | Diclofenac-Induced Immune Hemolytic Anemia: A Case Report and Review of Literature.
Non-steroidal anti-inflammatory drugs are widely used for pain management. Most frequently, adverse reactions affect the gastrointestinal tract and hematological side effects usually relate to the gastrointestinal manifestations. Drug-induced immune hemolytic anemia is a rare and frequently underdiagnosed complication that is associated with poor outcomes including organ failure and even death. A 76-year-old female patient was treated with intramuscular diclofenac, thiocolchicoside, and diazepam for low back pain. Five days following diclofenac exposure, the patient was admitted to the Emergency Department with complaints of asthenia, nausea, vomiting, and diarrhea. Hemolysis and a positive direct antiglobulin test were detected on laboratory testing. Further causes of hemolytic anemia were excluded and a diagnosis of diclofenac-induced immune hemolytic anemia was established. Glucocorticoid therapy initiated on admission and drug eviction led to complete recovery. Long-term follow-up showed no recurrence of anemia. Here, we present the unusual case of a successful recovery of a 76-year-old patient with diclofenac-induced immune hemolytic anemia, a rare but immediate life-threatening condition of a frequently used drug in clinical practice.
Introduction
Autoimmune hemolytic anemia (AIHA) ensues when the host’s immune system acts against its own red cell antigens and has an estimated prevalence of approximately 1 in 100,000 individuals [1]. Approximately 50% of the cases refer to primary or idiopathic AIHA, where an associated disorder is not found [2]. Secondary causes of AIHA depend on the studied population. Current series estimate that half are associated with hematological malignancy, a third with infection, a sixth with collagen vascular disorders, and a tenth with drug-induced immune hemolytic anemia (DIIHA), the latter reaching an estimated incidence of one per million per year [1,3].
Diclofenac is one of the non-steroidal anti-inflammatory drugs (NSAIDs) most used for the treatment of rheumatoid arthritis and osteoarthritis [4]. Though generally well tolerated, over 400 adverse reactions have been documented. Most frequently, adverse reactions affect the gastrointestinal tract, the skin, and the central nervous system [5]. Direct hematological side effects such as leukopenia, thrombocytopenia, and aplastic anemia have been described only in limited cases [6-9].
We present the case of a 76-year-old patient with diclofenac DIIHA and a summary of the pathophysiology and therapeutic options.
Case presentation
A 76-year-old woman presented to the Emergency Department (ED) with recent onset of fatigue. She had a previous medical history of essential arterial hypertension, dyslipidemia, and spinal osteoarthritis with sporadic episodes of lumbosciatic pain. Regular medications initiated several years prior included perindopril 8 mg and rosuvastatin 10 mg. No allergies, alcohol, tobacco, toxins, or animal exposures were known, and she had no other relevant personal or familiar history.
Three weeks before admission the patient had an exacerbation of right lumbosciatic pain. This episode was similar to the previous ones, for which she usually was prescribed oral NSAIDs, acetaminophen, general physical therapy, massages, and rest with complete recovery. However, this time the pain was refractory to general measures, and eight days before admission, she was prescribed a combination of a daily intramuscular administration of 4 mg thiocolchicoside, 75 mg diclofenac, and 5 mg diazepam for a total of six days.
On the fifth day of treatment, she developed generalized malaise, fatigue, nausea, postprandial vomiting, and diarrhea with up to six soft, brownish dejections per day.
Despite resolution of nausea, vomiting, and diarrhea, she experienced progressive worsening of fatigue and was admitted to the ED. Detailed medical history was negative for other symptoms, namely, fever, coluria, acholia, melena, and other evident blood losses, either on admission or in the past.
Physical examination revealed jaundice and pallor of the skin and mucous membranes. No epistaxis, gingivorrhagia, adenopathies, ecchymosis, or other skin lesions were found. Blood pressure was 137/62 mmHg and heart rate was 96 beats per minute, respiratory rate was 16 beats per minute, and peripheral oxygenation saturation was 96%. No fever or other abnormalities were noted.
Blood examination showed normocytic normochromic anemia (hemoglobin: 7.9 g/dL, reference median globular volume: 88 fL), reticulocytosis (9.2%), leucocytosis (white blood cells: 13.8 × 10 9/L), hyperbilirubinemia at the expense of unconjugated bilirubin (total bilirubin: 4.09 mg/dL, conjugated bilirubin: 0.97 mg/dL), elevated lactic dehydrogenase (805 UI/L), and sedimentation rate (VS: 76 mm). Serum iron concentration, ferritin, total iron-binding capacity, folic acid, or vitamin B12 showed no significant changes and haptoglobin levels were undetectable. Peripheral blood smear revealed exuberant erythrocyte rouleaux and spherocytes. The direct antiglobulin test (DAT) was positive for immunoglobulin G (IgG). Chest radiography, abdominal ultrasound, and electrocardiogram performed in the ED were normal.
The hypothesis of AIHA was considered in the ED. The patient was started on 60 mg of prednisolone per day (1 mg/kg/day) and was admitted to the medical ward.
The hypothesis of secondary AIHA to an infectious or a connective tissue disease was ruled out. Gastrointestinal complaints were compatible with side effects of NSAIDs, viral serologies, blood cultures, rheumatoid factor, antinuclear antibody, antineutrophil cytoplasmic antibodies, and cyclic citrullinated peptide antibody were negative, and complement (both C3 and C4 studies) was normal. Lymphoproliferative disease was excluded due to the absence of adenopathies both on physical examination and in imaging studies, as well as normal immunoglobulin levels (IgG, IgM, and IgA) and a normal serum protein electrophoresis. Inflammatory bowel disease and digestive tract tumors were also excluded by endoscopic observation and anatomopathological analysis of biopsies made in macroscopically normal mucosa.
During hospitalization, glucocorticoid therapy was maintained, and folic acid supplementation of 5 mg per day was started. The patient had clinical improvement with resolution of asthenia and jaundice, as well as progressive normalization of the hemoglobin and bilirubin values. On discharge, 13 days after admission, anemia was mild (hemoglobin: 11 g/dL) and no signs of hemolysis were noted. Table 1 shows the laboratory data during hospitalization.
Table 1 Laboratory data during hospitalization.
ALP: alkaline phosphatase; ALT: alanine aminotransferase; ANA: antinuclear antibodies; ANCA: antineutrophil cytoplasmic antibody; anti-CCP: anti-cyclic citrullinated peptides; AST: aspartate aminotransferase; GGT: gamma-glutamyl transferase; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; Ig: immunoglobulin; LDH: lactate dehydrogenase, MCV: mean corpuscular volume, TIBC: total iron binding capacity
Results
Variable Reference range (adults) Day 1 Day 2 Day 5 Day 7 Day 9 Day 13
Hemoglobin (g/dL) 11.8-15.8 7.9 7.8 8.2 9.1 10.3 11
Hematocrit (%) 36.0-46.0 21.9 22.1 24.4 26.7 30.6 33
Red blood cells (106/µL) 4.2-5.4 2.47 2.42 2.48 2.63 2.97 3.14
MCV (fL) 80.4-96.4 88.7 91.3 98.4 101.5 103 105.1
White cell count (103/µL) 4.0-10.0 13.88 12.49 18.09 15.62 11.43 11.82
Differential cell count (103/L)
Neutrophils 1.5-8.0 9.1 8.3 11.448 9.4 5.9 7.2
Lymphocytes 0.8-4.0 3.3 2.7 5.5 5.2 4.7 3.8
Platelet count (103/µL) 150-400 353 353 381 377 392 362
Reticulocytes (%) 0.5-1.5 9.22
Sedimentation rate (mm) 4-10 103 9
C-reactive protein (mg/dL) <0.51 3.23 2.67 0.69 0.41 0.23 0.14
Urea (mg/dL) 17.0-43.0 40 31 39 35 29 33
Creatinine (mg/dL) 0.6-1.0 0.84 0.78 0.8 0.78 0.84 0.79
Sodium (mmol/L) 136-145 140 141 138 143 141 142
Potassium (mmol/L) 3.5-5.1 4.2 4.2 3 3.7 4 3.9
Calcium (mg/dL) 8.6-10.3 8.7
Uric acid (mg/dL) 2.6-6 7
Bilirubin (mg/dL)
Total 0.3-1.2 4.09 4.01 2.16 2.29 2.27 1.28
Direct <0.5 0.07 0.82 0.71 0.75 0.75 0.46
LDH (UI/L) 125-220 805 632 467 436 388 309
ALP (UI/L) 30-120 152 135 96 93 90 76
GGT (UI/L) <38 83 70 55 56 54 43
ALT (UI/L) 7-45 44 19 23 30 31
AST (UI/L) 8-35 30 22 15 21 21 23
Iron (µ/dL) 70-180 124
TIBC (µ/dL) 250-245 300
Folic acid (ng/mL) 2.34-17.56 5.8
Vitamin B12 (pg/mL) 187-883 414
Haptoglobin (mg/dL) 35-250 <8
Direct antiglobulin test Positive for IgG
Protein electrophoresis No monoclonal spikes
Total proteins (g/dL) 6.4-8.2 6.1
Albumin (g/dL) 3.5-5.2 3.6
Immunoglobulins
IgA (mg/dL) 60-400 192
IgG (mg/dL) 70-1,600 1,008
IgM (mg/dL) 40-230 131
ANA Negative
ANCA Negative
Rheumatoid factor Negative
anti-CCP Negative
Serology
HIV Negative
HBV Negative
HCV Negative
Given the acute clinical context after diclofenac intake and absence of evidence for other secondary etiologies, the diagnosis of acquired hemolytic anemia secondary to NSAIDs was made. Follow-up three years later found the patient asymptomatic with no recurrence of anemia or hemolysis.
Discussion
Drugs are generally small molecules unable to elicit an immune response, however, they can function as haptens, bind to larger proteins, become immunogenic, and lead to antibody production. These antibodies can be further classified as drug-induced, drug-dependent, and drug-independent antibodies. Drug-induced antibodies can bind to red blood cells (RBCs) and lead to hemolysis by non-immunological modification of erythrocyte membranes known as adsorption of non-immunological proteins. Drug-dependent antibodies bind to RBCs only in the presence of the drug or its metabolites, causing abrupt complement-mediated intravascular hemolysis. In vitro tests searching for lysis, DAT, or indirect antiglobulin test can be performed to confirm the diagnosis using the offending drug or its metabolites and the patient’s plasma or serum. Drug-independent antibodies can react with RBCs even in the absence of the drug and, therefore, are indistinguishable from autoantibodies mediating warm autoimmune hemolytic anemia (WAIHA) [1,10,11].
WAIHA is named after warm agglutinins, usually IgG autoantibodies, that bind to antigens on erythrocytes at a temperature of 37°C, leading to RBC destruction and a chronic or relapsing disease with an almost pathognomonic positive DAT [2].
Patients are treated with glucocorticoids 1 to 2 mg/kg of body weight/day of prednisone administered orally or an equivalent dose of methylprednisolone administered intravenously. Though most patients recover to an hemoglobin level above 10 g/dL within two to three weeks of treatment, relapse after treatment discontinuation is common, with retrospective case studies suggesting long-term remission rates as low as 20% to 30% [2].
DIIHA is identified by clinical evidence of hemolysis associated with drug therapy. Although many drugs have anedoctally reported isolated cases of DIIHA, over 130 drugs have reasonable evidence that supports an immune etiology [12]. It has been speculated that DIIHA is far more common than previously estimated, as most reports usually refer to more severe cases, either presenting with shock, multiorgan damage, or renal failure, and most mild cases being unreported [6].
Drugs most frequently associated with DIIHA are second and third generation of cephalosporins, diclofenac, oxaliplatin, and fludarabine. In European cohorts where diclofenac is the most frequently used NSAID, case reviews reported diclofenac as the most frequently implicated drug, with a fatal outcome being estimated in 15% to 21% of the reported cases [6,12-16]. Diclofenac-induced immune hemolytic anemia has been demonstrated in few cases, where the exposure to the drug or its metabolites lead to developing both drug-independent IgG autoantibodies and antibodies that reacted with diclofenac and its metabolites [8].
Signs and symptoms of DIIHA, as any other hemolytic anemia, are proportional to the degree and time of onset and can present withing hours to weeks of drug exposure. These include fatigue, dyspnea, and thoracic or abdominal pain. Late symptoms are usually due to complications of decompensated hemolysis, usually shock or renal failure. Laboratory abnormalities include low hemoglobin and haptoglobin levels, elevated lactate dehydrogenase and indirect bilirubin levels, reticulocytosis, and a positive DAT [1,10].
The DAT is positive in all the described forms of DIIHA, either for IgG, C3, or both. Rare cases with negative DAT reported either low antibody density, massive intravascular hemolysis, or red cell transfusion administered prior to testing [1,10]. When approaching a case where there is evidence of hemolysis and an established temporal relationship with a drug known to induce autoantibody production, investigation for drug-dependent antibodies can be performed in adequate laboratory settings, with quality ensured expertise and appropriate controls [1,3].
As there are no defining clinical features and drug-induced autoantibodies are indistinguishable from idiopathic autoantibodies, misdiagnosis in DIIHA is extremely common, with some patients dying because of late diagnosis. Furthermore, hemolysis and serological results can persist for up to months after withdrawal of the drug, leading to erroneous attribution of recovery on the administered treatment and not to the interruption of the drug [6].
If DIIHA is suspected, relevant medication should be withdrawn immediately. In mild cases, recovery usually happens within one to two weeks after drug suspension, with no other necessary measures. As most drugs have a relatively short half-life, even a strong drug-dependent antibody loses its effect shortly after drug suspension [1]. Failure to recognize DIIHA can have disastrous consequences, especially when patients present complaints for which the offending drug was prescribed. Regarding diclofenac DIIHA, some cases have been reported of patients receiving the drug again for “low back pain” during the early onset of hemolysis [9].
In acute severe DIIHA, recommendations suggest close monitoring of clinical and laboratory signs, early intravenous access, and fluid resuscitation. Blood transfusion should not be withheld in patients with severe anemia [3]. Even though crossmatch-compatible blood can be difficult to find, a review of 134 patients showed that 68 (55%) patients received blood transfusions. Though most patients (85%) received glucocorticoids, its benefit is uncertain and its routine use is not recommended as drug eviction is usually enough to stop the immune response [14].
Applying the criteria of the World Health Organization causality assessment method to assess a possible drug‐induced etiology of IHA we are confident the most likely diagnosis for our patient was diclofenac-induced IHA [17]. Our analysis is supported by: (a) the presence of autoantibodies in the patient’s eluate was demonstrated; (b) diclofenac is known to induce DIIHA; (c) there is a chronological relationship between hemolysis and diclofenac administration; (d) a review of the literature failed to show cases of DIIHA induced by any of the other drugs taken by the patient; (e) symptoms and laboratory signs significantly improved after discontinuation of diclofenac; (f) no coexistent neoplastic, autoimmune, or infectious diseases known to be secondary causes of AIHA were found after systematic and comprehensive studies; and (g) though glucocorticoids were started on admission, no recurrence of anemia was verified in a three-year follow-up period, which would be uncommon if the patient suffered from WAIHA.
Conclusions
As a potentially fatal complication of a widely used drug in clinical practice such as diclofenac, early and correct diagnosis of DIIHA and prompt removal of the offending drug is crucial for the patient’s recovery. Our case highlights the need for both prescribing physicians and patients to be aware of this frequently underreported and usually misdiagnosed entity.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
Appendices
Table 2 Causality categories. Adapted from the WHO-UMC system for standardized case causality assessment. The usual approach is to choose one of the causality terms’ categories and to test if the various criteria fit the content of the case report. All assessment criteria should be reasonably complied to assume a category. The WHO-UMC causality assessment system can be used for the assessment of case reports of adverse drug reactions or drug-drug interactions.
WHO-UMC, World Health Organization-Uppsala Monitoring Centre
Causality term Assessment criteria
Certain • Event or laboratory test abnormality, with plausible time relationship to drug intake • Cannot be explained by disease or other drugs • Response to withdrawal plausible (pharmacologically, pathologically) • Event definitive pharmacologically or phenomenologically (i.e., an objective and specific medical disorder or a recognized pharmacological phenomenon) • Rechallenge satisfactory, if necessary
Probable/Likely • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Unlikely to be attributed to disease or other drugs • Response to withdrawal clinically reasonable • Rechallenge not required
Possible • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Could also be explained by disease or other drugs • Information on drug withdrawal may be lacking or unclear
Unlikely • Event or laboratory test abnormality, with a time to drug intake that makes a relationship improbable (but not impossible) • Disease or other drugs provide plausible explanations
Conditional/Unclassified • Event or laboratory test abnormality • More data for proper assessment needed • Additional data under examination
Unassessable/Unclassifiable • Report suggesting an adverse reaction • Cannot be judged because information is insufficient or contradictory • Data cannot be supplemented or verified | Recovered | ReactionOutcome | CC BY | 33654588 | 19,027,243 | 2021-01-25 |
What was the outcome of reaction 'Nausea'? | Diclofenac-Induced Immune Hemolytic Anemia: A Case Report and Review of Literature.
Non-steroidal anti-inflammatory drugs are widely used for pain management. Most frequently, adverse reactions affect the gastrointestinal tract and hematological side effects usually relate to the gastrointestinal manifestations. Drug-induced immune hemolytic anemia is a rare and frequently underdiagnosed complication that is associated with poor outcomes including organ failure and even death. A 76-year-old female patient was treated with intramuscular diclofenac, thiocolchicoside, and diazepam for low back pain. Five days following diclofenac exposure, the patient was admitted to the Emergency Department with complaints of asthenia, nausea, vomiting, and diarrhea. Hemolysis and a positive direct antiglobulin test were detected on laboratory testing. Further causes of hemolytic anemia were excluded and a diagnosis of diclofenac-induced immune hemolytic anemia was established. Glucocorticoid therapy initiated on admission and drug eviction led to complete recovery. Long-term follow-up showed no recurrence of anemia. Here, we present the unusual case of a successful recovery of a 76-year-old patient with diclofenac-induced immune hemolytic anemia, a rare but immediate life-threatening condition of a frequently used drug in clinical practice.
Introduction
Autoimmune hemolytic anemia (AIHA) ensues when the host’s immune system acts against its own red cell antigens and has an estimated prevalence of approximately 1 in 100,000 individuals [1]. Approximately 50% of the cases refer to primary or idiopathic AIHA, where an associated disorder is not found [2]. Secondary causes of AIHA depend on the studied population. Current series estimate that half are associated with hematological malignancy, a third with infection, a sixth with collagen vascular disorders, and a tenth with drug-induced immune hemolytic anemia (DIIHA), the latter reaching an estimated incidence of one per million per year [1,3].
Diclofenac is one of the non-steroidal anti-inflammatory drugs (NSAIDs) most used for the treatment of rheumatoid arthritis and osteoarthritis [4]. Though generally well tolerated, over 400 adverse reactions have been documented. Most frequently, adverse reactions affect the gastrointestinal tract, the skin, and the central nervous system [5]. Direct hematological side effects such as leukopenia, thrombocytopenia, and aplastic anemia have been described only in limited cases [6-9].
We present the case of a 76-year-old patient with diclofenac DIIHA and a summary of the pathophysiology and therapeutic options.
Case presentation
A 76-year-old woman presented to the Emergency Department (ED) with recent onset of fatigue. She had a previous medical history of essential arterial hypertension, dyslipidemia, and spinal osteoarthritis with sporadic episodes of lumbosciatic pain. Regular medications initiated several years prior included perindopril 8 mg and rosuvastatin 10 mg. No allergies, alcohol, tobacco, toxins, or animal exposures were known, and she had no other relevant personal or familiar history.
Three weeks before admission the patient had an exacerbation of right lumbosciatic pain. This episode was similar to the previous ones, for which she usually was prescribed oral NSAIDs, acetaminophen, general physical therapy, massages, and rest with complete recovery. However, this time the pain was refractory to general measures, and eight days before admission, she was prescribed a combination of a daily intramuscular administration of 4 mg thiocolchicoside, 75 mg diclofenac, and 5 mg diazepam for a total of six days.
On the fifth day of treatment, she developed generalized malaise, fatigue, nausea, postprandial vomiting, and diarrhea with up to six soft, brownish dejections per day.
Despite resolution of nausea, vomiting, and diarrhea, she experienced progressive worsening of fatigue and was admitted to the ED. Detailed medical history was negative for other symptoms, namely, fever, coluria, acholia, melena, and other evident blood losses, either on admission or in the past.
Physical examination revealed jaundice and pallor of the skin and mucous membranes. No epistaxis, gingivorrhagia, adenopathies, ecchymosis, or other skin lesions were found. Blood pressure was 137/62 mmHg and heart rate was 96 beats per minute, respiratory rate was 16 beats per minute, and peripheral oxygenation saturation was 96%. No fever or other abnormalities were noted.
Blood examination showed normocytic normochromic anemia (hemoglobin: 7.9 g/dL, reference median globular volume: 88 fL), reticulocytosis (9.2%), leucocytosis (white blood cells: 13.8 × 10 9/L), hyperbilirubinemia at the expense of unconjugated bilirubin (total bilirubin: 4.09 mg/dL, conjugated bilirubin: 0.97 mg/dL), elevated lactic dehydrogenase (805 UI/L), and sedimentation rate (VS: 76 mm). Serum iron concentration, ferritin, total iron-binding capacity, folic acid, or vitamin B12 showed no significant changes and haptoglobin levels were undetectable. Peripheral blood smear revealed exuberant erythrocyte rouleaux and spherocytes. The direct antiglobulin test (DAT) was positive for immunoglobulin G (IgG). Chest radiography, abdominal ultrasound, and electrocardiogram performed in the ED were normal.
The hypothesis of AIHA was considered in the ED. The patient was started on 60 mg of prednisolone per day (1 mg/kg/day) and was admitted to the medical ward.
The hypothesis of secondary AIHA to an infectious or a connective tissue disease was ruled out. Gastrointestinal complaints were compatible with side effects of NSAIDs, viral serologies, blood cultures, rheumatoid factor, antinuclear antibody, antineutrophil cytoplasmic antibodies, and cyclic citrullinated peptide antibody were negative, and complement (both C3 and C4 studies) was normal. Lymphoproliferative disease was excluded due to the absence of adenopathies both on physical examination and in imaging studies, as well as normal immunoglobulin levels (IgG, IgM, and IgA) and a normal serum protein electrophoresis. Inflammatory bowel disease and digestive tract tumors were also excluded by endoscopic observation and anatomopathological analysis of biopsies made in macroscopically normal mucosa.
During hospitalization, glucocorticoid therapy was maintained, and folic acid supplementation of 5 mg per day was started. The patient had clinical improvement with resolution of asthenia and jaundice, as well as progressive normalization of the hemoglobin and bilirubin values. On discharge, 13 days after admission, anemia was mild (hemoglobin: 11 g/dL) and no signs of hemolysis were noted. Table 1 shows the laboratory data during hospitalization.
Table 1 Laboratory data during hospitalization.
ALP: alkaline phosphatase; ALT: alanine aminotransferase; ANA: antinuclear antibodies; ANCA: antineutrophil cytoplasmic antibody; anti-CCP: anti-cyclic citrullinated peptides; AST: aspartate aminotransferase; GGT: gamma-glutamyl transferase; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; Ig: immunoglobulin; LDH: lactate dehydrogenase, MCV: mean corpuscular volume, TIBC: total iron binding capacity
Results
Variable Reference range (adults) Day 1 Day 2 Day 5 Day 7 Day 9 Day 13
Hemoglobin (g/dL) 11.8-15.8 7.9 7.8 8.2 9.1 10.3 11
Hematocrit (%) 36.0-46.0 21.9 22.1 24.4 26.7 30.6 33
Red blood cells (106/µL) 4.2-5.4 2.47 2.42 2.48 2.63 2.97 3.14
MCV (fL) 80.4-96.4 88.7 91.3 98.4 101.5 103 105.1
White cell count (103/µL) 4.0-10.0 13.88 12.49 18.09 15.62 11.43 11.82
Differential cell count (103/L)
Neutrophils 1.5-8.0 9.1 8.3 11.448 9.4 5.9 7.2
Lymphocytes 0.8-4.0 3.3 2.7 5.5 5.2 4.7 3.8
Platelet count (103/µL) 150-400 353 353 381 377 392 362
Reticulocytes (%) 0.5-1.5 9.22
Sedimentation rate (mm) 4-10 103 9
C-reactive protein (mg/dL) <0.51 3.23 2.67 0.69 0.41 0.23 0.14
Urea (mg/dL) 17.0-43.0 40 31 39 35 29 33
Creatinine (mg/dL) 0.6-1.0 0.84 0.78 0.8 0.78 0.84 0.79
Sodium (mmol/L) 136-145 140 141 138 143 141 142
Potassium (mmol/L) 3.5-5.1 4.2 4.2 3 3.7 4 3.9
Calcium (mg/dL) 8.6-10.3 8.7
Uric acid (mg/dL) 2.6-6 7
Bilirubin (mg/dL)
Total 0.3-1.2 4.09 4.01 2.16 2.29 2.27 1.28
Direct <0.5 0.07 0.82 0.71 0.75 0.75 0.46
LDH (UI/L) 125-220 805 632 467 436 388 309
ALP (UI/L) 30-120 152 135 96 93 90 76
GGT (UI/L) <38 83 70 55 56 54 43
ALT (UI/L) 7-45 44 19 23 30 31
AST (UI/L) 8-35 30 22 15 21 21 23
Iron (µ/dL) 70-180 124
TIBC (µ/dL) 250-245 300
Folic acid (ng/mL) 2.34-17.56 5.8
Vitamin B12 (pg/mL) 187-883 414
Haptoglobin (mg/dL) 35-250 <8
Direct antiglobulin test Positive for IgG
Protein electrophoresis No monoclonal spikes
Total proteins (g/dL) 6.4-8.2 6.1
Albumin (g/dL) 3.5-5.2 3.6
Immunoglobulins
IgA (mg/dL) 60-400 192
IgG (mg/dL) 70-1,600 1,008
IgM (mg/dL) 40-230 131
ANA Negative
ANCA Negative
Rheumatoid factor Negative
anti-CCP Negative
Serology
HIV Negative
HBV Negative
HCV Negative
Given the acute clinical context after diclofenac intake and absence of evidence for other secondary etiologies, the diagnosis of acquired hemolytic anemia secondary to NSAIDs was made. Follow-up three years later found the patient asymptomatic with no recurrence of anemia or hemolysis.
Discussion
Drugs are generally small molecules unable to elicit an immune response, however, they can function as haptens, bind to larger proteins, become immunogenic, and lead to antibody production. These antibodies can be further classified as drug-induced, drug-dependent, and drug-independent antibodies. Drug-induced antibodies can bind to red blood cells (RBCs) and lead to hemolysis by non-immunological modification of erythrocyte membranes known as adsorption of non-immunological proteins. Drug-dependent antibodies bind to RBCs only in the presence of the drug or its metabolites, causing abrupt complement-mediated intravascular hemolysis. In vitro tests searching for lysis, DAT, or indirect antiglobulin test can be performed to confirm the diagnosis using the offending drug or its metabolites and the patient’s plasma or serum. Drug-independent antibodies can react with RBCs even in the absence of the drug and, therefore, are indistinguishable from autoantibodies mediating warm autoimmune hemolytic anemia (WAIHA) [1,10,11].
WAIHA is named after warm agglutinins, usually IgG autoantibodies, that bind to antigens on erythrocytes at a temperature of 37°C, leading to RBC destruction and a chronic or relapsing disease with an almost pathognomonic positive DAT [2].
Patients are treated with glucocorticoids 1 to 2 mg/kg of body weight/day of prednisone administered orally or an equivalent dose of methylprednisolone administered intravenously. Though most patients recover to an hemoglobin level above 10 g/dL within two to three weeks of treatment, relapse after treatment discontinuation is common, with retrospective case studies suggesting long-term remission rates as low as 20% to 30% [2].
DIIHA is identified by clinical evidence of hemolysis associated with drug therapy. Although many drugs have anedoctally reported isolated cases of DIIHA, over 130 drugs have reasonable evidence that supports an immune etiology [12]. It has been speculated that DIIHA is far more common than previously estimated, as most reports usually refer to more severe cases, either presenting with shock, multiorgan damage, or renal failure, and most mild cases being unreported [6].
Drugs most frequently associated with DIIHA are second and third generation of cephalosporins, diclofenac, oxaliplatin, and fludarabine. In European cohorts where diclofenac is the most frequently used NSAID, case reviews reported diclofenac as the most frequently implicated drug, with a fatal outcome being estimated in 15% to 21% of the reported cases [6,12-16]. Diclofenac-induced immune hemolytic anemia has been demonstrated in few cases, where the exposure to the drug or its metabolites lead to developing both drug-independent IgG autoantibodies and antibodies that reacted with diclofenac and its metabolites [8].
Signs and symptoms of DIIHA, as any other hemolytic anemia, are proportional to the degree and time of onset and can present withing hours to weeks of drug exposure. These include fatigue, dyspnea, and thoracic or abdominal pain. Late symptoms are usually due to complications of decompensated hemolysis, usually shock or renal failure. Laboratory abnormalities include low hemoglobin and haptoglobin levels, elevated lactate dehydrogenase and indirect bilirubin levels, reticulocytosis, and a positive DAT [1,10].
The DAT is positive in all the described forms of DIIHA, either for IgG, C3, or both. Rare cases with negative DAT reported either low antibody density, massive intravascular hemolysis, or red cell transfusion administered prior to testing [1,10]. When approaching a case where there is evidence of hemolysis and an established temporal relationship with a drug known to induce autoantibody production, investigation for drug-dependent antibodies can be performed in adequate laboratory settings, with quality ensured expertise and appropriate controls [1,3].
As there are no defining clinical features and drug-induced autoantibodies are indistinguishable from idiopathic autoantibodies, misdiagnosis in DIIHA is extremely common, with some patients dying because of late diagnosis. Furthermore, hemolysis and serological results can persist for up to months after withdrawal of the drug, leading to erroneous attribution of recovery on the administered treatment and not to the interruption of the drug [6].
If DIIHA is suspected, relevant medication should be withdrawn immediately. In mild cases, recovery usually happens within one to two weeks after drug suspension, with no other necessary measures. As most drugs have a relatively short half-life, even a strong drug-dependent antibody loses its effect shortly after drug suspension [1]. Failure to recognize DIIHA can have disastrous consequences, especially when patients present complaints for which the offending drug was prescribed. Regarding diclofenac DIIHA, some cases have been reported of patients receiving the drug again for “low back pain” during the early onset of hemolysis [9].
In acute severe DIIHA, recommendations suggest close monitoring of clinical and laboratory signs, early intravenous access, and fluid resuscitation. Blood transfusion should not be withheld in patients with severe anemia [3]. Even though crossmatch-compatible blood can be difficult to find, a review of 134 patients showed that 68 (55%) patients received blood transfusions. Though most patients (85%) received glucocorticoids, its benefit is uncertain and its routine use is not recommended as drug eviction is usually enough to stop the immune response [14].
Applying the criteria of the World Health Organization causality assessment method to assess a possible drug‐induced etiology of IHA we are confident the most likely diagnosis for our patient was diclofenac-induced IHA [17]. Our analysis is supported by: (a) the presence of autoantibodies in the patient’s eluate was demonstrated; (b) diclofenac is known to induce DIIHA; (c) there is a chronological relationship between hemolysis and diclofenac administration; (d) a review of the literature failed to show cases of DIIHA induced by any of the other drugs taken by the patient; (e) symptoms and laboratory signs significantly improved after discontinuation of diclofenac; (f) no coexistent neoplastic, autoimmune, or infectious diseases known to be secondary causes of AIHA were found after systematic and comprehensive studies; and (g) though glucocorticoids were started on admission, no recurrence of anemia was verified in a three-year follow-up period, which would be uncommon if the patient suffered from WAIHA.
Conclusions
As a potentially fatal complication of a widely used drug in clinical practice such as diclofenac, early and correct diagnosis of DIIHA and prompt removal of the offending drug is crucial for the patient’s recovery. Our case highlights the need for both prescribing physicians and patients to be aware of this frequently underreported and usually misdiagnosed entity.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
Appendices
Table 2 Causality categories. Adapted from the WHO-UMC system for standardized case causality assessment. The usual approach is to choose one of the causality terms’ categories and to test if the various criteria fit the content of the case report. All assessment criteria should be reasonably complied to assume a category. The WHO-UMC causality assessment system can be used for the assessment of case reports of adverse drug reactions or drug-drug interactions.
WHO-UMC, World Health Organization-Uppsala Monitoring Centre
Causality term Assessment criteria
Certain • Event or laboratory test abnormality, with plausible time relationship to drug intake • Cannot be explained by disease or other drugs • Response to withdrawal plausible (pharmacologically, pathologically) • Event definitive pharmacologically or phenomenologically (i.e., an objective and specific medical disorder or a recognized pharmacological phenomenon) • Rechallenge satisfactory, if necessary
Probable/Likely • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Unlikely to be attributed to disease or other drugs • Response to withdrawal clinically reasonable • Rechallenge not required
Possible • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Could also be explained by disease or other drugs • Information on drug withdrawal may be lacking or unclear
Unlikely • Event or laboratory test abnormality, with a time to drug intake that makes a relationship improbable (but not impossible) • Disease or other drugs provide plausible explanations
Conditional/Unclassified • Event or laboratory test abnormality • More data for proper assessment needed • Additional data under examination
Unassessable/Unclassifiable • Report suggesting an adverse reaction • Cannot be judged because information is insufficient or contradictory • Data cannot be supplemented or verified | Recovered | ReactionOutcome | CC BY | 33654588 | 19,027,243 | 2021-01-25 |
What was the outcome of reaction 'Normochromic normocytic anaemia'? | Diclofenac-Induced Immune Hemolytic Anemia: A Case Report and Review of Literature.
Non-steroidal anti-inflammatory drugs are widely used for pain management. Most frequently, adverse reactions affect the gastrointestinal tract and hematological side effects usually relate to the gastrointestinal manifestations. Drug-induced immune hemolytic anemia is a rare and frequently underdiagnosed complication that is associated with poor outcomes including organ failure and even death. A 76-year-old female patient was treated with intramuscular diclofenac, thiocolchicoside, and diazepam for low back pain. Five days following diclofenac exposure, the patient was admitted to the Emergency Department with complaints of asthenia, nausea, vomiting, and diarrhea. Hemolysis and a positive direct antiglobulin test were detected on laboratory testing. Further causes of hemolytic anemia were excluded and a diagnosis of diclofenac-induced immune hemolytic anemia was established. Glucocorticoid therapy initiated on admission and drug eviction led to complete recovery. Long-term follow-up showed no recurrence of anemia. Here, we present the unusual case of a successful recovery of a 76-year-old patient with diclofenac-induced immune hemolytic anemia, a rare but immediate life-threatening condition of a frequently used drug in clinical practice.
Introduction
Autoimmune hemolytic anemia (AIHA) ensues when the host’s immune system acts against its own red cell antigens and has an estimated prevalence of approximately 1 in 100,000 individuals [1]. Approximately 50% of the cases refer to primary or idiopathic AIHA, where an associated disorder is not found [2]. Secondary causes of AIHA depend on the studied population. Current series estimate that half are associated with hematological malignancy, a third with infection, a sixth with collagen vascular disorders, and a tenth with drug-induced immune hemolytic anemia (DIIHA), the latter reaching an estimated incidence of one per million per year [1,3].
Diclofenac is one of the non-steroidal anti-inflammatory drugs (NSAIDs) most used for the treatment of rheumatoid arthritis and osteoarthritis [4]. Though generally well tolerated, over 400 adverse reactions have been documented. Most frequently, adverse reactions affect the gastrointestinal tract, the skin, and the central nervous system [5]. Direct hematological side effects such as leukopenia, thrombocytopenia, and aplastic anemia have been described only in limited cases [6-9].
We present the case of a 76-year-old patient with diclofenac DIIHA and a summary of the pathophysiology and therapeutic options.
Case presentation
A 76-year-old woman presented to the Emergency Department (ED) with recent onset of fatigue. She had a previous medical history of essential arterial hypertension, dyslipidemia, and spinal osteoarthritis with sporadic episodes of lumbosciatic pain. Regular medications initiated several years prior included perindopril 8 mg and rosuvastatin 10 mg. No allergies, alcohol, tobacco, toxins, or animal exposures were known, and she had no other relevant personal or familiar history.
Three weeks before admission the patient had an exacerbation of right lumbosciatic pain. This episode was similar to the previous ones, for which she usually was prescribed oral NSAIDs, acetaminophen, general physical therapy, massages, and rest with complete recovery. However, this time the pain was refractory to general measures, and eight days before admission, she was prescribed a combination of a daily intramuscular administration of 4 mg thiocolchicoside, 75 mg diclofenac, and 5 mg diazepam for a total of six days.
On the fifth day of treatment, she developed generalized malaise, fatigue, nausea, postprandial vomiting, and diarrhea with up to six soft, brownish dejections per day.
Despite resolution of nausea, vomiting, and diarrhea, she experienced progressive worsening of fatigue and was admitted to the ED. Detailed medical history was negative for other symptoms, namely, fever, coluria, acholia, melena, and other evident blood losses, either on admission or in the past.
Physical examination revealed jaundice and pallor of the skin and mucous membranes. No epistaxis, gingivorrhagia, adenopathies, ecchymosis, or other skin lesions were found. Blood pressure was 137/62 mmHg and heart rate was 96 beats per minute, respiratory rate was 16 beats per minute, and peripheral oxygenation saturation was 96%. No fever or other abnormalities were noted.
Blood examination showed normocytic normochromic anemia (hemoglobin: 7.9 g/dL, reference median globular volume: 88 fL), reticulocytosis (9.2%), leucocytosis (white blood cells: 13.8 × 10 9/L), hyperbilirubinemia at the expense of unconjugated bilirubin (total bilirubin: 4.09 mg/dL, conjugated bilirubin: 0.97 mg/dL), elevated lactic dehydrogenase (805 UI/L), and sedimentation rate (VS: 76 mm). Serum iron concentration, ferritin, total iron-binding capacity, folic acid, or vitamin B12 showed no significant changes and haptoglobin levels were undetectable. Peripheral blood smear revealed exuberant erythrocyte rouleaux and spherocytes. The direct antiglobulin test (DAT) was positive for immunoglobulin G (IgG). Chest radiography, abdominal ultrasound, and electrocardiogram performed in the ED were normal.
The hypothesis of AIHA was considered in the ED. The patient was started on 60 mg of prednisolone per day (1 mg/kg/day) and was admitted to the medical ward.
The hypothesis of secondary AIHA to an infectious or a connective tissue disease was ruled out. Gastrointestinal complaints were compatible with side effects of NSAIDs, viral serologies, blood cultures, rheumatoid factor, antinuclear antibody, antineutrophil cytoplasmic antibodies, and cyclic citrullinated peptide antibody were negative, and complement (both C3 and C4 studies) was normal. Lymphoproliferative disease was excluded due to the absence of adenopathies both on physical examination and in imaging studies, as well as normal immunoglobulin levels (IgG, IgM, and IgA) and a normal serum protein electrophoresis. Inflammatory bowel disease and digestive tract tumors were also excluded by endoscopic observation and anatomopathological analysis of biopsies made in macroscopically normal mucosa.
During hospitalization, glucocorticoid therapy was maintained, and folic acid supplementation of 5 mg per day was started. The patient had clinical improvement with resolution of asthenia and jaundice, as well as progressive normalization of the hemoglobin and bilirubin values. On discharge, 13 days after admission, anemia was mild (hemoglobin: 11 g/dL) and no signs of hemolysis were noted. Table 1 shows the laboratory data during hospitalization.
Table 1 Laboratory data during hospitalization.
ALP: alkaline phosphatase; ALT: alanine aminotransferase; ANA: antinuclear antibodies; ANCA: antineutrophil cytoplasmic antibody; anti-CCP: anti-cyclic citrullinated peptides; AST: aspartate aminotransferase; GGT: gamma-glutamyl transferase; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; Ig: immunoglobulin; LDH: lactate dehydrogenase, MCV: mean corpuscular volume, TIBC: total iron binding capacity
Results
Variable Reference range (adults) Day 1 Day 2 Day 5 Day 7 Day 9 Day 13
Hemoglobin (g/dL) 11.8-15.8 7.9 7.8 8.2 9.1 10.3 11
Hematocrit (%) 36.0-46.0 21.9 22.1 24.4 26.7 30.6 33
Red blood cells (106/µL) 4.2-5.4 2.47 2.42 2.48 2.63 2.97 3.14
MCV (fL) 80.4-96.4 88.7 91.3 98.4 101.5 103 105.1
White cell count (103/µL) 4.0-10.0 13.88 12.49 18.09 15.62 11.43 11.82
Differential cell count (103/L)
Neutrophils 1.5-8.0 9.1 8.3 11.448 9.4 5.9 7.2
Lymphocytes 0.8-4.0 3.3 2.7 5.5 5.2 4.7 3.8
Platelet count (103/µL) 150-400 353 353 381 377 392 362
Reticulocytes (%) 0.5-1.5 9.22
Sedimentation rate (mm) 4-10 103 9
C-reactive protein (mg/dL) <0.51 3.23 2.67 0.69 0.41 0.23 0.14
Urea (mg/dL) 17.0-43.0 40 31 39 35 29 33
Creatinine (mg/dL) 0.6-1.0 0.84 0.78 0.8 0.78 0.84 0.79
Sodium (mmol/L) 136-145 140 141 138 143 141 142
Potassium (mmol/L) 3.5-5.1 4.2 4.2 3 3.7 4 3.9
Calcium (mg/dL) 8.6-10.3 8.7
Uric acid (mg/dL) 2.6-6 7
Bilirubin (mg/dL)
Total 0.3-1.2 4.09 4.01 2.16 2.29 2.27 1.28
Direct <0.5 0.07 0.82 0.71 0.75 0.75 0.46
LDH (UI/L) 125-220 805 632 467 436 388 309
ALP (UI/L) 30-120 152 135 96 93 90 76
GGT (UI/L) <38 83 70 55 56 54 43
ALT (UI/L) 7-45 44 19 23 30 31
AST (UI/L) 8-35 30 22 15 21 21 23
Iron (µ/dL) 70-180 124
TIBC (µ/dL) 250-245 300
Folic acid (ng/mL) 2.34-17.56 5.8
Vitamin B12 (pg/mL) 187-883 414
Haptoglobin (mg/dL) 35-250 <8
Direct antiglobulin test Positive for IgG
Protein electrophoresis No monoclonal spikes
Total proteins (g/dL) 6.4-8.2 6.1
Albumin (g/dL) 3.5-5.2 3.6
Immunoglobulins
IgA (mg/dL) 60-400 192
IgG (mg/dL) 70-1,600 1,008
IgM (mg/dL) 40-230 131
ANA Negative
ANCA Negative
Rheumatoid factor Negative
anti-CCP Negative
Serology
HIV Negative
HBV Negative
HCV Negative
Given the acute clinical context after diclofenac intake and absence of evidence for other secondary etiologies, the diagnosis of acquired hemolytic anemia secondary to NSAIDs was made. Follow-up three years later found the patient asymptomatic with no recurrence of anemia or hemolysis.
Discussion
Drugs are generally small molecules unable to elicit an immune response, however, they can function as haptens, bind to larger proteins, become immunogenic, and lead to antibody production. These antibodies can be further classified as drug-induced, drug-dependent, and drug-independent antibodies. Drug-induced antibodies can bind to red blood cells (RBCs) and lead to hemolysis by non-immunological modification of erythrocyte membranes known as adsorption of non-immunological proteins. Drug-dependent antibodies bind to RBCs only in the presence of the drug or its metabolites, causing abrupt complement-mediated intravascular hemolysis. In vitro tests searching for lysis, DAT, or indirect antiglobulin test can be performed to confirm the diagnosis using the offending drug or its metabolites and the patient’s plasma or serum. Drug-independent antibodies can react with RBCs even in the absence of the drug and, therefore, are indistinguishable from autoantibodies mediating warm autoimmune hemolytic anemia (WAIHA) [1,10,11].
WAIHA is named after warm agglutinins, usually IgG autoantibodies, that bind to antigens on erythrocytes at a temperature of 37°C, leading to RBC destruction and a chronic or relapsing disease with an almost pathognomonic positive DAT [2].
Patients are treated with glucocorticoids 1 to 2 mg/kg of body weight/day of prednisone administered orally or an equivalent dose of methylprednisolone administered intravenously. Though most patients recover to an hemoglobin level above 10 g/dL within two to three weeks of treatment, relapse after treatment discontinuation is common, with retrospective case studies suggesting long-term remission rates as low as 20% to 30% [2].
DIIHA is identified by clinical evidence of hemolysis associated with drug therapy. Although many drugs have anedoctally reported isolated cases of DIIHA, over 130 drugs have reasonable evidence that supports an immune etiology [12]. It has been speculated that DIIHA is far more common than previously estimated, as most reports usually refer to more severe cases, either presenting with shock, multiorgan damage, or renal failure, and most mild cases being unreported [6].
Drugs most frequently associated with DIIHA are second and third generation of cephalosporins, diclofenac, oxaliplatin, and fludarabine. In European cohorts where diclofenac is the most frequently used NSAID, case reviews reported diclofenac as the most frequently implicated drug, with a fatal outcome being estimated in 15% to 21% of the reported cases [6,12-16]. Diclofenac-induced immune hemolytic anemia has been demonstrated in few cases, where the exposure to the drug or its metabolites lead to developing both drug-independent IgG autoantibodies and antibodies that reacted with diclofenac and its metabolites [8].
Signs and symptoms of DIIHA, as any other hemolytic anemia, are proportional to the degree and time of onset and can present withing hours to weeks of drug exposure. These include fatigue, dyspnea, and thoracic or abdominal pain. Late symptoms are usually due to complications of decompensated hemolysis, usually shock or renal failure. Laboratory abnormalities include low hemoglobin and haptoglobin levels, elevated lactate dehydrogenase and indirect bilirubin levels, reticulocytosis, and a positive DAT [1,10].
The DAT is positive in all the described forms of DIIHA, either for IgG, C3, or both. Rare cases with negative DAT reported either low antibody density, massive intravascular hemolysis, or red cell transfusion administered prior to testing [1,10]. When approaching a case where there is evidence of hemolysis and an established temporal relationship with a drug known to induce autoantibody production, investigation for drug-dependent antibodies can be performed in adequate laboratory settings, with quality ensured expertise and appropriate controls [1,3].
As there are no defining clinical features and drug-induced autoantibodies are indistinguishable from idiopathic autoantibodies, misdiagnosis in DIIHA is extremely common, with some patients dying because of late diagnosis. Furthermore, hemolysis and serological results can persist for up to months after withdrawal of the drug, leading to erroneous attribution of recovery on the administered treatment and not to the interruption of the drug [6].
If DIIHA is suspected, relevant medication should be withdrawn immediately. In mild cases, recovery usually happens within one to two weeks after drug suspension, with no other necessary measures. As most drugs have a relatively short half-life, even a strong drug-dependent antibody loses its effect shortly after drug suspension [1]. Failure to recognize DIIHA can have disastrous consequences, especially when patients present complaints for which the offending drug was prescribed. Regarding diclofenac DIIHA, some cases have been reported of patients receiving the drug again for “low back pain” during the early onset of hemolysis [9].
In acute severe DIIHA, recommendations suggest close monitoring of clinical and laboratory signs, early intravenous access, and fluid resuscitation. Blood transfusion should not be withheld in patients with severe anemia [3]. Even though crossmatch-compatible blood can be difficult to find, a review of 134 patients showed that 68 (55%) patients received blood transfusions. Though most patients (85%) received glucocorticoids, its benefit is uncertain and its routine use is not recommended as drug eviction is usually enough to stop the immune response [14].
Applying the criteria of the World Health Organization causality assessment method to assess a possible drug‐induced etiology of IHA we are confident the most likely diagnosis for our patient was diclofenac-induced IHA [17]. Our analysis is supported by: (a) the presence of autoantibodies in the patient’s eluate was demonstrated; (b) diclofenac is known to induce DIIHA; (c) there is a chronological relationship between hemolysis and diclofenac administration; (d) a review of the literature failed to show cases of DIIHA induced by any of the other drugs taken by the patient; (e) symptoms and laboratory signs significantly improved after discontinuation of diclofenac; (f) no coexistent neoplastic, autoimmune, or infectious diseases known to be secondary causes of AIHA were found after systematic and comprehensive studies; and (g) though glucocorticoids were started on admission, no recurrence of anemia was verified in a three-year follow-up period, which would be uncommon if the patient suffered from WAIHA.
Conclusions
As a potentially fatal complication of a widely used drug in clinical practice such as diclofenac, early and correct diagnosis of DIIHA and prompt removal of the offending drug is crucial for the patient’s recovery. Our case highlights the need for both prescribing physicians and patients to be aware of this frequently underreported and usually misdiagnosed entity.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
Appendices
Table 2 Causality categories. Adapted from the WHO-UMC system for standardized case causality assessment. The usual approach is to choose one of the causality terms’ categories and to test if the various criteria fit the content of the case report. All assessment criteria should be reasonably complied to assume a category. The WHO-UMC causality assessment system can be used for the assessment of case reports of adverse drug reactions or drug-drug interactions.
WHO-UMC, World Health Organization-Uppsala Monitoring Centre
Causality term Assessment criteria
Certain • Event or laboratory test abnormality, with plausible time relationship to drug intake • Cannot be explained by disease or other drugs • Response to withdrawal plausible (pharmacologically, pathologically) • Event definitive pharmacologically or phenomenologically (i.e., an objective and specific medical disorder or a recognized pharmacological phenomenon) • Rechallenge satisfactory, if necessary
Probable/Likely • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Unlikely to be attributed to disease or other drugs • Response to withdrawal clinically reasonable • Rechallenge not required
Possible • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Could also be explained by disease or other drugs • Information on drug withdrawal may be lacking or unclear
Unlikely • Event or laboratory test abnormality, with a time to drug intake that makes a relationship improbable (but not impossible) • Disease or other drugs provide plausible explanations
Conditional/Unclassified • Event or laboratory test abnormality • More data for proper assessment needed • Additional data under examination
Unassessable/Unclassifiable • Report suggesting an adverse reaction • Cannot be judged because information is insufficient or contradictory • Data cannot be supplemented or verified | Recovered | ReactionOutcome | CC BY | 33654588 | 19,027,243 | 2021-01-25 |
What was the outcome of reaction 'Pallor'? | Diclofenac-Induced Immune Hemolytic Anemia: A Case Report and Review of Literature.
Non-steroidal anti-inflammatory drugs are widely used for pain management. Most frequently, adverse reactions affect the gastrointestinal tract and hematological side effects usually relate to the gastrointestinal manifestations. Drug-induced immune hemolytic anemia is a rare and frequently underdiagnosed complication that is associated with poor outcomes including organ failure and even death. A 76-year-old female patient was treated with intramuscular diclofenac, thiocolchicoside, and diazepam for low back pain. Five days following diclofenac exposure, the patient was admitted to the Emergency Department with complaints of asthenia, nausea, vomiting, and diarrhea. Hemolysis and a positive direct antiglobulin test were detected on laboratory testing. Further causes of hemolytic anemia were excluded and a diagnosis of diclofenac-induced immune hemolytic anemia was established. Glucocorticoid therapy initiated on admission and drug eviction led to complete recovery. Long-term follow-up showed no recurrence of anemia. Here, we present the unusual case of a successful recovery of a 76-year-old patient with diclofenac-induced immune hemolytic anemia, a rare but immediate life-threatening condition of a frequently used drug in clinical practice.
Introduction
Autoimmune hemolytic anemia (AIHA) ensues when the host’s immune system acts against its own red cell antigens and has an estimated prevalence of approximately 1 in 100,000 individuals [1]. Approximately 50% of the cases refer to primary or idiopathic AIHA, where an associated disorder is not found [2]. Secondary causes of AIHA depend on the studied population. Current series estimate that half are associated with hematological malignancy, a third with infection, a sixth with collagen vascular disorders, and a tenth with drug-induced immune hemolytic anemia (DIIHA), the latter reaching an estimated incidence of one per million per year [1,3].
Diclofenac is one of the non-steroidal anti-inflammatory drugs (NSAIDs) most used for the treatment of rheumatoid arthritis and osteoarthritis [4]. Though generally well tolerated, over 400 adverse reactions have been documented. Most frequently, adverse reactions affect the gastrointestinal tract, the skin, and the central nervous system [5]. Direct hematological side effects such as leukopenia, thrombocytopenia, and aplastic anemia have been described only in limited cases [6-9].
We present the case of a 76-year-old patient with diclofenac DIIHA and a summary of the pathophysiology and therapeutic options.
Case presentation
A 76-year-old woman presented to the Emergency Department (ED) with recent onset of fatigue. She had a previous medical history of essential arterial hypertension, dyslipidemia, and spinal osteoarthritis with sporadic episodes of lumbosciatic pain. Regular medications initiated several years prior included perindopril 8 mg and rosuvastatin 10 mg. No allergies, alcohol, tobacco, toxins, or animal exposures were known, and she had no other relevant personal or familiar history.
Three weeks before admission the patient had an exacerbation of right lumbosciatic pain. This episode was similar to the previous ones, for which she usually was prescribed oral NSAIDs, acetaminophen, general physical therapy, massages, and rest with complete recovery. However, this time the pain was refractory to general measures, and eight days before admission, she was prescribed a combination of a daily intramuscular administration of 4 mg thiocolchicoside, 75 mg diclofenac, and 5 mg diazepam for a total of six days.
On the fifth day of treatment, she developed generalized malaise, fatigue, nausea, postprandial vomiting, and diarrhea with up to six soft, brownish dejections per day.
Despite resolution of nausea, vomiting, and diarrhea, she experienced progressive worsening of fatigue and was admitted to the ED. Detailed medical history was negative for other symptoms, namely, fever, coluria, acholia, melena, and other evident blood losses, either on admission or in the past.
Physical examination revealed jaundice and pallor of the skin and mucous membranes. No epistaxis, gingivorrhagia, adenopathies, ecchymosis, or other skin lesions were found. Blood pressure was 137/62 mmHg and heart rate was 96 beats per minute, respiratory rate was 16 beats per minute, and peripheral oxygenation saturation was 96%. No fever or other abnormalities were noted.
Blood examination showed normocytic normochromic anemia (hemoglobin: 7.9 g/dL, reference median globular volume: 88 fL), reticulocytosis (9.2%), leucocytosis (white blood cells: 13.8 × 10 9/L), hyperbilirubinemia at the expense of unconjugated bilirubin (total bilirubin: 4.09 mg/dL, conjugated bilirubin: 0.97 mg/dL), elevated lactic dehydrogenase (805 UI/L), and sedimentation rate (VS: 76 mm). Serum iron concentration, ferritin, total iron-binding capacity, folic acid, or vitamin B12 showed no significant changes and haptoglobin levels were undetectable. Peripheral blood smear revealed exuberant erythrocyte rouleaux and spherocytes. The direct antiglobulin test (DAT) was positive for immunoglobulin G (IgG). Chest radiography, abdominal ultrasound, and electrocardiogram performed in the ED were normal.
The hypothesis of AIHA was considered in the ED. The patient was started on 60 mg of prednisolone per day (1 mg/kg/day) and was admitted to the medical ward.
The hypothesis of secondary AIHA to an infectious or a connective tissue disease was ruled out. Gastrointestinal complaints were compatible with side effects of NSAIDs, viral serologies, blood cultures, rheumatoid factor, antinuclear antibody, antineutrophil cytoplasmic antibodies, and cyclic citrullinated peptide antibody were negative, and complement (both C3 and C4 studies) was normal. Lymphoproliferative disease was excluded due to the absence of adenopathies both on physical examination and in imaging studies, as well as normal immunoglobulin levels (IgG, IgM, and IgA) and a normal serum protein electrophoresis. Inflammatory bowel disease and digestive tract tumors were also excluded by endoscopic observation and anatomopathological analysis of biopsies made in macroscopically normal mucosa.
During hospitalization, glucocorticoid therapy was maintained, and folic acid supplementation of 5 mg per day was started. The patient had clinical improvement with resolution of asthenia and jaundice, as well as progressive normalization of the hemoglobin and bilirubin values. On discharge, 13 days after admission, anemia was mild (hemoglobin: 11 g/dL) and no signs of hemolysis were noted. Table 1 shows the laboratory data during hospitalization.
Table 1 Laboratory data during hospitalization.
ALP: alkaline phosphatase; ALT: alanine aminotransferase; ANA: antinuclear antibodies; ANCA: antineutrophil cytoplasmic antibody; anti-CCP: anti-cyclic citrullinated peptides; AST: aspartate aminotransferase; GGT: gamma-glutamyl transferase; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; Ig: immunoglobulin; LDH: lactate dehydrogenase, MCV: mean corpuscular volume, TIBC: total iron binding capacity
Results
Variable Reference range (adults) Day 1 Day 2 Day 5 Day 7 Day 9 Day 13
Hemoglobin (g/dL) 11.8-15.8 7.9 7.8 8.2 9.1 10.3 11
Hematocrit (%) 36.0-46.0 21.9 22.1 24.4 26.7 30.6 33
Red blood cells (106/µL) 4.2-5.4 2.47 2.42 2.48 2.63 2.97 3.14
MCV (fL) 80.4-96.4 88.7 91.3 98.4 101.5 103 105.1
White cell count (103/µL) 4.0-10.0 13.88 12.49 18.09 15.62 11.43 11.82
Differential cell count (103/L)
Neutrophils 1.5-8.0 9.1 8.3 11.448 9.4 5.9 7.2
Lymphocytes 0.8-4.0 3.3 2.7 5.5 5.2 4.7 3.8
Platelet count (103/µL) 150-400 353 353 381 377 392 362
Reticulocytes (%) 0.5-1.5 9.22
Sedimentation rate (mm) 4-10 103 9
C-reactive protein (mg/dL) <0.51 3.23 2.67 0.69 0.41 0.23 0.14
Urea (mg/dL) 17.0-43.0 40 31 39 35 29 33
Creatinine (mg/dL) 0.6-1.0 0.84 0.78 0.8 0.78 0.84 0.79
Sodium (mmol/L) 136-145 140 141 138 143 141 142
Potassium (mmol/L) 3.5-5.1 4.2 4.2 3 3.7 4 3.9
Calcium (mg/dL) 8.6-10.3 8.7
Uric acid (mg/dL) 2.6-6 7
Bilirubin (mg/dL)
Total 0.3-1.2 4.09 4.01 2.16 2.29 2.27 1.28
Direct <0.5 0.07 0.82 0.71 0.75 0.75 0.46
LDH (UI/L) 125-220 805 632 467 436 388 309
ALP (UI/L) 30-120 152 135 96 93 90 76
GGT (UI/L) <38 83 70 55 56 54 43
ALT (UI/L) 7-45 44 19 23 30 31
AST (UI/L) 8-35 30 22 15 21 21 23
Iron (µ/dL) 70-180 124
TIBC (µ/dL) 250-245 300
Folic acid (ng/mL) 2.34-17.56 5.8
Vitamin B12 (pg/mL) 187-883 414
Haptoglobin (mg/dL) 35-250 <8
Direct antiglobulin test Positive for IgG
Protein electrophoresis No monoclonal spikes
Total proteins (g/dL) 6.4-8.2 6.1
Albumin (g/dL) 3.5-5.2 3.6
Immunoglobulins
IgA (mg/dL) 60-400 192
IgG (mg/dL) 70-1,600 1,008
IgM (mg/dL) 40-230 131
ANA Negative
ANCA Negative
Rheumatoid factor Negative
anti-CCP Negative
Serology
HIV Negative
HBV Negative
HCV Negative
Given the acute clinical context after diclofenac intake and absence of evidence for other secondary etiologies, the diagnosis of acquired hemolytic anemia secondary to NSAIDs was made. Follow-up three years later found the patient asymptomatic with no recurrence of anemia or hemolysis.
Discussion
Drugs are generally small molecules unable to elicit an immune response, however, they can function as haptens, bind to larger proteins, become immunogenic, and lead to antibody production. These antibodies can be further classified as drug-induced, drug-dependent, and drug-independent antibodies. Drug-induced antibodies can bind to red blood cells (RBCs) and lead to hemolysis by non-immunological modification of erythrocyte membranes known as adsorption of non-immunological proteins. Drug-dependent antibodies bind to RBCs only in the presence of the drug or its metabolites, causing abrupt complement-mediated intravascular hemolysis. In vitro tests searching for lysis, DAT, or indirect antiglobulin test can be performed to confirm the diagnosis using the offending drug or its metabolites and the patient’s plasma or serum. Drug-independent antibodies can react with RBCs even in the absence of the drug and, therefore, are indistinguishable from autoantibodies mediating warm autoimmune hemolytic anemia (WAIHA) [1,10,11].
WAIHA is named after warm agglutinins, usually IgG autoantibodies, that bind to antigens on erythrocytes at a temperature of 37°C, leading to RBC destruction and a chronic or relapsing disease with an almost pathognomonic positive DAT [2].
Patients are treated with glucocorticoids 1 to 2 mg/kg of body weight/day of prednisone administered orally or an equivalent dose of methylprednisolone administered intravenously. Though most patients recover to an hemoglobin level above 10 g/dL within two to three weeks of treatment, relapse after treatment discontinuation is common, with retrospective case studies suggesting long-term remission rates as low as 20% to 30% [2].
DIIHA is identified by clinical evidence of hemolysis associated with drug therapy. Although many drugs have anedoctally reported isolated cases of DIIHA, over 130 drugs have reasonable evidence that supports an immune etiology [12]. It has been speculated that DIIHA is far more common than previously estimated, as most reports usually refer to more severe cases, either presenting with shock, multiorgan damage, or renal failure, and most mild cases being unreported [6].
Drugs most frequently associated with DIIHA are second and third generation of cephalosporins, diclofenac, oxaliplatin, and fludarabine. In European cohorts where diclofenac is the most frequently used NSAID, case reviews reported diclofenac as the most frequently implicated drug, with a fatal outcome being estimated in 15% to 21% of the reported cases [6,12-16]. Diclofenac-induced immune hemolytic anemia has been demonstrated in few cases, where the exposure to the drug or its metabolites lead to developing both drug-independent IgG autoantibodies and antibodies that reacted with diclofenac and its metabolites [8].
Signs and symptoms of DIIHA, as any other hemolytic anemia, are proportional to the degree and time of onset and can present withing hours to weeks of drug exposure. These include fatigue, dyspnea, and thoracic or abdominal pain. Late symptoms are usually due to complications of decompensated hemolysis, usually shock or renal failure. Laboratory abnormalities include low hemoglobin and haptoglobin levels, elevated lactate dehydrogenase and indirect bilirubin levels, reticulocytosis, and a positive DAT [1,10].
The DAT is positive in all the described forms of DIIHA, either for IgG, C3, or both. Rare cases with negative DAT reported either low antibody density, massive intravascular hemolysis, or red cell transfusion administered prior to testing [1,10]. When approaching a case where there is evidence of hemolysis and an established temporal relationship with a drug known to induce autoantibody production, investigation for drug-dependent antibodies can be performed in adequate laboratory settings, with quality ensured expertise and appropriate controls [1,3].
As there are no defining clinical features and drug-induced autoantibodies are indistinguishable from idiopathic autoantibodies, misdiagnosis in DIIHA is extremely common, with some patients dying because of late diagnosis. Furthermore, hemolysis and serological results can persist for up to months after withdrawal of the drug, leading to erroneous attribution of recovery on the administered treatment and not to the interruption of the drug [6].
If DIIHA is suspected, relevant medication should be withdrawn immediately. In mild cases, recovery usually happens within one to two weeks after drug suspension, with no other necessary measures. As most drugs have a relatively short half-life, even a strong drug-dependent antibody loses its effect shortly after drug suspension [1]. Failure to recognize DIIHA can have disastrous consequences, especially when patients present complaints for which the offending drug was prescribed. Regarding diclofenac DIIHA, some cases have been reported of patients receiving the drug again for “low back pain” during the early onset of hemolysis [9].
In acute severe DIIHA, recommendations suggest close monitoring of clinical and laboratory signs, early intravenous access, and fluid resuscitation. Blood transfusion should not be withheld in patients with severe anemia [3]. Even though crossmatch-compatible blood can be difficult to find, a review of 134 patients showed that 68 (55%) patients received blood transfusions. Though most patients (85%) received glucocorticoids, its benefit is uncertain and its routine use is not recommended as drug eviction is usually enough to stop the immune response [14].
Applying the criteria of the World Health Organization causality assessment method to assess a possible drug‐induced etiology of IHA we are confident the most likely diagnosis for our patient was diclofenac-induced IHA [17]. Our analysis is supported by: (a) the presence of autoantibodies in the patient’s eluate was demonstrated; (b) diclofenac is known to induce DIIHA; (c) there is a chronological relationship between hemolysis and diclofenac administration; (d) a review of the literature failed to show cases of DIIHA induced by any of the other drugs taken by the patient; (e) symptoms and laboratory signs significantly improved after discontinuation of diclofenac; (f) no coexistent neoplastic, autoimmune, or infectious diseases known to be secondary causes of AIHA were found after systematic and comprehensive studies; and (g) though glucocorticoids were started on admission, no recurrence of anemia was verified in a three-year follow-up period, which would be uncommon if the patient suffered from WAIHA.
Conclusions
As a potentially fatal complication of a widely used drug in clinical practice such as diclofenac, early and correct diagnosis of DIIHA and prompt removal of the offending drug is crucial for the patient’s recovery. Our case highlights the need for both prescribing physicians and patients to be aware of this frequently underreported and usually misdiagnosed entity.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
Appendices
Table 2 Causality categories. Adapted from the WHO-UMC system for standardized case causality assessment. The usual approach is to choose one of the causality terms’ categories and to test if the various criteria fit the content of the case report. All assessment criteria should be reasonably complied to assume a category. The WHO-UMC causality assessment system can be used for the assessment of case reports of adverse drug reactions or drug-drug interactions.
WHO-UMC, World Health Organization-Uppsala Monitoring Centre
Causality term Assessment criteria
Certain • Event or laboratory test abnormality, with plausible time relationship to drug intake • Cannot be explained by disease or other drugs • Response to withdrawal plausible (pharmacologically, pathologically) • Event definitive pharmacologically or phenomenologically (i.e., an objective and specific medical disorder or a recognized pharmacological phenomenon) • Rechallenge satisfactory, if necessary
Probable/Likely • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Unlikely to be attributed to disease or other drugs • Response to withdrawal clinically reasonable • Rechallenge not required
Possible • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Could also be explained by disease or other drugs • Information on drug withdrawal may be lacking or unclear
Unlikely • Event or laboratory test abnormality, with a time to drug intake that makes a relationship improbable (but not impossible) • Disease or other drugs provide plausible explanations
Conditional/Unclassified • Event or laboratory test abnormality • More data for proper assessment needed • Additional data under examination
Unassessable/Unclassifiable • Report suggesting an adverse reaction • Cannot be judged because information is insufficient or contradictory • Data cannot be supplemented or verified | Recovered | ReactionOutcome | CC BY | 33654588 | 19,027,243 | 2021-01-25 |
What was the outcome of reaction 'Vomiting'? | Diclofenac-Induced Immune Hemolytic Anemia: A Case Report and Review of Literature.
Non-steroidal anti-inflammatory drugs are widely used for pain management. Most frequently, adverse reactions affect the gastrointestinal tract and hematological side effects usually relate to the gastrointestinal manifestations. Drug-induced immune hemolytic anemia is a rare and frequently underdiagnosed complication that is associated with poor outcomes including organ failure and even death. A 76-year-old female patient was treated with intramuscular diclofenac, thiocolchicoside, and diazepam for low back pain. Five days following diclofenac exposure, the patient was admitted to the Emergency Department with complaints of asthenia, nausea, vomiting, and diarrhea. Hemolysis and a positive direct antiglobulin test were detected on laboratory testing. Further causes of hemolytic anemia were excluded and a diagnosis of diclofenac-induced immune hemolytic anemia was established. Glucocorticoid therapy initiated on admission and drug eviction led to complete recovery. Long-term follow-up showed no recurrence of anemia. Here, we present the unusual case of a successful recovery of a 76-year-old patient with diclofenac-induced immune hemolytic anemia, a rare but immediate life-threatening condition of a frequently used drug in clinical practice.
Introduction
Autoimmune hemolytic anemia (AIHA) ensues when the host’s immune system acts against its own red cell antigens and has an estimated prevalence of approximately 1 in 100,000 individuals [1]. Approximately 50% of the cases refer to primary or idiopathic AIHA, where an associated disorder is not found [2]. Secondary causes of AIHA depend on the studied population. Current series estimate that half are associated with hematological malignancy, a third with infection, a sixth with collagen vascular disorders, and a tenth with drug-induced immune hemolytic anemia (DIIHA), the latter reaching an estimated incidence of one per million per year [1,3].
Diclofenac is one of the non-steroidal anti-inflammatory drugs (NSAIDs) most used for the treatment of rheumatoid arthritis and osteoarthritis [4]. Though generally well tolerated, over 400 adverse reactions have been documented. Most frequently, adverse reactions affect the gastrointestinal tract, the skin, and the central nervous system [5]. Direct hematological side effects such as leukopenia, thrombocytopenia, and aplastic anemia have been described only in limited cases [6-9].
We present the case of a 76-year-old patient with diclofenac DIIHA and a summary of the pathophysiology and therapeutic options.
Case presentation
A 76-year-old woman presented to the Emergency Department (ED) with recent onset of fatigue. She had a previous medical history of essential arterial hypertension, dyslipidemia, and spinal osteoarthritis with sporadic episodes of lumbosciatic pain. Regular medications initiated several years prior included perindopril 8 mg and rosuvastatin 10 mg. No allergies, alcohol, tobacco, toxins, or animal exposures were known, and she had no other relevant personal or familiar history.
Three weeks before admission the patient had an exacerbation of right lumbosciatic pain. This episode was similar to the previous ones, for which she usually was prescribed oral NSAIDs, acetaminophen, general physical therapy, massages, and rest with complete recovery. However, this time the pain was refractory to general measures, and eight days before admission, she was prescribed a combination of a daily intramuscular administration of 4 mg thiocolchicoside, 75 mg diclofenac, and 5 mg diazepam for a total of six days.
On the fifth day of treatment, she developed generalized malaise, fatigue, nausea, postprandial vomiting, and diarrhea with up to six soft, brownish dejections per day.
Despite resolution of nausea, vomiting, and diarrhea, she experienced progressive worsening of fatigue and was admitted to the ED. Detailed medical history was negative for other symptoms, namely, fever, coluria, acholia, melena, and other evident blood losses, either on admission or in the past.
Physical examination revealed jaundice and pallor of the skin and mucous membranes. No epistaxis, gingivorrhagia, adenopathies, ecchymosis, or other skin lesions were found. Blood pressure was 137/62 mmHg and heart rate was 96 beats per minute, respiratory rate was 16 beats per minute, and peripheral oxygenation saturation was 96%. No fever or other abnormalities were noted.
Blood examination showed normocytic normochromic anemia (hemoglobin: 7.9 g/dL, reference median globular volume: 88 fL), reticulocytosis (9.2%), leucocytosis (white blood cells: 13.8 × 10 9/L), hyperbilirubinemia at the expense of unconjugated bilirubin (total bilirubin: 4.09 mg/dL, conjugated bilirubin: 0.97 mg/dL), elevated lactic dehydrogenase (805 UI/L), and sedimentation rate (VS: 76 mm). Serum iron concentration, ferritin, total iron-binding capacity, folic acid, or vitamin B12 showed no significant changes and haptoglobin levels were undetectable. Peripheral blood smear revealed exuberant erythrocyte rouleaux and spherocytes. The direct antiglobulin test (DAT) was positive for immunoglobulin G (IgG). Chest radiography, abdominal ultrasound, and electrocardiogram performed in the ED were normal.
The hypothesis of AIHA was considered in the ED. The patient was started on 60 mg of prednisolone per day (1 mg/kg/day) and was admitted to the medical ward.
The hypothesis of secondary AIHA to an infectious or a connective tissue disease was ruled out. Gastrointestinal complaints were compatible with side effects of NSAIDs, viral serologies, blood cultures, rheumatoid factor, antinuclear antibody, antineutrophil cytoplasmic antibodies, and cyclic citrullinated peptide antibody were negative, and complement (both C3 and C4 studies) was normal. Lymphoproliferative disease was excluded due to the absence of adenopathies both on physical examination and in imaging studies, as well as normal immunoglobulin levels (IgG, IgM, and IgA) and a normal serum protein electrophoresis. Inflammatory bowel disease and digestive tract tumors were also excluded by endoscopic observation and anatomopathological analysis of biopsies made in macroscopically normal mucosa.
During hospitalization, glucocorticoid therapy was maintained, and folic acid supplementation of 5 mg per day was started. The patient had clinical improvement with resolution of asthenia and jaundice, as well as progressive normalization of the hemoglobin and bilirubin values. On discharge, 13 days after admission, anemia was mild (hemoglobin: 11 g/dL) and no signs of hemolysis were noted. Table 1 shows the laboratory data during hospitalization.
Table 1 Laboratory data during hospitalization.
ALP: alkaline phosphatase; ALT: alanine aminotransferase; ANA: antinuclear antibodies; ANCA: antineutrophil cytoplasmic antibody; anti-CCP: anti-cyclic citrullinated peptides; AST: aspartate aminotransferase; GGT: gamma-glutamyl transferase; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; Ig: immunoglobulin; LDH: lactate dehydrogenase, MCV: mean corpuscular volume, TIBC: total iron binding capacity
Results
Variable Reference range (adults) Day 1 Day 2 Day 5 Day 7 Day 9 Day 13
Hemoglobin (g/dL) 11.8-15.8 7.9 7.8 8.2 9.1 10.3 11
Hematocrit (%) 36.0-46.0 21.9 22.1 24.4 26.7 30.6 33
Red blood cells (106/µL) 4.2-5.4 2.47 2.42 2.48 2.63 2.97 3.14
MCV (fL) 80.4-96.4 88.7 91.3 98.4 101.5 103 105.1
White cell count (103/µL) 4.0-10.0 13.88 12.49 18.09 15.62 11.43 11.82
Differential cell count (103/L)
Neutrophils 1.5-8.0 9.1 8.3 11.448 9.4 5.9 7.2
Lymphocytes 0.8-4.0 3.3 2.7 5.5 5.2 4.7 3.8
Platelet count (103/µL) 150-400 353 353 381 377 392 362
Reticulocytes (%) 0.5-1.5 9.22
Sedimentation rate (mm) 4-10 103 9
C-reactive protein (mg/dL) <0.51 3.23 2.67 0.69 0.41 0.23 0.14
Urea (mg/dL) 17.0-43.0 40 31 39 35 29 33
Creatinine (mg/dL) 0.6-1.0 0.84 0.78 0.8 0.78 0.84 0.79
Sodium (mmol/L) 136-145 140 141 138 143 141 142
Potassium (mmol/L) 3.5-5.1 4.2 4.2 3 3.7 4 3.9
Calcium (mg/dL) 8.6-10.3 8.7
Uric acid (mg/dL) 2.6-6 7
Bilirubin (mg/dL)
Total 0.3-1.2 4.09 4.01 2.16 2.29 2.27 1.28
Direct <0.5 0.07 0.82 0.71 0.75 0.75 0.46
LDH (UI/L) 125-220 805 632 467 436 388 309
ALP (UI/L) 30-120 152 135 96 93 90 76
GGT (UI/L) <38 83 70 55 56 54 43
ALT (UI/L) 7-45 44 19 23 30 31
AST (UI/L) 8-35 30 22 15 21 21 23
Iron (µ/dL) 70-180 124
TIBC (µ/dL) 250-245 300
Folic acid (ng/mL) 2.34-17.56 5.8
Vitamin B12 (pg/mL) 187-883 414
Haptoglobin (mg/dL) 35-250 <8
Direct antiglobulin test Positive for IgG
Protein electrophoresis No monoclonal spikes
Total proteins (g/dL) 6.4-8.2 6.1
Albumin (g/dL) 3.5-5.2 3.6
Immunoglobulins
IgA (mg/dL) 60-400 192
IgG (mg/dL) 70-1,600 1,008
IgM (mg/dL) 40-230 131
ANA Negative
ANCA Negative
Rheumatoid factor Negative
anti-CCP Negative
Serology
HIV Negative
HBV Negative
HCV Negative
Given the acute clinical context after diclofenac intake and absence of evidence for other secondary etiologies, the diagnosis of acquired hemolytic anemia secondary to NSAIDs was made. Follow-up three years later found the patient asymptomatic with no recurrence of anemia or hemolysis.
Discussion
Drugs are generally small molecules unable to elicit an immune response, however, they can function as haptens, bind to larger proteins, become immunogenic, and lead to antibody production. These antibodies can be further classified as drug-induced, drug-dependent, and drug-independent antibodies. Drug-induced antibodies can bind to red blood cells (RBCs) and lead to hemolysis by non-immunological modification of erythrocyte membranes known as adsorption of non-immunological proteins. Drug-dependent antibodies bind to RBCs only in the presence of the drug or its metabolites, causing abrupt complement-mediated intravascular hemolysis. In vitro tests searching for lysis, DAT, or indirect antiglobulin test can be performed to confirm the diagnosis using the offending drug or its metabolites and the patient’s plasma or serum. Drug-independent antibodies can react with RBCs even in the absence of the drug and, therefore, are indistinguishable from autoantibodies mediating warm autoimmune hemolytic anemia (WAIHA) [1,10,11].
WAIHA is named after warm agglutinins, usually IgG autoantibodies, that bind to antigens on erythrocytes at a temperature of 37°C, leading to RBC destruction and a chronic or relapsing disease with an almost pathognomonic positive DAT [2].
Patients are treated with glucocorticoids 1 to 2 mg/kg of body weight/day of prednisone administered orally or an equivalent dose of methylprednisolone administered intravenously. Though most patients recover to an hemoglobin level above 10 g/dL within two to three weeks of treatment, relapse after treatment discontinuation is common, with retrospective case studies suggesting long-term remission rates as low as 20% to 30% [2].
DIIHA is identified by clinical evidence of hemolysis associated with drug therapy. Although many drugs have anedoctally reported isolated cases of DIIHA, over 130 drugs have reasonable evidence that supports an immune etiology [12]. It has been speculated that DIIHA is far more common than previously estimated, as most reports usually refer to more severe cases, either presenting with shock, multiorgan damage, or renal failure, and most mild cases being unreported [6].
Drugs most frequently associated with DIIHA are second and third generation of cephalosporins, diclofenac, oxaliplatin, and fludarabine. In European cohorts where diclofenac is the most frequently used NSAID, case reviews reported diclofenac as the most frequently implicated drug, with a fatal outcome being estimated in 15% to 21% of the reported cases [6,12-16]. Diclofenac-induced immune hemolytic anemia has been demonstrated in few cases, where the exposure to the drug or its metabolites lead to developing both drug-independent IgG autoantibodies and antibodies that reacted with diclofenac and its metabolites [8].
Signs and symptoms of DIIHA, as any other hemolytic anemia, are proportional to the degree and time of onset and can present withing hours to weeks of drug exposure. These include fatigue, dyspnea, and thoracic or abdominal pain. Late symptoms are usually due to complications of decompensated hemolysis, usually shock or renal failure. Laboratory abnormalities include low hemoglobin and haptoglobin levels, elevated lactate dehydrogenase and indirect bilirubin levels, reticulocytosis, and a positive DAT [1,10].
The DAT is positive in all the described forms of DIIHA, either for IgG, C3, or both. Rare cases with negative DAT reported either low antibody density, massive intravascular hemolysis, or red cell transfusion administered prior to testing [1,10]. When approaching a case where there is evidence of hemolysis and an established temporal relationship with a drug known to induce autoantibody production, investigation for drug-dependent antibodies can be performed in adequate laboratory settings, with quality ensured expertise and appropriate controls [1,3].
As there are no defining clinical features and drug-induced autoantibodies are indistinguishable from idiopathic autoantibodies, misdiagnosis in DIIHA is extremely common, with some patients dying because of late diagnosis. Furthermore, hemolysis and serological results can persist for up to months after withdrawal of the drug, leading to erroneous attribution of recovery on the administered treatment and not to the interruption of the drug [6].
If DIIHA is suspected, relevant medication should be withdrawn immediately. In mild cases, recovery usually happens within one to two weeks after drug suspension, with no other necessary measures. As most drugs have a relatively short half-life, even a strong drug-dependent antibody loses its effect shortly after drug suspension [1]. Failure to recognize DIIHA can have disastrous consequences, especially when patients present complaints for which the offending drug was prescribed. Regarding diclofenac DIIHA, some cases have been reported of patients receiving the drug again for “low back pain” during the early onset of hemolysis [9].
In acute severe DIIHA, recommendations suggest close monitoring of clinical and laboratory signs, early intravenous access, and fluid resuscitation. Blood transfusion should not be withheld in patients with severe anemia [3]. Even though crossmatch-compatible blood can be difficult to find, a review of 134 patients showed that 68 (55%) patients received blood transfusions. Though most patients (85%) received glucocorticoids, its benefit is uncertain and its routine use is not recommended as drug eviction is usually enough to stop the immune response [14].
Applying the criteria of the World Health Organization causality assessment method to assess a possible drug‐induced etiology of IHA we are confident the most likely diagnosis for our patient was diclofenac-induced IHA [17]. Our analysis is supported by: (a) the presence of autoantibodies in the patient’s eluate was demonstrated; (b) diclofenac is known to induce DIIHA; (c) there is a chronological relationship between hemolysis and diclofenac administration; (d) a review of the literature failed to show cases of DIIHA induced by any of the other drugs taken by the patient; (e) symptoms and laboratory signs significantly improved after discontinuation of diclofenac; (f) no coexistent neoplastic, autoimmune, or infectious diseases known to be secondary causes of AIHA were found after systematic and comprehensive studies; and (g) though glucocorticoids were started on admission, no recurrence of anemia was verified in a three-year follow-up period, which would be uncommon if the patient suffered from WAIHA.
Conclusions
As a potentially fatal complication of a widely used drug in clinical practice such as diclofenac, early and correct diagnosis of DIIHA and prompt removal of the offending drug is crucial for the patient’s recovery. Our case highlights the need for both prescribing physicians and patients to be aware of this frequently underreported and usually misdiagnosed entity.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study
Appendices
Table 2 Causality categories. Adapted from the WHO-UMC system for standardized case causality assessment. The usual approach is to choose one of the causality terms’ categories and to test if the various criteria fit the content of the case report. All assessment criteria should be reasonably complied to assume a category. The WHO-UMC causality assessment system can be used for the assessment of case reports of adverse drug reactions or drug-drug interactions.
WHO-UMC, World Health Organization-Uppsala Monitoring Centre
Causality term Assessment criteria
Certain • Event or laboratory test abnormality, with plausible time relationship to drug intake • Cannot be explained by disease or other drugs • Response to withdrawal plausible (pharmacologically, pathologically) • Event definitive pharmacologically or phenomenologically (i.e., an objective and specific medical disorder or a recognized pharmacological phenomenon) • Rechallenge satisfactory, if necessary
Probable/Likely • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Unlikely to be attributed to disease or other drugs • Response to withdrawal clinically reasonable • Rechallenge not required
Possible • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Could also be explained by disease or other drugs • Information on drug withdrawal may be lacking or unclear
Unlikely • Event or laboratory test abnormality, with a time to drug intake that makes a relationship improbable (but not impossible) • Disease or other drugs provide plausible explanations
Conditional/Unclassified • Event or laboratory test abnormality • More data for proper assessment needed • Additional data under examination
Unassessable/Unclassifiable • Report suggesting an adverse reaction • Cannot be judged because information is insufficient or contradictory • Data cannot be supplemented or verified | Recovered | ReactionOutcome | CC BY | 33654588 | 19,027,243 | 2021-01-25 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pancreatitis acute'. | Meloxicam-Induced Pancreatitis.
There are 525 drugs that have been identified by the World Health Organization (WHO) as having the potential to cause pancreatitis. The most well-known drugs include mesalamine, azathioprine, and simvastatin, all of which have been well described in the literature. However, drug-induced pancreatitis only used to account for about 1%-2% of cases in the 1990s; this number has increased to up to 5% in some studies. By accounting for over 100,000 cases per year in the United States alone, it is important to be able to recognize these cases and act rapidly and appropriately to remove the offending agent. The vast majority of cases occur within six weeks of initiating or increasing the dosage of such medications. Here we present an interesting case of meloxicam-induced pancreatitis.
Introduction
Pancreatitis is the leading cause of gastrointestinal-related hospitalizations in the United States. Although the etiology may vary slightly depending on what part of the world you find yourself in, the top three causes include gallstone induced, alcohol intake, and hypertriglyceridemia. Other less common but important etiologies include trauma, medication-induced, and medical procedures such as endoscopic retrograde cholangiopancreatography (ERCP). There are well-documented cases of medication-induced pancreatitis even though the mechanism of action by which this occurs is not fully understood by a majority of them. In addition, some of these medications have not been well documented. To the best of our knowledge, the number of meloxicam-induced pancreatitis reports is few. Herein we report such a case.
Case presentation
A 59-year-old Caucasian male with a past medical history of diabetes mellitus type II presented to the emergency department complaining of abdominal pain. He reported the pain started three days prior after having finished eating his dinner; it started suddenly and was localized to his epigastrium with radiation to his back. He described the pain as sharp and constant, rated it a 9/10, and was associated with nausea and three episodes of non-bloody, non-bilious emesis. Moving seemed to make the pain worse and nothing made it better. He denied any fever, chills, changes in bowel movement. He also denied any previous similar episodes in the past. The pain became progressively worse through the days which is what made him come into the hospital. On admission, his vitals were stable and labs were remarkable for leukocytosis and elevated pancreatic enzymes (Table 1).
Table 1 Laboratory values upon admission
Values Normal Range
White blood cell count 29.6 (4.8-10.8)
Lipase 522 (8-78)
Calcium 9.3 (8.4-10.2)
AST (Aspartate Aminotransferase) 19 (5-34)
ALT (Alanine Transaminase) 26 (11-55)
Total Bilirubin 1.0 (0.1-1.3)
Direct Bilirubin 0.5 (0.0-0.4)
Alkaline Phosphatase 108 (38-126)
Cholesterol 120 (130-200)
Triglycerides 78 (10-150)
LDL (low-density lipoprotein) 67 (83-210)
COVID-19 Antigen Negative Negative
An ultrasound of the abdomen was performed which showed a normal gallbladder without cholelithiasis and a lack of evaluation of the pancreas secondary to obscuration by overlying bowel gas. A computed tomography (CT) of the abdomen without contrast was then obtained which demonstrated diffuse peri-pancreatic stranding suggestive of acute pancreatitis (Figure 1).
Figure 1 CT abdomen without contrast demonstrating diffuse peripancreatic stranding
He was subsequently made NPO, started on normal saline at 125 ml/hr, and given morphine 2 mg PRN Q4. After ruling out the main causes of pancreatitis and upon chart review of his medications, it was found that his meloxicam dose had just been doubled from 7.5 mg to 15 mg two weeks prior to presentation. Meloxicam was withheld during his hospital stay and discontinued upon discharge. Of note, the patient did spike a fever two nights in a row with some increase in his pain, both of which resolved on their own. But due to these events, a follow-up CT of the abdomen and pelvis was conducted which ruled out any complications such as fluid collection or pancreatic necrosis. The patient remained stable and was able to go home six days after admission.
Discussion
Within the field of gastroenterology, pancreatitis continues to maintain its position as one of the most common causes of hospitalizations secondary to a gastrointestinal disturbance in the developed world [1]. Pancreatitis is represented as inflammation of the pancreas through a specific path of physiologic mechanisms that cause the destruction of pancreatic acinar cells. Pancreatic acinar cell destruction may cascade into further inflammation secondary to activation of pro-inflammatory cell lines including granulocytes and macrophages. The physiology of pro-inflammatory cytokines depends on the acuity of pancreatitis. Pancreatitis typically is characterized as either chronic, acute, or acute on chronic [2]. In regards to this particular presentation, drug-induced pancreatitis usually presents as acute pancreatitis. In order to diagnose pancreatitis, several criteria must be met including two or more of the following: abdominal pain consistent with acute pancreatitis; this typically includes abdominal pain with radiation toward the back. The second criteria includes serum amylase and/or lipase which must be greater than three times the normal upper limit, the third criteria are suggestive findings seen on abdominal imaging such as pancreatic inflammation on abdominal CT scan.
Within the United States, the two most prevalent etiologies of acute pancreatitis are secondary to gallstones (which represented 35%-40% of cases), as well as ethanol (EtOH) use which represents approximately 30% of cases. Although these two factors account for the majority of cases, there is a plethora of other etiology such as hypertriglyceridemia, autoimmune pancreatitis, and drug-induced mechanism systems which may contribute to acute pancreatitis [3]. This particular case presentation represents acute pancreatitis secondary to a drug-induced mechanism. In order to diagnose drug-induced pancreatitis, the clinician must rule out all other etiologies which may contribute to pancreatitis including the mentioned gallstones, elevated triglycerides, and alcohol abuse. Then, a thorough review of the patient's lifestyle and medications must be achieved to observe for any particular inciting factors. This particular patient was noted to be taking meloxicam which was recently increased in dosage two weeks prior to presentation. This suspicious increase of the dosage of this nonsteroidal anti-inflammatory drug (NSAID) in combination with the lack of other known inciting etiologies which may contribute to pancreatitis helped determine that a drug-induced mechanism was likely the etiology. Although the mechanism to explain why NSAIDs may be implicated in acute pancreatitis has not been thoroughly confirmed, there has been speculation that NSAIDs may cause a lack of appropriate response directed against oxidative stress secondary to a reduction in systemic glutathione that results from decreased superoxide dismutase activity, as well as a possible destabilization effect of the NSAID on the pancreatic cell membrane secondary to their effects on prostaglandins [4]. A direct hypersensitivity and/or immune-mediated response directly from the NSAID in a particular individual who developed drug-induced pancreatitis cannot be completely ruled out [5].
The best treatment approach in these particular individuals is early identification of the pancreatitis and prompt discontinuation of the offending agent in order to mitigate the deleterious effects of continuous pancreatic inflammation [6]. Typically, drug-induced pancreatitis improves upon cessation of the offending agent, this leads to decreased morbidity and mortality from advanced pancreatitis including the possibility of developing a pancreatic pseudocyst, chronic pancreatitis as well necrotizing pancreatitis [7]. For these reasons, it is crucial to keep a high index of clinical suspicion for drug-induced etiologies when evaluating a patient with pancreatitis in whom all other common scenarios have been ruled out.
Conclusions
Though not uncommon, we are starting to see more and more cases of drug-induced pancreatitis across the world. Although physicians might not think about such an etiology right away, it is important to keep it in mind and do a thorough review of the patient's medications. We present this case in order to bring attention to an important etiology that might not be very obvious at first.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study | MELOXICAM | DrugsGivenReaction | CC BY | 33654637 | 21,016,122 | 2021-01-28 |
What was the outcome of reaction 'Pancreatitis acute'? | Meloxicam-Induced Pancreatitis.
There are 525 drugs that have been identified by the World Health Organization (WHO) as having the potential to cause pancreatitis. The most well-known drugs include mesalamine, azathioprine, and simvastatin, all of which have been well described in the literature. However, drug-induced pancreatitis only used to account for about 1%-2% of cases in the 1990s; this number has increased to up to 5% in some studies. By accounting for over 100,000 cases per year in the United States alone, it is important to be able to recognize these cases and act rapidly and appropriately to remove the offending agent. The vast majority of cases occur within six weeks of initiating or increasing the dosage of such medications. Here we present an interesting case of meloxicam-induced pancreatitis.
Introduction
Pancreatitis is the leading cause of gastrointestinal-related hospitalizations in the United States. Although the etiology may vary slightly depending on what part of the world you find yourself in, the top three causes include gallstone induced, alcohol intake, and hypertriglyceridemia. Other less common but important etiologies include trauma, medication-induced, and medical procedures such as endoscopic retrograde cholangiopancreatography (ERCP). There are well-documented cases of medication-induced pancreatitis even though the mechanism of action by which this occurs is not fully understood by a majority of them. In addition, some of these medications have not been well documented. To the best of our knowledge, the number of meloxicam-induced pancreatitis reports is few. Herein we report such a case.
Case presentation
A 59-year-old Caucasian male with a past medical history of diabetes mellitus type II presented to the emergency department complaining of abdominal pain. He reported the pain started three days prior after having finished eating his dinner; it started suddenly and was localized to his epigastrium with radiation to his back. He described the pain as sharp and constant, rated it a 9/10, and was associated with nausea and three episodes of non-bloody, non-bilious emesis. Moving seemed to make the pain worse and nothing made it better. He denied any fever, chills, changes in bowel movement. He also denied any previous similar episodes in the past. The pain became progressively worse through the days which is what made him come into the hospital. On admission, his vitals were stable and labs were remarkable for leukocytosis and elevated pancreatic enzymes (Table 1).
Table 1 Laboratory values upon admission
Values Normal Range
White blood cell count 29.6 (4.8-10.8)
Lipase 522 (8-78)
Calcium 9.3 (8.4-10.2)
AST (Aspartate Aminotransferase) 19 (5-34)
ALT (Alanine Transaminase) 26 (11-55)
Total Bilirubin 1.0 (0.1-1.3)
Direct Bilirubin 0.5 (0.0-0.4)
Alkaline Phosphatase 108 (38-126)
Cholesterol 120 (130-200)
Triglycerides 78 (10-150)
LDL (low-density lipoprotein) 67 (83-210)
COVID-19 Antigen Negative Negative
An ultrasound of the abdomen was performed which showed a normal gallbladder without cholelithiasis and a lack of evaluation of the pancreas secondary to obscuration by overlying bowel gas. A computed tomography (CT) of the abdomen without contrast was then obtained which demonstrated diffuse peri-pancreatic stranding suggestive of acute pancreatitis (Figure 1).
Figure 1 CT abdomen without contrast demonstrating diffuse peripancreatic stranding
He was subsequently made NPO, started on normal saline at 125 ml/hr, and given morphine 2 mg PRN Q4. After ruling out the main causes of pancreatitis and upon chart review of his medications, it was found that his meloxicam dose had just been doubled from 7.5 mg to 15 mg two weeks prior to presentation. Meloxicam was withheld during his hospital stay and discontinued upon discharge. Of note, the patient did spike a fever two nights in a row with some increase in his pain, both of which resolved on their own. But due to these events, a follow-up CT of the abdomen and pelvis was conducted which ruled out any complications such as fluid collection or pancreatic necrosis. The patient remained stable and was able to go home six days after admission.
Discussion
Within the field of gastroenterology, pancreatitis continues to maintain its position as one of the most common causes of hospitalizations secondary to a gastrointestinal disturbance in the developed world [1]. Pancreatitis is represented as inflammation of the pancreas through a specific path of physiologic mechanisms that cause the destruction of pancreatic acinar cells. Pancreatic acinar cell destruction may cascade into further inflammation secondary to activation of pro-inflammatory cell lines including granulocytes and macrophages. The physiology of pro-inflammatory cytokines depends on the acuity of pancreatitis. Pancreatitis typically is characterized as either chronic, acute, or acute on chronic [2]. In regards to this particular presentation, drug-induced pancreatitis usually presents as acute pancreatitis. In order to diagnose pancreatitis, several criteria must be met including two or more of the following: abdominal pain consistent with acute pancreatitis; this typically includes abdominal pain with radiation toward the back. The second criteria includes serum amylase and/or lipase which must be greater than three times the normal upper limit, the third criteria are suggestive findings seen on abdominal imaging such as pancreatic inflammation on abdominal CT scan.
Within the United States, the two most prevalent etiologies of acute pancreatitis are secondary to gallstones (which represented 35%-40% of cases), as well as ethanol (EtOH) use which represents approximately 30% of cases. Although these two factors account for the majority of cases, there is a plethora of other etiology such as hypertriglyceridemia, autoimmune pancreatitis, and drug-induced mechanism systems which may contribute to acute pancreatitis [3]. This particular case presentation represents acute pancreatitis secondary to a drug-induced mechanism. In order to diagnose drug-induced pancreatitis, the clinician must rule out all other etiologies which may contribute to pancreatitis including the mentioned gallstones, elevated triglycerides, and alcohol abuse. Then, a thorough review of the patient's lifestyle and medications must be achieved to observe for any particular inciting factors. This particular patient was noted to be taking meloxicam which was recently increased in dosage two weeks prior to presentation. This suspicious increase of the dosage of this nonsteroidal anti-inflammatory drug (NSAID) in combination with the lack of other known inciting etiologies which may contribute to pancreatitis helped determine that a drug-induced mechanism was likely the etiology. Although the mechanism to explain why NSAIDs may be implicated in acute pancreatitis has not been thoroughly confirmed, there has been speculation that NSAIDs may cause a lack of appropriate response directed against oxidative stress secondary to a reduction in systemic glutathione that results from decreased superoxide dismutase activity, as well as a possible destabilization effect of the NSAID on the pancreatic cell membrane secondary to their effects on prostaglandins [4]. A direct hypersensitivity and/or immune-mediated response directly from the NSAID in a particular individual who developed drug-induced pancreatitis cannot be completely ruled out [5].
The best treatment approach in these particular individuals is early identification of the pancreatitis and prompt discontinuation of the offending agent in order to mitigate the deleterious effects of continuous pancreatic inflammation [6]. Typically, drug-induced pancreatitis improves upon cessation of the offending agent, this leads to decreased morbidity and mortality from advanced pancreatitis including the possibility of developing a pancreatic pseudocyst, chronic pancreatitis as well necrotizing pancreatitis [7]. For these reasons, it is crucial to keep a high index of clinical suspicion for drug-induced etiologies when evaluating a patient with pancreatitis in whom all other common scenarios have been ruled out.
Conclusions
Though not uncommon, we are starting to see more and more cases of drug-induced pancreatitis across the world. Although physicians might not think about such an etiology right away, it is important to keep it in mind and do a thorough review of the patient's medications. We present this case in order to bring attention to an important etiology that might not be very obvious at first.
The authors have declared that no competing interests exist.
Human Ethics
Consent was obtained or waived by all participants in this study | Recovered | ReactionOutcome | CC BY | 33654637 | 21,016,122 | 2021-01-28 |
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